Nephrol Dial Transplant (2003) 18: Editorial Comments

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Nephrol Dial Transplant (2003) 18: 24712474

DOI: 10.1093/ndt/gfg427

After all those fat years: renal consequences of obesity

Gunter Wolf
Department of Medicine, Division of Nephrology, Rheumatology and Osteology, University of Hamburg,
Hamburg, Germany

Keywords: adipocyte; diabetes type 2; hypertension;

leptin; obesity; progression of renal disease

proteinuria after only moderate weight loss [7]. A

problem with all these studies is the fact that confounding factors such as hypertension were not totally
ruled out.

Our genetic background and physiological homeostasis, orchestrated through endocrine and neuronal
networks, are optimized for a world with intermittent
food supply and permit us to survive periods of
starvation [1]. However, these systems are counterproductive in our current industrial society with fast-food
restaurants, an abundance of high energy food and an
increasingly sedentary life-style. The consequence is an
alarming increase in obese adults and, even more
disturbing, of overweight children [1]. The consequences of obesity such as the metabolic syndrome
with its ultimate development of type 2 diabetes
mellitus, cardiovascular diseases, an increased incidence of certain types of cancer, musculoskeletal
disorders and pulmonary diseases are well known.
What about renal diseases? Almost 30 years ago,
Weisinger et al. [2] described focal-segmental glomerulosclerosis with nephrotic syndrome in four extremely
obese patients. Only two of them exhibited hypertension by ofce blood pressure measurements [2]. In
the following years, several case reports describing
glomerulosclerosis in very obese patients have been
published, but this entity was considered as rare and
rather bizarre. However, a recent study showed a
dramatic increase of histologically proven renal disease
in obese patients in the absence of diabetes [3]. The
patients had rapidly progressive renal disease [4].
Furthermore, obesity is an important risk factor for
the progression of renal disease in IgA nephropathy [5],
and is also associated with an enhanced risk of chronic
graft dysfunction after renal transplantation [6].
On the other hand, overweight patients with a body
mass index (BMI) >27 kg/m2 with various chronic
renal diseases experienced a signicant reduction in
Correspondence and offprint requests to: Gunter Wolf, MD,
University of Hamburg, University Hospital Eppendorf,
Department of Medicine, Division of Nephrology, Rheumatology
and Osteology, Pavilion N26, Martinistrae 52, D-20246 Hamburg,
Germany. Email: Wolf@uke.uni-hamburg.de

Adipose tissue as a source of hormones and

cytokines
Fat cells are much more than a passive store of excess
energy. Adipose tissue is a source of various hormones
that may very well inuence renal function [8,9]. An
incomplete list of these factors is shown in Table 1.
Some of these hormones and growth factors could
reach the kidney and exert their pathophysiological effects [8]. For example, transgenic mice with
angiotensinogen expression restricted to adipose
tissue have increased circulating angiotensinogen, and
the angiotensin II thus generated has renal effects
[10]. Overexpression of angiotensinogen in adipocytes
leads to hypertension [10]. Thus, the adipose tissue
reninangiotensinogen system could exert direct effects
on the kidney. The detrimental effects of continuously
enhanced angiotensin II concentrations on renal function and structure are well appreciated [11]. Although
not the subject of this review, an increase in local
formation of angiotensin II in adipose tissue probably
contributes to the development of insulin resistance and
promotes the metabolic syndrome [12]. Renal effects of
tumour necrosis factor- (TNF-) through the induction of proinammatory cytokines and the
probrogenic role of plasminogen activator inhibitor1 (PAI-1) have been studied in detail. Other factors
such as adiponectin may inhibit some of TNF-s
Table 1. Some hormones, cytokines and growth factors produced
in adipose tissue
Angiotensinogen
Renin
TNF-
Interleukin-6
Leptin
Plasminogen activator inhibitor-1 (PAI-1)
TGF-
Resistin
Adiponectin

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Bigger is not better

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proinammatory effects, but circulating adiponectin

levels are paradoxically lower in obese individuals and
patients with type 2 diabetes [9].

What about leptin?

between glomerular endothelial and mesangial cells

that is mediated by leptin. Leptin-induced TGF- from
endothelial cells could easily reach mesangial cells
where it binds to the leptin-induced upregulated TGF-
type II receptors [18]. The consequence is an increase in
extracellular matrix deposition. To test a potential role
for leptin in vivo, recombinant leptin was infused
with osmotic minipumps into normal rats. Short-term
infusion for 72 h stimulated glomerular TGF-,
expression and increased in parallel the number of
cells expression proliferating cell nuclear antigen
(PCNA). After 3 weeks of leptin infusion into rats,
glomerular expression of type IV collagen was signicantly enhanced compared with pair-fed controls
[19]. Leptin did no inuence blood pressure, but
proteinuria was signicantly enhanced in leptin-infused
animals [19]. These studies provide for the rst time
evidence that leptin exerts pathophysiological effects in
the kidney. However, retrospective measurements of
serum leptin at a single time point did not correlate with
the decline in renal function in non-diabetic patients
from the Modication of Diet in Renal Disease Study
(MDRD [21]).

Obesity and kidney function and structure

Obese patients without diabetes mellitus type 2 exhibit
a signicant increase in glomerular ltration rate (GFR),
compared with controls with normal BMI [22]. This
hyperltration is caused by dilation of the afferent
arteriole [22]. One explanation for these haemodynamic
changes could be an activated glomerulo-tubular
feedback caused by enhanced sodium reabsorption in
the proximal tubule. Leptin, through activation of the
sympathetic nervous system as well as direct effects on
angiotensin II and insulin, could contribute to the
increase in sodium reabsorption. It is intriguing to
speculate that fat tissue may contribute to the increase
in angiotensin II that enhances sodium transport.
Glomerular hyperltration is a well known pathophysiological link to glomerulosclerosis and proteinuria
[11]. In addition, many animal studies demonstrated
that chronic intravenous or intracerebroventricular
infusion of leptin increases sympathetic activity in
the kidneys and induces hypertension [23]. Fat tissue
completely encapsulates the kidney of obese animals
and increases intrarenal pressure [23]. This mechanism
is similar to the well known wrap kidney model,
originally developed by Grollmann in the 1940s. This
mechanism may increase blood pressure further in
obese individuals [24]. In addition, this observation
may also explain why abdominal obesity correlates
better with hypertension than BMI [23].
In an experimental study in dogs, Henegar et al. [25]
found that a high calorie diet induces within no more
than 7 weeks an increase in mean arterial blood pressure
and GFR. Moreover, histological changes including
glomerular cell proliferation, thickening of glomerular
and tubular basement membranes, increased matrix
expansion and glomerular TGF- expression were

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Leptin, the product of the ob gene, is a satiety factor

produced in adipocytes. It acts on specic receptors
localized in the hypothalamus and inuences other
neurohormones [13]. Leptin suppresses food intake
by inhibiting neuropeptide Y and by increasing
melanocyte-stimulating hormone (MSH), and decreasing agouti-related peptide, an antagonist of MSH at the
MC4 receptor [14]. Interestingly, an experimentally
induced disruption of the MSH system induces saltsensitive hypertension, indicating a central role for these
peptides in blood pressure regulation [15]. Leptin
centrally stimulates sympathetic nerve action; transgenic mice overexpressing leptin are hypertensive and
have elevated urinary catecholamine excretion [16].
However, despite high circulating leptin concentrations,
obese individuals are characterized by a relative leptin
resistance [17]. The molecular mechanisms of this leptin
resistance are subject to active current research and may
be heterogeneous. As a small peptide hormone, leptin is
cleared by the kidney [14,18]. Consequently, patients
with impaired renal function have high circulating
leptin concentrations.
Mice with a decient leptin gene (ob/ob) as well as
animals with a defect for the long leptin receptor (db/db)
are both obese and develop type 2 diabetes. However,
only db/db mice with high circulating leptin concentrations show histological changes reminiscent of diabetic
nephropathy, whereas the kidneys of ob/ob mice appear
relatively normal [18]. This provided the impetus for us
to study whether leptin could have direct renal effects
[18]. Leptin stimulates the proliferation of cultured rat
glomerular endothelial cells [19]. Angiotensin II and
leptin have additive proliferative effects on glomerular
endothelial cells [19]. This proliferation is cell type
specic because mesangial cells failed to replicate in the
presence of leptin [19]. Glomerular endothelial cells
express the short leptin receptor previously thought
to act solely as a clearance receptor without signal
transduction. However, leptin induces STAT1 phosphorylation, suggesting active signal transduction,
but further studies are necessary to dene whether
the signals are indeed mediated through the short
leptin receptor [19]. Moreover, leptin induces mRNA
expression and protein secretion of transforming growth
factor- (TGF-) in glomerular endothelial cells [19].
Leptin increases the expression of TGF- type II
receptors on mesangial cells from the rat and from
db/db mice, suggesting that the long leptin receptor is
not necessary for this effect [20]. In addition, exogenous
leptin increases cellular glucose uptake and enhanced
type I collagen synthesis [20]. The addition of both
TGF- and leptin increases mesangial cell type I
collagen secretion more than either stimulus alone
[20]. These ndings suggest a paracrine TGF- pathway

Nephrol Dial Transplant (2003) 18: Editorial Comments

Nephrol Dial Transplant (2003) 18: Editorial Comments

present [25]. These structural ndings are similar to

those reported by us in leptin-infused rats [19].

What could be done?

Conclusion
Although the incidence of obesity-related glomerulosclerosis is increasing, which carries a poor renal
prognosis, overweight is probably more important as
a progression factor in patients with known primary
chronic renal diseases. Certainly, more research is
needed to understand better how obesity inuences
renal function. The adipocyte is a source of several
hormones, including leptin, that may have detrimental
effects on the kidney, indicating that fat tissue itself
could be a major culprit. Our genetic hardwiring
with neuronalhormonal loops mainly fostering energy
conservation served our ancestors in times of starvation
well, but poses a major problem for successful weight
reduction. Nevertheless, structured weight reduction
and control programmes may help to overcome this
difculty. Good luck!
Acknowledgements. Many of the views expressed in this article were
developed together with my friend and colleague Fuad N. Ziyadeh,
MD, University of Pennsylvania, Philadelphia, USA.
Conict of interest statement. None declared.

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3. Kambham N, Markowitz GS, Valeri Am, Lin J, DAgati VD.
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4. Praga M, Hernandez E, Morales E et al. Clinical features and
long-term outcome of obesity-associated focal segmental glomerulosclerosis. Nephrol Dial Transplant 2001; 16: 17901798
5. Bonnet F, Deprele C, Sassolas A et al. Excessive body weight
as a new independent risk factor for clinical and pathological
progression in primary IgA nephritis. Am J Kidney Dis 2001;
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6. Meier-Krische HU, Arndorfer JA, Kaplan B. The impact of
body mass index on renal transplant outcomes: a signicant
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7. Morales E, Valero A, Leon M, Hernandez E, Praga M.
Benecial effects of weight loss in overweight patients with
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8. Wiecek A, Kokot F, Chudek J, Adamczak M. The adipose
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9. Zoccali C, Mallamaci F, Tripepi G. Adipose tissue as a source
of inammatory cytokines in health and disease: focus on endstage renal disease. Kidney Int 2003; 63 [Suppl 84]: S65S68
10. Massiera F, Bloch-Faure M, Ceiler D et al. Adipose angiotensinogen is involved in adipose tissue growth and blood
pressure regulation. FASEB J 2001; 15: 27272729
11. Wolf G, Butzmann U, Wenzel UO. The reninangiotensin
system and progression of renal disease: from hemodynamics to
cell biology. Nephron Physiol 2003; 93: 313
12. Engeli S, Schling P, Gorzelniak K et al. The adipose-tissuereninangiotensinaldosterone system: role in the metabolic
syndrome? Int J Biochem Cell Biol 2003; 35: 807825
13. Cummings DE, Schwartz MW. Genetics and pathophysiology
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14. Stenvinkel P, Lonnqvist F, Schalling M. Molecular studies of
leptin: implications for renal disease. Nephrol Dial Transplant
1999; 14: 11031112
15. Ni XP, Pearce D, Butler AA, Cone RD, Humphreys MH.
Genetic disruption of -melanocyte-stimulating hormone
signaling leads to salt-sensitive hypertension in the mouse. J
Clin Invest 2003; 111: 12511258
16. Aizawa-Abe M, Ogawa Y, Masuzaki H et al. Pathophysiological
role of leptin in obesity-related hypertension. J Clin Invest 2000;
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17. Sharma K, Considine RV. The Ob protein (leptin) and the
kidney. Kidney Int 1998; 53: 14831487
18. Wolf G, Chen S, Han DC, Ziyadeh FN. Leptin and renal
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19. Wolf G, Hamann A, Han DC et al. Leptin stimulates
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20. Han DC, Isono M, Chen S et al. Leptin stimulates type I
collagen production in db/db mesangial cells: role of increased
glucose uptake and TGF- type II receptor expression. Kidney
Int 2001; 59: 13151323
21. Sarnak MJ, Poindexter A, Wang SR et al. Serum C-reactive
protein and leptin as predictors of kidney disease progression in
the Modication of Diet in Renal Disease Study. Kidney Int
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It is obvious that life-style changes with weight loss

are the key element of any successful therapy of
obesity [26]. However, although it has been shown that
initial successful weight loss is possible with several
structured programmes, only a few patients maintain
their reduced weight [26]. Many clinical diet trials
have shown a high drop-out rate [27]. Treatment
with anti-obesity substances such as orlistat and
sibutramine have modest weight-reducing effects, but
carry the denite risk of side effects [26]. A consistent
effective treatment for hypertension is mandatory.
First line therapies are angiotensin-converting enzyme
(ACE) inhibitors because of the pathophysiological role
of the reninangiotensin system in obesity-mediated
renal changes and hypertension [26]. Some clinical
observations suggest that -blockers are associated
with additional weight gain [26]. Although it is premature to make general recommendations, clinical studies
indicate that acarbose, metformin and ACE inhibitors
may delay development of type 2 diabetes in obese
subjects [28]. Consequently, an interdisciplinary management of type 2 diabetes is necessary to prevent
nephropathy [29]. The family physician needs expert
help for dealing with this important problem.

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22. Chagnac A, Weinstein T, Korzerts A, Ramadan E, Hirsch J,
Gafter U. Glomerular hemodynamics in severe obesity. Am J
Physiol 2000; 278: F817F822
23. Hall JE, Crook ED, Jones DW, Wofford MR, Dubbert PM.
Mechanisms of obesity-associated cardiovascular and renal
disease. Am J Med Sci 2002; 324: 127137
24. Grollmann A. A simplied procedure for inducing chronic
renal hypertension in the mammal. Proc Soc Exp Biol Med
1944; 57: 102104
25. Henegar JR, Bigler SA, Henegar LK, Tyagi SC, Hall
JE. Functional and structural changes in the kidney in
the early stages of obesity. J Am Soc Nephrol 2001; 12: 12111217

Nephrol Dial Transplant (2003) 18: Editorial Comments

26. Pischon T, Sharma AM. Recent developments in the treatment
of obesity-related hypertension. Curr Opin Nephrol Hypertens
2002; 11: 497502
27. Foster GD, Wyatt HR, Hill JO et al. A randomized trial of a
low-carbohydrate diet for obesity. N Engl J Med 2003; 348:
20822090
28. McFarlane SI, Shin JJ, Rundek T, Bigger JT. Prevention of
type 2 diabetes. Curr Diabetes Rep 2003; 3: 235241
29. Wolf G, Ritz E. Diabetic nephropathy in type 2 diabetes
prevention and patient managment. J Am Soc Nephrol 2003;
14: 13961405

Nephrol Dial Transplant (2003) 18: 24742478

DOI: 10.1093/ndt/gfg322

Senescence of renal cells: molecular basis and clinical implications

Division of Nephrology and Immunology, University of Alberta, Edmonton, Canada

Keywords: allograft nephropathy; cellular senescence;

kidney ageing; p16INK4a; renal senescence; telomere

Introduction
Age-associated changes of the kidney are important not
only because normal ageing alters renal function but
also because of the high frequency of end-stage renal
disease in the elderly (ERAEDTA Registry Report
2000). Old kidneys perform poorly when transplanted,
and donor age is a major determinant of graft survival
[1]. It has been proposed that interactions between
ageing and diseases may contribute to these problems.
Understanding the mechanisms of declining organ
function with age may be instructive concerning the
mechanisms of decline in disease states, since stress
might accelerate ageing changes. Kidney ageing is also
of interest as a general model for organ ageing, because
renal function can be assessed with relative ease in
clinical practice and has been quantied in longitudinal
studies [2]. The molecular basis of ageing changes in
organs is not known, but organ ageing may reect
aspects of cellular senescence which are understood
better now than a few years ago.
Here, I will review recent progress in dening the
molecular changes and pathways involved in cellular
senescence, their relative contribution in cells from
different species, in particular human and mouse, and
their relevance to renal ageing and disease.
Correspondence and offprint requests to: Anette Melk, MD, PhD,
Division of Nephrology and Immunology, University of Alberta,
250 Heritage Medical Research Centre, Edmonton, Alberta, T6G
2S2, Canada. Email: anettemelk@yahoo.de

Terms and denitions

Cellular senescence describes a phenotype of permanent and irreversible growth arrest shown by mammalian cells in culture. Originally described in human
broblasts by Hayick and Moorhead [3], this term
was used synonymously with replicative senescence.
However, in recent years, the concept of cellular
senescence has been expanded to include other forms
of permanent, irreversible cell-cycle arrest. The reason
for this extension comes partly from the observation
that mouse embryonic broblasts in culture do not use
replicative senescence to cease replication, but share
other senescence features with human broblasts such
as altered morphology, greater heterogeneity, expression of senescence-associated -galactosidase (SA-GAL) and accumulation of lipofuscin granules. This
had been referred to as premature senescence, stressinduced senescence and most recently stimulation
and stress-induced senescent-like arrest (STASIS) [4].
The term renal senescence reects the structural and
functional phenotype associated with aged kidneys.

The phenotype of renal senescence

The phenotype of human renal senescence can be
described as a phenotype of loss: the loss of mass,
particularly in cortex [5,6], and the loss of function, as
reected by increased renal vascular resistance, reduced
renal plasma ow and increased ltration fraction [6,7].
The glomerular ltration rate (GFR), as described by
multiple equations such as CockcroftGault [8] and
MDRD [9], is not an ideal measurement to assess this
malfunction. Although studies in selected populations
[2,10], excluding all renal diseases, hypertension and

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Anette Melk