Dataset Information

A Systematic Review of Renal Pathology in Chronic Kidney Disease of Uncertain Etiology.

ABSTRACT:

Introduction

Despite much research on chronic kidney disease of uncertain etiology (CKDu) in Sri Lanka and the Mesoamerican nephropathy, the etiology and pathogenesis of this disease remains elusive. The pathology has broadly been described as chronic tubulointerstitial nephritis and no specific signature lesions have been identified.

Methods

A scoping review was conducted through MEDLINE and Google Scholar databases for peer-reviewed publications on biopsy studies related to CKDu - Sri Lanka and Mesoamerican nephropathy to develop a comparative and critical analysis of the renal pathology found in these patients.

Results

Thirteen studies met the selection criteria. Interstitial fibrosis was the predominant lesion in all the studies. Tubulointerstitial and glomerular abnormalities showed a more variable distribution. No characteristic histopathological feature was reported other than a proximal tubular lysosomal inclusion body which was claimed to indicate a toxic etiology. Three main pathogenetic mechanisms were postulated: repeated acute insults leading to scarring, low-grade chronic insults leading to non-inflammatory fibrosis, and tubulointerstitial damage in combination with glomerular injury. The main limitations in the interpretation and comparative analysis of these studies were the heterogeneity in case selection and biopsy reporting.

Conclusions

Although no characteristic histopathological feature could be found in CKDu-Sri Lanka or Mesoamerican nephropathy, there are noticeable differences between these two groups in the frequency and severity of the glomerular and tubulointerstitial changes which warrant more explorative studies preferably on kidneys in early stages of the disease. Future strategies should ensure that more uniform selection criteria and reporting methods are used.

SUBMITTER: Gunawardena S

PROVIDER: S-EPMC8207327 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:The main causes of chronic kidney disease (CKD) globally are diabetes and hypertension but epidemics of chronic kidney disease of unknown etiology (CKDu) occur in Central America, Sri Lanka, India and beyond. Althoug also being observed in women, CKDu concentrates among men in agricultural sectors. Therefore, suspicions fell initially on pesticide exposure, but currently chronic heat stress and dehydration are considered key etiologic factors. Responding to persistent community and scientific concerns about the role of pesticides, we performed a systematic review of epidemiologic studies that addressed associations between any indicator of pesticide exposure and any outcome measure of CKD. Of the 21 analytical studies we identified, seven were categorized as with low, ten with medium and four with relatively high explanation value. Thirteen (62%) studies reported one or more positive associations, but four had a low explanation value and three presented equivocal results. The main limitations of both positive and negative studies were unspecific and unquantified exposure measurement ('pesticides'), the cross-sectional nature of most studies, confounding and selection bias. The four studies with stronger designs and better exposure assessment (from Sri Lanka, India and USA) all showed exposure-responses or clear associations, but for different pesticides in each study, and three of these studies were conducted in areas without CKDu epidemics. No study investigated interactions between pesticides and other concommittant exposures in agricultural occupations, in particular heat stress and dehydration. In conclusion, existing studies provide scarce evidence for an association between pesticides and regional CKDu epidemics but, given the poor pesticide exposure assessment in the majority, a role of nephrotoxic agrochemicals cannot be conclusively discarded. Future research should procure assessment of lifetime exposures to relevant specific pesticides and enough power to look into interactions with other major risk factors, in particular heat stress.

Project description:Chronic Kidney Disease of uncertain etiology (CKDu) is an emerging epidemic among farming communities in rural Sri Lanka. Victims do not exhibit common causative factors, however, histopathological studies revealed that CKDu is a tubulointerstitial disease. Urine albumin or albumin-creatinine ratio is still being used as a traditional diagnostic tool to identify CKDu, but accuracy and prevalence data generated are questionable. Urinary biomarkers have been used in similar nephropathy and are widely recognised for their sensitivity, specificity and accuracy in determining CKDu and early renal injury. However, these biomarkers have never been used in diagnosing CKDu in Sri Lanka. Male farmers (n = 1734) were recruited from 4 regions in Sri Lanka i.e. Matara and Nuwara Eliya (farming locations with no CKDu prevalence) and two CKDu emerging locations from Hambantota District in Southern Sri Lanka; Angunakolapelessa (EL1) and Bandagiriya (EL2). Albuminuria (ACR ≥ 30mg/g); serum creatinine based estimation of glomerular filtration rate (eGFR); creatinine normalized urinary kidney injury molecule (KIM-1) and neutrophil gelatinase-associated lipocalin (NGAL) were measured. Fourteen new CKDu cases (18%) from EL1 and nine CKDu cases (9%) from EL2 were recognized for the first time from EL1, EL2 locations, which were previously considered as non-endemic of the disease and associated with persistent albuminuria (ACR ≥ 30mg/g Cr). No CKDu cases were identified in non-endemic study locations in Matara (CM) and Nuwara Eliya (CN). Analysis of urinary biomarkers showed urinary KIM-1 and NGAL were significantly higher in new CKDu cases in EL1 and EL2. However, we also reported significantly higher KIM-1 and NGAL in apparently healthy farmers in EL 1 and EL 2 with comparison to both control groups. These observations may indicate possible early renal damage in absence of persistent albuminuria and potential capabilities of urinary KIM-1 and NGAL in early detection of renal injury among farming communities in Southern Sri Lanka.