Introduction {#sec1}
============

Weil disease is a rare autoimmune complication of leptospirosis. It develops following a phase of bacteremia, after the pathogens have been eliminated from the bloodstream, but antibody-mediated processes continue to affect the patient's internal organs. In most cases, symptoms appear around 3 weeks after exposure, presenting as acute kidney injury and high-grade hyperbilirubinemia.

Case Presentation {#sec2}
=================

A 72-year old Caucasian man with no prior medical history was admitted with acute renal failure and hyperbilirubinemia. Three weeks prior to hospitalization, he experienced an episode of fever, accompanied by chills. The initial symptoms were followed by muscle pain and decreased exercise tolerance. Visible jaundice and steadily decreasing urinary output appeared soon thereafter. Three days later he was admitted to a provincial hospital.

Initial tests revealed high total bilirubin levels in the serum, exceeding 20 mg/dl, predominantly conjugated, increased serum inflammatory factors (C-reactive protein levels \>90 mg/l), and an elevation of both creatinine and urea serum levels (8 mg/dl and 300 mg/dl, respectively). Serum concentrations of other markers of hepatic damage, such as alanine- and glutamate-pyruvate transaminase, prothrombin time, and alkaline phosphatase, were all within normal ranges. A decrease in both total serum protein (44 g/l) and albumin (24 g/l) was noted. Urinalysis revealed erythrocyturia and proteinuria exceeding the nephrotic-range threshold. Full blood count analysis showed a decreased platelet count (30,000/ml) and mild anemia (Hgb level 9.2 g/dl). A chest X-ray and abdominal computed tomography scan were normal. Serological tests for hepatitis B virus and hepatitis C virus infection were negative.

Initial treatment involved continuous renal replacement therapy and empirical antibiotic therapy with cephalosporin (cefotaxime).

The patient was transferred to our hospital for further investigation and treatment. At the time of transfer, the patient exhibited cognitive impairment, disorientation, hiccups, and Cheyne−Stokes breathing. Physical examination revealed normal vital signs, jaundice, bilateral conjunctivitis, generalized edema, and signs of thrombocytopenic purpura. There were no signs of circulatory or respiratory failure, and no focal neurological signs. Urinalysis showed severe proteinuria (urinary protein 475 mg/dl) accompanied by erythrocyturia (erythrocytes were covering the whole field of vision, and the number of leukocytes were 2 and 5 in the field of vision). The creatinine level was 7.5 mg/dl. The serum level of creatinine phosphokinase (CPK) was CK = 31 U/l (normal), and the serum level of potassium was 5.0 mmol/l.

As jaundice and oliguria requiring renal replacement therapy persisted and a review of the patient's history revealed that he lived close to a river bank and a lake, the suspicion of a Leptospira infection was raised. Blood and urine samples were collected for polymerase chain reaction evaluation of Leptospira pathogen presence and a microscopic agglutination test. In the presence of the severe encephalopathy observed, the decision was made to perform albumin plasmapheresis. After 2 sessions, the mental status of the patient markedly improved. After that point, the patient continued only treatment with hemodialysis, and his urine output started to increase significantly. Subsequently, Leptospira tests showed the microscopic agglutination test results as highly positive with an antibody titer of 1:3600, but the polymerase chain reaction test was negative in both urine and blood.

The patient's physical condition continued to improve, with most of the signs present on admission subsiding completely. In view of persistent renal dysfunction, kidney biopsy was performed ([Table 1](#tbl1){ref-type="table"}). Using Grocott's methenamine silver staining protocol, cellular inclusions resembling intact Leptospira were found in the tubular lumen of the kidney biopsy specimen ([Figure 1](#fig1){ref-type="fig"}).Table 1Kidney biopsy resultsBioptate 12 mm long (preserved in paraffin block), containing mostly renal cortexGlomeruli (n = 27) • 1 glomerulus sclerotic • 26 glomeruli without pathological findingsInterstitial tissue • Lymphoid cells, plasmocytes, and single neutrophil; infiltration of up to 10% of bioptate surface • EdemaTubules • Atrophy of 2 tubules • Some tubules presenting signs of ATN • Some tubules containing erythrocyte rollsVessels • Arteries: small-grade fibrosis of internal membrane • Arterioles: unchanged • Inflammatory cells present in peritubular capillariesImmunohistochemistryGlomerular deposits • IgA (--), IgG (--), IgM (+ in mesangium) • C1 (+ in mesangium), C3 (--), C9 (--)Conclusion: Histopathological image together with clinical data suggest changes secondary to leptospirosis.[^1]Figure 1Kidney biopsy specimen. Grocott's methenamine silver staining revealing inclusions (arrows) resembling *Leptospira* in the lumen of renal tubules (original magnification ×100).

Following the biopsy, a 3-day course of i.v. methylprednisolone infusions (250 mg/d) was prescribed, followed by a conversion to oral prednisone (20 mg per day). This resulted in a marked increase in the patient's urinary output, which rose up to 6000 ml per day, accompanied by a continuous drop in serum creatinine and bilirubin levels ([Figure 2](#fig2){ref-type="fig"}). Within 1 week, the dialysis treatment was suspended, and bilirubin and hematological parameters returned to normal levels. Three more weeks of continued prednisone therapy resulted in a serum creatinine level of 1.3 mg/dl, with no proteinuria or other abnormal findings on urinalysis. The serum bilirubin and inflammatory marker concentrations all returned to normal. At the time of discharge, the patient was on 20 mg of prednisone, with a planned weekly dose reduction of 5 mg. During a clinic visit 4 weeks later, the patient was asymptomatic, with normal physical examination findings.Figure 2Graph showing serum creatinine and total bilirubin levels during treatment. Treatment regimen: Biotaksime 2 × 1 g i.v. 28.09 to 21.10.2016; methylprednisolone (250 mg) i.v. 14 to 16.10.2016; Encortone 20 mg orally 17.10.2016; hemodialysis sessions (8 in total) 28.08, 30.09, 02.10, 04.10, 08.10, 12.10, 14.10, and 17.10.2016; plasmapheresis sessions (2 in total) 27.09 and 29.09.2016.

Discussion {#sec3}
==========

Weil disease is the most severe presentation of leptospirosis, with a reported mortality rate often exceeding 22%.[@bib1] In most cases, kidney involvement in Weil disease presents as acute renal failure involving oliguria, hypokalemia, loss of urinary concentration ability, albuminuria and hematuria.[@bib1], [@bib2] Most commonly, the renal involvement occurs as a result of interstitial damage (inflammation or necrosis), with the glomeruli remaining unaffected. On admission, our patient suffered from nephrotic-range proteinuria accompanied by anasarca, with the kidney biopsy specimen revealing typical interstitial inflammation without any glomerular involvement on light microscopy. In the course of the treatment, urinalysis results returned to normal. Electron microscopic evaluation of the biopsy specimen was not performed; however, podocytopathy (e.g., minimal change disease) is a highly possible explanation of nephrotic-range proteinuria in this case.

The treatment of Weil disease is not standardized. Typically, improvement in kidney function usually can be achieved within several days of antimicrobial and dialysis treatment.[@bib3], [@bib4] However, in our case, the time interval between the onset of initial symptoms (fever, fatigue, myalgia) and the hospital admission exceeded 3 weeks, with persistence of symptoms despite antibiotics. Following corticosteroids, continued antibiotics, plasmapheresis, and a hemodialysis regimen, the patient's general condition began to improve. His mental status improved significantly after 2 plasmapheresis sessions. It is hypothesized that antibody-mediated damage to the nervous system could lead to encephalopathy, and prompt neurological recovery following plasmapheresis[@bib5] with no recovery of the kidney function.

I.v. methylprednisolone infusions, on the other hand, led to polyuria and a decrease in serum creatinine level. The improvement in kidney function was parallel to jaundice resolution.

Leptospira tests showed polymerase chain reaction−negative results and positive microscopic agglutination test results confirming *Leptospirosis* infection.[@bib6] Because Leptospira are present in the bloodstream for about 7 to 14 days following infection, with urinary presence lasting for about 1 month, no bacterial DNA was found in either of the samples collected for polymerase chain reaction testing, suggesting that the persistent symptoms were from the immune response to infection.[@bib7]

Conclusion {#sec4}
==========

In severe persistent Weil disease, treatment with combined therapy involving antibiotics, plasmapheresis, hemodialysis, and glucocorticosteroid therapy may be required to accelerate recovery ([Table 2](#tbl2){ref-type="table"}).[@bib4]Table 2Teaching points1.Kidney injury in leptospirosis can present as nephritic-range proteinuria2.Combined treatment with plasmapheresis, dialysis, and glucocorticosteroid therapy seems a proper treatment option for a severe course of leptospirosis complicated by kidney injury3.A microscopic agglutination test is the best diagnostic tool for confirming infection with leptospira4.Weil disease is a life-threatening condition with a mortality rate exceeding 20%5.In most cases, kidney damage is limited to the interstitial tissue; glomeruli remain intact6.Antibiotic therapy with cephalosporins or β-lactam antibiotics should be started in every case of confirmed leptospirosis; in most cases, patients treated with antibiotic with early-diagnosed Weil disease do not need kidney replacement therapy

Disclosure {#sec5}
==========

All the authors declared no competing interests.

[^1]: ATN, acute tubular necrosis.
