R E V I E W
Growth Hormone, Insulin-Like Growth Factor-1, and
the Kidney: Pathophysiological and Clinical
Implications
Peter Kamenický, Gherardo Mazziotti, Marc Lombès, Andrea Giustina,
and Philippe Chanson
Assistance Publique-Hôpitaux de Paris (P.K., M.L., P.C.), Hôpital de Bicêtre, Service d’Endocrinologie et des Maladies de
la Reproduction, Centre de Référence des Maladies Endocriniennes Rares de la Croissance, Le Kremlin Bicêtre F-94275,
France; Univ Paris-Sud (P.K., M.L., P.C.), Faculté de Médecine Paris-Sud, Le Kremlin Bicêtre F-94276, France; Inserm
Unité 693 (P.K., M.L., P.C.), Le Kremlin Bicêtre F-94276, France; and Department of Clinical and Experimental Sciences
(A.G., G.M.), Chair of Endocrinology, University of Brescia, 25125 Brescia, Italy
Besides their growth-promoting properties, GH and IGF-1 regulate a broad spectrum of biological functions in several
organs, including the kidney. This review focuses on the renal actions of GH and IGF-1, taking into account major advances
in renal physiology and hormone biology made over the last 20 years, allowing us to move our understanding of GH/IGF-1
regulation of renal functions from a cellular to a molecular level. The main purpose of this review was to analyze how GH
and IGF-1 regulate renal development, glomerular functions, and tubular handling of sodium, calcium, phosphate, and
glucose. Whenever possible, the relative contributions, the nephronic topology, and the underlying molecular mechanisms of GH and IGF-1 actions were addressed. Beyond the physiological aspects of GH/IGF-1 action on the kidney, the
review describes the impact of GH excess and deficiency on renal architecture and functions. It reports in particular new
insights into the pathophysiological mechanism of body fluid retention and of changes in phospho-calcium metabolism
in acromegaly as well as of the reciprocal changes in sodium, calcium, and phosphate homeostasis observed in GH
deficiency. The second aim of this review was to analyze how the GH/IGF-1 axis contributes to major renal diseases such
as diabetic nephropathy, renal failure, renal carcinoma, and polycystic renal disease. It summarizes the consequences of
chronic renal failure and glucocorticoid therapy after renal transplantation on GH secretion and action and questions the
interest of GH therapy in these conditions. (Endocrine Reviews 35: 234–281, 2014)
I. Introduction
A. GH and IGF-1: their receptors and intracellular
signaling
B. Anatomic and functional segmentation of the
nephron
II. Molecular Bases of GH and IGF-1 Action in the Kidney
A. GHR expression in the kidney
B. Local IGF-1 and IGF-2 synthesis in the kidney
C. IGF-1R expression in the kidney
III. The GH/IGF-1 Axis and Renal Physiology
A. GH/IGF-1 in kidney growth and development
B. GH/IGF-1 and glomerular function
C. GH/IGF-1 and tubular function
IV. Renal Consequences of GH Hypersecretion
A. Renal hypertrophy
B. Changes in glomerular function
C. Pathophysiology of body fluid retention
D. Changes in phospho-calcium metabolism
V. Renal Consequences of GH Deficiency
A. Consequences for kidney size
ISSN Print 0163-769X ISSN Online 1945-7189
Printed in U.S.A.
Copyright © 2014 by the Endocrine Society
Received July 18, 2013. Accepted November 15, 2013.
First Published Online December 20, 2013
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B. Changes in glomerular function
C. Changes in body fluid homeostasis
D. Changes in phospho-calcium metabolism
VI. The GH/IGF-1 Axis in Renal Diseases
A. GH/IGF-1 and diabetic nephropathy
B. GH/IGF-1 in renal impairment
C. GH/IGF-1 in kidney transplantation
D. GH/IGF-1 and renal cancer
E. GH/IGF-1 and polycystic kidney disease
VII. Conclusion
I. Introduction
he kidney plays a central homeostatic role by adapting
renal excretion of fluids and electrolytes to bodily
needs. The kidney maintains a stable composition of the
T
Abbreviations: ANP, atrial natriuretic peptide; BNP, brain natriuretic peptide; ENaC, epithelial sodium channel; GFR, glomerular filtration rate; GHR, GH receptor; GOAT, ghrelin
O-acyltransferase; GW, gestational week; IGFBP, IGF binding protein; IGF-1R, IGF-1 receptor; JAK2, Janus kinase 2; MRI, magnetic resonance imaging; NADPH, nicotinamide
adenine dinucleotide phosphate; Na-Pi, sodium-phosphate; NKCC2, renal-specific Na-K2Cl cotransporter; RAAS, renin-angiotensin-aldosterone system; rh, recombinant human;
SDS, SD score; Sgk1, serum- and glucocorticoid-induced kinase 1; STAT5, signal transducer
and activator of transcription 5; STZ, streptozotocin; TmPO4, maximum tubular phosphate
reabsorption rate; WT, wild-type; ZEB2, zinc finger E-box-binding homeobox 2.
Endocrine Reviews, April 2014, 35(2):234 –281
doi: 10.1210/er.2013-1071
doi: 10.1210/er.2013-1071
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235
Figure 1.
dependent actions (6, 7). IGF-1 may
also be synthesized independently of
GH, under the control of other regA
B
ulatory factors (8). In a given tissue
or cell, GH and IGF-1 may act either
synergistically, as illustrated by their
bone-growth-promoting properties,
or antagonistically, on hepatic glucose metabolism for instance (8).
Considerable advances have been
made in our understanding of the relative contributions of GH and IGF-1
to the regulation of physiological
processes such as somatic growth,
through both genetic manipulations
in mice and studies of human pathophysiological situations.
At the cellular level, GH actions
are mediated by its receptor, GH receptor (GHR), expressed on the
plasma membrane of GH target cells
Figure 1. A, Schematic representation of a nephron. PCT, proximal convoluted tubule; PST,
(9). GHR is a member of the cytokine
proximal straight tubule; thin DL, thin descending limb of Henle’s loop; thin AL, thin ascending
receptor superfamily (10). GH bindlimb of Henle’s loop; MTAL, medullary thick ascending limb of Henle’s loop; CTAL, cortical thick
ing to its receptor activates intracelascending limb of Henle’s loop; DCT, distal convoluted tubule; CD, connecting duct; CCD,
cortical collecting duct; OMCD, outer medullary collecting duct; IMCD, inner medullary collecting
lular signaling pathways, of which
duct. B, Schematic representation of the glomerulus and macula densa.
the Janus kinase-2 (JAK2)/signal
transducer and activator of transcription 5 (STAT5) and ERK1/2
extracellular compartment despite large quantitative and
pathways
are
the
most
prominent (11–13). IGF-1, like
qualitative variations in dietary intake of water and solIGF-2,
acts
through
the
IGF-1
receptor (IGF-1R) belongutes (1). This vital function is controlled by complex intrarenal and neurohumoral regulatory mechanisms (2). In ing to the family of tyrosine-kinase receptors. IGF-1 bindparallel to their growth-promoting properties, GH and ing activates canonical intracellular signaling cascades
IGF-1 regulate a broad spectrum of biological functions in such as the ERK1/2 and phosphatidylinositol 3several organs, including the kidney. This review focuses kinase/AKT pathways, reviewed in Refs. 14 and 15).
on the renal actions of GH and IGF-1, taking into account
advances made since this issue was last reviewed in this
journal nearly 20 years ago (3). The first three sections are
devoted to molecular and physiological aspects of GH and
IGF-1 actions on the nephron. The following two sections
describe the impact of GH excess and deficiency on renal
architecture and functions. The final part summarizes the
involvement of the GH/IGF-1 axis in major renal diseases.
A. GH and IGF-1: their receptors and
intracellular signaling
GH plays an essential role in normal postnatal growth
and development and regulates a wide variety of other
biological functions, including intermediate metabolism
and homeostasis. Most GH actions are mediated by
growth factors induced by GH in target tissues, of which
IGF-1 is physiologically the most relevant and the most
extensively studied (4, 5). GH also has direct, IGF-1-in-
B. Anatomic and functional segmentation of
the nephron
A brief description of renal functional segmentation is
necessary before addressing the main focus of this review.
Interested readers will find detailed information on renal
architecture and physiology in nephrology textbooks.
Composed of approximately 1 million nephrons, the
human kidney ensures body-fluid homeostasis by sequential blood filtration in the glomeruli and through highly
regulated transport processes that take place in the successive tubular segments. The renal glomerulus (Figure 1),
a small ball of capillaries (0.1 mm diameter) through
which the blood is filtered, is composed of a capillary
network formed by a thin layer of fenestrated endothelial
cells, a central region of mesangial cells and matrix, a layer
of visceral epithelial cells (podocytes), and a layer of parietal epithelial cells, the latter two layers forming Bow-
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GH, IGF-1, and Kidney
man’s capsule. Podocytes are dynamic cells characterized
by extensive interdigitating foot processes containing actin filaments. They are involved in several important cellular and physiological processes governing glomerular
function, such as glomerular filtration, maintenance of the
glomerular basement membrane, regulation of capillary
shape and integrity, and signal transduction. In humans,
approximately 170 L of plasma is ultrafiltrated daily in the
“urinary space” between these two layers. The filtration
barrier between blood and the urinary space is composed
of a fenestrated endothelium, basement membrane, and
pores between podocyte foot processes (16).
Nearly all the filtered fluid and NaCl are reabsorbed
along the nephron, only 1% being excreted in urine. This
necessitates a high degree of functional coordination to
prevent excessive losses of fluid and electrolytes. In contrast, catabolic end products and xenobiotics are almost
entirely excreted. The role of the renal tubule is thus to
adjust the quantity and composition of excreted urine to
maintain an appropriate composition of the interior milieu. Schematically, the renal tubule can be subdivided in
three functional parts: the proximal tubule, Henle’s loop,
and the distal tubule.
The proximal tubule begins at the urinary pole of the
glomerulus and consists of an initial convoluted portion
(proximal convoluted tubule) and a straight portion
(proximal straight tubule), located in the medullary ray.
The proximal tubule reabsorbs nearly all the glucose,
amino acids, and phosphate; more than 70% of the water,
sodium, potassium, and chloride; and a large fraction of
other solutes filtered in the glomeruli (17–20). The thin
descending limb of Henle’s loop begins at the boundary
between the outer and inner stripes of the outer medulla
and continues after the hairpin turn into the thin ascending
limb. The transition between the thin and thick ascending
limbs of Henle’s loop forms the border between the inner
and outer medulla. The thick ascending limb expands
through the medulla (medullary segment) and the cortex
(cortical segment) to the glomerulus of the nephron of
origin, where it ends in a specialized region called the macula densa. Henle’s loop reabsorbs 20 –30% of the sodium,
30% of the calcium, and up to 70% of the magnesium
filtered in the glomeruli (21). The corticomedullar osmotic
gradient initiated by the Henle’s loop and maintained by
countercurrent circulation in vasa recta is essential for
urine concentration. By exerting tubuloglomerular feedback, the macula densa adjusts glomerular filtration and
thereby maintains a constant urinary flow to the distal
nephron (22). The distal tubule begins beyond the macula
densa as a distal convoluted tubule and is connected by the
connecting tubule to the collecting duct. Expanding from
the outermost cortex to the tip of the renal papilla, the
Endocrine Reviews, April 2014, 35(2):234 –281
collecting duct is usually subdivided into three parts: the
cortical collecting duct, the outer medullary collecting
duct, and the inner medullary collecting duct. The distal
nephron reabsorbs less than 10% of filtered electrolytes
but plays an essential role in fine-tuning hydroelectrolytic
transport, itself regulated by several hormonal systems,
including aldosterone and vasopressin (22). Figure 1 represents the topological organization of the nephron. The
segmental organization and functional complexity of the
nephron should be kept in mind when envisaging GH/
IGF-1 actions in the kidney.
II. Molecular Bases of GH and IGF-1 Action in
the Kidney
Functional GHRs are a prerequisite for direct GH actions
in the kidney. Circulating and locally produced IGF-1 also
requires IGF-1R to exert its biological actions. The choice
of the experimental model is important because the
nephron is composed of several morphologically distinct
and functionally specialized cell types (2). Several rat,
mouse, and human renal tissues, including the whole kidney, separated kidney zones, microdissected nephron segments, and renal cell lines, have been used to examine the
anatomical pattern of GHR and IGF-1R receptor expression at both mRNA and protein levels.
A. GHR expression in the kidney
Successful cloning of the human GHR in 1987 (9) enabled studies of its anatomical distribution. GHR was
found to be expressed in most tissues (10). However, the
complexity of the renal architecture hindered precise analysis of the GHR expression profile along the nephron.
Mathews et al (23), using an RNA probe in a solution
hybridization assay, were the first to report GHR mRNA
expression in a variety of rat tissues. Although GHR transcripts were most abundant in the liver, substantial
amounts of GHR transcripts were also detected in the
whole kidney, reaching adult levels 5 weeks after birth
(23). Northern blotting identified two isoforms of GHR
transcripts in rat kidney (24): a long transcript encoding
membrane-bound GHR, and a shorter transcript generated by alternative splicing of the primary transcript encoding GH binding protein (GHBP) in rodents (25). Chin
et al (26) analyzed the topology of GHR mRNA expression in the rat kidney by in situ hybridization during fetal
development and adulthood. GHR mRNA was detected
from embryonic day 20 in the outer stripe of the outer
medulla and in the medullary rays, suggesting that GHR
is mainly expressed in the proximal straight tubules. The
abundance of transcripts increased until postnatal day 40,
doi: 10.1210/er.2013-1071
when steady-state adult levels were reached. In adult animals, GHR mRNA was also most abundant in the proximal straight tubule, with lower levels in the medullary
thick ascending limb of Henle’s loop (26). A subsequent in
situ hybridization study of rat kidney, using a probe specifically recognizing GHR but not GHBP, confirmed this
distribution (27).
In contrast to this restricted transcript expression, immunohistochemical mapping of GHR and GHBP proteins
in rat kidney revealed substantial immunoreactivity in all
nephronic segments, with the strongest signals in the distal
convoluted tubule and the collecting duct, and a very weak
signal in the glomeruli (28). Using the same anti-GHR
antibody, the same group examined GHR expression in
early second-trimester (14- to 16-wk) human fetal tissues
and reported positive staining of epithelial cells in the
proximal and distal tubules, mainly at the apical membrane (29). Simard et al (30) further described GHRspecific immunostaining in the human fetal kidney as early
as 8.5 to 9 weeks and found that most renal tubule epithelial cells became positive by week 13. The staining was
stronger in the outer medulla than in the cortex and remained similar at midgestation and after birth. Interestingly, weak staining was also found in immature glomeruli
in early gestation but disappeared at later developmental
stages (30), suggesting specific GH involvement in glomerular morphogenesis. Because transgenic mice overexpressing human or bovine GH (contrary to mice overexpressing IGF-1) develop progressive glomerulosclerosis
(31), GH was proposed to have direct, IGF-1-independent
effects on glomerular functions, even in adult animals.
More recent observations based on the use of highly sensitive and specific quantitative real-time RT-PCR and
more efficient and selective antibodies have extended
GHR expression to mesangial cells (31, 32), as well as to
podocytes in both mice and humans (33). The abundance
of GHR transcripts in isolated murine glomeruli was similar to that found in the liver (33). While GHR expression
was well established in the proximal straight tubule and in
the medullary thick ascending limb of Henle’s loop, it remained controversial in the distal parts of the nephron.
The first evidence of GHR expression in the collecting duct
came from functional studies showing a rise in IGF-1
mRNA levels after GH exposure (34). More recently, we
reported the expression profiles of GHR in isolated murine nephronic segments, based on quantitative real-time
PCR. Besides the well-described expression of GHR in the
proximal tubule and Henle’s loop, we detected substantial
amounts of GHR mRNA in the distal nephron, with a
descending expression gradient from the cortex to the medulla. Transcript levels were approximately 10 –20 times
higher in the proximal tubule (104 molecules/mm of tu-
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bule) than in downstream segments. In a cortical collecting
duct cell line obtained by targeted oncogenesis in transgenic mice, we confirmed the presence of GHR at both the transcript and protein levels and showed that GHR mRNA levels
increased during renal cell differentiation (35).
During the last decade, modern genomic techniques
have been used to obtain exhaustive characterization of
the renal transcriptome, thereby expanding our knowledge of gene networks involved in kidney functions (36).
However, to the best of our knowledge, no genomic or
proteomic studies have examined GHR expression along
the nephron. Serial analysis of gene expression in isolated
human nephronic segments established a high-resolution
map of the human kidney (37). No significant amounts
of GHR mRNA were detected in any of the nephron segments, most likely owing to extremely weak GHR expression, representing a major limitation of these global
molecular approaches (personal communication from
Jean-Marc Elalouf, CEA Saclay).
There have been few studies of the regulation of GHR
expression in nonhepatic tissues. GHR expression is generally controlled by multiple factors, including sex steroids, glucocorticoids, nutrients, and GH itself (38 – 41).
Results concerning homologous regulation of GHR levels
by GH are conflicting and largely dependent on the time
of GH exposure and the concentration used (32, 39). For
example, hypophysectomy reduced GHR mRNA levels in
rat tissues, including the kidney, whereas GH supplementation restored them in some studies (24, 26, 42), but not
others (23). Treatment of dwarf dw/dw rats with bovine
GH even resulted in a reduction in GHR and GHBP
mRNA levels in the kidney (43). In human mesangial cells,
GHR transcripts were either up- or down-regulated depending on the GH concentrations used (32). The regulation of GHR expression by GH involves, at least in the
liver, binding of the transcription factor STAT5a to a canonical STAT response element located in the GHR promoter (44).
GHR activation initiates a cascade of intracellular signaling leading to various cell-specific biological responses.
A detailed description of GHR-activated intracellular signaling pathways is available in Refs. 12 and 13. Functional
integrity of GHR signaling, including the canonical JAK2/
STAT5 and ERK1/2 pathways, has been demonstrated in
some renal cell lines (33, 35).
B. Local IGF-1 and IGF-2 synthesis in the kidney
Renal IGF-1 originates from two different sources: 1)
circulating IGF-1, mainly synthesized in the liver, accounts
for 75% of circulating IGF-1 in experimental animals (45,
46) and acts in an endocrine manner on target tissues when
extracted from blood and bound to the cell surface by IGF
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GH, IGF-1, and Kidney
binding proteins (IGFBPs); and 2) IGF-1 synthesized locally in kidney acts as an autocrine or paracrine regulatory
factor for renal cell metabolism (47, 48). IGF-1 levels are
higher in renal venous blood than in renal arterial blood,
suggesting renal IGF-1 biosynthesis (49). In their seminal
contributions, D’Ercole et al (48) demonstrated that ovine
GH administration to hypophysectomized rats increased
the amount of extractable IGF-1 in several tissues, including the whole kidney, thus pioneering the concept of paracrine/autocrine IGF-1 effects. Further studies showed that
GH treatment increased IGF-1 mRNA levels in the kidney
of hypophysectomized rats (50, 51), confirming local renal IGF-1 production.
The spatiotemporal pattern of IGF-1 expression in the
kidney is unclear. Local IGF-1 synthesis usually takes
place in connective tissue cell types such as stromal cells
and may act on adjacent (epithelial) cells that do not actually synthesize IGF-1 (8). In human fetal kidney, IGF-1
mRNA was not detected in the nephrogenic zone, including the glomeruli and tubules, whereas IGF-1 immunostaining was positive in the epithelium of proximal and
distal tubules, probably reflecting sequestration of this
peptide from the circulation (52). Bortz et al (34), by applying immunohistochemistry and a soluble hybridization
assay to rat isolated nephronic segments, identified IGF-1
peptide and IGF-1 mRNA in the collecting ducts and inferred that local synthesis of IGF-1 took place in this
nephronic segment. The same group showed elevated
IGF-1 immunolabeling in collecting ducts in two rat models of acromegaly (53), as well as increased IGF-1 mRNA
levels in rat isolated renal collecting ducts after in vitro
incubation with GH (54). In situ hybridization mapping in
the rat kidney showed an alternative pattern of IGF-1
mRNA distribution, exclusively in the medullary thick ascending limb of Henle’s loop (26, 55), long considered the
only site of IGF-1 synthesis along the nephron (3). Studies
of IGF-1 expression during mouse kidney development
revealed IGF-1 mRNA expression in all renal cells at embryonic day 15, with a drastic decrease after birth. Interestingly, 2 weeks after birth, IGF-1 mRNA was only found
in the peritubular capillaries of the outer medulla and inner cortex (56). In addition, no IGF-1 mRNA was detected
either at baseline or after GH treatment in cultures of differentiated podocytes (33) and principal cells of the cortical collecting duct (35), despite the functional integrity of
GHR and its signaling pathways. Thus, IGF-1 synthesis
has been clearly demonstrated in renal connective tissue
but is questionable in renal epithelial cells (8). The local
tissue availability and distribution of IGF-1 is regulated by
six high-affinity IGFBPs. The renal expression profile of
IGFBPs is summarized in Ref. 57.
Endocrine Reviews, April 2014, 35(2):234 –281
IGF-2 plays an important role during embryonic and
fetal development, but its function after birth has not been
fully elucidated (5, 58). IGF-2 mRNA is strongly expressed in the rat and mouse fetal kidney and falls markedly after birth, except in blood-vessel endothelial cells
(56, 59). GH increases IGF-2 levels only minimally compared to IGF-1 levels (8, 58).
C. IGF-1R expression in the kidney
Initial evidence for a direct IGF-1 action in the kidney
came from studies showing that prolonged treatment with
recombinant human (rh) IGF-1 increased kidney size in
hypophysectomized rats (60) and enhanced the glomerular filtration rate (GFR) in healthy men (61). Molecular
cloning of genes encoding the IGF-1R a and b subunits
enabled studies of their tissue expression and ontogenesis
(62, 63). The first studies were performed in rats by in situ
hybridization. During early embryogenesis (E14-E15), the
receptor mRNA is expressed in the rat mesonephros (59,
63). In adult rat kidney, IGF-1R mRNA was detected
throughout the nephron, including the glomerulus, the
thick ascending limb of Henle’s loop, and along the distal
nephron and collecting duct, with the lowest levels in the
proximal tubules (26, 55, 64). In the human kidney, the
pattern of IGF-1R gene expression is very similar to that
found in rats, with strong expression in glomeruli and the
tubular epithelium of the medulla, whereas IGF-1R transcripts are barely detectable in proximal tubules (65, 66).
Lindenberg-Kortleve et al (56) used in situ hybridization
and quantitative RT-PCR to investigate IGF-1R expression during mouse kidney development. IGF-1R mRNA
levels were highest during the initial period of metanephric
development, with transcripts being detected throughout
the kidney, whereas their levels declined during further
development, being lowest in the postnatal period. In
proximal tubules, the receptor was expressed until birth.
In the mature mouse kidney, the distribution of IGF-1R
mRNA largely matched that previously reported in rats
and humans (56). We used RT-PCR to quantify the expression profile of IGF-1R in freshly isolated murine
nephronic segments obtained by microdissection and detected substantial amounts of IGF-1R transcripts throughout the tubular system (⬎104 molecules/mm of tubule). In
contrast to previous studies, we found the strongest expression (⬎105 molecules/mm of tubule) in the proximal
tubule (35). Global analysis of gene expression in human
isolated nephronic segments did not reveal significant
amounts of IGF-1 mRNA in any of the portions (37). As
already stated, this was probably due to the limited sensitivity of the transcriptomic approach.
IGF-1R mRNA expression is modulated by a number
of physiological and pathophysiological stimuli (15). Fast-
doi: 10.1210/er.2013-1071
ing, for instance, increases IGF-1 binding and IGF-1R
mRNA abundance in rat tissues, including the kidney (67).
Experimental diabetes in rats also induces an increase in
renal IGF-1R mRNA levels (68), likely contributing to the
renal hypertrophy observed in diabetic nephropathy (15).
Unilateral nephrectomy in immature rats leads to a significant increase in IGF-1R mRNA in the remaining kidney, mediating its compensatory growth (69). Although
an increase in IGF-1 levels usually reduces IGF-1R levels
in cell lines (15), hypophysectomy did not significantly
affect IGF-1 mRNA levels in rat kidney (55). In murine
cortical collecting duct cells, IGF-1R expression increased
with cell differentiation (35). Several studies of renal cell
lines have shown the functional integrity of IGF-1R-associated signaling (35, 70, 71).
III. The GH/IGF-1 Axis and Renal Physiology
A. GH/IGF-1 in kidney growth and development
Given that GH and IGF-1 play critical roles as regulators of renal development, growth, and function, it was
anticipated that animal models of gene inactivation, as
well as pathophysiological models, would provide important new insights into the mechanisms and role of the GH/
IGF-1 axis in renal organogenesis. We will first briefly
summarize renal ontogenesis in mammals, focusing on
humans, to facilitate understanding of the potential impact of these growth factors on renal development. The
pronephros emerges during the first 3 gestational weeks
(GWs) and disappears after 4 GWs, leading to the development of the mesonephros, which itself vanishes during
the fourth month of gestation. Metanephronic development occurs from the fifth GW when the first nephrons
start to appear, becoming functional around the eighth
GW. Nephronic development takes place in a centrifugal
manner from the medulla to the renal cortex. Twenty percent of nephrons are formed at 3 months gestation,
whereas nephronic development is achieved by the 34th
GW, with approximately 106 nephrons per kidney (72).
Consistent with the pivotal role of GH in IGF-1 secretion, GHR knockout leads to dwarfism in mice, but the
body weight deviation only became apparent at 3 weeks of
age. Interestingly, at variance with most other organs that
were proportionally smaller and allosterically scaled, even
after normalizing to body weight, the kidneys of GHR⫺/⫺
mice were smaller than those of controls (73), indicating
that GH and its renal receptor exert important and unique
actions on renal development. However, to our knowledge the renal histology of these animals has not been
directly assessed, and there are no detailed reports of their
development or renal function. Compelling evidence for a
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direct role of GH in renal growth came from the unambiguous demonstration, in uninephrectomized model
mice, that compensatory renal hypertrophy was directly
dependent on GH-induced, locally secreted IGF-1, as revealed by blunted responses in the presence of a GHR
antagonist (74).
IGF-1⫺/⫺ mice do not exhibit major renal abnormalities (75). Except for a massive reduction in body weight at
birth, associated with 95% perinatal lethality, surviving
homozygous mutant newborns have a proportional reduction in kidney weight (76). Subtle abnormalities of
nephrogenesis are observed, with smaller glomeruli and a
20% reduction in the number of glomeruli in IGF-1⫺/⫺
mice (77). Although IGF-1 appears to be required for normal murine embryonic growth (78), its absence was not
crucial for survival, thus pointing to the existence of another, partially redundant, overlapping growth factor required for metanephric development.
As mentioned in other sections of this review, the relative growth contributions of circulating IGF-1 and of
locally produced, GH-driven IGF-1 are poorly understood. Using a very elegant, specific knockout mouse
model in which the major GH signaling mediator JAK2
was specifically invalidated in the liver, Nordstrom et al
(79) demonstrated that hepatic IGF-1 production was crucial for GH-mediated kidney mass stimulation, suggesting
that locally produced renal IGF-1 had little or no effect on
kidney growth, as opposed to skeletal muscle for instance.
It has also been shown that both IGF-1 and IGF-2 are
produced locally by the metanephros, thus participating in
renal development (80). Results obtained in several rodent
models show the importance of the GH/IGF-1 axis in renal
growth during ontogenesis and development. In sharp
contrast, little attention has been paid to kidney growth in
human disorders associated with defective GH/IGF-1
signaling.
B. GH/IGF-1 and glomerular function
Our understanding of glomerular structure and function in physiological and pathophysiological conditions
has improved markedly in recent decades, especially the
functional properties of the glomerular barrier (16). In
humans, close to 170 L of primary urine is produced each
day. This clearly requires fine regulation of glomerular
functions and the participation of various hormonal
systems.
More than 50 years ago, Corvilain et al (81) demonstrated in humans that short-term treatment with GH increased the GFR. This GH action is due to an IGF-1-mediated decrease in renal vascular resistance, leading to
increased glomerular perfusion (61, 82– 86). The decreased renal vascular resistance is due to an IGF-1-in-
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GH, IGF-1, and Kidney
duced decrease in both afferent and efferent arteriolar resistance (83). The effect of IGF-1 on peripheral resistance
requires nitric oxide release and cGMP signaling (87), as
well as cyclooxygenase metabolites such as vasodilating
prostaglandins (3). In addition to increasing glomerular
perfusion, GH and IGF-1 augment extracellular volume
and plasma volume (88), thereby also contributing to increased glomerular filtration.
Recently, a direct IGF-1-independent action of GH on
the glomerulus was demonstrated by Reddy et al (33), who
detected GHR mRNA and protein by real-time PCR, immunohistochemistry, and Western blot analysis in murine
podocyte cells (MPC-5) and murine kidney glomeruli. GH
treatment of both murine and human podocytes was associated with increases in STAT5, JAK2, and ERK1/2 proteins. Exposure of podocytes to GH modified the intracellular distribution of JAK2 SH2-B and Janus kinase-2
adapter protein Src homology 2-B and also stimulated
focal adhesion kinase expression, increased reactive oxygen species production, and induced reorganization of the
actin cytoskeleton (33). By using microarray and quantitative RT-PCR analyses of immortalized human podocytes, the same group showed that zinc finger E-boxbinding homeobox 2 (ZEB2) was up-regulated in a GH
dose- and time-dependent manner, and that the increased
ZEB2 expression was partly related to an increase in the
expression of a ZEB2 natural antisense transcript. The
same authors showed that the GH-dependent increase in
ZEB2 expression resulted in a loss of P- and E-cadherins
in podocytes, thus explaining the increased podocyte permeability to albumin (89).
The GH/IGF-1 axis exerts effects on all the component
cells of the glomerulus. GH and especially IGF-1 stimulate
mesangial cell proliferation and migration. The physiological role of GH and IGF-1 in podocyte function is complex because dual effects of these hormones have been
observed. In a model of hyperhomocysteinemia-induced
podocyte dysfunction, GH inhibited the epithelial-to-mesenchymal transition (a crucial event leading to glomerulosclerosis) by blocking nicotinamide adenine dinucleotide phophate (NADPH) oxidase activation (90). IGF-1
inhibited podocyte apoptosis by concomitant stimulation
of cell migration and differentiation (91). Negative effects
of GH on podocyte function were also described, with
increased production of reactive oxygen species that affected reorganization of the podocyte actin cytoskeleton
and increased the permeability of the filtration barrier
(33). These latter effects were subsequently implicated in
the pathogenesis of baseline and exercise-induced proteinuria occurring in clinical disorders such as diabetes mel-
Endocrine Reviews, April 2014, 35(2):234 –281
litus (92) and acromegaly, although hemodynamic factors
could be more important than structural abnormalities in
this latter condition (93).
C. GH/IGF-1 and tubular function
Over the last two decades, major efforts have been
made to describe the transport properties of the kidney
tubule and to identify regulatory factors at the cellular and
molecular levels (20). Cloning of membrane transporters
and hormone receptors, involved in solute transport and
its hormonal control, and deciphering of intracellular signaling pathways were essential prerequisites for fine analysis of these highly regulated transport processes. GH and
IGF-1 are involved in hormonal fine-tuning of tubular
handling of sodium, water, and phosphate and, to a lesser
extent, other electrolytes, and are also known to regulate
tubular gluconeogenesis (3). This section will describe the
principal physiological actions of GH and IGF-1 in the
renal tubule, examine the relative contributions of GH and
IGF-1, and clarify the tubular topology of transport processes and their underlying molecular mechanisms.
1. Regulation of renal sodium reabsorption
The kidney tubule plays a pivotal role in regulating
body fluid homeostasis and blood pressure by adjusting
renal excretion of sodium and water to dietary intake (1).
The GH-IGF-1 system has long been recognized as a hormonal modulator of renal tubular sodium and water reabsorption (88). Soon after the isolation and purification
of GH in 1944 (94), the sodium-retaining properties of
extracted GH were clearly demonstrated in rats (95) and
healthy volunteers (96, 97). A large number of metabolic
studies in rodents and uncontrolled studies in humans
have analyzed the effects of chronic and acute GH administration on sodium and water homeostasis, confirming
initial observations (88). The impact of GH and IGF-1 on
extracellular volume and sodium balance is revealed in
situations of GH hypersecretion and deficiency. Acromegaly and GH deficiency thus represent important pathophysiological models for studying, in parallel to physiological approaches, the mechanisms underlying the
sodium-retaining action of GH (reviewed in Sections IV
and V). The first controlled study in healthy men showed
an increase in extracellular volume, as shown by 82Br dilution, after short-term treatment with GH, with no
change in plasma volume or blood pressure (98). Another
study showed that this effect was stronger in men than in
women (99). Recently, similar conclusions were drawn in
a large study of 96 recreational athletes, with 10.2 and
7.9% increases in extracellular volume (measured by 82Br
dilution) in GH-treated subjects of both genders and in
women, respectively (100).
doi: 10.1210/er.2013-1071
Although the antinatriuretic action of the GH/IGF-1
axis in the kidney is well established, the underlying mechanisms were controversial. The first important question
was whether the antinatriuretic effect resulted from a direct GH/IGF-1 action on the kidney tubule or from indirect mechanisms involving the renin-angiotensin-aldosterone system (RAAS) or antinatriuretic peptides. Increased
aldosterone excretion after GH administration to hypophysectomized rats (101) and to humans (96, 97) indeed
suggested RAAS stimulation, but the pituitary-extracted
GH used in these studies might have contained contaminating pituitary peptides. Ho and Weissberger (102) reported for the first time that biosynthetic human GH induced a rapid increase in plasma renin activity and
aldosterone levels in healthy men.
Treatment with captopril, an angiotensin-convertingenzyme inhibitor, and spironolactone, a mineralocorticoid receptor antagonist, abolished the GH-induced increase in extracellular volume, further suggesting the
involvement of the RAAS system (103). However, this
concept of an indirect, RAAS-dependent antinatriuretic
action of GH was subsequently challenged by several studies. The first conflicting evidence came from the demonstration that sodium retention after GH administration
could also occur in the absence of the adrenal glands (104,
105). In the study by Møller et al, plasma angiotensin II
and aldosterone concentrations did not increase during
GH treatment, but atrial natriuretic peptide (ANP) concentrations fell significantly (98). A study by Christiansen’s group (106) in healthy volunteers and two important
studies of GH-deficient subjects (107, 108) (see Section
V.C) further demonstrated a RAAS-independent sodiumretaining action of GH. Despite some divergences, most
recent data favor a direct stimulatory action of GH on
sodium and water reabsorption in the kidney tubule.
Few studies have attempted to distinguish the intrinsic
effects of GH and those mediated by IGF-1. Guler et al (61)
were the first to investigate the metabolic effects of infused
recombinant IGF-1 in two healthy subjects. Because body
weight and sodium excretion did not change, the authors
inferred that fluid accumulation might be a direct, IGF1-independent effect of GH (61, 84). Another study
showed no change in sodium homeostasis in subjects
treated with IGF-1 sc (109, 110). Yet the antinatriuretic
properties of IGF-1 were clearly documented in children
with GH insensitivity due to inactivating GH receptor mutations (111). The respective effects of GH, IGF-1, and
their combination on extracellular volume were first compared in obese postmenopausal women. Extracellular volume estimated by 82Br dilution increased similarly in all
the treatment groups, pointing to an absence of synergy
between GH and IGF-1 (112). The fluid- and sodium-
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retaining properties of IGF-1 have also been convincingly
documented in healthy men (113).
The precise nephron segment where GH/IGF-1 regulates sodium reabsorption has been a subject of debate.
As described in detail in Section II, GH and IGF-1Rs are
expressed all along the nephron. Microperfusion of rabbit proximal tubules exposed to GH and IGF-1 (114)
and measurements of lithium clearance (an important
index of proximal tubular sodium reabsorption) in rats
(115) and GH-treated patients (106, 107) ruled out a
prominent role of the proximal tubule in GH-induced
sodium transport. A recent study showed that acute GH
injection in rats resulted in increased phosphorylation
of the renal-specific Na-K-2Cl cotransporter (NKCC2)
cotransporter in the thick ascending limb of Henle’s
loop (115). NKCC2 phosphorylation is associated with
short-term actions of vasopressin in this nephron segment (116). Nevertheless, the lack of a concomitant
GH-induced change in sodium transport in the microperfused murine thick ascending limb of Henle’s
loop (115) challenged the physiological relevance of this
observation and suggested that the putative site of GHmediated sodium reabsorption would lie beyond Henle’s loop. Indeed, the above-mentioned human metabolic studies suggested that GH might exert its effects in
the distal tubule (106, 107), a nephron segment with a
pivotal role in fine-tuning sodium homeostasis, via its
regulation by several hormonal systems, including the
mineralocorticoid hormone aldosterone (117, 118).
The molecular mechanisms by which GH and IGF-1
regulate sodium transport in the distal nephron have been
studied in several cell-based systems, leading to the identification of their main molecular targets. The role of
IGF-1 in the regulation of transepithelial sodium transport
in the distal nephron has been convincingly documented in
amphibian (119, 120) and mammalian (70, 71) cell systems. Such an action could have been anticipated from the
well-known effects of insulin on sodium handling in the
distal tubule (121, 122). The first study was performed on
the toad bladder epithelium, an experimental system that
was critical in early demonstrations of the actions of aldosterone on sodium transport (123). IGF-1, like insulin,
rapidly stimulated transcellular sodium transport. The effect of both hormones was blocked by amiloride (119),
suggesting the involvement of the epithelial sodium channel (ENaC), a key regulator of sodium entry through the
apical membrane of polarized epithelial cells (124). These
findings were later confirmed in the murine cell lines
mCCDcl1 and mpkCCDc14 derived from the principal cells
of the collecting duct (70, 71). Rossier’s group (70) compared the effects of insulin and IGF-1 in mCCDcl1 cells and
showed that concentrations of insulin 50 times higher than
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Endocrine Reviews, April 2014, 35(2):234 –281
␣-subunit of the ENaC. This effect
appeared to be related to JAK2/
STAT5 activation because GH treatment led to phospho-STAT5 binding
to a response element located in the
promoter of the SCNN1A gene (encoding the ␣ENaC subunit), highly
conserved among mice, rats, and humans (35). However, these in vitro
observations of ␣ENaC transcriptional regulation do not directly
demonstrate that GH activates
ENaC- dependent sodium transport
in the distal tubule. Convincing evidence from amiloride-sensitive,
short-circuit current measurements
or patch clamp experiments, especially on isolated kidney tubules, is
lacking. Because cross talk between
cytokine receptor signaling pathways and steroid receptors had been
documented (131), a functional link
Figure 2. Proposed model of cooperative GH and IGF-1 action on cortical collecting duct cells. GH
binding to GHR triggers activation of the JAK2/STAT5 and MAPK pathways, leading to
between the mineralocorticoid retranscriptional activation of kidney-specific GH target genes, including ␣ENaC. IGF-1, either
ceptor (the key transcriptional regusynthesized locally or trapped from the circulation, binds to IGF-1R and regulates the apical
lator in collecting duct cells) and
membrane abundance of ENaC via phosphatidylinositol 3-kinase (PI-3K)-dependent Sgk1
STAT5 was very likely, given the
activation, as well as its open probability. The two hormones act synergistically to stimulate
transepithelial sodium transport (35). P, phosphorylated; Ub, ubiquitinylated; STAT-RE, STAT
proximity of their respective reresponse element; MR, mineralocorticoid receptor; MRE, MR response element.
sponse elements on the SCNN1A
promoter. Based on these data, we
IGF-1 were needed to obtain the same effect on sodium proposed a model of cooperative GH and IGF-1 action in
transport. Both hormones are thus likely to regulate so- the distal tubule, providing intricate control of transepidium transport through the IGF-1R rather than the insulin thelial sodium reabsorption, as schematized in Figure 2.
receptor.
Another point of convergence of GH and IGF-1 signaling
Aldosterone regulates ENaC-dependent sodium reab- in the control of sodium transport may be ERK1/2, which
sorption in the kidney via various transcriptional and has been shown to stimulate the activity of Na/K-ATPase
post-transcriptional mechanisms, including induction of in some (132) but not all studies (133).
the ␣ENaC gene (125, 126) and of the serum- and glucoIt is interesting to note that prolactin and GH signaling
corticoid-induced kinase 1 (Sgk1) (127). Sgk1, once phos- plays an important role in the osmoregulation and salinity
phorylated, inhibits the ubiquitin-ligase Nedd4 –2 (128) adaptation of teleost fish (134, 135). Prolactin also inand subsequently increases the membrane residency of ac- duces sodium transport via stimulation of ENaC and Na/
tive ENaCs. Insulin (129) and IGF-1 (70) regulate ENaCs K-pump activities in amphibian skin (136). Lactogen/GHmainly through Sgk1 activation. Patch-clamp experiments dependent ENaC activation could thus represent an
on renal tubular cells and isolated cortical collecting ducts important phylogenetic axis in the control of sodium and
of rats showed that IGF-1 acutely regulates the open prob- water homeostasis, conserved through hundreds of milability of individual ENaCs through inositol-triphosphate lions of years of evolution.
production (71). IGF-1, which displays stable plasma concentrations throughout the day, may play a physiological 2. Regulation of renal phosphate reabsorption
The kidney ensures body phosphate homeostasis by
role in maintaining basal sodium transport in the distal
adjusting renal phosphate excretion to dietary intake. In
tubule, irrespective of aldosterone status (70).
Using highly differentiated KC3AC1 cortical collecting physiological conditions, 80 –90% of the filtered phosduct cells (130), we showed that GH exerts direct phate load is reabsorbed. Renal phosphate reabsorption
stimulatory effects on transcriptional regulation of the occurs almost exclusively in the proximal tubule (19).
Figure 2.
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GH and IGF-1 play important roles in adapting phosphate metabolism to increased requirements during juvenile growth, a period of increased bone formation. The
renal phosphate-retaining action of GH was first observed
more than 50 years ago in studies of anterior pituitary
extracts, showing decreased urinary phosphate excretion
and increased plasma phosphate concentrations in men
after GH treatment (137). Corvilain and Abramow demonstrated in healthy men (81) and dogs (138) that this
antiphosphaturic action of GH was due to an increase in
the maximum tubular phosphate reabsorption rate
(TmPO4). GH enhanced renal phosphate reabsorption independently of PTH because a similar antiphosphaturic
effect was observed in parathyroidectomized dogs (138).
Conversely, hypophysectomy and selective inhibition of
pulsatile GH release in rats causes a significant decline in
TmPO4 and increased urinary phosphorus losses (139,
140). Several clinical trials of rhGH confirmed these observations in subjects without GH deficiency (141–143)
and also in GH-deficient patients (144 –146).
The impact of GH and IGF-1 on the phosphate balance
also becomes apparent during GH hypersecretion (Section
IV). Although chronic GH treatment increases renal tubular transport of phosphate, acute GH administration
does not produce similar effects. For instance, tubular
phosphate reabsorption remained unchanged 2 hours after GH injection to normal and parathyroidectomized
dogs (147), suggesting an indirect, IGF-1-mediated action.
Elegant in vitro perfusion studies on rabbit isolated proximal convoluted tubules by Quigley and Baum (114)
clearly showed that the phosphate-retaining action of GH
is entirely IGF-1 mediated and, as expected, takes place in
the proximal tubule. IGF-1 was shown to stimulate phosphate transport via both the basolateral and apical membranes of proximal tubular cells. However, when IGF-1
was added to the apical membrane, the maximal response
was greater (up to a 46% increase in phosphate transport),
and phosphate transport was stimulated by IGF-1 concentrations 100 times lower (114).
The cellular and molecular mechanisms of phosphate
transport in the proximal tubule are comprehensively
summarized in Ref. 19. Phosphate is taken up from tubular fluid by apical membrane sodium-phosphate (Na-Pi)
cotransporters and leaves cells through basolateral transport pathways. Apical Na-Pi cotransporters are key players in transcellular phosphate flux and are molecular targets for various physiological regulatory mechanisms,
including IGF-1 (19). IGF-1 was first shown to stimulate
Na-Pi cotransport in brush-border membrane vesicles isolated from rat renal cortex (148). Experiments with OK
cells, a model of proximal tubule cells, further showed that
IGF-1 directly increased levels of a specific type IIa Na-Pi
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cotransporter protein at the plasma membrane (149). The
IGF-1 effect on Na-Pi-dependent transport is mediated by
IGF-1Rs because it can be blocked by anti-IGF-1R monoclonal antibodies (150). GH and IGF-1 are crucial for
early developmental up-regulation of brush-border membrane Na-Pi-II cotransporters in juvenile growing rats,
leading to enhanced phosphate reabsorption along the
proximal tubule and thereby ensuring the positive phosphate balance critical for increased bone formation during
this life period (151).
3. Regulation of renal calcium reabsorption
The plasma calcium concentration is kept within narrow limits by coordination of intestinal absorption, renal
reabsorption, and bone resorption. The kidney tubule has
a central role in maintaining calcium homeostasis by adjusting renal calcium losses to highly variable dietary calcium intake. Two major calciotropic hormones tightly
control the calcium balance, namely the vitamin D metabolite calcitriol and PTH (152).
GH and IGF-1 play an important role in adapting calcium homeostasis to the increased demands during the
period of juvenile growth with accelerated bone formation. Indeed, during childhood and early adolescence, 24hour urinary calcium excretion is low, increasing from 1
mmol/24 h in young children to 2 mmol/24 h just before
puberty and reaching adult levels by the end of puberty.
This rise in urinary calcium excretion at the end of adolescence reflects decreased skeletal calcium requirements
(153). GH and IGF-1 affect calcium homeostasis mainly
through their effect on vitamin D metabolism, whereas
their relationship with PTH is controversial. Indeed, Spanos et al (154, 155) reported more than three decades ago
that GH stimulated calcitriol production in experimental
animals (154) and men (155), whereas further investigations in mice and isolated cells showed that this GH action
was mediated by IGF-1 stimulation of 1␣-hydroxylase in
the proximal tubule (156).
Interestingly, acute administration of recombinant IGF-1
to healthy volunteers had only modest effects on calcium
handling, leading to a reduction in calcium excretion only
during the first day of treatment in normovolemic subjects
(109, 110). In situations of GH hypersecretion and GH deficiency, renal calcium excretion is modified, but the renal
action of GH/IGF-1 is difficult to evaluate because of parallel
changes in intestinal calcium absorption and, consequently,
in filtered calcium loads. Indeed, GH/IGF-1-induced calcitriol production increases intestinal calcium absorption via
the epithelial calcium channel TRPV6, resulting in a positive
calcium balance (152, 157). However, the calcitriol-mediated calcium-retaining effect of IGF-1 also involves the kidney. We have recently demonstrated in acromegalic patients
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(for more details, see Section IV.D) that, during GH/IGF-1
excess, renal calcium reabsorption is stimulated in the distal
tubule, whereas paracellular transport in Henle’s loop is unaffected (158).
In the distal tubule, calcium enters the luminal membrane of tubular cells via the epithelial calcium channel
TRPV5 (152). Like ENaC, the TRPV5 channel is expressed exclusively in the aldosterone-sensitive distal parts
of the nephron (159) and represents a privileged molecular
target for hormonal regulation of renal calcium transport
(152, 157). Calcitriol controls calcium reabsorption
through TRPV5 expression in distal tubular cells (160).
IGF-1-stimulated calcitriol production is thus likely to increase distal calcium reabsorption by increasing TRPV5
channel expression, but an additional (direct?) molecular
mechanism cannot be ruled out.
GH stimulates renal tubular gluconeogenesis directly
via GH receptors expressed in proximal tubular cells (26).
In a suspension of canine renal proximal tubular segments,
bovine recombinant GH induced a 55% increase in glucose production from alanine and lactate, without increasing IGF-1 levels. The stimulation of renal gluconeogenesis
resulted from a direct, IGF-1-independent action of GH
(169). The molecular mechanisms of this renal action need
further investigation. Given the important contribution of
renal neoglucogenesis to endogenous glucose production
during starvation and the well-established role of GH in
energy homeostasis in these conditions, it is very likely that
the GHR-mediated direct action of GH on proximal tubules is essential for maintaining plasma glucose levels in
fasting conditions.
4. GH and tubular gluconeogenesis
IV. Renal Consequences of GH Hypersecretion
Gluconeogenesis in proximal tubular cells contributes
to endogenous glucose production. In the normal postabsorptive state, glucose produced in the renal cortex is almost entirely consumed by medullary cells, which are in
profound hypoxic conditions, possess only glycolytic enzymes, and are thus obligate glucose users. As a result, the
kidney does not release large amounts of glucose into the
circulation in the postabsorptive state (161). In contrast,
renal glucose release becomes significant during starvation, contributing up to 50% of endogenous glucose production (162–164)! Mice with liver-specific deletion of the
glucose-6-phosphatase gene, encoding an enzyme mandatory for glucose production, even show compensatory gluconeogenesis in the kidneys and intestine during fasting,
thus maintaining euglycemia (165).
During prolonged fasting, GH secretion is strongly enhanced, whereas insulin and IGF-1 secretion decreases
(166). GH is crucial for adapting energy homeostasis to
prolonged caloric restriction, mainly by stimulating lipolysis and thereby increasing free fatty acid production and
generating ketone bodies to prevent major muscle protein
breakdown (167). Recently, in mice lacking ghrelin Oacyltransferase (GOAT), the group of Brown and Goldstein (168) demonstrated that ghrelin secretion is essential
for GH-mediated survival during caloric restriction.
When faced with a 60% calorie-restricted diet, GOAT⫺/⫺
mice failed to maintain glycemia and became moribund by
day 7, whereas wild-type (WT) animals stabilized their
plasma glucose levels after an initial fall and showed normal physical activity. The caloric restriction-induced rise
in GH was lower in GOAT⫺/⫺ mice, and hypoglycemia
and death were prevented by both ghrelin and GH administration (168).
As summarized in the previous section, GH and IGF-1 are
clearly involved in the physiological regulation of renal
growth and function. Consequently, in acromegaly,
chronic kidney exposure to excessive GH and IGF-1 levels
(170, 171) is associated with major changes in renal morphology and in both glomerular and tubular functions.
These effects take place in a context of chronic systemic
complications such as hypertension and diabetes mellitus
(172, 173), which themselves may also affect the kidney in
patients with acromegaly. The following section describes
the pathophysiological bases of the main renal consequences of GH and IGF-1 hypersecretion, with a special
focus (where possible) on the underlying molecular
mechanisms.
A. Renal hypertrophy
The first transgenic mouse models overexpressing the
rat and human GH genes described by Palmiter et al (174,
175) opened up an exciting approach to identifying new
GH functions in different tissues. These mice present a
giant phenotype (2-fold increase in body size and weight)
associated with accelerated linear somatic growth and organomegaly (174, 175). The kidneys of GH transgenic
mice are even larger when normalized to body weight,
indicating disproportional renal growth. GH transgenic
mice consistently develop kidney damage (176). The most
detailed studies of the renal architecture were carried out
in mice transgenic for bovine GH. These animals develop
glomerular hypertrophy and mesangial proliferation at 4
to 5 weeks, followed by progressive mesangial sclerosis at
19 weeks, resulting in complete glomerulosclerosis at 30
to 37 weeks. In contrast, mice transgenic for IGF-1 do not
develop glomerulosclerosis and have less severe glomeru-
doi: 10.1210/er.2013-1071
lar hypertrophy (177, 178). Similar observations have
been made in acromegalic rats bearing GH-secreting tumors of somatotrope GC cells (179). These rats exhibit
3.5-fold renal hypertrophy leading to a 1.6-fold increase in
the kidney weight to body weight ratio compared to WT
rats (Figure 3). This renal enlargement is mainly due to
severe glomerular hypertrophy and interstitial edema,
with no concomitant increase in tubule diameter (35). Acromegalic rats also exhibit severe glomerulosclerosis (Kamenický, P.K., M. L. Lombès, and P. C. Chanson unpublished data; Figure 3).
In humans, gigantism and acromegaly are also associated with renal hypertrophy (82). A recent case-control
study of healthy volunteers and patients with active and
controlled acromegaly, in which renal size was assessed by
ultrasonography, showed a significant increase in longitudinal and transversal kidney diameter in patients with
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both active and treated disease as compared to controls
(180). Few data are available on the renal architecture in
acromegalic patients. Isolated studies of patients who underwent renal biopsy for proteinuria showed glomerular
hypertrophy with focal segmental glomerular sclerosis
(181, 182), but such changes in renal architecture seem to
be rare. Findings in transgenic mice and acromegalic rats
must thus be interpreted carefully because these animal
models represent a caricature of gigantism/acromegaly
that is rarely encountered in humans.
B. Changes in glomerular function
Acromegalic patients exhibit a remarkable increase in
glomerular filtration and renal plasma flow, first described several decades ago (183–185). The GFR in these
studies was assessed in terms of inulin or radioisotope
clearance (186). However, the anabolic effect of GH on
Figure 3.
Figure 3. Renal hypertrophy in acromegalic GC rats. A, Morphological features of WT and GC rat kidney (scale in millimeters). B, Comparison of
kidney weight (left panel) and the kidney weight/body weight ratio (right panel) in WT and GC rats; body weight of WT and GC rats was 207 ⫾
3.7 g and 434.7 ⫾ 16.4 g, respectively (mean ⫾ SEM; n ⫽ 10; **, P ⬍ .01). C, Histological features of WT and GC rat kidneys (magnification,
⫻10; scale bar ⫽ 100 mm). D, Representative microdissected cortical collecting duct from WT and GC rats (magnification, ⫻2.5; scale bar ⫽ 100
mm). E, Focal (left) and global (right) glomerulosclerosis. F, Hyaline cylinders with tubular dilation in GC rat kidneys. [Modified from P. Kamenicky
et al.: Epithelial sodium channel is a key mediator of growth hormone-induced sodium retention in acromegaly. Endocrinology. 2008;149:3294 –
3305 (35), with permission. © The Endocrine Society.]
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GH, IGF-1, and Kidney
skeletal muscle must be taken into account when assessing
glomerular function in acromegaly by plasma creatinine
measurement because it may lead to an increase in plasma
creatinine concentrations (186). Recently, we studied 16
acromegalic patients before and after treatment and found
a consistent 15% increase in the GFR in patients with
active disease (158, 187). As stated above (Section III.B),
GH enhances glomerular filtration (81) through an IGF1-mediated decrease in renal vascular resistance, leading
in turn to increased glomerular perfusion (61, 82– 86). On
the other hand, glomerular hyperfiltration does not seem
to be linked to extracellular volume expansion (see Section
IV.C) (188) or to renal hypertrophy because it rapidly
disappears after acromegaly treatment, before any significant changes in kidney architecture would have time to
occur (185).
Patients with acromegaly seem to have higher albuminuria than the normal population (93, 186, 189). In a recent
study, microalbuminuria was observed in 55% of acromegalic patients but in no healthy volunteers. Not surprisingly, microalbuminuria was more frequent in patients with impaired glucose tolerance, diabetes, and
hypertension (190).
C. Pathophysiology of body fluid retention
Acromegaly is often accompanied by soft-tissue enlargement, contributing to these patients’ dysmorphic features (170, 171, 191). Glycosaminoglycan deposition and
increased collagen production by connective tissue contribute to this soft-tissue infiltration, but generalized
edema may also play a role. In 1954, in their seminal work,
Ikkos et al (188) demonstrated that the acromegalic state
is associated with an increase in body water and sodium.
In 18 acromegalic patients and nine healthy volunteers,
they measured several parameters including total body
water (assessed by the volume of antipyrine distribution),
extracellular water (estimated by the volume of inulin or
thiosulfate distribution), and exchangeable sodium (determined by the volume of distribution of the radioactive
isotope 24Na). Intracellular water was calculated as the
difference between total body water and extracellular water. The authors showed that, compared with healthy volunteers, acromegalic patients had a significant increase in
total body water (56 vs 50% of body weight), extracellular
water (20 vs 15% of body weight), and exchangeable sodium, with no difference in intracellular water content
(188). Several metabolic studies confirmed this initial observation (88). Ho’s group (192) compared acromegalic
patients, before and after treatment, with age-, sex-,
weight-, and height-matched healthy volunteers and assessed their body composition by means of dual-energy
x-ray absorptiometry and their extracellular water con-
Endocrine Reviews, April 2014, 35(2):234 –281
tent by using the 24Na dilution procedure. They found
that untreated acromegalic patients had increased lean
mass due to an increased extracellular water content
(192). Plasma volume is also increased in acromegalic
patients, as shown by measurements of radiolabeled
albumin distribution (193–195). The increase in plasma
volume can be reversed by effective treatment of acromegaly (194, 196).
Increased body water and sodium, responsible for softtissue swelling, leads to a broad spectrum of acromegalic
symptoms and complications (171, 172, 191) and may be
related to increased mortality in untreated patients (197).
The increase in plasma volume contributes to acromegalic
patients’ higher prevalence of arterial hypertension (171,
172, 191), a major prognostic factor for excess mortality
(197). Increased myocardial water content, as shown by
cardiac magnetic resonance imaging (MRI) with T2 mapping assessments (198), contributes to the impaired diastolic ventricular function and ventricular hypertrophy
commonly seen in acromegalic cardiomyopathy (179).
This myocardial edema is rapidly reversible upon effective
acromegaly treatment (198). This certainly contributes to
the observed effects of medical treatment on heart morphology and function in these patients (199). Furthermore, MRI studies of the median nerve (200) and, more
recently, ultrasound studies of the ulnar nerve (201) have
linked common neurological symptoms such as hand paresthesias (frequently misdiagnosed as carpal or cubital
tunnel syndrome and operated on unnecessarily) to reversible edema of these peripheral nerves. Obstructive
sleep apnea syndrome, another common complication of
GH excess, is partially due to infiltration of the pharyngeal
walls and tongue and can also be rapidly improved by acromegaly treatment (202, 203). Finally, the very rapid improvement in dysmorphic features, occurring only hours or
days after successful surgery or medical treatment of acromegaly, especially when a GHR antagonist is used, further
illustrates the importance of water infiltration in the acromegalic phenotype. Some clinical manifestations of water
infiltration in acromegaly are illustrated in Figure 4.
The physiological bases of the antinatriuretic effect of
GH and IGF-1 in the kidney have been reviewed in detail
in Section III.C. As already stated, the sodium-retaining
action of GH and IGF-1 seems to exclude a major contribution of RAAS or antinatriuretic peptides. Forty years
ago, Strauch et al (194) showed that RAAS levels were
normal in normotensive patients with acromegaly. Other
studies showed unchanged (204 –207) or suppressed (208)
RAAS activity in acromegalic patients. More recently, increased aldosterone concentrations were found in acromegalic patients before surgical treatment and in transgenic mice overexpressing GH alone or together with
doi: 10.1210/er.2013-1071
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247
Figure 4.
Figure 4. Some clinical consequences of sodium and water retention in acromegaly. A, Tongue edema and soft-tissue swelling contributing to
facial dysmorphic features. B, Upper airways infiltration, as shown by MRI, in a patient before and after treatment of acromegaly. C, Myocardial
edema. [Modified from H. Gouya et al.: Rapidly reversible myocardial edema in patients with acromegaly: assessment with ultrafast T2 mapping in
a single-breath-hold MRI sequence. AJR Am J Roentgenol. 2008;190:1576 –1582 (198), with permission. © American Roentgen Ray Society.] D,
median nerve edema as shown by ultrasonography in a patient with acromegaly compared with a normal healthy subject. [Modified from A.
Tagliafico et al.: Ultrasound measurement of median and ulnar nerve cross-sectional area in acromegaly. J Clin Endocrinol Metab. 2008;93:905–
909 (201), with permission. © The Endocrine Society.] E, Increased extracellular water in patients with acromegaly compared with normal healthy
subjects. ECW, extracellular water; BCM, body cell mass. [Modified from A. J. O’Sullivan et al.: Body composition and energy expenditure in
acromegaly. J Clin Endocrinol Metab. 1994;78:381–386 (192), with permission. © The Endocrine Society.]
IGFBP-2. Aldosterone concentrations did not differ between these two transgenic mouse models, indicating that
elevated aldosterone levels were directly due to the GH
excess and not to elevated IGF-1, which is known to be
blocked by IGFBP-2 overexpression (209). We recently
investigated 16 acromegalic patients on a high-sodium
diet (Na intake, 150 mmol/d) (187). As expected in
subjects with chronic volume expansion during a high-
sodium diet (210), we found that RAAS activity was partially suppressed and that it did not change after acromegaly treatment (187). An association between acromegaly
and primary hyperaldosteronism has also been reported
(194, 211), but it was not confirmed in larger controlled
studies using modern hormone assessments and may thus
have been a random observation in meticulously explored
patients participating in clinical research.
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GH, IGF-1, and Kidney
An inadequate response of natriuretic peptides to hypervolemia (212) was also considered as a possible pathophysiological mechanism for body fluid retention in the
acromegalic state. Baseline plasma ANP concentrations
are similar in acromegalic patients and healthy controls
(205–207). An inadequate increase in plasma ANP in response to stimulation by saline infusion was found in one
study (205), but this observation was not reproduced by
our group (206) or by others (207). In addition, we have
recently reported unchanged brain natriuretic peptide
(BNP) concentrations before vs after treatment of acromegaly (187). Thus, sodium and water expansion in acromegaly seems to result from a direct action of GH and
IGF-1 in the kidney, rather than from a RAAS- or natriuretic peptide-mediated effect.
By studying acromegalic rats bearing somatotropic tumors, we obtained the first evidence that a GH excess has
a direct stimulatory effect on ENaC-dependent sodium
transport in the late distal nephron. Acromegalic GC rats
were subjected to pharmacological challenges and exhibited an increased natriuretic response to amiloride (a specific ENaC blocker) and a decreased natriuretic response
to furosemide (NKCC2 inhibitor in Henle’s loop) compared to controls. This was accompanied by enhanced
Na/K-ATPase activity selectively in the cortical collecting
ducts, providing additional evidence for increased sodium
reabsorption in the late distal nephron during a chronic
GH excess. The GC rats also showed major changes in
proteolytic maturation of both the ␣- and ␥-subunits of
ENaC in kidney (35). These changes in ENaC subunit
proteins are associated with increased ENaC activities
(213) and are induced by hyperaldosteronism due either to
sodium restriction or to aldosterone administration (126,
214). However, acromegalic GC rats had low plasma aldosterone concentrations compared to controls (35), providing additional evidence that GH/IGF-1 directly control
ENaC activity, irrespective of mineralocorticoid status.
More recently, we extended this observation to humans
in a randomized crossover study of 16 patients before and
after effective acromegaly treatment. As in GC rats, we
compared acute natriuretic and kaliuretic responses to diuretics targeting either ENaC (amiloride) in the distal
nephron or NKCC2 (furosemide) in Henle’s loop. We
found that active acromegaly was associated with an increased response to amiloride and a reduced response to
furosemide, providing the first evidence in humans of increased renal ENaC activity when GH/IGF-1 is secreted in
excess (187). Because ENaC expression is not restricted to
the kidneys but these channels are active in other sodiumtransporting epithelia, particularly in the colonic (215)
and respiratory mucosae (216), we also measured nasal
amiloride-sensitive potential, reflecting intranasal ENaC
Endocrine Reviews, April 2014, 35(2):234 –281
activity, in the same patients. We found that ENaC activity
in patients with active acromegaly was also increased in
the nasal mucosa (187). Inadequate renal and extrarenal
ENaC activation may thus contribute to the pathogenesis
of altered water and sodium homeostasis in acromegaly
(Figure 5). Our study was not designed to distinguish between direct GH- and IGF-1-mediated regulation of ENaC
but, as already reported in Section III.C, it is likely that the
two hormones act together to stimulate ENaC-dependent
transepithelial sodium transport in the distal nephron.
These novel observations raised a number of questions.
Constitutive ENaC hyperactivation in Liddle’s syndrome
(217) and inappropriate ENaC activation secondary to
chronic aldosterone action in primary hyperaldosteronism (218) are usually associated with hypertension and
hypokalemia, without edema. In contrast, acromegalic
patients have soft-tissue swelling and arterial hypertension but are usually free of hypokalemia. Interestingly,
other pathological situations such as puromycin-induced
nephrosis are also associated with increased ENaC activation and a concomitant increase in potassium secretion
(219, 220), but the underlying molecular mechanism remains to be elucidated.
Finally, another possible molecular target of GH/IGF-1
in the kidney tubule is the sodium pump Na/K-ATPase.
GH has been shown to enhance the hydrolytic activity of
Na/K-ATPase in rat kidney homogenates (221). Increased
Na/K-ATPase activity was also found in leukocytes (222)
and skeletal muscle (223) of acromegalic patients. Nevertheless, other authors identified a circulating endogenous digitalis-like factor in the plasma of acromegalic patients, which inhibited sodium pump activity (195). The
literature on the putative effect of GH on Na/K-ATPase
thus needs to be revisited.
D. Changes in phospho-calcium metabolism
Patients with acromegaly frequently have phosphate
and calcium abnormalities, such as mild hyperphosphatemia, a tendency toward increased plasma calcium
levels, and hypercalciuria (170, 224). The effect of acromegaly on calcium and phosphate metabolism has long
been a matter of interest. Molinatti et al (225) described
increased plasma calcium concentrations and increased
urinary calcium excretion in some acromegalic patients,
with a return to normal values after treatment. These observations were confirmed in several other studies (158,
180, 224, 226).
The pathophysiological mechanisms underlying these
changes in calcium homeostasis in acromegaly have
mainly been studied with respect to the two main calciotropic hormones, PTH and calcitriol. The role played by
PTH is controversial. Indeed, low PTH concentrations in
doi: 10.1210/er.2013-1071
Figure 5.
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249
ported an increase in 24-hour mean
PTH concentrations, together with a
decrease in PTH target organ sensiA
tivity, after successful treatment of
acromegaly. These discrepancies
might also be due to the pulsatile nature of PTH secretion (232), which
may compromise conclusions based
on random baseline PTH levels.
Involvement of calcitriol is more
convincing because several studies
have consistently demonstrated increased calcitriol concentrations in
acromegaly (154, 233). The hypercalciuria observed in acromegalic
patients is classically linked to increased intestinal calcium absorption driven by calcitriol (154, 233).
In addition to this absorptive mechanism, increased bone turnover may
also participate because calcium exB
cretion is also increased in fasting
conditions (158, 228). Moreover,
the elevated fasting plasma calcium
levels in acromegalic patients, despite their increased glomerular filtration (81, 184), in parallel with the
low calcium excretion observed during childhood (153), suggest that the
calcitriol-mediated calcium-saving
effect of acromegaly also involves
the kidney. This was recently confirmed in a controlled clinical study
showing increased tubular calcium
reabsorption in the whole nephron
and, more precisely, in the distal tubule (during functional exclusion of
Henle’s loop by furosemide) in patients with active acromegaly comFigure 5. Increased renal and extrarenal ENaC activity in acromegaly. A, Effect of amiloride and
pared to treated patients (Figure 6).
furosemide on the urinary Na/K ratio before and after treatment of acromegaly. B, AmilorideInterestingly, total and furosemidesensitive nasal potential in patients with active disease and in the same patients after effective
sensitive magnesium reabsorption
treatment of acromegaly. [Adapted from P. Kamenicky et al.: Body fluid expansion in acromegaly
was unaffected by treatment of acis related to enhanced ENaC activity. J Clin Endocrinol Metab. 2011;96:2127–2135 (187), with
permission. © The Endocrine Society.]
romegaly (158). Unlike in Henle’s
loop, where paracellular calcium
acromegaly, in response to increased plasma calcium con- and magnesium transports are coupled, the two cations
centrations, have been reported in some (227, 228), but are reabsorbed in the distal nephron through distinct monot all studies (224, 229). This discordance might be ex- lecular mechanisms. The increase in distal calcium reabplained by enrollment of acromegalic patients with pri- sorption in acromegaly is probably driven by calcitriol via
mary hyperparathyroidism that, independently of multi- the TRPV5 epithelial calcium channel (152, 157) and is
ple endocrine neoplasia type 1, seems to be more prevalent usually masked in nonfasting conditions by absorptive hyin acromegaly (230). More recently, White et al (231) re- percalciuria (Figure 6).
250
Kamenický et al
GH, IGF-1, and Kidney
Endocrine Reviews, April 2014, 35(2):234 –281
Figure 6.
apical membrane Na-Pi II cotransporters by IGF-1 (19, 148, 149) as
described in detail in Section III.C.
The permissive action of low PTH
levels is controversial (224, 227–
229, 234). Similarly, levels of fibroblast growth factor 23, another major phosphaturic hormone, have
been found to be elevated or unchanged (thus inappropriate) in acromegalic patients (158, 235). The
relation between the GH/IGF-1 axis
and hormonal systems including
PTH and fibroblast growth factor
23/Klotho thus needs further
investigation.
Disturbances in calcium and
phosphate handling in acromegaly
may well contribute to the recent
finding of increased spinal skeletal
fragility in acromegaly (236), as supported by both cross-sectional and
longitudinal studies (237–239).
A
B
V. Renal Consequences of GH
Deficiency
Figure 6. Effect of acromegaly on renal tubular calcium handling. A, Acromegaly is associated
with an IGF-1-mediated increase in calcitriol production, responsible for enhanced intestinal
dietary calcium absorption and, consequently, for absorptive hypercalciuria. However, the
calcitriol-mediated calcium-saving effect of GH/IGF-1 excess also involves the kidney because
acromegalic patients have enhanced renal calcium reabsorption in the distal tubule. B, Calcium
fluxes along the nephron at baseline and during furosemide administration before and after
acromegaly treatment. [Adapted from P. Kamenický et al.: Pathophysiology of renal calcium
handling in acromegaly: what lies behind hypercalciuria? J Clin Endocrinol Metab.
2012;97:2124 –2133 (158), with permission. © The Endocrine Society.]
These elevated plasma phosphate concentrations are
related both to increased calcitriol-stimulated dietary
phosphate absorption (154, 233) and to a direct antiphosphaturic action of IGF-1 in the proximal tubule (81, 114).
Patients with active acromegaly have an increased renal
threshold for the TmPO4. In our recent study, TmPO4 was
51% higher before acromegaly treatment than after treatment (158). The molecular mechanism underlying this enhanced phosphate reabsorption involves stimulation of
Chronic GH and IGF-1 deficiency is
accompanied by significant changes
in renal morphology and functions,
as well as by altered body composition, osteoporosis with fractures,
and an increased cardiovascular risk
(240 –243). In general, the renal consequences of GH and IGF-1 deficiency mirror the changes observed
in acromegalic patients. The advent
of rhGH enabled extensive studies of
the effects of GH replacement in GHdeficient children and adults, including effects on the kidney.
A. Consequences for kidney size
Various hormones and growth factors, including the
GH/IGF-1 system, participate in the control of appropriate somatic growth. Animal models in which genes encoding components of the GH/IGF-1 axis were disrupted
have largely contributed to our understanding of the respective roles of GH and IGF-1 and their receptors in preand postnatal somatic growth and development. Some of
these animal studies include data on the kidney. GHR⫺/⫺
doi: 10.1210/er.2013-1071
mice, reproducing GH insensitivity in humans, have a normal body size and weight at birth but develop dwarfism
from the third week of life, with an adult weight approximately half that of their littermate controls (244). Interestingly, even after normalization to body weight, the kidneys are smaller in GHR⫺/⫺ mice than in controls (73).
The pioneering work of Efstratiadis and colleagues (245)
unambiguously demonstrated that components of the IGF
system are major determinants of mammalian somatic
growth. IGF-1⫺/⫺ mice exhibit both intrauterine growth
retardation and marked postnatal growth impairment
with generalized organ hypoplasia (75). Kidney size in
adult IGF-1⫺/⫺ mice is only 37 and 47% that of their male
and female WT littermates, respectively (246). IGF-2 disruption similarly impairs intrauterine growth but not
postnatal growth, suggesting that this growth factor is
essential for embryonic but not postnatal growth (247).
Interestingly, IGF-2 overexpression does not rescue the
postnatal growth deficit of IGF-1-deficient mice but selectively increases the absolute and relative kidney weights
of normal and IGF-1-deficient male mice, suggesting a
gender-specific role of IGF-2 in kidney growth (246). IGF1R⫺/⫺ mice exhibit severe intrauterine growth retardation, with 100% mortality at birth and generalized organ
hypoplasia (75). IGF-2R⫺/⫺ mice showed increased IGF-2
concentrations and increased kidney size (248). To our
knowledge, there are no animal models of kidney-specific
disruption of the GHR, IGF-1, or IGF-1R genes. Experimental IGF-1R deficiency in various tissues, induced by
Cre-lox-mediated dosage of a floxed IGF-1R gene, leads to
a relative increase in kidney size normalized to body
weight. This may be due to increased GH concentrations
inducing other growth factors locally in the kidney (249).
Both GH and IGF-1 treatment of Snell dwarf mice bearing
mutations in the PIT1 gene increased kidney size, whereas
only IGF-1 increased glomerular volume (250, 251).
Studies of growth retardation in patients bearing homozygous mutations of the GH, GHR, and IGF-1 genes
indicate similar functions of these genes in humans (252–
254). Several studies have analyzed kidney size in human
GH deficiency. After hypophysectomy, kidney size fell by
20% after 5 months (185). Interestingly, GH-untreated
dwarfs bearing homozygous null mutations in the GHRH
receptor gene had larger ultrasonographic measured kidneys than control subjects when corrected for body surface
area (255). Subjects with GHR insensitivity have small
kidneys (256).
GH treatment of adults with childhood-onset GH deficiency increases kidney length (257), but no such increase was found in patients with adult-onset GH deficiency due to pituitary adenomas (258). Long-term
treatment with recombinant IGF-1 in subjects with GHR
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251
insensitivity also increases kidney size (256). To the best of
our knowledge, the kidney architecture (nephron number
and size, etc) has not been studied in detail in human GH
and IGF-1 deficiency.
B. Changes in glomerular function
As already stated above, GH increases glomerular filtration (81) through an IGF-1-mediated increase in glomerular perfusion due to decreased renal vascular resistance (249). The GH- and IGF-1-induced increase in
extracellular volume and plasma volume also contributes
to increased glomerular filtration (88). Hypophysectomy
in humans receiving replacement therapy for all pituitary
deficiencies except GH is followed by a rapid decrease in
glomerular filtration, before any changes in renal mass or
architecture (185). GH and IGF-1 deficiency are associated with decreased glomerular filtration and renal plasma
flow (259 –261). Interestingly, GH replacement therapy
increased the GFR and renal plasma flow in some (259,
260) but not all studies (107, 258, 262), depending on the
dose and duration of treatment. Treatment with recombinant IGF-1 in patients with GH insensitivity also increases glomerular filtration (261). Care should be taken
when estimating the GFR in terms of creatinine clearance
because GH deficiency is associated with decreased protein synthesis that can be corrected by GH and IGF-1 supplementation (263, 264).
C. Changes in body fluid homeostasis
GH deficiency in children and adults is associated with
major changes in body composition, mainly featuring an
increase in sc and visceral fat mass and a low sodium and
water body content (88, 265, 266). Parra et al (267), using
the bromide and antipyrine dilution methods in hypopituitary dwarfs, showed that total body water and extracellular water contents were lower than calculated normal
values. De Boer et al (263) assessed the body composition
of GH-deficient adult men and sex- and age- matched controls by means of anthropometry and bioimpedance and
found a lower lean body mass due to lower hydration. This
was confirmed in a large study using isotope dilution techniques in adult GH-deficient patients and sex- and agematched controls (268).
The pioneering study by Parra et al (267) in hypopituitary children and young adults showed an increase in total
body volume, extracellular volume, and intracellular volume after 1 year of rhGH therapy. Two parallel clinical
trials in GH-deficient adults subsequently showed beneficial effects of GH treatment on body composition, with
an increase in lean body mass (259, 267, 269). In some
patients, high-dose GH treatment (ⱖ0.07 U/kg/d) was accompanied by early fluid retention with transient edema,
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GH, IGF-1, and Kidney
weight gain, and carpal tunnel syndrome, all of which
disappeared either after a dose reduction or spontaneously
after 2–3 months without dose adjustment (269 –271).
Physiological GH production in healthy adults is estimated at 0.02– 0.03 U/kg/d (265). No adverse effects related to fluid retention were observed when low-dose GH
replacement was used (272). How precisely GH impacts
body hydration was further investigated in a number of
clinical studies. Bengtsson et al (144) analyzed body composition in GH-deficient adults receiving high-dose GH
replacement therapy by means of computed tomography,
bioelectric impedance, and a four-compartment model
based on total body potassium and total body water (estimated by tritiated water dilution). GH treatment increased both the extracellular fluid volume and the body
cell mass (144). Short-term treatment of GH-deficient
adults with physiological and supraphysiological doses of
GH also led to an increase in extracellular water, as measured by 22Na dilution (262). Møller et al (273) also observed an acute increase in extracellular volume by means
of bromide dilution after GH administration and a concomitant reduction in sodium excretion. Although the GH
treatment-related increase in extracellular volume is a consistent finding, an increase in total body water during GH
treatment was seen in some (144, 267, 274) but not all
studies (273).
The impact of GH treatment on plasma volume is less
clear-cut. In two pediatric studies, GH replacement increased the plasma volume, as assessed with iodinated albumin (275). In more recent studies of adult GH-deficient
patients receiving recombinant GH, the impact on plasma
volume (estimated by 125I-albumin dilution) seemed to be
dependent on the treatment duration. Short-term GH
treatment did not modify the plasma volume, whereas
chronic GH administration increased it (262, 273, 276).
The availability of recombinant IGF-1 for the treatment
of IGF-1 deficiency has provided a precious tool for clinical investigation of its direct effects on body hydration
(277). Walker et al (111) clearly documented the antinatriuretic properties of short-term IGF-1 infusion in a child
with GHR insensitivity. The fluid- and sodium-retaining
properties of GH are thus at least partly mediated by
IGF-1.
From the pathophysiological point of view, as already
stated in Section III.C, the sodium-retaining action of GH
and IGF-1 does not seem to involve a major contribution
of RAAS or antinatriuretic peptides. The involvement of
RAAS has been investigated in several studies of GH-deficient subjects, the results pointing to a direct, RAASindependent antinatriuretic action of GH. Along the same
lines, the authors of two controlled studies of GH-deficient subjects receiving physiological and supraphysi-
Endocrine Reviews, April 2014, 35(2):234 –281
ological doses of GH also came to the conclusion that GH
acts directly on the tubule (262, 278). Johannsson et al
(107) investigated the effects of GH substitution during 7
days, followed by an open 12-month phase of GH replacement in patients with severe GH deficiency (Table 1). Although short-term treatment increased plasma renin activity and reduced plasma BNP levels, plasma aldosterone
concentrations did not increase. In the long term, all
RAAS, ANP, and BNP parameters were comparable in the
treated and untreated groups. As expected, GH treatment
was associated with extracellular volume expansion and
with decreased urinary sodium excretion. Because lithium
clearance, which reflects proximal tubular sodium reabsorption, was not affected, the authors localized the sodium-saving effect of GH to beyond the proximal tubule,
in the distal nephron (107). Similar conclusions were
drawn in a subsequent study of the effects of GH and T
replacement in 12 hypopituitary men (108). Involvement
of Henle’s loop was not considered in these two studies but
was ruled out in further animal studies (35, 115) and in a
study in acromegalic patients (187).
Current knowledge of the molecular mechanisms by
which GH and IGF-1 regulate sodium transport in the
distal nephron is summarized in Section III.C. Note that
these molecular bases have not been specifically analyzed
in GH-deficient subjects. In view of the increased ENaC
activity we have observed in acromegalic patients (187), it
would be of interest to analyze the consequences of GH
and IGF-1 treatment on ENaC-dependent sodium transport in the distal nephron and on extrarenal ENaC activity. The sodium overload observed in the initial phase of
GH supplementation might, in theory, be prevented by
coadministration of the ENaC blocker amiloride.
D. Changes in phospho-calcium metabolism
GH and IGF-1 are important regulators of bone homeostasis and are central to normal longitudinal bone
growth in childhood and to maintenance of bone mass
throughout life (236). Indeed, adult GH deficiency causes
low-bone-turnover osteoporosis with a high risk of vertebral and nonvertebral fractures. Low bone mass can be
partially improved by GH replacement (279 –282). These
abnormalities of bone homeostasis in GH-deficient patients are accompanied by significant changes in phosphocalcium metabolism.
The effects of GH on phospho-calcium homeostasis in
GH-deficient children and adults have mainly been studied since rhGH became available. Uncontrolled open-label
studies of GH-deficient children have yielded conflicting
results, with unchanged or even decreased calcium levels
during long-term GH replacement (282–285). In contrast,
several randomized, double-blind, placebo-controlled tri-
doi: 10.1210/er.2013-1071
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253
Table 1. Effect of GH/Placebo Treatment in a Randomized Double Blind Crossover 7-Day Period, Followed by 12
Months of Open GH Replacement Therapy in 10 GH-Deficient Patients (Adapted from Ref. 107)
Measure
Changes in IGF-I, ECW, natriuresis,
norepinephrine excretion,
and natriuretic peptides
IGF-1, ␮g/L
GH
Placebo
ECW, kg
GH
Placebo
24-h U-sodium, mmol
GH
Placebo
24-h NE, mmol/creatinine
GH
Placebo
ANP, ng/L
GH
Placebo
BNP, ng/L
GH
Placebo
Changes in RAAS in supine position and
after 30 min of upright position
Supine posture
PRA, ng AI/mL䡠h
GH
Placebo
Angiotensin II, pg/mL
GH
Placebo
Aldosterone, pg/mL
GH
Placebo
Upright posture
PRA, ng AI/mL䡠h
GH
Placebo
Angiotensin II, pg/mL
GH
Placebo
Aldosterone, pg/mL
GH
Placebo
Baseline
119 (72–116)
125 (107–165)
128 (72–167)
21.2 (19.5–22.6)
20.9 (19.5–23.1)
21.9 (18.8 –23.5)
172 (123–190)
143 (123–166)
152 (106 –188)
25.0 (20.6 –36.4)
22.4 (16.1–26.0)
19.9 (18.2–25.5)
18.7 (10.1–26.8)
19.0 (12.1–26.6)
18.2 (9.1–24.6)
8.6 (4.8 –19.9)
9.7 (4.7–19.6)
6.9 (5.3–20.3)
0.54 (0.21– 0.70)
0.58 (0.26 – 0.71)
0.56 (0.21–1.04)
2.4 (2.0 –3.2)
2.9 (2.0 – 4.0)
3.8 (2.3–5.0)
92 (75–113)
81 (68 –113)
100 (75–118)
0.96 (0.35–3.02)
0.96 (0.26 –1.55)
1.67 (0.46 –3.02)
4.7 (2.0 –10.0)
4.7 (4.0 –5.8)
6.7 (3.5–10.0)
195 (121–240)
155 (121–247)
178 (101–240)
Day 7
Median Treatment
Response
12 Months
272 (212–318)a
b
372 (262– 433)
112 (94 –145)
231 (206 –278)
⫺4 (⫺22 to 3)
22.5 (20.4 –24.7)
22.3 (19.2–23.8)
1.1 (0.8 –1.6)b
0.3 (0.2– 0.5)
128 (106 –141)
169 (116 –188)
⫺ 13.8 ( ⫺ 43.6 to ⫺ 6.7)b
6.0 (⫺12.7 to 30.9)
26.4 (20.0 –29.1)
20.2 (18.2–22.4)
4.1 (1.0 –7.3)b
⫺1.1 (⫺1.9 to 0.0)
16.6 (11.7–19.0)
24.6 (9.8 –30.2)
⫺1.6 (⫺10.2 to 0.9)
1.8 (0.3–9.4)
7.5 (2.0 –14.5)
11.9 (4.3–19.8)
⫺1.9 (⫺2.7 to 0.0)b
0.5 (⫺0.7 to 4.5)
0.94 (0.49 –1.29)
0.53 (0.20 –1.14)
0.29 (0.11– 0.78)a
⫺0.07 (⫺0.13 to 0.01)
4.9 (2.0 –7.2)
4.0 (2.0 – 4.6)
0.2 (0.0 – 4.6)
⫺0.1 (⫺1.3 to 1.9)
71 (41–96)
78 (52–97)
⫺9 (⫺38 to 4)
⫺3 (⫺12 to 0)
3.26 (0.68 –3.64)
1.55 (0.64 –2.07)
1.98 (0.34 –2.37)a
⫺0.43 (⫺0.70 to 0.18)
10.1 (5.5–13.5)
5.7 (3.0 –9.0)
6.2 (1.2–7.7)a
⫺0.2 (⫺5.0 to 1.0)
216 (137–252)
174 (121–235)
40 (8 –132)
11 (⫺40 to 30)
22.3 (20.7–23.9)a
129 (120 –159)
21.6 (15.7–28.7)
10.4 (7.0 –16.3)
5.6 (2.0 –9.0)
0.77 (0.64 – 0.92)
4.8 (2.0 – 6.4)
89 (78 –131)
1.42 (0.71–3.23)
5.8 (3.8 –9.8)
183 (168 –258)
Abbreviations: AI, angiotensin I; ECW, extracellular fluid volume; 24-h U-sodium, 24-hour urinary sodium excretion; 24-h NE, 24-hour urinary norepinephrine excretion;
PRA, plasma renin activity. Data are expressed as median (25th to 75th percentiles). For each parameter, on the first line, baseline and 12-months values for all patients
are given.
a
P ⬍ .01 as compared with baseline.
b
P ⬍ .01 as compared with changes during the placebo treatment.
als in GH-deficient adults have clearly documented increased plasma calcium concentrations and urinary calcium excretion during GH replacement (144, 286 –288).
Bengtsson et al (144) observed increased plasma calcium
concentrations, whereas plasma magnesium concentrations remained unchanged. Beshyah et al (286) reported
transiently increased plasma calcium levels in hypopituitary adults receiving GH, returning to baseline by 6
months of treatment. No effect on urinary calcium excre-
tion was observed in this latter study (286). The same
group further reported small increases in plasma calcium
concentrations by 12 months of GH treatment, disappearing by 18 months of treatment (287). Hansen et al (288)
found an increase in serum total and ionized calcium after
3 months of GH treatment, with a concomitant increase in
urinary calcium excretion after 3 and 6 months of treatment and a gradual return of both parameters to baseline
after 9 and 12 months of treatment. GH replacement ther-
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Kamenický et al
GH, IGF-1, and Kidney
apy in GH-deficient adults thus causes a transient increase
in plasma calcium concentrations and urinary calcium excretion, generally persisting for 3– 6 months.
The respective impacts of GH and IGF-1 on calcium
homeostasis have been investigated in several studies. Infusion of recombinant IGF-1 in a child with GH insensitivity syndrome led to a 2.5-fold increase in renal calcium
excretion (111). A hypercalciuric effect of IGF-1, with no
change in plasma calcium concentrations, was also demonstrated in adult patients with GH insensitivity receiving
sc IGF-1 injections (289). In a controlled study, short-term
treatment with GH or IGF-1 did not significantly increase
plasma calcium concentrations (290). Furthermore, neither GH nor IGF-1 administered for 8 weeks significantly
influenced intestinal calcium absorption or bone calcium
fluxes analyzed by using isotopic calcium tracers (264).
Long-term GH treatment consistently increases plasma
phosphate concentrations in GH-deficient children (282,
284) and adults (144, 145, 288). In contrast to plasma
calcium concentrations, this rise in plasma phosphate persisted during 12–24 months of GH replacement (145, 282,
284, 288). Concomitantly with the increase in plasma
phosphate concentrations, long-term GH replacement reduced urinary phosphate excretion and increased TmPO4
(145, 284, 288). As already stated, the increase in plasma
phosphate concentrations is mainly related to a direct antiphosphaturic action of IGF-1 in the proximal tubule (81,
114). Interestingly, short-term treatment with GH or
IGF-1 did not influence plasma phosphate concentrations
(290).
These effects of GH replacement on phospho-calcium
metabolism are accompanied by changes in calciotropic
hormone levels. The place of PTH is controversial. Several
studies failed to show any consistent changes in PTH concentrations during GH treatment (144, 282–286, 290).
Patients with GH deficiency exhibit decreased end-organ
sensitivity to PTH, leading to a mild state of PTH resistance and increased serum PTH levels (145, 146, 291).
Parathyroid responsiveness to hypocalcemic and hypercalcemic stimuli is reduced in adult GH deficiency and can
be restored by GH replacement therapy (291). Abnormalities in the circadian rhythm of PTH levels were also observed in young and older GH-deficient patients and could
be restored by GH treatment (145, 146, 292).
Short- and long-term treatment with GH in children
and adults increased calcitriol levels in a number of studies
(145, 282–285, 290, 292). This GH action is due to IGF-1mediated stimulation of 1␣-hydroxylase in the proximal
tubule (154–156). In GH-deficient patients, IGF-1 therapy
increases calcitriol concentrations after only 3 days (290).
The calcium-saving action of GH and IGF-1 treatment in
GH deficiency seems to be mediated mainly by increased
Endocrine Reviews, April 2014, 35(2):234 –281
calcitriol production leading to enhanced intestinal calcium and phosphate absorption, and also probably by
increased renal calcium reabsorption. Consequences of
GH replacement therapy on phospho-calcium metabolism
and calciotropic hormones in GH-deficient patients are
summarized in Figure 7.
VI. The GH/IGF-1 Axis in Renal Diseases
GH/IGF-1 dysfunction is a hallmark of many renal diseases, leading to proposals to therapeutically manipulate the GH/IGF-1 axis, particularly in growth disorders
associated with chronic renal failure and kidney
transplantation.
A. GH/IGF-1 and diabetic nephropathy
Diabetic nephropathy is characterized by excessive deposition of extracellular matrix in the kidney, due to glomerular mesangial expansion and tubulointerstitial fibrosis. It is one of the most serious complications of diabetes
mellitus and the most common cause of end-stage renal
failure in Western countries. Moreover, diabetic nephropathy is the largest contributor to the total cost of diabetes
care worldwide, accounting for approximately 40% of all
dialysis prescriptions. Extensive research has identified
several metabolic pathways, beyond the role of high blood
glucose, that play a role in the development and/or progression of diabetic kidney disease (293). Features of early
diabetic renal changes include glomerular hyperfiltration,
glomerular and renal hypertrophy, and increased basement membrane thickness. However, many authors have
reported that widening of the glomerular basement membrane and expansion of the extracellular matrix area in the
mesangium are the most relevant pathological features
(294). It has become clear that the glomerular epithelial
cell, or podocyte, is also damaged early in diabetes (295).
Indeed, loss of glomerular podocytes is an early event in
diabetic nephropathy and is highly predictive of both progressive glomerular injury and long-term albumin excretion in diabetic patients (296).
Excessive GH secretion is a hallmark of poorly controlled type 1 diabetes mellitus (297), and GH has been
implicated as a causative factor in the onset of microangiopathic complications of diabetes (298, 299) (Figure 8).
Specifically, there is convincing evidence that GH and
IGFs play an important role in the early development of
diabetic renal disease (300). Most GH effects in glomerular hypertrophy appear to be mediated by IGF-1, but
some GH effects on glomerular sclerosis may be IGF-1independent (301). Besides the systemic effects of GH and
IGF-1, there is mounting evidence that autocrine and/or
doi: 10.1210/er.2013-1071
Figure 7.
edrv.endojournals.org
255
other microvascular complications
such as diabetic retinopathy and
choroidal neovascularization (306).
A
IGF-1 is a potent mitogen for glomerular mesangial cells, inducing
concomitant stimulation of cell migration as well as proteoglycan,
laminin, fibronectin, and type IV collagen production (307–310). Moreover, the actions of IGF-1 on mesangial cells appear to include inhibition
of apoptosis and of DNA damage induced by high glucose levels (311,
312). The effects of IGF-1 on mesangial cells can be counteracted by
bradykinin activation (313), providing evidence for a possible protective
effect of angiotensin-converting enzyme inhibitors, which activate the
bradykinin receptor, on IGF-1-induced glomerulosclerosis associated
with diabetic nephropathies.
B
The IGF-1 system is complex, being
regulated by interactions of IGF-1
with several IGFBPs (314). The net result of this complex interaction between IGF-1, IGFBPs, and IGF-1Rs is
an increase or decrease in insulin receptor substrate-1 phosphorylation.
The principal IGFBP produced by
mesangial cells is IGFBP-2, which has
been shown to inhibit IGF-1 actions
(315, 316). Hyperglycemia was found
to reduce IGFBP-2 expression, thereby
favoring the effects of IGF-1 on mesFigure 7. Schematic representations of the consequences of GH replacement therapy on calcium
angial cells (317), and also to increase
(A) and phosphorus (B) metabolism and calciotropic hormones in GH-deficient patients.
the expression of IGFBP-3, which mediates mesangial cell apoptosis (91).
paracrine activation of the IGF-1 signaling system in mesangial cells may contribute to the development of diabetic Moreover, IGF-1 was shown to induce nitric oxide synthesis
nephropathy in response to various signals such as hyper- and release by cultured vascular endothelial cells via an effect
on its receptors (3).
glycemia and angiotensin II (302).
It was recently demonstrated that glomerular podocytes express functional GHRs and that GH increases lev1. Involvement of GH and IGF-1
The expression of IGF-1R in mesangial cells is related els of reactive oxygen species and induces actin cytoskelto plasma glucose levels (303). Mesangial cells isolated eton reorganization in these cells (33). It was postulated
from experimental models of diabetic nephropathy dis- that this increase in reactive oxygen species could cause
play the same biological characteristics in vitro as those apoptosis and loss of glomerular podocytes, an early event
observed in vivo. Specifically, these cells exhibit altered in diabetic nephropathy (33, 296, 318). Moreover, it was
IGF-1 synthesis, IGF-1 pathway activation, and higher suggested that GH-dependent reorganization of the podoIGF-1R expression and activation than control mesangial cyte cytoskeleton could result in abnormal functioning of
cells (302, 304, 305). It is noteworthy that autocrine ac- the slit diaphragm and, hence, in increased permeability of
tivation of the IGF-1 system has also been reported in the filtration barrier with ensuing proteinuria (33, 89).
256
Kamenický et al
Figure 8.
GH, IGF-1, and Kidney
Endocrine Reviews, April 2014, 35(2):234 –281
with an intact pituitary (328). The
early increase in IGF-1 was shown to
mediate the rise in GFR by reducing
renal arteriolar resistance and increasing the glomerular ultrafiltration coefficient, possibly by relaxing
the mesangium. These effects of IGF-1
on renal hemodynamics are mediated
through IGF-1Rs and by the induction
and release of nitric oxide. Modulation of IGF-1 availability in the kidney
by nitric oxide synthase inhibition significantly reduced renal hypertrophy
and hyperfiltration during the first
week of STZ-induced diabetes mellitus (329). GH does not appear to directly influence renal hemodynamics,
but as mentioned in Section III, GH
increases GFR and renal plasma flow
by inducing IGF-1 (3).
A direct role for GH/GHR in the
pathogenesis of diabetic nephropathy is supported by studies of GH
Figure 8. Abnormal GH secretion in patients with type-1 diabetes and its potential involvement in
and GH antagonist transgenic mice,
the pathogenesis of diabetic renal disease. SSA, somatostatin.
total GHR knockout mice, and pharmacological blockade of GHR with
An increase in circulating GH was observed in a nono- pegvisomant (323, 330 –332). These studies demonbese mouse model of type 1 diabetes mellitus. This was strated that the absence of functional GHR protects
associated with decreased liver GHR mRNA expression against diabetic nephropathy in murine models of type 1
and decreased GH binding to liver membranes (319), sug- diabetes mellitus. Moreover, treatment of rats with ocgesting a state of GH resistance. However, kidney expres- treotide from diabetes onset completely inhibits the initial
sion of GHR was elevated in these animals (320), suggest- renal hypertrophy and renal IGF-1 accumulation (333),
ing tissue-specific expression of GHR. GHR signaling whereas later treatment only partially inhibits renal hypathways are more active in the kidneys of rodent models pertrophy (334). The effects of somatostatin analogs on
of type 1 diabetes mellitus than in their controls (321). nephropathy in type 1 diabetes appear to be comparable
Moreover, GH administration to rats with streptozotocin to those obtained with angiotensin-converting enzyme in(STZ)-induced diabetes exacerbated their diabetic ne- hibitor (335).
phropathy (322).
In experimental models of diabetic renal disease, the 2. GH and IGF-1 levels in diabetic patients
Elevated mean 24-hour concentrations of circulating
initial increase in renal growth and function is preceded by
a rise in renal IGF-1 (323, 324), IGFBP (325), and IGF- GH and an exaggerated GH response to several physio2/man-6-PR concentrations (326). Moreover, an increase logical and pharmacological provocative stimuli are charin mesangial IGF-1R expression was observed in STZ- acteristic features of patients with type 1 diabetes mellitus.
diabetic rats (327). It is noteworthy that, in the absence of By contrast, GH secretion is blunted in type 2 diabetes
insulin, as in STZ-diabetic rats, the effects of IGF-1 on (298). The exaggerated GH response to provocative stimmesangial effects were favored by low expression of uli was shown to be sustained by a spontaneous decrease
SOCS2 (suppressor of cytokine signaling 2) in glomerular in hypothalamic somatostatin tone (297, 336, 337), which
tissue (327). On the other hand, IGF-1 action on mesan- appeared to be due either to altered feedback mechanisms
gial cells is counteracted by insulin (327), and STZ-dia- (338) or to abnormalities of brain neurotransmitters
betic dwarf rats with isolated GH and IGF-1 deficiency (339). Hepatic GHR expression is decreased in type 1 dishow less renal and glomerular hypertrophy and a smaller abetes due to insulin deficiency resulting in GH resistance
rise in urinary albumin excretion than diabetic control rats (340). Decreased IGF-1 levels and retarded growth have
doi: 10.1210/er.2013-1071
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257
Figure 9.
medulla is poorly oxygenated and
vulnerable to ischemic injury. A coordinated homeostatic mechanism
in the kidney reduces the risk of medullary injury during hypoperfusion
and mediates recovery from ischemic
damage (346). Much of our understanding of the pathophysiology in
acute renal failure and of cellular and
molecular events is based on a rat
model in which renal failure is
caused by arterial clamping (3). In
this model, IGF-1 was shown to be
involved in mediating renal self-repair, as suggested by the presence in
proximal tubule cells of IGF-1Rs, expression of which was up-regulated
in the first days after injury (347).
Moreover, IGF-1 expression was
shown to be strictly restricted to reFigure 9. Disturbed somatotropic axis in patients with chronic renal failure.
generating cells, whereas cells not
been reported in human diabetes (341). However, IGF-1 undergoing regeneration did not express IGF-1 (348). The
levels in various tissues, including kidney and bone, often transient expression of IGF-1 in rat proximal tubules durdiffer from plasma levels. This implies that local produc- ing regeneration after acute renal injury provided a ratiotion and metabolism of IGF-1 within the kidney may be nale for using recombinant IGF-1 to treat acute renal failthe most important determinant of its renal effects. The ure. In experimental models of acute renal failure, IGF-1
involvement of GH in diabetic end-organ damage was first treatment accelerated the recovery of normal renal funcsuggested by the finding that pituitary ablation could ar- tion and the regeneration of damaged proximal tubular
rest or retard the development of proliferative retinopathy epithelium (349 –351). Moreover, IGF-1 increased the
(342). As in rodent models, evidence has been obtained in GFR through a direct action on the glomerular vasculahumans that the GH/IGF-1 axis is involved in the patho- ture, with a decrease in afferent and efferent arterioral
genesis of diabetic nephropathy, with a specific effect on resistance mediated by local production of nitric oxide and
urinary albumin excretion. A correlation between urinary vasodilatory prostaglandins (83). The beneficial effects of
GH and IGF-1 levels and microalbuminuria was observed IGF-1 were reproduced by ghrelin in mice with ischemiain children and adolescents with type 1 diabetes, suggest- induced acute renal failure (352). This treatment was
ing an important role of the GH-IGF-1 system in the out- shown to protect the kidneys from ischemia/reperfusion
come of diabetic nephropathy during puberty, when both injury, and the effect was related to an improvement in
GH and IGF-1 levels are physiologically elevated (343, endothelial function through an IGF-1-mediated pathway
344). In normo- and microalbuminuric adult patients, uri- (352). The successful use of IGF-1 in rats led to clinical
nary IGF-1 levels correlated strongly with kidney volume, trials, but no clinically significant effect of this treatment
and both urinary IGF-1 and GH correlated positively with on renal function or outcome was found (110, 353, 354).
microalbuminuria (343). In contrast, plasma GH and Moreover, questions were raised regarding the safety of
IGF-1 concentrations did not correlate with GFR in nor- GH/IGF-1 axis manipulation in acute critical illness after
moalbuminuric type 1 diabetic patients (345).
excess mortality in some trials of GH (355, 356).
B. GH/IGF-1 in renal impairment
1. Acute renal failure
Although acute renal failure may result from several
acute renal disorders, the term is usually reserved for ischemic or toxic acute renal injury. The kidney is one of the
most highly oxygenated organs in the body, but the bulk
of its blood supply is delivered to the cortex, whereas the
2. Chronic renal failure
Chronic renal failure is associated with many severe
metabolic and hormonal derangements, including alterations of the GH/IGF-1 axis (Figure 9), which plays an
important pathogenetic role in the growth retardation,
catabolism, malnutrition, and glucose intolerance commonly observed in patients with uremia.
258
Kamenický et al
GH, IGF-1, and Kidney
a. GH and IGF-1 levels in chronic renal failure. The kidneys
contribute significantly to GH degradation, and the serum
half-life of GH is significantly increased in patients with
chronic renal failure (3). Random fasting serum GH levels
were shown to be normal or increased in patients with
chronic renal failure, depending on the extent of renal
dysfunction and age (357, 358). High-normal GH secretion and a higher number of GH secretory bursts were
reported in prepubertal children with end-stage renal disease (357, 358) and in adults on hemodialysis (359). In
contrast, GH secretion was decreased in pubertal patients
with advanced chronic renal failure, likely due to altered
sensitivity of the GH/IGF-1 axis to sex steroids, at least
during this developmental stage (360). Moreover, fasting
GH levels were higher in patients on peritoneal dialysis
than in those on hemodialysis, likely reflecting a more
profound state of GH resistance in the former (361).
Serum IGF-1 levels are normal in patients with preterminal chronic renal failure, whereas they are slightly reduced in end-stage renal disease (362, 363). However, the
level of free IGF-1 and its bioactivity are markedly reduced
in patients with chronic renal failure, in a close relationship with the impairment of glomerular filtration (364).
Indeed, “normal” serum total IGF-1 values in chronic renal failure appear to be inadequate because the liver does
not compensate for the low peripheral bioactivity of this
hormone (358). Based on a mathematical approach, IGF-1
production by the liver was predicted to be reduced in
chronic renal failure (364). Free IGF-1 and its bioactivity
tend to be lower during hemodialysis, potentially contributing to the catabolism caused by this treatment (361).
Moreover, IGF-1 bioactivity, assessed using an in vitro
approach, correlated positively with growth velocity, and
serum IGF-1 levels were found to correlate with cardiovascular risk factors in adults with renal failure (365).
b. Chronic renal failure: a GH-resistant state. The increased
GH secretion observed in most patients with chronic renal
failure was assumed to be due to decreased GH clearance
caused by impaired kidney function and to attenuated bioactive IGF-1 feedback of the somatotropic axis (Figure 9)
(see below). The apparent discrepancy between normal or
elevated GH serum levels and impaired growth in children
with chronic renal failure led to the concept of GH insensitivity in the uremic state. This resistant state appeared to
be linked to alterations at several levels of the GH/IGF-1
axis, namely GHRs, GH signal transduction, and IGF-1
action (366). Some but not all reports suggested that GHR
levels were decreased in uremia. Other authors described
reduced hepatic receptor mRNA and growth plate receptor protein levels in rats with chronic renal failure (367,
368). GH resistance in chronic renal failure was also sug-
Endocrine Reviews, April 2014, 35(2):234 –281
gested by low serum GHBP concentrations and activity,
closely related to the degree of renal dysfunction (368).
This finding likely reflects a decrease in GHR density in the
liver, induced by the uremic milieu and associated metabolic disorders. GHBP has been used as a surrogate
marker for GHR numbers because the protein is generated
by enzymatic cleavage of the GHR in humans, releasing
the extracellular domain into the circulation (369 –371).
An important contributor to GH resistance in uremia was
reported to be a defect in the postreceptor GH-activated
JAK2 signal transducer and the STAT transduction pathway (370, 372). Phosphorylation of JAK2 and downstream proteins phosphorylated by this kinase, namely
STAT5, STAT3, and STAT1, was impaired (370). Moreover, it was suggested that uremia might be associated
with increased expression of genes encoding suppressors
of cytokine signaling, which in turn might inhibit JAK2
kinase activity and both GHR and STAT phosphorylation
(366, 373).
The discrepancy between the normal total IGF-1 and
decreased IGF-1 bioactivity was explained by the presence
of IGF inhibitors in the serum of patients with chronic
renal failure (Figure 9). The prevailing inhibitory effects
were suggested to be caused by an excess of IGFBPs such
as IGFBP-1, -2, -4, and -6, related to renal impairment.
Indeed, impaired renal handling of peptides cannot be the
only mechanism involved in elevated serum IGFBP levels
in chronic renal failure. Increased liver production of
IGFBP-1 and -2 appears to contribute to the high levels of
these proteins in chronic renal failure (368). In addition,
these IGFPBs were found to reduce IGF-1 bioactivity in
vitro and in vivo (358). In children with chronic renal
failure, IGFBP-1, -2, and -4 levels correlate negatively with
height, implying that they may contribute to the observed
growth failure (363, 374, 375). Serum IGFBP-1 and -2
levels were shown to be responsible for about 75% of the
variation in free IGF-1 levels in chronic renal failure (364).
The potential role of IGFBP-3 in the pathogenesis of
growth failure related to chronic renal failure is complex.
Patients with chronic renal failure exhibit not only elevated serum levels of IGFBP-3 but also increased levels of
IGFBP-3 proteases, which produce increased amounts of
low-molecular-weight IGFBP-3 fragments that have decreased binding affinity for IGF-1. Indeed, these modifications of IGFBP-3 and its fragments may be seen as a
compensatory mechanism intended to increase free IGF-1
levels (376). However, some of the fragments produced by
IGFBP-3 proteases have no ligand binding ability and inhibit the actions of IGF-1. Thus, IGFBP-3 proteolysis may
either enhance or inhibit IGF-1 activity (358).
doi: 10.1210/er.2013-1071
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3. Treatment with GH
Despite the GH insensitivity observed in chronic renal
failure, there is a valid rationale for the use of recombinant
GH in this setting. Indeed, GH therapy lowers serum
IGFBP-1 levels by about 50%, concomitantly to increased
serum insulin levels, whereas serum levels of IGF-1,
IGFBP-3 and -5 rise during GH treatment (358, 377). All
these changes lead to a 3-fold increase in IGF-1 bioactivity,
with beneficial effects on growth and catabolic status in
patients with renal failure.
a. Children. Growth retardation is one of the main compli-
cations of chronic kidney disease in children, and growth
failure persists in most cases despite aggressive conventional
treatments (transplantation, dialysis, and nutritional support). More than one-third of children with chronic renal
failure have a standardized height below the third percentile
for age, even in centers with optimal nutritional strategies
(378). The impairment of growth velocity is even more severe
in children with chronic kidney disease during the first 2
259
years of life, a period when normal children usually grow by
about 37 cm (379, 380). During childhood, when normal
children usually grow 5– 6 cm/y, children with chronic kidney disease usually have a normal growth velocity and maintain a stable Z-score and therefore remain significantly
growth-retarded. Further growth impairment occurs during
adolescence, when patients with chronic kidney disease fail
to experience an optimal growth spurt (379, 380). It is noteworthy that the quality of life of patients with chronic kidney
disease is adversely impacted by this growth retardation
(381). Finally, delayed growth may be associated with a
higher risk of death and hospitalization due to infectious
diseases, suggesting that it might also be a marker of poor
nutritional status (382).
The first trial to show the efficacy of GH on height in
these patients was published in 1991 (383). Other studies
confirmed this result, showing an increase in all height
indices in predialysis and dialysis children receiving GH
therapy (Table 2) (377, 384 –399). A recent Cochrane re-
Table 2. Effects of Recombinant GH in Children With Chronic Renal Failure
Height During rGH Therapy
Author, Year (Ref.)
Pts, n
Mean
Age, y
Hokken-Koelega, 1991 (383)a
Fine, 1994 (388)a
8
55
8.7
6.0
Hokken-Koelega, 1994 (393)
b
CKD
Stage
rGH Dose
Duration of
Treatment,
mo
preD, D
preD
28 IU/m2/wk
28 IU/m2/wk
6
12
2
Height
SDS
Height
Velocity,
cm
Height
Velocity,
SDS
⫹7.7
⫹1.09
⫹2.9
⫹4.2
⫹6.0
8
7.5
preD, D
28 IU/m /wk
18
Fine, 1995 (386)a
8
19
6.6
1.4
preD, D
preD
14 IU/m2/wk
0.35 IU/kg/wk
18
24
⫹2.1
⫹6.5
Fine, 1996 (387)b
20
preD
0.35 IU/kg/wk
60
⫹1.9
⫹6.2
Wuhl, 1996 (398)b
38
18
30
74
29
7
preD
D
preD
preD
D
preD, D
28 –30 IU/m2/wk
28 –30 IU/m2/wk
28 IU/m2/wk
28 –30 IU/m2/wk
28 –30 IU/m2/wk
NS
12
12
12
12
12
24
⫹1.1
⫹0.5
⫹0.8
⫹1.5
⫹0.5
⫹1.1
⫹9.5
⫹7.3
⫹6.7
⫹4.0
⫹4.9
⫹4.6
⫹3.6
⫹2.8
2
a
Powell, 1997 (377)
Haffner, 1998 (390)b
Postlethwaite, 1998 (396)b
Hokken-Koelega, 2000 (392)
Haffner, 2000 (389)b
Hertel, 2002 (391)a
de Graaff, 2003 (385)b
Bérard, 2008 (384)b
Nissel, 2008 (395)b
Mehls, 2010 (394)b
Santos, 2010 (397)a
Youssef, 2012 (399)b
b
6.5
6.5
5.6
8.3
8.8
6.2
Other Outcomes and AE
7BA, 7BP, no reported AE
7BA, 7BP, asthma/wheezing
(n ⫽ 8)
7 lipid profile, 7 bone
metabolism, no reported AE
⫹3.6
7
328
14
7.3
10
10.3
preD, D
preD, D, T
preD, D
28 IU/m /wk
1 IU/kg/wk
28 IU/m2/wk
96
60
12
⫹2.6
⫹1.4
⫹0.5
15
5
178
193 (M)
47 (F)
208
7
15
9.7
6.8
10.8
13.6
13.8
6.6
14
10.6
preD, D
preD, D
preD, D, T
preD, D, T
preD, D, T
preD, D
preD, D
D
14 IU/m2/wk
28 IU/m2/wk
1 IU/kg/wk
1 IU/kg/wk
1 IU/kg/wk
1 IU/kg/wk
28 IU/m2/wk
0.8 IU/kg/wk
12
48
12
57.6
46.8
12
12
12
⫹0.4
⫹2.1
⫹0.5
⫹1.2
⫹1.6
⫹3.6
⫹1.5
⫹9.2
⫹5.0
⫹4.1
⫹3.6
⫹3.8
⫹2.6
⫹3.0
7BA, 1BW, 1 MAC, 7
bone metabolism, 7
glucose metabolism,
no reported AE
1BA, 1BW, 1MAC, 1Cr, 7
glucose metabolism,
2serum calcium, avascular
necrosis (n ⫽ 1)
No reported AE
No reported AE
No reported AE
Priaprism (n ⫽ 1), avascular
necrosis (n ⫽ 1)
7BA, 1ALP, 7renal function
No reported AE
DM (n ⫽ 1), hypertension (n ⫽ 1),
injection pain (n ⫽ 2)
7BP, no reported AE
No reported AE
No reported AE
⫹0.75
No reported AE
7BA, 7BP, no reported AE
1 BW, 1MAC, 7bone
metabolism
Abbreviations: Pts, patients; CKD, chronic kidney disease; pre-D, predialysis; D, dialysis; T, transplantation; BA, bone age; BP, body proportion; AE, adverse effects; BW,
body weight; MAC, midarm muscle circumference; Cr, creatinine; ALP, alkaline phosphatase; DM, diabetes mellitus; rGH, recombinant GH; NS, not specified; M, males;
F, females.
a
Comparisons with untreated children at the same time points.
b
Comparison with pretreatment values.
260
Kamenický et al
GH, IGF-1, and Kidney
Endocrine Reviews, April 2014, 35(2):234 –281
view showed that 1 year of GH therapy in children increased the growth velocity and height velocity SD score
(SDS) by 3.88 cm/y and 6 SDS, respectively (400). The
optimal dose yielding a clinically significant improvement
in height velocity in children with chronic renal disease
was higher than that usually used in GH-deficient children
with normal renal function (401), reflecting their GH insensitivity and high IGFBP levels associated with chronic
renal failure. A GH dose of 28 IU/m2/wk proved to be
more effective than 14 IU/m2/wk in improving height velocity by about 1.5 cm/y, whereas a further increase to 56
IU/m2/wk did not provide a statistically significant improvement in growth indices (400). Although most data
came from short-term studies (about 1 y of follow-up), the
beneficial effects of GH have been shown to persist during
5– 6 years of treatment (389, 402). In addition, the firstyear response is predictive of the long-term results (390).
In long-term studies, final adult height was considered
normal (⬎ ⫺2SD) in two-thirds of cases (384, 389).
A suboptimal response to GH was linked to the onset
or progression of renal osteodystrophy with persistent secondary hyperparathyroidism, as well as inadequate GH
dosing (the dose should be adjusted to weight gain), nonadherence to daily drug injections, uncorrected nutritional
defects, and acidosis (388). Note that acidosis and nutritional defects should be corrected before starting GH therapy. The growth response to rhGH was also shown to be
related to the underlying renal disease. Children with renal
hypo/dysplasia, by far the most frequent primary renal
disease leading to chronic renal failure in childhood, responded better than children with glomerulonephritis and
other hereditary renal disorders (394). The improvement
in growth correlated negatively with lower baseline
height, younger age, and the duration of treatment (389,
390). Prepubertal children and/or patients with stage 3 or
4 chronic kidney disease responded better to GH treatment than postpubertal patients and/or patients with stage
5 chronic kidney disease, respectively (384, 389, 398).
These differences could be related to differences in the
degree of abnormalities in the IGFBP concentration and
GHR density. These findings suggested that GH therapy
should be started early to obtain the best possible effect on
growth (403). Poorer responses to GH were noted in patients on dialysis and/or with severely delayed puberty
(395).
b. Adults. Besides its positive effects on growth in children,
GH has been shown to stimulate anabolism and to improve body-composition indicators known to be associated with increased survival in adults with end-stage renal
disease (Table 3). Treatment with rhGH was shown to
reduce protein catabolism, to increase muscle area and
strength, and to improve bone mineral density and erythropoietin synthesis, inflammatory status, and quality of
life (Table 3) (404 – 412). Moreover, GH treatment improved lean body mass and reduced cardiovascular risk
factors in both adults and children with chronic renal disease (404, 413), as demonstrated in patients with primary
GH deficiency (240, 242, 414).
c. Is GH treatment safe in patients with chronic renal failure?
Concerns were raised by the observation that patients with
chronic renal failure had a GH metabolic clearance rate
about half that of healthy controls (415– 417). However,
GH did not seem to persist in the circulation of end-stage
renal disease patients longer than in healthy individuals,
Table 3. Effects of Recombinant GH in Adults With Chronic Renal Failure
Body Composition During rGH Therapy
First Author, Year (Ref.)
Pts, n
Mean
Age, y
CKD Stage
rGH Dose
Duration of
Treatment, mo
Iglesias, 1998 (407)b
8
63.9
D
1.4 IU/kg/wk
1
⫹1.2 kg
Johannsson, 1999 (409)a
10
73.5
D
0.6 IU/kg/wk
6
7
Jensen, 1999 (408)b
Hansen, 2000 (406)a
Garibotto, 1997 (405)b
9
9
6
49.0
44.4
60
D
D
D
28 IU/m2/wk
28 IU/wk
45 IU/wk
6
6
6
7
7
⫹3.18 kg
⫹2.1 kg
⫺3.33 kg
⫺3.0 kg
Feldt-Rasmussen, 2007 (404)a
34
34
37
9
58
60
61
59
D
D
D
D
9.5 mg/wk
15.9 mg/wk
34.5 mg/wk
45 IU/wk
6
6
6
3
⫺0.8 kg
⫹2.3 kg
⫹2.7 kg
⫹3.5 kg
⫺0.1 kg
⫺3.1 kg
⫺3.2 kg
⫺4.9 kg
⫺0.6%
Kotzmann, 2001 (410)a
Weight
LBM
FM
⫹5.1 kg
Other Outcomes
and AE
1MAC, 1transferrin, 1FPG, injection
pain (n ⫽ 1), headache (n ⫽ 1), nausea
and vomiting (n ⫽ 3), hypotension (n ⫽ 2),
pruritus (n ⫽ 4), hand paresthesias
(n ⫽ 2)
1muscle area, 2protein catabolic rate,
1albumin, 7 glucose metabolism
1insulin, 7FPG, no reported AE
1PIIINP, no reported AE
1muscle protein synthesis, 7 muscle
protein degradation, 7 glucose
metabolism
1transferrin, 1role physical (in all
groups), 7AE (vs placebo)
7 lipid profile, 1bone turnover, 1QoL
Abbreviations: Pts, patients; CKD, chronic kidney disease; D, dialysis; LBM, lean body mass; FM, fat mass; MAC, midarm muscle circumference; FPG, fasting plasma
glucose; PIIINP, type III collagen N-terminal propeptide; AE, adverse effects; QoL, quality of life; rGH, recombinant GH.
a
Comparisons with untreated adults at the same time points.
b
Comparison with pretreatment values.
doi: 10.1210/er.2013-1071
indicating that the difference in the metabolic clearance
rate was unlikely to have major clinical significance (418).
Studies of children with chronic kidney disease who
were treated with GH to increase their stature indicated
that GH is substantially safe in this clinical context, although the relevant studies were underpowered to detect
clinically important differences in adverse events (400).
After an initial impairment of insulin sensitivity, the
subsequent improvement in lean body mass and the decrease in fat mass induced by GH treatment led to an
improvement in insulin sensitivity (404). This biphasic response may explain the early initial rise in fasting plasma
glucose that occurs in GH-treated patients, with a return
to baseline levels as treatment continues. Indeed, no cases
of irreversible diabetes mellitus were observed in patients
with renal impairment, with the exception of patients with
nephropathic cystinosis in whom diabetes commonly occurs during adolescence unless they are treated with cysteamine (419, 420).
Body segment growth remained appropriate during
treatment, indicating that GH did not influence body proportions during catch-up growth (383, 393). Moreover,
GH did not cause significant changes in bone age as compared to untreated patients (Table 2) (377, 383, 388, 397).
Experimental models of chronic renal failure provided
evidence for a role of GH in the development of glomerular
sclerosis and the induction of glomerular hyperfiltration,
edrv.endojournals.org
261
potentially favoring the progression of kidney disease (3).
This experimental finding was of great concern to clinicians because anecdotal reports suggested that long-term
treatment with GH could accelerate the progression of
renal failure and necessitate early dialysis or renal transplantation (3). However, long-term and controlled studies
demonstrated that exogenous GH did not accelerate the
loss of kidney function with respect to baseline status
(377, 383, 388, 397, 421, 422).
GHR are present in B lymphocytes, and GH treatment
was shown to be associated with an increased risk of lymphoproliferative disease in children transplanted for
chronic renal failure (423, 424). However, it is unclear
whether this was caused by GH itself or by other factors
such as Epstein-Barr virus infection. Current evidence
does not conclusively show that exogenous GH predisposes patients to tumor development.
A frequent clinical manifestation in chronic renal failure
patients receiving GH is benign intracranial hypertension
(425). However, when the frequency of intracranial hypertension in renal patients without GH treatment is taken into
account, the frequency of this disorder during GH treatment
is lower than first anticipated.
The results of the seminal trial led the US Food and
Drug Administration to approve GH therapy for children
with chronic renal failure and retarded growth (below the
fifth centile of the growth curve) (388). Provocative tests
are not required before initiating
GH, as long as growth retardation
Figure 10.
criteria are present. Although the efficacy and safety of GH therapy used
to promote growth in children with
chronic renal failure have been demonstrated, GH is seldom prescribed
to pediatric nephrology patients.
The most significant barriers to GH
use in children with kidney disease
include the unwillingness of the patient and the family to begin and
comply with treatment, difficulties
with reimbursement, and the increasingly short period before transplantation (403).
Because children with short stature and renal failure likely have a
form of functional IGF-1 deficiency,
IGF-1 would theoretically be a more
specific therapy for growth failure
Figure 10. An integrated model of the biphasic, dose-dependent effect of glucocorticoids on GH
secretion. Low glucocorticoid levels cause GH deficiency that is reversible by glucocorticoid
associated with kidney disease.
replacement therapy (giustina’s effect). Treatment with “pharmacological doses” of
However, studies of experimental
glucocorticoids again causes GH deficiency. [Modified from G. Mazziotti and A. Giustina:
uremia showed no significant advanGlucocorticoids and the regulation of growth hormone secretion. Nat Rev Endocrinol. 2013;9:
265–276 (431), with permission. © Nature Publishing Group.]
tage of recombinant IGF-1 over GH
262
Kamenický et al
Figure 11.
GH, IGF-1, and Kidney
Endocrine Reviews, April 2014, 35(2):234 –281
drawal, have been proposed to improve final height in these subjects
(433– 436).
2. Growth failure in kidney recipients
Renal transplantation is considered to be the optimal therapy for
patients with end-stage renal disease
(437). Although the ultimate goal of
renal transplantation in children is
the attainment of a target height,
growth retardation remains common in pediatric allograft recipients
(380). Although the percentage of
patients currently achieving a normal final height is significantly
higher than that reported in the past,
final height remains 2 SD lower than
target height in more than 20% of
recipients (380). Several factors may
impact these children’s growth after
Figure 11. Pathophysiology of growth impairment after renal transplantation. SSA, somatostatin.
renal transplantation (Figure 11).
(426, 427). By contrast, combined therapy with GH and The age of the recipient is an important factor: children
recombinant IGF-1 had an additive effect on longitudinal younger than 6 years show substantial catch-up growth,
growth and anabolism in experimental uremia, and had the whereas the improvement is more limited in children older
added advantage of preventing IGF-1-induced hypoglyce- than 6 years (380). However, even in younger children
mia (426, 427). Finally, IGF-1 had specific anabolic effects with a good response to kidney transplantation, catch-up
and also positive effects on renal function, potentially delay- growth is observed only during the first 2–3 years after
ing the onset of end-stage renal disease (61, 84, 428).
transplant, with no significant improvement thereafter.
The prepubertal growth deceleration that occurs in the
C. GH/IGF-1 in kidney transplantation
normal population is prolonged after transplantation, and
puberty is usually delayed (438). However, although
1. The GH/IGF-1 axis in kidney recipients
The GH/IGF-1 axis tends to remain abnormal in kidney growth continues for longer than usual, height gain is usutransplant recipients because of nutritional factors (ie, ally lower than expected.
protein restriction leading to GH resistance), persistently
impaired renal function (even if minimal), metabolic aci- 3. GH treatment in kidney recipients
Growth retardation observed in children after kidney
dosis, and especially glucocorticoid treatment (Figure 4)
(429, 430). The latter is likely the most important factor transplantation, as well as after transplantation of other
impacting GH secretion and growth in kidney recipient organs such as the liver (338), led to many clinical trials of
children. Exposure to a glucocorticoid excess inhibits GH GH to achieve better growth velocity (Table 4) (393, 439 –
secretion (Figure 10) mainly through an increase in hypo- 447). Current evidence suggests that GH is effective in
thalamic somatostatin tone, and growth retardation is improving growth velocity after kidney transplantation,
commonly experienced by children exposed to a gluco- with positive effects on final height (400, 442, 448). Incorticoid excess (431). Besides their effect on GH secre- deed, children’s response curves after renal transplantation, glucocorticoids also have direct effects on the growth tion during treatment with GH did not seem to be different
plates by inhibiting collagen synthesis, cartilage sulfation, from those of children with chronic kidney disease before
chondrocyte mitosis, GHR binding, and IGF-1 activity. transplantation (449). Despite these results, GH has not
All these effects are thought to contribute to the growth yet been approved for the treatment of growth failure after
impairment associated with a glucocorticoid excess (Fig- transplantation, owing to safety concerns. Besides the
safety issues regarding patients with chronic kidney disure 10) (432).
Indeed, over the last 40 years, steroid-sparing and ste- ease (see Section VI.B), a specific concern in allograft reroid-avoidance protocols, as well as early steroid with- cipients is a possible increase in rejection during GH ther-
doi: 10.1210/er.2013-1071
edrv.endojournals.org
263
Table 4. Effects of Recombinant GH in Kidney Transplant Recipients
Height During rGH Therapy
First Author, Year (Ref.)
Pts, n
Mean Age, y
rGH Dose
Duration of
Treatment, mo
Height
SDS
Height
Velocity, cm
Hokken-Koelega, 1994 (393)c
Broyer, 1996 (439)a
Hokken-Koelega, 1996 (444)a
Guest, 1998 (443)a
Postlethwaite, 1998 (396)b
Maxwell, 1998 (445)a
Fine, 2002 (441)a
7
66
6
41
4
9
31
15.7
12.1
12.1
12.2
13.4
13.0
56 IU/m2/wk
30 IU/m2/wk
28 IU/m2/wk
30 IU/m2/wk
NS
28 IU/m2/wk
30 IU/m2/wk
24
12
6
12
24
12
12
⫹0.30
⫹0.3
⫹1.1
⫹3.2
⫹2.9
⫹3.2
Sanchez, 2002 (446)a
Fine, 2005 (440)a
Seikaly, 2009 (447)a
Gil, 2012 (442)a
11
513
220
33
9.7
NS
7.7
13.2
28 IU/m2/wk
NS
NS
10 mg/m2/wk
24
60
24
36
⫹1.7
⫹0.3
⫹0.8
⫹0.9
⫹0.4
⫹5.4
⫹4.4
⫹3.2
⫹3.6
⫹0.56
⫹1.7
Height
Velocity, SDS
⫹7.9
⫹6.6
Other Outcomes and AE
No reported AE
7BA, BIH (n ⫽ 1), graft rejection (n ⫽ 10)
7BA, no reported AE
1ALP, 7renal function, 7graft rejection
2GFR (n ⫽ 1)
Graft rejection (69%), hyperglycemia (7.7%)
PTLD (n ⫽ 1), DM (n ⫽ 1), infection (n ⫽ 3), TIA (n ⫽ 1),
genu valgum (n ⫽ 1)
7BA, no reported AE
7AE (as compared to controls)
7BMI, 7renal function
7renal function, no reported AE
Abbreviations: Pts, patients; BA, bone age; NS, not specified; AE, adverse effects; ALP, alkaline phosphatase; DM, diabetes mellitus; BIH, benign intracranial
hypertension; PTLD, post-transplant lymphoproliferative disease; TIA, transient ischemic attack; BMI, body mass index.
a
Comparisons with untreated patients at the same time points.
b
Comparison with pretreatment values.
c
Comparison with a control group treated with GH at lower doses (28 IU/m2/wk).
apy because experimental findings indicate that GH might
interact with immune-stimulating cytotoxic T cells (450 –
452). This possibility of rejection episodes has prevented
regular use of GH in transplanted children during the last
two decades. However, data from clinical trials suggest
that a direct role of GH in predisposing patients to graft
rejection is questionable (453). Allograft rejection was detected by biopsy in only a few trials, and its frequency did
not appear to be influenced by GH treatment. Moreover,
pretreatment rejection rates were shown to be an important potential confounding factor when assessing the effects of GH on graft rejection. When GH treatment was
prescribed to stable patients (those in whom renal biopsy
excluded even mild rejection), the rejection rate was low
(441, 443). In addition, the rejection rate was not clearly
increased by GH in patients with chronic rejection and
repeated rejection episodes (453). On the contrary, GH
therapy could be beneficial in these patients, given their
poor growth due to impaired renal function and concurrent use of glucocorticoids to prevent rejection. Glucocorticoid treatment may further impair the catabolic status of
patients with chronic kidney disease, mainly through an
increase in proteolysis (454). Generally, GH treatment has
been shown to prevent and/or counteract the protein catabolic effects of pharmacological glucocorticoid doses
(455). The American Association of Clinical Endocrinology does not recommend the use of GH in transplant patients outside research studies (401), whereas Kidney
Disease Improving Global Outcomes recommends GH
therapy in this setting when height is below the third centile for age and sex and when renal function is impaired
(456). Limited data are available on the most appropriate
dose and duration of GH therapy after renal transplantation. However, data on children with chronic kidney dis-
ease also seem to be relevant to post-transplant patients. It
is unclear how long after renal transplantation GH therapy should be initiated, but many clinicians prefer to wait
6 –12 months after successful transplantation to detect
persistent growth failure. GH treatment should be discontinued on achievement of final height, although careful
monitoring is necessary to avoid a reduction in growth
velocity after GH withdrawal (387). GH should also be
withdrawn if intracranial hypertension or progressive renal osteodystrophy occurs and if scoliosis develops or progresses (380). Benign intracranial hypertension is the result of the physiological antidiuretic effect of GH, whereas
scoliosis may result from rapid longitudinal growth induced by GH (457). The accelerated growth induced by
GH treatment may be accompanied by a worsening of
renal osteodystrophy if secondary hyperparathyroidism
and high bone turnover are not corrected before starting
GH (458). Finally, potential drawbacks of GH therapy in
patients chronically exposed to a glucocorticoid excess
include worsening of insulin resistance in hepatic and peripheral tissues and, potentially, glucose intolerance
(459 – 461).
D. GH/IGF-1 and renal cancer
Human renal cell carcinomas are thought to arise from
a variety of specialized cells located along the nephron.
Clear-cell and papillary carcinomas are thought to arise
from the epithelium of the proximal tubule, whereas chromophobe, oncocytoma, and collecting duct carcinomas
are believed to arise from the distal nephron. The most
common histological type is clear-cell carcinoma, also
called conventional renal cell carcinoma (462). Renal cell
carcinoma accounts for 2–3% of all adult cancers and for
2% of cancer-related deaths. The incidence of renal cell
264
Kamenický et al
GH, IGF-1, and Kidney
carcinoma has been rising steadily by 2– 4% each year;
compared to 40 years ago, there has been a 5-fold increase
in its incidence and a 2-fold increase in related mortality
(463).
1. GH/IGF-1 in the pathogenesis of renal carcinoma
IGFs are candidate proliferation markers in renal cell
carcinoma because of their importance in embryogenesis
(renal growth and development), somatic growth, differentiation, and tumor genesis. IGF-1 is produced by renal
cell carcinoma, which also expresses active IGF-1Rs (464).
Indeed, IGF-1 expression was shown to be predominant in
clear cell tumors, whereas IGF-1R was strongly expressed
by papillary tumors, suggesting differential expression of
the IGF system in different tumor types (465). Simultaneous expression of the ligand (IGF-1 and/or IGF-2) and the
receptor (IGF-1R) in the same tumor provides evidence for
an autocrine-paracrine loop of cancer cell stimulation.
IGF binding to the extracellular subunit of IGF-1R activates the receptor’s tyrosine kinase activity and leads to
activation of MAPK and phosphoinositol-3-kinase cascades, thereby mediating mitogenic, differentiative, and
antiapoptotic effects (466). In addition, IGF-1R signaling
is thought to be involved in cell transformation and in the
maintenance of the transformed phenotype by modulating
cancer cell motility, adhesion, and angiogenesis
(467– 469).
Renal cell carcinoma is a highly vascularized tumor,
and blockade of vascular-endothelial growth factor signaling is beneficial in patients with advanced forms. IGF-1
induces and activates hypoxia-inducible factor-1␣, as well
as its target gene vascular-endothelial growth factor, in a
hypoxia-independent manner through regulatory mechanisms that involve MAPK and phosphatidylinositol
3-kinase/Akt signaling pathways (470, 471). Moreover,
IGF-1 may act directly on endothelial cells, thereby stimulating angiogenesis. One of the mechanisms by which IGF-1
stimulates cell proliferation in renal cell carcinoma is through
increased survivin expression (472). Survivin is an inhibitor
of apoptosis detected in many tumors, including lung, colon,
breast, prostate, and pancreas cancers and high-grade lymphoma but is absent from most normal differentiated adult
tissues (473). Survivin is the only apoptosis inhibitor that is
expressed in a cell cycle-dependent manner (in the G2 and M
phases), associating with microtubules in the mitotic spindle.
When overexpressed, survivin can have an oncogenic action
by overcoming the G2/M checkpoint and ensuring mitotic
progression (474).
This experimental evidence suggests that intervention
along the IGF-1R signaling pathway could ultimately affect cell proliferation, differentiation, and apoptosis, and
Endocrine Reviews, April 2014, 35(2):234 –281
that this might in turn affect tumor development and
growth (475).
2. Epidemiological studies
Epidemiological data indicate that increased circulating levels of IGF-1 are associated with an increased risk of
epithelial cancers (476, 477). Patients with IGF-1R-positive clear-cell renal carcinoma have significantly poorer
cancer-specific survival than those whose tumors are IGF1R-negative, and this association is strongest in the earlier
stages of the disease (464, 478, 479). In addition, elevated
pretreatment IGF-1 levels in renal cell carcinoma patients
have been linked to poor responses to cytokine-based
treatment (480). However, IGF-1 seems to be involved
only during the early stages of renal tumorigenesis: established or progressive renal cell carcinoma appears to be
desensitized to IGF-1-stimulated proliferation. This loss
of responsiveness is not associated with altered IGF-1R
expression (479).
3. GH therapy and renal cancer
Although experimental findings suggest a role for GH
and IGF-1 in the pathogenesis of renal carcinoma, it is
unclear whether manipulation of the GH/IGF-1 axis modifies the cancer risk in patients with chronic renal disease.
The risk of sporadic renal cell carcinoma is greatly increased in patients on long-term dialysis, especially those
with acquired cystic kidney disease (481). Transplantation also carries an increased risk of kidney cancer (estimated to be 15-fold during the first 3 years), and this risk
increases with the extent of exposure to immunosuppressive agents (482). After the first description of renal cancer
occurrence during GH therapy (483), the possible risk of
renal cancer associated with GH treatment in transplanted
patients has been considered (484). The cancer risk should
thus be considered when GH treatment is planned in kidney recipients, and regular imaging of the native and transplanted kidneys should be performed during GH therapy.
E. GH/IGF-1 and polycystic kidney disease
Polycystic kidney disease is characterized by massive
kidney enlargement due to the development of epitheliallined cysts derived from renal tubules and collecting ducts.
There are two forms of polycystic kidney disease with
different patterns of genetic transmission: autosomal
dominant (adult type), and autosomal recessive (infantile
type), the former being the most common inherited human
renal disease and an important cause of end-stage renal
failure.
There is experimental evidence that overexpression of
mitogenic growth factors and attenuated sensitivity to inhibitory factors may underlie the inappropriate epithelial
doi: 10.1210/er.2013-1071
proliferation associated with renal cyst enlargement
(485). Several lines of evidence suggested that IGF-1 may
play a role in mediating tubular cell proliferation in the
cystic kidney. In animal models, renal IGF-1 content increased in parallel with the severity of polycystic kidney
disease, whereas diet-induced lowering of renal IGF-1
concentrations resulted in a parallel reduction in cystic
disease severity (485, 486). Polycystin-1 deficiency, which
occurs in polycystic kidney disease, was associated with
increased sensitivity to IGF-1 as well as with a permissive
effect of cAMP on cell growth (487). Mice transgenic for
human GH display a range of renal pathological changes,
including pronounced cystic tubule dilation (488). Cases
of coexisting acromegaly and autosomal-dominant polycystic kidney disease have been reported (489).
Despite experimental evidence of IGF-1 involvement in
the pathogenesis of polycystic kidney disease, GH treatment has been shown to be effective and safe in children
with autosomal recessive polycystic kidney disease and
growth retardation (490). Specifically, GH was shown to
enhance growth by about 50% (an effect most evident
during the first 18 months), with no significant effects on
kidney function or kidney cyst dimensions (490).
VII. Conclusion
In this review, we have summarized the current knowledge
on the implications of GH and IGF-1 in renal physiology
and pathophysiology. Characterization of the structural
and functional properties of the glomerular membrane,
cloning of membrane transporters and hormone receptors
involved in tubular solute transport and its hormonal control, and deciphering of intracellular signaling pathways
were essential prerequisites for better understanding of
renal GH and IGF-1 actions at the molecular level. GH and
IGF-1 play critical roles in renal development and growth.
Both are also involved in hormonal regulation of glomerular filtration and in fine-tuning of tubular handling of
sodium, water, calcium, and phosphate and of tubular
gluconeogenesis. The impact of GH and IGF-1 on renal
architecture and function becomes clearly apparent in
pathophysiological situations of GH hypersecretion and
deficiency. One of the best-established effects of GH and
IGF-1 on the kidney, responsible for extracellular volume
expansion, contributing to soft-tissue swelling and arterial
hypertension in acromegalic patients, is their sodiumretaining action in the distal tubule, linked to enhanced
ENaC-dependent sodium transport. Changes in phosphocalcium metabolism in acromegaly and in GH deficiency
may be associated with increased skeletal fragility observed in these diseases. GH and IGF-1 also play a signif-
edrv.endojournals.org
265
icant role in the pathogenesis of several major kidney
diseases including diabetic glomerulopathy, renal impairment, renal carcinoma, and polycystic kidney disease.
Chronic renal impairment and chronic glucocorticoid
therapy prescribed to kidney transplant recipients both
have profound effects on the GH/IGF-1 axis, leading us to
propose GH treatment in selected patients.
Acknowledgments
We thank Dr Anne Blanchard (Centre d’Investigation Clinique , Hôpital
Européen Georges Pompidou, Paris, France), Dr Say Viengchareun (Inserm Unité 693, Le Kremlin Bicêtre, France) Pr Argiris Efstratiadis (Biomedical Research Foundation, Academy of Athens, Greece and Columbia University, New York, New York), Pr Etienne Larger (Université
Paris Descartes, Paris, France), and Dr Jean-Marc Elalouf (CEA Saclay,
France) for their helpful advice and critical discussions.
Address all correspondence and requests for reprints to: Philippe
Chanson, MD, Service d’Endocrinologie et des Maladies de la Reproduction, Hôpital de Bicêtre, 78 rue du Général Leclerc, F-94275 Le
Kremlin-Bicêtre, France. E-mail: [email protected].
This work was supported by Grant CRC 06 062-P061012 from Assistance Publique-Hôpitaux de Paris and by a grant from Pfizer. P.K. was
the recipient of a fellowship from Ministère de l’Enseignement Supérieur
et de la Recherche, France. M.L. is the recipient of a Contrat d’Interface
grant from Inserm and Assistance Publique-Hôpitaux de Paris. This
work was also partially supported by CROMO (Center for Research in
Osteoporosis and Bone Metabolism), University of Brescia Italy, and by
MIUR (Italian Ministry for University and Research).
Disclosure Summary: G.M. and M.L. have nothing to declare. A.G.
is a consultant for Pfizer, Novartis, and Ipsen. The institutions of P.C.,
M.L., and P.K. received educational and research grants from Ipsen,
Novartis, and Pfizer. P.C. is a consultant for Pfizer, Novartis, and Ipsen,
and his institution received the consulting and lecture fees.
References
1. Guyton AC. Blood pressure control–special role of the kidneys and body fluids. Science. 1991;252:1813–1816.
2. Morel F, Doucet A. Hormonal control of kidney functions
at the cell level. Physiol Rev. 1986;66:377– 468.
3. Feld S, Hirschberg R. Growth hormone, the insulin-like
growth factor system, and the kidney. Endocr Rev. 1996;
17:423– 480.
4. Salmon WD Jr, Daughaday WH. A hormonally controlled
serum factor which stimulates sulfate incorporation by cartilage in vitro. J Lab Clin Med. 1957;49:825– 836.
5. Le Roith D, Bondy C, Yakar S, Liu JL, Butler A. The somatomedin hypothesis: 2001. Endocr Rev. 2001;22:
53–74.
6. Isaksson OG, Jansson JO, Gause IA. Growth hormone
stimulates longitudinal bone growth directly. Science.
1982;216:1237–1239.
7. Morikawa M, Nixon T, Green H. Growth hormone and
the adipose conversion of 3T3 cells. Cell. 1982;29:783–
789.
8. Clemmons DR. Modifying IGF1 activity: an approach to
266
9.
10.
11.
12.
13.
14.
15.
16.
17.
18.
19.
20.
21.
22.
23.
24.
25.
26.
27.
Kamenický et al
GH, IGF-1, and Kidney
treat endocrine disorders, atherosclerosis and cancer. Nat
Rev Drug Discov. 2007;6:821– 833.
Leung DW, Spencer SA, Cachianes G, et al. Growth hormone receptor and serum binding protein: purification,
cloning and expression. Nature. 1987;330:537–543.
Kelly PA, Djiane J, Postel-Vinay MC, Edery M. The prolactin/growth hormone receptor family. Endocr Rev.
1991;12:235–251.
Herrington J, Carter-Su C. Signaling pathways activated
by the growth hormone receptor. Trends Endocrinol
Metab. 2001;12:252–257.
Rosenfeld RG, Belgorosky A, Camacho-Hubner C, Savage
MO, Wit JM, Hwa V. Defects in growth hormone receptor
signaling. Trends Endocrinol Metab. 2007;18:134 –141.
Pilecka I, Whatmore A, Hooft van Huijsduijnen R,
Destenaves B, Clayton P. Growth hormone signalling:
sprouting links between pathways, human genetics and
therapeutic options. Trends Endocrinol Metab. 2007;18:
12–18.
Jones JI, Clemmons DR. Insulin-like growth factors and
their binding proteins: biological actions. Endocr Rev.
1995;16:3–34.
LeRoith D, Werner H, Beitner-Johnson D, Roberts CT Jr.
Molecular and cellular aspects of the insulin-like growth
factor I receptor. Endocr Rev. 1995;16:143–163.
Haraldsson B, Nyström J, Deen WM. Properties of the
glomerular barrier and mechanisms of proteinuria. Physiol
Rev. 2008;88:451– 487.
Wright EM, Loo DD, Hirayama BA. Biology of human
sodium glucose transporters. Physiol Rev. 2011;91:733–
794.
Bröer S. Amino acid transport across mammalian intestinal and renal epithelia. Physiol Rev. 2008;88:249 –286.
Murer H, Hernando N, Forster I, Biber J. Proximal tubular
phosphate reabsorption: molecular mechanisms. Physiol
Rev. 2000;80:1373–1409.
Féraille E, Doucet A. Sodium-potassium-adenosine
triphosphatase-dependent sodium transport in the kidney:
hormonal control. Physiol Rev. 2001;81:345– 418.
Russell JM. Sodium-potassium-chloride cotransport.
Physiol Rev. 2000;80:211–276.
Reilly RF, Ellison DH. Mammalian distal tubule: physiology, pathophysiology, and molecular anatomy. Physiol
Rev. 2000;80:277–313.
Mathews LS, Enberg B, Norstedt G. Regulation of rat
growth hormone receptor gene expression. J Biol Chem.
1989;264:9905–9910.
Tiong TS, Herington AC. Tissue distribution, characterization, and regulation of messenger ribonucleic acid for
growth hormone receptor and serum binding protein in the
rat. Endocrinology. 1991;129:1628 –1634.
Smith WC, Kuniyoshi J, Talamantes F. Mouse serum
growth hormone (GH) binding protein has GH receptor
extracellular and substituted transmembrane domains.
Mol Endocrinol. 1989;3:984 –990.
Chin E, Zhou J, Bondy CA. Renal growth hormone receptor gene expression: relationship to renal insulin-like
growth factor system. Endocrinology. 1992;131:3061–
3066.
Mertani HC, Morel G. In situ gene expression of growth
Endocrine Reviews, April 2014, 35(2):234 –281
28.
29.
30.
31.
32.
33.
34.
35.
36.
37.
38.
39.
40.
41.
42.
43.
hormone (GH) receptor and GH binding protein in adult
male rat tissues. Mol Cell Endocrinol. 1995;109:47– 61.
Lobie PE, García-Aragón J, Wang BS, Baumbach WR, Waters MJ. Cellular localization of the growth hormone binding protein in the rat. Endocrinology. 1992;130:3057–
3065.
Hill DJ, Riley SC, Bassett NS, Waters MJ. Localization of
the growth hormone receptor, identified by immunocytochemistry, in second trimester human fetal tissues and in
placenta throughout gestation. J Clin Endocrinol Metab.
1992;75:646 – 650.
Simard M, Manthos H, Giaid A, Lefèbvre Y, Goodyer CG.
Ontogeny of growth hormone receptors in human tissues:
an immunohistochemical study. J Clin Endocrinol Metab.
1996;81:3097–3102.
Doi SQ, Jacot TA, Sellitti DF, et al. Growth hormone increases inducible nitric oxide synthase expression in mesangial cells. J Am Soc Nephrol. 2000;11:1419 –1425.
Meinhardt U, Eblé A, Besson A, Strasburger CJ, Sraer JD,
Mullis PE. Regulation of growth-hormone-receptor gene
expression by growth hormone and pegvisomant in human
mesangial cells. Kidney Int. 2003;64:421– 430.
Reddy GR, Pushpanathan MJ, Ransom RF, et al. Identification of the glomerular podocyte as a target for growth
hormone action. Endocrinology. 2007;148:2045–2055.
Bortz JD, Rotwein P, DeVol D, Bechtel PJ, Hansen VA,
Hammerman MR. Focal expression of insulin-like growth
factor I in rat kidney collecting duct. J Cell Biol. 1988;107:
811– 819.
Kamenicky P, Viengchareun S, Blanchard A, et al. Epithelial sodium channel is a key mediator of growth hormoneinduced sodium retention in acromegaly. Endocrinology.
2008;149:3294 –3305.
Firsov D. Revisiting sodium and water reabsorption with
functional genomics tools. Curr Opin Nephrol Hypertens.
2004;13:59 – 65.
Chabardès-Garonne D, Mejéan A, Aude JC, et al. A panoramic view of gene expression in the human kidney. Proc
Natl Acad Sci USA. 2003;100:13710 –13715.
Baumbach WR, Bingham B. One class of growth hormone
(GH) receptor and binding protein messenger ribonucleic
acid in rat liver, GHR1, is sexually dimorphic and regulated by GH. Endocrinology. 1995;136:749 –760.
Schwartzbauer G, Menon RK. Regulation of growth hormone receptor gene expression. Mol Genet Metab. 1998;
63:243–253.
Leung KC, Johannsson G, Leong GM, Ho KK. Estrogen
regulation of growth hormone action. Endocr Rev. 2004;
25:693–721.
Thimmarayappa J, Sun J, Schultz LE, et al. Inhibition of
growth hormone receptor gene expression by saturated
fatty acids: role of Kruppel-like zinc finger factor, ZBP-89.
Mol Endocrinol. 2006;20:2747–2760.
Frick GP, Leonard JL, Goodman HM. Effect of hypophysectomy on growth hormone receptor gene expression in
rat tissues. Endocrinology. 1990;126:3076 –3082.
Butler AA, Funk B, Breier BH, LeRoith D, Roberts CT Jr,
Gluckman PD. Growth hormone (GH) status regulates GH
receptor and GH binding protein mRNA in a tissue- and
transcript-specific manner but has no effect on insulin-like
doi: 10.1210/er.2013-1071
44.
45.
46.
47.
48.
49.
50.
51.
52.
53.
54.
55.
56.
57.
58.
growth factor-I receptor mRNA in the rat. Mol Cell Endocrinol. 1996;116:181–189.
Jiang H, Wang Y, Wu M, Gu Z, Frank SJ, Torres-Diaz R.
Growth hormone stimulates hepatic expression of bovine
growth hormone receptor messenger ribonucleic acid
through signal transducer and activator of transcription 5
activation of a major growth hormone receptor gene promoter. Endocrinology. 2007;148:3307–3315.
Sjögren K, Liu JL, Blad K, et al. Liver-derived insulin-like
growth factor I (IGF-I) is the principal source of IGF-I in
blood but is not required for postnatal body growth in
mice. Proc Natl Acad Sci USA. 1999;96:7088 –7092.
Yakar S, Liu JL, Stannard B, et al. Normal growth and
development in the absence of hepatic insulin-like growth
factor I. Proc Natl Acad Sci USA. 1999;96:7324 –7329.
D’Ercole AJ, Applewhite GT, Underwood LE. Evidence
that somatomedin is synthesized by multiple tissues in the
fetus. Dev Biol. 1980;75:315–328.
D’Ercole AJ, Stiles AD, Underwood LE. Tissue concentrations of somatomedin C: further evidence for multiple sites
of synthesis and paracrine or autocrine mechanisms of action. Proc Natl Acad Sci USA. 1984;81:935–939.
Schimpff RM, Donnadieu M, Duval M. Serum somatomedin activity measured as sulphation factor in peripheral,
hepatic and renal veins in normal mongrel dogs: early effects of intravenous injection of growth hormone. Acta
Endocrinol (Copenh). 1980;93:155–161.
Murphy LJ, Bell GI, Friesen HG. Growth hormone stimulates sequential induction of c-myc and insulin-like
growth factor I expression in vivo. Endocrinology. 1987;
120:1806 –1812.
Roberts CT Jr, Lasky SR, Lowe WL Jr, Seaman WT, LeRoith D. Molecular cloning of rat insulin-like growth factor I complementary deoxyribonucleic acids: differential
messenger ribonucleic acid processing and regulation by
growth hormone in extrahepatic tissues. Mol Endocrinol.
1987;1:243–248.
Han VK, Hill DJ, Strain AJ, et al. Identification of somatomedin/insulin-like growth factor immunoreactive cells in
the human fetus. Pediatr Res. 1987;22:245–249.
Miller SB, Rotwein P, Bortz JD, et al. Renal expression of
IGF I in hypersomatotropic states. Am J Physiol. 1990;
259:F251–F257.
Rogers SA, Miller SB, Hammerman MR. Growth hormone
stimulates IGF I gene expression in isolated rat renal collecting duct. Am J Physiol. 1990;259:F474 –F479.
Chin E, Zhou J, Bondy C. Anatomical relationships in the
patterns of insulin-like growth factor (IGF)-I, IGF binding
protein-1, and IGF-I receptor gene expression in the rat
kidney. Endocrinology. 1992;130:3237–3245.
Lindenbergh-Kortleve DJ, Rosato RR, van Neck JW, et al.
Gene expression of the insulin-like growth factor system
during mouse kidney development. Mol Cell Endocrinol.
1997;132:81–91.
Cingel-Ristic V, Flyvbjerg A, Drop SL. The physiological
and pathophysiological roles of the GH/IGF-axis in the
kidney: lessons from experimental rodent models. Growth
Horm IGF Res. 2004;14:418 – 430.
Daughaday WH, Rotwein P. Insulin-like growth factors I
and II. Peptide, messenger ribonucleic acid and gene struc-
edrv.endojournals.org
59.
60.
61.
62.
63.
64.
65.
66.
67.
68.
69.
70.
71.
72.
73.
267
tures, serum, and tissue concentrations. Endocr Rev. 1989;
10:68 –91.
Bondy CA, Werner H, Roberts CT Jr, LeRoith D. Cellular
pattern of insulin-like growth factor-I (IGF-I) and type I
IGF receptor gene expression in early organogenesis: comparison with IGF-II gene expression. Mol Endocrinol.
1990;4:1386 –1398.
Guler HP, Zapf J, Scheiwiller E, Froesch ER. Recombinant
human insulin-like growth factor I stimulates growth and
has distinct effects on organ size in hypophysectomized
rats. Proc Natl Acad Sci USA. 1988;85:4889 – 4893.
Guler HP, Schmid C, Zapf J, Froesch ER. Effects of recombinant insulin-like growth factor I on insulin secretion
and renal function in normal human subjects. Proc Natl
Acad Sci USA. 1989;86:2868 –2872.
Ullrich A, Gray A, Tam AW, et al. Insulin-like growth
factor I receptor primary structure: comparison with insulin receptor suggests structural determinants that define
functional specificity. EMBO J. 1986;5:2503–2512.
Wada J, Liu ZZ, Alvares K, et al. Cloning of cDNA for the
␣ subunit of mouse insulin-like growth factor I receptor
and the role of the receptor in metanephric development.
Proc Natl Acad Sci USA. 1993;90:10360 –10364.
Rabkin R, Brody M, Lu LH, Chan C, Shaheen AM, Gillett
N. Expression of the genes encoding the rat renal insulinlike growth factor-I system. J Am Soc Nephrol. 1995;6:
1511–1518.
Chin E, Bondy C. Insulin-like growth factor system gene
expression in the human kidney. J Clin Endocrinol Metab.
1992;75:962–968.
Chin E, Michels K, Bondy CA. Partition of insulin-like
growth factor (IGF)-binding sites between the IGF-I and
IGF-II receptors and IGF-binding proteins in the human
kidney. J Clin Endocrinol Metab. 1994;78:156 –164.
Lowe WL Jr, Adamo M, Werner H, Roberts CT Jr, LeRoith
D. Regulation by fasting of rat insulin-like growth factor I
and its receptor. Effects on gene expression and binding.
J Clin Invest. 1989;84:619 – 626.
Werner H, Shen-Orr Z, Stannard B, Burguera B, Roberts
CT Jr, LeRoith D. Experimental diabetes increases insulinlike growth factor I and II receptor concentration and gene
expression in kidney. Diabetes. 1990;39:1490 –1497.
Mulroney SE, Haramati A, Werner H, Bondy C, Roberts
CT Jr, LeRoith D. Altered expression of insulin-like
growth factor-I (IGF-I) and IGF receptor genes after unilateral nephrectomy in immature rats. Endocrinology.
1992;130:249 –256.
Gonzalez-Rodriguez E, Gaeggeler HP, Rossier BC. IGF-1
vs insulin: respective roles in modulating sodium transport
via the PI-3 kinase/Sgk1 pathway in a cortical collecting
duct cell line. Kidney Int. 2007;71:116 –125.
Staruschenko A, Pochynyuk O, Vandewalle A, Bugaj V,
Stockand JD. Acute regulation of the epithelial Na⫹ channel by phosphatidylinositide 3-OH kinase signaling in native collecting duct principal cells. J Am Soc Nephrol. 2007;
18:1652–1661.
Quigley R. Developmental changes in renal function. Curr
Opin Pediatr. 2012;24:184 –190.
List EO, Sackmann-Sala L, Berryman DE, et al. Endocrine
parameters and phenotypes of the growth hormone recep-
268
74.
75.
76.
77.
78.
79.
80.
81.
82.
83.
84.
85.
86.
87.
88.
89.
Kamenický et al
GH, IGF-1, and Kidney
tor gene disrupted (GHR⫺/⫺) mouse. Endocr Rev. 2011;
32:356 –386.
Flyvbjerg A, Bennett WF, Rasch R, et al. Compensatory
renal growth in uninephrectomized adult mice is growth
hormone dependent. Kidney Int. 1999;56:2048 –2054.
Liu JP, Baker J, Perkins AS, Robertson EJ, Efstratiadis A.
Mice carrying null mutations of the genes encoding insulinlike growth factor I (Igf-1) and type 1 IGF receptor (Igf1r).
Cell. 1993;75:59 –72.
Rogers SA, Powell-Braxton L, Hammerman MR. Insulinlike growth factor I regulates renal development in rodents.
Dev Genet. 1999;24:293–298.
Hammerman MR. The growth hormone-insulin-like
growth factor axis in kidney re-revisited. Nephrol Dial
Transplant. 1999;14:1853–1860.
Powell-Braxton L, Hollingshead P, Warburton C, et al.
IGF-I is required for normal embryonic growth in mice.
Genes Dev. 1993;7:2609 –2617.
Nordstrom SM, Tran JL, Sos BC, Wagner KU, Weiss EJ.
Liver-derived IGF-I contributes to GH-dependent increases in lean mass and bone mineral density in mice with
comparable levels of circulating GH. Mol Endocrinol.
2011;25:1223–1230.
Rogers SA, Ryan G, Hammerman MR. Insulin-like growth
factors I and II are produced in the metanephros and are
required for growth and development in vitro. J Cell Biol.
1991;113:1447–1453.
Corvilain J, Abramow M, Bergans A. Some effects of human growth hormone on renal hemodynamics and on tubular phosphate transport in man. J Clin Invest. 1962;41:
1230 –1235.
Hirschberg R, Rabb H, Bergamo R, Kopple JD. The delayed effect of growth hormone on renal function in humans. Kidney Int. 1989;35:865– 870.
Hirschberg R, Kopple JD, Blantz RC, Tucker BJ. Effects of
recombinant human insulin-like growth factor I on glomerular dynamics in the rat. J Clin Invest. 1991;87:1200 –
1206.
Guler HP, Eckardt KU, Zapf J, Bauer C, Froesch ER. Insulin-like growth factor I increase glomerular filtration rate
and renal plasma flow in man. Acta Endocrinol (Copenh).
1989;121:101–106.
Hirschberg R, Kopple JD. Evidence that insulin-like
growth factor I increases renal plasma flow and glomerular
filtration rate in fasted rats. J Clin Invest. 1989;83:326 –
330.
Hirschberg R, Kopple JD. Effects of growth hormone and
IGF-I on renal function. Kidney Int Suppl. 1989;27:S20 –
S26.
Haylor J, Singh I, el Nahas AM. Nitric oxide synthesis
inhibitor prevents vasodilation by insulin-like growth factor I. Kidney Int. 1991;39:333–335.
Møller J. Effects of growth hormone on fluid homeostasis.
Clinical and experimental aspects. Growth Horm IGF Res.
2003;13:55–74.
Kumar PA, Kotlyarevska K, Dejkhmaron P, et al. Growth
hormone (GH)-dependent expression of a natural antisense transcript induces zinc finger E-box-binding homeobox 2 (ZEB2) in the glomerular podocyte: a novel action of
GH with implications for the pathogenesis of diabetic nephropathy. J Biol Chem. 2010;285:31148 –31156.
Endocrine Reviews, April 2014, 35(2):234 –281
90. Li CX, Xia M, Han WQ, et al. Reversal by growth hormone
of homocysteine-induced epithelial-to-mesenchymal transition through membrane raft-redox signaling in podocytes. Cell Physiol Biochem. 2011;27:691–702.
91. Vasylyeva TL, Chen X, Ferry RJ Jr. Insulin-like growth
factor binding protein-3 mediates cytokine-induced mesangial cell apoptosis. Growth Horm IGF Res. 2005;15:
207–214.
92. Romanelli G, Giustina A, Cimino A, et al. Short term effect
of captopril on microalbuminuria induced by exercise in
normotensive diabetics. BMJ. 1989;298:284 –288.
93. Manelli F, Bossoni S, Burattin A, et al. Exercise-induced
microalbuminuria in patients with active acromegaly:
acute effects of slow-release lanreotide, a long-acting somatostatin analog. Metabolism. 2000;49:634 – 639.
94. Li CH, Evans HM. The isolation of pituitary growth hormone. Science. 1944;99:183–184.
95. Whitney JE, Bennett LL, Li CH. Reduction of urinary sodium and potassium produced by hypophyseal growth
hormone in normal female rats. Proc Soc Exp Biol Med.
1952;79:584 –587.
96. Beck JC, McGarry EE, Dyrenfurth I, Venning EH. Metabolic effects of human and monkey growth hormone in
man. Science. 1957;125:884 – 885.
97. Beck JC, McGarry EE, Dyrenfurth I, Venning EH. The
metabolic effects of human and monkey growth hormone
in man. Ann Intern Med. 1958;49:1090 –1105.
98. Møller J, Jørgensen JO, Møller N, Hansen KW, Pedersen
EB, Christiansen JS. Expansion of extracellular volume
and suppression of atrial natriuretic peptide after growth
hormone administration in normal man. J Clin Endocrinol
Metab. 1991;72:768 –772.
99. Ehrnborg C, Ellegård L, Bosaeus I, Bengtsson BA, Rosén
T. Supraphysiological growth hormone: less fat, more extracellular fluid but uncertain effects on muscles in healthy,
active young adults. Clin Endocrinol (Oxf). 2005;62:449 –
457.
100. Meinhardt U, Nelson AE, Hansen JL, et al. The effects of
growth hormone on body composition and physical performance in recreational athletes: a randomized trial. Ann
Intern Med. 2010;152:568 –577.
101. Venning EH, Lucis OJ. Effect of growth hormone on the
biosynthesis of aldosterone in the rat. Endocrinology.
1962;70:486 – 491.
102. Ho KY, Weissberger AJ. The antinatriuretic action of biosynthetic human growth hormone in man involves activation of the renin-angiotensin system. Metabolism. 1990;
39:133–137.
103. Møller J, Møller N, Frandsen E, Wolthers T, Jørgensen JO,
Christiansen JS. Blockade of the renin-angiotensin-aldosterone system prevents growth hormone-induced fluid retention in humans. Am J Physiol. 1997;272:E803–E808.
104. Stein JD Jr, Bennett LL, Batts AA, Li CH. Sodium, potassium and chloride retention produced by growth hormone
in the absence of the adrenals. Am J Physiol. 1952;171:
587–591.
105. Ludens JH, Bach RR, Williamson HE. Characteristics of
the antinatriuretic action of growth hormone. Proc Soc
Exp Biol Med. 1969;130:1156 –1158.
106. Hansen TK, Møller J, Thomsen K, et al. Effects of growth
hormone on renal tubular handling of sodium in healthy
doi: 10.1210/er.2013-1071
107.
108.
109.
110.
111.
112.
113.
114.
115.
116.
117.
118.
119.
120.
121.
122.
humans. Am J Physiol Endocrinol Metab. 2001;281:
E1326 –E1332.
Johannsson G, Sverrisdóttir YB, Ellegård L, Lundberg PA,
Herlitz H. GH increases extracellular volume by stimulating sodium reabsorption in the distal nephron and preventing pressure natriuresis. J Clin Endocrinol Metab.
2002;87:1743–1749.
Johannsson G, Gibney J, Wolthers T, Leung KC, Ho KK.
Independent and combined effects of testosterone and
growth hormone on extracellular water in hypopituitary
men. J Clin Endocrinol Metab. 2005;90:3989 –3994.
Hirschberg R. Effects of growth hormone and IGF-I on
glomerular ultrafiltration in growth hormone-deficient
rats. Regul Pept. 1993;48:241–250.
Hirschberg R, Brunori G, Kopple JD, Guler HP. Effects of
insulin-like growth factor I on renal function in normal
men. Kidney Int. 1993;43:387–397.
Walker JL, Ginalska-Malinowska M, Romer TE,
Pucilowska JB, Underwood LE. Effects of the infusion of
insulin-like growth factor I in a child with growth hormone
insensitivity syndrome (Laron dwarfism). N Engl J Med.
1991;324:1483–1488.
Thompson JL, Butterfield GE, Gylfadottir UK, et al. Effects of human growth hormone, insulin-like growth factor
I, and diet and exercise on body composition of obese postmenopausal women. J Clin Endocrinol Metab. 1998;83:
1477–1484.
Møller J, Jørgensen JO, Marqversen J, Frandsen E, Christiansen JS. Insulin-like growth factor I administration induces fluid and sodium retention in healthy adults: possible
involvement of renin and atrial natriuretic factor. Clin Endocrinol (Oxf). 2000;52:181–186.
Quigley R, Baum M. Effects of growth hormone and insulin-like growth factor I on rabbit proximal convoluted
tubule transport. J Clin Invest. 1991;88:368 –374.
Dimke H, Flyvbjerg A, Bourgeois S, et al. Acute growth
hormone administration induces antidiuretic and antinatriuretic effects and increases phosphorylation of NKCC2.
Am J Physiol Renal Physiol. 2007;292:F723–F735.
Giménez I, Forbush B. Short-term stimulation of the renal
Na-K-Cl cotransporter (NKCC2) by vasopressin involves
phosphorylation and membrane translocation of the protein. J Biol Chem. 2003;278:26946 –26951.
Fuller PJ, Young MJ. Mechanisms of mineralocorticoid
action. Hypertension. 2005;46:1227–1235.
Viengchareun S, Le Menuet D, Martinerie L, Munier M,
Pascual-Le Tallec L, Lombès M. The mineralocorticoid
receptor: insights into its molecular and (patho)physiological biology. Nucl Recept Signal. 2007;5:e012.
Blazer-Yost BL, Cox M, Furlanetto R. Insulin and IGF I
receptor-mediated Na⫹ transport in toad urinary bladders. Am J Physiol. 1989;257:C612–C620.
Matsumoto PS, Ohara A, Duchatelle P, Eaton DC. Tyrosine kinase regulates epithelial sodium transport in A6
cells. Am J Physiol. 1993;264:C246 –C250.
DeFronzo RA, Goldberg M, Agus ZS. The effects of glucose and insulin on renal electrolyte transport. J Clin Invest. 1976;58:83–90.
Féraille E, Rousselot M, Rajerison R, Favre H. Effect of
insulin on Na⫹,K(⫹)-ATPase in rat collecting duct.
J Physiol. 1995;488:171–180.
edrv.endojournals.org
269
123. Crabbe J. Stimulation of active sodium transport by the
isolated toad bladder with aldosterone in vitro. J Clin Invest. 1961;40:2103–2110.
124. Canessa CM, Horisberger JD, Rossier BC. Epithelial sodium channel related to proteins involved in neurodegeneration. Nature. 1993;361:467– 470.
125. Escoubet B, Coureau C, Bonvalet JP, Farman N. Noncoordinate regulation of epithelial Na channel and Na pump
subunit mRNAs in kidney and colon by aldosterone. Am J
Physiol. 1997;272:C1482–C1491.
126. Masilamani S, Kim GH, Mitchell C, Wade JB, Knepper
MA. Aldosterone-mediated regulation of ENaC ␣, ␤, and
␥ subunit proteins in rat kidney. J Clin Invest. 1999;104:
R19 –R23.
127. Chen SY, Bhargava A, Mastroberardino L, et al. Epithelial
sodium channel regulated by aldosterone-induced protein
sgk. Proc Natl Acad Sci USA. 1999;96:2514 –2519.
128. Debonneville C, Flores SY, Kamynina E, et al. Phosphorylation of Nedd4 –2 by Sgk1 regulates epithelial Na(⫹)
channel cell surface expression. EMBO J. 2001;20:7052–
7059.
129. Wang J, Barbry P, Maiyar AC, et al. SGK integrates insulin
and mineralocorticoid regulation of epithelial sodium
transport. Am J Physiol Renal Physiol. 2001;280:F303–
F313.
130. Viengchareun S, Kamenicky P, Teixeira M, et al. Osmotic
stress regulates mineralocorticoid receptor expression in a
novel aldosterone-sensitive cortical collecting duct cell
line. Mol Endocrinol. 2009;23:1948 –1962.
131. Stöcklin E, Wissler M, Gouilleux F, Groner B. Functional
interactions between Stat5 and the glucocorticoid receptor. Nature. 1996;383:726 –728.
132. Michlig S, Mercier A, Doucet A, et al. ERK1/2 controls
Na,K-ATPase activity and transepithelial sodium transport in the principal cell of the cortical collecting duct of the
mouse kidney. J Biol Chem. 2004;279:51002–51012.
133. Soundararajan R, Zhang TT, Wang J, Vandewalle A,
Pearce D. A novel role for glucocorticoid-induced leucine
zipper protein in epithelial sodium channel-mediated sodium transport. J Biol Chem. 2005;280:39970 –39981.
134. Liu NA, Liu Q, Wawrowsky K, Yang Z, Lin S, Melmed S.
Prolactin receptor signaling mediates the osmotic response
of embryonic zebrafish lactotrophs. Mol Endocrinol.
2006;20:871– 880.
135. Sakamoto T, McCormick SD. Prolactin and growth hormone in fish osmoregulation. Gen Comp Endocrinol.
2006;147:24 –30.
136. Takada M, Hokari S. Prolactin increases Na⫹ transport
across adult bullfrog skin via stimulation of both ENaC
and Na⫹/K⫹-pump. Gen Comp Endocrinol. 2007;151:
325–331.
137. Henneman PH, Forbes AP, Moldawer M, Dempsey EF,
Carroll EL. Effects of human growth hormone in man.
J Clin Invest. 1960;39:1223–1238.
138. Corvilain J, Abramow M. Effect of growth hormone on
tubular transport of phosphate in normal and parathyroidectomized dogs. J Clin Invest. 1964;43:1608 –1612.
139. Caverzasio J, Faundez R, Fleisch H, Bonjour JP. Tubular
adaptation to Pi restriction in hypophysectomized rats.
Pflugers Arch. 1981;392:17–21.
140. Mulroney SE, Lumpkin MD, Haramati A. Antagonist to
270
141.
142.
143.
144.
145.
146.
147.
148.
149.
150.
151.
152.
153.
154.
155.
156.
Kamenický et al
GH, IGF-1, and Kidney
GH-releasing factor inhibits growth and renal Pi reabsorption in immature rats. Am J Physiol. 1989;257:F29 –F34.
Marcus R, Butterfield G, Holloway L, et al. Effects of short
term administration of recombinant human growth hormone to elderly people. J Clin Endocrinol Metab. 1990;
70:519 –527.
Holloway L, Butterfield G, Hintz RL, Gesundheit N, Marcus R. Effects of recombinant human growth hormone on
metabolic indices, body composition, and bone turnover in
healthy elderly women. J Clin Endocrinol Metab. 1994;
79:470 – 479.
Joseph F, Ahmad AM, Ul-Haq M, et al. Effects of growth
hormone administration on bone mineral metabolism,
PTH sensitivity and PTH secretory rhythm in postmenopausal women with established osteoporosis. J Bone Miner
Res. 2008;23:721–729.
Bengtsson BA, Edén S, Lönn L, et al. Treatment of adults
with growth hormone (GH) deficiency with recombinant
human GH. J Clin Endocrinol Metab. 1993;76:309 –317.
Ahmad AM, Thomas J, Clewes A, et al. Effects of growth
hormone replacement on parathyroid hormone sensitivity
and bone mineral metabolism. J Clin Endocrinol Metab.
2003;88:2860 –2868.
White HD, Ahmad AM, Durham BH, et al. Growth hormone replacement is important for the restoration of parathyroid hormone sensitivity and improvement in bone metabolism in older adult growth hormone-deficient patients.
J Clin Endocrinol Metab. 2005;90:3371–3380.
Westby GR, Goldfarb S, Goldberg M, Agus ZS. Acute effects of bovine growth hormone on renal calcium and
phosphate excretion. Metabolism. 1977;26:525–530.
Caverzasio J, Montessuit C, Bonjour JP. Stimulatory effect
of insulin-like growth factor-1 on renal Pi transport and
plasma 1,25-dihydroxyvitamin D3. Endocrinology. 1990;
127:453– 459.
Jehle AW, Forgo J, Biber J, Lederer E, Krapf R, Murer H.
IGF-I and vanadate stimulate Na/Pi-cotransport in OK
cells by increasing type II Na/Pi-cotransporter protein stability. Pflugers Arch. 1998;437:149 –154.
Hirschberg R, Ding H, Wanner C. Effects of insulin-like
growth factor I on phosphate transport in cultured proximal tubule cells. J Lab Clin Med. 1995;126:428 – 434.
Woda CB, Halaihel N, Wilson PV, Haramati A, Levi M,
Mulroney SE. Regulation of renal NaPi-2 expression and
tubular phosphate reabsorption by growth hormone in the
juvenile rat. Am J Physiol Renal Physiol. 2004;287:F117–
F123.
Hoenderop JG, Nilius B, Bindels RJ. Calcium absorption
across epithelia. Physiol Rev. 2005;85:373– 422.
Peacock M. Calcium absorption efficiency and calcium requirements in children and adolescents. Am J Clin Nutr.
1991;54:261S–265S.
Spanos E, Barrett D, MacIntyre I, Pike JW, Safilian EF,
Haussler MR. Effect of growth hormone on vitamin D
metabolism. Nature. 1978;273:246 –247.
Brown DJ, Spanos E, MacIntyre I. Role of pituitary hormones in regulating renal vitamin D metabolism in man. Br
Med J. 1980;280:277–278.
Menaa C, Vrtovsnik F, Friedlander G, Corvol M, Garabédian M. Insulin-like growth factor I, a unique calciumdependent stimulator of 1,25-dihydroxyvitamin D3 pro-
Endocrine Reviews, April 2014, 35(2):234 –281
157.
158.
159.
160.
161.
162.
163.
164.
165.
166.
167.
168.
169.
170.
171.
172.
173.
174.
175.
duction. Studies in cultured mouse kidney cells. J Biol
Chem. 1995;270:25461–25467.
Suzuki Y, Landowski CP, Hediger MA. Mechanisms and
regulation of epithelial Ca2⫹ absorption in health and disease. Annu Rev Physiol. 2008;70:257–271.
Kamenický P, Blanchard A, Gauci C, et al. Pathophysiology of renal calcium handling in acromegaly: what lies
behind hypercalciuria? J Clin Endocrinol Metab. 2012;97:
2124 –2133.
Loffing J, Loffing-Cueni D, Valderrabano V, et al. Distribution of transcellular calcium and sodium transport pathways along mouse distal nephron. Am J Physiol Renal
Physiol. 2001;281:F1021–F1027.
Hoenderop JG, Müller D, Van Der Kemp AW, et al. Calcitriol controls the epithelial calcium channel in kidney.
J Am Soc Nephrol. 2001;12:1342–1349.
Gerich JE, Meyer C, Woerle HJ, Stumvoll M. Renal gluconeogenesis: its importance in human glucose homeostasis. Diabetes Care. 2001;24:382–391.
Owen OE, Felig P, Morgan AP, Wahren J, Cahill GF Jr.
Liver and kidney metabolism during prolonged starvation.
J Clin Invest. 1969;48:574 –583.
Cahill GF Jr. Starvation in man. N Engl J Med. 1970;282:
668 – 675.
Cahill GF Jr. Fuel metabolism in starvation. Annu Rev
Nutr. 2006;26:1–22.
Mutel E, Gautier-Stein A, Abdul-Wahed A, et al. Control
of blood glucose in the absence of hepatic glucose production during prolonged fasting in mice: induction of renal
and intestinal gluconeogenesis by glucagon. Diabetes.
2011;60:3121–3131.
Ho KY, Veldhuis JD, Johnson ML, et al. Fasting enhances
growth hormone secretion and amplifies the complex
rhythms of growth hormone secretion in man. J Clin Invest. 1988;81:968 –975.
Møller N, Jørgensen JO. Effects of growth hormone on
glucose, lipid, and protein metabolism in human subjects.
Endocr Rev. 2009;30:152–177.
Zhao TJ, Liang G, Li RL, et al. Ghrelin O-acyltransferase
(GOAT) is essential for growth hormone-mediated survival of calorie-restricted mice. Proc Natl Acad Sci USA.
2010;107:7467–7472.
Rogers SA, Karl IE, Hammerman MR. Growth hormone
directly stimulates gluconeogenesis in canine renal proximal tubule. Am J Physiol. 1989;257:E751–E756.
Melmed S. Medical progress: acromegaly. N Engl J Med.
2006;355:2558 –2573.
Melmed S. Acromegaly pathogenesis and treatment. J Clin
Invest. 2009;119:3189 –3202.
Colao A, Ferone D, Marzullo P, Lombardi G. Systemic
complications of acromegaly: epidemiology, pathogenesis,
and management. Endocr Rev. 2004;25:102–152.
Giustina A, Casanueva FF, Cavagnini F, et al. Diagnosis
and treatment of acromegaly complications. J Endocrinol
Invest. 2003;26:1242–1247.
Palmiter RD, Brinster RL, Hammer RE, et al. Dramatic
growth of mice that develop from eggs microinjected with
metallothionein-growth hormone fusion genes. Nature.
1982;300:611– 615.
Palmiter RD, Norstedt G, Gelinas RE, Hammer RE, Brin-
doi: 10.1210/er.2013-1071
176.
177.
178.
179.
180.
181.
182.
183.
184.
185.
186.
187.
188.
189.
190.
ster RL. Metallothionein-human GH fusion genes stimulate growth of mice. Science. 1983;222:809 – 814.
Kopchick JJ, Bellush LL, Coschigano KT. Transgenic
models of growth hormone action. Annu Rev Nutr. 1999;
19:437– 461.
Doi T, Striker LJ, Quaife C, et al. Progressive glomerulosclerosis develops in transgenic mice chronically expressing growth hormone and growth hormone releasing factor
but not in those expressing insulinlike growth factor-1.
Am J Pathol. 1988;131:398 – 403.
Doi T, Striker LJ, Gibson CC, Agodoa LY, Brinster RL,
Striker GE. Glomerular lesions in mice transgenic for
growth hormone and insulinlike growth factor-I. I. Relationship between increased glomerular size and mesangial
sclerosis. Am J Pathol. 1990;137:541–552.
Timsit J, Riou B, Bertherat J, et al. Effects of chronic
growth hormone hypersecretion on intrinsic contractility,
energetics, isomyosin pattern, and myosin adenosine
triphosphatase activity of rat left ventricle. J Clin Invest.
1990;86:507–515.
Auriemma RS, Galdiero M, De Martino MC, et al. The
kidney in acromegaly: renal structure and function in patients with acromegaly during active disease and 1 year
after disease remission. Eur J Endocrinol. 2010;162:1035–
1042.
Yoshida H, Akikusa B, Saeki N, et al. Effect of pituitary
microsurgery on acromegaly complicated nephrotic syndrome with focal segmental glomerulosclerosis: report of a
rare clinical case. Am J Kidney Dis. 1999;33:1158 –1163.
Takai M, Izumino K, Oda Y, Terada Y, Inoue H, Takata
M. Focal segmental glomerulosclerosis associated with acromegaly. Clin Nephrol. 2001;56:75–77.
Luft R, Sjogren B. The significance of endocrine factors on
renal function and blood pressure as revealed by a case of
chromophobe adenoma of the pituitary. Acta Med Scand
Suppl. 1950;246:129 –136.
Ikkos D, Ljunggren H, Luft R. Glomerular filtration rate
and renal plasma flow in acromegaly. Acta Endocrinol
(Copenh). 1956;21:226 –236.
Falkheden T, Sjoegren B. Extracellular fluid volume and
renal function in pituitary insufficiency and acromegaly.
Acta Endocrinol (Copenh). 1964;46:80 – 88.
Grunenwald S, Tack I, Chauveau D, Bennet A, Caron P.
Impact of growth hormone hypersecretion on the adult
human kidney. Ann Endocrinol (Paris). 2011;72:485–
495.
Kamenicky P, Blanchard A, Frank M, et al. Body fluid
expansion in acromegaly is related to enhanced epithelial
sodium channel (ENaC) activity. J Clin Endocrinol Metab.
2011;96:2127–2135.
Ikkos D, Luft R, Sjogren B. Body water and sodium in
patients with acromegaly. J Clin Invest. 1954;33:989 –
994.
Hoogenberg K, Sluiter WJ, Dullaart RP. Effect of growth
hormone and insulin-like growth factor I on urinary albumin excretion: studies in acromegaly and growth hormone
deficiency. Acta Endocrinol (Copenh). 1993;129:151–
157.
Baldelli R, De Marinis L, Bianchi A, et al. Microalbuminuria in insulin sensitivity in patients with growth hormone-
edrv.endojournals.org
191.
192.
193.
194.
195.
196.
197.
198.
199.
200.
201.
202.
203.
204.
205.
206.
207.
208.
209.
271
secreting pituitary tumor. J Clin Endocrinol Metab. 2008;
93:710 –714.
Chanson P, Salenave S. Acromegaly. Orphanet J Rare Dis.
2008;3:17.
O’Sullivan AJ, Kelly JJ, Hoffman DM, Freund J, Ho KK.
Body composition and energy expenditure in acromegaly.
J Clin Endocrinol Metab. 1994;78:381–386.
Hirsch EZ, Sloman JG, Martin FI. Cardiac function in acromegaly. Am J Med Sci. 1969;257:1– 8.
Strauch G, Vallotton MB, Touitou Y, Bricaire H. The
renin-angiotensin-aldosterone system in normotensive and
hypertensive patients with acromegaly. N Engl J Med.
1972;287:795–799.
Deray G, Rieu M, et al. Evidence of an endogenous digitalis-like factor in the plasma of patients with acromegaly.
N Engl J Med. 1987;316:575–580.
Chanson P, Timsit J, Masquet C, et al. Cardiovascular
effects of the somatostatin analog octreotide in acromegaly. Ann Intern Med. 1990;113:921–925.
Sherlock M, Ayuk J, Tomlinson JW, et al. Mortality in
patients with pituitary disease. Endocr Rev. 2010;31:301–
342.
Gouya H, Vignaux O, Le Roux P, et al. Rapidly reversible
myocardial edema in patients with acromegaly: assessment
with ultrafast T2 mapping in a single-breath-hold MRI
sequence. AJR Am J Roentgenol. 2008;190:1576 –1582.
Maison P, Tropeano AI, Macquin-Mavier I, Giustina A,
Chanson P. Impact of somatostatin analogs on the heart in
acromegaly: a metaanalysis. J Clin Endocrinol Metab.
2007;92:1743–1747.
Jenkins PJ, Sohaib SA, Akker S, et al. The pathology of
median neuropathy in acromegaly. Ann Intern Med. 2000;
133:197–201.
Tagliafico A, Resmini E, Nizzo R, et al. Ultrasound measurement of median and ulnar nerve cross-sectional area in
acromegaly. J Clin Endocrinol Metab. 2008;93:905–909.
Attal P, Chanson P. Endocrine aspects of obstructive sleep
apnea. J Clin Endocrinol Metab. 2010;95:483– 495.
Davi’ MV, Dalle Carbonare L, Giustina A, et al. Sleep
apnoea syndrome is highly prevalent in acromegaly and
only partially reversible after biochemical control of the
disease. Eur J Endocrinol. 2008;159:533–540.
Cain JP, Williams GH, Dluhy RG. Plasma renin activity
and aldosterone secretion in patients with acromegaly.
J Clin Endocrinol Metab. 1972;34:73– 81.
McKnight JA, McCance DR, Hadden DR, et al. Basal and
saline-stimulated levels of plasma atrial natriuretic factor
in acromegaly. Clin Endocrinol (Oxf). 1989;31:431– 438.
Deray G, Chanson P, Maistre G, et al. Atrial natriuretic
factor in patients with acromegaly. Eur J Clin Pharmacol.
1990;38:409 – 413.
Soszynski P, Slowinska-Srzednicka J, Zgliczynski S.
Plasma concentrations of atrial natriuretic hormone in acromegaly: relationship to hypertension. Acta Endocrinol
(Copenh). 1991;125:268 –272.
Karlberg BE, Ottosson AM. Acromegaly and hypertension: role of the renin-angiotensin-aldosterone system.
Acta Endocrinol (Copenh). 1982;100:581–587.
Bielohuby M, Roemmler J, Manolopoulou J, et al. Chronic
growth hormone excess is associated with increased aldosterone: a study in patients with acromegaly and in growth
272
210.
211.
212.
213.
214.
215.
216.
217.
218.
219.
220.
221.
222.
223.
224.
225.
Kamenický et al
GH, IGF-1, and Kidney
hormone transgenic mice. Exp Biol Med (Maywood).
2009;234:1002–1009.
Williams GH, Cain JP, Dluhy RG, Underwood RH. Studies of the control of plasma aldosterone concentration in
normal man. I. Response to posture, acute and chronic
volume depletion, and sodium loading. J Clin Invest. 1972;
51:1731–1742.
Mantero F, Opocher G, Armanini D, Paviotti G, Boscaro
M, Muggeo M. Plasma renin activity and urinary aldosterone in acromegaly. J Endocrinol Invest. 1979;2:13–18.
Lang RE, Thölken H, Ganten D, Luft FC, Ruskoaho H,
Unger T. Atrial natriuretic factor–a circulating hormone
stimulated by volume loading. Nature. 1985;314:264 –
266.
Hughey RP, Bruns JB, Kinlough CL, et al. Epithelial sodium channels are activated by furin-dependent proteolysis. J Biol Chem. 2004;279:18111–18114.
Ergonul Z, Frindt G, Palmer LG. Regulation of maturation
and processing of ENaC subunits in the rat kidney. Am J
Physiol Renal Physiol. 2006;291:F683–F693.
Duc C, Farman N, Canessa CM, Bonvalet JP, Rossier BC.
Cell-specific expression of epithelial sodium channel ␣, ␤,
and ␥ subunits in aldosterone-responsive epithelia from the
rat: localization by in situ hybridization and immunocytochemistry. J Cell Biol. 1994;127:1907–1921.
Farman N, Talbot CR, Boucher R, et al. Noncoordinated
expression of ␣-, ␤-, and ␥-subunit mRNAs of epithelial
Na⫹ channel along rat respiratory tract. Am J Physiol.
1997;272:C131–C141.
Shimkets RA, Warnock DG, Bositis CM, et al. Liddle’s
syndrome: heritable human hypertension caused by mutations in the ␤ subunit of the epithelial sodium channel.
Cell. 1994;79:407– 414.
Conn JW. Aldosterone in clinical medicine; past, present,
and future. AMA Arch Intern Med. 1956;97:135–144.
Deschênes G, Doucet A. Collecting duct (Na⫹/K⫹)-ATPase activity is correlated with urinary sodium excretion in
rat nephrotic syndromes. J Am Soc Nephrol. 2000;11:
604 – 615.
Lourdel S, Loffing J, Favre G, et al. Hyperaldosteronemia
and activation of the epithelial sodium channel are not
required for sodium retention in puromycin-induced nephrosis. J Am Soc Nephrol. 2005;16:3642–3650.
Shimomura Y, Lee M, Oku J, Bray GA, Glick Z. Sodium
potassium dependent ATPase in hypophysectomized rats:
response to growth hormone, triiodothyronine, and cortisone. Metabolism. 1982;31:213–216.
Ng LL, Evans DJ. Leucocyte sodium transport in acromegaly. Clin Endocrinol (Oxf). 1987;26:471– 480.
Landin K, Petruson B, Jakobsson KE, Bengtsson BA. Skeletal muscle sodium and potassium changes after successful
surgery in acromegaly: relation to body composition,
blood glucose, plasma insulin and blood pressure. Acta
Endocrinol (Copenh). 1993;128:418 – 422.
Takamoto S, Tsuchiya H, Onishi T, et al. Changes in calcium homeostasis in acromegaly treated by pituitary adenomectomy. J Clin Endocrinol Metab. 1985;61:7–11.
Molinatti GM, Camanni F, Losana O, Olivetti M. Changes
in the metabolism of calcium and phosphorus in the various phases of acromegaly and following the implantation
Endocrine Reviews, April 2014, 35(2):234 –281
226.
227.
228.
229.
230.
231.
232.
233.
234.
235.
236.
237.
238.
239.
240.
241.
of the pituitary gland with 90Y. Acta Endocrinol (Copenh). 1961;36:161–179.
Ajmal A, Haghshenas A, Attarian S, et al. The effect of
somatostatin analogs on vitamin D and calcium concentrations in patients with acromegaly [published online September 4, 2013]. Pituitary. doi:10.1007/s11102-0130514-0.
Fredstorp L, Pernow Y, Werner S. The short and long-term
effects of octreotide on calcium homeostasis in patients
with acromegaly. Clin Endocrinol (Oxf). 1993;39:331–
336.
Parkinson C, Kassem M, Heickendorff L, Flyvbjerg A,
Trainer PJ. Pegvisomant-induced serum insulin-like
growth factor-I normalization in patients with acromegaly
returns elevated markers of bone turnover to normal. J Clin
Endocrinol Metab. 2003;88:5650 –5655.
Ezzat S, Melmed S, Endres D, Eyre DR, Singer FR. Biochemical assessment of bone formation and resorption in
acromegaly. J Clin Endocrinol Metab. 1993;76:1452–
1457.
Hai N, Aoki N, Shimatsu A, Mori T, Kosugi S. Clinical
features of multiple endocrine neoplasia type 1 (MEN1)
phenocopy without germline MEN1 gene mutations: analysis of 20 Japanese sporadic cases with MEN1. Clin Endocrinol (Oxf). 2000;52:509 –518.
White HD, Ahmad AM, Durham BH, et al. Effect of active
acromegaly and its treatment on parathyroid circadian
rhythmicity and parathyroid target-organ sensitivity.
J Clin Endocrinol Metab. 2006;91:913–919.
Bonadonna S, Burattin A, Nuzzo M, et al. Chronic glucocorticoid treatment alters spontaneous pulsatile parathyroid hormone secretory dynamics in human subjects. Eur
J Endocrinol. 2005;152:199 –205.
Sigurdsson G, Nunziata V, Reiner M, Nadarajah A, Joplin
GF. Calcium absorption and excretion in the gut in acromegaly. Clin Endocrinol (Oxf). 1973;2:187–192.
Legovini P, De Menis E, Breda F, et al. Long-term effects
of octreotide on markers of bone metabolism in acromegaly: evidence of increased serum parathormone concentrations. J Endocrinol Invest. 1997;20:434 – 438.
Ito N, Fukumoto S. FGF23-related hypophosphatemic
rickets/osteomalacia [in Japanese]. Clin Calcium. 2007;
17:1514 –1520.
Giustina A, Mazziotti G, Canalis E. Growth hormone,
insulin-like growth factors, and the skeleton. Endocr Rev.
2008;29:535–559.
Bonadonna S, Mazziotti G, Nuzzo M, et al. Increased prevalence of radiological spinal deformities in active acromegaly: a cross-sectional study in postmenopausal women.
J Bone Miner Res. 2005;20:1837–1844.
Mazziotti G, Gola M, Bianchi A, et al. Influence of diabetes
mellitus on vertebral fractures in men with acromegaly.
Endocrine. 2011;40:102–108.
Mazziotti G, Bianchi A, Porcelli T, et al. Vertebral fractures in patients with acromegaly: a 3-year prospective
study. J Clin Endocrinol Metab. 2013;98:3402–3410.
Gola M, Bonadonna S, Doga M, Giustina A. Clinical review: growth hormone and cardiovascular risk factors.
J Clin Endocrinol Metab. 2005;90:1864 –1870.
Mazziotti G, Bianchi A, Bonadonna S, et al. Increased
prevalence of radiological spinal deformities in adult pa-
doi: 10.1210/er.2013-1071
242.
243.
244.
245.
246.
247.
248.
249.
250.
251.
252.
253.
254.
255.
tients with GH deficiency: influence of GH replacement
therapy. J Bone Miner Res. 2006;21:520 –528.
Maison P, Griffin S, Nicoue-Beglah M, Haddad N, Balkau
B, Chanson P. Impact of growth hormone (GH) treatment
on cardiovascular risk factors in GH-deficient adults: a
metaanalysis of blinded, randomized, placebo-controlled
trials. J Clin Endocrinol Metab. 2004;89:2192–2199.
Maison P, Chanson P. Less is more risky? Growth hormone and insulin-like growth factor 1 levels and cardiovascular risk. Nat Clin Pract Endocrinol Metab. 2006;2:
650 – 651.
Zhou Y, Xu BC, Maheshwari HG, et al. A mammalian
model for Laron syndrome produced by targeted disruption of the mouse growth hormone receptor/binding protein gene (the Laron mouse). Proc Natl Acad Sci USA.
1997;94:13215–13220.
Lupu F, Terwilliger JD, Lee K, Segre GV, Efstratiadis A.
Roles of growth hormone and insulin-like growth factor 1
in mouse postnatal growth. Dev Biol. 2001;229:141–162.
Moerth C, Schneider MR, Renner-Mueller I, et al. Postnatally elevated levels of insulin-like growth factor (IGF)-II
fail to rescue the dwarfism of IGF-I-deficient mice except
kidney weight. Endocrinology. 2007;148:441– 451.
DeChiara TM, Efstratiadis A, Robertson EJ. A growthdeficiency phenotype in heterozygous mice carrying an
insulin-like growth factor II gene disrupted by targeting.
Nature. 1990;345:78 – 80.
Ludwig T, Eggenschwiler J, Fisher P, D’Ercole AJ, Davenport ML, Efstratiadis A. Mouse mutants lacking the type
2 IGF receptor (IGF2R) are rescued from perinatal lethality
in Igf2 and Igf1r null backgrounds. Dev Biol. 1996;177:
517–535.
Holzenberger M, Hamard G, Zaoui R, et al. Experimental
IGF-I receptor deficiency generates a sexually dimorphic
pattern of organ-specific growth deficits in mice, affecting
fat tissue in particular. Endocrinology. 2001;142:4469 –
4478.
Van Buul-Offers SC, Van Kleffens M, Koster JG, et al.
Human insulin-like growth factor (IGF) binding protein-1
inhibits IGF-I-stimulated body growth but stimulates
growth of the kidney in snell dwarf mice. Endocrinology.
2000;141:1493–1499.
van Kleffens M, Lindenbergh-Kortleve DJ, Koster JG, et al.
The role of the IGF axis in IGFBP-1 and IGF-I induced renal
enlargement in Snell dwarf mice. J Endocrinol. 2001;170:
333–346.
Goossens M, Brauner R, Czernichow P, Duquesnoy P,
Rappaport R. Isolated growth hormone (GH) deficiency
type 1A associated with a double deletion in the human GH
gene cluster. J Clin Endocrinol Metab. 1986;62:712–716.
Amselem S, Duquesnoy P, Attree O, et al. Laron dwarfism
and mutations of the growth hormone-receptor gene.
N Engl J Med. 1989;321:989 –995.
Woods KA, Camacho-Hübner C, Savage MO, Clark AJ.
Intrauterine growth retardation and postnatal growth failure associated with deletion of the insulin-like growth factor I gene. N Engl J Med. 1996;335:1363–1367.
Oliveira CR, Salvatori R, Nóbrega LM, et al. Sizes of abdominal organs in adults with severe short stature due to
severe, untreated, congenital GH deficiency caused by a
edrv.endojournals.org
256.
257.
258.
259.
260.
261.
262.
263.
264.
265.
266.
267.
268.
269.
270.
273
homozygous mutation in the GHRH receptor gene. Clin
Endocrinol (Oxf). 2008;69:153–158.
Chernausek SD, Backeljauw PF, Frane J, Kuntze J, Underwood LE. Long-term treatment with recombinant insulinlike growth factor (IGF)-I in children with severe IGF-I
deficiency due to growth hormone insensitivity. J Clin Endocrinol Metab. 2007;92:902–910.
Link K, Bülow B, Westman K, Salmonsson EC, Eskilsson
J, Erfurth EM. Low individualized growth hormone (GH)
dose increased renal and cardiac growth in young adults
with childhood onset GH deficiency. Clin Endocrinol
(Oxf). 2001;55:741–748.
Riedl M, Hass M, Oberbauer R, Gisinger J, Luger A,
Mayer G. The effects of prolonged substitution of recombinant human growth hormone on renal functional reserve
in growth hormone-deficient adults. J Am Soc Nephrol.
1995;6:1434 –1438.
Jørgensen JO, Pedersen SA, Thuesen L, et al. Beneficial
effects of growth hormone treatment in GH-deficient
adults. Lancet. 1989;1:1221–1225.
Caidahl K, Edén S, Bengtsson BA. Cardiovascular and renal effects of growth hormone. Clin Endocrinol (Oxf).
1994;40:393– 400.
Klinger B, Laron Z. Renal function in Laron syndrome
patients treated by insulin-like growth factor-I. Pediatr
Nephrol. 1994;8:684 – 688.
Hoffman DM, Crampton L, Sernia C, Nguyen TV, Ho KK.
Short-term growth hormone (GH) treatment of GH-deficient adults increases body sodium and extracellular water,
but not blood pressure. J Clin Endocrinol Metab. 1996;
81:1123–1128.
De Boer H, Blok GJ, Voerman HJ, De Vries PM, van der
Veen EA. Body composition in adult growth hormonedeficient men, assessed by anthropometry and bioimpedance analysis. J Clin Endocrinol Metab. 1992;75:833–
837.
Mauras N, O’Brien KO, Welch S, et al. Insulin-like growth
factor I and growth hormone (GH) treatment in GH-deficient humans: differential effects on protein, glucose,
lipid, and calcium metabolism. J Clin Endocrinol Metab.
2000;85:1686 –1694.
Jørgensen JO. Human growth hormone replacement therapy: pharmacological and clinical aspects. Endocr Rev.
1991;12:189 –207.
de Boer H, Blok GJ, Van der Veen EA. Clinical aspects of
growth hormone deficiency in adults. Endocr Rev. 1995;
16:63– 86.
Parra A, Argote RM, García G, Cervantes C, Alatorre S,
Pérez-Pasten E. Body composition in hypopituitary dwarfs
before and during human growth hormone therapy. Metabolism. 1979;28:851– 857.
Rosén T, Bosaeus I, Tölli J, Lindstedt G, Bengtsson BA.
Increased body fat mass and decreased extracellular fluid
volume in adults with growth hormone deficiency. Clin
Endocrinol (Oxf). 1993;38:63–71.
Salomon F, Cuneo RC, Hesp R, Sönksen PH. The effects of
treatment with recombinant human growth hormone on
body composition and metabolism in adults with growth
hormone deficiency. N Engl J Med. 1989;321:1797–1803.
Whitehead HM, Boreham C, McIlrath EM, et al. Growth
hormone treatment of adults with growth hormone defi-
274
271.
272.
273.
274.
275.
276.
277.
278.
279.
280.
281.
282.
283.
284.
Kamenický et al
GH, IGF-1, and Kidney
ciency: results of a 13-month placebo controlled cross-over
study. Clin Endocrinol (Oxf). 1992;36:45–52.
Binnerts A, Deurenberg P, Swart GR, Wilson JH, Lamberts
SW. Body composition in growth hormone-deficient
adults. Am J Clin Nutr. 1992;55:918 –923.
Amato G, Carella C, Fazio S, et al. Body composition, bone
metabolism, and heart structure and function in growth
hormone (GH)-deficient adults before and after GH replacement therapy at low doses. J Clin Endocrinol Metab.
1993;77:1671–1676.
Møller J, Frandsen E, Fisker S, Jørgensen JO, Christiansen
JS. Decreased plasma and extracellular volume in growth
hormone deficient adults and the acute and prolonged effects of GH administration: a controlled experimental
study. Clin Endocrinol (Oxf). 1996;44:533–539.
Janssen YJ, Deurenberg P, Roelfsema F. Using dilution
techniques and multifrequency bioelectrical impedance to
assess both total body water and extracellular water at
baseline and during recombinant human growth hormone
(GH) treatment in GH-deficient adults. J Clin Endocrinol
Metab. 1997;82:3349 –3355.
Jepson JH, McGarry EE. Hemopoiesis in pituitary dwarfs
treated with human growth hormone and testosterone.
Blood. 1972;39:229 –248.
Christ ER, Cummings MH, Westwood NB, et al. The importance of growth hormone in the regulation of erythropoiesis, red cell mass, and plasma volume in adults with
growth hormone deficiency. J Clin Endocrinol Metab.
1997;82:2985–2990.
Rosenfeld RG, Rosenbloom AL, Guevara-Aguirre J.
Growth hormone (GH) insensitivity due to primary GH
receptor deficiency. Endocr Rev. 1994;15:369 –390.
Hayes FJ, Fiad TM, McKenna TJ. Activity of the reninangiotensin-aldosterone axis is dependent on the occurrence of edema in growth hormone (GH)-deficient adults
treated with GH. J Clin Endocrinol Metab. 1997;82:322–
323.
Kaufman JM, Taelman P, Vermeulen A, Vandeweghe M.
Bone mineral status in growth hormone-deficient males
with isolated and multiple pituitary deficiencies of childhood onset. J Clin Endocrinol Metab. 1992;74:118 –123.
O’Halloran DJ, Tsatsoulis A, Whitehouse RW, Holmes SJ,
Adams JE, Shalet SM. Increased bone density after recombinant human growth hormone (GH) therapy in adults
with isolated GH deficiency. J Clin Endocrinol Metab.
1993;76:1344 –1348.
Holmes SJ, Economou G, Whitehouse RW, Adams JE,
Shalet SM. Reduced bone mineral density in patients with
adult onset growth hormone deficiency. J Clin Endocrinol
Metab. 1994;78:669 – 674.
Boot AM, Engels MA, Boerma GJ, Krenning EP, De
Muinck Keizer-Schrama SM. Changes in bone mineral
density, body composition, and lipid metabolism during
growth hormone (GH) treatment in children with GH deficiency. J Clin Endocrinol Metab. 1997;82:2423–2428.
Burstein S, Chen IW, Tsang RC. Effects of growth hormone replacement therapy on 1,25-dihydroxyvitamin D
and calcium metabolism. J Clin Endocrinol Metab. 1983;
56:1246 –1251.
Saggese G, Baroncelli GI, Bertelloni S, Cinquanta L, Di
Nero G. Effects of long-term treatment with growth hor-
Endocrine Reviews, April 2014, 35(2):234 –281
285.
286.
287.
288.
289.
290.
291.
292.
293.
294.
295.
296.
297.
298.
mone on bone and mineral metabolism in children with
growth hormone deficiency. J Pediatr. 1993;122:37– 45.
Wei S, Tanaka H, Kubo T, Ono T, Kanzaki S, Seino Y.
Growth hormone increases serum 1,25-dihydroxyvitamin
D levels and decreases 24,25-dihydroxyvitamin D levels in
children with growth hormone deficiency. Eur J Endocrinol. 1997;136:45–51.
Beshyah SA, Thomas E, Kyd P, Sharp P, Fairney A, Johnston DG. The effect of growth hormone replacement therapy in hypopituitary adults on calcium and bone metabolism. Clin Endocrinol (Oxf). 1994;40:383–391.
Beshyah SA, Kyd P, Thomas E, Fairney A, Johnston DG.
The effects of prolonged growth hormone replacement on
bone metabolism and bone mineral density in hypopituitary adults. Clin Endocrinol (Oxf).1995;42:249 –254.
Hansen TB, Brixen K, Vahl N, et al. Effects of 12 months
of growth hormone (GH) treatment on calciotropic hormones, calcium homeostasis, and bone metabolism in
adults with acquired GH deficiency: a double blind, randomized, placebo-controlled study. J Clin Endocrinol
Metab. 1996;81:3352–3359.
Vaccarello MA, Diamond FB Jr, Guevara-Aguirre J, et al.
Hormonal and metabolic effects and pharmacokinetics of
recombinant insulin-like growth factor-I in growth hormone receptor deficiency/Laron syndrome. J Clin Endocrinol Metab. 1993;77:273–280.
Bianda T, Glatz Y, Bouillon R, Froesch ER, Schmid C.
Effects of short-term insulin-like growth factor-I (IGF-I) or
growth hormone (GH) treatment on bone metabolism and
on production of 1,25-dihydroxycholecalciferol in GHdeficient adults. J Clin Endocrinol Metab. 1998;83:81– 87.
Ahmad AM, Hopkins MT, Thomas J, Durham BH, Fraser
WD, Vora JP. Parathyroid responsiveness to hypocalcemic
and hypercalcemic stimuli in adult growth hormone deficiency after growth hormone replacement. Am J Physiol
Endocrinol Metab. 2004;286:E986 –E993.
White HD, Ahmad AM, Durham BH, et al. PTH circadian
rhythm and PTH target-organ sensitivity is altered in patients with adult growth hormone deficiency with low
BMD. J Bone Miner Res. 2007;22:1798 –1807.
Schrijvers BF, De Vriese AS, Flyvbjerg A. From hyperglycemia to diabetic kidney disease: the role of metabolic,
hemodynamic, intracellular factors and growth factors/cytokines. Endocr Rev. 2004;25:971–1010.
Brosius FC 3rd. Trophic factors and cytokines in early
diabetic glomerulopathy. Exp Diabesity Res. 2003;4:225–
233.
Hoshi S, Shu Y, Yoshida F, et al. Podocyte injury promotes
progressive nephropathy in Zucker diabetic fatty rats. Lab
Invest. 2002;82:25–35.
Meyer TW, Bennett PH, Nelson RG. Podocyte number
predicts long-term urinary albumin excretion in Pima Indians with type II diabetes and microalbuminuria. Diabetologia. 1999;42:1341–1344.
Giustina A, Bossoni S, Cimino A, Pizzocolo G, Romanelli
G, Wehrenberg WB. Impaired growth hormone (GH) response to pyridostigmine in type 1 diabetic patients with
exaggerated GH-releasing hormone-stimulated GH secretion. J Clin Endocrinol Metab. 1990;71:1486 –1490.
Giustina A, Wehrenberg WB. Growth hormone neu-
doi: 10.1210/er.2013-1071
299.
300.
301.
302.
303.
304.
305.
306.
307.
308.
309.
310.
311.
312.
313.
314.
315.
roregulation in diabetes mellitus. Trends Endocrinol
Metab. 1994;5:73–78.
Blankestijn PJ, Derkx FH, Birkenhäger JC, et al. Glomerular hyperfiltration in insulin-dependent diabetes mellitus
is correlated with enhanced growth hormone secretion.
J Clin Endocrinol Metab. 1993;77:498 –502.
Flyvbjerg A. Putative pathophysiological role of growth
factors and cytokines in experimental diabetic kidney disease. Diabetologia. 2000;43:1205–1223.
Baud L, Fouqueray B, Bellocq A, Doublier S, Dumoulin A.
Growth hormone and somatostatin in glomerular injury.
J Nephrol. 1999;12:18 –23.
Elliot SJ, Striker LJ, Hattori M, et al. Mesangial cells from
diabetic NOD mice constitutively secrete increased
amounts of insulin-like growth factor-I. Endocrinology.
1993;133:1783–1788.
Vasylyeva TL, Ferry RJ Jr. Novel roles of the IGF-IGFBP
axis in etiopathophysiology of diabetic nephropathy. Diabetes Res Clin Pract. 2007;76:177–186.
Oemar BS, Foellmer HG, Hodgdon-Anandant L, Rosenzweig SA. Regulation of insulin-like growth factor I receptors in diabetic mesangial cells. J Biol Chem. 1991;266:
2369 –2373.
Tack I, Elliot SJ, Potier M, Rivera A, Striker GE, Striker LJ.
Autocrine activation of the IGF-I signaling pathway in
mesangial cells isolated from diabetic NOD mice. Diabetes. 2002;51:182–188.
Poulaki V, Joussen AM, Mitsiades N, Mitsiades CS, Iliaki
EF, Adamis AP. Insulin-like growth factor-I plays a pathogenetic role in diabetic retinopathy. Am J Pathol. 2004;
165:457– 469.
Feld SM, Hirschberg R, Artishevsky A, Nast C, Adler SG.
Insulin-like growth factor I induces mesangial proliferation and increases mRNA and secretion of collagen. Kidney Int. 1995;48:45–51.
Gooch JL, Tang Y, Ricono JM, Abboud HE. Insulin-like
growth factor-I induces renal cell hypertrophy via a calcineurin-dependent mechanism. J Biol Chem. 2001;276:
42492– 42500.
Haylor J, Hickling H, El Eter E, et al. JB3, an IGF-I receptor
antagonist, inhibits early renal growth in diabetic and uninephrectomized rats. J Am Soc Nephrol. 2000;11:2027–
2035.
Schreiber BD, Hughes ML, Groggel GC. Insulin-like
growth factor-1 stimulates production of mesangial cell
matrix components. Clin Nephrol. 1995;43:368 –374.
Kang BP, Frencher S, Reddy V, Kessler A, Malhotra A,
Meggs LG. High glucose promotes mesangial cell apoptosis by oxidant-dependent mechanism. Am J Physiol Renal
Physiol. 2003;284:F455–F466.
Yang S, Chintapalli J, Sodagum L, et al. Activated IGF-1R
inhibits hyperglycemia-induced DNA damage and promotes DNA repair by homologous recombination. Am J
Physiol Renal Physiol. 2005;289:F1144 –F1152.
Alric C, Pecher C, Cellier E, et al. Inhibition of IGF-I-induced Erk 1 and 2 activation and mitogenesis in mesangial
cells by bradykinin. Kidney Int. 2002;62:412– 421.
Clemmons DR. Role of insulin-like growth factor binding
proteins in controlling IGF actions. Mol Cell Endocrinol.
1998;140:19 –24.
Horney MJ, Shirley DW, Kurtz DT, Rosenzweig SA. Ele-
edrv.endojournals.org
316.
317.
318.
319.
320.
321.
322.
323.
324.
325.
326.
327.
328.
329.
330.
275
vated glucose increases mesangial cell sensitivity to insulinlike growth factor I. Am J Physiol. 1998;274:F1045–
F1053.
Wolf E, Lahm H, Wu M, Wanke R, Hoeflich A. Effects of
IGFBP-2 overexpression in vitro and in vivo. Pediatr Nephrol. 2000;14:572–578.
Fornoni A, Rosenzweig SA, Lenz O, Rivera A, Striker GE,
Elliot SJ. Low insulin-like growth factor binding protein-2
expression is responsible for increased insulin receptor
substrate-1 phosphorylation in mesangial cells from mice
susceptible to glomerulosclerosis. Endocrinology. 2006;
147:3547–3554.
Pagtalunan ME, Miller PL, Jumping-Eagle S, et al. Podocyte loss and progressive glomerular injury in type II diabetes. J Clin Invest. 1997;99:342–348.
Landau D, Segev Y, Eshet R, Flyvbjerg A, Phillip M.
Changes in the growth hormone-IGF-I axis in non-obese
diabetic mice. Int J Exp Diabetes Res. 2000;1:9 –18.
Landau D, Domene H, Flyvbjerg A, et al. Differential expression of renal growth hormone receptor and its binding
protein in experimental diabetes mellitus. Growth Horm
IGF Res. 1998;8:39 – 45.
Thirone AC, Scarlett JA, Gasparetti AL, et al. Modulation
of growth hormone signal transduction in kidneys of streptozotocin-induced diabetic animals: effect of a growth hormone receptor antagonist. Diabetes. 2002;51:2270 –
2281.
Landau D, Israel E, Rivkis I, et al. The effect of growth
hormone on the development of diabetic kidney disease in
rats. Nephrol Dial Transplant. 2003;18:694 –702.
Flyvbjerg A, Bennett WF, Rasch R, Kopchick JJ, Scarlett
JA. Inhibitory effect of a growth hormone receptor antagonist (G120K-PEG) on renal enlargement, glomerular hypertrophy, and urinary albumin excretion in experimental
diabetes in mice. Diabetes. 1999;48:377–382.
Segev Y, Landau D, Marbach M, Shehadeh N, Flyvbjerg A,
Phillip M. Renal hypertrophy in hyperglycemic non-obese
diabetic mice is associated with persistent renal accumulation of insulin-like growth factor I. J Am Soc Nephrol.
1997;8:436 – 444.
Park IS, Kiyomoto H, Alvarez F, Xu YC, Abboud HE,
Abboud SL. Preferential expression of insulin-like growth
factor binding proteins-1, -3, and -5 during early diabetic
renal hypertrophy in rats. Am J Kidney Dis. 1998;32:
1000 –1010.
Flyvbjerg A, Kessler U, Kiess W. Increased kidney and liver
insulin-like growth factor II/mannose-6-phosphate receptor concentration in experimental diabetes in rats. Growth
Regul. 1994;4:188 –193.
Isshiki K, He Z, Maeno Y, et al. Insulin regulates SOCS2
expression and the mitogenic effect of IGF-1 in mesangial
cells. Kidney Int. 2008;74:1434 –1443.
Grønbaek H, Volmers P, Bjørn SF, Osterby R, Orskov H,
Flyvbjerg A. Effect of GH/IGF-I deficiency on long-term
renal changes and urinary albumin excretion in diabetic
dwarf rats. Am J Physiol. 1997;272:E918 –E924.
Levin-Iaina N, Iaina A, Raz I. The emerging role of NO and
IGF-1 in early renal hypertrophy in STZ-induced diabetic
rats. Diabetes Metab Res Rev. 2011;27:235–243.
Bellush LL, Doublier S, Holland AN, Striker LJ, Striker
GE, Kopchick JJ. Protection against diabetes-induced ne-
276
331.
332.
333.
334.
335.
336.
337.
338.
339.
340.
341.
342.
343.
344.
345.
Kamenický et al
GH, IGF-1, and Kidney
phropathy in growth hormone receptor/binding protein
gene-disrupted mice. Endocrinology. 2000;141:163–168.
Chen NY, Chen WY, Bellush L, et al. Effects of streptozotocin treatment in growth hormone (GH) and GH antagonist transgenic mice. Endocrinology. 1995;136:660 –
667.
Chen NY, Chen WY, Kopchick JJ. Liver and kidney
growth hormone (GH) receptors are regulated differently
in diabetic GH and GH antagonist transgenic mice. Endocrinology. 1997;138:1988 –1994.
Flyvbjerg A, Frystyk J, Thorlacius-Ussing O, Orskov H.
Somatostatin analogue administration prevents increase in
kidney somatomedin C and initial renal growth in diabetic
and uninephrectomized rats. Diabetologia. 1989;32:261–
265.
Grønbaek H, Nielsen B, Frystyk J, Orskov H, Flyvbjerg A.
Effect of octreotide on experimental diabetic renal and glomerular growth: importance of early intervention. J Endocrinol. 1995;147:95–102.
Segev Y, Eshet R, Rivkis I, et al. Comparison between somatostatin analogues and ACE inhibitor in the NOD
mouse model of diabetic kidney disease. Nephrol Dial
Transplant. 2004;19:3021–3028.
Giustina A, Bodini C, Bossoni S, Valentini U, Wehrenberg
WB. Variability in the growth hormone response to growth
hormone-releasing hormone alone or combined with pyridostigmine in type 1 diabetic patients. J Endocrinol Invest.
1993;16:585–590.
Giustina A, Desenzani P, Perini P, et al. Hypothalamic control of growth hormone (GH) secretion in type I diabetic
men: effect of the combined administration of GH-releasing hormone and hexarelin, a novel GHRP-6 analog. Endocr Res. 1996;22:159 –174.
Giustina A, Bossoni S, Bodini C, et al. Effects of exogenous
growth hormone pretreatment on the pituitary growth
hormone response to growth hormone-releasing hormone
alone or in combination with pyridostigmine in type I diabetic patients. Acta Endocrinol (Copenh). 1991;125:
510 –517.
Giustina A, Desenzani P, Perini P, et al. Glutamate decarboxylase autoimmunity and growth hormone secretion in
type I diabetes mellitus. Metabolism. 1997;46:382–387.
Mercado M, Molitch ME, Baumann G. Low plasma
growth hormone binding protein in IDDM. Diabetes.
1992;41:605– 609.
Tattersall RB, Pyke DA. Growth in diabetic children. Studies in identical twins. Lancet. 1973;2:1105–1109.
Orskov H. Somatostatin, growth hormone, insulin-like
growth factor-1, and diabetes: friends or foes? Metabolism. 1996;45:91–95.
Cummings EA, Sochett EB, Dekker MG, Lawson ML,
Daneman D. Contribution of growth hormone and IGF-I
to early diabetic nephropathy in type 1 diabetes. Diabetes.
1998;47:1341–1346.
Verrotti A, Cieri F, Petitti MT, Morgese G, Chiarelli F.
Growth hormone and IGF-I in diabetic children with and
without microalbuminuria. Diabetes Nutr Metab. 1999;
12:271–276.
Bacci S, De Cosmo S, Garruba M, et al. Role of insulin-like
growth factor (IGF)-1 in the modulation of renal haemo-
Endocrine Reviews, April 2014, 35(2):234 –281
346.
347.
348.
349.
350.
351.
352.
353.
354.
355.
356.
357.
358.
359.
360.
361.
362.
dynamics in type I diabetic patients. Diabetologia. 2000;
43:922–926.
Brezis M, Epstein FH. Cellular mechanisms of acute ischemic injury in the kidney. Annu Rev Med. 1993;44:27–37.
Matejka GL, Jennische E. IGF-I binding and IGF-I mRNA
expression in the post-ischemic regenerating rat kidney.
Kidney Int. 1992;42:1113–1123.
Andersson G, Jennische E. IGF-I immunoreactivity is expressed by regenerating renal tubular cells after ischaemic
injury in the rat. Acta Physiol Scand. 1988;132:453– 457.
Imberti B, Morigi M, Tomasoni S, et al. Insulin-like
growth factor-1 sustains stem cell mediated renal repair.
J Am Soc Nephrol. 2007;18:2921–2928.
Miller SB, Martin DR, Kissane J, Hammerman MR. Insulin-like growth factor I accelerates recovery from ischemic
acute tubular necrosis in the rat. Proc Natl Acad Sci USA.
1992;89:11876 –11880.
Yasuda H, Kato A, Miyaji T, Zhou H, Togawa A, Hishida
A. Insulin-like growth factor-I increases p21 expression
and attenuates cisplatin-induced acute renal injury in rats.
Clin Exp Nephrol. 2004;8:27–35.
Takeda R, Nishimatsu H, Suzuki E, et al. Ghrelin improves
renal function in mice with ischemic acute renal failure.
J Am Soc Nephrol. 2006;17:113–121.
Franklin SC, Moulton M, Sicard GA, Hammerman MR,
Miller SB. Insulin-like growth factor I preserves renal function postoperatively. Am J Physiol. 1997;272:F257–F259.
Hladunewich MA, Corrigan G, Derby GC, et al. A randomized, placebo-controlled trial of IGF-1 for delayed
graft function: a human model to study postischemic ARF.
Kidney Int. 2003;64:593– 602.
Bengtsson BA. Rethink about growth-hormone therapy
for critically ill patients. Lancet. 1999;354:1403–1404.
Takala J, Ruokonen E, Webster NR, et al. Increased mortality associated with growth hormone treatment in critically ill adults. N Engl J Med. 1999;341:785–792.
Tönshoff B, Veldhuis JD, Heinrich U, Mehls O. Deconvolution analysis of spontaneous nocturnal growth hormone secretion in prepubertal children with preterminal
chronic renal failure and with end-stage renal disease. Pediatr Res. 1995;37:86 –93.
Tönshoff B, Kiepe D, Ciarmatori S. Growth hormone/insulin-like growth factor system in children with chronic
renal failure. Pediatr Nephrol. 2005;20:279 –289.
Veldhuis JD, Iranmanesh A, Wilkowski MJ, Samojlik E.
Neuroendocrine alterations in the somatotropic and lactotropic axes in uremic men. Eur J Endocrinol. 1994;131:
489 – 498.
Schaefer F, Veldhuis JD, Stanhope R, Jones J, Schärer K.
Alterations in growth hormone secretion and clearance in
peripubertal boys with chronic renal failure and after renal
transplantation. Cooperative Study Group of Pubertal Development in Chronic Renal Failure. J Clin Endocrinol
Metab. 1994;78:1298 –1306.
Ivarsen P, Chen JW, Tietze I, Christiansen JS, Flyvbjerg A,
Frystyk J. Marked reductions in bioactive insulin-like
growth factor I (IGF-I) during hemodialysis. Growth
Horm IGF Res. 2010;20:156 –161.
Tönshoff B, Blum WF, Mehls O. Serum insulin-like
growth factors and their binding proteins in children with
doi: 10.1210/er.2013-1071
363.
364.
365.
366.
367.
368.
369.
370.
371.
372.
373.
374.
375.
end-stage renal disease. Pediatr Nephrol. 1996;10:269 –
274.
Tönshoff B, Blum WF, Wingen AM, Mehls O. Serum insulin-like growth factors (IGFs) and IGF binding proteins
1, 2, and 3 in children with chronic renal failure: relationship to height and glomerular filtration rate. The European
Study Group for Nutritional Treatment of Chronic Renal
Failure in Childhood. J Clin Endocrinol Metab. 1995;80:
2684 –2691.
Frystyk J, Ivarsen P, Skjaerbaek C, Flyvbjerg A, Pedersen
EB, Orskov H. Serum-free insulin-like growth factor I correlates with clearance in patients with chronic renal failure.
Kidney Int. 1999;56:2076 –2084.
Abdulle AM, Gillett MP, Abouchacra S, et al. Low IGF-1
levels are associated with cardiovascular risk factors in
haemodialysis patients. Mol Cell Biochem. 2007;302:
195–201.
Rabkin R, Sun DF, Chen Y, Tan J, Schaefer F. Growth
hormone resistance in uremia, a role for impaired JAK/
STAT signaling. Pediatr Nephrol. 2005;20:313–318.
Edmondson SR, Baker NL, Oh J, Kovacs G, Werther GA,
Mehls O. Growth hormone receptor abundance in tibial
growth plates of uremic rats: GH/IGF-I treatment. Kidney
Int. 2000;58:62–70.
Tönshoff B, Cronin MJ, Reichert M, et al. Reduced concentration of serum growth hormone (GH)-binding protein in children with chronic renal failure: correlation with
GH insensitivity. The European Study Group for Nutritional Treatment of Chronic Renal Failure in Childhood.
The German Study Group for Growth Hormone Treatment in Chronic Renal Failure. J Clin Endocrinol Metab.
1997;82:1007–1013.
Amit T, Youdim MB, Hochberg Z. Clinical review 112:
does serum growth hormone (GH) binding protein reflect
human GH receptor function? J Clin Endocrinol Metab.
2000;85:927–932.
Schaefer F, Chen Y, Tsao T, Nouri P, Rabkin R. Impaired
JAK-STAT signal transduction contributes to growth hormone resistance in chronic uremia. J Clin Invest. 2001;
108:467– 475.
Tönshoff B, Edén S, Weiser E, et al. Reduced hepatic
growth hormone (GH) receptor gene expression and increased plasma GH binding protein in experimental uremia. Kidney Int. 1994;45:1085–1092.
Sun DF, Zheng Z, Tummala P, Oh J, Schaefer F, Rabkin R.
Chronic uremia attenuates growth hormone-induced signal transduction in skeletal muscle. J Am Soc Nephrol.
2004;15:2630 –2636.
Greenhalgh CJ, Bertolino P, Asa SL, et al. Growth enhancement in suppressor of cytokine signaling 2 (SOCS2)-deficient mice is dependent on signal transducer and
activator of transcription 5b (STAT5b). Mol Endocrinol.
2002;16:1394 –1406.
Powell DR, Durham SK, Brewer ED, et al. Effects of
chronic renal failure and growth hormone on serum levels
of insulin-like growth factor-binding protein-4 (IGFBP-4)
and IGFBP-5 in children: a report of the Southwest Pediatric Nephrology Study Group. J Clin Endocrinol Metab.
1999;84:596 – 601.
Ulinski T, Mohan S, Kiepe D, et al. Serum insulin-like
growth factor binding protein (IGFBP)-4 and IGFBP-5 in
edrv.endojournals.org
376.
377.
378.
379.
380.
381.
382.
383.
384.
385.
386.
387.
388.
277
children with chronic renal failure: relationship to growth
and glomerular filtration rate. The European Study Group
for Nutritional Treatment of Chronic Renal Failure in
Childhood. German Study Group for Growth Hormone
Treatment in Chronic Renal Failure. Pediatr Nephrol.
2000;14:589 –597.
Baxter RC. Insulin-like growth factor (IGF)-binding proteins: interactions with IGFs and intrinsic bioactivities.
Am J Physiol Endocrinol Metab. 2000;278:E967–E976.
Powell DR, Liu F, Baker BK, et al. Modulation of growth
factors by growth hormone in children with chronic renal
failure. The Southwest Pediatric Nephrology Study Group.
Kidney Int. 1997;51:1970 –1979.
Lewis M, Shaw J, Reid C, Evans J, Webb N, Verrier-Jones
K. Growth in children with established renal failure–a Registry analysis (chapter 14). Nephrol Dial Transplant. 2007;
22(suppl 7):vii176-vii180.
Betts PR, Magrath G. Growth pattern and dietary intake of
children with chronic renal insufficiency. Br Med J. 1974;
2:189 –193.
Fine RN. Etiology and treatment of growth retardation in
children with chronic kidney disease and end-stage renal
disease: a historical perspective. Pediatr Nephrol. 2010;
25:725–732.
Rosenkranz J, Reichwald-Klugger E, Oh J, Turzer M,
Mehls O, Schaefer F. Psychosocial rehabilitation and satisfaction with life in adults with childhood-onset of endstage renal disease. Pediatr Nephrol. 2005;20:1288 –1294.
Furth SL, Hwang W, Yang C, Neu AM, Fivush BA, Powe
NR. Growth failure, risk of hospitalization and death for
children with end-stage renal disease. Pediatr Nephrol.
2002;17:450 – 455.
Hokken-Koelega AC, Stijnen T, de Muinck KeizerSchrama SM, et al. Placebo-controlled, double-blind,
cross-over trial of growth hormone treatment in prepubertal children with chronic renal failure. Lancet. 1991;338:
585–590.
Bérard E, André JL, Guest G, et al. Long-term results of
rhGH treatment in children with renal failure: experience
of the French Society of Pediatric Nephrology. Pediatr
Nephrol. 2008;23:2031–2038.
de Graaff LC, Mulder PG, Hokken-Koelega AC. Body proportions before and during growth hormone therapy in
children with chronic renal failure. Pediatr Nephrol. 2003;
18:679 – 684.
Fine RN, Attie KM, Kuntze J, Brown DF, Kohaut EC.
Recombinant human growth hormone in infants and
young children with chronic renal insufficiency. Genentech
Collaborative Study Group. Pediatr Nephrol. 1995;9:
451– 457.
Fine RN, Brown DF, Kuntze J, Wooster P, Kohaut EE.
Growth after discontinuation of recombinant human
growth hormone therapy in children with chronic renal
insufficiency. The Genentech Cooperative Study Group.
J Pediatr. 1996;129:883– 891.
Fine RN, Kohaut EC, Brown D, Perlman AJ. Growth after
recombinant human growth hormone treatment in children with chronic renal failure: report of a multicenter
randomized double-blind placebo-controlled study. Genentech Cooperative Study Group. J Pediatr. 1994;124:
374 –382.
278
Kamenický et al
GH, IGF-1, and Kidney
389. Haffner D, Schaefer F, Nissel R, Wühl E, Tönshoff B,
Mehls O. Effect of growth hormone treatment on the adult
height of children with chronic renal failure. German Study
Group for Growth Hormone Treatment in Chronic Renal
Failure. N Engl J Med. 2000;343:923–930.
390. Haffner D, Wühl E, Schaefer F, Nissel R, Tönshoff B,
Mehls O. Factors predictive of the short- and long-term
efficacy of growth hormone treatment in prepubertal children with chronic renal failure. The German Study Group
for Growth Hormone Treatment in Chronic Renal Failure.
J Am Soc Nephrol. 1998;9:1899 –1907.
391. Hertel NT, Holmberg C, Rönnholm KA, et al. Recombinant human growth hormone treatment, using two dose
regimens in children with chronic renal failure–a report on
linear growth and adverse effects. J Pediatr Endocrinol
Metab. 2002;15:577–588.
392. Hokken-Koelega A, Mulder P, De Jong R, Lilien M, Donckerwolcke R, Groothof J. Long-term effects of growth
hormone treatment on growth and puberty in patients with
chronic renal insufficiency. Pediatr Nephrol. 2000;14:
701–706.
393. Hokken-Koelega AC, Stijnen T, De Jong MC, et al. Double
blind trial comparing the effects of two doses of growth
hormone in prepubertal patients with chronic renal insufficiency. J Clin Endocrinol Metab. 1994;79:1185–1190.
394. Mehls O, Lindberg A, Nissel R, Haffner D, HokkenKoelega A, Ranke MB. Predicting the response to growth
hormone treatment in short children with chronic kidney
disease. J Clin Endocrinol Metab. 2010;95:686 – 692.
395. Nissel R, Lindberg A, Mehls O, Haffner D. Factors predicting the near-final height in growth hormone-treated
children and adolescents with chronic kidney disease.
J Clin Endocrinol Metab. 2008;93:1359 –1365.
396. Postlethwaite RJ, Eminson DM, Reynolds JM, Wood AJ,
Hollis S. Growth in renal failure: a longitudinal study of
emotional and behavioural changes during trials of growth
hormone treatment. Arch Dis Child. 1998;78:222–229.
397. Santos F, Moreno ML, Neto A, et al. Improvement in
growth after 1 year of growth hormone therapy in wellnourished infants with growth retardation secondary to
chronic renal failure: results of a multicenter, controlled,
randomized, open clinical trial. Clin J Am Soc Nephrol.
2010;5:1190 –1197.
398. Wühl E, Haffner D, Nissel R, Schaefer F, Mehls O. Short
dialyzed children respond less to growth hormone than
patients prior to dialysis. German Study Group for Growth
Hormone Treatment in Chronic Renal Failure. Pediatr
Nephrol. 1996;10:294 –298.
399. Youssef DM. Results of recombinant growth hormone
treatment in children with end-stage renal disease on regular hemodialysis. Saudi J Kidney Dis Transpl. 2012;23:
755–764.
400. Hodson EM, Willis NS, Craig JC. Growth hormone for
children with chronic kidney disease. Cochrane Database
Syst Rev. 2012;2:CD003264.
401. Gharib H, Cook DM, Saenger PH, et al. American Association of Clinical Endocrinologists medical guidelines for
clinical practice for growth hormone use in adults and children–2003 update. Endocr Pract. 2003;9:64 –76.
402. Fine RN, Kohaut E, Brown D, Kuntze J, Attie KM. Longterm treatment of growth retarded children with chronic
Endocrine Reviews, April 2014, 35(2):234 –281
403.
404.
405.
406.
407.
408.
409.
410.
411.
412.
413.
414.
415.
416.
417.
renal insufficiency, with recombinant human growth hormone. Kidney Int. 1996;49:781–785.
Mahan JD, Warady BA. Assessment and treatment of short
stature in pediatric patients with chronic kidney disease: a
consensus statement. Pediatr Nephrol. 2006;21:917–930.
Feldt-Rasmussen B, Lange M, Sulowicz W, et al. Growth
hormone treatment during hemodialysis in a randomized
trial improves nutrition, quality of life, and cardiovascular
risk. J Am Soc Nephrol. 2007;18:2161–2171.
Garibotto G, Barreca A, Russo R, et al. Effects of recombinant human growth hormone on muscle protein turnover in malnourished hemodialysis patients. J Clin Invest.
1997;99:97–105.
Hansen TB, Gram J, Jensen PB, et al. Influence of growth
hormone on whole body and regional soft tissue composition in adult patients on hemodialysis. A double-blind,
randomized, placebo-controlled study. Clin Nephrol.
2000;53:99 –107.
Iglesias P, Díez JJ, Fernández-Reyes MJ, et al. Recombinant human growth hormone therapy in malnourished dialysis patients: a randomized controlled study. Am J Kidney Dis. 1998;32:454 – 463.
Jensen PB, Hansen TB, Frystyk J, Ladefoged SD, Pedersen
FB, Christiansen JS. Growth hormone, insulin-like growth
factors and their binding proteins in adult hemodialysis
patients treated with recombinant human growth hormone. Clin Nephrol. 1999;52:103–109.
Johannsson G, Bengtsson BA, Ahlmén J. Double-blind,
placebo-controlled study of growth hormone treatment in
elderly patients undergoing chronic hemodialysis: anabolic effect and functional improvement. Am J Kidney Dis.
1999;33:709 –717.
Kotzmann H, Yilmaz N, Lercher P, et al. Differential effects of growth hormone therapy in malnourished hemodialysis patients. Kidney Int. 2001;60:1578 –1585.
Pupim LB, Flakoll PJ, Yu C, Ikizler TA. Recombinant human growth hormone improves muscle amino acid uptake
and whole-body protein metabolism in chronic hemodialysis patients. Am J Clin Nutr. 2005;82:1235–1243.
Sohmiya M, Ishikawa K, Kato Y. Stimulation of erythropoietin secretion by continuous subcutaneous infusion of
recombinant human GH in anemic patients with chronic
renal failure. Eur J Endocrinol. 1998;138:302–306.
Lilien MR, Schröder CH, Levtchenko EN, Koomans HA.
Growth hormone therapy influences endothelial function
in children with renal failure. Pediatr Nephrol. 2004;19:
785–789.
Gola M, Giustina A. Growth hormone deficiency and cardiovascular risk: do we need additional markers? Endocrine. 2012;42:240 –242.
García-Mayor RV, Pérez AJ, Gandara A, Andrade A,
Mallo F, Casanueva FF. Metabolic clearance rate of biosynthetic growth hormone after endogenous growth hormone suppression with a somatostatin analogue in chronic
renal failure patients and control subjects. Clin Endocrinol
(Oxf). 1993;39:337–343.
Haffner D, Schaefer F, Girard J, Ritz E, Mehls O. Metabolic clearance of recombinant human growth hormone in
health and chronic renal failure. J Clin Invest. 1994;93:
1163–1171.
Schaefer F, Baumann G, Haffner D, et al. Multifactorial
doi: 10.1210/er.2013-1071
418.
419.
420.
421.
422.
423.
424.
425.
426.
427.
428.
429.
430.
431.
432.
433.
control of the elimination kinetics of unbound (free)
growth hormone (GH) in the human: regulation by age,
adiposity, renal function, and steady state concentrations
of GH in plasma. J Clin Endocrinol Metab. 1996;81:
22–31.
Langbakke IH, Nielsen JN, Skettrup MP, et al. Pharmacokinetics and pharmacodynamics of growth hormone in
patients on chronic haemodialysis compared with matched
healthy subjects: an open, nonrandomized, parallel-group
trial. Clin Endocrinol (Oxf). 2007;67:776 –783.
Fine RN, Ho M, Tejani A, Blethen S. Adverse events with
rhGH treatment of patients with chronic renal insufficiency and end-stage renal disease. J Pediatr. 2003;142:
539 –545.
Wühl E, Haffner D, Offner G, Broyer M, van’t Hoff W,
Mehls O. Long-term treatment with growth hormone in
short children with nephropathic cystinosis. J Pediatr.
2001;138:880 – 887.
Tönshoff B, Heinrich U, Mehls O. How safe is the treatment of uraemic children with recombinant human growth
hormone? Pediatr Nephrol. 1991;5:454 – 460.
Tönshoff B, Tönshoff C, Mehls O, et al. Growth hormone
treatment in children with preterminal chronic renal failure: no adverse effect on glomerular filtration rate. Eur
J Pediatr. 1992;151:601– 607.
Dharnidharka VR, Talley LI, Martz KL, Stablein DM, Fine
RN. Recombinant growth hormone use pretransplant and
risk for post-transplant lymphoproliferative disease–a report of the NAPRTCS. Pediatr Transplant. 2008;12:689 –
695.
Hattori N, Saito T, Yagyu T, Jiang BH, Kitagawa K, Inagaki C. GH, GH receptor, GH secretagogue receptor, and
ghrelin expression in human T cells, B cells, and neutrophils. J Clin Endocrinol Metab. 2001;86:4284 – 4291.
Malozowski S, Tanner LA, Wysowski D, Fleming GA.
Growth hormone, insulin-like growth factor I, and benign
intracranial hypertension. N Engl J Med. 1993;329:665–
666.
Hazel SJ, Gillespie CM, Moore RJ, Clark RG, Jureidini KF,
Martin AA. Enhanced body growth in uremic rats treated
with IGF-I and growth hormone in combination. Kidney
Int. 1994;46:58 – 68.
Kovács GT, Oh J, Kovács J, et al. Growth promoting effects of growth hormone and IGF-I are additive in experimental uremia. Kidney Int. 1996;49:1413–1421.
Clark RG. Recombinant insulin-like growth factor-1 as a
therapy for IGF-1 deficiency in renal failure. Pediatr Nephrol. 2005;20:290 –294.
Harmon WE, Jabs K. Factors affecting growth after renal
transplantation. J Am Soc Nephrol. 1992;2:S295–S303.
Thissen JP, Ketelslegers JM, Underwood LE. Nutritional
regulation of the insulin-like growth factors. Endocr Rev.
1994;15:80 –101.
Mazziotti G, Giustina A. Glucocorticoids and the regulation of growth hormone secretion. Nat Rev Endocrinol.
2013;9:265–276.
Hochberg Z. Mechanisms of steroid impairment of
growth. Horm Res 58 Suppl. 2002;1:33–38.
Broyer M, Guest G, Gagnadoux MF. Growth rate in children receiving alternate-day corticosteroid treatment after
kidney transplantation. J Pediatr. 1992;120:721–725.
edrv.endojournals.org
279
434. Ellis D. Growth and renal function after steroid-free tacrolimus-based immunosuppression in children with renal
transplants. Pediatr Nephrol. 2000;14:689 – 694.
435. Höcker B, John U, Plank C, et al. Successful withdrawal of
steroids in pediatric renal transplant recipients receiving
cyclosporine A and mycophenolate mofetil treatment: results after four years. Transplantation. 2004;78:228 –234.
436. Jabs K, Sullivan EK, Avner ED, Harmon WE. Alternateday steroid dosing improves growth without adversely affecting graft survival or long-term graft function. A report
of the North American Pediatric Renal Transplant Cooperative Study. Transplantation. 1996;61:31–36.
437. Gulati A, Sarwal MM. Pediatric renal transplantation: an
overview and update. Curr Opin Pediatr. 2010;22:189 –
196.
438. Nissel R, Brázda I, Feneberg R, et al. Effect of renal transplantation in childhood on longitudinal growth and adult
height. Kidney Int. 2004;66:792– 800.
439. Broyer M. Results and side-effects of treating children with
growth hormone after kidney transplantation–a preliminary report. Pharmacia & Upjohn Study Group. Acta Paediatr Suppl. 1996;417:76 –79.
440. Fine RN, Stablein D. Long-term use of recombinant human
growth hormone in pediatric allograft recipients: a report
of the NAPRTCS Transplant Registry. Pediatr Nephrol.
2005;20:404 – 408.
441. Fine RN, Stablein D, Cohen AH, Tejani A, Kohaut E. Recombinant human growth hormone post-renal transplantation in children: a randomized controlled study of the
NAPRTCS. Kidney Int. 2002;62:688 – 696.
442. Gil S, Vaiani E, Guercio G, et al. Effectiveness of rhGH
treatment on final height of renal-transplant recipients in
childhood. Pediatr Nephrol. 2012;27:1005–1009.
443. Guest G, Bérard E, Crosnier H, Chevallier T, Rappaport R,
Broyer M. Effects of growth hormone in short children
after renal transplantation. French Society of Pediatric Nephrology. Pediatr Nephrol. 1998;12:437– 446.
444. Hokken-Koelega AC, Stijnen T, de Jong RC, et al. A placebo-controlled, double-blind trial of growth hormone
treatment in prepubertal children after renal transplant.
Kidney Int Suppl. 1996;53:S128 –S134.
445. Maxwell H, Rees L. Randomised controlled trial of recombinant human growth hormone in prepubertal and pubertal renal transplant recipients. British Association for
Pediatric Nephrology. Arch Dis Child. 1998;79:481– 487.
446. Sanchez CP, Kuizon BD, Goodman WG, et al. Growth
hormone and the skeleton in pediatric renal allograft recipients. Pediatr Nephrol. 2002;17:322–328.
447. Seikaly MG, Waber P, Warady BA, Stablein D. The effect
of rhGH on height velocity and BMI in children with CKD:
a report of the NAPRTCS registry. Pediatr Nephrol. 2009;
24:1711–1717.
448. Wu Y, Cheng W, Yang XD, Xiang B. Growth hormone
improves growth in pediatric renal transplant recipients–a
systemic review and meta-analysis of randomized controlled trials. Pediatr Nephrol. 2013;28:129 –133.
449. Mahan JD, Warady BA, Frane J, et al. First-year response
to rhGH therapy in children with CKD: a National Cooperative Growth Study Report. Pediatr Nephrol. 2010;25:
1125–1130.
280
Kamenický et al
GH, IGF-1, and Kidney
450. Kelley KW. Growth hormone, lymphocytes and macrophages. Biochem Pharmacol. 1989;38:705–713.
451. Snow EC, Feldbush TL, Oaks JA. The effect of growth
hormone and insulin upon MLC responses and the generation of cytotoxic lymphocytes. J Immunol. 1981;126:
161–164.
452. Tydén G, Berg U, Reinholt F. Acute renal graft rejection
after treatment with human growth hormone. Lancet.
1990;336:1455–1456.
453. Mehls O, Fine RN. Growth hormone treatment after renal
transplantation: a promising but underused chance to improve growth. Pediatr Nephrol. 2013;28:1– 4.
454. Horber FF, Scheidegger JR, Grünig BE, Frey FJ. Thigh
muscle mass and function in patients treated with glucocorticoids. Eur J Clin Invest. 1985;15:302–307.
455. Horber FF, Haymond MW. Human growth hormone prevents the protein catabolic side effects of prednisone in
humans. J Clin Invest. 1990;86:265–272.
456. Kidney Disease: Improving Global Outcomes (KDIGO)
Transplant Work Group. KDIGO clinical practice guideline for the care of kidney transplant recipients. Am J
Transplant. 2009;9(suppl 3):S1–S155.
457. Bell J, Parker KL, Swinford RD, Hoffman AR, Maneatis T,
Lippe B. Long-term safety of recombinant human growth
hormone in children. J Clin Endocrinol Metab. 2010;95:
167–177.
458. Takao M, Hashimoto J, Sakai T, Nishii T, Sugano N,
Yoshikawa H. Metaphyseal bone collapse mimicking
slipped capital femoral epiphysis in severe renal osteodystrophy. J Clin Endocrinol Metab. 2012;97:3851–3856.
459. Giustina A, Bussi AR, Jacobello C, Wehrenberg WB. Effects of recombinant human growth hormone (GH) on
bone and intermediary metabolism in patients receiving
chronic glucocorticoid treatment with suppressed endogenous GH response to GH-releasing hormone. J Clin Endocrinol Metab. 1995;80:122–129.
460. Bismuth E, Chevenne D, Czernichow P, Simon D. Moderate deterioration in glucose tolerance during high-dose
growth hormone therapy in glucocorticoid-treated patients with juvenile idiopathic arthritis. Horm Res Paediatr. 2010;73:465– 472.
461. Mazziotti G, Gazzaruso C, Giustina A. Diabetes in Cushing syndrome: basic and clinical aspects. Trends Endocrinol Metab. 2011;22:499 –506.
462. Cairns P. Renal cell carcinoma. Cancer Biomark. 2010;9:
461– 473.
463. Russo P. Contemporary understanding and management
of renal cortical tumors. Urol Clin North Am. 2008;35:
xiii-xvii.
464. Parker AS, Cheville JC, Blute ML, Igel T, Lohse CM, Cerhan JR. Pathologic T1 clear cell renal cell carcinoma: insulin-like growth factor-I receptor expression and diseasespecific survival. Cancer. 2004;100:2577–2582.
465. Schips L, Zigeuner R, Ratschek M, Rehak P, Rüschoff J,
Langner C. Analysis of insulin-like growth factors and insulin-like growth factor I receptor expression in renal cell
carcinoma. Am J Clin Pathol. 2004;122:931–937.
466. LeRoith D, Roberts CT Jr. The insulin-like growth factor
system and cancer. Cancer Lett. 2003;195:127–137.
467. André F, Rigot V, Thimonier J, et al. Integrins and E-cad-
Endocrine Reviews, April 2014, 35(2):234 –281
468.
469.
470.
471.
472.
473.
474.
475.
476.
477.
478.
479.
480.
481.
482.
483.
herin cooperate with IGF-I to induce migration of epithelial colonic cells. Int J Cancer. 1999;83:497–505.
Mauro L, Salerno M, Morelli C, Boterberg T, Bracke ME,
Surmacz E. Role of the IGF-I receptor in the regulation of
cell-cell adhesion: implications in cancer development and
progression. J Cell Physiol. 2003;194:108 –116.
Reinmuth N, Fan F, Liu W, et al. Impact of insulin-like
growth factor receptor-I function on angiogenesis, growth,
and metastasis of colon cancer. Lab Invest. 2002;82:1377–
1389.
Akeno N, Robins J, Zhang M, Czyzyk-Krzeska MF, Clemens TL. Induction of vascular endothelial growth factor
by IGF-I in osteoblast-like cells is mediated by the PI3K
signaling pathway through the hypoxia-inducible factor2␣. Endocrinology. 2002;143:420 – 425.
Carroll VA, Ashcroft M. Role of hypoxia-inducible factor
(HIF)-1␣ versus HIF-2␣ in the regulation of HIF target
genes in response to hypoxia, insulin-like growth factor-I,
or loss of von Hippel-Lindau function: implications for
targeting the HIF pathway. Cancer Res. 2006;66:6264 –
6270.
Sato A, Oya M, Ito K, et al. Survivin associates with cell
proliferation in renal cancer cells: regulation of survivin
expression by insulin-like growth factor-1, interferon-␥
and a novel NF-␬B inhibitor. Int J Oncol. 2006;28:841–
846.
Ambrosini G, Adida C, Altieri DC. A novel anti-apoptosis
gene, survivin, expressed in cancer and lymphoma. Nat
Med. 1997;3:917–921.
Li F, Ambrosini G, Chu EY, et al. Control of apoptosis and
mitotic spindle checkpoint by survivin. Nature. 1998;396:
580 –584.
Prager D, Li HL, Asa S, Melmed S. Dominant negative
inhibition of tumorigenesis in vivo by human insulin-like
growth factor I receptor mutant. Proc Natl Acad Sci USA.
1994;91:2181–2185.
Chan JM, Stampfer MJ, Giovannucci E, et al. Plasma insulin-like growth factor-I and prostate cancer risk: a prospective study. Science. 1998;279:563–566.
Hankinson SE, Willett WC, Colditz GA, et al. Circulating
concentrations of insulin-like growth factor-I and risk of
breast cancer. Lancet. 1998;351:1393–1396.
Parker A, Cheville JC, Lohse C, Cerhan JR, Blute ML.
Expression of insulin-like growth factor I receptor and survival in patients with clear cell renal cell carcinoma. J Urol.
2003;170:420 – 424.
Rosendahl AH, Holly JM, Celander M, Forsberg G. Systemic IGF-I administration stimulates the in vivo growth of
early, but not advanced, renal cell carcinoma. Int J Cancer.
2008;123:1286 –1291.
Lissoni P, Barni S, Ardizzoia A, et al. Clinical efficacy of
cancer subcutaneous immunotherapy with interleukin-2 in
relation to the pretreatment levels of tumor growth factor
insulin-like growth factor-1. Tumori. 1995;81:261–264.
Schwarz A, Vatandaslar S, Merkel S, Haller H. Renal cell
carcinoma in transplant recipients with acquired cystic
kidney disease. Clin J Am Soc Nephrol. 2007;2:750 –756.
Scandling JD. Acquired cystic kidney disease and renal cell
cancer after transplantation: time to rethink screening?
Clin J Am Soc Nephrol. 2007;2:621– 622.
Tydén G, Wernersson A, Sandberg J, Berg U. Development
doi: 10.1210/er.2013-1071
484.
485.
486.
487.
edrv.endojournals.org
of renal cell carcinoma in living donor kidney grafts. Transplantation. 2000;70:1650 –1656.
Mehls O, Wilton P, Lilien M, et al. Does growth hormone
treatment affect the risk of post-transplant renal cancer?
Pediatr Nephrol. 2002;17:984 –989.
Nakamura T, Ebihara I, Fukui M, et al. Increased endothelin and endothelin receptor mRNA expression in polycystic kidneys of cpk mice. J Am Soc Nephrol. 1993;4:
1064 –1072.
Aukema HM, Housini I. Dietary soy protein effects on
disease and IGF-I in male and female Han:SPRD-cy rats.
Kidney Int. 2001;59:52– 61.
Parker E, Newby LJ, Sharpe CC, et al. Hyperproliferation
281
of PKD1 cystic cells is induced by insulin-like growth factor-1 activation of the Ras/Raf signalling system. Kidney
Int. 2007;72:157–165.
488. Wanke R, Hermanns W, Folger S, Wolf E, Brem G. Accelerated growth and visceral lesions in transgenic mice
expressing foreign genes of the growth hormone family: an
overview. Pediatr Nephrol. 1991;5:513–521.
489. Syro LV, Sundsbak JL, Scheithauer BW, et al. Somatotroph
pituitary adenoma with acromegaly and autosomal dominant polycystic kidney disease: SSTR5 polymorphism and
PKD1 mutation. Pituitary. 2012;15:342–349.
490. Lilova M, Kaplan BS, Meyers KE. Recombinant human
growth hormone therapy in autosomal recessive polycystic
kidney disease. Pediatr Nephrol. 2003;18:57– 61.
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