Increased frequency and progression of kidney disease in HIV positive people
Gareth Hardy, HIV i-Base
A recent review in JID reported higher rates of renal complications in HIV positive people that was not explained by traditional risk factors.
Chronic kidney disease (CKD) is known to be more prevalent in people with HIV infection, but it is not certain if this is due to HIV infection, ART or traditional CKD risk factors, like hypertension, smoking or diabetes. Exposure to certain ARVs, such as tenofovir or atazanavir is known to cause renal dysfunction.
Furthermore, elevated markers of chronic inflammation that result from HIV infection, are also associated with renal dysfunction. A team of researchers at the Amsterdam Institute for Global Health Development in the Netherlands, investigated the relationship between these factors and the prevalence of CKD by comparing markers of renal impairment in middle-aged HIV positive men with those of HIV negative men, alongside information about medical histories and socio-demographic categories. 
Comparisons of renal impairment, albuminuria and proximal renal tubular dysfunction were made between 596 HIV positive middle-aged men and 544 HIV negative men in the AGE IV Cohort Study. In addition, longitudinal follow up was conducted to asses whether being on ART was associated with worsening renal impairment or albuminuria, and data was censored at the point of any change in ART regimen.
Renal impairment was determined as estimated glomerular filtration rate (eGFR) of <60 mL/min/1.73 m2, while albuminuria was defined as albumin/creatinine ratio of ≥3 mg/mmol, and proximal renal tubular dysfunction was defined as a retinol-binding protein/creatinine ratio of >2.93 mcg/mmol and/or fractional phosphate excretion of >20% with plasma phosphate <0.8 mmol/L.
Mean age at baseline for the study was 52.7 years for HIV positive people and 52.1 years for HIV negative people. Out of the HIV positive people in the study, 95% were currently taking ART and 94.3% had undetectable viral loads (200 copies/mL plasma). Current tenofovir use was reported for 73.3% of HIV positive participants while prior use was reported for 12.3%. Median total cumulative exposure to tenofovir was 4.0 years (IQR: 2.1 to 6.5). Significantly higher proportions of the HIV positive participants were of African descent, had HCV infection, were smokers, had dyslipdemia, cardiovascular disease or elevated inflammatory markers, than the HIV negative participants.
Renal impairment was significantly more prevalent in HIV positive compared to HIV negative participants (4.7% vs 2%, p = 0.01). Similar differences were found for albuminuria (24.4% vs 5.6%, p<0.001), and proximal renal tubular dysfunction (40.1% vs 8.6%, p<0.001).
In HIV positive people, renal impairment was most prevalent in people who had previously taken tenofovir (16.4%) compared to those who had either never taken it (4.7%) or were currently taking it (2.8%). The authors suggest the latter group might by definition be people who have not experienced tenofovir toxicity. Albuminuria and proximal renal tubular dysfunction were not different between tenofovir usage groups.
After adjusting for age, sex, being of African descent, smoking, HCV infection, hypertension, diabetes and dyslipidaemia, HIV infection remained independently associated with renal impairment (adjusted odds ratio [OR] 2.1; 95% confidence interval [95%CI] 1.0 to 4.4, p=0.05), albuminuria (OR 5.8; 3.7 to 9.0; p<0.001), and proximal renal tubular dysfunction (OR 7.1; 4.9 to 10.2, p<0.001).
Traditional CKD risk factors and older age were also both independently associated with all three markers of impaired renal function. Proximal renal tubular dysfunction was associated with a post HIV diagnosis low nadir body weight (OR 0.59; 95%CI: 0.50 to 0.70. p <0.001), exposure to a protease inhibitor (OR 1.54; 95%CI: 1.00 to 2.30, p=0.03) and cumulative exposure to tenofovir (OR 1.54; 95%CI: 1.00 to 2.30, p=0.03).
Longitudinal analysis was performed with 377 of the HIV positive study participants who had 3.9 years of median follow up and 479 of the HIV negative participants who had 4.1 years of median follow up. Rapid eGFR decline occurred more frequently in HIV positive participants (5.8%) than HIV negative (2.3%, p=0.008).
The rate of decline in renal impairment was significantly greater for HIV positive people than HIV negative people, with an unadjusted eGFR slope of −1.36 (95%CI: −1.59 to −1.14) mL/min/1.73 m2/year in HIV positive and −0.71 (95%CI :−0.90 to −0.51) mL/min/1.73 m2/year in HIV negative participants. After adjusting for all other variables, HIV infection was independently associated with greater eGFR decline. Adjustment for diabetes, dyslipidemia, hypertension and baseline cardiovascular disease had little effect on the association between eGFR decline and HIV infection. Exposure to tenofovir was not independently associated with rate of eGFR decline (OR 1.6; 95%CI: 0.5 to 5.2; p = 0.41).
In summary, HIV positive people in this study were more likely than HIV negative people to have renal impairment, albuminuria and proximal renal tubular dysfunction, as well as more rapid eGFR decline during follow up.
The authors state that their data could not explain the association between HIV infection and the prevalence or progression of CKD by a higher prevalence of traditional CKD risk factors alone. Importantly the association of proximal renal tubular dysfunction was particularly prevalent in HIV positive people with current or historical exposure to tenofovir.
Data from this large representative cohort indicate that people living with HIV (PLHIV) are at greater risk of kidney disease (progression) than those without HIV. This is thought to be due to the generally higher rate of traditional risk factors for kidney disease in PLHIV, HIV-induced inflammation and the effects of antiretroviral therapy on the kidney.
Tenofovir (TDF), atazanavir (ATV) and lopinavir (LPV) have been associated with kidney disease progression in several studies, although the contribution of these antiretrovirals to the reported increased prevalence of kidney dysfunction is probably limited: kidney dysfunction is a relatively uncommon complication of these medications, the effects of these antiretrovirals on the kidney are often reversible once discontinued, and other factors such as uncontrolled hypertension, diabetes and non-antiretroviral medications – especially non-steroidals) are major confounders.
The increased rate of kidney disease in PLHIV underscores the importance of preserving kidney function and managing renal (cardiovascular) risk factors: smoking cessation, blood pressure management, avoiding obesity and nephrotoxic medications.
Fully suppressive ART is of key importance to preserve and restore immune function, reduce inflammation and maintaining general health, and this can be achieved with regimens that contain TDF and/or ATV.
However, these drugs are best avoided or discontinued in those with evidence of kidney dysfunction (impaired renal function or overt albuminuria) or who experience progressive eGFR decline on ART.
Katherine Kooij et al. Higher prevalence and faster progression of chronic kidney disease in HIV positive middle-aged individuals compared with HIV negative controls. JID 2017. 216(6);622–631. (15 September 2017).