APOL1 Risk Variants Are Strongly Associated with HIV-Associated Nephropathy in Black South Africans.

APOL1 variants are associated with HIV-associated nephropathy and FSGS in African Americans. The prevalence of these variants in African populations with CKD in HIV-1 infection has not been investigated. We determined the role of APOL1 variants in 120 patients with HIV-associated nephropathy and CKD and 108 controls from a South-African black population. Patients with CKD were selected on the basis of histology. Genotypes were successfully determined for APOL1 G1 and G2 variants and 42 single nucleotide polymorphisms, including 18 ancestry informative markers, for 116 patients with CKD (96.7%; 38 patients with HIV-associated nephropathy, 39 patients with HIV-positive CKD, and 39 patients with HIV-negative CKD), and 108 controls (100%). Overall, 79% of patients with HIV-associated nephropathy and 2% of population controls carried two risk alleles. In a recessive model, individuals carrying any combination of two APOL1 risk alleles had 89-fold higher odds (95% confidence interval, 18 to 912; P<0.001) of developing HIV-associated nephropathy compared with HIV-positive controls. Population allele frequencies were 7.3% for G1 and 11.1% for G2. APOL1 risk alleles were not significantly associated with other forms of CKD. These results indicate HIV-positive, antiretroviral therapy-naïve South-African blacks with two APOL1 risk alleles are at very high risk for developing HIV-associated nephropathy. Further studies are required to determine the effect of APOL1 risk variants on kidney diseases in other regions of sub-Saharan Africa.

The association of RBBP6 variant 3 expressions with apoptosis in human immunodeficiency virus-associated nephropathy (HIVAN).

South Africa has one of the highest HIV infection rates in the world. One of the complications of HIV infection is the development of HIV-associated nephropathy (HIVAN), which is characterized by deregulation in tubular epithelial apoptosis. The pathways that HIV-1 promotes in the pathogenesis of HIVAN remain less understood. There are many genes that have not been characterized in the pathogenesis of HIVAN. On the other hand, RBBP6 has been shown to play a role in both promoting and inhibiting apoptosis in human cancers. This study was aimed at determining an association between RBBP6 isoform 3 expression and the levels of apoptosis in HIVAN cases. HIVAN biopsy tissues from Johannesburg patients in South Africa were used in this study. These tissues were stained for RBBP6 expression and apoptosis levels using immunohistochemistry staining and TUNEL method respectively. Image analysis was used for quantitative analysis and GraphPad Version 4 was used for statistical analysis. High expression levels of RBBP6 were found in HIVAN cases (n=30) relative to the normal tissues (n=10). High apoptosis levels were also obtained in the HIVAN tissues. This direct association between RBBP6 expression and apoptosis levels suggests that RBBP6 may play a role in HIVAN pathogenesis. RBBP6 may then be targeted for both diagnostic and therapeutic strategies in HIVAN.

The clinical and histological response of HIV-associated kidney disease to antiretroviral therapy in South Africans.

BACKGROUND: Little is known about the progression of kidney disease in HIV-infected patients in developing countries in the era of antiretroviral therapy (ART). METHODS: HIV-infected patients were screened for kidney disease. Kidney biopsies were performed before and after initiation of ART to assess the clinical and histological response to treatment. Data were collected from all participants in accordance with the study protocol. The mean follow-up was 2.4 patient years on ART. RESULTS: There was a rapid immunological and renal response to ART. The renal response was reflected by a significant rise in the estimated glomerular filtration rate (eGFR) and rapid regression of proteinuria. The histological patterns were highly variable, ranging from non-specific lesions such as mesangial hyperplasia and interstitial nephritis to HIV-immune complex disease (HIV-ICD) with or without features of HIV-associated nephropathy (HIVAN). In the follow-up biopsies, the histological response to treatment was variable with a combination of no change, progression or regression of lesions. CONCLUSIONS: This study demonstrated a spectrum of renal histological lesions in HIV-associated kidney disease. Initiation of ART produced a rapid and sustained clinical renal response in all participants, irrespective of the histology. Follow-up biopsies showed an inconsistent histological response of lesions to treatment. In lesions that regressed, there appeared to be a discrete lag in histological response when compared with the rapid clinical response.

Infection and glomerulonephritis.

Glomerular injury, occurring either as primary glomerular disease or as part of a systemic disease process, is usually a result of immune-mediated mechanisms. The morphologic reaction pattern has a diverse spectrum of appearance, ranging from normal by light microscopy in minimal change disease to crescentic forms of glomerulonephritis, with conspicuous disruption of the normal glomerular morphology. The mechanisms of glomerular immune deposit formation include trapping of circulating antigen-antibody complexes and the in situ formation of immune complexes within the glomerulus. While the majority of postinfectious immune-complex-mediated glomerulonephritides are believed to result from the deposition of circulating antigen-antibody complexes, preformed outside of the kidney and secondarily deposited in the kidney, the notion of forming in situ antigen-antibody complexes to either planted antigens or to integral structural components of the glomerulus, through "cross-reacting" autoimmune reactions, is gaining popularity in a variety of forms of glomerulonephritides. Patients with HIV infection may develop a spectrum of renal pathology, the glomerular manifestations of which include both antigen-antibody complex and nonimmune-complex-mediated pathogenetic mechanisms. Similarly, patients with Streptococcal infections, Hepatitis B virus, or Hepatitis C virus infection may develop a spectrum of glomerulonephritides, which are predominantly immune-complex-mediated. Therapy for glomerular diseases due to HIV, hepatitis B, or C virus infections remains a challenge.