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Background:  Recent reports of renal insufficiency associated with the nucleoside reverse transcriptase inhibitors (NRTI) have included elevations in serum creatinine, proximal tubular dysfunction, nephrogenic diabetes insipidus, renal failure, Fanconi-like syndrome, and death. Appropriate methods for identification of patients at risk for severe renal injury are needed for monitoring and clinical dosage modification.

Methods:  Using an antiretroviral known to cause renal impairment (tenofovir disproxil fumarate [TDF]), we evaluated the rate of grade 1 and grade 4 renal insufficiency using serum creatinine and a method to more precisely evaluate glomerular filtration. Literature suggests that even minor changes in serum creatinine result in substantial decreases in glomerular filtration. Moreover, serum creatinine is influenced by other factors including age, race, sex, and body mass. According to the National Kidney Foundation, glomerular filtration is the “best overall indicator of the level of kidney function.” This is especially true in patients with co-morbid conditions. Multivariable Cox models were fit to consider age, race, study site, sex, route of HIV infection, AIDS, baseline viral load and CD4, baseline renal function, concurrent use of other nephrotoxic drugs, history of renal disease, hypertension, and diabetes as predictors of renal insufficiency in patients treated with TDF.

Results:  A total of 1298 patients were initiated first TDF on or after consent to CHORUS. Using a combined endpoint of serum creatinine and clinical events, 22 patients (1.7%) experienced a grade-1 event, 1 patient (< 0.1%) experienced a grade 4 event. Using a combined endpoint of glomerular filtration and clinical events, 128 patients (9.9%) experienced a grade-3 event, 7 patients (< 0.1%) experienced a grade-4 event. Multivariable analysis identified past history of renal disease (hazard ratio = 4.9; 95% CI = 2.7 to 8.8), abnormal baseline glomerular filtration (18.9; 9.2 to 39.1), hypertension (1.6; 1.1 to 2.3), and concurrent use of other nephrotoxic medications (2.7; 1.9 to 3.9) as important predictors of renal insufficiency.

Conclusions:  The elevations in serum creatinine observed in CHORUS are consistent with those seen in other populations, observational or otherwise. The proportion of patients with extreme grade 4+ glomerular filtration values is comparable to results seen for grade 4+ serum creatinine in other studies. However, nearly 10% of our patients have renal dysfunction using the grade 3+ glomerular filtration criterion. The National Kidney Foundation defines this level as chronic kidney disease. Glomerular filtration should be considered for the evaluation of renal insufficiency in HIV.

Keywords: HIV; Nephrotoxicity; GFR