title: A comparative study on renal biopsy before and after long-term calcineurin inhibitors therapy: an insight for pathogenesis of its toxicity.
abstract: Calcineurin inhibitors (CNIs) are effective immunosuppressive agents for the successful treatment of childhood steroid-resistant nephrotic syndrome (SRNS). Because these patients require long-term treatment, the identification of early markers of CNI-induced nephrotoxicity (CNIN) is imperative. The monitoring of CNI trough levels, serum creatinine, and glomerular filtration rate is not an accurate marker of CNIN. The present study has been undertaken to identify early markers of CNIN in SRNS patients. Twenty-four pediatric SRNS patients were included with paired renal biopsies, before initiation (time zero biopsy) and at least 1 year after CNI therapy (protocol renal biopsy) with standard dosage. Semiquantitative morphologic grading of the histologic features was done for assessing CNIN. Immunohistochemical markers for oxidative stress (nitrotyrosine [NT]), fibrogenic cytokine (transforming growth factor β1 [TGF-β1]), and endothelial injury (endothelial nitric oxide synthase [eNOS]) were evaluated. In addition, ultrastructural study was done to assess mitochondrial injury in endothelial and tubular epithelial cells. The protocol renal biopsies in comparison with time zero biopsies showed significant increase in glomerulosclerosis, juxtaglomerular apparatus hyperplasia, tubular atrophy, interstitial fibrosis, arteriolar hyalinosis, and smooth muscle vacuolization (P < .05 - P < .001). Significantly higher immunoexpression of eNOS (91.6%), NT (71%), and TGF-β1 (87.5%) was noted in posttreatment biopsies. Mean mitochondrial injury grade among post-CNI cases in endothelial cells and proximal tubular cells was 2.28 and 1.4, whereas in pre-CNI, it was 0.28 and 0.27, respectively. We propose that immunohistochemical overexpression of NT, eNOS, and TGF-β1 is an early marker of CNIN. Endothelial and proximal tubular mitochondrial injury may play an important role in the pathogenesis of CNIN.
authors.affiliation: Department of Pathology, AIIMS, New Delhi, India 110029. Electronic address: singhlavleen04@gmail.com.
authors.forename: Lavleen
authors.initials: L
authors.lastname: Singh
authors.affiliation: Department of Pathology, AIIMS, New Delhi, India 110029. Electronic address: ggmed22@gmail.com.
authors.forename: Geetika
authors.initials: G
authors.lastname: Singh
authors.affiliation: Department of Pathology, AIIMS, New Delhi, India 110029. Electronic address: dralok.path@gmail.com.
authors.forename: Alok
authors.initials: A
authors.lastname: Sharma
authors.affiliation: Department of Pediatrics, AIIMS, New Delhi, India 110029. Electronic address: aditisinhaaiims@gmail.com.
authors.forename: Aditi
authors.initials: A
authors.lastname: Sinha
authors.affiliation: Department of Pediatrics, AIIMS, New Delhi, India 110029. Electronic address: arvindbagga@hotmail.com.
authors.forename: Arvind
authors.initials: A
authors.lastname: Bagga
authors.affiliation: Department of Pathology, AIIMS, New Delhi, India 110029. Electronic address: dindaaiims@gmail.com.
authors.forename: A K
authors.initials: AK
authors.lastname: Dinda
mesh_terms: D000293:Adolescent; D001284:Atrophy; D015415:Biomarkers / Q000378:metabolism; D001706:Biopsy; D065095:Calcineurin Inhibitors / Q000009:adverse effects*; D002648:Child; D002675:Child, Preschool; D042241:Early Diagnosis; D042783:Endothelial Cells / Q000187:drug effects / Q000378:metabolism / Q000648:ultrastructure; D005260:Female; D005355:Fibrosis; D006801:Humans; D006965:Hyperplasia; D007150:Immunohistochemistry; D007166:Immunosuppressive Agents / Q000009:adverse effects*; D007223:Infant; D007668:Kidney / Q000187:drug effects* / Q000378:metabolism / Q000648:ultrastructure; D007674:Kidney Diseases / Q000139:chemically induced* / Q000378:metabolism / Q000473:pathology; D007687:Kidney Tubules, Proximal / Q000187:drug effects / Q000378:metabolism / Q000648:ultrastructure; D008297:Male; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism / Q000648:ultrastructure; D009404:Nephrotic Syndrome / Q000151:congenital* / Q000188:drug therapy / Q000473:pathology; D052250:Nitric Oxide Synthase Type III / Q000378:metabolism; D018384:Oxidative Stress / Q000187:drug effects; D011237:Predictive Value of Tests; D013997:Time Factors; D053773:Transforming Growth Factor beta1 / Q000378:metabolism; D016896:Treatment Outcome; D014443:Tyrosine / Q000031:analogs & derivatives / Q000378:metabolism; D015854:Up-Regulation
chemical_list: D015415:Biomarkers; D065095:Calcineurin Inhibitors; D007166:Immunosuppressive Agents; C508960:TGFB1 protein, human; D053773:Transforming Growth Factor beta1; C002744:3-nitrotyrosine; D014443:Tyrosine; C496314:NOS3 protein, human; D052250:Nitric Oxide Synthase Type III
keywords: Calcineurin inhibitor--induced nephrotoxicity; Immunohistochemistry; Protocol renal biopsy; Steroid-resistant nephrotic syndrome; Time zero biopsy