Masahiro Kyo

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.

Prevalence, characteristics, and outcome of BK virus nephropathy in Japanese renal transplant patients: analysis in protocol and episode biopsies

Abstract:  Background:  BK virus nephropathy (BKN) is recognized as a cause of graft loss in renal transplant patients. This may be related to the introduction of new and potent immunosuppressive regimens. In Japan, our experience regarding its prevalence, clinical significance, and outcome is still limited. In this study, our primary purpose is to outline the prevalence, outcome, and clinical characteristics of BKN as observed at Osaka University Hospital.

Factors influencing vertebral bone density after renal transplantation

Abstract To improve our understanding of the mechanisms underlying osteoporosis following renal transplantation, we compared bone mineral density (BMD) in 158 transplant recipients and in 293 patients undergoing maintenance hemodialysis with age‐ and sex‐matched normal controls. Observations in graft recipients were made up to several years following transplantation. Dual‐energy X‐ray absorptiometry was used to measure BMD. Correlations with clinical variables including serum concentration of parathyroid hormone (PTH) and steroid therapy were evaluated. Lumbar BMD was lower in transplant patients than in dialysis patients at all ages, and continued to decrease with increasing interval posttransplant until the second year after transplantation. Persistent hyperparathyroidism and daily prednisolone dosage were both associated with decreased BMD. Age and creatinine clearance were independent long‐term predictors of BMD by multiple regression analysis. Treatment of renal graft recipients with calcium and vitamin D supplements or calcitonin may be indicated in the early months after transplantation.

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.

Association of treatment with 15-deoxyspergualin and BK virus nephropathy in kidney allograft recipients

Abstract:  Objective:  BK virus nephropathy (BKVN) has been proposed as an important cause of allograft dysfunction and loss in kidney allograft recipient over the last decade. Intense immunosuppression and tubular injury have been shown to promote the replication of polyomavirus. 15‐deoxyspergualin (DSG), an effective immunosuppressive agent, is used as a rescue drug for acute rejection in clinical renal transplantation in Japan. To determine whether DSG is a risk factor for BKVN and outline the relationship among BKVN, DSG, and other risk factors, we analyzed 88 patients who received living‐related renal transplantation between January 1999 and April 2003.

Prevalence of the metabolic syndrome in kidney transplantation.

OBJECTIVES We investigated the prevalence of the metabolic syndrome (MS) in kidney transplantation patients and assessed its development based on plasma adiponectin levels and the results of an oral glucose tolerance test (OGTT). METHODS We performed a cross-sectional study of 94 recipients with stable graft function who underwent kidney transplantation between January 1999 and October 2008. The presence of MS was determined using National Cholesterol Education Program Adult Treatment Panel III (NCEP-ATP III) criteria with body mass index (BMI) used in place of waist circumference. In addition, we measured plasma adiponectin level and performed a 75-g oral GTT. RESULTS Fourteen (14.9 %) recipients suffered from MS for a mean period of 46.7 months (range, 1-106) after transplantation. BMI at the time of transplantation was significantly greater in the MS group (23.4 +/- 3.24 vs 20.1 +/- 2.50; P < .0001), whereas plasma adiponectin level was significantly lower (11.95 +/- 5.13 vs 17.71 +/- 8.47; P = .0158). The insulinogenic index values were similar, whereas the homeostatic model assessment of insulin resistance was greater in the MS group (2.598 +/- 1.918 vs 1.340 +/- 0.934; P = .0002). CONCLUSION The level of adiponectin, which was lower in kidney transplant recipients who developed MS, was negatively correlated with insulin sensitivity. We concluded that a low adiponectin level may correlate with the prevalence of MS in kidney transplantation in association with impaired insulin sensitivity.

Low-dose tacrolimus (FK506)-based immunosuppressive protocol in living donor renal transplantation

Abstract In order to avoid the side effects of tacrolimus (FK506), a low‐dose FK506‐based regimen was started from 1 June 1991. The dose was adjusted to maintain the FK506 whole blood trough level at 15–20 ng/ml for 7 days postoperatively, at 10–15 ng/ml for 2 months, and under 10 ng/ml thereafter. The graft survival rates at 3 years and 5 years were 87.8 and 82.3 % (FK506) vs 86.8 and 86.8% [cy‐closporine (CyA)]. The incidence of acute rejection within the first 90 days was 31.6% in the FK506 group which was lower than the 57.1% of the CyA group (P ‐ 0.0585). Grades of acute rejection episodes over IIA in the FK506 group were 20 %, which was lower than the 37 % in the CyA group. The mean oral dosages of FK506 were 0.061 and 0.04 mg/kg per day at 3 and 5 years, respectively. The incidence of new onset diabetes was 27.8% in the FK506 group and 17.1 % in the CyA group. However, insulin therapy was withdrawn in all patients of the FK506 group within 5 months. The percentage of patients who required an antihypertensive agent was 28.6 % and 40 % in the FK506 group and 73.2% and 88 % in the CyA group at 1 and 3 years, respectively (P < 0.05). Nephrotoxicity was seen in 20% of the FK506 group and 14.3 % of the CyA group. Hypercholesterolemia was less frequent in the FK506 group than the CyA group. The FK506‐based regimen described here is a protocol with the potential to reduce its adverse effects. The whole blood concentration of FK506 should be monitored and blood levels maintained in the range of 5–10 ng/ml after 90 postoperative days for optimal efficacy and minimal toxicity.

Extracorporeal Shock Wave Lithotripsy for Ureteral Stones Using the Dornier Lithotriptor MFL5000

A total of 157 ureteral stones in 150 patients were treated by extracorporeal shock wave lithotripsy (ESWL) using the Dornier lithotriptor MFL5000. Stones were treated in situ in 149 cases and with a double-J ureteral stent bypass in 8 cases due to large stone burden or failure of the preceding in situ ESWL. The average number of ESWL sessions and shock waves were 1.6 and 4,446, respectively. Multiple sessions were required in 58 cases (36.9%) for satisfactory fragmentation. At a 3-month follow-up, 91.7% of the cases treated by in situ ESWL and 50% of those treated with a stent bypass were rendered stone-free, achieving an overall stone-free rate of 89.4%. Ureteroscopic extraction or open ureterolithotomy was performed in 4 cases with an impacted stone for the removal of the residual fragments. No serious complications related to ESWL were observed. In situ ESWL is an effective and noninvasive method of treating ureteral stones. Large and/or impacted stones can also be successfully treated by ESWL with or without a stent bypass, but ureteroscopic or surgical procedures may be necessary to salvage fragments packed in the ureteral edema.

A case of relapse of C-ANCA-associated glomerulonephritis in post-transplant patients

We experienced a case of relapse of proteinase 3‐specific antineutrophil cytoplasmic autoantibody (C‐ANCA)‐associated rapid progressive glomerulonephritis (RPGN) in a patient after renal transplantation. A 19‐yr‐old man, who underwent a living donor kidney transplantation, presented a rapid renal function deterioration along with a sign of infection. Initially he was treated as acute rejection, but renal function did not improve. Renal biopsy revealed crescentic glomerulonephritis, and C‐ANCA titer was 12 EU/mL, resulting in the diagnosis of C‐ANCA‐associated RPGN. He was treated with three consecutive methylprednisolone pulses twice in addition to the basal immunosuppressive medications (cyclosporine A and mizoribine), then his renal function improved to normal. Bearing the possibility of recurrence of glomerulonephritis in mind, we re‐evaluated the nature and disease course of renal failure of original kidney. He experienced a rapid deterioration of renal function in 1992, and eventually CAPD was started in 1992. His serum in 1992 revealed high titer of C‐ANCA (24 EU/mL), and renal biopsy performed in 1992 showed a crescentic glomerulonephritis. Taken together, we diagnosed this event as a relapse of C‐ANCA‐associated GN. 
Lessons from our experience are: 1) steroid pulse and high‐dose corticosteroid therapy may be useful for the treatment of relapse of C‐ANCA‐associated GN patients after renal transplantation; 2) the possibility of a relapse of C‐ANCA‐associated GN following renal transplantation has to be kept in mind, especially when infection precedes the deterioration of allograft kidney function.