Treatment with Tenofovir Is Associated with Mild Renal Dysfunction

Tenofovir (Viread) shares some of its molecular structure with adefovir (Hepsera), a nucleotide analogue that is limited in its clinical use by nephrotoxicity. In particular, a dose and time-dependent development of a Fanconi-like syndrome was reported. In contrast, tenofovir has not shown overt nephrotoxic effects in clinical trials. In the present study, published in AIDS (January 3, 2005), German researchers assessed the effect of tenofovir on glomerular and tubular renal function.

Fanconi's syndrome and renal failure induced by tenofovir have been reported in anecdotal cases after tenofovir was granted approval for the treatment of HIV infection. Patients treated with tenofovir (n = 82) were compared with patients on antiretroviral therapy never treated with tenofovir (n = 92). From each patient a blood sample was drawn, blood pressure was measured and 24-h urine was collected.

Diabetes mellitus, hypertension as defined as systolic blood pressure greater than 160 mmHg or diastolic blood pressure greater than 95 mmHg, liver cirrhosis or known renal disease were exclusion criteria.

Creatinine, urea, uric acid, cystatin C, sodium, potassium, calcium, phosphate and chloride were measured in serum. In urine collected over 24-h the excretion rate of total protein, creatinine, urea, uric acid, sodium, potassium, calcium, phosphate and chloride was analyzed. A variety of other tests were performed in the tenofovir-treated group and compared with the control group.

Results

Creatinine clearance was not different in both groups (tenofovir 106 ± 54 ml/min 1.73m² versus control 104 ± 22 ml/min 1.73m², P = 0.375).

Patients on tenofovir had a higher mean protein content in urine. In total, 24 patients on tenofovir (30%) versus five control patients (5%) had proteinuria greater than 130 mg/day (P < 0.001). The majority of patients showed a tubular pattern (14/24 versus 3/5).

Combined tubular and glomerular proteinuria was found in seven out of 24 patients on tenofovir compared with one out of five control patients. A glomerular pattern was observed in three out of 24 patients on tenofovir and in one out of five control patients.

The excretion rate in urine of creatinine, urea, uric acid, sodium, potassium, calcium, phosphate and chloride were in the normal range and were not significantly different between both groups.

In the analysis of variance no association was found between an impaired GFR or proteinuria and sex, age, previous use of indinavir or time on antiretroviral drugs.

In one patient with marked proteinuria (170 mg/day), proteinuria was reversible after the discontinuation of tenofovir with a decrease to 93 mg/day 3 weeks after stopping.

No patient in the study fulfilled the criteria for nephrotic syndrome or Fanconi-like syndrome.

In conclusion, treatment with tenofovir was associated with a lower mean GFR as estimated by creatinine clearance or serum cystatin C. It has to be noted, however, that the mean GFR was still within the normal range. In addition, there was a higher number of patients with a pathological GFR calculated by creatinine clearance or cystatin C in the tenofovir group compared with control patients. Interestingly, these differences were not detected by creatinine clearance as calculated on the basis of serum creatinine using the MDRD formula. This method was recently used in some reports on the effect of tenofovir on renal function.

In addition, in the tenofovir-treated group an increased number of patients with significant proteinuria predominantly of tubular origin were observed. This pattern may support a mechanism related to the nephrotoxic effect of adefovir, which was also associated with tubular renal dysfunction. It has to be noted, however, that in contrast to the findings reported for adefovir no enhanced renal loss of electrolytes was found in patients treated with tenofovir.

Other factors, such as exposure to indinavir, an antiretroviral agent with known nephrotoxic potential, time on antiretroviral drugs, sex or age did not change the association between tenofovir and a decreased GFR or proteinuria.

In conclusion, the authors write, “Treatment with tenofovir may induce mild renal dysfunction in a higher proportion of patients compared with patients never treated with tenofovir. Treatment with tenofovir may render the kidney more vulnerable to concomitant treatment with nephrotoxic drugs. Therefore, a detailed functional assessment of renal function should be included in the design of future trials including treatment with tenofovir.”

Center for HIV and Hepatogastroenterology, Duesseldorf; Germany.

Reference
S Mauss and others. Antiretroviral therapy with tenofovir is associated with mild renal dysfunction. AIDS 19(1): 93-95, January 3, 2005.