NDT Advance Access originally published online on September 28, 2007
Nephrology Dialysis Transplantation 2007 22(12):3656-3659; doi:10.1093/ndt/gfm467
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Fanconi syndrome and nephrogenic diabetes insipidus associated with didanosine therapy in HIV infection: a case report and literature review
1Department of Nephrology, 2Department of Internal Medicine, Kremlin-Bicêtre Hospital, AP-HP, Le Kremlin-Bicêtre and 3INSERM UMR 542, Paris-Sud University, Paul Brousse Hospital, Villejuif, France
Correspondence to: Dr Renaud Snanoudj, Service de Néphrologie, CHU Bicêtre, 78 rue du Général Leclerc, 94275 Le Kremlin-Bicêtre Cedex, France. Email: renaud.snanoudj{at}bct.aphp.fr
Keywords: Fanconi syndrome; nephrogenic diabetes insipidus; drugs nephrotoxicity; HIV infection
HIV-infected patients are now treated with combined antiretroviral therapy (CART). Many drugs and/or metabolites are excreted by the kidneys. Furthermore, HIV-infected patients have a high prevalence of pre-existing nephropathies, which may or may not be related to HIV [1].
The nucleotide reverse transcriptase inhibitor tenofovir induces tubulopathies and renal insufficiency [2–4]. Nucleoside analogs essentially have mitochondrial toxicity. Nephrotoxicity of these nucleoside analogs is rare. Indeed, didanosine has a good kidney safety profile and only two cases of severe tubular toxicity have been reported [5,6]. Various authors have raised questions about the cumulative nephrotoxicity of didanosine and tenofovir and their respective roles, as their association leads to unexpected side effects in the kidney [7].
Here, we report a case of Fanconi syndrome and nephrogenic diabetes insipidus in an HIV-infected patient receiving a CART regimen including didanosine. We also review the cases that have been published previously, including patients treated with didanosine alone or in combination with tenofovir. We highlight the toxic role of didanosine in this association.
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Case report |
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A 40-year-old Caucasian man was admitted to the internal medicine unit for weight loss and fatigue. His medical history began in 1998 with a progressive multifocal leukoencephalopathy that revealed HIV-1 infection. At diagnosis, he had an advanced HIV disease, with a CD4+ lymphocyte count of 96 cells/µl and a plasma HIV-RNA level of 201 700 copies/ml. His status was stable from 1998 to 2005, when an abdominoperineal amputation with permanent colostomy was performed for an anal carcinoma.
After staying in bed for six months due to general weakness, neurological aggravation and weight loss, he was finally admitted to our hospital in January 2006. His treatment since 1998 included sodium valproate, paroxetine, allopurinol and baclofene. He was treated for HIV infection with didanosine, lamivudine, atazanavir and norvir booster for 2 years, with an undetectable viral load. He had a severe lipoatrophic syndrome, revealing mitochondrial toxicity. He complained of polydipsia and polyuria reaching 6 l/day for at least two months. Signs of major global dehydration and malnutrition were found on physical examination. An abdominal CT scan did not find relapse of cancer.
Blood and urine analyses on admission (Table 1) indicated the presence of two major biological syndromes. One of these is Fanconi syndrome including hypophosphataemia, hypouricaemia, hyperchloraemic metabolic acidosis with normal anion gap, normoglycaemic glycosuria and a low molecular weight proteinuria determined by urine protein electrophoresis. Urinary phosphate excretion above 100 mg/day (32.3 mmol/day) and the very high fractional excretion of phosphate (much higher than five per cent) were indicative of renal phosphate wasting. Natriuresis and kaliuresis were high, but difficult to interpret because of vigorous parenteral rehydration. Red and white blood cells were not detected in the urine. The other syndrome is nephrogenic diabetes insipidus (NDI), with polyuro-polydipsia and hypernatraemia. The 24 h urine output reached up to 6 l per day and natraemia up to 158 mEq/l. The antidiuretic hormone (ADH) level was high at 4.8 pg/ml (4.4 pmol/l, normal values are 
1.4 pmol/l). The patient had transient hypercalcaemia which we concluded was due to immobilization (1–84 parathyroid hormone (PTH) level was normal; no relapse of hypercalcaemia occurred after one injection of zolendronate).
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The patient was diagnosed with didanosine-associated Fanconi syndrome and administration of this drug was stopped, but treatment with lamivudine, atazanavir and ritonavir was continued. Glycosuria, tubular proteinuria, metabolic acidosis and hypernatraemia completely regressed one month after withdrawal of didanosine. The patient's performance status improved and he regained the weight he had lost. A second protease inhibitor was then added to his treatment regimen.
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Discussion |
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Various types of renal injury due to reverse transcriptase inhibitors have been reported, as reviewed by Izzedine et al. [8]. These include acute tubular necrosis, isolated tubular defects as in Fanconi syndrome, distal tubular acidosis and NDI. Large intracellular influx of drugs is the main culprit of this tubular toxicity, resulting in transporter defects, apoptosis or mitochondrial injury. Tenofovir, a nucleotide analog, is the drug most frequently involved in this tubular toxicity, but other acyclic nucleotide phosphonates, including cidofovir and high-dose adefovir also have this effect [8]. In contrast, renal toxicity of nucleoside analogs (didanosine, lamivudine, stavudine) has been reported far less frequently, though they have been used for more than 15 years. Only one case of renal tubular acidosis and hypophosphataemia has been associated with lamivudine and stavudine and two cases have been associated with didanosine [5,6].
Here we report a third case of complex tubular dysfunction associated with didanosine therapy. The first case [5] was reported in 1993 in a 46-year-old man presenting with Fanconi syndrome and nephrogenic diabetes insipidus resulting in severe polyuria (Table 2). Urine output and proximal tubulopathy returned to normal after didanosine discontinuation. The patient also had biological pancreatitis which resolved after cessation of didanosine treatment. Treatment with concomitant medication was restarted without a problem, supporting the implication of didanosine in the renal toxicity. In the second case [6], the patient was diagnosed with Fanconi syndrome after seven years of didanosine therapy. He had a peripheral neuropathy ascribable to didanosine therapy. All renal abnormalities resolved after didanosine discontinuation.
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Involvement of didanosine in Fanconi syndrome and nephrogenic diabetes insipidus is probable in the case reported here. However, implication of the other anti-retroviral drugs concurrently received by the patient—lamivudine, atazanavir and ritonavir—could be questioned. The complete and rapid resolution of all signs of proximal and distal tubulopathy after discontinuation of didanosine, whereas the patient was still receiving the three other antiretroviral drugs, is a strong argument for the role of didanosine. Furthermore, renal injuries have rarely been reported with atazanavir, lamivudine or ritonavir, but Fanconi syndrome or NDI have never been described [8–10]. We can not totally exclude a drug interaction that leads to an unexpected didanosine nephrotoxicity. Lamivudine may compete with didanosine for the human organic anion transporter-1 (hOAT1), on the basolateral membrane of the proximal tubules, resulting in an increased didanosine concentration, as reported with tenofovir [7]. However, a high number of patients received the combination of didanosine and lamivudine in clinical trials and outside of them, without increased nephrotoxicity. Ritonavir and atazanavir are both inhibitors of the cytochrome P450, and of various transporter molecules such as the multidrug resistance-associated proteins 1 and 2 (MRP-1 and -2) and P-glycoprotein (P-gp) [11]. Nevertheless, didanosine is not metabolized by the CYP450 enzymes, is not handled by MRPs and P-gp, and exhibits no significant interaction with ritonavir [11–14]. On the contrary, a food effect was observed when didanosine was co-administered with atazanavir, which reduced didanosine exposure [15]. In conclusion, to date, no interaction between atazanavir and didanosine susceptible to enhance didanosine exposure or toxicity has been described.
Four other cases of tubular dysfunction occurring with didanosine therapy have been reported (Table 2); however, these patients were also treated with tenofovir, which can cause Fanconi syndrome and NDI [2–4,7]. Three of these patients presented with Fanconi syndrome, acute renal failure and NDI. All antiretroviral drugs, including tenofovir and didanosine, were discontinued in the case reported by Creput et al. [4] allowing resolution of Fanconi syndrome. Thus, both drugs could consequently have been implicated. Tenofovir withdrawal was sufficient to correct the tubulopathy in two other cases [2,3], so the authors ruled out didanosine toxicity. In the case published by Rollot et al. [7], plasma drug monitoring on admission for renal failure showed that the concentration of didanosine was 100 times higher and that of tenofovir four times higher than target values.
Although proximal tubular toxicity (Fanconi syndrome) of tenofovir has been reported without association with didanosine, all the cases of NDI were reported in association with didanosine [2,3,7]. Resolution of NDI—and maybe also of proximal tubulopathy—after cessation of tenofovir treatment in these cases may be explained by a decrease in didanosine concentrations. Here we report a case of NDI occurring with didanosine alone, reinforcing the hypothesis that NDI associated with tenofovir is due to high didanosine concentrations.
Didanosine is eliminated by glomerular filtration and active tubular secretion. Competition between tenofovir and didanosine for the hOAT1 in the proximal tubules is a possible explanation for the increase in plasma didanosine concentration [7]. It is also possible that tenofovir inhibits the purine nucleoside phosphorylase (PNP), which is involved in degradation of didanosine [7,16].
Didanosine may enter the tubular cells and the mitochondria to exert its toxic effect whether or not it follows increased systemic exposure [17]. Didanosine is a substrate of human equilibrative nucleoside transporter 1 localized at the basolateral membrane of tubular cells and at the mitochondrial membrane [18]. In vitro experiments in renal proximal tubule cells have recently shown that didanosine, unlike tenofovir, was very toxic and had negative effects on mitochondrial DNA and cytochrome oxidase II mRNA. This effect was enhanced in the presence of tenofovir, suggesting that didanosine cellular clearance was inhibited [12,17].
In conclusion, didanosine may itself induce Fanconi syndrome and NDI, when given in a combined antiretroviral therapy. Moreover, administration of didanosine to patients also receiving tenofovir may increase the risk of tenofovir-associated proximal tubulopathy and may be responsible for NDI. Consequently, we and others recommend careful follow-up of renal parameters in patients receiving didanosine in combination with other antiretroviral drugs, especially the more recent ones. This is particularly important for patients with low weight and a pre-existing decline in renal function, requiring precise estimation of the glomerular filtration rate before initiation of treatment.
Conflict of interest statement. None declared.
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Notes |
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See http://www.oxfordjournals.org/our_journals/ndtplus/
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Accepted in revised form: 19. 6.07
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