Beneficial Effects of Weight Loss in Overweight Patients WithChronic Proteinuric Nephropathies

Enrique Morales, MD, Ma Angeles Valero, MD, Miguel Leon, MD, Eduardo Hernandez, MD,and Manuel Praga, MD

● Background: Proteinuria is a recognized complication of obesity, but no study has investigated the effect ofweight loss in overweight patients with chronic proteinuric nephropathies of different causes. Methods: Werandomly assigned (in a 2:1 ratio) 30 overweight patients (body mass index [BMI] > 27 kg/m2) with diabetic andnondiabetic proteinuric nephropathies to either follow a low-calorie normoproteinic diet or maintain their usualdietary intake for 5 months. The primary outcome was change in urinary protein excretion. Secondary outcomeswere changes in renal function (serum creatinine level and Cockcroft-Gault creatinine clearance) and lipid profile.Results: Patients in the diet group showed a significant decrease in body weight and BMI, whereas patients in thecontrol group showed a significant increase in body weight and BMI (between-group comparison, P < 0.05). Meanweight loss in the diet group was 4.1% � 3%, and 14 of 20 patients in this group lost more than 3%. Proteinuriadecreased by 31.2% � 37% in the diet group (from protein of 2.8 � 1.4 to 1.9 � 1.4 g/24 h; P < 0.005), whereas ittended to increase in the control group (between-group comparison, P < 0.05). Changes in renal function did notdiffer significantly between groups, although renal function remained stable in the diet group and showedsignificant worsening in the control group. Serum triglyceride levels remained stable in the diet group and tended toincrease in the control group (between-group comparison, P < 0.05). Conclusion: Moderate weight loss inoverweight patients with chronic proteinuric nephropathies induces a significant decrease in proteinuria. Am JKidney Dis 41:319-327.© 2003 by the National Kidney Foundation, Inc.

INDEXWORDS: Weight loss; proteinuria decrease; overweight; low-calorie diet; type 2 diabetes.

PROTEINURIA is a recognized complicationof obesity. Several studies have shown that

obese patients can develop proteinuria, fre-quently in the nephrotic range, followed by pro-gressive loss of renal function in a substantialproportion of cases.1-5 Lesions of focal and seg-mental glomerulosclerosis, together with glo-merulomegaly, are the most common histologi-cal findings in renal biopsies.1-5

The increasing prevalence of obesity and over-weight in the general population currently is aworldwide health concern, and a striking in-crease in the number of patients diagnosed withobesity-related nephropathy in the last years re-cently has been reported.3 It has been shown thatweight loss induced a dramatic decrease in pro-teinuria in patients with obesity-related protein-uria.6 Nevertheless, little knowledge exists aboutthe possible role of obesity in the evolution ofchronic renal diseases, and no study has investi-gated the influence of weight loss in overweightpatients with proteinuric nephropathies of causesother than obesity. We therefore designed thepresent prospective study to determine effects ofa low-calorie normoproteinic diet designed topromote weight loss without protein restrictionon proteinuria, renal function, and metabolicprofile in overweight patients with diabetic andnondiabetic chronic proteinuric nephropathies.

METHODS

PatientsParticipants in the study were recruited from our outpa-

tient clinic. We selected patients who met the followingcriteria: a chronic (disease duration � 1 year before thestudy) proteinuric (proteinuria with � 1 g/24 h of protein onat least three consecutive determinations in the 6-monthperiod before the study) nephropathy of diabetic or nondia-betic cause, presence of overweight or obesity (body massindex [BMI] � 27 kg/m2), and serum creatinine level lessthan 2 mg/dL. Excluded were patients with an unstableclinical condition, rapid loss of renal function, nephroticsyndrome requiring diuretic therapy, immunosuppressivetreatments, and hypertension requiring more than two antihy-pertensive drugs for its control. The study was approved bythe Ethical Committee of Hospital 12 de Octubre (Madrid,Spain).

Study DesignAll patients completed a 2-month observational period in

which a full history and physical evaluation (including blood

From the Departments of Nephrology and Endocrinology,Hospital Universitario 12 de Octubre, Madrid, Spain.Received July 1, 2002; accepted in revised form October

1, 2002.Address reprint requests to Manuel Praga, MD, Ser-

vicio de Nefrologıa, Hospital 12 de Octubre, Carretera deAndalucıa Km 5,400, 28041 Madrid, Spain. E-mail:mpragat@senefro.org© 2003 by the National Kidney Foundation, Inc.0272-6386/03/4102-0005$35.00/0doi:10.1053/ajkd.2003.50039

American Journal of Kidney Diseases, Vol 41, No 2 (February), 2003: pp 319-327 319

pressure and BMI determinations), as well as laboratorytests (including 24-hour urine collection estimates of pro-tein, creatinine, and urea), were performed repeatedly toconfirm inclusion and exclusion criteria. Angiotensin-converting enzyme (ACE) inhibitors, angiotensin-receptorblockers (ARBs), and nondihydropyridine calcium channelblockers were withdrawn in patients treated with these drugsat least 6 weeks before randomization because of theirknown antiproteinuric effect. Patients also were instructed toavoid nonsteroidal anti-inflammatory drugs during the study.Patients administered statins for hyperlipidemia or antihyper-tensives other than ACE inhibitors, ARBs, or nondihydro-pyridine calcium channel blockers (including diuretics and�-blockers) were instructed to continue these treatmentsduring the study, but with no change in dose.Blood pressure of 140 mm Hg or less systolic and 90 mm

Hg or less diastolic was targeted as the upper limit ofaccepted values. Doxazosin was selected as the first antihy-pertensive option to be introduced, adding amlodipine (adihydropyridine calcium channel blocker) if needed to ob-tain the targeted blood pressure.After baseline measurements were obtained, patients were

randomly assigned in a 2:1 ratio to the low-calorie normopro-teinic diet group or control group and observed for 5 months.Clinical evaluations were performed at baseline and 1, 3,and 5 months and included a complete physical examinationwith estimation of BMI, blood pressure measurement, andinterview with the Clinical Nutrition Unit of our hospital.Laboratory evaluations were performed at baseline and 1and 5 months and included a complete blood count, serumbiochemistry (including creatinine, glucose, urea, uric acid,calcium, phosphorus, sodium potassium, total cholesterol,high-density lipoprotein [HDL] and low-density lipoprotein[LDL] cholesterol fractions, triglycerides, total proteins,albumin, bilirubin, alkaline phosphatase, aspartate amino-transferase, alanine aminotransferase, and lactate dehydroge-nase), and 24-hour urine collection estimation of sodium,urea, protein, and creatinine. Glycosylated hemoglobin wasmeasured in patients with diabetes at baseline and 1 and 5months.

DietAll patients were attended by the same physicians (M.A.V.

and M.L.) of the Clinical Nutrition Unit throughout thestudy. During the observational prerandomization periodand 3 months after randomization, patients completed a3-day food diary, including 1 weekend day. Total caloricrequirements were calculated according to sex, height, andweight (Harris-Benedict formula)7 as 150% of basal energyexpenditure. In this formula, we used adjusted body weight(adjusted body weight � [actual body weight � ideal bodyweight (IBW) � 0.25] � IBW).8 Patients randomly assignedto the diet group were prescribed a diet with an energyreduction of 500 kcal with respect to their usual diet, basedon macronutrient content as 25% to 30% fat and 55% to 60%carbohydrate of total caloric intake. Protein content wasadjusted to 1 to 1.2 g/kg/d. This hypocaloric diet wasmaintained for 5 months.Patients randomly assigned to the control group com-

pleted a 3-day food diary, including a weekend day. Norecommendations were made to modify their diets except to

provide a protein intake of 1 to 1.2 g/kg/d. A new 3-day fooddiary was completed at 3 months to make sure the diet hadnot changed during this interval.

Clinical and Laboratory MeasurementsBMI was calculated as weight in kilograms divided by

square of height in meters. Overweight is defined as BMIgreater than 27 kg/m2, and obesity, BMI greater than 30kg/m2. Blood pressure was measured using a standard mer-cury sphygmomanometer. Systolic and diastolic blood pres-sures were measured after 5 minutes of rest in a sittingposition; the average of two measurements was recorded.Blood for laboratory evaluations was drawn after an

overnight fast. Creatinine clearance was estimated fromplasma creatinine concentration using the Cockcroft-Gaultformula9 and standardized to a body surface area of 1.73 m2.Standard autoanalyzer methods were used for measurementof biochemical parameters.

Outcome MeasuresThe primary outcome was change in urinary protein

excretion. The number of patients who showed a proteinuriareduction greater than 30% of baseline during the study wasanalyzed in the diet and control groups. Secondary outcomeswere changes in renal function (estimated by serum creati-nine level and Cockcroft-Gault creatinine clearance) andlipid profile (serum total cholesterol, HDL and LDL choles-terol fractions, and serum triglycerides).

Statistical AnalysisAnalyses of the primary and secondary outcomes were

performed according to the intention-to-treat principle. Re-sults are given as mean � SD and minimum to maximum.Baseline comparisons between groups were performed us-ing Student’s t-test and Mann-Whitney test. For within-group analysis, we used Student’s t-test for paired compari-sons or Wilcoxon’s test for matched pairs. Between-groupcomparisons were performed by Kruskal-Wallis test forrepeated measurements and Mann-Whitney test. Correla-tions were evaluated by Pearson’s r. The significance levelfor the primary end point (change in urine protein excretion)was set at 0.017 with the use of Bonferroni correction. Forother outcomes, P less than 0.05 is considered statisticallysignificant. Multiple logistic regression analysis was per-formed to determine the influence of different parameters ondecrease in proteinuria (�30%). Statistics were calculatedusing SPSS, version 8.0 (SSPS Inc, Chicago, IL).

Sample-Size CalculationIn a previous study, we found that body weight loss

induced a 58% decrease in proteinuria (from protein of2.9 � 1.7 to 1.2 � 1 g/24 h) after 6 months of hypocaloricdiet in nine patients with obesity-related proteinuria.6 Inthe present study, patients were randomly assigned to thediet and control groups in a 2:1 ratio. Assuming an SD ofreduction in proteinuria of 1.5 g/24 h to detect a differ-ence of 1.5 g/24 h mean reduction in protein excretionbetween the diet and control groups with a power equal to80% and an � error of 0.05, a sample size of 20 patients in

MORALES ET AL320

the diet group and 10 patients in the control group isnecessary.

RESULTS

Thirty patients were enrolled in the study; 20patients (11 men, 9 women) were randomly as-signed to the diet group, and 10 patients (7 men,3 women), to the control group. There were nosignificant differences between the two groups inbaseline clinical characteristics (Table 1). Clini-cal diagnoses in the diet group were type 2diabetic nephropathy (10 patients), mesangialglomerulonephritis (3 patients), hypertensivenephrosclerosis (3 patients), reflux nephropathy(2 patients), healed necrotizing glomerulonephri-tis (1 patient), and focal segmental glomeruloscle-rosis (1 patient). In the control group, diagnoseswere type 2 diabetic nephropathy (4 patients),hypertensive nephrosclerosis (2 patients), refluxnephropathy (2 patients), mesangial glomerulo-nephritis (1 patient), and focal segmental glomer-ulosclerosis (1 patient).According to the design of the study (see

Methods), the following drugs were withdrawnin the diet group from 6 to 12 weeks (mean, 10 �2.2 weeks) before randomization: enalapril in 4patients (5 to 20 mg/d; mean dose, 12.5 � 8.6mg/d), losartan in 3 patients (50 mg/d), captoprilin 2 patients (50 mg/d), lisinopril in 2 patients (5and 20 mg/d), and verapamil in 1 patient (80mg/d). Drugs withdrawn before randomization

(6 to 11 weeks; mean, 9.6 � 2.3 weeks) in thecontrol group were enalapril in 3 patients (5 to 20mg/d; mean dose, 15 � 8.6 mg/d), captopril in 2patients (50 and 75 mg/d), and losartan in 2patients (50 mg/d).During the 5 months of the study, body weight

decreased from 87.5 � 11.1 to 83.9 � 10.9 kg(P � 0.01) in the diet group, whereas it showed asignificant increase from 96.1 � 16.6 to 98 �16.4 kg (P� 0.05) in the control group (between-group comparison, P � 0.05). BMI decreasedfrom 33 � 3.5 to 31.6 � 3.2 kg/m2 (P � 0.01) inthe diet group and increased from 34.3 � 5.7 to35 � 5.8 kg/m2 (P � 0.05) in the control group(between-group comparison, P � 0.05; Table 2).Patients in the diet group lost 4.1% � 3% of theirbaseline weight. Weight loss oscillated between0.3 and 11.4 kg in 18 of 20 diet-group patients(equivalent to 0.3% and 11% of baseline bodyweight), and the 2 remaining patients in thisgroup gained 0.5 and 1.1 kg. Fourteen patients inthe diet group (70%) achieved a weight lossgreater than 3% of baseline weight. Weight losswas already significant by the first month of thestudy (2.8% � 2.1% with respect to baselinevalues; Table 2).Proteinuria showed a significant decrease in

diet-group patients during the 5 months of thestudy from protein of 2.8 � 1.4 to 1.9 � 1.4 g/24h (P � 0.005), whereas it tended to increase in

Table 1. Baseline Characteristics of Study Patients

Diet Group (N � 20) Control Group (N � 10) P

Age (y) 56.5 � 15.2 (17-74) 56.1 � 10.1 (34-68) NSHeight (m) 1.62 � 7.9 (1.41-1.74) 1.67 � 9.3 (1.48-1.80) NSWeight (kg) 87.5 � 11.1 (62.2-103.6) 96.1 � 16.6 (77.4-133.5) NSBMI (kg/m2) 33 � 3.5 (28-42.2) 34.3 � 5.7 (27.9-47.8) NSSystolic blood pressure (mm Hg) 140 � 24.1 (110-210) 135 � 12.4 (120-160) NSDiastolic blood pressure (mm Hg) 79.6 � 8.3 (70-90) 83 � 9.7 (70-100) NSSerum creatinine (mg/dL) 1.5 � 0.7 (0.7-3.2) 1.6 � 0.5 (1-2.7) NSCreatinine clearance (mL/min/1.73 m2) 68.1 � 33.6 (25.9-151.2) 61.8 � 22.1 (29.8-90.7) NSTotal cholesterol (mg/dL) 213.2 � 52.5 (115-330) 209.3 � 39.5 (148-263) NSHDL cholesterol (mg/dL) 41.4 � 11.9 (21-67) 41.5 � 10.6 (26-59) NSLDL cholesterol (mg/dL) 142.2 � 35.2 (62-190) 133.5 � 32.1 (84-175) NSTriglycerides (mg/dL) 114 � 50.6 (48-250) 141.8 � 41.5 (41.5) NSUrinary sodium (mEq/24 h) 209.8 � 58.5 (124-324) 192 � 95.5 (54-364) NSUrinary urea (g/24 h) 32.6 � 8.1 (21.4-42.3) 30.9 � 9.7 (18.4-48.3) NSProteinuria (g/24 h) 2.8 � 1.4 (1-6.6) 3 � 2.2 (1-7.8) NS

NOTE. Values expressed as mean� SD (range). To convert to SI units, for serum creatinine (�mol/L), multiply by 88.4; forcreatinine clearance (mL/s), multiply by 0.0167; for total, HDL, and LDL cholesterol (mmol/L), multiply by 0.0259; and fortriglycerides (mmol/L), multiply by 0.0113.

WEIGHT LOSS IN PROTEINURIC NEPHROPATHIES 321

the control group from 3 � 2.2 to 3.5 � 2.1 g/24 h (Table 2; Fig 1). These differences betweengroups were significant (P � 0.05). The reduc-tion in proteinuria in the diet group was equiva-lent to a 31.2% � 37% reduction in baselineproteinuria values. The decrease in proteinuriawas already significant (a 26.4% � 30% reduc-tion from baseline values) by the first month ofthe study. Decrease in proteinuria and weightloss showed a significant correlation (r � 0.62;P � 0.01; Fig 2). Among the 14 of 20 diet-grouppatients who achieved a weight loss greater than3% of baseline values, proteinuria decreasedfrom protein of 2.7 � 1.3 to 1.3 � 0.8 g/24 h atthe end of study, equivalent to a 50.4% � 20.9%reduction from baseline values. Thirteen of 20patients (65%) in the diet group and 3 of 10

patients (30%) in the control group showed adecrease in proteinuria greater than 30% of base-line values during the study; multiple logisticregression analysis showed that percentage ofweight loss was the only factor statistically sig-nificantly correlated with a decrease in protein-uria greater than 30% of the baseline valueduring the study (odds ratio [OR], 1.725; 95%confidence interval [CI], 1.16 to 2.55; P �0.0062).Other variables included in the analysis, such

as creatinine clearance (OR, 1.03; 95% CI, 1.08to 2.29; P � not significant [NS]) and bloodpressure changes (OR, 0.92; 95% CI, 0.84 to1.02; P � NS), did not show statistical correla-tion.Renal function, estimated by serum creatinine

Table 2. Changes in Clinical and Biochemical Variables in the Two Groups

Diet Group Control Group

Baseline Month 1 Month 5 Baseline Month 1 Month 5

Weight (kg) 87.5 � 11.1 85.5 � 10.7*† 83.9 � 10.9*†‡ 96.1 � 16.6 96.5 � 16.3 98 � 16.4*†§(62.2-103.6) (61.5-101.7) (57.7-102.8) (77.4-133.5) (79.6-134) (81.1-135.2)

BMI (kg/m2) 33 � 3.5 32.2 � 3.2*† 31.6 � 3.2*†‡ 34.3 � 5.7 34.5 � 5.7 35 � 5.8*†§(28-42.2) (27.2-40.2) (26.7-40) (27.9-47.8) (27.8-48) (27.7-48.4)

Systolic blood pressure 140 � 24.1 141.8 � 20.5 138.5 � 14.1 135 � 12.4 140.4 � 8 140.4 � 18.3(mm Hg) (110-210) (110-180) (110-160) (120-160) (130-155) (110-170)

Diastolic blood pressure 79.6 � 8.3 80.4 � 9.3 76.6 � 8.8 83 � 9.7 84.3 � 9.2 88.5 � 11.1(mm Hg) (70-90) (65-95) (69-96) (70-100) (69-98) (60-100)

Serum creatinine (mg/dL) 1.5 � 0.7 1.4 � 0.8 1.5 � 0.8 1.6 � 0.5 1.8 � 0.6 1.8 � 0.6*†(0.7-3.2) (0.6-3.4) (0.7-3.5) (1-2.7) (1-3) (1.2-2.9)

Creatinine clearance 68.1 � 33.6 69.2 � 33.8 67 � 34.1 61.8 � 22.1 56.92 � 21.7* 56 � 19.9*†(mL/min/1.73 m2) (25.9-151.2) (24.2-131.2) (26.4-129.8) (29.8-90.7) (26.5-90.3) (27.7-83.5)

Total cholesterol (mg/dL) 213.2 � 52.5 216.9 � 52.6 210.8 � 38.8 209.3 � 39.5 222.1 � 36.4 224.6 � 36.4*(115-330) (128-318) (134-298) (148-263) (159-269) (160-265)

HDL cholesterol (mg/dL) 41.4 � 11.9 45.2 � 8.8 53.6 � 10.2*†§ 41.5 � 10.6 46.3 � 11.7 59.6 � 31.1*(21-67) (33-63) (38-67) (26-59) (34-64) (34-138)

LDL cholesterol (mg/dL) 142.2 � 35.2 149.4 � 44.6 131.5 � 27.6§ 133.5 � 32.1 141.3 � 25.5 128.9 � 36.2(62-190) (60-241) (73-172) (84-175) (102-185) (84-193)

Triglycerides (mg/dL) 114 � 50.6 110.5 � 31.4 112.4 � 41.7 141.8 � 41.5 151.9 � 55.6 179.2 � 81.4(48-250) (58-160) (58-222) (91-229) (84-264) (71-298)

Urinary sodium (mEq/24 h) 209.8 � 58.5 194.7 � 58.6 201.2 � 57 192 � 95.5 166.4 � 61.4 188.8 � 75.1(124-324) (100-320) (95-339) (54-364) (69-241) (52-292)

Urinary urea (g/24 h) 32.6 � 8.1 27.4 � 7.1 29.8 � 6.2 30.9 � 9.7 24.3 � 10.1 28.3 � 15(21.4-42.3) (16-48.2) (14.6-38.3) (18.4-48.3) (8.4-39.8) (7.8-53)

Proteinuria (g/24 h) 2.8 � 1.4 2 � 1.5*† 1.9 � 1.4*† 3 � 2.2 3.1 � 1.9 3.5 � 2.1(1-6.6) (0.5-7.7) (0.3-6.4) (1-7.8) (1.2-6.8) (0.7-8.1)

NOTE. Values expressed as mean� SD (range); To convert to SI units: for serum creatinine (�mol/L), multiply by 88.4; forcreatinine clearance (mL/s), multiply by 0.0167; for total, HDL, and LDL cholesterol (mmol/L), multiply by 0.0259; fortriglycerides (mmol/L), multiply by 0.0113.*P � 0.05 versus baseline values.†P � 0.017, Bonferroni correction.‡P � 0.05 versus baseline and month 1.§P � 0.05 versus month 1.

MORALES ET AL322

level and Cockcroft-Gault creatinine clearance,remained stable in the diet-group patients duringthe study. Conversely, within-group analysis ofcontrol patients showed significant worsening ofrenal function during the study: serum creatininelevels increased from 1.6 � 0.5 mg/dL (141 �44 �mol/L) to 1.8 � 0.6 mg/dL (159 � 53�mol/L; P � 0.01), and Cockcroft-Gault creati-nine clearance decreased from 61.8 � 22.1 mL/min/1.73 m2 (1 � 0.3 mL/s) to 56 � 19.9mL/min/1.73 m2 (0.9 � 0.3 mL/s; P � 0.05;Table 2). Changes in renal function (serum creat-inine level and Cockcroft-Gault creatinine clear-ance) did not differ significantly between groups.

A significant increase in HDL cholesterol lev-els without changes in total serum cholesterollevels, together with a tendency to a decrease inLDL cholesterol levels, was observed in the dietgroup, whereas patients in the control groupshowed a significant increase in total serum

cholesterol levels (Table 2). Changes in total andHDL cholesterol levels did not differ signifi-cantly between groups. Serum triglyceride levelsremained stable in the diet group, whereas anonsignificant increase was observed in the con-trol group (Table 2). The between-group differ-ence was statistically significant (P � 0.05).There were no significant changes in blood

pressure (systolic or diastolic) during the study,and no significant differences in these parame-ters between groups were observed along thestudy (Table 2). Numbers, classes, and doses ofantihypertensive drugs administered to bothgroups were similar.Eight of 20 patients in the diet group (40%)

and 5 of 10 subjects in the control group (50%)were administered statins before randomization.This treatment was maintained during the studywith no change in doses. There were no signifi-cant changes in serum total protein levels, serumalbumin levels, natriuresis, or protein intake (es-timated by urinary urea excretion) during thestudy (Table 2).There was no difference in degree of protein-

uria reduction between patients in the diet groupin whom urinary urea excretion decreased duringthe study (n � 10; proteinuria decreased fromprotein of 3.1 � 1.8 to 1.9 � 1.8 g/24 h; P �0.05) and those in whom urinary urea excretionremained stable or increased (n � 10; proteinuriadecreased from protein of 2.5 � 0.8 to 1.9 �1 g/24 h; P � 0.05). Proteinuria and body weightchanges showed a significant correlation (r �0.5; P � 0.01) during the study in all 30 patientsincluded in both groups.

Fig 2. Relationship of proteinuria and weightchanges in diet-group patients (N � 20). Changes areexpressed as percentage of positive or negativechange with respect to baseline values.

Fig 1. Changes in BMI (�) and proteinuria (line) inthe (top) diet group and (bottom) control group.

WEIGHT LOSS IN PROTEINURIC NEPHROPATHIES 323

Patients with type 2 diabetes included in thediet group (n � 10) showed a significant weightloss (mean weight loss, 3.6% � 3%) and BMIdecrease that were accompanied by a significantreduction in proteinuria (protein from 2.9 � 1.4to 1.9 � 1 g/24 h; P � 0.05; a 28.8% � 40.4%reduction from baseline values; Table 3). HDLcholesterol levels showed a significant increase,without changes in total serum cholesterol orLDL cholesterol levels (Table 3). There were nosignificant changes or differences between groupsin glycosylated hemoglobin levels. Patients with-out diabetes included in the diet group (n � 10)also showed a significant weight loss (from91.3 � 8.9 to 87.1 � 1.7 kg; P � 0.05), signifi-cant BMI decrease (from 33.7 � 4.1 to 32.1 �3.7 kg/m2; P � 0.05), and significant reductionin proteinuria (protein from 2.8 � 1.5 to 1.9 �1.7 g/24 h; P � 0.05).

DISCUSSION

This study shows that moderate weight lossinduces a significant decrease in proteinuria inoverweight patients with different proteinuricnephropathies. Mean percentage of weight losswith respect to baseline values was 4.1% � 3%in the diet group, and 18 of 20 patients includedin this group lost between 0.3 and 11.4 kg during

the study. These moderate weight losses wereaccompanied by a 31.2% � 37% decrease inbaseline urinary protein excretion at the end ofthe study (5 months), but the beneficial influenceof weight loss on proteinuria was already signifi-cant by the first month of the study (26.4% �30% proteinuria decrease). There was a closesignificant positive correlation between amountof weight loss and influence on protein excretion.Thus, when we analyzed only patients in the dietgroup who lost more than 3% of their baselinevalues (14 patients), we found a very significantproteinuria reduction from protein of 2.7 � 1.3to 1.3 � 0.8 g/24 h, equivalent to a 50.4% �20.9% decrease from baseline values.There is growing experimental evidence that

proteins abnormally filtered by glomeruli mayhave an important role in the progressive renalinjury of proteinuric nephropathies through adirect toxic effect on mesangial and tubular epi-thelial cells.10,11 In the last years, several prospec-tive clinical studies have shown that proteinuriais a significant independent determinant of pro-gression of chronic renal diseases, reporting astrong association of greater proteinuria withmore rapid decline in renal function.12-16 Con-versely, therapeutic measures that induce a de-crease in proteinuria are accompanied by signifi-

Table 3. Changes in Clinical and Biochemical Variables in Patients With Diabetes in the Diet Group

Baseline Month 1 Month 5

Weight (kg) 83.7 � 12.3 (62.2-99.1) 81.5 � 11.8 (61.5-96)*† 80.7 � 12.3 (57.7-95.8)*†BMI (kg/m2) 32.3 � 2.7 (28-36) 31.5 � 2.7 (27.2-35.8)*† 31.1 � 2.8 (26.9-35.8)*†Systolic blood pressure(mm Hg) 145.5 � 8 (130-154) 151.5 � 19.2 (125-180) 142.3 � 10.8 (120-159)

Diastolic blood pressure(mm Hg) 78.3 � 8.5 (70-90) 79.6 � 6.4 (70-90) 77.1 � 8.4 (69-92)

Serum creatinine (mg/dL) 1.4 � 0.7 (0.7-3.1) 1.3 � 0.7 (0.6-3.3) 1.4 � 0.7 (0.7-3)Creatinine clearance (mL/min/1.73 m2) 68.1 � 37.8 (25.9-151.2) 71.9 � 39.4 (24.2-131.2) 65.6 � 36.2 (26.4-132.4)

Total cholesterol (mg/dL) 186.3 � 69.1 (115-330) 205.6 � 64.2 (128-318) 196.9 � 43.8 (134-298)HDL cholesterol (mg/dL) 34.3 � 8.9 (21-44) 45 � 11.5 (33-63) 53.1 � 12.2 (38-67)*LDL cholesterol (mg/dL) 114.6 � 35.7 (62-154) 136.3 � 53.2 (60-241) 111.4 � 23 (73-135)Triglycerides (mg/dL) 99.8 � 34.9 (48-150) 91.1 � 24.4 (58-130) 102.2 � 25.2 (61-139)Urinary sodium (mEq/24 h) 214.5 � 76.8 (124-324) 186.6 � 54 (100-264) 202.8 � 72.7 (95-339)Urinary urea (g/24 h) 31.8 � 9.1 (21.4-42.3) 26 � 6.2 (16-32.7) 27.9 � 6.6 (14.6-34.1)Proteinuria (g/24 h) 2.9 � 1.4 (1.3-6.6) 1.7 � 0.8 (0.5-3.5)* 1.9 � 1 (0.5-3.5)*

NOTE. Values expressed as mean� SD (range). To convert to SI units: for serum creatinine (�mol/L), multiply by 88.4; forcreatinine clearance (mL/s), multiply by 0.0167; for total, HDL, and LDL cholesterol (mmol/L), multiply by 0.0259; fortriglycerides (mmol/L), multiply by 0.0113.*P � 0.05 versus baseline values.†P � 0.017, Bonferroni correction.

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cant slowing in the rate of renal failureprogression. Most of these data come from pro-spective studies performed with ACE inhibitorsthat showed a beneficial influence of these drugson the long-term evolution of both diabetic andnondiabetic proteinuric renal diseases.14-18 It hasbeen shown that the renal protection afforded byACE inhibitors in the long term is associatedclosely with the antiproteinuric effect of thesedrugs, already evident within the first weeks oftherapy.15,18,19

The antiproteinuric effect of weight loss ob-served in our study resembles that ofACE inhibi-tors in both the rapidity (proteinuria significantlyreduced within the first month of a low-caloriediet) and achieved amount of proteinuria reduc-tion. Therefore, a long-term beneficial effect onthe evolution of renal function could be pre-dicted, taking into account the referred studies.Despite the short duration of our study (5months),different trends between the diet and controlgroups were observed in the progression of renaldisease.Although changes in renal function (esti-mated by serum creatinine level and Cockcroft-Gault creatinine clearance) did not differ signifi-cantly between the groups, it remained stable inthe diet group and showed significant intragroupworsening in the control group. However, itshould be considered that the Cockcroft-Gaultformula is less accurate in obese than nonobesesubjects.20 Studies with a longer follow-up andmore precise estimations of renal function arerequired to confirm the beneficial influence ofweight loss on the evolution of overweight pa-tients with chronic proteinuria.One half of our diet-group patients (n � 10)

had type 2 diabetic nephropathy. When analyzedseparately, they reproduced results of the entiregroup: a moderate weight loss (3.6% � 3% ofbaseline values) induced a significant decrease inproteinuria from protein of 2.9 � 1.4 to 1.9 � 1g/24 hr. These results are particularly interestingconsidering that type 2 diabetic nephropathycurrently is the most common cause of end-stagerenal disease in developed countries and mostpatients with type 2 diabetes are obese.21 Recentstudies have shown that treatment with ARBs inpatients with type 2 diabetic nephropathy leadsto lower levels of proteinuria, lower rates ofdecline in glomerular filtration rate, and lateronset of end-stage renal disease than other antihy-

pertensive drugs.22,23 However, bothACE inhibi-tors and ARBs provide imperfect protectionagainst the progression of diabetic nephropa-thy.24 Our findings suggest that weight loss shouldbe an important additional therapeutic objectivein overweight patients with type 2 diabetic ne-phropathy.Several experimental and clinical studies sug-

gest that hyperlipidemia may contribute to theprogression of chronic nephropathies.25,26 Pa-tients in the diet group showed a favorable changein lipid profiles, with a significant increase inHDL cholesterol levels and a significant de-crease in LDL cholesterol levels, whereas serumtotal cholesterol levels remained unchanged. Inaddition, serum triglycerides levels remainedstable in the diet group and tended to increase inthe control group, with a significant differencebetween groups. Beneficial effects of a low-calorie diet and weight loss on the hyperlipid-emia of overweight patients is well established,but it is likely that the decrease in proteinuriaduring the study also collaborated in the improve-ment in lipid profile, taking into account theclose relationship between proteinuria and dysli-pemia.Adequate blood pressure control and reduc-

tion in protein intake are therapeutic measureswith a well-known beneficial effect on the pro-gression of chronic nephropathies.27 Blood pres-sure tended to decrease in the diet group andincrease in the control group by the end of study.It could be argued that these changes in bloodpressure values, although statistically nonsignifi-cant, might influence the changes in proteinuriaobserved in both groups during the study. How-ever, it is unlikely that the striking reduction inproteinuria (�30% of baseline values) observedin the diet group could be caused by such a mildreduction in blood pressure. Furthermore, protein-uria had already shown a significant decrease inthe diet group by the first month of the study,when both systolic and diastolic blood pressurewere slightly higher than at baseline in this group(Table 2). Both groups were targeted to a similarobjective of blood pressure control, avoiding theuse of ACE inhibitors, ARBs, or other drugs thatcould modify proteinuria. Similarly, protein re-striction was avoided in both groups and nochanges in urinary urea excretion (a reflection ofprotein intake) were observed during the study.

WEIGHT LOSS IN PROTEINURIC NEPHROPATHIES 325

The pathogenic mechanisms through whichobesity could induce proteinuria are largely un-known, but several data point to a pathogenicrole of glomerular hyperfiltration secondary tovasodilation of afferent glomerular arterioles andincreased hydrostatic pressure within the glomer-ular capillaries. These hemodynamic changeshave been described in obese subjects28,29 andmay be related to the characteristic insulin resis-tance and hyperinsulinemia of obesity.30,31

In addition, studies in the obese Zucker rat, amodel of obesity, hyperinsulinemia, and hyperlip-idemia that develops glomerulosclerosis and re-nal insufficiency, have suggested an importantrole for hyperlipidemia.32 Recent experimentalstudies have shown that leptin, a hormone pro-duced by adipocytes that has serum levels closelyrelated to body weight, can induce proteinuria,glomerulosclerosis, and increased synthesis oftransforming growth factor-� and collagen.33 Ourstudy showing the antiproteinuric effect of weightloss in a variety of chronic proteinuric nephropa-thies suggests that these harmful pathogenicmechanisms induced by obesity also could beoperative in any type of proteinuric renal disease,independent of its cause. Unlike the diet group,patients in the control group who maintainedtheir usual dietary habits during the study showeda significant increase in body weight and BMI.Proteinuria tended to increase in this group, withprotein increasing from 3 � 2.2 to 3.5 � 2.1 g/24 h. Although statistically nonsignificant, thisincrease in proteinuria suggests that weight gainin overweight patients with chronic proteinuricnephropathies could increase proteinuria throughthe exacerbation of glomerular hyperfiltrationand the other harmful effects of obesity on kid-ney function summarized.In conclusion, our study shows for the first

time that a moderate weight loss induced by ahypocaloric and normoproteinic diet in over-weight patients with chronic proteinuric ne-phropathies is followed by a significant decreasein proteinuria. This beneficial influence also wasremarkable in patients with type 2 diabetic ne-phropathy who followed the low calorie diet.

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