Trypanolytic variants in APOL1, which encodes apolipoprotein L1, associate with kidney disease in African Americans, but whether APOL1-associated glomerular disease has a distinct clinical phenotype is unknown. Here we determined APOL1 genotypes for 271 African American cases, 168 European American cases, and 939 control subjects. In a recessive model, APOL1 variants conferred seventeenfold higher odds (95% CI 11 to 26) for focal segmental glomerulosclerosis (FSGS) and twenty-ninefold higher odds (95% CI 13 to 68) for HIV-associated nephropathy (HIVAN). FSGS associated with two APOL1 risk alleles associated with earlier age of onset (P ϭ 0.01) and faster progression to ESRD (P Ͻ 0.01) but similar sensitivity to steroids compared with other subjects. Individuals with two APOL1 risk alleles have an estimated 4% lifetime risk for developing FSGS, and untreated HIVinfected individuals have a 50% risk for developing HIVAN. The effect of carrying two APOL1 risk alleles explains 18% of FSGS and 35% of HIVAN; alternatively, eliminating this effect would reduce FSGS and HIVAN by 67%. A survey of world populations indicated that the APOL1 kidney risk alleles are present only on African chromosomes. In summary, African Americans carrying two APOL1 risk alleles have a greatly increased risk for glomerular disease, and APOL1-associated FSGS occurs earlier and progresses to ESRD more rapidly. These data add to the evidence base required to determine whether genetic testing for APOL1 has a use in clinical practice.
The increased burden of chronic kidney and end-stage kidney diseases (ESKD) in populations of African ancestry has been largely unexplained. To identify genetic variants predisposing to idiopathic and HIV-1-associated focal segmental glomerulosclerosis (FSGS), we carried out an admixture-mapping linkage-disequilibrium genome scan on 190 African American individuals with FSGS and 222 controls. We identified a chromosome 22 region with a genome-wide logarithm of the odds (lod) score of 9.2 and a peak lod of 12.4 centered on MYH9, a functional candidate gene expressed in kidney podocytes. Multiple MYH9 SNPs and haplotypes were recessively associated with FSGS, most strongly a haplotype spanning exons 14 through 23 (OR = 5.0, 95% CI = 3.5-7.1; P = 4 × 10 −23 , n = 852). This association extended to hypertensive ESKD (OR = 2.2, 95% CI = 1.5-3.4; n = 433), but not type 2 diabetic ESKD (n = 476). Genetic variation at the MYH9 locus substantially explains the increased burden of FSGS and hypertensive ESKD among African Americans.The prevalence of chronic kidney disease (CKD) in the United States is currently estimated at 13% and is associated with significant morbidity and mortality 1 . Approximately 100,000 Americans develop end-stage kidney (renal) disease (ESKD) each year. The cumulative lifetime risk for ESKD varies by ancestry, and is approximately 7.5% for African Americans and 2.1% for European Americans2. African Americans have a disproportionate risk for several forms of CKD, among them diabetic nephropathy3, hypertensive nephrosclerosis4, lupus nephritis5, focal segmental glomerulosclerosis (FSGS) 6 and HIV-associated nephropathy (a distinct form of FSGS, also termed collap-sing glomerulopathy)7 , 8. The disproportionate risk for CKD may be partially explained by differences in social-economic status, lifestyle factors and clinical factors such as blood pressure control, but most of the increased risk remains unexplained9.FSGS is a clinical syndrome involving podocyte injury and glomerular scarring, and includes genetic forms with autosomal dominant or recessive mendelian inheritance, reactive forms associated with other illnesses (including HIV-1 disease) or medications, and a sporadic, idiopathic form, which accounts for the majority of cases 10 . Recent data suggest an increase in the incidence of FSGS, which currently accounts for up to 3% of ESKD cases6. African Americans have a fourfold increased risk for sporadic FSGS11 and an 18-to 50-fold increased risk for HIV-1-associated FSGS7 ,12 . Individuals of African descent also have increased risk for FSGS in other geographic regions, further suggesting that genetic factors contribute to these disparities 11 .A strategy for identifying genes underlying such ancestry-driven health disparities is mapping by admixture linkage disequilibrium (MALD). MALD has successfully identified a genomic region associated with prostate cancer 13 subsequently replicated by a genome-wide association study14, as well as genes associated with hypertension15, multiple scl...
Abstract. Percutaneous renal biopsy (PRB) is a safe and effective tool in the diagnosis and management of renal disease; however, the optimal timing of observation after biopsy is not clearly established. With the use of real-time ultrasound guidance, PRB of native kidneys was performed in 750 adult patients at an academic institution by an attending nephrologist or fellow between June 1983 and June 2002. All patients were observed for 23 to 24 h after biopsy for the presence, severity, and timing of complications. Biopsy-related complications occurred in 98 (13%) patients; minor complications occurred in 50 (6.6%) patients, and major complications occurred in 48 (6.4%) patients. One (0.1%) patient died as a result of the biopsy. Multivariate analysis using logistic regression found only serum creatinine at baseline predictive of a complication. Patients with a serum creatinine Ն5.0 mg/dl were 2.3 times as likely to have a complication (odds ratio, 2.3; 95% confidence interval, 1.3 to 4.1; P Ͻ 0.005). Complications were identified in 38 (42%) patients by Յ4 h, in 61 (67%) patients by Յ8 h, in 77 (85%) patients by Յ12 h, and in 81 (89%) patients at Յ24 h. The PRB remains a safe procedure, but the risk of complication is higher in patients with advanced renal insufficiency. After biopsy, an observation time of up to 24 h remains optimal as an observation period of Յ8 h risks missing Ն33% of complications.
Abstract. The histopathologic diagnosis of primary focal segmental glomerulosclerosis (FSGS) has come to include a number of histologic lesions (variants), but the prognostic significance of these discrete lesions is controversial because published information regarding the presentation, course, and response to treatment is limited. A retrospective analysis was conducted of 87 nephrotic adult patients with biopsy-proven primary FSGS. Patients were categorized on the basis of histologic criteria into those with a classic scar (36 patients), the cellular or collapsing lesion (40 patients), or the tip lesion (11 patients) of FSGS to evaluate differences in presentation, response to therapy, and clinical outcomes. The clinical features at biopsy were similar among the three groups with the exception that patients with the tip lesion were older and patients with the collapsing lesion had more severe proteinuria. Over the course of follow-up, 63% of patients treated attained remission and the response to steroid therapy was similar among the groups (classic scar 53% versus collapsing lesion 64% versus tip lesion 78%; P ϭ 0.45). The overall renal survival was significantly better for patients who entered remission compared with patients who did not enter remission (92% versus 33% at 10 yr; P Ͻ 0.0001). The renal survival at 10 yr for patients who entered remission was similar among the three groups (classic scar 100% versus tip lesion 100% versus collapsing lesion 80%; P ϭ 0.61). In patients who did not enter remission, the renal survival at 10 yr was significantly worse for patients with collapsing lesion and tip lesion (classic scar 49% versus tip lesion 25% versus collapsing lesion 21%; P ϭ 0.002). In conclusion, the prognosis for nephrotic FSGS patients who enter remission is excellent regardless of the histologic lesion. Because the remission rate after treatment is similar among patients with the histologic variants, response to therapy cannot be predicted on the basis of histology alone. Thus, nephrotic patients with primary FSGS should receive a trial of therapy irrespective of the histologic lesion when not contraindicated.Focal segmental glomerulosclerosis (FSGS) is a pattern of injury defined by a segmental scar, which involves some but not all glomeruli. When all of the secondary causes of this pattern of injury are eliminated, the remaining patients receive a diagnosis of primary FSGS. Although patients with primary FSGS may present with any level of proteinuria, clinical concern is greatest for those who present with nephrotic-range proteinuria because without treatment, they have an extremely poor prognosis, progressing to ESRD over the course of 3 to 6 yr (1,2). However, it is widely recognized that the prognosis in nephrotic patients with primary FSGS is significantly improved when remission of proteinuria is achieved. Because Ͼ50% of nephrotic adult patients with FSGS respond to an aggressive course of steroids, a trial of therapy has been recommended (1,3-5).Over the last 20 yr, in addition to the "c...
This study assessed whether certain clinicopathologic variables could explain the impact of race on outcome in 86 patients who had severe lupus nephritis and were available for long-term follow-up after participating in a prospective, controlled, clinical trial. Fifty-four (63%) patients were white, 21 (24%) were black, and 11 (13%) were categorized as other. The proportion of patients with anti-Ro, anti-nRNP, and anti-Sm was significantly greater among black patients. Biopsies with segmental active proliferative and necrotizing lesions that involved >50% of glomeruli ؎ membranous glomerulonephritis (class III >50%؎V) were significantly more common (white 44%, black 76%, other 36%; P < 0.05) and diffuse proliferative glomerulonephritis ؎ membranous glomerulonephritis (class IV؎V) was less common (white 54%, black 24%, other 64%) among black patients. Attainment of a remission was greatest among white patients (white 52%, black 29%, other 27%; P ؍ 0.09). Features that were predictive of a remission were white race, baseline serum creatinine, and class IV؎V lesions. Patient survival at 10 yr (white 81%, black 59%, other 73%; P ؍ 0.029) and renal survival at 10 yr (white 68%, black 38%, other 61%; P ؍ 0.015) were significantly poorer in black patients. Predictors of ESRD were serum creatinine, the presence of anti-Ro antibodies, class III >50%؎V lesions, and failure to achieve a remission. In conclusion, racial differences were observed in the serologic and histologic features at presentation, response to treatment, and outcome of patients with severe lupus nephritis. In a population of patients with severe lupus nephritis, black patients were significantly more likely to have a serologic profile and renal lesions that were associated with more aggressive renal disease and resulted in worse outcomes than white patients.
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