Produção Nacional
Revisado por pares
Renal tubular dysfunction in patients with American cutaneous leishmaniasis
2011; Elsevier BV; Volume: 80; Issue: 10 Linguagem: Inglês
10.1038/ki.2011.251
ISSN1523-1755
AutoresRodrigo Azevedo de Oliveira, Lucyo Flávio Bezerra Diniz, Leonardo O. Teotônio, Cláudio G. Lima, Rosa Maria Salani Mota, Alice Maria Costa Martins, Talita Rojas Sanches, Antônio Carlos Seguro, Lúcia Andrade, Geraldo Bezerra da Silva, Alexandre Braga Libório, Elizabeth De Francesco Daher,
Tópico(s)Trypanosoma species research and implications
ResumoRenal dysfunction seen in patients with American cutaneous leishmaniasis (ACL) has been attributed to the use of antimonials for treatment. To determine whether ACL itself causes tubular dysfunction, we measured renal function in 37 patients with ACL prior to their treatment and compared results to that in 10 healthy volunteers of similar mean age. None of the patients presented with glomerular dysfunction; however, 27 had a urinary concentrating defect. There was no statistical difference between groups in the pre- and post-desmopressin test of urine osmolality, but the post-test urine osmolality of the controls was significantly higher. Urinary AQP2 levels, determined by western blot of isolated exosomes, were found to be significantly lower in patients than in controls, whereas that of the cotransporter (NKCC2) was significantly higher. A urinary acidification defect (post-test pH greater than 5.50 following calcium chloride) was found in 15 patients. Pretest plasma bicarbonate was below normal in 12 patients as was the pretest plasma pH in 14. Expression of the Na/H exchanger (NHE3), H+-ATPase, and pendrin were all significantly higher in patients with ACL than in controls. A combined urinary concentration and acidification defect was found in 12 patients. Thus, the urinary concentrating defect of ACL may be caused by decreased AQP2, with increased NKCC2 compensatory. Pendrin upregulation may be related to the urinary acidification defect with increased NHE3 and H+-ATPase also compensatory. Hence, ACL can cause asymptomatic renal tubular dysfunction. Renal dysfunction seen in patients with American cutaneous leishmaniasis (ACL) has been attributed to the use of antimonials for treatment. To determine whether ACL itself causes tubular dysfunction, we measured renal function in 37 patients with ACL prior to their treatment and compared results to that in 10 healthy volunteers of similar mean age. None of the patients presented with glomerular dysfunction; however, 27 had a urinary concentrating defect. There was no statistical difference between groups in the pre- and post-desmopressin test of urine osmolality, but the post-test urine osmolality of the controls was significantly higher. Urinary AQP2 levels, determined by western blot of isolated exosomes, were found to be significantly lower in patients than in controls, whereas that of the cotransporter (NKCC2) was significantly higher. A urinary acidification defect (post-test pH greater than 5.50 following calcium chloride) was found in 15 patients. Pretest plasma bicarbonate was below normal in 12 patients as was the pretest plasma pH in 14. Expression of the Na/H exchanger (NHE3), H+-ATPase, and pendrin were all significantly higher in patients with ACL than in controls. A combined urinary concentration and acidification defect was found in 12 patients. Thus, the urinary concentrating defect of ACL may be caused by decreased AQP2, with increased NKCC2 compensatory. Pendrin upregulation may be related to the urinary acidification defect with increased NHE3 and H+-ATPase also compensatory. Hence, ACL can cause asymptomatic renal tubular dysfunction. Leishmaniasis is an infectious, non-contagious, zoonotic disease caused by intra-macrophage protozoa of the genus Leishmania, which are transmitted by a vector belonging to the family Psychodidae.1.Herwaldt B.L. Leishmaniasis.Lancet. 1999; 354: 1191-1199Abstract Full Text Full Text PDF PubMed Scopus (1375) Google Scholar The disease has a wide geographical distribution, occurring on nearly every continent. It is endemic in tropical and subtropical regions, such as Northeast Africa and the Middle East, as well as parts of Europe, Central America, and South America.2.Roberts L.J. Handeman E. Foote S.J. Science, medicine and the future Leishmaniasis.Br Med J. 2000; 321: 801-804Crossref PubMed Scopus (59) Google Scholar There are three clinical types of leishmaniasis: visceral (kala-azar), cutaneous, and mucosal. The parasite proliferates into the mononuclear phagocytic system, dermis, and nasopharyngeal mucosa, respectively.1.Herwaldt B.L. Leishmaniasis.Lancet. 1999; 354: 1191-1199Abstract Full Text Full Text PDF PubMed Scopus (1375) Google Scholar The cutaneous form is known as American cutaneous leishmaniasis (ACL). Eight countries account for ∼90% of all cases of ACL: Afghanistan, Pakistan, Syria, Saudi Arabia, Nigeria, Iran, Brazil, and Peru.3.Desjeux P. Leishmaniasis: current situation and new perspectives.Comp Immunol Microbiol Infect Dis. 2004; 27: 305-318Crossref PubMed Scopus (1735) Google Scholar Traditionally, ACL has been classified as Old-World leishmaniasis (species found in the Mediterranean region, the Middle East, and Africa) or New-World leishmaniasis (species found in Mexico, Central America, and South America), the virulence, pathogenicity, and clinical manifestations depending on the species involved.4.David C.V. Craft N. Cutaneous and mucocutaneous leishmaniasis.Dermatologic Therapy. 2009; 22: 491-502Crossref PubMed Scopus (209) Google Scholar Studies of visceral leishmaniasis (VL) have demonstrated renal involvement ranging from nonspecific abnormalities on urinalysis to various types of glomerulonephritis.5.Dutra M. Martinelli M. de Carvalho E.M. et al.Renal involvement in visceral leishmaniasis.Am J Kidney Dis. 1985; 6: 22-27Abstract Full Text PDF PubMed Scopus (83) Google Scholar, 6.Salgado Filho N. Ferreira T.M. Costa J.M. Envolvimento da função renal em pacientes com leishmaniose visceral (calazar).Rev Soc Bras Med Trop. 2003; 36: 217-221Crossref PubMed Google Scholar, 7.Chaigne V. Knefati Y. Lafarge R. et al.A patient with visceral leishmaniasis and acute renal failure in necrotizing glomerulonephritis.Nephrologie. 2004; 25: 179-183PubMed Google Scholar, 8.Duvic C. Nedelec G. Debord T. et al.Important parasitic nephropathies: update from recent literature.Nephrologie. 1999; 20: 65-74PubMed Google Scholar In animal and human studies of VL, acute kidney injury (AKI) has been attributed to a number of mechanisms: interstitial nephritis secondary to the deposition of parasite antigens in the renal interstitium;9.Councilman W.T. Acute interstitial nephritis.J Experiment Med. 1988; 3: 393-420Crossref Scopus (106) Google Scholar hypersensitivity to antimonials;10.Cucé L.C. Belda Jr., W. Dias W. Nephrotoxicity to Glucantime® in the treatment of leishmaniasis.Rev Inst Med Trop S Paulo. 1990; 32: 249-251Crossref PubMed Google Scholar,11.Duarte M.I. Silva M.R. Gotto H. Interstitial nephritis in human kala-azar.Trans R Soc Trop Med Hyg. 1983; 77: 531-537Abstract Full Text PDF PubMed Scopus (47) Google Scholar and deposition of immune complexes, leading to rapidly progressive glomerulonephritis.12.Caravaca F. Munoz A. Pizarro J.L. et al.Acute renal failure in visceral leishmaniasis.Am J Nephrol. 1991; 11: 350-352Crossref PubMed Scopus (44) Google Scholar In the presence of leishmaniasis, AKI increases mortality.13.Oliveira M.J. Silva Júnior G.B. Abreu K.L. et al.Risk factors for acute kidney injury in visceral leishmaniasis.Am J Trop Med Hyg. 2010; 82: 449-453Crossref PubMed Scopus (32) Google Scholar Renal tubular dysfunction has also been described in VL, manifesting as urinary concentrating defect, with or without urinary acidification defect. In a prospective study of 50 patients with VL, urinary concentrating defect was found in 68%, urinary acidification defect was found in 64%, and complete renal tubular acidosis was found in 30%.14.Lima Verde E.M. Lima Verde F.A. Lima Verde F.A. et al.Evaluation of renal function in human visceral leishmaniasis (kala-azar): a prospective study on 50 patients from Brazil.J Nephrol. 2007; 20: 432-438Google Scholar Another prospective study of VL patients demonstrated proximal tubular dysfunction, as determined by urinary levels of retinol-binding protein, in nearly half of the patients.6.Salgado Filho N. Ferreira T.M. Costa J.M. Envolvimento da função renal em pacientes com leishmaniose visceral (calazar).Rev Soc Bras Med Trop. 2003; 36: 217-221Crossref PubMed Google Scholar In the literature, there are very few data regarding renal dysfunction in ACL, and the renal abnormalities described have been associated with the use of pentavalent antimonials.10.Cucé L.C. Belda Jr., W. Dias W. Nephrotoxicity to Glucantime® in the treatment of leishmaniasis.Rev Inst Med Trop S Paulo. 1990; 32: 249-251Crossref PubMed Google Scholar Patients with ACL can develop AKI due to massive deposition of immune complexes that appear after the destruction of the parasites (Leishman–Donovan bodies), a phenomenon similar to the Herxheimer reaction.15.Rodrigues M.L. Costa R.S. Souza C.S. et al.Nephrotoxicity attributed to meglumine antimoniate (Glucantime) in the treatment of generalized cutaneous leishmaniasis.Rev Inst Med Trop S Paulo. 1999; 41: 1-5Crossref PubMed Scopus (1) Google Scholar Sampaio et al.,16.Sampaio R.N. Paula C.D. Sampaio J.H. et al.Avaliação da tolerância e nefrotoxicidade do antimonial pentavalente administrado na dose de 40mg Sbv/kg/dia por 30 dias na forma cutânea-mucosa de leishmaniose.Rev Soc Bras Med Trop. 1997; 30: 457-467Crossref PubMed Google Scholar in a prospective study of 11 patients with ACL, who received a high daily dose of an antimonial (40mg/kg body weight (BW)) for 30 days, observed one case of AKI.16.Sampaio R.N. Paula C.D. Sampaio J.H. et al.Avaliação da tolerância e nefrotoxicidade do antimonial pentavalente administrado na dose de 40mg Sbv/kg/dia por 30 dias na forma cutânea-mucosa de leishmaniose.Rev Soc Bras Med Trop. 1997; 30: 457-467Crossref PubMed Google Scholar The authors found that, after 30 days of treatment, eight patients showed a reduction in the glomerular filtration rate (GFR), accompanied by tubular dysfunction, together with a reduction in urinary concentrating ability and an increase in the fractional excretion of sodium.16.Sampaio R.N. Paula C.D. Sampaio J.H. et al.Avaliação da tolerância e nefrotoxicidade do antimonial pentavalente administrado na dose de 40mg Sbv/kg/dia por 30 dias na forma cutânea-mucosa de leishmaniose.Rev Soc Bras Med Trop. 1997; 30: 457-467Crossref PubMed Google Scholar When administered at low doses and for a short period, antimonials have low renal toxicity. However, in the treatment of ACL, it is often necessary to use higher doses for a longer period, which can increase toxicity. There are also reports of proteinuria and AKI in patients with ACL.10.Cucé L.C. Belda Jr., W. Dias W. Nephrotoxicity to Glucantime® in the treatment of leishmaniasis.Rev Inst Med Trop S Paulo. 1990; 32: 249-251Crossref PubMed Google Scholar,16.Sampaio R.N. Paula C.D. Sampaio J.H. et al.Avaliação da tolerância e nefrotoxicidade do antimonial pentavalente administrado na dose de 40mg Sbv/kg/dia por 30 dias na forma cutânea-mucosa de leishmaniose.Rev Soc Bras Med Trop. 1997; 30: 457-467Crossref PubMed Google Scholar, 17.Balsan M. Fenech F. Acute renal failure in visceral leishmaniasis treated with sodium stibogluconate.Trans Royal Soc Trop Med Hyg. 1992; 86: 515-516Abstract Full Text PDF PubMed Scopus (19) Google Scholar, 18.Sampaio R.N. Veiga J.P.R. Limeira O.M. et al.Insuficiência renal aguda em leishmaniose tegumentar americana tratada com a associação de glucantime e alopurinol.Anais Brasileiros de Dermatologia. 1991; 66: 133-134Google Scholar In an experimental animal study,19.Veiga J.P. Khanan R. Rosa T.T. et al.Pentavalent antimonial nephrotoxicity in the rat.Rev Inst Med Trop São Paulo. 1990; 32: 304-309Crossref PubMed Scopus (14) Google Scholar high doses of an antimonial were shown to result in impaired urinary concentrating ability without a reduction in GFR. This abnormality was attributed to inhibition of antidiuretic hormone secretion and to a direct effect of the drug on tubular cells. In some animals, high doses of the antimonial also caused a reduction in the GFR.19.Veiga J.P. Khanan R. Rosa T.T. et al.Pentavalent antimonial nephrotoxicity in the rat.Rev Inst Med Trop São Paulo. 1990; 32: 304-309Crossref PubMed Scopus (14) Google Scholar To determine whether ACL itself causes tubular dysfunction, we studied the renal function of 37 ACL patients before antimonial treatment. All of the 59 patients recruited had previously been diagnosed with ACL on the basis of epidemiological, clinical, biochemical, and histopathological findings. Of those 59 patients, 22 were excluded: eight for testing negative on a new histopathological exam; nine for being under 15 years of age or over 60 years of age; two for subsequently declining to participate in the study; one for having hypertension; one for having diabetes mellitus; and one for having used an antimonial (meglumine antimoniate) within the last 30 days. Therefore, the study group comprised 37 ACL patients. The mean age was 35.6±12 years in the study group and 32.2±11.7 years in the control group. In the study group, 19 (51.4%) were male. Twenty-two (59.5%) of the patients tested positive on the Montenegro skin test. All 37 patients had isolated skin lesions: 27 had only one lesion; 7 had two to four lesions; and 3 had more than four lesions. The mean duration of disease was 28.5±20.6 days (range, 7–90 days). Demographic and clinical data are shown in Table 1.Table 1Demographic and clinical characteristics, by groupCharacteristicACL (n=37)Control (n=10)PaStudent's t-test.Age (years), mean±s.d.35.6±1232.3±11.70.442Gender, n (%) Male19 (51.4)6 (60)0.73 Female18 (48.6)4 (40)Duration of disease (days), mean±s.d.28.5±20.6——Montenegro skin test (±), n22/37——Number of skin lesions, n (%) 127 (72.9)—— 2–47 (18.9)—— >43 (8.1)——Systolic blood pressure (mmHg), mean±s.d.122±10117±9.50.221Diastolic blood pressure (mmHg), mean±s.d.80±4.775±8.50.079Abbreviation: ACL, American cutaneous leishmaniasis.a Student's t-test. Open table in a new tab Abbreviation: ACL, American cutaneous leishmaniasis. In comparison with the controls, none of the patients had significant glomerular dysfunction (109.6±32 vs 116.3±23ml/min per 1.73m2, P=0.694). None of the patients presented a GFR of <60ml/min. Post-desmopressin test urinary concentrating ability was lower in ACL patients than in controls. Urinary concentrating defect, defined as a urine osmolality (Uosm)/plasma osmolality (Posm) ratio <2.8, was observed in 27 patients (77%). Although pre- and post-desmopressin test values of Uosm were comparable in the study group, Uosm was significantly lower in the patients than in the controls (618±202 vs 985±81, P<0.05). Urinary acidification defect, defined as the inability to reduce urinary pH (UpH) to <5.50 after CaCl2 administration, was observed in 15 patients (40.5%). Although there was no significant difference between patients and controls in terms of the mean plasma bicarbonate concentration, the pre-CaCl2 plasma bicarbonate concentration was <22mEq/l in 12 of the 15 patients with urinary acidification defect. Combined urinary concentration and acidification defect was observed in 12 patients. Only five patients had no defect in urinary concentration or acidification. Figure 1a and b illustrate Uosm and UpH before and after the test with desmopressin and CaCl2 in the ACL patients. Comparing the patients who presented tubular (concentration or acidification) defects with the remaining patients, we found no differences in relation to age, gender, duration of disease, number of skin lesions, Montenegro skin test positivity, or body mass index. We detected no abnormalities in relation to plasma concentrations or fractional excretions of sodium, potassium, calcium, or phosphorus. Comparing the ACL patients with the controls, we found that the former showed higher urinary fractional excretion of calcium, potassium, and magnesium (Table 2). However, we found no difference between the groups in terms of serum electrolyte levels. It is noteworthy that plasma magnesium levels differed only between the patients with urinary acidification defect and those without (2.15±0.06 vs 2.33±0.04, P=0.02).Table 2Renal function, by groupVariableACL (n=37), mean±s.d.Control (n=10), mean±s.d.Pcreat (mg/dl)0.81±0.160.85±0.18CrCl (ml/min per 1.73m2)109.6±31.5116.4±22.7Post-DT U/Posm2.19±0.733.47±0.33*P<0.05 (Student's t-test; Mann–Whitney test).Post-CaCl2 UpH5.45±0.644.82±0.20*P<0.05 (Student's t-test; Mann–Whitney test).Post-DT Uosm (mOsm/kg H2O)618±202965±81*P<0.05 (Student's t-test; Mann–Whitney test).FENa (%)1.15±0.740.73±0.39FEK (%)10±6.67.50±2.8*P<0.05 (Student's t-test; Mann–Whitney test).FECa (%)1.07±0.720.62±0.34*P<0.05 (Student's t-test; Mann–Whitney test).FEP (%)10.9±9.989.10±6.4FEMg (%)1.81±1.700.90±0.40*P<0.05 (Student's t-test; Mann–Whitney test).Albumin/creatinine ratio (mg/g)23.6±266.12±4.06*P<0.05 (Student's t-test; Mann–Whitney test).Abbreviations: ACL, American cutaneous leishmaniasis; CaCl2, calcium chloride test; CrCl, creatinine clearance; DT, desmopressin test; FE, fractional excretion; Pcreat, plasma creatinine; U/Posm, urinary/plasma osmolality ratio; Uosm, urinary osmolality; UpH, urinary pH.* P 30mg/g, was detected in 12 (35.3%) of 34 patients tested (Table 2). Two patients had microalbuminuria alone, nine had microalbuminuria and urinary concentration defect, and another had urinary acidification defect alone. None of the patients with urinary acidification defect and urinary concentration defect had an albumin/creatinine ratio >30mg/g. As can be seen in Figure 2a, urinary protein expression of the collecting duct water channel aquaporin 2 (AQP2) was significantly lower in the patients than in the controls (38.5±12 vs 99.5±0.5%, P=0.006). Figure 2b shows that the expression of Na-K-2Cl cotransporter (NKCC2) was significantly higher in the patients than in the controls (147±12 vs 102±2.5%, P=0.02). In addition, Figures 3, 4a and b show that urinary protein expression of the Na/H exchanger (NHE3), H+-ATPase, and pendrin, respectively, was significantly higher in the patients than in the controls (176±15 vs 100±0.6%, P=0.015; 190±8 vs 98±0.2%, P=0.04; and 176±15 vs 100±0.6%, P=0.015).Figure 3Abundance of NHE3 by western blotting analysis in the urinary exosome fraction, normalized to urinary creatinine, in controls and in patients with ACL. ACL, American cutaneous leishmaniasis; NHE3, Na/H exchanger.View Large Image Figure ViewerDownload (PPT)Figure 4Western blotting analysis in the urinary exosome fraction, normalized to urinary creatinine, in controls and in patients with ACL. Abundance of (a) H+-ATPase and (b) pendrin. ACL, American cutaneous leishmaniasis.View Large Image Figure ViewerDownload (PPT) Here, we have demonstrated that ACL can cause tubular dysfunction without a drop in GFR. Our findings also indicate that, in patients with ACL, reduced expression of AQP2 leads to impaired urine concentrating ability. In addition, ACL patients showed a marked increase in the urinary protein expression of NKCC2. In this study, ACL was associated with dysregulation of major acid–base transporters in the proximal tubule (NHE3) and the distal nephron (H+-ATPase and pendrin). Therefore, ACL can impair the ability of the kidneys to respond appropriately to an acute acid load. Although it has been shown that patients with VL develop renal dysfunction,5.Dutra M. Martinelli M. de Carvalho E.M. et al.Renal involvement in visceral leishmaniasis.Am J Kidney Dis. 1985; 6: 22-27Abstract Full Text PDF PubMed Scopus (83) Google Scholar, 6.Salgado Filho N. Ferreira T.M. Costa J.M. Envolvimento da função renal em pacientes com leishmaniose visceral (calazar).Rev Soc Bras Med Trop. 2003; 36: 217-221Crossref PubMed Google Scholar, 7.Chaigne V. Knefati Y. Lafarge R. et al.A patient with visceral leishmaniasis and acute renal failure in necrotizing glomerulonephritis.Nephrologie. 2004; 25: 179-183PubMed Google Scholar, 8.Duvic C. Nedelec G. Debord T. et al.Important parasitic nephropathies: update from recent literature.Nephrologie. 1999; 20: 65-74PubMed Google Scholar there are few data regarding such dysfunction in patients with ACL. Studies of ACL have attributed renal dysfunction to the use of pentavalent antimonials.10.Cucé L.C. Belda Jr., W. Dias W. Nephrotoxicity to Glucantime® in the treatment of leishmaniasis.Rev Inst Med Trop S Paulo. 1990; 32: 249-251Crossref PubMed Google Scholar However, in this study, we showed that, before antimonial treatment, patients with ACL had asymptomatic renal tubular dysfunction, as evidenced by their inability to concentrate and acidify urine, albeit without glomerular dysfunction. Because the development of ACL depends solely on the level of exposure to the vector, it can occur at any age.1.Herwaldt B.L. Leishmaniasis.Lancet. 1999; 354: 1191-1199Abstract Full Text Full Text PDF PubMed Scopus (1375) Google Scholar The mean age of the patients studied by Lima Verde et al.14.Lima Verde E.M. Lima Verde F.A. Lima Verde F.A. et al.Evaluation of renal function in human visceral leishmaniasis (kala-azar): a prospective study on 50 patients from Brazil.J Nephrol. 2007; 20: 432-438Google Scholar was 29±11 years, compared with 36±15 years for those studied by Oliveira et al.13.Oliveira M.J. Silva Júnior G.B. Abreu K.L. et al.Risk factors for acute kidney injury in visceral leishmaniasis.Am J Trop Med Hyg. 2010; 82: 449-453Crossref PubMed Scopus (32) Google Scholar The mean age of our study sample was 35.6±12 years. Therefore, patient age cannot be considered a source of bias in this study. Among our patients, the mean duration of disease was 28.5±20.6 days (range, 7–90 days), which is not characteristic of chronic exposure to highly antigenic material. In a previous retrospective study of 151 patients with ACL, 97.2% tested positive on the Montenegro skin test, higher than the 59.0% observed in our study.20.Schubach A.O. Marzochi K.B. Moreira J.S. et al.Retrospective study of 151 patients with cutaneous leishmaniasis treated with meglumine antimoniate.Rev Soc Bras Med Trop. 2005; 38: 213-217Crossref PubMed Google Scholar In our study sample, 72.9% of the patients had only one skin lesion, compared with 69.5% in a study conducted by Schubach et al.20.Schubach A.O. Marzochi K.B. Moreira J.S. et al.Retrospective study of 151 patients with cutaneous leishmaniasis treated with meglumine antimoniate.Rev Soc Bras Med Trop. 2005; 38: 213-217Crossref PubMed Google Scholar In studies involving only patients with localized disease, Montenegro skin test positivity has been shown to be 82–89%.21.Sassi A. Louzir H. Ben Salah A. et al.Leishmanin skin test lymphoproliferative responses and cytokine production after symptomatic or asymptomatic Leishmania major infection in Tunisia.Clin Exp Immunol. 1999; 116: 127-132Crossref PubMed Scopus (78) Google Scholar,22.Reed S.G. Diagnosis of leishmaniasis.Clin Dermatol. 1996; 24: 471-478Abstract Full Text PDF Scopus (36) Google Scholar The test does not distinguish recent infection from past infection, and its importance in endemic areas is questionable. Various studies of VL have reported glomerular involvement. In a prospective study of 50 patients with VL, Lima Verde et al.14.Lima Verde E.M. Lima Verde F.A. Lima Verde F.A. et al.Evaluation of renal function in human visceral leishmaniasis (kala-azar): a prospective study on 50 patients from Brazil.J Nephrol. 2007; 20: 432-438Google Scholar observed that 14 (28%) had a reduction in GFR of <80ml/min per 1.73m2. In another study of VL patients, AKI was observed in 76 (33.9%) of the 224 patients evaluated.13.Oliveira M.J. Silva Júnior G.B. Abreu K.L. et al.Risk factors for acute kidney injury in visceral leishmaniasis.Am J Trop Med Hyg. 2010; 82: 449-453Crossref PubMed Scopus (32) Google Scholar Reports of glomerular dysfunction in ACL have been associated with the use of pentavalent antimonials.10.Cucé L.C. Belda Jr., W. Dias W. Nephrotoxicity to Glucantime® in the treatment of leishmaniasis.Rev Inst Med Trop S Paulo. 1990; 32: 249-251Crossref PubMed Google Scholar Other infectious diseases that primarily affect the skin and nerves, such as leprosy, can also lead to glomerular dysfunction. In a prospective study of 59 patients with leprosy, Oliveira et al.23.Oliveira R.A. Silva Jr., G.B. Souza C.J. et al.Evaluation of renal function in leprosy: a study of 59 consecutive patients.Nephrol Dial Transplant. 2008; 23: 256-262Crossref PubMed Scopus (17) Google Scholar observed a reduction in GFR in 50% of the cases. However, in our study sample, no significant GFR abnormality was observed, suggesting that ACL, per se, does not cause glomerular dysfunction. There is considerable evidence that antimonial treatment causes impaired urine concentrating ability in ACL. In a study involving 11 ACL patients treated with meglumine antimoniate at a daily dose of 40mg/kg BW (double dose) for 30 days, Sampaio et al.16.Sampaio R.N. Paula C.D. Sampaio J.H. et al.Avaliação da tolerância e nefrotoxicidade do antimonial pentavalente administrado na dose de 40mg Sbv/kg/dia por 30 dias na forma cutânea-mucosa de leishmaniose.Rev Soc Bras Med Trop. 1997; 30: 457-467Crossref PubMed Google Scholar found that 8 of the patients had impaired urine concentrating ability after 16h of water deprivation. Veiga et al.24.Veiga J.P. Wolff E.R. Sampaio R.N. et al.Renal tubular dysfunction in patients with mucocutaneous leishmaniasis treated with pentavalent antimonials.Lancet. 1983; 3: 359Google Scholar reported that five ACL patients treated with a conventional dose, but for a longer period, developed an inability to concentrate urine after treatment.24.Veiga J.P. Wolff E.R. Sampaio R.N. et al.Renal tubular dysfunction in patients with mucocutaneous leishmaniasis treated with pentavalent antimonials.Lancet. 1983; 3: 359Google Scholar Lima Verde et al.14.Lima Verde E.M. Lima Verde F.A. Lima Verde F.A. et al.Evaluation of renal function in human visceral leishmaniasis (kala-azar): a prospective study on 50 patients from Brazil.J Nephrol. 2007; 20: 432-438Google Scholar reported impaired post-desmopressin test urine concentrating ability in 68% of the 50 VL patients studied.14.Lima Verde E.M. Lima Verde F.A. Lima Verde F.A. et al.Evaluation of renal function in human visceral leishmaniasis (kala-azar): a prospective study on 50 patients from Brazil.J Nephrol. 2007; 20: 432-438Google Scholar In an experimental study with toad bladder, which has a phylogenetic structure similar to the renal collecting tubule, it was demonstrated that antimonial administration inhibits osmotic stimulated water flow.25.Gagliardi A.R. Veiga J.P. Rosa T.T. et al.Pentavalent antimonial inhibition of the osmotic effect of oxytocin on the isolated toad bladder.Braz J Med Bio Res. 1985; 18: 567-571PubMed Google Scholar In an experimental study with rats receiving the antimonial sodium stibogluconate at a daily dose of 30mg/100g for 30 days, there was post-treatment tubular abnormality, without glomerular dysfunction. However, when a dose of 200mg/100g was administered, there was significant glomerular dysfunction.19.Veiga J.P. Khanan R. Rosa T.T. et al.Pentavalent antimonial nephrotoxicity in the rat.Rev Inst Med Trop São Paulo. 1990; 32: 304-309Crossref PubMed Scopus (14) Google Scholar Nevertheless, in our sample of ACL patients evaluated before treatment, we demonstrated that Uosm was significantly reduced, indicating that ACL, in and of itself, can impair urine concentrating ability. According to the literature on leishmaniasis, urinary acidification defect is less common than is urinary concentrating defect. In a study of patients with VL treated with the standard dose of meglumine antimoniate, 64% showed an inability to reduce UpH to <5.50 after the CaCl2 test.19.Veiga J.P. Khanan R. Rosa T.T. et al.Pentavalent antimonial nephrotoxicity in the rat.Rev Inst Med Trop São Paulo. 1990; 32: 304-309Crossref PubMed Scopus (14) Google Scholar Although the patients evaluated in this study had ACL rather than VL, we identified an inability to acidify urine in 46%, calling into question the role that antimonial treatment has in the development of tubular dysfunction in leishmaniasis. It has been demonstrated that, in patients with VL, hypomagnesemia is accompanied by an increase in urinary excretion of magnesium.26.Lima Verde F.A.A. Lima Verde F.A. Daher E.F. et al.Renal tubular dysfunction in human visceral leishmaniasis (Kala-azar).Clin Nephrol. 2009; 71: 492-500Crossref PubMed Google Scholar In ACL patients, we demonstrated an increase in the fractional excretion of magnesium. However, we found that serum levels of magnesium were depressed only in patients with urinary acidification defect. We speculate that the tubular defects seen in VL are also present in ACL, although they are probably less common in the latter. There have been few studies evaluating microalbuminuria in leishmaniasis. In one study of patients with VL, 81.8% presented microalbuminuria.6.Salgado Filho N. Ferreira T.M. Costa J.M. Envolvimento da função renal em pacientes com leishmaniose visceral (calazar).Rev Soc Bras Med Trop. 2003; 36: 217-221Crossref PubMed Google Scholar In a study of patients with multibacillary leprosy, Oliveira et al.23.Oliveira R.A. Silva Jr., G.B. Souza C.J. et al.Evaluation of renal function in leprosy: a study of 59 consecutive patients.Nephrol Dial Transplant. 2008; 23: 256-262Crossref PubMed Scopus (17) Google Scholar identi
Referência(s)