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PubMed1996

Muromonab CD3: a reappraisal of its pharmacology and use as prophylaxis of solid organ transplant rejection.

The murine monoclonal antibody muromonab CD3 (OKT3) is directed against the CD3 antigen on peripheral human T cells and effectively blocks all T cell function. Prophylaxis with muromonab CD3 (5mg intravenously once daily for 10 to 14 days) as induction therapy together with corticosteroids, azathioprine and delayed cyclosporin (sequential therapy) optimises early graft function by delaying the potentially nephrotoxic and hepatotoxic effects of cyclosporin until graft function is established. Although clinical data are limited (by inconsistencies in trial design and trial size), prophylactic muromonab CD3-based sequential therapy is significantly more effective than standard triple therapy in the prophylaxis of allograft rejection in renal and hepatic, but not cardiac, transplant recipients. Benefits are particularly notable in patients with delayed graft function. No significant between-treatment differences in patient survival have been observed. The overall efficacy of muromonab CD3- and polyclonal-based prophylactic regimens appears to be similar, although results vary between investigators and confirmation is needed. An anti-interleukin-2 monoclonal antibody-based prophylactic regimen improved graft and patient survival compared with muromonab CD3-based prophylaxis in hepatic transplant recipients. Antimuromonab CD3 antibodies may develop; however, muromonab CD3 may be successfully reused in patients with low titres. Preliminary pharmacoeconomic data suggest that mean drug costs are greater with quadruple immunosuppressive regimens containing muromonab CD3, antithymocyte globulin (ATG) or antilymphocyte globulin (ALG) than with triple therapy. Drug costs with prophylactic muromonab CD3-based regimens were similar or greater than those with polyclonal-based protocols. The first doses of muromonab CD3 are associated with the 'cytokine-release syndrome'. More severe first-dose events include aseptic meningitis, intragraft thromboses, seizures and potentially fatal pulmonary oedema. The incidence and/or severity of cytomegalovirus infection with prophylactic muromonab CD3 based immunosuppression is similar to or greater than that with triple therapy and ATG- or ALG-based regimens. However, the risk of infection and also the observed increase in lymphoproliferative disorders appears to be related to the degree of immunosuppression rather than to the drug itself Thus, sequential muromonab CD3-based therapy is more effective than standard triple therapy (in renal and hepatic transplant recipients) and appears to be similar to that of polyclonal-based regimens in the prophylaxis of transplant rejection. Although the routine use of prophylactic muromonab CD3 in low-risk patients with primary graft function does not appear to be justified, prophylactic muromonab CD3-based therapy has a role in patients at high risk of rejection.

Animals↗
PubMed2002

Duration of donor brain death and its influence on kidney graft function.

Short- and long-term rates of success after cadaveric kidney transplantation are significantly inferior to those from living related or unrelated donors. The major difference between cadaveric and living donation is brain death. In the present study we analyzed the influence of duration of brain death on short- and long-term graft function after cadaveric kidney transplantation. The interval between declaration of donor brain death and the beginning of the cold ischemia time before graft explantation was defined as duration of brain death (DBD). The influence of DBD on incidence of primary graft function and on duration of delayed kidney graft function as well as on kidney graft survival was analyzed in 1106 patients transplanted in one center and confirmed in a validation study of a second series of 752 kidney graft recipients from another transplant center. Kidney grafts harvested from donors with longer DBD (>470 min) exhibited a significantly higher incidence of primary graft function and a significantly better graft survival rate in comparison to kidneys from donors with a shorter DBD (<470 min). The tendency of these results could be confirmed in an independent validation study; however, the differences were not statistically significant. Although the dramatic hemodynamic and immunological changes in brain-dead donors may impair the quality of a potential kidney transplant, a longer duration of donor brain death did not deteriorate early and long-term kidney graft function.

Brain Death↗
PubMed2004

Risk factors for graft survival in sensitized recipients of kidney transplantation.

OBJECTIVE: To investigate the independent prognostic factors for graft survival in sensitized recipients undergoing kidney transplantation, so as to identify the individuals at high risk of graft loss before transplantation. METHODS: A retrospective investigation was conducted in 102 sensitized kidney transplant recipients and 31 relative variables were analyzed with SPSS10.0 software. Using log-rank method, the influence of these variables on short- and long-term graft survivals was evaluated, and Kaplan-Meier analysis was performed to estimate the 1-, 3- and 5-year graft survival rates and half-life. Proportional hazards regression analysis (Cox model) was used to assess the relative risks of the potential variables. RESULTS: In the recipients with a mean half-life of 8.9 years, the 1-, 3- and 5-year graft survival rates were 90%, 85%, and 75%, respectively. By log-rank analysis, the factors affecting short- and long-term graft survivals were identified, namely the recipient age, times of transplantation, levels of panel reactive antibody and the post-operative anti-HLA-IgG antibody, HLA mismatch, renal function, time needing for graft function recovery, presence of acute rejection, delay of graft function recovery and infection, which affected the graft survival demonstrated by Cox model multivariate analysis. CONCLUSION: High-quality donor kidney and minimization of the risk factors for graft survival may insure successful kidney transplantation in sensitized recipients.

Adult↗
PubMed2005

Comparison of renal allograft fibrosis after transplantation from heart-beating and non-heart-beating donors.

BACKGROUND: Renal transplants from non-heart-beating donors (NHBDs) yield acceptable function and allograft survival rates in the medium term. However, the long-term results are less certain and there is a paucity of information relating to the development of chronic allograft nephropathy. The aim of this study was to compare allograft fibrosis in kidneys transplanted from NHBDs and conventional heart-beating donors (HBDs). METHODS: A series of 37 NHBD and 75 HBD renal transplants were studied. Protocol renal transplant biopsies were performed at 6 and 12 months after transplantation. Biopsy sections were stained with Sirius red to demonstrate interstitial extracellular matrix. Renal allograft fibrosis was quantified using a computerized image analysis system. RESULTS: The mean first warm ischaemia time for kidneys from NHBDs was 24 min. A significant delay in graft function occurred in eight of 75 recipients in the HBD group and 31 of 37 in the NHBD group (P < 0.001). There were no significant differences in the level of allograft fibrosis between the two groups at any time point. CONCLUSION: Despite high rates of delayed graft function secondary to a prolonged warm ischaemia time, NHBD kidneys do not appear to be more susceptible to the development of renal allograft fibrosis. This study supports the growing body of evidence that kidneys from NHBDs are an acceptable alternative to those from HBDs.

Adult↗
PubMed2006

The association between angiotensin converting enzyme inhibitor or angiotensin receptor blocker use during postischemic acute transplant failure and renal allograft survival.

BACKGROUND: Postischemic acute renal transplant failure occurs in approximately one fourth of all dead donor transplantations. Uncertainty exists regarding the putative association between the use of angiotensin converting enzyme inhibitors (ACEIs) or angiotensin II AT1 receptor blockers (ARBs) and kidney transplant graft survival in patients with delayed allograft function. METHODS: We conducted an open cohort study of all 436 patients who experienced an acute renal transplant failure out of all 2,031 subjects who received their first kidney transplant at the Medical University of Vienna between 1990 and 2003. Actual and functional graft survival was compared between users and nonusers of ACEI/ARB using exposure propensity score models and time-dependent Cox regression models. RESULTS: Ten-year actual graft survival averaged 44% in the ACEI/ARB group, but only 32% in patients without ACEI/ARB (P=0.002). The hazard ratio of actual graft failure was 0.58 (95% confidence interval: 0.35-0.80, P=0.002) for ACEI/ARB users compared with nonconsumers. Seventy-one percent of subjects with ACEI/ARB had a functional graft at 10 years versus 64% of ACEI/ARB nonusers (P=0.027). The hazard ratio of functional graft loss was 0.48 (95% confidence interval: 0.24-0.91, P=0.025). CONCLUSIONS: Use of ACEI/ARB in patients experiencing delayed allograft function was associated with longer actual and functional transplant survival.

Angiotensin II Type 1 Receptor Blockers↗
PubMed1988

Recipient and donor sex.

1. During the past 7 years, recipient sex had no apparent effect on transplant survival. 2. Recipients of female cadaver donor regrafts had an 8-12% lower graft survival rates at 1 year than recipients of male donor kidneys. Graft survival was poorer in both first and second transplants when the female donor was aged 31-50. 3. When graft function was delayed, 1-year graft survival was 6% lower for recipients of first transplants when the donor was female and 12% lower for retransplanted recipients of female donor grafts. 4. The striking effect of donor sex on regraft survival may be a transitory product of the "learning curve" for CsA. The difference between 1-year graft survival of male and female donor retransplants was 14% in 1984, 7% in 1985, and 5% in 1986.

Adult↗
PubMed1976

Influence of warm and cold ischemia time on initial function and one-year survival of renal allografts.

The influence of the duration of warm and cold ischemia on initial graft function on patient survival, graft survival, and graft function one year after transplantation was assessed in 234 consecutive cadaveric renal transplants. The number of grafts with delayed function was found to increase with increasing duration of the warm and cold ischemia times. On the other hand, the duration of the ischemia times and consequently the initial function, whether immediate or delayed, did not influence the survival of graft and patient nor the function of the graft one year after transplantation.

Adult↗
PubMed1988

Factors influencing early renal function in cadaver kidney transplants. A case-control study.

We performed a multicenter study to investigate the problem of cadaver kidney transplants that never achieve function, or that recover after a period of delayed function, and we used multivariate techniques to model the results. Sixty-nine patients who received cadaver kidney transplants that never functioned (NF) were compared with 69 kidney recipients with early graft function (EF), and 69 with delayed but recovering graft function (DF), matched for transplant hospital and time. The results were analyzed using an unconditional logistic regression model. Risk factors for never-function transplants compared to immediate-function transplants were as follows: previous failed transplant, no polyclonal antilymphocyte globulin (ALG) prophylaxis, increasing anastomosis time, decreasing donor blood pressure, and prior transfusions in first but not subsequent transplant recipients. When technical failures were excluded, 88% of NF grafts displayed severe rejection, suggesting that rejection in a poorly functioning kidney is the principal cause of the NF outcome. Risk factors for delayed function compared to immediate function were these: increasing anastomosis time, no ALG, increasing total cold ischemia time, duration of end-stage renal disease (ESRD), and male sex. Thus ischemic and immunologic risk factors contributed to the DF and NF outcomes. This study suggests that efforts to reduce the delayed and never-function outcomes should be directed to the use of ALG prophylaxis and to the reduction of cold ischemia and anastomosis times, particularly in recipients who have lost a previous transplant.

Adolescent↗
PubMed1995

A single-center experience with six-antigen-matched kidney transplants.

OBJECTIVES: To review our center's experience with the United Network of Organ Sharing six-antigen-matched (6-AgM) kidney program. Specifically, to determine whether recipients of 6-AgM cadaver kidney transplants have less perioperative and short-term (< 1 year) morbidity in comparison with living-related donor (LRD) recipients and a control group of immunologically less well-matched cadaver recipients. DESIGN: A retrospective review of all solitary kidney transplantations performed over a 24-month period, from 1992 to 1993. SETTING: A large urban tertiary care referral center with a long history of renal and extrarenal transplantation. PATIENTS: Adult patients receiving a solitary kidney transplant from either a cadaver or a living donor. MAIN OUTCOME MEASURES: Mortality, morbidity, and patient and graft survival. Other variables measured included rejection episodes, length of stay, readmissions, postoperative complications, waiting time, and delayed postoperative graft function. RESULTS: Recipients of 6-AgM kidney transplants were at higher risk than the control groups of cadaver and LRD recipients, with more retransplantations, higher sensitization, and more with diabetes. There were fewer rejection episodes in the 6-AgM group, and these were more steroid responsive. They had fewer hospital days (22.6 days) in the first year following transplantation, compared with the remaining cadaver group (28 days). The delayed postoperative graft function rate was also significantly lower than that of the cadaver control group. Graft and patient survival were excellent for all groups. Analysis of these factors showed similar results when comparing the LRD and 6-AgM groups and a marked improvement over the cadaver control group. CONCLUSIONS: Identical HLA matching for cadaver recipients provides superior results for graft and patient survival. There is much less perioperative morbidity in comparison with the less well-matched cadaver recipients. The effect of HLA matching is reflected in the perioperative courses of these patients, in addition to the long-term benefits of graft survival. Allograft survival is superior for this select group of cadaver recipients. The 6-AgM recipients behave similarly to LRD recipients in this cohort of patients. Our results would support the continued sharing of 6-AgM kidneys to optimize outcome and best use the limited resources available to the patients undergoing transplantation.

Adult↗
PubMed1989

OKT3 prophylaxis versus conventional drug therapy: single-center perspective, part of a multicenter trial.

As part of a collaborative study, Orthoclone OKT3 (Ortho Pharmaceutical Corporation, Raritan, NJ) monoclonal anti-T-cell antibody was used prophylactically for 14 days following cadaveric renal transplantation. Patients were randomized before treatment and compared with a control group treated with triple-drug immunosuppressant therapy consisting of cyclosporine, azathioprine, and prednisone. The OKT3 group (also treated with prednisone and azathioprine) had significantly fewer patients with acute rejection during the first year (27% v 60%), significantly delayed onset of acute rejection (median number of days to rejection, 56 v 10), and shortened duration of delayed initial graft function (median number of days on nonfunction, 5.5 v 9.0). OKT3 was safely administered intraoperatively. The study group included diabetics and patients over the age of 50 years. There was an increased incidence of benign fungal infection in patients treated with OKT3. The outcome data of both the prophylactic and control groups in this single-center trial was different from the multicenter experience in that patient and graft survival was 100% in both groups. The only difference in the immunosuppressive protocol was the use of 2 g intravenous methylprednisolone intraoperatively. The combination of intraoperative OKT3 with 2 g methylprednisolone may merit further study. It was concluded that OKT3 prophylaxis reduces the incidence of rejection episodes, delays the occurrence of rejection, and may reduce the duration of delayed initial graft function. It is not associated with an increase in serious infection and can be administered safely to a variety of cadaver transplant recipients.

Antibodies, Monoclonal↗
PubMed1989

Pediatric liver transplantation: the Montreal experience.

The introduction of cyclosporine A in 1980 greatly improved the survival of children with end-stage liver disease undergoing orthotopic liver transplantation. The average 1-year survival rate following hepatic transplantation increased from 30% in 1963 to 70% in 1980. This report summarizes the initial experience of two pediatric hospitals in Montreal--Hôpital Ste-Justine and Montreal Children's Hospital. Since December 1985, 13 orthotopic liver transplantations have been performed in 11 patients: six females and five males. The median age was 18 months (range, 13 months to 17 years) and the median weight was 10 kg (range, 8.5 to 38 kg). The indications for transplantation were biliary atresia (5 patients), tyrosinemia (2 patients), biliary hypoplasia (1 patient), Amerindian cirrhosis (1 patient), Crigler-Najjar syndrome, type I (1 patient), and fulminant non-A, non-B hepatitis with grade IV encephalopathy (1 patient). Immunosuppression was ensured by cyclosporine A, azathioprine, and steroids. The function of 11 grafts was immediate following revascularization of the grafts. One graft had delayed function due to preservation injury, and one had primary nonfunction. Surgical complications included bile peritonitis (1), ruptured aneurysm of an aortic conduit (1), and thrombosis of the hepatic artery necessitating retransplantation (2). Three of our patients died, one from postoperative cerebral edema, one of primary nonfunction of the graft, and one of ruptured aneurysm of an aortic conduit. Our overall survival rate was 72% with a follow-up of 3 to 32 months. Pediatric liver transplantation can now provide successful treatment and cure of liver diseases considered, until recently, dismal and hopeless.

Adolescent↗
PubMed2000

Horseshoe kidney transplantation: an overview.

The horseshoe kidney is the most common anatomical renal variation. It represents a fusion anomaly, mainly at the lower poles, occurring between the 4th and 6th week of gestation. Horseshoe kidneys display a great variation in origin, number and size of the vasculature. Transplantation of these deviant kidneys can be done en bloc or they can be split into two halves and transplanted into two recipients, depending on the number of vessels and the anatomy of the urinary collecting system. A literature review reveals 31 case histories, published between 1975 and 1998. Of these 21 were transplanted into 38 recipients after division and ten were implanted en bloc. Nineteen grafts (41%) showed immediate function and 21 grafts (46%) showed delayed function. Thrombosis and acute rejection, leading to non-function was seen in six grafts (13%). The overall success rate was 87%) with a mean follow-up of 22 months. The results of horseshoe kidney transplantation are good. provided that attention is paid to certain technical details. Because of donor scarcity, horseshoe kidneys should be used for transplantation.

Graft Survival↗
PubMed1993

The influence of delayed renal allograft function on long-term outcome in the cyclosporine era.

The influence of delayed renal graft function on long-term allograft outcome remains uncertain. All 495 cyclosporine treated cadaver donor renal transplants within a single center were analyzed with respect to dialysis dependence in the early posttransplant period. When compared with immediate allograft function, dialysis dependence for more than one week posttransplant was associated with prolonged cold ischemia time (27 +/- 11 vs 32 +/- 12 hours), cytotoxic antibodies > 30% (14% vs 25%), black race (29% vs 41%), increased incidence of acute rejection in the first year posttransplant (31% vs 67%) and inferior 1-year (85% vs 52%) and 5-year (68% vs 33%) graft survival among primary transplants. No adverse effect however was noted on renal function in long-term survivors.

Adult↗
PubMed1991

Acute cyclosporin A induced nephrotoxicity in renal allografts.

Immunosuppression with Cyclosporin A has resulted in dramatic improvements in the results of cadaveric kidney transplantation in Singapore. However, its major limitation is its nephrotoxicity which can appear in various forms after transplantation including a delay in graft function and chronic renal dysfunction. The clinical course of two patients with initial function but delayed onset of acute functional Cyclosporine nephrotoxicity are described. Recovery was documented in both cases with reduction of Cyclosporine dosage. A decline in renal blood flow and increase in renal vascular resistance is likely to have played a role in the pathogenesis of the acute functional nephrotoxicity. Cyclosporine induced imbalance in Prostaglandin synthesis within the kidney has been implicated.

Acute Disease↗
PubMed2004

Excellent outcome following transplantation of a domino donor liver with high-grade macrosteatosis.

Severe macrosteatosis in the donor liver is considered a major predictive factor of primary graft non-function. Such livers are usually discarded despite an ever-growing need for donor livers. We report our recent experience in a patient (#1) who had an excellent outcome following liver transplantation (LT) of a 65-70% macrosteatotic graft and compare his findings with those of two other (#2 and #3) recipients of moderate to severe macrosteatotic grafts. Both patients (#2 and #3) had initial diminished function, with recovery in patient #2 but delayed graft non-function requiring re-LT (day 24) in patient #3. Patient #1 had no intra-operative complications, while patient #2 had mild complications due to prior adhesions and graft capsular laceration. In patient #3, extensive intra-abdominal adhesions resulting in excessive bleeding occurred during recipient hepatectomy. Total ischemic times: 2.48, 6.10, and 8.18 h; total blood product usage: 43, 81, and 223 units; post-LT hospital stay: 9, 21, and 69 days were seen in patients #1, #2 and #3, respectively. In conclusion, post-LT excellent graft function was seen in one recipient of 65-70% macrosteatotic graft. Transplantation of grafts with moderate/severe macrosteatosis may be inadvisable in patients with extensive intra-abdominal adhesions with expectant excessive bleeding and long ischemia times.

Abdomen↗
PubMed2006

Maintaining urine production and early allograft function during laparoscopic donor nephrectomy.

OBJECTIVES: Intraoperative oliguria and its impact on early postoperative allograft function have been expressed as potential concerns of laparoscopic kidney donation. We evaluated our ability to maintain adequate diuresis during laparoscopic donor nephrectomy and its potential impact on early graft function compared with open donation. METHODS: We performed a retrospective review of 98 laparoscopic and 80 open donor nephrectomies from 1999 to 2002. All laparoscopic donors received infusions of mannitol (grams of mannitol equaled patient weight in kilograms) and dopamine (2 to 3.0 microg/kg/min) throughout the pneumoperitoneum. All open donors received a single dose of mannitol (12.5 g). Multiple donor variables were compared, including operative time, estimated blood loss, intraoperative fluid administration (in milliliters per kilogram per hour), intraoperative urine production (milliliters per kilogram per hour), and change in creatinine at discharge. The postoperative recipient data were compared, including initial 24-hour urine output, 1-week creatinine level, 1-month creatinine level, and need for postoperative hemodialysis. RESULTS: No significant differences were noted in the donor groups with respect to age, weight, intraoperative fluid administration, or change in creatinine at discharge. The mean operative urine production was greater in the laparoscopic group at 5.22 mL/kg/hr than in the open group at 2.43 mL/kg/hr (P = 0.0001). The mean estimated blood loss was significantly lower (P = 0.0001) for the laparoscopic donors (106.7 mL) than for the open donors (184.7 mL). No significant differences were seen among the recipient groups. CONCLUSIONS: The use of mannitol and dopamine infusions during laparoscopic donor nephrectomy provided superior intraoperative urine production in the donor and equivalent early graft function in the recipient compared with the open approach.

Adult↗
PubMed2000

Extracorporeal membrane oxygenation support of donor abdominal organs in non-heart-beating donors.

Both family consent and legal consent were required for organ/tissue donation from non-heart-beating donors (NHBD) in Taiwan. A district attorney had to come to the bedside to confirm the donor's asystole, confirm the family consent, and complete some legal documents before a legal consent was issued for organ donation. The resultant warm ischemic time would be unpredictably long and in fact precluded the organ donation from NHBD in Taiwan. We developed a method of using extracorporeal membrane oxygenation (ECMO) to maintain NHBD for a longer time and prevent warm ischemic injury of the donor abdominal organs. After ventilator disconnection in NHBD, phentolamine and heparin were injected and mannitol infusion was given. After the donor's asystole was confirmed by the electrocardiogram (EKG) strip recording, the ECMO support was set up through the right femoral veno-arterial route, an occlusion balloon catheter was inserted through the left femoral artery to occlude the thoracic aorta, and bilateral femoral arteries were ligated. Usually, the ECMO could begin within 10 min after the donor's asystole. The ECMO, combined with a cooler, provided cold oxygenated blood to the abdominal visceral organs, and prevented their warm ischemic injuries. Under the ECMO support (range: 45-70 min), eight renal grafts were procured from 4 NHBD. With the exception of the first two renal grafts with delayed function, all others had immediate function postoperatively and dialysis was no longer needed. In conclusion, by our ECMO technique, NHBD could be maintained for a longer time and the renal grafts had better immediate postoperative function than those reported by other methods.

Adrenergic alpha-Antagonists↗
PubMed2000

Simultaneous cadaver pancreas living-donor kidney transplantation: a new approach for the type 1 diabetic uremic patient.

OBJECTIVE: To review the authors' experience with a new approach for type I diabetic uremic patients: simultaneous cadaver-donor pancreas and living-donor kidney transplant (SPLK). SUMMARY BACKGROUND DATA: Simultaneous cadaver kidney and pancreas transplantation (SPK) and living-donor kidney transplantation alone followed by a solitary cadaver-donor pancreas transplant (PAK) have been the transplant options for type I diabetic uremic patients. SPK pancreas graft survival has historically exceeded that of solitary pancreas transplantation. Recent improvement in solitary pancreas transplant survival rates has narrowed the advantage seen with SPK. PAK, however, requires sequential transplant operations. In contrast to PAK and SPK, SPLK is a single operation that offers the potential benefits of living kidney donation: shorter waiting time, expansion of the organ donor pool, and improved short-term and long-term renal graft function. METHODS: Between May 1998 and September 1999, the authors performed 30 SPLK procedures, coordinating the cadaver pancreas transplant with simultaneous transplantation of a laparoscopically removed living-donor kidney. Of the 30 SPLKs, 28 (93%) were portally and enterically drained. During the same period, the authors also performed 19 primary SPK and 17 primary PAK transplants. RESULTS: One-year pancreas, kidney, and patient survival rates were 88%, 95%, and 95% for SPLK recipients. One-year pancreas graft survival rates in SPK and PAK recipients were 84% and 71%. Of 30 SPLK transplants, 29 (97%) had immediate renal graft function, whereas 79% of SPK kidneys had immediate function. Reoperative rates, early readmission to the hospital, and initial length of stay were similar between SPLK and SPK recipients. SPLK recipients had a shorter wait time for transplantation. CONCLUSIONS: Early pancreas, kidney, and patient survival rates after SPLK are similar to those for SPK. Waiting time was significantly shortened. SPLK recipients had lower rates of delayed renal graft function than SPK recipients. Combining cadaver pancreas transplantation with living-donor kidney transplantation does not harm renal graft outcome. Given the advantages of living-donor kidney transplant, SPLK should be considered for all uremic type I diabetic patients with living donors.

Adult↗