Cadaveric Renal Transplant Recipients Research Articles

No myelosuppression when mizoribine is combined with allopurinol for the treatment of hyperuricemia in renal transplant patients

Background. In cadaveric renal transplant recipients, a commonly used triple immunosuppression regimen includes azathioprine, cyclosporin, and prednisolone. Azathioprine is a potential bone marrow suppressant. Allopurinol is a commonly used drug to treat hyperuricemia, which frequently occurs in kidney transplant recipients. Azathioprine is metabolized by xanthine oxidase, which is inhibited by allopurinol, leading to accumulation of its active metabolites, which are potential myelosuppressants. Moreover, in certain clinical situations, azathioprine is contraindicated. The immunosuppressive drug mizoribine has been used to prevent rejection of organ allografts in humans. Its effect is mediated through a different pathway in purine metabolism, and allopurinol does not interfere with its metabolism. Therefore, a combination of mizoribine with allopurinol does not cause myelosuppression. Methods. Thirteen cadaveric renal transplant recipients who had hyperuricemia were treated with allopurinol and mizoribine as an alternative to azathioprine, along with steroids and cyclosporin A. They were followed up for 12 months. Results. None of these patients developed bone marrow suppression and all had adequate control of hyperuricemia and had no deterioration in allograft function. Conclusions. Mizoribine can be safely combined with allopurinol in cadaveric renal transplant recipients who have hyperuricemia, without causing bone marrow suppression.

Cold ischemia time: an independent predictor of increased HLA class I antibody production after rejection of a primary cadaveric renal allograft.

Cadaveric kidneys experiencing longer cold ischemia time (CIT) are associated with higher levels of delayed graft function, acute rejection, and early graft loss. One mechanism to explain these results is that ischemia/reperfusion (I/R) injury makes the allograft more immunogenic by upregulating molecules involved in the immune response (e.g., HLA Class I/II). We evaluated the influence of CIT on the production of HLA Class I antibody level, measured by an antihuman globulin panel reactive antibody (AHG PRA) level, in 90 unsensitized recipients of primary cadaveric renal transplants (from a total of 1442 between 1985 and 1997) who rejected their kidneys. By multivariate analysis, a CIT of 15 hr or more (vs. < 15 hr) independently increased the risk of the AHG Class I PRA level being > or = 20% after unsensitized patients rejected their first kidneys (relative risk=3.57; 95% confidence interval=1.26 to 10.14; P=0.01), despite the same degree of Class I/II mismatch between the two CIT groups. The overall mean peak PRA level after primary kidney rejection was significantly lower for the CIT < 15 hr group (25.9%+/-33.9; n=24) compared with the CIT > or = 15 hr group (46.3%+/-36.5; n=66) (P<0.001). Longer CIT induces a humorally more immunogenic kidney.

Six-year clinical effect of donor bone marrow infusions in renal transplant patients.

To date, several single- and multicenter clinical trials have attempted to induce specific immunological unresponsiveness using donor bone marrow cell infusions to augment solid organ transplantation, but the outcomes have not been definitive. Between September 1994 and May 1998, 63 cadaver (CAD) renal transplant recipients of either one or two postoperative donor bone marrow cell (DBMC) infusions were prospectively compared with 219 non-infused controls given equivalent immunosuppression. There was at least a 1 HLA DR antigen match present between donors and recipients. The immunosuppressive regimen included a 10-day course of OKT3 induction, and tacrolimus, mycophenolate mofetil, and methylprednisolone maintenance. A total 7.01x10(8)+/-1.9x10(8) (SD) DBMC/kg was infused into the CAD recipients on either days 4 and 11 (n=42) or one half of that dose on day 4 (n=21) postoperatively. Clinical follow-up has ranged from 2.9 to 6.3 years (mean, 4.7 years). Studies were also performed of humoral immunity and quantitative cellular chimerism. There is clear-cut equivalence in immunosuppressive dosaging and in the other major demographic variables in both groups. However, only 2/63 DBMC recipients had biopsy-proven chronic rejection, whereas 41/219 showed chronic rejection in the controls (P = <0.01). In both groups, mortality was not associated with rejection. The actuarial graft survival at 6.3 years in the CAD DBMC group was 84.3% compared with 72.2% in the control group (not statistically significant). However, if death with a functioning graft was excluded, graft survival was 94.1% in the DBMC group and 79.8% in the controls (P=0.039). Forty patients in the control group continue to have deteriorating renal function (increasing serum creatinine concentrations to 2 mg/dl and higher), compared with 2 patients in the DBMC group (P=0.04). In the DBMC group, chimerism in iliac crest marrow aspirates has increased 3-fold in yearly sequential measurements between 1 and 4 years postoperatively averaging 1.3+/-0.36% (SE) most recently. This has not occurred in the controls. There now appears to be more solid long-term evidence, in kidney transplant recipients prospectively receiving DBMC infusions, of an improvement in long-term graft survival, and of the degree of chimerism positively correlating with the absence of graft loss.

The impact of recipient cytokine genotype on acute rejection after renal transplantation.

Acute allograft rejection remains an important cause of morbidity after kidney transplantation, and has been shown to be a crucial determinant of long-term graft function. As cytokines are major regulators of the immune system, genetic variation in cytokine production or activity may influence susceptibility to acute rejection. This study sought to determine the impact of recipient cytokine and cytokine receptor polymorphisms on acute rejection after renal transplantation. A total of 209 cadaveric renal transplant recipients were selected for analysis according to the presence or absence of graft rejection in the first 30 days after transplantation. DNA was genotyped for 22 polymorphisms in 11 cytokine and cytokine receptor genes using the polymerase chain reaction with sequence specific primers. Results were stratified by incidence and severity of rejection, and by HLA-DR mismatching. No association between any polymorphism and the incidence or severity of acute rejection was detected. In particular, no association was seen with tumor necrosis factor or interleukin-10 genotype, either alone or in combination. We have failed to demonstrate any association between recipient cytokine genotype and acute rejection after cadaveric renal transplantation. Although more extensive studies may disprove these findings, it would seem premature to use recipient cytokine genotyping to predict transplant outcome, or to guide immunosuppressive therapy after transplantation.

Impact of proteinuria in cyclosporine-treated cadaveric renal transplant recipients

Impact of proteinuria in cyclosporine-treated cadaveric renal transplant recipients

The economic benefit of allocation of kidneys based on cross-reactive group matching.

Recently the United Network for Organ Sharing (UNOS) began a pilot study to evaluate prospectively the merits of an allocation of cadaveric kidneys based on broader classes of HLA antigens, called cross-reactive groups (CREG). The objectives of the pilot study consider patient outcomes, but not the potential economic impact of a CREG-based allocation. This study predicts the impact of a CREG-based local allocation of cadaveric kidneys on 3-year Medicare payments and graft survival. The UNOS renal transplant registry was merged to Medicare claims data for 1991-1997 by the United States Renal Data System. Average accumulated Medicare payments and graft survival up to 3 years posttransplant for first cadaveric renal transplant recipients were stratified by cross-reactive group mismatch categories. The economic impact was defined as the difference in average 3-year costs per transplant between the current and proposed allocation algorithms. Average 3-year costs were computed as a weighted average of costs, where the weights were the actual and predicted distributions of transplants across cross-reactive group categories. Results suggest that an organ allocation based on cross-reactive group matching criteria would result in a 3-year cost savings of $1,231 (2%) per transplant, and an average 3-year graft survival improvement of 0.6%. Cost savings and graft survival improvements can be expected if CREG criteria were to replace current criteria in the current allocation policy for cadaveric kidneys, although the savings appear to be smaller than may be achievable through expanded HLA matching.

Flow cytometry crossmatching as a predictor of acute rejection in sensitized recipients of cadaveric renal transplants

Flow cytometry crossmatching (FCXM) was developed as a more sensitive assay than the standard complement-dependent cytotoxicity crossmatch (CDCXM) for the detection of anti-donor antibodies, that mediate hyperacute rejection and graft loss in the early post-transplant period in renal transplant recipients. The role of FCXM in predicting long-term clinical outcome in renal allograft recipients is unclear. This study examines the role of FCXM in predicting long-term clinical outcome in highly sensitized recipients of cadaveric renal transplants. All patients (n = 100) with peak panel reactive antibody (PRA) levels > 30%, who received cadaveric renal transplants between 1/1/'90 and 12/31/'95 at our institution, were divided into FCXM + and FCXM - groups. The incidence of acute rejection was determined for each group during the first yr after transplant. Graft survival rates at 1, 2, and 3 yr, and creatinine levels were also compared between groups. FCXM + patients experienced a higher incidence of acute rejection during the first yr after transplant (69 vs. 45%), and a higher percentage of FCXM + patients had more than one episode of acute rejection during the first yr after transplant (34 vs. 8%) when compared to FCXM - patients. There was no statistically significant difference in 1-, 2-, or 3-yr graft survival between FCXM + and FCXM - patients (76 vs. 83, 62 vs. 80, 62 vs. 72%, respectively). These results suggest that sensitized FCXM + cadaveric renal transplant recipients have a higher incidence of acute rejection episodes in the first yr after transplant. Given the association of multiple rejection episodes with poor long-term allograft survival, FCXM may be a useful predictor of long-term clinical outcome in this sub-group of renal transplant recipients.

Conversion from tacrolimus to cyclosporine in stable renal transplant patients: safety, metabolic changes, and pharmacokinetic comparison.

Although conversion between tacrolimus and cyclosporine has been performed when indicated for rejection or adverse effects, the safety and metabolic outcome of elective conversion from tacrolimus to cyclosporine has not previously been examined. Conversion from tacrolimus to cyclosporine was performed in 19 recipients of cadaver renal transplants at 3-6 months after transplantation. Pharmacokinetic profiles and biochemical studies were performed three times, in steady state, before, and after conversion. Patient and graft survival was 100% at 3 months after conversion, with no rejection episodes. Three patients have been subsequently converted back to tacrolimus, two for rejection and one for hirsutism. There were no significant changes in creatinine, urate, or blood sugar levels after conversion, but the mean plasma magnesium rose from 0.73 (0.63-0.97) to 0.82 (0.65-1) mmol/L (P=0.037), and the mean plasma cholesterol rose from 5.2 (3.4-6.8) to 5.5 (3.8-7.6) mmol/L (P=0.033). Pharmacokinetic profiles were measured before and after conversion, and showed that cyclosporine (Neoral) exhibited significantly less interpatient and intrapatient variability than tacrolimus, for area under the curve (AUC), maximum concentration after dose (Cmax), minimum concentration after dose (Cmin), and time to maximum concentration (Tmax). This is the first study that has examined the outcome of conversion from tacrolimus- to cyclosporine-based immunosuppression in stable patients after renal transplantation. This conversion was performed without early immunological hazard, but there was a small rise in blood cholesterol levels after conversion. Pharmacokinetic studies showed that cyclosporine in the form of Neoral exhibited less inter- and intrapatient variability than tacrolimus, although this is of uncertain clinical significance.

Time dependency of factors affecting renal allograft survival.

The function of renal transplants can deteriorate at any time posttransplant, but the risks and mechanisms may differ at different times posttransplant. Survival of 522 consecutive cadaveric renal transplant recipients followed for at least 6 mo were analyzed, with patient death censored. The overall risk factors in univariate analysis were acute rejection requiring antibody therapy (AR), delayed graft function, elevated serum creatinine at 6 mo, high panel-reactive antibodies, and donor age > or =55 yr, with borderline effects of recipient age and female gender. These risks were studied in each of three intervals posttransplantation: < or =6 mo, 6 mo to 5 yr, and >5 yr. Of the 135 graft failures, 53 occurred < or =6 mo, 61 between 6 mo and 5 yr, and 21 beyond 5 yr. By multivariate analysis. the risks for graft failure in interval < or =6 mo were AR (hazard ratio (HR) = 4.86, P < 0.001); delayed graft function (HR = 1.47, P = 0.06): and high panel-reactive antibodies (HR = 2.04, P = 0.0(3). Between 6 mo and 5 yr, the risks for graft loss were AR (HR = 2.87, P < 0.001) and serum creatinine at 6 mo > or =150 micromol/L (HR = 3.69, P < 0.001). Beyond 5 yr the risk factors were donor age > or =55 yr (HR = 5.87, P = 0.002), with a borderline effect of kidneys from female donors (HR = 2.28, P = 0.07). HLA-A, -B, and -DR matching and presensitization had most of their effect through early AR and impaired function. The results indicate that risks for graft loss are time-dependent: early losses correlate with injury and rejection, but late events correlate with donor age and possibly workload.

Tacrolimus and mycophenolate mofetil in cadaveric renal transplant recipients

Tacrolimus and mycophenolate mofetil in cadaveric renal transplant recipients

The human bone marrow as an immunoregulatory organ.

It was 45 years ago that in a virtual revolution in thinking in immunology there developed the acceptance and the subsequent expansion of two new dogmas: (1) that to eliminate toxins and pathogens as the major mode of defense, individual immune cells were, in their ontogeny of differentiation, internally programmed to react singly and then clonally against the virtually limitless individual stimuli of the outside world (1–3); (2) that before this programming was manifested the immune system would fail to recognize any antigenic stimulus as foreign, thereby not differentiating non-self from self-recognition. This allowed for non-self-antigens, if introduced in this early stage, to be immunologically tolerated on subsequent testing. In the chronology of the evolution of these two dogmas, there were the earlier descriptions of specific immunological paralysis and unresponsiveness to certain defined polysaccharides and haptens demonstrated in adult mice and guinea pigs respectively by Felton (4) and Chase (5). It remained for Medawar and his colleagues (6) in allotransplantation experiments to clearly define “acquired specific immunological tolerance” as an ontogenic concept involving the lack of maturation or differentiation were tolerance to be evoked. As early as 1953, Billingham, Brent, and Medawar demonstrated that allogeneic donor bone marrow-derived cells could confer such a specifically acquired tolerant state to the immune system of the murine recipient before self versus non-self recognition occurred in immune ontogeny, the test being subsequent acceptance of skin allografts from the same donors. The developmental processes of positive versus negative selection only a decade later began to be demonstrated to predominantly involve the thymus gland in maturational events of cells of the recipient immune system in studies first performed in neonatal rodents (7). By experimental manipulation of the immune system predominantly involving immunoablation by whole body x-irradiation, these findings of specific immunological tolerance as a result of the infusion of bone marrow-derived cells could be extended to adult animals as the system regenerated from stem cells in the bone marrow of either that of the donor (8), the recipient (9), or both (10). Nonetheless, except in the setting of clinical bone marrow transplantation using major (lethal) immunoablation followed by the salvage and replacement of the recipient immunohematopoietic system with donor cell lineages and only in the context of little or no donor-recipient MHC disparity, with few exceptions (11–15), to date, specific immunological tolerance in organ transplantation in humans has not been possible.

Deleterious Effects of Delayed Graft Function in Cadaveric Renal Transplant Recipients Independent of Acute Rejection

Background. In cadaveric renal transplantation, delayed graft function (DGF) correlates with poor long-term graft survival; however, whether its effects are independent of acute rejection is controversial. We wished to study the effect of DGF on graft survival, controlling for acute rejection, discharge creatinine, and human leukocyte antigen match. Methods. We analyzed 27,096 first cadaveric donor renal transplants reported to the UNOS Scientific Renal Transplant Registry between January 1994 and November 1997. DGF was defined as dialysis need in the first week. Acute rejection was recorded for initial hospitalization and within 6 months. Kaplan Meier survival curves were analyzed with the log rank test. Results. DGF increased the incidence of acute rejection before discharge (8% without DGF; 25% with DGF, P<0.01) and any acute rejections by 6 months (25% without DGF, 42% with DGF, P<0.01). Without early rejection, DGF reduced 1-year graft survival from 91 to 75% (P<0.0001) and graft half-life from 12.9 to 8.0 years. In kidneys with acute rejection within 6 months, DGF decreased 3-year graft survival from 77 to 60% and graft half-life from 9.4 to 6.2 years (P<0.001). With a discharge creatinine of less than 2.5 mg/dl, the difference in graft half-life between no DGF and no rejection (13.4 years) and DGF with rejection (9.8 years) was significant (P<0.001). Increased donor age and cold ischemia time additionally decreased graft survival, whereas a good human leukocyte antigen match could not overcome the deleterious effects of DGF or acute rejection. Conclusions. DGF is an important independent predictor of poor graft survival. Newer immunosuppressive strategies must minimize nonimmune and immune renal injury if long-term graft survival is to improve.

Intragraft expression of transforming growth factor beta1 gene in isolated glomeruli from human renal transplants.

Experimental evidence suggests that transforming growth factor (TGF) beta1 is a fibrogenic cytokine. The histopathological changes of chronic renal allograft nephropathy are dominated by fibrotic changes and TGF-beta may have an important aetiological role. This study investigated the relationship between intragraft TGF-beta gene expression and extracellular matrix protein deposition in human renal allografts. Sixteen cadaveric renal transplant recipients immunosuppressed with cyclosporin and steroids were studied. Individual glomeruli were isolated from protocol needle-core biopsies and, following messenger RNA extraction, intragraft gene expression was studied by reverse transcriptase-polymerase chain reaction. Collagen III deposition in these renal transplant biopsies was examined by immunohistochemistry and quantified by computerized histomorphometry. There was a positive correlation between renal cortical collagen III immunostaining and the levels of glomerular complementary DNA for TGF-beta1. TGF-beta1 is a profibrotic influence in human renal transplants. The methods described should prove of benefit in investigating the mechanisms of chronic renal allograft damage.

HEPATITIS C INFECTION CONFERS INCREASED RISK OF IMMUNOLOGIC FAILURE FOLLOWING RENAL TRANSPLANTATION.

138 Introduction. It has been observed that hepatitis C (HCV) infection confers an increased risk of acute rejection following liver transplantation. We examined our experience in renal transplantation with patients seropositive for HCV at the time of transplant, to assess the influence of HCV on immunologic outcome. Methods. We performed 180 transplants at our center from January 1, 1996 to December 31, 1997. We reviewed 88 adult recipients of primary cadaveric renal transplants. 73 patients were HCV negative; 15 were HCV Ab positive. None of the seropositive patients exhibited clinical signs of liver disease. We do not use HCV positive kidneys for HCV negative recipients; however, two seropositive patients received kidneys from HCV Ab positive donors. Our standard immunosuppression protocol is cyclosporine (CsA)/azathioprine/prednisone without induction therapy. CsA levels are titrated to 200-400 ng/ml postoperatively and are not adjusted for the presence of HCV infection. Results.(Table)TableConclusions. Our data, based on a retrospective review of renal transplant recipients with a minimum of 1 year follow-up, suggests that hepatitis C infection confers increased risk of acute rejection and graft loss. This phenomenon has also been observed in liver transplant patients. These data should prompt further investigation of the mechanism by which hepatitis C infection confers this increased immunologic risk.

IS HOMOCYSTEINE AN IMPORTANT RISK FACTOR FOR THE TRANSPLANT RECIPIENT?

313 Hyperhomocysteinaemia is widely recognised as an independent risk factor for the development of atherosclerotic cardiovascular disease. The aim of this study was to document plasma homocysteine levels in end-stage renal failure and sequentially following renal transplantation, and to correlate these findings with clinical outcome and renal function. As part of an ongoing study, homocysteine levels were measured in the plasma of cadaveric renal transplant recipients at baseline (n=87) and at follow-up of 3 months (n=62), 6 months (n=44) and 1 year (n=25). The samples were analysed by high performance liquid chromatography and a level of 16μmol/l was taken as the upper limit of normal. At each time point serum creatinine, albumin and drug trough levels were also assessed as was a urinary protein. An ultrasound-guided renal biopsy was performed and histological changes classified according to the Banff criteria. The homocysteine levels are summarised below: (Table)TableThere was a significant correlation between homocysteine and creatinine at 3 months, 6 months and 1 year (Pearson coefficients - 0.511, 0.37 & 0.616). There was no difference in homocysteine levels between individuals treated with tacrolimus (Prograf) or cyclosporin (Neoral) and there was no correlation between homocysteine and either age, sex, serum albumin, urinary protein, immunosuppressant trough levels or the development of histologically diagnosed chronic graft nephropathy. Whilst hyperhomocysteinaemia is a significant finding in the renal-failure population, the majority of patients with satisfactory function following renal transplantation have restoration of their plasma homocysteine towards the levels of the normal population, though this may take up to 1 year. We therefore conclude that homocysteine remains an important risk factor for the first year post-transplant year.

COST OF HLA MISMATCHES IN CADAVERIC RENAL TRANSPLANT

426 HLA mismatches, cold time, extended donors, an other factors influence the cost and outcome of cadaveric renal transplantation. We isolated and analyzed the economic costs of HLA mismatches in cyclosporine era patients. Methods: We merged the UNOS renal transplant registry to Medicare claims data for 1991 - 1996 using identifiers provided by the USRDS. Complete Medicare claims and HLA matching data were available for 26,329 first cadaveric renal transplant recipients. All payments (PMT) made by Medicare for these patients were stratified by the number of HLA-A, B, and DR mismatches (mm). Payments were projected from one-year pre-transplant for these patients while they were on dialysis to determine the time to financial break-even of transplant versus dialysis (TXP vs D). This is the point where the cumulative cost of transplantation becomes less than dialysis. Actuarial graft survival was calculated by the Kaplan-Meier method. Results: There were no differences in pre-transplant payments stratified by number of HLA mismatches. Total payments from the day of transplant through 30 days post-transplant: 0mm $42,222; 1mm $43,148; 2mm $43,242; 3mm $43,374; 4mm $43,679; 5mm $43,871; 6mm $45,331. Total payments from 30 days to 5 years post-transplant: 0mm $55,880; 1mm $60,025; 2mm $63,635; 3mm $66,457; 4mm $72,580; 5mm $76,130; 6mm $82,924. Graft survival, and break-even points were also exactly ordered from low to high between zero and six mismatches. Certain results are highlighted in the table.TableConclusions: First cadaveric renal transplantation is a cost saving alternative to dialysis regardless of the number of HLA mismatches with an expected maximum break-even time of 5.2 years. The effect of HLA mismatches on the cost of renal transplantation is minimal in the short term. However, HLA mismatches are a tremendously important determinant of the long term cost of care. These findings strongly support the use of HLA matching in first cadaveric renal transplantation.

A prospective randomized trial comparing the efficacy of tacrolimus versus cyclosporine in black recipients of primary cadaveric renal transplants

BACKGROUND: We performed a prospective randomized trial to compare the efficacy and safety of tacrolimus (FK506) versus cyclosporine (CSA) in black primary cadaveric renal transplant (CRT) recipients. METHODS: Between December 1994 and February 1997, 35 black primary CRT recipients were enrolled in this trial. All patients received 7 days of induction therapy with OKT3. Fourteen patients received FK506 and prednisone only. Twenty-one patients received CSA, azathioprine, and prednisone. The two groups were comparable in terms of age, gender, plasma renin activity, human leukocyte antigen mismatches, and cause of renal failure. RESULTS: Patient and graft survival were 12 of 14 (86%) for the FK506 group and 20 of 21 (95%) for the CSA group ( P = 0.71). Three patients died owing to cardiac events with functioning grafts. Acute rejection was 2 of 14 (14%) for the FK506 and 8 of 21 (38%) for the CSA group ( P = 0.25). Two other patients on CSA were converted to FK506 as rescue for OKT3-resistant rejection. Mean serum cholesterol at 1 year was 198 ± 45 mg/dL for the FK506 group and 244 ± 49 mg/dL for the CSA group ( P = 0.03). Mean serum creatinine at 1 year was 1.39 ± 0.38 mg/dL for the FK506 group and 1.94 ± 0.64 mg/dL for the CSA group ( P = 0.02). CONCLUSION: Patient and graft survival were similar in both groups at 1 year posttransplant. Although statistically not significant, the incidence of acute rejection was lower in the FK506 group. Furthermore, FK506-treated patients had significantly lower serum creatinine and cholesterol levels at 1 year posttransplant.

COLD ISCHEMIA TIME INCREASES HLA CLASS I ANTIBODIES AFTER REJECTION OF A PRIMARY CADAVERIC RENAL ALLOGRAFT

679 Ischemic injury to kidneys up-regulates many of the molecules, cytokines, and co-stimulatory molecules that may precipitate, or be involved with an immune response to the kidney. Such up-regulation due to ischemic injury may contribute to delayed graft function (DGF) and/or acute rejection. To extend our understanding of the mechanism(s) involved in the injury/stress, inflammation, immunity triad, we measured the production of HLA Class I antibodies (PRA) in 90 recipients of primary cadaveric renal transplants done between 1985 and 1997 who were unsensitized before transplantation (each had at least 3 PRAs, all ≤9%); rejected their first kidney; and had at least three PRA tests performed after this rejection. The data in the table below show the effect of increasing cold ischemia time (CIT) of the rejected primary kidney on Class I antibody production.TableThe data show that Class I PRA levels are lower in the group of patients with CITs of less than 14 hours compared with each of the other CIT groups (< 0.02 for > 14 to ≤ 18; <0.001 for > 18 to ≤ 24; and <0.05 for ≥ 24 hours). The only other major influence on PRA levels was the number of HLA Class I mismatches between donor and recipient, with the 1 to 2 antigen mismatched group having lower PRA levels (28% ± 31; n=39) than those with 3 or 4 mismatches (51% ± 38; n=49) (p< 0.01). Furthermore, multivariate analysis showed that a CIT > 15 hours (odds ratio=3.5; 95% CI=1.2 to 10.1; p=0.01) and an HLA-A & B mismatch >2 (odds ratio=2.9; 95% CI=1.1 to 7.5; p=0.02) independently influenced the risk of developing anti-HLA Class I peak PRA > 20% after rejecting a first cadaveric kidney. Conclusion: These data suggest one additional explanation for the known association between CIT and DGF and/or acute rejection. They are also consistent with the possibility that once certain CIT levels are passed, the immunologic load induces more antibodies to donor HLA Class I antigens.

Delayed graft function: risk factors and the relative effects of early function and acute rejection on long-term survival in cadaveric renal transplantation.

Delayed graft function (DGF) and acute rejection have both been associated with reduced renal allograft survival. In some studies, they have been shown to have an interactive effect. We studied the risk factors for DGF and the relative impact of DGF and rejection on both short- and long-term survival in recipients of cadaveric renal transplants. Data from the Oxford Transplant Centre Database were assessed on 710 cadaver allografts over a 10-yr period, during which time all recipients received cyclosporin-based immunosuppressive protocols. The interaction between DGF and acute rejection was examined using logistic and Cox multivariate regression. Long cold ischaemia time (CIT), sensitisation and older donor age were found to be independent predictors of DGF. The occurrence of DGF resulted in a reduced 5-yr survival (56 vs. 75%). However, the effect of DGF was confined to the first year post-transplant, as there was no significant difference in survival, as measured by half-life (t1/2) of grafts functioning at 1 yr, with DGF alone and a group with good early function (t1/2 = 21.3 vs. 20.0 yr). There was no increase in acute rejection in grafts with DGF. However, the combination of DGF and acute rejection resulted in the worst short-term graft survival (68% at 1 yr, compared to 92.3% in those grafts with no DGF or acute rejection) and this continued over the long term (t1/2 = 10.5 yr). These data suggest that early function is critical to the success of renal transplantation. The effects of DGF are limited to the first year post-transplant. Long-term graft survival may be improved by efforts to limit CITs, particularly for grafts from older donors and sensitised recipients.

Improved outcome of steroid withdrawal in mycophenolate mofetil-treated primary cadaveric renal transplant recipients

Improved outcome of steroid withdrawal in mycophenolate mofetil-treated primary cadaveric renal transplant recipients