IntroductionChronic 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.MethodsA 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.ResultsA 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.ConclusionIn 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.

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Aim Anaemia is a well‐known complication of chronic kidney disease but there are no published studies on the pattern of anaemia in chronic kidney disease of uncertain aetiology (CKDu). This study aims to find out the prevalence, causes and associations of anaemia in CKDu to identify any unique features which are different from already described anaemia in chronic kidney disease. Method All (119) biopsy‐confirmed CKDu patients in two endemic clinics (Girandurukotte and Wilgamuwa) were selected as cases. Blood samples (10 mL) were collected from the peripheral veins into Potassium‐Ethylenediaminetetraacetic acid (K‐EDTA) tubes, plain tubes and Na‐citrated tubes. Serum was separated immediately by centrifugation at 3000 rpm for 10 min. Spot urine samples were collected into empty, sterile, polypropylene urine containers. All analyses were performed in IBM spss statistics version 23 (IBM Corp, Armonk, New York). Results The overall prevalence of anaemia in 119 non‐dialysis CKDu patients was 72.3% with the highest prevalence seen in females compared to males (P < 0.001). The prevalence of anaemia in CKDu patients with progression to renal failure was 66.7% – stage 1, 60% – stage 2, 50% – stage 3a, 95% – stage 3b, 79.2% – stage 4 and 100% – stage 5 (P = 0.005). Of CKDu patients, 44.3% had anaemia of chronic disease with iron deficiency. CKDu patients with anaemia had a high inflammatory score were seen in both early and late stages of CKDu. There were a similar proportion of patients with both early and late CKDu having unexplained anaemia. Conclusion The current study showed a significant association of anaemia with disease severity among CKDu patients. Iron deficiency is a crucial aetiology factor of anaemia in CKDu and inflammation likely to effects adversely on anaemia of CKDu.

Chronic Kidney Disease of uncertain etiology (CKDu) is an endemic, disease that mostly affects young agricultural workers in the rural dry zone of Sri Lanka. This study was designed to identify specific biochemical manifestations of CKDu cases. All (119) nondialysis definite CKDu patients in Girandurukotte and Wilgamuwa were selected. Blood and urine samples were collected and measured biochemical parameters. All analyses were performed in IBM SPSS statistics version 23 (IBM Corp, USA). The median blood pressure was normal though nearly half of the patients (45.4%) who were in the advanced stages (Stage 3b, 4 and 5) of CKDu. Patients without a history of hypertension before the diagnosis of CKDu (100%) and minimal proteinuria (26%) are similar to the previous findings. Patients without a history of diabetes before the CKDu diagnosis had high percentages of diabetes (15.7%) and pre-diabetes (59.8%) and hence indicated the possibility of uremia induced impaired glucose intolerance in the rural areas of the country. There were 62.2% patients who had low vitamin D and only a minority had evidence of bone mineral diseases. Out of liver disease markers serum glutamic pyruvic transaminases (SGPT), serum glutamic oxaloacetic transaminases (SGOT), gamma-glutamyl transferase (GGT), and Lactic acid degydrogenase (LDH) had an inverse correlation with the advancement of the disease indicating subclinical liver disease. Osmolality in serum and urine showed a discrepancy despite > 50% of CKDu patients had increased their serum osmolality. The current study supports most of the previously described manifestations of CKDu. Moreover, some specific patterns have been identified which need to be validated in a larger group.

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.