Acute kidney injury (AKI) is a syndrome that is associated with a major burden of morbidity and mortality in a variety of high risk patient populations, many of them cared for by intensivists. Following renal transplantation, delayed graft function (DGF) caused by severe acute tubular necrosis (ATN), defined by a requirement for dialysis during the initial post-transplant week, complicates postoperative management, and if prolonged (>14 days), adversely affects allograft survival. Neutrophil gelatinase-associated lipocalin (NGAL) and other novel biomarkers can detect AKI earlier than serum creatinine, and can predict AKI severity in high risk patient populations, including kidney transplant recipients. Hollmen and colleagues now demonstrate that elevated urine NGAL in deceased kidney donors is a significant risk factor for prolonged post-transplant DGF in recipients. These findings have clear implications with regard to potentially improved assessment of deceased donor suitability for potential renal allograft donation. These findings are also consistent with the growing evidence that severe ATN diagnosed by markedly elevated levels of AKI biomarkers is a useful predictor of the requirement for acute renal replacement therapy in AKI patients.
Expanding the criteria for deceased organ donors increases the risk of delayed graft function (DGF) and complicates kidney transplant outcome. We studied whether donor neutrophil gelatinase-associated lipocalin (NGAL), a novel biomarker for acute kidney injury, could predict DGF after transplantation.
We included 99 consecutive, deceased donors and their 176 kidney recipients. For NGAL detection, donor serum and urine samples were collected before the donor operation. The samples were analyzed using a commercial enzyme-linked immunosorbent assay kit (serum) and the ARCHITECT method (urine).
Mean donor serum NGAL (S-NGAL) concentration was 218 ng/mL (range 27 to 658, standard deviation (SD) 145.1) and mean donor urine NGAL (U-NGAL) concentration was 18 ng/mL (range 0 to 177, SD 27.1). Donor S-NGAL and U-NGAL concentrations correlated directly with donor plasma creatinine levels and indirectly with estimated glomerular filtration rate (eGFR) calculated using the modification of diet in renal disease equation for glomerular filtration rate. In transplantations with high (greater than the mean) donor U-NGAL concentrations, prolonged DGF lasting longer than 14 days occurred more often than in transplantations with low (less than the mean) U-NGAL concentration (23% vs. 11%, P = 0.028), and 1-year graft survival was worse (90.3% vs. 97.4%, P = 0.048). High U-NGAL concentration was also associated with significantly more histological changes in the donor kidney biopsies than the low U-NGAL concentration. In a multivariate analysis, U-NGAL, expanded criteria donor status and eGFR emerged as independent risk factors for prolonged DGF. U-NGAL concentration failed to predict DGF on the basis of receiver operating characteristic curve analysis.
This first report on S-NGAL and U-NGAL levels in deceased donors shows that donor U-NGAL, but not donor S-NGAL, measurements give added value when evaluating the suitability of a potential deceased kidney donor.
To better understand the implications for considering delayed graft function (DGF) a performance measure, we compared outcomes associated with a 2- to 3-fold difference in the incidence of DGF at 2 transplant centers. We analyzed 5072 kidney transplantations between 1984–2006 at the University of Minnesota Medical Center (UMMC) and Hennepin County Medical Center (HCMC). In logistic regression the adjusted odds ratio for DGF at HCMC versus UMMC was 3.11 (95% Confidence Interval [CI]=2.49–3.89) for deceased donors and 2.24 (CI=1.45–3.47) for living donors. In Cox analysis of 4957 transplantations, slow graft function [SGF; creatinine >3.0 mg/dL (230 μmol/L) on day 5 without dialysis] was associated with graft failure at UMMC (Relative Risk [RR] =1.43, CI=1.25–1.64), but not HCMC (RR=0.99, CI=0.77–1.28). RR’s of DGF were similar at both centers. Thus, the lower incidence of DGF at UMMC likely resulted in a higher incidence and higher risk of SGF compared to HCMC. Indeed, graft survival for recipients with DGF at HCMC was similar (p=0.3741) to that of recipients with SGF at UMMC. We conclude that dialysis per se is likely not a cause of worse graft outcomes. A better definition is needed to measure early graft dysfunction and its effects across transplant programs.
Acute kidney injury occurs with kidney transplantation and too frequently progresses to the clinical diagnosis of delayed graft function (DGF). Poor kidney function in the first week of graft life is detrimental to the longevity of the allograft. Challenges to understand the root cause of DGF include several pathologic contributors derived from the donor (ischemic injury, inflammatory signaling) and recipient (reperfusion injury, the innate immune response, and the adaptive immune response). Progressive demand for renal allografts has generated new organ categories which continue to carry high risk for DGF for deceased donor organ transplantation. New therapies seek to subdue the inflammatory response in organs with high likelihood to benefit from intervention. Future success in suppressing the development of DGF will require a concerted effort to anticipate and treat tissue injury throughout the arc of the transplantation process.
Background. The term delayed graft function (DGF) is commonly used to describe the need for dialysis after receiving a kidney transplant. DGF increases morbidity after transplantation, prolongs hospitalization and may lead to premature graft failure. Various definitions of DGF are used in the literature without a uniformly accepted technique to identify DGF.
Methods. We performed a systematic review of the literature to identify all of the different definitions and diagnostic techniques to identify DGF.
Results. We identified 18 unique definitions for DGF and 10 diagnostic techniques to identify DGF.
Conclusions. The utilization of heterogeneous clinical criteria to define DGF has certain limitations. It will lead to delayed and sometimes inaccurate diagnosis of DGF. Hence a diagnostic test that identifies DGF reliably and early is necessary. Heterogeneity, in the definitions used for DGF, hinders the evolution of a diagnostic technique to identify DGF, which requires a gold standard definition. We are in need of a new definition that is uniformly accepted across the kidney transplant community. The new definition will be helpful in promoting better communication among transplant professionals and aids in comparing clinical studies of diagnostic techniques to identify DGF and thus may facilitate clinical trials of interventions for the treatment of DGF.
delayed graft function; definition; diagnosis
Recent studies have demonstrated that the actions of platelets may unfavorably influence post-transplant function of organ allografts. In this study, the association between post-transplant graft function and the perioperative activity of platelet antioxidants was examined among kidney recipients divided into early (EGF), slow (SGF), and delayed graft function (DGF) groups.
Activities of superoxide dismutase, catalase, glutathione transferase (GST), glutathione peroxidase, and glucose-6-phosphate dehydrogenase (G6P) were determined and levels of glutathione, oxidized glutathione, and isoprostane were measured in blood samples collected immediately before and during the first and fifth minutes of renal allograft reperfusion. Our results demonstrated a significant increase in isoprostane levels in all groups. Interestingly, in DGF patients, significantly lower levels of perioperative activity of catalase (p<0.02) and GST (p<0.02) were observed. Moreover, in our study, the activity of platelet antioxidants was associated with intensity of perioperative oxidative stress. For discriminating SGF/DGF from EGF, sensitivity, specificity, and positive and negative predictive values of platelet antioxidants were 81–91%, 50–58%, 32–37%, and 90–90.5%, respectively.
During renal transplantation, significant changes occur in the activity of platelet antioxidants. These changes seem to be associated with post-transplant graft function and can be potentially used to differentiate between EGF and SGF/DGF. To the best of our knowledge, this is the first study to reveal the potential protective role of platelets in the human transplantation setting.
Delayed renal allograft survival (DGF) after a deceased donor kidney transplant is associated with an increased risk of allograft loss. Inflammatory response and apoptosis are associated with increased risk of DGF.
Cross Sectional Study
Setting & Participants
We first recruited 616 recipients of kidneys from 512 deceased kidney donors and the donor DNA was genotyped. These recipients who were included in a prospective cohort study of 9 transplant centers in the Delaware Valley region, had their DGF outcome obtained through medical record abstraction. Then, we identified the recipient (n=349) of the contralateral deceased kidney donor, if not part of the cohort, through the USRDS registry. The final cohort consisted of 965 recipients of deceased donor kidneys from 512 donors.
Donor single nucleotide polymorphisms (SNPs) in genes for tumor necrosis factor α (TNF), transforming growth factor β1 (TGFB1), interleukin 10 (IL10), p53 (TP53), and heme oxygenase 1 (HMOX1).
DGF, defined as need for dialysis in the first week post-transplant. Secondary outcomes included acute rejection and eGFR.
Information on DGF, acute rejection and eGFR for recipients in the Delaware Valley Cohort was obtained through medical record abstraction. For other recipients, information on DGF was obtained from UNOS forms and CMS claims in the USRDS registry.
The TGFB1, IL10, TP53 and HMOX1 genes were not associated with DGF. The G allele of TNF polymorphism rs3093662 was associated with DGF in an adjusted analysis (OR= 1.85 compared to A allele, 95% C.I.=1.16–2.96, p=0.01). However this association does not achieve statistical significance after adjusting for multiple comparisons.
Inadequate sample size for infrequent genotypes and multiple comparisons.
Due to the low frequency of donor SNPs of interest, a larger sample size and replication are necessary for conclusive evidence for the association of donor genotypes with DGF.
Kidney Transplant; Deceased Donor Genotypes; Delayed Graft Function
To investigate the possibility that we have been underestimating the true incidence of acute rejection, we began to perform protocol biopsies after kidney transplantation. This analysis looks at the one-week biopsies. Between March 1 and October 1, 1999, 100 adult patients undergoing cadaveric kidney or kidney/pancreas transplantation, or living donor kidney transplantation, underwent 277 biopsies. We focused on the subset of biopsies in patients without delayed graft function (DGF) and with stable or improving renal function, who underwent a biopsy 8.2 ± 2.6 d (range 3–18 d) after transplantation (n = 28). Six (21 %) patients with no DGF and with stable or improving renal function had borderline histopathology, and 7 (25%) had acute tubulitis on the one-week biopsy. Of the 277 kidney biopsies, there was one (0.4%) serious hemorrhagic complication, in a patient receiving low molecular weight heparin; she ultimately recovered and has normal renal function. Her biopsy showed Banff 1 B tubulitis. In patients with stable or improving renal allograft function early after transplantation, subclinical tubulitis may be present in a substantial number of patients. This suggests that the true incidence of rejection may be higher than is clinically appreciated.
High incidence; protocol biopsies; subclinical acute tubulitis
Pulsatile machine perfusion (PMP) has been shown to reduce delayed graft function (DGF) in expanded criteria donor (ECD) kidneys. Here, we investigate whether there is a cost benefit associated with PMP utilization in ECD kidney transplants. We analyzed United States Renal Data System (USRDS) data describing Medicare-insured ECD kidney transplant recipients in 1995-2004 (N=5,840). We examined total Medicare payments for transplant hospitalization and annually for three years post-transplant according to PMP utilization. After adjusting for other recipient, donor and transplant factors, PMP utilization was associated with a $2,131 reduction (p = 0.007) in hospitalization costs. PMP utilization was also associated with lower DGF risk (p<0.0001). PMP utilization did not predict differences in rejection, graft survival, patient survival, or costs at one, two and three years post transplant. PMP utilization is correlated with lower costs for the transplant hospitalization, which is likely due to the associated reduction in DGF among recipients of PMP kidneys. However, there is no difference in long-term Medicare costs for ECD recipients by PMP utilization. A prospective trial is necessary as it will help determine if the associations seen here are due to PMP utilization and not differences in the population studied.
kidney transplantation; expanded criteria donors; pulsatile machine perfusion; delayed graft function; Medicare; cost benefits
The association between pre-transplant serum albumin concentration and post-transplant outcomes in kidney transplant recipients is unclear. We hypothesized that in transplant-waitlisted hemodialysis patients, lower serum albumin concentrations are associated with worse post-transplant outcomes.
Linking the 5-year patient data of a large dialysis organization (DaVita) to the Scientific Registry of Transplant Recipients, we identified 8961 hemodialysis patients who underwent first kidney transplantation. Mortality or graft failure and delayed graft function (DGF) risks were estimated by Cox regression (hazard ratio [HR]) and logistic regression (Odds ratio [OR]), respectively.
Patients were 48±13 years old and included 37% women and 27% diabetics. The higher pre-transplant serum albumin was associated with lower mortality, graft failure and DGF risk even after multivariate adjustment for case-mix, malnutrition-inflammation complex and transplant related variable. Every 0.2 g/dL higher pre-transplant serum albumin concentration was associated with 13% lower all-cause mortality (HR=0.87 [95% confidence interval: 0.82-0.93]), 17% lower cardiovascular mortality (HR=0.83[0.74-0.93]), 7% lower combined risk of death or graft failure (HR=0.93[0.89-0.97]), and 4% lower DGF risk (OR=0.96[0.93-0.99]).
Hence, lower pre-transplant serum albumin level is associated with worse post-transplant outcomes. Clinical trials to examine interventions to improve nutritional status in transplant-wait-listed hemodialysis patients and their impacts on post-transplant outcomes are indicated.
Hypoalbuminemia; kidney transplantation; malnutrition-inflammation complex; mortality; cardiovascular death; graft failure; delayed graft function (DGF)
Administration of HMG-CoA reductase inhibitors (statins), prior to ischemia or prior to reperfusion has been shown to decrease ischemia-reperfusion renal injury in animal studies. It is unknown whether this protective effect is applicable to renal transplantation in humans. The aim of this study was to determine the relationship between prior statin use in renal transplant recipients and the subsequent risk of delayed graft function.
All patients who underwent deceased or living donor renal transplantation at the Princess Alexandra Hospital between 1 July 2008 and 1 August 2010 were included in this retrospective, observational cohort study. Graft function was classified as immediate graft function (IGF), dialysis-requiring (D-DGF) and non-dialysis-requiring (ND-DGF) delayed graft function. The independent predictors of graft function were evaluated by multivariable logistic regression, adjusting for donor characteristics, recipient characteristics, HLA mismatch and ischaemic times.
Overall, of the 266 renal transplant recipients, 21% exhibited D-DGF, 39% had ND-DGF and 40% had IGF. Statin use prior to renal transplantation was not significantly associated with the risk of D-DGF (adjusted odds ratio [OR] 1.05, 95% CI 0.96 – 1.15, P = 0.28). This finding was not altered when D-DGF and ND-DGF were pooled together (OR 0.98; 95% CI 0.89-1.06, p = 0.56).
The present study did not show a significant, independent association between prior statin use in kidney transplant recipients and the occurrence of delayed graft function.
Delayed graft function (DGF), defined as the need for dialysis during the first week after renal transplantation, is an important adverse clinical outcome. A previous model relied on 16 variables to quantify the risk of DGF, thereby undermining its clinical usefulness. We explored the possibility of developing a simpler, equally accurate and more user-friendly paradigm for renal transplant recipients from deceased donors.
Logistic regression analyses addressed the occurrence of DGF in 532 renal transplant recipients from deceased donors. Predictors consisted of recipient age, gender, race, weight, number of HLA-A, HLA-B and HLA-DR mismatches, maximum and last titre of panel reactive antibodies, donor age and cold ischemia time. Accuracy was quantified with the area under the curve. Two hundred bootstrap resamples were used for internal validation.
Delayed graft function occurred in 103 patients (19.4%). Recipient weight (p < 0.001), panel of reactive antibodies (p < 0.001), donor age (p < 0.001), cold ischemia time (p = 0.005) and HLA-DR mismatches (p = 0.05) represented independent predictors. The multivariable nomogram relying on 6 predictors was 74.3% accurate in predicting the probability of DGF.
Our simple and user-friendly model requires 6 variables and is at least equally accurate (74%) to the previous nomogram (71%). We demonstrate that DGF can be accurately predicted in different populations with this new model.
Most studies have found cold ischemic time to be an important predictor of delayed graft function in kidney transplantation. Relatively less is known about the warm time associated with vascular anastomosis and early outcomes.
A retrospective cohort of 298 consecutive solitary deceased donor kidney recipients from January 2006 to August 2012 was analyzed to examine the association between anastomosis time and delayed graft function (need for dialysis) and length of hospital stay.
Delayed graft function (DGF) was observed in 56 patients (18.8%). The median anastomosis time was 30 minutes (interquartile range 24, 45 minutes). Anastomosis time was independently associated with DGF in a multivariable, binary logistic regression analysis (odds Ratio (OR) 1.037 per minute, 95% CI 1.016, 1.057, P = 0.001). An anastomosis time >29 minutes was also associated with a 3.5 fold higher (OR 3.5, 95% CI 1.6, 7.3, P = 0.001) risk of DGF. Median days in hospital was 9 (interquartile range 7, 14 days). Every 5 minutes of longer anastomosis time (0.20 days per minute, 95% CI 0.13, 0.27, P <0.001) was associated with 1 extra day in hospital in a multivariable linear regression model. An anastomosis time >29 minutes was associated with 3.8 (95% CI 1.6, 6.0, P <0.001) more days in hospital.
Anastomosis time may be an underappreciated but modifiable variable in dictating use of hospital resources. The impact of anastomosis time on longer term outcomes deserves further study.
Delayed graft function; Warm ischemic time; Cold ischemic time; Hospitalization
Primary nonfunction (PNF) accounts for 0.6 to 8% of renal allograft failure, and the focus on causes of PNF has changed from rejection to other causes. Calcium oxalate (CaOx) deposition is common in early allograft biopsies, and it contributes in moderate intensity to higher incidence of acute tubular necrosis and poor graft survival. A-49-year old male with ESRD secondary to polycystic kidney disease underwent extended criteria donor kidney transplantation. Posttransplant, patient developed delayed graft function (DGF), and the biopsy showed moderately intense CaOx deposition that persisted on subsequent biopsies for 16 weeks, eventually resulting in PNF. The serum oxalate level was 3 times more than normal at 85 μmol/L (normal <27 μmol/L). Allograft nephrectomy showed massive aggregates of CaOx crystal deposition in renal collecting system. In conclusion, acute oxalate nephropathy should be considered in the differential diagnosis of DGF since optimal management could change the outcome of the allograft.
Donation after cardiac death (DCD) has led to an increase of up to 40% in the number of kidney transplants in some programs. Unfortunately, the increase in warm ischemic time results in higher rates of delayed graft function (DGF). The purpose of our study was to examine our initial 5-year experience with DCD kidney transplantation and to determine the factors involved in early postoperative function and function at 1 year.
This retrospective study included a review of the recipient and donor charts of 63 DCD kidneys retrieved and transplanted by the London Multi-Organ Transplant Program between July 2006 and October 2011. Comparisons were carried out between our early (n=31, July 2006 to January 2009) and our recent experience (n=32, March 2009 to October 2011). DGF and creatinine clearance at 3, 7 and 365 days were examined with regression analyses.
DGF was seen in 65% of transplanted kidneys. Mean creatinine clearance (CrCl) at 1 year was 66.7 mL/min. Low pre-transplant recipient daily urine output was the most statistically significant predictor of DGF in multivariate analysis (p < 0.001). In comparisons between our early and more recent results, improvements were noted in time from asystole to flush (16.0 vs. 12.0 minutes, p = 0.003), while cold ischemic time increased (464 vs. 725 minutes, p = 0.006). Experience contributed to a significant reduction in hospital length of stay (16 vs. 13 days, p = 0.035) and improved early renal function (CrCl at 3 days 7.8 vs. 11.9 mL/min, p = 0.027). The use of machine cold perfusion and higher recipient preoperative daily urine output predicted improved early renal function, while increasing donor age predicted poorer function at 1 year.
Despite early DGF, our results justify the continued transplantation of kidneys from DCD donors.
The purpose of this human study was to investigate the effect of oxygen pretreatment in living kidney donors on early renal function of transplanted kidney. Sixty living kidney donor individuals were assigned to receive either 8–10 L/min oxygen (Group I) by a non-rebreather mask with reservoir bag intermittently for one hour at four times (20, 16, 12, and 1 hours before transplantation) or air (Group II). After kidney transplantation, urine output, blood urea nitrogen (BUN), serum creatinine, need to additional diuretics (NTADs) in the first 24 hours after transplantation, delayed graft function (DGF), the creatinine clearance (CrCL) on 10th day, and duration of hospital stay from the first posttransplant day till normalization of renal function was recorded and compared in two groups. Mean CrCL in posttransplant day 10, NTAD after 24 hours of transplantation, and urine output during 6 hours after operation were significantly better in Group I compared with Group II (P < .05). Also, DGF during the first week after operation and duration of hospital stay was less in Group I compared with Group II. Intermittent exposure of human living kidney donor to hyperoxic environment may improve renal function following kidney transplantation.
The role of pre-transplant erythropoiesis-stimulating agent (ESA) responsiveness in affecting post-transplant outcomes is not clear.
Linking the 5-year patient data of a large dialysis organization to the ‘Scientific Registry of Transplant Recipients’, we identified 8795 hemodialyzed patients who underwent first kidney transplantation. Mortality or graft failure, delayed graft function (DGF) and acute rejection risks were estimated by Cox regression [hazard ratio (HR)] and logistic regression, respectively.
Patients were 48 ± 14 years old and included 38% women and 36% diabetics. Compared to renal allograft recipients who were in the first quartile of pre-transplant ESA responsiveness index (ERI), i.e. ESA dose divided by hemoglobin and weight, recipients in second, third and fourth quartiles had higher adjusted graft-censored death HR (and 95% confidence intervals) of 1.7 (1.0–2.7), 1.8 (1.1–2.9) and 2.3 (1.4–3.9) and higher death-censored graft failure HR of 1.6 (1.0–2.5), 2.0 (1.2–3.1) and 1.6 (0.9–2.6), respectively. No significant association between pre-transplant ERI and post-transplant DGF or acute rejection was detected.
Higher pre-transplant ERI during the hemodialysis treatment period was associated with worse post-transplant long-term outcomes including increased all-cause death and higher risk of graft failure.
anemia; erythropoietin-stimulating agent therapy; graft failure; kidney transplantation; mortality
Delayed graft function (DGF) following transplantation necessitates support in the form of hemodialyis (HD) or peritoneal dialysis (PD). However, post-transplant PD-related complication and failure rates are unknown.
We studies patients who were on PD at the time of kidney transplantation over a 4-year period at two separate institutions.
Of the 137 PD patients, 19 had their catheters removed at the time of transplant. Of the remaining 118 patients, 89% had immediate graft function. PD-related complications in this group included peritonitis (n=5), catheter-related infections (n=2) and emergency laparotomy (n=1). Of the 15 patients requiring post-transplant PD, 33% developed peritonitis and 20% had fluid-leaks necessitating HD. Overall, leaving a PD catheter in situ post- transplantation is associated with 7% rate of peritonitis versus 0% if removed (p < 0.05).
PD catheter removal should be considered at the time of renal transplantation, as postoperative PD-related failure/complication rates are high.
Many hypothesize that subtle inflammation and immune activity detected in the intraoperative period are linked to adverse postkidney transplant clinical outcomes. To this end, renal allografts were analyzed for expression of pro-inflammatory, inflammation-induced adhesion molecules, immune activation as well as anti-apoptotic genes expressed 15 min after vascular reperfusion (zero-hour) to determine whether this analysis can aid in predicting the occurrence of delayed graft function (DGF), acute rejection (AR), and the quality of graft function at 6 mo. Intraoperative biopsies were obtained from 75 consecutively performed renal allografts in which consent was obtained 15 min after vascular reperfusion. These biopsies were analyzed by quantitative real-time PCR for transcription of 15 select genes and by standard histopathology. Posttransplant clinical outcomes were also analyzed in respect to intraoperative transcriptional profiles and clinical parameters available at the time of transplantation. This study demonstrates that a limited and hypothesis-driven PCR-based transcriptional profile of the zero-hour kidney biopsy predicts posttransplant clinical outcomes including DGF, early AR, and the quality of renal function 6 mo posttransplantation. For some clinical endpoints, the combined use of molecular analysis and established clinical indicators available at the time of transplantation further enhances the quality of prognosis. The transcriptional profiling data provide absolutely essential data to the predictive models, particularly with respect to AR and renal function 6 mo posttransplantation.
In India, there are a large number of end-stage renal disease (ESRD) patients waiting for renal transplant. Deceased donor organ transplantation (DDOT) is the possible solution to bridge the disparity between organ supply and demand. The concept of expanded criteria donors (ECDs) was developed to combat the huge discrepancy between demand and organ availability. However, ECD kidneys have a higher propensity for delayed graft function (DGF), and therefore worse long-term survival. We present our experience of deceased donor renal transplantation.
We report single centre experience on DDOT including ECDs vis-à-vis patient/graft survival, graft function in terms of serum creatinine (SCr), rejection episodes, and delayed graft function in 44 DDOT
Materials and Methods:
Between August 1998 and April 2011, 44 renal transplants from 35 deceased donors were performed, of which 37.2% were expanded criteria donors. Results were analyzed in terms of age of donor, terminal SCr, graft ischemia time, graft function, post-transplant complications, and graft and patient survival. All recipients received sequential triple drug immunosuppression and induction with rabbit antithymocyte globulin (rATG). The induction is commenced by giving first dose of rATG intraoperatively (dose 1.5 mg/kg) and subsequent rATG infusions were administered daily for a minimum of 5 and maximum of 7 doses depending on initial graft function.
We have been able to achieve a mean cold ischemia time of 6.25 ± 2.55 h due to the coordinated team efforts. Delayed graft function occurred in 34% patients and 31.8% had prolonged drainage. There were no urinary leaks. Seven (16%) patients had biopsy-proven rejection episodes, all of which were reversed with treatment. Two patients underwent graft nephrectomy. One of these was due to hyperacute rejection and another due to anastomotic hemorrhage. One-year graft survival was 92.4% and the patient survival was 83.8%.
Deceased donor renal transplants have satisfactory graft function and patient survival despite the high incidence of delayed graft function. Retrieving kidneys from marginal donors can add to the donor pool.
Cold ischemia time; deceased donor; delayed graft function; end-stage renal disease
Urinary neutrophil gelatinase-associated lipocalin (uNGAL) is known to predict the prolonged delayed graft function after kidney transplantation. We examined the relation of uNGAL with histological findings of acute tubular injury (ATI). Analyses were made in biopsies taken at 6 weeks, 3 months, and 6 months after kidney transplantation. uNGAL was measured in the spot urines, normalized to urinary creatinine excretion, and correlated to biopsy findings and clinical, laboratory, and demographic variables. Controls included healthy individuals, individuals after kidney donation and ICU patients with acute kidney failure. Renal transplant recipients without ATI did not display elevated uNGAL levels compared to the healthy controls. Transplant patients with ATI had a higher uNGAL excretion at 6 weeks than patients without ATI (27,435 versus 13,605 ng/g; P = 0.031). This increase in uNGAL was minor compared to ICU patients with acute renal failure (2.05 × 106 ng/g). Patients with repeated findings of ATI or severe ATI did not have higher urinary NGAL levels compared to those with only one ATI finding or moderate ATI. Female recipient gender and urinary tract infection were identified as potential confounders. uNGAL has a relation with histological signs of acute tubular injury. The usability of this biomarker in renal allograft recipients is limited because of the low sensitivity.
Robust biomarkers are needed to identify donor kidneys with poor quality associated with inferior early and longer-term outcome. The occurrence of delayed graft function (DGF) is most often used as a clinical outcome marker to capture poor kidney quality. Gene expression profiles of 92 preimplantation biopsies were evaluated in relation to DGF and estimated glomerular filtration rate (eGFR) to identify preoperative gene transcript changes associated with short-term function. Patients were stratified into those who required dialysis during the first week (DGF group) versus those without (noDGF group) and subclassified according to 1-month eGFR of >45 mL/min (eGFRhi) versus eGFR of ≤45 mL/min (eGFRlo). The groups and subgroups were compared in relation to clinical donor and recipient variables and transcriptome-associated biological pathways. A validation set was used to confirm target genes. Donor and recipient characteristics were similar between the DGF versus noDGF groups. A total of 206 probe sets were significant between groups (P < 0.01), but the gene functional analyses failed to identify any significantly affected pathways. However, the subclassification of the DGF and noDGF groups identified 283 probe sets to be significant among groups and associated with biological pathways. Kidneys that developed postoperative DGF and sustained an impaired 1-month function (DGFlo group) showed a transcriptome profile of significant immune activation already preimplant. In addition, these kidneys maintained a poorer transplant function throughout the first-year posttransplant. In conclusion, DGF is a poor marker for organ quality and transplant outcome. In contrast, preimplant gene expression profiles identify “poor quality” grafts and may eventually improve organ allocation.
The improvement in the field of kidney transplantation, during the last decades, has brought kindey transplantation to the top of patient preference as the best kidney replacement therapy1. The use of marginal kidney grafts, which are highly immunogenic has become common practice because of lack of kidney donors. Inflammatory activity in the kidneys after brain death is an ongoing phenomenon. The inappropriate treatment of brain dead donor may result to primary non function (PNF) of the graft, delayed graft function (DGF) or to long term graft dysfunction and shortened graft survival. Therefore correct handling of the brain dead donor is of paramount importance. The impact of various pharmacologic agents (catecholamines, glucocorticoids, carbamylated recombinant human erythropoietin, recombinant soluble P-selectin glycoprotein ligant, heme oxygenase-1, carbon monoxide, and mycophenolate mofetil) on the immunogemicity of brain dead donor kidneys is discussed.
brain death; kidney donor; kidney transplantation; immunosuppression; immunointervention; cortico steroids; mycophenolate mofetil; cyclosporine A
Increasing evidence accumulates on the central involvement of microRNAs (miRNAs) in disease pathophysiology. We identified distinctly deregulated miRNAs in human renal allograft biopsies from patients undergoing acute cellular rejection, antibody-mediated rejection (ABMR), and delayed graft function (DGF).
Sixty-five posttransplantation kidney biopsy samples covering 41 cases with acute rejection (15 vascular rejection, 15 interstitial rejection, and 11 ABMR), 14 DGF cases, and 10 protocol biopsies serving as controls were analyzed using the Affymetrix GeneChip miRNA Array. Differentially regulated miRNAs were identified by Student’s t test and Bonferroni correction. Target genes for the set of miRNAs were retrieved from miRTarBase (experimentally verified targets) as well as by applying the target prediction routines DIANAmT, miRanda, and Targetscan.
Patients with acute cellular rejection, ABMR, and DGF discriminate from the control group (protocol biopsies) in unsupervised clustering of miRNA profiles, clearly identifying deregulated miRNAs in rejection and DGF. Angiogenesis, apoptosis, and transforming growth factor-β signaling were identified as relevant pathways in ischemic response following an integrative analysis of miRNA targets and mRNA expression profiles. Inflammation by chemokine and cytokine signaling, T-cell activation, and B-cell activation were identified as relevant in acute rejection accordingly.
These data suggest that distinct miRNA signatures playing a role in specific biological pathways discriminate acute cellular and humoral rejection and DGF. This finding serves as valuable tool for a rational selection of diagnostic, prognostic, and potentially therapeutic molecular targets of posttransplantation events.
Acute rejection; Antibody-mediated rejection; Delayed graft function; miRNA; Integrative bioinformatics
Impaired renal function and/or pre-existing atherosclerosis in the deceased donor increase the risk of delayed graft function and impaired long-term renal function in kidney transplant recipients.
We report delayed graft function occurring simultaneously in two kidney transplant recipients, aged 57-years-old and 39-years-old, who received renal allografts from the same deceased donor. The 62-year-old donor died of cardiac arrest during an asthmatic state. Renal-allograft biopsies performed in both kidney recipients because of delayed graft function revealed cholesterol-crystal embolism. An empiric statin therapy in addition to low-dose acetylsalicylic acid was initiated. After 10 and 6 hemodialysis sessions every 48 hours, respectively, both renal allografts started to function. Glomerular filtration rates at discharge were 26 ml/min/1.73m2 and 23.9 ml/min/1.73m2, and remained stable in follow-up examinations. Possible donor and surgical procedure-dependent causes for cholesterol-crystal embolism are discussed.
Cholesterol-crystal embolism should be considered as a cause for delayed graft function and long-term impaired renal allograft function, especially in the older donor population.