Does DCD Donor Time-to-Death Affect Recipient Outcomes? Implications of Time-to-Death at a High-Volume Center in the United States.

For donation after circulatory death (DCD), many centers allow 1 h after treatment withdrawal to donor death for kidneys. Our center has consistently allowed 2 h. We hypothesized that waiting longer would be associated with worse outcome. A single-center, retrospective analysis of DCD kidneys transplanted between 2008 and 2013 as well as a nationwide survey of organ procurement organization DCD practices were conducted. We identified 296 DCD kidneys, of which 247 (83.4%) were transplanted and 49 (16.6%) were discarded. Of the 247 recipients, 225 (group 1; 91.1%) received kidneys with a time to death (TTD) of 0-1 h; 22 (group 2; 8.9%) received grafts with a TTD of 1-2 h. Five-year patient survival was 88.8% for group 1, and 83.9% for group 2 (p = 0.667); Graft survival was also similar, with 5-year survival of 74.1% for group 1, and 83.9% for group 2 (p = 0.507). The delayed graft function rate was the same in both groups (50.2% vs. 50.0%, p = 0.984). TTD was not predictive of graft failure. Nationally, the average maximum wait-time for DCD kidneys was 77.2 min. By waiting 2 h for DCD kidneys, we performed 9.8% more transplants without worse outcomes. Nationally, this practice would allow for hundreds of additional kidney transplants, annually.

The impact of social, cognitive and attitudinal dimensions on college students' support for organ donation.

This study investigates how college students can be social support catalysts for organ donation and how social, cognitive and attitudinal dimensions impact organ donor registration. A total of 317 people participated in the exploratory portion of the project and a total of 1800 responses were obtained from an online survey to members of a national student organization. The findings show that perceptions of the benefits of organ donation and altruistic motives had the greatest impact on the support for organ donation while respondents' knowledge about how to register to be an organ donor was the dominant dimension for donor registration status. Social-based communications had the next greatest impact for both support and donor registration. Based on the findings, an 18-month social media campaign was launched with the student organization that had 20 421 website visitors, 4473 Facebook members, 1189 YouTube video submissions with 164 000 views, motivated 19 623 people to go to a state's organ donor registration page, and had 9000 documented organ donor registrations. Within the student organization, organ donor registration increased by 28%. On the basis of these project results, Donate Life America and other sponsors have provided funding for two additional years.

A hierarchical communication model of the antecedents of health care professionals' support for donations after cardiac death.

Using structural equation modeling, the direct and indirect impact of five variables on the support of donation after cardiac death from the perspective of health care professionals were investigated: knowledge, trust in the transplant team, whether patients are in a state of irreversibility, whether health care professionals participate in a patient's death, and perceptions about the brain death versus cardiac death donation process. In total, 10/15 relationships posited in the model had significant pathways. The results provide insight into sequential communication strategies for generating support for donations after cardiac death.

The significance of donor-specific HLA antibodies in rejection and ductopenia development in ABO compatible liver transplantation.

The role of humoral alloreactivity in ABO-compatible liver transplantation remains unclear. To understand the significance of donor-specific HLA alloantibodies (DSA) in liver rejection, we applied the currently used strategy for detection of antibody-mediated rejection of other solid allografts. For this purpose we reviewed the data on 43 recipients of ABO identical/compatible donor livers who had indication liver biopsy stained for complement element C4d and contemporaneous circulating DSA determination. Seventeen (40%) patients had significant circulating DSA in association with diffuse portal C4d deposition (DSA+/diffuse C4d+). These DSA+/diffuse C4d+ subjects had higher frequency of acute cellular rejection (ACR) 15/17 versus 13/26 (88% vs. 50%), p = 0.02, and steroid resistant rejection 7/17 versus 5/26 (41% vs. 19%), p = 0.03. Based on detection of the combination DSA+/diffuse C4d+, 53.6% of cases of ACR had evidence of concurrent humoral alloreactivity. Six of the 10 patients with ductopenic rejection had circulating DSA and diffuse portal C4d, three of whom (2 early and 1 late posttransplantation) developed unrelenting cholestasis, necessitating specific antibody-depleting therapy to salvage the allografts. Thus, in ABO-compatible liver transplantation humoral alloreactivity mediated by antibodies against donor HLA molecules appears to be frequently intertwined with cellular mechanisms of rejection, and to play a role in ductopenia development.

Possible involvement of advanced glycation end products in periodontal diseases.

Periodontal diseases are considered as multifactorial conditions initiated by infection with pathogenic bacteria, promoted by inflammation and immune response against bacteria and modified by different environmental and genetic factors. Recently, interest in periodontal diseases has been increasing due to the awareness that the hyperinflammatory status associated with this disorder could impose a significant increase of reactive oxygen species (ROS) relevant to numerous systemic diseases driven by a pro-oxidant profile. A highly complex interplay occurs between oxidative stress and AGEs (Advanced Glycation End products), a group of heterogeneous compounds that form constantly under physiologic conditions, although their rate of formation is markedly increased in hyperglycemia and oxidizing conditions. Starting from the most relevant hypotheses on the pathogenesis of periodontal diseases, the present review outlines its relationship with oxidative stress and inflammation response in order to make a critical evaluation of the potential role of AGEs in periodontal deterioration. Although direct evidence for the presence of AGEs in the periodontal ligament is still lacking, valuable approaches based on the use of periodontal cells along with genetic and biochemical studies in animal models and chronic periodontal patients support a potential role for protein glycation in the aetiology and severity of this disease. Following a review of the current literature, the present study highlights the need for further investigation on the presence of AGEs in the periodontal ligament as a means for the comprehension of the pathogenic mechanisms underlying periodontal diseases in order to develop prevention and treatment modalities for this dysfunction.

Increasing organ donations after cardiac death by increasing DCD support among health care professionals: a case report.

This case report focuses on the University of Wisconsin Hospital and Clinics Organ Procurement Organization (UWHC-OPO) efforts to produce a verifiable and demonstrable increase in organ donations by developing a replicable, transferable and feasible model intervention for increasing health care professionals' support for donation after cardiac death (DCD). A grant from the US Department of Health and Human Services funded a 3-year study allowing the UWHC-OPO to (i) identify barriers to and opportunities for increasing DCD support among those involved in the donation request process, (ii) implement this better understanding of these support factors in the creation of intervention materials designed to increase knowledge of and support for DCD and finally (iii) to track and document the progress made in increasing knowledge, support, number of hospitals with DCD protocols, actual requests made and number of DCD donors. The results of the model intervention were extremely positive, showing lasting increases in DCD knowledge and support, adoption of DCD protocols and referrals in the two tracking survey stages following the intervention. Perhaps most notably, DCD donor numbers within the UWHC-OPO region increased 93% in the year following the intervention and 179% to date.

An empirical examination of the antecedents of the acceptance of donation after cardiac death by health care professionals.

Findings are reported from a US Department of Health and Human Services (DHHS) funded study to identify barriers to increasing support for donations after cardiac death by health professionals. A donations after cardiac death (DCD) acceptance model is conceptualized and tested via 806 survey responses from certified requestors, all of whom had their identities protected through Institutional Review Board (IRB) protocol. The overall model was significant and explained 35% of the variation in DCD support. Greater knowledge about DCD, greater trust in the organ procurement organization (OPO) and a belief that futility has been reached were all positively associated with DCD acceptance. Negative perceptions of DCD versus brain death, transitioning from caregiving to donation advocate, concerns about the DCD process and the idea that DCD leads to active participation in the death reduced its support. The three greatest impediments to support of DCD exist when health professionals feel they are playing an active role in killing the patient, that a state of death has not yet been reached, and that DCD has more psychological barriers than does the brain death donation process. Opportunities and strategic initiatives are discussed to overcome these barriers, including the value of communication and education initiatives and the need for well-trained requestors. The implementation of these strategic guidelines helped to increase the number of DCD donors by 225%.

The impact of donor variables on the outcome of orthotopic liver transplantation for hepatitis C.

Morphologic characteristics of the graft have been proposed as a major contributor to the long-term outcomes in orthotopic liver transplantation (OLT). Our objective was to determine the impact of donor variables, including donor age, donor-recipient HLA match, and type of donation (DCD vs donation after brain death [DBD]), on the outcome of OLT in 192 patients with hepatitis C virus (HCV). Fourteen patients underwent OLT from donation after cardiac death (DCD) donors and 188 from DBD donors. Mean donor age, warm ischemia time at recovery, and cold ischemia time were similar between the groups. Overall graft survival rate at 1 year (55% DCD vs 85% DBD) and 5 years (46% DCD vs 78% DBD) was significantly lower in the DCD group (P = .0003). Similarly, patient survival rate at 1 year (62% DCD vs 93% DBD) and 5 years (62% DCD vs 82% DBD) was significantly lower in the DCD group (P = .0295). Incidences of hepatic artery thrombosis, portal vein thrombosis, and primary nonfunction were similar between the DCD and DBD groups. The incidence of liver abscess with ischemic-type biliary stricture was higher in recipients from DCD as compared with DBD (42% vs 2%). A trend toward lower graft survival was noted in recipients from donors older than 60 years of age in the HCV population (P = .07), with statistically lower patient survival (P = .02). Donor- recipient HLA matching did not appear to correlate with OLT outcome in patients with HCV. DCD donors and donors older than 60 years of age significantly impact patient and graft survival. Lower graft and patient survival in recipients from DCD donors does not appear to be related to early disease recurrence.

Predicting Donor Death: Early Changes in Oxygen Saturation After Withdrawal of Support Predict Successful Donation During Donation After Circulatory Death.

BACKGROUND: We have previously shown that approximately 27% of patients do not progress to death in time to donate organs after attempted donation after circulatory death (DCD). As such, nearly 1000 transplants per year are not possible. One way to convert unsuccessful donations to successful donations is to increase procurement team "stand-down" times; however, increased stand-down times may predispose transplantable organs to increased ischemic damage. METHODS: Hemodynamics for successful and unsuccessful donations, occurring between 2011 and 2014, were characterized to determine if some unsuccessful DCDs could have donated successfully, had procurement teams waited longer. RESULTS: Analysis of 169 DCDs demonstrated statistically significant differences in hemodynamic profiles after withdrawal of support (WOS) between successful and unsuccessful donations. Early decreases in oxygen saturation were predictive of successful organ donation. We observed that for unsuccessful DCDs, patients who died in more than 2 hours but less than 12 hours were agonal within 10 minutes of WOS, suggesting that increasing stand-down times would result in prohibitive warm ischemia time. CONCLUSIONS: Early changes in oxygen saturation after withdrawal of support predict donor death. Alternative approaches that convert unsuccessful DCDs to successful DCDs but that do not result in low-quality organs should be explored.

3'-Azido-3'-deoxythymidine reduces the rate of transferrin receptor endocytosis in K562 cells.

K562 cells, exposed for at least 24 h to 5 microM 3'-azido-3'-deoxythymidine (AZT), gave rise to an overall increase in the number of cell surface transferrin binding receptors (18-20%). This effect was ascertained either with binding experiments by using 125I-transferrin and with immunoprecipitation by using a specific monoclonal antibody against the transferrin receptor. At higher AZT concentrations (20 and 40 microM), a further increase was found, that is, up to 23% by binding experiments and up to 110% by immunoprecipitation. However, Scatchard analysis of the binding data indicated that although the number of cell surface transferrin receptors increased, the affinity of transferrin for its receptor did not change (Ka=4.0x108 M). Surprisingly, immunoprecipitation of total receptor molecules showed that the synthesis of receptor was not enhanced by the drug treatment. The effect of AZT on transferrin internalization and receptor recycling was also investigated. In this case, data indicated that the increase in the number of receptors at the cell surface was probably due to a slowing down of endocytosis rate rather than to an increased recycling rate of the receptor to cell surface. In fact, the time during which half the saturated amount of transferrin had been endocytosed (t1/2) was 2.15 min for control cells and 3.41, 3.04, and 3.74 min for 5, 20, and 40 microM AZT-treated cells, respectively. Conversely, recycling experiments did not show any significant differences between control and treated cells. A likely mechanism through which AZT could interfere with the transferrin receptor trafficking, together with the relevance of our findings, is extensively discussed.

Purification of a 76-kDa iron-binding protein from human seminal plasma by affinity chromatography specific for ribonuclease: structural and functional identity with milk lactoferrin.

A pink-colored iron-binding protein has been found in large amount in human seminal plasma and identified as a lactoferrin isoform. Its purification, by a modification of a three-step chromatography procedure developed in an attempt to purify a ribonuclease from the same fluid, provided about 15-18 mg of pure protein from 100 ml of seminal plasma. Despite its ability to bind a ribonuclease ligand during the affinity step, the iron-binding protein did not display any detectable RNase activity in a standard assay with yeast RNA as substrate. It showed an apparent molecular weight of 76 kDa and resulted to be quite similar, if not identical, to human milk lactoferrin in many respects. Its N-terminal sequence (31 amino acid residues) starting with Arg-3 was identical to that of one of the N-terminally truncated lactoferrin variants isolated from human milk. Moreover, the amino acid sequence of a number of peptides, which represented about 23% of the entire sequence, has been also shown to be identical to that of the corresponding peptides of human milk lactoferrin. Double diffusion analysis revealed full recognition by antibodies anti-human milk lactoferrin of the human seminal plasma protein. Using immunoblotting analysis, both human milk lactoferrin and human seminal protein were recognized by antibodies anti-milk lactoferrin. When tested for its iron binding capacity, with Fe-NTA as iron donor, the protein purified was able to bind iron up to 100% saturation, as judged by absorbance at 465 nm.

Early detection of rejection in pancreas transplantation.

A major dilemma in pancreas transplantation is the lack of reliable methods for the early detection of allograft rejection. Over a 26-mo period, 70 rejection episodes occurred in 36 patients (13 isolated-pancreas, 23 simultaneous pancreas-kidney recipients) with pancreaticoduodenocystostomy. A total of 300 radionuclide pancreas examinations were performed (mean 8.3/patient) utilizing 99mTc-labeled DTPA. Computer analysis generated a quantitative measure of blood flow to the allograft (technetium index, TI). Rejection episodes were defined as isolated pancreas, isolated kidney, or combined pancreas-kidney. Mean urinary amylase (UA) levels and TI during normal allograft function were 30,256 U/L and 0.57%, respectively, whereas levels heralding rejection were 6873 U/L and 0.39% (P less than .05). The treatment of rejection based on kidney dysfunction or combined pancreas-kidney dysfunction resulted in significantly higher graft salvage and a lower incidence of hyperglycemia compared with isolated-pancreas-allograft rejection. After therapy, a TI greater than 0.3% was associated with 95.9% graft survival, whereas levels less than 0.3% resulted in a 72.7% rate of graft loss (P less than .001). Similarly, pancreas allografts with a UA greater than 10,000 U/L had 92.2% functional survival, whereas levels less than 10,000 U/L resulted in a 53.3% rate of graft loss (P less than 0.001). Overall, reversal of rejection occurred in 80% of cases, with 10 pancreas and 2 kidney allografts lost due to rejection. Monitoring pancreas-allograft function by UA, TI, and renal function in simultaneous transplants allows for the timely diagnosis and successful treatment of pancreas-allograft rejection.

Use of UW solution in pancreas transplantation.

We have recently reported successful 72-h preservation of the canine pancreas with a new cold-storage solution developed at the University of Wisconsin (UW solution). Over 10 mo, we performed 11 combined pancreas-kidney and 4 isolated-pancreas transplants with this solution. In situ cooling of the donor pancreas was performed with 1000 ml of UW solution followed by ex vivo perfusion with an additional 250-500 ml. Graft preservation times ranged from 3 to 19 h (mean 10.2 h). Pancreas transplants were vascularized whole-organ grafts with pancreaticoduodenocystostomy. Early graft function was excellent as assessed by immediate insulin independence, high urinary amylase and low serum amylase levels, and a technetium perfusion index indicating good pancreatic blood flow. There were no episodes of primary nonfunction, graft pancreatitis, or vascular thrombosis. Actuarial patient and graft survival at 1 mo was 92.9%. We conclude that UW solution provides excellent early graft function for up to 19 h of cold storage. Based on previously reported data on its efficacy in liver and kidney preservation, UW solution seems ideally suited as a universal intra-aortic flush and cold-storage solution.

OKT3 rescue therapy in pancreas-allograft rejection.

OKT3 has emerged as a highly effective antirejection therapy, but its efficacy in pancreas transplantation remains to be determined. During a 26-mo period, 46 vascularized pancreas transplants were performed with pancreaticoduodenocystostomy. Twenty-one patients (45.7%) were treated with OKT3. Indications for OKT3 use included steroid- and/or antilymphoblast globulin-resistant rejection in isolated-pancreas transplant (n = 8) or simultaneous pancreas-kidney-transplant (n = 13) recipients. A total of 46 rejection episodes occurred (mean 2.2). OKT3 was administered for a 14-day course concomitant with pulsed corticosteroids, azathioprine, and cyclosporin. OKT3 rescue therapy was successful in 13 cases (61.9%). The mean time to rejection reversal was 8.8 days (range 5-14 days). In isolated-pancreas transplants, OKT3 reversed only 1 episode of rejection (12.5%). In contrast, 12 episodes (92.3%) of allograft rejection were responsive to OKT3 in simultaneous pancreas-kidney recipients (P less than .05). Graft loss from rejection occurred at a mean 5.5 mo posttransplantation. OKT3 therapy was more successful in the setting of early rejection, rejection in combined pancreas-kidney transplants, and rejection not associated with hyperglycemia. No graft loss due to infection or patient death has occurred after OKT3 therapy. After a mean follow-up of 17.3 mo, patient survival was 89.1%, and allograft survival was 26.3% in isolated-pancreas and 85.2% in simultaneous pancreas-kidney transplants (P less than .05). Salvage therapy with OKT3 is a safe and effective means of reversing rejection in pancreas-allograft recipients. OKT3 is more effective in simultaneous pancreas-kidney recipients due to the earlier diagnosis of rejection.

The effect of AZT and chloroquine on the activities of ricin and a saporin-transferrin chimeric toxin.

This study deals with the combination of chloroquine (CQ, an anti-malaric drug) and 3'-azido-3'-deoxythymidine (AZT, anti-human immuno-deficiency virus (HIV) drug) with a chimeric toxin (TS) obtained by chemical linking of saporin (a ribosome inactivating protein from the plant Saponaria officinalis) and human transferrin, in the intoxication of the human chronic myeloid leukaemia cells (K562). Our data demonstrate that AZT, at concentrations comparable to those reached in the blood of HIV-infected patients under pharmacological treatment with this drug, can increase the toxicity of TS in cooperation with CQ inducing an increased effect on protein synthesis in K562 cells ( approximately 50% inhibition of protein synthesis for TS alone, and TS with AZT and approximately 70% with both AZT and CQ). Furthermore, pre-treatment of cells with AZT alone can induce an increase of apoptosis in K562 cells intoxicated with TS. By comparing data obtained with the model toxin ricin, we get indications that the two toxins partially differ in their intracellular routes, also suggesting that chimeric constructs containing ricin-like toxins (i.e. immunotoxins) could be coupled with the use of common and cheap drugs for the treatment of cancer in HIV-infected patients.

Alternative therapy of earth elements increases the chondroprotective effects of chondroitin sulfate in mice.

The administration of mineral sulphur water is an alternative experimental approach for the treatment of rheumatic diseases, such as osteoarthritis (OA), that cause the degeneration of bone and cartilage and sufferance to the patients. Chondroitin sulfate (CS) is a symptomatic slow acting nutropeucital agent currently used in molecular therapy of OA. Therefore, we have studied the role and efficacy of the selective soil paste from the mineral sulphur enriched spring (mud)-therapy alone or in combination with CS in the treatment of OA. The study was performed on 40 C57 Black 6N mice, an experimental model which spontaneously develop an osteoarthritic process. The animals were divided in 4 groups and were treated with the single agents or with the combination. After 30 days of treatment all the mice were sacrificed and right knees and blood were collected. It was found that CS determined a reduction of radiological and histological features of chondrodegeneration and that mud-therapy increased the effects of CS in the animal group treated with the combination. However, the effects of thermal therapy alone were not statistically significant. Since OA is characterized by an increase of the production of nitric oxide (NO) by chondrocytes in extracellular matrix with its consequent elevation in serum and synovial fluid, we have evaluated the effects of the treatments on serum NO levels. CS alone induced a statistically significant reduction of NO serum levels (90+/-13 micromM vs 219+/-60 microM of control group, P<0.05) while mud-therapy alone induced a not statistically significant reduction of serum NO (170+/-62 microM, P>0.05). However, the latter strongly potentiated the decrease of serum NO induced by CS (31+/-1.5 microM) with a high statistical significance if compared to both the control group (P<0.01) and the CS-treated group (P<0.05). In conclusion, this study demonstrates that mud-therapy with sulphur mineral water could represent an important phase of the therapeutic strategy of OA. This experimental strategy could integrate and potentiate the standard pharmacological tools. Moreover, we have set a valid experimental in vivo model for the study of the thermal effects on the development of OA.

The binding of human serum transferrin to its specific receptor reconstituted into liposomes.

Human placental transferrin receptor (HPTR), purified following a procedure based on affinity chromatography step, was reconstituted by the detergent dialysis method into various kinds of phosphatidylcholine vesicles and the receptor ability to bind 125I-labelled human serum transferrin (HST) was then evaluated. In our experimental conditions, the binding of the labelled protein to its specific receptor showed several features, in particular: (1) in cholesterol/1-alpha-dipalmitoylphosphatidyl choline (CHO/DPPC) liposomes, a positive cooperatively of the transferrin binding resulted at the lowest cholesterol/phospholipids (C/P) ratio; 1-alpha-dioleylphosphatidyl choline (DOPC) and phosphatidic acid (PA) containing liposomes showed an opposite binding curve trend; (2) the apparent dissociation constant (K'd) did not change significantly as a function of the lipid composition, being always around 1.00 x 10(-6) M; (3) the encapsulation capacity of liposomes decreased from 27% to about 13% with increasing amounts of cholesterol and was around 20% in the presence of DOPC or PA; about 8-13% of this receptor was found to be functional; (4) receptor-loaded liposomes treated with polyclonal anti-HPTR rabbit antibodies showed a remarkable binding decrease for transferin. All these results seem to point out the crucial role played by the environment in the binding behaviour of the transferrin receptor.

Radiation therapy for renal transplant rejection refractory to pulse steroids and OKT3.

PURPOSE: To determine the response rate and kidney graft survival following local irradiation to the transplanted renal graft undergoing persistent rejection after medical management including pulse steroids and OKT3. The role of radiation for renal transplant rejection after failure of OKT3 has not been previously reported. METHODS AND MATERIALS: From July 1, 1988 to July 1, 1994, 72 consecutive patients with kidney graft rejection were treated with local irradiation to the transplanted renal graft following failure of medical management. All patients received pulse steroids and OKT3, an anti-CD3 immunosuppressant. Patients who failed to respond to methylprednisolone and OKT3 therapy were referred for radiation therapy. The median time from the diagnosis of rejection to irradiation was 8 days. All kidney grafts received local graft irradiation to a total of 8 Gy delivered in four daily fractions. RESULTS: Sixty (83%) patients initially responded to radiotherapy at 7 days after completion of radiotherapy, as defined by a decrease in serum creatinine. Thirty-five responding patients have not experienced a second episode of graft rejection. Overall, 43 (60%) patients have renal graft survival, with a median follow-up of 16 months (range of 6-73 months)> CONCLUSION: It is concluded that there is a subgroup of kidney graft patients undergoing graft rejection who are refractory to pulse steroids and OKT3 therapy where irradiation may be an effective modality with high rates of response and a moderate rate of graft survival. However, a prospective, randomized trial in these medically refractory patients is needed to ascertain whether these results are clinically significant.

A study comparing mycophenolate mofetil to azathioprine in simultaneous pancreas-kidney transplantation.

BACKGROUND: Mycophenolate mofetil (MMF; Cell-Cept) is a potent and selective inhibitor of B and T lymphocyte proliferation that has proven effective in reducing the incidence of acute rejection in cadaveric kidney transplant recipients in several randomized, blinded clinical studies. Because the frequency and characteristics of rejection episodes may be different and more severe after combined pancreas-kidney transplantation, we hypothesized that MMF would have a significant impact on pancreas-kidney rejection and graft outcome. Therefore, we compared the efficacy of MMF versus azathioprine (AZA) in cyclosporine-treated simultaneous pancreas-kidney transplantations. METHODS: A retrospective comparison of 358 consecutive primary SPK transplantations performed from 1990 to 1997 was conducted. Patients received either MMF (n=109, 3 g/day) or AZA (n=249, 2 mg/kg q.d.) in combination with cyclosporine-based immunosuppression. All patients received a quadruple-drug sequential induction protocol with either OKT3 or Atgam. Several outcome parameters, including patient and graft survival rates and frequency of rejection, were analyzed. RESULTS: MMF-treated patients demonstrated a markedly reduced rate of biopsy-proven kidney rejection (31 vs. 75% AZA, P=0.0001), clinically significant pancreas rejection (7 vs. 24% AZA; P=0.003), and steroid-refractory rejection (15 vs. 52% AZA; P=0.01). As a result, kidney and pancreas allograft survival was significantly better in MMF patients compared with AZA patients (2-year survival rates: kidney, 95 vs. 86%; and pancreas, 95 vs. 83%). Although surgical infections after transplantation were more frequent in MMF patients, MMF patients were more likely to have undergone enteric drainage. Importantly, we did not observe an increased incidence of any of the bacterial, fungal, or viral infections that typically plague immunosuppressed transplant recipients. CONCLUSIONS: This retrospective study demonstrates that MMF is a highly effective immunosuppressant in SPK transplantation. It is not associated with an increased risk of opportunistic infections when a balanced immunosuppressive management approach is used. MMF strikingly reduces the frequency of acute cellular and steroid-resistant rejection. As a result of this combined experience, it is not unexpected then that we observe significantly improved graft survival rates in MMF-treated SPK patients compared with patients receiving a more traditional immunosuppressive regimen.

OKT3 salvage therapy in a quadruple immunosuppressive protocol in cadaveric renal transplantation.

Since the introduction of OKT3 at our center in January 1986, we have performed 246 cadaveric renal transplants (220 primary, 26 nonprimary). All patients received quadruple immunosuppression consisting of prednisone, azathioprine, and the sequential use of Minnesota antilymphoblast globulin (MALG) and cyclosporine. OKT3 (Orthoclone OKT3) therapy was reserved for corticosteroid- and/or ALG-resistant rejection. Of the 246 patients, 138 developed one or more rejection episodes (56.1%). Ninety-seven (70.3%) were successfully reversed with prednisone and/or ALG, whereas 41 (29.7%) required additional treatment with OKT3. Initial graft salvage occurred in 34 (82.9%) patients treated with OKT3, but rejection recurred in 18 (52.9%) and was successfully reversed in only 6 patients. However, the rate of recurrent rejection was much lower in patients given OKT3 early (14%), shortly after it was apparent that high-dose corticosteroid therapy was proving ineffective, than in patients who received OKT3 after a prolonged or second course of corticosteroids (64%) or ALG (60%). Graft survival after a mean follow-up interval of 11 months in all OKT3-treated patients was 54%. One or more infections occurred in 19 (46%) patients treated with OKT3. Patients developing infections following OKT3 therapy received significantly larger total doses of prednisone during graft rejection (46.3 mg/kg vs. 27.9 mg/kg, P less than .05) than OKT3-treated patients who did not develop infectious complications. Our experience shows that use of OKT3 for treatment of corticosteroid- and/or ALG-resistant rejection is associated with a high rate of recurrent rejection, except when given early, as soon as it is clear that high-dose corticosteroid therapy is not reversing the rejection episode. It further suggests that prolonged administration of high-dose corticosteroids and possibly ALG for the treatment of rejection prior to beginning OKT3 greatly increases the rate of infection following OKT3 therapy.