NPHS2 variation in sporadic focal segmental glomerulosclerosis.

Mutations in NPHS2, the gene that encodes podocin, are well-established causes of both familial and sporadic steroid-resistant focal segmental glomerulosclerosis (FSGS) in the pediatric population, but have not been well-characterized in late-onset disease. To investigate the role of NPHS2 polymorphisms in sporadic cases of late-onset FSGS, we studied 377 biopsy-confirmed FSGS cases and 919 controls. We identified 18 single nucleotide polymorphisms (SNPs) by resequencing a subgroup of cases and controls, and subsequently genotyped African-American and European-American cases and controls for five missense SNPs, three SNPs within introns, and four SNPs in the 3' untranslated region. No homozygotes or compound heterozygotes were observed for any missense mutation. R138Q carriers were more frequent among FSGS cases relative to controls (OR = 4.9, P = 0.06), but heterozygosity for the other four missense mutations was equally distributed among FSGS cases and controls. Finally, a common haplotype of noncoding SNPs carried by 20% of African-Americans, but not observed in European-Americans, was strongly associated with a 50% reduction in risk for sporadic FSGS (OR = 0.5, P = 0.001). These results indicate that genetic variation or mutation of NPHS2 may play a role in late-onset sporadic FSGS.

Variants in the Wilms' tumor gene are associated with focal segmental glomerulosclerosis in the African American population.

Wilms' tumor gene (WT1) is important for nephrogenesis and gonadal growth. WT1 mutations cause Denys-Drash and Frasier syndromes, which are characterized by glomerular scarring. To test whether genetic variations in WT1 and WIT1 (gene immediately 5' to WT1) associate with focal segmental glomerulosclerosis (FSGS), patients with biopsy-proven idiopathic and HIV-1-associated FSGS were enrolled in a multicenter study. We genotyped SNP rs6508 located in WIT1 exon 1, three SNPs (rs2301250, rs2301252, rs2301254) in the promoter shared by WT1 and WIT1, rs2234590 in exon 6, rs2234591 in intron 6, rs16754 in exon 7, and rs1799937 in intron 9 of WT1. Cases (n = 218) and controls (n = 281) were compared in the African American population. Stratification by HIV-1 infection status showed that SNPs rs6508, rs2301254, and rs1799937 were significantly associated with FSGS [rs6508 odds ratio (OR) 1.82, P = 0.006; rs2301254 OR 1.65, P = 0.049; rs1799937 OR 1.91, P = 0.005] in the non-HIV-1 group and rs2234591 (OR 0.234, P = 0.011) in the HIV-1 group. Haplotype analyses in the population revealed that seven SNPs were associated with FSGS; five SNPs had the highest contingency score [-log10(P value) = 13.57] in the HIV-1 group. This association could not be explained by population substructure. We conclude that SNPs in WT1 and WIT1 genes are significantly associated with FSGS, suggesting that variants in these genes may mediate pathogenesis by altering WT1 function. Furthermore, HIV-1 infection status interacts with genetic variations in both genes to influence this phenotype. We speculate that nephropathy liability alleles in WT1 pathway genes cause podocyte dysfunction and glomerular scarring.

High-dose mycophenolate mofetil in the treatment of posttransplant glomerular disease in the allograft: a case series.

BACKGROUND: Glomerular disease is an important cause of allograft loss. Treatment regimens for posttransplant glomerular disease are not well defined. Several reports have demonstrated that mycophenolate mofetil (MMF) is effective in treating native kidney glomerular disease. The effects of MMF are dose related. Therefore, we hypothesized that high-dose MMF (3 g/day) would be effective in treating glomerular disease in the allograft, minimizing the need for intravenous steroids and/or cyclophosphamide. This case series describes the results of the use of high-dose MMF in 6 patients. METHODS: High-dose MMF (3 g/day) was used to treat biopsy-proven glomerular disease (focal segmental glomerulosclerosis, membranoproliferative glomerulonephritis, proliferative lupus nephritis, and perinuclear antineutrophil cytoplasmic antibodies glomerulonephritis) in 6 renal transplant recipients. Patients were offered this treatment if they had failed or did not tolerate standard treatment regimens. Remission was defined by a decrease or stabilization of serum creatinine, decrease in proteinuria and, where applicable, improvement in immunological markers of disease. RESULTS: All 6 patients had disease remission after starting MMF with the most common side effect being leukopenia, which responded to dose reduction. CONCLUSIONS: High-dose MMF may be an effective agent in treating glomerular disease in the allograft.

Serum phosphate levels and risk of infection in incident dialysis patients.

BACKGROUND AND OBJECTIVES: Hyperphosphatemia is highly prevalent in dialysis patients and may be associated with immune dysfunction. The association of serum phosphate level with infection remains largely unexamined. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: In an incident cohort of 1010 dialysis patients enrolled from 1995 to 1998 and treated in 80 US clinics, the association of phosphate level (low <3.5; normal 3.5 to 5.5; high >5.5 mg/dl) at baseline and during follow-up with the risk for incident inpatient and outpatient infection-related events was examined. Infectious events were identified from US Renal Data System data (mean follow-up 3.3 yr). Incidence rate ratios for all infections, sepsis, respiratory tract infections, and osteomyelitis were obtained using multivariable Poisson models, adjusting for potential confounders (age, race, gender, smoking, comorbidity, and laboratory values). RESULTS: Infections of any type (n = 1398) were more frequent among patients with high phosphate levels at baseline, relative to normal; this association was not changed by adjustment for parathyroid hormone level. Similarly, high versus normal baseline phosphate was associated with increased risk for sepsis and osteomyelitis but not respiratory tract infections. Associations with calcium were generally NS, and results with calcium-phosphate product mirrored the phosphate results. CONCLUSIONS: High phosphate levels may be associated with increased risk for infection, contributing further to the rationale for aggressive management of hyperphosphatemia in dialysis patients.

Mycophenolate mofetil treatment for primary glomerular diseases.

BACKGROUND: Treatment of primary glomerular diseases may be unsuccessful or have potential toxicities. Therefore, we evaluated the use of mycophenolate mofetil (MMF) for empirical treatment of primary glomerulopathies. METHODS: Forty-six patients with biopsy-proven primary glomerulopathies received MMF for > or =3 months as adjunctive or primary treatment. Median (range) 24-hour urine protein to creatinine ratio (Up/c) and serum creatinine at the start and end of MMF therapy were compared using the Wilcoxon signed-ranks test. RESULTS: Overall, the median Up/c decreased from 4.7 (range <0.1, 20.3) to 1.1 (<0.1, 14.3; P < 0.001) at the end of MMF treatment with no significant change in median serum creatinine 1.3 (0.6 to 6.1) to 1.2 (0.5 to 6.5) mg/dL. Median serum albumin increased from 3.4 (1.4, 4.6) to 4.1 (1.7, 48) g/dL (P < 0.001) and the median serum cholesterol decreased from 270 (148, 795) to 220 (140, 309) mg/dL (P < 0.001) post-treatment. For those with minimal change disease, a complete steroid withdrawal was accomplished in 5/6 steroid dependent patients. Focal segmental glomerulosclerosis (FSGS) patients had a median Up/c that decreased from 2.7 (0.1, 20.3) to 0.8 (<0.1, 8.2; P = 0.001) in 18 patients. In membranous nephropathy (MN) patients, the median Up/c decreased from 7.3 (0.1, 18.5) to 1.5 (<0.1, 14.3) (P = 0.001) in 17 patients. No significant change in median serum creatinine was detected in FSGS or MN patient groups during treatment. CONCLUSIONS: Empirical MMF therapy in the majority of patients with primary glomerulopathies was well tolerated and achieved the goals of steroid withdrawal, improvement of nephrotic syndrome, and stabilization of renal function.