Screening for chronic kidney disease of uncertain aetiology in Sri Lanka: usability of surrogate biomarkers over dipstick proteinuria

Abstract

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.

Pilot Study of Renal Urinary Biomarkers for Diagnosis of CKD of Uncertain Etiology

“…For example, CST3 is reported to better predict the clinical outcomes of CKD than creatinine 20 . More recently, CST3 was also reported to show a higher efficacy in detecting CKDu in endemic regions 14 . On screening a set of 8 selected biomarkers, we found that not all markers perform uniformly well across all groups.…”

“…These tests are highly sensitive in the early stages of proteinuric CKD, and are cost-effective for community screening 13 . However, the applicability of these tests is limited in diagnosing early CKDu, owing to the minimally proteinuric nature of this disease 14 . Another marker, serum creatinine is a routine test for assessing renal function.…”

“…This suggests that the serum creatinine test may not be ideal for detection of early kidney damage. In comparison with serum creatinine and albumin creatinine ratio, serum CST3 has been reported as a good functional marker for CKDu 14 . Urine is considered an excellent source for biomarkers, as markers resulting from pathophysiological processes in the kidney are directly “deposited” in the urine.…”

A pilot study of behavioral, environmental, and occupational risk factors for chronic kidney disease of unknown etiology in Sri Lanka

“…The appearance and progression of CKDu can involve non-specific symptoms, making the disease challenging to diagnose in the early, pre-clinical stages limiting the population of cases in this study to those that were in advanced stages of the disease. Studies suggest using more sensitive methods for detecting early CKDu, with measurement of microalbuminuria and functional markers such as Cyst C, creatinine or tubular proteins like RBP4, NGAL or KIM would be beneficial in capturing a greater number of early-stage CKDu cases so that exposures can be better assessed and treatment initiated earlier [64-66].…”

A Pilot Case-Control Study Using a One Health Approach to Evaluate Behavioral, Environmental, and Occupational Risk Factors for Chronic Kidney Disease of Unknown Etiology in Sri Lanka

“…The appearance and progression of CKDu can involve non-speci c symptoms, making the disease challenging to diagnose in the early, pre-clinical stages limiting the population of cases in this study to those that were in advanced stages of the disease. Studies suggest using more sensitive methods for detecting early CKDu, with measurement of microalbuminuria and functional markers such as Cystain C, creatinine or tubular proteins like RBP4, NGAL or KIM would be bene cial in capturing a greater number of early-stage CKDu cases so that exposures can be better assessed and treatment initiated earlier [64][65][66].…”