Diabetes Mellitus: A Risk Factor for Delayed Graft Function after Deceased Donor Kidney Transplantation

Early graft function is a major determinant of long‐term outcomes after renal transplantation. Recently, recipient diabetes was identified as a risk factor for poor initial graft function in living donor renal transplantation. To further explore this association, we performed a paired analysis of deceased donor renal transplants from January 1994 to December 2005. A total of 25,523 transplant pairs were analyzed via conditional logistic regression. Diabetic recipients were older (53.16 vs. 46.75 years, p < 0.01), had a lower average panel reactive antibody (12% vs. 15%, p < 0.01) and fewer prior transplants (0.07 vs. 0.12, p < 0.01). Recipient diabetes, age, male gender, African American race, elevated peak panel reactive antibody and increased cold ischemia time were independent risk factors for delayed graft function. Specifically, diabetic recipients had increased risk of DGF on univariate analysis (odds ratio [OR] 1.32, 95% confidence interval [CI] 1.23–1.42, p < 0.01). Multivariable analysis confirmed this association but the risk differed by recipient gender; with diabetes having a greater effect in women (OR 1.66, 95% CI 1.45–1.91, p < 0.01) compared to men (OR 1.28, 95% CI 1.15–1.43, p < 0.01). It is unknown whether the deleterious impact of recipient diabetes on graft function after renal transplantation results from perioperative hyperglycemia or the chronic sequelae of diabetes.     

Non-Heart Beating Donor Kidneys with Delayed Graft Function Have Superior Graft Survival Compared with Conventional Heart-Beating Donor Kidneys That Develop Delayed Graft Function

Delayed graft function may have an association with reduced graft survival, and nonheart-beating donor (NHBD) kidneys have higher rates of delayed graft function (DGF) than heart-beating donor (HBD) kidneys. This study compared outcome of renal transplants from HBDs who developed DGF, with NHBDs who developed DGF. All recipients of HBD and NHBD kidneys who developed DGF were identified during a 10-year period. All patients with graft primary nonfunction were excluded from analysis. Four hundred and fifty-six functioning transplants were performed. Delayed graft function occurred in 69 (17%) HBD and 55 (93%) NHBD kidneys. The grafts developing DGF were well matched for donor and recipient age. The rate of acute rejection was similar; [n = 16/69 (23%) HBD vs. n = 13/55 (24%) NHBD]. Cold ischaemia was 21 h in the HBD group and 17 h in NHBD group (p > 0.05). Serum creatinine was similar for both groups at 1.3 and 6 years (p > 0.05 for all time points). Graft survival in the NHBD recipients with DGF was significantly better at 3 years (84%) compared with recipients of a HBD renal transplant that developed DGF (73%) (p < 0.05), and at 6 years (62% survival for HBDs and 84% survival for NHBDs). This study shows that graft survival was better for NHBD kidneys up to 6 years after transplantation.     

Targeting Complement Pathways During Cold Ischemia and Reperfusion Prevents Delayed Graft Function

The complement system plays a critical role in ischemia–reperfusion injury (IRI)–mediated delayed graft function (DGF). To better understand the roles of complement activation pathways in IRI in kidney transplantation, donor kidneys were treated ex vivo with terminal complement pathway (TP) inhibitor, anti‐rat C5 mAb 18A10, or complement alternative pathway (AP) inhibitor TT30 for 28 h at 4°C pretransplantation in a syngeneic kidney transplantation rat model. All 18A10‐ and 67% of TT30‐pretreated grafts, but only 16.7% of isotype control‐pretreated grafts, survived beyond day 21 (p < 0.01). Inhibitor treatment in the final 45 min of 28‐h cold ischemia (CI) similarly improved graft survival. Systemic posttransplant treatment with 18A10 resulted in 60% increased graft survival beyond day 21 (p < 0.01), while no TT30‐treated rat survived > 6 days. Our results demonstrate that AP plays a prominent role during CI and that blocking either the AP or, more effectively the TP prevents ischemic injury and subsequent DGF. Multiple complement pathways may be activated and contribute to reperfusion injury; blocking the TP, but not the AP, posttransplant is effective in preventing reperfusion injury and increasing graft survival. These results demonstrate the feasibility of using complement inhibitors for prevention of DGF in humans.     

The Detrimental Effect of Poor Early Graft Function After Laparoscopic Live Donor Nephrectomy on Graft Outcomes

We undertook this study to assess the rate of poor early graft function (EGF) after laparoscopic live donor nephrectomy (lapNx) and to determine whether poor EGF is associated with diminished long-term graft survival. The study population consisted of 946 consecutive lapNx donors/recipient pairs at our center. Poor EGF was defined as receiving hemodialysis on postoperative day (POD) 1 through POD 7 (delayed graft function [DGF]) or serum creatinine ≥ 3.0 mg/dL at POD 5 without need for hemodialysis (slow graft function [SGF]). The incidence of poor EGF was 16.3% (DGF 5.8%, SGF 10.5%), and it was stable in chronologic tertiles. Poor EGF was independently associated with worse death-censored graft survival (adjusted hazard ratio (HR) 2.15, 95% confidence interval (CI) 1.34–3.47, p = 0.001), worse overall graft survival (HR 1.62, 95% CI 1.10–2.37, p = 0.014), worse acute rejection-free survival (HR 2.75, 95% CI 1.92–3.94, p < 0.001) and worse 1-year renal function (p = 0.002). Even SGF independently predicted worse renal allograft survival (HR 2.54, 95% CI 1.44–4.44, p = 0.001). Risk factors for poor DGF included advanced donor age, high recipient BMI, sirolimus use and prolonged warm ischemia time. In conclusion, poor EGF following lapNx has a deleterious effect on long-term graft function and survival.     

A Risk Prediction Model for Delayed Graft Function in the Current Era of Deceased Donor Renal Transplantation

Delayed graft function (DGF) impacts short‐ and long‐term outcomes. We present a model for predicting DGF after renal transplantation. A multivariable logistic regression analysis of 24 337 deceased donor renal transplant recipients (2003–2006) was performed. We developed a nomogram, depicting relative contribution of risk factors, and a novel web‐based calculator ( http://www.transplantcalculator.com/DGF ) as an easily accessible tool for predicting DGF. Risk factors in the modern era were compared with their relative impact in an earlier era (1995–1998). Although the impact of many risk factors remained similar over time, weight of immunological factors attenuated, while impact of donor renal function increased by 2‐fold. This may reflect advances in immunosuppression and increased utilization of kidneys from expanded criteria donors (ECDs) in the modern era. The most significant factors associated with DGF were cold ischemia time, donor creatinine, body mass index, donation after cardiac death and donor age. In addition to predicting DGF, the model predicted graft failure. A 25–50% probability of DGF was associated with a 50% increased risk of graft failure relative to a DGF risk <25%, whereas a >50% DGF risk was associated with a 2‐fold increased risk of graft failure. This tool is useful for predicting DGF and long‐term outcomes at the time of transplant.     

Prolonged Ischemic Time,Delayed Graft Function,and Graft and Patient Outcomes in Live Donor Kidney Transplant Recipients

The association between prolonged cold ischemic time (CIT) and graft and patient outcomes in live donor kidney transplant recipients remains unclear. The aims of this study were to examine the association of CIT with delayed graft function and graft loss in live donor kidney transplant recipients and those who participated in the Australian Paired Kidney Exchange program using data from the Australia and New Zealand Dialysis and Transplant (ANZDATA) registry. Of 3717 live donor transplant recipients between 1997 and 2012 who were followed for a median of 6.6 years (25 977 person‐years), 224 (25%) experienced CIT >4–8 h. Donor age was an effect modifier between CIT and graft outcomes. In recipients who received kidneys from older donors aged >50 years, every hour of increase in CIT was associated with adjusted odds of 1.28 (95% confidence interval [CI] 1.07–1.53, p = 0.007) for delayed graft function, whereas CIT >4–8 h was associated with adjusted hazards of 1.93 (95% CI 1.21–3.09, p = 0.006) and 1.91 (95% CI 1.05–3.49, p = 0.035) for overall and death‐censored graft loss, respectively, compared with CIT of 1–2 h. Attempts to reduce CIT in live donor kidney transplants involving older donor kidneys may lead to improvement of graft outcomes.     

Sirolimus Prolongs Recovery from Delayed Graft Function After Cadaveric Renal Transplantation

Sirolimus, lacking known nephrotoxicity, appeared to be an ideal immunosuppressive agent in the setting of delayed graft function (DGF) after renal transplantation. Coincident with our use of sirolimus however, we noticed prolongation of DGF. To investigate possible causes of prolonged DGF, extensive donor, recipient, transplant, and post-transplant data were collected on 132 consecutive cases of DGF at the University of California, San Francisco between 1/1/97 and 6/30/01. Cox proportional hazards analysis of time to graft function was used in univariate and multivariate models to identify factors that prolong DGF. Sirolimus had a large and highly significant effect on time to graft function (hazard ratio 0.48, p = 0.0007). The hazard ratio indicates that a recipient on sirolimus is half as likely to resolve DGF or twice as likely to remain on dialysis as a recipient without sirolimus. Two other factors had less potent but still significant association with DGF duration: recipient sensitization (hazard ratio 0.66, p = 0.037), and Novartis score (hazard ratio 0.93 per 1.0 increase; p = 0.034). Sirolimus retained its profound negative association with time to graft function in all multivariate models. Because sirolimus appears to prolong DGF, it may not be the optimal immunosuppressive choice in the DGF setting.     

Prediction of Delayed Graft Function by Means of a Novel Web‐Based Calculator: A Single‐Center Experience

Renal failure persisting after renal transplant is known as delayed graft function (DGF). DGF predisposes the graft to acute rejection and increases the risk of graft loss. In 2010, Irish et al. developed a new model designed to predict DGF risk. This model was used to program a web‐based DGF risk calculator, which can be accessed via http://www.transplantcalculator.com . The predictive performance of this score has not been tested in a different population. We analyzed 342 deceased‐donor adult renal transplants performed in our hospital. Individual and population DGF risk was assessed using the web‐based calculator. The area under the ROC curve to predict DGF was 0.710 (95% CI 0.653–0.767, p < 0.001). The “goodness‐of‐fit” test demonstrates that the DGF risk was well calibrated (p = 0.309). Graft survival was significantly better for patients with a lower DGF risk (5‐year survival 71.1% vs. 60.1%, log rank p = 0.036). The model performed well with good discrimination ability and good calibration to predict DGF in a single transplant center. Using the web‐based DGF calculator, we can predict the risk of developing DGF with a moderate to high degree of certainty only by using information available at the time of transplantation.     

Outcome of Nonheart-Beating Donor Kidneys with Prolonged Delayed Graft Function after Transplantation

Nonheart-beating donor (NHBD) kidneys are frequently associated with delayed graft function (DGF), with a deleterious effect on kidney function and allograft survival. The influence and the duration of DGF on the outcome of NHBD kidneys are assessed. All recipients of an NHBD kidney in the period 1993-2003 were reviewed. Excluded from analysis were patients with primary nonfunction (PNF). One hundred and five patients with a functioning NHBD graft were reviewed: 23 (22%) had immediate function (group 1), 40 (38%) had DGF < or = 2 weeks (group 2), 31 (30%) had DGF 15 days to 4 weeks (group 3) and 11 (10%) had DGF for > 4 weeks (group 4). Creatinine clearance at 3 months was higher in groups 1 and 2 versus group 4 (p = 0.015 and p = 0.006, respectively) and was higher in group 2 versus group 4, at 1 year (p = 0.01). Graft survival was 95%, 98%, 97% and 89%, respectively, at 1 year and 95%, 85%, 77% and 89%, respectively, at 5 years, which was not significantly different. The duration of DGF in NHB kidneys has a negative effect on creatinine clearance, but no effect on graft survival.     

High Dose Epoetin Beta in the First Weeks Following Renal Transplantation and Delayed Graft Function: Results of the Neo‐PDGF Study

Erythropoietin promotes nephroprotection in animal models of ischemia‐reperfusion injury. Neorecormon^® and Prevention of Delayed Graft Function (Neo‐PDGF) is a French open‐label multicenter randomized study to evaluate the effect of high doses of epoetin beta (EPO‐β) during the first 2 weeks of renal transplantation on renal function in patients at risk for delayed graft function (DGF). One hundred and four patients were included in the study. Patients randomized in treatment group (A) received four injections of EPO‐β (30.000 UI each), given before surgery and at 12 h, 7 days and 14 days posttransplantation. Patients randomized in control group (B) did not receive EPO‐β. Immunosuppression included induction with basiliximab and maintenance therapy with steroids, mycophenolate mofetil and tacrolimus. At 1 month posttransplant, the estimated glomerular filtration rate (MDRD formula) was 42.5 ± 19.0 mL/min in the EPO‐β group and 44.0 ± 16.3 mL/min in the control group (p = ns). The frequency of DGF was similar in both groups (32% vs. 38.8%; p = ns). No difference in the incidence of serious adverse events was observed. (ClinicalTrials.gov number, NCT00815867.)     

Earlier Is Not Necessarily Better in Preemptive Kidney Transplantation

While preemptive (before chronic dialysis) transplantation is associated with improved graft survival, it is unclear whether higher versus lower pretransplant kidney function is associated with even better graft survival after preemptive transplantation. We examined 671 first, preemptive, kidney‐only transplantations at Hennepin County Medical Center and the University of Minnesota Medical Center 1984–2006. We estimated pretransplant glomerular filtration rate (eGFR, mL/min/1.73 m²) using the Modification of Diet in Renal Disease (MDRD) equation with Group 1: <10.0 (7.3 ± 1.7, N = 324), Group 2: 10.0–14.9 (12.0 ± 1.4, N = 217) and Group 3: ≥15.0 (21.1 ± 10.0, N = 130). The mean difference in eGFR for Group 1 versus 3 was 13.8 pretransplant, 16.3 on day 1 and 13.9 on day 2 posttransplant. By week 1 and year 1 posttransplant, the differences between Groups 1 and 3 reduced to 6.3 and 4.5 mL/min/1.73 m², respectively. The adjusted relative risk (RR; Cox analysis) for graft failure was not significantly lower with higher pretransplant eGFR (reference eGFR <10.0); RR = 0.99 (95% confidence interval = 0.68–1.44, p = 0.9432) for eGFR 10.0–14.9; RR = 1.35 (0.89–2.05, p = 0.1588) for eGFR ≥15. Thus, early preemptive transplantation with higher eGFR does not necessarily improve graft survival after kidney transplantation, compared to preemptive transplantation with lower pretransplant eGFR.     

尿液中性粒细胞明胶酶相关脂质运载蛋白和白细胞介素18水平检测在移植肾功能延迟恢复早期预测中的应用价值

目的 评价尿液中性粒细胞明胶酶相关脂质运载蛋白(NGAL)和白细胞介素18(IL-18)水平检测在早期预测移植肾功能延迟恢复(DGF)中的价值.方法 采用ELISA法,连续监测86例肾移植患者术前和术后12、24 h尿液标本中NGAL,IL-18及视黄醇结合蛋白(RBP)水平,并分析其与DGF的关系. 结果 86例中发生DGF 15例.术后12 h DGF组尿NGAL(ng/mg)水平明显高于非DGF组(1712.7±474.6比863.1±199.8,P<0.001),尿IL-18(ng/mg)水平与非DGF组比较差异无统计学意义(29.2±4.1比28.7±4.2,P>0.05);术后24 h DGF组尿NGAL和IL-18水平均明显高于非DGF组(分别为2905.0±1108.1比911.8±221.0,211.3±34.0比86.9±22.8,均P<0.001);而尿RBP(μg/mmol)(92.7±17.1比92.8±13.8,P>0.05)和SCr值(μmol/L)(608.1±85.5比542.3±99.6,P>0.05)与非DGF组比较差异无统计学意义.ROC曲线下面积分析结果显示,术后12 h尿NGAL曲线下面积为0.90,cut-off值为996.5 ng/mg时,诊断敏感性90.2%,特异性82.6%;术后24 h IL-18曲线下面积为0.76,cut-off值为148.5 ng/mg时,诊断敏感性76.3%,特异性66.4%. 结论 尿NGAL及IL-18水平变化对早期预测DGF发生有重要的临床意义.     

Risk Factors and Impact of Delayed Graft Function after Pancreas Transplants

Delayed graft function (DGF) occurs after many pancreas transplants (PTx), but is poorly characterized. We studied its incidence, course, and impact in a series of 531 pancreas transplants. Between January 1997 and September 2002, we performed 531 technically successful primary PTx. Of these 531 recipients, 176 (33%) had DGF, defined by their need for exogenous insulin at the time of hospital discharge. The incidence of DGF was roughly equivalent in the three transplant categories: SPK (36%), PAK (32%), and PTA (31%) (p = NS). By 3 months posttransplant, only 19 (3.5%) of all recipients remained on insulin. Only three recipients (0.56%) did not achieve insulin independence. The mean donor age of recipients with DGF was 35.1 years vs. 28.8 years without DGF (p = 0.003). By multivariate analysis, the most significant risk factor for DGF was donor age > 45 years (RR = 4.3, p = 0.0001). For SPK recipients with DGF, graft survival was 87% at 1 year and 82% at 3 years posttransplant; without DGF, 94% at 1 year and 87% at 3 years (p = 0.07). For PAK and PTA recipients, no difference was noted. Acute rejection rates were somewhat higher in recipients with DGF, but this did not reach statistical significance.     

Fate of the Mate: The Influence of Delayed Graft Function in Renal Transplantation on the Mate Recipient

Delayed graft function (DGF) in a deceased-donor renal recipient is associated with allograft dysfunction 1-year posttransplant. There is limited research about the influence to allograft function on the mate of a DGF recipient over time . Using a retrospective cohort design, we studied 55 recipients from a single center. The primary outcome was the change in glomerular filtration rate (GFR) 1-year posttransplant. The secondary outcome was the GFR at baseline. We found that mates to DGF recipients had a mean change in GFR 1-year posttransplant of −11.2 mL/min, while the control group had a mean change of −0.4 mL/min. The difference in the primary outcome was significant (p = 0.025) in a multivariate analysis, adjusting for cold ischemic time, panel reactive antibody level, allograft loss, human leukocyte antibody (HLA)-B mismatches and HLA-DR mismatches. No significant difference between groups was found in baseline GFR. In conclusion, mates to DGF recipients had a significantly larger decline in allograft function 1-year posttransplant compared to controls with similar renal function at baseline. We believe strategies that may preserve allograft function in these ' at-risk ' recipients should be developed and tested.     

Creatinine Reduction Ratio on Post-Transplant Day Two as Criterion in Defining Delayed Graft Function

Delayed graft function (DGF) is a common complication after renal transplant, affecting its outcome. A common definition of DGF is the need for dialysis within the first week of transplantation, but this criterion has its drawbacks. We tried to validate an earlier and better defined parameter of DGF based on the creatinine reduction ratio on post-transplant day 2 (CRR2). We analyzed the clinical charts of 291 cadaver kidney recipients to compare the outcome of patients with immediate graft function (IGF), dialyzed patients (D-DGF) and nondialyzed CRR2-defined DGF patients (ND-DGF) and to identify risk factors for D-DGF and ND-DGF. Creatinine reduction ratio on post-transplant day 2 correlates significantly with renal function during the first year. Patients with IGF have significantly better renal function throughout the first year and better graft survival than patients with D-DGF and ND-DGF, while we found no differences either in renal function from days 30-365 or in graft survival between D-DGF and ND-DGF patients. Defining DGF by CRR2 allows an objective and quantitative diagnosis after transplantation and can help to improve post-transplant management. Creatinine reduction ratio on post-transplant day 2 correlates with renal function throughout the first year. The worse survival in the ND-DGF group is an important finding and a major advantage of the CRR2 criterion.     

Pulsatile Perfusion Reduces the Incidence of Delayed Graft Function in Expanded Criteria Donor Kidney Transplantation

The use of expanded criteria donors (ECD) has been proposed to help combat the discrepancy between organ availability and need. ECD kidneys are associated with delayed graft function (DGF) and worse long-term survival. The aim of this study is to evaluate the impact of pulsatile perfusion (PP) on DGF and graft survival in transplanted ECD kidneys. From January 2000 to December 2003, 4618 ECD kidney-alone transplants were reported to the United Network for Organ Sharing. PP was performed on 912 renal allografts. The prognostic factors of DGF were analyzed using multivariate logistic regression analysis. Risk factors for reduced allograft viability were greater in donors and recipients of PP kidneys. Three-year graft survival of ECD kidneys preserved with PP was similar to cold storage (CS) kidneys. The incidence of DGF in PP kidneys was significantly lower than CS kidneys (26% vs. 36%, p < 0.001). Despite having a greater number of risk factors for reduced graft viability, the ECD-PP kidneys had similar graft survival compared to ECD-CS kidneys. The use of PP, by decreasing the incidence of DGF, may possibly lead to lower overall costs and increased utilization of donor kidneys.