John O. Colonna

Increased Rates of Donation With Laparoscopic Donor Nephrectomy

ObjectiveTo examine the impact of laparoscopic nephrectomy and recipient education on the proportion of kidney recipients who could identify a potential live donor, and on the live donor (LD) transplantation rate. Summary Background DataLaparoscopic donor nephrectomy (LDN) results in less postoperative surgical pain, a shorter hospital stay, and quicker recovery than the standard open donor nephrectomy (ODN). The authors hypothesized that the availability of this less invasive surgical technique would enhance the willingness of family and friends to donate. MethodsThe study population consisted of 3,298 end-stage renal disease patients referred for kidney transplant evaluation between November 1991 and February 2000, divided into three groups. The first group received no formal LD education and had only ODN available. The second group received formal education about the LD process and had only ODN available. The third group had both formal LD education and LDN available. Records were examined to determine what proportion of each group had any potential donors tissue-typed, and the rate at which they received an LD transplant. ResultsBefore LDN availability and formal LD education, only 35.1% of referrals found a potential donor, and only 12.2% received an LD transplant within 3 years. Institution of a formal education program increased the volunteer rate to 39.0%, and 16.5% received an LD transplant. When LDN became available, 50% of patients were able to find at least one potential donor, and within 3 years 24.7% received an LD transplant. Regression analysis indicated that availability of LDN was independently associated with a 1.9 relative risk of receiving an LD transplant. Kaplan-Meier death-censored 1- and 3-year graft survival rates for ODN transplants were 95.8% and 90.6%, versus 97.5% and 94.8% for LDN. ConclusionsThe availability of LDN and an LD family education program has doubled the live donor transplantation rate, and outcomes remain excellent.

A high panel-reactive antibody rescue protocol for cross-match-positive live donor kidney transplants.

Background. Alloimmunization can present a virtually insurmountable barrier to kidney transplantation. Past protocols to desensitize patients using plasmapheresis and cyclophosphamide have not been broadly applied because of the fear of complications, including high rates of immunologic failure. Methods. Fifteen patients with a positive donor-recipient cross-match were desensitized with plasmapheresis to permit live donor (LD) transplantation under newer maintenance immunosuppressants. Pretransplant the patients received plasmapheresis three times weekly for a planned maximum of six treatments, plus intravenous hyperimmune globulin, tacrolimus, mycophenolate mofetil, and prednisone. Patients who were successfully desensitized and received transplants were given 10 days of OKT3 postoperatively. Results. Eleven of the 15 patients became anti-human globulin cross-match-negative after one to five plasmapheresis treatments and underwent LD transplantation. Relatively low initial titers of donor-specific antibody were predictive of successful attainment of a negative cross-match. Few side effects and rejection episodes were observed. All transplant patients remain dialysis-free after 3–26 months of follow-up. Conclusion. A positive cross-match is not necessarily a contraindication to LD transplantation, especially for patients with low donor-specific alloantibody titers.

Induction Therapy With Monoclonal Antibodies Specific For Cd80 And Cd86 Delays The Onset Of Acute Renal Allograft Rejection In Non-human Primates1

CD80 and CD86 (also known as B7–1 and B7–2, respectively) are both ligands for the T cell costimulatory receptors CD28 and CD152. Both CD80 and CD86 mediate T cell costimulation, and as such, have been studied for their role in promoting allograft rejection. In this study we demonstrate that administering monoclonal antibodies specific for these B7 ligands can delay the onset of acute renal allograft rejection in rhesus monkeys. The most durable effect results from simultaneous administration of both anti-B7 antibodies. The mechanism of action does not involve global depletion of T or B cells. Despite in vitro and in vivo evidence demonstrating the effectiveness of the anti-B7 antibodies in suppressing T cell responsiveness to alloantigen, their use does not result in durable tolerance. Prolonged therapy with murine anti-B7 antibodies is limited by the development of neutralizing antibodies, but that problem was avoided when humanized anti-B7 reagents are used. Most animals develop rejection and an alloantibody response although still on antibody therapy and before the development of a neutralizing antibody response. Anti-B7 antibody therapy may have use as an adjunctive agent for clinical allotransplantation, but using the dosing regimens we used, is not a tolerizing therapy in this non-human primate model.

Superiority of portal venous drainage over systemic venous drainage in pancreas transplantation: a retrospective study.

ObjectiveTo compare portal and systemic venous drainage of pancreas transplants and demonstrate an immunologic and survival superiority of portal venous drainage. Summary Background DataTraditionally, solitary pancreas transplants have been performed using systemic venous and bladder drainage, but more recently, the advantages of enteric drainage have been well documented. Although physiologic benefits for portal venous drainage have been described, the impact of portal venous drainage, especially with solitary pancreas transplants, has yet to be determined. MethodsSince August 1995, 280 pancreas transplants with enteric duct drainage were analyzed. One hundred and seventeen were simultaneous pancreas and kidney (SPK), 63 with systemic venous drainage (SV) and 54 with portal venous drainage (PV). The remainder were solitary transplants; 97 pancreas after kidney (PAK; 42 SV and 55 PV) and 66 transplants alone (PTA; 26 SV and 40 PV). Immunosuppressive therapy was equivalent for both groups. ResultsThe groups were similar with respect to recipient characteristics and HLA matching. Thirty-six month graft survival for all transplants was 79% for PV and 65% for SV (P = .008). By category, SPK graft survival was 74% for PV and 76% for SV, PAK graft survival was 70% for PV and 56% for SV, and PTA graft survival was 84% for PV and 50% for SV. The rate of at least one rejection episode was also significantly higher in the SV group. At 36 months, for all pancreas transplants, the rejection rate was 21% for PV and 52% for SV (P < .0001). For SPK, rejection rates were 9% for PV and 45% for SV. For PAK, rejection rates were 16% for PV and 65% for SV, and for PTA 36% for PV and 51% for SV. The rejection rates for kidneys following SPK were also lower in the PV group (26% versus 43% for SV). Furthermore, the grades of rejection were milder in PV for all transplants (P = .017). By multivariate analysis, portal venous drainage was the only parameter that significantly affected rejection. ConclusionGraft survival and rejection is superior for PV. These clinical findings are consistent with published reports of experimentally induced portal tolerance and strongly argue that PV drainage should be the procedure of choice for pancreas transplantation.

A comparison of renal function in cyclosporine- and FK-506-treated patients after primary orthotopic liver transplantation

In this randomized controlled trial comparing FK-506 to CsA, we report parameters of nephrotoxicity in adult patients surviving >90 days after orthotopic liver transplant (OLT). Patients randomized to FK-506 first received 0.15 mg/kg IV/day followed by 0.3 mg/kg PO/day. Doses were modified to avoid toxicity and to achieve FK-506 levels of 0.5 to 1.5 ng/ml. CsA was administered in the usual manner with dose adjustments to whole blood HPLC levels. A pre-OLT glomerular filtration rate (GFR) of ≥30 ml/min/1.73/m2 and/or serum creatinine ≤2.0 mg/dl were required for inclusion in the study. GFRs were obtained at post OLT days 28, 180, and 360. Other parameters of renal function evaluated were creatinine, magnesium, serum electrolytes, blood pressure, use of antihypertensives, and magnesium supplements. There were 38 patients in the FK-506 group and 34 in the CsA group. The mean days of follow up for each group was similar: 456 ± 135 days for the FK-506 group and 451 ± 112 days for the CsA group. The mean oral dose for the FK-506 group ranged from 0.13–0.16 mg/kg/day with mean FK-506 levels of 0.6–0.8 ng/ml. In the FK-506 group, there was a significant fall in the pre-transplant GFR from 89 ± 31 ml/min/173 m2 to 43 ± 15 ml/min/173 m2 at day 360. Similarly, for the CsA group, the pre-transplant GFR of 75 ± 31 ml/min/1.73 m2 fell to 49 ± 17 ml/min/1.73 m2 at day 360. At each time point studied, there was no significant difference in mean GFR between the two groups. There were no significant differences in the monthly mean values for creatinine, electrolytes, magnesium, or blood pressure between the two groups. Magnesium levels were in the low normal range (1.4–1.6 mEq/L), and the mean potassium levels in the high normal range (4.4–4.7 mEq/L). In both groups, a similar number of patients required magnesium supplementation or hypertensive medications. The nephrotoxicity of FK-506 given at low oral doses and with concomitant low levels was comparable to that of CsA. The two drugs were remarkably similar in their spectrum of electrolyte disturbances and incidence of hypertension.

The interrelation between sclerosing cholangitis and ulcerative colitis in patients undergoing liver transplantation.

Thirty-six patients underwent orthotopic liver transplantation (OLT) for primary sclerosing cholangitis under cyclosporine, azathioprine, and steroid immunosuppression. Of these patients, 29 suffered from chronic ulcerative colitis. The purpose of this study is to determine (1) whether replacement of the diseased liver and the altered immunocompetence suppresses the manifestation of chronic ulcerative colitis, and (2) if active colonic disease alters allograft function. Thirty of 36 patients survived OLT. After OLT, seven of 14 patients with symptomatic colon disease at the time of transplantation continue to suffer from active chronic ulcerative colitis, and three of 13 who were asymptomatic developed clinically active disease. Intractable colonic disease was the indication for post-OLT proctocolectomy in three patients, and one refused an indicated colectomy. Despite the long duration of the disease, none developed colonic malignancy. Long-term graft assessment showed good hepatocyte synthetic function in patients suffering from either active or inactive disease. Liver alkaline phosphatase, however, was significantly higher in patients suffering from active colonic disease. Furthermore, the alkaline phosphatase in symptomatic patients was higher than that seen in a matched cohort undergoing OLT for chronic active hepatitis or primary biliary cirrhosis. These results suggest that (1) liver replacement and immunosuppression in patients suffering from sclerosing cholangitis and ulcerative colitis do not alter the course of the colon disease, and (2) active chronic ulcerative colitis does not adversely affect allograft function, although elevation of alkaline phosphatase may be the harbinger of recurrence over the long term.

Effect of a prior portasystemic shunt on subsequent liver transplantation.

Fifteen patients who had a prior portasystemic shunt underwent orthotopic liver transplantation. Shunt types were portacaval in six patients, H-graft mesocaval in six, distal splenorenal in two, and proximal splenorenal in one. Mean blood loss and hospital stay were highest in the portacaval group. Retransplants (two patients) and deaths (two patients) also were limited to this group. In this report, technical considerations, advantages, and disadvantages of the various shunt types are described. Management of patients with late stages of portal hypertension must include estimation of the effects of a portasystemic shunt on subsequent liver transplantation. It is concluded that portacaval shunts should be avoided in patients who may be considered for transplantation. Distal splenorenal shunts are best performed in younger patients with intractable variceal bleeding who are not expected to require transplantation in the near future. A mesocaval H-graft is the shunt of choice in patients who are current liver transplant candidates.

Simultaneous Cadaver Pancreas Living-Donor Kidney Transplantation: A New Approach for the Type 1 Diabetic Uremic Patient

ObjectiveTo 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 DataSimultaneous 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. MethodsBetween 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. ResultsOne-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. ConclusionsEarly 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.

Randomized prospective trial of OKT3 for early prophylaxis of rejection after liver transplantation

A group of 52 liver transplant patients was prospectively randomized to receive prophylactic immunosuppressive therapy consisting of either Orthoclone OKT3 for 14 days, azathioprine, and steroids (25 patients); or cyclosporine, azathioprine, and steroids (27 patients). The groups were similarly matched for age, diagnosis, and Childs classification. The patients were studied to determine the effect of these two regimens on the incidence of rejection, infection, renal dysfunction, and mortality. Seven rejection episodes, as determined by clinical and histological criteria, occurred in seven of 25 patients (28%) receiving OKT3 compared with 18 episodes in 27 patients (67%) receiving cyclosporine during the first 14 days after transplantation (P less than 0.02). In 20% of the OKT3 patients, CD3+ levels of greater than 10% developed during therapy, and 16% of the patients developed anti-OKT3 antibodies during OKT3 treatment. Five patients were retreated with OKT3 for steroid-resistant acute rejection episodes; all had resolution of the rejection episode. Infectious complications were similar in each group. Renal function, as measured by serum creatinine, was significantly better with OKT3 than with cyclosporine (P less than 0.003) at 14 days. We conclude that prophylactic OKT3 is effective in reducing the number of early rejection episodes after liver transplantation; after 14 days the incidence of rejection is similar; reuse of OKT3 has been successful in liver transplant patients; infectious complications are similar between OKT3 and cyclosporine; and OKT3 preserves renal function better than cyclosporine and is thus indicated in patients with compromised preoperative renal function.

Financial incentives for cadaver organ donation: An ethical reappraisal

A panel of ethicists, organ procurement organization executives, physicians, and surgeons was convened by the sponsorship of the American Society of Transplant Surgeons to determine whether an ethically acceptable pilot trial could be proposed to provide a financial incentive for a family to consent to the donation of organs from a deceased relative. An ethical methodology was developed that could be applied to any proposal for monetary compensation to elucidate its ethical acceptability. An inverse relationship between financial incentives for increasing the families’ consent for cadaver donation that clearly would be ethically acceptable (e.g., a contribution to a charity chosen by the family or a reimbursement for funeral expenses) and those approaches that would more likely increase the rate of donation (e.g., direct payment or tax incentive) was evident. The panel was unanimously opposed to the exchange of money for cadaver donor organs because either a direct payment or tax incentive would violate the ideal standard of altruism in organ donation and unacceptably commercialize the value of human life by commodifying donated organs. However, a majority of the panel members supported reimbursement for funeral expenses or a charitable contribution as an ethically permissible approach. The panel concluded that the concept of the organ as a gift could be sustained by a funeral reimbursement or charitable contribution that conveyed the appreciation of society to the family for their donation. Depending on the amount of reimbursement provided for funeral expenses, this approach could be ethically distinguished from a direct payment, by their intrusion into the realm of altruism and voluntariness. We suggest that a pilot project be conducted to determine whether this kind of a financial incentive would be acceptable to the public and successful in increasing organ donation.