CKDu may be preceded by an acute episode of tubulointerstitial nephritis (TIN).

Background and objectives A kidney disease of unknown cause is common in Sri Lanka's lowland (dry) region. Detailed clinical characterizations of patients with biopsy-proven disease are limited, and there is no current consensus on criteria for a noninvasive diagnosis. Design, setting, participants, & measurements We designed a prospective study in a major Sri Lankan hospital servicing endemic areas to ascertain pathologic and clinical characteristics of and assess risk factors for primary tubulointerstitial kidney disease. We used logistic regression to determine whether common clinical characteristics could be used to predict the presence of primary tubulointerstitial kidney disease on kidney biopsy. Results From 600 new patients presenting to a tertiary nephrology clinic over the course of 1 year, 87 underwent kidney biopsy, and 43 (49%) had a biopsy diagnosis of primary tubulointerstitial kidney disease. On detailed biopsy review, 13 (30%) had evidence of moderate to severe active kidney disease, and six (15%) had evidence of moderate to severe chronic tubulointerstitial kidney disease. Patients with tubulointerstitial kidney disease were exclusively born in endemic provinces; 91% spent a majority of their lifespan there. They were more likely men and farmers (risk ratio, 2.0; 95% confidence interval, 1.2 to 2.9), and they were more likely to have used tobacco (risk ratio, 1.7; 95% confidence interval, 1.0 to 2.3) and well water (risk ratio, 1.5; 95% confidence interval, 1.1 to 2.0). Three clinical characteristics-age, urine dipstick for protein, and serum albumin-could predict likelihood of tubulointerstitial kidney disease on biopsy (model sensitivity of 79% and specificity of 84%). Patients referred for kidney biopsy despite comorbid diabetes or hypertension did not experience lower odds of tubulointerstitial kidney disease. Conclusions A primary tubulointerstitial kidney disease occurs commonly in specific regions of Sri Lanka with characteristic environmental and lifestyle exposures.

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.

BackgroundThe 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.MethodsForty-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.ResultsIn 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.ConclusionsAmongst 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.

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.

23Mobile. +260 96 3088750 | +1 936-661-6885 24 ABSTRACT 25 Chronic kidney disease of unknown etiology (CKDu) was first recognized in Sri Lanka in the early 26 1990s, and since then it has reached epidemic levels in the North Central Province of the country.27 The prevalence of CKDu is reportedly highest among communities that engage in chena and paddy 28 farming, which is most often practiced in the dry zone including the North Central and East Central 29 Provinces of Sri Lanka. Previous studies have suggested varied hypotheses for the etiology of 30 CKDu; however, there is not yet a consensus on the primary risk factors, possibly due to disparate 31 study designs, sample populations, and methodologies. The goal of this pilot case-control study 32 was to evaluate the relationships between key demographic, cultural, and occupational variables 33 as risk factors for CKDu, with a primary interest in pesticide exposure both occupationally and 34 through its potential use as an ingredient in brewed kasippu alcohol. A total of 56 CKDu cases 35 and 54 control individuals were surveyed using a proctored, self-reported questionnaire. 36 Occupational pesticide exposure and alcohol consumption were not found to be significant risk 37 factors for CKDu. However, a statistically significant association with CKDu was observed with 38 chewing betel (OR: 6.11, 95% CI: 1.93, 19.35), age (OR: 1.07, 95% CI: 1.02, 1.13), owning a pet 39 dog (OR: 3.74, 95% CI: 1.38, 10.11), water treatment (OR: 3.68, 95% CI: 1.09, 12.43) and pests 40 in the house (OR: 5.81, 95% CI: 1.56, 21.60). The findings of this study suggest future research 41 should focus on practices associated with chewing betel, potential animal interactions including 42 pests in the home and pets, and risk factors associated with water.

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.

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