Long-term results of protocol kidney biopsy directing steroid withdrawal in simultaneous pancreas-kidney transplant patients

Introduction: We sought to determine whether protocol biopsies could be used to guide treatment and improve outcomes in simultaneous pancreas-kidney (SPK) patients.Methods: Between 2004 and 2013, protocol biopsies were performed on SPK patients at 3–6 months and one year post-transplant. Maintenance immunosuppression consisted of a calcineurin inhibitor, anti-proliferative agent, and corticosteroid. Corticosteroid was withdrawn in negative early biopsies, maintained in subclinical/ borderline biopsies, and increased if Banff IB or greater rejection was identified. Endpoints included presence of interstitial fibrosis and tubular atrophy on biopsy at one year (IF/TA), rejection episodes, and renal and pancreas function at five years’ followup.Results: Forty-one SPK transplant patients were reviewed and a total of 75 protocol biopsies were identified. On early biopsy, 51% had negative biopsies, 44% had borderline rejection, and 5% had subclinical rejection. Renal and pancreas function were not significantly different at one, two, and five years post-transplant between negative vs. borderline early biopsy patients. No difference in the degree of IF/TA was found between these two groups.Conclusions: To our knowledge, this is the first study to evaluate protocol biopsies as an investigative tool prior to steroid withdrawal in SPK patients. Our study suggests that there are no detrimental functional or histological effects at five years post-transplant, despite weaning steroids in the negative biopsy group.

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Deep learning identifies pathological abnormalities predictive of graft loss in kidney transplant biopsies

10.1101/2021.04.18.440166 ◽

2021 ◽

Author(s):

Zhengzi Yi ◽

Fadi Salem ◽

Madhav C Menon ◽

Karen Keung ◽

Caixia Xi ◽

...

Keyword(s):

Deep Learning ◽

Interstitial Fibrosis ◽

Periodic Acid ◽

Graft Loss ◽

Kidney Tissue ◽

Tubular Atrophy ◽

Post Transplant ◽

Pathological Lesions ◽

Protocol Biopsies ◽

Tissue Compartments

Background: Interstitial fibrosis, tubular atrophy, and inflammation are major contributors to renal allograft failure. Here we seek an objective, quantitative pathological assessment of these lesions to improve predictive utility. Methods: We constructed a deep–learning–based pipeline recognizing normal vs. abnormal kidney tissue compartments and mononuclear leukocyte (MNL) infiltrates from Periodic acid–Schiff (PAS) stained slides of transplant biopsies (training: n=60, testing: n=33) that quantified pathological lesions specific for interstitium, tubules and MNL infiltration. The pipeline was applied to 789 whole slide images (WSI) from baseline (n=478, pre–implantation) and 12–month post–transplant (n=311) protocol biopsies in two independent cohorts (GoCAR: 404 patients, AUSCAD: 212 patients) of transplant recipients to correlate composite lesion features with graft loss. Results: Our model accurately recognized kidney tissue compartments and MNLs. The digital features significantly correlated with Banff scores, but were more sensitive to subtle pathological changes below the thresholds in Banff scores. The Interstitial and Tubular Abnormality Score (ITAS) in baseline samples was highly predictive of 1–year graft loss (p=2.8e–05), while a Composite Damage Score (CDS) in 12–month post–transplant protocol biopsies predicted later graft loss (p=7.3e–05). ITAS and CDS outperformed Banff scores or clinical predictors with superior graft loss prediction accuracy. High/intermediate risk groups stratified by ITAS or CDS also demonstrated significantly higher incidence of eGFR decline and subsequent graft damage. Conclusions: This deep–learning approach accurately detected and quantified pathological lesions from baseline or post–transplant biopsies, and demonstrated superior ability for prediction of post–transplant graft loss with potential application as a prevention, risk stratification or monitoring tool.

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Long-term impact of CMV infection on allografts and on patient survival in renal transplant patients with protocol biopsies

AJP Renal Physiology ◽

10.1152/ajprenal.00317.2015 ◽

2015 ◽

Vol 309 (11) ◽

pp. F925-F932 ◽

Cited By ~ 16

Author(s):

U. Erdbrügger ◽

I. Scheffner ◽

M. Mengel ◽

A. Schwarz ◽

H. Haller ◽

...

Keyword(s):

Patient Survival ◽

Interstitial Fibrosis ◽

Graft Loss ◽

Cmv Infection ◽

Tubular Atrophy ◽

Transplant Patients ◽

Protocol Biopsies ◽

Glomerular Lesions ◽

Long Term Impact

Cytomegalovirus (CMV) infection is a frequent complication of early posttransplantation. This study examines its impact on chronic allograft changes, long-term graft loss, and patient survival. We studied 594 patients who had protocol biopsies at 6 wk, and 3 and 6 mo posttransplantation. Chronic allograft changes were evaluated according to the updated Banff classification [interstitial fibrosis/tubular atrophy (IF/TA), vascular and glomerular lesions]. Follow-up data were available for up to 10 yr. CMV infection was diagnosed in 153 of 594 patients (26%) in the first year after transplantation, mostly within the first 3 mo. Graft survival was reduced in patients with CMV ( P = 0.03) as well as the combined allograft/patient survival ( P = 0.008). Prevalence of IF/TA at 6 wk after transplantation was already threefold higher in patients who experienced CMV infection later on compared with patients without CMV ( P = 0.005). In multivariate analyses, CMV viremia or disease was not a significant factor for graft loss or death. In conclusion, patients with CMV infection posttransplantation show more chronic allograft changes early on, even before CMV infection, and development of IF/TA is not more prevalent in patients with CMV. Our data do not support a significant role of CMV in patient and graft outcomes.

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Intragraft Expression of the IL-10 Gene Is Up-Regulated in Renal Protocol Biopsies with Early Interstitial Fibrosis, Tubular Atrophy, and Subclinical Rejection

American Journal Of Pathology ◽

10.2353/ajpath.2010.090411 ◽

2010 ◽

Vol 176 (4) ◽

pp. 1696-1704 ◽

Cited By ~ 16

Author(s):

Miguel Hueso ◽

Estanis Navarro ◽

Francesc Moreso ◽

Francisco O'Valle ◽

Mercè Pérez-Riba ◽

...

Keyword(s):

Interstitial Fibrosis ◽

Tubular Atrophy ◽

Protocol Biopsies ◽

Subclinical Rejection

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Expression of pro- and antifibrotic genes in protocol biopsies from renal allografts with interstitial fibrosis and tubular atrophy

Clinical Nephrology ◽

10.5414/cnp69408 ◽

2008 ◽

Vol 69 (06) ◽

pp. 408-416 ◽

Cited By ~ 14

Author(s):

M. Mengel ◽

O. Bock ◽

M. Priess ◽

H. Haller ◽

H. Kreipe ◽

...

Keyword(s):

Interstitial Fibrosis ◽

Tubular Atrophy ◽

Renal Allografts ◽

Protocol Biopsies

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Pilot Analysis of Late Conversion to Belatacept in Kidney Transplant Recipients for Biopsy-Proven Chronic Tacrolimus Toxicity

Journal of Transplantation ◽

10.1155/2018/1968029 ◽

2018 ◽

Vol 2018 ◽

pp. 1-6 ◽

Cited By ~ 2

Author(s):

Shruti Gupta ◽

Ivy Rosales ◽

David Wojciechowski

Keyword(s):

Interstitial Fibrosis ◽

Calcineurin Inhibitors ◽

Transplant Recipients ◽

Kidney Transplant Recipients ◽

Tubular Atrophy ◽

Transplant Patients ◽

Number Of Patients ◽

Allograft Function ◽

The Mean ◽

Arteriolar Hyalinosis

Background. Calcineurin inhibitors are associated with chronic nephrotoxicity, manifesting as interstitial fibrosis/tubular atrophy (IF/TA) and arteriolar hyalinosis. Conversion from tacrolimus to belatacept may be one strategy to preserve renal function. Methods. We conducted a retrospective review of renal transplant patients followed at our institution who were converted to belatacept and found to have chronic tacrolimus toxicity on biopsy. The primary outcome was eGFR at conversion as compared to eGFR at 3, 6, 12, and 24 months after conversion. We also assessed incidence of infection and rates of allograft survival at 1 year. Results. The average time between transplant and conversion was 11.9 years. There was no decrease in eGFR at any postconversion time point as compared with preconversion. The mean eGFR at time of preconversion was 32.9 mL/min, as compared with 35.6 mL/min at 3 months (p=0.09), 34.1 mL/min at 6 months (p=0.63), 34.9 mL/min at 12 months (p=0.57), and 39.6 mL/min at 24 months after conversion (p=0.92). Four of 7 patients had increases in their eGFR after conversion. All grafts were functioning at 1 year after conversion. Conclusion. While this study was limited by a small number of patients, belatacept conversion stabilized eGFR at all time points in patients with late allograft function due to chronic tacrolimus toxicity, with a trend towards increased eGFR at 3 months.

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P1741TACROLIMUS FAST METABOLIZERS SHOW A HIGHER PROGRESSION OF INTERTITIAL FIBROSIS AND TUBULAR ATROPHY DURING THE FIRST YEAR AFTER RENAL TRASPLANTATION

Nephrology Dialysis Transplantation ◽

10.1093/ndt/gfaa142.p1741 ◽

2020 ◽

Vol 35 (Supplement_3) ◽

Author(s):

Betty Chamoun Huacon ◽

Irina Torres ◽

Alejandra Gabaldon ◽

Néstor Toapanta ◽

Joana Sellares ◽

...

Keyword(s):

Interstitial Fibrosis ◽

Univariate Analysis ◽

First Year ◽

Prolonged Release ◽

Dose Ratio ◽

Tubular Atrophy ◽

Protocol Biopsies ◽

The Difference ◽

Independent Association ◽

Allograft Loss

Abstract Background and Aims Fast tacrolimus metabolizers (expressed as the blood concentration/ dose ratio; C / D; ng / mL * mg) showed poorer renal function at 2 years, a higher incidence of nephrotoxicity and BK polyomavirus infection. Greater variability of tacrolimus trough levels (CV) from six to twelve months is associated with the appearance of HLA antibodies, interstitial fibrosis / tubular atrophy (IFTA) progression and allograft loss. We evaluate the relationship between C / D, CV and IFTA progression. Method We evaluated a cohort of 87 low immunological risk renal transplants treated with prolonged-release tacrolimus, mycophenolate mofetil and steroids. We analyzed paired protocol biopsies at 4 and 18 months. Biopsies were evaluated according to the Banff classification and the progression of IFTA was defined as the difference of ci + ct score> 0 between 18 and 4 months. The C / D ratio was calculated as the average of the value recorded at 3, 6 and 12 months of follow-up. The tacrolimus CV between 6 and 12 months was calculated using all the available determinations. Results IFTA progression was observed in 36 cases (41%). In the univariate analysis, it was found that the progression of IFTA was associated with the ci + ct score at 4 months (0.92 ± 0.94 for progressors vs. 1.89 ± 1.26 not progressors, p = 0.0003), and with the average of the C / D ratio (1.70 ± 0.73 for progressors vs. 2.28 ± 1.25 not progressors; p = 0.0144, table 1). An independent association between the C/D ratio and the progression of IFTA was observed in the multivariate analysis (OR: 0.42; 95% CI: 0.22-0.82, p = 0.027). Conclusion The results of our work suggest that fast tacrolimus metabolizers (lower C / D ratio) are more susceptible to the nephrotoxic effect of tacrolimus.

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Transcriptome changes in renal allograft protocol biopsies at 3 months precede the onset of interstitial fibrosis/tubular atrophy (IF/TA) at 6 months

Nephrology Dialysis Transplantation ◽

10.1093/ndt/gfp183 ◽

2009 ◽

Vol 24 (8) ◽

pp. 2567-2575 ◽

Cited By ~ 35

Author(s):

Andreas Scherer ◽

Wilfried Gwinner ◽

Michael Mengel ◽

Torsten Kirsch ◽

Friedrich Raulf ◽

...

Keyword(s):

Renal Allograft ◽

Interstitial Fibrosis ◽

Tubular Atrophy ◽

Protocol Biopsies

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Risk factors for death in kidney transplant patients: analysis from a large protocol biopsy registry

Nephrology Dialysis Transplantation ◽

10.1093/ndt/gfy131 ◽

2018 ◽

Vol 34 (7) ◽

pp. 1171-1181 ◽

Cited By ~ 8

Author(s):

Tanja Abeling ◽

Irina Scheffner ◽

Annika Karch ◽

Verena Broecker ◽

Armin Koch ◽

...

Keyword(s):

Heart Failure ◽

Risk Assessment ◽

Renal Transplant ◽

Graft Loss ◽

Individual Risk ◽

Protocol Biopsy ◽

Post Transplant ◽

Transplant Patients ◽

Living Donor Transplantation ◽

Protocol Biopsies

Abstract Background Identification and quantification of the relevant factors for death can improve patients’ individual risk assessment and decision-making. We used a well-documented patient cohort (n = 892) in a renal transplant programme with protocol biopsies to establish multivariable Cox models for risk assessment at 3 and 12 months post-transplantation. Methods Patients transplanted between 2000 and 2007 were observed up to 11 years (total observation 5227 patient-years; median 5.9 years). Loss to follow-up was negligible (n = 15). A total of 2251 protocol biopsies and 1214 biopsies for cause were performed. All rejections and clinical borderline rejections in protocol biopsies were treated. Results Overall 10-year patient survival was 78%, with inferior survival of patients with graft loss and superior survival of patients with living-donor transplantation. Eight factors were common in the models at 3 and 12 months, including age, pre-transplant heart failure and a score of cardiovascular disease and type 2 diabetes, post-transplant urinary tract infection, treatment of rejection, new-onset heart failure, coronary events and malignancies. Additional variables of the model at 3 months included deceased donor transplantation, transplant lymphocele, BK virus nephropathy and severe infections. Graft function and graft loss were significant factors of the model at 12 months. Internal validation and validation with a separate cohort of patients (n = 349) demonstrated good discrimination of the models. Conclusions The identified factors indicate the important areas that need special attention in the pre- and post-transplant care of renal transplant patients. On the basis of these models, we provide nomograms as a tool to weigh individual risks that may contribute to decreased survival.

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Working to establish ‘normality’ post-transplant: A qualitative study of kidney transplant patients

Chronic Illness ◽

10.1177/1742395313504789 ◽

2013 ◽

Vol 10 (4) ◽

pp. 247-258 ◽

Cited By ~ 19

Author(s):

Annette Boaz ◽

Myfanwy Morgan

Keyword(s):

Side Effects ◽

Kidney Transplant ◽

Personal Construct ◽

Post Transplant ◽

Transplant Patients ◽

Wide Range ◽

Transplant Failure ◽

Kidney Transplant Patients ◽

One Year

Objectives To explore patients’ perceptions and experiences of ‘normality’ and the influences on this at three time points post-transplant. Methods In-depth interviews with 25 patients at three months, one year and more than three years following kidney transplant. Patients’ accounts were compared with Sanderson et al.’s typology of types of normality. Findings Post-transplant, patients worked hard to re-establish normality, albeit in a ‘reset’ form. This normality was a very personal construct, shaped by a wide range of factors including age, gender and personal circumstances. Some patients encountered significant challenges in regaining normality, both at three months for those experiencing acute and distressing side effects, and later relating to the long-term side effects of transplant medication and co-morbidities. However, the most dramatic threat to normality (disrupted normality) came from episodes of rejection and transplant failure. Conclusions The main types of normality achieved vary for different conditions. Moreover, despite improvements in health post-transplant and opportunities to build a new, reset normality, the participants recognised the need to pay careful attention to the spectre of future ill health and transplant failure. Transplant failure was therefore a source of disruption that was central to their illness narratives and perceived as an ever present risk.

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