Introduction
American visceral leishmaniasis (AVL) is a neglected tropical disease with a cosmopolitan distribution.1 Brazil, Ethiopia, India, Kenya, Somalia, Sudan and South Sudan represent 94% of the world cases of human visceral leishmaniasis.2 In the Americas, Brazil accounts for 97% of cases, with infected individuals in 22 states of the five Brazilian regions.3
The Central West region of São Paulo State is considered endemic since 2004, with the first reports of AVL in the Adamantina microregion, spreading to adjacent municipalities through the Comandante João Ribeiro de Barros highway.4
It is estimated that 20% of immunocompetent individuals living in endemic areas will develop clinical manifestations of the disease.5 However, immunosuppressed patients, having human immunodeficiency virus - acquired immunodeficiency syndrome (HIV-AIDS) patients as a prototype, present a 100 to 1000 times greater chance of developing clinically active disease in relation to the general population in the same locations.6
Considered rare in solid organ transplant (SOT) recipients, AVL may evolve with complications such as disease reactivation and successive relapses, especially in the face of impaired immunological response.7) Most reported cases are the result of kidney transplants, accounting for more than 75% of SOT, and proceeded from southern Europe.7) Therefore, this makes infections in SOT recipients caused by Leishmania infantum chagasi, the etiologic agent in the American continent, scarce in the literature.7
Thus, this report aims to describe a case of a renal transplanted patient, resident in an endemic area and infected by AVL, assisted at the Hospital das Clínicas of Marília Medical School (HC - Famema) who died probably due to complications from haemodialysis after the loss of the renal graft because of the treatment toxicity for this disease.
Clinical case
A 22-year-old female, caucasian, housewife, graduated from high school, born, and coming from a city in the West of São Paulo State, weighing 44 kg, that underwent a kidney transplantation surgery when she was eighteen years old. She was referred from another service to HC - Famema, on suspicion of visceral leishmaniasis relapse.
Concerning her preceding personal history, the patient was diagnosed at six months of age with congenital cardiopathic interventricular communication, which presented moderate hemodynamic repercussion. Six-year-old electrocardiogram (EKG) suggestive of right ventricular overload. At the age of 16, severe arterial hypertension with target-organ damage was observed in ophthalmological evaluation of the macular scar type with bilaterally perimacular hard exudates, associated with renal functional deficit.
She started hemodialysis at 17-year-old in order to chronic kidney disease secondary to hypertensive nephrosclerosis, receiving after 13 months’ kidney transplantation from previously healthy deceased donor, victim of traumatic brain injury, with creatinine of 0.9 mg/dl, 1A1DR compatibility and negative panel for lymphocyte reactivity. It was initiated immunosuppression with methylprednisolone (DEPO-MEDROL®) 500 mg, single dose, intravenous, and maintenance therapeutic with prednisone (METICORTEN®) (0.73 mg/kg/day), orally, once a day in the morning, continuous use; azathioprine (IMURAN®) (1.8 mg/kg/day) orally, once a day in the afternoon, continuous use; and tacrolimus (PROGRAF®) (0.29 mg/kg/day) orally, twice a day, continuous use, with control blood measurements every three months, featuring good evolution with serum creatinine of 0.7 mg/dl and no side effects. In the tenth month after transplantation, she developed diabetes mellitus (DM), starting treatment with oral hypoglycemic agent.
Four years later, the patient presented diarrhea, febrile hepatosplenomegaly, with polyclonal elevation of plasma gamma globulin and negative serology for cytomegalovirus. She was diagnosed with AVL by bone marrow aspirate smear (BMAS) from sternum, in another service, being treated with liposomal amphotericin B (AmBisome®) (LAB). In the same year, she started prenatal care in the first trimester of pregnancy and follow-up in a high-risk prenatal outpatient clinic at “Hospital Materno-Infantil” HCII - Famema. At 12 weeks of gestational age, she had first AVL relapse, with pancytopenia, splenomegaly and positive BMAS, from sternum bone sample. Then, LAB in scheme 4.8 mg/kg/day, intravenous, for seven days was introduced, with reinforcement in tenth day (total dose of 38.4 mg/kg). No side effects were observed. She started hemodialysis therapy three times a week requiring blood components transfusion. Echocardiography indicated a valvular lesion, a moderate tricuspid regurgitation. She evolved with preeclampsia, with worsening of renal function and fetal death in the twenty-third week by intrauterine anoxia.
Renal biopsy revealed chronic graft nephropathy, interstitial fibrosis and tubular atrophy, segmental and focal secondary glomerulosclerosis 5/20 and global sclerosis 3/20 glomeruli. Due to renal function deterioration and decompensation of DM, insulin therapy and angiotensin-converting-enzyme inhibitor were initiated.
After two months of the first relapse, she was referred to our infectology service, as initially mentioned, due to suspicion of new relapse of AVL. The diagnosis was confirmed by BMAS, from sternum, in which frequent free and intracellular amastigote forms of Leishmania were observed, and at the same time, the rapid immunochromatographic test for AVL (LSH Ab ECO Teste) was negative. She remained hospitalized for eight days, being treated with LAB 4 mg/kg/day, intravenous, for 7 days and reinforcement on the tenth day (total dose of 32 mg/kg). At this time, secondary prophylaxis was initiated with LAB 4 mg/kg/dose fortnightly, continuously, according to the guidance of the Epidemiological Surveillance Center of São Paulo State.8
In one month of prophylaxis, ahead the laboratory tests within the normal range, we opted to maintain the LAB 4 mg/kg/day, intravenous, regimen every 21 days. Despite the prophylaxis, she presented the third relapse, being treated with LAB 4 mg/kg/day regimen for 10 days, with reinforcement on 14th and 21th days (total dose of 48 mg/kg) and adjustment of prophylaxis for LAB 4 mg/kg/day weekly.
After eight months, at fourth relapse episode, we started on LAB 4.4 mg/kg/day for 10 days, prophylactic LAB dose of 4 mg/kg/day weekly, with patient’s clinical improvement and no side effects. In a new hospitalization after 4 months, due to fifth episode of AVL relapse, the patient was treated with LAB dose of 5 mg/kg/day for 10 days, but we extend the therapy in a dosing schedule of LAB 1mg/kg/day, totalling 25 days (total dose of 75 mg/kg) and concomitantly introduced antimoniate of N-methyl glucamine (GLUCANTIME®), henceforth pentavalent antimony, 10 mg/kg/day, intravenous, for 20 days. The rapid immunochromatography test remained negative, but numerous amastigote forms were observed in BMAS. Thus, the LAB was suspended due to drug resistance, and prophylaxis was initiated with pentavalent antimony, 850mg, intravenous, every 14 or 21 days, depending on laboratory tests. In the following fifteen months, she presented two episodes of drug-induced pancreatitis, secondary to pentavalent antimony, with an interval of one year between incidents. Prophylactic treatment was suspended until laboratory tests were normalized and then reintroduced (Table).
Haematological, Immunological and biochemical parameters (Reference interval) | First episode | Second episode |
---|---|---|
Hemoglobin (12-16 g/dL) | 6.3 | 9.6 |
Hematocrit (37-47%) | 19.6 | 27.6 |
Leukocytes (4,000-11,000 /mm3) | 1,420 | 4,690 |
Band neutrophils (2-4%) | 3 | 0 |
Segmented neutrophils (36-66%) | 64 | 66 |
Eosinophil (2-4%) | 0 | 1 |
Basophils (0-1%) | 0 | 0 |
Lymphocytes (25-45%) | 22 | 25 |
Monocytes (2-10%) | 11 | 8 |
Platelets (150,000-400,000/mm3) | 70,000 | 151,000 |
Creatinine (0.5-1.1 mg/dL) | 1.8 | 2.6 |
Urea (10-50 mg/dL) | 69 | 145 |
Creatinine Clearance-Cockroft-Gault Equation - (≥ 120 mL/min/1,73m²) | 33.19 | 22.78 |
Sodium (136-145 mEq/L) | 139 | 143 |
Potassium (3.5-5.0 mEq/L) | 4.7 | - |
Phosphate (3.0-4.5 mg/dL) | 5.4 | - |
C-reactive protein (≤ 0.8 mg/dL) | 48.1 | - |
Albumin (3.5-5.5 g/dL) | 1.4 | - |
Amylase (25-125 U/L) | 605 | 474 |
Lipase (10-40 U/L) | 6,869 | 2,593 |
After eight months, the patient evolved with drug nephrotoxicity by pentavalent antimony use and consequent loss of kidney graft, which was maintained for 9 years, and then she was submitted to transplantectomy and subsequent interruption of immunosuppressants. Hemodialysis was initiated three times a week and, after another eight months, a new BMAS from sternum was performed, with no Leishmania amastigote forms observed, and a negative rapid immunochromatography test for AVL. She progressed to death by ischemic stroke after nine months of negative results.
Discussion
Renal transplantation constitutes the majority fraction within SOT and presents the highest absolute records of parasitosis resulting from immunosuppression.7 In this context, it is imperative to consider AVL in the face of fever of unknown origin or pancytopenia as a differential diagnosis of natural or endemic patients, submitted to SOT. In these individuals the infection is highly associated with dysfunction and accelerated loss of the renal graft, and consequently, decreased survival rate of these patients.8,9
The therapy in renal transplants with AVL is a difficult decision, since there is no highly safe drug treatment for these individuals, however, it is considered that LAB is superior in terms of efficacy and safety profile in relation to pentavalent antimony.10,11 Some studies have reported the use of LAB for the treatment of AVL in renal transplants, ranging from 85 to 100% cure, 10% relapse and 15% mortality.12,13 The action mechanism of this drug involves direct injury to Leishmania’s cell membrane, differently from antimonials, which does not have a well-elucidated mechanism of action, but acts in adjuvant to a functioning cellular immune response, with limitations on SOT.10
However, the five relapses suggested therapeutic failure and secondary prevention with the same drug, despite the prospective study by Lauchaud et al.,14 in which there was no relationship between relapse in immunosuppressed by HIV and in vitro resistance of parasites to the drug.
Thus, due to refractoriness, the introduction of antimony pentavalent was necessary, although this drug has a well-established causal relationship with drug-induced pancreatitis and renal injury, as observed in this patient.15 According to Antinori et al.,10) this drug presents toxicity around 34% in organs such as heart, liver, kidneys and high pancreatitis rate (20%), besides an additive adverse effect when associated with immunosuppressants used in TOS.
It is noteworthy that in the years in which the relapse occurred, serological tests were negative, despite the presence of numerous amastigote forms observed in BMAS. False-negative results of antibody detection by serological tests are frequent in immunosuppressed individuals, since some types of test display less than 50% sensitivity.16 According to the American Society of Transplants, serological tests are generally negative in these patients, probably due to severe T and B cell dysfunction.17
As a consequence of the continuous aggressions of parasitic and drug character, there was loss of the renal graft and return to hemodialysis. Despite the negativity of the BMAS, for AVL, in a possible remission of the disease, the risks of hemodialysis, which promotes thromboembolic events and mortality, such as chronic renal disease itself and other comorbidities, were superimposed on the clinical outcome.18 The patient then evolves with an ischemic stroke, in an even more reserved prognosis, and death in the following months.
Conclusion
This report describes a rare case of successive relapses of AVL and difficult medical decision due to the therapeutic impasse between the use of immunosuppressive drugs for renal graft maintenance and treatment for this disease. The condition that is normally responsive to the available drug protocols, has undergone refractoriness even with individualization of treatment, optimization of doses and off-label drug combinations. It is not described similar refractory in scientific literature or even such therapeutic schemes applied in this case. Initially, we opted for the maintenance of immunosuppression, however, the nephrotoxicity of antiparasitic drugs, administered simultaneously with immunosuppressants, culminated in the loss of the renal graft. The parasitological control was observed with the immunosuppression suspension, demonstrating the importance of a competent immune system in the adjuvant of specific drugs, although of direct action to the parasite in the search for curative treatment of the disease.
This report was approved by the Research Ethics Committee of Marília Medical School under number CAAE 44289221.0.0000.5413.