Kazuharu Uchida

Excellent Long‐term Outcome of ABO‐Incompatible Living Donor Kidney Transplantation in Japan

Owing to the severe shortage of cadaveric grafts in Japan, we have performed ABO‐incompatible living donor kidney transplantation since 1989. This study assessed short‐ and long‐term outcomes in 441 patients who received ABO‐incompatible living donor kidney transplants between January 1989 and December 2001. We compared our results with historical data from 1055 recipients of living kidney transplantation. Overall patient survival rates 1, 3, 5, 7, and 9 years after ABO‐incompatible transplantation were 93%, 89%, 87%, 85%, and 84%, respectively. Corresponding overall graft survival rates were 84%, 80%, 71%, 65%, and 59%. After ABO‐incompatible transplantation, graft survival rates were significantly higher in patients 29 years or younger than in those 30 years or older and in patients who received anticoagulation therapy than in those who did not receive such therapy. There were no significant differences between A‐incompatible and B‐incompatible recipients with respect to clinical outcomes. The graft survival rate at 1 year in the historical controls was slightly but not significantly higher than that in our recipients of ABO‐incompatible transplants. We conclude that long‐term outcome in recipients of ABO‐incompatible living kidneys is excellent. Transplantation of ABO‐incompatible kidneys from living donors is a radical, but effective treatment for end‐stage renal disease.

Patient management by Neoral C2 monitoring: An international consensus statement1

The Consensus on Neoral C2: Expert Review in Transplantation (CONCERT) attendees achieved consensus on the following points, based on currently available data from independent clinical studies using Neoral (cyclosporine microemulsion): 1. Scientific validation of Neoral C2 monitoring1.1 An understanding of cyclosporine pharmacokinetics is critical for designing a monitoring strategy that maximizes clinical outcome following organ transplantation1.2 Neoral absorption during the first 4 hours postdose (AUC0–4) represents the period of greatest variability among patients. Adequate CsA absorption during this period is important for effective rejection prophylaxis in the early posttransplant phase1.3 C0 does not correlate well with AUC0–4 in patients receiving Neoral1.4 C2 is the best single time-point predictor of AUC0–4 in all types of Neoral-treated transplant patient populations that have been studied (adult renal, liver, heart and lung patients, and pediatric renal and liver transplant recipients)1.5 Additional CsA concentration sampling beyond the C2 time point, such as C6, may be required in low absorbers of CsA2. Clinical data in de novo adult renal transplant patients2.1 C0 monitoring in patients receiving Neoral distinguishes poorly between those who will experience acute rejection and those who will remain rejection-free2.2 Existing data indicate that higher C2 levels are highly correlated with a lower risk of acute rejection during the early posttransplant period in patients receiving Neoral. Data on outcomes beyond 1 year are awaited2.3 The association between C2 and risk of acute rejection is maintained in Neoral-treated patients who receive an antibody induction agent or concomitant mycophenolate mofetil (MMF) therapy2.4 Achieving an adequate C2 level early after transplantation is associated with reduced risk of acute rejection in adult renal transplant recipients2.5 Adjustment of Neoral dose based on C2 monitoring does not appear to result in impaired early renal function in the short-term, if slow absorbers are identified and managed appropriately. Long-term data are pending3. Clinical data in de novo adult liver transplant patients3.1 Patient management with Neoral C2 monitoring reduces the incidence and severity of acute rejection compared to C0 monitoring3.2 Renal function is not compromised by C2 monitoring in adult liver transplant patients receiving Neoral4. Clinical outcomes in maintenance renal and liver transplant patients4.1 Patient management with Neoral C2 monitoring can improve renal function in maintenance patients by identifying patients who are receiving excessive CsA4.2 Using C2 monitoring in maintenance patients can also reduce the incidence and severity of hypertension by identifying patients who are receiving excessive CsA4.3 Current data suggest that there is an association between C2 level and risk of chronic allograft nephropathy, in adult renal transplant patients receiving Neoral5. C2 targets for adult renal transplant patients5.1 Guideline C2 targets have been proposed for the first month posttransplant in adult renal transplant patients receiving Neoral, with subsequent step-wise reductions in C2 target over time5.2 Long-term target C2 levels for prevention of chronic allograft nephropathy remain to be confirmed6. C2 targets for adult liver transplant patients6.1 Guideline C2 targets have been proposed for adult liver transplant recipients receiving Neoral7. C2 targets for other transplant patient types7.1 C2 target levels have not yet been established for cardiothoracic organ recipients, living-related liver transplant recipients, kidney-pancreas transplant patients, or pediatric transplant patients receiving Neoral8. Accuracy of C2 sampling8.1 There is a 15-minute “window of opportunity” before and after the 2-hour time point during which the C2 sample can be taken in order to remain within a 10% margin of error8.2 In most instances, C2 targets do not require adjustment for different immunoassay types currently available9. Pharmacoeconomics9.1 Neoral C2 monitoring is at least cost neutral compared to C0 monitoring and may generate cost savings in adult renal transplant patients10. Conclusions of the CONCERT conference10.1 C2 monitoring is the optimal method to monitor Neoral in adult de novo renal and liver transplant patients (2)10.2 Preliminary data indicate that Neoral C2 monitoring may have clinical benefits in maintenance adult renal and liver transplant recipients who are receiving excessive CsA and in whom the Neoral dose is reduced10.3 Maintenance patients who are experiencing suspected CsA-related toxicity may benefit from use of Neoral C2 monitoring to detect CsA overexposure10.4 Further data sre required from prospective, randomized multicenter trials to evaluate the possible long-term clinical benefits of adopting Neoral C2 monitoring in de novo and maintenance transplant patients, both in terms of rejection prophylaxis and overall safety profile

Clonal analysis of nodular parathyroid hyperplasia in renal hyperparathyroidism

Abstract. Although it is well known that chronic renal failure induces parathyroid hyperplasia, the pathogenesis and development of this parathyroid lesion in this disease are poorly understood. Histopathologically, there is progression from diffuse to nodular hyperplasia, and each nodule consists of a single cell type with aggressive proliferative potential. Pathophysiologic and clinical investigations have suggested that neoplastic tumors may emerge from nodular hyperplasia. In this study the clonality of parathyroid tissue in nodular and diffuse hyperplasia in renal hyperparathyroidism was analyzed by a method based on restriction fragment length polymorphism of the X chromosome-linked phosphoglycerokinase gene and on random inactivation of the gene by methylation. DNA of peripheral lymphocytes was screened in 43 women undergoing parathyroidectomy for advanced renal hyperparathyroidism, and 10 of these patients appeared to be heterozygous. Fourteen specimens from these patients were available for clonal analysis. The analysis showed that all four specimens of diffuse hyperplasia were polyclonal, whereas all seven specimens from nodules in nodular hyperplasia and all three samples representing parathyroid tissue removed from forearm because of graft-dependent recurrence were revealed to be monoclonal. It is likely that the clonal origin of each nodule is independent. These results suggest that in renal hyperparathyroidism parathyroid glands initially grow diffusely and polyclonally, and then the cells in the nodules are later transformed monoclonally and proliferate aggressively. From the present study it can be concluded that nodular hyperplasia represents monoclonal parathyroid neoplasia, which might explain why patients with nodular hyperplasia in renal hyperparathyroidism are refractory to medical treatment, requiring parathyroidectomy. To prevent recurrences, nodular hyperplastic tissue should not be left at surgery.

Outbreak of Pneumocystis jiroveci pneumonia in renal transplant recipients: P. jiroveci is contagious to the susceptible host.

Background. Prophylaxis against Pneumocystis jiroveci pneumonia (PCP) is only recommended during some periods after renal transplantation. Recent advances in immunosuppressive therapy have considerably reduced acute rejection. However, the reported PCP outbreaks are increasing in renal transplant recipients. Methods. Only three sporadic PCP cases had occurred since 1976 in our Renal Transplant Unit until the index case in July 2004. A PCP outbreak of 27 cases occurred mainly in the outpatient clinic within 1 year, followed by six additional cases during the next 3 years. Molecular analysis of P. jiroveci and surveys of reservoir were performed. Results. Molecular analysis documented that all cases were caused by the same strain. Among 27 cases of the outbreak, human-to-human transmissions were traceable in 22 cases based on dates of outpatient clinic visits and in four cases during hospitalization. Based on the confirmed cases, airborne transmission was suspected with an estimated median PCP incubation period of 53 days (range 7–188 days). Surveys for reservoir of P. jiroveci identified asymptomatic carriers and environmental contamination. Some sporadic cases might be caused by reservoirs. Among the 33 cases, none had received PCP prophylaxis, 22 cases had PCP over 12 months, and six cases over 10 years after renal transplantation. Conclusion. On documentation of a PCP case, we recommend PCP prophylaxis for a maximum period of 6 months (upper limit of incubation period) in all renal transplant recipients including those on regular maintenance immunosuppressive therapy.

Surgical Significance of Supernumerary Parathyroid Glands in Renal Hyperparathyroidism

Abstract. In secondary hyperparathyroidism (2HPT) fundamentally all parathyroid glands, including supernumerary glands, become hyperplastic, and stimulation of parathyroid glands continues after parathyroidectomy (PTx). Therefore supernumerary glands have special significance during surgery for 2HPT, whether persistent or recurrent HPT. In the present study 570 patients underwent initial total PTx with a forearm autograft. The frequency, type, location, histopathology, and clinical significance of the supernumerary glands were evaluated. At the initial operation 90 supernumerary glands were removed from 82 of 570 patients (14.4%); 12 patients (2.1%) required extirpation of supernumerary glands for persistent/recurrent HPT. Altogether 104 supernumerary glands were identified at operation in 94 of the 570 patients (16.5%). Among these 104 glands, 25 (24.0%) were of the rudimentary, or split, type and 79 (76.0%) of the proper type. Supernumerary glands were most frequently identified in the thymic tongue (53/104, 51.0%); 32 (60.4%) of these 53 glands were identified only microscopically. In 6 of the 570 cases (1.1%), reoperation was required for persistent HPT due to supernumerary glands located in the mediastinum, and 6 patients underwent neck reexploration for recurrence. Histopathologically, 61 of 104 (58.7%) supernumerary glands, including 36 glands recognized only microscopically, showed diffuse hyperplasia, and 43 (41.3%) displayed nodular hyperplasia. Residual small supernumerary glands with diffuse hyperplasia have the potential to be transformed to nodular hyperplasia during long-term hemodialysis. Therefore all parathyroid glands including supernumerary glands should, if possible, be removed at the initial operation. Routine removal of the thymic tongue and careful examination of the regions surrounding the lower poles of the thyroid, especially on the left side, are important steps in the surgical treatment.

Surgical treatment of renal hyperparathyroidism

Advanced secondary (renal) hyperparathyroidism induced by chronic renal disturbance is one of the most serious complications for long-term hemodialysis patients. Parathyroidectomy is indicated in patients with severely advanced renal hyperparathyroidism refractory to medical treatment (including calcitriol pulse therapy) and the clinical effect of parathyroidectomy is striking. However, skeletal deformity, vessel calcification, and remarkable reduction of bone content is irreversible, and it is important to perform parathyroidectomy at right time. Based on histopathological and pathophysiological investigations, nodular hyperplasia is monoclonal neoplasia with abnormal parathyroid hormone (PTH) response to extracellular calcium and vitamin D. When parathyroid hyperplasia progresses to nodular hyperplasia, parathyroidectomy should be required. Total parathyroidectomy with forearm autograft is the preferable procedure for renal hyperparathyroidism, especially for patients who need to continue hemodialysis treatment after parathyroidectomy. Removal of all parathyroid glands, including supernumerary glands, at the initial operation, and proper choice of adequate parathyroid tissue for autograft, are important to prevent persistent and recurrent hyperparathyroidism. Preoperative image diagnosis is useful for localization, and routine resection of thymic tissue is necessary to remove supernumerary glands. In our series of 548 patients, graft-dependent recurrent hyperparathyroidism was not negligible and the incidence was about 20% at the 5th year postoperatively. Enlarged autografts of parathyroid tissue could be removed from forearm under local anesthesia with fewer invasions. The function of autografted parathyroid tissue is nearly satisfactory and no re-transplantation of cryopreserved parathyroid tissue was necessary. To avoid adynamic bone disease, relatively high PTH level is required-over-suppression of PTH by excess of vitamin D and calcium salts should be avoided. In our experience, total parathyroidectomy with forearm autograft is very effective and adequate treatment for advanced renal hyperparathyroidism, and parathyroid function can be controlled after parathyroidectomy.

Introduction of α(1,2)‐fucosyltransferase and its effect on a‐Gal epitopes in transgenic pig

Abstract: Hyperacute rejection (from pig to human) is thought to result from activation of complement initiated by the binding of host natural antibodies to α‐galactosyl (α‐Gal) epitopes of donor endothelial cells. However, α‐Gal epitope shares a common precursor with H antigen in humans. This means that H antigens as well as α‐Gal epitopes are synthesized in a competitive manner by different enzymes. We thought that it would be possible to convert α‐Gal epitopes into H antigens by introducing cDNA of α(1,2)‐fucosyltransferase (α1–2FT) into porcine cells, and so, pig embryos were microinjected with αl‐2FT cDNA. Transgenic pigs that carried α1–2FT were thus established. Cytotoxicity of fibrocytes derived from skin of transgenic pig was measured by 51Cr release assay, which showed that H antigen‐expressing cells were significantly resistant to a challenge with human sera. These experiments indicate that our method provides a new strategy which contributes to a successful discordant xenotransplantation.

Subtotal versus total parathyroidectomy with forearm autograft for secondary hyperparathyroidism in chronic renal failure

Forty-three patients with chronic renal failure and secondary hyperparathyroidism underwent parathyroidectomy; 20 of the 43 underwent subtotal parathyroidectomy (Group A) and 23 patients underwent total parathyroidectomy and parathyroid autotransplant in the forearm (Group B). Postoperative clinical improvement was similar in both groups. In the immediate postoperative period eight patients in Group A who had severe bone changes and 21 patients in Group B needed supplemental calcium administration. The grafted tissues in all cases functioned well; ***relmplantation of the cryopreserved parathyroid tissues was unnecessary. One case in each group showed a recurrence. One patient in Group A was submitted to reexploration of the neck with a lateral approach. The other patient in Group B underwent excisions of the transplanted parathyroid tissues on three separate occasions under local anesthesia. The second operation was definitely easier and safer to manage after a total parathyroidectomy with autotransplantation to the forearm.

Diabetes mellitus after transplant: relationship to pretransplant glucose metabolism and tacrolimus or cyclosporine A-based therapy.

Objective. The purpose of this study was to identify pretransplantation and posttransplantation indicators for the development of diabetes mellitus in the first 2 months after renal transplantation and to examine the influence of a cyclosporine A (CsA)-based versus a tacrolimus-based immunosuppressive regimen on these risk factors. Methods. Key variables associated with the development of posttransplant diabetes mellitus (PTDM) in the first 2 months after transplantation were assessed in 48 patients who underwent living-related renal transplantation and who were treated with a CsA-based or a tacrolimus-based immunosuppressive regimen. The insulinogenic index (I Index) and glucose infusion rate (GIR) were measures of insulin secretion and insulin sensitivity, respectively. Results. Eight patients developed PTDM. I Index (odds ratio, 0.000384) and GIR (odds ratio, 0.349) were significant risk factors for PTDM development. The cumulative steroid dose had a borderline association. PTDM developed in 4 of 28 CsA-treated patients and in 4 of 20 tacrolimus-treated patients. CsA therapy increased the mean I Index from 0.713±0.071 preoperatively to 1.130±0.140 postoperatively (P <0.01), whereas in tacrolimus-treated patients, I Index remained unchanged (1.09±0.264 preoperatively and 0.949±0.296 postoperatively; P =not significant). Age, duration of pretransplant dialysis, and body mass index did not predict PTDM development. All eight patients with PTDM had hypertension. Conclusions. Pre- and posttransplant abnormalities of insulin secretion and sensitivity are significant predictors of PTDM. Corticosteroid cumulative dose may affect the incidence of PTDM during the first 2 months after transplantation. CsA treatment increases insulin secretion in patients with a high pretransplant risk of PTDM.

Amlodipine, but not MDR1 polymorphisms, alters the pharmacokinetics of cyclosporine A in Japanese kidney transplant recipients

Background. Cyclosporine A (CsA) is a critical immunosuppressive drug with a narrow therapeutic range and wide interindividual variation in its pharmacokinetics. Many factors, including P-glycoprotein (PGP), influence the oral bioavailability and interpatient variability of CsA. A number of polymorphisms have been identified in the human MDR1 gene, and some of them have been found to be associated with an altered expression of PGP. We have investigated the role of these polymorphisms in CsA absorption from kidney transplant recipients. In addition, we also investigated the effect of amlodipine on CsA absorption. Methods. The area under the time-concentration curve from 0 to 2 hr (AUC0–2) estimated by the trapezoidal rule was used for the evaluation of extent of CsA absorption. The genotypes were identified by a polymerase chain reaction, restriction fragment length polymorphism analysis. Results. No association was found between polymorphisms in the MDR1 and CsA AUC0–2/dose/kg. In contrast, the combination of amlodipine significantly increased CsA AUC0–2/dose/kg (706.2 &mgr;g·hr/L to 819.2 &mgr;g·hr/L, P <0.05). Furthermore, we attempted to compare MDR1 polymorphisms and the absorption of CsA again without patients receiving amlodipine, but there was still no significant difference. Conclusions. There is no relationship between polymorphisms for MDR1 and CsA absorption, suggesting polymorphisms for MDR1 cannot account for the interpatient variability of CsA. Amlodipine, which is the substrate of PGP, significantly increased CsA absorption. These results indicate that PGP plays a significant role in CsA absorption, but its polymorphisms could not influence the CsA absorption.