The majority of published data on chronic kidney disease of uncertain etiology (CKDu) is on asymptomatic patients who were detected in screening programs. The clinicopathological profile of a group of patients presenting with acute symptoms and renal dysfunction from CKDu endemic regions in Sri Lanka was studied. 59 patients > 10 years of age with backache, feverish fatigue feeling, dysuria, joint pain, or dyspepsia, singly or in combination with elevated serum creatinine (> 116 and > 98 µmol/L for male and females, respectively) were included in the study. Those patients who had normal-sized kidneys were biopsied after excluding clinically detectable causes for renal dysfunction. Histology was scored with activity and chronicity indices. These patients' urinary sediment and inflammatory markers were checked. Patients were stratified into three groups based on duration of symptom onset to the time of biopsy. The natural course of the disease was described using serial mean serum creatinine and histological activity as well as chronicity indices in these 3 groups. These patients' mean age, occupation, and sex ratio were 44 (9) years, 57 farmers, and male : female 55 : 4, respectively. Mean serum creatinine at biopsy was 143.8 (47.9) µmol/L. Elevated inflammatory markers and active urine sediment were reported. Histology was compatible with an interstitial nephritis with a mixture of acute and chronic tubulointerstitial lesions and glomerular scarring. In the natural course of an acute episode of CKDu, serum creatinine and histological activity were reduced while histological chronicity increased. CKDu may be preceded by an acute episode of tubulointerstitial nephritis (TIN).

Chronic kidney disease of uncertain etiology (CKDu), an emerging chronic kidney disease (CKD) subtype, contributes to significant morbidity and mortality in certain tropical countries. Although several indicators of CKDu have been previously suggested, sensitive and specific tests to detect early disease or predict disease progression are currently unavailable. This study focused on evaluating 8 renal urinary markers, namely neutrophil gelatinase-associated lipocalin (NGAL), Kidney Injury Molecule-1 (KIM1), cystatin C (CST3), beta 2 microglobulin (B2M), osteopontin (OPN), alpha 1 microglobulin (A1M), tissue inhibitor of metalloproteinase 1 (TIMP1), and retinol binding protein 4 (RBP4), with the hypothesis that these have distinct expression patterns in patients with CKDu. A cross-sectional study was conducted with 5 study groups comprising subjects from CKDu, endemic CKD, nonendemic CKD, and endemic healthy and nonendemic healthy controls. The urinary levels of the 8 selected renal biomarkers were quantified using multiplex biomarker assay, and the data were subjected to systematic analysis using logistic regression algorithm aiming to extract the best marker combination that could distinctly identify the disease groups noninvasively from the healthy controls. A 3-marker signature panel comprising A1M, KIM1, and RBP4 was identified to represent the best minimum marker combination for differentiating all CKD categories, including CKDu, from healthy controls with an overall sensitivity of ≥0.867 and specificity ≥0.765. The marker combination comprising OPN, KIM1, and RBP4 showed high predictive performance for distinguishing patients with CKDu from patients with CKD with both sensitivity and specificity ≥0.93, which was superior to any existing noninvasive indicator. In all, our systematic evaluation of urinary markers previously linked to CKD, in general, allowed identification of exclusive marker panel combination for early diagnosis and confirmation of CKDu.

The use of dipstick proteinuria to screen Chronic Kidney Disease of uncertain aetiology (CKDu) in Sri Lanka is a recently debated matter of dispute. The aim of this study was to assess the suitability of biomarkers: serum creatinine, cystatin C and urine albumin to creatinine ratio (ACR) for screening CKDu in Sri Lanka. Forty-four male CKDu patients and 49 healthy males from a CKDu-endemic region were selected. Meanwhile, 25 healthy males from a non-endemic region were selected as an absolute control. The diagnostic accuracy of each marker was compared using the above three study groups. In receiver operating characteristics (ROC) plots for creatinine, cystatin C and ACR, values of area under the curve (AUC) were 0.926, 0.920 and 0.737 respectively when CKDu was compared to non-endemic control. When CKDu was compared to endemic control, AUCs of above three analytes were distinctly lower as 0.718, 0.808 and 0.678 respectively. Cystatin C exhibited the highest sensitivity for CKDu when analyzed against both control groups where respective sensitivities were 0.75 against endemic control and 0.89 against non-endemic control. ROC-optimal cutoff limits of creatinine, cystatin C and ACR in CKDu vs non-endemic control were 89.0 μmol/L, 1.01 mg/L and 6.06 mg/g-Cr respectively, whereas in CKDu vs endemic control the respective values were 111.5 μmol/L, 1.22 mg/L and 12.66 mg/g-Cr. Amongst the three biomarkers evaluated in this study, our data suggest that Cystatin C is the most accurate functional marker in detecting CKDu in endemic regions, yet the high cost hinders its usability on general population. Creatinine is favorable over dipstick proteinuria owing to its apparent accuracy and cost efficiency, while having the ability to complement the kidney damage marker (ACR) in screening. ACR may not be favorable as a standalone screening marker in place of dipstick proteinuria due to its significant decline in sensitivity against the CKDu-endemic population. However, creatinine and ACR in a complementary manner could overcome current shortcomings of dipstick proteinuria and such a dual marker tool could be commodious in screening CKDu-type tubulointerstital diseases. Furthermore, use of ACR may also increase the ability to clinically discriminate CKDu from other glomerular nephropathies.

Background: Patients presenting with acute interstitial nephritis (AIN) of unknown aetiology, probably the earliest presentation of chronic kidney disease of unknown aetiology (CKDu), have been treated with oral prednisolone and doxycycline by physicians in Sri Lanka. This trial assessed the effectiveness of prednisolone and doxycycline based on eGFR changes at 6 months in patients with AIN of unknown aetiology. Method: A randomized clinical trial with a 2 × 2 factorial design for patients presenting with AIN of unknown aetiology (n = 59) was enacted to compare treatments with; A-prednisolone, B-doxycycline, C-both treatments together, and D-neither. The primary outcome was a recovery of patients’ presenting renal function to eGFR categories: 61–90 ml/min/1.73m² (complete remission– CR) to 31–60 ml/min/1.73m² (partial remission– PR) and 0–30 ml/min/1.73m² no remission (NR) by 6 months. A secondary outcome was progression-free survival (not reaching < 30 ml/min/1.73m² eGFR), by 6–36 months. Analysis was by intention to treat. Results: Seventy patients compatible with a clinical diagnosis of AIN were biopsied for eligibility; 59 AIN of unknown aetiology were enrolled, A = 15, B = 15, C = 14 and D = 15 randomly allocated to each group. Baseline characteristics were similar between groups. The number of patients with CR, PR and NR, respectively, by 6 months, in group A 3:8:2, group B 2:8:3 and group C 8:5:0 was compared with group D 8:6:1. There were no significant differences found between groups A vs. D (p = 0.2), B vs. D (p = 0.1) and C vs. D (p = 0.4). In an exploratory analysis, progression-free survival in prednisolone-treated (A + C) arms was 0/29 (100%) in comparison to 25/30 (83%) in those not so treated (B + D) arms, and the log-rank test was p = 0.02, whereas no such difference found (p = 0.60) between doxycycline-treated (B + C) arms 27/29 (93%) vs those not so treated (A + D) arms 27/30 (90%). Conclusion: Prednisolone and doxycycline were not beneficial for the earliest presentation of CKDu at 6 months. However, there is a potential benefit of prednisolone on the long-term outcome of CKDu. An adequately powered steroid trial using patients reaching < 30 ml/min/1.73m² eGFR by 3 years, as an outcome is warranted for AIN of unknown aetiology. Trial registration: Sri Lanka Clinical Trial Registry SLCTR/2014/007, Registered on the 31st of March 2014.

Background: A chronic interstitial disease, chronic kidney disease of uncertain etiology (CKDu), has emerged as a notable contributor to the CKD burden in rural Sri Lanka. Most therapeutic and diagnostic approaches to CKD focus on glomerular diseases, and thus are not fully applicable to CKDu. Serum proteins, specifically those with the profile of markers representing different facets of a disease, are beneficial for a comprehensive evaluation of diseases, and hence in CKD. Our aim was to identify the role of serum-retinol-binding protein 4 (RBP4), a marker of the proximal tubule, in the diagnosis of CKDu. Methods: Definite CKDu cases were recruited from the renal clinic in Girandurukotte and Wilgamuwa (endemic regions). Healthy controls were recruited from Mandaramnuwara (nonendemic area). The levels of RBP4 and creatinine in serum were measured. An immunoassay (ELISA) was performed on the serum samples. The stages of CKD/ CKDu were classified according to eGFR. Results: Serum RBP4 was significantly increased in CKDu patients compared to CKD patients and healthy controls. The results show that the ratio of normalized serum RBP4 to serum creatine (S.cr) acts as a better competitive marker for CKDu (AUC 0.762, sensitivity 0.733) than CKD (AUC 0.584, sensitivity 0.733) when compared against healthy controls. Furthermore, the RBP4:S.cr ratio showed higher discriminating power (AUC 0.743) between CKDu and CKD, suggesting that the RBP4: S.cr ratio has potential as a serum marker to differentiate CKDu from CKDu. Conclusion: The RBP4: S.cr ratio was identified as a plausible indicator for differentiating CKDu from CKD with >70% sensitivity and specificity. Therefore, it could be used in the evaluation of the tubular interstitial involvement of CKD.