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Kidney Week

Abstract: FR-OR095

Chronic Interstitial Nephritis in Agricultural Communities (CINAC): A Toxin-Induced Proximal Lysosomal Tubulopathy

Session Information

Category: CKD (Non-Dialysis)

  • 2101 CKD (Non-Dialysis): Epidemiology, Risk Factors, and Prevention

Authors

  • Vervaet, Benjamin Arthur, University Antwerp, Antwerp, Belgium
  • Nast, Cynthia C., Cedars-Sinai Medical Center, Los Angeles, California, United States
  • Jayasumana, Channa, Faculty of Medicine, Anuradhapura, Sri Lanka
  • Schreurs, Gerd, University of Antwerp, Antwerp, Belgium
  • Roels, Frank, Ghent University, Gent, Belgium
  • Herath, Chulani Aravinda, Sri Jayawardenepura General Hospital, Colombo 5, Sri Lanka
  • Kojc, Nika, Medical faculty Ljubljana, Ljubljana, Slovenia
  • Rodrigo, Anne Sonali, Sri Jayawardenepura General Hospital, Colombo 5, Sri Lanka
  • Gowrishankar, Swarnalata, Apollo Hospitals, Hyderabad, Hyderabad, India
  • Mousson, Christiane I., University Hospital Dijon, Dijon, France
  • Dassanayake, Rajeewa Thilanka, General hospital Polonnaruwa Sri Lanka, Polonnaruwa, Sri Lanka
  • Orantes, Carlos Manuel, National Direction of Non-communicable diseases of Ministry of Health, San Salvador, El Salvador
  • D'Haese, Patrick C., University Antwerp, Antwerp, Belgium
  • De Broe, Marc E., University of Antwerp, Antwerp, Belgium
Background

There is no consensus on the etiology of CINAC. Heat stress/dehydration and toxic exposure are the two most likely etiologies. There are no direct diagnostic criteria to identify CINAC patients.

Methods

Renal CINAC biopsies (18 Sri Lanka, 10 El Salvador, 1 India, 3 France) were examined by light (LM) and electron microscopy (EM) in comparison to 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 compared histopathology of heat stress with cyclosporine nephrotoxicity.

Results

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 lesions were observed in 55-80% of renal transplant protocol biopsies at 6 and 12 months of CNI therapy and in indication biopsies. In implantation biopsies the prevalence was 6%. Several cases of nephrotoxic drugs (lomustine, clomiphene, lithium) and some patients with light chain disease, all conditions linkable to CNI, presented the same lesion. Controls (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 by EM. Rats treated with cyclosporine for 4 weeks developed similar PTC lysosomal alterations, that were 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 indirect effect of pesticides.