Mechanism underlying the negative effect of prostate volume on the outcome of extensive transperineal ultrasound-guided template prostate biopsy.

Previous studies have indicated a possible relationship between increased prostate volume (PV) and decreased biopsy yield, although the mechanism involved is unclear. We evaluated 1650 patients who underwent template biopsy. The distribution of 993 cancer lesions in 302 prostatectomy specimens was compared with the biopsy data to determine whether each lesion was detected. A receiver operating characteristic (ROC) model was used to determine the diagnostic accuracy of prostate-specific antigen (PSA) and related markers. A medical record number (MRN) was used as a negative control. The cancer positive rate did not change as PSA increased in patients with PV ≥50 mL (P = 0.466), although it increased as PSA increased in patients with PV<50 mL (P = 0.001). The detection rate of cancer lesions decreased as the diameter of the lesions decreased (P = 0.018), but remained unchanged with respect to PV. The diameters of the maximum lesions in patients with PV ≥ 50 mL were significantly smaller than those in patients with PV<50 mL (P = 0.003). In patients with PV ≥ 50 mL, the areas under the ROC curves for PSA-related markers did not differ significantly from that for MRN, although they were significantly greater than that for MRN in patients with PV<50 mL (P < 0.001). These results suggest that an increase in PV is associated with a decrease in size and detectability of cancer lesions resulting in a decrease in biopsy yield. Loss of diagnostic accuracy of markers in patients with PV ≥ 50 mL indicates a decrease in serum levels of PSA produced by prostate cancer, which suggests growth inhibition of the cancer.

[A case of advanced renal cell carcinoma with inferior vena cava thrombus treated with sunitinib as neoadjuvant therapy].

A 70 year old woman had a right renal tumor with vena cava thrombus up to right atrium. We started medical treatment with sunitinib at a dose of 50 mg as neoadjuvant therapy. In 2 months, the vena cava thrombus shrank to the same level of the diaphragm. After stopping sunitinib for 2 weeks, a nephrectomy and thrombectomy was performed with extracorporeal circulation. Pathological diagnosis was clear cell carcinoma, G2. The TNM stage was pT3bN0M0. There were no viable cells at the tip of the thrombus. There is no recurrence during 9 months after the operation. Although we had to stop medication due to thrombocytopenia, it was possible to continue to take sunitinib for 3 months and achieved the operation. Because of down-staging of the tumor thrombus, we didn't have to do thoracic surgery. These results suggest that neoadjuvant therapy with molecular target drug may reduce surgical invasion.

A case of progressive thrombotic microangiopathy after ABO-incompatible renal transplantation.

A 21-yr-old man of blood type O receiving hemodialysis for IgA nephropathy underwent living-related ABO-incompatible (ABOI) renal transplantation from his mother, whose blood type is A. He was negative for flow cross-match, anti-human leukocyte antigen (HLA) antibody, and anti-MICA antibody. Pre-treatment anti-A IgG titer was 1:256. Desensitization consisted of tacrolimus, mycophenolate mofetil, methylprednisolone, rituximab, and plasmapheresis. He developed acute antibody rejection at day 2 post-transplant, which was successfully treated. After renal artery reconstruction surgery at day 91 for renovascular hypertension caused by renal artery stricture, the patient suffered from acute prostatitis, which subsequently induced type III acute antibody-mediated rejection. Even after recovery from the rejection after temporary hemodialysis, graft function progressively deteriorated and consecutive allograft biopsy showed progressive thrombotic microangiopathy (TMA) without any evidence of donor-specific antibody other than anti-A antibody. The tacrolimus dose was kept low for fear of tacrolimus-induced TMA. Despite these efforts, the patient resumed hemodialysis six months' post-transplant.

CXC chemokine ligand (CXCL) 9 and CXCL10 are antagonistic costimulation molecules during the priming of alloreactive T cell effectors.

Donor Ag-reactive CD4 and CD8 T cell production of IFN-gamma is a principal effector mechanism promoting tissue injury during allograft rejection. The CXCR3-binding chemokines CXCL9 and CXCL10 recruit donor-reactive T cells to the allograft, but their role during the priming of donor-reactive T cells to effector function is unknown. Using a murine model of MHC-mismatched cardiac transplantation, we investigated the influence of CXCL9 and CXCL10 during donor-reactive T cell priming. In allograft recipient spleens, CXCL9 and CXCL10 were expressed as early as 24 h posttransplant and increased with similar kinetics, concurrently with CXCR3 expression on T cells. CXCL9, but not CXCL10, expression required NK cell production of IFN-gamma. The absence of CXCL9 in donor allografts, recipients, or both significantly decreased the frequency of donor-reactive CD8 T cells producing IFN-gamma and increased the frequency of donor-reactive CD8 T cells producing IL-17A. In contrast, the absence of CXCL10 increased the frequency of IFN-gamma-producing CD8 T cells in a CXCL9-dependent manner. These data provide novel evidence that donor-reactive CD8 T cells use the CXCR3 chemokine axis as a costimulation pathway during priming to allografts where CXCL9 promotes the development of IFN-gamma-producing CD8 T cells, and CXCL10 antagonizes this skewing.

Clinicopathologic evaluation of short-term outcome after early corticosteroid discontinuation in kidney transplantation.

OBJECTIVES: Steroids have been a gold-standard drug of immunosuppressive regimens in kidney transplantation. Steroid minimization protocols have been applied to minimize the adverse effects of steroids. We have evaluated the short-term outcomes of our early steroid discontinuation regimen. METHODS: A total of 128 recipients who received kidney from ABO-compatible, flow crossmatch-negative living-related donors were included in this study. Immunosuppressive regimens consisted of tacrolimus (TAC), mycophenolate mofetil (MMF), and basiliximab. In a cohort of recipients, designated as a steroid early discontinuation (ESD) group, only three doses of methylprednisolone (MP) were given (500, 250, 125 mg). In the other cohort of recipients, designated as a chronic steroid (CS) group, MP was given chronically, being tapered to 4 mg at one month post-transplant. TAC and mycophenolic acid (MPA) blood levels were monitored. The following data were retrospectively compared between the two groups at 1, 3, 6, 9, 12 months post-transplant: serum creatinine (sCr), urine protein per gCr (uP/Cr), the incidence of biopsy-proven acute rejection (BPAR), graft survival (GS), area-under-the-curve of blood levels of tacrolimus (TAC-AUC(0-12), ng h/mL) and mycophenolic acid (MPA-AUC(0-12), mug h/mL), MMF dose (mg), the incidence of opportunistic infection, post-transplant diabetes mellitus (PTDM), and histopathologic findings of protocol biopsy according to the Banff '07 classification. RESULTS: sCr and uP/Cr were comparable between the two groups up to 12 months except for sCr at one month (ESD group > CS group). TAC-AUC(0-12) was significantly higher in ESD group at one month but was equivalent thereafter, while the prevalence of biopsy-proven tubulotoxicity was not different. MMF dose was comparable throughout the period between two groups. The incidence of BPAR until 12 months was equivalent. Of note, 60% of BPAR cases in ESD group occurred within one month. Prevalence of opportunistic infection or PTDM was equivalent. Graft survival was 100% in both groups. The following histopathologic scores up to 12 months were also equivalent: t, i, g, v, ci, ct, cg, cv, mm, ah, and ptc. CONCLUSIONS: Favorable short-term outcomes were achieved both clinically and histologically using our early steroid discontinuation protocol compared with the conventional protocol with chronic steroid treatment.

Monokine induced by interferon-gamma (MIG/CXCL9) is derived from both donor and recipient sources during rejection of class II major histocompatibility complex disparate skin allografts.

Chemokines, including monokine induced by interferon-gamma (Mig/CXCL9), are produced both in allografts and during the direct T-cell infiltration that mediates graft rejection. Neither the specific production nor contribution of allograft donor versus recipient Mig in allograft rejection is currently known. C57BL/6 mice with a targeted deletion in the Mig gene were used as both skin allograft donors and recipients in a class II major histocompatibility complex-mismatched graft model to test the requirement for donor- versus recipient-derived Mig for acute rejection. B6.Mig(-/-) allografts had a 10-day prolonged survival in B6.H-2(bm12) recipients when compared with wild-type C57BL/6 allograft donors, and B6.H-2(bm12) skin allografts had a 5-day prolonged survival in B6.Mig(-/-) versus wild-type recipients. Transplantation of B6.Mig(-/-) skin grafts onto B6.H-2(bm12).Mig(-/-) recipients resulted in further prolonged allograft survival with more than 30% of the grafts surviving longer than 60 days. Prolonged allograft survival was also associated with delayed cellular infiltration into grafts but not with altered T-cell proliferative responses to donor stimulators. Immunohistochemical staining of allograft sections indicated that Mig is produced by both donor- and recipient-derived sources, but Mig from each of these sources appeared in different areas of the allograft tissue. These results therefore demonstrate the synergy of donor- and recipient-derived Mig in promoting T-cell infiltration into allografts.

Lower urinary tract symptoms and their impact on quality of life after successful renal transplantation.

OBJECTIVE: To investigate lower urinary tract symptoms (LUTS) and their impact on quality of life (QOL) in patients having undergone renal transplantation (RTX). METHODS: Forty-three patients (25 males and 18 females; age 20-68 years) undergoing RTX at Hokkaido University Hospital were included in this study. Median follow-up after RTX was 41 months (range 6-184). Pre-transplant dialysis had been carried out in 38 patients (median: 4.3 years, range: 1 month-31 years). All patients were assessed by uroflowmetry (UFM), postvoid residual urine volume (PVR), 24 h bladder diary, and International Prostate Symptom Score (IPSS). QOL score and King's Health Questionnaire (KHQ) were used for the assessment of LUTS-related QOL. RESULTS: Mean fluid intake volume and urine output volume for 24 h were 2136 mL (1150-3430 mL) and 2446 mL (1336-4733 mL), respectively. Voiding dysfunction assessed by UFM and PVR was observed in 12 patients (28%) showing higher IPSS. QOL score and overall QOL in KHQ were not different between patients with and without voiding dysfunction. Although 19 (49%) had polyuria, 20 (51%) had nocturnal polyuria, which affected nocturia in IPSS as well as sleep/energy disturbances in KHQ compared with patients without nocturnal polyuria. CONCLUSIONS: Patients having RTX frequently present voiding dysfunction and nocturia basically caused by nocturnal polyuria. We should focus on LUTS in these patients to provide an appropriate management.

Pediatric kidney transplantation is safe and available for patients with urological anomalies as well as those with primary renal diseases.

The aim of the current study was to evaluate long-term outcomes of pediatric live kidney transplantation in patients with genitourinary anomalies relative to those with primary kidney diseases. The study included 35 pediatric patients who received a live kidney transplantation during the last 25 yr (28 males, six females). Median age at the time of transplantation was nine yr (range 1-15 yr), and the median follow-up period was 151 months (range 6-239 month). The patients were divided into two groups. The urological group (n = 14) included patients with primary obstructive/reflux nephropathy. The renal group (n = 20) included patients with primary renal disorders. Differences between groups in graft survival, clinical course, and final graft function were evaluated. Original diseases represented in the urological group included five cases with primary VUR and eight cases with secondary VUR. Diseases in the renal group included eight cases with bilateral hypo-dysplastic kidney, three cases with focal/segmental glomerular sclerosis, two cases with membranous proliferative glomerulonephritis, two cases with congenital nephrotic syndrome and five cases with other forms of chronic nephritis. Ten of 14 cases in the urological group, relative to six of 20 in the renal group, were preemptive. Median age at transplantation was 7.5 or 10 yr old, respectively, in the urological or renal group. Twelve kidney recipients in the urological group had also undergone other urinary surgeries, including upper urinary tract drainage, ureteroneocystostomy, augmentation cystoplasty, endoscopic incision of posterior-urethral valve, urethroplasty, etc. Cumulative post-operative complications occurred in nine or 16, respectively, in the urological or renal group. The acute rejection free and overall graft survival were similar in both groups. One patient in the urological group lost his graft while six patients in the renal group lost their grafts. Thus, the post-transplant clinical outcome of pediatric transplantation in patients with urological anomalies is comparable to that of recipients with primary renal disease. Appropriate urinary tract reconstruction and management is essential to reduce the risk of graft dysfunction because of urinary problems.

Cathepsin g is required for sustained inflammation and tissue injury after reperfusion of ischemic kidneys.

Neutrophil activation to release granules containing proteases and other enzymes is a primary cause of tissue damage during ischemia/reperfusion injury. Because the contribution of specific granule enzymes to this injury remains poorly defined, the role of cathepsin G in renal ischemia/reperfusion injury was tested. Bilateral renal ischemia led to the expiration of 64% of wild-type mice within 4 days of reperfusion, whereas all cathepsin G-deficient mice survived. Serum creatinine increased to similar levels at 24 hours after reperfusion and then decreased to background in both groups of mice. Ischemic kidneys from both groups had similar levels of neutrophil infiltration and of CXCL1, CXCL2, and myeloperoxidase protein 9 hours after reperfusion, but at 24 hours, these acute inflammatory response components were decreased more than 50% in kidneys from cathepsin G-deficient versus wild-type mice. Ischemic kidneys from surviving wild-type mice had severe tubular necrosis and tubular cell apoptosis 24 hours after reperfusion with subsequent development of fibrosis 30 days later. In contrast, ischemic kidneys from cathepsin G-deficient mice had a 70% decrease in tubular cell apoptosis with little detectable collagen deposition. These data identify cathepsin G as a critical component sustaining neutrophil-mediated acute tissue pathology and subsequent fibrosis after renal ischemia/reperfusion injury.

[Relationship between dose of mycophenolate mofetil and the occurrence of cytomegalovirus infection and diarrhea in renal transplant recipients].

To establish guidelines for avoiding the side effects of mycophenolate mofetil (MMF) in renal transplant recipients with tacrolimus (TAC)-based immunosuppression, the relationship between the daily dose of MMF and the occurrence of side effects was analyzed in this study. The frequency of side effects was investigated retrospectively in 28 renal transplant recipients treated with immunosuppression (men 14 : women 14, age: 33.0+/-12.4 years, weight: 50.9+/-10.7 kg). Cytomegalovirus (CMV) infection and diarrhea were the most frequent side effects in the early transplant phase (from transplantation to 3-month biopsy) in the recipients. In 18 recipients, excluding the recipients with risk factors for CMV infection (ABO-incompatible transplantation, donor (+)/recipient (-) CMV serostatus, etc.), no significant correlation was shown between the daily dose of MMF and the occurrence of CMV infection in the two-sample t-test. On the other hand, the daily dose in the diarrhea group (33.2+/-4.3 mg/kg/day, n = 5) was significantly higher than that in the no-diarrhea group at 30 days (28.4+/-3.7 mg/kg/day, n = 23, p < 0.05) and 90 days (25.7+/-4.4 mg/kg/day, n = 21, p < 0.005) after transplantation, respectively. The receiver-operating characteristic (ROC) curve also revealed that the risk of diarrhea increased with a daily MMF dose higher than 30 mg/kg/day. In conclusion, to decrease the risk of diarrhea in the early transplant phase in renal transplant recipients with TAC-based immunosuppression, the daily dose of MMF should not be more than 30 mg/kg/day.