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Kidney Int. 2020 Feb;97(2):350-369. doi: 10.1016/j.kint.2019.11.009. Epub 2019 Nov 23.

Chronic interstitial nephritis in agricultural communities is a toxin-induced proximal tubular nephropathy.

Author information

1
Laboratory of Pathophysiology, University Antwerp, Antwerp, Belgium. Electronic address: benjamin.vervaet@uantwerpen.be.
2
Cedars-Sinai Medical Center, Los Angeles, California, USA.
3
Faculty of Medicine, Rajatrata University of Sri Lanka, Anuradhapura, Sri Lanka.
4
Laboratory of Pathophysiology, University Antwerp, Antwerp, Belgium.
5
Department of Pathology, Ghent University, Gent, Belgium.
6
Department of Nephrology, Sri Jayewardenepura General Hospital, Colombo, Sri Lanka.
7
Institute of Pathology, Faculty of Medicine, University of Ljubljana, Ljubljana, Slovenia.
8
Electron Microscopy for Materials Science (EMAT), University of Antwerp, Antwerp, Belgium.
9
Department of Pathology, Apollo Hospitals, Hyderabad, India.
10
Department of Nephrology, Centre Hospitalier Universitaire de Dijon, Dijon, France.
11
Renal Unit, General Hospital, Polonnaruwa, Sri Lanka.
12
National Institute of Health, Ministry of Health of El Salvador, San Salvador, El Salvador.
13
Departments of Nephrology and Renal Pathology, Centre Hospitalier Universitaire de Reims, Reims, France.
14
Service Néphrologie, Transplantation, Dialyse et Aphérèses, Centre Hospitalier Universitaire de Bordeaux, Bordeaux, France.
15
Laboratory of Pathophysiology, University Antwerp, Antwerp, Belgium. Electronic address: marc.debroe@uantwerpen.be.

Abstract

Almost 30 years after the detection of chronic interstitial nephritis in agricultural communities (CINAC) its etiology remains unknown. To help define this we examined 34 renal biopsies from Sri Lanka, El Salvador, India and France of patients with chronic kidney disease 2-3 and diagnosed with CINAC by light and electron microscopy. In addition to known histopathology, we identified a unique constellation of proximal tubular cell findings including large dysmorphic lysosomes with a light-medium electron-dense matrix containing dispersed dark electron-dense non-membrane bound "aggregates". These aggregates associated with varying degrees of cellular/tubular atrophy, apparent cell fragment shedding and no-weak proximal tubular cell proliferative capacity. Identical lysosomal lesions, identifiable by electron microscopy, were observed in 9% of renal transplant implantation biopsies, but were more prevalent in six month (50%) and 12 month (67%) protocol biopsies and in indication biopsies (76%) of calcineurin inhibitor treated transplant patients. The phenotype was also found associated with nephrotoxic drugs (lomustine, clomiphene, lithium, cocaine) and in some patients with light chain tubulopathy, all conditions that can be directly or indirectly linked to calcineurin pathway inhibition or modulation. One hundred biopsies of normal kidneys, drug/toxin induced nephropathies, and overt proteinuric patients of different etiologies to some extent could demonstrate the light microscopic proximal tubular cell changes, but rarely the electron microscopic lysosomal features. Rats treated with the calcineurin inhibitor cyclosporine for four weeks developed similar proximal tubular cell lysosomal alterations, which were absent in a dehydration group. Overall, the finding of an identical proximal tubular cell (lysosomal) lesion in CINAC and calcineurin inhibitor nephrotoxicity in different geographic regions suggests a common paradigm where CINAC patients undergo a tubulotoxic mechanism similar to calcineurin inhibitor nephrotoxicity.

KEYWORDS:

CKD lysosomes; agrochemicals; calcineurin inhibition; diagnosis; proximal tubule

PMID:
31892415
DOI:
10.1016/j.kint.2019.11.009
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