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1.  Diagnosis of kidney damage using novel acute kidney injury biomarkers: assessment of kidney function alone is insufficient 
Critical Care  2011;15(4):170.
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.
PMCID: PMC3226312  PMID: 21740601
2.  Gene Expression Profile in Delay Graft Function: Inflammatory Markers Are Associated with Recipient and Donor Risk Factors 
Mediators of Inflammation  2014;2014:167361.
Background. Delayed graft function (DGF) remains an important problem after kidney transplantation and reduced long-term graft survival of the transplanted organ. The aim of the present study was to determine if the development of DGF was associated with a specific pattern of inflammatory gene expression in expanded criteria of deceased donor kidney transplantation. Also, we explored the presence of correlations between DGF risk factors and the profile that was found. Methods. Seven days after kidney transplant, a cDNA microarray was performed on biopsies of graft from patients with and without DGF. Data was confirmed by real-time PCR. Correlations were performed between inflammatory gene expression and clinical risk factors. Results. From a total of 84 genes analyzed, 58 genes were upregulated while only 1 gene was downregulated in patients with DGF compared with no DGF (P = 0.01). The most relevant genes fold changes observed was IFNA1, IL-10, IL-1F7, IL-1R1, HMOX-1, and TGF-β. The results were confirmed for IFNA1, IL-1R1, HMOX-1 and TGF-β. A correlation was observed between TGF-β, donor age, and preablation creatinine, but not body mass index (BMI). Also, TGF-β showed an association with recipient age, while IFNA1 correlated with recipient BMI. Furthermore, TGF-β, IFNA1 and HMOX-1 correlated with several posttransplant kidney function markers, such as diuresis, ultrasound Doppler, and glycemia. Conclusions. Overall, the present study shows that DGF is associated with inflammatory markers, which are correlated with donor and recipient DGF risk factors.
PMCID: PMC4052172  PMID: 24959002
3.  Deceased donor neutrophil gelatinase-associated lipocalin and delayed graft function after kidney transplantation: a prospective study 
Critical Care  2011;15(3):R121.
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.
PMCID: PMC3218974  PMID: 21545740
4.  Similar Outcomes with Different Rates of Delayed Graft Function May Reflect Center Practice, Not Center Performance 
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.
PMCID: PMC2758075  PMID: 19459804
5.  Delayed Graft Function in the Kidney Transplant 
American Journal of Transplantation  2011;11(11):2279-2296.
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.
PMCID: PMC3280444  PMID: 21929642
6.  Marked variation in the definition and diagnosis of delayed graft function: a systematic review 
Nephrology Dialysis Transplantation  2008;23(9):2995-3003.
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.
PMCID: PMC2727302  PMID: 18408075
delayed graft function; definition; diagnosis
7.  Neutrophil Gelatinase-Associated Lipocalin in Kidney Transplantation Is an Early Marker of Graft Dysfunction and Is Associated with One-Year Renal Function 
Journal of Transplantation  2013;2013:650123.
Urinary neutrophil gelatinase-associated lipocalin (uNGAL) has been suggested as potential early marker of delayed graft function (DGF) following kidney transplantation (KTx). We conducted a prospective study in 40 consecutive KTx recipients to evaluate serial changes of uNGAL within the first week after KTx and assess its performance in predicting DGF (dialysis requirement during initial posttransplant week) and graft function throughout first year. Urine samples were collected on post-KTx days 0, 1, 2, 4, and 7. Linear mixed and multivariable regression models, receiver-operating characteristic (ROC), and areas under ROC curves were used. At all-time points, mean uNGAL levels were significantly higher in patients developing DGF (n = 18). Shortly after KTx (3–6 h), uNGAL values were higher in DGF recipients (on average +242 ng/mL, considering mean dialysis time of 4.1 years) and rose further in following days, contrasting with prompt function recipients. Day-1 uNGAL levels accurately predicted DGF (AUC-ROC = 0.93), with a performance higher than serum creatinine (AUC-ROC = 0.76), and similar to cystatin C (AUC-ROC = 0.95). Multivariable analyses revealed that uNGAL levels at days 4 and 7 were strongly associated with one-year serum creatinine. Urinary NGAL is an early marker of graft injury and is independently associated with dialysis requirement within one week after KTx and one-year graft function.
PMCID: PMC3833111  PMID: 24288591
8.  Association between the Perioperative Antioxidative Ability of Platelets and Early Post-Transplant Function of Kidney Allografts: A Pilot Study 
PLoS ONE  2012;7(1):e29779.
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.
Methodology/Principal Findings
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.
PMCID: PMC3261166  PMID: 22279544
9.  Association of Donor Inflammation– and Apoptosis-Related Genotypes and Delayed Allograft Function after Kidney Transplantation 
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.
Study Design
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.
PMCID: PMC2562522  PMID: 18640487
Kidney Transplant; Deceased Donor Genotypes; Delayed Graft Function
10.  Influence of steroid maintenance on the outcomes in deceased donor kidney transplant recipients experiencing delayed graft function 
Indian Journal of Nephrology  2013;23(6):403-408.
Delayed graft function (DGF) is a risk factor for poor long-term graft and patient survival after kidney transplantation. The aim of our study was to explore the beneficial effect of steroid maintenance on outcomes in deceased donor kidney (DDK) transplant recipients with DGF. Using organ procurement and transplant network/United network of organ sharing (OPTN/UNOS) database, we identified adult patients who developed DGF following DDK transplantation performed between January 2000 and December 2008. They received induction with rabbit antithymocyte globulin (r-ATG), alemtuzumab or an interluekin-2 receptor blocker (IL-2B) and were discharged on a calcineurin inhibitor (CNI)/mycophenolate (MMF) based immunosuppression with or without steroids. Adjusted graft and patient survivals were compared between steroid versus no steroid groups for each induction modality. Median follow-up was 29.6 months for the 10,058 patients who developed DGF. There were 5624 patients in r-ATG (steroid, n = 4569, no steroid, n = 1055), 819 in alemtuzumab (steroid, n = 301, no steroid, n = 518) and 3615 in IL-2B (steroid, n = 3380, no steroid, n = 235) groups. Adjusted graft survivals were similar for steroid versus no-steroid groups in patients who received r-ATG (HR: 0.98, 95% CI 0.85-1.13, P = 0.75), alemtuzumab (HR 0.88, 95% CI 0.65-1.19, P = 0.41), and IL-2B (HR 1.01, 95%CI 0.78-1.30, P = 0.96) inductions. The adjusted patient survivals were also similar in r-ATG (HR: 1.19, 95% CI 0.96-1.46, P = 0.19), alemtuzumab (HR: 0.89, 95% CI: 0.57-1.39, P = 0.96), and IL-2R (HR: 1.07, 95% CI: 0.77-1.49, P = 0.96) groups. Our study failed to show any significant graft or patient survival benefits associated with steroid addition to CNI/MMF regimen in DDK recipients with DGF. This may be related to the early immunogenic and non-immunogenic allograft damage from DGF with long-term consequences that are unaltered by steroids.
PMCID: PMC3841505  PMID: 24339515
Deceased donor transplantation; delayed graft function; graft survival; steroid maintenance
11.  Is Delayed Graft Function Causally Associated with Long-Term Outcomes after Kidney Transplantation? Instrumental Variable Analysis1 
Transplantation  2013;95(8):1008-1014.
While 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.
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 loss and mortality at 1 and 5 years post-transplant, controlling for an array of characteristics known to affect patient and graft survival. We compared our IVM results to a multivariable linear probability model (LPM).
DGF occurred in 27% of our sample. Graft loss 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 LPM, DGF was associated with increased risk of both graft loss 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 loss 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.
Instrumental variables analysis supports a causal relationship between DGF and both graft loss and mortality.
PMCID: PMC3629374  PMID: 23591726
delayed graft function; kidney transplantation; outcomes; cold ischemia time; allograft failure
12.  An Analysis of Early Renal Transplant Protocol Biopsies – the High Incidence of Subclinical Tubulitis 
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.
PMCID: PMC2955896  PMID: 12095037
High incidence; protocol biopsies; subclinical acute tubulitis
13.  Association of lower costs of pulsatile machine perfusion in renal transplantation from expanded criteria donors 
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.
PMCID: PMC2596761  PMID: 18925906
kidney transplantation; expanded criteria donors; pulsatile machine perfusion; delayed graft function; Medicare; cost benefits
14.  The Utility of Serial Allograft Biopsies during Delayed Graft Function in Renal Transplantation under Current Immunosuppressive Regimens 
ISRN Nephrology  2014;2014:292305.
Delayed graft function (DGF) of kidney transplants increases risk of rejection. We aimed to assess the utility of weekly biopsies during DGF in the setting of currently used immunosuppression and identify variables associated with rejection during DGF. We reviewed all kidney transplants at our institution between January 2008 and December 2011. All patients received rabbit antithymocyte globulin/Thymoglobulin (ATG) or Basiliximab/Simulect induction with maintenance tacrolimus + mycophenolate + corticosteroid therapy. Patients undergoing at least one weekly biopsy during DGF comprised the study group. Eighty-three/420 (19.8%) recipients during this period experienced DGF lasting ≥1 week and underwent weekly biopsies until DGF resolved. Biopsy revealed significant rejection only in 4/83 patients (4.8%) (one Banff 1-A and two Banff 2-A cellular rejections, and one acute humoral rejection). Six other/83 patients (7.2%) had Banff-borderline rejection of uncertain clinical significance. Four variables (ATG versus Basiliximab induction, patient age, panel reactive anti-HLA antibody level at transplantation, and living versus deceased donor transplants) were statistically significantly different between patients with and without rejection, though the clinical significance of these differences is questionable given the low incidence of rejection. Conclusions. Under current immunosuppression regimens, rejection during DGF is uncommon and the utility of serial biopsies during DGF is limited.
PMCID: PMC4045441  PMID: 24967241
15.  Association of pre-transplant statin use with delayed graft function in kidney transplant recipients 
BMC Nephrology  2012;13:111.
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.
PMCID: PMC3507677  PMID: 22985048
16.  Associations of Pre-Transplant Serum Albumin with Post-Transplant Outcomes in Kidney Transplant Recipients 
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.
PMCID: PMC3083471  PMID: 21449945
Hypoalbuminemia; kidney transplantation; malnutrition-inflammation complex; mortality; cardiovascular death; graft failure; delayed graft function (DGF)
17.  Glutathione S-transferase iso-enzymes in perfusate from pumped kidneys are associated with delayed graft function 
Accurate and reliable assessment tools are needed in transplantation. The objective of this prospective, multicenter study was to determine the associations of the alpha and pi iso-enzymes of glutathione S-transferase (GST), measured from perfusate solution at the start and end (base and post) of kidney allograft machine perfusion, with subsequent delayed graft function (DGF). We also compared GST iso-enzyme perfusate levels from discarded versus transplanted kidneys. A total of 428 kidneys were linked to outcomes as recorded by the United Network of Organ Sharing. DGF, defined as any dialysis in the first week of transplant, occurred in 141 recipients (32%). Alpha and pi-GST levels significantly increased during machine perfusion. The adjusted relative risks (95% confidence interval) of DGF with each log-unit increase in base and post pi-GST were 1.14 (1.0-1.28) and 1.33 (1.02-1.72), respectively. Alpha-GST was not independently associated with DGF. There were no significant differences in GST values between discarded and transplanted kidneys, though renal resistance was significantly higher in discarded kidneys. We found pi-GST at the end of machine perfusion to be independently associated with DGF. Further studies should elucidate the utility of GST for identifying injured kidneys with regard to organ allocation, discard and recipient management decisions.
PMCID: PMC4051136  PMID: 24612768
Perfusion pumping; kidney injury; ischemia; biomarker
18.  Prediction of delayed graft function after renal transplantation 
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.
PMCID: PMC2758516  PMID: 19829730
19.  The impact of vascular anastomosis time on early kidney transplant outcomes 
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.
PMCID: PMC3662631  PMID: 23675703
Delayed graft function; Warm ischemic time; Cold ischemic time; Hospitalization
20.  Primary Nonfunction of Renal Allograft Secondary to Acute Oxalate Nephropathy 
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.
PMCID: PMC3504227  PMID: 23213607
21.  Karyopherins: potential biological elements involved in the delayed graft function in renal transplant recipients 
BMC Medical Genomics  2014;7:14.
Immediately after renal transplantation, patients experience rapid and significant improvement of their clinical conditions and undergo considerable systemic and cellular modifications. However, some patients present a slow recovery of the renal function commonly defined as delayed graft function (DGF). Although clinically well characterized, the molecular mechanisms underlying this condition are not totally defined, thus, we are currently missing specific clinical markers to predict and to make early diagnosis of this event.
We investigated, using a pathway analysis approach, the transcriptomic profile of peripheral blood mononuclear cells (PBMC) from renal transplant recipients with DGF and with early graft function (EGF), before (T0) and 24 hours (T24) after transplantation.
Bioinformatics/statistical analysis showed that 15 pathways (8 up-regulated and 7 down-regulated) and 11 pathways (5 up-regulated and 6 down-regulated) were able to identify DGF patients at T0 and T24, respectively. Interestingly, the most up-regulated pathway at both time points was NLS-bearing substrate import into nucleus, which includes genes encoding for several subtypes of karyopherins, a group of proteins involved in nucleocytoplasmic transport. Signal transducers and activators of transcription (STAT) utilize karyopherins-alpha (KPNA) for their passage from cytoplasm into the nucleus. In vitro functional analysis demonstrated that in PBMCs of DGF patients, there was a significant KPNA-mediated nuclear translocation of the phosphorylated form of STAT3 (pSTAT3) after short-time stimulation (2 and 5 minutes) with interleukin-6.
Our study suggests the involvement, immediately before transplantation, of karyopherin-mediated nuclear transport in the onset and development of DGF. Additionally, it reveals that karyopherins could be good candidates as potential DGF predictive clinical biomarkers and targets for pharmacological interventions in renal transplantation. However, because of the low number of patients analyzed and some methodological limitations, additional studies are needed to validate and to better address these points.
PMCID: PMC3975142  PMID: 24625024
Delayed graft function; Renal transplantation; Microarray
22.  Five-year experience with donation after cardiac death kidney transplantation in a Canadian transplant program: Factors affecting outcomes 
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.
PMCID: PMC3526629  PMID: 23282662
23.  Short-Time Intermittent Preexposure of Living Human Donors to Hyperoxia Improves Renal Function in Early Posttransplant Period: A Double-Blind Randomized Clinical Trial 
Journal of Transplantation  2011;2011:204843.
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.
PMCID: PMC3087885  PMID: 21559250
24.  Donor Race and Outcomes in Kidney Transplant Recipients 
Clinical transplantation  2012;27(1):37-51.
African Americans are at greater risk to reach end stage renal disease and this risk may carry over in a kidney transplant recipient after kidney transplantation.
Linking the 5-year patient data of a large dialysis organization to the Scientific Registry of Transplant Recipients, we identified 13,692 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 95% CI) and logistic regression, respectively.
Patients were 48±14 years old and included 39% women and 26% diabetics. After adjusting for several relevant clinical and transplant-related variables, African American donor race was associated with higher all-cause mortality, with hazard ratios of 1.39 (1.09–1.78) for all-cause mortality, 1.80 (1.17–2.76) for cardiovascular mortality, 1.30 (1.03–1.64) for death-censored graft loss and 1.31 (1.10–1.57) for combined outcome over the 6-year observation period. In the non-African American recipient sub-cohort, but not in the African American recipient sub-cohort, African American donor race was associated with higher risk of death-censored graft loss (2.24(1.44–3.49)) in our fully adjusted model.
African American donor race was associated with increased all-cause and cardiovascular mortality and graft loss.
PMCID: PMC3593049  PMID: 22830989
Donor race/ethnicity; kidney transplantation; malnutrition-inflammation complex; mortality; cardiovascular death; graft failure; delayed graft function
25.  Association of pre-transplant erythropoiesis-stimulating agent responsiveness with post-transplant outcomes 
Nephrology Dialysis Transplantation  2012;27(8):3345-3351.
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.
PMCID: PMC3408941  PMID: 22499025
anemia; erythropoietin-stimulating agent therapy; graft failure; kidney transplantation; mortality

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