Ichiro Nakai

Effect of Cyclosporine on the Endocrine and Exocrine Pancreas in Kidney Transplant Recipients

In order to assess whether cyclosporine (CsA) affects the endocrine and exocrine pancreas, 105 patient courses comprised of 87 living related donor (LRD) and 18 cadaver donor (CAD) transplants treated with cyclosporine and prednisolone (Pred) were compared with the results of historical controls of 170 LRD and 10 CAD transplants treated with azathioprine (Az) and Pred. All of the recipients were followed for over 6 months after transplantation. There were no differences in age, sex, Broca index, family history, and preoperative evaluation on diabetic dispositions between the two treatment groups. The incidence of diabetes mellitus (DM) requiring insulin therapy was higher in CsA-treated recipients (18/105, 17.1%) than in Az-treated recipients (23/180, 12.8%; P less than 0.05), although both the daily Pred and cumulative doses of methylprednisolone (MP) at the onset of DM were significantly smaller in the CsA group than in the Az group (26.1 +/- 2.2 mg v 41.4 +/- 3.4 mg, P less than 0.01 and 3,086 +/- 626 mg v 7,133 +/- 1,129 mg, P less than 0.01, respectively). Diabetic patients with CsA showed higher levels of blood glucose (401 +/- 46 mg/dL), but lower amounts of urinary glucose (40 +/- 4.3 g/d) compared with patients treated with Az (239 +/- 31 mg/dL, and 61.4 +/- 4.6 g/d, respectively, P less than 0.05). In the CsA group, the onset of DM was related to high CsA plasma trough levels (greater than 350 ng/mL) in 23% of patients. Insulin could be withdrawn within 3 months in six of eight patients who had been converted from CsA to Az.(ABSTRACT TRUNCATED AT 250 WORDS)

Experience with 247 living related donor nephrectomy cases at a single institution in Japan

There is currently much concern over the morbidity and mortality of donors undergoing nephrectomy for living related renal transplants. Between April, 1970 and July, 1986, 247 cases of living related renal transplants were performed at the Second Department of Surgery, Kyoto Prefectural University of Medicine. The average age of the donors was 50.3±9.7 years, 81 per cent of the donors being parents of the recipients. Minor abnormalities which did not affect the donors suitability were found in 71 cases. Nephrectomies were performed extraperitoneally in all cases. Peri-operative complications, including wound complications in 13 cases, urinary infection in 12 cases and pulmonary complications and arrythmia in 4 cases, were considered to be minor in nature. A variety of renal function tests, carried out two weeks after nephrectomy revealed normal levels, although they had become slightly worse than those estimated pre-operatively. Long-term sequalae in the follow-up period from 18 months to 16 years and 2 months, was studied on 124 donors who answered questionnaires. Currently, there are 5 late deaths, none of which are directly related to the nephrectomy. Of the 124 donors, 85.5 per cent stated that there had been no change in their physical states following surgery. Pain or a feeling of discomfort at the wound site was reported by 10 donors (8.1 per cent) and hypertension was observed only in 3 (2.4 per cent). No major complication directly related to the donor nephrectomy was found, except for one case of incisional hernia. The donor nephrectomy operation thus appeared to be quite safe, and successful long-term sequelae can be obtained if the donor is selected carefully, according to the strict prospective evaluation of medical state and renal functions.

Breast cancer arisingde novo in recipients of kidney allograft

Immunosuppressive therapy is not only an etiologic factor ofde novo malignant disease but it also accelerates progression of the already developed malignant disease in immunosuppressed recipients. Two cases ofde novo breast cancer arising in kidney transplant recipients are reported herein. A 25 year-old woman, transplanted one haploidentical kidney transplant 4 years and 9 months ago, developed a left breast tumor. Within one month the tumor had rapidly enlarged from 3.5 cm to 8 cm in diameter by the time she underwent a radical mastectomy. Nine axillary lymph nodes were positive for metastasis. Although her graft function had been poor due to chronic rejection, she was treated with standard immunosuppressive therapy, but not adjuvant therapy. Since local recurrent disease appeared two months postoperatively, the immunosuppressive therapy was ceased and60Co therapy started. Recurrent disease progressed rapidly, however, and she died 7 months after her operation. A 27 year-old woman, having allograft from an identical sibling, noted a right breast tumor, 8 years and 7 months later. Again the tumor had grown rapidly from 1.8 cm to 3 cm in diameter within one month. She underwent a standard radical mastectomy. One axillary lymph nodes was positive for metastasis. She has been treated with standard immunosuppressive therapy and adjuvant endocrinochemotherapy. Presently, she is alive with a well functioning graft and no disease.

Improved outcome of renal transplantation with cyclosporine compared with azathioprine —Experience in 33 recipients followed for over one year—

Long-term clinical aspects after kidney transplantation using cyclosporine (CsA) were studied in 33 patients who received kidney grafts from one haplotype identical living related donor and who were followed for at least one year. Both actual graft and patient survival rates were 97 per cent at one year. Incidence and severity of acute rejection were reduced to a greater extent in patients treated with CsA than in patients treated with azathioprine (AZ). The incidence of infections was low, and no serious bacterial infection occurred in these 33 patients. In 17 of 33 patients with a deteriorative graft function caused by intractable nephrotoxicity, CsA was converted to AZ. The mean serum creatinine level of converted patients was significantly higher than that of patients maintained with CsA at each time when a dose of CsA was stepwise reduced from 14 mg/kg/day to 6 mg/kg/day. Conversion to AZ improved graft function dramatically, although it resulted in reversible acute rejections in 4 patients. CsA induced hepatotoxicity occurred in 10 patients, but in all normal liver function was restored with decrease in the dose. The potent immunosuppressive effect of CsA compensates for its side effects. However, CsA should be converted to AZ when the chronic nephrotoxicity persists at a late stage of post-transplantation.

Effect of troglitazone on blood insulin levels after pancreas transplantation with systemic venous drainage in rats

BACKGROUND Troglitazone is a new oral antidiabetic agent and has been reported to reduce insulin resistance and improve peripheral hyperinsulinemia in patients with noninsulin-dependent diabetes mellitus. To examine the effect of troglitazone on insulin regulation after pancreas transplantation with systemic venous drainage, we measured peripheral glucose and insulin levels and performed an intravenous glucose tolerance test. METHODS We divided the rats into four groups: diabetic rats with a pancreas graft and administration of troglitazone at 40 mg/day orally (group P+T, n=4), rats with a pancreas graft only (group P, n=4), age-matched normal rats (group N, n=5), and diabetic rats (group DM, n=4). RESULTS Fasting insulin levels in group P were relatively higher than those in group N, whereas the values in group P+T were normalized. In the intravenous glucose tolerance test, troglitazone clearly regulates sigma immunoreactive insulin levels of pancreas transplanted rats (P vs. P+T: 244+/-23 vs. 145+/-14 microU/ml, P<0.05). CONCLUSION Hyperinsulinemia induced by systemic venous drainage, which may progress atherosclerosis, can be controlled with troglitazone treatment.

Quantitative Analysis of Microvasculature of Rat Pancreas Transplants in Acute Rejection

The changes of the microvasculature of rat pancreas transplants during acute rejection were investigated and quantitatively analyzed. The vessels in pancreas transplants increased in caliber and decreased in density during acute rejection. These changes were marked in the exocrine pancreas, especially in central zones, whereas changes in islets were mild. These results indicate that the early deterioration of exocrine function is closely related to vascular destruction.

Clinical factors which influence the long-term survival of kidney allografts donated from haploidentical donors.

All patients with renal transplants are very much concerned about their chance of long-term graft function. Chronic rejection is the most common cause of decline in function and graft failure, and after the first post-transplant year, 3-4% of recipients lose their graft every year. However, the cause, time of onset and mechanism of decline in graft function are not clear. Also unclear is whether clinical and laboratory parameters may predict patients who are at risk of developing chronic rejection. The aim of this study was to find the marker which may determine long-term graft survival in the azathioprine era and in the cyclosporine era.

The effect of cyclosporine on mortality and renal function in living related pediatric kidney transplant recipients.

The outcome, incidence of acute rejection episodes, complications and cyclosporine (CyA) induced nephrotoxicity were studied in 10 pediatric kidney transplant recipients who were grafted from one-haplotype indentical parent with immunosuppression of CyA and prednisolone (Pred). Excellent patient and graft survival could be achieved in this population with low incidences of acute rejection or serious complications as when compared with the results of azathioprine (AZ) treated pediatric patients. With a mean follow-up of 12.9 months (range 1 to 50 months), the patient survival rate was 100 per cent and the graft survival rate was 100, 84, 84 and 84 per cent at 1, 2, 3 and 4 years post transplantation, respectively. Serum creatinine levels in the group were 0.97, 1.17, 1.14 and 1.2 mg/dl at 3, 6, 12 and 24 months post transplantation, respectively. The incidence of treated acute rejection episodes was 20 per cent (2 out of 10) in the CyA-treated children, whereas it was 53 per cent (9 of 17) in the Az-treated children. Five children who had undergone transplant surgery before they were 11 years old displayed linear growth in height after their transplantation. There have been no opportunistic infections, aseptic necrosis or peptic ulcers in this group and cyclosporine nephrotoxicity has not been a serious problem in the pediatric recipients. Only 10 per cent (1 out of 10) of the recipients displayed acute nephrotoxicity and only one recipient has converted from CyA+Pred to CyA+AZ+Pred (Three drug therapy) due to persistent nephrotoxicity. Cyclosporine and prednisolone have therefore constituted a relatively safe, effective immunosuppressive regimen for pediatric renal allograft recipients.

Combined Pancreas and Kidney Transplantation

Most pancreas transplant recipients are currently patients with end-stage diabetic nephropathy undergoing a simultaneous renal transplant to treat uremia [1]. Because of the proximity of the organs in the donor and the use of the bladder as a common drainage site in the recipient, en bloc transplantation has some potential advantages, e.g., utilization of an aortic segment as a common channel for blood supply to both organs, requiring only one arterial anastomosis. Even if surgeons are reluctant to apply it clinically, the technique has experimental advantages, including shortened operative time. In this chapter, we describe a non-cuff technique for en bloc kidney and whole pancreaticoduodenal transplantation with bladder drainage, with a success rate sufficiently high for experimental use.

The successful outcome of second kidney transplantation and its contributing factors

Fourteen out of 301 patients who underwent allogeneic kidney transplantations, between April, 1970 and December, 1987, received second kidney allografts, including 4 living and 10 cadaveric grafts. The survival of the second grafts transplanted in those 14 recipients was superior to that of the first grafts transplanted in the other 287 recipients. Furthermore, the survival of the second grafts from 4 years onwards was significantly higher than that of the first grafts, in spite of a higher population of cadaveric grafts used in the second transplantation than in the first. Although it was impossible to determine the main factor which induced the improved survival of the second grafts when compared with that of the the first, a combination of beneficial factors, such as a high rate of living related transplantation resulting in long-term graft survival of the first transplantation, the administration of immunosuppressive drugs during the period of re-hemodialysis and blood transfusion prior to the second transplantation, was considered to be the reason why successful second graft survival was achieved.