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Background/Purpose Urinary tract infection (UTI) is the most common type of infectious complication among kidney transplant patients. However, the antibiotic susceptibility of causative microorganisms and risk factors for concomitant bacteremia and recurrent infection are rarely discussed. Methods This was a retrospective cohort review of kidney transplant recipients who had received follow-up in the past 10 years at the Chung-Shan Medical University (Taichung, Taiwan). Only community-acquired and symptomatic UTIs were included in this study. Results During the 53±22 months of follow-up, 99 patients developed 167 episodes of UTI. Forty-two (25%) episodes had concomitant bacteremia. Escherichia coli was the most common causative microorganism, and strains with resistance to multiple commonly used empirical antibiotics began to emerge. The independent risk factors for UTI with concomitant bacteremia in multivariate analysis were immunosuppression with tacrolimus (adjusted odds ratio [AOR] 3.17; 95% confidence interval [CI] 1.29–7.75; P = 0.011) and baseline serum creatinine level >1.3 mg/dL before first UTI (AOR 2.55; 95% CI 1.02–6.36; P = 0.045). However, there were no factors that were significantly associated with recurrent infection. Conclusion From this study, we found that E coli tends to have resistance to commonly used empirical antibiotics in this modern era and that patients who use the immunosuppressant tacrolimus and have baseline serum creatinine level >1.3 mg/dL before their first UTI have a tendency to suffer from concomitant bacteremia and even sepsis.

Despite improved post-transplantation care, progress in long-term kidney allograft survival of diabetic renal transplant recipients (pre-DM RTR) is worse than that of non-diabetic recipients (non-DM). We hypothesized that there are other potential risk factors, that predispose RTR to adverse renal allograft outcomes. A total of 323 transplant recipients who underwent renal transplantation between March 2000 and January 2008 were recruited. The composite end-point consisted of serum creatinine (SCr) doubling, graft failure, and death. Baseline clinical data were recorded, and polymerase chain reaction-restriction fragment length polymorphism measurements of interleukin (IL)-4, IL-10, IL-23, glutathione S-transferase (GST)A1, GSTM1, and GSTP1 polymorphisms were determined. The risk factors for developing the primary outcome were analyzed among these clinical and genetic factors. Within a mean follow-up of 71.1 ± 24 months, there were 43 (13.3 %) patients with the primary outcome. Stepwise multivariate Cox regression analysis was used to determine the risk factors for the primary outcome of RTR. Renal transplant recipients who possessed the GSTM1 null genotype had a 2.2-fold risk (95 % CI: 1.10–4.40; P = 0.026) of developing the primary outcome. Additionally, RTR that had DM before transplantation (aHR: 3.31; 95 % CI: 1.77–6.20; P = 0.0002) or changes in SCr 6 to 12 months after transplantation (aHR: 2.83; 95 % CI: 1.29–6.19; P = 0.0095) had an increased risk of developing the primary outcome. In addition to the adverse role played by DM, the GSTM1 null genotype also has an unfavorable influence on the long-term allograft outcome of RTR.

The purpose of the present study was to evaluate graft and patient survival and long-term outcomes of primary endoluminal stenting (PES) as an initial treatment for transplant renal artery stenosis (TRAS).From December 1999 to March 2010, 744 consecutive patients undergoing renal transplantation were enrolled. Patients were divided into one of two groups: the study group, comprised of 18 patients who underwent PES for TRAS60%, and a control group, including the remaining 726 recipients who did not develop TRAS post-transplantation. Primary outcome measures were death-censored graft failure and all-cause mortality. The immediate and long-term effects of PES were evaluated by assessing blood pressure (BP) control and biochemical graft function.The technical success rate for PES was 100%, and minor complication occurred in only one case (5.6% of the study group). With a mean follow-up of 7.1 ± 3.7 and 6.9 ± 2.4 years in the study and control groups, respectively, 4 patients in the study group and 113 patients in the control group reached the primary outcome (log rank P = 0.418). The reduction in stenosis resulted in immediate improvement in BP control and graft function, which persisted throughout the 6 year follow-up period. Restenosis occurred in only one patient (5.6%), but restenosis was not the cause of graft failure.This study indicated that both the long-term graft and patient survival were as good in TRAS patients treated with PES as in patients without TRAS. The data also supported the use of PES as an initial treatment for TRAS.

Objective Plasminogen activator inhibitor 1 (PAI-1) is thought to play a role in the pathogenesis of obesity and insulin resistance. A connection between gestational diabetes mellitus and the functional -675 PAI-1 genotype has been reported. Therefore, we examined the role of the PAI-1 gene polymorphism in kidney transplant recipients. Methods A total of 376 kidney transplant recipients were prospectively screened for posttransplant diabetes mellitus (PTDM). Eighty-one (21.5%) patients were diagnosed with PTDM and the other 295 patients were non-diabetic following kidney transplantation. DNA samples were isolated from the sera and analyzed for the functional − 675 4G/5G promoter polymorphisms of the PAI-1 gene. Results Kidney transplant recipients with PTDM were significantly associated with tacrolimus use (p = 0.03), older age (p = 0.036), and higher body mass index (p = 0.001). The genotype distribution was significantly different between the patients with PTDM (genotype 4G/4G:4G/5G:5G/5G = 33.3%:60.5%:6.2%) and those without PTDM (genotype 4G/4G:4G/5G:5G/5G = 36.9%:44.1%:19.0%) (p = 0.018). Patients with homozygosity for 5G had a significantly lower rate of PTDM (aOR, 0.286, p = 0.022) and higher cumulative event-free probability of time to PTDM (log rank test, p = 0.0058). Conclusion Homozygosity for the 5G allele of the PAI-1 gene constitutes a protecting factor for the development of PTDM. Our findings are similar to a previous study on gestational diabetes mellitus, and strongly support a possible genetic role of PAI-1 in the development of PTDM.

Urothelial cell carcinoma is the most common type of malignancy found in long-term dialysis patients and kidney transplant recipients in Taiwan. Surgical specimens of tumorous and non-tumorous bladder tissues were collected from 12 patients with bladder cancer. Increased expressions of Ras, RhoA, Akt, PI-3K were demonstrated in the tumors as compared to adjacent control tissues. To understand the impact of Ras over-expression on bladder cancer progression, human bladder cancer TSGH 8301 cells were transfected with Ras DNA. The Ras-transfected cells were then treated with either a PI-3K inhibitor (wortmannin) or Rho kinase inhibitor (Y-27632) and the expressions of Ras, PI-3K, Akt, NF-kappaB, and RhoA were analyzed. Fluorescent phalloidin staining demonstrated more intense F-actin staining in the Ras over-expressed cells than in the control cells, and the intensity of F-actin was inhibited by Y-27632. A gelatin zymography study demonstrated that the MMP-2 and MMP-9 expressions of the Ras-transfected cells were enhanced, and Y-27632 treatment reduced the levels of MMP-2 and MMP-9. Similarly, a wound healing assay revealed that the ability of cell migration was markedly increased by Ras transfection and the healing rate after treatment of Y-27632 was delayed. Our results provide evidence that Ras-induced RhoA and NF-kappaB activation was involved in the invasion/migration of bladder cancer. Through Ras and/or RhoA inhibition, there might be an opportunity for new therapeutic interventions in bladder cancer.

SUMMARY: Background: While polyomavirus nephropathy (PVN) is recognized as an emerging cause of graft loss in renal transplants, the prevalence rate of PVN in renal grafts is unclear in Taiwan. Methods: Biopsies (n = 412) from 323 Taiwanese renal transplant patients were retrospectively analysed. PVN was diagnosed by the characteristic viropathic change in epithelial cells under light microscopic examination and a positive immunohistochemistry staining of anti-SV40 large T antigen. The viral cytopathic changes, interstitial inflammation, fibrosis and tubular atrophy were semiquantitatively assessed, based on the Banff 1997 classification and scoring for renal allograft. Results: Seventeen cases were identified with evidence of PVN; the prevalence rate is 5.26%. Compared with non-PVN patients, they were more likely to have had previous rejection episodes, higher graft loss and shorter graft survival. Conclusion: This retrospective study showed that we have similar findings to other reports with at least 5% prevalence of PVN and that patients diagnosed early do better, while those diagnosed with severe inflammation or damage do worse or are likely to lose their grafts.

Background: Kidney transplantation using organs from executed prisoners is a subject of controversy from the viewpoint of ethics. However, few reports have addressed the clinical outcome beyond the ethical issue. Methods: Between January 1990 and September 2004, a total of 435 kidney transplant recipients (group M) who underwent transplantation in 26 different hospitals in China were followed up at our hospital. It is believed that all the organs came from executed prisoners. The clinical data were retrieved and compared to those of 200 kidney transplant recipients (group T) who underwent transplantation in our hospital during the same period. Results: There was no significant difference between these 2 groups (T vs. M) in terms of hepatitis B virus infection (10.5% vs. 12.1%) or surgical complication rate (6.5% vs. 5.6%). The 1 st -year acute rejection rate was significantly lower in group M (31.1% vs. 24.5%, p = 0.015). The 1-year, 5-year, and 10-year patient survival rates were 94.3%, 89.5%, and 85.2%, respectively, for group T and 92.6%, 83.6%, and 76.7%, respectively, for group M (p > 0.05); the corresponding graft survival rates were 91.4%, 82.6%, and 66.9%, respectively, for group T and 91.6%, 80.0%, and 61.4%, respectively, for group M (p > 0.05). When patients were stratified according to the year of transplantation, patients who underwent transplantation between 2000 and 2004 had significantly better graft survival rates in both groups. Conclusion: We conclude that kidney transplantation using organs from executed prisoners had a clinical outcome similar to that of transplantation performed in our hospital during the same period. [J Chin Med Assoc 2007;70(5):193–199]

Tuberculosis (TB) is one of the major causes of morbidity and mortality worldwide. Post-transplant (post-Tx) TB is a problem in successful long-term outcome of renal transplantation recipients. It is a life-threatening opportunistic infection that is frequently encountered but the diagnosis is often delayed. With the emergence of newer potent immunosuppressive regimens and an increased incidence of TB in the general population post-Tx TB among transplant recipients can be anticipated. Our objective was to describe the pattern and risk factors of TB infection and the prognosis in an endemic area. This study was a retrospective review of the records of 756 renal transplant recipients in our hospital during the period from January 1983 to December 2003. The demographic data transplant characteristics clinical manifestations diagnostic criteria treatment protocol and longterm outcome of this cohort of patients were analyzed. Thirty-one episodes developed into TB in 29 patients (3.8%) with a mean age of 45.5 (range: 24.2^66.2) years and a mean post-Tx period of 57.9 (range: 1.2^145.2) months. The forms of the diseases were pulmonary in 22/31 (71%) disseminated in 1/31 (3%) miliary in 1/31 (3%) and extrapulmonary in 7/31 (23%). All patients initially received 4-drug combination therapy and then dosage was adjusted based on clinical condition. Because of drug interaction a mean 2-fold increase in the dose of calcineurium inhibitor but no change in steroid was required. Twenty-two patients (71%) had an elevated creatinine (Cr) level and 6 (19%) patients did not recover owing to tissue-proof acute rejection (3 cases) and chronic allograft nephropathy (3 cases) respectively after treatment. The serum Cr level on diagnosis of TB was 1.9 ± 0.7mg/dL; it then deteriorated to 2.4 ± 1.5 mg/dL (P = 0.134). Hepatotoxicity developed in 11 patients (35.5%) during treatment. Twenty-five patients were successfully treated 2 patients remain under treatment and 4 (12.9%) died. Based on univariate analysis we found the post-Tx TB risk factors were diabetes and more than 3 episodes of rejection modalities for acute rejection (high-dose steroid and anti-lymphocyte globulin) and maintenance therapy with steroid. Post-Tx TB is a serious problem worldwide and a high index of suspicion is warranted to ensure early diagnosis and prompt initiation of treatment for TB among renal transplant patients. The use of optimal immunosuppressive agents to minimize acute rejection seems reasonable to prevent TB infection in endemic areas like Taiwan. More than 9 months of treatment may be necessary to prevent recurrence. (authors)

It has been proven that extracellular matrix turnover is involved in the pathogenesis of various renal fibrosis diseases. Matrix metalloproteinase-2 and -9 (MMP-2 and -9) are the extracellular matrix degrading enzymes that are believed to play important roles in renal diseases. However, the relationship of circulating levels of MMP-2, -9 and serum creatinine in the patients of chronic kidney disease (CKD) has not yet been investigated.Gelatin zymography and ELISA were employed to measure MMP-2 and MMP-9 activities in the plasma samples of 60 CKD patients and 40 control subjects.Serum creatinine concentrations and MMP-2 activities were significantly higher (p0.001) while MMP-9 activity and creatinine clearance (CCr) were significantly lower (p0.05 and p0.001, respectively) in CKD patients, as compared with those of control subjects. In addition, serum creatinine concentrations correlated with MMP-2 activity (R=0.288, p0.05) and inversely correlated with that of MMP-9 (R=0.344, p0.01).This study demonstrated a correlation between MMP-2, -9 and serum creatinine in CKD patients to suggest that MMP-2 and MMP-9 might contribute in the pathogenesis of CKD.

Aristolochic acid (AA) has been implicated in urothelial carcinoma in humans. However, the mechanism by which AA induces this cancer has not been completely established. To evaluate the effects of AA on the urinary bladder of rats, a histopathological study of three-month intragastric feeding with mixture of AA (41% AA I, 56% AA II) was carried out. A total of 18 experimental rats were divided into three feeding regimens, with six rats in each group (group I, normal basal diet; groups II and III received intragastric 5 mg and 10 mg isolated AA mixture/kg/day for 5 days/week for 12 weeks). Dosage-dependent urothelial proliferation, but not carcinoma, was found in the urothelium of the bladder of the rats administered with AA mixture. Immunoprecipitation showed elevations of cyclin D 1 /cdk4 (increased induction by 1.57- and 1.95-fold in the groups II and III) and/or cyclin E/cdk2 complex (increased induction by 1.46- and 1.62-fold in the groups II and III), which promote the increasing phosphorylation of Rb (increased induction by 1.75- and 2.07-fold in the groups II and III) and result in decrease of the Rb/E2F complex (decreased expression by 0.65- and 0.24-fold in the groups II and III). Our results provide evidence to suggest that exposure to AA results in urothelial proliferation in rats through cell cycle progression via activation of cyclin D 1 /cdk4 and cyclin E/cdk2.

Transitional cell carcinoma (TCC) of the urinary tract is the most frequent malignancy following renal transplantation reported in Taiwan. A 67-year-old female underwent bilateral nephrouretectomy and bladder cuff excision because of bilateral hydronephrosis 5 years after cadaveric renal transplantation. The pathologic report was only atrophied kidney. Pelvic sonography and abdominal computed tomography showed a pelvic mass 8 years after transplantation. After gynecological surgery, the pathologic report of the left ovarian tumor was TCC, high grade, stage IIA. The patient then underwent four cycles of postoperative chemotherapy with carboplatin and gemcitabine. TCC of the ovary is a rare, recently recognized subtype of ovarian surface epithelial cancer. We present the first case of primary ovarian TCC following renal transplant.

Although the genetic polymorphism of Stromal Cell-Derived Factor 1 (SDF-1) is associated with higher mortality of liver allograft recipients, the role of SDF-1 in the modulation of renal allograft outcomes is unclear. Between March 2000 and January 2008, we recruited 252 non-diabetic renal transplant recipients (RTRs). Baseline characteristics and blood chemistry were recorded. Genomic DNA extraction with polymerase chain reaction-restriction fragment length polymorphism was utilized to analyze the genetic polymorphisms of SDF-1 (rs1801157). The influence of SDF-1 on an adverse renal allograft outcome, defined as either a doubling of serum creatinine, graft failure, or patient death was evaluated. Sixteen patients with the SDF-1 AA/AG genotype and nine with the SDF-1 GG genotype reached an adverse outcome. According to Kaplan-Meier analysis, patients carrying the SDF-1 AA/AG genotype or A allele showed a significantly higher risk of reaching an adverse outcome than those carrying the SDF-1 GG genotype or G allele (p = 0.041, p = 0.0051, respectively, log rank test). Stepwise multivariate Cox proportional regression analysis revealed that patients carrying the SDF-1 AA/AG genotype and A allele had a 2.742-fold (95% CI. 1.106–6.799, p = 0.03) and 2.306-fold (95% CI. 1.254–4.24, p = 0.008) risk of experiencing an adverse outcome. The SDF-1 AA/AG genotype and A allele have a detrimental impact on the long-term outcome of RTRs.

Chronic liver disease and its complications are major problems in renal transplant recipients. Our aim was to elucidate the influence of hepatitis B, C virus infection on the long-term outcome of renal transplantation. Four hundred and seventy-seven patients who received renal transplantation between January 1984 and December 1999, and who were followed up at our hospital were enrolled. HBsAg was detected by the RIA method and anti-HCV Ab was assayed by the second-generation RIA kit. SGOT/ SGPT were checked every 3 months. Hepatoma was diagnosed by dynamic CT scan, elevated α-fetoprotein, hypervascularity by angiography and confirmed by pathological examination. The prevalence of HBV, HCV, coinfected HBV/HCV was 9.9% (n = 47), 28.5% ( n = 136), 3.1% (n = 15), respectively. The incidences of hepatoma in the HBV–/HCV–, HBV–/HCV+, HBV+/HCV–, HBV+/HCV+ groups were 1.4% (n = 4), 4.4% (n = 6), 6.4% (n = 3), 6.7% (n = 1), respectively (p = 0.114). The incidences of liver cirrhosis/hepatic failure were 3.2% (n = 9) , 6.6% (n = 9) , 21.3% (n = 10) , 20% (n = 3), respectively (p < 0.001). The frequencies of chronic liver disease were 10.4% (n = 29) , 45.6% (n = 62) , 66% (n = 31) , 80% (n = 12), respectively (p < 0.001). Patient and graft survival rates were lower in the HBV-infected group than in the other groups. Cox regression analysis revealed that HBV infection is likely an independent risk factor for patient mortality although the statistical significance was only borderline. Patients with HBV as well as HCV infection were not at risk of graft loss according to this model of analysis. Patients with HBV infection showed higher incidences of hepatoma, hepatic failure, graft failure and death. Therefore, HBV-infected patients who are candidates for renal transplantation should be carefully evaluated. It seems that HCV infection has little influence on the outcome of renal transplant recipients. A longer period of follow-up is needed to clarify the impact of HCV on renal transplant recipients.

Posttransplantation diabetes mellitus (PTDM) is a major complication in renal transplant recipients. Some studies have demonstrated that tumor necrosis factor alpha (TNF-α) expression and its genetic polymorphism are associated with diabetes mellitus. We investigated this association in Asian renal transplant recipients. Polymerase chain reaction-restriction-fragment length polymorphism was used to measure TNF-α G-238A and G-308A gene polymorphisms among 241 nonposttransplantation diabetic subjects and 73 PTDM patients. PTDM patients showed higher values of body weight and body mass index (BMI) than the non-PTDM group. However, no significant association was observed between TNF-α G-238A and TNF-α G-308A polymorphisms with PTDM incidence, gender, age at transplantation, follow-up duration, BMI, or type of immunosuppression.

Impact of interleukin-1 receptor antagonist and tumor necrosis factor-α gene polymorphism on IgA nephropathy.BackgroundIt is evident that cytokines play an important role in the pathogenesis as well as disease progression in IgA nephropathy (IgAN). The level of cytokine production is influenced by different genotypes that reflect gene polymorphism of the pertinent cytokine. Interleukin-1 receptor antagonist (IL-1ra) and tumor necrosis factor-α (TNF-α) gene polymorphism have been found to affect disease susceptibility and activity in several inflammatory diseases. However, the impact of these polymorphisms in IgAN patients has not previously been thoroughly studied.MethodsWe investigated 111 cases of biopsy-proven IgAN and 100 healthy, normal controls for their IL-1ra and TNF-α gene polymorphism. IL-1ra gene polymorphism was characterized as a variable number of tandem repeats of a 86 bp sequence within intron 2. Five alleles were identified and were designated as IL1RN*1, IL1RN*2, IL1RN*3, IL1RN*4, and IL1RN*5, corresponding to 4, 2, 5, 3, 6 repeats, respectively. A polymorphism in the promoter region of the TNF-α gene was also studied. This polymorphism involved a guanidine to adenosine transition at position -308 and was designated as TNF1 (-308G) and TNF2 (-308A).ResultsThere were 54 male and 57 female patients with a mean age of 30.3 ± 12.5 years and a disease duration of 66.8 ± 47.2 months. The mean duration of the follow-up period was 47.3 ± 32.6 months. In the patient group, the allele frequencies of IL1RN*1, IL1RN*2, IL1RN*3, IL1RN*4, and IL1RN*5 were 89.6%, 9.9%, 0%, 0.5%, and 0%, respectively, whereas the corresponding carriage rates were 100%, 19.8%, 0%, 0.9%, and 0%, respectively. An excessive carriage of IL2RN*2 was found in the patients when compared with normal controls (allele frequency, 9.9 vs. 2.5%, P < 0.0001). The allele frequencies of TNF1 and TNF2 were 94.1 and 5.9%, respectively, and the carriage rates were 99.1 and 10.8%, respectively, in the patients, which was not significantly different from those of normal controls. When the patients were stratified into mild and severe groups according to their initial presentation, none of the studied alleles correlated with the severity. However, patients with gross hematuria were associated with a higher carriage rate of TNF2 when compared with patients without gross hematuria (allele frequency, 15.4 vs. 4.6%, P = 0.0552; carriage rate, 30.8% vs. 8.2%, P = 0.0272). Renal survival analysis revealed that the TNF2 carrier had a renal survival comparable with TNF2 (-) patients. However, the carriage of the IL1RN*2 allele was associated with a significantly poorer long-term outcome with a median survival time of 72 months, as compared with those without IL1RN*2 (134 months, P < 0.01).ConclusionIL-1ra and TNF-α gene polymorphism may affect disease susceptibility as well as disease activity and long-term outcome in human IgAN. Treatment with an IL-1ra or IL-1 blocking agent may be relevant in those carrying the IL1RN*2 allele.

Background/Aim: The purpose of this study was to evaluate pusled-field gel electrophoresis (PFGE) for distinguishing between relapse and reinfection of Staphylococcus aureus infections in patients on continuous ambulatory peritoneal dialysis (CAPD). Methods: Between July 1993 and May 1997, 4 patients with recurrent CAPD-associated infections caused by S. aureus we enrolled in this study. There were nine episodes of peritonitis, one episode of temporary double lumen catheter infection, and one episode of Hickman catheter infection. A total of eleven S. aureus isolates were collected from peritoneal fluid (n = 9) and blood (n = 2). PFGE typing was applied. Results: In our study, from PFGE typing, the 11 S. aureus isolates were classified into seven patterns. Antibiogram profiling classified only four patterns. Patient A had a reinfection by another strain of S. aureus, and patient B had three episodes of peritonitis caused by the same strain of S. aureus due to exit site infections. Patient C had two episodes of CAPD peritonitis caused by two different strains, respectively. Patient D had four episodes of S. aureus infection (three CAPD peritonitis and one bacteremia); the first two episodes of peritonitis were caused by an identical strain of S. aureus, whereas the subsequent two infections were caused by other organisms. Conclusion: PFGE has a high discriminatory power and can be an assistant method to antibiogram profiling for distinguishing relapse from reinfection in CAPD-associated peritonitis.

PRINCIPLES The once-daily tacrolimus formulation (Advagraf®), with the potential for improving medical adherence, has been advocated to improve long-term kidney allograft outcomes. However, experience with late conversion from the twice-daily tacrolimus formulation (Prograf®) to Advagraf in the daily care of stable kidney transplant recipients has been limited. METHODS The aim of this study was to observe the efficacy and safety of conversion from Prograf to Advagraf in chronic stable kidney transplant recipients in routine clinical practice. The recruited patients had postconversion follow-up at least once monthly for a total of six months, unless they had discontinued the use of Advagraf, had been lost the follow-up or had lost the graft. RESULTS The mean age of the 199 patients was 51.5 ± 10.4 years (60.8% male). The mean time from transplantation to the conversion to Advagraf was 8.3 ± 3.2 years and the mean tacrolimus trough level at conversion was 4.2 ± 1.4 ng/ml. After conversion, 147 patients (73.8 %) had a reduced trough level at one month and the mean change in trough level postconversion was -13.5%. The mean serum creatinine level between conversion and six months postconversion was not significantly different (1.12 ± 0.36 vs 1.10 ± 0.42 mg/dl). Thirty-four patients (17%) discontinued the treatment with Advagraf and two (1%) developed biopsy-proved acute rejection. CONCLUSIONS In conclusion, frequent conversion caused by a high discontinuation rate may further raise the potential risk of allograft rejection and increase unnecessary cost. In view of this, the policy of converting to Advagraf with the purpose of improving medical adherence should be individualised in routine clinical practice.

Peripheral arterial disease (PAD) is a common finding in patients at various stages of chronic kidney disease; however, there has only been a limited amount of data that have been published regarding the prevalence and associated risk factors of subclinical PAD in renal transplant recipients.The authors cross sectionally investigated the prevalence of PAD using ankle-brachial index (ABI) in 304 renal transplant recipients with no previous diagnosis of PAD. Patients were considered to have subclinical PAD when ABI0.9. The authors also determined the associated risk factors for subclinical PAD.The mean age of the 304 patients was 53 years, and 30 patients (9.9%) had a history of atherosclerotic event (including past cardiovascular and cerebrovascular events). Twenty-five of the 304 patients (8%) had ABI0.9 and 1 had (0.3%) ABI1.3. Compared to patients with normal ABI, a history of atherosclerotic events is the only independent risk factor for patients with subclinical PAD (P = 0.0468).Subclinical PAD is an inadvertent issue in renal transplant patients, especially those with a history of atherosclerotic events. Further research is needed on the long-term clinical impact and optimal treatment of subclinical PAD among renal transplant patients.

The risk of developing chronic kidney disease (CKD) among living kidney donors (LKDs) is seldom included in evaluations of patients' outcomes. Potential risk factors and new criteria for estimating the glomerular filtration rate (eGFR) indexed for body surface area (BSA) were investigated with a view to prevent the development of CKD in LKDs.We conducted a retrospective study of LKDs from May 1983 to March 2011. The Mann-Whitney U test and χ(2) test were used to analyze the male versus female groups. Survival analysis was plotted as CKD-free survival and analyzed separately by different eGFR index classifications. The Cox regression model was used to identify potential risk factors for development of CKD.A total of 105 LKDs with a mean age of 46.3 ± 12.5 years had a mean eGFR indexed for BSA of 88.9 ± 21.5 ml/min per 1.73 m(2). After a mean duration of 5.4 ± 4.9 years' follow-up, eGFR dropped to 61.4 ± 16.4 ml/min per 1.73 m(2) (p = 0.002). Median CKD-free survival was only 5.7 years. The difference between eGFR ≥ 80 ml/min per 1.73 m(2) and80 ml/min per 1.73 m(2) was not statistically significant (p = 0.980). Multivariate Cox regression analysis showed that higher eGFR at donation (HR = 0.952, p = 0.0199) could be a protective factor. The receiver operating characteristic (ROC) curve for initial eGFR with best sensitivity of 52.78 % and specificity of 81.40 % was obtained with a cutoff value of 90.2 ml/min per 1.73 m(2) for preoperative eGFR. An eGFR of 90 ml/min per 1.73 m(2) yielded a significant survival curve (p = 0.0199) after 21 years of follow-up. Further classifications of eGFR90 ml/min per 1.73 m(2) into 90-99 ml/min per 1.73 m(2), 100-109 ml/min per 1.73 m(2), and ≥110 ml/min per 1.73 m(2) were examined, but this survival curve was not statistically significant (p = 0.1247).Living kidney donors will develop CKD after a long duration of follow-up if there is insufficiently high eGFR at donation. An eGFR above 90 ml/min per 1.73 m(2) before donation is the only factor that predicts prevention of CKD. Larger studies with longer duration of follow-up are necessary to clarify the clinical outcome of this postoperative CKD group, especially for patients with eGFR between 80 and 90 ml/min per 1.73 m(2).

Interferon treatment of hepatitis C virus (HCV) infection in transplant recipients carries a high risk of rejection. We treated these patients with ultralow-dose interferon-alpha (1 x 10 units subcutaneously three times/week) plus ribavirin (600 mg/day) for 48 weeks. Treatment efficacy was evaluated by the changes of serum liver enzymes and viral load. A total of 11 patients were recruited for the study; biochemical response was obtained in all patients but one. Three patients terminated the therapy prematurely because of acute graft failure (one case) and urosepsis (two cases). Of the eight patients who completed a full course of therapy, five cleared HCV RNA at the end of treatment. Sustained biochemical and virologic responses were obtained in three patients (37.5%). Our regimen seemed to be relatively safe for renal transplant recipients with HCV. A significant portion of patients may achieve sustained biochemical and virologic responses.

The chronic shortage of kidneys for transplantation has increased the number of living donations, but demand remains high, which has created a long waiting list of end-stage kidney disease patients. Donors with decreased renal mass may suffer a higher risk of developing proteinuria, hypertension (HTN), and chronic renal disease (CKD) during long-term follow-up.We retrospectively retrieved medical data of living kidney donors at our hospital over the past 28 years.There were 45 male and 60 female donors with a mean donation age of 46.34 ± 12.47 years (range = 20-70y). The mean follow-up duration was 4.67 ± 4.78 years. The serum creatinine (Cr) at donation was 0.93 ± 0.22 mg/dL, while the latest Cr was 1.26 ± 0.45 mg/dL (P.001). The mean age at follow-up was 50.95 ± 14.57 years. At last follow-up, eight subjects (7.6%) displayed HTN requiring treatment, 10 (9.5%), proteinuria and 55.4%, an estimated glomerular filtration rate (eGFR) of less than 60 mL/min, including one with diabetic nephropathy at 10 years after donation who required long-term hemodialysis. Although gender did not correlate with occurrence of HTN, proteinuria, and CKD, the occurrence of CKD was associated with age at donation (P.001, odds ratio [OR] = 1.076), and age at follow-up (P.001, OR = 1.071). HTN donors were older (P = .036, OR = 1.057) with longer follow-up durations (P = .007, OR = 1.166) and had higher Cr values at donation (P = .044, OR = 94.4). Donors with proteinuria were not related to gender, follow-up duration, initial Cr, warm ischemic time, or duration of admission. eGFR was indeed worse after donation (P = .002).Our results indicated a significant proportion of living donors may develop CKD upon long-term follow-up. The factors affecting donor risk of CKD were baseline renal function, older age, and duration after kidney donation.

Glutathione S‐transferase (GST) M1 null genotype has been reported playing a significant role in the diabetes mellitus (DM) susceptibility in Turkish population. We investigated whether the GSTM1, GSTA1, and GSTP1 gene polymorphisms are associated with posttransplantation diabetes mellitus (PTDM) in Taiwan. There were 283 renal transplant recipients (RTRs) enrolled. Polymerase chain reaction–restriction fragment length polymorphism was used for the measurement of GSTA1, M1, and P1 genetic polymorphisms. PTDM was diagnosed according to the American Diabetes Association guidelines. Eight‐five patients (30%) were diagnosed with PTDM. The averaged posttransplant follow‐up period was 77.9 ± 27.2 months. Duration from transplantat to diagnosis of PTDM ranged from 0.2 to 103.1 months (19.2 ± 26.3 months). There were significantly differences between non‐DM and PTDM groups in age (50.6 ± 11.0 vs. 54.6 ± 9.36 years, P = 0.005), BMI (22.4 ± 3.6 vs. 24.3 ± 3.8, P

Background. Aristolochic acid I (AAI) has been implicated in urothelial cell carcinoma (UCC) in humans. However, whether AAI promotes invasion/migration of UCC has not been established. Methods. A study of human UCC TSGH cells cultured with AAI was conducted. Cell viability, the effects of AAI on the activity of matrix metalloproteinase (MMP)9, the abilities of invasion/migration and the migrationrelated proteins (Ras, RhoA, ROCK1, PI-3K, pAkt and nuclear factor-kappaB) of the TSGH cells were assessed. The TSGH cells were subcategorized to 1-day or 30-day AAI exposure. An in vivo study using a nude mice xenograft model was employed to test the antitumor effects of Rho kinase inhibitor or Y27632. Results. A time- and dose-dependent increase in both activity and messenger RNA (mRNA) level of MMP-9 were demonstrated. The mRNA level of urokinase-type plasminogen activator was increased and tissue inhibitor of metalloproteinase-1 was decreased in the cells with 30-day but not 1-day AAI exposure. A dose-dependent enhancement in wound-healing rate and cell migration was demonstrated, especially in the 30-day AAI-exposed cells. Expressions of Ras/RhoA and other migration-related proteins were increased after AAI treatment, which could be inhibited by Y27632. The in vivo results demonstrated that Y27632 was able to attenuate the speed of growth of the inoculated tumors in nude mice. Conclusion. Clinically, the patients with prolonged AAI exposure are highly associated UCC, our results provided in vitro and in vivo evidence that prolonged AAI exposure enhances invasion and migration of human TSGH cells.

Objective Interleukin 23 receptor (IL-23R) plays a role in the pathogenesis of multiple autoimmune processes. The relationship between allograft outcomes and the IL-23Rvariant genotypes has not been reported on previously. Therefore, we examined the relationship between this genetic polymorphism and kidney transplant outcomes. Methods This is an observational cohort study and 422 renal transplant recipients (RTRs) were enrolled. Polymerase chain reaction-restriction fragment length polymorphism was used for the measurement of IL-23R genetic polymorphisms. We used a composite end-point incorporating serum creatinine (SCr) doubling, graft failure and death as the primary outcome. Secondary outcomes included biopsy-proven acute rejection (BPAR), biopsy-proven interstitial fibrosis/tubular atrophy (IF/TA) and individual primary outcome. The risks of developing primary and secondary outcomes were compared between the different IL-23R genotypes and alleles. Results With a mean follow-up of 79.3 ± 28.8 months, 26 patients in the IL-23R genotype AA group and 32 patients in the IL-23R genotype AC/CC group reached the primary outcome (p = 0.061). RTRs who carried the IL-23R AC/CC genotype (aHR 1.78; 95% CI. 1.01–3.12; p = 0.046) and C allele (aHR 1.48; 95% CI. 0.96–2.28; p = 0.075) had a higher risk of developing primary outcome as compared to those with IL-23R AA genotype and A allele, respectively. Moreover, RTRs who carried the IL-23R AC/CC genotype and C allele had a higher risk of developing biopsy-proven IF/TA (p = 0.012; p = 0.012) and SCr doubling (p = 0.024; p = 0.042) as compared to those with IL-23R AA genotype and A allele, respectively. The risk of BPAR, graft failure and death between the IL-23R genotypes and alleles were comparable. Conclusion IL-23R polymorphism may have a potential immuno-modulating role in long-term allograft outcome.

Silibinin is a flavonoid antioxidant that is widely used for its anti-hepatotoxic properties. It exerts a dose-dependent inhibition on the invasion and migration of 786-O renal cell carcinoma (RCC) cells in the absence of cytotoxicity. 786-O cells were treated with silibinin at various concentrations, up to 50 µM, for a defined period and then subjected to gelatin zymography, casein zymography, and Western blot to investigate the impacts of silibinin on metalloproteinase (MMP) -2, -9, urokinase plasminogen activator (u-PA), and MAPK pathway signaling proteins, respectively. The results showed that silibinin decreased MMP-2, MMP-9, u-PA, p-p38, and p-Erk1/2 expressions in a concentration-dependent manner. The reduced expressions of MMP-2 and u-PA, as well as inhibition of cell invasion were obtained in the cultures pre-treated with PD98059 (Erk1/2 inhibitor) and SB203580 (p38 inhibitor). An in vivo anti-tumor study with a nude mice xenograft model by a subcutaneous inoculation of 786-O cells demonstrated small solid tumors after eight days following cell inoculation. There was a 70.1% reduction in tumor volume and 69.7% reduction in tumor weight by silibinin feeding on day 44, compared to those of controls. Moreover, combination treatment with silibinin and 5-fluorouracil, paclitaxel, vinblastine, or RAD-001 enhanced the chemosensitivity of 5-fluorouracil and paclitaxel. In conclusion, silibinin inhibits the invasion and migration of 786-O cells in vitro, inhibits the growth of xenografts in vivo, and enhances chemosensitivity to 5-fluorouracil and paclitaxel. © 2011 Wiley-Liss, Inc.

Chronic kidney disease (CKD) has adverse impacts on mortality and morbidity of renal transplant recipients. Serum cystatin C (sCysC) is a novel marker in predicting the CKD. We therefore compare sCysC and serum creatinine (sCr) with the aim of improving the detection of CKD in renal transplant recipients.We enrolled 106 renal transplant recipients and estimated glomerular filtration rates (GFR) using the Cockcroft-Gault (GFR(CG)) and the abbreviated Modification of Diet in Renal Disease (GFR(aMDRD)) formulae. We defined CKD as the presence of structural or functional kidney damage, irrespective of the diagnosis. Comparisons of sCysC and sCr in detecting CKD were analyzed.sCysC correlates with sCr significantly (r = 0.87; P.001). The receiver operating characteristic curve demonstrates that sCysC has a better specificity and area under the curve, but less sensitivity than sCr in predicting CKD in renal transplant recipients if GFR is estimated by GFR(CG). Additionally, if GFR was estimated by GFR(aMDRD), the role of sCysC or sCr in prediction of CKD was comparable.sCysC may be better than sCr to detect CKD in renal transplant recipients using the GFR(CG).

Human polyomaviruses (PV), including JC and BK virus, have been reported to cause polyomavirus-associated nephropathy (PVAN), in renal transplant patients. PV infection has been demonstrated to be associated with malignancies in animals; however, the association between malignancy and viral infections in humans is not clear. We retrospectively reviewed our 864 (M:F = 502:362) kidney transplant patients over the past 25 years. We identified PVAN in 6 patients (0.69%), including BK nephropathy (n = 5) and JC nephropathy (n = 1). Three patients (50%) improved after reducing the immunosuppression, but 3 (50%) progressed to graft loss despite this reduction. Malignancy occurred in 5 out of the 6 patients (83%; P < .0001 compared with patients without PVAN), including transitional cell carcinoma (n = 2), renal cell carcinoma (n = 1), squamous cell carcinoma of skin (n = 1) and Kaposi sarcoma (n = 1). We concluded that kidney transplant patients with PVAN are at a significantly greater risk to develop malignancy. Whether this is due to a direct effect of PV infection or the result of overimmunosuppression remains to be determined in a future study.

Human immunoglobulin (Ig) E synthesis is regulated by T-cell-derived binding factors which include potentiating factors and suppressor factors (IgE-SFs) and B-cell-derived factors. Seventeen cases of primary glomerulonephritis (GN) with nephrotic syndrome and high serum IgE were studied for their serum IgE-SFs. These include 8 cases of minimal-change disease (MCD), 3 cases of IgM nephropathy, 4 cases of focal segmental glomerulosclerosis, and 2 cases of IgA nephropathy, aged between 20 and 60 years (mean: 37.2). A significantly lower activity of these factors was noted in the patient group as shown by a lower overall inhibition rate on in vitro IgE synthesis (median: 22.9 vs. 53.2%, p less than 0.05). Some of them even exhibited an enhancing activity in their serum as shown by a negative inhibition rate. These findings suggest that there is a T cell disorder in some of the primary GNs with high serum IgE, especially in MCD, which causes an abnormal regulation of IgE synthesis.

Background: Plasminogen activator inhibitor-1 (PAI-1) plays an important role in renal fibrosis. We conducted this study to examine whether serum PAI-1 has a role in predicting chronic allograft nephropathy (CAN). Methods: Fifty kidney transplant recipients receiving graft biopsies were enrolled. The pathologic diagnoses were acute tubular necrosis (ATN; n = 12), borderline rejection (BR; n = 7), acute rejection (ACR; n = 12), CAN (n = 11), polyomavirus nephropathy (PVN; n = 3) and others (n = 5; glomerulopathy, n = 4; calcineurin inhibitor nephropathy, n = 1). The serum level of PAI-1 and chronic allograft damage index (CADI) score of each patient were determined. Results: The CADI score of all patients was 4 (0–10) (median and range) and in each group was ATN 0.5 (0–4), BR 2.0 (1–4), ACR 4.0 (2–8), CAN 5.0 (4–10), PVN 7 (4–8) and others 2 (0–8). The serum PAI-1 level of each group was ATN 9.38 (2.35–14.52) ng/mL, BR 10.09 (0.61–18.06) ng/mL, ACR 11.08 (2.32–20.68) ng/mL, CAN 14.51 (3.66–21.12), PVN 14.79 (13.94–21.94) and others 16.35 (4.05–21.01) ng/mL. CADI score is associated with serum PAI-1 activity (r = 0.405, p = 0.003) and is inversely associated with serum creatinine (r = −0.348, p = 0.011), but not with estimated glomerular filtration rate (p = 0.124). Conclusion: Serum PAI-1 level has the potential to be a marker to predict CADI score, the quantitative score of CAN.

Background. Polyomavirus-associated nephropathy (PVAN) has an unfavourable impact on graft survival. The cornerstone of therapy is early reduction of immunosuppressive medications; however, the rate of graft failure is still high. Antiviral drugs, such as cidofovir, are thought to have therapeutic effects, but the benefits of cidofovir in retarding the deterioration of PVAN are still a controversial issue. Methods. Fourteen renal kidney recipients were diagnosed to have biopsy-proven PVAN between 2001 and 2006 in Chung-Shan Medical University Center with nearly 600 renal transplant recipients. After the diagnosis of PVAN, all patients were treated with a reduction of their original immunosuppressive medications with/without converting tacrolimus to cyclosporine. Eight of the 14 patients agreed to receive low-dose cidofovir (0.5 mg/kg) every 2 weeks for a total of six doses. Results. During 30 ± 18 months of follow-up, three (37%) patients in the cidofovir-treated and three (50%) patients in the non-cidofovir-treated group experienced graft loss (P = 0.64). The rejection rate before PVAN diagnosis or other baseline characteristics of the patients between two groups were not significantly different. The long-term survival rate to graft loss and major graft functional decline with Kaplan–Meier analysis between the two groups were not significantly different (P = 0.898 and P = 0.243). In all demographic and clinical characteristics, we found that there was a tendency towards long-term major graft functional decline in the patients with acute rejection prior to PVAN diagnosis (P = 0.04). Conclusions. We concluded that (1) there was no obvious effect of low-dose cidofovir on long-term graft survival in patients with PVAN, and (2) acute rejection prior to PVAN diagnosis was a potential risk factor for poorer long-term graft outcome.

Polyomavirus type BK (BKV) nephropathy is increasingly a significant cause of graft dysfunction and even failure. Early diagnosis followed by reduction of immunosuppression has been associated with an improved prognosis. We screened 250 patients with the urine qualitative polymerase chain reaction (PCR) for BKV DNA. We followed with blood BKV PCR if the urine screen was positive and then reduced immunosuppression in viremic patients. One hundred ninety-nine patients (80%) had no viuria; 43 (17%) viuria; and 8 (3%) both viuria and viremia. Graft biopsy performed in three patients (1%) with viremia and impaired graft function all revealed BKV nephropathy. After 6 months of follow-up, seven out of eight viremic patients (88%) had negative repeat blood PCR and stabilized graft function. An early diagnosis of BKV infection with reduction of immunosuppression may reverse viremia and retard progression of BKV nephropathy. BKV screening by PCR assays should be considered in kidney transplant recipients, especially those with impaired graft function.

Idiopathic membranous nephropathy (MN) is one of the most common causes of nephrotic syndrome in adults, and 25% of MN patients proceed to end-stage renal disease. Plasminogen activator inhibitor type 1 (PAI-1) activity plays an important role in renal fibrosis. The objective of this study was to clarify the relationship between PAI-1 gene polymorphisms and the progression of MN-associated pathologies.We recruited a cohort of 104 biopsy-diagnosed MN patients and 142 healthy subjects that served as controls. Genotyping of PAI-1 gene polymorphisms was performed using allele-specific polymerase chain reaction methods. We then analysed associations between PAI-1 gene 4G/5G polymorphisms and clinical manifestations and progression of MN.The genotype distribution had no effect on the development of MN. The last measured creatinine clearance in MN patients having the 4G/4G genotype was significantly lower than in patients having the 4G/5G or 5G/5G genotypes (43.6 +/- 33.6, 55.8 +/- 44.3 and 73.3 +/- 29.8 ml/min, respectively, P = 0.008). Coronary artery diseases were more prevalent in patients having the 4G5G (14/32%) and 4G4G genotypes (4/11%) than in those having the 5G5G genotype (1/5%, P = 0.008). Peripheral vascular events were more prevalent in patients having the 4G5G (18/41%) and 4G4G (6/16%) genotypes than in those having the 5G5G genotype (3/14%, P = 0.021). Disease progression occurred more frequently in patients having the 4G4G (20/53%) and 4G5G (25/57%) genotypes compared with those having the 5G5G genotype (5/23%, P = 0.026).The presence of the 4G allele was associated with renal deterioration and increased cardiovascular as well as other vascular events in MN patients. These findings should prompt specific considerations for the treatment of MN in patients having the 4G4G genotype.

Studies have indicated that matrix metalloproteinase-2 (MMP-2) is vital for the patient's condition after renal transplantation. Although the allograft survival rate has been improved, the relationships between various clinical parameters in stable graft function and serum MMP-2 still need to be clarified. In this study, gelatin zymography and enzyme-linked immunosorbent assay were employed to measure MMP-2 level in the plasma of 152 kidney transplant recipients, 41 chronic kidney disease patients, and 50 healthy control subjects. The creatinine and the MMP-2 levels in the transplant recipients were significantly greater (P < 0.001) than those of control subjects. Univariate and stepwise regression analysis demonstrated the MMP-2 level was associated with cystatin C level (P < 0.001), creatinine level (P = 0.036), proteinuria (P = 0.043), posttransplant days (P = 0.025), and posttransplant diabetes mellitus (P = 0.03). We conclude that circulating MMP-2 is associated with cystatin C, posttransplant duration, and diabetes mellitus in kidney transplant recipients and suggest that MMP-2 may be critical for graft survival.

The objective of this study was to evaluate the relationship between variability of cyclosporine (CsA) absorption and tacrolimus (TAC) conversion seeking factors that predict improvement in allograft function after TAC conversion. We performed a retrospective study of 44 adult kidney transplant recipients undergoing conversion from CsA to TAC-based immunosuppression. Before TAC conversion, patients had complete, consecutive, 6 monthly C2 levels and a follow-up duration beyond 6 months after TAC conversion. The patients were divided into 2 groups: one (n=23) with low variability of CsA absorption and one (n=21) with high variability of CsA absorption. At TAC conversion, the estimated glomerular filtration rate (eGFR) was similar in both patient groups. Six months after TAC conversion, eGFR improved in both groups. Stepwise regression analysis revealed the DeltaSCr6 (change in serum creatinine level at 6 months) to be independently associated with the preconversion serum creatinine (SCr; P.0001) and the percent coefficient of variation (%CV) of SCr (P=.0034). DeltaSCr6 was inversely associated with posttransplantation years (P=.0033), and 6-month TAC blood levels (P=.0053). The DeltaSCr6 was not associated with variability of oral CsA absorption. The cutoff value of baseline SCr at TAC conversion differentiated an increase in or reduction of SCr to be about 1.0 mg/dL. Our study of CsA-treated kidney transplant recipients who underwent TAC conversion showed that a preconversion SCr1.0 mg/dL, a high variability of SCr, and early TAC conversion predicted greater short-term benefit on graft function.

Azotemic patients are usually characterized by a state of so-called preactivation resulting in excessive expression of interleukin 2 receptors (IL-2R) on T lymphocytes. The etiological mechanism of this preactivation is, however, still speculative. We studied the serum level of the soluble form of IL-2R (sIL-2R) in azotemic patients on either hemodialysis (HD) (n = 49) or continuous ambulatory peritoneal dialysis (CAPD) (n = 45). Both patient groups had significantly higher sIL-2R levels (1,750+/-664 U/ml in the HD group and 1,769+/-647 U/ml in the CAPD group, respectively) p < 0.00001 as compared to the normal control group (511+/-436 U/ml). However, there was no significant difference between the levels of the HD and CAPD group patients. When clinical parameters were studied for their influence on sIL-2R levels, none of the following caused any significant changes: blood transfusion, type of dialyzer used, type of dialysis fluid used, treatment with erythropoietin, hepatitis B infection, or liver function profile. We conclude that chronic renal failure per se is the major cause of the preactivation of T lymphocytes. The modes of treatment and various clinical variables in these patients have no significant influence on sIL-2R levels.

Aristolochic acid (AA) has been implicated in urothelial carcinoma in humans. To evaluate the impact of AA on the human urinary tract epithelium cells, a study of SV-HUC-1 cells cultured with mixture of AA (AAM; 41% AA I, 56% AA II) was conducted. Cell viability was assayed in cultures exposed to 0.0125-0.2mM AAM for 1, 3, and 5 days, a concentration-dependent inhibition on the growth of SV-HUC-1 cells was demonstrated. Cell cycle distribution determined by flow cytometry revealed an accumulation of cells in the G0/G1 phase (from 37.6% to 49.2%). Regarding the cell cycle control proteins, the levels of p53, p21 and p27 increased in a concentration-dependent manner. Immunoprecipitation demonstrated a decrease in the formation of cyclin E/cdk2 complex, but not cyclin D1/cdk4 complex, which leads to an increase in the free form of cdk2. Additionally, a decrease in the phospho-Rb correlates with an increase in Rb/E2F-1 complex which prevents the release of E2F transcription factor, thus preventing the transcription of the genes required for cell proliferation. Our results provide evidence that AAM induce cell cycle arrest in SV-HUC-1 cells. Whether this cell cycle block is associated with AA-related human urothelial carcinoma requires further study to clarify.

We retrospectively analyzed the impact of sirolimus addition (SRL) with a 25% dosing reduction in calcineurin inhibitors on liver function among patients with or without hepatitis B virus (HBV) or hepatitis C virus (HCV) infection.Forty-eight renal transplant recipients (HBsAg-positive, n = 5; anti-HCV-positive, n = 7) with allograft dysfunction (serum creatinine: mean 2.7, median 2.0 mg/dL) and normal liver function were enrolled. The duration of the SRL add-on therapy was 8.0 +/- 3.6 months. SRL trough levels were maintained within 6.5 +/- 3.7 ng/mL. The trough levels of tacrolimus and the 2-hour cyclosporine postdose levels were tapered to 4.6 +/- 1.9 ng/mL (24.6% reduction) and 650 +/- 170 ng/mL (24.3% reduction), respectively. SRL-related hepatitis was defined as a rise in liver transferase or alkaline phosphatase or bilirubin over twice the upper limit of normal. Thirty-six HBsAg-negative and anti-HCV-negative patients served as the controls.Hepatotoxicity developed in 6 (12.5%) of the 48 patients and in 3 (8.3%) of 36 control subjects. One (20.0%) of five HBsAg-positive patients (P = .959) and two (28.6%) of seven anti-HCV-positive patients (P = .496) developed hepatotoxicity, respectively. Three (25.0%) of the 12 HBsAg-positive or anti-HCV-positive patients developed hepatotoxicity (P = .420).Patients with seropositivity of HBsAg or anti-HCV had an insignificantly higher percentage of hepatitis. Use of SRL in the HBV/HCV patients is not contraindicated, but needs monitoring for HBV/HCV activation.

Leprosy is rarely seen in organ transplant patients; only ten cases of leprosy in organ transplant recipients have been reported. We herein report a Taiwanese renal transplant recipient concomitantly infected with borderline lepromatous leprosy. A 68-year-old male received renal transplantation at Guilin, China, in 2000, and then received immunosuppressive therapy with prednisolone, tacrolimus, and mycophenolate. Three years after transplantation, multiple erythematous tender nodules and plaques over the face and lower limbs developed. Biopsies and histopathological examination confirmed the diagnosis of leprosy. We treated the patient with a multidrug regimen including dapsone, clofazimine, and rifampine since November of 2003 with a good response. Unfortunately, he suffered from a cluster of complications after an accidental fall, finally leading to septic shock and death five months later. In summary, we report a rare case of new-onset leprosy after renal transplantation in Taiwan and suggest leprosy should be listed in the differential diagnosis of unusual skin manifestations in organ transplant patients.

NOx causes DNA damage due to an inflammatory effect of gouty arthritis. We investigated the concentration of 8-nitroguanine (8-NO(2)-G) in the blood of patients with arthritis.Subjects were divided into 3 groups: (1) high inflammatory (HI) group (n = 21) with hyperuricemia (mean, 8.9 mg/dl) and leukocytosis, (2) low inflammatory (LI) group (n = 14) with mild hyperuricemia (mean, 7.6 mg/dl) but normal leukocyte count, (3) non-inflammatory (NI) healthy control (n = 19) with mean serum uric acid concentration 5.3 mg/dl and normal leukocyte count. Serum C-reactive protein (CRP) concentrations were measured by a visual agglutination method. The blood concentrations of 8-NO(2)-G were determined by high performance liquid chromatography-electrochemical detection and were compared between groups.There was significant difference in percentage of positive CRP (NI: 55.6%, LI: 64.3%, HI: 100%, p = 0.003) between the 3 groups. The leukocyte count (mean +/- S.E., NI: 7400 +/- 528, LI: 7686 +/- 433, HI: 10952 +/- 691/mm(3), p0.001), uric acid (NI: 5.3 +/- 0.24, LI: 7.6 +/- 0.4, HI: 8.9 +/- 0.36 mg/dl, p0.001), NO(2) (NI: 6.5 +/- 1.2, LI: 11.1 +/- 2.9, HI: 35.6 +/- 5.1 microg/ml, p0.001) and the 8-NO(2)-G (NI: 0.08 +/- 0.03; LI: 0.34 +/- 0.13; HI: 0.59 +/- 0.09 ng/microg DNA, p = 0.002) were significantly increased by inflammation.Gouty inflammation induces DNA damage by increasing 8-NO(2)-G through endogenous NO and ROS formation.

Introduction We sought to evaluate the efficacy of enteric-coated mycophenolate sodium (EC-MPS) and the gastrointestinal (GI) adverse events in de novo kidney transplant recipients. Methods This noncontrolled, retrospective review includes 22 de novo kidney transplant recipients. All patients received a standard course of basiliximab and were maintained on triple-drug therapy with EC-MPS, cyclosporine microemulsion (CsA), and prednisolone. The follow-up lasted 7.9 ± 1.2 months. The incidence of GI adverse effects were compared with those of historical mycophenolate mofetil (MMF) studies. Results The serum creatinine was maintained within 1.4 ± 0.7 mg/dL. The 2-hour CsA postdose level was 1080 ± 327 ng/mL initially and gradually tapered to 851 ± 435 ng/mL. The daily EC-MPS dose was 1404 ± 180 mg initially and gradually tapered to 1098 ± 288 mg. The GI adverse effects at the daily dose of EC-MPS 1422 ± 126 mg included dyspepsia 27%, acid regurgitation 18.2%, epigastralgia 9%, nausea 9%, vomiting 4.5%, and poor appetite 4.5%. In comparison those from historical MMF 2 g/d studies included dyspepsia 3.1% to 40%, epigastralgia 10%, nausea 3.7% to 34%, and vomiting 0.6% to 10.7%. Conclusion Immunosuppression with CsA, EC-MPS, and steroids maintains stable graft functions. Minimal dose reduction of EC-MPS decreases GI adverse events but without significance. EC-MPC and MMF have respective GI side effects; they can be used alternatively in patients with individual GI intolerance.

Cancer is a well-documented complication after kidney transplantation. Increased incidence of bladder cancer had been reported in long-term hemodialysis patients in Taiwan. Herein, the authors report a very high cumulative incidence of transitional cell carcinoma (TCC) of the urinary tract after kidney transplantation in Taiwan.The authors retrospectively reviewed the clinical data, medical records, and outcome of 730 kidney transplant (KT) recipients. The cumulative incidence of TCC was computed. The Cox regression method was used to analysis the role of potential risk factors.After a mean follow-up duration of 72.2 +/- 54.4 months, 69 cancers were diagnosed in 63 (8.6%) KT recipients. Of them, 30 cases (4.1%) were TCC. The cumulative incidence for TCC was 3.0% after 3 years of graft survival, increasing to 7.2% at 6 years and 17.5% at 10 years. Compared with the general population in Taiwan, the standardized mortality ratio was 398.4 (male, 192.6; female, 875.6). Painless gross hematuria was the cardinal initial symptom in 22 (73.3%) of the 30 KT recipients with TCC. Another 4 (13.3%) KT recipients with TCC presented with chronic urinary tract infection (UTI). Bilateral nephroureterectomy with removal of bladder cuffs was performed in 18 (60%) patients. Synchronous TCC in bilateral upper urinary tracts was confirmed in 11 (36.7%) of KT recipients with TCC. The age at the time of KT, female sex, compound analgesics usage, Chinese herb usage, and underground water intake had statistical significance as risk factors (P0.05).The KT recipients are at extremely high risk for TCC in Taiwan, with an incidence of 4.1%. This study indicates that hematuria and chronic UTI are the initial presentation of TCC in KT recipients. Carefully urologic screening is indicated for patients with high risk for TCC, including those with older age, compound analgesics usage, Chinese herbs usage, and underground water intake as well as women.