RENAL INVOLVEMENT IN LEPTOSPIROSIS

SUMMARY: Renal involvement is a common feature of leptospirosis. It is variable from mild to severe acute renal failure. Materials and methods: We performed analysis of 100 consecutive leptospirosis cases treated in Clinic of Infectious Diseases at University Hospital – Pleven (1976-2012) (90 male, age 37±18 years, lethal outcome in 13%), followed by comparative analysis of group with renal involvement (n1=59) versus group without renal involvement (controls: n2=41). Results: Fever (100%), hepatomegaly (92%), myalgia (86%), nausea and vomiting (84%), splenomegaly (74%), oliguria (69%), headache (67%), jaundice (63%), hypotension (49%), abdominal pain (41%), and hemorrhagic diathesis (37%) were the characteristic manifestations and had had a significantly higher prevalence in the group with renal involvement. Blood urea nitrogen (mean 27.9±16.9 mmol/L) and serum creatinine (mean 349.9±190.1 µmol/L) were the main laboratory parameters that expressed renal dysfunction in this group. Dialysis was performed in twelve severe cases. Conclusion: Leptospirosis with acute renal failure is a severe disease and requires early diagnosis and prompt treatment.


MATERIALS AND METHODS:
A retrospective database for patients presenting with leptospirosis (1976-1984) was initiated and continued prospectively to the March 31st 2012.Subjects were screened by microscopic agglutination test (MAT) for leptospirosis (in the National Reference Laboratory at National Center of Infectious and Parasitic Diseases -Sofia).A positive diagnosis was confirmed if an initial titre of ≥100 for MAT was observed.The following items were included in the database, for each patient: demographic data, clinical symptoms and laboratory parameters on admission, and outcome.
The patients were grouped in group with renal involvement (serum creatinine level >135 µmol/L) and control group (serum creatinine level <135 µmol/L) after analysis of data for whole series.Comparative analysis was performedgroup with renal involvement (n1=59) versus control group (n2=41).The data were analysed using the Statgraphics Plus Version 2.1.package.We used the t-test and for nonparametric distributions, the χ 2 test; p<0.05 was considered to be significant.

RESULTS:
One hundred patients -age 37±18 (8-78) years, 90 males, urban residents 61%, with leptospirosis were treated in Clinic of Infectious Diseases at University Hospital -Pleven, Bulgaria since January 1st 1976 to March 31st 2012.The mean annual incidence of leptospirosis for 36-year period in Pleven' region was 0.37 per 100 000 population.It correlated with those for the country but significantly differed in some of years (Figure 1).An clinical diagnosis of leptospirosis was established before referral to our clinic in 60% of the cases, although exposure to animal excrements after water and animal contacts (57% and 34%, respectively) was certified in 88% of the cases.Summer predominance (78 cases) was observed -number of cases during June, July, August and September was 12, 25, 29 and 12, respectively.
Laboratory investigations revealed that blood urea nitrogen, serum creatinine, serum bilirubin, and serum amylase levels were significantly higher in the group with renal involvement.Total proteins and albumins were decreased in the same group due to ARF and hepatic dysfunction (Table 2).
There were thirteen deaths -all in the group with renal involvement.All patients with unfavorable outcome had, besides ARF, at least two other major organ failures.Affected consciousness and multi-site bleeding were seen in all deceased patients.

DISCUSSION:
Although the most widespread zoonosis, and a frequent disease in warm, humid climate countries, leptospirosis is a rare condition in economically developed regions, accounting for <1.2 new cases/100 000 population/ year in United States and Western Europe 8 .Leptospirosis is usually spread to man, the final host, from animal reservoirs (especially rats) and depends upon chronic renal infection and shedding of virulent Leptospira interrogans in infected animals' urine.Infection by L.interrogans can cause renal tubular and microvascular injury, interstitial nephritis and ultimately, in 10% of cases, ARF 4 .
We report a large series of cases due to leptospirosis.The annual incidence of leptospirosis ARF in the region of Pleven (central-northtern part of Bulgaria) is 0.37/100 000 (mean 11.6 cases/year).This incidence is explained in part by the presence of four rivers in this region of the country -Danube, Iskar, Vit and Osam.The common features were fever, hepatomegaly, conjunctival suffusions, myalgia (pathognomonic in calf muscles), nausea and vomiting, splenomegaly, oligoanuria, headache, jaundice, leukocytosis, thrombocytopenia, elevated blood nitrogen parameters and slightly elevated transaminases.Compared to the other series featuring ARF in leptospirosis 3 , there were significant differences in the prevalence of haemorrhagic diathesis, which we found to be more than two times less frequent, but compared with series studied by Yang CW et al. (2001) it is compatible with our patients 7 .
Hypotension was encountered in approximately half of cases.Dehydration (previously reported as an aetiological factor of ARF) may have a role 5 .We consider myocarditis as probable cause, a hypothesis supported by the evidence of numerous ECG abnormalities recorded in patients with circulatory failure.
We found a lower prevalence of gastrointestinal symptoms such as abdominal pain (41%), diarrhoea (15%), although digestive involvement is reported by other retrospective series 1,3 .
Aseptic meningitis (in 21% of our cases) indicates the importance of neurological involvement in leptospirosis, secondary to direct meningeal infection or possibly more frequently to the host immune response 4 .There was no different prevalence of meningitis in two groups of patients in our study (p>0.05).
We consider that when ARF is presented, leptospirosis is a serious infection with severe multi-systemic organ involvement and ultimately failure.There are several ways in which the kidney is injured in leptospirosis: a classical immuno-allergic reaction to leptospira endotoxins 11 , direct inhibition of Na/K/ATPase in renal epithelial cells and cells from renal medulla 12 or, as Yang C. et al (2001) demonstrated, induction of pro-inflammatory pathways in the medullary thick ascending limb cells 7 .The addition of outer membrane protein extract from L.shermani to cultured medullary thick ascending limb cells induces a significant nuclear DNA binding of the NF-κ-B transcription factor.In line with these findings, pathological data obtained from deceased patients and reported by Covic A. et al. (2003) showed important tubulo-interstitial lesions.There was a high prevalence of tubular dysfunctions in that report: K + -and Na + -wasting defects, incomplete tubular type II acidosis 3 .Hypokalaemia was found in our series with a prevalence of 38%, similar to found by Covic et al. (37%) 3 .Therefore these defects should be actively and routinely investigated in all leptospira cases, as well as particular attention being given to hypokalaemia and hyponatraemia in the management of these patients.Other causes of tubular dysfunction are only indirectly related to leptospira infection: hypotension (in half of our patients), endotoxin-induced vasoconstriction and renal ischaemia secondary to the circulatory failure 5 .
Survival was comparable in our population with other leptospiral ARF series 1,7 , supporting a major role of severity of renal dysfunction.Liver dysfunction was reversible in all patients.Deceased patients had severe multi-organ failure syndrome, with respiratory and circulatory failure, multi-site bleeding and meningo-cerebral involvement.Five of deceased patients had a severe pancreatic involvement.
In conclusion: Leptospirosis with ARF is a severe disease, frequently leading to multi-organ failure, and death.
The prompt dialysis and adequate treatment improve prognosis.

Table 1 .
Leptospirosis in Pleven region (1976-2012) -prevalence of symptoms in whole series and compared in group with renal involvement versus control group (without renal involvement).

Table 2 .
Leptospirosis in Pleven region (1976-2012) -laboratory findings in whole series and compared in group with renal involvement versus control group (without renal involvement).