Acute Renal Failure: A Common Manifestation of Leptospirosis

Abstract

Leptospirosis is an infectious disease caused by pathogenic leptospires and may vary in degree from an asymptomatic infection to severe and fatal illness. Sixteen patients (all males; aged 40 ± 17 years) with leptospirosis were admitted to Şişli Etfal Training and Research Hospital between July 1998 and August 2003 and were retrospectively reviewed. Age, gender, occupation, clinical presentation, laboratory features, seasonal distribution of the disease, diagnostical approach, and prognostic factors were evaluated. Eleven patients were cured with no complication; four patients died of hepatic and/or renal failure. Eight patients presented with acute renal failure; seven of them needed dialytic support. One patient developed chronic renal failure and had to undergo regular hemodialysis. All deceased patients (aged 61 ± 7 years) were anuric at admission and their serum bilirubin changed between 39–44 mg/dL (mean 41.3 ± 2.2 mg/dL). Cured patients ranged in age from 14–62 years (34 ± 14 years) and their serum bilirubin levels ranged from 9–35 mg/dL (23.1 ± 11.4 mg/dL). Crystalline penicillin G 12 million U/day was administered to all patients. Six patients also received hepatic coma treatment. This study emphasizes that leptospirosis presenting with renal failure is a severe disease, and mortality is frequently related to delays in diagnosis due to lack of clinical understanding. The association of acute renal failure and jaundice should lead the clinician to suspect leptospirosis. We concluded that old age, oliguria/anuria, high serum bilirubin levels (> 36 mg/dL), and high serum potassium levels might be risk factors that increase mortality in leptospirosis.

• Leptospirosis
• Renal failure
• Prognostic factors

Introduction

Leptospirosis is an infectious disease characterized by widespread vasculitis caused by pathogenic leptospires and is primarily a disease of wild and domestic mammals.[1] Transmission to humans is usually directly by contact with urine and/or any other tissue of infected animal that can be a carrier for long periods, or indirectly by contaminated water, soil, or vegetables. Certain occupational groups, including farmers, fishermen, sewer workers, and veterinarians, are considered to be at increased risk.[2] Leptospira, after entering the body through intact mucosa or traumatized skin, can spread to all parts of the body hematogenously.[3] The clinical presentation of the disease can change from the subclinical form to self‐limited systemic form, and finally the severe, fatal form. The severe form, known as Weil's disease,[1] is characterized by jaundice, hepatic and renal dysfunction, hemorrhagic complications, and circulatory collapse.

Renal involvement is common in leptospirosis. Clinical manifestations vary from urinary sediment changes to acute renal failure. Renal failure is observed in 44–67% of patients.[4]

In the absence of severe disease, death due to leptospirosis is not common. The reported mortality due to leptospirosis varies from 19% in Barbados[5] to 5% in Korea.[6] The reported mortality rate due to leptospirosis with acute renal failure is high: 36% in Barbados,[7] 26% in Sri Lanka,[8] and 17% in Turkey.[9] Some factors seem to be related to mortality rate such as age, gender, presence of oliguria, jaundice, and pulmonary involvement.[5], [6], [8], [10], [11]

Leptospirosis presenting with renal failure is a severe disease frequently leading to multiorgan failure and to death. Few large series describe in detail clinical and laboratory features of patients with leptospirosis and their outcome. This retrospective study describes the epidemiologic and clinical aspects of 16 patients with leptospirosis. Diagnostic approach and prognostic factors of the disease are also investigated in the study.

Patients and Methods

Sixteen patients (all males; aged 40 ± 17 years) with leptospirosis were admitted to our hospital between July 1998 and August 2003 and were evaluated respectively by age, gender, occupation, clinical presentation, laboratory findings, and seasonal distribution of the disease, diagnostic approach, and prognostic factors. The presence of oliguria (urinary volume < 500 mL/day after hydration), the need for dialysis, the presence of hemorrhagic phenomena (hematuria, melena, epistaxis), time (in days) between admission, and discharge or death were also analyzed.

Infection was confirmed by determining agglutinating antibodies with a latex agglutination assay (Bio‐rat Laboratories, USA) and by the presence of leptospira in urine using dark‐field microscopy.

Complete blood counts and biochemical analyses were carried out on hospital admission and throughout the course of the illness.

Acute renal failure was defined as an acute reduction in renal function associated with a serum creatinine level higher than 1.5 mg/dL.

Bilirubin level > 2 mg/dL, transaminases > 50 U/L, low‐density lipoprotein (LDH) > 480 U/L, creatine phosphokinase (CPK) > 190 U/L, urea > 50mg/dL, creatinine > 1.5 mg/dL, albumin < 3 g/dL, PT > 13 sec, leucocyte count > 10000/mm³, platelet count < 70000/mm³, hematocrit < 35%, C‐reactive protein (CRP) > 48 mg/L, and erythocyte sedimentation rate (ESR) > 30 mm/h were accepted as pathologic values.

Statistical Analysis

SPSS for Windows 10.0 was used for the data analysis. The Mann–Whitney U test was used for the analysis of continuous variables. For the analysis of categorical variables, Fisher's exact test was used. A p‐value < 0.05 was accepted as statistically significant.

Results

Epidemiological Aspects

In our study, all patients were males and their ages ranged between 14–67 (mean 40 ± 17) years. Three of them were fishermen, three sewer workers, and three farmers. Most of the cases occurred in the summer and autumn months.

Clinical and Laboratory Findings

The mean duration of symptoms was 8 ± 5 days. The duration of hospitalization ranged between 1–26 days (mean 15 ± 9 days).

Clinical characteristics and laboratory findings of the patients enrolled in the study are shown in Table 1. The minimum, mean, and maximum laboratory values found at hospital admission are shown in Table 2. Table 3 shows the demographic, clinical, and laboratory findings in the patients and their relation to prognosis.

Table 1. Symptoms, Clinical Signs, and Laboratory Findings Observed in Patients

	n		n
Icterus	16	Increase in LDH	16
Conjunctival hyperemia	14	Increase in CPK	16
High fever	14	Hypoalbuminemia	16
Myalgia	12	Leucocytosis	16
Nausea	12	Increase in CRP	16
Abdominal pain	7	Increase in ESR	16
Headache	8	Anemia	14
Diarrhea	4	Thrombocytopenia	13
Vomiting	4	Hematuria	12
Rash	4	Elongation of prothrombin time	10
Hepatomegaly	11	Proteinuria	11
Splenomegaly	4	Positive latex agglutination test	14
Hyperbilirubinemia	16	Presence of leptospira in dark‐field examination	13
Increase in transaminases	16	Negative acute hepatitis markers	16
Increase in urea levels	16

Table 2. The Minimum, Mean, and Maximum Laboratory Values Observed in the Active Infection Period

Parameters	Values			Parameters	Values
	min	mean	max		min	mean	max
Total bilirubin (mg/dL)	9.3	30.5	44.0	Albumin (g/dL)	1.1	2.1	3.3
Direct bilirubin (mg/dL)	1.5	22.9	35.1	PT (sec)	11.7	18.5	60.1
AST (U/L)	54	172	371	Leucocyte (count/mm^3)	10.300	17.746	28.200
ALT (U/L)	37	103	228	Thrombocyte (count/mm^3)	20.000	70.000	313.000
LDH (U/L)	711	838	1259	Hematocrit (%)	16	27	41
CPK (U/L)	97	2366	7740	CRP (mg/L)	24	130	190
Urea (mg/dL)	56	216	424	ESR (mm/h)	41	107	145
Creatinine (mg/dL)	1.4	7.1	10.0

Table 3. Demographic, Clinical, and Laboratory Findings in Our Patients and Their Relation with Prognosis

Risk factors	Patients who died				Patients who were cured
	n:1	n:2	n:3	n:4	n:5	n:6	n:7	n:8	n:9	n:10	n:11	n:12	n:13	n:14	n:15	n:16
Age	52	60	64	67	14	30	60	30	28	35	17	37	32	23	41	62
Bilirubin (mg/dL)	40	42	39	44	27	32	35	9	18	13	29	30	39	6	9	30
Oliguria	(+)	(+)	(+)	(+)	(−)	(−)	(+)	(−)	(−)	(−)	(+)	(+)	(−)	(−)	(+)	(−)
Bleeding	Hematuria	Hematuria Epistaxis Melena	Hematuria	Hematuria Hemoptysis	Melena	(−)	Hematuria Melena	(−)	(−)	Melena	Hematuria	Hematuria	Hematuria	(−)	Hematuria Epistaxis Melena	(−)
Cardiac disease	(−)	(+)	(−)	(+)	(−)	(−)	(+)	(−)	(−)	(−)	(−)	(−)	(−)	(−)	(−)	(−)
Pulmonary involvement	(−)	(−)	(−)	(+)	(+)	(−)	(+)	(−)	(−)	(−)	(−)	(−)	(−)	(−)	(−)	(−)
CPK (U/L)	420	446	2808	1638	208	2699	97	1216	3204	125	518	6714	7740	2141	252	250
K (mEq/L)	6.2	5.9	6.5	5.4	3.5	3.4	5.7	3.5	3.6	3.3	5.1	5.5	3.1	5	7.1	5.5

In our study, in 14 patients latex agglutination assay was positive and in 13 cases leptospira were seen in dark‐field examination of the urine. Therapy was administered when the diagnosis had been confirmed.

Crystalline penicillin G 12 million U/day six times daily for 12–14 days was administered in all patients. Six patients also received hepatic coma treatment. The adjunctive treatment consisted mainly of fluid and electrolytes replacement and diuretics, depending on each case. Reduction of urinary output (urine volume less than 500 mL/day) was recorded in eight patients (50%). Regarding the need for dialysis, seven patients (44%) underwent hemodialysis due to onset of acute renal failure that was not responsive to hydration and diuretic use.

Eleven patients were cured with no complication; four patients died of hepatic and/or renal failure. One patient had chronic renal failure and had to undergo regular hemodialysis. Oliguria/anuria was found to be a risk factor for mortality in our study (p < 0.038; Table 4).

Table 4. Relation Between Clinical Findings and Prognosis

Clinical findings	Deceased patients (n %)	Cured patients n (%)	Fisher's exact test (p‐value)
Oliguria	4 (100.0)	4 (33.3)	0.038
Bleeding	4 (100.0)	7 (58.3)	> 0.05
Cardiac disease	2 (50.0)	1 (8.3)	> 0.05
Pulmonary involvement	1 (25.0)	2 (16.7)	> 0.05

Oliguria is found to be a risk factor.

Icterus at hospital admission was observed in all patients (100%). Jaundice with high levels of serum bilirubin (mainly direct bilirubin) and a mild elevation of aspartate aminotranferase (AST) and alanine aminotranferase (ALT) were recorded. Deceased patients were 52–67 years of age (mean age 61 ± 7 years) and their bilirubin levels changed between 39–44 mg/dL (41.3 ± 2.2 mg/dL). Survivors were 14–62 years of age (mean 34 ± 14 years) and had bilirubin levels of 9–35 mg/dL (mean 23.1 ± 11.4 mg/dL). High serum bilirubin levels were associated with a poor prognosis (p < 0.001; Table 5). Old age was also found to be a risk factor for mortality (p < 0.008; Table 5).

Table 5. Relation Between Age, Laboratory Findings, and Prognosis

Prognosis	Factors
	Bilirubin (mg/dL)	CPK (U/L)	Potassium (mEq/L)	Age
Died (n = 4)	41.2 ± 2.21	1328 ± 138.5	6.0 ± 0.46	60.7 ± 6.5
Cured (n = 16)	20.8 ± 12.5	2097 ± 2630.5	4.5 ± 1.2	34.0 ± 14.7
Mann–Whitney U test	0.001	> 0.05	0.042	0.008

Bilirubin level, serum potassium level, and age are found to be associated risk factors with prognosis.

Leucocytosis was evident in all patients (100%). Anemia was observed in 13 patients (81%), and 12 patients (75%) had an important decrease in platelet count.

All patients presented with hypoalbuminemia; seven patients had serum albumin levels lower than 2.0 g/dL.

Eleven patients (69%) presented with some form of bleeding during hospital stay; four (25%) exhibited more than one form of bleeding. The hemorrhagic phenomena observed were: macroscopic hematuria (50%) in eight patients, melena in 5 patients (31%) and epistaxis in two patients (13%).

Some risk factors seen in the patients at the time of admission are reported in Table 3.

Discussion

Leptospirosis is one of the commonly seen zoonotic infections. It causes clinical conditions that change from flu‐like symptoms to Weil's disease characterized by multiorgan failure.[12] The infection spreads to humans either by direct contact with carrier animals or indirectly by water, soil, and vegetables.[13] In a study, in three patients diagnosed as leptospirosis, there was a history of contact with contaminated water and/or urine.[14] In another study, contamination was reported to be by contact with a sick animal, as a result of agriculture/watering and because of contact with river water; and the infection emerged most commonly in July and in August. The patients at high risk were males, characteristically 20–39 of age and worked in fishing, cattle breeding, and agriculture.[15] In our study, three patients were fishermen, three sewer workers, and three farmers; and the disease was seen mostly in summer and in autumn. All of our patients were males and their ages ranged between 14 and 67 years (mean 40 ± 17 years).

Leptospira infections can be in a subclinical form, a self‐limited systemic disease, or in a severe, fatal form. The acute systemic stage begins with remittent fever (38–40°C) that rises abruptly, headache, tremor and myalgia, conjunctival hyperemia, abdominal pain, nausea vomiting, diarrhea, cough, and pretibial maculopapular cutaneous eruption. After the acute septicemic stage, hyperbilirubinemia is seen at a rate of 85%.[1] In a study by Stephan et al.,[14] the initial signs of the disease were reported as high fever, tremor, headache with meningismus or facial paralysis, and mild signs of hepatic and renal involvement. Resano et al.[16] found high fever, myalgia, and jaundice as three main clinical signs of leptospirosis. In our series, jaundice was seen in all of our patients (100%). Fever and conjunctival hyperemia was seen in 14 patients (88%), myalgia in 12 patients (75%), headache in eight patients (50%), and abdominal pain in seven patients (44%); vomiting, diarrhea, and maculopapular rash was observed in four patients (25%).

Renal involvement is common in leptospirosis. Clinical manifestations vary from urinary sediment changes to acute renal failure. The renal involvement in leptospirosis is characterized by acute interstitial nephritis that may be associated with acute tubular necrosis. Interstitial involvement is the main 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. As in other infectious diseases, hypovolemia, decreased renal blood flow, and decreased glomerular filtration cause acute tubular necrosis and consequently oliguria/anuria. Renal failure is observed in 44–67% of patients with leptospirosis.[4] When the disease is cured, the renal functions improve completely. In our series, eight patients (50%) presented with renal failure. Acute renal failure is characterized by uremia, oliguria/anuria commonly seen in the second week of the disease, and emerges commonly with jaundice. Seven (44%) patients in this study required dialytic treatment during hospital stay. The dialytic indication was due to uremia and/or volume overload unresponsive to clinical treatment with hydration and diuretic use. Mel'nik et al.[17] reported that renal damage may tend to progress to icterohemorrhagic leptospirosis. They also mentioned that pyelonephritis and tubulointerstitial nephritis developed due to immunopathological reaction may progress to chronic renal failure in these patients. One patient in our series showed progressive renal dysfunction and had to undergo maintenance dialysis three times a week. Mild renal dysfunction might have been present in this patient before leptospirosis infection.

Thrombocytopenia is also commonly seen in leptospirosis.[1] Twelve patients enrolled to our study had an important decrease in platelet count. The hemorrhagic manifestations (macroscopic hematuria, melena, epistaxis) occurred after one week following symptoms onset. Thrombocytopenia in the acute phase of the disease may play a role in hemorrhagic disturbances. Uremia may be another factor that contributes to bleeding in the acute phase of the disease.

Jaundice occurs as a result of vascular damage in hepatic capillaries without hepatocellular necrosis. Serum bilirubins are usually > 20 mg/dL and hepatomegaly is seen in 25% of the cases. Creatine phosphokinase (CPK) commonly rises independently from the transaminases.[1] Eleven of our patients had hepatomegaly, four of which also had splenomegaly (Table 1). Levels of AST and ALT were rarely > 200 U/L. In all patients levels of bilirubin, transaminases, urea, low‐density lipoprotein, CPK, leukocyte, ESR, and CRP were found to be above normal values and albumin level was found to be below normal values. The minimum, mean, and maximum laboratory values observed in the active infection period are shown in Table 2. Anemia was observed in 14 cases, thrombocytopenia in 13, and hematuria in 12; there was an increase in PT in 10 and in proteinuria in 11 patients (Table 1). We found that albumin levels and platelet count decreased remarkably; anemia and a significant increase in PT, CRP, and ESR were observed in leptospirosis.

In our study, in 14 patients the latex agglutination test was positive and in 13 cases leptospira were seen in a dark‐field examination of the urine. As a result, we conclude that it is still important to see the agent directly in urine specimens.

Crystalline penicillin G is effective in the treatment of all leptospira infections, including severe forms. Also ampicillin, amoxicillin, tetracycline, and doxycycline are found to be effective in mild and moderately severe infections.[1] In our study, crystalline penicillin G 12 million U/day was used in the treatment of all of our patients. Six of our patients also received hepatic coma treatment and seven underwent hemodialysis. While twelve of our patients survived, four of them died as a result of hepatic and/or renal failure.

Daher et al.[11] found that the only independent factor associated with death was oliguria. Dupont et al.[10] found that oliguria, cardiac arrhythmias, dyspnea, and pulmonary involvement to be independent factors associated with mortality; they did not find age to be a risk factor for death. Hemodynamic instability, CPK > 265 U/L, and K > 4 mmol/L are evaluated as three independent mortality criteria by Marotto et al.[18] In our series, bilirubin levels in survivors and in nonsurvivors were 9–35 (23.08 ± 11.43) mg/dL and 39–44 (41.25 ± 2.22) mg/dL, respectively. We found that high serum bilirubin levels were an associated risk factor for mortality (p < 0.001; Table 5). We also observed that age (p < 0.008), oliguria/anuria (p < 0.038), and serum potassium levels > 5.5 mEq/dL (p < 0.042) were risk factors for mortality (Tables 4 and 5).

The symptoms of leptospirosis are nonspecific and laboratory tests in some cases can be negative. This increases the importance of clinical findings in diagnosis. In our study, we stated that patients with negative hepatitis markers who have low transaminase levels despite marked hyperbilirubinemia, high CPK levels in earlier stages, and impairment in renal function should be investigated for leptospirosis.

This study emphasizes that renal failure is a commonly seen manifestation of severe leptospirosis, and mortality is frequently related to delays in diagnosis due to lack of clinical suspicion. The association of acute renal failure and jaundice should lead the clinician to suspect leptospirosis. We also found that leptospirosis was frequently observed in certain occupational groups (farmers, sewer workers, and fishermen) and most commonly in summer and autumn months. In conclusion, our study has shown that old age, oliguria/anuria, high serum bilirubin levels (> 36 mg/dL), and high serum potassium levels (> 5.5 mEq/L) might be risk factors that increase mortality in leptospirosis.