Part 1:Chronic Interstitial Nephritis in Agricultural Communities Is A Toxin-induced Proximal Tubular Nephropathy
Mar 24, 2022
Contact: Audrey Hu Whatsapp/hp: 0086 13880143964 Email: audrey.hu@wecistanche.com
Benjamin A.Vervaet'， Cynthia C. Nast'， Channa Jayasumana³， Gerd Schreurs'， Frank Roels4， Chula Herath'， Nika Kojc°， Vahid Samaee'， Sonali Rodrigo³，
Swarnalata Gowrishankar， Christiane Mousson, Rajeewa Dassanayake', Carlos M. Orantes1, Vincent Vuiblet 2, Claire Rigothier13 Patrick C. D'Haese' and Marc E. De Broe
'Laboratory of Pathophysiology, University Antwerp, Antwerp, Belgium; 2Cedars-Sinai Medical Center, Los Angeles, California, USA;3Faculty of Medicine, Rajatrata University of Sri Lanka, Anuradhapura, Sri Lanka; 4Department of Pathology, Ghent University, Gent, Belgium; 5Department of Nephrology, Sri Jayewardenepura General Hospital, Colombo, Sri Lanka;°Institute of Pathology, Faculty of Medicine, University of Ljubljana, Ljubljana, Slovenia; 'Electron Microscopy for Materials Science (EMAT), University of Antwerp, Antwerp, Belgium; °Department of Pathology, Apollo Hospitals, Hyderabad, India; >Department of Nephrology, Centre Hospitalier Universitaire de Dijon, Dijon, France; Renal Unit, General Hospital, Polonnaruwa, Sri Lanka;' National Institute of Health, Ministry of Health of EI Salvador, San Salvador, EI Salvador;'Departments of Nephrology and Renal Pathology, Centre Hospitalier Universitaire de Reims, Reims, France; and 13Service Nephrologie, Transplantation, Dialyse et Aphéreses, Centre Hospitalier Universitaire de Bordeaux, Bordeaux, France
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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, EI 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".
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These aggregates are 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 months (50%) and 12 months (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.
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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.
cistanche extract
In the last decade of the 20th century, alert clinicians in Central America and Sri Lanka described a large number of patients in their rural agricultural communities with relatively rapidly progressive chronic kidney disease(CKD)without hypertension or diabetes. Males were predominantly affected, including sugar cane workers in Central America and paddy farmers in Sri Lanka. In Central America, the disease was named"Meso-American Nephropathy"(MeN), whereas in Sri Lanka, "CKD of un-known etiology"(CKDu) was the preferred terminology.
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In light of the comparable clinical, pathological, and epidemiological expression of the disease, the term Chronic Interstitial Nephritis in Agricultural Communities (CINAC)was proposed to describe both entities.2 Classic presentations of CINAC are young men, primarily agri-cultural workers, with common socioeconomic and occupational determinants including a hot tropical climate, poverty, and exposure to potentially toxic agrochemicals through ingestion of contaminated food, drinking water from shallow contaminated wells, inhalation etc.
