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PubMed1991

Risk factors for second renal allografts immunosuppressed with cyclosporine.

Second renal allograft survival rates are lower than those of primary allografts. For recipients immunosuppressed with azathioprine, prednisone, and Minnesota ALG (conventional immunosuppression), risk factors associated with decreased second graft survival have been identified: age greater than 40, cadaver donor, less than 6 months between primary graft loss and retransplantation, duration of primary graft function (6 months or 1 year, depending on the study), high peak panel-reactive antibody, number of human leukocyte antigen mismatches, and delayed graft function. In this study, we used a multivariate analysis to identify risk factors associated with decreased second graft survival in patients who did or did not receive cyclosporine. Results were compared with primary graft survival rates. Risk factors for patients receiving conventional immunosuppression were: (a) primary graft loss caused by rejection greater than or equal to 6 months (P = 0.01 vs. either rejection less than 6 months or nonimmunologic loss); (b) cadaver donor (P = 0.005 vs. living related); and (c) interval between primary graft loss and retransplantation of greater than or equal to 6 months (P = 0.05 vs. less than 6 months). For CsA, risk factors that most decreased second graft survival were: (a) primary graft loss caused by rejection less than 6 months (P = 0.11 vs. nonimmunologic loss); (b) conventional immunosuppression for the primary graft (P = 0.08 vs. CsA immunosuppression); and (c) a peak PRA of greater than or equal to 21 (P = 0.14 vs. peak PRA of 1-20). For second graft recipients immunosuppressed with CsA, primary graft loss to either rejection greater than 6 months posttransplant or nonimmunologic causes was not a risk factor for second graft survival. These data extend the recent reports of other investigators by identifying risk factors for retransplant recipients treated with CsA and by demonstrating that subgroups of patients in the retransplant population can be retransplanted without additional risk (i.e., their second graft survival rates are similar to primary graft survival rates). This may become more important if, in the future, organ distribution is based on graft survival data. If so, our data would support retransplantation in patients who are immunosuppressed with CsA, especially those who lost their primary graft to either rejection greater than or equal to 6 months posttransplant or nonimmunologic causes; who receive living related grafts; and who have a peak PRA of 1-20.

Adult↗
PubMed1994

Nonheart-beating donors: the Maastricht experience.

The growing gap between the number of organs available for transplantation and patients on waiting lists demands additional donor sources. Nonheart-beating (NHB)-donor programs are known to increase the number of kidneys available. The group of potential NHB donors is very diverse and therefore 4 categories have been identified. At the University Hospital Maastricht, a NHB-donor program was implemented in 1980 to harvest kidneys after an in situ perfusion technique. In order to evaluate the function of kidney grafts from NHB donors, a retrospective multicenter study on the NHB-donor kidneys transplanted until 1992 was performed, using a control group of kidneys from heart-beating (HB) donors. The short-term results showed more delayed function (DF) in the NHB-donor group accompanied by higher serum creatinine levels at one-month posttransplant. The long-term outcome, however, was equal in both groups showing similar graft and patient survival rates up to 5 years. Apart from the type of donor, HB or NHB, only the number of HLA-DR mismatches could be identified as a potential risk factor for delayed graft function. NHB donors contribute considerably to reducing the gap between offer and demand in kidney transplantation and transplant centers should include NHB donors in their procurement programs. Meanwhile, efforts should be made to improve the short-term posttransplant graft function. Together with reducing DF, searching for valuable tools in viability assessment should also be an objective. Past viability tests never found broad clinical use but might be important in the optimal and safe usage of the potential NHB donor pool.

Adolescent↗
PubMed1991

Renal transplantation despite a positive antiglobulin crossmatch with and without prophylactic OKT3.

The antiglobulin crossmatch (AGXM) is a sensitive technique employed by many transplant centers to enhance detection of preformed antibody to donor antigens that may cause hyperacute rejection. However, positive AGXM may detect irrelevant or very low titers of anti-HLA antibody precluding transplantation in suitable recipients. To investigate the significance of a positive AGXM, cadaveric renal transplantation was carried out despite a weakly positive AGXM (defined as cell killing above background but not greater than 20%) in 48 recipients. In an initial group (n = 10), maintained on triple therapy (cyclosporine, azathioprine, and prednisone), accelerated acute rejection occurred in 4 recipients and 3 grafts were lost. A subsequent group (n = 38) was treated with a prophylactic course of OKT3 then triple therapy. There were no episodes of accelerated acute rejection (P less than 0.01) although clinical hyperacute rejection claimed one graft and the incidence of delayed graft function was high (75%). The prophylactic OKT3 group had a reduced incidence of acute rejection (0.5 versus 1.0) per recipient and the onset of first episodes was delayed (mean onset: 13 versus 35 days after transplantation). One year actuarial primary graft survival was 88% in the prophylactic OKT3 group as compared with only 50% in the initial group. The outcome in the positive AGXM group was similar to a concurrent group (n = 32) with a negative AGXM and immediate graft function. On the other hand, the subset of positive AGXM regraft recipients treated with prophylactic OKT3 fared poorly, with a 36% (4/11) incidence of primary nonfunction. In summary, a positive AGXM, as defined in this report, is not a contraindication to primary renal transplantation--in fact, the use of the AGXM will identify recipients that would benefit from prophylactic OKT3.

Adult↗
PubMed1991

The use of "marginal" donors for organ transplantation. The influence of donor age on outcome.

The influence of donor age on outcome was studied in the recipients of 12,131 cadaveric renal allografts, 3026 heart allografts, and 2913 liver allografts with followup information in the UNOS data base for transplants performed between 10/1/87 and 12/31/89. For recipients of kidney transplants, donors of ages 6-15 had significantly better 1-year graft survival than donors of ages 56-65, but the difference was only 7.0%. Donors of age greater than 65 actually did better than donors ages 56-65, but donors less than or equal to 5 were less satisfactory. Kidneys from older donors survived as well as kidneys from younger donors in patients with repeat transplants, diabetes, black race, age over 45, O HLA or 5 and 6 HLA matches, delayed graft function, shared kidneys and PRA greater than 50. For kidney recipients, multifactorial analysis by Cox regression showed that donor age was less important than the use of ALG, donor race, diabetes or peak PRA in ages 16-45, delayed function, repeat transplant, and HLA match. Recipients of heart transplants from donors ages 45-55 had 1-year graft survival that was 8.4% less than recipients of hearts from donors age 16-45. However, 32.7% of heart patients died during the first 12 months after listing without benefit of a transplant. Liver transplant recipients of donor ages 16-45 had 10.8% better 1-year graft survival than recipients of donors greater than 45, but a greater percentage of older donors were transplanted to high risk and older recipients. Tragically, 24.3% of patients listed for liver transplantation died within 12 months without a transplant. This analysis shows that satisfactory graft survival can be achieved using older donors and that age in itself should not be a barrier to organ donation, providing that organ function is normal and that specific disease of the organ is absent.

Adolescent↗
PubMed1986

Assessment of plasma neopterin in clinical kidney transplantation.

Serial plasma samples of 172 kidney transplant recipients and 42 chronic dialysis patients were evaluated retrospectively in a radioimmunoassay to determine the clinical relevance of plasma neopterin levels. Dialysis patients had a higher neopterin level 196 +/- 82 nmol/L (mean +/- SD) than 70 healthy controls (7 +/- 4 nmol/L). In 45 patients with a completely uneventful postoperative course, elevated pretransplant neopterin levels dropped rapidly within a week to a mean of 30 nmol/L and remained stable thereafter. In 22 outpatients with stable graft function there was a highly significant correlation between 170 paired serum creatinine and plasma neopterin values (r = 0.94). A group of 13 patients had experienced delayed graft function (ATN) without rejection. Their one-week mean neopterin level was 100 nmol/L and continued to drop in parallel with the serum creatinine. Another 15 patients rejected their kidneys irreversibly within 3 weeks-6 of them had extremely high neopterin levels during the rejection process (range 500-1000 nmol/L) that were not seen in other patients. A total of 169 rejection episodes in 43 patients were treated with bolus-dose cortisone. On the day of bolus therapy, both serum creatinine (P less than 0.002) and neopterin (P less than 0.005) were elevated. At 24 hours prior to bolus cortisone therapy, creatinine levels were not significantly elevated, whereas there was a significant rise in plasma neopterin (P less than 0.01). The overall sensitivity of neopterin increase was 86% with a 17% probability of false positives, and the sensitivity was 95% in biopsy-proved rejections. Plasma neopterin appears to be a useful marker for early detection of rejection and for identifying severe rejections that are not responsive to treatment.

Biopterins↗
PubMed2006

Perioperative fluid management in renal transplantation: a narrative review of the literature.

Adequate volume maintenance is essential to prevent acute renal failure during major surgery or to ensure graft function after renal transplantation. The various recommendations on the optimum fluid therapy are based, at best, on sparse evidence only from observational studies. This article reviews the literature on perioperative fluid management in renal transplantation. Crystalloid solutions not exerting any specific side-effects are the first choice for volume replacement in kidney transplantation. The use of colloids should be restricted to patients with severe intravascular volume deficits necessitating high volume restoration. The routine application of albumin, dopamine, and high dose diuretics is no longer warranted. Mannitol given immediately before removal of the vessel clamps reduces the requirement of post-transplant dialysis, but has no effects on graft function in the long term. There is insufficient evidence on the best use of dialysis, but it seems peritoneal dialysis pretransplant is associated with less delayed graft function, whereas the preference of dialysis post-transplant is not yet well-founded. This review article should provide better guidance for fluid management in kidney transplantation until best-evidence guidelines can be established based upon more research.

Colloids↗
PubMed2004

Achieving adequate cyclosporine exposure in liver transplant recipients: a novel strategy for monitoring and dosing using intravenous therapy.

It has been demonstrated that achieving therapeutic levels of cyclosporine (CsA) exposure in the first days posttransplant is critical for effective prevention of rejection. In patients receiving oral CsA, it has been shown that C(2)-monitoring is superior to trough (trough level [C(0)]) measurement. Intravenous administration may overcome the problem of CsA absorption dysfunction seen in some patients. Currently, little evidence is available concerning CsA exposure after intravenous application. Twenty de novo liver transplant recipients were given twice-daily 4-hour infusions of intravenous CsA, with full pharmacokinetic profiles undertaken during the first postoperative week. The greatest CsA exposure occurred during the period 2 to 4 hours after the start of infusion. The correlation between C(0) and area under the curve (AUC(0-12)) was r(2) = 0.18; the correlation between C(2) and AUC(0-12) was r(2) = 0.82. The best 2-point predictive model included both C(2) and C(4) (r(2) = 0.90). There was a poor correlation between CsA dose per kilogram of body weight and AUC(0-12) (r(2) = 0.19); total CsA dose also showed a weak relationship to exposure (r(2) = 0.37). When patients were divided according to initial or delayed graft function, there was good correlation between total CsA dose and AUC(0-12) (initial function, r(2) = 0.71; delayed function, r(2) = 0.86). In conclusion, previous discouraging results with intravenous CsA in liver transplant patients may have been due to a limited understanding of CsA pharmacokinetics. Our results show that C(2)-monitoring during 4 hour infusion provides a reliable indication of CsA exposure. Calculation of starting dose based on initial graft function is more precise than use of body weight. Using C(2)-monitoring to individualize dosing and function-based calculations of starting dose could be expected to improve clinical outcomes in patients receiving intravenous CsA.

Adult↗
PubMed2006

Should we discard the renal allografts from cardiac death donors that have total ischemic time longer than 24 hours?

PURPOSE: The objective of this study was to investigate the outcome of transplantation using kidney grafts donated after cardiac death (DCD) with a total ischemic time (TIT) longer than 24 hours. PATIENTS AND METHODS: We followed 373 kidneys recovered from DCD donors and transplanted at 41 centers. All kidneys were procured from uncontrolled DCD donors. Grafts were classified into two groups according to TIT. We recorded renal function and duration of the survival period for each graft. RESULTS: Fifty-three grafts had a TIT longer than 24 hours (group 1). The other 320 grafts had a TIT less than 24 hours (group 2). The number of never functioning grafts were three in group 1 (5.7%) and 17 in group 2 (5.3%). Delayed graft function (DGF) occurred in 44 group 1 (83.0%) and 254 group 2 kidneys (79.4%) for intervals of 13.5 +/- 12.6 versus 10.9 +/- 12.6 days, respectively. Graft survival rates at 3, 5, and 10 years posttransplant were 84.9%, 73.0%, 64.1% for group 1, and 76.3%, 69.9%, 57.1% for group 2. In a Cox proportional hazards model, TIT longer than 24 hours was not a significant independent risk factor. CONCLUSION: Our results showed that even kidneys with TITs of over 24 hours yielded comparable results despite a higher incidence of DGF.

Death, Sudden, Cardiac↗
PubMed2002

Risk factors for slow graft function after kidney transplants: a multivariate analysis.

BACKGROUND: We previously defined an intermediate group of cadaver kidney transplant recipients who do not have immediate graft function (IGF), but do not have sufficient graft dysfunction to be classified as having delayed graft function (DGF). We showed that this group with slow graft function (SGF) had an increased risk of rejection and inferior long-term results vs. recipients with IGF. The aim of our current study was to determine risk factors for SGF, which have not been well defined (in contrast to risk factors for DGF). METHODS: Between January 1, 1984 and September 30, 1999, we performed 896 adult cadaver kidney transplants at the University of Minnesota. Recipients were analysed in three groups based on initial graft function: IGF [creatinine (Cr) < 3 mg/dL by post-operative day (POD) no. 5], SGF (Cr > 3 mg/dL on POD no. 5, but no need for dialysis), and DGF (need for dialysis in the first week post-transplant). A multivariate analysis looked specifically at risk factors for SGF, as compared with risk factors for DGF. Outcomes with regard to graft survival and acute rejection (AR) rates were determined for the three groups. RESULTS: Of the 896 recipients, 425 had IGF, 238 had SGF, and 233 had DGF. A multivariate analysis of risk factors for SGF showed donor age >50 yr (RR=3.3, p=0.0001) and kidney preservation time >24 h (RR=1.6, p=0.01) to be the most significant risk factors. A multivariate analysis of risk factors for DGF showed similar findings, although high panel-reactive antibodies (PRA) and donor Cr >1.7 mg/dL were also significant risk factors for DGF. Initial function of the graft significantly influenced the subsequent risk of AR: at 12 months post-transplant, the incidence of AR was 28% for those with IGF, 38% for those with SGF, and 44% for those with DGF (p=0.04 for SGF vs. DGF). Initial graft function also significantly influenced graft survival: the 5-yr death-censored graft survival rate was 89% for recipients with IGF, 72% for those with SGF, and 67% for those with DGF (p=0.01 for IGF vs. SGF; p=0.03 for SGF vs. DGF). CONCLUSIONS: SGF represents part of the spectrum of graft injury and post-transplant graft dysfunction. Risk factors for SGF are similar to those seen for DGF. Even mild to moderate graft dysfunction post-transplant can have a negative impact on long-term graft survival.

Female↗
PubMed2004

Prospective randomised trial of the use of Daclizumab in renal transplantation using kidneys from non heart beating donors.

OBJECTIVES: Transplantation using non-heart beating donors (NHBD) is one way of reducing the global kidney shortage. Unfortunately the large warm ischaemic insult sustained by the graft leads to a high rate of delayed graft function (DGF). We have investigated the use of a regimen utilising an II-2r blocker (DZB) in place of Tacrolimus for the initial post-operative immunosupression with the aim of reducing the incidence of DGF. METHODS: Prospective randomised controlled trial based in two NHBD UK centres (Leicester and Newcastle). 51 patients were enrolled over two years and randomised into two treatment arms: 1. DZB/MMF/Steroids (Tacrolimus started when creatinine dropped below 350 micromol/l) 2. Tacro/MMF/Steroids. RESULTS: There was one death, during the study period, in a patient who had had a non-functioning graft removed. The overall incidence of immediate function (IF) was higher than expected (28%), no significant difference was found in the incidence of immediate graft function between the two groups (35% group 1 and 22% group 2). Sub-group analysis however has shown a significant advantage for the delayed introduction of Tacrolimus for machine perfused grafts (IF: 53% vs 13%, chi2 p=0.015). There was no difference in the rate of rejection. CONCLUSIONS: The delayed introduction of Tacrolimus reduces the incidence of DGF in machine-perfused NHBD kidney transplantation.

Antibodies, Monoclonal↗
PubMed2000

Glutathione supplementation during cold ischemia does not confer early functional advantage in renal transplantation.

BACKGROUND: Reduced glutathione (GSH), a component of University of Wisconsin (UW) solution, is reported to oxidize during storage. Consequently the commercial manufacturer of UW recommends the supplemental addition of GSH to UW before utilization. We investigated the influence of supplemental GSH during cold ischemia on early renal allograft function. METHODS: One hundred kidneys were locally procured from heart-beating donors, preserved in our laboratory, and transplanted during an 18-month period. Selected donor, preservation, and outcome characteristics were collected and compared by presence of supplemental GSH and method of preservation. All kidneys were randomized to receive 3.0 mM supplemental GSH to perfusate or no supplementation (control) and were preserved by either cold storage (CS) in UW or machine perfused (MP) in UW-machine perfusate solution (MPS). During MP, perfusion characteristics (flow, resistance, perfusate electrolytes, and pH) were serially measured. RESULTS: There were no significant differences among the groups when the donor characteristics of age, serum creatinine, and intra-operative urine output were compared. Preservation characteristics were similar among the groups with the exception of cold ischemia time, which was longer in the MP group compared to CS (26.1 h vs. 21.9 h, P=0.03). When compared with CS, kidneys preserved by MP exhibited a 33.4% increase in immediate function (93% vs. 62%, P=0.01), a corresponding 29.4% decrease in the incidence of delayed graft function (10% vs. 34%, P=0.02), and a 10% improvement in short-term (6-month) graft survival (98% vs. 88%, P=0.02). The addition of GSH supplementation to perfusate resulted in no significant differences in graft outcomes. CONCLUSIONS: Despite recommendations by the manufacturer that UW solution be routinely supplemented with GSH, supplemental GSH does not influence early renal allograft function. Our data suggest that a far greater beneficial impact on early graft function is achieved by machine perfusion. We conclude that GSH supplementation of commercially available UW is not necessary.

Adenosine↗
PubMed2005

Keratinocyte-derived chemokine is an early biomarker of ischemic acute kidney injury.

Renal ischemia-reperfusion injury (IRI) is the leading cause of acute kidney injury [AKI; acute renal failure (ARF)] in native kidneys and delayed graft function in deceased donor kidney transplants. Serum creatinine rises late after renal IRI, which results in delayed diagnosis. There is an important need to identify novel biomarkers for early diagnosis and prognosis in renal IRI. Given the inflammatory pathophysiology of renal IRI, we used a protein array to measure 18 cytokines and chemokines in a mouse model of renal IRI at 3, 24, and 72 h postischemia. A rise in renal keratinocyte-derived chemokine (KC) was the earliest and most consistent compared with other molecules, with 3-h postischemia values being 9- and 13-fold greater than sham and normal animals, respectively. Histological changes were evident within 1 h of IRI but serum creatinine only increased 24 h after IRI. With the use of an ELISA, KC levels in serum and urine were highest 3 h postischemia, well before a significant rise in serum creatinine. The human analog of KC, Gro-alpha, was markedly elevated in urine from humans who received deceased donor kidney transplants that required dialysis, compared with deceased donor kidney recipients with good graft function and live donor recipients with minimal ischemia. Measurement of KC and its human analog, Gro-alpha, could serve as a useful new biomarker for ischemic ARF.

Acute Disease↗
PubMed2001

Hand assisted laparoscopic donor nephrectomy: a comparison with the open approach.

PURPOSE: Hand assisted laparoscopy combines aspects of open and laparoscopic surgery. A hand in the abdomen may facilitate laparoscopic live donor nephrectomy, allowing more urologists to participate. We report and compare our initial series of hand assisted laparoscopy donor nephrectomy with nephrectomy performed by standard open methods. MATERIALS AND METHODS: In the last 18 months 60 patients at 2 institutions underwent hand assisted laparoscopy donor nephrectomy. This cohort was compared to a contemporary group of 31 patients who underwent open donor nephrectomy via a flank incision at our 2 institutions. Demographic and outcome data were compared retrospectively in a nonrandomized fashion in the 2 groups. RESULTS: Demographic data on patient age, male-to-female ratio and body mass index were similar in the 2 groups. Operative time, transfusion rate, time to oral intake and complications were also similar. However, estimated blood loss, change in hematocrit preoperatively to postoperatively, hospitalization, parenteral and oral narcotic requirement, and donor convalescence were significantly less in the hand assisted laparoscopy versus open groups. In terms of allograft function, nadir creatinine, time to nadir creatinine, creatinine clearance at 6, 12, and 18 months, delayed graft function, episodes of acute rejection and ureteral stricture were similar in the groups. CONCLUSIONS: Hand assisted laparoscopy is safe, efficacious and reproducible for living related donor nephrectomy. Compared with the open technique hand assisted laparoscopy provides the donor with significantly decreased postoperative morbidity, while enabling excellent allograft function. Further randomized prospective studies are warranted.

Adult↗
PubMed1994

A report of the eurotransplant randomized multicenter study comparing kidney graft preservation with HTK, UW and EC solutions. HTK study group.

Special attention has been focused in this randomized study on the primary function of renal allografts preserved with different solutions. Histidine-Tryptophane-Ketoglutarate (HTK) and University of Wisconsin (UW) solutions provided a significantly lower incidence of delayed graft function compared to Euro-Collins solution. Improved renal function after transplantation was observed in the HTK and UW groups compared to the EC group.

Adenosine↗
PubMed2002

Utility and limitations of serum creatinine as a measure of renal function in experimental renal ischemia-reperfusion injury.

BACKGROUND: Ischemia-reperfusion injury (IRI) is the major cause of delayed graft function in renal allografts. The present study was performed to investigate the validity of serum creatinine (SCr) level as an indicator of postischemic renal dysfunction in mice. METHODS: Renal IRI or sham surgery was induced in C57BL/6 mice, and SCr level and inulin clearance (Cin) were measured between 24 hr and 7 days after ischemia. RESULTS: Cin in IRI mice was reduced 75% at 72 hr after ischemia in association with a nearly threefold increase in SCr level. Cin in IRI mice did not recover between 72 hr and 7 days after ischemia, even though SCr level at 7 days was not different between control and IRI mice. In IRI mice, SCr level measured at 24, 48, and 72 hr after ischemia correlated inversely with Cin measured at 72 hr, but not 7 days, after ischemia. CONCLUSIONS: SCr level in the early postischemic period (24-72 hr) seems to be a valid indicator of early postischemic renal dysfunction, and that renal function remains markedly depressed at 7 days despite suggestion from the SCr value that renal function is improving.

Animals↗
PubMed2006

Kidney transplantation with grafts from non-heart-beating donors.

We analyzed the function and outcome of 16 kidney transplants performed in our hospital from non-heart-beating donors who were harvested at other hospitals. The cold ischemia times were longer and the delayed graft function rates higher. However, graft function was no different from that of kidneys from heart-beating donors. This experience has encouraged us to use this type of donor to reduce the transplant waiting list.

Aged↗
PubMed2005

Assessment of two strategies of neoral administration, early versus delayed, on renal function and efficacy in de novo renal transplant patients receiving myfortic, steroids, and anti-IL2R antibodies: 12-month results of a randomized, multicentre, open, prospective controlled study.

UNLABELLED: The optimal immunosuppressive strategy and benefit of delaying Neoral to prevent delayed graft function (DGF) have not been clearly established. Renal function was assessed by estimated creatinine clearance (Cockcroft-Gault) at 3 months, and efficacy by treatment failure and BPAR at 6 and 12 months after renal transplantation. Two hundred three patients were enrolled after stratification according to DGF risk (USRDS criteria). One hundred ninety-seven were randomized to receive either early (E; day 0; n = 97) or delayed (D; day 6; n = 100) Neoral in combination with myfortic, steroids, and anti-IL2R antibodies. Neoral was adjusted using C2. Six patients who were not randomized have been excluded from the intention-to-treat (ITT) analysis. RESULTS: There was no significant difference in the demographic or baseline parameters between the two groups. The risk of DGF(score > or = 5) was similar in both groups: 32 of 97 in E-Neoral versus 33 of 100 in D-Neoral. In the group at high risk for DGF, the incidence of DGF was 13 of 32 pts in E-Neoral versus 14 of 33 in D-Neoral. Renal function was not statistically different between the two groups in both the ITT and per-protocol (PP) populations at 3, 6, or 12 months. Over 12 months, the evidence of treatment failure and BPAR were not statistically different: 24 of 97 (24.7%) versus 27 of 100 (27%) and 18 of 97 (18.6%) versus 24 of 100 (24%) for E-Neoral and D-Neoral, respectively. The severity of acute rejection was mild in 83% patients. CONCLUSION: These data suggest that there is no significant impact on renal function and immunosuppressing efficacy of early versus delayed introduction of Neoral, in combination with myfortic and steroids among renal transplant patients with or without a risk of DGF.

Acute Disease↗
PubMed2001

Results of 3-year phase III clinical trials with daclizumab prophylaxis for prevention of acute rejection after renal transplantation.

BACKGROUND: Daclizumab (Zenapax, Roche Pharmaceuticals), a humanized monoclonal antibody directed against the alpha chain of the interleukin 2 receptor, has been shown to reduce the incidence of acute rejection at 6 months after renal transplantation in two phase III clinical trials. This report presents the combined 1- and 3-year outcomes of kidney transplant recipients who participated in these two phase III clinical trials. METHODS: Data from two multicenter, randomized, placebo-controlled trials were evaluated with regard to graft survival, patient survival, incidence of malignancies (including lymphoma), renal function (serum creatinine and glomerular filtration rate [GFR]), and current maintenance immunosuppressive regimen. In addition, the impact of acute rejection and acute rejection requiring treatment with antilymphocyte therapy upon 3-year graft survival was evaluated. Daclizumab was compared to placebo on a background of cyclosporine (CsA), azathioprine, and corticosteroids (triple therapy, TT) or CsA and corticosteroids (double therapy, DT). RESULTS: Treatment with daclizumab in the pooled analysis demonstrated a significant reduction in the incidence of biopsy-proven acute rejection episodes at 12 months posttransplant (43% vs. 28%, P<0.001). The 3-year graft survival was not significantly different between placebo and daclizumab-treated patients in the TT trial (83% vs. 84%) or in the DT trial (78% vs. 82%). Pooled patient survival was excellent in both placebo- (91%) and daclizumab- (93%) treated patients. The incidence of malignancies or posttransplant lymphoproliferative disorder (PTLD) in placebo- versus daclizumab-treated groups was comparable in both clinical trials. Renal function was similar between placebo- and daclizumab-treated groups in both the TT and DT trials. The occurrence of delayed graft function, acute rejection requiring antilymphocyte therapy at 6 months, and acute rejection at 12 months posttransplant were associated with decreased graft survival rates at 3 years posttransplant. CONCLUSIONS: The beneficial effect of daclizumab prophylaxis upon the incidence of acute rejection after renal transplant with TT or with DT was not associated with adverse clinical sequelae, including the development of PTLD, at 3 years posttransplant. There was no beneficial effect of daclizumab on graft survival at 3 years, but the trial was inadequately powered to detect this. Both studies showed excellent graft and patient survival at 3 years.

Acute Disease↗