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Renal involvement in leptospirosis--our experience in Madras City. MA Muthusethupathi, S Shivakumar, R Vijayakumar, M JayakumarDepartment of Nephrology, Government General Hospital, Madras.
Correspondence Address: Source of Support: None, Conflict of Interest: None PMID: 0008699377 Keywords: Adult, Aged, Developing Countries, Female, Human, Incidence, India, epidemiology,Kidney Failure, Acute, epidemiology,microbiology,therapy,Leptospirosis, complications,epidemiology,therapy,Male, Middle Age, Risk Factors, Rural Population, Survival Rate,
Leptospirosis is now recognized as one of the important causes of acute renal failure (ARF) in Madras City[1],[2],[3]. It has been underdiagnosed in other parts of the country probably due to lack of diagnostic facilities. In Thailand and Singapore, it is the leading cause of ARF[4]. In this article, we shall discuss the various aspects of leptospirosis and give our experience over the past few years.
Leptospirosis is an infectious disease caused by Leptospira interrogans  complex, which has over 20 serogroups and more than 200 serovars. The major vectors to humans are rodents, though other animals such as cattle, dogs and pigs can also transmit the illness.These organisms are excreted in the urine of the animals and they affect man when he comes into contact with the urine of infected animals directly or indirectly when he is exposed to an environment contaminated by the urine of the infected animals such as soil or surface water following monsoon rains. Therefore, this illness commonly occurs during the monsoon. These organisms survive for 6 hours in dry soil and for 6 months in flooded conditions. They enter the host through abrasions of the skin (of the feet when they come into contact with infected water) or intact mucus membranes of the eye, throat and gut, when contaminated food is ingested. In urban areas of developing countries, a contaminated environment due to various factors such as overcrowded slums, inadequate drainage and sanitation facilities for both man and animals, presence of stray dogs, cattle, pigs and domestic rats and bandicoots, poor condition of slaughterhouses and people walking barefooted, contributes to the spread of this illness[5],[6]. In rural areas, high-risk groups are workers in rice- fields, cane-fields and other agricultural crops and animal husbandry staff. In addition, workers in sewers, mines and military operations are also at risk. Though leptospirosis is considered an occupational disease, a contaminated environment makes any person vulnerable to infection. In Madras city, we have noted a dramatic increase in leptospirosis during the past few years. Between 1979-84, there were only 10 cases of renal failure due to leptospirosis, but between 1987- 91, there were 120 cases[1] in the last 2 years (1992-93), there were only 15 cases of leptospiral ARF. The reasons for the decline are not clear. The annual incidence is shown in [Table - 1]. Most of these patients were males, and were seen during the monsoon months. The infection is probably transmitted to people when they wade through stagnant rain water contaminated by infected urine of animals. There was no relationship to any specific occupation though most of them were outdoor manual laborers. These patients were seen from various parts of the city and there was no geographical clustering. This emphasizes the epidemiological importance of a contaminated environment in the spread of leptospirosis. A sero survey conducted among conservancy workers in Madras city has revealed a prevalence rate of about 33%[7]. The common reservoirs appear to be rodents such as bandicoots, though it has been reported in domestic animals such as dogs, cattle, goat, sheep and buffaloes[8],[9]. Studies have revealed that the common serogroup is L. autumnalis though other groups such as L. icterohaemorrhagia, L. canicola and L. pomona have been reported[1].[2].
The clinical features vary from a mild anicteric illness characterized by fever, myalgia and conjunctival suffusion, to a severe illness in which jaundice, renal failure, bleeding diathesis, meningitis and myocarditis (Wells syndrome or Icteric Leptospirosis) occur. The incubation period is 7-14 days but ranges from 2 to 21 days. Ninety percent or more of all cases of leptospirosis are anicteric[11]. Most patients noted by us presented with fever, myalgia, conjunctival suffusion, jaundice and renal failure. The comparison of various clinical studies are shown in [Table - 2], Although, the clinical course of loptospiral infection may vary in individual cases, in general, it is predictable in that both anicteric and ictoric cases follow a biphasic course. The initial or "septicemic phase" is characterized by development of fever, myalgia, conjunctival suffusion, headache and vomiting. Termination of this phase occurs after 4 to 7 days, with defervescence of fever and symptomatic improvement coincident with the disappearance of leptospires from the blood, cerebrospinal fluid and all other tissues with the exception of the aqueous humor and renal parenchyma. Circulating antibody titres to leptospires develop rapidly and this immune response ushers in the second or "immune stage" of the illness, which varies in duration from 4 to 30 days or longer. The Immune stage" is characterized by manifestations of the immune response of the host to the infecting microorganisms. Loptospires are found only in renal or ocular tissue during this phase. Leptospiruria, a hallmark of this stage, generally continues for 1 to 3 weeks, but rarely longer than 1 month, and is unaffected by antimicrobial therapy. Meningitis and uveitis become apparent and reach 'peak' intensity during this stage of the disease. The demarcation between the first and second stages is rarely as distinct in patients with severe icteric illness as it is in anicteric cases. In the former, the biphasic course of disease often is obscured. Although many authors have regarded the onset of jaundice as the beginning of immune phaso, it is not always a reliable index because sone investigators have been able to isolate organisms from the blood of patienis who have been icteric for 24 to 48 hours." It is considered that jaundice, renal failure and other features of Weil's syndrome are “first-stage” features and are due to leptospiremia, rather than to immune mechanisms. Data on anicteric illness have not been adequately reported from our country probably due to lack of awareness. Available data only reveal a high incidence of severe leptospirosis with jaundice and renal failure. Renal involvement is the most serious complication and is the commonest cause of death. Renal manifestations range from urinary sediment changes (pyuda, hematuria and granular casts) to renal failure. Renal manifestations are observed commonly in all forms of Leptospirosis regardless of severity of disease or of the infecting serogroup. In anictoric patients, proteinuria, microscopic hematuria and azotemia have been noted. Proteinuria is mild and is due to the febrile state. Hematuria may be due to hemorrhagic diathesis rather than glomerular injury. Azotemia has been divided into two groups[15],[16]. The first is characterized by decreased renal perfusion with diagnostic indices suggestive of pro-renal azotemia, with a good response to fluid administration. The second is characterized by features, consistent with tubular necrosis with no response to fluid challenge. It has been emphasized that hemodynamic alterations (hypotension, volume depletion) responsible for the former, may result in acute tubular necrosis if uncorrected. In addition, acute interstitial nephritis may account for renal failure regardless of the hemodynamic state. Renal failure occurs in the second week but it can occur as early as the fourth day. It may be short-lived or prolonged for upto two weeks. The pathogenesis of renal failure in leptospirosis is multifactorial and may include a) Hypoxia secondary to hypovolemia / hypotension b) direct nephrotoxicitydue to toxic by-products of leptospires. The possible causes of hypovolemia and hypotension must be considered. Body-fluid loss due to vomiting, 'Increased insensible water losses, and diminished intake of fluid are responsible for hypovolemia and hypotension in some cases. Decreased intravascular volume secondary to a shift in fluid from the intra - to extravascular space as a result of severe endothelial injury has been suggested, which result in hypotension and shock. Massive gastrointestinal haemorrhage is an important cause of hypovolemia. Adrenal insufficiency secondary to adrenal haemorrhage is a rare cause of hypotension. Hypoperfusion may also be the result of cardiac dysfunction. Cytotoxic factors may be responsible for toxic tubular injury though no such toxin has been isolated so far. In the kidney, leptospires initially cause glomerular injury and by hematogenous spread, the organisms reach pentubular capillaries and migrate to the interstitium, renal tubules and tubular lumen causing interstitial nephritis and tubular necrosis[17]. The kidneys are greatly swollen with pale cortex and congested medulla. Glomerular changes are mesangial proliferation with polymorphonuclear infiltration. On immunofluorescence staining, nonspecific tests, C3 uptake is reported in the mesangial area and occasionally in the affected arterioles. Clq and IgM deposition may be noted occasionally in the mesangial area. On electron microscopy, occasional dense deposits are seen in the mesangial, paramesangial and intramembranous location. Vascular changes in the kidney consist of endothelial swelling and necrosis with platelet aggregation, especially in the cortico-medullary region. Interstitial nephritis is the basic renal lesion characterized by mononuclear cells infiltration[17]. Renal failure in leptospirosis is primarily the result of tubular damage. Though some investigators have emphasized that interstitial nephritis is the fundamental renal lesion of leptospirosis others have found that it occurs only in patients who have survived until inflammation has had an opportunity to develop[17],[18]. Evidence of interstitial nephritis frequently is absent in patients whose disease is characterized by a rapid, fulminant course. Sequential observations of histologic, enzymatic and functional renal changes in both animal and human leptospirosis suggest that the initial and most prominent renal lesion is tubular and that In many cases it is unaccompanied by interstitial inflammatory infiltrates. These tubular lesions are similar to acute tubular necrosis of other causes[18]. We did not do biopsy in most of our patients as serology was adequate for diagnosis and there are no pathognomonic changes in leptospirosis. In addition, as bleeding diathesis is an important component of this illness we did not take the risk of renal biopsy. In an earlier study, we did biopsy in a few patients and they revealed acute interstitial nephritis. Most patients with renal failure 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 9th 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. Death is rarely due to hepatic failure in our patients, marked elevation of serum bilirubin with near-normal or mildly elevated SGOT and SGPT levels were characteristic.
Laboratory diagnosis involves the isolation of leptospira in culture of blood and urine and serological tests.
- Isolation of leptospires from blood or cerebrospinal fluid generally can be achieved only during the first 10 days of clinical illness. Leptospires usually appear in the urine during the 2nd week of disease and may persist for 30 days or longer. In general, other than blood, urine or cerebrospinal fluid, only tissue sections obtained by biopsy or at necropsy serve as sources from which organisms can be isolated. Fletcher's semisolid medium or EMJH semisolid medium are the media often used.
a) Microscopic agglutination test (MAT) - MAT is considered the comer-stone of serodiagnosis[19]. Rising titres or initial high titres are diagnostic of leptospiral infection. The main advantage of MAT is that the serovars can beidentified which is of epidemiological importance. The main disadvantage is that the titres rise late and peak about the third or fourth week. The high titres of MAT take a much longer time to decline, which is of value for epidemiological studies, but the presence of high titres from previous infection complicate the diagnosis of current infection[6]. b) ELISA - The ELISA is now the test of choice for the diagnosis of current infection. It detects specific IgM and IgG antibodies. Detection of specific Ig M antibodies helps in the rapid diagnosis of current infection[6],[20]. This test detects genus-specific antibodies, which tend to become positive early in the disease and also revert early. It is a relatively simple test as the antigen used is genus specific. This test cannot determine the infecting serogroup. A high titre in a single sample can be diagnostic though repeat samples may be necessary if initial titres are low. Recently, a collaborative study done with Leptospira Laboratory Barbados, using ELISA for estimating elevated specific IgM titres, has confirmed the diagnosis of current leptospiral infection in Madras city[10]. In addition, MAT study revealed L. autumnalis to be the commonest serogroup. L autumnalis was isolated from the blood of one of our patients at the Royal Tropical Institute, Amsterdam.
The conservative treatment of Leptospirosis consists of giving antibiotics (Penicillin Doxyeycline) and adequate hydration. The efficacy of antibiotics in the treatment of leptospirosis remains controversial because of conflicting data[22],[23]. It is generally believed that antibiotics are effective only if given early in the course of disease and their efficacy is unknown in late or severe disease. Watt et al[22] conducted a placebo controlled trial of intravenous penicillin for severe (S.Cr > 177 micromoles/L) and late (symptoms > 4 days) leptospirosis in 42 patients and included that antibiotic therapy was definitely useful in these patients. Fever lasted more in the placebo group compared to the treated group (11.6 vs 4.7 days). Creatinine rises persisted more than thrice as long in the patients receiving only placebo (8.3 vs 2.7 days). Penicillin also shortened the hospital stay and prevented leptospiruria[22]. However, Edwards et al in a prospective controlled study in 70 patients concluded that penicillin therapy has no effect in severe leplospirosis. In animal studies, fewer deaths and less severe course of the disease among penicillin-treated, jaundiced puppies compared to untreated controls were noted by Yoder et al[24]. Hamsters severely ill with leptospirosis survived when given penicillin 1-2 days before the expected time of death[22]. The overall impression thus seems to be that antibiotics are useful even in severe or late leptospirosis. It has been our policy to treat all patients with intravenous crystalline penicillin. Of primary importance is the meticulous attention, which must be paid to fluid and electrolyte balance. Hypovolemia and hypotension needs prompt and specific treatment with intravenous fluids. In patients with oliguria, if prerenal azotemia is suspected, prompt diuresis should be attempted with fluid therapy. In patients who have no response to such therapy, they should be managed as for ARF. Peritoneal dialysis has been found to be a safe, simple and effective procedure in the management of leptospiral ARF, Peritoneal dialysis was adequate for most of our patients who needed dialysis [Table - 3]. The overall mortality was 20.8% in our experience.
[Table - 1], [Table - 2], [Table - 3]
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