Annals of Clinical & Laboratory Science, vol. 32, no. 4, 2002
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Case Report: A Tumor Lysis-Like Syndrome during Therapy of Visceral Leishmaniasis
Evagelos Liberopoulos, George Alexandridis, and Moses Elisaf Department of Internal Medicine, University of Ioannina, Ioannina, Greece Abstract. Reported herein for the first time in the literature is the case of a 41-yr-old woman who developed a tumor lysis-like syndrome, consisting of hyperkalemia, hyperphosphatemia, hyperuricemia, and acute renal insufficiency, soon after the initiation of chemotherapy for severe visceral leishmaniasis with liposomal amphotericin B. Allopurinol therapy, together with iv fluid administration and urine alkalization, resulted in full recovery of the metabolic abnormalities. Awareness of this condition can lead to prophylactic treatment as well as the early recognition and management of susceptible patients. (received 1 April 2002; accepted 8 June 2002)
Keywords: tumor lysis syndrome, leishmaniasis, hyperphosphatemia, hyperkalemia, hyperuricemia Introduction
Case report
The tumor lysis syndrome is a constellation of metabolic disorders that are usually encountered after the initiation of chemotherapy for rapidly proliferating malignancies, such as high-grade lymphomas or acute leukemias [1-3]. The syndrome is characterized by the presence of rapid and severe metabolic changes, including hyperkalemia, hyperuricemia, hyperphosphatemia, and hypocalcemia, with accompanying renal insufficiency [13]. To the best of our knowledge, a tumor lysis-like syndrome has not been described in the literature after the initiation of chemotherapy for visceral leishmaniasis or other infectious diseases. Reported herein is the case of a 41-yr-old woman who developed hyperkalemia, hyperphosphatemia, hyperuricemia, and acute renal impairment 3 days after the initiation of chemotherapy for kala-azar (visceral leishmaniasis).
A 41-yr-old woman without relevant medical history was admitted to our clinic because of fever of 3 mo duration, accompanied by nocturnal diaphoresis, anorexia, and weight loss. On admission, her temperature was 37.4 °C, blood pressure 120/80 mmHg, respirations 15/min, and pulse rate 90/min. There was marked hepatomegaly and splenomegaly on physical examination. Laboratory studies revealed anemia (hemoglobin concentration, 8.6 g/dl), mild leukopenia and thrombocytopenia (leukocyte and platelet counts, 2,310/ µl and 110,000/ µl, respectively), elevated erythrocyte sedimentation rate (112 mm/hr), increased serum C-reactive protein (69 mg/L), and marked hypergammaglobulinemia (10.4 g/dl). Serum glucose and electrolyte concentrations, indices of renal function, and 24hr creatinine clearance were all within the reference limits (Table 1). Visceral leishmaniasis was diagnosed by the presence of high titers of anti-leishmania antibodies (1:10,240 by indirect immunofluorescence assay) and the demonstration of numerous intracellular parasites in a bone marrow aspirate.
Address correspondence to Moses Elisaf, M.D., Department of Internal Medicine, University of Ioannina, 451 10 Ioannina, Greece; tel 30 651 097509; fax 30 651 097016; e-mail
[email protected].
0091-7370/02/0400/0419 $0.75. © 2002 by the Association of Clinical Scientists, Inc.
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Table 1. Changes in the patient’s biochemical parameters after the initiation of antileishmania treatment. Serum parameter Reference Glucose (mg/dl) Creatinine (mg/dl) Urea nitrogen (mg/dl) Uric acid (mg/dl) Potassium (mmol/L) Magnesium (meq/L) Total calcium (mg/dl) Phosphate (mg/dl) Creatinine clearance (ml/min)
On admission
Period after initiation of therapy 3 days 10 days 3 mo
123 0.8 18 5.1 4.1 1.42 8.5 3.5 85
Therapy with liposomal amphotericin B (AmBisome, 3 mg/Kg/day, days 1 to 5 and day 10) was started immediately. Three days later there was laboratory evidence of a tumor lysis-like syndrome, consisting of hyperuricemia, hyperkalemia, hyperphosphatemia, elevated levels of serum urea nitrogen, and acute renal dysfunction (ie, the 24-hr creatinine clearance was decreased to half the initial value), while serum glucose and total calcium levels remained unchanged (Table 1). Serum lactate dehydrogenase activity, an indicator of tissue destruction, was elevated at that time (564 IU/L compared to 245 IU/L on admission; normal values 255-450 IU/L), whereas serum creatine kinase activity remain unchanged (46 IU/L vs 48 IU/L on admission; normal values 40-190 IU/L)], showing that no muscle, cardiac, or brain damage occured. Microscopic examination of a urine specimen at that time disclosed granular casts and uric acid crystals. Allopurinol therapy, aggressive iv fluid administration, and urine alkalization were immediately initiated. Seven days later, significant improvement was achieved in the patient’s hepatosplenomegaly and metabolic profile (Table 1). Three mo later, the patient remains in good health with normal renal function and laboratory profile. Discussion Although the Jarisch-Herxheimer reaction and the release of endotoxins [4] are well recognized
121 1.5 61 9.8 5.9 1.51 8.3 5.2 43
126 0.8 15 5.1 4.4 1.37 8.5 3.1 83
115 0.8 22 4.4 4.8 1.44 9.8 3.2 85
range 70-110 0.6-1.2 8-25 2.4-6.1 3.5-5.5 1.30-2.10 8.2-10.6 2.5-5.0 80-120
consequences of bacterial lysis after the initiation of antibiotic chemotherapy, this is the first time that a tumor lysis-like syndrome is reported. Massive death of parasites and amastigote-containing mononuclear phagocytes after the initiation of treatment for visceral leishmaniasis could have led to increased release of intracellular contents (potassium, phosphorus, proteins, and nucleic acids), resulting in hyperkalemia, hyperphosphatemia, and increased production of uric acid and urea. The disproportionately elevated concentration of serum nitrogen urea, in comparison to the serum creatinine level at that time, could reflect either dehydration or increased production of urea attributable to increased catabolism of proteins released during the lysis syndrome. Renal impairment could have been the result of precipitation of urate and calcium phosphate crystals in renal tubules and intravascular volume depletion. The remarkably high titers of antileishmania antibodies and the numerous parasites in the bone marrow aspirate point to the presence of a high parasite load in our patient, which could explain the observed metabolic changes after the initiation of chemotherapy. Prophylactic therapy with allopurinol, plasma volume expansion, and urine alkalization should be initiated under such circumstances. Therapy with liposomal amphotericin B was started in our patient. Although pentavalent antimonials have been the mainstays of therapy for visceral leishmaniasis for many years, newer
Tumor lysis-like syndrome in visceral leishmaniasis
formulations of amphotericin B, although expensive, have now become the treatment of choice in many countries because of fewer therapeutic failures, reduced untoward effects, and shorter duration of therapy [5,6]. Alternative regimens include pentamidine, paromomycin, and atovaquone. A new antileishmanial drug, miltefosine, may be used in the future [7]. In the literature, there has been no report of tumor lysis-like syndrome with any of these drugs. Possible amphotericin B-related nephrotoxicity could not explain the observed metabolic changes, since amphotericin B-induced nephrotoxicity is usually accompanied by hypokalemia and hypomagnesemia [8], which was not seen in our patient. Furthermore, the brief interval between initiation of treatment and the observed metabolic abnormalities, as well as the relatively low dosage, make this hypothesis improbable. Finally, liposomal amphotericin B is less nephrotoxic than the classic preparations [8]. The authors conclude that a tumor lysis-like syndrome can complicate the treatment of visceral leishmaniasis, especially in patients with high parasite loads. Awareness of this condition can lead
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to the initiation of prophylactic therapy as well as to early recognition and effective management, thereby preventing renal failure or fatal hyperkalemia and improving the prognosis in susceptible patients. References 1. 2.
3. 4. 5. 6. 7. 8.
Arrambide K, Toto RD. Tumor lysis syndrome. Semin Nephrol 1993;13:273-280. Jones DP, Mahmoud H, Chesney RW. Tumor lysis syndrome: pathogenesis and management. Pediatr Nephrol 1995;9:206-212. Jeha S. Tumor lysis syndrome. Semin Hematol 2001; 38(Suppl 10):4-8. Hurley JC. Antibiotic-induced release of endotoxin: a reappraisal. Clin Infect Dis 1992;15:840-854. Davidson RN. Practical guide for the treatment of leishmaniasis. Drugs 1998;56:1009-1018. Herwaldt BN. Leishmaniasis. Lancet 1999;354: 1191-1199. Croft SL, Yardley V. Chemotherapy of leishmaniasis. Curr Pharm Des 2002;8:319-342. Bennett JE. Amphotericin B. In: Goodman & Gilman’s The Pharmacological Basis of Therapeutics, 10th ed (Hardman JG, Limbird LE, Eds), McGrawHill, New York, 2001; pp 1295-1299.
