es involved, the clinical findings differ from, eg, Fanconi syndrome to a combination of decreased eGFR and tubular dysfunction. The Danoprevir ITMN-191 clinical presentation also varies from asymptomatic to, eg, nephritic syndrome, nephrogenic diabetes insipidus, AKI, or CKD. In the following, focus will be mainly on tenofovir, atazanavir, indinavir, boosted lopinavir, and ritonavir. Other ARVs have also been associated with renal impairment, but data is limited. Assessment of the frequency of ARV associated nephrotoxicity is difficult as confirmatory biopsies are not performed systematically, and multiple etiologies of renal impairment are possible in HIV positive individuals. Most studies, however, conclude that the occurrence is relatively low, but warrant clinical attention due to the potentially serious complications.
One study found that ARV related nephrotoxicity accounted for 14% of all AKI cases among HIV positive individuals. Another study, including 60 kidney biopsies performed during AKI, found 5% were ARV related. For tenofovir, Gilead have reported a 0.5% incidence of serious adverse renal events, this is lower than reported in other studies, but the used definitions differ substantially. Regorafenib Raf inhibitor Important to consider is that other drugs commonly used in HIV positive persons also have known nephrotoxic properties including drugs used to treat infections, NSAIDs, and several illicit drugs. Equally important is the common occurrence of other comorbidities which may increase underlying risk of kidney disease such as diabetes and hepatitis C.
Individual ARVs Tenofovir Tenofovir was approved by the FDA in 2001 for treatment of HIV, and is currently among the first choices for antiretroviral Amonafide naïve patients due to effectiveness, simple administration, and a generally favorable safety profile. Tenofovir is structurally similar to adefovir and cidofovir, which have well established nephrotoxic effects. Tenofovir is eliminated through glomerular filtration and active proximal tubular secretion. The drug enters tubular cells via human organic anion transporters and is secreted into urine via the multidrug resistance associated protein 2 or 4. Potential Mechanisms for Tenofovir Nephrotoxicity An exact mechanism by which tenofovir causes nephrotoxicity is not known, but several harmful processes have been proposed.
In animal studies nephrotoxicity developed when tenofovir was administered in high doses, and high intracellular concentrations were found to interfere with mitochondrial DNA replication. Other studies showed that rodents receiving high tenofovir doses experienced significant loss of kidney weight, dilation of the proximal tubules, and enlarged number, shape, and size of tubular mitochondria compared to controls. Conversely the relative low tenofovir potential to induce mitochondrial dysfunction, the fact that HIV itself can cause mtDNA depletion, and that increased lactate levels would be expected more commonly argue against this theory. Another suggested mechanism involves dysfunction/inhibition/ under expression of MRP4, possibly by drug interactions or genetic polymorphisms. Ritonavir is a known MRP4 inhibitor, and is found to increase intracellular tenofovir concentration. It has been suggested that 70% of tenofovir associated nephrotoxicity is seen