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The impact of acute kidney injury of donor kidneys transplanted with a low remuzzi score on incidence of delayed graft function and long term outcome L. Cima1 , A. Eccher1 , A. Caliò1 , A. Scarpa1 , S.Gobbo2 , D. Neill3 , C. Mescoli4 , F. Vanzo5 , A. D’Errico6 , M. Rugge4 , M. Brunelli1 Pathology Unit, Department of Diagnostics and Public Health, University and Hospital Trust of Verona, Verona, Italy Pathology Unit, Pederzoli Hospital, Peschiera Del Garda, Verona, Italy Pathology Unit, Department of Histopathology, Queen Elizabeth Hospital Birmingham, Birmingham, UK Department of Medicine (DIMED), Surgical Pathology and Cytopathology Unit, University and Hospital Trust of Padua, Padua, Italy Arsenàl, Veneto’s Research Center for eHealth Innovation, Veneto, Italy Pathology Unit, Department of Specialised, Experimental and Diagnostic Medicine, S.Orsola-Malpighi University Hospital of Bologna, Bologna, Italy

BACKGROUND – Status of Transplantation Activity Kidney Transplant Center 47 years of uninterrupted activity 2108 transplant from 1968 to 2016 90-100 transplants performed per year Liver Transplant Center 20 years of activity 20-30 transplants performed per year Other Transplant Activities lung heart cornea

BACKGROUND – Acute Kidney Injury DEFINITION: A clinical syndrome characterized by rapid reduction in renal excretory function underpinned by variety of causes CAUSES: Pre – Renal Renal (Intrinsic) Post – Renal Serum creatinine and urine output are considered the best existing markers for AKI

BACKGROUND – AKI Network (AKIN) Criteria

Group 2-3 sec. AKIN Criteria BACKGROUND – Deceased Donor Types DONATION AFTER BRAIN DEATH Standard criteria donors (SCD) Under 50 years old Expanded criteria donors (ECD) Over 60 years old Aged 50-59 years old with at least 2 of the following: Hypertension Cerebrovascular cause of brain death Pre-retrieval serum creatinine level > 1.5 mg/dl DONATION AFTER CIRCULATORY DEATH Group 2-3 sec. AKIN Criteria

BACKGROUND – Outcomes of Kidneys from donors with AKI DELAYED GRAFT FUNCTION (DGF) Low urine output and need for dialysis within first week after transplant EARLY GRAFT FAILURE Graft loss occurring within 30 days after kidney transplantation

BACKGROUND – Kidney Recovery From Forni et al. Renal Recovery After Kidney Injury Intensive Care Med (2017)

Appropriate Renal Replacement Therapy BACKGROUND – Kidney Recovery Appropriate Renal Replacement Therapy NO RECOVERY From Forni et al. Renal Recovery After Kidney Injury Intensive Care Med (2017)

BACKGROUND – Evaluation of Donors Kidneys From Irish et al. Nomogram for Predicting the Likelihood of Delayed Graft Function in Adult Cadaveric Renal Transplant Recipients JASN (2003)

BACKGROUND – Evaluation of Donors Kidneys AND KIDNEY BIOPSY…?

AIMS Assess the potential associations between clinically-defined donors with AKI, pre-implantation histological findings and recipient outcomes: Delayed Graft Function Serum Creatinine Levels Cumulative Rejection Rate Compare the recipient outcomes and the preimplantion biopsy report between the stage 3 AKIN group and the no AKIN, AKIN 1 and AKIN 2 groups

METHODS: Donors and Recipients 335 potential donors Mean age of 53 years AKIN Stage Groups Each donors underwent to pre-implantation histopathological examination by an on-call rota pathologists of the Pathology Unit 248 recipients Mean age of 48 years Each recipients underwent to a two years follow-up by the transplant team of the Kidney Transplant Center

METHODS – Remuzzi Score Glomerular Sclerosis (0-3) Vascular Narrowing (0-3) Interstitial Fibrosis (0-3) Score of 0 to 12 Score from 0 to 3: Use and implant singly 4 to 6: Dual transplant ≥ 7: Discard Tubular Atrophy (0-3)

METHODS – Acute Tubular Necrosis Mild: < 25% of tubular involvement Moderate: 25-50% of tubular involvement Severe: > 50% of tubular involvement

METHODS - Transplant Outcomes DELAYED GRAFT FUNCTION Recipients requiring dialysis within first 7 days after transplantation NO AKIN AKIN 1 AKIN 2 AKIN 3 SERUM CREATININE LEVELS Follow up of 1, 3, 12 and 24 Months CUMULATIVE REJECTION RATE

RESULTS – Donors Outcome NO AKIN 271 (81%) AKIN 1 37 (11%) AKIN 2 11 (3%) AKIN 3 16 (5%) Median Scr 77 umol/l 139 umol/l 186 umol/l 458 umol/l Remuzzi 0-3 216 26 6 14 Remuzzi 4-6 40 5 2 Remuzzi 7-12 15 1 Mild ATN 221 28 12 Moderate ATN 48 8 3 4 Severe ATN

RESULTS – Recipients Outcome NO AKIN AKIN 1 AKIN 2 AKIN 3 DGF 12% 11% 6% 47% Median Scr (1 month) 310,91 (± 143,86) umol/l 305,09 (± 151,85) umol/l 275,80 (± 99,82) umol/l 503 (± 187,61) umol/l (3 months) 143,60 (± 62.076) umol/l 146,31 (± 65,75) umol/l 127, 70 (± 49,405) umol/l 144,55 (± 74,181) umol/l Median Scr (1 year) 136,45 (± 53,723) umol/l 133,03 (± 54,033) umol/l 122,70 (± 39,398) umol/l 118, 67 (± 56,169) umol/l (2 years) 139,03 (± 76,548) umol/l 123,48 (± 39,520) umol/l 118,86 (± 133,75) umol/l 133,75 (± 65,713) umol/l Cumulative Rejection Rate (2 years) 38,5% 23% 30% 45,5% P =0,013 P =0,02 P =NS

Number of Donors with AKI DISCUSSION Authors Number of Donors with AKI AKI Definition DGF (AKI vs non AKI) Discard Rate Donor Kidney Biopsy Ugarte et al. (2005) 65 Terminal Cr ≥ 2.0 mg/dL 66% vs 27% (p < 0.001)   NA NO Kumar et al. (2006) 55 Terminal Cr ≥ 2.5 mg/dL 88% vs 46% (p = 0.03) Zuckerman et al. (2009) 17 32% vs 22% Kayler et al. (2010) 3537 SCD 767 ECD 36% vs 21% SCD 41% vs 32% ECD 29% vs 8% Lee et al. (2014) 43 AKIN Stage 1-3 42% vs 12% (p < 0.05) Hall et al. (2015) 443 41% vs 28% Heilman et al.(2015) 162 Cima et al. (2017) 64 47% vs 29% 29% vs 38,5% YES Cr: Creatinine ; SCD: standard criteria donors ; ECD: expanded criteria donors

DISCUSSION

CONCLUSIONS Donors with a severe acute kidney injury (stage 3 AKIN donors) could be used for kidney transplant Histopathology is a useful tool to decide that AKI Kidneys (even in the severe form) should not be discarded and expand the donor pool

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