A retrospective 5-year study in Moldova of acute renal failure due to leptospirosis: 58 cases and a review of the literature

Adrian Covic1,, David J. A. Goldsmith2, Paul Gusbeth-Tatomir1, Anca Seica1 and Maria Covic1

1 Dialysis and Transplantation Center, ‘C. I. Parhon’ University Hospital, Iasi, Romania and 2 Renal Unit, Guy's Hospital, London, UK



   Abstract
 Top
 Abstract
 Introduction
 Subjects and methods
 Results
 Discussion
 References
 
Background. Renal involvement [as acute renal failure (ARF)] is a prominent feature of both mild and severe leptospirosis—a re-emerging infectious disease. Few large series describe in detail clinical and laboratory features of cases with ARF and their outcome.

Methods. We performed a retrospective analysis (1997–2001) of all consecutive, serological confirmed leptospirosis cases with ARF (n=58, 53 male, age 44±13 years, rural residents=31%, animal contact=88%.

Results. Clinical manifestations (>50% prevalence): oliguria 95%, fever and jaundice 93%, nausea and vomiting 83%, haemorrhagic diathesis 80%, headache, hepatomegaly 76%, myalgias, abdominal pain 70%, hypotension 62%, disturbed consciousness 50%. A pattern of multiple organ failure (MOF) was frequent: ARF together with hepatic failure in 72%, respiratory failure in 38%, circulatory failure in 33%, pancreatitis in 25% and rhabdomyolysis in 5% of cases. Renal dysfunction: 35% of cases had a renal K+-wasting defect and 43% a FENa+>1% and low-osmolarity urine despite volume depletion. Haematuria was encountered in 12 and mild proteinuria in 10 subjects. Outcome: 26% deaths, 64% normal hepatic and renal function at 90 days from presentation (however 29% maintained the initial tubular defect), 10% persistent mild renal failure. All deceased patients had, beside ARF, at least two other organ failures, affected consciousness, and haemorrhagic diathesis vs a prevalence for the above features of only 34, 33, and 72%, respectively, in the survivors group (P<0.05).

Conclusions. Leptospirosis presenting with ARF is a severe disease, frequently leading to MOF and to death in one-third of the patients. In particular, the haemorrhagic diathesis and cerebral involvement are markers for unfavourable patient and renal outcomes.

Keywords: acute renal failure; epidemiology; hepatic dysfunction; leptospirosis; multiple organ failure; outcome



   Introduction
 Top
 Abstract
 Introduction
 Subjects and methods
 Results
 Discussion
 References
 
Leptospirosis, the most widespread zoonosis, presenting in humans with protean manifestations, is usually encountered in warm-climate and developing regions [15] but is also reported in European countries [6,7] and in the USA (where a mean annual incidence rate of 1.29 per 100 000 was reported in some regions [8]). Renal involvement is a prominent feature of both mild and severe forms of this re-emerging but frequently ignored infectious disease [911]. Subclinical infection, and even the anicteric febrile disease, are self-limiting forms and thus carry an excellent prognosis [9,12]. However, up to 10% of leptospirosis infections may induce acute renal failure (ARF) and are associated with significant morbidity and mortality [1,13]. Unfortunately, especially in the Western countries, leptospirosis is rarely considered as a possible cause of ARF, in part because there are few large series describing in detail the clinical and laboratory features of leptospirosis cases presenting as ARF, and their outcome.

In Romania due to the still large farming community, and more primitive sanitation conditions in the eastern (underdeveloped) part of the country, leptospirosis is much more common. In 1996 a database was initiated in North-Eastern Romania. We have recently reviewed our experience (published in abstract format in NDT 2002, [14]) and characterized in detail all consecutive ARF cases due to leptospirosis infection, treated in the ‘C. I. Parhon’ University Hospital (Iasi) Dialysis Center (a referral centre for renal disease and ARF serving a population base of nearly 5 000 000), during a 5-year period (1997–2001). A cohort of 58 post-leptospira ARF cases is reported—the largest series in Europe. We also reviewed the literature to compare the present series with other previous, comparable large cohorts.



   Subjects and methods
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 Abstract
 Introduction
 Subjects and methods
 Results
 Discussion
 References
 
In 1996 a database for patients presenting with ARF due to leptospirosis was initiated. Routinely, all subjects with ARF (defined as a serum creatinine>150 mmol/l on admission) and one of the following: (i) hepatic disease, (ii) bleeding disorders/thrombocytopenia, or (iii) fever in the context of exposure to animal dejects—87 cases in total—were screened by ELISA (IgM for leptospira, using leptospira biflexa Patoc I (serovar patoc) as antigen) and microscopic agglutination test (MAT) for leptospirosis (in-house preparation of the National Reference Center for 12 leptospira serovars encountered in the last 40 years in Moldova). A positive diagnosis was established and the patient included in the database if (i) a 4-fold increase in the initial ELISA titre was observed (n=58), or (ii) an initial titre of >=400 for MAT, or a 4-fold increase over 2 weeks (n=58, no difference between the two confirmatory immunological methods). Following a review of previously published series with leptospirosis, and of our past experience, the following items were included in the database, for each patient.

  1. Demographic data, symptoms and signs on admission: fever, jaundice, ecchymosis and petechiae, mucosal bleeding, myalgias, arthralgias, lymphadenopathy, cough, pharyngitis, blood pressure, nausea and vomiting, diarrhoea, abdominal pain, hepatomegaly, splenomegaly, oligoanuria, or anuria (defined as urinary output of<500 ml and 100 ml/24 h, respectively), cephalgia meningism and disturbed consciousness.
  2. Laboratory findings on admission and at 90 days from admission: serum urea and creatinine, serum Na+, K+ and Cl-, base excess, bilirubin, ALT and AST, urinary Na+, K+ and osmolarity, proteinuria (24-h-collection and spot urinary protein/creatinine ratio) urinary amylase, haematuria, serum amylase and lipase, serum creatine-kinase, blood count and blood film, fibrinogenaemia, APTT, ACT and prothrombin time.
  3. Outcome was recorded as: complete recovery of both renal (serum creatinine <=120 mmol/l) and hepatic functions (normal bilirubin and transaminases), complete recovery of hepatic function with mild persistent renal failure (<200 mmol/l plasma creatinine), persistent hepatic and renal dysfunction, and death. In all patients with normal renal function at 90 days from the initial presentation, tests for persistent tubular dysfunction were performed. The course of the renal failure was also evaluated by dialysis requirements, and evolution of plasma urea, creatinine and urine volumes.

The data were analysed using the C-STAT package (Oxford Statistics). We used the t-test and ANOVA and for non-parametric distributions, the {chi}2 test and Fisher's test; P<0.05 was considered to be significant.



   Results
 Top
 Abstract
 Introduction
 Subjects and methods
 Results
 Discussion
 References
 
Between 1.1.1997 and 31.12.2001, 58 patients [age 43.9±13.2 (17–75) years, 53 males, area of residence, urban 69.1%/rural 30.9%] with ARF due to severe leptospirosis were treated by the Dialysis and Transplantation Center at the ‘C. I. Parhon’ University Hospital. During the same period, 324 patients were treated for ARF with other causations (208 requiring dialysis). Thus, the incidence of leptospirosis ARF for the 5-year period was 17.9% (20.7% of the ARF population requiring dialysis). An aetiological diagnosis of leptospirosis was established before referral to our centre in only 34.5% of the cases, although exposure to animal excrement could be certified in 88.2% of the cases (and also 81% of the patients had ARF with hepatocytolysis, jaundice and thrombocytopenia—associations highly suggestive of leptospira- or hantavirus-induced ARF, see below for clinical and biochemical description). Yearly distribution of consecutive cases with ARF and leptospirosis in our unit is shown in Figure 1Go, demonstrating a high (51%) year-to-year coefficient of variation in the number of treated cases. No seasonal predominance was observed in this series.



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Fig. 1.  Yearly distribution of cases with ARF and leptospirosis.

 
Clinical presentation
Clinical signs and symptoms on admission in our unit are depicted in Figure 2Go. A biphasic clinical picture was evident in only 20 patients (34.5%). The haemorrhagic diathesis manifested as gingivorrhagia (23/46), petechiae, purpura and ecchymosis (21/46), macroscopic haematuria (12/46), haematemesis and melaena (11/46), diffuse/multi-site, severe bleeding (9/46); conjunctival suffusions, a previously reported ‘pathognomonic’ sign in leptospirosis were seen in only seven patients. All patients with cephalgia (n=44) were investigated for meningitis; disturbed consciousness was seen in 26 (59.1%) [vs 3/14 (21.4%) in patients without headaches, P=0.05], meningism in 16 (36.4%) (all with CSF examination showing aseptic white-cell pleocytosis, normoglycorrachia and a protein concentration <50 mg/dl). A comparison with data from the literature, including the largest ARF series to date [1,8,12,13], recent large leptospirosis infection series [4], and epidemiological/community investigations [2,3] is presented in Figure 2Go and Table 1Go.



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Fig. 2.  Clinical presentation of patients with leptospirosis and ARF (percentages showing the prevalence of various clinical features in the study population). Comparison with the second largest published ARF series. N/A, data not available.

 

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Table 1.  Prevalence of main clinical findings and outcome: comparison between recent largest ARF series, leptospirosis infection series and epidemiological, close-community population investigations

 
Laboratory findings are presented in Table 2Go.


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Table 2.  Laboratory findings in patients with leptospirosis and ARF

 

Renal dysfunction
All cases presented with ARF. Only 3/58 patients had hypokalaemic polyuria. The duration of the anuric phase was on average 9.4±7.0 days. Significant hypokalaemia (<3 mmol/l) was seen on admission in 22/58 (37.9%) patients (five with severe hypokalaemia, i.e. <2.5 mmol/l); of these, 20/22 had a urinary K+ excretion of >100 mmol/24 h, supporting a renal K+-wasting defect. Although physical signs compatible with dehydration and volume depletion were observed in 25/55 (40%) of the oliguric subjects, all these had a high (>1%) urinary fractional excretion of sodium and low osmolarity urine. A picture of incomplete type II renal tubular acidosis, determined by several tubular clearance tests, as described by [10], was encountered in 10 (17.2%) cases. Microscopic haematuria was encountered in 12 (20.7%) and a mild proteinuria (>1 g, <2 g/24 h) in 10 subjects (17.2%). Dialysis requirements are detailed below in the outcome section. Renal pathology was obtained only from the 15 deceased patients, the main type of lesion being that of acute interstitial nephritis [diffuse lymphocytic infiltrates (n=14), sparse lymphocytic infiltrates (n=1), tubular necrosis (n=13), interstitial oedema (n=3)], but notably with four cases with features of acute vasculitis. The histopathological features of swelling/necrosis of the tubular cells (n=2 cases) were not considered pathognomonic for leptospira since they are frequently encountered in post-mortem specimens. Renal short-term outcome is detailed below.

Cardiovascular dysfunction
Hypotension was seen in 62.1% of our patients (mean duration 3.0 days), but only 32.7% (n=19) required inotropic support (mean duration 3.8 days). All patients, including those with inotropic support, had normal cardiothoracic ratios. All ECG abnormalities (Table 2Go) were recorded only in patients with circulatory failure (14 of 19).

Multiple organ failure
Multiple organ failure (besides ARF) was frequently encountered in our study population (Table 3Go).


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Table 3.  Multiple organ failure in patients with ARF and leptospirosis

 

Treatment and outcome
These are detailed in Table 4Go and Figure 3Go. There were 15 deaths; a direct comparison between these and the 43 survivors is presented in Table 5Go. All patients with unfavourable outcome had, besides ARF, at least two other major organ failures vs only 33.7% of the survivors with the same pattern of MOF (P<0.05). Other abnormalities seen in all deceased patients were affected consciousness, multi-site haemorrhagic diathesis and hypochloraemia vs a prevalence of 32.6, 72.1 and 39.5%, respectively, in the survivors group. Similarly, factors predicting the renal short-term outcome were identified by comparing patients with a discharge serum creatinine of <200 µmol/l (n=14) with those having a creatinine >200 µmol/l (n=29); in the latter subgroup, significantly more patients required dialysis (25/41 vs 5/13), had disturbed conscious level at presentation, hepatic failure and haemorrhagic diathesis (all P<0.05) (Table 6Go). At 90 days, 63.8% of the patients completely recovered their renal function (however, persistent tubular dysfunction was still present in 29.3% of these subjects), while 10.3% had persisting mild renal insufficiency (creatinine <250 mmol/l).


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Table 4.  Outcome and treatment of leptospirosis with ARF

 


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Fig. 3.  Outcome of patients with leptospirosis and ARF.

 

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Table 5.  Comparison between leptospirosis ARF patients with favourable outcome (survivors) and unfavourable outcome (death, n=15)

 

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Table 6.  Comparison between leptospirosis ARF patients with short-term favourable renal outcome (serum creatinine <200 µmol/l) and unfavourable renal outcome (serum creatinine >200 µmol/l)

 



   Discussion
 Top
 Abstract
 Introduction
 Subjects and methods
 Results
 Discussion
 References
 
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/100000 population/year in United States and Western Europe [6,8,15]. 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. Although possible, person-to-person transmission is extremely rare. Infection by L.interrogans can cause renal tubular and microvascular injury, interstitial nephritis and ultimately, in 10% of cases, acute renal failure.

We report a large series of ARF cases due to leptospirosis, occurring in Europe. Only confirmed cases that met specific diagnostic criteria, similar to those in the largest study to date [8], were included, thereby allowing for a valid description of the disease patterns. The overall annual incidence of leptospirosis ARF in the north-eastern part of Romania, the historical province of Moldova (population of 4.5 million inhabitants) is 0.26/100 000 (11.6 cases/year), accounting for 20.7% of severe cases treated by dialysis. Such a high incidence (also reported in South-American countries [9] is explained in part by the existence of a large farming community and poorer sanitation conditions in the eastern (underdeveloped) part of the country. However, similarly to the active surveillance described by Yang et al. [10] we performed leptospira testing as a routine work-up for all ARF cases ‘at risk’ (see Subjects and methods). This approach is clearly likely to yield a higher incidence, by inclusion of previously unrecognized cases. From this series of severe leptospirosis (with ARF) it is concluded that pathognomonic features of the condition are fever, jaundice, oligoanuria, nausea and vomiting, haemorrhagic diathesis, headaches, elevated transaminases, leukocytosis and thrombocytopenia and hyponatraemia. Compared to the other series featuring ARF in leptospirosis [1,3,9,13,15] there were significant differences in the prevalence of haemorrhagic diathesis, and hepatomegaly, which we found to be two- to three-times more frequent; apparently, rhabdomyolysis, conjunctival suffusions and respiratory failure were less frequently observed in our patients. Complete information on the extent of extra-renal organ failure and system involvement is generally lacking in these previous studies; however the extent of extra-renal organ failure and of the MOF syndrome appears to be similar to the recent detailed description of Yersin et al. in 75 consecutive cases admitted over a 12-month period [2,8,16].

Hypotension was encountered in approximately two-thirds of our cases, half of these having in fact circulatory failure. Dehydration (previously reported as an aetiological factor of ARF) may have a role (prevalence of 40% in our oliguric subjects), but in agreement with Singh et al. [3], we consider myocarditis, underestimated in leptospirosis infection, the most probable cause, a hypothesis further supported by the evidence of numerous ECG abnormalities recorded exclusively in patients with circulatory failure. In a recent evaluation of cardiac involvement in serologically proved leptospirosis, Rajiv et al. [17] found that 36% of the patients had transient hypotension and a normal cardiac size; minor ECG abnormalities were common, being recorded in 70% of cases.

We also found an important prevalence of gastro-intestinal symptoms such as G-I intolerance (83%), abdominal pain (69%), diarrhoea (41%), not a ‘classical’ triad recognized for Weil's syndrome, although digestive involvement is reported by other retrospective series [1,9,15] (Table 2Go). Finally, cephalgia (76%), frequently associated (in 59% of cases) with disturbed consciousness, and aseptic meningitis (in 36% of cases), indicates the importance of neurological involvement (again underestimated, see Table 2Go) in leptospirosis, secondary to direct meningeal infection or possibly more frequently to the host immune response, as suggested by Berman and co-workers [18]. We can conclude that when ARF is present, leptospirosis is a serious infection with severe multi-systemic organ involvement and ultimately failure.

Our patients were not tested serologically for hantavirus. We consider this an important issue since similar pathological findings and frequent clinical findings (ARF with thrombocytopenia, G-I symptoms, myocarditis, tubular abnormalities), as revealed by the present evaluation may also be encountered in hantavirus nephropathy. Therefore we have now initiated a serological work-up for hantavirus in all ARF cases considered to be caused by Leptospira, a practice that probably should be routine in Europe.

There are several ways in which the kidney is injured in leptospirosis: a classical immuno-allergic reaction to leptospira endotoxins [19], direct inhibition of Na/K/ATPase in renal epithelial cells and cells from renal medulla [20] or, as recently demonstrated, induction of pro-inflammatory pathways in the medullary thick ascending limb cells (for a more detailed discussion see the excellent recent paper by Yang et al. [13]). 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-{kappa}-B transcription factor. In line with these findings, pathological data obtained from our deceased patients showed important tubulo-interstitial lesions (Table 4Go). Furthermore, there was a high prevalence of tubular dysfunctions in our population: K+- and Na+-wasting defects, incomplete tubular type II acidosis. In a very recent report [21] looking specifically at K abnormalities in a very large cohort (n=442) of patients with newly diagnosed leptospirosis, hypokalaemia was found with a prevalence of 41%, very similar to our cohort (37%). 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: hypovolaemia (again, frequent in our series), endotoxin-induced vasoconstriction and renal ischaemia secondary to the circulatory failure (see above).

Survival was comparable in our population with other leptospira ARF series [1,4,13], but significantly lower than that reported in other studies, with a lower incidence of ARF [2,9,15], supporting a major contributory role of the severe renal dysfunction. Liver failure was reversible in all patients. In contrast, a mild degree of renal failure was still evident in 9% of the patients 3 months after onset. Deceased patients had a more severe MOF syndrome, with a higher prevalence of hepatic, respiratory and circulatory failure; all these subjects also had evidence of severe multi-site bleeding and meningo-cerebral involvement. The last two conditions, together with the severity of hepatic involvement were also the best predictors for a slower recovery of the renal function. Our findings are in line with the recent 5-year study of Dupont et al. [22], where oliguria (ARF, dyspnoea and alveolar infiltrates), severe respiratory involvement, and repolarization abnormalities on ECG, possibly due to underlying myocarditis, were independent negative prognostic factors on multivariate analysis of 68 cases. We were not able to confirm a role for other previously reported risk factors such as leukocytosis [22], age [4] or hyperkalaemia [21].

Leptospirosis presenting with ARF is a severe disease, frequently leading to MOF, and death in one-third of the patients. Particularly, haemorrhagic diathesis and cerebral involvement are markers for unfavourable patient and renal outcomes.

Conflict of interest statement. None declared.



   Notes
 
Correspondence and offprint requests to: Dr Adrian Covic, MD, PhD, Associate Professor of Nephrology, Director, Dialysis Centre, Parhon Hospital, Bd Carol 1st, No. 50, Iasi, 6600, Romania. Email: acovic{at}xnet.ro Back



   References
 Top
 Abstract
 Introduction
 Subjects and methods
 Results
 Discussion
 References
 

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Received for publication: 14. 6.02
Accepted in revised form: 17. 1.03