Renal Involvement in Leptospirosis at Dr. Cipto Mangunkusumo and Persahabatan Hospitals

ORIGINAL ARTICLE Renal Involvement in Leptospirosis at Dr. Cipto Mangunkusumo and Persahabatan Hospitals HMS Markum ABSTRACT Aim: to describe clinical pattern of ARF caused by leptospirosis and its related factors. Methods: a cross-sectional study using medical record data of all leptospirosis cases admitted to Cipto Mangunkusumo and Persahabatan General Hospitals between January 1993 and December 1996. Patient identification included age, sex, and occupation. Clinical symptoms were described in details and followed by laboratory testing i.e. peripheral blood count, urinalysis, blood urea and creatinine, liver function test, and pancreatic enzymes assay. Results: Seventy-five percent were men and the mean age was 38.3 years old. Sixty out of 68 (88.2%) patients had ARF as defined by an increase of plasma creatinine level of > 1.5 mg/ml. The most common presenting symptoms in patients with ARF were fever (100%), nausea and vomiting (95.0%), muscle pain (88.1%) and jaundice (71.3%). The mean duration of fever 7.2 days. The most frequent laboratory abnormalities were increased erythrocyte sedimentation rate (100%), leukocytosis (90%) and increase total bilirubin level (87.5%). Only leukocytosis showed a significant difference between ARF and non-arf patients (p=0,014). Leptospira bataviae was found in 95.6% of patients and 96.7% of ARF patients. Penicillin was given to 80.9% of patients with only 2 (2.9%) deaths. Conclusion: Although significant correlation cannot be established, we concluded that nausea, vomiting, muscle pain, jaundice, increased ESR and total bilirubin level should alert the physician about the possibility of renal involvement in leptospirosis patients with prolonged fever. Leptospira bataviae was an important virulent pathogen. Treatment with penicillin may significantly improve organ failure and was considered the drug of choice in managing leptospiral infection. Key words: renal involvement, leptospirosis, ARF, creatinine level, leukocytosis. Division of Nephrology and Hypertension, Department of Internal Medicine, Dr. Cipto Mangunkusumo National Central General Hospital/Faculty of Medicine, University of Indonesia, Jakarta INTRODUCTION Leptospirosis is a worldwide zoonotic disease, which characterized by various clinical manifestations. Human plays an accidental role in the epidemiological chain. Although the majority of cases are self-limited, the most severe manifestation, known as Weil s syndrome, occurs in approximately 10% of cases and is typified by jaundice, renal dysfunction, hemorrhagic manifestations and pulmonary involvement. 1,2 Renal involvement is common in leptospirosis. Clinical manifestations vary from urinary sediment changes to acute renal failure. Renal failure is observed in 44% to 67% of patients and hypokalemia frequently occurs. Severe hypotension is an important warning sign for the later development of renal and pulmonary complications. Prognosis of the disease is usually good except for its association with pulmonary complications, especially pulmonary hemorrhage and acute respiratory distress syndrome. Interstitial nephritis is the basic renal lesion. Vasculitis is observed in the acute phase of the disease. Tubular necrosis and interstitial nephritis are responsible for renal failure. Glomerular changes usually are not remarkable. Hemodynamic alterations, immune response, and direct nephrotoxicity are responsible for the development of renal lesions. Like many infectious diseases, decreased renal blood flow and glomerular filtration rate play a basic role. Bacterial invasion and toxicity of outer membrane with generation of cytokines, chemokines, and cellular infiltration are important in cellular injury. 3 This study was carried out to describe the epidemiology and clinical pattern of acute renal failure caused by leptospirosis. METHODS This is a cross-sectional study using medical record data of all leptospirosis cases admitted to Cipto 148

Vol 36 Number 3 July-September 2004 Renal Involvement in Leptospirosis Mangunkusumo and Persahabatan General Hospitals between January 1993 and December 1996. Patient identification included age, sex, and occupation. Clinical symptoms were described in details and followed by laboratory testing i.e. peripheral blood count, urinalysis, blood urea and creatinine, liver function test, and pancreatic enzymes assay. Diagnosis of leptospirosis was made based on serological test via a microscopic agglutination test (MAT). Diagnosis of acute renal failure (ARF) was established if the plasma creatinine level increased to 1.5 mg/dl or more. Descriptive and analytical statistics were developed using the SPSS version 10.5 software. Correlations were made among patients with ARF and clinical presentations, laboratory testing, and serological testing to find factors attributable to ARF. A p value below 0.05 was regarded as significant using the chi-square test and analysis of variance (ANOVA). RESULTS Patients Demographic and Symptoms Forty-four (64.7%) patients from Cipto Mangunkusumo Central General Hospital and 24 (35.3%) patients from Persahabatan Hospital were recruited in this study. Most patients were men (75%) and the mean age was 38.3 years old (Table 1). Fever was the predominant symptom though the length varied between 1-21 days, followed by nausea and vomiting, muscle pain and jaundice. Laboratory Findings Leukocytosis (>10.000/mL) was very common (86.8%) and none was leukopenic. Thrombocytopenia (< 150.000/mL) occurred in 30 (44,1%) patients. Increased erythrocyte sedimentation rate was also a common feature, which occurred in all except one of 30 available data. Further laboratory testing showed slight increase of hepatic enzymes and bilirubin level, but the protein and blood glucose levels were within the normal limit. Marked elevations were also observed in the blood urea and creatinine levels (Table 2). Leptospirosis with Acute Renal Failure Sixty patients (88.2%) had plasma creatinine level more than 1.5 mg/dl, and thus, were diagnosed as ARF. Among these patients, nausea/ vomiting, muscle pain and jaundice were present in high percentage, but hepatomegaly and splenomegaly were uncommon. Leukocytosis and increased ESR were the most prominent abnormalities of peripheral blood test, whereas the total bilirubin level was the only liver function parameter, which increased markedly (Table 3). Among the presenting symptoms and laboratory testing, only leukocyte count showed a significant correlation with ARF (Table 4). Table 1. Patient Characteristics and Symptoms Age (n=68) Sex (n=68) Characteristic Mean Median Minimum Maximum Skewness Male Female 38.3 yr 38 yr 16 yr 65 yr 0.224 51 (75%) 17 (25%) Duration of fever (n=68) Mean 7.1 + 3.6 days Body temperature (n=68) Mean 38.1 + 0.7 o C Nausea/ vomiting (n=68) 65 (95.6%) 3 (4.4%) Muscle pain (n=67) 59 (86.8%) (11.8%) Jaundice (n=68) 47 (69.1%) 21 (30.9%) Headache (n=67) Yes 37 (54.4%) 30 (44.1%) Chills (n=68) Yes 13 (19.1%) 55 (80.9%) Cough (n=68) Yes 25 (36.8%) 43 (63.2%) Bleeding (n=68) 20 (20.4%) 48 (70.6%) Conjunctival suffusion (n=68) 58 (85.3%) 10 (14.7%) Hepatomegaly (n=68) 24 (35.3%) 44 (64.7%) Splenomegaly (n=68) 1 (1.5%) 67 (98.5%) Table 2. Peripheral Blood Test and Blood Chemistry Profile of The Patients Hb level (n=68) Mean 11.5 + 1.4 g/dl Leukocyte count (n=68) Mean 16.442 + 5625 / L Thrombocyte count Mean 184.641+123828/ L (n=67) Erythrocyte Mean 115.5 + 134.1 mm/hr sedimentation rate (n=30) Hematocrite (n=59) Mean 32.4 + 4,2 vol% Proteinuria (n=64) 39 (57.4%) 25 (36.8%) SGOT (n=60) Mean 48.3 + 40.7 mg/dl SGPT (n=60) Mean 41.67 +mg/dl Albumin (n=60) Mean 3.0 + 0.5 /dl Globulin (n=60) Mean 3.2 + 1.0 g/dl Total bilirubin (n=62) Mean 9.3 + 11.2 g/dl Fasting blood glucose Mean 100.3 + 37.0 g/dl (n=53) Post-prandial blood Mean 130.33 + 32.3 g/dl glucose (n=33) Blood urea (n=68) Mean 206 + 106 mg/dl Creatinine (n=68) Mean 5.1 + 3.3 mg/dl 149

HMS Markum Acta Med Indones-Indones J Intern Med Table 3. Clinical Manifestation and Laboratory Profile of Patients with Acute Renal Failure (N=60) n Valid % Data Fever 67 100 1 Nausea/ vomiting 57 95.0 - Muscle pain 52 88.1 1 Jaundice 43 71.3 - Headache 32 54.2 1 Hepatomegaly 23 38.3 - Splenomegaly 1 1.7 - Bleeding 17 28.3 - Increased ESR 28 100 32 Leukocytosis 54 90 - Thrombocytopenia 27 45 - Increased blood urea 52 86.7 - Increase SGOT level 25 47.2 7 Increased SGPT level 19 35.8 7 Increased total bilirubin level 49 87.5 4 Proteinuria 36 63 3 Microscopic Agglutination Test (MAT) Leptospira bataviae was a predominant serovar, which accounted for 95.6% of cases, either as a single or multiple infections. Other variants and combined infections are shown in (Table 5). Among 60 patients with ARF, 58 (96.7%) were L. bataviae positive, either as single or multiple infection. The other two patients were infected by L hardjo and combined infection of L. celedoni + L. rachmati. Among patients with L. bataviae positive, there was no correlation between the incidence of ARF and the number of serovar involved (Table 6). Treatment and Outcome About 90% of patients were treated with penicillin or ampicillin. Other antibiotics included chloramphenicol, tetracyclines and third-generation cephalosporin in small percentage. There were only two deaths (2.9%). One patient died because of respiratory failure due to pneumonia, and the other had respiratory failure and disseminated intravascular coagulation Table 7. DISCUSSION Clinical manifestations of leptospirosis may vary from subclinical infection to severe and potentially fatal disease. Five to 10 per cent infections could lead to multiple organ damage including kidney, liver and lung. The most severe form is Weil s syndrome, which presented by febrile illness with bleeding tendency, hepatic dysfunction and acute renal failure (ARF). Tubulo-interstitial nephritis is the main cause of acute renal injury in leptospirosis. An in vitro experiment has shown that the outer membrane proteins (OMPs) from Table 4. Correlation Between Clinical Manifestation and The Present of Acute Renal Failure Symptoms Creatinine level (mg/dl) ANOVA and signs < 1.5 > 1.5 p value Mean duration of fever 6.5 + 1.2 days Mean body 38.3 + 0.4 temperature C Mean leukocyte 11,912 + count 6417 / L Mean 192,375 + thrombocyte 164,783 / count L Mean ESR 64 + 79 mm/min Mean SGOT 50.9 + 49.4 level Mean SGPT 31.0 + 20.1 level Mean total 2.2 + 2.1 bilirubin level mg/dl Mean fasting 98 + 26.9 blood glucose mg/dl 7.2 + 3.9 days 0.622 38.0 + 0.8 o C 0.428 17,046 + 5281 0.014* / L 183,592 / ll 0.852 115 + 134 0.583 mm/min 48.1 + 40.0 0.866 43.0 + 31.9 0.335 10.0 + 11.5 0.103 mg/dl 100.5 + 38.1 0.905 mg/dl Chi-square p value Fever (n=67) 8 59 - Nausea/ vomiting (n=65) 8 57 (n=3) 0 3 0.683 Muscle pain (n=59) 7 52 (n=8) 1 7 0.660 Jaundice (n=47) 4 43 4 17 0.198 (n=21) Headache (n=37) 5 32 3 27 0.480 (n=30) Bleeding (n=20) 3 17 5 43 0.434 (n=48) Proteinuria (n=39) 3 36 (n=25) 4 21 0.261 * significant pathogenic leptospira activate nuclear NF-êB binding and stimulate downstream inducible nitric oxide (inos), monocyte chemoattractant protein-1 (MCP-1) and tumor necrosis factor-a (TNF-a) expression. These observations indicated that leptospiral infection may induce tubulo-interstitial nephritis through a toxic component in the outer membrane followed by the expression of inflammatory genes. 4 150

Vol 36 Number 3 July-September 2004 Renal Involvement in Leptospirosis Table 5. Serologic Testing Using MAT Name of variant n % L. bataviae 40 58.8 L. bataviae + L. hardjo 17 25.0 L. bataviae + L. icterohaemorrhagiae 3 4.4 L. bataviae + L. tarassovi 1 1.5 L. bataviae + L. australis 1 1.5 L. bataviae + L. javanica 1 1.5 L. bataviae + L. pomona 1 1.5 L. bataviae + L. icterohaemorrhagiae 1 1.5 + L. tarassovi L. hardjo 1 1.5 L. celedoni + L. rachmati 1 1.5 L. icterohaemorrhagiae + L. javanica + L. celedoni 1 1.5 Table 6. Correlation Between L. Bataviae Infection and The Present of Acute Renal Failure Serovariant Creatinine level (mg/dl) p value < 1.5 > 1.5 Chi-square test L bataviae only 5 35 L bataviae plus 2 23 0.448 other variant Table 7. Antibiotic Therapy and Treatment Outcome Recovered (n) Died (n) Refused further treatment (n) Total n (%) Penicillin 50 1 4 55 (80.9) Ampicillin 6 0 0 6 (8.8) Chloramphenicol 1 0 0 1 (1.5) Tetracyclines 1 0 0 1 (1.5) Cephtriaxone 2 0 0 2 (2.9) Ceftazidime 1 0 0 1 (1.5) Cefoperazone 0 1 0 1 (1.5) antibiotic 1 0 0 1 (1.5) Total 62 (91.2%) 2 (2.9%) 4 (5.9%) 68 (100) Almost 90% of our patients showed a high plasma creatinine level and thus, were diagnosed as ARF. Male predominance was very common in leptospirosis due to the risk of occupational exposure. Patients usually presented with fever, muscle pain, conjunctival suffusion, jaundice and renal failure. Our current report found the similar pattern; the most common symptoms and signs in patients presenting with acute renal failure were fever, nausea/ vomiting, muscle pain, jaundice, leukocytosis and increased ESR (Table 3). In attempt to find the risk factors contributing to the development of ARF, we found a significant difference in leukocyte count. This could probably due to the grade of inflammation in patients with acute tubular injury. Increased ESR above 100 mm/minute and high total bilirubin level might also be warning signs, although the differences were not statistically significant in this study. One important finding from our study was the late recognition of the disease. Most patients had fever for one week or more, suggesting that the time lapse might contribute to the development of ARF. However, the small number of patients with normal creatinine level could be the limitation to make proper statistical correlation tests to these factors. Most patients with ARF might also have significant hepatic involvement. Jaundice occurs between the fourth and sixth day but may occur as early as the second day or as late as the ninth day. Jaundice is partly due to hepatocellular damage. However, hepatocellular necrosis is usually mild and additional factors include intrahepatic cholestasis and increased bilirubin load from absorption of blood from tissue haemorrhage. 5 There are 240 serovars of leptospira worldwide. The main serovar in our patients was Leptospira bataviae, which infected 95% of total patients and 96.7% of patients with ARF. Because other serovars only found in a very small number, correlation test could not be performed. Among the Leptospira bataviae infections, there was also no significant difference between single and multiple infections. Currently, comparison study of pathogenicity among serovars that contribute to the development of ARF is not available, but a report in Taiwan showed that the outer membrane protein of Leptospira shermani induced a more significant nuclear DNA binding of the NF-êB transcription factor compared to Leptospira bratislava. 4 Our study showed that penicillin was still effective in the treatment of leptospirosis and has contributed to a low mortality. The study in Taiwan also confirmed that penicillin and tetracycline are the drugs of choice for leptospirosis treatment and may significantly improve multiple organ failure, although they had 3/12 cases died before given any treatment. 4 The reported mortality due to leptospirosis with acute renal failure was very high, from 17% in Turkey 6 to 36% in Barbados. 7 A study in Brazil has indicated that oligouria is a risk factor for death in leptospirosis with acute renal failure. 8 More recent study by Dupont et al found that dyspnea, oligouria, alveolar infiltrates, repolarization abnormalities, and leukocyte counts more than 12,900/ mm 3 are independent factors associated with death. 9 CONCLUSION Leptospirosis with acute renal failure (ARF) was frequently found and accounted for 88.2% of patients in this current study. Among all clinical signs and 151

HMS Markum Acta Med Indones-Indones J Intern Med symptoms, only leukocytosis that had a significant correlations to the development of ARF. Although no other significant correlation was found in this study, nausea, vomiting, muscle pain, jaundice, increased ESR and total bilirubin level should alert the physician about the possibility of renal involvement in patients with prolonged fever, who showed positive serological test of leptospirosis. Leptospira bataviae infection was found in almost all patients. Penicillin is still the treatment of choice and should be given as first-line therapy in patients with leptospira infection. REFERENCES 1. Edwards, C.N., Nicholson, G.D. & Everard, C.O.R. Thrombocytopenia in Leptospirosis. Am J Trop Med Hyg 1982;31: 827-9. 2. WATT, G. Leptospirosis. Curr Opin Infect Dis 1992;5:659-63. 3. Sitprija V, Losuwanrak K, Kanjanabuch T. Leptospiral nephropathy. Semin Nephrol 2003;23(1):42-8. 4. Yang C-W, Wu M-S, Pan M-J. Leptospirosis renal disease. Nephrol Dial Transplant 2001; 16(Suppl 5):73-7. 5. Muthusethupathi MA, Shivakumar S, Vijayakumar R, Jayakumar M. Renal involvement in leptospirosis our experience in Madras City. J Postgrad Med 1994;40:127-31. 6. Leblebicioglu H, Sencan I, Sunbul M, Altintop L, Gunnaydin M. Weil s disease. Report of 12 cases. Scan J Infect Dis 1996;28:637-9. 7. Nicholson GD, Edwards CN, Hassell TA, Everard COR, Calender J. Urinary diagnostic indices in the management of leptospirosis. Selection of patients for dialysis therapy. West Indian Med J 1989;38:33-8. 8. Daher E, Zanetta DMT, Cavalcante MB, Abdulkader RCRM. Risk factors for death and changing patterns in leptospirosis acute renal failure. Am J Trop Med Hyg 1999;61(4):630-4. 9. Dupont H, Dupont-Perdrizet D, Perie JL, Zehner-Hansen S, Jarige B, Daijardin JB. Leptospirosis: prognostic factors associated with mortality. Clin Infect Dis 1997;25:720-4. 152