Retrospective Study
Copyright ©The Author(s) 2019. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Transplant. Oct 28, 2019; 9(6): 123-133
Published online Oct 28, 2019. doi: 10.5500/wjt.v9.i6.123
Histopathological characteristics and causes of kidney graft failure in the current era of immunosuppression
Sandesh Parajuli, Fahad Aziz, Neetika Garg, Sarah E Panzer, Emily Joachim, Brenda Muth, Maha Mohamed, Justin Blazel, Weixiong Zhong, Brad C Astor, Didier A Mandelbrot, Arjang Djamali
Sandesh Parajuli, Fahad Aziz, Neetika Garg, Sarah E Panzer, Emily Joachim, Brenda Muth, Maha Mohamed, Justin Blazel, Brad C Astor, Didier A Mandelbrot, Arjang Djamali, Division of Nephrology, Department of Medicine, University of Wisconsin, Madison, WI 53705, United States
Weixiong Zhong, Department of Pathology, University of Wisconsin, Madison, WI 53705, United States
Brad C Astor, Department of Population Health Sciences, University of Wisconsin, Madison, WI 53705, United States
Arjang Djamali, Division of Transplantation, Department of Surgery, University of Wisconsin, Madison, WI 53705, United States
Author contributions: Parajuli S and Djamali S had an original idea, designed the study, analyzed the data, prepared the manuscript; Aziz F, Garg N, Panzer SE, Joachim E, Muth B, Mohamed M, Blazel J, Zhong W, Astor BC, and Mandelbrot DA analyzed the data and edited the manuscript.
Institutional review board statement: This study was approved by the Health Sciences Institutional Review Board at the University of Wisconsin.
Informed consent statement: Waiver of informed consent obtained due to: (1) The study involves no more than minimal risk to the subjects; (2) The waiver will not adversely affect the rights and welfare of the subjects; (3) The study could not practicably be carried out without the waiver.
Conflict-of-interest statement: The authors have no financial disclosures.
Open-Access: This is an open-access article that was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/
Corresponding author: Sandesh Parajuli, MBBS, MBBS, MD, Assistant Professor, Division of Nephrology, Department of Medicine, University of Wisconsin, 4175 UW Medical Foundation Centennial Building, 1685 Highland Avenue, Madison, WI 53705, United States. sparajuli@medicine.wisc.edu
Telephone: +1-608-2650152
Received: June 6, 2019
Peer-review started: June 9, 2019
First decision: August 2, 2019
Revised: September 17, 2019
Accepted: October 2, 2019
Article in press: October 2, 2019
Published online: October 28, 2019
Processing time: 145 Days and 5.3 Hours
ARTICLE HIGHLIGHTS
Research background

Although, there have been significant improvements in early graft survival due to advances in immunosuppression and the overall medical care of transplant recipients. However, long-term graft survival has only had modest improvement. The causes of “true” late kidney allograft failure remain unclear.

Research motivation

In this study, we explored the causes of graft failure based on various histopathological findings after transplant in the current era, which may allow providers to determine interventions to prevent poor outcomes.

Research objectives

The main objectives, of this study, was to identify the common causes of death censored graft failure among kidney transplant recipients. Knowing the causes may help provider to intervene on time and prevent for the graft loss.

Research methods

This was a single-center, retrospective study among kidney transplant recipients who were transplanted at the University of Wisconsin, and who had graft failure between January 1, 2006 and December 31, 2016 and transplanted between January 1, 1994 to December 31, 2016. Patients were included if they underwent a kidney biopsy within one year prior to the graft failure. We divided histopathological causes of graft failure based on the post-transplant interval divided into 2 years interval, based on the causes of ESRD and also the types of induction immunosuppressive medication. In cases where a patient had multiple biopsy diagnoses, all diagnoses were also reported separately, although the primary diagnosis (first diagnosis) was used for the cause of graft failure.

Research results

A total of 329 kidney transplant recipients fulfilled our selection criteria and were included in the study. The three most common biopsy findings were interstitial fibrosis and tubular atrophy (IFTA, 53%), acute rejection (AR, 43%) and transplant glomerulopathy (TG, 33%). Similarly, the three most common causes of graft failure based on the primary diagnosis were AR (40%), TG (17%), and IFTA (13%). Most grafts failed within two years of post-transplant (36%). Subsequently, approximately 10%-15% of grafts failed every two years: > 2-4 years (16%), > 4-6 years (13%), > 6-8 years (11%), > 8-10 years (9%) and > 10 years (16%). AR was the most common cause of graft failure in the first six years (48%), whereas TG was the most prevalent cause of graft failure after 6 years (32%) of transplant. Most early graft failures within the first six years of transplant are related to AR and are in theory preventable. Similarly, more effective diagnostic, monitoring, and therapeutic strategies for TG and IFTA are needed to improve long-term graft survival.

Research conclusions

In this study of the cause of graft failure among kidney transplant recipients, we found that the primary cause of graft failure varies with time after transplantation. AR, mainly antibody-mediated rejection (ABMR), was the most common cause of graft failure and accounted for 40% of graft failures, which peaked at 6 years post-transplant. After an AR, TG, one of the most specific histological findings of chronic ABMR, accounted for 17% of graft failure, which occurred mainly after 6-7 years post-transplant and was the most common cause of graft failure and even surpassed AR as a cause of graft failure. Interestingly, calcineurin inhibitor toxicity was not a common cause of graft failure.

Research perspectives

Further studies in this field and specifically effective treatment of AR is needed to prolong the graft survival. Most of the work is being conducted in the fields of prevention and treatment of AR, and in time we may be able to effectively manage AR including acute ABMR. However, chronic changes and the lesser understood mechanisms of TG and IFTA may hinder our aim of prolonged graft survival and study should focus on the field of prevention or treatment of TG and IFTA.