Efficacy and tolerability of magnesium plus protein for managing hypomagnesemia in pediatric kidney transplant patients.

We sought to investigate whether magnesium oxide bound to soy protein (MGP) increases serum magnesium concentrations with less diarrhea compared to commonly prescribed magnesium salts. Subjects were switched to MGP at a near-equivalent daily elemental magnesium dose. Mean serum magnesium levels were compared. If magnesium levels remained <1.7 mg/dL after switching to MGP, subjects were enrolled into Part 2 and received a one-time MGP dose adjustment. The MGP daily dose was increased by 266 mg. For both parts 1 and 2, subjects recorded the number and quality of their stools to assess gastrointestinal (GI) tolerability of MGP. Twelve pediatric kidney transplant recipients completed Part 1. Mean serum magnesium levels increased from 1.61 (SD 0.1) on standard MG to 1.69 (SD 0.1); t(11) = 2.6, P = .02 on MGP. Five subjects completed Part 2, and all achieved serum magnesium ≥1.7 mg/dL (mean 1.75 mg/dL, SD 0.06; t(4) = 2.7, P = .06). Subjects reported the same number of, but looser bowel movements with MGP; however, individuals did not perceive intolerable GI symptoms with MGP therapy and all chose to remain on MGP at the end of the study. At an equivalent mg/kg/d dose of elemental magnesium, serum magnesium levels on MGP were significantly higher.

Immunogenicity of Augmented Compared With Standard Dose Hepatitis B Vaccine in Pediatric Patients on Dialysis: a Midwest Pediatric Nephrology Consortium Study.

BACKGROUND AND OBJECTIVES: Patients on maintenance dialysis have a higher risk of unresponsiveness to hepatitis B vaccination and loss of hepatitis B immunity. Adult guidelines recommend augmented dosing (40 mcg/dose), resulting in improved response in adults. We sought to determine whether children on dialysis mount a similar antibody response when given standard or augmented dosing of hepatitis B vaccine. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: This is a retrospective review of patients on dialysis aged <19 years from May 1, 2008 to May 1, 2013 at 12 pediatric dialysis units. Hepatitis B surface antibody (HBsAb) titers ≥10 mIU/ml were defined as protective. RESULTS: A total of 187 out of 417 patients received one or more hepatitis B vaccine boosters. The median age was 13 years; the cohort was 57% boys and 59% white. Booster dose or HBsAb titers were missing in 17 patients. Conversion to protective HBsAb titers was achieved in 135 out of 170 patients (79%) after their first single-dose booster or multidose booster series. In patients receiving a single-dose booster, the response rate was 53% (nine out of 17) after a 10 mcg dose, 86% (65 out of 76) after a 20 mcg dose, and 65% (17 out of 26) after a 40 mcg hepatitis B vaccine dose. In patients receiving a multidose booster series, the response rate was 95% (19 out of 20) after a 10 mcg/dose series, 83% (20 out of 24) after a 20 mcg/dose series, and 71% (five out of seven) after a 40 mcg/dose series. Patients receiving a multidose booster series had a response rate of 86% (44 out of 51), compared with 76% (91 out of 119) in patients receiving a single-dose booster (P=0.21). Twenty-seven patients received more than one single-dose booster or multidose series, and 26 out of 27 (96%) eventually gained immunity after receiving one to three additional single-dose boosters or multidose booster series. CONCLUSIONS: There was no clear gradient of increasing seroconversion rate with increasing vaccine dose in this cohort of pediatric patients on dialysis.

Renal transplantation in Bardet-Biedl Syndrome.

BACKGROUND: Renal anomalies are common in patients with Bardet-Biedl syndrome (BBS), a renal cystic ciliopathy with multi-systemic features. Renal transplantation is indicated in cases of end-stage renal disease (ESRD), but transplant centers may be hesitant to perform the necessary transplant in light of the multitude of metabolic comorbidities these patients often face with the potential to complicate outcomes. METHODS: Data from the Clinical Registry Investigating BBS (CRIBBS) were used to investigate renal transplant outcomes in the largest BBS cohort described to date. RESULTS: Of the 206 patients enrolled in the CRIBBS, 21 children (10.2 %; 16 girls, 5 boys; median age 8.4 years) had been diagnosed with ESRD. Renal transplantation was performed in 18 of these individuals between 1982 and 2015, including repeat transplantation in some cases, for a total of 22 kidneys. Overall graft survival was 81.6 % at 1 year post-transplantation, 75.7 % at 5 years, 59 % at 10 years, and 49.2 % at 25 years. Patient survival was 94.4 % at 1 year post-transplantation, 87.2 % at 8 years, and 79.3 % at 25 years. CONCLUSIONS: At a median follow-up time of 97 months, relatively few complications of renal transplantation were reported in the patients of this study. However, body mass index was significantly elevated in transplanted individuals compared to non-transplanted individuals participating in CRIBBS at the most recent follow-up. Although the frequency of obesity and other manifestations of the metabolic syndrome warrant meticulous management in this high-risk population, favorable long-term outcomes suggest that renal transplantation is a viable option for patients with BBS and ESRD.

Applicability of the Schwartz Equation and the Chronic Kidney Disease in Children Bedside Equation for Estimating Glomerular Filtration Rate in Overweight Children.

STUDY OBJECTIVE: To determine if significant correlations exist between glomerular filtration rate (GFR) prediction equation values, derived by using the original Schwartz equation and the Chronic Kidney Disease in Children (CKiD) bedside equation with a 24-hour urine creatinine clearance (Clcr ) value normalized to a body surface area of 1.73 m(2) in overweight and obese children. DESIGN: Prospective analysis (20 patients) and retrospective analysis (43 patients). SETTING: Pediatric inpatient ward and pediatric nephrology clinic at a comprehensive academic medical center. PATIENTS: Sixty-three pediatric patients (aged 5-17 years), of whom 27 were overweight (body mass index [BMI] at the 85th percentile or higher) and 36 were not overweight (BMI lower than the 85th percentile [controls]) between 2007 and 2012. METHODS AND MAIN RESULTS: Data from the overweight patients were compared with nonoverweight controls. GFR values were calculated by using the original Schwartz equation and the CKiD bedside equation. Each patient's 24-hour urine Clcr value normalized to a body surface area of 1.73 m(2) served as the index value. A Pearson correlation coefficient model was used to determine association between the 24-hour urine Clcr value (index value) with the Schwartz and CKiD GFR estimations. Significant correlation was found to exist between the Schwartz and CKiD bedside GFR estimations relative to the 24-hour urine Clcr in the control subjects (r = 0.85, p<0.0001, and r = 0.85, p<0.0001, respectively). Significant correlation was also found to exist between the Schwartz and CKiD bedside GFR values with the 24-hour urine Clcr value in overweight subjects (r = 0.86, p<0.0001, and r = 0.86, p<0.0001, respectively). The Schwartz equation estimated average GFR 21.75 ml/minute/1.73 m(2) higher than 24-hour urine Clcr (p<0.0001) in overweight children with a kidney disorder. The CKiD bedside GFR estimations were not significantly different compared with 24-hour urine Clcr values for the overweight group with kidney disorder (p=0.85). CONCLUSION: The Schwartz and CKiD bedside estimations of GFR correlated with 24-hour urine Clcr values in both overweight and nonoverweight children. Compared with the Schwartz equation, which tended to overestimate renal function, the CKiD bedside equation appeared to approximate 24-hour urine Clcr more closely in overweight children with kidney disorder.

Comparison of cystatin C and Beta-2-microglobulin kinetics in children on maintenance hemodialysis.

Middle-molecules (MM) are not monitored in children on hemodialysis (HD), but are accumulated and increase the risk of cardiovascular disease and mortality. Molecular properties of Cystatin C (CyC), 13 kDa, potentially make it a preferred MM marker over Beta-2-Microglobulin (B2M), 12 kDa. We compared CyC and B2M kinetics to investigate if CyC can be used as preferred MM marker. CyC (mg/L) and B2M (µg/mL) were measured in 21 low-flux HD sessions in seven children. Blood samples were taken at HD start (pre), 1 and 2 hours into HD and at end of HD (post) for all sessions and 60 minutes after the first HD (Eq). PreCyC (9.85 ± 2.15) did not differ (P > 0.05) from postCyC (10.04 ± 2.83). PostB2M (38.87 ± 7.12) was higher (P < 0.05) than preHD B2M (33.27 ± 7.41). There was no change in CyC at 1 and 2 hours into HD, while B2M progressively increased. CyC or B2M changes did not significantly correlate with spKt/V (2.09 ± 0.86), ultrafiltration (4.61 ± 1.98%) or HD duration (218 ± 20 minutes). EqCyC was not different from postCyC (11.07 ± 3.14 vs. 10.71 ± 2.85, P > 0.05), while EqB2M was lower than postB2M (36.48 ± 7.68 vs. 41.09 ± 8.99, P < 0.05). MMs as represented by B2M and CyC are elevated in children on standard HD. Intensified HD modalities would be needed for their removal. B2M is affected by the dialytic process with a rise during HD independent of ultrafiltration and decrease 1 hour after, while CyC remains unchanged. We suggest that CyC be used as preferred marker of MM removal and as a marker of adequacy of intensified HD regimens.

Cystatin C in children on chronic hemodialysis.

BACKGROUND: Cystatin C (CyC) concentration has been suggested as a marker of middle-molecule accumulation, hemodialysis (HD) adequacy and for estimating residual renal function (RRF), but it has not been studied in pediatric HD. High CyC is associated with increased cardiovascular disease (CVD). We investigated CyC kinetics and the effect of RRF on CyC in a pediatric HD population. METHODS: A total of 21 HD sessions and 20 interdialytic periods were analyzed in seven patients, age 5-19 years, of whom four were anuric (A) and three were non-anuric (NA). CyC was measured before (preHD) and after (postHD) three standard HD sessions in 1 week and prior to the first session of the following week. RESULTS: We found no difference (p=0.67) in CyC concentration between preHD CyC (9.85 ± 2.15 mg/l; A vs. NA, p=0.37) and postHD CyC (10.04 ± 2.83 mg/l; A vs NA, p=0.28). The weekly average preHD CyC median concentration was 10.14 mg/l (A vs. NA, p=0.87) and correlated with age (r=0.808, p=0.03) and height measurement (r=0.799, p=0.03), but not with RRF, single-pool Kt/V, ultrafiltration, HD duration or blood liters processed. CONCLUSIONS: Cystatin C is very elevated in children on HD. It does not rise between HD sessions, is not removed by standard HD and remains at steady state; therefore, elimination is extrarenal. Low RRF does not affect CyC elimination. CyC increases with age and height. If a high CyC concentration can be proven to have a causative role in the development of CVD, routine intensified HD regimens in children may be indicated for its removal.

Association between common iron store markers and hemoglobin in children with chronic kidney disease.

BACKGROUND: Serum ferritin and transferrin saturation (TSAT) are used to assess iron status in children with chronic kidney disease (CKD), but their sensitivity in identifying those at risk of lower hemoglobin (HGB) values is unclear. METHODS: We assessed the association of iron status markers (ferritin, TSAT, and serum iron) with age- and gender-related HGB percentile in mild-to-moderate CKD in 304 children in the Chronic Kidney Disease in Children (CKiD) Study. Standardized HGB percentile values were examined by KDOQI-recommended ferritin (≥ 100 ng/ml) and TSAT (≥ 20 %) thresholds. Regression tree methods were used to identify iron status markers and clinical characteristics most associated with lower HGB percentiles. RESULTS: The cohort was 62 % male, 23 % African American, and 12 % Hispanic, median age 12 years, and median HGB 12.9 g/dl. 34 % had low TSAT and 93 % low ferritin as defined by KDOQI. Distribution of HGB percentile values was lower in those with ferritin ≥ 100 ng/ml, while TSAT ≥ 20 % was associated with only modest increase in HGB percentile. In regression tree analysis, lower glomerular filtration rate (GFR), serum iron <50 µg/dl and ferritin ≥ 100 ng/ml were most strongly associated with lower HGB percentile. CONCLUSIONS: The level of GFR was significantly associated with HGB. Higher serum ferritin was associated with lower HGB in this cohort. Low serum iron in the context of normal/increased ferritin and low HGB may be a useful indicator of iron-restricted erythropoiesis.

Prostaglandin E2 stimulates cystogenesis through EP4 receptor in IMCD-3 cells.

Previously, we demonstrated that prostaglandin E(2) (PGE(2)) induced cAMP and cyst formation through PGE(2) receptor-2 (EP2) activity in human autosomal-dominant polycystic kidney disease (ADPKD) epithelial cells. In this study, we determined the role of EP2 and EP4 receptors in mediating PGE(2) stimulation of cAMP signaling and cystogenesis in mouse renal epithelial cells using the inner medullary collecting duct-3 (IMCD-3) cell line. In contrast to human ADPKD cells, using novel EP2 and EP4 antagonists, we found that IMCD-3 cells expressed functional EP4 but not EP2, which stimulated cAMP formation and led to cyst formation in 3D culture system. The involvement of EP4 receptors in IMCD-3 cells was further supported by the specific effect of EP4 siRNA that inhibited PGE(2)-induced cystogenesis. We also observed different cellular localization of EP2 or EP4 receptors in IMCD-3 transfected cells. Collectively, our results suggest an important role of different expression of EP2 or EP4 receptors in the regulation of cystogenesis.

Transforming growth factor-ß inhibits cystogenesis in human autosomal dominant polycystic kidney epithelial cells.

Autosomal dominant polycystic kidney disease (ADPKD) is the most common inherited cause of kidney failure and characterized by the formation of multiple fluid-filled cysts in the kidneys. It is believed that environmental factors may play an important role in the disease progression. However, the molecular identity of autocrine/paracrine factors influencing cyst formation is largely unknown. In this study, we identified transforming growth factor-ß2 (TGF-ß2) secreted by normal human kidney (NHK) and ADPKD cells as an inhibitor of cystogenesis in 3D culture system using ADPKD cells from human kidneys. TGF-ß2 was identified in conditioned media (CM) of NHK and ADPKD cells as a latent factor activated by heat in vitro. While all TGF-ß isoforms recombinant proteins (TGF-ß1, -ß2, or -ß3) displayed a similar inhibitory effect on cyst formation, TGF-ß2 was the predominant isoform detected in CM. The involvement of TGF-ß2 in the suppression of cyst formation was demonstrated by using a TGF-ß2 specific blocking antibody and a TGF-ß receptor I kinase inhibitor. TGF-ß2 inhibited cyst formation by a mechanism other than activation of p38 mitogen-activated protein (MAP) kinase that mediated cell death in ADPKD cells. Further, we found that TGF-ß2 modulated expression of various genes involved in cell-cell and cell-matrix interactions and extracellular matrix proteins that may play a role in the regulation of cystogenesis. Collectively, our results suggest that TGF-ß2 secreted by renal epithelial cells may be an inhibitor of cystogenesis influencing the progression of ADPKD.

Arteriovenous fistulas for hemodialysis access in children and adolescents using the proximal radial artery inflow site.

INTRODUCTION: Hemodialysis (HD) for children and adolescents with renal failure is increasingly common in the United States. Consensus opinion views an arteriovenous fistula (AVF) as the best long-term access option, although catheter-based HD remains the most common vascular access in children and has greater risks of complications and higher mortality rates than AVF access. This report reviews our experience with children and adolescents undergoing vascular access operations. METHODS: We reviewed 721 consecutive vascular access patients who had vascular access surgery by a single surgeon during the previous 5 years. Ten patients 20 years or younger were included in this study. In addition to physical examination, each patient had preoperative vascular ultrasound mapping by the operating surgeon. A radiocephalic AVF (RC-AVF) at the wrist was the first choice for dialysis access when feasible; however, the patients in this report were generally seen after years of intravenous access and venipunctures that necessitated more proximal AVF constructions. A proximal radial artery AVF (PRA-AVF) was our most common choice for vascular access when an RC-AVF was not suitable. RESULTS: Patient ages were 9 to 20 years (mean, 16). Seven were male. Renal failure was caused by glomerulnephitis in 4 patients, 3 had a history of obstuctive uropathy, 2 were diabetic and one had congenital nephrotic syndrome. Eight patients had PRA-AVFs created, 1 had an RC-AVF, and 1 patient required a transposition AVF. Follow-up was 4 to 56 months (mean, 32 months). Primary, primary-assisted, and cumulative patencies were 77.8%, 100%, and 100% at 24 months. No prosthetic grafts were used in any vascular access patient during the study period. CONCLUSION: We found HD access in children and adolescents was reliably established through use of a PRA-AVF when an RC-AVF was not feasible. Access sites were often possible through the upper arm cephalic veins and/or with retrograde flow into the forearm. Cumulative (secondary) patency was 100% at 24 months.

Use of conivaptan to allow aggressive hydration to prevent tumor lysis syndrome in a pediatric patient with large-cell lymphoma and SIADH.

The available treatment options for hyponatremia secondary to SIADH are limited and not completely effective. Conivaptan is a vasopressin 1a and 2 receptor antagonist recently approved by the US Food and Drug Administration (FDA) for treating euvolemic and hypervolemic hyponatremia in adult patients. However, data on efficacy and safety of conivaptan in pediatrics are limited. We report a case of a 13-year-old boy with extensively metastasized anaplastic large-cell lymphoma. He also developed hyponatremia due to syndrome of inappropriate antidiuretic hormone secretion (SIADH) prior to chemotherapy initiation. SIADH management in this case was complicated when fluid restriction was not safely attainable. Conivaptan played a significant role in this situation by allowing provision of a large amount of intravenous fluid prior to and during induction chemotherapy. It proved to be an important component in preventing uric acid nephropathy/tumor lysis syndrome. Conivaptan induced free-water clearance as indicated by increased urine output and decreased urine osmolality. The patient responded to conivaptan without any adverse effects.

MKL1 mediates TGF-beta1-induced alpha-smooth muscle actin expression in human renal epithelial cells.

Transforming growth factor-beta1 (TGF-beta1) is known to induce epithelial-mesenchymal transition in the kidney, a process involved in tubulointerstitial fibrosis. We hypothesized that a coactivator of the serum response factor (SRF), megakaryoblastic leukemia factor-1 (MKL1), stimulates alpha-smooth muscle actin (alpha-SMA) transcription in primary cultures of renal tubular epithelial cells (RTC), which convert into myofibroblasts on treatment with TGF-beta1. Herein, we study the effect of MKL1 expression on alpha-SMA in these cells. We demonstrate that TGF-beta1 stimulation of alpha-SMA transcription is mediated through CC(A/T)(6)-rich GG elements known to bind to SRF. These elements also mediate the MKL1 effect that dramatically activates alpha-SMA transcription in serum-free media. MKL1 fused to green fluorescent protein localizes to the nucleus and induces alpha-SMA expression regardless of treatment with TGF-beta1. Using proteasome inhibitors, we also demonstrate that the proteolytic ubiquitin pathway regulates MKL1 expression. These data indicate that MKL1 overexpression is sufficient to induce alpha-SMA expression. Inhibition of endogenous expression of MKL1 by small interfering RNA abolishes TGF-beta1 stimulation of alpha-SMA expression. Therefore, MKL1 is also absolutely required for TGF-beta1 stimulation of alpha-SMA expression. Western blot and immunofluorescence analysis show that overexpressed and endogenous MKL1 are located in the nucleus in non-stimulated RTC. Chromatin immunoprecipitation assay demonstrates that TGF-beta1 induces binding of endogenous SRF and MKL1 to the alpha-SMA promoter in chromatin. Since MKL1 constitutes a potent factor regulating alpha-SMA expression, modulation of endogenous MKL1 expression or activity may have a profound effect on myofibroblast formation and function in the kidney.

Plasticity of epithelial cells derived from human normal and ADPKD kidneys in primary cultures.

Autosomal dominant polycystic kidney disease (ADPKD) is characterized by cyst formation initiated by dedifferentiation and proliferation of renal tubular epithelial cells. Renal tubular epithelial cells (RTC, derived from normal kidney tissue) in primary cultures exhibit both homogeneous expression of gamma-glutamyl transferase and low molecular weight cytokeratin, two different markers for proximal and distal renal epithelial cells, respectively. RTC in cultures also abnormally express the dedifferentiation markers vimentin and PAX-2, which are proteins normally expressed in epithelial cells lining cysts in ADPKD kidneys but not tubular cells in normal kidneys. In contrast, different cultures of cystic epithelial cells (CEC, derived from the cysts walls of polycystic kidneys) display variable expression of cytokeratin, gamma-glutamyl transferase, and PAX-2, but a constant level of vimentin. Importantly, RTC and CEC exhibit the capacity to convert to their respective original structures by forming tubules and cysts, respectively, when cultured in a three-dimensional gel matrix, whereas HK-2, LLC-PK1, and MDCK renal epithelial cell lines form cell aggregates or cysts. Our study demonstrates that the marker expression of the various epithelial cell types is not highly stable in primary cultures. Their modulation is different in cells originating from normal and ADPKD kidneys and in cells cultured in monolayer and three-dimensions. These results indicate the plasticity of epithelial cells that display a mixed epithelial/dedifferentiated/mesenchymal phenotype during their expansion in culture. However, RTC and CEC morphogenic epithelial properties in three-dimensional cultures are similar to those in vivo. Thus, this model is useful for studying the mechanisms leading to tubulogenesis and cystogenesis.

EP2 receptor mediates PGE2-induced cystogenesis of human renal epithelial cells.

Autosomal-dominant polycystic kidney disease (ADPKD) is characterized by formation of cysts from tubular epithelial cells. Previous studies indicate that secretion of prostaglandin E2 (PGE2) into cyst fluid and production of cAMP underlie cyst expansion. However, the mechanism by which PGE2 directly stimulates cAMP formation and modulates cystogenesis is still unclear, because the particular E-prostanoid (EP) receptor mediating the PGE2 effect has not been characterized. Our goal is to define the PGE2 receptor subtype involved in ADPKD. We used a three-dimensional cell-culture system of human epithelial cells from normal and ADPKD kidneys in primary cultures to demonstrate that PGE2 induces cyst formation. Biochemical evidence gathered by using real-time RT-PCR mRNA analysis and immunodetection indicate the presence of EP2 receptor in cystic epithelial cells in ADPKD kidney. Pharmacological evidence obtained by using PGE2-selective analogs further demonstrates that EP2 mediates cAMP formation and cystogenesis. Functional evidence for a role of EP2 receptor in mediating cAMP signaling was also provided by inhibiting EP2 receptor expression with transfection of small interfering RNA in cystic epithelial cells. Our results indicate that PGE2 produced in cyst fluid binds to adjacent EP2 receptors located on the apical side of cysts and stimulates EP2 receptor expression. PGE2 binding to EP2 receptor leads to cAMP signaling and cystogenesis by a mechanism that involves protection of cystic epithelial cells from apoptosis. The role of EP2 receptor in mediating the PGE2 effect on stimulating cyst formation may have direct pharmacological implications for the treatment of polycystic kidney disease.

Limitations of commonly used internal controls for real-time RT-PCR analysis of renal epithelial-mesenchymal cell transition.

BACKGROUND/AIMS: Progressive renal fibrotic disease is accompanied by the massive accumulation of myofibroblasts as defined by alpha smooth muscle actin (alphaSMA) expression. We quantitated gene expression using real-time RT-PCR analysis during conversion of primary cultured human renal tubular cells (RTC) to myofibroblasts after treatment with transforming growth factor-beta1 (TGF-beta1). We report herein the limitations of commonly used reference genes for mRNA quantitation. METHODS: We determined the expression of alphaSMA and megakaryoblastic leukemia-1 (MKL1), a transcriptional regulator of alphaSMA, by quantitative real-time PCR using three common internal controls, glyceraldehyde-3-phosphate dehydrogenase (GAPDH), cyclophilin A and 18S rRNA. RESULTS: Expression of GAPDH mRNA and cyclophilin A mRNA, and to a lesser extent, 18S rRNA levels varied over time in culture and with exposure to TGF-beta1. Thus, depending on which reference gene was used, TGF-beta1 appeared to have different effects on expression of MKL1 and alphaSMA. CONCLUSIONS: RTC converting to myofibroblasts in primary culture is a valuable system to study renal fibrosis in humans. However, variability in expression of reference genes with TGF-beta1 treatment illustrates the need to validate mRNA quantitation with multiple reference genes to provide accurate interpretation of fibrosis studies in the absence of a universal internal standard for mRNA expression.

Proteinuric nephropathy in acquired and congenital generalized lipodystrophy: baseline characteristics and course during recombinant leptin therapy.

Generalized lipodystrophy is characterized by adipose tissue absence, hypoleptinemia, hypertriglyceridemia, insulin resistance, diabetes, hepatomegaly, and nonalcoholic steatohepatitis. In the course of recruiting patients for treatment with recombinant leptin, we were struck by the frequency and severity of proteinuria. We evaluated 25 patients with generalized lipodystrophy. Eighteen were treated with recombinant leptin, and we have followed 15 on leptin for 4-36 months. We followed renal parameters at baseline and during follow-up visits. Renal biopsies were performed as clinically indicated. At baseline, 22 of 25 patients (88%) had elevated urine albumin excretion (>30 mg/24 h), 15 (60%) had macroalbuminuria (>300 mg/24 h), and five (20%) had nephrotic-range proteinuria (>3500 mg/24 h). Twenty-three (92%) had elevated creatinine clearance (>125 ml/min.1.73 m(2)). Eleven of 15 patients (73%) treated with recombinant leptin exhibited reduction in proteinuria, associated with reduction of hyperfiltration. Four patients who did not improve are discussed individually. Renal biopsy findings were remarkable for focal segmental glomerulosclerosis in four patients, membranoproliferative glomerulonephritis in two patients, and diabetic nephropathy in one patient. In conclusion, generalized lipodystrophy is associated with proteinuria and unique renal pathologies, including focal segmental glomerulosclerosis and membranoproliferative glomerulonephritis. The majority treated with recombinant leptin demonstrated reduction in proteinuria and hyperfiltration.