Mo063chronic Interstitial Nephritis in Agricultural Communities Is a Toxin-Induced Proximal Tubular Nephropathy

Abstract

Background and Aims 30 years after the detection of CINAC, there is no consensus on its etiology. Heat stress/dehydration and toxic exposure are the two most likely etiologies. There are no diagnostic criteria that can directly identify CINAC patients. Method Renal biopsies (RB) (18 Sri Lanka, 10 El Salvador, 1 India, 3 France) of patients with CINAC (CKD2-3) were examined by light (LM) and electron microscopy (EM) in comparison to RB of normal kidneys at implantation and 6 and 12 months of calcineurin inhibitor (CNI) therapy, transplant patients on CNI with indication biopsies (n=24), proteinuric nephropathies (n=15), light chain disease (n=4), cases on nephrotoxic drugs (lomustine, clomiphene, lithium, tenofovir, cisplatinum) and CKD of various causes (n=20). A rat study was conducted comparing histopathology of heat stress/dehydration with cyclosporine nephrotoxicity. Results In addition to previously described histopathological changes, there was a unique constellation of proximal tubular cell (PTC) findings: cellular/tubular atrophy, cell fragment shedding, weak to non-proliferative capacity of the PTC and dysmorphic lysosomes increased in size and number with a light-medium electron-dense matrix containing dispersed dark electron-dense non-membrane bound “aggregates”. Identical renal lesions were observed in 55-80% of renal transplant protocol biopsies taken after 6 and 12 months of calcineurin inhibitor (CNI) therapy and in indication biopsies, in implantation biopsies the prevalence was 6%. Several cases of nephrotoxic drugs (lomustine, clomiphene, lithium) and a subset of patients with light chain disease, all conditions that can be linked to CNI, presented the same lesion. Control RBs (n=66) of normal kidney, toxic nephropathies (tenofovir, cisplatinum), and overt proteinuric patients of different etiology to some extent could demonstrate the tubular cell changes observed by LM, but not or very rarely those that were observed by EM. Rats treated with cyclosporine for 4 weeks developed similar PTC lysosomal alterations, absent in a dehydration group. Conclusion A sensitive constellation of renal PTC lesions was detected associated with CINAC and CNI nephrotoxicity in several countries, suggesting a common new paradigm where CINAC patients are experiencing a tubulotoxic mechanism similar to CNI nephrotoxicity, the latter also being known as a direct or suggested indirect effect of pesticides.

Is an Environmental Nephrotoxin the Primary Cause of CKDu (Mesoamerican Nephropathy)? PRO

“…CINAC, MeN, and CKDu from different regions (Sri Lanka, El Salvador, India, and France) express the same morphologic lesions, epidemiologic profiles, and clinical manifestations, indicating a comparable renal disease around the globe (7). A CINAC histopathologic constellation of lesions has been identified to be useful in routine investigation of renal biopsies of patients clinically suspected of CINAC, provided they meet the specific morphologic criteria (7).…”

“…According to M. Haas on our recent study (7,32): "Although multiple questions remain, related to the pathways involved in this toxic nephropathy, to the possible treatment/reversibility of CINAC as well as its prevention, the study from Vervaet and coworkers represents an important step forward in our understanding of this devastating condition, and one that will undoubtedly stimulate additional investigation" and animate debates.…”

Environmental Risks to Kidney Health

“…Vervaet et al (10) have recently published another potential technique for identifying chemical nephrotoxicity. Although several biopsy series in patients with CKDu have been published, these investigators have expanded on these biopsy studies.…”