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Background: The number of donors from donation after circulatory determination of death (DCDD) has increased by at least 4-fold over the past decade. This study evaluated the association between the antecedent cardiac arrest status of controlled DCDD donors and the risk of delayed graft function (DGF)., Methods: Using data from the Australia and New Zealand Dialysis and Transplant, the associations between antecedent cardiac arrest status of DCDD donors before withdrawal of cardiorespiratory support, DGF, posttransplant estimated glomerular filtration rate (eGFR), and allograft loss were examined using adjusted logistic, linear mixed modeling, and cox regression, respectively. Among donors who experienced cardiac arrest, we evaluated the association between duration and unwitnessed status of arrest and DGF., Results: A total of 1173 kidney transplant recipients received DCDD kidneys from 646 donors in Australia between 2014 and 2019. Of these, 335 DCDD had antecedent cardiac arrest. Compared with recipients of kidneys from donors without antecedent cardiac arrest, the adjusted odds ratio (95% confidence interval) for DGF was 0.85 (0.65-1.11) among those with kidneys from donors with cardiac arrest. There was no association between antecedent cardiac arrest and posttransplant eGFR or allograft loss. The duration of cardiac arrest and unwitnessed status were not associated with DGF., Conclusions: This focused analysis in an Australian population showed that the allograft outcomes were similar whether DCDD donors had experienced a prior cardiac arrest, with no associations between duration or unwitnessed status of arrest and risk of DGF. This study thus provides important reassurance to transplant programs and the patients they counsel, to accept kidneys from donors through the DCDD pathway irrespective of a prior cardiac arrest., Competing Interests: G.W. is supported by an NHMRC Career Development Fellowship. The other authors declare no conflicts of interest., (Copyright © 2024 The Author(s). Published by Wolters Kluwer Health, Inc.)

Delayed graft function (DGF) is a form of acute kidney injury (AKI) and a common complication following kidney transplantation. It adversely influences patient outcomes increases the financial burden of transplantation, and currently, no specific treatments are available. In developing this form of AKI, activation of the renin-angiotensin system (RAS) has been proposed to play an important role. In this review, we discuss the role of RAS activation and its contribution to the pathophysiology of DGF following the different stages of the transplantation process, from procurement and ischemia to transplantation into the recipient and including data from experimental animal models. Deceased kidney donors, whether during cardiac or brain death, may experience activation of the RAS. That may be continued or further potentiated during procurement and organ preservation. Additional evidence suggests that during implantation of the kidney graft and reperfusion in the recipient, the RAS is activated and may likely remain activated, extrapolating from other forms of AKI where RAS overactivity is well documented. Of particular interest in this setting is the status of angiotensin-converting enzyme 2, a key RAS enzyme essential for the metabolism of angiotensin II and abundantly present in the apical border of the proximal tubules, which is the site of predominant injury in AKI and DGF. Interventions aimed at safely downregulating the RAS using suitable shorter forms of angiotensin-converting enzyme 2 could be a way to offer protection against DGF., Competing Interests: D.B. is a consultant for AstraZeneca, Renibus, and Advicenne; has ownership interest in Angiotensin Therapeutics Inc; received research funding from AstraZeneca, Feinberg Foundation, and the National Institutes of Health; and patents or royalties and founder of Angiotensin Therapeutics Inc. D.B. is the coinventor of patents: “Active Low Molecular Weight Variants of Angiotensin Converting Enzyme 2” and “Soluble ACE2 variants and uses therefore.” The other authors declare no conflicts of interest., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Background: Deceased-donor kidneys experience extensive injury, activating adaptive and maladaptive pathways therefore impacting graft function. We evaluated urinary donor uromodulin (UMOD) and osteopontin (OPN) in recipient graft outcomes., Methods: Primary outcomes: all-cause graft failure (GF) and death-censored GF (dcGF). Secondary outcomes: delayed graft function (DGF) and 6-month estimated glomerular filtration rate (eGFR). We randomly divided our cohort of deceased donors and recipients into training and test datasets. We internally validated associations between donor urine UMOD and OPN at time of procurement, with our primary outcomes. The direction of association between biomarkers and GF contrasted. Subsequently, we evaluated UMOD:OPN ratio with all outcomes. To understand these mechanisms, we examined the effect of UMOD on expression of major histocompatibility complex II in mouse macrophages., Results: Doubling of UMOD increased dcGF risk (adjusted hazard ratio [aHR], 1.1; 95% confidence interval [CI], 1.02-1.2), whereas OPN decreased dcGF risk (aHR, 0.94; 95% CI, 0.88-1). UMOD:OPN ratio ≤3 strengthened the association, with reduced dcGF risk (aHR, 0.57; 0.41-0.80) with similar associations for GF, and in the test dataset. A ratio ≤3 was also associated with lower DGF (aOR, 0.73; 95% CI, 0.60-0.89) and higher 6-month eGFR (adjusted β coefficient, 3.19; 95% CI, 1.28-5.11). UMOD increased major histocompatibility complex II expression elucidating a possible mechanism behind UMOD's association with GF., Conclusions: UMOD:OPN ratio ≤3 was protective, with lower risk of DGF, higher 6-month eGFR, and improved graft survival. This ratio may supplement existing strategies for evaluating kidney quality and allocation decisions regarding deceased-donor kidney transplantation., Competing Interests: S.G.M. supported by the American Heart Association (18CDA34110151) and Patterson Trust Fund. P.P.R. supported by epidemiology consulting from COHRDATA related to dialysis outcomes. This study received grant/research support from Merck, CVS and initiated grants from Merck to the University of Pennsylvania to support the THINKER (kidney), USHER (heart), and SHELTER (lung) trials of transplanting organs from donors with Hepatitis C into Hepatitis C negative recipients. It initiated grants from CVS to the University of Pennsylvania to support studies of medication adherence. I.E.H. received NIH grant support from NCATS (UL1TR002538 and KL2TR002539). T.M.E.-A. received grant support from NIDDK and US Department of Veterans Affairs. M.D.D. obtained the salary support from NIDDK. S.M. received grant/research support from NIH (NIDDK/NIAID/NIHMD/NIBIB) and consulting fees from Angion Pharmaceuticals. A.Z.R. received NDAs with Pliant Therapeutics and xMD Diagnostics, advisory board of Escala Therapeutics. C.R.P. received consulting fee from Renalytix and grant/research support from National Institute of Diabetes and Digestion and Kidney Diseases, National Heart, Lung, and Blood Institute and Data Safety and Monitoring Board of Genfit, Abbott. M.N.H. received grant support from NIH/NIDDK. The other authors declare no conflicts of interest., (Copyright © 2020 Wolters Kluwer Health, Inc. All rights reserved.)

Background: Patients (20%-50%) undergoing renal transplantation experience acute kidney injury resulting in delayed graft function. ANG-3777 is an hepatocyte growth factor mimetic that binds to the c-MET receptor. In animal models, ANG-3777 decreases apoptosis, increases proliferation, and promotes organ repair and function., Methods: This was a randomized, double-blind, placebo-controlled, phase 2 trial of patients undergoing renal transplantation with <50 cc/h urine output for 8 consecutive hours over the first 24 hours posttransplantation, or creatinine reduction ratio <30% from pretransplantation to 24 hours posttransplantation. Subjects were randomized as 2:1 to 3, once-daily IV infusions of ANG-3777, 2 mg/kg (n = 19), or placebo (n = 9). Primary endpoint: time in days to achieve ≥1200 cc urine for 24 hours., Results: Patients treated with ANG-3777 were more likely to achieve the primary endpoint of 1200 cc urine for 24 hours by 28 days posttransplantation (83.3% versus 50% placebo; log-rank test: χ2 = 2.799, P = 0.09). Compared with placebo, patients in the ANG-3777 arm had larger increases in urine output; lower serum creatinine; greater reduction in C-reactive protein and neutrophil gelatinase-associated lipocalin; fewer dialysis sessions and shorter duration of dialysis; fewer hospital days; significantly less graft failure; and higher estimated glomerular filtration rate. Adverse events occurred in a similar percentage of subjects in both arms. Events per subject were twice as high in the placebo arm., Conclusions: There was an efficacy signal for improved renal function in subjects treated with ANG-3777 relative to placebo, with a good safety profile., (Copyright © 2020 The Author(s). Published by Wolters Kluwer Health, Inc.)

Background: During organ retrieval, surgeons estimate the degree of arteriosclerosis and this plays an important role in decisions on organ acceptance. Our study aimed to elucidate the association between macroscopic renal artery arteriosclerosis, donor kidney discard, and transplant outcome., Methods: We selected all transplanted and discarded kidneys in the Netherlands between January 1, 2000, and December 31, 2015, from deceased donors aged 50 y and older, for which data on renal artery arteriosclerosis were available (n = 2610). The association between arteriosclerosis and kidney discard, the relation between arteriosclerosis and outcome, and the correlation between macroscopic and microscopic arteriosclerosis were explored., Results: Macroscopic arteriosclerosis was independently associated with kidney discard (odds ratio [OR], 1.36; 95% confidence interval [CI], 1.02-1.80; P = 0.03). Arteriosclerosis (any degree) was not significantly associated with delayed graft function (OR, 1.16; 95% CI, 0.94-1.43; P = 0.16), estimated glomerular filtration rate 1-y posttransplant (B, 0.58; 95% CI, -2.07 to 3.22; P = 0.67), and long-term graft survival (hazard ratio, 1.07; 95% CI, 0.86-1.33; P = 0.55). There was a significant association between mild arteriosclerosis and primary nonfunction (OR, 2.14; 95% CI, 1.19-3.84; P = 0.01). We found no correlation between macroscopic and histological arteriosclerosis, nor between histological arteriosclerosis and transplant outcome., Conclusions: Macroscopic arteriosclerosis of the renal artery was independently associated with kidney discard and somewhat associated with primary nonfunction posttransplant. However, there was no effect of arteriosclerosis on delayed graft function, estimated glomerular filtration rate at 1 y, or long-term graft survival. Our results are valid only after inevitable exclusion of discarded kidneys that had on average more arteriosclerosis. Hence, conclusions should be interpreted in the light of this potential bias.

Background: Consider a theoretical situation in which 2 patients with similar baseline characteristics receive a kidney transplant on the same day: 1 from a standard criteria deceased donor, the other from a living donor. Which kidney transplant will last longer?, Methods: We conducted a population-based cohort study using linked administrative healthcare databases from Ontario, Canada, from January 1, 2005, to March 31, 2014, to evaluate several posttransplant outcomes in individuals who received a kidney transplant from a standard criteria deceased donor (n = 1523) or from a living donor (n = 1373). We used PS weighting using overlap weights, a novel weighting method that emphasizes the population of recipients with the most overlap in baseline characteristics., Results: Compared with recipients of a living donor, the rate of all-cause graft failure was not statistically higher for recipients of a standard criteria deceased donor (hazard ratio, 1.1; 95% confidence interval [CI], 0.8-1.6). Recipients of a standard criteria deceased donor, compared with recipients of a living donor had a higher rate of delayed graft function (23.6% versus 18.7%; odds ratio, 1.3; 95% CI, 1.0-1.6) and a longer length of stay for the kidney transplant surgery (mean difference, 1.7 d; 95% CI, 0.5-3.0)., Conclusions: After accounting for many important donor and recipient factors, we failed to observe a large difference in the risk of all-cause graft failure for recipients of a standard criteria deceased versus living donor. Some estimates were imprecise, which meant we could not rule out the presence of smaller clinically important effects.

Although over 90 000 people are on the kidney transplant waitlist in the United States, some kidneys that are viable for transplantation are discarded. Transplant surgeons are more likely to discard deceased donors with acute kidney injury (AKI) versus without AKI (30% versus 18%). AKI is defined using changes in creatinine from baseline. Transplant surgeons can use DonorNet data, including admission, peak, and terminal serum creatinine, and biopsy data when available to differentiate kidneys with AKI from those with chronic injury. Although chronic kidney disease is associated with reduced graft survival, an abundance of literature has demonstrated similar graft survival for deceased donors with AKI versus donors without AKI. Donors with AKI are more likely to undergo delayed graft function but have similar long-term outcomes as donors without AKI. The mechanism for similar graft survival is unclear. Some hypothesized mechanisms include (1) ischemic preconditioning; (2) posttransplant and host factors playing a greater role in long-term survival than donor factors; and (3) selection bias of transplanting only relatively healthy donor kidneys with AKI. Existing literature suggests transplanting more donor kidneys with stage 1 and 2 AKI, and cautious utilization of stage 3 AKI donors, may increase the pool of viable kidneys. Doing so can reduce the number of people who die on the waitlist by over 500 every year.

Background: Better preservation strategies for the storage of donation after circulatory death grafts are essential to improve graft function and to increase the kidney donor pool. We compared continuous normothermic ex vivo kidney perfusion (NEVKP) with hypothermic anoxic machine perfusion (HAMP) and static cold storage (SCS) in a porcine kidney autotransplantation model., Methods: Porcine kidneys were exposed to 30 minutes of warm ischemia and then reimplanted following either 16 hours of either SCS, HAMP (LifePort 1.0), or NEVKP before autotransplantation (n = 5 per group). The contralateral kidney was removed. Animals were followed for 8 days., Results: Grafts preserved by NEVKP demonstrated improved function with more rapid recovery compared with HAMP and SCS (mean peak serum creatinine: 3.66 ± 1.33 mg/dL [postoperative d 1 [(POD1)], 8.82 ± 3.17 mg/dL [POD2], and 12.90 ± 2.19 mg/dL [POD3], respectively). The NEVKP group demonstrated significantly increased creatinine clearance calculated on POD3 (63.6 ± 19.0 mL/min) compared with HAMP (13.5 ± 10.3 mL/min, P = 0.001) and SCS (4.0 ± 2.6 mL/min, P = 0.001). Histopathologic injury scores on POD8 were lower in both perfused groups (NEVKP and HAMP, score: 1-1.5) compared with SCS (score: 1-3, P = 0.3), without reaching statistical significance., Conclusions: NEVKP storage significantly improved early kidney function compared with both cold preservation strategies, although HAMP also demonstrates improvement over SCS. NEVKP may represent a novel, superior preservation option for donation after circulatory death renal grafts compared with conventional hypothermic methods.

Background: The benefits of cold pulsatile machine perfusion (MP) for the storage and transportation of kidneys donated after circulatory death are disputed. We conducted a UK-based multicenter, randomized controlled trial to compare outcomes of kidneys stored with MP versus static cold storage (CS)., Methods: Fifty-one pairs of kidneys donated after circulatory death were randomly allocated to receive static CS or cold pulsatile MP. The primary endpoint, delayed graft function, was analyzed by "intention-to-treat" evaluation., Results: There was no difference in the incidence of delayed graft function between CS and MP (32/51 (62.8%) and 30/51 (58.8%) P = 0.69, respectively), although the trial stopped early due to difficulty with recruitment. There was no difference in the incidence of acute rejection, or in graft or patient survival between the CS and MP groups. Median estimated glomerular filtration rate at 3 months following transplantation was significantly lower in the CS group compared with MP (CS 34 mL/min IQR 26-44 vs MP 45 mL/min IQR 36-60, P = 0.006), although there was no significant difference in estimated glomerular filtration rate between CS and MP at 12 months posttransplant., Conclusions: This study is underpowered, which limits definitive conclusions about the use of MP, as an alternative to static CS. It did not demonstrate that the use of MP reduces the incidence of delayed graft function in donation after circulatory death kidney transplantation.

Background: An elevated terminal creatinine is frequently used as a reason for organ refusal in pediatric kidney transplantation. There is increasing evidence that adults who receive kidneys from donors with moderate to severe acute kidney injury (AKI) have similar outcomes to recipients who receive kidneys from donors with none to mild AKI., Methods: We used the Scientific Registry of Transplant Recipients to determine how many pediatric kidney transplant recipients developed delayed graft function (DGF) between 2000 and 2010., Results: When stratified by the donor terminal creatinine, there was no significant difference in the recipient discharge creatinine or the likelihood of developing DGF. In a logistic regression model, older donor age, male donors, and a longer cold ischemia time but not donor terminal creatinine were independent predictors of DGF. There were very few graft loss events documented in this study., Conclusions: Our results are in agreement with previously published data; a high donor terminal creatinine is not significantly associated with DGF in pediatric renal transplant recipients. Additional studies investigating the risk of rejection and long-term graft function are needed before adopting the practice of accepting kidneys with moderate to severe AKI in pediatric kidney transplant recipients.

Background: Delayed graft function (DGF) is associated with inferior posttransplant outcomes in kidney transplantation. Given these adverse outcomes, we sought to determine the incidence, unique risk factors, and posttransplant outcomes for simultaneous liver kidney (SLK) transplant recipients developing DGF., Methods: We studied 6214 adult SLK recipients from March 2002 to February 2017 using the Scientific Registry of Transplant Recipients. We determined associations between risk factors and DGF using Poisson multivariate regression and between DGF and graft failure and mortality using Cox proportional hazard analysis., Results: The overall rate of DGF was 21.8%. Risk factors for DGF in the hepatitis C virus (HCV)-negative recipient population included pretransplant dialysis (adjusted incident rate ratio [aIRR] 3.26, P = 0.004), donor body mass index (aIRR 1.25 per 5 kg/m, P = 0.01), and transplantation with a donation after circulatory death (aIRR 5.38, P = 0.001) or imported donor organ (regional share aIRR 1.69, P = 0.03; national share aIRR 4.82, P < 0.001). DGF was associated with a 2.6-fold increase in kidney graft failure (adjusted hazard ratio [aHR] 2.63, P < 0.001), 1.6-fold increase in liver graft failure (aHR 1.62, P < 0.001), and 1.6-fold increase in mortality (aHR 1.62, P < 0.001)., Conclusions: In HCV-negative SLK recipients, recipient pretransplant dialysis and components of kidney graft quality comprise significant risk factors for DGF. Regardless of HCV status, DGF is associated with inferior posttransplant outcomes. Understanding these risk factors during clinical decision-making may improve prevention of DGF and may represent an opportunity to improve posttransplant outcomes.

Background: Urological obstructive complications (UOC) affect up to 15% of kidney transplants (KTX). Most cases are excluded by ultrasonography (US); however, accuracy may be limited in the early transplant phase. Features of acute tubular injury (ATI) in KTX biopsy may be informative but histological features indicating UOC are ill defined. Tubular ectasia (TE) was shown to be associated with UOC in experimental data. We evaluated the association of histomorphological features, particularly TE, with occult (=without relevant hydronephrosis in US) UOC and renal outcomes., Methods: We included all recipients with an early indication biopsy (976 of 1537 consecutive KTX). The biopsy finding of TE classified as "suspicious of UOC" was compared with the following endpoints: delayed graft function, estimated glomerular filtration rate, and occult UOC. Additionally, histopathological features of ATI were reevaluated by a single pathologist to increase diagnostic accuracy., Results: Fifty-eight (5.9%) patients presented with TE, which was not related to delayed graft function or estimated glomerular filtration rate. Forty percent of patients had a UOC (most frequently ureteral stenosis) close to biopsy. Comparing these biopsies to matched controls, TE was significantly associated with UOC (odds ratio 2.69; P = 0.018). After histopathological reevaluation of these biopsies including additional features of ATI, we developed a final multivariate model with a highly significant relationship to UOC (Receiver operating characteristic-area under the curve: 0.77; P = 0.001). The model provides a specificity of 78% and negative predictive value of 73%., Conclusions: TE together with additional signs of ATI indicates occult UOC. This histological phenotype should trigger more detailed evaluation for UOC when there is no evidence of relevant hydronephrosis in the ultrasonography.

Background: Urinary tissue inhibitor of metalloproteinases-2 (TIMP-2) and insulin-like growth factor binding protein-7 (IGFBP7) have been validated as biomarkers for acute kidney injury. We investigated the performance of both markers in predicting the occurrence and duration of functionally defined delayed graft function (fDGF) in donation after circulatory death (DCD) kidney transplant recipients., Methods: Urine samples of 74 DCD recipients were analyzed. TIMP-2 and IGFBP7 were measured with ELISA on postoperative days 1 to 7, day 10, week 6, and month 6, and values were corrected for osmolality (mOsm). Immunosuppression consisted of anti-CD25 antibody induction and triple maintenance therapy (steroids, mycophenolate mofetil, and calcineurin inhibitor). Statistical analysis included receiver operating characteristic curves and multivariate logistic regression., Results: Fifty-one (69%) renal transplant recipients had fDGF, of which 14 experienced prolonged fDGF (≥21 days). TIMP-2/mOsm on day-1 and day-10 adequately identified patients with fDGF (area under the curve [AUC], 0.91) and prolonged fDGF (AUC, 0.80), respectively, whereas IGFBP7/mOsm did not (AUC, 0.63 and 0.60). Multivariate analysis on day 1 identified 24-hour urinary creatinine excretion and TIMP-2/mOsm as significant predictors of fDGF (AUC, 0.90, 95% confidence interval, 0.80-0.98). The best predictors of prolonged fDGF on day 10 were 24-hour urinary creatinine excretion, TIMP-2/mOsm, and total warm ischemia time with an AUC of 0.85 (95% confidence interval, 0.72-0.95). Consecutive TIMP-2/mOsm values showed a decrease in TIMP-2/mOsm before an increase in estimated glomerular filtration rate, enabling us to monitor fDGF and predict resolution of fDGF., Conclusions: Urinary TIMP-2, but not IGFBP7, is a promising biomarker to predict the occurrence and duration of fDGF in DCD kidney transplant recipients.

Background: Prolonged cold ischemia is a risk factor for delayed graft function of kidney transplants, and is associated with caspase-3-mediated apoptotic tubular cell death. We hypothesized that treatment of tubular cells and donor kidneys during cold storage with a caspase inhibitor before transplant would reduce tubular cell apoptosis and improve kidney function after transplant., Methods: Mouse tubular cells were incubated with either dimethyl sulfoxide (DMSO) or Q-VD-OPh during cold storage in saline followed by rewarming in normal media. For in vivo studies, donor kidneys from C57BL/6 mice were perfused with cold saline, DMSO (vehicle), or QVD-OPh. Donor kidneys were then recovered, stored at 4°C for 60 minutes, and transplanted into syngeneic C57BL/6 recipients., Results: Tubular cells treated with a caspase inhibitor had significantly reduced capsase-3 protein expression, caspase-3 activity, and apoptotic cell death compared with saline or DMSO (vehicle) in a dose-dependent manner. Treatment of donor kidneys with a caspase inhibitor significantly reduced serum creatinine and resulted in significantly less tubular cell apoptosis, BBI, tubular injury, cast formation, and tubule lumen dilation compared with DMSO and saline-treated kidneys., Conclusions: Caspase inhibition resulted in decreased tubular cell apoptosis and improved renal function after transplantation. Caspase inhibition may be a useful strategy to prevent cold ischemic injury of donor renal grafts.

Background: Ischemia-reperfusion injury (IRI) leading to delayed graft function (DGF), defined by the United Network for Organ Sharing as dialysis in the first week (UNOS-DGF), associates with poor kidney transplant outcomes. Controversies remain, however, about dialysis initiation thresholds and the utility for other criteria to denote less severe IRI, or slow graft function (SGF)., Methods: Multicenter, prospective study of deceased-donor kidney recipients to compare UNOS-DGF to a definition that combines impaired creatinine reduction in the first 48 hours or greater than 1 dialysis session for predicting 12-month estimated glomerular filtration rate (eGFR). We also assessed 10 creatinine and urine output-based SGF definitions relative to 12-month eGFR., Results: In 560 recipients, 215 (38%) had UNOS-DGF, 330 (59%) met the combined definition, 14 (3%) died, and 23 (4%) had death-censored graft failure by 12 months. Both DGF definitions were associated with lower adjusted 12-month eGFR (95% confidence interval)-by 7.3 (3.6-10.9) and 7.4 (3.8-11.0) mL/min per 1.73 m, respectively. Adjusted relative risks for 12-month eGFR less than 30 mL/min per 1.73 m were 1.9 (1.2-3.1) and 2.1 (1.1-3.7), with unadjusted areas under the curve of 0.618 and 0.627, respectively. For SGF definitions, postoperative day (POD) 7 creatinine had the strongest association with 12-month eGFR, and POD5 creatinine and creatinine reduction between POD1 and POD2 demonstrated modest separations in 12-month eGFR., Conclusions: Although UNOS-DGF does not adequately predict 12-month function on its own, our findings do not support changing the definition. Postoperative day 7 creatinine is correlated with 12-month eGFR, but large translational studies are needed to understand the biological link between IRI severity at transplant and longer-term outcomes.

Background: Extracellular histones are cytotoxic molecules that are related to cell stress and death. They have been shown to play a crucial role in multiple pathophysiologic processes like sepsis, inflammation, vascular dysfunction, and thrombosis. Their role in organ donation and graft function and survival is still unknown. The aim of this study was to assess whether an association exists between the presence of extracellular histones in machine perfusates and deceased donor kidney viability., Methods: Machine perfusates of 390 donations after circulatory death kidneys were analyzed for histone concentration, and corresponding graft function and survival were assessed., Results: Extracellular histone concentrations were significantly higher in perfusates of kidneys with posttransplant graft dysfunction (primary nonfunction and delayed graft function) and were an independent risk factor for delayed graft function (odds ratio, 2.152; 95% confidence interval [95% CI], 1.199-3.863) and 1 year graft failure (hazard ratio, 1.386; 95% CI, 1.037-1.853), but not for primary nonfunction (odds ratio, 1.342; 95% CI, 0.900-2.002). One year graft survival was 12% higher in the group with low histone concentrations (P = 0.008) as compared with the group that contained higher histone concentrations., Conclusions: This study warrants future studies to probe for a possible role of cytotoxic extracellular histones in organ viability and suggests that quantitation of extracellular histones might contribute to assessment of posttransplant graft function and survival.

Background: Donation after circulatory death (DCD) is current clinical practice to increase the donor pool. Deleterious effects on renal graft function are described for hypothermic preservation. Therefore, current research focuses on investigating alternative preservation techniques, such as normothermic perfusion., Methods: We compared continuous pressure-controlled normothermic ex vivo kidney perfusion (NEVKP) with static cold storage (SCS) in a porcine model of DCD autotransplantation. After 30 minutes of warm ischemia, right kidneys were removed from 30-kg Yorkshire pigs and preserved with 8-hour NEVKP or in 4°C histidine-tryptophan-ketoglutarate solution (SCS), followed by kidney autotransplantation., Results: Throughout NEVKP, electrolytes and pH values were maintained. Intrarenal resistance decreased over the course of perfusion (0 hour, 1.6 ± 0.51 mm per minute vs 7 hours, 0.34 ± 0.05 mm Hg/mL per minute, P = 0.005). Perfusate lactate concentration also decreased (0 hour, 10.5 ± 0.8 vs 7 hours, 1.4 ± 0.3 mmol/L, P < 0.001). Cellular injury markers lactate dehydrogenase and aspartate aminotransferase were persistently low (lactate dehydrogenase < 100 U/L, below analyzer range; aspartate aminotransferase 0 hour, 15.6 ± 9.3 U/L vs 7 hours, 24.8 ± 14.6 U/L, P = 0.298). After autotransplantation, renal grafts preserved with NEVKP demonstrated lower serum creatinine on days 1 to 7 (P < 0.05) and lower peak values (NEVKP, 5.5 ± 1.7 mg/dL vs SCS, 11.1 ± 2.1 mg/dL, P = 0.002). The creatinine clearance on day 4 was increased in NEVKP-preserved kidneys (NEVKP, 39 ± 6.4 vs SCS, 18 ± 10.6 mL/min; P = 0.012). Serum neutrophil gelatinase-associated lipocalin at day 3 was lower in the NEVKP group (1267 ± 372 vs 2697 ± 1145 ng/mL, P = 0.029)., Conclusions: Continuous pressure-controlled NEVKP improves renal function in DCD kidney transplantation. Normothermic ex vivo kidney perfusion might help to decrease posttransplant delayed graft function rates and to increase the donor pool.

Background: Delayed graft function (DGF) and slow graft function (SGF) are ischemia-reperfusion-associated acute kidney injuries (AKI) that decrease long-term graft survival after kidney transplantation. Regulatory T (Treg) cells are protective in murine AKI, and their suppressive function predictive of AKI in kidney transplantation. The conventional Treg cell function coculture assay is however time-consuming and labor intensive. We sought a simpler alternative to measure Treg cell function and predict AKI., Methods: In this prospective observational cohort study, pretransplant recipient circulating CD4+CD25+CD127lo/- and CD4+CD127lo/- tumor necrosis factor receptor 2 (TNFR2)+ Treg cells were measured by flow cytometry in 76 deceased donor kidney transplant recipients (DGF, n = 18; SGF, n = 34; immediate graft function [IGF], n = 24). In a subset of 37 recipients, pretransplant circulating Treg cell-suppressive function was also quantified by measuring the suppression of autologous effector T-cell proliferation by Treg cell in coculture., Results: The TNFR2+ expression on CD4+CD127lo/- T cells correlated with Treg cell-suppressive function (r = 0.63, P < 0.01). In receiver operating characteristic curves, percentage and absolute number of CD4+CD127lo/-TNFR2+ Treg cell predicted DGF from non-DGF (IGF + SGF) with area under the curves of 0.75 and 0.77, respectively, and also AKI (DGF + SGF) from IGF with area under the curves of 0.76 and 0.72, respectively (P < 0.01). Prediction of AKI (DGF + SGF) from IGF remained significant in multivariate logistic regression accounting for cold ischemic time, donor age, previous transplant, and pretransplant dialysis modality., Conclusions: Pretransplant recipient circulating CD4+CD127lo/-TNFR2+ Treg cell is potentially a simpler alternative to Treg cell function as a pretransplant recipient immune marker for AKI (DGF + SGF), independent from donor and organ procurement characteristics.

Background: Antioxidant donor pretreatment is one of the pharmacologic strategy proposed to prevent renal ischemia-reperfusion injuries and delayed graft function (DGF). The aim of the study was to investigate whether a donor pretreatment with N-acetylcysteine (NAC) reduces the incidence of DGF in adult human kidney transplant recipients., Methods: In this randomized, open-label, monocenter trial, 160 deceased heart-beating donors were allowed to perform 236 renal transplantations from September 2005 to December 2010. Donors were randomized to receive, in a single-blind controlled fashion, 600 mg of intravenous NAC 1 hr before and 2 hr after cerebral angiography performed to confirm brain death. Primary endpoint was DGF defined by the need for at least one dialysis session within the first week or a serum creatinine level greater than 200 μmol/L at day 7 after kidney transplantation., Results: The incidence of DGF was similar between donors pretreated with or without NAC (39/118; 33% vs. 30/118; 25.4%; P = 0.19). Requirement for at least one dialysis session was not different between the NAC and No NAC groups (17/118; 14.4% vs. 14/118; 11.8%, P = 0.56). The two groups had comparable serum creatinine levels, estimated glomerular filtration rates, and daily urine output at days 1, 7, 15, and 30 after kidney transplantation as well as at hospital discharge. No difference in recipient mortality nor in 1-year kidney graft survival was observed., Conclusion: Donor pretreatment with NAC does not improve delayed graft function after kidney transplantation.

Background: Compared with the impact of delayed graft function (DGF) after renal transplantation, DGF after pancreas transplantation has not been fully evaluated., Methods: We retrospectively verified the impact of DGF on long-term pancreas graft survival in surgically successful cases. Pancreas graft failure was defined by the recipient's return to exogenous insulin administration., Results: Between May 2004 and April 2013, we performed 135 technically successful primary pancreas transplantations. Delayed graft function was defined as a total cumulative insulin requirement of 19 UI or greater within postoperative 7 days. Of the 135 recipients in our study cohort, 47 (34.8%) developed DGF after the pancreas transplantation. By multivariate analysis, DGF was found to be associated with a donor age of 30 years or older (odds ratio, 3.4; 95% confidence interval, 1.50-7.69; P=0.003) and the increased ratio of body mass index in a recipient to a donor (odds ratio, 26.1; 95% confidence interval, 2.53-270.0; P=0.006). There was a trend toward higher acute rejection (P=0.622) and mortality (P=0.49) rates in recipients with versus without DGF, although this did not reach statistical significance. Delayed graft function was found to be associated with a greater risk of overall pancreas graft failure (P=0.016) and death-censored graft failure (P=0.037)., Conclusion: Delayed graft function after pancreas transplantation was found to be associated with a greater risk of overall pancreas graft failure and death-censored graft failure.

Background: Delayed graft function (DGF) after renal transplantation can be diagnosed according to several different definitions, complicating comparison between studies that use DGF as an endpoint. This is a particular problem after transplantation with kidneys from donation after circulatory death (DCD) kidneys, because DGF is common, and its relationship to early graft failure may differ depending on the definition of DGF., Methods: The presence of DGF in 213 donation after brain death (DBD) and 312 DCD kidney transplants from October 2005 to August 2011 was determined according to 10 different, but widely used, definitions (based on dialysis requirements, creatinine changes, or both). The relationship of DGF to graft function and graft survival was determined., Results: The incidence of DGF varied widely depending on the definition used (DBD; 24%-70%: DCD; 41%-91%). For kidneys from DCD donors, development of DGF was only associated with poorer 1-year estimated glomerular filtration rate for 1 of 10 definitions of DGF, and no definition of DGF was associated with impaired graft survival. Conversely, for DBD kidneys, DGF, as defined in 9 of 10 different ways, was associated with poorer 1-year estimated glomerular filtration rate and inferior graft survival. Importantly, the predictive power for poorer transplant outcome was comparable for all definitions of DGF., Conclusion: No definition of DGF is superior. We suggest that the most widely used and most easily calculated definition--the use of dialysis in the first postoperative week--should be universally adopted as the definition of DGF clinically and as a study endpoint.

Background: Although some studies have found an association between delayed graft function (DGF) after kidney transplantation and worse long-term outcomes, a causal relationship remains controversial. We investigated this relationship using an instrumental variables model (IVM), a quasi-randomization technique for drawing causal inferences., Methods: We identified 80,690 adult, deceased-donor, kidney-only transplant recipients from the Scientific Registry of Transplant Recipients between 1997 and 2010. We used cold ischemia time (CIT) as an instrument to test the hypothesis that DGF causes death-censored graft failure and mortality at 1 and 5 years after transplantation, controlling for an array of characteristics known to affect patient and graft survival. We compared our IVM results with a multivariable linear probability model., Results: DGF occurred in 27% of our sample. Graft failure rates at 1 and 5 years were 6% and 22%, respectively, and 1-year and 5-year mortality rates were 5% and 20%, respectively. In the linear probability model, DGF was associated with increased risk of both graft failure and mortality at 1 and 5 years (P<0.001). In the IVM, we found evidence suggesting a causal relationship between DGF and death-censored graft failure at both 1 year (13.5% increase; P<0.001) and 5 years (16.2% increase; P<0.001) and between DGF and mortality at both 1 year (7.1% increase; P<0.001) and 5 years (11.0% increase; P<0.01). Results were robust to exclusion of lower quality as well as pumped kidneys and use of a creatinine-based definition for DGF., Conclusion: Instrumental variables analysis supports a causal relationship between DGF and both graft failure and mortality.

Background: The newly transplanted kidney is difficult to monitor with regard to postoperative vascular thrombosis, especially when there is delayed graft function. We evaluated microdialysis as a tool for early ischemia detection in porcine kidneys with delayed graft function early after transplantation., Methods: Sixteen pigs were transplanted with 26-hr cold ischemia kidneys. A microdialysis catheter was placed in the lateral renal cortex. Five hours after graft reperfusion, the pigs were randomized to renal arterial clamping or open artery, n=8 in each group, and further observed for 2 hr., Results: The diuresis and glomerular filtration rate were low and decreasing throughout the study, with no significant differences between groups. Until arterial clamping, there were no significant differences in the development of local renal metabolites between the two groups. Renal artery clamping immediately caused significantly different development of all metabolites (P<0.02 for all) compared to the open artery group. After clamping, levels of glutamate and glycerol were significantly increased within 30 min (P=0.0049 and P=0.0061, respectively)., Conclusions: Microdialysis provided an early warning of arterial occlusion in transplanted grafts with delayed graft function. It may become a valuable tool for postoperative monitoring and detection of thrombosis after renal transplantation.

Background: The traditional definition of delayed graft function (DGF) rests on dialysis requirement during the first postoperative week. Subsequently, a more objective and "functional" definition of DGF (fDGF) has been proposed as an alternative to this dialysis-based definition of DGF (dDGF) and defined as a failure of the serum creatinine to decrease by at least 10% daily on 3 successive days during the first week posttransplantation, irrespective of dialysis requirement. However, an association between fDGF and long-term graft failure has not been fully established, and it is unknown whether fDGF is a better marker of subsequent outcomes than dDGF., Methods: We studied 750 adult deceased donor kidney transplant recipients (1996-2006) and analyzed the association between these two DGF definitions and long-term graft outcome., Results: Univariable associations with death-censored graft failure were seen for both dDGF and fDGF (hazard ratio [HR] 1.59; 95% confidence interval [CI] 1.16-2.18; P=0.004 and HR 1.72; 95% CI 1.26-2.36; P=0.001, respectively). On bivariable analysis (dDGF vs. fDGF), dDGF lost significance, whereas the effect of fDGF persisted (HR 1.52; 95%CI 1.03-2.25; P=0.04). This was also the case in a multivariable model, where fDGF but not dDGF was significantly associated with graft failure (HR 1.47; 95%CI 1.06-2.03; P=0.02). Results were similar for overall graft failure., Conclusions: This study confirms the utility of fDGF as an early marker of subsequent inferior allograft outcomes, suggesting superiority over the traditional (often subjective) dialysis-based definition. Wider adoption of the fDGF definition should be considered, both as a risk-stratification tool in clinical practice and a clinical trial endpoint.

Background: Chronic loss of renal allograft function is associated with interstitial fibrosis and tubular atrophy (IF/TA). Independent of the underlying reason, one initial step in the development of fibrosis is chemokine-driven invasion of leukocytes from the blood vessels into the allograft. We studied the role of chemokines in kidney allografts with delayed graft function and the subsequent long-term outcome of renal function and fibrosis., Methods: We examined repetitive biopsies of 30 patients without signs of acute rejection but with initially delayed graft function for IF/TA. In addition, we examined the expression of chemokine receptor (CCR)-1 and CCR2 on invaded leukocytes and macrophages and the corresponding ligands regulated upon activation, normal t-cell expressed, and secreted (RANTES) and monocyte chemotactic protein-1 on residential kidney cells., Results: The initial expression of CCR1 positive invading cells and RANTES in glomerular cells correlated with the allograft function 12 months after transplantation and at last follow-up. The expression was independent of donor characteristics such as age, gender, infectious state, cause of death, or use of vasopressive agents. Furthermore, it did not correlate with the duration of cold ischemia time. Among the patients with the most progressive loss of allograft function follow-up biopsy specimen did not reveal any signs of rejection but showed increased CCR1 and RANTES expression in the interstitium suggesting ongoing inflammation and fibrosis., Conclusion: An early expression of RANTES in renal allografts with delayed graft function with consecutive invasion of CCR1 positive cells seems to promote ongoing IF/TA and to worse renal allograft outcome.

Introduction: Delayed graft function (DGF) has a major impact on long-term renal transplant survival. However, it is a diagnosis made retrospectively with little opportunity to modify treatment protocols. A classification based on creatinine reduction ratio between days 1 and 2 (CRR2) suggests that patients with CRR2 less than or equal to 30% (nondialysis requiring DGF [ND-DGF]) have similar outcomes to those with dialysis-requiring delayed graft function (D-DGF). We retrospectively applied this definition in our cohort of patients to examine outcomes., Methods: We studied the association between CRR2 and graft outcomes in all 367 patients transplanted between 1996 and 2004 at our center. Patients were divided into the following three groups: IGF (immediate graft function; CRR2 >30%), D-DGF, and ND-DGF. Mean follow-up was 4.2 years., Results: IGF accounted for 36% of patients, D-DGF for 22%, and ND-DGF for 42%. CRR2 was inversely correlated with serum creatinine on days 7, 30, 90, and 365 (r ranging from -0.65 to -0.22, P<0.001). Graft survival at 5 years was 98% (IGF), 74% (D-DGF), and 89% (ND-DGF). There was a significant difference in graft survival between IGF and D-DGF (P<0.001) and IGF and ND-DGF (P=0.005). In a multivariate analysis adjusting for recipient age and sex, donor age and sex, and human leukocyte antigen mismatch, graft failure was 2.4 times more likely to occur in patients with D-DGF than those with ND-DGF(P=0.02)., Conclusions: Our study shows CRR2 influences long-term graft outcomes. Unlike the original description, patients with ND-DGF carry an intermediate risk and perhaps should be considered on day 2 for alternative treatment protocols.

Use of pulsatile perfusion to optimize outcomes in deceased donor kidney transplantation remains controversial. This study is a retrospective analysis of all cadaveric renal allografts procured locally by our center over a 3-year period. Kidney pairs were identified in which one kidney underwent pulsatile perfusion and transplantation at our center, whereas the contra-lateral kidney underwent cold storage and transplantation at another center. Eighty-eight percent of the exported kidneys were six-antigen matches. Study outcomes included 1-year graft and patient survival, delayed graft function, and need for posttransplant dialysis. Recipients had similar demographic and disease characteristics. Survival for pulsatile perfusion and cold storage were 95% and 88% (graft, P=0.43) and 98% and 90% (patient, P=0.36), respectively. The incidence of delayed graft function was 5% and 35% (P<0.01), whereas posttransplant dialysis was 5% and 30% (P<0.01), for pulsatile perfusion and cold storage, respectively. These data support routine use of pulsatile perfusion.

Background: Older and marginal donors, increasingly used to overcome organ shortness, often have a cerebrovascular accident as cause of death and could have vascular lesions in their kidneys., Methods: In this literature study, we evaluated the predictive value of vasculopathy in the renal allograft at the time of transplantation, on the subsequent graft function., Results: Short-term graft survival rates do not seem to be diminished by suboptimal donor histology. When vasculopathy is clearly present at the time of transplantation, impaired kidney function is showed at 1-week posttransplantation, at hospital discharge, or at 3 months and an increased frequency of delayed graft function. The long-term graft survival rate, in the studies of Pokorna and Taub, was significantly lower in the group with arteriolosclerosis. Wang et al. concluded in their study that arterial fibrous intimal thickening is the single most important histological predictor of both graft loss and delayed graft function. However, Minakawa et al. observed no significant correlation between 1 or 2-year graft survival and vasculopathy score. Severe vascular lesions in the donor kidney do affect the level of kidney function in the later posttransplant period as described in different studies (follow-up till 7 years posttransplantation)., Conclusions: Data obtained from the studies of donor biopsies sustain the notion that vasculopathy is a major determinant of the short-term and the long-term outcome of the kidney allograft.

Background: The aim of our study was to examine, in a recent cohort of kidney transplant recipients who have received modern immunosuppressive therapy, the respective role of cold ischemia time (CIT) and delayed graft function (DGF) on acute rejection (AR) rates and long-term graft survival., Methods: We retrospectively reviewed the charts of 611 renal transplantations between 1996 and 2005. Most patients received a calcineurin inhibitor as maintenance therapy, either cyclosporine (43%) or tacrolimus (52%) and 76% of the patients received an antilymphocyte induction therapy. Study endpoints were DGF, first-year AR, and long-term graft survival. Uni- and multivariate analyses were performed to determine factors that may have influenced the study outcomes., Results: DGF was observed in 16.2% of patients. Both older donor age and longer CIT were significant risk factors for DGF. DGF rates were similar whether patients received a calcineurin inhibitor before transplantation or not. AR occurred in 16.5% of grafts during the first year. Independent predictors of AR by multivariate analysis were duration of dialysis, CIT, current panel-reactive lymphocytotoxic antibody more than 5%, and the number of human leukocyte antigen-A, B, and DR mismatches. Each hour of cold ischemia increases the risk of rejection by 4%. With respect to death-censored graft survival, three pretransplant parameters emerged as independent predictors of graft loss: younger recipient age, peak panel-reactive lymphocytotoxic antibody more than 5% and longer CIT. The detrimental effect of CIT on graft survival was entirely because of its propensity to trigger AR. When AR was added to the multivariate Cox model, CIT was no longer significant whereas first-year AR became the most important predictor of graft loss (Hazards ratio, 4.6)., Conclusion: Shortening CIT will help to decrease not only DGF rates but also AR incidence and hence graft loss. Patients with prolonged CIT should receive adequate immunosuppression, possibly with antilymphocyte preparations, to prevent AR occurrence.

Dialyzed delayed graft function (DGF) and nondialyzed slow graft function (SGF) both determine a large portion of the negative impact on patient and graft survival, on early acute rejection incidence, on tubulointerstitial fibrosis/tubular atrophy, and on graft function. In an era where expanded-criteria donors, including older donors, and non-heart beating donors are used to overcome organ shortage, the long-term results of kidney transplantation are influenced by the events occurring within the first 24 hr before and after the transplantation procedure. The ischemia-reperfusion injury is initiated in the brain-death donor and continues during preservation and engraftment of the transplant. The determinants of this DGF/SGF complex intervene in five chronologically related stages--donor tissue quality, brain death and related stress, preservation variables, immune factors, and recipient variables. For each of these five stages, therapeutic interventions or preventive measures are capable of partially reversing the expected dismal outcome of DGF/SGF; these measures are discussed in this article. Donor selection and pharmacologic modulations do have an effect on DGF/SGF.

Background: In 2003, Irish and colleagues published a weighted nomogram designed to predict the risk of delayed graft function (DGF) in a given transplant. It was anticipated that the predictive nomogram would permit preemptive therapies or allocation decisions based on the risk of DGF. The potential for reducing unfavorable outcomes and expenses appeared significant. This nomogram, however, was developed using population data found in the United States Renal Data System and has not been prospectively validated., Methods: We evaluated the accuracy and utility of this nomogram in all cadaver renal transplants performed at a single transplant center. In addition, we correlated DGF with a variety of independent donor and recipient variables outside the established nomogram., Results: The average nomogram DGF risk was 0.41 (a 41% chance of DGF) among the 169 cases in our population. The mean was 0.45+/-0.14 (confidence interval: 0.40-0.49) for the 42 DGF-positive subjects, and 0.40+/-0.14 (confidence interval: 0.38-0.43) for the 127 DGF-negatives (t=1.80; P=0.07)., Conclusions: Although there was a trend showing the predictive value of the nomogram the overlap was tremendous, limiting the accuracy of the calculation for any single recipient. Prospective application of a nomogram on a case-by-case basis did not contribute meaningful information that could guide clinical decision-making regarding use, allocation or immunosuppressive regimen aimed at minimizing DGF.

Background: The clinical impact of chronic transplant glomerulopathy (CTG) on the outcome of kidney allograft receiving calcineurin inhibitors (CNIs) remains uncertain. A retrospective study of renal transplant recipients at Ospedale Maggiore of Milan was undertaken to evaluate the clinical outcome of patients with CTG., Methods: Among 666 biopsies taken at least 6 months after transplantation (Tx) in 498 transplant patients treated with CNIs, 28 cases (5.6%) of chronic transplant glomerulopathy (CTG) were identified and their clinical features at Tx, at follow-up and graft survival were compared with those of 56 controls transplanted in the same period and with kidney functioning 12 months after Tx. Clinical characteristics at biopsy and at 1 year after Tx were similar in the two groups., Results: After diagnosis graft function deteriorated in 22 patients (78.5%), while it remained stable in 6. Graft loss developed in 92 % of patients with proteinuria >2.5 g/day and in 33 % of those with lower proteinuria (P<0.005). In cases with more severe CTG the rate of graft loss was higher, though not significantly. Graft survival at 10 years was 48% in patients with CTG and 88% in controls (P<0.0001)., Conclusions: The incidence and clinical course of CTG do not seem to be modified by CNI-based immunosuppression. The evolution is unpredictable but the severity of glomerulopathy and proteinuria at follow-up are associated with progression to graft failure. Patients with CTG have a graft survival significantly worse than that of the general population of transplanted patients.