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Clinical Profile and Outcomes of Acute Kidney Injury Associated with Scrub Typhus Infection: A Systematic Review
Corresponding author: Priti Meena, Department of Nephrology, All India Institute of Medical Sciences- Bhubaneswar, Bhubaneswar, Odisha, India. E-mail: pritimn@gmail.com
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Received: ,
Accepted: ,
How to cite this article: Meena P, Sanjeevani S, Mylliemngap B, Rai Kumari P, Panda S, Krishnakumar VR. Clinical Profile and Outcomes of Acute Kidney Injury Associated with Scrub Typhus Infection: A Systematic Review. Indian J Nephrol. doi: 10.25259/IJN_188_2025
Abstract
Background
AKI remains a significant global health burden, with infectious etiologies predominant in tropical regions. Among these, scrub typhus, caused by Orientia tsutsugamushi, has emerged as a critical cause, particularly in endemic areas. Kidney involvement in scrub typhus varies widely, ranging from mild abnormalities to severe renal failure requiring dialysis.
Materials and Methods
A systematic review was conducted by searching PubMed/MEDLINE, EMBASE, and Cochrane CENTRAL databases for studies published between January 2000 and December 2024 on scrub typhus-associated AKI. Extracted data included demographics, clinical characteristics, AKI details, dialysis requirements, and long-term outcomes.
Results
Of the 1,969 records retrieved, 14 studies comprising 4,290 scrub typhus patients were included, with 1,094 (28.7%) developing AKI. The studies, conducted in India, Nepal, and South Korea, reported an AKI incidence of 13.16% to 53%. Diagnosis was based on RIFLE and KDIGO criteria in seven and six studies, respectively. AKI predominantly affected males (48-77.1%), with ages ranging from 30-71 years. Fever (94-100%) was universal, while eschar was more frequent in Korean studies. Key AKI predictors included older age, pre-existing CKD, hypoalbuminemia, and multi-organ dysfunction syndrome. Mortality ranged from 0.7% to 35.7%. Dialysis requirement varied (0.21-46.7%), but no study reported dialysis dependency at follow-up. Most patients recovered renal function within 3 months, though 1-2% had persistent dysfunction.
Conclusion
Scrub typhus-associated AKI is a significant complication with high morbidity and mortality. Early identification of risk factors and timely intervention can improve renal and patient outcomes.
Keywords
Acute kidney injury
Dialysis
Mortality
Orientia tsutsugamushi
Scrub typhus
Introduction
AKI remains a significant global health challenge, with its etiology differing markedly between developed and developing nations. In tropical regions, infections such as malaria, leptospirosis, dengue, typhoid, and acute gastroenteritis are leading causes of community-acquired AKI.1 Among these, scrub typhus has emerged as an increasingly recognized contributor, particularly in endemic areas. Scrub typhus, caused by the obligate intracellular bacterium Orientia tsutsugamushi, is transmitted to humans through the bite of larval trombiculid mites, also known as chiggers.2 This vector-borne disease predominantly affects the “tsutsugamushi triangle,” a geographical region spanning Asia-Pacific countries and the Indian subcontinent.3 However, its reach has expanded in recent years, with cases and outbreaks reported in the Middle East, Africa, and South America, and among travelers in endemic areas.4 The World Health Organization (WHO) recognizes scrub typhus as a re-emerging disease in Southeast Asia and the Southwestern Pacific, highlighting its potential case fatality rate of up to 30% in untreated cases and the urgent need for enhanced surveillance and management strategies.5 The clinical manifestations of scrub typhus are highly variable, ranging from nonspecific febrile illness with symptoms such as fever, rash, myalgia, and headache to severe complications involving multiorgan dysfunction.6 Severe disease presentations may affect the kidneys, liver, lungs, and central nervous system (CNS), with circulatory collapse observed in critical cases. Kidney involvement is a frequent and important feature, reported in 10% to 60% of cases, and can range from mild urinary abnormalities to severe AKI necessitating renal replacement therapy.7-9 Additionally, complications such as acute lung injury, myocarditis, meningitis, and multiorgan dysfunction syndrome (MODS) are common in severe cases, contributing to high morbidity and mortality.8 The diagnostic challenges have historically hindered its recognition. However, significant variability exists in the reported prevalence, clinical profiles, and kidney outcomes, reflecting diverse study settings and diagnostic criteria. This systematic review aims to comprehensively evaluate the clinical profile, kidney involvement, predictive parameters, and outcomes of scrub typhus-associated AKI. By synthesizing findings from diverse studies, this review seeks to bridge gaps in understanding and informing strategies for effective management of scrub typhus-associated AKI in endemic and non-endemic settings.
Materials and Methods
This systematic review was conducted in accordance with the guidelines outlined in the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) statement. The review protocol was registered with the PROSPERO database (Registration number: CRD42024590416, http://www.crd.york.ac.uk/PROSPERO).
We included studies that specifically reported kidney involvement and outcomes in patients with scrub typhus-associated AKI. Cohort, randomized controlled trials (RCTs), case-control, and cross-sectional studies published as full-text articles in English were included. No geographical restrictions were applied. In vitro studies, letters to the editor, review articles, editorials, articles published in languages other than English, animal studies, Studies solely done in pediatric population, studies not reporting separate kidney outcomes, or those mentioning kidney dysfunction solely as part of multi-organ failure were excluded.
A comprehensive literature search was performed across PubMed/MEDLINE, EMBASE, and the Cochrane CENTRAL databases. The search spanned studies published between January 2000 and Dec 31, 2024. Search terms included a combination of Medical Subject Headings (MeSH) and keywords such as “scrub typhus,” “Rickettsia,” “acute kidney injury,” “acute renal injury,” “acute renal insufficiency,” and “acute renal failure.” A detailed search strategy has been provided in Supplementary Data 1.
The article selection process followed a systematic approach as depicted in the PRISMA flowchart [Figure 1]. After the removal of duplicates, two independent reviewers (PM and BM) screened the titles and abstracts for relevance. Full-text articles of potentially eligible studies were subsequently reviewed by two additional independent reviewers (PR and SS). Any disagreements were resolved by consensus with a third reviewer (SP). In instances of multiple publications from the same study, the most comprehensive dataset was selected.
- Prisma flowchart of the study.
Data were extracted using a standardized form to ensure consistency. Extracted data included study information, like author, year, and site of the study; population details, like the number of patients and those diagnosed with scrub typhus-associated AKI, definitions and criteria like those used for defining AKI, patient demographics (age, sex), clinical characteristics, associated complications, laboratory parameters, staging of AKI, requirement of dialysis, mortality, and kidney histopathology reports (if available).
Case definitions
Scrub typhus cases: Febrile illness with or without eschar, confirmed by a laboratory-based diagnostic method, including IgM or IgG ELISA, immunofluorescence assay (IFA), polymerase chain reaction (PCR), or culture, as reported in the included studies.
Multi organ dysfunction syndrome: Dysfunction of two or more organ systems.
Acute respiratory distress syndrome (ARDS): Patients with PaO2/FiO2 ratio<200 mmHg and/or low saturation with bilateral infiltrates on a chest radiograph in the absence of heart failure/cardiomegaly.
Shock: An arterial systolic blood pressure <90 mmHg and/or refractory shock requiring inotropes.
Thrombocytopenia: Platelet count <100000/cmm
AKI: We defined scrub typhus-associated AKI as any kidney dysfunction reported in patients with laboratory-confirmed scrub typhus, meeting standardized diagnostic criteria. AKI was defined according to either the RIFLE (Risk, Injury, Failure, Loss, End-stage kidney disease) or KDIGO classification, as used in the individual studies. When studies reported kidney involvement without explicit staging, patients with a serum creatinine ≥1.5 mg/dL or a ≥50% increase from baseline were considered to have AKI.
Renal recovery was defined as return of serum creatinine to baseline or <1.5 mg/dL within the follow-up period, while persistent renal dysfunction referred to incomplete recovery at follow up.
CKD development was defined as sustained kidney impairment (eGFR <60 mL/min/1.73m2 or structural abnormalities) beyond 3 months
Dialysis dependency was defined as ongoing requirement for renal replacement therapy at the latest reported follow-up.
Case fatality proportion: The proportion of deaths among individuals diagnosed with scrub typhus.
Outcome measurement
The primary outcomes assessed were the incidence and severity of AKI among patients with laboratory-confirmed scrub typhus, along with the requirement for kidney replacement therapy (KRT). Secondary outcomes included the identification of clinical and laboratory predictors associated with AKI development, overall mortality, and long-term renal outcomes, including persistent renal dysfunction, CKD development, and dialysis dependency at follow up. Where available, renal histopathological findings from kidney biopsies were also documented.
These outcome measures were chosen to enable a detailed characterization of the clinical course, risk factors, and prognosis of scrub typhus-associated AKI, distinguishing it from generalized multi-organ involvement and informing priorities for future research.
Quality assessment
The quality of included observational studies was assessed using the Newcastle-Ottawa Quality Assessment Scale. The strengths and limitations of each study have been detailed in Supplementary Table 1. Additionally, the GRADE (Grading of Recommendations Assessment, Development, and Evaluation) approach was employed to evaluate the certainty of evidence for each reported outcome. Two independent reviewers (PM and SP) conducted the quality assessments, and any discrepancies were resolved through discussion. Four authors conducted data extraction and independently verified by two additional reviewers to ensure accuracy.
Data synthesis
Descriptive analysis was performed using ReviewManager 5.4 (RevMan) software. Proportions and percentages were calculated for each reported outcome among patients with scrub typhus-associated AKI. Due to heterogeneity in study designs, varying definitions of AKI, and the absence of RCTs among the included studies, a narrative synthesis approach was adopted. Meta-analysis was not conducted owing to inconsistencies in outcome reporting.
Results
A total of 1,969 records were initially retrieved, of which 1,800 duplicates were removed. After screening, 1,496 studies were excluded due to the absence of kidney involvement and unrelated content. Twenty full-text articles were assessed for eligibility, with 299 further exclusions, including 214 case reports, 45 review articles, and 40 conference abstracts. One study was excluded due to the unavailability of the full text. Ultimately, 14 studies met the inclusion criteria.6-19 See Figure 1 for Prisma flowchart. These studies collectively included 4,290 scrub typhus-infected patients, among whom 1,094 (28.7%) developed AKI.
The AKI incidence in scrub typhus varied widely, ranging from 13.16% to 53% across the studies. The highest incidence was reported by Kumar V et al.8 at 53%, while the lowest was noted by Grover et al.16 at 13.16%. Male predominance was noted, with 4877.1% of affected patients being male, with the highest percentage of male patients reported in Paul A et al.19 at 77.1%. The included studies were conducted in India, Nepal, and South Korea, representing regions where scrub typhus is endemic. The highest number of studies originated from India,6-8,13,14,16,18,19 followed by South Korea (4 studies)9,10,12,17 and Nepal (1 study).11 Studies from South Korea9,10 reported relatively lower AKI incidence rates (21-35.9%), while higher rates were observed in studies from India (Kumar V et al., 2014; Gaba et al., 2020).8,14 The Nepalese study11 documented an AKI incidence of 40.4%, reflecting regional variations in disease severity and healthcare infrastructure [Table 1].
| First author, year of publication | Country | Study design, setting | Method of scrub typhus diagnosis | Number of scrub typhus patients | Number of scrub typhus patients with AKI | AKI Incidence (%) | AKI definition used in the study | Mean age pts (in years) | Males | Mortality |
|---|---|---|---|---|---|---|---|---|---|---|
| Vikrant et al. 20136 | India | Retrospective study | IgM ELISA test | 498 | 174 | 35 | RIFLE criteria | 41 | 42 (24) | 28 (16.1)* |
| Attur et al. 20137 | India | Prospective Observational study | IgM ELISA test | 259 | 60 | 23.2 | RIFLE criteria | Median- 38 | 139 (53.7) | 2 (0.7)* |
| Kumar V, et al. (2014)8 | India | Retrospective study | IgM ELISA test and nested PCR for O. tsutsugamushi | 49 | 26 | 53 | KDIGO criterion | 34 | 29 (59) | 8 (30.7) |
| Sun et al., 20149 | Republic of Korea | Prospective Observational study | IgM ELISA test | 223 | 47 | 21 | RIFLE criteria | 63 | 84 (38) | NR |
| Hwang K, et al. 201710 | South Korea | Retrospective study | Indirect immunofluorescent antibody titer. | 510 | 183 | 35.9 | RIFLE criteria | 57.9 | 245 (48) | 4 (0.8)* |
| Sedhain et al., 201711 | Nepal | Prospective Analytical study | IgM ELISA test | 502 | 203 | 40.4 | KDIGO criterion | 30.37 ± 18.81 | 275 (54.9) | 8 (1.79) |
| Sun et al., 201712 | Republic of Korea | Prospective Observational study | IgM ELISA test | 138 | 25 | 18.11 | RIFLE criteria | 65 | 49 (36) | 1 (0.72) |
| Jaya prakash et al., 201913 | India | Retrospective Observational study | IgM ELISA test | 274 (adults-193, childen-81) | 36 adults + 3 children | 39 14.2 | KDIGO |
45.7±15 (Adults) 8.56 ± 5.1 (children) |
72 adult male (37.3) | 9 (3.3) |
| Gaba et al. 202014 | India | Retrospective study | IgM ELISA test | 176 | 49 | 27.8 | KDIGO criterion | 32 | 93 (52.8) | 23 (13) |
| Yang et al., 202015 | Republic of Korea | Prospective Observational study | IgM ELISA test | 467 | 106 | 21.6 | RIFLE criteria | 71 ± 10 | 39 (38.6) | 167 (35.7) |
| Grover et al., 202116 | India | Prospective Observational study | IgM ELISA test | 38 | 5 | 13.16 | KDIGO criterion | NR | 23 *(60) | NR |
| Oh JH et al. 202117 | Korea | Retrospective study | IgM ELISA test | 611 | 141 | 23 | RIFLE criteria | NR | 271* (44.35) | NR |
| Bal M et al., 202118 | India | Prospective study | IgM ELISA and RT PCR | NR | 45 | NR | RIFLE criteria | Median age:47 | 66.7 | 9 (20) |
| Paul A et al., 202419 | India | Cross-sectional study | IgM ELISA test | 45 | 45 | NR | KDIGO | 44.58 ± 15.66 | 77.1 | 5 (11.1) |
NR: Not reported, RIFLE: Risk, injury, and failure; and Loss, KDIGO: Kidney disease: Improving global outcomes, ELISA: Enzyme-linked immunosorbent assay, RT-PCR: Reverse transcription-polymerase chain reaction, AKI: Acute kidney injury, NA: Not available, RIFLE: Risk, injury, and failure and Loss. *Denominator is taken as total number of scrub typhus infected patients.
Study designs and AKI criteria used
The included studies had diverse study designs, with seven retrospective studies and seven prospective observational studies. The RIFLE criteria were used in seven studies (Vikrant et al.,6 2013; Attur et al.,7 2013; Sun et al.,9 2014; Hwang K et al.,10 2017; Sun et al.,12 2017; Yang et al.,15 2020; Oh JH et al.,17 2021), while the KDIGO criteria were applied in six studies (Kumar V et al.,8 2014; Sedhain et al.,11 2017; Jayaprakash et al.,13 2019; Gaba et al.,14 2020; Grover et al.,16 2021; Paul A et al.,19 2024).
Patient demographics
The mean age of patients with AKI ranged between 30.37 ± 18.81 years to 71 ± 10 years. The youngest cohort was observed in a Nepalese study by Sedhain et al.11 with a mean age of 30.37 years, whereas the oldest cohort was from South Korea by Yang et al.15 at 71 years.
Clinical features and laboratory parameters
The most reported clinical manifestations were fever (94-100%), eschar (6.57-94%), lymphadenopathy (15.5-35.5%), jaundice (5.2-61.5%), altered sensorium (10-30.7%), and oliguria (5-89.3%). Fever was reported universally across all studies, while eschar was more commonly noted in studies from Korea (Sun et al.,2,12). Gastrointestinal symptoms such as vomiting (19-75.5%), diarrhea (10.2-22.2%), and abdominal pain (19.5-23.07%) were variably reported, with Bal M et al.18 documenting 22.2% of patients presenting with vomiting. Hematological abnormalities included anemia (30.7-63.2%), thrombocytopenia (55-76.6%), and leukocytosis, with thrombocytopenia most frequently reported by Sedhain et al.11 at 66.73%. Electrolyte imbalances such as hyponatremia (9.54-76.6%) were particularly noted in Grover et al.16 at 73.8%, suggesting a potential association with disease severity. Mean peak serum creatinine levels varied widely, ranging from 1.07 ± 0.58 mg/dL12 to 6.50 ± 2.94 mg/dL18 [Table 2].
| Symptoms and laboratory parameters | Author first name with year | ||||||
|---|---|---|---|---|---|---|---|
| Vikrant S et al. 2013*6 | Attur et al., 20137 | Kumar V et al., 20148 | Sun et al. 20149 | Hwang K, et al. 201710 | Sedhain et al., 2017*11 | In O. Sun, 201712 | |
| Fever | 174 (100) | NR | 26 (100) | 209 (94) | 3128 (87.1) | 502 (100) | 132 (96) |
| Eschar | 32 (18.4) | 13 (21.6) | 9 (18.3) | 162 (92) | 80 (43.7) | 33 (6.57) | 130 (94) |
| Lymphadenopathy | 27 (15.5) | NR | 4 (15.3) | NR | NR | 79 (15.73) | NR |
| Abdomen pain | 34 (19.5) | NR | 6 (23.07) | NR | NR | NR | NR |
| Diarrhea | 10 (5.7) | NR | 2 (10.2) | NR | NR | NR | NR |
| Vomiting | 33 (19) | NR | 7 (26.9) | NR | NR | NR | NR |
| Jaundice | 9 (5.2) | NR | 16 (61.5) | NR | NR | 67 (13.35) | NR |
| Altered sensorim | 28 (16.1) | 6 (10) | 8 (30.7) | NR | NR | 32 (6.37) | NR |
| Oliguria | 60 (34.5) | 43 (71.6) | 13 (50) | 37 (46.7) | NR | 130 (26) | 7(5) |
| Hematuria | NR | 35 (13.5) | 8 (16)* | 30 * (13.5) | 179 *(36.5) | 23 (4.5) | NR |
| Proteinuria | 74 (28.6) + or more by urine dipstick (20 mg/dL) | 27 (55)* | 88 * (39.5) | 159 *(32.3) | 118 (23.7) | NR | |
| Creatinine (mg/dL) | 3.1 ± 1.7 | Peak median creatinine was 1.8 mg/dL in the AKI group | 2.86 ±1.5 | 2.02 0.92 | 0.74±0.22 | 1.37 ± 0.69 | 1.07 ± 0.58 |
| Hyponatremia | 62 (35.6) | 44 (76.6) | NR | NR | NR | 48 (9.54) | NR |
| Hypernatremia | 5 (2.9) | NR | NR | NR | NR | 3 (0.53) | NR |
| Hyperkalemia | 20 (11.5) | NR | NR | NR | NR | 32 (6.26) | NR |
| Hypokalemia | 21 (12.1) | NR | NR | NR | NR | 7 (1.34) | NR |
| Anemia | 110 (63.2) | NR | 8 (30.7) | NR | NR | 177 (35.28) | NR |
| Thrombocytopenia | 107 (61.5) | 46 (76.6) | NR | 139 ± 59 (× 103/mL) | NR | 334 (66.73) | 134 ± 55 (× 103/mL) |
| Jayaprakash et al., 2019*13 | Gaba et al. 202014 | Yang et al., 202015 | Grover et al., 202116 | Ju Hwan Oh et al. 202117 | Bal M et al., 202118 | Paul A et al., 202419 | |
| Fever | 272 (100) | NR | 467 (100) | NR | NR | 39 (86.7) | NR |
| Eschar | 55 (28.49) | 66* (37.5) | NR | NR | NR | 7 (15.6) | None |
| Lymphadenopathy | NR | NR | NR | NR | NR | 16 (35.5) | 2 (4.4) |
| Abdomen pain | NR | NR | NR | NR | @ | NR | NR |
| Diarrhea | NR | NR | NR | NR | @ | 10 (22.2) | # |
| Vomiting | 41 (21.24) | NR | NR | NR | @ | 34 (75.5) | # |
| Jaundice | 12 (6.2) | NR | NR | NR | @ | 23 (51.1) | # |
| Altered sensorium | NR | NR | NR | NR | NR | 10 (22.2) | 5 (11.1) |
| Oliguria | NR | NR | NR | NR | 126 (89.3) | 23 (51.5) | 6 (13.33) |
| Hematuria | NR | 55 (31.2) | NR | NR | 1 (2) | NR | NR |
| Proteinuria | 55 | NR | NR | 15 (32) | NR | NR | |
| creatinine (mg/dL) | 3.20 ± 1.86 | 1.51 ± 0.98 | 1.42 ± 0.71 | 1.53 ± 1.70 | 1.5 ± 0.7 | 6.50 ± 2.94 | 3.02 ± 1.33 |
| Hyponatremia | NR | NR | NR | 28 (73.8) | NR | NR | NR |
| Hypernatremia | NR | NR | NR | None | NR | NR | NR |
| Hyperkalemia | NR | NR | NR | 4 (10.5) | NR | NR | NR |
| Hypokalemia | NR | NR | NR | 4 (10.5) | NR | NR | NR |
| Anemia (Hb) (g/dL) | 11.09 ± 2.05 | NR | 12.0 ± 1.80 | 11.56 ± 1.75 | NR | 9.80 ± 2.83, | NR |
| Thrombocytopenia (platelets) (103/µL) | 1.63 ± 0.78 | NR | 121 ± 54 | 1.28 ± 0.79 | NR | 1.08 ± 6.2 | 137 ± 25.12 |
NR: Not reported, gastrointestinal symptoms like vomiting, diarrhea and jaundice (26.6%), @Involvement of Gastrointestinal tract: 76 (1.2%), Respiratory system: 112 (17.8%), Cardiovascular system: 80 (12.7%), Central nervous system: 9 (1.4%). *Denominator is taken as total number of scrub typhus infected patients.
Predictors of AKI
Key predictors of AKI included older age, pre-existing CKD, hypoalbuminemia, hypertension, time to hospital presentation, leukocytosis, thrombocytopenia, and lung involvement. Hwang K et al.10 identified age, CKD, and low serum albumin as independent predictors, while Sedhain et al.11 found pneumonia, shock, and ARDS to be significant risk factors. Jaiprakash et al.13 further highlighted hypotension, CNS involvement, and MODS as determinants of AKI progression [Table 3]. Table 4 shows non-AKI complications in patients with scrub typhus.
| Authors name with year of publication | Predictors |
|---|---|
| Attur et al., 20137 | Requirement of intensive care and thrombocytopenia |
| Sun et al., 20149 | Presence of a comorbidity (hypertension and CKD) and older age |
| Hwang K et al., 201710 | Age, presence of CKD, serum albumin level and time to hospital presentation after onset |
| Sedhain et al., 201711 | Presence of pneumonia, shock, and acute respiratory distress syndrome |
| Sun et al., 201712 | Serum NGAL and the presence of CKD |
| Jaiprakash et al., 201913 | Hypotension, lung involvement, CNS involvement and MODS |
| Yang et al., 202015 | Age, CKD, hypertension, hypoalbuminemia, leukocytosis, and chest radiographic abnormalities on admission |
| Oh JH et al. 202117 | Age, Comorbidities- CKD, total bilirubin, leukocytosis, Hypoalbuminemia |
MODS: Multi organ dysfunction syndrome, CNS: Central nervous system, NGAL: Neutrophil gelatinase-associated lipocalin, CKD: Chronic kidney disease
| Authors with year of publication | MODS | ARDS | Stroke | Shock | ICU requirement | Mechanical ventilation | Any Co-infection |
|---|---|---|---|---|---|---|---|
| Vikrant et al. 20136 | 18 (10.3) | 20 (11.5) | NR | 10 (3.4) | 25 (14.5) | NR | NR |
| Kumar V et al., 20148 | NR | 17 (65.3) | NR | 6 (23.07) | NR | NR | NR |
| Sun et al., 20149 | NR | NR | NR | 45 (25) | 9 (4) | NR | NR |
| Hwang K et al. 201710 | NR | NR | NR | 8 (4.4) | 5 (2.7) | NR | NR |
| Sedhain et al.,* 201711 | NR | 266 (53) | NR | 155 (30.9) | 94 (18.73) | 43 (8.57) | NR |
| Sun et al., 201712 | NR | NR | NR | 8 (6) | 5 (4%) | NR | NR |
| Jayaprakash et al., 201913 | 16 (8.29) | 9 (4.66) | 5 (2.59) | 13 (6.73) | NR | NR | NR |
| Oh JH et al., 202117 | NR | NR | NR | NR | 27 (4.2)* | NR | NR |
| Bal M et al., 202118 | 11 (24.4) | 8 (17.8) | NR | 1 (2.2) | NR | NR | 4 (8.8) (Malaria) |
| Paul A et al., 202419 | NR | NR | NR | NR | NR | NR | 4 (leptospirosis) |
NR: Not reported/not sure, MODS: Multi organ dysfunction syndrome, ARDS: Acute respiratory distress syndrome, ICU: Intensive care unit. *Denominator is taken as total number of scrub typhus infected patients.
Mortality and AKI outcomes
The overall mortality among patients with scrub typhus infected patients ranged from 0.7%7 to 35.7%15, with a higher mortality rate noted in studies with a greater proportion of severe AKI cases. Oliguric AKI and MODS were strong predictors of mortality, as evidenced by Kumar V et al. (2014),8 where MODS was present in 8.29% of patients, and 23.07% of those with shock did not survive [Table 5].
| Author first name with year | AKI staging | Dialysis requirement | Follow up duration | Persistent renal dysfunction | CKD development | Dialysis Dependency at follow up |
|---|---|---|---|---|---|---|
| Sanjay V et al. 20136 | RIFLE criteria, risk, injury, failure class of AKI was present in 78 (44.6%), 60 (34.5%), 36 (20.7%), respectively. | 7 (4) | NR | NR | NR | NR |
| Attur et al., 20137 |
R- 23 (38.33%) I- 13 (21.67%) Failure-24 (40.0%) |
6 (10) | Till recovery of renal function/≥3 months | 1 (creatinine- 1.8 at end of 3 months) | 1 | 0 |
| Kumar V et al., 20148 | KDIGO: A total of five (10%) patients in stage 2, four (8%) in stage 3, and 17 (35%) in stage 3. | 3 (6.1) | 3 months | 0 | 0 | 0 |
| Sun et al., 20149 | R-24 (51%), I- 21 (45%), F-2 (4%) | 0 (0) | 3 months | All patients with AKI recovered within three months After recovery, the mean serum creatinine of the AKI group was higher than that of the non-AKI group (83 20 vs. 70 23 mL/min/1.73 m2, p¼ 0.01) | 0 | 0 |
| Hwang K, et al. 201710 |
R: 32(25.9%) I: 37 (7.3%) and F: 14 (2.7%) |
NR | 3 months | 1 (pre-existing CKD) | 0 | 0 |
| Sedhain et al., 201711 | KDIGO stage 1: (66%), 2: (33%), 3:1% | 20 (3.94) | Not done | NR | NR | NR |
| Sun et al. 201712 | R:16 (64%), I:6 (24%), and F: 3 (12%) | NR | 3 months | 0 | 0 | 0 |
| Jayaprakash et al., 201913 |
KDIGO Stage 1- 21 (10.88%) Stage 2 - 7 (3.67%) Stage 3 - 8 (4.14%) |
7 (18) | NR | NR | NR | NR |
| Gaba et al. 202014 |
KDIGO Stage 1 - 13% (23) 2: 11.3% (20) 3: 3.4% (6) |
6 (3.4) * | NR | 0 | NR | NR |
| Yang et al. 202015 | R: 58 (57.4%), I: 37 (36.6%), and F: 6 (5.9%) | 1 (0.21) | 3 months | 1 | 0 | 0 |
| Grover et al., 202116 | KDIGO: stage 3 in n=5 (100%) | NR | NR | NR | NR | NR |
| Oh JH et al. 202117 | R: 14.9%, I: 7%, F: 1.2% | NR | NR | NR | NR | NR |
| Bal M et al., 202118 |
R:5(11.1%) I:6 (13.3%) F:27 (60%) L:0 E: 4 (4.4%) |
21 (46.7) | NR | NR | NR | NR |
| Paul A et al., 202419 |
KDIGO Stage 2: 82.2% Stage II: 11.1% Stage 2: 6.7% |
3 (6.8) | NR | NR | NR | NR |
AKI: Acute kidney injury, CKD: Chronic kidney disease, NR: Not reported, RIFLE: Risk, injury, and failure; and loss, KDIGO: Kidney Disease: Improving global outcomes
Based on the available data, the proportion of patients in various AKI stages was: RIFLE criteria: Risk (14.9-64%), Injury (7-45%), Failure (1.2-60%).9,10,15 KDIGO criteria: stage I (10-82.2%), stage II (3.67-33%), stage III (3.4-35%).8,13,19 Dialysis requirement ranged from 0.21%15 to 46.7%,18 with the highest reported rates in studies with severe AKI cohorts. Vikrant S et al.6 and Attur et al.7 documented lower dialysis requirements at 4% and 10%, respectively.
Follow-up periods varied between till of recovery to 3 months. Among the few studies reporting 3 months renal outcomes, most patients recovered completely, with persistent renal dysfunction reported in 1-2%, as documented in Attur et al. (2013) and Yang et al. (2020).7,15 Recovery of renal function was noted in most patients. Dialysis dependency at follow-up was not reported in any study.
Kidney biopsies were performed in three patients, reporting findings of acute tubular necrosis (ATN), tubulointerstitial nephritis with lymphoplasmacytic infiltration, interstitial edema, and mesangial hypercellularity with IgA deposition.6-8 Vikrant S et al.6 noted severe ATN with multifocal interstitial nephritis, while Kumar V et al.8 described mesangial IgA deposition, suggesting an immune-mediated component to the disease.
Discussion
This systematic review provides a comprehensive analysis of scrub typhus-associated AKI, highlighting its incidence, severity, clinical predictors, and short- and long-term outcomes across different endemic regions. While most AKI cases recover with appropriate treatment, severe presentations remain associated with high mortality and dialysis requirement. Scrub typhus-associated AKI presents a significant and underrecognized challenge in endemic regions, with a reported incidence ranging from 13.16% to 53%. This wide variability emphasize on the heterogeneity of study populations, diagnostic criteria, and healthcare accessibility across different regions. The variation in AKI incidence may also reflect differences in host susceptibility, genetic diversity of Orientia tsutsugamushi strains, and environmental factors influencing disease severity. Majority of studies used positive IgM ELISA test for diagnosis of scrub typhus. While studies from India (Kumar V et al., 2014;8 Gaba et al., 2020)14 reported higher AKI incidence, those from South Korea9,10 documented relatively lower rates, possibly attributable to earlier disease recognition and improved supportive care. The geographical distribution of scrub typhus-associated AKI highlights important epidemiological differences. Studies from India, Nepal, China and South Korea constituted the bulk of the evidence, reflecting endemicity in the Asia-Pacific region. We could not include Chinese studies due to the unavailability of articles in English. The highest AKI rates were observed in India and Nepal, where delayed healthcare-seeking behavior, late-stage presentations, and limited access to intensive care services may contribute to a greater disease burden. Additionally, regional differences in vector density and strain virulence may play a role in disease severity. An important observation across studies was the male predominance, which may be attributed to occupational exposure, outdoor activities, and increased risk of mite bites among men. Only in one study by Gaba et al., four pregnant patients were included, one of whom, in the third trimester, developed acute liver failure with seizures and succumbed to MODS.14 The remaining three, all in the second trimester, experienced pregnancy loss. Multiple predictors of AKI severity emerged across studies, reflecting the complex pathophysiology of scrub typhus-induced kidney injury. Key risk factors included pre-existing CKD, MODS, septic shock, ARDS, and hypoalbuminemia. Mortality among scrub typhus-associated AKI patients varied widely, ranging from 0.7% to 35.7%, with the highest rates observed in studies reporting severe AKI and MODS. Oliguric AKI was consistently identified as a strong predictor of mortality,8 emphasizing the importance of early fluid resuscitation and renal support in preventing adverse outcomes. Dialysis requirements also exhibited significant variability, with rates ranging from 0.21%15 to 46.7%.18 The higher dialysis rates in some studies may reflect delayed presentations and a greater proportion of severe AKI cases, while lower rates in others may indicate better fluid management and early disease recognition. ELISA titers do not appear to correlate with the occurrence of AKI. Sedhain et al. found no significant association between ELISA titers and AKI incidence in their study.11 Despite the high initial morbidity, most patients with scrub typhus-associated AKI demonstrated full recovery, with minimal cases progressing to CKD. Persistent renal dysfunction was reported in only 1% of cases, with no significant evidence of long-term dialysis dependency. This favorable renal recovery distinguishes scrub typhus from other tropical infections such as leptospirosis and malaria, which are more frequently associated with long-term renal impairment. However, the lack of long-term follow-up data in most studies limits the ascertainment of the true burden of CKD following scrub typhus. Renal biopsy findings provided valuable insights into the pathophysiology of AKI in scrub typhus. Histopathological analysis revealed ATN, tubulointerstitial nephritis, and mesangial IgA deposition, indicating a multifactorial pathogenesis involving ischemic injury, inflammation, and potential immune-mediated mechanisms. Scrub typhus-associated AKI is primarily driven by endothelial activation, systemic vasculitis, and capillary leak syndrome. Inflammatory cytokines, oxidative stress, and microvascular thrombosis further contribute to tubular injury and multiple organ dysfunction.20-23 Figure 2 shows the mechanism of AKI in scrub typhus. Early identification of AKI biomarkers such as neutrophil gelatinase-associated lipocalin (NGAL) and kidney injury molecule-1 (KIM-1) could facilitate timely diagnosis and risk stratification. Furthermore, a structured approach to volume management, role of early initiation of KRT, and optimized antibiotic therapy is essential in reducing morbidity and mortality. Several knowledge gaps remain in the understanding of scrub typhus-associated AKI. Studies focusing on genetic susceptibility, host immune responses, and emerging biomarkers could provide deeper insights into disease mechanisms. Investigations into novel therapeutic interventions, including endothelial-protective agents and immunomodulators, may help mitigate kidney injury and improve patient outcomes. This systematic review comprehensively synthesizes data on the incidence, predictors, outcomes, and pathological findings of scrub typhus-associated AKI across diverse geographical regions. However, the systematic review has some limitations, most of which reflect the quality and scope of the available evidence rather than methodological shortcomings of the review itself. The included studies displayed considerable heterogeneity in diagnostic criteria for AKI, with seven using RIFLE and six using KDIGO classifications, which limits comparability across cohorts. There was also substantial variation in study designs (seven retrospective and prospective each) and study populations, with mean ages ranging from 30 to 71 years, contributing to wide ranges in AKI incidence (13-53%) and outcomes. The over-representation of Indian studies (6/14) and absence of data from several endemic regions, partly due to the exclusion of non-English publications, may reduce the generalizability of findings and could underestimate the true burden in countries like China, Thailand, and Japan. Furthermore, sample sizes were small in several studies, and follow-up durations were inconsistent, with most studies reporting outcomes only up to recovery or 3 months, leaving long-term renal outcomes including persistent dysfunction, CKD progression, and dialysis dependence largely undefined. Pediatric and pregnant populations were markedly underreported, with only one study each reporting on these groups, despite their clinical vulnerability. Histopathological data were also scarce, with only three renal biopsies performed across all studies, limiting insights into disease mechanisms. The absence of RCTs precluded causal inferences, and given the marked heterogeneity, no pooled incidence estimates or meta-analysis could be performed without risking misleading conclusions. These limitations emphasize the urgent need for large, multicenter, prospective studies with standardized AKI definitions, extended follow-up, inclusion of vulnerable populations, and systematic histopathological assessments to accurately delineate the spectrum and long-term impact of scrub typhus-associated kidney injury.
- Mechanism of AKI in scrub typhus patients. MyD88: Myeloid differentiation primary response 88, NF-kB: Nuclear factor kappa-light-chain-enhancer of activated B cells, TMA: Thrombotic microangiopathy, AIN: Acute interstitial nephritis, ATN: Acute tubular necrosis, MODS: Multiorgan dysfunction syndrome, ROS: Reactive oxygen species, PAMPS: Pathogen-associated molecular patterns, ICAM: Intercellular adhesion molecule, VCAM: Vascular cell adhesion molecule, MCP: Monocyte chemoattractant protein.
Acknowledgment
Figure 2 has been made on https://www.biorender.com/
Conflicts of interest
There are no conflicts of interest.
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