A comparative study on renal biopsy before and after long-term calcineurin inhibitors therapy: an insight for pathogenesis of its toxicity - PubMed

Comparative Study

A comparative study on renal biopsy before and after long-term calcineurin inhibitors therapy: an insight for pathogenesis of its toxicity

Lavleen Singh et al. Hum Pathol. 2015 Jan.

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.

Keywords: Calcineurin inhibitor--induced nephrotoxicity; Immunohistochemistry; Protocol renal biopsy; Steroid-resistant nephrotic syndrome; Time zero biopsy.

Similar articles

• Early withdrawal of calcineurin inhibitor from a sirolimus-based immunosuppression stabilizes fibrosis and the transforming growth factor-β signalling pathway in kidney transplant.

  Rivelli RF, Gonçalves RT, Leite M Jr, Santos MA, Delgado AG, Cardoso LR, Takiya CM. Rivelli RF, et al. Nephrology (Carlton). 2015 Mar;20(3):168-76. doi: 10.1111/nep.12368. Nephrology (Carlton). 2015. PMID: 25404086 Clinical Trial.

• Calcineurin Inhibitor Nephrotoxicity Through the Lens of Longitudinal Histology: Comparison of Cyclosporine and Tacrolimus Eras.

  Nankivell BJ, PʼNg CH, OʼConnell PJ, Chapman JR. Nankivell BJ, et al. Transplantation. 2016 Aug;100(8):1723-31. doi: 10.1097/TP.0000000000001243. Transplantation. 2016. PMID: 27306529

• Chronic allograft dysfunction: can we use mammalian target of rapamycin inhibitors to replace calcineurin inhibitors to preserve graft function?

  Wali RK, Weir MR. Wali RK, et al. Curr Opin Organ Transplant. 2008 Dec;13(6):614-21. doi: 10.1097/MOT.0b013e3283193bad. Curr Opin Organ Transplant. 2008. PMID: 19060552 Review.

• Calcineurin inhibitors and nephrotoxicity in children.

  Liu F, Mao JH. Liu F, et al. World J Pediatr. 2018 Apr;14(2):121-126. doi: 10.1007/s12519-018-0125-y. Epub 2018 Mar 12. World J Pediatr. 2018. PMID: 29532435 Review.

Cited by

• Early Minocycline and Late FK506 Treatment Improves Survival and Alleviates Neuroinflammation, Neurodegeneration, and Behavioral Deficits in Prion-Infected Hamsters.

  Shah SZA, Zhao D, Taglialatela G, Khan SH, Hussain T, Dong H, Lai M, Zhou X, Yang L. Shah SZA, et al. Neurotherapeutics. 2017 Apr;14(2):463-483. doi: 10.1007/s13311-016-0500-0. Neurotherapeutics. 2017. PMID: 28083805 Free PMC article. Retracted.

• IPNA clinical practice recommendations for the diagnosis and management of children with steroid-resistant nephrotic syndrome.

  Trautmann A, Vivarelli M, Samuel S, Gipson D, Sinha A, Schaefer F, Hui NK, Boyer O, Saleem MA, Feltran L, Müller-Deile J, Becker JU, Cano F, Xu H, Lim YN, Smoyer W, Anochie I, Nakanishi K, Hodson E, Haffner D; International Pediatric Nephrology Association. Trautmann A, et al. Pediatr Nephrol. 2020 Aug;35(8):1529-1561. doi: 10.1007/s00467-020-04519-1. Epub 2020 May 7. Pediatr Nephrol. 2020. PMID: 32382828 Free PMC article. Review.

• Cyclosporine A induced histological changes of Cathepsin L and CD2AP expression in renal glomeruli and tubules.

  Sugimoto K, Miyazawa T, Enya T, Miyazaki K, Okada M, Takemura T. Sugimoto K, et al. Clin Exp Nephrol. 2017 Feb;21(1):83-91. doi: 10.1007/s10157-016-1257-9. Epub 2016 Mar 14. Clin Exp Nephrol. 2017. PMID: 26975192

• The exacerbated hypokalemia in membranous glomerulonephritis due to proximal tubular injury: a neglect issue from a case report and literature review.

  Chang CH, Yu HJ, Hou YC. Chang CH, et al. BMC Nephrol. 2023 Apr 15;24(1):98. doi: 10.1186/s12882-023-03130-4. BMC Nephrol. 2023. PMID: 37061666 Free PMC article. Review.

• Calcineurin A-α suppression drives nuclear factor-κB-mediated NADPH oxidase-2 upregulation.

  Cheriyan AM, Ume AC, Francis CE, King KN, Linck VA, Bai Y, Cai H, Hoover RS, Ma HP, Gooch JL, Williams CR. Cheriyan AM, et al. Am J Physiol Renal Physiol. 2021 May 1;320(5):F789-F798. doi: 10.1152/ajprenal.00254.2020. Epub 2021 Feb 22. Am J Physiol Renal Physiol. 2021. PMID: 33615888 Free PMC article.

Publication types

MeSH terms

Substances

Supplementary concepts

LinkOut - more resources

• Full Text Sources

  • ClinicalKey
  • Elsevier Science

• Medical

  • MedlinePlus Health Information

• Research Materials

  • NCI CPTC Antibody Characterization Program

• Miscellaneous

  • NCI CPTAC Assay Portal