Out of Africa: Kidney disease is more common in African Americans than in Americans of European descent, and genetics is likely to be a major contributing factor. Genovese et al. (p. 841 , published online 15 July) now show that African Americans who carry specific sequence variants in a gene on chromosome 22 encoding apolipoprotein L-1 (APOL1) have an increased risk of developing hypertension-attributed end-stage kidney disease or focal segmental glomerulosclerosis. These variants are absent from European chromosomes. Among the functions ascribed to APOL1 is the ability to lyse and kill trypanosomes. Intriguingly, APOL1 derived from the risk alleles, but not the “wild-type” allele, killed Trypanosoma brucei rhodesiense , which causes African sleeping sickness.

The glomerular microvasculature is particularly susceptible to injury in thrombotic microangiopathy, but the mechanisms by which this occurs are unclear. We report the cases of six patients who were treated with bevacizumab, a humanized monoclonal antibody against vascular endothelial growth factor (VEGF), in whom glomerular disease characteristic of thrombotic microangiopathy developed. To show that local reduction of VEGF within the kidney is sufficient to trigger the pathogenesis of thrombotic microangiopathy, we used conditional gene targeting to delete VEGF from renal podocytes in adult mice; this resulted in a profound thrombotic glomerular injury. These observations provide evidence that glomerular injury in patients who are treated with bevacizumab is probably due to direct targeting of VEGF by antiangiogenic therapy.

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-nine-fold 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 = 0.01) and faster progression to ESRD (P < 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 HIV-infected 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.

Among patients in the United States with chronic kidney disease, black patients are at increased risk for end-stage renal disease, as compared with white patients. In two studies, we examined the effects of variants in the gene encoding apolipoprotein L1 (APOL1) on the progression of chronic kidney disease. In the African American Study of Kidney Disease and Hypertension (AASK), we evaluated 693 black patients with chronic kidney disease attributed to hypertension. In the Chronic Renal Insufficiency Cohort (CRIC) study, we evaluated 2955 white patients and black patients with chronic kidney disease (46% of whom had diabetes) according to whether they had 2 copies of high-risk APOL1 variants (APOL1 high-risk group) or 0 or 1 copy (APOL1 low-risk group). In the AASK study, the primary outcome was a composite of end-stage renal disease or a doubling of the serum creatinine level. In the CRIC study, the primary outcomes were the slope in the estimated glomerular filtration rate (eGFR) and the composite of end-stage renal disease or a reduction of 50% in the eGFR from baseline. In the AASK study, the primary outcome occurred in 58.1% of the patients in the APOL1 high-risk group and in 36.6% of those in the APOL1 low-risk group (hazard ratio in the high-risk group, 1.88; P<0.001). There was no interaction between APOL1 status and trial interventions or the presence of baseline proteinuria. In the CRIC study, black patients in the APOL1 high-risk group had a more rapid decline in the eGFR and a higher risk of the composite renal outcome than did white patients, among those with diabetes and those without diabetes (P<0.001 for all comparisons). Renal risk variants in APOL1 were associated with the higher rates of end-stage renal disease and progression of chronic kidney disease that were observed in black patients as compared with white patients, regardless of diabetes status. (Funded by the National Institute of Diabetes and Digestive and Kidney Diseases and others.)

Oxygen sensing is essential for homeostasis in all aerobic organisms, but its mechanism is poorly understood. Data suggest that a phagocytic-like NAD(P)H oxidase producing reactive oxygen species serves as a primary sensor for oxygen. We have characterized a source of superoxide anions in the kidney that we refer to as a renal NAD(P)H oxidase or Renox. Renox is homologous to gp91^phox(91-kDa subunit of the phagocyte oxidase), the electron-transporting subunit of phagocytic NADPH oxidase, and contains all of the structural motifs considered essential for binding of heme, flavin, and nucleotide.In situRNA hybridization revealed that renox is highly expressed at the site of erythropoietin production in the renal cortex, showing the greatest accumulation of renox mRNA in proximal convoluted tubule epithelial cells. NIH 3T3 fibroblasts overexpressing transfected Renox show increased production of superoxide and develop signs of cellular senescence. Our data suggest that Renox, as a renal source of reactive oxygen species, is a likely candidate for the oxygen sensor function regulating oxygen-dependent gene expression and may also have a role in the development of inflammatory processes in the kidney.