Single-Needle Intensive Granulocyte and Monocyte Adsorptive Apheresis Is Suitable for Elderly Patients With Active Ulcerative Colitis Taking no Corticosteroids or Biologics.

Twice-weekly intensive granulocyte/monocyte adsorptive apheresis is effective and safe for ulcerative colitis, but maintaining two blood access routes is problematic. We previously reported that intensive granulocyte/monocyte adsorptive apheresis using a single needle in ulcerative colitis is effective and safe. We hypothesized that the efficacy and safety of single-needle intensive granulocyte/monocyte adsorptive apheresis for ulcerative colitis would especially benefit the elderly. We enrolled 17 elderly ulcerative colitis patients to receive single-needle intensive granulocyte/monocyte adsorptive apheresis, 27 elderly ulcerative colitis patients to receive double-needle intensive granulocyte/monocyte adsorptive apheresis, and 52 nonelderly ulcerative colitis patients to receive single-needle intensive granulocyte/monocyte adsorptive apheresis. Remission and mucosal healing rates after treatment did not differ significantly between elderly ulcerative colitis patients receiving single-needle apheresis and the other two groups. In addition, no serious adverse effects, including blood clots, were observed in single-needle intensive granulocyte/monocyte adsorptive apheresis patients. Single-needle intensive granulocyte/monocyte adsorptive apheresis might be a novel alternative therapeutic option for elderly ulcerative colitis patients before considering corticosteroids.

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

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. METHODS: A total of 114 biopsy specimens from 88 living-related kidney transplantation recipients (performed between January 1999 to April 2003) were retrospectively analyzed. Patients received immunosuppression therapy based on calcineurin inhibitors and corticosteroid [tacrolimus (TAC) 33 and cyclosporin (CyA) 55]. Additionally, mycophenolate mofeteil (MMF) was used in 21 patients; DSG was used in seven patients; and anti-CD3 monoclonal antibody was used in 16 patients. We analyzed the degree of donor/recipient human leucocyte antigen (HLA) compatibility assessed by the number of HLA-A, -B, and -DR-mismatched antigens in 88 patients. The diagnosis of BKVN was made by the light microscopic examination and a positive immunohistochemical staining of anti-40 antibody in biopsy specimens. Patients were divided into two groups of group A (mild histological change) and group B (moderate or severe histological change) to determine the risk factors in different histological staging. The clinical course of two typical patients in different histological stage is described briefly to outline the risk factors of BKVN. RESULTS: We identified seven cases of BKVN (8.0%) from 88 transplanted patients. Significantly higher incidence of combination regimen consisting of TAC and MMF in BKVN group was noticed compared with non-BKVN group (57.1% vs. 9.9%; p = 0.003). BKVN was associated with a significantly higher incidence of DSG administration compared with non-BKVN group (57.1% vs. 3.7%; p

Erythropoietin protects the kidneys against ischemia reperfusion injury by activating hypoxia inducible factor-1alpha.

BACKGROUND: Ischemia/reperfusion (I/R) injury is closely associated with tissue damage in various organs, as well as in kidney transplants. Erythropoietin (EPO) has been shown to have a cytoprotective effect against hypoxia. We examined the effect of EPO against renal I/R injury and the underlying mechanism. METHODS: Human umbilical vein endothelial cells and human renal proximal tubular epithelial cells were cultured under hypoxic conditions with various EPO concentrations at 37 degrees C and examined the mechanism of cell proliferation by EPO. Moreover, to demonstrate the renoprotective effect in vivo, we treated Sprague-Dawley rats with 100 IU/kg EPO every 2 days for 2 weeks (a total of 6 doses). One day after the last injection, the operations to produce renal I/R injury (bilateral renal occlusion for 60 min) were done, and rats were killed at the end of the reperfusion period (24 hr and 72 hr after reperfusion began). RESULTS: First, we demonstrated in vitro that EPO increased hypoxia inducible factor-1alpha (HIF-1alpha) expression and stimulated proliferation of both cells under hypoxic conditions. Next, we demonstrated in vivo that EPO treatment increased the number of HIF-1alpha-positive cells, and markedly induced the expression of vascular endothelial growth factor messenger RNA. Using pimonidazole, a molecular probe that detects hypoxia, we found that EPO markedly attenuated tubular hypoxia, and reduced the number of terminal transferase dUTP nick end labeling-positive apoptotic cells and alpha-smooth muscle actin-positive interstitial cells. CONCLUSIONS: We suggested a novel HIF-1alpha induction pathway by EPO under hypoxic conditions. Thus, EPO may protect the kidneys against ischemia reperfusion injury by activating HIF-1alpha.

Risk factors for malignancy in Japanese renal transplant recipients.

BACKGROUND: Among recipients of renal transplants, the incidences of renal cancer and gastrointestinal cancer are higher and that of skin cancer is much lower in Japan than in Europe and North America. METHODS: The risk factors for the development of malignant tumors were examined in Japanese recipients of renal transplants. A total of 556 patients underwent renal transplantation at the Department of Urology, Osaka University Faculty of Medicine between March 1, 1965, and April 31, 2004. Of these patients, 366 were retrospectively studied in whom risk factors potentially related to the development of malignancy could be evaluated on the basis of medical records. The incidence of malignancy, survival rate, and risk factors for malignancy were examined. RESULTS: The overall incidence of malignancy was 6.8% (25/366 patients). Six of the 25 patients with malignancy died of cancer, but there was no correlation between the occurrence of malignancy and the survival rate (P = .8058, log-rank test). A Cox proportional-hazards model identified treatment with tacrolimus (hazard ratio [HR] = 4.376; 95% confidence interval [CI]: 1.647-11.627; P = .0031) and age at transplantation (HR = 1.562; 95% CI: 1.089-2.240; P = .0155) as risk factors for malignancy. CONCLUSIONS: The results of multivariate analysis suggested that age at transplantation and the use of tacrolimus were independent risk factors for the development of malignancy in recipients of renal transplants.

[Living unrelated renal transplantation in an eldery couple: a case report].

We present a 60-year-old female who underwent living unrelated renal transplantation from her 62-year-old husband. The primary immunosuppression consisted of tacrolimus, mycophenolate mofetil and steroid. We did not recognize any rejection in a histopathological study. The total ischemic time to carry out anastomosis of the two renal arteries was 121 minutes. After hemodialysis 5 times for acute tubular necrosis, her renal function improved. She was discharged on the 33rd postoperative day when her serum cretinine level was 1.0 mg/dl. The graft function was stable at 6 months after transplantation. We discussed living unrelated renal transplantation in the elderly population in Japan.

Incidence of positive C4d deposition in long-term survival cases over 10 yr after renal transplantation.

BACKGROUND: The incidence of positive C4d deposition in peritubular capillaries (PTC) in long-term survival cases remains controversial. Some incidences of positive C4d deposition in PTC in cases of long-term survival less than 10 yr have been reported. We retrospectively examined the incidence of positive C4d deposition in long-term survival cases over 10 yr after renal transplantation and the histological and clinical characteristics of the positive C4d staining cases. METHODS: We examined 14 protocol biopsy cases performed at Osaka University Hospital between March 2004 and March 2005. The average interval between the operation and the day of biopsy was 15.4 yr. Histological diagnosis was made in accordance with the Banff 97 classification. Paraffin-embedded tissue was stained with polyclonal anti-C4d antibody. Detection of donor-specific antibody (DSA) was determined by flow cytometric assay. The cases were divided according to C4d positivity. RESULTS: Three of 14 cases (21.4%) were C4d positive and belonged to the C4d+/DSA+ group, while 11 cases were of the C4d-/DSA- group. There were no significant differences between the two groups in serum creatinine (sCr) or proteinuria at the time of biopsy. A trend towards decreasing rate of the inverse of sCr (1/sCr) in the C4d+/DSA+ group was noted. In the C4d+/DSA+ group, three transplant glomerulopathy (TGP) were identified. On the other hand, TGP were identified in six of 11 cases of the C4d-/DSA- group. We investigated the relevance of typical chronic rejection (CR) features and the positivity of C4d. No significant differences were observed between the CR features and C4d depositions in PTC (p = 0.26). CONCLUSION: In long-term survival cases with positive C4d, a trend towards decreasing rate of 1/sCr was revealed, but their histological characteristic features was not recognized.

ABO-incompatible kidney transplantation with anti-CD20 monoclonal antibodies, intravenous immunoglobulin and plasmapheresis without splenectomy: a case report.

A 24-yr-old man was admitted to our hospital for ABO-incompatible kidney transplantation. His blood type was O, and the donor's (his father's) blood type was B. The recipient had pancytopenia, splenomegaly, splenorenal shunts and esophageal varices due to congenital hepatic fibrosis. Therefore, if splenorectomy was performed, the blood pressure of the portal vein and the growth of esophageal varices were predicted. Eventually, in return for splenectomy, anti-CD20 monoclonal antibodies (rituximab), intravenous immunoglobulin and plasmapheresis was performed for additional immunosuppression. Because of progression of pancytopenia, we had to decrease the dose of mycophenolate mofetil and gave up on using deoxyspagalin. Nevertheless the serum creatinine level decreased and remained in the 1.6 to 1.8 mg/dl range.

[A case of further significant anastomotic rupture after gentle traction of urethral catheter for minimal anastomotic leakage after radical retropubic prostatectomy].

A 76-year-old man with clinical stage T1c adenocarcinoma of the prostate underwent radical retropubic prostatectomy. After a cystography on postoperative day 7 demonstrated minimal contrast extravasation, gentle catheter traction was performed. However, a cystography on postoperative day 21 showed a displacement of the catheter out of the bladder due to more significant anastomotic rupture. The catheter was preserved without catheter traction for two months. A cystography revealed complete healing of anastomosis without extravasation. This case suggests that catheter traction for anastomotic leakage should be performed carefully because of a potential risk of further anastomotic leakage.

Long term efficacy of simvastatin in renal transplant recipients treated with cyclosporine or tacrolimus.

BACKGROUND: Hyperlipidemia is frequently developed following renal transplantation and results in worsening of the patient's prognosis. METHODS: In this study, 14 patients who had hypercholesterolemia [total cholesterol (TC) >200 mg/dL] and hypertriglyceridemia [triglyceride (TG) >150 mg/dL] 1 month after renal transplantation (post-transplantation), seven patients each under the treatment with immunosuppressant, either cyclosporine or tacrolimus started simvastatin treatment of 5-10 mg/d and continued the treatment for 4 yr. The effect of simvastatin treatment was assessed by comparison in serum lipid levels (TC, TG, cholesterol in lipoprotein fractions, and apolipoproteins) and the lipid metabolism related enzyme activities for post-transplantation, after 6-month and 4-yr simvastatin treatment. RESULTS: Simvastatin treatment of 4 yr significantly decreased the elevated levels of serum TC from 234.5 +/- 30.8 to 186.3 +/- 20.5 mg/dL (p < 0.001), low density lipoprotein cholesterol (LDL-C) from 116.7 +/- 22.5 to 82.7 +/- 16.6 mg/dL (p < 0.05) and TG from 200.3 +/- 109.2 to 97.0 +/- 45.2 mg/dL (p < 0.001). In addition, there were significant decreases in elevated serum very-low-density lipoprotein cholesterol (VLDL-C) from 47.8 +/- 18.4 to 28.6 +/- 9.5 mg/dL (p < 0.001) and LDL2 cholesterol (LDL2-C) from 20.8 +/- 8.2 to 5.7 +/- 1.8 mg/dL (p < 0.001). CONCLUSION: The results indicate that 4-yr treatment of simvastatin improves profiles of the atherogenic lipids in renal transplant patients with immunosuppressant caused hypercholesterolemia and hypertriglyceridemia treated either cyclosporine or tacrolimus in similar manner.

[Predictive factors associated with successful varicocele repair a study of 139 infertile men with valicocele].

PURPOSE: To determine pretreatment parameters which predict improvements following varicocele repaire in semen quality. MATERIALS AND METHODS: We retrospectively evaluated a total of 139 infertile patients who underwent varicocelectomy from February 1995 to March 2000. A logistic regression analysis was performed to identify parameters associated with improvements in semen quality. Parameters evaluated included varicocele grade, age, testicular volume, serum testosterone, liteinizing hormone (LH), follicle-stimulating hormone (FSH), preoperative sperm density and sperm motility. RESULTS: Of 139 patients 71 (51.0%) improved sperm concentration and 59 (42.4%) improved sperm motility postoperatively. Overall, median sperm density significantly increased from 10 x 10(6)/ml preoperatively to 30 x 10(6)/ml postoperatively. Sperm motility also significantly increased 33% to 45%. In logistic regression analysis, varicocele grade (odds ratio [OR] = 5.7; 95% confidential interval [CI : 1.9-17), FSH level ([OR] = 0.76; [CI]: 0.60-0.96) and sperm motility ([OR] = 1.03; [CI]: 1.0-1.1) were independent predictive factors for improvement in sperm concentration. CONCLUSION: Varicocelectomy improves sperm concentration and motility. Our data suggest that patients with grade 3 varicocele, low serum FSH level and high sperm motility are more likely to benefit from varicocele repair in sperm concentration.

[Safety and efficacy of a new vessel-sealing device for laparoscopic varicocelectomy].

PURPOSE: To evaluate the safety and efficacy of a new vessel-sealing device (LigaSure) for laparoscopic varicocelectomy. MATERIALS AND METHODS: To evaluate the safty, after elective varicocelectomy, the internal spermatic veins (n = 8) were sealed ex vivo with a 5-mm laparoscopic Maryland-style LigaSure (LigaSure Lap), and bursting pressures were measured. To evaluate the efficacy, a retrospective review of our clinical experience with LigaSure (n = 13) and clip (n = 13) in laparoscopic bilatelal varicocelectomy from June 2000 to October 2002 was performed and certain parameters were abstracted, including operative time, estimated blood loss and perioperative complications. RESULT: In the ex vivo study the mean varicocele vessele diameter was 2.5 +/- 0.8 mm (mean +/- SD) and bursting pressure was 449 +/- 95.2 mmHg. Six were burst in normal vessel walls at the average bursting pressure of 442 mmHg and two in the occlusions at the average bursting pressure of 508 mmHg. The difference was not statistically significant. Reliable vessel sealing was achieved in all the patients. The mean operative time showed significant decrease in the LigaSure group compared with the clip group, 70 +/- 20 minutes versus 117 +/- 27 minutes (p < 0.05). Estimated blood loss was minimal and no perioperative complications occurred in both groups. CONCLUSIONS: Our study suggests that a vessel-sealing device appears to be a safe and feasible alternative to the clip in laparoscopic varicocelectomy. It offers the advantage of reducing operative time.

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

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. METHODS: We retrospectively analyzed 112 biopsy specimens from 87 renal transplant patients. All transplantations were from living donors. Of the 112 biopsy specimens, 71 were from protocol biopsies and 41 were from episode biopsies. Calcineurin inhibitors and corticosteroid were used in all patients (tacrolimus 32 and cyclosporin 55). In addition, azathioprine was used in 43 patients, mizoribine was used in 24 patients, and mycophenolate mofetil was used in 20 patients. BKN was diagnosed by light microscopic examination and a positive immunohistochemical staining of anti-SV40 antibody in a biopsy specimen. In order to investigate the outcome and potential risk factors of patients with different histological staging, we divided the patients into groups A (mild histological change) and B (moderate or severe histological change). RESULTS: Of the 87 patients, six were diagnosed with BKN. There were no significant differences between BKN patients and non-BKN patients, except for the number of patients with graft loss (p < 0.001). Of the six BKN patients, three were in group A, and three were in group B. We recognized a significant difference between group A and group B in terms of anti-rejection treatment including glucocorticoid, tacrolimus trough levels of over 8 ng/mL, episode of acute rejection within 1-month post-transplantation, and the time period between transplantation and BKN diagnosis. CONCLUSIONS: This is the first report of BKN in Japanese renal allograft recipients. In our hospital, the prevalence, risk factors, and outcome were similar to those previously for non-Japanese recipients.

Direct transfer of hepatocyte growth factor gene into kidney suppresses cyclosporin A nephrotoxicity in rats.

BACKGROUND: The clinical utility of cyclosporin A (CsA) has been limited by its nephrotoxicity, which is characterized by tubular atrophy, interstitial fibrosis and progressive renal impairment. Hepatocyte growth factor (HGF), which plays diverse roles in the regeneration of the kidney following acute renal failure, has been reported to protect against and salvage renal injury by acting as a renotropic and anti-fibrotic factor. Here, we investigated protective effects of HGF gene therapy on CsA-induced nephrotoxicity by using an electroporation-mediated gene transfer method. METHODS: CsA was orally administered as a daily dose of 30 mg/kg in male Sprague-Dawley rats receiving a low sodium diet (0.03% sodium). Plasmid vector encoding HGF (200 micro g) was transferred into the kidney by electroporation. RESULTS: HGF gene transfer resulted in significant increases in plasma HGF levels. Morphological assessment revealed that HGF gene transfer reduced CsA-induced initial tubular injury and inhibited interstitial infiltration of ED-1-positive macrophages. In addition, northern blot analysis demonstrated that cortical mRNA levels of TGF-beta and type I collagen were suppressed in the HGF group. Finally, HGF gene transfer significantly reduced striped interstitial phenotypic alterations and fibrosis in CsA-treated rats, as assessed by alpha-smooth muscle actin expression and Masson's trichrome staining. CONCLUSIONS: These results suggest that HGF may prevent CsA-induced tubulointerstitial fibrosis, indicating that HGF gene transfer may provide a potential strategy for preventing renal fibrosis.

Correlation between the Banff 97 classification of renal allograft biopsies and clinical outcome.

The 1997 fourth Banff meeting revised the consensus for describing transplant biopsies. We have conducted a retrospective analysis of biopsies correlated between the Banff 97 classification and clinical outcome. The patients ( n=149), who had a total of 404 biopsy-proven rejections, were assessed and the biopsies taken from these patients were re-examined and classified according to the Banff 97 classification. Morphological changes in the glomeruli (g), interstitium (i), tubules(t), and arterial vessels (v) were scored. Severity of acute rejection was statistically associated with unresponsiveness to anti-rejection treatment ( P<0.0001) and predicted an increased risk of graft failure ( P<0.05). Each quantitative criterion (g, i, t, and v) was also statistically associated with unresponsiveness to anti-rejection treatment. Mean serum creatinine levels were significantly higher in the groups graded Banff 97 type I-III after 1 and 2 years of follow-up. The Banff 97 classification correlated with reversibility of rejection episodes and long-term graft survival.

[A case report of BK virus nephropathy after an ABO-incompatible living kidney transplantation].

We present a case of 29-year-old female who underwent an ABO-incompatible living kidney transplantation from her father. The serum creatinine (s-Cr) level of this patient was stabilized about 1.1-1.2 mg/dl during the first 3 months after the transplantation. Thereafter, the function of allograft was deteriorated gradually. A biopsy performed on post-transplant day (PTD) 520 to evaluate a rise in creatinine revealed an interstitial nephritis and chronic renal allograft nephropathy. The renal function worsened persistently, although we increased the dosage of immunosuppressant subsequently. The following biopsy performed on PTD 630 showed a suspicion of BK virus nephropathy, with a mass of tubular epithelial nuclear inclusions and an interstitial nephritis. The diagnosis of BK virus nephropathy was confirmed on the immunohistochemistry staining using anti-SV40 antibody and PCR analysis. Despite reducing the immunosuppressants, the function of the allograft worsened progressively and was lost on PTD 912.

Differential diagnosis of kidney transplant rejection and cyclosporin/tacrolimus nephropathy using urine cytology.

A total of 9000 urine samples from 69 kidney transplant recipients were studied for differential diagnoses of transplant rejection and cyclosporin/tacrolimus toxicity. New-Sternheimer and Papanicolaou staining were used to differentiate cells in urine. We also employed an immunocytochemical technique for further identification of exfoliated cells. With New-Sternheimer and Papanicolaou staining, the predominance of proximal tubular cells was useful to differentiate cyclosporin/tacrolimus toxicity from acute rejection in cases of increased serum creatinine level. During rejection episodes, an increased number of mononuclear cells and renal epithelial cells were found. Immunocytochemical analysis showed a significant increase of CD2-, CD4- CD8-, CD25- and HLA-DR-positive cells with rejection. However, there was no relationship between Banff criteria rejection grade and the increase of mononuclear cells.