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dr. Ayuhati Siregar dr. Sumi Ramadani,SpPD dr. Sumi Ramadani,SpPD

ACUTE KIDNEY INJURY IN WEIL’S DISEASE COINSIDENT WITH HEPATITIS C


ON HEMODIALYSIS PATIENT
Ayuhati Siregar, Sumi Ramadani, Bayu Nasution,Feldy Nasution, Radar Tarigan, Riri A.M,Alwi
Thamrin, Syafrizal Nasution
Division of Nephrology and Hypertension
Department of Internal Medicine

ABSTRACK

Weil's disease is a condition of severe leptospirosis with characteristic jaundice, fever,


kidney failure, hepatic necrosis, pulmonary involvement, collapse of the cardiovascular system,
neurological changes and tendency for bleeding. Leptospirosis itself is a zoonotic disease caused
by a spiral infection called Leptospira interrogans, a type of spirochete pathogen. Weil disease is
usually found in 1-6% of cases with leptospirosis. Acute kidney abnormalities occur due to
immune complexes and the direct toxic effects of Leptospira which damage tubules, vasculitis,
endothelial damage, hypoxemia, interstitial nephritis, acute tubular necrosis. In Medan, weil's
disease coincidence with hepatitis C has never been found. Our therapy is the same as weil's
disease therapy.
We reported a case of weil's disease, a man, 34 years old, who came to RSUP HAM Medan
with complaints of fever, reddish yellow eyes accompanied by yellow on the whole body for 1
week before being admitted to hospital. Nausea is sometimes accompanied by vomiting and pain
in the muscles experienced since 1 week before being admitted to hospital, spontaneous and
recurrent bleeding ie bleeding gums experienced since 3 days before being admitted to hospital.
the yellow urine was recognized by the patient within 1 week before being admitted to hospital,
with a urine volume of ± 1000 cc / 24 hours. During this time the patient worked in the factory,
and 1 week before the complaint arose, the patient received instructions to clean the trenches and
stoppers in the neighborhood where he worked.
From the physical examination it was found hyperthermia, scleral jaundice, conjuctival
suffusion, jaundice and tenderness of the femoral region and m.gastrocnemius. On laboratory tests:
anemia, thrombocytopenia, decreased kidney function is characterized by Ureum (278 mg / dl),
Creatinin (7.75 g / dl) and increased total bilirubin and metabolic acidosis. Anti HCV reactive.
IgM antibody of Leptospira were found to be positive. Patients were diagnosed with Acute Kidney
Injury in Weil's Disease with coinsident Hepatitis C. Patients were given supportive therapy and
kidney replacement therapy in the form of Hemodialysis (HD). After being given antibiotics for
11 days and performed hemodialysis 3 times, patients experience clinical improvement and
laboratory parameters that return to normal, so outpatient care is recommended.

Keywords: Weil's disease, Acute Kidney Injury, Hemodialysis.


1. INTRODUCTION
Weil's disease is a severe condition of leptospirosis with characteristic jaundice, kidney
failure, hepatic necrosis, pulmonary involvement, collapse of the cardiovascular system,
neurological changes and a tendency for bleeding to occur. Leptospirosis itself is an infectious
disease caused by spiral pathogenic bacteria (obligate spirochete aerobes) of the genus leptospira,
where globally there are 2 types of distribution namely L.interrogants (pathogen) and L.biflexa
(non-pathogenic and saprophytic). L.interrogants are transmitted directly or indirectly from
animals to humans. Therefore it is also called zoonotic disease. There are 210 similar serovariants
that can cause different clinical symptoms. Leptospira can live in host animals or live freely in
water, soil, and mud (International Leptospirosis Society World Health Organization, 2003;
Washington State Department of Health, 2013 / Daher et.al, 2010).
Leptospirosis reservoir is a wild and domestic animal, most of these animals have
asymptomatic infections and transmit leptospira through urine (leptospiruria). In general,
leptospira infection is found in rodents, livestock (cows, horses, sheep, goats, pigs), dogs and other
wild mammals. In addition to livestock and rice fields, dense cities that are easily affected by
floods and have a large population of mice are ideal conditions for the transmission of this disease.
In industrial areas, exposure to water when recreation can also be a source of disease, such as
sailing, canoeing, water skiing and others. After a number of spirochaetes circulate in the blood
(leptospiremia), infected animals will expel the spirochaete in their urine, and contaminate the
environment. Transmission from animals to humans is through direct or indirect contact nasally,
orally, the mucous membrane of the eye or through a wounded skin against contaminated urine or
infected animal carcasses. Exposure can be indirectly through water, soil or food contaminated
with urine from infected animals. Inhalation of aerosol droplets from contaminated fluids can also
occur. But human to human transmission is rare (Massachusetts Department of Public Health,
2006; Watt George, 2013).
The incidence of leptospira worldwide is not known, but from recent reports it is estimated
that the incidence is around 0.1-1 per 100,000 per year in temperate climates to 10-100 per 100,000
in humid tropics. The incidence of leptospirosis in endemic countries continues to increase each
year. During outbreaks in high-risk groups, the incidence of disease can reach more than 100 per
100,000 population. In Thailand, it was reported that the incidence of leptospirosis from 1995 to
2000 reached 30 times. While in Brazil, based on data from the minister of health there were
33,174 cases of leptospirosis from 1996-2005.(International Leptospirosis Society, World Health
Organization, 2003; Lestariningsih, 2002).
Leptospirosis can appear with highly variable clinical manifestations. Starting from a mild
flu-like illness to a serious and fatal condition. Symptoms that appear can also resemble other
diseases such as jaundice which is commonly found in diseases involving the liver such as
hepatitis, or other symptoms resembling dengue fever and other viral diseases. Therefore, the
symptoms of leptospirosis are sometimes not recognized as a condition of leptospirosis. Diagnosis
modalities through laboratory tests are sometimes also not available especially in developing
countries, therefore leptospirosis sometimes becomes underreported and neglected in some regions
of the world (International Leptospirosis Society World Health Organization, 2003).
2. LEPTOSPIROSIS ASSOCIATED AKI
In developed countries, leptospirosis is a rare occurrence as a cause of acute kidney failure
(AKI). Meanwhile, in tropical countries where endemic conditions often occur, leptospirosis is the
most important cause of an AKI. The incidence rate itself varies, namely 10% -60%, depending
on the severity of the disease, over and defined by AKI itself. In a number of countries such as
Thailand and Singapore, 20% of leptospirosis related to AKI was recorded. While in Brazil, the
incidence of AKI due to leptospirosis was 22.3% (Daher et al, 2010).
Renal involvement in leptospirosis cases varies greatly, depending on the clinical
symptoms that occur, starting with mild proteinuria and abnormal urine sediment to severe AKI.
Leukocytes and red blood cells can be found in urine sediments. Proteinuria is usually under 1g /
24 hours. AKI is characterized by a very rapid increase in serum urea and creatinine levels and can
occur together with jaundice. AKI with hyperbilirubinemia shows a severe condition. AKI
associated with leptospirosis, shows a non-oligouric state with hypokalemia, which can occur in
41% -45% of cases. A recent study showed, of 58 leptospirosis patients related to AKI the risk of
bleeding (80%), liver failure (72%), respiratory failure (38%), circulatory failure (33%),
pancreatitis (25%) and rhabdomyolysis (5%) . Arterial hypotension often occurs. Hemodynamic
status and degree of awareness in patients with severe leptospirosis conditions are similar to those
of septic patients. Because of systemic vasodilation, plasma aldosterone levels and antidiuretic
hormones increase. Renal vasoconstriction and decreased urine production occur. Renal tubular
damage often occurs in the proximal part, even without AKI.
Changes in bicarbonaturia reabsorption, glycosuria and reduced proximal sodium and
excretion of uric acid and posphat should be observed. Deficits that occur in urine can last for a
long time. Hypokalemia is a common finding in AKI associated with leptospirosis, can be found
in 45% -74% of hospitalized patients, requiring treatment with IV potassium as much as 80% of
cases. In AKI associated with leptospirosis even though the patient is in oliguric conditions there
is usually no hyperkalemia. Hypokalemia is a characteristic marker of laboratory examination in
AKI patients associated with leptospirosis. Other characteristics of AKI associated with
leptospirosis are findings on ultrasound where we will get kidney enlargement, with relatively
normal echogenisity of the renal parenchyma, giving a picture of a tubulointerstitial nephritis.
Kidney size will return to normal after treatment and effective treatment of leptospirosis.
Histological examination through biopsy will be found in an acute intertial nephritis and acute
tubular necrosis. The leptospirosis mortality rate associated with AKI is 22% (Sitprija V et.al,
2003).
3. CASE REPORT
We reported, a man, 34 years old, admitted to RSUP HAM Medan with the main complaint
was fever since 1 week before admitted to hospital
3.1 History: Fever is experienced since 1 week before admitted to hospital, fever is up and down
where fever can go down with drug of fever. Fever is accompanied by pain in the entire body
of the patient, especially in the thighs and calf patient. Reddish yellow eyes are experienced
since 1 week before admitted to hospital followed by an increasingly yellowing body. A
history of jaundice was previously denied by patient. Nausea is experienced since 1 week
before admitted to hospital, vomiting is not found. History of bleeding and bleeding gums
experienced since 3 days before admitted to hospital. Urinate colored like concentrated tea is
recognized by the patient in 1 week, with a urine volume of ± 1000 cc / 24 hours. During this
time the patient worked in the factory, and 1 week before the complaint arose, the patient
received instructions to clean the trenches and stoppers in the neighborhood where he worked.
3.2 Physical examination: compos mentis, blood pressure 100/50 mmHg, regular heart rate 98 x/i,
breathing 24 x/i, body temperature 38.4 ̊ C. In the eye was found sklera jaundice with ciliary
injection. The neck, thorax and abdomen are normal, jaundice is found in the body, and pain
in gastrocnemius musculus was found.
3.3 Laboratory: Hb: 9.3 g%, Ht 26%, Leukocytes 10.950 / mm3, Platelets 98,000 / mm3, MCV
75 fL, MCH 26.6 pg, MCHC 35.5 g / dl. Sodium: 142 mEq / L, Potassium 3.3 mEq / L,
Chlorida 104 mEq / L, Ureum 278 mg / dl, Creatinine 7.75 mg / dl, ad random KGD 88 mg /
dl, SGOT 40 U / L, SGPT 36 U / L, total Bilirubin 32.18 mg / dl, Bilirubin direct 29.50 mg /
dl, ALP 187, Protein total 4.8 g / dl, Albumin 2.4 g / dl, Amylase 354 U / L, Lipase 143 U /
L, Ig M leptospira (+) 36.0, Ig G leptospira (+) 0.680. malaria (-), HBsAg: negative, Anti
HAV Ig M: negative, Anti HCV: positive. PT: 20.3 '' (C: 14.50) ratio 1.4, INR 1.39, aPTT:
38.0 '' (C: 35.0) ratio 1.08, TT: 17.3 '' (C: 18.0) ratio 0.96, D dimer 340. Urinalisa: brown tea
color, turbidity: somewhat cloudy, bilirubin (+), urobilinogen (+), ketones (-), glucose (-),
protein (+ ), pH 6.5, nitrite: (-), leukocytes (-), erythrocyte sediments 0-1, leukocytes 2-3,
epithelium 2-3. An ECG with a sinus rhythm, a chest image in the normal range. Kidney
ultrasound and urinary tract show both the appearance of acute kidney nephritis. Ultrasound
of the abdomen, the impression of hepatitis.
Patient were diagnosed with weil’s disease + Acute Kidney Injury + hepatitis C, and then were
given injection therapy of ampicillin 1 g / 6j and oral doxycycline 2x 100 mg for 10 days,
hemodialysis was performed 3 times. After an 11-day treatment period, patients can go home for
treatment with increasingly recovery of clinical and laboratory conditions

4. DISCUSSION
Adolf Weil described leptospirosis as an illness in 1886. His name is still associated with
a serious form of leptospirosis called weil's disease (International Leptospirosis Society World
Health Organization, 2003).Leptospira is a spiral, thin and moving organ with flagella. The most
common serovar is icterohaemorhagiae, which is usually found in mice (Rattus norvegicus).
Transmission through urine from infected organisms is the main source of leptospirosis infection,
because the spirochete can live for a long time in the kidney tubules (Maroun et al, 2011).
4.1 Symptom
The natural course of leptospirosis consists of two phases, septicemia and the immune
phase. Humans generally get sick after 7 to 12 days after exposure to leptospira. The first stage is
called the septicemia phase (leptospiremic phase) because bacteria can be isolated from blood
cultures and cerebrospinal fluid (CSF). This phase is characterized by non-specific flu-like illness
with sudden high fever, headache, myalgia (classically involving the paraspinal, abdominal and
calf muscles) and suffusion conjunctiva. Suffusion conjunctiva (redness of the eye surface) is a
typical physical examination in leptospirosis and the appearance of this sign in fever patients who
are not specific should be suspected as leptospirosis (Maroun et al, 2011)

Figure 1. Suffusion of conjunctiva


Stadium kedua disebut fase imun ( fase leptospirurik ) dimana antibodi yang bersirkulasi
dapat dideteksi dan bakteri dapat diisolasi dari urine. Fase ini muncul sebagai hasil dari respons
imun biologis yang memproduksi immunoglobulin M antibodi dan dapat bertahan lebih dari
sebulan. Sepanjang fase ini, kerusakan organ spesifik dapat terjadi. Aseptik meningitis adalah satu
dari sindroma klinis penting yang terjadi pada 80 % pasien selama fase imun. Gejala gangguan
ginjal, seperti uremia, azotemia, pyuria, dan hematuria dapat terjadi. Manifestasi paru walaupun
ringan dapat mengancam jiwa, keluhan bervariasi mulai dari nyeri dada, batuk dan sesak napas
sampai ke perdarahan pulmonal atau sindroma distres pernafasan akut. Peningkatan enzim hati
dapat terjadi ( sampai lima kali nilai normal ) dengan nilai total bilirubin yang tinggi, dapat
digunakan sebagai indikator prognostik pada leptospirosis. Selain itu, jaundice, pankreatitis,
hepatomegali dan myokarditis dapat pula terjadi ( Maroun et al, 2011 ).
Weil's disease is a severe form of leptospirosis. Patients can present with high fever (> 40 ̊
C), significant jaundice, kidney failure, hepatic necrosis, pulmonary involvement, cardiovascular
collapse, neurological changes, as well as a tendency for bleeding with various clinical features.
Weil's disease can occur at the end of the first phase and reach a peak during the second phase but
can also occur at any time during leptospirosis infection as a progressive disease (Maroun et al,
2011).
Acute kidney injury is the most frequent complication of severe leptospirosis.
Leptospirosis renal is usually described as a combination of acute tubular damage and intersisial
nephritis, renal glomerular and vascular lesions can cause uremia and oliguria / anuria.
(International Leptospirosis Society World Health Organization, 2003; Maroun et al, 2011).
Hepatic dysfunction is usually mild and reversible. Liver dysfunction in severe
leptospirosis can be seen in conjugated bilirubin which rises above 80 mg / dl, followed by a slight
increase in transaminases which usually rarely exceed 200 U / L (Maroun et al, 2011).
Various degrees of thrombocytopenia are reported in leptospirosis conditions. The
pathogenesis of thrombocytopenia and bleeding in leptospirosis is not fully understood (Maroun
et al, 2011).
Serious pulmonary involvement, called severe pulmonary hemorrhagic syndrome, is
referred to as the leading cause of death in weil sufferers in developing countries. Inflammation of
the meninges can cause headache, neck stiffness, confusion, psychosis and delirium (Maroun et
al, 2011).
The overall clinical manifestations that occur above are caused by damage to the
endothelial lining of small blood vessels by a mechanism that is not yet fully understood. This
explains the magnitude of the influence of leptospirosis infection on internal organs with various
clinical manifestations.
In this case there is a suffusion conjunctiva, myalgia, kidney involvement (azotemia with
creatinine clearance 7.75 ml / min and hypokalemia), impaired liver function
(hyperbilirubinemia accompanied by increased transaminases, amylase and lipase) and
bleeding manifestations of epistaxis and bleeding in the gums .
4.2 Diagnosis
Definitive diagnosis of leptospirosis depends on examination: (TK Dutta, 2005)
a. Isolation of organisms
b. Serological test
c. Detect specific DNA
4.2.1 Isolation of Organisms
- Blood: these organisms can be identified using checks on the dark field of the patient's blood or
semisolid medium culture (Fletcher's EMJH (Ellinghausen-McCullough Johnson Harris), if taken
before the 10th day of the disease. Culture takes 1-6 weeks to be positive.
- Urine: Organisms can be isolated from urine seen using a dark field microscope. And in patients
who don't get therapy, within a few months the results of urine culture examination can still show
positive results.
4.2.2 Serological Test
Diagnosis can be made through a variety of serological tests available, including:
- Agglutination test
Microscopically uses living organisms and macroscopically using dead antigens. The test will be
positive after 7- 10 days of suffering from this disease, and can last a high level for many years.
Diagnosis is made if there is an increase in titers 4 or more times. This agglutination test is not
practical and requires trained personnel to do it.
- ELISA Ig M and slide agglutination test (SAT)
ELISA and SAT Ig M are simple and sensitive tests for measuring IgM antibodies. This test is
used to diagnose leptospirosis at a very early stage and a single sample is sufficient to make a
diagnosis. ELISA IgM is very useful in making diagnoses from the start, because the value has
been positive since the 2nd day of the disease, which may be clinically not so specific. In one
study, this test was said to have a sensitivity of 100% and specificity of 93%. Currently there are
Dot -ELISA and dip stick methods to detect IgM antibodies as a newer screening tool.
4.2.3 PCR Test
The PCR method is said to be sensitive, specific and positive in the early stages of the disease and
can detect DNA leptospira in the blood, urine and cerebrospinal fluid (CSF) and aqueous humor.
But this test has limitations, where this test is a specific genus not specific
The examination to find out the specific serovar was microscopic aglutination test (MAT)
and culture isolation. But it took several weeks to get the results of the culture. The gold standard
for enforcing the diagnosis of leptospirosis is MAT, but the examination is quite complicated and
less sensitive than the newer tests, IgM ELISA and SAT (TK.Dutta, 2005).
In this case the definitive diagnosis of weil disease (severe leptospirosis) is confirmed by
leptospira Ig M examination with results (+)
4.2.4 Scoring System
Because laboratory diagnosis is sometimes still a problem in developing countries, various
attempts have been made to create a system scoring consisting of assessment of clinical,
epidemiological and laboratory symptoms to describe the possibility of a person suffering from
leptospirosis. The following is a scoring system made by WHO:
Part A Clinical signs and symptoms ( score )
- Fever > 39,0̊C (2 points)
- Conjunctival suffusion (4 points)
- Myalgias (4 points)
- Meningeal signs (4 points )
- Jaundice (1 points)
- Proteinuria (1 points)
Part B Risk Factors for exposure ( score )
- Heavy rainfall (5 points)
- Flooding (5 points)
- Animal contact (1 points)
Part C Laboratory test results ( score )
- Positive IgM ELISA (15 points)
- Microscopic agglutination (15 points)
- Test ( MAT ) –single high titer
- MAT fourfold rise in titer (25 points)
Interpretation :
Presumptive leptospirosis if score > 25 points
Possible leptospirosis if score between 20-25 points.
MAT, microscopic agglutination test
Table 1. Modified World Health Organization (WHO) Criteria for Diagnosis of Leptospirosis
(Watt George, 2013)
4.3 THERAPY
Antibiotic therapy for leptospirosis should be started as soon as possible after the diagnosis
of leptospirosis, without weighing the phase of the disease or the duration of symptoms.In mild
leptospirosis, doxycycline (hydrochloride, hyclate) is the drug of choice. Alternative drugs that
can be used are amoxicillin and azithromycin dihydrate.In moderate to severe leptospirosis,
penicillin G is still the drug of choice. Other drugs that can be used as alternatives are ampicillin
parenteral, 3rd generation cephalosporin (cefotaxime, ceftriaxone) and parenteral azithromycin
dihydrate.Antibiotics should be given for 7 days, except for azithromycin dihydrate which can be
given for 3 days. The following is a table that describes the dosage of antibiotics that can be used
in leptospirosis cases (The Leptospirosis Task Force of the Philippine Society for Microbiology
and Infectious Disease, 2010).
Table.2 Antibiotic doses in leptospirosis

Table 3. Antibiotic doses in leptospirosis patients with kidney disorders


In addition to antibiotic therapy, patients with leptospirosis must also be observed for
evidence of kidney problems, and treated, if necessary hemodialysis is carried out. In general,
indications of hemodialysis in leptospirosis patients can be seen in the table below (The
Leptospirosis Task Force of the Philippine Society for Microbiology and Infectious Disease, 2010)

Table.4 Indications for dialysis


Weil's disease patients with manifestations of bleeding can require transfusion of blood
components, such as platelets.
In this case, patients get IVFD 0.9% NaCl 20 macro tissue, Inj. Ampicillin 1 gr / 6
hours, Doxycycline 2x100 mg, Sistenol 3x 500 mg, and hemodialysis interval 1 day with 3
times improvement in kidney function, and the hemodialysis action is stopped.
4.4 PROGNOSIS
The fatality rate of weil disease ranges from 15-40% and is higher in patients over 60 years
of age (TK.Dutta, 2005). In this case, after undergoing a treatment period of 11 days, the patient's
clinical and laboratory conditions showed improvement. And finally patients can go home for
treatment.
4 juli 2016 5 juli 2016 8 juli 10 juli 2016 11 juli 2016
16
Hb g% 9,3 11,5 10,6 10,5 10,7
Leukosit/mm3 10.960 12.520 18.000 10.780 10.900
Platelet/mm3 98.000 99.000 122.000 357.000 440.000
Ht % 26 31 30 30,30 % 31
Ureum mg/dl 278 mg/dl 175 73 60 51
Cr mg/dl 7.75 mg/dl 3,37 1,13 1,09 0,85

SGOT U/L 40 30
SGPT U/L 36 40
Bilirubin total 32,18 11,56 3,4
mg/dl
Bilirubin direct 29,5 8,46 2,1
mg/dl
ALP U/L 187
Na+ mEq/L 142 137 135
K+ mEq/L 3,3 3,0 3,8
Cl- mEq/L 104 104 100
KGD ADR 80
mg/dl
HbSAg NEGATIF
Anti HAV IgM NEGATIF
Anti HCV
POSITIF
IgMleptospira (+)
5. CONCLUSION
Weil's disease, which is a severe manifestation of leptospirosis infection, is still a major
problem for developing countries, because mortality still relies heavily on diagnostic capabilities
that are fast, precise and require sufficient clinical ability. Early recognition of weil disease is very
important so that the use of antimicrobial agents can be immediately given and is expected to
reduce the severity and duration of the disease, so that the final results are expected to be achieved.
A case of weil's disease was reported to a 34-year-old man with a history of contact with a
toilet canal and a ditch suspected of being contaminated with rat urine. After obtaining an injection
of ampicillin antibiotics and a combination of oral doxycycline and supportive hemodialysis,
patients showed improvement both clinically and laboratory.
REFERANCE
- Daher et.al. Leptospirosis-associated acute kidney injury.J.Bras Nefrol 2010;32(4): 400-
407.
- International Leptospirosis Society World Health Organization. Human Leptospirosis :
Guidance for Diagnosis, Surveillance and Control. WHO 2003
- Maroun et al.Fulminant Leptospirosis ( Weil’s disease ) in an urban setting as an
overlooked cause of multiorgan failure : a cse report . Journal of Medical Case Reports
2011,5:7.
- Massachusetts Department of Public Health, Bureau of Communicable Disease Control.
Leptospirosis (Also known as Weil Disease, Hemorrhagic Jaundice, Mud Fever,Swineherd
Disease, Canicola Fever) .Guide to Surveillance, Reporting and Control. 2006.
- Sitprija V et.al.Leptospiralnephropathy.Semin Nephrol 2003; 23:42-48
- The Leptospirosis Task Force Philippine Society for Microbiology and Infectious Disease.
Leptospirosis CPG 2010.
- TK Dutta, Christopher M. Leptospirosis-An overview. JAPI.Vol 53. 2005.
- Washington State Department of Health. Leptospirosis Reporting and Surveillance
Guidelines. 2013
- Watt George. Leptospirosis on Hunter’s Tropical Medicine and Emerging Infectious
Diseases Ninth Editionp, 597-601. Saunders Elsevier. 2013