Novel urinary biomarkers and their association with urinary heavy metals in chronic kidney disease of unknown aetiology in Sri Lanka: a pilot study

Abstract

Introduction Chronic kidney disease of unknown etiology (CKDu) has emerged as a significant public health problem in Sri Lanka. The role of environmental exposure to cadmium and arsenic in the aetiology of CKDu is still unclear. Identification of a panel of novel urinary biomarkers would be invaluable in the study of toxin mediated damage postulated to be the aetiology of CKDu.Objectives The aims of this study were to evaluate the profile of novel urinary biomarkers in CKDu patients and identify any association with environmental exposure to heavy metals.Methods Thirty seven randomly selected CKDu patients attending a renal clinic in the North Central Province and two control groups namely a farmer group (n=39) and a non-farmer group (n=40) from a non-endemic area were included in this comparative cross sectional study. Urine samples were analyzed for heavy metals and five urinary biomarkers.Results CKDu patients had significantly elevated urinary levels of fibrinogen (198.2 ng/mg creatinine p<0.001), clusterin (3479 ng/mg creatinine p<0.001), cystatin-C (5124.8 ng/mg creatinine p<0.001) and β2-microglobulin (9913.4 ng/mg creatinine p<0.001) compared to the control groups. Fibrinogen and β2-microglobulin were the best to discriminate CKDu patients from normal individuals with the receiver operator areas under the curve being 0.867 and 0.853, respectively. Urinary fibrinogen and KIM-1 levels correlated positively with urinary arsenic levels. KIM-1 levels correlated positively with urinary mercury and lead levels but no correlation was seen with urinary cadmium levels.Conclusions Fibrinogen and β2-microglobulin have the potential of being a screening tool for detection of CKDu and may aid the early diagnosis of toxin mediated tubular injury in CKDu. Their usefulness need to be further validated in a larger epidemiological study of patients with early stages of CKDu. IntroductionChronic kidney disease of unknown aetiology (CKDu), which emerged at the beginning of this century, has reached epidemic proportions in the North Central Dry Zone of Sri Lanka [1,2]. The disease burden is most prominent in the North Central Province and has extended to two adjacent provinces, namely, Uva and North Western provinces. The disease is not due to conventional risk factors such as diabetes, hypertension, chronic glomerulonephritis. The diagnosis of CKDu is based on exclusion of known aetiological factors of chronic kidney disease and presence of tubulo-interstitial pathology on renal biopsy [3,4].The population in the North Central Province is around 2.5 million according to the last census conducted in 2012 and farming is the main livelihood of the majority. CKDu mainly affects farming communities with poor socioeconomic background [5]. The estimated prevalence of CKDu in a community based study was reported as 16.9% in women and 12.9% in men, but the severe stages were seen more frequently in men, leading to a higher mortality and morbidity in men [5,6].Based on CKDu's clinical profile and risk factors, it was postulate...

Evaluation of biochemical profile of Chronic Kidney Disease of uncertain etiology in Sri Lanka

“…Nanayakkara et al (2012) indicated a tubular marker, Alpha 1 microglobulin was elevated in more than 55% of CKDu cases and sensitive marker for early diagnosis and screening [30] and some studies have been described other interstitial nephropathies [31,32]. There were several studies investigating the effectiveness of tubular markers, including KIM1 and NGAL for screening and diagnosis of CKDu [30,[33][34][35]. Even though tubular manifestations like hypokalaemia, hyperuricaemia, renal tubular acidosis, have been described in CKDu [36].…”

Occupational Paraquat and Glyphosate Exposure May Decline Renal Functions among Rural Farming Communities in Sri Lanka

“…The other main limitation is the lack of reference urinary biomarker levels that reflect subclinical damage in Sri Lankan nephropathy which prevents comparison among herbicide exposed and non-exposed farming communities. Despite recent studies [54,82], validation of normal levels of NGAL and KIM-1 in larger populations has not been carried out. Previously, Jayasumana et al (year) reported glyphosate and heavy metals (Cd, & As) as the main etiological factor in CKDu among farmers [27] and were shown to affect KIM-1 expression in an animal model [26].…”

Chronic kidney disease of unknown aetiology in Sri Lanka; a journey to unravel the mystery

“…Urine samples were analyzed for heavy metals and five biomarkers at the Harvard School of Public Health Trace Metals Analysis Laboratory (Boston, USA). 11 Urinary cadmium level in CKDu patients was lower than the farmer control and non farmer control groups [Mean (SD) 0.68 (0.39), 1.32 (1.27), 0.54 (0.31), respectively]. However, the farmer control group had a significantly higher urinary cadmium level (p<0.001) than the other two groups.…”

“…Only 32.4% had albumin-creatinine ratio (ACR) above 300 mg/g creatinine, the level which can be detected by the albustix method. 11 . CKDu patients had significantly elevated urinary levels of fibrinogen (p<0.001), clusterin (p<0.001), cystatin C (p<0.001) and beta-2 microglobulin (nine p<0.001) compared to the control groups.…”

“…The comparison of ROC of biomarker levels revealed that Fibrinogen and β2 microglobulin has the potential of being candidates for use as a screening tool for detection of CKDu. 11 Their usefulness needs to be further validated in patients with early CKDu.…”