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PubMed2004

Factors related to delayed graft function after laparoscopic live donor nephrectomy.

PURPOSE: Delayed graft function after live donor transplantation affects 5% to 10% of recipients regardless of procurement technique. This delay in function is associated with an increased risk of rejection and decreased graft survival. In the present study we critically assess allograft recovery to identify the risk factors related to delayed graft function. MATERIALS AND METHODS: We retrospectively reviewed donor and recipient medical records from 100 consecutive laparoscopic live donor nephrectomies from August 1997 to October 2001. Four criteria were used to classify delayed graft function: I) requirement of dialysis in postoperative week 1, II) creatinine 2.5 mg/dl or greater at postoperative day 5, III) time to half peak activity (mercaptoacetyltriglycine renal scan) at postoperative day 5 greater than 12.2 minutes (normal range 1 to 12.2) and IV) time to peak activity (mercaptoacetyltriglycine renal scan) at day 5 greater than 6.5 minutes (normal range 2.1 to 6.5). Patients could qualify for multiple outcome categories. Patients who did not match any of these criteria were classified as having normal renal function (outcome 0). RESULTS: The number of patients in the delayed graft function categories were 5 with outcome I, 14 with outcome II, 39 with outcome III and 24 with outcome IV. There were 23 patients represented in more than 1 category and 59 patients were classified as having normal function. Recipient age, donor/recipient gender relationship, unrelated highly mismatched donors and cold/total preservation time were identified as risk factors related to impaired early renal function recovery. None of the variables related to the laparoscopic technique itself represented risk factors for delayed graft function. CONCLUSIONS: Female donor kidneys into male recipients and highly HLA mismatched donors represent factors that may be controlled by donor selection when feasible. All attempts should be made to decrease cold ischemia time and, therefore, total preservation time. Prolonged carbon dioxide pneumoperitoneum, warm ischemia time, renal artery length or use of right kidney did not adversely affect the functional outcome of the allografts procured laparoscopically.

Adult↗
PubMed2006

Urine NGAL and IL-18 are predictive biomarkers for delayed graft function following kidney transplantation.

Delayed graft function (DGF) due to tubule cell injury frequently complicates deceased donor kidney transplants. We tested whether urinary neutrophil gelatinase-associated lipocalin (NGAL) and interleukin-18 (IL-18) represent early biomarkers for DGF (defined as dialysis requirement within the first week after transplantation). Urine samples collected on day 0 from recipients of living donor kidneys (n = 23), deceased donor kidneys with prompt graft function (n = 20) and deceased donor kidneys with DGF (n = 10) were analyzed in a double blind fashion by ELISA for NGAL and IL-18. In patients with DGF, peak postoperative serum creatinine requiring dialysis typically occurred 2-4 days after transplant. Urine NGAL and IL-18 values were significantly different in the three groups on day 0, with maximally elevated levels noted in the DGF group (p < 0.0001). The receiver-operating characteristic curve for prediction of DGF based on urine NGAL or IL-18 at day 0 showed an area under the curve of 0.9 for both biomarkers. By multivariate analysis, both urine NGAL and IL-18 on day 0 predicted the trend in serum creatinine in the posttransplant period after adjusting for effects of age, gender, race, urine output and cold ischemia time (p < 0.01). Our results indicate that urine NGAL and IL-18 represent early, predictive biomarkers of DGF.

Acute-Phase Proteins↗
PubMed2004

Risk factors and impact of delayed graft function after pancreas transplants.

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

Adult↗
PubMed1988

Individualization of immediate posttransplant immunosuppression. The value of antilymphocyte globulin in patients with delayed graft function.

In patients with delayed graft function (DGF), the use of cyclosporine (CsA) has been reported to prolong DGF, increase the number of required dialyses, increase the duration of hospitalization, and be associated with decreased graft survival. Routine postoperative antilymphocyte globulin (ALG) use has been advocated, but ALG is associated with increased viral infection. We studied outcome of individualization of immunosuppression. Between 11/84 and 8/86, first-cadaver transplant recipients whose serum creatinine (Cr) fell greater than or equal to 30% in the first 24 hr (immediate function) were started on CsA and prednisone (P) (group 1, n = 26). The remainder were randomized to P and azathioprine (group 2, n = 32) or P and ALG (group 3, n = 26), and switched to CsA when serum Cr fell greater than 30% (minimum 5 days ALG for the ALG group). P taper was the same in all groups. Patients with DGF (groups 2 and 3) had longer preservation time and higher peak PRA (P less than .05) than group 1. Groups were otherwise equivalent. One and 2-year patient survival was 96% (3 cardiovascular deaths; all with functioning grafts). One-year graft survival was 87% for group 1, 87% for group 2, and 82% for group 3(NS). In patients requiring dialysis, mean day off dialysis was 12 +/- 3 in both groups 2 and 3. Mean hospital stay was 12.5 +/- 1.3 days for group 1, 21.6 +/- 2.1 days for group 2 (P less than .05 vs. 1 & 3), and 14.5 +/- 1.2 days for group 3 (NS vs. 1). The increased hospital stay for group 2 patients was mainly due to increased in-hospital rejections: 75% for group 2, (P less than .05 vs. group 1 [35%], and group 3 [11.5%]). In addition, more group 2 in-hospital 1st rejections were steroid resistant as compared to group 1; 46% group 1 patients have remained rejection free as compared to 0% group 2 (P less than .05 vs. 1 and 3) and 35% of group 3 (P less than .05 vs. 1 and 2). Mean serum creatinine at 6-12 months remained higher in patients with DGF (group 1 P less than .05 vs. 2 and 3). Rejection was the major cause of graft loss in all groups.(ABSTRACT TRUNCATED AT 400 WORDS)

Actuarial Analysis↗
PubMed1996

Acute rejection and delayed graft function--risk factors of graft loss.

Acute graft rejection and delayed function are considered to be the major risk factors of short-term as well as long-term graft survival. We studied the impact of these factors on graft outcome among 109 renal transplant recipients. All recipients were treated with triple drug protocol. The recipients were divided into two groups: I group included 57 patients with delayed graft function (DGF), II group included 52 patients with immediate graft function (IGF). We studied graft survival, incidence of acute rejection, serum creatinine levels and the cause of graft loss for patients in both groups. Acute rejection episodes occurred in 49% of patients from DGF group and 45% of patients from IGF group. Graft survival in IGF group was better than in DGF group. Actuarial graft survival at 1, 2, 3 and 4 years in examined groups was 84%, 82%, 72%, 65% vs. 92%, 86%, 84%, 84%, respectively. One-year graft survival in patients with acute rejection from DGF group and IGF group was significantly lower than in patients who remained rejection free (69%, 74% vs. 94%, 96%). We concluded that delayed graft function decreases long-term graft survival, while immediate graft function has an excellent impact on graft outcome. Acute graft rejection is the strongest risk factor of graft loss.

Adult↗
PubMed1994

Increased incidence of rejection in patients with delayed graft function.

Because of the difficulties in diagnosing rejection in patients with delayed graft function, such patients were routinely biopsied 7-10 days after kidney transplantation. We found histologic evidence of rejection in 48% of the cases during the lst month posttransplant, a proportion that was significantly higher than in patients with immediate graft function. Furthermore, the 2-year graft survival in patients with delayed graft function and rejection, but not in those without rejection, was significantly lower than in patients with immediate function. The results suggest that there is an association between delayed graft function and rejection and that rejection is the component responsible for the decreased graft survival previously reported for patients with delayed graft function.

Adult↗
PubMed1995

Delayed graft function, acute rejection, and outcome after cadaver renal transplantation. The multivariate analysis.

The impact of delayed graft function on outcome after cadaver renal transplantation has been controversial, but most authors fail to control their analyses for the presence or absence of rejection. We studied 457 adult recipients of primary cadaver allografts at a single institution during the cyclosporine era. All patients received sequential immunosuppression. The incidence of delayed graft function (defined as dialysis being required during the first week after transplant) was 23%. There was a significant association between delayed graft function and cold ischemia time > 24 hr (P = 0.0001) and between delayed graft function and the occurrence of at least one biopsy-proven rejection episode (P = 0.004). Actuarial graft survival was not significantly different when comparing delayed graft function versus no delayed graft function for patients without rejection (P = 0.02). However, it was significantly worse for patients with both delayed graft function and rejection versus those with delayed graft function but no rejection (P = 0.005), as well as for grafts preserved > 24 hr versus < or = 24 hr (P = 0.007). By multivariate analysis, delayed graft function per se was not a significant risk factor for decreased graft survival for patients without rejection (P = 0.42). In contrast, rejection significantly decreased graft survival for grafts with immediate function (relative risk = 2.3, P = 0.0002), particularly in combination with delayed graft function (relative risk = 4.2, P < 0.0001). While cold ischemia time > 24 hr was also a significant risk factor (relative risk = 1.9, P = 0.02), other variables (preservation mode, 0 HLA Ag mismatch, age at transplantation, gender, diabetic status, and panel-reactive antibody at transplantation) had no impact on graft survival. Patient survival was significantly affected by the combination of delayed graft function and rejection (relative risk = 3.1, P < 0.0001), age at transplantation > 50 years (relative risk = 2.6, P < 0.0001), and diabetes (relative risk = 1.8, P = 0.006). Further studies are necessary to elucidate the mechanisms linking delayed graft function and rejection, which, in combination, lead to poor allograft outcome.

Adult↗
PubMed2005

[Delayed graft function and its impact on the antigraft response after cadaver kidney transplantation].

The purpose of this study was to evaluate the incidence of delayed graft function and its impact on the antigraft response after cadaver kidney transplantation. The analysis is based on 183 consecutive cadaver kidney transplantations performed in Vilnius University Hospital Santariskiu klinikos from January 2000 to December 2004. Delayed graft function occurred in 21.3% (39/183) of kidney transplantations. The frequency and severity of acute rejection episodes in recipients during first three months after transplantation and graft survival rate at one and two years were evaluated. Group 1 consisted of 39 patients with delayed graft function and group 2 (control group) of 144 patients with graft function immediately after transplantation. The maintenance immunosuppressive therapy consisted of cyclosporine, mycophenolate mofetil/azathioprine and prednisolone. The proportion of patients treated with monoclonal antibodies was similar in both groups (35.9% vs. 33.3%). Actuarial graft survival was estimated by the modified Kaplan-Meier method, graft loss was censored for death of recipient with functioning transplant and other causes of loss not related to rejection. There were no significant differences in the age of recipients (42.3+/-11.3 vs. 39.4+/-14.1), as well as in HLA matching (2.2/6 M vs. 2.2/6 M), in the number retransplanted patients (10.3% vs. 10.4%) and in highly sensitized patients (plasma renin activity >50.0%) (5.1% vs. 4.8%) between those groups. Significant differences were observed in donors over 50 year (33.3% vs. 18.7%; p<0.05), in cold ischemic time over 20 h (53.8 vs. 32.6%, respectively). The occurrence of acute rejection episodes was higher in group 1 than in group 2 (69.2% (27/39) vs. 34.7% (50/144); chi2=14.9945, p<0.05). Graft survival was 88.5%, 84.3% at one year and two years in group 1 and 94.7%, 93.8% at one year and two years in group 2 (ns). Donor age >50, cerebral vascular disease as cause of donor death, and cold ischemic time >20 h are the main risk factors for delayed graft function. Delayed graft function is a risk factor for acute rejection episodes, but it has no impact on graft loss due to immunological reason at one and two years. These data may serve for tailoring immunosuppressive protocols.

Acute Disease↗
PubMed1991

Highly sensitized patients with delayed graft function: a management protocol.

The postoperative management of the highly sensitized renal transplant recipient with delayed graft function on cyclosporine is complicated. Allografts with delayed graft function are reported to have a 20 to 30% poorer 1-year survival than allografts without delayed graft function. Several factors may be implicated in this poorer 1-year survival. A decrease in or cessation of cyclosporine dosage frequently is used in an attempt to minimize nephrotoxicity. Such under-immunosuppression can result in irreversible rejection. Occasionally, a pessimistic view of the prognosis for the transplant may result in early abandonment of the allograft with discontinuation of immunosuppression and allograft nephrectomy. We report on 3 highly sensitized patients whose kidneys had delayed graft function and were deliberately maintained on high doses of cyclosporine throughout the period of delayed graft function. Each graft achieved function (2, 4 and 5 months) after transplantation. The serum creatinine levels 20, 28 and 38 months after transplantation were 2.7, 2.0 and 1.0 mg./dl., respectively. We suggest that the maintenance of high cyclosporine levels throughout the delayed graft function period is useful in highly sensitized recipients and was an important factor in their successful outcome. A management protocol for such patients is proposed.

Adolescent↗
PubMed2005

Use of IL-2 receptor antagonists to reduce delayed graft function following renal transplantation: a review.

Delayed graft function (DGF) occurs in approximately 30% of renal transplant patients, and significantly increases risk of long-term graft loss. This article reviews the potential for use of interleukin-2 receptor (IL-2R) antagonists to reduce the burden of DGF. IL-2R antagonists decrease incidence of acute rejection without increasing risk of cytomegalovirus infection or malignancy, and show equivalent efficacy to lymphocyte-depleting antibody agents in standard risk patients with immediate graft function. The nephrotoxicity associated with calcineurin inhibitors (CNIs) has led to use of delayed or low-dose CNI regimens with induction therapy in patients with DGF. In this setting, use of an IL-2R antagonist with mycophenolate mofetil and steroids with delayed cyclosporine appears to be associated with a low incidence of biopsy-proven rejection and comparable renal function to patients with immediate function. Additionally, there is intriguing evidence to suggests that IL-2R antagonists may reduce risk of DGF occurring. A number of large-scale and smaller studies have reported a trend to reduced incidence of DGF or improved early renal function using IL-2R antagonists compared with placebo, although data are not entirely consistent. In conclusion, the ability of IL-2R antagonists to reduce acute rejection with no additional safety concerns makes them an attractive option for patients with DGF.

Antibodies, Monoclonal↗
PubMed2005

H-NMR-based metabolic signatures of mild and severe ischemia/reperfusion injury in rat kidney transplants.

BACKGROUND: Severe ischemia/reperfusion (IR) injury is a risk factor for delayed graft function. Delayed graft function remains difficult to predict, and it currently relies primarily on serum creatinine (SCr), urine output, and occasionally on graft biopsy. (1)H-NMR (nuclear magnetic resonance spectroscopy) based metabolomics was used to establish IR-specific metabolic markers in both blood and kidney tissue. These markers were compared to SCr and graft histology. METHODS: Male Lewis rats were used for kidney transplantation. Two cold ischemia (CI) groups (24- and 42-hour) and two transplantation groups [after 24 (TX24) and after 42 hours (TX42) of CI] were compared to a control group. Whole blood and kidney tissue were collected for further analysis. RESULTS: SCr levels taken 24 hours after transplantation were 1.6 +/- 0.12 mg/dL (TX24) and 2.1 +/- 0.5 mg/dL (TX42), (P= n.s.). Histology samples revealed mild injury in the TX24 group and severe injury in the TX42 group. A significantly decreased level of polyunsaturated fatty acids (PUFA) and elevated levels of allantoin, a marker of oxidative stress, was found in the renal tissue. In the blood, both trimethylamine-N-oxide (TMAO), a marker of renal medullary injury, and allantoin were significantly increased. Allantoin levels were low in both the control and CI groups. Levels were significantly increased after reperfusion (control 0.02 +/- 0.03 micromol/mL, TX24 1.13 +/- 0.22, and TX42 1.89 +/- 0.38, P < 0.001), and correlated with cold ischemia time (r= 0.96) and TMAO (r= 0.94). CONCLUSION: The (1)H-NMR metabolic profiles of both the mild and severe IR groups revealed significant changes consistent with graft histology, while the SCr did not.

Allantoin↗
PubMed2004

The influence of delayed graft function.

We study the incidence of delayed graft function (DGF) in a group of 3365 renal transplant recipient patients from various Spanish centres, its clinical consequences, and the evolution in time (transplants performed in 1990, 1994 and 1998) of the factors that determine its presence. The incidence of DGF remained constant in the 3 years studied (30.4, 30.8 and 29.2%, respectively) when contrasting the following factors involved in the establishment of DGF were studied: body mass of recipient, donor age, non-heart beating donation, type of replacement treatment in the pre-transplant period, time of vascular anastomosis and time of cold ischaemia. DGF was not associated with graft or patient survival. In the transplants performed with elderly donors, the cold ischaemia time was associated with greater incidence of DGF, and the latter with less survival of the graft when censored for death. The presence of DGF was significantly associated with acute rejection, cytomegalovirus infection, worse renal function and arterial hypertension at 3 months post-transplantation. In conclusion, the incidence of DGF remained stable in our patients over the years studied and, although not directly, it can affect graft survival as it is associated with acute rejection, arterial hypertension and worse renal graft function. A shortening of ischaemia times may reduce the incidence of DGF and improve transplant results.

Adult↗
PubMed1991

The outcome of delayed graft function in cadaveric renal transplants treated with low dose cyclosporine.

Thirty-three consecutive cadaveric renal transplantations performed at the National Taiwan University Hospital from November 1985 to December 1989 were reviewed to determine the effect of early function on the 1-year patient and graft survival rates. Immediate function was present in 17 transplants; delayed graft function with acute tubular necrosis occurred in 16 cases. The 16 transplants with acute tubular necrosis (ATN) were treated with low dose cyclosporine. Among them, 13 patients had delayed function which resolved after 2 to 60 days of hemodialysis, but 3 grafts did not regain function. The allograft survival rate at 1-year was 68.7% for the delayed function group and 88.2% for the immediate function group. This difference was not statistically significant (p greater than 0.05). The 1-year patient survival rate was also not significantly different (87.5% vs 88.2%). There was no relationship between graft loss and duration of ATN. However, the graft survival rate in patients with a serum creatinine level below 2 mg/dL, after recovery either from ATN or non-ATN, was better than that for patients with a serum creatinine level of more than 2 mg/dL. The difference was statistically significant (95.8% vs 50.0%, p less than 0.02). It is concluded that delayed allograft function with acute tubular necrosis does not significantly alter the 1-year survival rates of patients and grafts in low-dose cyclosporine therapy. However, it is deleterious to the 1-year survival rate of an allograft when poor functional recovery occurs in an ATN or non-ATN condition.

Adult↗
PubMed1999

Immediate and long-term results of ATG induction therapy for delayed graft function compared to conventional therapy for immediate graft function.

The use of polyclonal antibodies for delayed graft function (DGF) was tested in 83 renal allograft recipients. Conventional immunosuppression (CI) was given to 52 patients with immediate graft function (IGF) while 31 patients with DGF received the polyclonal antibody ATG. Administration of OKT3 was restricted to steroid-resistant acute rejections in both groups. The incidence and severity of acute rejections, graft survival rate, CMV infections, and lymphocyte subsets were examined. ATG patients experienced a total of 0.6 acute rejections per patient, whereas CI patients had 0.9 on the average (P < 0.05). Second and third acute rejections occurred less frequently and later in the ATG group than in the CI group (P < 0.01). Steroid-resistant acute rejections occurred in 20 of the CI patients (38 %) but in only 7 of ATG patients (23 %). One-year graft survival in the CI and ATG groups was 98.1% and 93.2%, respectively. A decreased CD4 + to CD8 + T-lymphocyte ratio of about 0.5 was still detectable 5 years after the initial ATG administration. Hence, patients with DGF appear to benefit from induction therapy with ATG.

Adult↗
PubMed1987

Timing of cyclosporine administration in patients with delayed graft function.

Cyclosporine in renal transplant recipients with delayed graft function (DGF) has been reported to decrease graft survival and prolong both DGF and hospitalization. In some centers, antilymphocyte globulin (ALG) has been used perioperatively to obviate these problems, but ALG is associated with increased viral infections. In this study, first cadaver transplant recipients with a fall in serum creatinine level of greater than or equal to 30% in the first 24 hr were started on prednisone (P) and cyclosporine (Group 1, n = 18). Those whose creatinine level did not fall were started on P and azathioprine (Group 2, n = 23) and switched to P and cyclosporine when serum creatinine fell 30%. One-year patient survival was 98%. One-year graft survival was 83% for both Groups 1 and 2 (NS). Results were compared to historical controls with DGF who received P and cyclosporine (Group 3, n = 19). Patients with DGF and requiring dialysis had fewer dialyses (P less than 0.05) and a shorter hospital stay (P less than 0.05) if started on azathioprine, as compared to those started on cyclosporine. Patients with DGF had a higher serum creatinine at 12 months than those with immediate function (P less than 0.05). We conclude that withholding cyclosporine until DGF is resolving decreases the duration of dialysis, decreases hospital stay, and without the use of prophylactic ALG, is associated with graft survival equivalent to that in patients with immediate function.

Adult↗
PubMed2003

Nomogram for predicting the likelihood of delayed graft function in adult cadaveric renal transplant recipients.

Delayed graft function (DGF) is the need for dialysis in the first week after transplantation. Studied were risk factors for DGF in adult (age >/=16 yr) cadaveric renal transplant recipients by means of a multivariable modeling procedure. Only donor and recipient factors known before transplantation were chosen so that the probabilities of DGF could be calculated before transplantation and appropriate preventative measures taken. Data on 19,706 recipients of cadaveric allografts were obtained from the United States Renal Data System registry (1995 to 1998). Graft losses within the first 24 h after surgery were excluded from the analysis (n = 89). Patients whose DGF information was missing or unknown (n = 2820) and patients missing one or more candidate predictors (n = 2951) were also excluded. By means of a multivariable logistic regression analysis, factors contributing to DGF in the remaining 13,846 patients were identified. After validating the logistic regression model, a nomogram was developed as a tool for identifying patients at risk for DGF. The incidence of DGF was 23.7%. Sixteen independent donor or recipient risk factors were found to predict DGF. A nomogram quantifying the relative contribution of each risk factor was created. This index can be used to calculate the risk of DGF for an individual by adding the points associated with each risk factor. The nomogram provides a useful tool for developing a pretransplantation index of the likelihood of DGF occurrence. With this index in hand, better informed treatment and allocation decisions can be made.

Adolescent↗
PubMed1996

Delayed graft function in renal transplantation: etiology, management and long-term significance.

PURPOSE: In cadaveric renal transplantation a period of delayed graft function postoperatively is not uncommon and often associated with a poor outcome. We reviewed the biology of reperfusion injury and delayed graft function in renal transplantation, as well as its prevention, management and long-term effects. MATERIALS AND METHODS: The medical literature covering acute tubular necrosis, delayed graft function in renal transplantation and immunology of ischemia reperfusion injury was reviewed. RESULTS: Delayed graft function is clearly associated with poor allograft survival, and is caused by an interaction of ischemic and immunological factors. Technical and pharmacological maneuvers can improve early function rates. The response to ischemic injury is complex, and may increase graft immunogenicity and promote the chronic proliferative changes seen in chronic allograft nephropathy. CONCLUSIONS: Improvement in early renal function should be a primary goal in renal transplantation to enhance early and long-term results. Basic research into the injury response may yield insights into renal pathophysiology.

Cadaver↗