Kidney and liver transplantation in the elderly.

BACKGROUND: Transplant surgery is facing a shortage of deceased donor organs. In response, the criteria for organ donation have been extended, and an increasing number of organs from older donors are being used. For recipients, the benefits of transplantation are great, and the growing ageing population has led to increasing numbers of elderly patients being accepted for transplantation. METHODS: The literature was reviewed to investigate the impact of age of donors and recipients in abdominal organ transplantation, and to highlight aspects of the fine balance in donor and recipient selection and screening, as well as allocation policies fair to young and old alike. RESULTS: Overall, kidney and liver transplantation from older deceased donors have good outcomes, but are not as good as those from younger donors. Careful donor selection based on risk indices, and potentially biomarkers, special allocation schemes to match elderly donors with elderly recipients, and vigorous recipient selection, allows good outcomes with increasing age of both donors and recipients. The results of live kidney donation have been excellent for donor and recipient, and there is a trend towards inclusion of older donors. Future strategies, including personalized immunosuppression for older recipients as well as machine preservation and reconditioning of donor organs, are promising ways to improve the outcome of transplantation between older donors and older recipients. CONCLUSION: Kidney and liver transplantation in the elderly is a clinical reality. Outcomes are good, but can be optimized by using strategies that modify donor risk factors and recipient co-morbidities, and personalized approaches to organ allocation and immunosuppression.

In situ normothermic regional perfusion for controlled donation after circulatory death--the United Kingdom experience.

Organs recovered from donors after circulatory death (DCD) suffer warm ischemia before cold storage which may prejudice graft survival and result in a greater risk of complications after transplant. A period of normothermic regional perfusion (NRP) in the donor may reverse these effects and improve organ function. Twenty-one NRP retrievals from Maastricht category III DCD donors were performed at three UK centers. NRP was established postasystole via aortic and caval cannulation and maintained for 2 h. Blood gases and biochemistry were monitored to assess organ function. Sixty-three organs were recovered. Forty-nine patients were transplanted. The median time from asystole to NRP was 16 min (range 10-23 min). Thirty-two patients received a kidney transplant. The median cold ischemia time was 12 h 30 min (range 5 h 25 min-18 h 22 min). The median creatinine at 3 and 12 months was 107 µmol/L (range 72-222) and 121 µmol/L (range 63-157), respectively. Thirteen (40%) recipients had delayed graft function and four lost the grafts. Eleven patients received a liver transplant. The first week median peak ALT was 389 IU/L (range 58-3043). One patient had primary nonfunction. Two combined pancreas-kidney transplants, one islet transplant and three double lung transplants were performed with primary function. NRP in DCD donation facilitates organ recovery and may improve short-term outcomes.

Uncovering a rare but critical complication following thyroid surgery: an audit across the UK and Ireland.

OBJECTIVE: Serious wound infection after thyroidectomy is uncommon, but actual incidence is not well documented in the literature. In the past a patient in our unit died secondary to fulminant streptococcal sepsis after thyroidectomy for benign disease. This prompted us to audit experience of serious wound infection among British Association of Endocrine Surgery (BAES) members. DESIGN: A questionnaire was posted to BAES members inquiring about experience of major wound infection following cervicotomy, incidence of minor wound infection, and prophylactic and therapeutic antibiotic usage. MAIN OUTCOME: Eight respondents experienced a case of fulminant wound infection after cervicotomy (8% total respondents). Five patients died and, in 6 patients, cases of streptococci were cultured. Then, 9% of respondents used prophylactic antibiotics routinely, 16% sometimes and 75% never. The most commonly used antibiotic was augmentin, and the most common reasons for use among those with a selective policy were re-operative cases (38%) and immunocompromised patients (38%). Also, 40% of respondents experienced major wound infection requiring intravenous antibiotics or surgical drainage. The most common choices of antibiotic used before sensitivities were obtained were augmentin (43%) and flucloxacillin (35%). CONCLUSIONS: Although rare, fulminant streptococcal wound infection after cervicotomy does occasionally occur and carries a high mortality.

Graft function and other risk factors as predictors of cardiovascular disease outcome.

The high incidence of cardiovascular disease after renal transplantation is related to a high prevalence and accumulation of risk factors before and after transplantation. Hypertension, posttransplantation diabetes, and hyperlipidemia are well-recognized risk factors for the development of cardiovascular events after renal transplantation and are strongly associated with immunosuppressive therapy. Hyperhomocysteinemia is a potential risk factor for cardiovascular disease in renal transplant recipients, but although a growing matter of study, a direct association with immunosuppressive agents is not yet proven. In addition to treatment intervention, risk management should also involve tailoring the immunosuppressive regimen to minimize the more indirect cardiovascular risk factors such as renal dysfunction and acute rejection.

Renal allograft rejection. Tubular epithelial cells present alloantigen in the presence of costimulatory CD28 antibody.

Renal tubular epithelial cells can be induced to express potentially immunogenic levels of class II MHC antigens but fail to stimulate the activation of allospecific T lymphocytes. The current series of experiments was performed to determine whether the failure of lymphocyte activation in this system is caused by defective T cell costimulation. It was found that cultured renal epithelial cells expressed class II MHC antigens and the immunoregulatory adhesion molecules intercellular adhesion molecule-1, vascular cell adhesion molecule-1, and lymphocyte function-associated antigen-3 after stimulation with IFN-gamma, but that the B7 ligand for CD28 was not expressed. Mixed cell culture experiments were set up in which lymphocytes were mixed with IFN-gamma-treated allogeneic renal cells. Lymphoproliferation and IL-2 production were only observed if bivalent anti-CD28 antibodies were titrated into these cultures. The requirement for antigen stimulation was retained by these lymphocytes, as no proliferation was observed after stimulation by class II MHC antigen nonexpressing, resting renal cells. Further experiments demonstrated that the effectiveness of the anti-CD28 antibody-mediated signal was enhanced by cross-linking with a secondary anti-kappa-chain antibody. These data are consistent with the concept that a costimulatory signal generated by ligation of CD28 is of central importance to the development of an immune response to alloantigen. Furthermore, these results indicate that tubular epithelial cells within a rejecting renal allograft are unlikely to initiate direct activation of infiltrating allospecific lymphocytes.

Renal allograft rejection. Possible involvement of antibody-dependent cell-mediated cytotoxicity.

We have demonstrated that serum from appropriately sensitized patients can contain IgG antibodies that bind to cultured renal epithelial cells. The presence of such antibodies on the surface of renal cells enables otherwise nonlytic PBMC to lyse these renal cells by an antibody-dependent cell-mediated cytotoxicity (ADCC) mechanism. Experiments involving cell-sorting and specific complement-mediated lysis showed that the ADCC effector cells were of the CD3 -ve, C16 +ve phenotype characteristic of NK cells. In this report it is argued that an ADCC mechanism may be of importance in mediating chronic renal cell damage in the absence of acute allograft rejection.

Late perfusion. A simple remedy for renal allograft primary nonfunction.

Primary nonfunction in renal allografts makes the diagnosis of allograft dysfunction more difficult and may effect long-term graft survival. The prevention of primary nonfunction by a reperfusion technique has been assessed in a prospective analysis of 145 consecutive renal transplants performed in a single center. All kidneys were retrieved using an in situ perfusion method, and all but 13 recipients received a standardized immunosuppressive protocol with cyclosporine. The first 106 transplants were performed without the benefit of any additional perfusion, and the incidence of primary nonfunction was 57.5% in these patients. The last 39 kidneys received additional perfusion with kidney perfusion fluid immediately prior to implantation (late perfusion). In the latter group, the incidence of primary nonfunction was 30.8% (P = 0.007). Using logistic regression analysis, only three factors were found to be associated with primary nonfunction: immunosuppression with cyclosporine (P = 0.01), a second warm ischemia time of greater than 35 min (P = 0.002), and late perfusion (P = 0.003). In this study, the use of late perfusion alone has reduced the incidence of primary nonfunction by almost one half. The technique is simple, safe, inexpensive, and effective. Its routine use is now advocated in all renal transplants.

The value of posttransplant monitoring of interleukin (IL)-2, IL-3, IL-4, IL-6, IL-8, and soluble CD23 in the plasma of renal allograft recipients.

Over the past few years, the central role of cytokines in the amplification of the immune response has been reported and several studies have examined the relationship between the plasma level of individual lymphokines during renal allograft rejection. The aim of the present investigation was to study simultaneously IL-2, IL-3, IL-4, IL-6, IL-8, and soluble CD23. Analysis of results has allowed both the prognostic value and any possible interrelationships between the measured cytokines to be determined. We studied 16 renal transplant recipients for the first 14 days after transplantation. Seven patients showed clinical evidence of acute allograft rejection and 5 showed excellent stable graft function with no signs of rejection. Primary nonfunction was seen in 4 patients. The plasma levels of each cytokine were measured by commercially available ELISA and immunoradiometric assay kits. As reported in previous studies, plasma IL-2 levels, whenever found at detectable levels, were predictive of impending graft rejection. Serial monitoring of IL-4 and IL-6 was more reliable for the differential diagnosis of rejection, particularly toward the end of the first week after transplantation. IL-3, IL-8, and soluble CD23 were not diagnostic or predictive of rejection, due to the occurrence of significantly high levels in transplant patients who showed no evidence of clinical rejection. While the value of cytokine monitoring has been shown in this study, it should be remembered that infection, although not seen in these studies, may have a profound affect on the results obtained.

Dose optimization of mycophenolate mofetil when administered with a low dose of tacrolimus in cadaveric renal transplant recipients.

BACKGROUND: Supplementation of immunosuppressive therapy with mycophenolate mofetil (MMF) has been found to reduce the rate of acute rejection in renal transplantation. We report a dose-finding study for MMF when administered in combination with low-dose tacrolimus and corticosteroid prophylaxis in cadaveric renal transplant recipients. METHODS: Two hundred thirty-two patients at 16 centers were enrolled in this randomized, parallel-group study. The three treatment groups were tacrolimus and corticosteroids (MMF-0 group, n=82); tacrolimus, corticosteroids, and 1 g of MMF daily (MMF-1 g group, n=79); and tacrolimus, corticosteroids, and 2 g of MMF daily (MMF-2 g group, n=71). Study duration was 6 months, and patients were followed up for patient and graft survival for 12 months. RESULTS: At 6 months posttransplantation, daily doses of 1 g and 2 g of MMF were associated with significantly lower rates of acute rejection compared with tacrolimus alone. The Kaplan-Meier rates were 48.5%, 24.9%, and 22.9%, respectively, for the three treatment groups when acute rejection was determined by clinical criteria (P=0.007). At month 12, patient survival rates were 100%, 97.5%, and 97.2% and graft survival rates were 90.2%, 92.4%, and 93.0% for the MMF-0 group, MMF-1 g group, and the MMF-2 g group, respectively. Gastrointestinal adverse events and leukopenia were higher in the MMF groups, especially in the MMF-2 g group (P<0.05). CONCLUSIONS: Low-dose tacrolimus combined with a MMF dose of 1 g daily and corticosteroids provided an optimized efficacy and safety profile. A higher dose of MMF (2 g) was associated with greater toxicity without a significant improvement in efficacy.

Multicenter randomized trial comparing tacrolimus (FK506) and cyclosporine in the prevention of renal allograft rejection: a report of the European Tacrolimus Multicenter Renal Study Group.

BACKGROUND: To confirm the results of a number of studies conducted in Europe, the United States, and Japan, this multicenter, randomized trial compared the 12-month efficacy and safety of tacrolimus- and cyclosporine-based immunosuppressive regimens in the prevention of renal allograft rejection. METHODS: A total of 448 renal transplant recipients were recruited from 15 centers and assigned to receive triple-drug therapy consisting of tacrolimus (n=303) or cyclosporine (n=145) in conjunction with azathioprine and low-dose corticosteroids. RESULTS: At 12 months after transplantation, tacrolimus therapy was associated with a significant reduction in the frequency of both acute (tacrolimus 25.9% vs. cyclosporine 45.7%; P<0.001 [absolute difference: 19.8%, 95% confidence interval: 10.0-29.6%]) and corticosteroid-resistant rejection (11.3% vs. 21.6%; P=0.001 [absolute difference: 10.3%, 95% confidence interval: 2.5-18.2%]). Actuarial 1-year patient (tacrolimus 93.0% vs. cyclosporine 96.5%; P=0.140) and graft survival rates (82.5% vs. 86.2%; P=0.380) did not differ significantly between the two treatment groups. Overall, the safety profiles of the tacrolimus- and cyclosporine-based regimens were quite comparable. Infections, renal impairment, neurological complications, and gastrointestinal complaints were frequently reported but were mostly reversible in both groups. Higher incidences of elevated serum creatinine, tremor, diarrhea, hyperglycemia, diabetes mellitus, and angina pectoris were reported in the tacrolimus treatment group, whereas acne, arrhythmia, gingival hyperplasia, and hirsutism were more frequent with cyclosporine treatment. CONCLUSIONS: The significant reduction in the incidence of episodes of allograft rejection observed with tacrolimus therapy may have important long-term implications given the prognostic influence of rejection on graft survival.

Xenotransplantation: an examination of the adhesive interactions between human lymphocytes and porcine renal epithelial cells.

Specific adhesion molecules stabilize the binding between lymphocytes and antigen bearing cells; this intercellular adhesion is vital to both the affector and effector phases of an immune response. It is not known whether adhesion molecules and their counter-receptors can form the cross-species interactions that will facilitate human T cell recognition of xenogeneic porcine target cells. In this report it is demonstrated that a higher proportion of mitogen-activated than of resting human lymphocytes adhere to cultured porcine renal epithelial cells. Furthermore, antibody blocking experiments demonstrated that at least part of this cell-cell binding is stabilized by the human adhesion molecules LFA-1 (lymphocyte function-associated antigen-1) and the alpha 4-containing integrins. It is possible that this capacity for cross-species adhesion will play a role during the cell-mediated rejection of clinical porcine xenografts.

Flow cytometric crossmatching in renal transplantation--the long-term outcome.

The association of a positive flow cytometric crossmatch between recipient IgG directed against donor T lymphocytes and poor outcome is well described in renal transplantation. Until now no long-term follow-up on such patients has been available. In this study, 117 renal transplant patients were followed up for a period of 5 years. Of these 21 were known to have donor T cell directed IgG and five had B lymphocyte directed IgG. Both groups of patients with these antibodies had a significantly poorer outcome at 5 years than did the group of patients without IgG (p < 0.0001, Handel Maenzel test). Patients with antibody detected preoperatively were tested again either at the time of graft failure or at 5 years post-transplantation. The sera were tested against stored donor cells and the intensity of surface IgG compared with the preoperative levels. In those recipients who lost their grafts the levels increased in 60% of cases, but those who retained their grafts also had an increase in levels of donor directed antibody in 50% of cases. The changing levels of antibody therefore appeared to have little relevance to outcome. However when IgG isotypes were considered, in those who experienced graft failure and also had a gamma 3 isotype, a rise in IgG was demonstrated in all cases. Conversely, successful grafts with gamma 3 had a decline in levels between preoperative and 5-year samples in three of the four cases (not significant).

Surgical aspects of chronic peritoneal dialysis in the neonate and infant under 1 year of age.

Since 1982 eight patients under 1 year of age with end-stage renal failure have been treated by chronic peritoneal dialysis (CPD) following insertion of an abdominal Tenckhoff catheter. We routinely perform a partial omentectomy now, and in males undertake bilateral exploration of the groins at the time of catheter insertion, with herniotomy or ligation of the patent processus vaginalis as required. Up to January 1990, 19 straight double-cuff catheters had been inserted with a total follow-up of 244.5 patient months. The median age at the initial catheter insertion was 14.6 weeks (range, 2 days to 11 months) and the median weight was 3.89 kg (range, 2.2 to 5.5). Peritonitis was the most common complication, with 46 episodes, representing one episode of peritonitis per 5.3 patient months on dialysis. The frequency of peritonitis has decreased in the last 6 months since all patients have been dialysed by two caregivers. The present rate of peritonitis is 1 episode per 10 patient months on dialysis. One patient has died of septicemia secondary to associated congenital abnormalities, one patient has regained renal function, and two patients have been transplanted, one successfully. Five patients are currently dialysing via their abdominal Tenckhoff catheters and awaiting transplantation. We conclude that neonates and infants under 1 year of age can be treated satisfactorily by CPD to enable successful preparation for transplantation later in childhood.

Impact of patient characteristics and comorbidity profile on activation of patients on the kidney transplantation waiting list.

BACKGROUND: The aim of this study was to examine which demographic and comorbidity factors affected the activation of patients with end-stage renal disease on the national kidney transplantation waiting list. METHODS: This was a prospective cohort study across 13 transplantation centers in the United Kingdom from October 1, 2006 to September 30, 2007. Data were collected for all new adult patients (n = 1530) referred to the renal transplantation assessment clinic. The proportion of patients who were activated to the waiting list after a minimum one year follow-up was estimated. Factors influencing activation of patients on the waiting list were examined. RESULTS: A total of 872 (58.9%) patients were activated to the transplantation waiting list. The likelihood of activation to the transplantation waiting list was lower in patients older than 65 years (P = .021), nonwhite ethnicity (P < .0001), smokers (P < .0001), and those in whom diabetes was the cause of renal failure (P = .004). Multivariate analysis showed that there was an adverse impact of comorbidity such as ischemic heart disease (P = .003), diabetes (P = .006), and peripheral vascular disease (P = .007) on the likelihood of activation to the waiting list. CONCLUSION: Patient characteristics and comorbidity are associated with the probability of activation of patients to the waiting list.