The renal transplant patient with visceral leishmaniasis who could not tolerate meglumine antimoniate—cure with ketoconazole and allopurinol

Migue Hueso1, Jordi Bover1, Daniel Serón1, Salvador Gil-vernet1, Gabriel Rufí2, Jeroni Alsina1 and Josep M. Grinyó1

1 Departments of Nephrology and 2 Infectious Diseases, Ciutat Sanitària i Universitària de Bellvitge, L'Hospitalet de Llobregat, Barcelona, Spain

Correspondence and offprint requests to: Josep M. Grinyó MD, Department of Nephrology, Hospital de Bellvitge, C. Feixa Llarga s/n, 08907 L'Hospitalet, Barcelona, Spain.

Keywords: acute pancreatitis; allopurinol; leishmaniasis; ketoconazole; pentavalent antimonial drugs; renal transplantation



   Introduction
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 Introduction
 Case
 Discussion
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Visceral leishmaniasis is an endemic parasitic infection in the Mediterranean area [1]. Shortly after the initial infection, the parasite spreads through the monocyte macrophage system and a granulomatous cellular immune response develops, leaving the parasite in a latent form. Therefore, hosts may remain free of clinical symptoms for long periods of time. Although impairment of cellular immunity could trigger overt disease, visceral leishmaniasis is uncommon in allograft recipients, even in endemic areas. However, immunocompromised hosts have a worse outcome since the disease behaves more aggressively. These individuals have an atypical clinical presentation and course of disease, which may delay the diagnosis, and they respond more poorly to therapy [2,3].

Pentavalent antimonial drugs have been classically considered the therapy of choice, but the frequency of serious adverse events and the increasing incidence of primary parasitic resistance or relapses have stressed the need for alternative treatments. However, information is insufficient and an optimal therapeutic regime lacking adverse effects has not yet been described should any problem occur [4].

We report the case of a renal allograft recipient with visceral leishmaniasis who developed acute pancreatitis during the initial phase of treatment with meglumine antimoniate. We then successfully treated the patient using a novel combination of ketoconazole and allopurinol, two drugs that have been individually suggested as second line treatments.



   Case
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 Introduction
 Case
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A 66-year-old white Caucasian man was admitted to our hospital 21 weeks after renal transplantation for the evaluation of mild heart failure, low-grade fever and weight loss. Before renal transplantation, he had been treated with haemodialysis for a period of 3 years for end-stage renal disease of unknown aetiology. Immunosuppression for renal transplantation consisted of a monotherapy with cyclosporin A (Sandimmun Neoral®). The early post-transplantation period was uneventful and he was discharged 9 days later with a serum creatinine of 150 µmol/l. During the first 3 months, he experienced three episodes of graft rejection, which were each treated with three pulses of 500 mg/day of 6-methylprednisolone. After the last graft rejection episode (8 weeks before admission), 1.5 g/12 h of mycophenolate mofetil were added to the immunosuppression regime. Serum creatinine at his discharge was 398 µmol/l.

On admission, physical examination revealed paleness, tachycardia, a few basilar rales and peripheral pitting oedema. A grade 2 soft systolic murmur was heard along the lower left sternal border. No diastolic murmur or pericardial friction rub was detected. Abdominal examination revealed a firm and non-tender 8-cm splenomegaly and a normal renal allograft. Funduscopic examination was normal. Thoracic radiographs showed a mild cardiac enlargement and some fluid in fissures. Laboratory tests revealed: serum creatinine 292 µmol/l (creatinine clearance: 18 ml/min/1.73 m2); urea nitrogen (BUN) 10.9 mmol/l; whole-blood cyclosporin levels 102 ng/ml (RIA specific monoclonal antibody, CYCLO-Trac-SP, Incstar, Stillwater, MN); serum alanine aminotransferase 0.17 µkat/l; serum albumin 34 g/l; serum total proteins 51 g/l; serum protein electrophoresis {alpha}1 11.7 g/l, {alpha}2 29.4 g/l, ß 23.5 g/l, {gamma} 31 g/l; haemoglobin 6.8 g/dl; WBC 4000/mm3 and a differential count with 75% N; 20% L; 3.5% M; 0.5% B; 1% E; and 264000 platelets/mm3. He was receiving 1.5 g/day of mycophenolate mofetil, 140 mg/day of cyclosporin, 5 mg/day of prednisone, 1 g/day of sodium bicarbonate and 150 mg/day of ranitidine. The patient's status improved with diuretic treatment. Abdominal ultrasonography revealed a homogeneous 14-cm splenomegaly without hepatomegaly or signs of portal hypertension. The CMV viral culture was negative. The titre of antibodies against leishmania (indirect immunofluorescence) was 1:16 (normal level <1:16). Culture and Giemsa staining of a bone marrow aspirate revealed massive intracellular and extracellular amastigotes, confirming the diagnosis of leishmaniasis. Therapy with meglumine antimoniate (glucantime®, 850 mg/Sb) was immediately started. Four days later, an asymptomatic rise in serum amylase levels was detected (from 1.34 to 39.2 nkat/l; normal values: 0.88–2.05 nkat/l). The treatment was not initially interrupted, but 4 days later the patient complained of abdominal pain, nausea and vomiting so that meglumine antimoniate was discontinued. Symptoms improved within 24 h after drug withdrawal. Consequently, both oral ketoconazole (200 mg/12 h) and allopurinol (300 mg/day) were administered for a full-course of treatment lasting 30 days. Additionally, only one-third of the previous cyclosporin dose was administered to maintain the blood levels between 50–100 ng/ml. After the treatment a new bone marrow aspirate was carried out and revealed the complete absence of leishmania. After 8 months of follow-up, the patient is in good clinical condition, free of symptoms, the renal function has improved (creatinine 194 µmol/l, creatinine clearance 20 ml/min/1.73 m2, cyclosporin levels 108 ng/ml) and there is no evidence of relapse. The splenomegaly has completely disappeared, and current haemoglobin and platelet levels are 11.6 g/dl and 252000/mm3, respectively.



   Discussion
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 Introduction
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The increasing knowledge about leishmania and adverse effects of classical therapy have indicated the need to replace the standard drugs which have been the therapy of choice since 1947 [4]. Information regarding alternative treatments is scarce, and almost absent in the context of kidney transplantation should any adverse events or treatment failures occur. For these patients, the choice of alternative therapy is limited by the condition that it be non-nephrotoxic since the allograft is already exposed to several injuries that contribute to loss of renal mass. Thus, successful treatment of leishmaniasis with combination therapy consisting of ketoconazole and allopurinol in a kidney transplant recipient is especially relevant.

Our patient was initially treated with meglumine antimoniate. It is well known that antimonials are frequently associated with adverse effects such as myalgia, arthralgia, pancytopenia, reversible peripheral neuropathy, hepatotoxicity, cardiotoxicity, a direct toxic renal tubular effect or acute pancreatitis [4,5]. Many of these untoward effects are dose-dependent. Moreover, since antimonial drugs are mainly excreted by the kidney, it is important to bear in mind that a dose adjustment is recommended when the glomerular filtration rate is lower than 15 ml/min [6]. This fact is especially important in recipients of a kidney allograft. Renal transplant patients usually have renal function impairment and the glomerular filtration rate may further decrease for several reasons. In addition to nephrotoxic properties, antimonial drugs may also increase serum cyclosporin levels by competing for hepatic cytochrome P450. Visceral leishmaniasis itself may cause both glomerular and interstitial renal damage [7], and finally the necessity of reducing the dose of immunosuppressive drugs in such a serious infectious condition carries an increased risk of acute rejection.

Four days after antimonial drug therapy was started, serum amylase increased nearly 30-fold over the previously normal levels. Nevertheless, the drug was not discontinued because it is well known that an increase in serum amylase levels occurs in 98% of treated patients [5]. However, 4 days later the patient developed full-blown acute pancreatitis although no criteria of high degree of severity were met. Meglumine antimoniate was withdrawn since antimonial-related symptomatic acute pancreatitis is more aggressive in renal allograft recipients (one out of four reported patients died). The high incidence of severe acute pancreatitis in this population is suspected to be due to interaction with other therapies, which are toxic for the pancreas, such as azathioprine, cyclosporin or glucocorticosteroids [5].

Antimonial treatment for leishmaniasis should last 28 days, and it is advised to prolong it to 40 days in regions where clinical resistance has been observed [4]. Ideal alternative therapy for renal allograft recipients would be a drug with proven efficacy against leishmania without side effects. Moreover, this potential drug should have a good oral biodisponibility and a biliary route of excretion, making its administration easier and independent of renal function fluctuations. A low economical cost would also be appealing.

Several second-line drugs have been recommended in the literature as valid alternatives for the treatment of visceral leishmaniasis. Intravenous paromomycin (Aminosidine®) has been successfully used as monotherapy in conjunction with antimonial drugs. However, an aminoglycoside seems not to be the best choice in renal transplantation patients due to its nephrotoxicity [4]. Similarly, the well-known toxic effects of amphotericin B have widely limited its use [8]. Moreover, this drug has a synergistic nephrotoxic effect with CsA [9]. For this reason, new clinical formulations of this drug with less toxic effects such as liposomal amphotericin B (AmBisome®), amphotericin B lipid complex (Abelcet®) and amphotericin B colloidal dispersion (Amphocil®), have been recently introduced and a lot of experience already exists regarding their clinical use. Unfortunately, these new costly formulations are still nephrotoxic, mainly excreted by the kidney, and are only for intravenous administration [4,9]. Although Ringdén et al. stressed the safety aspects of AmBisome® in a review of 187 CsA-treated transplant recipients (of whom 20 were kidney recipients), the authors described an increase of serum creatinine in 31% of patients, with an overall mean increase of 20% [9]. There are also several reports that recommend the use of systemic human recombinant interferon-{gamma} as an adjunct to antimonial therapy in order to increase its efficacy [4]. However, such therapy may trigger an acute rejection episode in allograft recipients. Finally, pentamidine is associated with an important degree of toxicity, and acute renal failure has been described in almost 25% of patients treated with this drug.

Oral agents, such as allopurinol, have been used to treat leishmaniasis for nearly 15 years. It is believed that the inhibition of xanthine-oxidase would induce either an accumulation of oxypurines or a deficit of other metabolites that would eventually be lethal for the parasite. A large number of uncontrolled studies have shown its usefulness either as a single drug or in conjunction with others [4]. This drug has the advantages of a low cost and very good oral bioavailability and tolerance. However, a recent controlled study has concluded that allopurinol monotherapy is ineffective against some forms of the disease [10]. Whether the combination with other drugs may exhibit synergistic properties has not yet been clearly demonstrated.

Finally, the effectiveness of imidazoles such as ketoconazole, and triazoles such as itraconazole, have also been suggested in some uncontrolled studies. These drugs inhibit sterol synthesis disrupting parasitic membranes. Itraconazole has only been used in cutaneous leishmaniasis and several clinical notes report attempts to treat visceral leishmaniasis with ketoconazole [4]. Wali et al. successfully used ketoconazole in four out of five patients with visceral leishmaniasis [11], and in seven out of nine patients with antimonial or pentamidine resistance [12]. However, Sundar et al. reported the failure of this drug to reduce the parasite load in six patients [4]. It should be kept in mind that ketoconazole and cyclosporin share the same hepatic metabolic route and, thus, a reduction in the cyclosporin dose and close monitoring of serum cyclosporin levels are needed.

The combination of two drugs with two different mechanisms of action to increase their individual therapeutic effectiveness and decrease the risk of adverse effects is a therapeutic option. The case of a renal transplant recipient successfully treated with ketoconazole and allopurinol was recently reported. However, the patient had already restarted haemodialysis when therapy was initiated and, hence, the absence of nephrotoxicity could not be demonstrated [13].

In summary, we have shown that treatment with allopurinol and ketoconazole for 30 days may be effective and safe in patients with a functioning renal allograft diagnosed of visceral leishmaniasis. Therefore, the combination of ketoconazole and allopurinol might be of great benefit when antimonials have to be withdrawn for the presence of their frequent adverse side effects. Whether antimonials should be completely avoided in these patients remains a matter of debate.



   Acknowledgments
 
Miguel Hueso is supported by a grant from the Fundació August Pi i Sunyer, L'Hospitalet de Llobregat, Barcelona, Spain. Jordi Bover is supported by a grant from Novartis.



   References
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 Introduction
 Case
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 References
 

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Received for publication: 9. 7.99
Accepted in revised form: 12. 7.99