Renal problems Tenofovir

Tenofovir has been approved since 2001 and is, like the two nephrotoxic drugs, adefovir and cidofovir, a nucleotide analog. Animal studies showed a dose-related nephrotoxicity. Severe renal toxicity occurs rarely, but a significant proportion of patients develop kidney dysfunction (Crane 2007, Sax 2007). In one study graded elevation of serum creatinine occurred in 2,2 % of the patients (Nelson 2007) ). Acute renal failure and proximal tubulopathy with Fanconi's syndrome and nephrogenic diabetes insipidus and rarely hypophosphatemic osteomalacia have been reported Rollot 2003,Saumoy 2004). Proximal tubular damage manifests as proximal tubular acidosis, normoglycemic glycosuria, hypophosphatemia, hypouricemia, hypokalemia, generalized aminoaciduria, and proteinuria. Renal toxicity occurs after some months, rarely at the beginning of therapy (Hansen 2004, Izzedine 2004, Rifkin 2004). Risk factors include a relatively high tenofovir exposure, pre-existing renal impairment, low body weight, increased age, co-administration of nephrotoxic drugs, amprenanvir and didanosine. Furthermore, extensive pre-treatment with nu-cleoside reverse transcriptase inhibitors seems to be another risk factor (Saumoy 2004). However, even in patients without any predisposing factors, nephrotoxicity may occur (Barrios 2004).

Case reports suggested that the use of lopinavir/ritonavir, atazanavir and ritonavir with tenofovir is associated with a higher risk of kidney dysfunction through the interaction of PIs with the renal transport of organic anions, leading to proximal tubular intracellular accumulation of tenofovir (Izzedine 2004, Rollot 2003, Zimmermann 2006). However, three studies did not find an increase in tenofovir-asscociated kidney dysfunction among patients receiving lopinavir/ritonavir, ata-zanavir, or ritonavir (Gallant 2005, Antoniou 2005, Crane 2007)

In case of renal dysfunction, especially in patients with low body weight, tenofovir should be avoided if possible, or the dosing interval should be adjusted. The manufacturer recommends administering tenofovir every 48 hours in patients with a cre-

atinine clearance between 30 and 49 ml/min and twice a week between 10 and 29 ml/min.In these cases therapeutic drug monitoring is recommended. Normal creatinine levels may be misleading especially in subjects with low body weight, which is why creatinine clearance should be measured before initiating tenofovir treatment. Urine-beta2 microglobuline might be a more sensitive marker of renal tubular injury caused by tenofovir (Gatanaga 2006). Renal function tests including creatinine, urea, creatinine clearance, proteinuria, glycosuria, blood and urine phosphate should be monitored every other week.

Tenofovir is not recommended for use in patients with pre-existing renal insufficiency. It should also be avoided with concomitant or recent use of nephrotoxic agents such as aminoglycosides, amphotericin B, foscarnet, ganciclovir, pentami-dine, vancomycin, cidofovir or interleukin-2. Usually the abnormalities resolve after discontinuation of the drug (Izzedine 2004, Rifkin 2004, Roling 2006).

An increase in creatine kinase (CK, CK-MB) is common with tenofovir (Shere-Wolfe 2002). Analysis of CK-MB isoenzyme activity and mass concentration revealed evidence for Macro CK 2 (Schmid 2006). Therefore, the elevated CK might not be an indicator of ischemic heart disease but Macro CK-2 appearance on teno-fovir treatment. The CK elevation resolves after discontinuation of tenofovir.

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