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...

Intensive renal support in critically ill patients with acute kidney injury did not decrease mortality, improve recovery of kidney function, or reduce the rate of nonrenal organ failure as compared with less-intensive therapy involving a defined dose of intermittent hemodialysis three times per week and continuous renal-replacement therapy at 20 ml per kilogram per hour. (ClinicalTrials.gov number, NCT00076219.)

Excretion of acid (or generation of bicarbonate) by the kidneys is necessary for acid-base homeostasis. Most of this acid is excreted in the form of ammonia and titratable acid, the latter representing the amount of acid required to titrate the urine buffers from the plasma pH to urine pH. The transport of ammonia in the kidney is now recognized to entail more than simple nonionic diffusion of NH3 and trapping of NH4+. NH4+ transport in the kidney probably occurs by passive diffusion and by transport on the Na+-H+ exchanger, the Na+-K+-2Cl- transporter and on Na+-K+-ATPase. NH3 diffusion is stimulated by an acid disequilibrium pH in various nephron segments. Also, diffusion equilibrium of NH3 in various regions of the kidney has now been disproved. These various mechanisms of ammonia transport are considered in terms of their possible changes with acid-base disturbances. Phosphate is the most predominant urine buffer; its urinary excretion increases with acidosis. The mechanisms probably involve a decrease in the preferentially transported species, HPO4(2-), and a direct effect of pH on proximal tubule apical phosphate transport. With chronic acidosis, changes in the activity of the apical Na+-phosphate transporter occur. These effects of systemic acid-base balance interact with parathyroid hormone and dietary phosphate status to alter phosphate reabsorption. Citrate transport in the kidney is analyzed because of its sensitivity to systemic pH and because of the possible influence on systemic acid-base status in certain circumstances. Alterations in citrate excretion with acid-base disturbances depend on changes in the concentration of the transported species, citrate2-, and on changes in renal metabolism.

BackgroundWe studied the association of inflammatory biomarkers including C-reactive protein (CRP), tumor necrosis factor-alpha (TNF-α), and interleukin-6 (IL-6) with chronic kidney disease (CKD).MethodsWe conducted a case–control study among 201 CKD patients and 201 community-based controls in the greater New Orleans area. CKD was defined as estimated-glomerular filtration rate (eGFR) <60 mL/min/1.73 m2 or albuminuria ≥30 mg/24-h. Serum CRP, TNF-α, and IL-6 were measured using standard methods. Multivariable regression models were used to examine associations between the inflammatory biomarkers and CKD adjusting for important CKD risk factors, history of cardiovascular disease, and use of antihypertensive, antidiabetic, and lipid-lowering agents and aspirin.ResultsThe multivariable-adjusted medians (interquartile-range) were 2.91 (1.47, 5.24) mg/L in patients with CKD vs. 1.91 (0.99, 3.79) mg/L in controls without CKD (p = 0.39 for group difference) for CRP; 1.86 (1.51, 2.63) pg/mL vs. 1.26 (1.01, 1.98) pg/mL (p < 0.0001) for TNF-α; and 2.53 (1.49, 4.42) pg/mL vs. 1.39 (0.95, 2.15) pg/mL (p = 0.04) for IL-6, respectively. Compared to the lowest tertile, the highest tertile of TNF-α (OR 7.1, 95 % CI 3.2 to 15.5) and IL-6 (OR 2.5, 95 % CI 1.1 to 5.5) were significantly associated with higher odds of CKD in multivariable-adjusted models. Additionally, higher TNF-α and IL-6 were independently and significantly associated with lower eGFR and higher albuminuria.ConclusionsOur data suggest that TNF-α and IL-6, but not CRP, are associated with the prevalence and severity of CKD, independent from established CKD risk factors, history of cardiovascular disease, and use of antihypertensive, antidiabetic, and lipid-lowering agents and aspirin.