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Abstract: TH-PO425

Electron Microscopic Description of a Sensitive Diagnostic Proximal Tubular Lysosomal Lesion in Patients with CINAC/CKDu/MeN and Calcineurin Inhibitor Nephrotoxicity

Session Information

Category: CKD (Non-Dialysis)

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

Authors

  • Vervaet, Benjamin Arthur, University of Antwerp, Antwerp, Belgium
  • Nast, Cynthia C., Cedars-Sinai Medical Center, Los Angeles, California, United States
  • Schreurs, Gerd, University of Antwerp, Antwerp, Belgium
  • Jayasumana, Channa, Faculty of Medicine, Anuradhapura, Sri Lanka
  • 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 of Antwerp, Antwerp, Belgium
  • De Broe, Marc E., University of Antwerp, Antwerp, Belgium
Background

In Sri Lankan CINAC patients, we observed a constellation of proximal tubular cell findings including cellular/tubular atrophy, cell fragment shedding and the presence of an increased number of enlarged lysosomes. Here we define the EM lysosomal phenotype and evaluate its presence in CINAC/MeN/CKDu cases and controls.

Methods

Renal biopsies (18 Sri Lanka, 10 El Salvador, 1 India, 3 France) of patients with a diagnosis of CINAC (CKD 1-3A, 3B) were examined by electron microscopy (EM) in comparison to renal biopsies of normal kidneys at implantation, patients with calcineurin inhibitor (CNI) toxicity (n=17), proteinuric nephropathies (n=15), light chain disease (n=4), cases on nephrotoxic drugs (lomustine, clomiphene, lithium, tenofovir, cisplatinum) and patients with reduced renal function of various causes (n=20).

Results

The aberrant lysosomal phenotype can be defined as enlarged (>1.2µm) and dysmorphic with a light-medium electron-dense matrix containing dispersed dark electron-dense non-membrane bound “aggregates”. Clusters of 4-6 smaller lysosomes with the same features could be observed. No cristae or other features of mitochondria, autophagic vacuoles, lipofuscin/ceroid droplets, peroxisomes, myeloid bodies or laminated inclusions were observed. Patients with CNI nephrotoxicity and several nephrotoxic cases (lomustine, clomiphene, lithium) and a subset light chain disease patients, all conditions directly or indirectly linked to calcineurin inhibition, presented the same lesions. We present an image set of the consistency of the diagnostic lysosomal lesion versus similar non-diagnostic features.

Conclusion

A rather sensitive constellation of lysosomal lesions in renal proximal tubular cells was detected associated with CINAC/CKDu/MeN and CNI nephrotoxicity in several countries, suggesting a common pathomechanistic paradigm where CINAC patients are experiencing a tubulotoxic mechanism similar to CNI nephrotoxicity.

Funding

  • Government Support - Non-U.S.