HYPERTENSION AND METABOLIC DISARRAY (E REISIN, SECTION EDITOR)

The Effect of Weight Loss in Obesity and ChronicKidney Disease

Enrique Morales & Manuel Praga

Published online: 19 January 2012# Springer Science+Business Media, LLC 2012

Abstract Several epidemiologic investigations have con-firmed that obesity is a significant risk factor for the appear-ance of proteinuria and end-stage kidney disease in a normalpopulation. Weight loss induced by low-calorie diets, phys-ical exercise, or bariatric surgery is accompanied by animportant antiproteinuric effect. Reduction in proteinuria isalready observed after a few weeks from the onset of weightloss and it is evident even in patients with modest weightlosses. Reduction in proteinuria by weight loss has beendescribed in chronic proteinuric nephropathies of differentetiologies. The mechanisms through which weight loss mayreverse proteinuria are likely to be plural: better control ofblood pressure, improvement of serum lipid profile, improve-ment of insulin sensitivity, better glycemic control in diabetespatients, decrease of circulating leptin levels, reversal of glo-merular hyperfiltration, and decreased activation of the renin-angiotensin-aldosterone system.

Keywords Obesity . Proteinuria . Kidney disease .

Hyperfiltration .Weight loss . Renin-angiotensin-aldosteronesystem . RAAS

Introduction

The relationship between obesity and proteinuria has beenknown to exist for more than two decades, when the firststudies in which a minority of obese patients developed

proteinuria were published [1]. Focal segmental glomeru-losclerosis (FSGS) is the most frequently encounteredhistologic lesion in the renal biopsies of these patients[2]. In the past decade, obesity-related nephropathy hasbecome an increasingly more frequent diagnosis [3], andepidemiologic studies published recently have unequivo-cally demonstrated a close relationship between bodymass index (BMI), the most precise parameter in quanti-fying the degree of obesity, and the risk of developingchronic kidney disease (CKD) in the normal population[4]. A better knowledge of this entity has probably playeda role in such a significant increase, but taking intoaccount the epidemic proportions that obesity has reachedin developed societies, related renal complications maybecome an increasing clinical problem in the comingyears. In this regard, the beneficial effects obtained byweight loss for the kidney have become a key element inclinical and experimental studies.

Obesity as a Risk Factor for End-Stage Kidney Disease

Obese patients present a much higher risk of developinghyperlipidemia, cardiovascular complications, hypertension,diabetes mellitus, and sleep apnea syndrome [5]; however,there is scant information on the relationship between obe-sity and the risk of developing CKD. In recent years, newpublications have appeared that answer the question of therelationship of BMI to the risk of developing CKD. Fox etal. [4], in a study of 2,585 Americans with normal renalfunction, established the risk factors that shape the develop-ment of kidney failure. After an 18-year follow-up, 9.4%(244/2,585) of the participants developed CKD. BMI was asignificant risk factor (OR 1.23) for the development ofkidney failure, together with age, baseline glomerular

E. Morales (*) :M. Praga (*)Nephrology Department, Hospital 12 de Octubre,Avda. Andalucía s/n.,Madrid 28231, Spaine-mail: emoralesr@senefro.orge-mail: mpragat@senefro.org

Curr Hypertens Rep (2012) 14:170–176DOI 10.1007/s11906-012-0247-x

filtration rate (GFR), and other classic cardiovascular riskfactors (diabetes, hypertension, low HDL cholesterol values,and smoking). More recent publications have confirmedthese data, verifying the influence of BMI on the evolutionof renal function in the general population. An epidemio-logic study performed on 320,252 patients who volunteeredto be studied between 1964 and 1985 found 1,471 cases ofadvanced CKD during follow-up. High BMI was a highlysignificant risk factor for the development of kidney failure,following the adjustment of other variables. When thesepatients were compared with the normal-weight population,the relative risk for the development of CKD was 1.87 forthose who were overweight (BMI 25–29 kg/m2), 3.57 forthose with type I obesity (BMI 30–34.9 kg/m2), 6.12 forthose with type II obesity (BMI 35–39.9 kg/m2) and 7.07 forthose presenting type III obesity (BMI >40 kg/m2) [6].

Gelber et al. [7], in a study of a cohort of 11,104 healthyparticipants, found that 1,377 participants (12.4%) had devel-oped CKD (defined as a GFR <60 mL/min/1.73 m2) after14 years of follow-up. A high BMI at the beginning of thestudy was shown to be a risk factor for the development ofCKD. Participants whose BMI increased by more than 10%during follow-up had a significant increase in their risk ofdeveloping CKD (OR 1.27). Recently, in an epidemiologicstudy that monitored more than 75,000 patients in the Norwe-gian population for 21 years, the increase in BMI was corre-lated with the risk of developing terminal CKD or death withCKD [8•].

Effects of Obesity on the Kidney

One of the deficiencies of these important epidemiologicstudies is the absence of the clinical findings found in theparticipants that developed this complication. Obesity-related glomerulopathy may be explained by different path-ogenic mechanisms, but its usual clinical presentation con-sists of a variable-range proteinuria without any noteworthyalterations in urine sediment [9, 10]. The appearance ofproteinuria precedes the loss of GFR over the years [3, 11,12]. Proteinuria reaches a nephrotic range in a substan-tial number of cases, and in our experience it may bemassive, with eliminations of greater than 15–20 gramsper 24 hours. Nevertheless, the typical characteristics ofnephrotic syndrome (hypoproteinemia, hypoalbuminemia)are not observed, even in patients with greater proteinuria[13–15]. This absence of a biochemical repercussion of pro-teinuria (in other words, nephrotic proteinuria but withoutbiochemical nephrotic syndrome) is also seen in other entitieswhose pathogenic base is hyperfiltration (reduction of func-tioning renal mass, reflux nephropathy) and has a considerablepractical importance for differential diagnosis with other glo-merular entities. Moreover, in view of the absence of

hypoalbuminemia and edema, a substantial number of casesare detected casually, when the disease (kidney failure, glo-merulosclerosis, and interstitial fibrosis lesions) is veryadvanced. In this regard, we performed a study [11] in 15obese patients (BMI >30 kg/m2) with FSGS lesions detectedby kidney biopsy. We compared this group of patients withobesity-related FSGS (O-FSGS) with a control group of 15patients with idiopathic FSGS (I-FSGS) selected on the basisof similar renal function. After a follow-up of more than5 years, proteinuria reached nephrotic range in 6 patients(40%) at the time of the biopsy, and 12 (80%) of the patientswith O-FSGS presented proteinuria greater than 3.5 grams per24 hours during the follow-up. Nevertheless, none of thesepatients presented edema or the usual nephrotic syndromebiochemical characteristics. However, proteinuria was greaterin the cases with I-FSGS, andmost of the patients in this grouppresented edema and the characteristic repercussions ofnephrotic syndrome during follow-up. Seven (46%) of thepatients with O-FSGS presented a progressive deteriorationin renal function, and five of them began chronic dialysis. Theremaining eight had stable renal function throughout follow-up. The basic difference between the patients who had stablerenal function and those who showed progressive deteriora-tion corresponded to the initial renal function, which wasnormal in the former and was already deteriorated in the latter.

The physiopathologic causes of this absence of biochem-ical repercussions of proteinuria secondary to obesity areunknown. In a preliminary study, we presented evidencethat the patients with massive proteinuria without biochem-ical repercussions (the majority due to hyperfiltration pro-cesses) presented urine eliminations of β-2 microglobulinand different tubular enzymes such as N-acetyl-B-glucosa-minidase (NAG) significantly lower than those of patientswith similar proteinurias with full-blown biochemicalnephrotic syndrome [14]. This finding may point to a differenttubular management of the proteins filtered in the glomerule:in hyperfiltration nephropathies, the tubular reabsorption anddegradation of proteins may be lower than in other diseasesthat cause nephrotic syndrome, thus contributing to the lowerbiochemical repercussions of the protein loss. Nevertheless,experimental data that explore this aspect further have notbeen published. The usefulness of the absence or presence ofbiochemical repercussions in the differential diagnosis of anephrotic proteinuria has been acknowledged [16].

Weight Loss Interventions in Chronic Kidney Disease:Reduction in Proteinuria or Albuminuria

Logically, weight reduction must be the most decisiveaspect of therapy, but the evidence available regarding itsinfluence is somewhat scant [17]. In recent years, two inter-esting reviews (clinical trials and studies from the literature)

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have analyzed in depth the effect of weight loss and itsinfluence on proteinuria and renal function [18••, 19••]. It isimportant to emphasise that these meta-analyses uncover asubstantial number of limitations in the works reviewed: smallpatient number, heterogeneous populations, short follow-upperiods, and absence of control groups. Nevertheless, one ofthe conclusions drawn by these studies is that weight loss inoverweight patients or obese patients with a certain degree ofkidney failure produces a significant reduction in albuminuria,proteinuria, or both, regardless of the study design and themethods used to lose weight.

Some studies have highlighted the relationship betweenweight loss and reductions in proteinuria or albuminuria inobese patients on a low-calorie diet. One of the first studieswas conducted in 1984 by Vasquez et al. [20] in 24 diabeticand obese patients (BMI, 39.1±8.3 kg/m2) who were on alow-calorie diet (500 kcal/day) for 6 months. After a weightloss of 13.6±1.6%, baseline values of proteinuria and albu-minuria were reduced by 50%. This initial study was fol-lowed by others that confirmed the results described. Solerteet al. [21] evaluated hemodynamic and proteinuria changesin 24 obese patients with type 1 and type 2 diabetesafter a low-calorie diet (1,410 kcal/day). After 12 monthsof treatment, BMIwas reduced from 33.5±1.6 to 26±1.8 kg/m2,and this change was accompanied by a major reduction inproteinuria from 1,280±511 to 623±307 mg per 24 hours.Blood pressure and levels of cholesterol and triglyceride alsofell significantly at the same time as weight loss. Saiki et al. [22]conducted a prospective, observational study with 22 obesepatients (BMI, 30.4±5.3 kg/m2) with proteinuria (3.3±2.6 g/24 hours) who followed a low-calorie diet (11–19 kcal/kg per day) for 4 weeks. After weight reduction(6.2±3 kg), reductions occurred in systolic blood pressure,serum creatinine, proteinuria, and blood urea nitrogen.

A reduction in proteinuria induced by weight loss hasalso been observed in nondiabetic obese patients. Praga etal. [23] studied 17 nondiabetic obese patients with protein-uria above 1 g per 24 hours. Obesity-related proteinuria wasthe diagnosis in most cases because of an absence of otheridentifiable renal conditions and the characteristics of clin-ical presentation: a slow progression of proteinuria paralle-ling the progression of obesity with the absence ofhypoalbuminemia or edema, even although the patientspresented proteinurias in the nephrotic range [11, 15]. Akidney biopsy was performed in five patients: FSGS lesionswere found in two, minimal glomerular lesions in anothertwo, and mesangial proliferation in one. In this randomizedstudy, one group (9 patients) followed a low-calorie diet(1,000–1,400 kcal/day) and the other group (8 patients)received treatment with captopril with no changes in thediet. After 12 months of follow-up, BMI fell from 37.1±3 to32.6±3.2 kg/m2 in the group of patients receiving the low-calorie diet. At the end of the study, these patients presented

a reduction of proteinuria from 2.9±1.7 to 0.4±0.6 gramsper 24 hours. All patients presented a proteinuria reductionbetween 52% and 100% of the initial values. There was asignificant correlation between weight reduction and reduc-tion in proteinuria. In the group of patients treated withcaptopril, weight remained stable during follow-up, butproteinuria reduction was similar to that of the group onthe low-calorie diet: from 3.4±1.7 to 0.7±1 grams per24 hours (40–100% of the baseline values). Blood pressureand lipid levels decreased during the study in bothgroups, although there was no correlation between thereduction in proteinuria and the changes observed inblood pressure.

We performed a prospective and randomized study toassess the influence of weight loss in inducing a reductionin proteinuria in patients with different proteinuric nephrop-athies [24]. We selected patients who were obese or over-weight (BMI >27 kg/m2) and had a chronic proteinuricnephropathy of any etiology, with proteinuria >1 gram per24 hours and serum creatinine below 2 mg/dL. Patients wererandomized to receive a low-calorie diet (500 kcal less thantheir usual diet) or to maintain their usual diet for 5 months.Of the 30 patients included, 14 presented with diabeticnephropathy, 7 had different types of chronic glomerulone-phritis, 5 patients presented with nephroangiosclerosis, and4 had reflux nephropathy. In the low-calorie diet group,body weight and BMI fell significantly (body weight, 87.5±11.1 to 83.9±10.9 kg, P<0.01; BMI, 33±3.5 to 31.6±3.2 kg/m2). Weight loss was 4.1±3% with regard to thebaseline value. Proteinuria presented a significant reduc-tion, from 2.8±1.4 to 1.9±1.4 grams per 24 hours. Thereduction in proteinuria was 31.2±37% of the baselinevalues. The degree of reduction in proteinuria was alreadysignificant in the first month of the study (26.4±30%), whenweight loss was 2.8±2.1% of the baseline value. A significantcorrelation was observed between weight loss and proteinuriareduction. Weight loss was the only variable with statisticalsignificance with regard to a reduction in proteinuria greaterthan 30% (OR 1.72). With regard to lipid profile, HDL cho-lesterol increased significantly and there was tendencytowards a reduction in LDL cholesterol. There were nosignificant variations in blood pressure in any of thegroups throughout the study. Renal function remainedstable during follow-up.

On the other hand, the group of patients on their usualdiet presented an increase in weight and proteinuria through-out follow-up. Similarly, this group presented a significantdeterioration in renal function at the end of the study (serumcreatinine increased from 1.6±0.5 to 1.8±0.6 mg/dL,and creatinine clearance fell from 61.8±22.1 to 56±19.9 mL/min/1.73 m2).

In the low-calorie diet group, 10 of the 20 patients had atype 2 diabetic nephropathy.Weight and BMI fell significantly

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in these patients, with a mean reduction in body weightof 3.6±3% with regard to the baseline values. This reductionwas accompanied by a reduction in proteinuria from 2.9±1.4to 1.9±1 (28.8%±40.4% with regard to the baseline values).We conclude that the antiproteinuric effect of weight loss isobserved in obese patients with type 2 diabetes mellitus and inpatients with obesity-related glomerulopathy, but also in obesepatients with a renal condition not related to hyperfiltrationpathogenesis (primary glomerulonephritis).

However, other studies question hyperfiltration and itsconsequences. Recently, Friedman et al. [25•] analyzed theeffect of a high-protein diet (140 g/day) or a low-protein diet(50 g/day) in 17 obese patients. The patients were random-ized to a crossover study in which they were given a 1-weekhigh-protein diet and subsequently a 1-week low-proteindiet, separated by a 1-week washout phase. The authorsfound that the high-protein diet was associated with anincrease in GFR (114±25 vs 109±26 mL/min). Proteinuriatended to increase (188±73 vs 173±84 mg/day) and albu-minuria decreased, although these values were not statisti-cally significant. There were no changes in serum creatinine,cystatin C, blood pressure, or glycemia. The authors con-cluded that a low-calorie diet is insufficient to explainchanges in GFR and proteinuria associated with obesity-related nephropathy.

Bariatric Surgery in Patients with Proteinuria

The number of patients undergoing weight reduction sur-gery (bariatric surgery) has increased in recent years. Todate, operations of this type are the most efficacious forlosing weight in the population with morbid obesity [26].Weight reductions surpassing 30% may be achieved andmaintained throughout follow-up in this type of patient.Recent studies have analyzed the effect of bariatric surgeryin patients with morbid obesity, proving that weight loss isclearly correlated with reduced proteinuria [27, 28]. Palomaret al. [29] studied the evolution of 35 patients with morbidobesity who underwent bariatric surgery. Weight loss was67% at the end of the first year. The ensemble of car-diovascular risk factors (hypertension, diabetes, dyslipi-demia) improved significantly during follow-up, andmicroalbuminuria and proteinuria drastically decreased.Agrawal et al. [30], in a retrospective study of 94 patientswith morbid obesity (BMI, 49.1±8 kg/m2), observed thatweight reduction is accompanied by an improvement in lipidprofile, glucose control, blood pressure, and albuminuria.These changes were more marked in the population withdiabetes or metabolic syndrome.

The beneficial effect of bariatric surgery is independentof the type of surgery performed; the same benefits wereobserved with the gastric bypass or gastric bands.

Pharmacotherapy and Lifestyle Modifications

In the past decade, we have witnessed the development ofnumerous drugs for obesity [31]. Recent studies have dem-onstrated that the use of various drugs for weight reduction(sibutramine, rimonabant, orlistat), together with low-calorie diets, increases weight loss in obese patients with asuitable safety profile [31–33]. Changes in lifestyle (regularphysical exercise, absence of sedentary life) are other meas-ures used tomaintain weight loss [32]. An important improve-ment in cardiovascular risk factors (dyslipidemia, insulinresistance) has been observed after weight loss in obesepatients treated with pharmacotherapy and lifestyle modifica-tion [31–33]. However, the influence on other parameters suchas albuminuria, proteinuria, renal function, or histologiclesions has not been investigated.

Mechanisms of Obesity Related to Kidney Disease:Weight Loss Effects

The weight loss achieved by diet, physical exercise, or drugsmay reduce proteinuria by a number of mechanisms[31–33]: better blood pressure control, improved lipid pro-file (increase in HDL cholesterol, reduction in LDL choles-terol, reduction in triglycerides), improved insulin sensitivity,better glucose control in diabetic patients, a reduction in theconcentration of leptin [34], reduction of glomerular hyper-filtration [35], a fall in activated components of the renin-angiotensin-aldosterone system (RAAS) [36], and a reductionin inflammatory and oxidative stress processes. Naturally, thereduction in proteinuria that occurs after weight loss may bepartly explained by the sum of these favorable changes. How-ever, in the few clinical studies that have investigated theinfluence of these pathogenic mechanisms, the reduction inproteinuria is independent of blood pressure figures or lipidprofile changes [37].

Weight loss induces important changes in cytokines andhormones caused by the central adipose tissue. Obesepatients present elevated levels of leptin, a hormone pro-duced by adipocytes that has a decisive influence on foodregulation [38••]. Experimental studies have shown that theadministration of leptin in rats induces the appearance ofproteinuria and glomerulosclerosis lesions. There is also anincrease in the synthesis of transforming growth factor(TGF)-β and type IV collagen, factors with a marked capacityfor sclerosis-fibrosis formation [34]. Recent studies have dem-onstrated how low levels of adiponectin and high levels offetuin-A are associated with obesity, metabolic syndrome, andalbuminuria [39•]. This research illustrates how thesetwo proteins work in opposing directions and may linkthe adipose tissue, the kidney, and the liver. Inhibition of theactivity of the 5′ adenosine monophosphate-activated protein

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kinase (AMPK) sensor produces a loss of adiponectin stimu-lation and plays a pivotal role in the negative consequences ofobesity for the kidney and the liver. It should be rememberedthat a low-calorie diet causes a reduction in fetuin-A levels, anincrease in the levels of adiponectin, and a stimulation ofAMPK [39•]. Visfatin, regarded as a proinflammatory cyto-kine, can bind to the insulin receptor and mimic its action; onthe other hand, it can induce the expression of interleukin-6(IL-6) and other proinflammatory cytokines that contribute toinsulin resistance and vascular damage [34]. Consequently,the modifications of leptin, adiponectin, and other substancesproduced by adipocytes play a pivotal role in the antiprotei-nuric effect of weight loss and have become new fields ofextraordinary clinical interest and research in the relationshipsof diet and obesity-related nephropathy.

GFR is very high in experimental studies and in obesepatients, a characteristic sign of hyperfiltration [40]. In astudy performed in obese patients, Chagnac et al. observedhow GFR increased by 51% and renal plasma flow (RPF) by31% versus the control group (healthy volunteers) [41].Moreover, obese patients presented the characteristic hyper-filtration hemodynamic profile, with preglomerular vasodi-latation and increased filtration fraction. Because thedevelopment of FSGS lesions is the histologic outcome ofhyperfiltration situations, both experimental and clinical,one may simply conclude that the nephropathy of obesityis another hyperfiltration-mediated condition [17]. Thesedata complement findings in obese patients who present areduction in GFR after drastic weight losses following bari-atric surgery [35]. On the other hand, studies performed inobese patients show an increase in sodium reabsorption, afactor that may play a fundamental role in the vasodilatationof the afferent glomerular arteriole, and consequently in thetransmission of the increase in pressure to the glomerularcapillary [42]. One illustrative example of obesity-inducedhyperfiltration can be found in the role of overweight orobesity in patients with reduced renal mass [43]. Becauseproteinuria is the main symptom of hyperfiltration, theimprovement in hemodynamic changes accompanyingweightloss makes it a decisive factor in the reduction of proteinuria inthese patients.

Blocking RAAS with angiotensin-converting enzyme(ACE) inhibitors and with angiotensin II receptor antago-nists (ARA-II) has produced a marked favorable influencein all conditions caused by experimental and clinical hyper-filtration [17]. The reduction in proteinuria is, at the clinicallevel, an excellent marker of the favorable influence of thistreatment in any type of proteinuric nephropathy [44].Therefore, the ACE inhibitors and ARA-II may efficaciousas part of the therapy for obesity-induced nephropathy, inwhich, as we have seen, hyperfiltration seems to play afundamental role. In our experience [23], captopril induceda very evident antiproteinuric effect, superimposable on the

effect obtained with weight reduction in patients withobesity-induced proteinuria. Extrapolating experience withother proteinuric nephropathies, we may assume that thisantiproteinuric effect foretells a favorable influence on thelong-term evolution of renal function.

Various studies present a fact of great pathogenic interest:adipose tissue, particularly the visceral type, is a knownsource of all the components of RAAS [45, 46]. Moderateweight losses (about 5% of baseline values) with low-caloriediets produce important reductions in the levels of angio-tensinogen, renin, aldosterone, and ACE activity in plasmaand in adipocytes [36, 47•]. Thus, this block on the RAAScould explain the reduction in proteinuria after weight loss,similar to the effect seen with RAAS-blocking agents. Thespeed and magnitude of proteinuria reduction is reminiscentof the antiproteinuric effects of RAAS-blocking agents.Therefore, significant weight reduction and treatment withACE inhibitors or ARA-II should be used as complementarytherapeutic measures to boost their action.

Finally, we should highlight how recent research showsthat obesity is a condition of partial resistance to the anti-proteinuric and renoprotective effect of RAAS-blockingagents [11]. The concentrations of aldosterone in plasmaare disproportionately high in obese hypertensive patients,particularly those presenting abdominal obesity [48], andthis elevation is independent of renin plasma values. Humanadipocytes are capable of secreting factors that directlyinfluence the genesis of aldosterone from the adrenalglands [49•]. These data suggest that these obese indi-viduals may be particularly sensitive to the recentlyhighlighted antiproteinuric, renoprotective, and cardioprotec-tive effects of spironolactone and other aldosterone antago-nists [50, 51].

Conclusions

Weight loss induces an important reduction in protein-uria in obese patients. It is important to point out thatthe antiproteinuric effect of weight loss is observed notonly in obese patients with type 2 diabetes and inobesity-related glomerulopathy but also in obese patientspresenting kidney diseases whose pathogenesis is notrelated to hyperfiltration. The reduction in proteinuria is rap-idly observed and presents a significant correlation with thepercentage of weight reduction. All this evidence clearlysuggests that weight loss is a potent—but scantly investigatedand frequently overlooked—antiproteinuric therapeuticmeasure, which furthermore provides a general improvementin the patient’s metabolic profile.

Acknowledgments This paper was partially supported by grantsfrom Fondo de Investigaciones Sanitarias (FIS 10/02668) to MP and

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Asociación para la Investigación y Tratamiento de las EnfermedadesRenales (AITER) to EM.

Disclosure Conflicts of Interest: E. Morales: Consultancy fees fromNovartis, Roche, Celgene; payment for lectures from Novartis, Shire,Abbott, Amgen. M. Praga: Consultancy fees from Novartis, Roche,Astellas, Fresenius, Gambro, Abbott; payment for lectures from Novar-tis, Astellas, Abbott.

References

Papers of particular interest, published recently, have beenhighlighted as:• Of importance•• Of major importance

1. Weisinger JR, Kempson RL, Eldridge FL, Swenson RS. Thenephrotic syndrome: A complication of massive obesity. AnnIntern Med. 1974;81:440–7.

2. Verani RR. Obesity-related focal segmental glomerulosclerosis:pathological features of the lesions and relationship with cardio-megaly and hyperlipidemia. Am J Kidney Dis. 1992;20:629–34.

3. Kambham N, Markowitz G, Valeri AM, et al. Obesity-relatedglomerulopathy: an emerging epidemic. Kidney Int. 2001;59:1498–509.

4. Fox CS, Larson MG, Leip EP, et al. Predictors of new-onset kidneydisease in a community-based population. JAMA. 2004;291:844–50.

5. Must A, Spadano J, Coakley EH, et al. The disease burden asso-ciated with overweight and obesity. JAMA. 1999;282:1523–9.

6. Hsu CY, McCulloch CE, Iribarren C, et al. Body mass index andrisk for end-stage renal disease. Ann Intern Med. 2006;144:21–8.

7. Gelber RP, Kurth T, Kausz AT, et al. Association between bodymass index and CKD in apparently healthy men. Am J Kidney Dis.2005;46:871–80.

8. • Munkhaugen J, Ludersen S, Wideroe TE, Hallan S. Prehyperten-sion, obesity, and risk of kidney disease: 20 year follow-up of theHUNT I study in Norway. Am J Kidney Dis. 2009;54:638–646.Among 75,000 adults followed over 21 years, increased BMIdramatically correlated with initiation of renal replacement ordeath with CKD. Prehypertension adversely affected outcome onlyin those with obesity.

9. Praga M. Obesity: a neglected culprit in renal disease. NephrolDial Transplant. 2002;17:1157–9.

10. Kasiske BL, Napier J. Glomerular sclerosis in patients with mas-sive obesity. Am J Nephrol. 1985;5:45–50.

11. Praga M, Hernández E, Morales E, et al. Clinical features and longterm outcome of obesity-related focal segmental glomerulosclerosis.Nephrol Dial Transplant. 2001;16:1790–8.

12. Adelman RD, Restaino IG, Alon US, Blowey DL. Proteinuria andfocal segmental glomerulosclerosis in severely obese adolescents.J Pediatr. 2001;138:481–5.

13. Praga M, Morales E, Herrero JC, et al. Disminución de masa renalfuncionante y proteinuria. Nefrología. 1998;18:17–22.

14. Praga M, Bornstein B, Andrés A, et al. Nephrotic proteinuriawithout hypoalbuminemia: clinical characteristics and responseto angiotensin-converting enzyme inhibition. Am J Kidney Dis.1991;17:330–8.

15. Praga M, Morales E, Herrero JC, et al. Absence of hypoalbuminemiadespite massive proteinuria in focal segmental glomerulosclerosissecondary to hyperfiltration. Am J Kidney Dis. 1999;33:52–8.

16. D’Agati V. The many masks of focal segmental glomerulosclero-sis. Kidney Int. 1994;46:1223–41.

17. Praga M, Morales E. Obesity, proteinuria and progression of renalfailure. Curr Opin Nephrol Hypertens. 2006;15:481–6.

18. •• Afshinnia F, Wilt TJ, Duval S et al. Weight loss and proteinuria:systematic review of clinical trials and comparative cohorts. Neph-rol Dial Transplant. 2010;25:1173–1183. Evidence supports thebeneficial effect of weight loss on the surrogate outcomes of thedecrease of urinary protein excretion. There are no data on theeffect of weight loss on the progression to CKD.

19. •• Navaneethan SD, Yehnert H, Moustarah F et al. Weight lossinterventions in chronic kidney disease: a systematic review andmeta-analysis. Clin J Am Soc Nephrol. 2009;4:1565–1574. Thissystematic review demonstrated that weight loss may offer renalbenefits in addition to cardiovascular benefits. The evidence support-ing the role of intentional weight loss in slowing the progression ofkidney disease in patients with mild to moderate CKD is modest.

20. Vasquez B, Flock EV, Savage PV, et al. Sustained reduction ofproteinuria in type 2 (non-insulin-dependent) diabetes followingdiet-induced reduction of hyperglycaemia. Diabetologia.1984;26:127–33.

21. Solerte SB, Fioravanti M, Schifino N, et al. Effects of diet-therapyon urinary protein excretion albuminuria and renal haemodynamicfunction in obese diabetic patients with overt nephropathy. Int JObes. 1989;13:203–11.

22. Saiki A, Nagayama D, Ohhira M, et al. Effect of weight loss usingformula diet on renal function in obese patients with diabeticnephropathy. Int J Obesity (Lond). 2005;29:1115–20.

23. Praga M, Hernández E, Andres A, et al. Effects of body-weight lossand captopril treatment on obesity-related proteinuria. Nephron.1995;70:35–41.

24. Morales E, Valero MA, León M, et al. Beneficial effects of weightloss in overweight patients with chronic proteinuric nephropathies.Am J Kidney Dis. 2003;41:319–27.

25. • Friedman AN, Yu Z, Juliar BE, et al. Independent influence ofdietary protein in markers of kidney function and disease in obe-sity. Kidney Int. 2010;78:693–697. In this study, 17 obese patientswere randomly enrolled in a doubled-blind crossover design toreceive a high-protein diet for 1 week, followed by a washoutperiod, followed by a low-protein diet for 1 week. The authorsconcluded that dietary protein is unlikely to explain obesity-relatedelevations in GFR and proteinuria.

26. Brolin RE. Bariatric surgery and long-term control of morbidobesity. JAMA. 2002;288:2793–6.

27. Soto FC, Higa-Sansone G, Copley JB, et al. Renal failure,glomerulonephritis and morbid obesity: improvement after rapidweight loss following laparoscopic gastric bypass. Obes Surg.2005;15:137–40.

28. Izzedine H, Coupaye M, Reach I, Deray G. Gastric bypass andresolution of proteinuria in obese diabetic patient. Diabetes Med.2005;22:1761–2.

29. Palomar R, Fernández-Fresnedo G, Dominguez-Diez A, et al.Effects of weight loss after biliopancreatic diversion on metabo-lism and cardiovascular profile. Obes Surg. 2005;15:794–8.

30. Agrawal V, Khan I, Rai B, et al. The effect of weight loss afterbariatric surgery on albuminuria. Clin Nephrol. 2008;70:194–202.

31. Yanovski SZ, Yanosvski JA. Obesity. N Eng J Med. 2002;346:591–602.

32. Wadden TA, Berkowitz RI, Womble LG, et al. Randomized trial oflifestyle modification and pharmacotherapy for obesity. N Engl JMed. 2005;353:2111–20.

33. Despres JP, Golay A, Sjöström L. Effects of rimonabant on meta-bolic risk factors in overweight patients with dyslipidemia. N EnglJ Med. 2005;353:2121–34.

34. Wolf G, Hamann A, Han DC, et al. Leptin stimulates prolif-eration and TGF-beta expression in renal glomerular endothelialcells: potential role in glomerulosclerosis. Kidney Int. 1999;56:860–72.

Curr Hypertens Rep (2012) 14:170–176 175

35. Chagnac A, Weinstein T, Herman M, et al. The effects of weightloss on renal function in patients with severe obesity. J Am SocNephrol. 2003;14:1480–6.

36. Engeli S, Bohnke J, Gorzelniak K, et al. Weight loss and the renin-angiotensin-aldosterone system. Hypertension. 2005;45:356–62.

37. Praga M, Morales E. Obesity-related renal damage: changing dietto avoid progression. Kidney Int. 2010;78:633–5.

38. •• Iglesias P, Díez JJ. Adipose tissue in renal disease: clinicalsignificance and prognostic implications. Nephrol Dial Transplant.2010;25:2066–2077. This review of the clinical and experimentaldata supports a key role of adipose tissue in renal disease. Thekidney plays an important role in the regulation of adipokines thatmay contribute to increases in uremia-associated risk of cardio-vascular disease and mortality.

39. • Ix JH, Sharma K. Mechanisms linking obesity, chronic kidneydisease, and fatty liver disease; the roles of fetuin-A, adiponectin,and AMPK. J Am Soc Nephrol. 2010;21:406–412. This reviewshows that lower adiponectin and higher fetuin-A serum levels areassociated with obesity, metabolic syndrome, and albuminuria.

40. Hall JE, Brandy MW, Henegar JR, Shek EW. Abnormal kidneyfunction as a cause and a consequence of obesity hypertension.Clin Exp Pharmacol Physiol. 1998;25:58–64.

41. Chagnac A, Weinstein T, Korzets A. et al: Glomerular hemody-namics in severe obesity. Am J Physiol. 2000;278:F817–22.

42. Bickel CA, Verbalis JG, Knepper MA, Ecelbarger CA. Increasedrenal Na-K-ATPase, NCC, and beta-ENaC abundance in obeseZucker rats. Am J Physiol Renal Physiol. 2001;281:F639–648.

43. González E, Gutierrez E, Morales E, et al. Factors influencing theprogresión of renal damage in patients with unilateral renal agen-esis and remmant kidney. Kidney Int. 2005;68:263–70.

44. Jafar TH, Schmid CH, Landa M, et al. Angiotensin-convertingenzyme inhibitors and progression of nondiabetic renal disease.A meta-analysis of patient-level data. Ann Intern Med.2001;135:73–87.

45. Hall JE. The kidney, hypertension and obesity. Hypertension.2003;41:625–33.

46. El-Atat FA, Stas SN, McFarlane SI, Sowers JR. The relationshipbetween hyperinsulinemia, hypertension and progressive renal dis-ease. J Am Soc Nephrol. 2004;15:2816–27.

47. • Hunley TE, Ma LJ, Kon V. Scope and mechanisms of obesity-related renal disease. Curr Opin Nephrol Hypertens. 2010;19:227–234. Experimental and clinical studies reveal that adipose tissue,especially visceral fat, is a source of bioactive substances thatcontribute to pathophysiologic renal hemodynamic and structuralchanges leading to obesity-related nephropathy.

48. De Paula RB, Da Silva AA, Hall JE. Aldosterone antagonism attenu-ates obesity-induced hypertension and glomerular hyperfiltration.Hypertension. 2004;43:41–7.

49. • Bomback A, Klemmer PJ. Interaction of aldosterone and extra-cellular volume in the pathogenesis of obesity-related kidney dis-ease: a narrative review. Am J Nephrol. 2009;30:140–146. Thisreview suggests that elevated aldosterone levels and expandedextracellular volume are key components of obesity-induced renaldisease via aldosterone’s nonepithelial effects on the kidney.

50. Hostetter TH, Ibrahim M. Aldosterone in chronic kidney andcardiac disease. J Am Soc Nephrol. 2003;14:2395–401.

51. Morales E, Huerta A, Gutierrez E, et al. The antiproteinuric effectof the blockage of the renin-angiotensin-aldosterone system(RAAS) in obese patients. Which treatment option is the mosteffective? Nefrologia. 2009;29:421–9.

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