Hayakazu Nakazawa

Long-term results of ABO-incompatible living kidney transplantation: a single-center experience.

Background. Despite great efforts to promote the donation of cadaveric organs, the number of organ transplantations in Japan is not increasing and a serious shortage of cadaveric organs exists. These circumstances have forced a widening of indications for kidney transplantation. For this purpose, ABO-incompatible living kidney transplantations (LKTs) have been performed. Although we have already reported the short-term results of ABO-incompatible LKT, there is no report of long-term results in such cases; anti-A and anti-B antibodies could cause antibody-induced chronic rejection and result in poor long-term graft survival. In this study, we have reviewed the long-term results of ABO-incompatible LKT and tried to identify the most important factors for long-term renal function in ABO-incompatible LKT. Methods. Sixty-seven patients with end-stage renal failure underwent ABO-incompatible living kidney transplantation at our institute between January, 1989, and December, 1995. The mean age was 34.9 years (range, 8-58 years), with 38 males and 29 females. Incompatibility in ABO blood group antigens was as follows: A1<O, 23 patients; B→O, 19 patients; A1B→A1, 7 patients; B→A1, 8 patients; A1→B; 4 patients; A1B<B, 4 patients; A1B→O, 2 patients. The number of HLA-AB, and -DR mismatches were 1.6±1.1 and 0.76±0.6, respectively. Plasmapheresis and immunoadsorption were carried out to remove the anti-AB antibodies before the kidney transplantation. In the induction phase, methylprednisolone, cyclosporine, azathioprine, antilymphocyte globulin, and deoxyspergualin were used for immunosuppression. Local irradiation of the graft was performed at a dose of 150 rad, on the first, third, and fifth days after transplantation. Splenectomy was done at the time of kidney transplantation in all cases. Results. Patient survival was 93% at 1 year and 91% at 8 years. Graft survival was 79% at 1, 2, 3, and 4 years, 75% at 5 and 6 years, and 73% at 7 and 8 years. Patient survival was not significantly different from that of ABO-compatible patients. However, graft survival was significantly different between ABO-incompatible grafts and ABO-compatible grafts. Specifically, ABO-incompatible transplant recipients experienced a significantly higher rate of early graft loss up to 3 years but showed an equivalent graft loss by year 4. Among 67 patients, 16 grafts were lost during the observation period. Loss was due to acute rejection in 5 patients, followed by chronic rejection in 5 patients and death with function in 3 patients, whereas immunosuppression was withdrawn in 3 patients due to nonimmunological reasons. Of 16 grafts lost, 15 were lost within 1 year after transplantation. Of the 67 patients, 5 died during observation. Three patients with functioning grafts died of uncontrolled bleeding due to duodenal ulcer, malignant lymphoma, and cerebral hemorrhage (one patient each). One patient died of ischemic colitis due to secondary amyloidosis and one patient of cerebral hemorrhage after graft loss due to humoral rejection. There was no fatal infectious complication, whereas 10 patients had non-tissue-invasive cytomegalovirus infection. The stepwise logistic regression model was employed to identify the most important factors for long-term renal function.

Key predictive factors of axitinib (AG-013736)-induced proteinuria and efficacy: A phase II study in Japanese patients with cytokine-refractory metastatic renal cell Carcinoma

BACKGROUND Axitinib (AG-013736) is an oral, selective and potent inhibitor of vascular endothelial growth factor receptors (VEGFR)-1, 2 and 3. This phase II study investigated axitinib efficacy, safety and biomarkers in Japanese patients with cytokine-refractory metastatic renal cell carcinoma (mRCC). PATIENTS AND METHODS In an open-label, multicentre study, 64 patients received an axitinib starting dose of 5mg twice daily. RESULTS Objective response rate (ORR) was 50.0% and median progression-free survival (PFS) was 11.0 months per independent review committee. Common treatment-related adverse events were hypertension (84%; 70% grade ≥3), hand-foot syndrome (75%; 22% grade ≥3) and diarrhoea (64%; 5% grade ≥3). Eighteen patients (28%) developed proteinuria ≥2g/24h and required dose reduction or treatment interruption/discontinuation. Proteinuria was a major cause for treatment discontinuation. Baseline urine protein levels were associated with development of proteinuria ≥2g/24h (hazard ratio [HR]=5.457, P=0.0035 in patients with baseline proteinuria ≥1+ versus <1+). Baseline urine protein levels correlated more strongly with axitinib-related proteinuria than other baseline renal function test values or blood pressure. Patients with greater decreases in soluble VEGFR-2 concentrations had significantly higher ORR and longer PFS than those with smaller decreases (ORR: 64.5% versus 37.5%, P=0.045; median PFS: 12.9 months versus 9.2 months, HR=0.42, P=0.01). CONCLUSIONS Axitinib showed significant antitumour activity and was well tolerated in Japanese mRCC patients. Baseline proteinuria and soluble VEGFR-2 levels may be key indicators of axitinib-induced proteinuria and efficacy, respectively.

Favorable prognosis of renal cell carcinoma with increased expression of chemokines associated with a Th1-type immune response.

The potential role of chemokines in clinical tumors remains poorly understood. Recent investigations have shown the differential expression of chemokine receptors on lymphocytes mediating Th1‐ and Th2‐type immune responses. We examined Th1‐ and Th2‐associated cytokines and chemokines, as well as the expression of their receptors in tumor‐infiltrating lymphocytes in renal cell carcinoma (RCC). Sixty‐seven patients with sporadic RCC were analyzed for the expression of Th1‐ and Th2‐associated genes using real‐time polymerase chain reaction. Tumor infiltration by CXC chemokine receptor 3 (CXCR3)‐positive and CC chemokine receptor 5 (CCR5)‐positive cells was detected by immunohistochemistry and by flow cytometry. The expression of Th1‐associated genes was significantly increased in tumors compared to normal kidney tissues. The expression of interferon‐γ correlated positively with that of Th1 chemokines. Tumors expressing higher Th1 chemokines did not recur after curative surgery. Multivariate analysis showed that increased monokine induced by interferon (IFN)‐γ (MIG) expression was an independent favorable prognostic factor. Immunohistochemistry showed that the degree of CXCR3‐positive cell infiltration significantly correlated with IFN‐γ inducible protein 10, MIG and IFN‐γ‐inducible T cell a chemoattractant expression (I‐TAC). Flow cytometric analysis showed increased expression of CXCR3 and CCR5 in tumor‐infiltrating T lymphocytes compared to that in peripheral blood T cells. These results suggest that upregulation of the Th1‐type immune response in RCC tumors with a favorable prognosis may be mediated by Th1‐associated chemokines. Integrity of the Th1‐type immune response seems to be required for tumor regression, suggesting that detection and correction of a defect in the Th1‐type response cascade would thus be one of the main targets for tailor‐made immunotherapy and gene therapy in RCC. (Cancer Sci 2006; 97: 780–786)

Template-based lymphadenectomy in urothelial carcinoma of the upper urinary tract: Impact on patient survival

Objectives:  The benefit of lymphadenectomy (LND) in patients with urothelial carcinoma of the upper urinary tract (UCUUT) has remained controversial. The aim of this study was to examine the influence of the LND template and the total number of lymph nodes (LN) when increasing the number of patients undergoing complete dissection of regional nodes (CompLND).

Spoke‐wheel‐like enhancement as an important imaging finding of chromophobe cell renal carcinoma: A retrospective analysis on computed tomography and magnetic resonance imaging studies

Aim:  Little information has been reported with regard to the radiological features of chromophobe cell renal carcinomas (CCRC). The aim of the present study was to identify imaging characteristics which lead to the histological diagnosis of CCRC.

Prevalence of renal cell carcinoma: A nation-wide survey in Japan, 2002

Objective:  To investigate the incidence of renal cell carcinoma, classified by sex, age group and region in Japan, following a 5‐year interval after a previous survey performed in 1997.

The prevalence of renal cell carcinoma: A nation‐wide survey in Japan in 1997

Abstract Background: The present study was conducted to investigate the incidence of renal cell carcinoma by sex, age group and different regions in Japan.

Long-Term Outcome of Renal Transplantation in Hepatitis B Surface Antigen-Positive Patients in Cyclosporin Era

The impact of hepatitis B virus (HBV) infection on the outcome of renal transplantation (Tx) has been controversial. To determine the indication of renal Tx in patients infected by HBV, we investigated the long-term outcome of renal transplant patients with hepatitis B surface antigen (HBsAg). We analyzed 980 patients, including 18 HBsAg carriers, who underwent renal Tx and were immunosuppressed with cyclosporin in our institute. Fourteen out of 18 patients (77.8%) showed hepatic dysfunction after an average period of 17.8 months (range 1-65) after Tx. Four out of 14 patients (28.5%) with hepatic dysfunction died of liver failure due to fulminant hepatitis with functioning grafts between 15 and 71 months after Tx. The remaining 10 patients with hepatic dysfunction are alive up to the time of last follow-up; however, 5 of them lost their grafts because of rejection between 44 and 92 months after Tx. Their liver function improved after withdrawal of cyclosporin. Only 4 patients did not develop chronic liver disease and have had functioning grafts for between 44 and 147 months. One patient died of subarachnoid hemorrhage 22 months after Tx. HBe antigen, antibody and HCV antibody status were not related to the occurrence of liver dysfunction after Tx. Four HBV-DNA-positive patients showed deteriorated liver function. Three patients with chronic active hepatitis confirmed by the biopsy were treated with interferon. Interferon improved liver function in 2 patients, however, 1 patient died of liver failure despite interferon therapy. Our data suggested that the presence of HBsAg is often associated with chronic liver disease leading to liver failure regardless of HBe and HCV status after Tx. The indication of renal Tx in patients with HBsAg should be determined carefully giving consideration to these results.

Clinical Results and Pharmacokinetics of Sorafenib in Chronic Hemodialysis Patients with Metastatic Renal Cell Carcinoma in a Single Center

OBJECTIVE We investigated the safety and feasibility of sorafenib in patients with end-stage renal disease undergoing hemodialysis by examining the influence of pharmacokinetic parameters to their benefit and also the occurrence of drug-related adverse events of sorafenib. METHODS Ten patients with metastatic renal cell carcinoma undergoing hemodialysis received sorafenib. Initial dose was 200 mg once daily, and the dose was increased up to the maintenance dose of 200 mg twice daily. The pharmacokinetic study was performed after a steady state was reached with 200 mg twice daily in six patients. RESULTS Complete response occurred in one patient, partial response in three, stable disease in four and progressive disease in two. Median progression-free survival was 6.3 months. Serious adverse events were found in nine patients, including a Grade 5 subarachnoid hemorrhage and a Grade 4 cerebellar hemorrhage. In the pharmacokinetic study, the geometric mean of maximum concentration and area under the curve from 0 to 10 h of plasma concentration were similar on the day of hemodialysis and the day off hemodialysis. These data were lower than those from Japanese people with healthy kidneys and normal kidney function. There was no association between objective response or the occurrence of serious adverse events and pharmacokinetic parameters. CONCLUSIONS Treatment with sorafenib of patients with metastatic renal cell carcinoma undergoing hemodialysis appears to be feasible, but we express some concern about the higher incidence of serious adverse events even with the reduced dose. However, clinical efficacy was not compromised.

Impact of arterial occlusion during partial nephrectomy on residual renal function: an evaluation with (99m)technetium-dimercaptosuccinic acid scintigraphy.

Background: Partial nephrectomy (PNx) has been performed with temporary renal arterial occlusion and in situ renal hypothermia (conventional PNx). However, the impact of temporary renal arterial occlusion on residual renal function has not been well assessed. To address this question, we performed renal scintigraphy with 99mtechnetium‐dimercaptosuccinic acid (DMSA) for the quantitative measurement of postoperative residual renal function after conventional PNx and partial nephrectomy without arterial occlusion (non‐clamping PNx).