Loss of kidney function in men with HIV is most strongly associated with antiretroviral therapy, an 11-year study of men living with HIV and their HIV-negative counterparts has found. The study found that men with HIV lost twice as much of their kidney function each year as men without HIV – although the average rate of loss was less than 1% a year.
Prolonged treatment with tenofovir (TDF) or atazanavir increased the risk of a more rapid reduction in kidney function within a single year, but no specific drug was shown to lead to a consistent decline in kidney function throughout the 11-year follow-up period.
Risk factors such as high blood pressure, type 2 diabetes, co-infection with hepatitis C and age also raised the risk of a sharp decline in kidney function, and the investigators say that their findings confirm the importance of considering antiretroviral drug choices carefully in people with other risk factors for kidney disease, and monitoring kidney function on a regular basis in all people receiving antiretroviral therapy (ART).
Kidney function can decline with age in all people. It is also affected by hepatitis C infection, by type 2 diabetes, by high blood pressure and by injecting drug use.
HIV infection may also lead to kidney damage and people of West African origin and African Americans are particularly vulnerable to HIV-related kidney damage owing to a genetic variation that is especially common in these populations.
Some antiretroviral drugs may concentrate in the kidneys, or inhibit creatinine secretion in the kidneys, leading to damage to the kidney tubules.
Inflammation caused by HIV may also lead to kidney damage.
However, the relative importance of these various factors and the extent to which kidney function declines in people with HIV compared with others of the same age is unclear.
Researchers at Northwestern University, Chicago, set out to identify changes in kidney function over time that are specific to people living with HIV, the factors associated with these changes and the risk of experiencing a significant loss of kidney function over time.
The researchers used the Multicenter AIDS Cohort, a cohort of men with HIV and HIV-negative men with similar risk factors for HIV infection, to address these questions.
They studied changes in kidney function in 2381 men who provided blood and urine samples between 2003 and 2014.
Changes in kidney function were assessed by measurements of glomerular filtration rate (eGFR) and the prevalence of proteinuria (elevated ratio of protein-to-creatinine in urine > 0.2 at two consecutive visits). Proteinuria has been shown to predict a worsening of kidney function.
During the 11-year follow-up period, HIV-negative men and HIV-positive men on ART underwent a median of 19 eGFR assessments. HIV-positive men not on ART underwent a median of seven assessments.
At baseline, 54% of men were HIV negative, 39% were HIV positive and taking ART and 7% were HIV positive and untreated. Overall, 25% of the study population was African American, 7% was over 60 years of age, 11% had a history of diabetes, 65% a history of hypertension and 32% were current smokers at baseline. The median CD4 cell count at baseline was 499 cells/mm3 in ART-treated people and the nadir CD4 count was 248 cells/mm3. Sixty per cent of those on ART had an undetectable viral load (< 50 copies/ml) at baseline.
Normal kidney function is defined as an eGFR above 90 ml/min/1.73 m2, but the normal range for people over 60 is somewhat lower. An eGFR between 60 and 30 indicates moderately reduced kidney function and an eGFR below 30 indicates severely decreased kidney function. A higher level of proteinuria indicates a higher risk of progression of kidney disease for any given eGFR.
Forty-six per cent of the study population had an eGFR below 60 at baseline (4% < 30). The median baseline eGFR was 90 in HIV-negative men, 94 in HIV-positive men on ART and 97 in men with HIV not taking ART. During the follow-up period, eGFR declined by a median of 0.3% each year in HIV-negative men and 0.8% in HIV-positive men.
Fifteen per cent of all men experienced a median annual decline of 3% or more. The risk of a decline of this magnitude was greatest in men taking ART, who were almost three times more likely to experience this degree of decline when compared to HIV-negative men (adjusted odds ratio 2.91, 95% CI 2.21-3.8, P < 0.001). Men with HIV not taking ART were no more likely to experience a decline of this magnitude than HIV-negative men.
Current smoking, hepatitis C virus infection and age over 50 years were associated with a moderate increase in the risk of substantial annual decline (> 3%). A history of either diabetes or hypertension was associated with an intermediate increase in risk (approximately 70-90% increase in the risk of this outcome).
ART was also more strongly associated with the presence of proteinuria than any other risk factor. Men receiving antiretroviral treatment were seven times more likely to have proteinuria than HIV-negative men (aOR 6.99, 95% CI 4.72-10.36, p < 0.001). Proteinuria was also strongly associated with an eGFR below 60 (aOR 4.15, 95% CI 2.52-6.84, p < 0.001) and with a subsequent decline in eGFR of greater than 3% per year (aOR 1.90, 95% CI 1.58-2.0, p < 0.001).
The risk of a decline in eGFR > 3% within one year was associated with a greater duration of treatment with tenofovir (TDF), emtricitabine, or atazanavir. Each additional year of exposure to one of these drugs raised the risk of a > 3% decline by around 3%. The authors comment that the risk associated with emtricitabine is most likely a consequence of the drug always being taken alongside tenofovir in co-formulated regimens, rather than any harmful effect of emtricitabine itself.
Being aged 60 or over increased the risk of progression by around 50% (aOR 1.52, 95% CI 1.31-1.72, p < 0.001) and proteinuria increased the risk by around 80% (aOR 1.80, 95% CI 1.58-2.05, p < 0.001). Hypertension or diabetes had a modest impact on the risk of rapid progression.
The study authors say that further longitudinal research is needed to show whether avoidance of tenofovir or atazanavir reduces the risk of a decline in kidney function in ageing HIV-positive people with other risks for kidney disease. They also say that long-term follow-up is needed to clarify whether the use of tenofovir alafenamide – the new formulation of tenofovir that may be less harmful to the kidneys – reduces the loss of kidney function and whether NRTI-sparing regimens might reduce the burden of kidney disease.
By Keith Alcorn
Palella F et al. Long-term kidney function, proteinuria, and associated risks among HIV-infected and uninfected men. AIDS, advance online publication, May 2018.