and so is a single eGFR measurement. Tubular dysfunction is defined as an abnormal presence of markers in urine. Another frequently used, but poorly defined term is clinically significant nephrotoxicity. For example, one ENMD-2076 study found that tenofovir containing regimens were associated with decreasing creatinine clearance, but not with clinically significant renal toxicity. As there is no widely accepted or validated operational definition of this term, it should be avoided or at least be further specified. Studies should ensure that follow up has been adequately long to firmly conclude any lack of relevance acknowledging that the time gap between an occurrence of abnormal laboratory markers and development of symptoms may be substantial. Further, not all changes in renal markers have been related to clinical outcomes.
In general the use of different definitions contributes to difficulties in data interpretation and should preferably be standardized. cART and Renal Function in Overview cART availability has changed the natural history and spectrum of kidney disease in HIV positive persons. A 2005 model estimated that cART will reduce progression to NPI-2358 Vascular Disrupting Agent inhibitor ESRD by 38%. After cART initiation many patients experience improvement in renal function, as cART reverts impairment related to both the HIV virus and poor immune function. Others continue to lose renal function despite successful cART. This is common when the impairment is caused by other co morbidities. Results from clinical trials suggest that the majority proceed with unaffected renal function after cART initiation and only a small group experience new/accelerated decline in renal function, illustrated in Fig.
1. Mechanisms of ARV Associated Nephrotoxicity ARV associated nephrotoxicity has been described in many case reports and systematic observational studies. However, as neither BMS-707035 of these can demonstrate definitive causality, information on possible biological mechanisms is important to strengthen a suggestion for any causal link. There are several direct and indirect ways in which ARVs can induce damage to renal structures. Some ARVs, such as tenofovir, may exert a direct cytotoxic effect on cells within the renal tubules causing cell dysfunction and in severe cases apoptosis, tubular necrosis, and more widespread tubular dysfunction. Other ARVs induce inflammation in the interstitial space related to allergic reactions.
Some ARVs, including abacavir, can induce idiosyncratic drug reactions. Other ARVs, such as most PIs, can cause obstructing nephrolithiasis especially in the setting of dehydration. Damage to the glomerular structure is less commonly caused directly by drug toxicity, but is described. ARVs can, however, affect creatinine clearance indirectly by a number of mechanisms. For some ARVs an exact mechanismis not yet understood, eg, for tenofovir. Some have proposed that prolonged tenofovir exposure cause progressive tubular dysfunction with time possibly progressing to involve more structures and ultimately reducing creatinine clearance. ARV related nephrotoxicity can also occur indirectlyby drug drug interactions, eg, between PIs and lipid lowering drugs. Equally other ARVadverse events such as diabetes and severe dehydration may cause renal impairment. Depending on the structur