Nephrol Dial Transplant (2013) 28: 1061–1064
doi: 10.1093/ndt/gft094
In Focus
Spleen IL-10, a key player in obesity-driven renal risk
CNR-IBIM & Nephrology, Dialysis and Transplantation Unit of
Belinda Spoto
Reggio Calabria, Reggio Calabria, Italy
and Carmine Zoccali
Correspondence and offprint requests to:
Carmine Zoccali; E-mail: [email protected]
Obesity is now a well-recognized risk factor for the development and progression of chronic kidney disease (CKD) [1].
Several mechanisms may promote CKD in obese individuals
[2]. First and foremost, adiposity is strongly associated with
diabetes and hypertension which are two leading causes of
CKD. Second, excessive fat mass per se may induce podocyte
injury, mesangial expansion, glomerulomegaly, glomerulosclerosis and a clinical phenotype characterized by hyperfiltration and albuminuria [3].
Derangement in molecular mediators of inflammation triggered by nutrient excess appears to be the final, common
pathway conducive to CKD [4]. The inflammatory process
induced by obesity involves many components of innate immunity and includes a systemic increase in circulating inflammatory cytokines (i.e. TNF-α and IL-6), acute phase proteins
(i.e. C-reactive protein), leukocytes recruitment and generation
of cellular repair processes. Large-scale studies of gene
expression in adipose tissue identified a wide range of overexpressed inflammatory genes in obesity [5, 6], which suggests a
major role for adipose tissue in the mechanism(s) underlying
the activation of proinflammatory pathways. Overfeeding triggers inflammation and amplifies the inflammatory response
by several mechanisms including down-regulation of antiinflammatory pathways [7]. Adipose tissue adapts to nutrient
excess by hyperplasia of preadipocytes and hypertrophy of
mature adipocytes and fat sequestration in these cells serves to
prevent harmful ectopic lipid deposition. However, this is an
inherently limited process because excess of triglycerides in
adipocytes activates lipolysis and releases free fatty acids
(FFAs) into the circulation. FFAs are potent activators of Tolllike receptors [8], key molecules in the innate immune
response. In addition, the blood supply to adipose tissue
becomes insufficient to guarantee adequate oxygen delivery to
hypertrophic adipocytes which eventuates in cell necrosis. As
a response to hypoxia and cell necrosis, the adipose tissue is
infiltrated by macrophages which generate a positive paracrine
© The Author 2013. Published by Oxford University Press on behalf of ERAEDTA. All rights reserved.
loop that amplifies and perpetuates inflammation [9]. Adipokines have a special role in obesity. With their dual nature of
‘metabolic’ and ‘immunological’ regulators, they constitute the
remote signal that turns a localized inflammatory process into
a systemic phenomenon leading to obesity-related comorbidities. Importantly, adipokines can incite inflammatory changes
in the kidney as documented by an up-regulation of inflammatory genes (TNF-α and its receptors, IL-6 and interferon-γ) in
glomeruli of patients with obesity-related nephropathy [10].
Unlike TNF-α, which functions predominantly in a paracrine/
autocrine manner in adipose tissue, IL-6 may exert effects in
distant organs. Plasma levels of IL-6 are increased in obesity
and as much as 20% of circulating IL-6 derives from adipose
tissue [11]. In the kidney, IL-6 promotes the expression of
adhesion molecules and generates oxidative stress species in all
cell lines including epithelial, mesangial and endothelial cells.
Leptin, a fundamental adipose tissue hormone that modulates appetite and energy expenditure, has structural and functional resemblance to proinflammatory cytokines and exerts
proinflammatory activities through its interaction with
mediators of innate and adaptive immunity. Of note, receptors
for leptin are well expressed in the kidney [12]. In mesangial
cells, leptin stimulates cellular proliferation and expression of
the prosclerotic cytokine TGF-β1 leading to glomerulosclerosis [13]. Conversely, adiponectin (ADPN), another adipocytederived hormone with insulin-sensitizing and anti-atherogenic
properties, shows anti-inflammatory activity. ADPN-knockout
mice exhibit effacement and fusion of podocyte foot processes
as well as increased albuminuria [14]. Administration of
exogenous ADPN to ADPN-null mice leads to normalization
of albuminuria and improvement in podocyte morphology
[14]. The protective effects of ADPN in the kidney extend to
endothelial cells where this adipokine displays anti-inflammatory properties by inhibition of nuclear factor-kB (NF-kB) and
suppression of adhesion molecules expression (i.e. VCAM-1,
ICAM-1) [15].
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IN FOCUS
F I G U R E 1 : The spleen-derived IL-10 inhibits (red arrow) the production of proinflammatory cytokines by suppressing the NF-kB activation
both in macrophages and in adipocytes. In the hypertrophied adipocyte, cell enlargement per se induces (green arrow) the NF-kB activation
which promotes the secretion of adipokines and cytokines that, via renal receptors, trigger mesangial cell proliferation, glomerular hypertrophy,
expression of prosclerotic cytokines and glomerulosclerosis. IL-10 prevents renal injury both directly, reducing inflammation in renal cells and
indirectly, attenuating the release of molecules inciting renal cell proliferation and fibrosis.
Many, if not all, proinflammatory cytokines are counterbalanced by anti-inflammatory cytokines and a defective regulation of these protective molecules may per se engender
inflammation. The role of anti-inflammatory cytokines in
obesity has been very little investigated. IL-10, a cytokine with
pleiotropic effects, is a major inhibitor of TNF-α, IL-1 and IL6 [16] and down-regulates the production of chemokines including IL-8 [17] (Figure 1). It also suppresses the NF-kB activation (Figure 1) by binding to a heterodimer receptor
complex that inhibits the NF-kB nuclear translocation and
contributes to regulate the Janus kinases/signal transducers
and activators of the transcription (JAK-STAT) signalling
pathway [18]. In rodents and humans as well, obesity is independently associated with high IL-10, a phenomenon aimed at
limiting the effects of chronic inflammation by adiposity
excess. Interestingly, obese individuals with type 2 diabetes
have significantly lower IL-10 plasma levels when compared
with obese subjects unaffected by this metabolic alteration
[19], suggesting that a low IL-10 production may contribute to
metabolic derangements. Low circulating IL-10 has been
associated with a variety of adverse clinical outcomes including type 2 diabetes, atherosclerosis, stroke and endothelial dysfunction [19–21]. With respect to the kidney, IL-10 reduces
inflammation and mesangial cell proliferation in acute glomerulonephritis [22] and suppresses glomerulosclerosis and interstitial fibrosis in the remnant kidney model [23]. In this
model, IL-10 suppresses the local inflammatory response via
inhibition of monocyte chemoattractant protein-1 synthesis in
macrophages. Recently, an important crosstalk between spleen
and adipose tissue has been described [24] and spleen-derived
IL-10 seems to have a central role in this crosstalk. Indeed,
obesity suppresses IL-10 synthesis both in the spleen and at
the systemic level and this effect accounts at least in part for
obesity-related inflammation [24].
Based on these interesting experimental observations,
Gotoh et al. [25] hypothesized that spleen-derived IL-10 may
have a protective role in the inflammatory response induced
by obesity in CKD and in this issue of Nephrology Dialysis and
Transplantation, they test the hypothesis in various models in
the mouse. For the first time, they show that proinflammatory
(TNF-α, IL-1B, MCP-1) and anti-inflammatory cytokines (IL4, IL-13, IL-10) in the spleen of mice on a high-fat diet (HF)
are lower than in mice on a standard diet (control). In contrast
to measurements in the spleen, in measurements made in the
serum only IL-10 is significantly lower in HF mice than in
controls, clearly suggesting that the spleen is the major biological source of this molecule. Remarkably, both serum cystatin C
and systolic blood pressure are higher in mice with splenectomy (SPX) than in sham-treated mice. Consistent with these
functional alterations, renal histology in the SPX mice shows
glomerular hypertrophy, fibrosis, hyperplasia of mesangial
cells and podocyte injury. SPX prompts macrophage infiltration at glomerular and tubular levels as well as increased local
synthesis of proinflammatory cytokines accompanied by a
reduced secretion of IL-10. Furthermore, fatty diet-induced
kidney damage closely resembles that observed in SPX mice.
Of note, the structural and functional renal alterations are
even more marked in mice on high-fat diet with splenectomy
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B. Spoto and C. Zoccali
C O N F L I C T O F I N T E R E S T S TAT E M E N T
None declared
(See related article by Gotoh et al. Obesity-related chronic
kidney disease is associated with spleen-derived IL-10.
Nephrol Dial Transplant 2013; 28: 1120–1130.)
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(HF + SPX) than in those with intact spleen, once again pointing to the anti-inflammatory action of the spleen on kidney
injury. In these experiments, the prominent role of spleenderived IL-10 in systemic inflammation is also suggested by
the fact that the reduction in circulating IL-10 is proportionally more pronounced than the derangements in proinflammatory cytokines and by the fact that SPX potentiates the
proinflammatory component. In the Gotoh study, the causal
role of low IL-10 is documented by the observation that IL-10
administration ameliorates structural and functional alterations in the kidney both in HF and HF + SPX mice. Finally,
the IL-10 knock out mouse exhibits renal damage very similar
to that induced by SPX.
These intriguing, coherent results are consistent with a protective role for spleen-derived IL-10 on the effect of obesityrelated inflammation on the kidney. Evidence of the potential
reversibility of the renal effects of low IL-10 generates the
hypothesis that raising the levels of this cytokine may benefit
obesity-related CKD. However, IL-10 is a pluripotent cytokine
with effects on numerous cell populations and with a contextdependent action, i.e. under some conditions it may also incite
rather than attenuate inflammation [26]. This phenomenon
should be carefully considered when this molecule is tested in
clinical trials. Placebo-controlled double-blind trials in inflammatory bowel disease and rheumatoid arthritis showed that
the effectiveness of IL-10 treatment is lower than that of antiTNF-α antibodies and that a complete disease resolution after
IL-10 administration is usually a rare event [27]. Thus,
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molecular mechanisms of IL-10-mediated effects, it would be
interesting to evaluate in man whether improvement in albuminuria and favourable GFR changes after weight loss go
along with increasing levels of IL-10. The question is of importance because in mice with diet-induced obesity, a decrease in
body weight ameliorates the inflammation via processes
driven by IL-10 while, in the same animal model, it remains
still unknown whether weight loss translates into renal damage
regression. The issue should not be lightly taken because not
only weight loss but also the type of diet intervention may
have a dramatic effect on renal damage incited by obesity [28].
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Received for publication: 30.1.2013; Accepted in revised form: 12.3.2013
Nephrol Dial Transplant (2013) 28: 1064–1067
doi: 10.1093/ndt/gfs332
Advance Access publication 9 October 2012
IN FOCUS
Biomarkers for acute kidney injury: combining the new silver
with the old gold
1
Etienne Macedo1
Division of Nephrology, University of São Paulo, São Paulo, SP,
Brazil and
and Ravindra L. Mehta2
2
Division of Nephrology, School of Medicine, University of
California, San Diego, CA, USA
Correspondence and offprint requests to: Ravindra
L. Mehta; E-mail: [email protected]
Over the last decade, the pursuit for drugs to prevent or treat
acute kidney injury (AKI) has been replaced by a search for
novel biomarkers of kidney damage. Prompted by expert
opinion that lack of sensitive and specific biomarkers has
thwarted progress in the field, several new biomarkers have
emerged and are jockeying to become the ‘golden’ test for
AKI. As clinical experience with these biomarkers accumulates, it is increasingly evident that no single biomarker will
likely take the crown. There is a slow realization that the consistent emphasis on the weakness and limitations of existing
markers may be misguided. In fact, there may be several opportunities to reevaluate existing techniques in combination
with newer biomarkers for managing patients with AKI.
Urine microscopy has long been considered to be a
window to the kidney; however, its clinical value was questioned after publications suggested that urinalysis was not
helpful in discriminating between functional and intrinsic
renal disorders, especially in sepsis [1–3]. Nevertheless, there
has been a recent resurgence in interest in urine microscopy
as a tool to characterize AKI spurred by data from two groups.
© The Author 2012. Published by Oxford University Press on
behalf of ERA-EDTA. All rights reserved.
Chawla et al. [4] developed an AKI cast scoring index to standardize urine sediment analysis and were able to show good
precision of the index to detect acute tubular necrosis (ATN).
In that study, urine sediment also correlated with outcomes in
patients with ATN. Renal recovery was worse in patients with
a higher cast scoring index (2.55 ± 0.9 versus 1.7 ± 0.79;
P = 0.04), and the area under the receiver operating characteristic (ROC) curve of the cast scoring index for the prediction
of non-renal recovery was 0.79. Perazella et al. [5] proposed a
different scoring system for differentiating ATN from decreased kidney perfusion in AKI ( pre-renal AKI). Using final
AKI diagnosis at discharge as the gold standard, urinary
microscopy on the day of nephrology consultation was highly
predictive of ATN. The odds ratio for ATN incrementally increased with a higher score. In patients with an initial diagnosis of ATN, any granular casts or renal epithelial tubular cells
(corresponding to a score of 2) resulted in a positive predictive
value of 100% and a negative predictive value of 44%. Lack of
renal epithelial tubular cells or granular casts in patients with
an initial diagnosis of decreased kidney perfusion (functional
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