Clinical characteristics and outcomes of HIV-associated immune complex kidney disease.

BACKGROUND: The pathogenesis and natural history of HIV-associated immune complex kidney disease (HIVICK) is not well understood. Key questions remain unanswered, including the role of HIV infection and replication in disease development and the efficacy of antiretroviral therapy (ART) in the prevention and treatment of disease. METHODS: In this multicentre study, we describe the renal pathology of HIVICK and compare the clinical characteristics of patients with HIVICK with those with IgA nephropathy and HIV-associated nephropathy (HIVAN). Poisson regression models were used to identify risk factors for each of these pathologies. RESULTS: Between 1998 and 2012, 65 patients were diagnosed with HIVICK, 27 with IgA nephropathy and 70 with HIVAN. Black ethnicity and HIV RNA were associated with HIVICK, receipt of ART with IgA nephropathy and black ethnicity and CD4 cell count with HIVAN. HIVICK was associated with lower rates of progression to end-stage kidney disease compared with HIVAN and IgA nephropathy (P < 0.0001). Patients with HIVICK who initiated ART and achieved suppression of HIV RNA experienced improvements in estimated glomerular filtration rate and proteinuria. CONCLUSIONS: These findings suggest a pathogenic role for HIV replication in the development of HIVICK and that ART may improve kidney function in patients who have detectable HIV RNA at the time of HIVICK diagnosis. Our data also suggest that IgA nephropathy should be viewed as a separate entity and not included in the HIVICK spectrum.

APOL1 Risk Variants Are Strongly Associated with HIV-Associated Nephropathy in Black South Africans.

APOL1 variants are associated with HIV-associated nephropathy and FSGS in African Americans. The prevalence of these variants in African populations with CKD in HIV-1 infection has not been investigated. We determined the role of APOL1 variants in 120 patients with HIV-associated nephropathy and CKD and 108 controls from a South-African black population. Patients with CKD were selected on the basis of histology. Genotypes were successfully determined for APOL1 G1 and G2 variants and 42 single nucleotide polymorphisms, including 18 ancestry informative markers, for 116 patients with CKD (96.7%; 38 patients with HIV-associated nephropathy, 39 patients with HIV-positive CKD, and 39 patients with HIV-negative CKD), and 108 controls (100%). Overall, 79% of patients with HIV-associated nephropathy and 2% of population controls carried two risk alleles. In a recessive model, individuals carrying any combination of two APOL1 risk alleles had 89-fold higher odds (95% confidence interval, 18 to 912; P<0.001) of developing HIV-associated nephropathy compared with HIV-positive controls. Population allele frequencies were 7.3% for G1 and 11.1% for G2. APOL1 risk alleles were not significantly associated with other forms of CKD. These results indicate HIV-positive, antiretroviral therapy-naïve South-African blacks with two APOL1 risk alleles are at very high risk for developing HIV-associated nephropathy. Further studies are required to determine the effect of APOL1 risk variants on kidney diseases in other regions of sub-Saharan Africa.

Plasma apolipoprotein L1 levels do not correlate with CKD.

Polymorphisms in APOL1 are associated with CKD, including HIV-related CKD, in individuals of African ancestry. The apolipoprotein L1 (APOL1) protein circulates and is localized in kidney cells, but the contribution of APOL1 location to CKD pathogenesis is unclear. We examined associations of plasma APOL1 levels with plasma cytokine levels, dyslipidemia, and APOL1 genotype in a nested case-control study (n=270) of HIV-infected African Americans enrolled in a multicenter prospective observational study. Patients were designated as having CKD when estimated GFR (eGFR) decreased to <60 ml/min per 1.73 m(2) (eGFR<60 cohort) or protein-to-creatinine ratios became >3.5 g/g (nephrotic proteinuria cohort). Circulating APOL1 levels did not associate with APOL1 genotype, CKD status, or levels of proinflammatory cytokines, but did correlate with fasting cholesterol, LDL cholesterol, and triglyceride levels. At ascertainment, CKD-associated polymorphisms (risk variants) in APOL1 associated with the eGFR<60 cohort, but not the nephrotic-range proteinuria cohort. Of note, in both the eGFR<60 and nephrotic proteinuria cohorts, CKD cases with two APOL1 risk variants had significant declines in eGFR over a median of 4 years compared with individuals with one or no risk variants. APOL1 risk genotype was not associated with changes in proteinuria. Higher circulating proinflammatory cytokine levels were independently associated with CKD but not APOL1 genotype. In conclusion, the function of variant APOL1 proteins derived from circulation or synthesized in the kidney, but not the level of circulating APOL1, probably mediates APOL1-associated kidney disease in HIV-infected African Americans.

Serum albumin and kidney function decline in HIV-infected women.

BACKGROUND: Serum albumin concentrations are a strong predictor of mortality and cardiovascular disease in human immunodeficiency virus (HIV)-infected individuals. We studied the longitudinal associations between serum albumin levels and kidney function decline in a population of HIV-infected women. STUDY DESIGN: Retrospective cohort analysis. SETTING & PARTICIPANTS: Study participants were recruited from the Women's Interagency HIV Study (WIHS), a large observational study designed to understand risk factors for the progression of HIV infection in women living in urban communities. 908 participants had baseline assessment of kidney function and 2 follow-up measurements over an average of 8 years. PREDICTOR: The primary predictor was serum albumin concentration. OUTCOMES: We examined annual change in kidney function. Secondary outcomes included rapid kidney function decline and incident reduced estimated glomerular filtration rate (eGFR). MEASUREMENTS: Kidney function decline was determined by cystatin C-based (eGFR(cys)) and creatinine-based eGFR (eGFR(cr)) at baseline and follow-up. Each model was adjusted for kidney disease and HIV-related risk factors using linear and relative risk regression. RESULTS: After multivariate adjustment, each 0.5-g/dL decrement in baseline serum albumin concentration was associated with a 0.56-mL/min faster annual decline in eGFR(cys) (P < 0.001), which was attenuated only slightly to 0.55 mL/min/1.73 m(2) after adjustment for albuminuria. Results were similar whether using eGFR(cys) or eGFR(cr). In adjusted analyses, each 0.5-g/dL lower baseline serum albumin level was associated with a 1.71-fold greater risk of rapid kidney function decline (P < 0.001) and a 1.72-fold greater risk of incident reduced eGFR (P < 0.001). LIMITATIONS: The cohort is composed of only female participants from urban communities within the United States. CONCLUSIONS: Lower serum albumin levels were associated strongly with kidney function decline and incident reduced eGFRs in HIV-infected women independent of HIV disease status, body mass index, and albuminuria.

HIV associated renal disease: a pilot study from north India.

BACKGROUND & OBJECTIVES: HIV/AIDS patients may have renal involvement also, however, Indian data are sparse. The present study was done to find the spectrum of renal diseases in HIV/AIDS patients in north India. METHODS: In this prospective pilot study, HIV positive patients aged >18 yr were screened for renal involvement [serum creatinine >1.5 mg% and/or significant proteinuria (>500 mg /day)]. Patients who were positive on screening were followed up prospectively and underwent kidney biopsy if indicated. RESULTS: A total of 526 patients were screened, of these, 91 (17.3%) were found to have renal involvement. Group A (Treatment naοve) comprised 392 patients who were not on antiretroviral treatment (ART) and group B (patients on ART) comprised 134 patients. More patients (74/392, 18.9%) in group A had renal involvement as compared to patients in group B (17/134, 12.7%). Of the 91 patients with renal involvement, 26 were followed up and underwent kidney biopsy. Thirteen patients had only proteinuria and another 13 had renal dysfunction with or without proteinuria. Most common histological diagnosis was mesangioproliferative glomerulonephritis (mes PGN) (10/26). Two patients had collapsing FSGS (focal segmental glomerulosclerosis) and three patients had immune complex glomerulonephritis. Seven patients had acute kidney injury, whom six totally recovered from their renal function. All patients with mesPGN tolerated angiotensin converting enzyme (ACE) inhibitors well. There was mixed response of collapsing FSGS to steroids. Both patients with MPGN (membranoproliferative glomerulonephritis) did well on low dose of steroid and ART. INTERPRETATION & CONCLUSIONS: Renal involvement was found to be common in HIV positive patients (17.3%). A low occurrence of renal involvement found in patients already on ART suggests some renoprotective effect of ART. Our preliminary results showed that collapsing FSGS was not rare in Indian HIV positive population, but classical HIV associated nephropathy was not seen. Longitudinal studies with robust study design and large sample size need to be done to confirm the findings.

Estimating glomerular filtration rate in HIV-infected adults in Africa: comparison of Cockcroft-Gault and Modification of Diet in Renal Disease formulae.

BACKGROUND: Cockcroft-Gault (CG) and Modification of Diet in Renal Disease (MDRD) formulae are recommended for glomerular filtration rate (GFR) estimation, but neither has been validated or directly compared longitudinally in HIV-infected patients or in Africa. METHODS: We investigated differences between formulae in baseline GFR, GFR changes and incidence of impaired GFR after initiation of antiretroviral therapy (ART) in 3,316 HIV-infected adults in Africa, considering sex, age, body mass index and baseline laboratory parameters as predictors. RESULTS: Participants were 65% women, median age 36.8 years, median weight 56.7 kg. Baseline GFR was lower using CG (median 89 ml/min/1.73 m2, 7.4% <60 ml/min/1.73 m2) versus MDRD (103 ml/min/1.73 m2, 3.1% <60 ml/min/1.73 m2). At 36 weeks, median CG-GFR increased (92 ml/min/1.73 m2), whereas MDRD-GFR decreased (96 ml/min/1.73 m2). Weight (explicitly a factor in CG only) concurrently increased to 62.0 kg. GFR changes from weeks 36-96 (after weight stabilization) were similar across formulae. By 96 weeks, 56 patients developed severe GFR impairment (<30 ml/min/1.73 m2) using one or both formulae (both n=45, CG n=7, MDRD n=4) compared with only 24 by serum creatinine alone. Multivariate models identified different sets of predictors for each formula. CONCLUSIONS: Although severe GFR impairments are similarly classified by different formulae, moderate impairments were more frequently identified using CG-GFR versus MDRD-GFR (with Black ethnicity correction factor 1.21), and creatinine alone had low sensitivity. Given overestimation in underweight patients and sensitivity to weight changes, this MDRD formula might not necessarily be superior for monitoring ART in African HIV-infected adults.

ABO incompatible renal transplantation in an HIV-seropositive patient.

To date, there have been no reports of successful ABO blood group incompatible renal transplantation in HIV patients. We describe a case of a 47-year-old African American man with end-stage renal disease secondary to HIV-induced nephropathy who underwent a live unrelated (spouse) donor ABO blood group incompatible transplant using an intravenous immunoglobulin/plasmapheresis preconditioning regimen with interleukin-2 receptor antagonist induction along with tacrolimus and mycophenolate mofetil maintenance. The postoperative course was complicated by two acute cellular rejection (Banff Ia) episodes that were successfully managed with corticosteroid boluses and the addition of corticosteroids to maintenance immunosuppression. Antibody-mediated rejection was not observed on biopsy. The patient reached a serum creatinine nadir of 2.0 mg/dL on postoperative day 20, which has now been maintained for 170 days. His current CD4 count was 410 cells/microL.

Sonographic evaluation of kidney echogenicity and morphology among HIV sero-positive adults at Lagos University Teaching Hospital.

AIM: To evaluate the role of kidney echogenicity and morphology in the diagnosis of human immunodeficiency virus-associated nephropathy (HIVAN). SUBJECTS AND METHODS: In the cross-sectional study, a sample of 340 anti-retroviral therapy (ART)-naïve AIDS patients underwent laboratory CD4+ count, serum creatinine determination and sonographic renal echogenicity grading and size measurement. Rounded kidneys were described as bulbous while bean-shaped kidneys were described as reniform; echogenicity was categorized into grades 0, 1, 2 and 3. Kidney length, width, thickness and volume were measured in HIVAN and control groups. RESULTS: Mean age of the population was 42.7 ± 9.4 years; 87.4% had HIVAN. Mean CD4+ count, serum creatinine and GFR for HIVAN patients were 153.1 ± 103.2 cells/mm3, 218.4 ± 147.4 mmol/L and 50.1 ± 23.6 mL/min/1.73 m2 for males and 121.9 ± 91.0 cells/mm3, and 222.0 ± 150.4 mmol/L and 39.3 ± 20.6 mL/min/1.73 m2 for females, respectively; control subjects and non-HIVAN patients had grade 0 renal echogenicity; 56.9% of HIVAN patients had echogenicity grade 3; 5.3% had kidney length < 10 cm; 73.9% had bulbous kidneys; the kidney was significantly wider and thicker in HIVAN (p < 0.05). CONCLUSION: Sonographic evaluation of renal echogenicity and morphology can reliably predict HIVAN diagnosis. Apathy to screening and late presentation were high while HIV/AIDS remains an important public health problem in the city of Lagos. Unilateral reduction in kidney size could be a major sequela of AIDS while sonographic measurement of absolute kidney length appears inadequate in the evaluation of AIDS patients with nephropathy.

HIV-associated nephropathy: case study and review of the literature.

Human immunodeficiency virus type 1 (HIV-1)-seropositive patients are at risk for the development of a variety of acute and chronic renal diseases. The most common cause of chronic renal failure in HIV-1-seropositive patients is HIV-associated nephropathy (HIVAN). HIVAN occurs almost exclusively in black patients and the majority of published cases are of patients who present with acquired immunodeficiency syndrome (AIDS). This disease is currently the third leading cause of end-stage renal disease in blacks aged 20-64. Because HIV-1-seropositive patients may develop a wide variety of acute and chronic renal diseases, definitive diagnosis requires renal biopsy. Emerging data suggest a direct role of HIV-1 infection of kidney cells in the pathogenesis of HIVAN. There have been no well-controlled clinical trials in the treatment of HIVAN. The therapeutic agents with the most promise are angiotensin-converting enzyme inhibitors and antiretroviral medications. Long-term renal prognosis may be changing in the setting of improved aggressive antiretroviral therapy. Patient survival is determined primarily by the stage of HIV-1 infection. In this article, we present the case history of a patient who developed HIVAN. We then review the current literature concerning the epidemiology, differential diagnosis, etiology, and treatment of HIVAN.

[Renal insufficiency with AIDS: ultrasonographic aspects]. / Insuffisance rénale associée au SIDA: aspects échographiques.

UNLABELLED: Renal pathologic changes in AIDS involve various factors and can also occur in several other forms of renal disease. Renal sonography was prospectively performed in 31 patients with laboratory evidence of AIDS and renal insufficiency. All patients included in this study were without clinical manifestations (group II of the CDC) and without risk factors of AIDS. AIM: to characterize renal pathologic changes underlying the sonographic findings in these patients. Sonographic evaluation included determination of renal sizes and renal echogenicity according to standard grading system. Sonography showed normal-sized or enlarge-sized kidneys. Enlarged kidneys were generally due to increased thickness rather than length or width; small-sized kidneys were not observed. Grading echogenicity showed: grade 0 in 3 patients, grade I in none, grade II in 11 patients and grade III in 17 patients. In six patients, we found "spotted" echostructural figure due to several hypoechoic and rounded zones. Echogenicity increased with the severity of renal insufficiency. Our study suggests that renal abnormalities are varied and can occur in all stages in the course of the disease. The particular "spotted" figure associated with enlarged size at the expense of thickness of kidneys must draw radiologist's attention to the probability of AIDS lesions. Further studies with large populations must be performed to confirm our observations.

[High levels of HIV-1 RNA Associated with Early-Onset Glomerulopathy in Patients with HIV Infection]. / Niveles altos de RNA VIH-1, asociados a glomerulopatía temprana, en pacientes con infección por VIH.

BACKGROUND: There is an association not yet known, between high levels of HIV-1 RNA and HIV-associated nephropathy (HIVAN). There is also a barely known association between HIV-1 RNA levels and HIV-associated glomerular disease. OBJECTIVE: To determine the association between high HIV-1 RNA levels and alterations in glomerular filtration rate (GFR) in patients with HIV infection. MATERIAL AND METHODS: We conducted a prospective trial involving 198 seropositive HIV patients. three groups were formed: 53 patients with abnormal GFR (group I); 48 patients with proteinuria greater than 300 mg and less than 1 g in 24 h urine collection and/or with urinary cast (group 2); and 87 patients without nephropathy (group 3). We carried out comparative analysis for the most common factors associated with nephropathy in HIV seropositive patients. RESULTS: Within factors associated with nephropathy, only RNA-HIV-1 plasma levels had a statistically significant association with altered GFR. (p = 0.008). CONCLUSION: High levels of HIV-1 RNA are associated with initial forms of HIV- associated glomerulopathy, which do not have a rapid course to end- stage renal disease, but that do cause glomerular dysfunction, that could be subjected to early interventions.

Pretransplantation pharmacokinetic curves of tacrolimus in HIV-infected patients on ritonavir-containing cART: a pilot study.

BACKGROUND: Ritonavir is an extremely strong inhibitor of P450 cytochrome 3A, which is the main metabolizing enzyme of tacrolimus. Subsequently, the pharmacokinetics of tacrolimus are affected to a large extend by the coadministration of ritonavir in HIV-infected transplant recipients. Therefore, to prevent overexposure directly posttransplantation in HIV-infected patients on ritonavir-containing cART, the predictive value of a pretransplantation pharmacokinetic curve of tacrolimus was explored. METHODS: A pretransplantation pharmacokinetic model of tacrolimus in these patients was developed, and a posttransplantation dosing advice was established for each individual patient. The pharmacokinetic population parameters were compared with HIV-negative patients, and predictive value of the pretransplantation curves was assessed in patients after the transplantation procedure. RESULTS: No significant difference was found between the model-predicted and actual posttransplantation 24 h-tacrolimus levels (14.6 vs. 17.8 ng/mL, P=0.19). As the simulated pharmacokinetic curves lacked an absorption peak every 12 h, the mean 12 h-AUC was approximately 40 % lower compared with AUC's reported in HIV-negative recipients, when similar trough levels were targeted. CONCLUSION: In conclusion, pretransplantation curves of tacrolimus seem a promising tool to prevent overexposure directly posttransplantation in patients on ritonavir-containing cART and raising trough levels to achieve an exposure equivalent to HIV-negative recipients is suggested.

Basic fibroblast growth factor in HIV-associated hemolytic uremic syndrome.

Endothelial injury is the primary pathogenic event leading to the renal thrombotic microangiopathic lesions typical of the hemolytic uremic syndrome (HUS). Basic fibroblast growth factor (bFGF) is an angiogenic growth factor released by injured endothelial cells. In a previous study we have found a significant accumulation of bFGF in human immunodeficiency virus (HIV)-transgenic mice with renal disease. Here we investigated whether bFGF was accumulated in the circulation and kidneys of two children with HIV-associated HUS (HIV-HUS), and studied the mechanisms involved in this process. The plasma levels of bFGF in children with HIV-HUS (124+/-20 pg/ml) were increased compared with five children with HIV nephropathy (49+/-6 pg/ml) and twenty HIV-infected children without renal disease (26+/-4 pg/ml, P<0.001). Immunohistochemistry and receptor binding studies showed that bFGF was accumulated bound to heparan sulfate proteoglycans in renal glomeruli and interstitium surrounding renal tubules in HIV-HUS kidneys. Basic FGF stimulated the proliferation of mesangial and urinary renal tubular epithelial cells isolated from both patients. These findings support the hypothesis that bFGF and its low-affinity binding sites may play a relevant role in modulating the process of glomerular and renal tubular regeneration during the acute stages of HIV-HUS. A follow-up study in a larger sample population is required to confirm these results.

Clinicopathologic correlates of prednisone treatment of human immunodeficiency virus-associated nephropathy.

A 43-year-old man with rapidly evolving renal failure from biopsy-proven human immunodeficiency virus (HIV)-associated nephropathy (HIVAN) and superimposed thrombotic microangiopathic changes was treated with prednisone. His serum creatinine decreased from 7.5 to 3.9 mg/dL, and the 24-hour protein excretion decreased from 15.7 to 6.1 g over 6 to 8 weeks. As the prednisone was tapered, however, the creatinine began to increase, and a repeat biopsy was done to assist with therapeutic decisions. The major differences from the pretreatment biopsy were marked reductions in interstitial lymphocytes and macrophages and absence of thrombotic microangiopathic lesions. This is the first report comparing pretreatment and posttreatment renal biopsy specimens and the findings provide some insight into the means by which prednisone exerts its beneficial clinical effects acutely on this disease.

Circulating immune complexes and analysis of renal immune deposits in feline immunodeficiency virus-infected cats.

Total immunoglobulin content and concentration of immune complexes (IC) were determined in the sera of 51 cats infected with feline immunodeficiency virus (FIV) and of 40 controls. IgG and IgM were quantified by radial immunodiffusion and circulating IC (CIC) by the CIC-conglutinin assay. IgG fractions were obtained by acid elution from kidney tissues of 15 FIV-infected and five negative control cats to investigate the possible role of IC in the genesis of renal damage observed in infected animals. Mean concentrations of IgG and circulating IC were higher in FIV-infected cats than in controls (29.6 +/- 6.7 versus 23.0 +/- 1.9 mg/dl (mean +/- s.d.) P < 0.001; and 66.5 +/- 17.0 versus 27.4 +/- 19.9% I, P < 0.001, respectively), while IgM levels were only slightly increased (0.9 +/- 0.05 versus 0.87 +/- 0.04 mg/dl, P < 0.02). Immunoglobulin fractions were eluted from 10 of the 15 renal tissue samples from FIV-infected cats and were found to be polyclonal and at least partly specific for FIV antigens. These findings confirm the presence of a B cell activation in FIV-infected cats and demonstrate the presence of high levels of CIC in their sera. The presence of immune deposits in renal tissues suggests that IC might play a role in the pathogenesis of the renal damage observed in FIV-infected cats.

Oncotic pressure and edema formation in hypoalbuminemic HIV-infected patients with proteinuria.

Human immunodeficiency virus nephropathy (HIVN) continues to challenge nephrologic consultative services at major urban institutions. Although noted in the literature, the decreased incidence of peripheral edema in HIVN has been unexplained to date. In HIV patients, total proteins frequently are found to be elevated due to an elevated globulin fraction. The impact that plasma proteins, specifically globulins, have on the total oncotic pressure has not been reported in HIVN, but may play a role in the paucity of edema noted in this proteinuric population. To evaluate the contributions of serum globulin to the total oncotic pressure and the presence or absence of edema in HIVN, we randomly selected 27 patients with proteinuria greater than 2.5 g/24 hr and serum albumin less than 3.1 g/dL from patients presenting to the nephrology outpatient clinic at the University of Miami/Jackson Memorial Hospital. Seventeen of the patients (63%) had a known diagnosis of HIV infection (group 1). These patients were subdivided into two subgroups: those presenting with clinically evident edema on physical examination (n = 7 [41%]; group 1A) and those who had an absence of edema (n = 10 [59%]; group 1B). Conversely, group 2 comprised 10 patients without known HIV infection, of whom six (60%) had edema (group 2A) and four (40%) did not (group 2B). Blood pressures were noted, and mean arterial pressure was calculated using standard formulas. Serum albumin, serum total proteins, and urine total proteins were measured using standard laboratory methods. Oncotic pressures for albumin (alpha), globulin (beta), and total protein (c) were calculated using the following formula: COPpl = alpha(2.8c + 0.18c2 + 0.012c3) + beta(0.9c + 0.12c2 + 0.004c3). We used Student's t-test to analyze the data. There is no significant difference between the albumin concentrations of HIV patients without edema (group 1B) and non-HIV patients with edema (group 2A), with mean concentrations of 2.3 +/- 0.1 g/dL versus 2.3 +/- 0.15 g/dL, respectively (P = NS). Group 1B, however, has a total oncotic pressure of 17.1 +/- 1.5 mm Hg, whereas both groups with edema (groups 1A and 2A) have statistically significant lower total oncotic pressures (12.1 +/- 2.3 mm Hg and 12.9 +/- 1.1 mm Hg, respectively; P < 0.05). The globulin oncotic pressures may account for some of the differences in total oncotic pressures, being significantly higher for those patients without edema in group 1B compared with group 2A (7.1 +/- 0.9 mm Hg v 3.9 +/- 0.4 mm Hg, respectively; P < 0.05). In patients with HIV, however, the presence or absence of edema is mandated by albumin concentration because both groups have similar globulin concentrations (group 1A 3.1 +/- 0.1 g/dL v group 1B 3.8 +/- 0.3 g/dL; P = NS). Mean arterial pressure does not play a role in edema formation in this study because the HIV patients without edema had the higher blood pressures (group 1B 97.8 +/- 4.7 mm Hg v group 2A 84.7 +/- 5.5 mm Hg; P < 0.05). We conclude that globulins play an important role in maintaining oncotic pressure in low albumin states. HIVN patients with increased serum immune globulin may benefit from higher globulin oncotic pressure, delaying the onset of clinical edema in the setting of proteinuria.