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A case of scrub typhus requiring maintenance hemodialysis

Renal failure caused by scrub typhus is known to be reversible. In most cases, renal function is almost fully restored after appropriate antibiotic treatment. A 71-year-old man was diagnosed with scrub typhus complicated by renal failure. A renal biopsy revealed histopathologic findings consistent with acute tubulointerstitial nephritis. Renal function did not improve 18 months after discharge and the patient required continuous hemodialysis. Although severe renal failure requiring dialysis is a rare complication of scrub typhus, we describe a case of scrub typhus requiring maintenance hemodialysis. To the best of our knowledge, this is the first such report.


Introduction
Scrub typhus is an acute febrile illness characterized by fever, chills, myalgia, skin rash, lymphadenopathy, and an eschar at the site of the inoculating chigger bite. Scrub typhus, rickettsial infection (Orientia tsutsugamushi), is transmitted by trombiculid chigger mites (Leptotrombidium species). It is endemic in Southern and Eastern Asia including Northern Australia, and the Western Pacific Islands [1,2]. The spectrum of the clinical severity of scrub typhus ranges from mild to severe with fatal complications such as meningoencephalitis, pneumonitis, acute respiratory distress syndrome, acute kidney injury (AKI), myocarditis, disseminated intravascular coagulation (DIC), and septic shock [2][3][4][5].
The reported incidence of renal failure caused by scrub typhus varies from 10.5% to 42.6% according to the criteria of renal failure [6,7]. In most case reports, the serum creatinine level was restored after the administration of appropriate antibiotics such as doxycycline and azithromycin although varying degrees of renal deterioration and recovery time have been reported. To the best of our knowledge, no case of progression to end-stage renal disease has been reported for this condition. This is the first reported case of scrub typhus requiring maintenance hemodialysis.

Case report
A 71-year-old man was transferred to our university hospital from a private clinic because of significantly elevated serum creatinine. His serum creatinine level had been 1.2 mg/dL in the health screening examination performed 6 months prior to admission. Routine urine analysis was not performed at that time. His past medical history included diabetes mellitus for 10 years treated with oral hypoglycemic agents. The patient reported climbing mountains in the Jeolla province of Korea, 2 weeks prior to admission to our hospital. Four days later, he developed fever, chills, myalgia, and cough. The serum creatinine level was 11.0 mg/ dL as measured at a private clinic, and the patient was transferred immediately to Soonchunhyang University Cheonan Hospital.
The patient had a history of outdoor activities and showed typical clinical manifestations of scrub typhus, especially an eschar in the right axillary area. The results of an immunochromatographic antibody assay test for O. tsutsugamushi was positive, and the immunofluorescent antibody assay test profile showed an immunoglobulin (Ig)M titer41:2048 and IgG titer41:2048. On the basis of these findings, he was diagnosed with scrub typhus. Doxycycline was administered 200 mg on the first day, followed by a maintenance dose of 100 mg once daily for 20 days.
For correction of hyperkalaemia, metabolic acidosis, and marked elevation of serum creatinine levels with uremic symptoms, the patient was started on hemodialysis on the first day of admission. After emergency management, he was placed on hemodialysis three times/week with conservative treatment. Clinically, the patient's symptoms improved dramatically while he was receiving doxycycline, showing a gradual decrease in inflammatory markers such as CRP. However, serum creatinine levels assessed prehemodialysis did not decrease continuously (Fig. 1).
We performed an ultrasonography-guided renal biopsy to rule out other underlying diseases, including diabetic nephropathy and primary glomerulonephritis, on Day 7 after admission. Microscopically, we detected diffuse lymphoplasmacytic infiltrations with scattered neutrophils in the edematous interstitium. Tubulitis and acute tubular necrosis were also observed. Detached tubular epithelial cells and neutrophils were detected in the tubular lumen. Mild tubular atrophy was also observed. The glomeruli were normal (Fig. 2), and no signs of mesangial expansion or glomerulosclerosis, which are common in diabetic nephropathy, were observed. However, vascular changes such as intimal fibrous thickening and medial sclerosis were severe.
The patient remained on hemodialysis three times/week, and he was discharged on Day 25 after admission. We expected the patient to recover his renal function gradually, but he remained on hemodialysis in an artificial kidney room of a private clinic for 18 months after discharge, and an arteriovenous fistula was formed. The patient's renal function did not improve, and his serum creatinine level remained at 8-10 mg/dL.

Discussion
In the present study, we describe a patient with renal failure caused by scrub typhus that did not show improvement of renal function despite a decrease in the levels of inflammatory markers such as CRP. The results of a renal biopsy showed microscopic findings suggestive of tubulointerstitial nephritis. Although case reports of patients with renal failure caused by scrub who underwent renal biopsy are rare, the presence of O. tsutsugamushi coccobacilli in the renal tubule has been reported previously [8]. In our patient, the presence of microorganisms was not verified.
Although the pathophysiology of renal failure as a complication of scrub typhus has not been fully elucidated, there are several possible hypotheses. First, because the basic pathologic characteristic of scrub typhus is multiorgan vasculitis of the small blood vessels, renal failure can be assumed to be associated with vasculitis [9,10]. A second possible explanation is DIC. Thrombosis and coagulation may induce microangiopathy and multiple organ damage, including AKI. A third explanation is prerenal azotemia caused by renal hypoperfusion Figure 1. Time course of the changes in serum creatinine levels. Hemodialysis is indicated by arrowheads, and renal biopsy was performed at 7 days after admission. associated with shock or volume depletion [8,9]. The effective renal blood flow decreases with increased vascular permeability, and this change is associated with systemic vasculitis. Widespread vascular damage causes leakage of plasma albumin into the perivascular space and hypoalbuminemia [11]. In addition, other nonspecific symptoms such as nausea, vomiting, poor oral intake, and diarrhea can be aggravated by volume depletion. However, in the present patient, there were no clinical and/or laboratory or histopathologic findings suggestive of vasculitis, DIC, or renal hypoperfusion. Finally, tubulointerstitial nephritis caused by direct invasion of the renal parenchyma by the microorganism may cause renal failure. Similar to our case, multifocal renal tubular necrosis and infiltration of inflammatory cells into the tubulointerstitium on renal biopsy were previously reported [8].
The reason for our patient's renal function not being fully recovered remains unclear. Several possible explanations associated with different pathophysiological mechanisms exist, as mentioned above. Renal hypoperfusion may have occurred prior to admission to our hospital. Because the patient was transferred from a private clinic, it is assumed that fluid therapy was performed to some extent. Infection by O. tsutsugamushi under these conditions may explain why renal function was not fully recovered. Another hypothesis is a superinfection or crossreaction. In Korea, serologic surveys of patients have confirmed the prevalence of spotted fever group rickettsioses, including Japanese spotted fever. Because the clinical symptoms and signs of Japanese spotted fever are similar to those of scrub typhus, Japanese spotted fever may be misdiagnosed as scrub typhus [12,13]. In our patient, the antibody titer for O. tsutsugamushi by immunofluorescent antibody assay was 41:2048 and that for Rickettsia japonica was 1:1280. Although this is difficult to determine exactly because the presence of microorganisms was not verified, superinfection is possible. Furthermore, cross-reactions between R. japonica and O. tsutsugamushi have been reported although to a lesser extent than between R. japonica and typhus group rickettsia [14]. Finally, it is possible that the patient's baseline renal function was not normal. The estimated glomerular filtration rate according to the Cockroft-Gault equation and considering age, sex, and weight was 50 mL/ minute 6 months prior to admission. In addition, severe vessel changes and mild tubular atrophy were observed in the biopsy specimen. According to the most recent report about renal failure due to scrub typhus, old age and underlying diseases such as hypertension, diabetes mellitus, and chronic kidney disease are predicting factor of AKI, but there are no cases of end-stage renal disease. Renal function of all patients was restored to the baseline after the administration of appropriate antibiotics. Therefore, although the patient's baseline renal function was slightly reduced, it is difficult to consider preexisting renal dysfunction as a critical cause of permanent renal damage [15].
Renal failure caused by scrub typhus is commonly known to be reversible with the appropriate antibiotic therapy, and there are no reports of healthy adults requiring maintenance hemodialysis after scrub typhus infection. Physicians should reco gnize the possibility of permanent renal damage in patients with scrub typhus.