NephrolDial Transplant(\996) 11: Editorial Comments
months after obtaining a steady-state because pursuing
chemotherapy does not improve overall survival. In
patients with myeloma kidney, no definite information
is available. In myeloma patients with stable chronic
renal failure, we occasionally observed an accelerated
course toward ESRF simultaneous with disruption of
antineoplastic drugs. Therefore we recommend longterm maintenance of well tolerated chemotherapy in
all patients exhibiting nephrotoxic light chains.
Due to poor prognosis of the disease, several groups
have developed an aggressive therapeutic approach
combining high-dose radiochemotherapy followed by
allogenic or autologous bone marrow transplantation
(BMT). This is currently applied in patients less than
55-60 years of age and having a severe form of multiple
myeloma. Serum creatinine below 300 umol/1 has been
regarded as an exclusion criteria. Compared with autologous BMT, allogenic transplantation results in better
efficiency with complete remission in 40% of the
patients and a survival rate of 40% at 5 years but only
applies to the rare patients who have an HLA-matched
sibling. Because of its wide availability, the shorter
period of cytopenia and the lesser risk of reinjecting
tumoral cells, autologous peripheral blood-stem cells
may be used after high dose chemotherapy (either
cyclophospamide and/or melphalan) with or without
total body irradiation. Current results are encouraging
with a median survival of 60 months and an event-free
survival time of 45 months after transplantation [7].
Using the same procedure Pruna al. (unpublished
observations) have treated 10 patients (median age
415
51 years) with myeloma renal failure (Ccr <60 ml/min,
including two with Ccr <20 ml/min). Duration of
aplasia was 15 days. No death was observed during
the acute phase of the treatment but three patients
required temporary haemodialysis. Four patients
remain in complete remission at three years. Longterm tolerance of kidney irradiation in this setting is
not yet known.
References
1. Solomon A, Weiss DT, Kattine AA. Nephrotoxic potential of
Bence-Jones protein. N EnglJ Med 1991; 324: 1845-1851
2. Huang ZQ, Kirk K, Connelly KG, Sanders PW. Bence-Jones
proteins bind to a common peptide binding segment of TammHorsfall glycoprotein to promote heterotypic aggregation. J Clin
Invest 1993; 92: 2975-2983
3. Sanders PW, Booker BB. Pathobiology of cast nephropathy
from human Bence Jones proteins. J Clin Invest 1992; 89:
630-639
4. Thomas DBL, Davies M, Williams JD. Release of gelatinase
and superoxide from human mononuclear phagocytes in
response to particulate Tamm-Horsfall protein. Am J Pathol
1993; 142: 249-260
5. Jonson WJ, Kyle RA, Pineda AA, O'Brien PC, Holley KE.
Treatment of renal failure associated with multiple myeloma.
Plasmapheresis, hemodialysis and chemotherapy. Arch Intern
Med 1990; 150: 863-869
6. Alexanian R, Dimopoulos MA. Management of multiple myeloma. Sent Hematology 1995; 32: 20-30
7. Fermand JP, Chevret S, Ravaud P, Divine M, Leblond V,
Dreyfus F, Mariette X, Brouet JC. High-dose chemoradiotherapy and autologous blood-stem cell transplantation in multiple
myeloma: Results of a phase II trial involving 63 patients. Blood
1993; 82: 2005-2009
Non-invasive circulating indicators of bone metabolism in uraemic
patients: can they replace bone biopsy?
H. Schmidt-Gayk1, T. Driieke2 and E. Ritz3
'Endocrine Laboratory, Laboratory Group, Heidelberg, Germany; 2INSERM Unit 90, Nephrology Department,
Necker Hospital, Paris, France; 'Department of Internal Medicine, University of Heidelberg, Germany
Key words: bone biopsy; PTH; aluminium; adynamic
bone disease; bone-specific alkaline phosphatase; osteocalcin; procollagen type I C-terminal; propeptide; tartrate-resistant acid phosphatase; type I collagen crosslinked telopeptide; pyridinolines (cross-links, XL); pyridinolines (PYD, free and total); deoxypyridinoline;
pyridinium cross-links
felt by most workers that the diagnosis of hyperparathyroid bone disease could be established with sufficient
reliability by a combination of X-rays of the hands,
the skull and the long bones, serum alkaline phosphatase (AP), and plasma parathyroid hormone (PTH).
The interest in bone biopsy was revived by the aluminium tragedy, as the extent of aluminium deposition
and toxicity in bone cannot be deduced simply from
plasma aluminium levels. With improved dialysis water
Introduction
treatment and the substitution of aluminium by calcium-containing phosphate binders it appeared that
Bone biopsy was indispensable in the early years of bone biopsies are unnecessary in most patients with
dialysis treatment, but in the following decades it was chronic renal failure (CRF) if adequate treatment is
provided and the serum chemistry (calcium, phosphate,
Correspondence and offprint requests to: H. Schmidt-Gayk, MD,
Endocrine Laboratory, Laboratory Group, Im Breitspiel 15, creatinine, AP, 25-hydroxyvitamin D, and PTH levels)
is adequately monitored. The introduction of plasma
D-69126 Heidelberg, Germany
416
intact PTH measurement was a major breakthrough
in the non-invasive diagnosis of osteitis fibrosa.
The situation, however, has changed again—the only
constant is change! We had to learn that there is no
simple relationship even between intact PTH concentration and bone histology. Bone turnover is altered
in renal failure due to many factors, and the end-organ
responsiveness of bone to PTH and other bonetargeted agents varies considerably from patient to
patient with CRF. Thus, 'normal' intact PTH plasma
values are not normal for uraemic patients since values
in the normal range generally are associated with low
bone turnover (so-called adynamic bone disease)
whereas normal bone turnover may be observed in the
presence of elevated plasma intact PTH levels (up to
200 pg/ml or 20 pmol/1 or even higher, for a normal
range between 10 and 65 pg/ml). It is currently unclear
to what extent this is due to changes in the PTH
receptor state, post-receptor events, non-PTH-mediated changes in bone metabolism, or a combination of
these factors. Therefore it is probably not sufficiently
safe to rely solely on intact PTH measurements when
assessing the indication for, and necessity of, pharmacological intervention to control hyperparathyroidism,
e.g. administration of calcitriol or alphacalcidol. It
should be noted in passing that for correct results the
stability of intact PTH is much better in EDTA plasma
than in serum.
What indicators of bone metabolism are available?
Schematically, the circulating indicators that can be
measured in the blood can be subdivided into two
major categories reflecting bone formation or resorption. The rate of formation or degradation of the bone
matrix can be assessed either by measuring prominent
enzymes of the bone-forming or bone-resorbing cells,
such as alkaline or acid phosphatases, or by measuring
bone matrix components released into the circulation
during formation or resorption, as shown in Table 1.
Circulating markers of bone formation
Total alkaline phosphatase (AP) and bone-specific
AP (BAP)
AP is the most commonly used marker of bone formation, but it lacks sensitivity and specificity, as in normal
adults about half of its activity is derived from bone
and the other half from liver. In addition, contributions
to total AP activity may be made from the intestine,
the kidney, and in some cases the placenta or certain
tumours. In uraemia the relative contributions of
osseous, hepatic, and intestinal isoenzymes are altered
because of changes in their respective half-lives.
Furthermore it is not possible to quantify exactly the
relative contributions of these various tissue sources to
serum AP activity. Because the protein structure of
many of the various forms of AP is similar, if not
identical, biochemical procedures designed to differentiate the bone alkaline phosphatase (BAP) from other
NephrolDial Transplant(\996)
11: Editorial Comments
forms of alkaline phosphatase have not been technically convenient or clinically reliable. This is not surprising because the distinguishing characteristics of BAP
are due primarily to its post-translational modification
by bone cells.
In diseases with significant skeletal involvement, e.g.
Paget's disease, AP remains a clinically useful parameter. It is remarkably constant from hour to hour
and from day to day. Increases or decreases of AP are
therefore important for monitoring patients over
extended time periods. Thus women may have a normal
activity of AP before the menopause and an increase
of 30-60% after the menopause, even though these
values still remain in the normal range [1]. We found
a normal range of AP in premenopausal women of
52-138 U/l and of 67-174 U/l in postmenopausal
women. This probably reflects repair mechanisms after
increased bone resorption. In a preliminary evaluation
of postmenopausal women on haemodialysis therapy
we found a mean AP of 110 U/l in oestrogensubstituted and 160 U/l in non-substituted women. An
AP in the upper quartile of the normal range should
alert the physician, and if no other cause is obvious,
AP determination should be completed by BAP
measurement.
High serum levels of BAP are often observed in
patients after kidney transplantation, in case they
receive cyclosporin A [2]. It was found that low levels
of AP and especially BAP may be helpful to detect so
called adynamic bone disease, if used in conjunction
with intact parathyroid hormone (PTH) levels [3,4].
An intact PTH less than three- to fourfold above
normal combined with a low or low-normal BAP is
suggestive of adynamic bone disease. The latter may
also occur during prolonged, aggressive treatment
of severe hyperparathyroidism with active vitamin
D derivatives, due to a suppression of osteoblastic
activity.
BAP may be measured by immunoradiometric assay,
enzyme-linked immunosorbent assay, or wheat germ
lectin precipitation methods. All three methods should
be used with caution if hepatic sources of AP are
suspected as in case of hepatitis. Because of some
cross-reactions of the antibodies between osseous and
hepatic isoenzymes, the immunolgical methods tend to
somewhat overestimate the osseous isoenzyme, particularly at low levels.
Osteocalcin (OC) or Bone Gla Protein (BGP)
BGP is considered to be inferior to BAP by some
authors at least in the field of osteoporosis, as it
increases less in women after the menopause compared
with BAP. It also increases less than BAP in patients
after kidney transplantation. It is degraded rapidly at
room temperature, whereas AP and BAP (and the
formation marker PICP) are stable for 24 h at room
temperature. In contrast to BAP, BGP in serum
increases also during bedrest (increased bone resorption), as it is released not only from osteoblasts but
also from bone matrix. Conflicting results have been
NephrolDial Transplant(\996) 11: Editorial Comments
417
Table 1. Circulating markers of bone formation and resorption
Formation
Resorption
Alkaline phosphatase (AP)
Bone-specific AP (BAP)
Osteocalcin (OC, BGP)
Procollagen type I C-terminal
Propeptide (PICP)
Tartrate-resistant acid phosphatase (TRAP)
Type I collagen cross-linked telopeptide (ICTP)
Pyridinolines (Cross-links, XL)
Pyridinoline (PYD, free and total)
Deoxypyridinoline (DPD, free and total)
reported as to the value of BGP in CRF patients since
BGP degradation products accumulate with decreasing
renal function. However, various BGP fragments,
including intact BGP, are currently evaluated and may
be useful as serum markers in CRF. Since BGP is
relatively unstable, an optimal conservation of blood
samples is mandatory.
ponents from bone undergoing resorption constitutes
the main source of both cross-links in serum. PYD has
a wider tissue distribution, it is found in bone, cartilage
and tendon. DPD is specific for bone degradation.
Pyridinium cross-links occur in free form (free PYD
and free DPD) and in peptide form. The free form can
be measured by ELISA technique or radioimmunoassay, the peptide-bound and the free form by HPLC
after acid hydrolysis (total PYD and total DPD).
Procollagen type I C-terminal propeptide (PICP)
The measurement of pyridinium cross-links was
As PICP is not cleared from the circulation by the introduced in urine samples. In serum, the concentrakidney but via the mannose-6-phosphate receptor in tions of these compounds were initially below the
the liver, it has been hypothesized that it could be an detection limit. We recently found a marked increase
interesting marker of bone formation in patients with of serum free PYD in chronic haemodialysis patients
CRF. However, PICP is not as sensitive as BAP, since compared with normal subjects, and higher values in
PICP increases little if at all after the menopause. In patients with osteitis fibrosa than in those with normal
patients with osteomalacia, PICP increases less com- or low bone turnover [6]. We also found a good
pared to AP. In haemodialysis patients with aluminium correlation with bone resorption parameters, based on
overload, serum AP and osteocalcin were significantly bone biopsy findings [7].
decreased, whereas serum PICP remained unchanged
As the free form shows larger variability from person
compared with a non-aluminium-overloaded group [5].
to person and increases less than the peptide-bound
PYD and DPD in many diseases with increased bone
resorption, total PYD and total DPD may offer even
Circulating markers of bone resorption
better correlations with resorption parameters.
Recently
an HPLC method was established for the
Tartrate-resistant acid phosphatase (TRAP)
determination of total PYD and total DPD in serum
The enzymatic activity of acid phosphatase associated and both correlated strongly with intact PTH, BGP
with osteoclasts must be distinguished from that of and BAP (total DPD yielded the highest coefficients
other sources, notably prostate, pancreas, and blood of correlation [8]).
cells. This is usually accomplished by determining its
mobility on acrylamide gel and by noting the resistance
of its activity to tartrate. Thus, bone acid phosphatase Conclusion
is usually referred to as tartrate-resistant acid phosphatase (TRAP). However, the specificity of TRAP is Currently bone alkaline phosphatase (BAP) is the best
doubtful. In the future, immunoassays for bone acid method for evaluating bone formation in the patient
phosphatase might offer increased specificity. Plasma with CRF or after kidney transplantation. Several
is preferred for the determination of TRAP, as the studies showed correlations between bone histology
release of platelet acid phosphatase during the clotting and BAP, a finding that is not too surprising. It is
process reduces its specificity.
plausible, but needs confirmation, whether BAP is
sensitive enough to detect dissociation between intact
PTH levels in the slightly supranormal range of bone
Type I collagen cross-linked telopeptide (ICTP)
turnover. This could really make it a suitable tool to
Serum ICTP is of limited sensitivity. It increases only target therapy with active vitamin D metabolites.
marginally after the menopause and also responds Serum pyridinolines are promising markers of bone
poorly to hormone replacement therapy after the resorption in patients with CRF.
menopause. ICTP accumulates in CRF, as its eliminaIt must be kept in mind that if both circulating
tion rate depends on the GFR.
markers of bone turnover and bone biopsy are useful
to evaluate bone remodelling, they may not always
Pyridinium crosslinks
provide the same information. Circulating bone
Bone collagen contains both pyridinoline (PYD) and markers theoretically are an index of the turnover of
deoxypyridinoline (DPD), and release of these com- the whole skeleton. The information provided by a
NephrolDial Transplant(l996) 11: Editorial Comments
418
bone biopsy is also expected to represent the whole
skeleton but sometimes it may reflect only regional
changes. Therefore studies comparing the two techniques—and maybe other non-invasive methods—are
urgently needed to define the clinical usefulness of
circulating bone markers in an appropriate manner.
Outlook
An immunoassay for the tartrate-resistant acid phosphatase (TRAP) in serum should be a very promising
tool for the quantitation of bone resorption, since it
reflects the enzymatic activity of the osteoclasts. By
combining TRAP with serum pyridinolines, one may
be able to monitor osteoclastic activity and efficiency.
2.
3.
4.
5.
6.
7.
References
8.
1. Kushida K, Takahashi M, Kawana K, Inoue T. Comparison of
markers for bone formation and resorption in premenopausal
and postmenopausal subjects, and osteoporosis patients. J Clin
Endocrinol Metab 1995; 80: 2447-2450
Withold W, Degenhardt S, Castelli D, Heins M, Grabensee B.
Monitoring of osteoblast activity with an immunoradiometric
assay for determination of bone alkaline phosphatase mass
concentration in patients receiving renal transplants. Clin Chim
Ada 1994; 225: 137-146
Couttenye MM, de Broe ME. Low bone alkaline phosphatase:
a sensitive, specific marker for adynamic bone disease in dialysis
patients. Nieren Hochdruckkr 1995; 24: 380-383
Salusky IB, Ramirez JA, Oppenheim W, Gales B, Segre GV,
Goodman WG. Biochemical markers of renal osteodystrophy
in pediatric patients undergoing CAPD/CCPD. Kidney Int 1994;
45: 253-258
Hamdy NAT, Risteli J, Risteli L el al. Serum type I procollagen
peptide: a non-invasive index of bone formation in patients on
haemodialysis? Nephrol Dial Transplant 1994; 9: 511-516
Ferreira A, Ure-a P, Ang KS el al. Relationship between serum
fS2-microglobulin, bone histology and dialysis membranes in
uraemic patients. Nephrol Dial Transplant 1995; 10: 1701-1707
Urena P, Ferreira A, Kung VT el al. Serum pyridinoline as a
specific marker of collagen breakdown and bone metabolism in
hemodialysis patients. J Bone Miner Res 1995; 10: 932-939
Niwa T, Shiobara K, Hamada T et al. Serum pyridinolines as
specific markers of bone resorption in haemodialyzed patients.
Clin Chim Acta 1995; 235: 33-40
Left ventricular hypertrophy in the dialysed patient. What can be done
about it?
G. Cannella
Divisione di Nefrologia e Dialisi, Ospedale San Martino, Genova, Italy
This paper is dedicated to the memory of Professor
Arturo Borsatti MD, Scientist and Nephrologist, Dean
of the Faculty School of Medicine, University of
Padua, who recently passed away, leaving his many
friends in great sadness.
The causes and patterns of left ventricular
hypertrophy (LVH)
Left ventricular hypertrophy (LVH) is considered to
be a compensatory response of the left ventricle (LV)
to increased haemodynamic load. It may exceed its
adaptive objective, however, and become a LV disease
in itself [1].
The stimulus for LVH is haemodynamic overload.
Translation of a mechanical stimulus into a growth
signal for ventricular cells involves activation of the
local renin-angiotensin system and of poorly characterized growth-promoting substances originating from the
interaction between circulating cells and endothelial
cells activated by stress and strain [2]. Endocrine
factors may modulate or amplify such paracrine
response, e.g. aldosterone, insulin, growth hormone,
testosterone, parathyroid hormone, circulating catecholamines [1,2]. The pattern of cardiac hypertrophy is
determined by the type of overload: an increase in LV
preload induces myocyte elongation, causing an
increase of intracavitary LV volume (eccentric hypertrophy), whereas an increase in afterload induces lateral expansion of myocytes with increased myocyte
volume as well as proliferation of fibroblasts causing
an increase of myocardial LV wall thickness (concentric
hypertrophy) [1,3]. Both types of hypertrophy are
reversible; this was observed after reconstructive surgery of regurgitating mitral and aortic valves in cases
with eccentric LVH and following prolonged antihypertensive therapy in cases with concentric LVH.
Left ventricular hypertrophy in the patient with
chronic renal failure
In studies using echocardiography the frequency of
LVH in haemodialysed patients is reported to range
from 60 to 70% [4]. A major concern with this type
of cardiac abnormality is its seemingly relentless progression,
since it tends to increase in subjects whose
Correspondence and offprint requests to: Giuseppe Cannella MD,
Divisione di Nefrologia e Dialisi M9, Ospedale San Martino, Viale left ventricular mass (LVM) is already elevated and to
Benedetto XV, 10, 16132, Genova, Italy.
develop de novo in those whose LVM is normal [4].