IAS: Kidney disease may be highly prevalent amongst HIV-infected in Africa

Renal (kidney) disease may be highly prevalent amongst treatment-naive HIV-positive individuals in Africa, according to two posters presented at the Third International AIDS Society Conference on HIV Pathogenesis and Treatment in Rio de Janeiro, affecting between 25% and 50% of HIV-positive individuals attending HIV clinics in Kenya and Uganda. The level of renal insufficiency identified suggests the need for extensive education on antiretroviral dosage adjustments necessary for patients with renal insufficiency, and the need for assessment of creatinine clearance whenever symptoms suggestive of kidney disease are present in people receiving antiretroviral treatment in Africa.

The findings also suggest that tenofovir (Viread) - which may worsen kidney function in people with pre-existing impairment - may be not appropriate for a large number of Africans at the standard dosage. A third poster presentation from the United Kingdom, however, suggests that highly active antiretroviral therapy (HAART) significantly improves HIV-associated nephropathy (kidney disease) outcomes.

HIV-associated nephropathy (HIVAN) is the leading cause of end-stage renal disease among HIV-positive individuals in well-resourced countries, most of whom are of African descent. However, although HIVAN is clearly linked to African ethnicity, until now information has been severely lacking about renal disease in HIV-infected populations in Africa.

Renal insufficiency found in one in four with HIV in Kenya

Researchers in western Kenya enrolled 219 antiretroviral-naïve individuals attending the HIV clinic in Eldoret, Kenya. Patients with a previous diagnosis of renal disease, and those with diabetes mellitus, pregnancy, sickle cell disease, or acute infection were excluded. All participants underwent a structured health history, a limited physical exam and had specimens collected for urine dip stick (to measure protein levels), serum creatinine, blood urea nitrogen, albumin, and CD4 cell count. Complete data (taken from the published abstract) were available on 216 participants, 68% of whom were female, the average age was 35 years, and the mean CD4 cell count was 383 cells/mm³.

Renal insufficiency (defined as creatinine clearance below 90 ml/min) was detected in 25%, with more severe renal insufficiency (defined as creatinine clearance below 60 ml/min) identified in 2%. Severe proteinuria (defined as greater than 1g/day) was detected in 8%.

Statistical analysis revealed that more severe renal insufficiency was found in those study participants with CD4 cell counts below 200 cells/mm³ compared to those with CD4 cell counts above 200 cells/ mm³ (p=0.05). Although not statistically significant, the researchers also found a trend towards significantly more proteinuria in individuals with CD4 cell counts below 200 cells/ mm³.

The investigators concluded that renal insufficiency and proteinuria are prevalent in this HIV-infected clinic population, which suggests that HIV-associated nephropathy may be common. They suggest that to avoid drug toxicity, renal function should be assessed prior to commencing HAART.

Almost 50% have renal disease in Uganda

Investigators from the HIV/AIDS clinic at Mbarara University Teaching Hospital, Uganda, enrolled all consenting adults who were seen for the first time at the clinic between June and August 2003. All patients were given a routine clinical assessment, and serum creatinine levels were measured and creatinine clearance calculated. Spot midstream urine samples were collected for protein level analysis. In addition, they performed ultrasounds on all participants' kidneys. A total of 299 participants were included in the analysis (data taken from the published abstract), of whom 65% were female, with an average age of 36 years. Although CD4 cell counts are not reported, 68% of the participants were in World Health Organisation's (WHO) clinical stage three (i.e. markedly symptomatic).

Renal insufficiency (defined as creatinine clearance below 80 ml/min) was detected in 48.5% of the participants, and 20% had proteinuria (defined as a positive urine dipstick test of 100mg/dl). The investigators also reported that many participants had clinical symptoms of kidney dysfunction: 60.8% needed to urinate during the night; 41.8% had flank pain and 24.1% had difficulty or pain urinating. In addition, 8.4% suffered from hypertension and 1% had noticeable swelling of the feet and legs.

Further tests revealed that 44.1% had pus cell on microscopy indicating infection; 9% had granular casts, indicating underlying kidney disease; 2.5% were diagnosed with hydronephrosis, indicating urinary tract blockage; and one patient (0.4%) was found to have kidney stones.

The investigators concluded that although the prevalence of renal disease was 48.5%, only one patient had a confirmed HIVAN diagnosis, leading them to conclude that "the higher prevalence of HIVAN in African patients in Europe and North America may be due to environmental factors as opposed to genetic predisposition."

Why the wide variation?

The only reliable test to establish (or rule out) the presence of HIVAN is renal biopsy. However, HIVAN is often diagnosed using laboratory markers, including severely impaired creatinine clearance or proteinuria. Enlarged kidneys seen through ultrasound may also be diagnostic of HIVAN, rather than other kidney disease. As seen in the studies above, different clinical markers and varying definitions were used in populations with or without prior diagnoses of kidney disease, leading to a wide variation in reporting of kidney disease and/or HIVAN.

However, these results confirm that kidney dysfunction is highly prevalent among Africans in Africa. These data should inform decisions regarding the rollout of tenofovir-containing HAART in sub-Saharan Africa, since studies have shown that underlying kidney dysfunction greatly increases the risk of tenofovir-related kidney toxicity.

Antiretroviral dosage adjustments

All nucleoside analogues and nucleotide analogues apart from abacavir require dosage adjustment if a patient has poor creatinine clearance. If dosage adjustment does not take place there may be an increased risk of drug-related toxicities. A full summary of manufacturer recommended dosage adjustments can be found at HIV Insite. Gilead Sciences is currently conducting a study (GS235) to determine the toxcity of tenofovir at different levels of renal impairment.

In particular reduced creatinine clearance increases the risk of developing lactic acidosis in people taking nucleoside analogues (NRTIs) (click here to view news report).

HAART significantly improves HIVAN outcome in UK African patients

A third study presented in Rio de Janeiro, from the HIVAN-London Collaborative Group, provided a retrospective review of the clinical outcome of HIVAN following HAART initiation, and identified factors associated with a favourable outcome. All HIVAN cases were diagnosed between January 1998 and May 2005 at three HIV clinics in London hospitals (Kings' College, the Royal London, and Guys & St. Thomas'). HIVAN was defined either as having proteinuria greater than 1.5 g/day (27%) or through renal biopsy (73%).

A total of 31 HIVAN cases were diagnosed during the study period. All were of African ethnicity (77% African, 19% Caribbean, 1% American) of whom 58% were female. At HIVAN diagnosis, the mean age was 36 years (range 24-57); median CD4 cell count 65 cells/mm³ (range 1-467); viral load 124,000 copies/ml (range 825-795,000); creatinine 261 mmol/L (range 97-1943); and proteinuria 4.58 g/day (range 440mg-25.6g/day). All were antiretroviral-naive and no-one was co-infected with either hepatitis B or C.

Sixteen patients (52%) presented with acute or chronic renal failure, 11 (35%) had chronic renal failure and four (13%) had end-stage kidney disease. HAART was commenced in 29 (94%) and 20 (64.5%) required dialysis at some time during follow-up. Of those that received HAART, 55% achieved a viral load below 50 copies/ml over a median follow-up of 2.2 years.

Four patients (12.9%, two of whom were dialysis dependent) died between 25 and 1983 days after initial presentation, and three (9.6%, none of whom were dialysis dependent) were lost to follow-up a median of 238 days after diagnosis.

The median follow-up of the 24 (77%) survivors was 821 days (range 272-2458). The majority (67%) who commenced HAART did not require chronic analysis and maintained stable renal function.

On analysis, the most significant predictor of favourable renal outcome was complete and durable suppression of HIV replication. Thirteen of 16 patients (81%) with a sustained viral load below 50 copies/ml were able to discontinue dialysis and/or had stable or improving renal function, compared to four of 14 patients (29%) who had persistently detectable viral loads (p

The investigators conclude by saying that "these preliminary findings suggest that complete suppression of HIV viral replication may preserve or improve renal function." HIVAN-London is now being extended to eight London hospitals, providing a cohort of more than 100 patients with HIVAN diagnosis, which should provide further data on the effect of HAART on HIVAN.