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PubMed2006

Major effects of delayed graft function and cold ischaemia time on renal allograft survival.

BACKGROUND: There is mounting evidence from experimental and clinical studies that the quality of organs from cadaver donors may be influenced by events occurring around the time of brain death, and that these may affect transplant outcome. The aim of this study is to investigate the influence of donor factors on renal allograft outcome in a homogeneous cohort of 518 patients transplanted in a single centre over a 9 year period. METHODS: Endpoints of the study were delayed graft function (DGF), acute rejection (AR), 1 year graft survival and long-term survival of those grafts that reached 1 year. Multivariate analysis was performed to determine factors that may have influenced the graft outcome indicators. RESULTS: DGF was the major predictor of graft failure overall with cold ischaemia time (CIT) as an important independent factor. The level of histocompatibility did not influence graft survival. DGF was the major factor affecting 1 year graft survival (P<0.0005) with effects persisting beyond 1 year. DGF was significantly influenced by CIT, donor age, female kidney into male recipient and donor creatinine (P<0.05). Other donor factors and factors associated with donor management were not risk factors for DGF, rejection episodes or graft survival. The risk factors for a number of AR episodes were HLA-DR mismatch and DGF (P<0.005). When grafts surviving for 1 year were considered, only CIT, recipient age and creatinine at 1 year (P<0.05) were found to affect graft survival significantly. CONCLUSIONS: The results of this analysis of well-matched transplant recipients show that CIT and DGF are the most important predictors of poor short and long-term graft survival. Therefore, in order to improve the long-term survival of renal allografts efforts should focus on limiting CIT and the damage that occurs during this period and on improving our understanding of DGF.

Adult↗
PubMed1996

Antilymphocyte induction immunosuppression in the post-Minnesota anti-lymphocyte globulin era: incidence of renal dysfunction and delayed graft function. A single center experience.

Between 4/91 and 12/93, 262 patients received cadaveric (CRT) (n = 205) or living donor (LRT) (non-HLA identical) renal transplants. All patients were treated with the same sequential induction immunosuppression protocol, with the exception of different forms of antilymphocyte sera: either Minnesota antilymphocyte globulin (MALG), antithymocyte globulin (ATG), orthoclone antibody (OKT3), d 1 postoperatively, or OKT3 intraoperatively. With the withdrawal of MALG from the market, we wished to prospectively analyze the influence of these other antilymphocyte therapies on the incidence of delayed graft function (DGF) (the requirement for hemodialysis within the first week postoperatively) and renal function during the first 3 d postoperatively and during the subsequent .6 months post-transplantation and compare that with our MALG experience. Of the 205 CRT, 76 received MALG with a DGF rate of 18.4%, 50 received ATGAM with a DGF rate of 22.0%, 38 received OKT3 postoperatively with a DGF rate of 39.5%, and 41 received OKT3 intraoperatively with a DGF rate of 39%. Of the 57 LRT, only two patients, one receiving intraoperatively OKT3 (secondary to graft thrombosis), and one MALG patient, suffered DGF. Serum creatinine values were obtained from postoperative d 1 through postoperative d 4 for 185 patients. Each of the four groups showed similar mean decrements in serum creatinine. The number of grafts functioning at 1, 2, 3 and 6 months postoperatively and serum creatinine values were not statistically different between the groups. We conclude that induction immunosuppression with MALG and ATGAM is associated with a lower DGF rate than OKT3 given either intraoperatively or postoperatively. However, with 6 months of follow-up, we do not observe any difference in the incidence of rejection or graft function between the therapies. Consequently, we have chosen ATGAM as our preferred inductive therapy in the absence of MALG owing to its lower associated DGF rate.

Adult↗
PubMed2006

Pretransplant calcium levels have no predictive value for delayed graft function, long-term graft function, cardiovascular events, or graft and patient survival in renal transplantation.

BACKGROUND: Disorders of calcium homeostasis are one of the most common problems in patients with end-stage renal disease (ESRD). Elevated calcium levels increase the incidence of cardiovascular mortality in ESRD patients, and appear to be a risk factor for the occurrence of delayed graft function (DGF) after kidney transplantation. Therefore, we investigated the impact of pretransplant serum calcium levels on outcomes after kidney transplantation: DGF, acute rejection, graft function, and survival, as well as the incidence of cardiovascular events. METHODS: We studied 285 patients (96.9% of all transplanted patients) who underwent their first transplantation between 1995 and 2004. Demographic data were extracted from hospital records or were documented during follow-up; serum samples were collected at the time of transplantation. RESULTS: In our cohort the incidence of DGF was 16.5% and 35.4% of acute rejection episodes (ARE). However, pretransplant calcium levels were not related to DGF or ARE in our patient cohort. Furthermore, there was no correlation between pretransplant serum calcium level with the incidence of cardiovascular events or mortality, as well as graft function or survival. CONCLUSION: In our study population pretransplant calcium levels showed no effect on DGF, ARE rate, the occurrence of cardiovascular events or death, renal graft function, or survival. Therefore, pretransplant calcium level is not a helpful marker for risk stratification at the time of transplantation.

Biomarkers↗
PubMed1998

Delayed graft function of more than six days strongly decreases long-term survival of transplanted kidneys.

BACKGROUND: We reviewed 843 first cadaver kidney transplants carried out consecutively at our center to examine the effect on long-term graft survival of the duration of delayed graft function (DGF), defined as the time taken for the kidney to attain the threshold of a Cockcroft calculated creatinine clearance (cCCr) > or = 10 ml/min. METHODS: Using a multivariate Cox survival analysis we evaluated the consequences of DGF on allograft survival, and then by regression analysis identified the factors contributing to the occurrence of DGF. Finally, using a Kaplan Meier analysis we compared the profiles of graft failure according to the duration of DGF. RESULTS: Defining DGF in terms of cCCr rather than necessity for dialysis after transplantation allowed better prediction of long-term graft loss. Indeed, patients with a Cockcroft-based DGF > six days who did not require dialysis (12%) had a significantly poorer long-term graft outcome than those with a DGF < or = six days. Furthermore, we showed that a DGF of six days could be taken as a cut-off point that marked a significant difference in the long-term graft survival rate (P < 0.0001). Surprisingly, further extension of the duration of DGF > six days was not associated with further worsening of graft survival (except in DGF > 30 days). CONCLUSION: Our results suggest a threshold effect in the lesions that ultimately results in long-term functional deficiency. In addition, we show that the need for dialysis is not an adequate criterium for DGF in terms of long-term outcome prediction.

Adolescent↗
PubMed2002

Association of factor V Leiden mutation with delayed graft function, acute rejection episodes and long-term graft dysfunction in kidney transplant recipients.

We analysed whether the factor V Leiden mutation--the most common hereditary predisposing factor for venous thrombosis--is associated with early and long-term graft dysfunction after kidney transplantation in 394 Caucasian kidney transplant recipients. The presence of factor V Leiden mutation was identified by allele specific PCR. The prevalence of the factor V Leiden mutation was compared to 32216 unselected neonates. The prevalence of the factor V Leiden mutation (GA genotype) was similar in 394 kidney transplant recipients and 32216 neonates. The frequency of known factors predicting long-term graft function were similar in patients with the GA genotype and with the normal factor V gene (GG genotype). The GA genotype was associated with the occurrence of no primary graft function (risk: 2.87: 95% confidence interval: 1.01-8.26; p < 0.05), the number of dialysis after transplantation in patients with no primary graft function until graft function (7.5 +/- 2.06 dialysis in GA patients; 4.2 +/- 0.36 dialyses in GG patients; p < 0.05), and the risk for at least one acute rejection episode (risk: 3.83; 95% confidence interval: 1.38-10.59; p < 0.02). The slope of l/creatinine per year was significantly lower in patients with the GA genotype (GA patients: -0.0204 +/- 0.008 dl/mg per year; GG patients: 0.0104 +/- 0.004 dl/mg per year; p < 0.02). The annual enhancement of the daily protein excretion rate was elevated in patients with the GA genotype (GA patients: 38.5 +/- 16.6 mg/24 h per year; GG patients: 4.9 +/- 4.4 mg/24 h per year; p < 0.02). Our study showed that the factor V Leiden mutation is associated with the occurrence of delayed graft function, acute rejection episodes and chronic graft dysfunction after kidney transplantation.

Activated Protein C Resistance↗
PubMed2002

Genetic determinants of delayed graft function after kidney transplantation.

BACKGROUND: Intracellular concentration of reactive oxygen species is held within tight physiological limits by enzymes with scavenging and repair functions. Under extreme conditions such as prolonged cold ischemia, these enzymes may be unable to adequately protect the organ, resulting in reperfusion injury that renders the graft dysfunctional after transplantation. In this study, we investigated normal human variation of some of these inducible enzymes to determine if certain phenotypes could be identified that are associated with a reduced risk of delayed graft function (DGF). METHODS: Polymerase chain reaction was performed to differentiate polymorphisms for manganese superoxide dismutase and three classes of glutathione-S-transferase in donors and recipients of transplants with over 24 hr of cold ischemia. The data attained was analyzed compared with the presence or absence of DGF, defined as the requirement of hemodialysis in the first week after transplantation. RESULTS: Enzyme polymorphisms were defined for 229 recipients and 104 of their respective donors. Patients receiving a kidney from a donor who expressed GSTM1*B either alone or in combination with GSTM1*A experienced significantly lower rates of DGF (P <0.05). No association was found between any enzyme polymorphism in the recipients and the development of DGF. CONCLUSIONS: The identification of a genetic allele, which is protective against reperfusion injury, generates the possibility for defining polymorphisms at the time of tissue typing to give insight to the inherent biological risk of DGF that an organ possesses.

Adult↗
PubMed2001

Effective renal plasma flow calculated from a single blood sample following Technetium-99m mercaptoacetyltriglycine renal scan can predict delayed graft function in renal transplantation.

PURPOSE: Effective renal plasma flow (ERPF) can be calculated by obtaining a single blood sample at a fixed time after injection in a patient undergoing a technetium-99m mercaptoacetyltriglycine (99mTc MAG3) renal scan. The purpose of this study was to determine whether the calculated ERPF following cadaveric renal transplantation could accurately predict the need fordialysis within the first 10 postoperative days or the serum creatinine at postoperative day 10. MATERIALS AND METHODS: Between February 1994 and September 1998, 41 patients underwent 45 99mTc MAG3 renal scans within the first 10 days following a cadaveric renal transplantation at Harbor-UCLA Medical Center. A blood sample was drawn 44 minutes after injection of 99mTc and was used to calculate ERPF. This calculated ERPF was compared to measures of early function, such as the need for dialysis and serum creatinine. RESULTS: Decreased ERPF strongly correlated with the need for dialysis within the first 10 postoperative days (p < .0001). No patient with ERPF >210 mL/min/1.7 M2 required dialysis, whereas 35% (6/17) of patients with ERPF < or =210 mL/min/1.7 M2 required dialysis within the first 10 postoperative days. For those patients who did not undergo dialysis, the calculated ERPF was significantly related to the serum creatinine on postoperative day 10 (p<.0001 ). CONCLUSIONS: ERPF can be calculated from a single blood sample when performing a 99mTc MAG3 renal scan following cadaveric renal transplantation. This calculated ERPF provides a useful clinical tool to identify patients at high risk for development of delayed graft function.

Cadaver↗
PubMed1999

Dialysis modality and delayed graft function after cadaveric renal transplantation.

The purpose of this investigation was to compare outcomes in the immediate posttransplant period for hemodialysis (HD) and peritoneal (PD) dialysis patients who received cadaveric renal transplantation. Data were obtained from the United Network of Organ Sharing on all cadaveric graft recipients who were dialysis-dependent at the time of transplantation between April 1994 and December 1995. Baseline characteristics were compared between groups, and multivariate logistic regression was performed with outcome measures including urine production in the first 24 h posttransplantation (U24), requirement for dialysis in the first week posttransplant (FWDIAL), and treatment for acute rejection during the initial hospitalization. The odds of oliguria (not producing urine in the first 24 h) were 1.49 (1.28 to 1.74) times higher in HD versus PD patients. After adjustment for other comorbid conditions including age, gender, race, HLA mismatch, time on dialysis, panel-reactive antibodies, and cold and warm ischemia time, the odds of oliguria were 1.60 (1.14 to 2.25) times higher in black HD patients compared with PD patients and 1.29 (1.06 to 1.57) times higher in white HD patients. In a similar manner, after adjustment for significant comorbid conditions, the odds of requiring dialysis in the first week were 1.56 (1.22 to 2.0) times higher in black HD patients versus PD patients and 1.40 (1.21 to 1.60) times higher in white HD patients. The rate of acute rejection was similar during the first hospitalization. These results suggest that there is an association between hemodialysis and delayed graft function. Differences in biocompatibility between the two modalities could potentially be responsible.

Adult↗
PubMed2004

Association of graft neutrophil sequestration with delayed graft function in clinical renal transplantation.

BACKGROUND: The authors studied the impact of neutrophil activation, detected in experimental models, on reperfusion injury in clinical renal transplantation. METHODS: Forty-five patients from a larger trial comparing three immunosuppressive protocols were recruited: perioperative antithymocyte globulin (ATG) with low initial cyclosporine A (CsA) triple therapy (group A, n=15); two-dose basiliximab with low initial CsA triple therapy (group B, n=16); and conventional triple therapy (group C, n=14). Blood samples were obtained preoperatively, before reperfusion, and at 1 and 5 min after reperfusion. During reperfusion, samples were collected from the iliac artery and the graft vein for calculation of transrenal differences (Delta) of study parameters. Leukocyte differential counts, plasma lactoferrin concentration, and neutrophil CD11b and L-selectin expressions were assessed. Graft blood flow was measured at 2 and 30 min after reperfusion. RESULTS: ATG induced neutrophil activation already before reperfusion. Thus, group A was excluded, but groups B and C were pooled for analysis of reperfusion-induced neutrophil activation. At 1 min after reperfusion, lactoferrin concentration was higher in graft vein than iliac artery, yielding Delta=15 microg/L (P<0.05). Concomitantly, Delta neutrophil count correlated with both Delta L-selectin expression (R=0.49, P=0.012) and graft blood flow at 2 min (R=0.51, P=0.007). At 5 min after reperfusion, 0.17 (-1.0-0.24)x10 cells/L neutrophils were sequestered in the graft (P<0.001). This sequestration correlated with graft blood flow at 30 min (R=0.53, P=0.005) and was stronger in patients with delayed graft function (DGF) (Delta = -0.38 [-1.45 to -0.2]) than those without (Delta = -0.12 [-0.41-0.24], P<0.001). In multiple regression analysis, sequestration was the most important parameter associated with DGF. CONCLUSIONS: Neutrophils are activated and sequestered in the reperfused graft during clinical renal transplantation. Neutrophil sequestration is a powerful independent factor explaining the incidence of DGF.

Adolescent↗
PubMed2000

Mycophenolate mofetil, with cyclosporine and prednisone, reduces early rejection while allowing the use of less antilymphocytic agent induction and cyclosporine in renal recipients with delayed graft function.

Antilymphocytic agent induction (ALAI), with antithymocyte globulin or monoclonal antibody, is generally used in renal transplantation (TX) to spare renal allografts with poor initial function from the toxic effects of cyclosporine (CsA) and/or to augment immunosuppression (IS) in the patient at a high risk for early rejection. ALAI, unfortunately, increases the cost of TX and the risk to the patient, having been associated with many adverse side effects. An IS protocol, which results in a low incidence of early rejection while using less CsA and ALAI, is a worthwhile goal. We compare our experience with mycophenolate mofetil (MMF), CsA, and prednisone (MMFCP; n = 62) to our azathioprine (AZA), CsA, and prednisone (AZACP; n = 50) triple-drug IS, with and without ALAI. The patient characteristics for age, race, first TX, cadaveric donor, pediatric recipient, and dialysis in the first post-op week (DGF) were not different for the MMFCP versus AZACP groups. There were more females in the MMFCP group (51.6% versus 30.0%, p = 0.022). We report that rejection-free survival at 6 months (RF6) was better in the MMFCP versus AZACP group (83.9% versus 60.0%, p = 0.005). Less ALAI and CsA were used in the MMFCP patients. At 1 year, actuarial graft survival was 91.9% in the MMFCP group and 81.9% in the AZACP group (p = 0.116). Actuarial 1-year patient survivals were not different in the two patient groups. In the sub-population of patients with DGF, the RF6 in the MMFCP (n = 13) group was 92.3% versus 57.1% in the AZACP (n = 14) group (p = 0.041). The reduction in early rejection episodes in the patients on MMFCP with DGF was accomplished while using half as much ALAI and lower CsA doses and levels. The African-American recipient sub-population on MMFCP also demonstrated an improvement in RF6 while using less ALAI and CsA (78.6% versus 48.0%, p = 0.022). We conclude that the use of MMF-based triple-drug IS results in fewer rejection episodes while allowing for lower CsA levels and less ALAI, even in patients with delayed graft function.

Actuarial Analysis↗
PubMedDate not supplied

The intrarenal vascular resistance parameters measured by duplex Doppler ultrasound shortly after kidney transplantation in patients with immediate, slow, and delayed graft function.

BACKGROUND: Evaluation of pulsatility (PI) and resistive (RI) indexes by duplex Doppler ultrasound shortly after kidney transplantation reflects the exacerbation of interstitial edema. The aim of study was to characterize factors that influence PI and RI in patients with immediate (IGF), slow (SGF), or delayed (DGF) kidney graft function. PATIENTS AND METHODS: PI and RI were measured in 200 transplanted patients at 2 to 4 days postoperatively. We excluded patients with acute rejection episodes within the first month. IGF, which was defined as serum creatinine <264 micromol/L at 3 days, SGF, which was defined as creatinine >264 micromol/L by day 3 with a maximum of one dialysis, and DGF, which was defined as more than 1 dialysis were observed in 33.3%, 41.5%, and 25.2% of patients, respectively. The examined donor parameters were age, hypotensive episodes, catecholamine infusion, central venous pressure, and glomerular filtration rate. The recipient factors were age, history of hypertension, diabetes mellitus, ischemic heart disease, and stroke. Additionally cold ischemia time (CIT), HLA mismatch, and PRA were analyzed. RESULTS: The lowest PI and RI values were observed among patients with IGF (PI 1.37 [1.28 to 1.46]; RI 0.72 [0.69 to 0.74]); moderate values in SGF (PI 1.65 [1.52 to 1.78]; RI 0.78 [0.76 to 0.80]) and the highest values in DGF (PI 2.09 [1.83 to 2.35]; RI 0.83 [0.80 to 0.86]) differences that were highly significant. Hypotensive episodes and catecholamine infusion in the preharvest period had essential impacts on PI or RI values in the early posttransplant period. There was no significant correlation between PI or RI values and CIT. A slower ATN resolution was observed in DGF patients with higher PI values. CONCLUSION: Ischemic injury, which occurred mainly prior to organ harvesting, played a dominant role determining intrarenal resistance in the early posttransplant period.

Adult↗
PubMed1997

Effect of machine perfusion preservation on delayed graft function in non-heart-beating donor kidneys--early results.

The functioning of non-heart-beating (NHB) donor kidneys upon transplantation is often delayed. To evaluate the effect of preservation by machine perfusion (MP) on early post-transplant function, 37 NHB donor kidneys were compared to 74 matched heart-beating (HB) donor kidneys preserved by cold storage (CS). The NHB donor kidneys were subject to 49 +/- 34 min of warm ischemia. Delayed function (DF) and primary nonfunction (PNF) rates were significantly higher for NHB than for HB donor kidneys (49% and 19% vs 34% and 7%, respectively). Consequently, renal function was impaired but recovered within 6 months. MP could not eliminate the differences in DF rate between NHB and HB donor kidneys. However, NHB donor kidneys preserved by MP showed less DF than that reported in kidneys preserved by CS. This suggests that MP has a beneficial effect on ischemically damaged kidneys. The similar results observed with category 2 and category 3 NHB donors also suggest this effect. The high PNF rate emphasizes the need for viability tests that prevent the transplantation of nonviable organs. We conclude that MP alone is not sufficient to reduce DF and PNF rates in NHB donor kidneys.

Adult↗
PubMed2003

A randomized, placebo-controlled trial of IGF-1 for delayed graft function: a human model to study postischemic ARF.

BACKGROUND: Insulin-like growth factor (IGF-1) has been shown in animal models to accelerate recovery from acute renal failure (ARF). However, a therapeutic trial of recombinant human (rh) IGF-1 in patients with ARF in the intensive care unit (ICU) failed to demonstrate efficacy [1]. Such patients often had multiple organ failure, recurrent renal injury, and a delay of several days before commencing treatment. METHODS: To circumvent these confounding factors, we randomized recipients of cadaveric renal allografts to immediate (<5 hours) rhIGF-1 versus placebo therapy (100 mg/kg subcutaneously twice a day for 6 days). Preliminary observations 3 hours posttransplantation in an additional 44 patients revealed a creatinine clearance < or = 20 mL/min to predict protracted ARF. Thus, this value was used to determine study eligibility. RESULTS: Creatinine clearance prior to commencing treatment was not significantly different between the two groups (8 +/- 5 mL/min for IGF-1 and 7 +/- 6 mL/min for placebo; P = 0.39). Inulin clearance on day 7, the primary outcome measure, was 21 +/- 22 mL/min and 19 +/- 19 mL/min in the IGF-1 (N = 19) and placebo (N = 24) groups, respectively (P = 0.67). Secondary outcome measures, including nadir serum creatinines after 6 weeks and need for dialysis, also did not differ between the two groups. We performed an analysis of statistical power using the placebo arm of the trial. Defining a twofold increase above placebo in day 7 glomerular filtration rate (GFR) as of meaningful biologic significance, we determined that the modest sample size used in the present study is adequate. CONCLUSION: We, thus, conclude that (1) IGF-1 treatment is unlikely to benefit ARF and (2) the transplanted kidney is a good model to screen new agents for ARF that have demonstrated promise in animal trials.

Acute Kidney Injury↗