Total HLA Mismatches Research Articles

Delayed Graft Function in Pediatric Kidney Transplant: Risk Factors and Outcomes.

We aimed to identify risk factors and outcomes of delayed graft function in pediatric kidney transplant. This retrospective study included all kidney transplant recipients ≤19 years old followed up in our department for a period of 34 years, from January 1989 to December 2022. We included 113 kidney transplant recipients. Delayed graft function occurred in 17 cases (15%). Posttransplant red blood cell transfusion was strongly associated with delayed graft function (adjusted odds ratio = 23.91; 95% CI, 2.889-197.915). Use of allografts with multiple arteries and cold ischemia time >20 hours were risk factors for delayed graft function (adjusted odds ratio = 52.51 and 49.4; 95% CI, 2.576-1070.407 and 1.833-1334.204, respectively). Sex-matched transplants and living donors were protective factors for delayed graft function (adjusted odds ratio = 0.043 and 0.027; 95% CI, 0.005-0.344 and 0.003-0.247, respectively). Total HLA mismatches <3 played a protective role for delayed graft function (adjusted odds ratio = 0.114; 95% CI, 0.020-0.662), whereas transplant within compatible but different blood types increased the risk of delayed graft function (adjusted odds ratio = 20.54; 95% CI, 1.960- 215.263). No significant correlation was shown between delayed graft function and allograft survival (P = .190). Our study suggested delayed graft function as a key factor in allograft rejection-free survival (adjusted odds ratio = 3.832; 95% CI, 1.186-12.377). Delayed graft function was a negative factor for early graft function; patients with delayed graft function had a lower estimated glomerular filtration rate at discharge (P = .024) and at 3 (P = .034), 6 (P = .019), and 12 months (P = .011) posttransplant. Delayed graft function is a major determinant of early graft function and allograft rejection-free survival. Further research is required to establish proper preventive measures.

Kidney Transplant-Associated Viral Infection Rates and Outcomes in a Single-Centre Cohort.

Opportunistic infections remain a significant cause of morbidity and mortality after kidney transplantation. This retrospective cohort study aimed to assess the incidence and predictors of post-transplant DNA virus infections (CMV, EBV, BKV and JCV infections) in kidney transplant recipients (KTR) at a single tertiary centre and evaluate their impact on graft outcomes. KTR transplanted between 2000 and 2021 were evaluated. Multivariate logistic regression analysis and Cox proportional hazard analyses were used to identify factors associated with DNA virus infections and their impact on allograft outcomes respectively. A sub-analysis of individual viral infections was also conducted to describe the pattern, timing, interventions, and outcomes of individual infections. Data from 962 recipients were evaluated (Mean age 47.3 ± 15 years, 62% male, 81% white). 30% of recipients (288/962) had infection(s) by one or more of the DNA viruses. Individually, CMV, EBV, BKV and JCV viruses were diagnosed in 13.8%. 11.3%, 8.9% and 4.4% of recipients respectively. Factors associated with increased risk of post-transplant DNA virus infection included recipient female gender, higher number of HLA mismatch, lower baseline estimated glomerular filtration rate (eGFR), CMV seropositive donor, maintenance with cyclosporin (rather than tacrolimus) and higher number of maintenance immunosuppressive medications. The slope of eGFR decline was steeper in recipients with a history of DNA virus infection irrespective of the virus type. Further, GFR declined faster with an increasing number of different viral infections. Death-censored graft loss adjusted for age, gender, total HLA mismatch, baseline eGFR and acute rejection was significantly higher in recipients with a history of DNA virus infection than those without infection (adjusted hazard ratio (aHR, 1.74, 95% CI, 1.08-2.80)). In contrast, dialysis-free survival did not differ between the two groups of recipients (aHR, 1.13, 95% CI, 0.88-1.47). Post-transplant DNA viral infection is associated with a higher risk of allograft loss. Careful management of immunosuppression and close surveillance of at-risk recipients may improve graft outcomes.

Human leukocyte antigen mismatch on lung transplantation outcomes.

Human leucocyte antigen (HLA) mismatch is a known risk factor for renal transplantation; however, there are conflicting and limited data on its ramifications within lung transplantation (LTx). Therefore, our study evaluated the effects of total HLA, HLA-A, -B and -DR mismatches on LTx outcomes. We retrospectively examined the United Network for Organ Sharing database for adult patients who had undergone LTx for the first time between January 2005 and July 2021. Total HLA mismatch (0-3, 4, 5 and 6) and HLA locus mismatch (0-1 and 2) were analysed, with the end points of interest being mortality and bronchiolitis obliterans syndrome (BOS) development. Kaplan-Meier curve analysis found a significant difference in both overall survival (n = 27 651; 11 830 events) and BOS development (n = 25 444; 8901 events) for the total number of HLA (P < 0.001, P < 0.001), HLA-A (P < 0.001, P = 0.006) and HLA-DR (P < 0.001, P < 0.001) mismatches. With reference to 0-3 total HLA mismatches, multivariable Cox regression model found that 6 mismatches had an increased risk of mortality (P = 0.002) while 4 (P = 0.010), 5 (P = 0.007) and 6 (P < 0.001) mismatches had an increased risk of BOS. HLA-B mismatch was not associated with an increased mortality (P = 0.975) or BOS risk (P = 0.512). This study demonstrates a significant relationship between increased HLA mismatches and BOS development, with decreased overall survival only apparent with 6 mismatches. HLA-A and -DR mismatches were associated with an increased risk of mortality and BOS development compared to groups with at least 1 locus match.

Graft Loss due to Chronic Rejection in Pancreas Transplantation: Impact of HLA Matching

Chronic rejection has remained the Achilles heel in improving the long-term graft survival in pancreas transplants. A single center retrospective analysis of outcomes was performed to determine if HLA mismatches were associated with graft loss due to chronic rejection. In this study, we analyzed all simultaneous kidney-pancreas transplants performed at our center between January 2000 to January 2011. Patients with functioning grafts (FG) were compared to those with grafts lost due to chronic rejection (CRG) with respect to their HLA A, B and DR matches and mismatches. Of the 112 kidney pancreas recipients, 72 recipients (64%) had functioning graft at more than 10 year follow up. 28 patients (25%) lost their graft to chronic rejection. Twelve recipients (11%) with failed grafts due to surgical or infectious complications were excluded from the study. The recipients with graft loss due to chronic rejection (CRG) were slightly younger (mean age 37 in comparison to 42) than recipients with functioning grafts (FG). Both groups had similar mean BMI of 25. Mean pancreas preservation time in FG and CRG groups were 12.5 and 12 hours respectively. The mean HLA A, B and DR mismatches in FG group (1.43,1.58,1.34) was comparable to those in CRG group (1.46,1.5,1.53). The mean total HLA mismatches in the FG and CRG groups were 4.36 and 4.5 respectively. Our data does not support the use of HLA matching to predict pancreas graft loss due to chronic rejection in simultaneous kidney pancreas transplant recipients.

Impact of human leukocyte antigen compatibility on outcomes of living donor liver transplantation: Experience from a tertiary care center.

The role of HLA compatibility in kidney, heart, and stem cell transplantation is well known, but with regard to living donor liver transplantation (LDLT), there is a different scenario. In the present study, we aim to examine the effects of donor-recipient HLA mismatches at A, B, and DR loci on various outcomes of LDLT-like graft survival, early allograft dysfunction (EAD), acute rejection, length of hospital (LOH) stay, sepsis, and cytomegalovirus (CMV) reactivation. This is a retrospective single center study of a cohort of adult patients who underwent first time ABO-compatible (ABOc) LDLT between January 2010 and December 2018. Transplants with incomplete records or without HLA typing data were excluded. Donor-recipient HLA-A, B, and DR mismatches were assessed in the host versus graft (HVG) direction and were correlated with various post-transplant outcomes. Among 140 transplants being evaluated, approximately two third had total HLA mismatches between 2 and 3. HLA mismatches at each locus as well as cumulative HLA mismatches did not show any association with overall graft survival, EAD, acute rejection episodes, and LOH stay. However, the presence of minimum one mismatch at HLA-A and DR loci was associated with the development of CMV reactivation (P=.03) and sepsis (P=.02) post-LDLT respectively. HLA mismatch is not associated with acute rejection, early graft dysfunction, and overall survival in LDLT. Its impact on CMV reactivation and sepsis needs further evaluation.

Impact of HLA Mismatching on Early Subclinical Inflammation in Low-Immunological-Risk Kidney Transplant Recipients.

The impact of human leukocyte antigen (HLA)-mismatching on the early appearance of subclinical inflammation (SCI) in low-immunological-risk kidney transplant (KT) recipients is undetermined. We aimed to assess whether HLA-mismatching (A-B-C-DR-DQ) is a risk factor for early SCI. As part of a clinical trial (Clinicaltrials.gov, number NCT02284464), a total of 105 low-immunological-risk KT patients underwent a protocol biopsy on the third month post-KT. As a result, 54 presented SCI, showing a greater number of total HLA-mismatches (p = 0.008) and worse allograft function compared with the no inflammation group (48.5 ± 13.6 vs. 60 ± 23.4 mL/min; p = 0.003). Multiple logistic regression showed that the only risk factor associated with SCI was the total HLA-mismatch score (OR 1.32, 95%CI 1.06–1.64, p = 0.013) or class II HLA mismatching (OR 1.51; 95%CI 1.04–2.19, p = 0.032) after adjusting for confounder variables (recipient age, delayed graft function, transfusion prior KT, and tacrolimus levels). The ROC curve illustrated that the HLA mismatching of six antigens was the optimal value in terms of sensitivity and specificity for predicting the SCI. Finally, a significantly higher proportion of SCI was seen in patients with >6 vs. ≤6 HLA-mismatches (62.3 vs. 37.7%; p = 0.008). HLA compatibility is an independent risk factor associated with early SCI. Thus, transplant physicians should perhaps be more aware of HLA mismatching to reduce these early harmful lesions.

Associations of interactions between NLRP3 SNPs and HLA mismatch with acute and extensive chronic graft-versus-host diseases

HLA matching is a well-known genetic requirement for successful bone marrow transplantation (BMT). However, the importance of non-HLA single-nucleotide polymorphisms (SNPs) remains poorly understood. The NLR family pyrin domain–containing 3 (NLRP3) inflammasome, a key regulator of innate immunity, is associated with multiple diseases. We retrospectively genotyped SNPs of NLRP1–3 and caspase recruitment domain family member 8 (CARD8), which are implicated in the interleukin 1β (IL-1β) signaling, in 999 unrelated BMT donor–recipient pairs. We identified an association of the interaction between the recipient NLRP3 SNP CC genotype and total HLA mismatches with grade 2–4 acute graft-versus-host disease (AGVHD), and an association of the interaction between the donor NLRP3 SNP T allele and HLA-C mismatch with extensive chronic GVHD (ECGVHD), in both adjusted and unadjusted regressions (P < 0.005). Importantly, the ECGVHD risk associated with HLA-C mismatch was not elevated when the donor NLRP3 genotype was CC. We also identified an association of the interaction between recipient NLRP3 SNP and donor cytomegalovirus seropositivity with overall survival in adjusted regressions (P < 0.005). These results suggest the importance of certain SNP–covariate interactions in unrelated BMT. The three identified interactions may be useful for donor selection or outcome prediction.

OR32 The new kidney allocation system disadvantages patients with cPRA 90–98% – A single center analysis

Aim The new UNOS kidney allocation system (KAS) awards 212 points to renal transplant candidates (RTC) with cPRA of 99% or 100%, allowing for national sharing. We hypothesized that this might disadvantage RTC whose cPRA is high (⩾90%) but less than 99%. Methods We analyzed all import organ offers to RTC at our center for 5 months before and after the 12/4/14 change to the new KAS. We counted offers where the top RTC had cPRA of 90–98% or >98%. We compared number of offers, matchrun sequence number (MSN), HLA mismatch (MM), kidney donor profile index (KDPI), and transplants for these groups. Results On 12/4/14 there were 13 RTC with cPRA 90–98% and 24 with cPRA >98% on the active kidney waitlist. Comparisons of organ offers are shown in table 1. Pre-KAS there were 379 total kidney offers: 17.2% to RTC with cPRA 90–98% and 3.2% to cPRA >98%. Post-KAS about 13% of offers ( N = 419) went to each group ( p 2 ). Pre-KAS the MSN for offers to cPRA >98% RTC was higher by 680 places than for cPRA 90–98% RTC. Post-KAS the MSN for the cPRA 90–98% RTC was higher by about 925 places, giving them lower priority for offers and making them less likely to receive the organ even when provisionally accepted. The mean total HLA MM (A + B + DR) was significantly higher for 90–98% RTC than for >98% RTC pre-KAS. This difference between the two groups decreased after KAS but still remained significant. The mean KDPI of donor offers did not differ between the two groups before or after KAS implementation. The number of transplants of >98% RTC increased dramatically from 0 to 5 (all import) post-KAS but transplants of 90–98% RTC decreased from 3 (1 import, 2 local) to 2 (1 local, 1 transplanted elsewhere). Conclusions The new KAS has benefitted the >98% cPRA RTC waiting for kidneys by increasing the number of organs offered and transplanted. The organs offered pre- and post-KAS to this group were not significantly different in terms of HLA MM and KDPI. In contrast, the 90–98% cPRA group had fewer offers post-KAS and fewer transplants, but the offered kidneys were better HLA matched. Download full-size image

Use of Heavy Drinking Donors in Heart Transplantation is Not Associated With Worse Mortality.

Although orthotopic heart transplantation (OHT) remains the preferred treatment for end-stage heart failure, there continues to be a critical shortage of organ donors. The goal of this study is to examine outcomes after orthotopic OHT using heavy drinking donors (HDDs) in a large, national database. The United Network for Organ Sharing database was examined for all primary, adult OHT carried out from 2005 to 2012. There were 14,928 total OHT performed during the study period with 2,274 (15.2%) using HDD. Recipients of HDD were older (53.4 vs. 51.9 years, P < 0.001), more likely men (80.7 vs 74.4%, P < 0.001), less likely sex mismatched (21.5 vs 27.5%, P < 0.001), more likely race mismatched (57.4 vs 52.4%, P < 0.001), and had less total HLA mismatches (4.55 vs 4.65, P < 0.001). The HDD were older (37.0 vs 30.5 years, P < 0.001), more likely men (82.2 vs 69.9%, P < 0.001), and more likely to have heavy cigarette use (38.1 vs 13.2%, P < 0.001). Length of stay was not different (20.3 vs 19.7 days, P = 0.02). On multivariate analysis, use of HDD was not associated with mortality at 30 days (hazards ratio [HR], 1.12; 95% confidence interval [95% CI], 0.90-1.39; P = 0.30), 1 year (HR, 0.96; 95% CI, 0.83-1.11; P = 0.56), and at 5 years (HR, 1.02; 95% CI, 0.91-1.13; P = 0.79). Variables associated with mortality at 5 years included increasing donor age, prolonged ischemic time, worsening recipient creatinine, recipient black race, sex mismatch, and extracorporeal membrane oxygenation or mechanical ventilation as a bridge to transplantation. Heart transplantation can be performed using carefully selected HDDs with good outcomes.

(731) - Use of Heavy Drinking Donors in Heart Transplantation is Not Associated With Worse Short- and Medium-Term Mortality

(731) - Use of Heavy Drinking Donors in Heart Transplantation is Not Associated With Worse Short- and Medium-Term Mortality

Cytomegalovirus Infectıon in Renal Transplant Recipients: One Center's Experience

BackgroundCytomegalovirus (CMV) is the most common opportunistic viral infection that causes morbidity, graft loss, and mortality among renal transplant recipients (RTRs). The aim of this study was to evaluate the impact of CMV infection on allograft function, graft/patient survival, and the possible asssociations between CMV infection and HLA typing. MethodThis retrospective study included 162 RTRs who had at least 1 year regular post-transplantatioin follow-up between January 2007 and December 2011. Recipients who had positive quantative CMV–polymerase chain reaction (PCR) were assigned to the study group (n = 17) and PCR-negative patients were assigned to the control group (n = 145). To determine whether CMV infection was related to HLA specificities, the incidence of CMV infection was analyzed in relation to HLA-A, -B, and -DR typing. ResultsStudy groups were similar in terms of demographic, clinical, and basal laboratory findings. Duration of dialysis before transplantation was significantly longer in this study group (P = .018). Although the total HLA mismatches of both groups were similar, we found that HLA-B51–positive recipients had a lower risk for CMV infection (P = .018). CMV infection was more frequent in patients with a double-J stent (P = .001). Although basal creatinine levels of the two groups were similar, the study group patients' creatinine levels were significantly increased during the 1-year post-transplantation period compared to controls (P = .0001). Frequency of acute rejection was significantly higher in the study group (41.2% vs 11%, P = .001). Graft loss due to any cause was also significantly higher in the study group (29.4% vs 6.9%, P = .01). Patients who had preoperative induction therapy and post-transplantatioin tacrolimus-based regimens were prone to CMV infection (P = .0001, .006). ConclusionsDespite recent advances in prophylaxis, CMV infection is still a risk factor for RTRs. According to our data, long pretransplantation dialysis duration, being HLA-B51–negative, having a double-J stent, preoperative induction therapy, and post-transplantation tacrolimus-based regimens might induce development of CMV infection by 1-year post-transplantation follow-up.

The Registry of the International Society for Heart and Lung Transplantation: Fifteenth Pediatric Heart Transplantation Report—2012

The Registry of the International Society for Heart and Lung Transplantation: Fifteenth Pediatric Heart Transplantation Report—2012

Long‐term kidney transplant outcome in obese patients in a predominantly African American population

The impact of obesity on long-term kidney transplant outcome has largely been studied in non-African American patients. This study seeks to determine differences in outcome between obese and non-obese patients after kidney transplantation, in a predominantly African American population. We reviewed 642 adult renal transplant recipients who received their transplants at SUNY Downstate Medical Center between 1998 and 2007. Sixty-six percent of the patients studied were African American. The patients were divided into five groups according to their BMI status: underweight <20, normal 20-24.9, overweight 25-29.9, obese 30-34.9, and morbidly obese ≥35. There were no differences in race, gender, cytomegalovirus infection, type of transplant, panel-reactive antibody, retransplant status, flow cytometry cross-match results, mycophenolate mofetil therapy, and total HLA mismatch status. The mean discharge serum creatinine in the morbidly obese group was significantly higher than in other groups (p < 0.001). The difference in creatinine level disappeared at six wk and six months (p > 0.5), respectively. Acute rejection rates, delayed graft function, graft survival, and patient survival were not different between the groups. The findings from this large single-center study suggest that obese and morbidly obese patients had similar outcomes compared to other weight groups. Obese and morbidly obese African American patients should not be excluded from kidney transplantation on the basis of weight alone.

Human Leukocyte Antigen Mismatch and Other Factors Affecting Cryopreserved Allograft Valve Function

The causes of cryopreserved allograft heart valve degeneration are poorly understood. We investigated HLA mismatch and other factors implicated in allograft valve degeneration. For this study we recruited 110 adult recipients of allograft heart valves who underwent surgery between June 1998 and March 2003 in the state of Victoria, Australia. Recipients and donors were HLA typed using serological and molecular methods. Valve function at most recent echocardiographic follow-up was examined for an association with the following variables using univariate and multivariate methods: HLA-A,-B, and -DR donor-recipient mismatch; HLA class I mismatch; total HLA mismatch; valve ischemic time; recipient age; donor age; ABO blood group donor-recipient match; and allograft size. Mean recipient age was 45 years (18-75 years), 75% were men. Seventy-four pulmonary (62 Ross procedure) and 36 aortic allografts were examined. Median valve ischemic time was 31 hours, range 20-48 hours. Echocardiographic follow-up was complete at a mean of 41 (+/-18) months, range 6-85 months. At univariate analysis longer ischemic time and younger recipient age were associated with valve dysfunction. HLA-A, -B, or DR mismatch, HLA class I mismatch, total HLA mismatch, donor age, ABO mismatch, and allograft size were not associated with valve dysfunction. Only younger recipient age remained significant at multivariate analysis. In conclusion, longer ischemic times and younger patient age predicted valve dysfunction at a mean of 3 years follow-up. Recipient age remained the strongest predictor of valve dysfunction. These results indicate that allograft ischemic times should be minimized.

Donor Origin of BK Virus in Renal Transplantation and Role of HLA C7 in Susceptibility to Sustained BK Viremia

In a previous study, we performed serial BK virus (BKV), polymerase chain reaction (PCR) and detected active BKV infection in 70 (35.4%) of 198 renal transplant recipients. In the current study, pre-transplant donor and recipient samples were analyzed for BKV antibody titer and HLA alleles. Donor antibody titer was inversely proportional to onset of viruria, p<0.001, directly proportional to duration of viruria, p=0.014 and directly proportional to peak urine viral titer p=0.005. Recipient pairs receiving kidneys from the same donor were concordant for BKV infection, p=0.017, and had matched sequences of segments of the NCCR and VP1 genes that tended to vary among recipients of kidneys from different donors. We did not see an association of HLA A, B, or DR, HLA allele mismatches or total HLA mismatches and BK infection. However, all 11 recipients with sustained BK viremia received kidneys from donors lacking HLA C7, and 10 recipients also lacked C7. These findings derive from the largest and most comprehensive prospective study of BKV infection in renal transplant recipients performed to date. Our data support donor origin for early BKV infection in kidney transplant recipients, and suggest that a specific HLA C locus may be associated with failure to control BKV infection.

A Multicenter Analysis of the Significance of HLA Matching on Outcomes After Kidney-Pancreas Transplantation

The purpose of this study was to determine the influence of HLA matching on outcomes in simultaneous kidney-pancreas transplant (SKPT) recipients in a multicenter trial. From March 1999 to May 2001, a total of 297 SKPT recipients were enrolled in a prospective randomized trial of 2 daclizumab dosing strategies versus no antibody induction in combination with tacrolimus, mycophenolate mofetil, and steroids in SKPT recipients. Subanalyses using both univariate and multivariate models were performed at 1 year to identify factors associated with acute rejection, graft loss, or death. Potential risk factors evaluated were treatment group, African American ethnicity, HLA-A mismatches (MM), HLA-B MM, HLA-DR MM, total HLA MM, surgical technique, cytomegalovirus status of donor and recipient, and delayed graft function (DGF). Univariate analyses revealed that treatment group, HLA-A MM, HLA-B MM, total HLA MM >3, and DGF were significantly associated with acute rejection. These variables were then entered into logistic and Cox regression analyses. HLA-A MM and DGF were the only variables that remained significantly associated with acute rejection in the multivariate model. The relative risk for acute rejection in recipients with HLA-A MM was 1.56 ( P = .02). In conclusion, despite contemporary immunosuppression, the degree of HLA MM, particularly HLA-A, and DGF are associated with an increased risk for acute rejection in SKPT recipients at 1 year. Less rejection was noted in patients with 0 MM at all 3 HLA loci and in patients with total HLA-MM <3. However, none of these factors affected short-term patient or graft survival rates.

Outcome after steroid withdrawal in pediatric renal transplant patients receiving tacrolimus-based immunosuppression.

Corticosteroids have always been an integral part of immunosuppressive regimens in renal transplantation. The primary goal of this analysis was to assess the safety of steroid withdrawal in our pediatric renal transplant recipients receiving tacrolimus-based immunosuppression. Between December 1989 and December 1996, 82 renal transplantations were performed in pediatric patients receiving tacrolimus-based immunosuppression. Two of these patients lost their grafts within 3 weeks of transplantation (and were still on steroids at the time of graft loss), and were excluded from further analysis. Seventy-four patients (92.5%) were taken off prednisone a median of 5.7 months after transplantation. Of these 74, 56 (70%) remained off prednisone (OFF), and 18 (22.5%) were restarted on prednisone a median of 14.8 months after discontinuing steroids (OFF --> ON). 6(7.5%) were never taken off prednisone (ON). The mean follow-up was 59 +/- 23 months. The 1-, 3-, and 5-year actuarial patient survival rates in the OFF group were 100%, 98%, and 96%, respectively; in the OFF --> ON group, they were 100%, 100%, and 100%, and in the ON group, they were 100%, 83%, and 83%. The 1-, 3-, and 5- year actuarial graft survival rates in the OFF group were 100%, 95%, and 82%, respectively; in the OFF --> ON group, they were 100%, 89%, and 83%; and in the ON group, they were 100%, 50%, and 33%. Two of the six graft losses in the OFF group, three out of four in the OFF --> ON Group, and two out of five in the ON group, were to chronic rejection. A time-dependent Cox regression analysis showed that the hazard for graft failure for those who came and stayed off prednisone was 0.178 relative to those who were never withdrawn from prednisone (P=0.005). Patients who were 10 years of age or younger were withdrawn from prednisone earlier (median: 5 months) than those older than 10 years (median: 7.3 months, P=0.02). In addition, patients who never had acute rejection were withdrawn from steroids earlier (median: 5 months) than those who had one or more episodes of acute rejection (median: 7.6 months, P=0.001). There was no effect of donor age, race, sex, recipient race, sex, cadaveric versus living donor, 48-hr graft function, panel reactive antibody, and total HLA mismatches or matches on the likelihood of being weaned off steroids. Serum creatinine at most recent follow-up in the OFF group was 1.2 +/- 0.5 mg/dl; in the OFF --> ON group, it was 1.8 +/- 0.9 mg/dl, and in the ON group it was 2.0 mg/dl (P<0.003). The incidence of rejection in the OFF, OFF --> ON, and ON groups was 39%, 77%, and 100%, respectively (P<0.05). These data suggest that steroid withdrawal in pediatric renal transplant patients receiving tacrolimus-based immunosuppression is associated with reasonable short- and medium-term patient and graft survival, and acceptable renal function. Patients who discontinue and then resume steroids had patient and graft survival rates comparable with those in patients who discontinue and stay off steroids, but had a higher serum creatinine and a higher incidence of rejection.

Clinical determinants of glucose homeostasis after pancreas transplantation.

Although successful simultaneous pancreas and kidney transplantation (SPK) achieves normoglycemia in the majority of diabetic recipients with end-stage renal disease, little is known about the factors that influence long-term endocrine function. In this prospective study of 48 bladder-drained SPK patients, 209 oral glucose tolerance tests were performed between 3 months and 6 years after transplantation. Normal fasting glucose levels and systemic hyperinsulinemia were stable for up to 6 years after SPK. Multivariate analysis revealed that increased area-under-curve (AUC) levels of C-peptide 3 months after transplantation were predicted by short surgical pancreas anastomosis time, greater recipient body weight, and total HLA mismatch score. Episodes of acute pancreas rejection were not associated with reduced allograft insulin output in the long term. Insulin output, stimulated by oral glucose tolerance tests and assessed by the ratio of AUC insulin to AUC glucose, fell gradually after transplantation and was decreased by an elevated serum calcium level and high cyclosporine dose. The ratio of fasting insulin to glucose, which acts as a marker of peripheral insulin resistance, fell with time after transplantation and was increased by greater body weight, higher prednisolone dose, and lower cyclosporine dose. The inhibitory effect of cyclosporine on both fasting and postprandial insulin output was, however, minor when quantified by multivariate analysis. Endocrine function of the transplanted pancreas was not correlated with its exocrine function measured by urinary amylase excretion, nor was there a correlation with change in renal function measured by isotopic glomerular filtration rate. In summary, simultaneous pancreas and kidney transplantation leads to excellent long-term glucose homeostasis maintained at the expense of systemic hyperinsulinemia. The key factors adversely affecting peripheral resistance in SPK were corticosteroid therapy, body weight, and time after transplantation. The susceptibility of islets to ischemia-reperfusion injury, as quantitated by surgical anastomosis time, may have implications for islet transplantation programs, as may the relative resistance of islets to allograft rejection. Glucose homeostasis after SPK, while remaining abnormal, may be used as the standard against which islet transplantation must be measured.