Obesity—a neglected culprit in renal disease

Manuel Praga

Servicio de Nefrología, Hospital 12 de Octubre, Madrid, Spain

Keywords: body mass index; focal and segmental glomerulosclerosis; obesity; obesity-related glomerulopathies; renin–angiotensin system; renal disease

Obesity-related glomerulopathies—clinical features and epidemiology

Proteinuria is a recognized complication of morbid obesity, although it develops only in a minority of patients. Renal biopsies and autopsy studies have shown that focal and segmental glomerulosclerosis (FSG) is the commonest histologic lesion in proteinuric obese patients [1]. Obesity-related FSG can be distinguished from idiopathic cases of FSG by glomerulomegaly and by less severe foot process effacement. From a clinical point of view, patients with obesity-related glomerulopathies (ORG) do not develop the nephrotic syndrome (hypoalbuminaemia, oedema) even when there is massive and sustained proteinuria. This clinical characteristic (that is also observed in other renal diseases related to hyperfiltration such as reflux nephropathy or proteinuria related to renal mass reduction) is very useful to distinguish these patients from idiopathic FSG in which a complete nephrotic syndrome usually accompanies the presence of nephrotic-range proteinuria [2]. The reasons why patients with ORG do not develop complete nephrotic syndrome remain unexplained but may relate to differences in the tubular management of filtered proteins and in a very slow proteinuria increase over the years which is characteristic of ORG and other hyperfiltering disorders.

Initial descriptions of ORG suggested a relatively benign clinical course, based on the normal renal function of reported cases and very short periods of follow up. Recently, we have shown, however, that the long-term prognosis of obese patients with biopsy-proven FSG is poor with almost one-half ultimately developing advanced renal failure [3]. These observations are of interest taking into account that a striking increase in the number of patients diagnosed with ORG in the last years has been reported recently. Thus, a retrospective analysis of all native renal biopsies received in the Renal Pathology Laboratory of Columbia University, New York (n=6818), revealed a progressive increase in biopsy incidence of ORG from 0.2% in 1986–2000 to 2% in 1996–2000 [1].

How could obesity induce proteinuria and glomerulosclerosis?

Glomerular hyperfiltration
Studies in obese animals have shown an increased renal blood flow and glomerular filtration rate (GFR), mediated by vasodilation of the afferent arterioles [4]. The cause of these haemodynamic changes could be related to an increased salt reabsorption in the loop of Henle. The elevated salt reabsorption at a segment proximal to the macula densa would induce a rise in GFR through tubuloglomerular feedback, in addition to shifting the pressure natriuresis relationship to higher blood pressure values. The mechanisms responsible for this increased tubular reabsorption are still unclear but several experimental studies have shown that insulin resistance, increased sympathetic activity, and activated renin–angiotensin system (RAS), i.e. disturbances consistently found in obesity, could all play an important role. Studies in humans have confirmed these experimental results, showing an increase in renal plasma flow and GFR, together with increased transcapillary hydraulic pressure and filtration fraction in non-diabetic, normotensive obese subjects in comparison with non-obese [5].

Hyperlipidaemia
Hyperlipidaemia is common in obese patients. Many experimental studies and some clinical data have shown that dyslipidaemia can contribute to renal injury, mainly through proliferation of mesangial cells and their extracellular matrix induced by LDL-cholesterol. The obese Zucker rat is an experimental model of obesity, hyperinsulinaemia, and hyperlipidaemia that develops glomerulosclerosis and progressive renal failure. Treatment of hyperlipidaemia reduces glomerular injury in obese Zucker rats. Therefore, treatment with statins and other hypolipaemic agents may induce a beneficial effect in ORG, although no clinical studies have addressed this specific issue.

Role of leptin and other adipocyte-derived hormones
Leptin, an adipocyte-derived hormone, plays a critical role in the control of appetite and energy expenditure. Non-diabetic obese subjects as well as obese type 2 diabetic patients exhibit high serum leptin levels. Mutations in the Ob-Rb leptin receptor in the db/db mouse lead to leptin resistance, hyperleptinaemia, obesity, and type 2 diabetes with glomerulosclerosis. Recent studies [6] have shown that leptin stimulates cellular proliferation and expression of the prosclerotic cytokine TGF-ß1 cytokine. Chronic leptin infusion into normal rats induced proteinuria and focal glomerulosclerosis accompanied by elevated glomerular TGF-ß1 and type IV collagen expression. These studies suggest that leptin could play an important role in the pathogenesis of glomerulosclerosis associated with obesity.

Other recent studies have provided exciting data about the active role of adipocytes in the hormonal regulation of energy balance. Resistin, another hormone secreted by adipocytes, appears to be crucial in the insulin resistance linked to obesity and type 2 diabetes [7]. Serum levels of resistin are increased markedly in obese experimental animals and are decreased by thiazolidinendiones, drugs currently used to improve sensitivity to insulin in type 2 diabetes. Thiazolidinendiones also inhibit leptin production and ameliorate microalbuminuria both in the streptozotocin-induced diabetic rat and type 2 diabetic patients [8].

Therapeutic interventions
Weight loss induces a clear decrease of proteinuria in patients with ORG. We have studied a group of patients with obesity-related proteinuria treated with hypocaloric diets during 1 year: mean weight loss was 12% and proteinuria decreased by >80% [9]. In another group of patients with similar clinical characteristics, we observed that inhibition of RAS system by captopril also induced a clearcut decrease of proteinuria (>70% of baseline values) without changes in body weight [9]. Combined weight loss (low calorie diets, physical exercise) and agents that inhibit RAS (ACE inhibitors and angiotensin II receptor antagonists) are therefore presumably the best therapeutic options in obese patients with proteinuria. However, in our experience, weight loss is only transient in most patients with ORG and the anti-proteinuric effect of RAS inhibition is frequently abrogated by a gain of body weight.

Influence of obesity on the evolution of other renal diseases
Considering that obesity is closely associated with glomerular hyperfiltration, as commented above, it is conceivable that being overweight further aggravates or unmasks the propensity to hyperfiltration in patients predisposed to this condition. Thus, we have reported recently that obesity is a significant risk factor for the appearance of progressive renal failure after unilateral nephrectomy. Twenty patients with normal renal function and no evidence of gross abnormalities in the remaining kidney showed a slowly progressive proteinuria and renal functional deterioration. Almost all (90%) of these patients were obese or overweight at the time of nephrectomy or during the follow up. Their body mass index (BMI) was significantly higher than that of patients who had maintained a normal renal function and negative proteinuria [10]. We have also observed (unpublished data) that obesity is associated with the appearance of proteinuria and renal failure in patients with unilateral renal agenesis.

A recent study has shown that obesity exerts a detrimental influence on the evolution of patients with IgA nephropathy [11]. However, no studies have so far been performed to investigate the effect of weight loss in overweight patients with proteinuric nephropathies of different etiologies other than obesity. We have performed recently a prospective study in overweight patients (BMI >27 kg/m2) with diabetic and non-diabetic chronic proteinuric nephropathies (unpublished data). They were assigned randomly either to follow a low calorie and normoproteic diet or to maintain their usual dietary intake for 5 months. Patients in the diet group showed a significant diminution of body weight and BMI (mean weight loss 4.1±3%) whereas patients in the control group showed a significant weight gain. Proteinuria decreased by 31.2±37% in the diet group whereas it tended to increase in the control group. There was a close positive correlation between weight loss and proteinuria decrease in the diet group. Stable renal function and a significant improvement of the lipid profile were observed in the diet group, whereas the control group showed a significant worsening of renal function. Patients with type 2 diabetic nephropathy included in the diet group also showed a significant proteinuria decrease and improvement of lipid profile. These results indicate that treatment of obesity should be an important target in chronic proteinuric nephropathies. The importance of this therapeutic intervention is obvious in view of the increasing prevalence of obesity in the general population and the fact that the great majority of patients with type 2 diabetic nephropathy (the leading cause of end-stage renal disease) is obese.

Notes

Correspondence and offprint requests to: Manuel Praga, Servicio de Nefrología, Hospital 12 de Octubre, Carretera de Andalucía, Km 5400, E-28041, Madrid, Spain. Email: mpragat{at}senefro.org Back

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