Yasuji Ichikawa

Retrospective study on the impact of hepatitis C virus infection on kidney transplant patients over 20 years.

BACKGROUND The majority of chronic hepatitis is ascribable to hepatitis C virus (HCV) infection, whereas the clinical impact has not been understood in kidney transplant recipients. Our current study was carried out to assess the impact of HCV infection on kidney recipients over the long-term, and to investigate the effect and risk of interferon-alpha (IFN-alpha) therapy for chronic active hepatitis C. METHODS Hepatitis B surface antigen (HBsAg) and antibody to HCV (HCVAb) were examined prospectively and retrospectively in 280 patients, who underwent kidney transplants in the period from 1973 to 1996. The patient survival rate, the graft survival rate, the incidence of liver dysfunction and the cause of mortality among the HCV infected and noninfected groups were analyzed. IFN-alpha therapy was performed on 10 patients with chronic active hepatitis C. RESULTS Prevalence of the hepatitis virus was quite high at 34.3% (96/280): the frequency of the HBsAg carrier was 3.2% (9/280), that of the HCVAb carrier was 28.6% (80/280) and that of the both carriers was 2.5% (7/280). The other 184 cases (65.7%) were negative for both HBsAg and HCVAb. Liver dysfunction developed at the significantly higher incidence of 55% in HCVAb carriers compared to the 9.2% of the noninfected group (P<0.01). HCVAb carriers had a poor survival rate in the second decade compared to the noninfected group: 83.7% vs. 88.91% for 10-year survival (P=0.44) and 63.9% vs. 87.9% for 20-year survival (P<0.05). The poor survival rate was a result of the mortality from liver disorder. Five patients died of such disease in the infected groups whereas no noninfected patient died in the same period (p<0.01). As the result of IFN-alpha therapy, biochemical activity normalized or improved in eight cases, whereas the HCV-RNA titer was reduced only in three patients. Only one patient maintained normal biochemical markers and undetectable levels of HCV-RNA for 2 years after treatment. The therapy was discontinued for five patients with the adverse effects of acute rejection, deterioration of diabetes, and depression. CONCLUSIONS HCV infection has a significant impact on kidney transplant recipients over the long term and in particular affects them in the second decade. Our pilot study revealed only partial efficacy of IFN-alpha therapy for HCV-infected recipients, but with the high risk of acute rejection.

Quality of life of living kidney donors: the short-form 36-item health questionnaire survey.

OBJECTIVES To determine the psychological and social effects of kidney donation on kidney donors by using the short-form 36-item health survey (SF-36) as the quality-of-life questionnaire. METHODS A total of 104 living donor nephrectomies have been performed at Kobe University Hospital and Nishinomiya Prefectural Hospital. We mailed the questionnaires to donors or handed them out directly at the outpatient clinic. The first part of the questionnaire consisted of the SF-36 (limitations on physical functioning because of health problems) and the second part consisted of 15 questions about donation-related stress, expenses incurred, physical changes, and pre-existing factors such as relationship to the recipients. RESULTS The SF-36 and the questionnaire about donor satisfaction were completed by 69 donors (48 women and 21 men; mean age 52.1 +/- 8.2 years), only 6 of whom (9%) reported minor complications with the donor operation. The SF-36 scores of our donors were not significantly different from that of the general U.S. population and U.S. donors. In some categories (physical functioning, role-physical, bodily pain, general health, vitality, and mental health), our donors scored slightly higher than the U.S. general population. Although 97% of the donors would make the same choice again, 3% believed that donating had had a negative impact on their health, and 16% reported negative financial consequences. CONCLUSIONS The quality of life for kidney donors was not affected by donor nephrectomy. Living kidney transplantation seems to be suitable for the rescue of patients with end-stage renal disease. Better psychological and technical preparation for surgery and more consistent follow-up may reduce the negative outcomes even further.

INTRA‐ AND INTERINDIVIDUAL VARIATION IN THE PHARMACOKINETICS OF TACROLIMUS (FK506) IN KIDNEY TRANSPLANT RECIPIENTS—IMPORTANCE OF TROUGH LEVEL AS A PRACTICAL INDICATOR

Background:Tacrolimus (FK506) is currently used as the primary immunosuppressant in clinical kidney transplantation in some centers. The purpose of this study was to evaluate the pharmacokinetics of this drug and to see if trough level, which has been used widely in therapeutic drug monitoring, can be used as an appropriate substitute for other pharmacokinetic measurement tests.

Predictability of renal allograft prognosis during rejection crisis by ultrasonic Doppler flow technique

Using the ultrasonic Doppler technique, renal blood flow was measured in 67 patients who underwent living related renal transplantation from January, 1976 to December, 1979. In 58 of 67 cases, 81 acute and 9 chronic rejection episodes occurred. In the initial stage of acute rejection, there are no particular changes in the pattern of systolic blood flow and by contrast marked changes of diastolic flow. The disappearance of the diastolic phase is indicative of an advanced stage of rejection, the reappearance indicative of recovery from rejection, and persistent loss accompanied by changes of systolic flow indicative of an unfavorable prognosis of rejection. In chronic rejection, there are rapid changes of neither systolic nor diastolic flow though the acceleration time in the systolic phase lengthens gradually. The ultrasonic Doppler flow technique for blood flowmetry of a transplanted kidney is a useful means of knowing the prognosis of rejection and provides an index for corticosteroid bolus therapy.

Malignant Neoplasm in Kidney Transplantation

Background: The kidney recipient is at a higher risk for cancer than is the general population, although the incidence of neoplasms in general is considered lower in Japan than in Western countries. The cause of this increased risk associated with either transplantation or geography has not yet been established.

Effects of flutamide as a second‐line agent for maximum androgen blockade of hormone refractory prostate cancer

Abstract:  We analyzed clinical effects of flutamide as a second‐line agent for maximum androgen blockade (MAB) in patients with relapsing prostate cancer who received bicalutamide as the first‐line MAB agent. This study included 13 patients with progressive prostate cancer who had relapsed after first‐line MAB, with bicalutamide at 80 mg/day. After checking for antiandrogen withdrawal syndrome, they were given flutamide at 375 mg/day as second‐line MAB. The effectiveness of that therapy was evaluated by changes in prostatic specific antigen (PSA) levels, with response defined as a decrease of greater than 50% from the start of therapy. We also compared several factors between responders and non‐responders. Nine (69.2%) of the 13 patients showed a decrease in PSA levels, of whom five (38.5%) had a greater than 50% decrease and were defined as responders. The median duration of PSA response was 11.0 months (range 5–20 months). Patients who had a longer duration of response to first‐line MAB had a significantly greater response to second‐line MAB. For advanced prostate cancer patients who progressed on first‐line MAB with bicalutamide, flutamide administration as a second‐line antiandrogen was found to be relatively effective, especially for those who showed a longer duration of response to the first‐line MAB. Our results confirm previous findings that MAB using flutamide is an effective second‐line hormonal therapy.

Effect of Renal Transplantation on Sexual Function

This investigation was conducted to determine whether renal transplantation can improve sexual function in male patients with chronic renal failure. The authors retrospectively studied 121 men undergoing renal transplantation who complained of any type or degree of sexual dysfunction pre-operatively. Sexual function was evaluated by questionnaire which included erectile, ejaculative, and orgasmic functions. Pre- and postoperative frequency of sexual intercourse was also recorded. Patient characteristics, laboratory data, and endocrinologic profiles were analyzed to identify factors that might influence sexual function. In patients with hormonal determinations, results essentially normalized after transplantation. However, only 43 patients (35.5%) reported improvement of overall sexual function after renal transplantation, while 34 (28.1%) reported worsening. Although frequency of sexual intercourse was unaffected by transplantation, 15 of 20 patients who had no intercourse before transplantation initiated intercourse afterward. These 15 patients all underwent transplantation before 40 years of age. Comparisons of variables by sexual function showed significant differences for type of immunosuppressive treatment, interval after renal transplantation, and serum concentration of hemoglobin A1c. It is concluded that renal transplantation cannot improve sexual function in allpatients, although hormonal profiles were largely normalized, and that renal transplantation should be encouraged at a younger age.

Pharmacokinetics of bredinin in renal transplant patients.

SummaryA pharmacokinetic study of bredinin, a new immunosupressive agent, was carried out in 28 renal transplant patients. Serum bredinin concentration-time curves were analyzed using a one-compartment open model with a first order absorption process. The peak serum bredinin level appeared 2.4 h after oral administration of bredinin 50–200 mg. The calculated mean peak serum level was 0.852 µg/ml/mg/kg, when the dose was adjusted to the body weight of the patient. In the dosage range used of 0.85–4.46 mg/kg, a linear relationship was observed between the dose and the peak serum bredinin level. The elimination rate of bredinin from serum was dependent on kidney function, and the elimination rate constant was well correlated with the endogenous creatinine clearance. No circadian rhythm was apparent in the elimination rate constant. The absorption rate of bredinin from the gastrointestinal (GI) tract was affected by GI diseases. The need for dosage adjustment based on the renal function of the transplant patient is suggested.

A 20-year case study of a kidney transplant recipient with chronic active hepatitis C : Clinical course and successful treatment for late acute rejection induced by interferon therapy

BACKGROUND The influence of hepatitis C virus (HCV) infection has been discussed in kidney transplantation. Our case study focused on four points: the clinical course of an HCV-infected recipient; the pathogenesis of hepatic disorders in such a patient; interferon (IFN)-alpha therapy; and the risk of IFN-alpha therapy. METHOD A patient was suspected of acquiring HCV via transfusion at kidney transplant. He was examined several times serologically, virologically, endoscopically, and pathologically during a 20-year follow-up. RESULTS Abnormal biochemical markers were found within a month after transplantation but recovery occurred without any treatment. Within 3 years postoperatively, hepatic disorder developed including peliosis hepatis, nodular regenerative hyperplasia, and cholestasis. These pathological conditions were ascribed to immunosuppressants: cyclophosphamide and azathioprine. Abnormal chemical markers decreased to normal values for 4 consecutive years with the substitution of cyclophosphamide and azathioprine for mizoribine. During the subsequent 13 years, the patient developed chronic hepatitis with clinical and morphological features of hepatitis C infection. Anti-HCV antibody was positive from the second post-transplant year and HCV genome was detected in the 17th year. IFN-alpha therapy was initiated in the 17th year and resulted in normal transaminase activities with no effect on viremia. However, acute cellular rejection developed. The rejection was steroid resistant but responsive to OKT3. CONCLUSION HCV might remain latent for approximately 7 years even in kidney recipients unless toxic hepatitis occurs. Hepatotoxic drugs may cause a wide spectrum of liver diseases in HCV carriers as a result of the overload of immunosuppressants on hepatocytes. IFN-alpha could induce acute cellular rejection even in the 17th year. Such acute rejection can be reversible with OKT3.

The significant effect of HLA-DRB1 matching on long-term kidney graft outcome.

Serotyping and genotyping (polymerase chain reaction with sequence-specific oligonucleotide probes method) were conducted on 520 unrelated individuals to determine the linkage disequilibrium of HLA-B and HLA-DRB1. Analyses of 511 kidney transplants (300 related and 211 cadaver recipients) were carried out at 4 transplant centers using the linkage disequilibrium of HLA-B and HLA-DRB1 established previously. All transplant recipients received CsA immunosuppression and were transplanted from June 1983 to December 1991. There were 51 significant linkages formed between HLA-B and HLA-DRB1 alleles (P<0.05). DRB1-compatible transplants experienced a comparable 5-year graft success rate of 94% as did the HLA-identical recipients with a 100% 5-year success rate. However DRB1-incompatible recipients displayed a significantly reduced 5-year graft survival rate of 73% (73% vs. 94% P<0.01). The 5-year graft survival rate of HLA-DR-incompatible recipients of 71% was compatible to the 73% for HLA-DRBl-incompatible recipients. No variation of rejection rate for DRB1-compatible grafts was seen in any of the 4 transplant centers. The results also indicated that HLA-DRB1 compatibility was essential for optimal success rate, regardless of HLA class I mismatches. The overall conclusion was that matching for HLA-DR was important to achieve optimal kidney graft survival on the molecular level but not on the serotyping level.