Renal Injury and Human Immunodeficiency Virus: What Remains After 30 Years?

Sophie de Seigneux; Gregory M. Lucas

Disclosures

Nephrol Dial Transplant. 2020;35(4):555-557. 

The human immunodeficiency virus (HIV) epidemic has changed its face in the Western world over the last two decades and so has renal disease in HIV-positive patients. Indeed, with widespread use of highly active antiretroviral therapies (HAARTs), the incidence of acquired immune deficiency syndrome–defining opportunistic conditions and the classical HIV-associated nephropathy (HIVAN) have declined markedly.[1,2] Whereas HIVAN- and infection-related kidney disease are still common in sub-Saharan Africa, HIV-related kidney disease is now often linked to metabolic and cardiovascular risk factors in an aging HIV-positive population and to long-term exposure to antiretroviral treatments in Western countries.[3–5] Co-infections, severity of immunosuppression prior to initiating HAART and pre-existing renal disease also influence renal prognosis.[6] These factors have been modelled in scoring systems that can be used to predict renal risk in HIV patients.[7]

Genetic risk factors and ethnicity play a large role in kidney disease, including in HIV-related kidney disease. For HIVAN, the main genetic predisposition to glomerular disease has been attributed to the APOL1 gene.[8] HIV patients of African descent, where the prevalence of APOL1 risk alleles is highest, have the highest risk of HIVAN, particularly if HIV is left untreated, and have a worse renal prognosis in albuminuria and glomerular injury.[9] Other genetic predispositions are also important and recently a genetic risk score, based on loci associated with renal function, was demonstrated to be associated with the risk of estimated glomerular filtration rate (eGFR) decline in HIV-positive persons of European ancestry, in complement with clinical risk scores.[10] This risk score included numerous single-nucleotide polymorphisms already shown to be associated with renal function and to the risk of chronic kidney disease (CKD) in the general population, and an unfavourable genetic background was associated in the Swiss HIV population to a 2-fold higher risk of developing CKD during follow-up, independent of other factors. Thus in HIV-related renal disease, genetic risk is now demonstrated to predict CKD risk as well as clinical factors.

Among nephrotoxic drugs, tenofovir disoproxil fumarate (TDF) is an important cause of renal function decline in HIV-positive patients. TDF was introduced in 2001 and became a cornerstone of HIV treatment, given its efficacy and tolerability. However, long-term use of TDF increases the risk of renal function decline and CKD in large cohorts, even in patients with normal renal function at baseline.[11] In addition, proximal tubulopathy, taking the form of incomplete Fanconi syndrome, has repeatedly been described with TDF use.[12] Recent consensus statements do not necessarily recommend routine screening for tubular dysfunction in HIV-positive patients receiving TDF.[13,14] This is mainly related to the fact that there is no clear definition of TDF-induced proximal tubulopathy, that the examinations are not always available and that there is no uniform demonstration of a single marker that is prognostic in the risk of CKD.

In this issue of NDT, Lescure et al.[15] study the prevalence, correlates and implications of proximal tubulopathy for renal function loss in a cohort of 694 HIV-positive patients in one center in Paris. The patient population was characterized by a median age of 44 years, nearly half of the patients were of sub-Saharan origin and the median HIV infection duration was 9.7 years. TDF exposure was present in almost half of the population. The presence of proximal tubular dysfunction was defined by the authors as the presence of glycosuria, decreased maximal tubular reabsorption of phosphate, increased urinary α1-microglobulin, low serum uric acid and low serum bicarbonate levels. Proximal dysfunction was defined as a combination of two criteria, whereas severe dysfunction was defined as a minimum of three criteria. Using this definition, proximal tubular dysfunction prevalence at inclusion was 14.3%, with 4.3% meeting the criteria for severe dysfunction. The clinical presentation was dominated by phosphaturia and increased urinary α1-microglobulin, which were each observed in ~30% of the sample, whereas glycosuria was rare. Tubular dysfunction was much less prevalent in patients of sub-Saharan origin compared with others. Moreover, in patients of sub-Saharan origin, tubular dysfunction was not associated with TDF use, whereas it was strongly associated with tubular dysfunction in non-African patients. Among African patients, the prevalence of proximal tubular dysfunction was 6.9% and 5.9% in those exposed and never exposed to TDF, respectively. In contrast, among non-Africans, the prevalence of tubular dysfunction was 37.2 and 10.3% among those exposed and not exposed to TDF, respectively. A total of 601 patients without CKD at baseline were then followed for a median of 4 years. Only 4.5% of patients progressed to Stage 3 CKD (eGFR<60 mL/min/1.73 m2) and 8.3% of patients experienced a decline of eGFR >5 mL/min/1.73 m2/year. While albuminuria was strongly associated with eGFR decline, neither proximal tubular dysfunction nor severe proximal tubular dysfunction, as defined by the authors, were independent predictors of CKD or rapid eGFR decline in multivariate models.

This study made three observations. First, the results suggested that non-African patients, including Caucasians and other ethnicities, were at substantially higher risk for developing proximal tubulopathy with TDF exposure than persons of African descent. This racial difference in susceptibility to TDF-associated proximal tubule toxicity has been described in other studies, although the cause of this difference is not completely understood.[16–19] It may likely rely on genetic differences, either of drug metabolism or excretion, such as adenosine triphosphate binding cassette efflux transporters, on lower drug exposure or a higher sensitivity to injury. This is an important factor to be taken into account when prescribing TDF. Second, this study confirms a high burden of CKD in HIV-positive individuals—5% had Stage 3 CKD at baseline, and of those free of CKD at baseline, 8.3% experienced rapid eGFR decline over a median of 4.5 years. Third, the presence of proximal tubular dysfunction at baseline was not independently associated with subsequent eGFR decline, although albuminuria was independently associated with eGFR decline, consistent with prior data.[20] Of note, proximal tubular dysfunction usually induces some degree of albuminuria, likely in relation to lower proximal tubular reabsorption, which may be a confounding factor. The question of whether subclinical proximal tubular dysfunction is a marker for subsequent decline of GFR remains open. One other study, in agreement with Lescure et al.,[15] found proximal tubule dysfunction to be independently associated with a lower baseline eGFR, but not with the subsequent eGFR slope.[19] However, a number of other studies have found associations between proximal tubular dysfunction and more rapid eGFR decline.[21–23] Such discrepancies may be related to the population observed, to the proximal tubular dysfunction biomarker used and to the observational nature of such studies, as it is possible that some patients with tubular dysfunction were switched from TDF to other therapies, thereby avoiding progression to CKD. This study also reminds us that there is no consensus definition of proximal tubular dysfunction in the context of HIV treatment, no rapid and easy sensitive screening tool and that this may also modify the results depending on the marker or combination of markers used. Finally, and maybe most importantly, TDF has been associated with eGFR decline in large population studies, even in the absence of markers of proximal tubular dysfunction.[24,25] The results from Lescure et al.[15] suggest that the overlap between TDF-associated eGFR declines and subclinical proximal tubular dysfunction may be relatively small, suggesting that these may be distinct toxicities. This hypothesis is bolstered by the observation that HIV-positive persons of African descent are at higher risk for clinically significant eGFR decline that white patients, while the latter group appears to be at greater risk of proximal tubular dysfunction.

This study underlines the high prevalence of CKD and renal function decline in the HIV population. Although TDF is an important predictor of renal function decline, it may lead to this complication without necessarily altering tubular function clinically. Signs of proximal tubular dysfunction are indicative of ongoing kidney injury but cannot yet be considered as a major predictor of renal function decline. Other factors, such as age, albuminuria, comorbidities, co-infections, untreated HIV, nephrotoxic drugs and pre-existing renal disease, are more important to evaluate the risk of CKD progression in this population. Nevertheless, apart from the implications of proximal tubular dysfunction for eGFR decline, it is also important to consider that proximal tubular dysfunction has been linked to low bone mineral density,[26] a marker that was not assessed in the Lescure et al. study.[15] Follow-up of HIV patients should include measurement of albuminuria and serum creatinine levels at least.

Since its approval by the US Food and Drug Administration 3 years ago, tenofovir alafenamide (TAF), a tenofovir prodrug that is concentrated in immune cells but at a greatly reduced systemic drug exposure than TDF (which is posited to reduce the risk of toxicity), has replaced TDF in many settings, although TDF use remains common worldwide. This study may also be a warning regarding studies showing the advantage of TAF over TDF, which currently relies mainly on tubular markers of injury and not on long-term renal function decline.[27] Although it is likely, given the short-term studies and pharmacokinetics of the drug, that TAF will be less nephrotoxic than its predecessor TDF, definitive evidence is awaited with long-term studies on renal function decline and CKD incidence. Finally, recent evidence in several cohorts has shown that genetic factors play a major role in the progression of CKD in the HIV population and that these factors may be as important as clinical ones for both renal disease directly related to HIV infection as well as for nephrotoxicities and other types of renal disease.

Renal disease is an important problem in the aging HIV-positive population. Regular screening by serum creatinine levels and albuminuria is recommended. In patients at high renal risk, defined by clinical and genetic factors, nephrotoxic treatments including TDF should be carefully evaluated. Subclinical tubulopathy associated with TDF is more prevalent in Caucasians than in non-Caucasians but is not necessarily indicative of renal function decline.

Comments

3090D553-9492-4563-8681-AD288FA52ACE

processing....