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Plasma cell-rich acute rejection (PCAR), a subtype of T cell-mediated rejection, is a relatively rare type of acute allograft rejection, that is usually associated with a higher rate of graft failure. However, it is difficult to diagnose PCAR precisely.A 45-year-old woman who had received a kidney transplant presented with acute kidney injury and uremic symptoms approximately 1 year after transplantation.A renal biopsy was performed and pathological examination revealed marked inflammation with abundant plasma cells in areas within interstitial fibrosis and tubular atrophy. The patient was diagnosed with PCAR and chronic active T cell-mediated rejection (CA-TCMR) grade IA.Immunosuppressants were administered as tacrolimus (2 mg twice daily), mycophenolate mofetil (250 mg twice daily), and prednisolone (15 mg/day) for suspected PCAR.The patients showed rapid deterioration in kidney function and reached impending graft failure.PCAR is often associated with poor graft outcome. The high variability in tacrolimus levels could contribute to poor patient outcomes, leaving aggressive immunosuppressive therapy as the remaining choice for PCAR treatment.

Background: Kidney transplantation is a lifesaving option of selected patients with end-stage kidney disease (ESKD). Urothelial carcinoma (UC) is the most common de novo cancer after kidney transplantation in Taiwan. UC has the characteristics of high mutational burden and elevated degree of molecular heterogeneity compared with other solid tumors. However, there are limited research exploring the genomic alterations in UC after kidney transplantation. Methods: In this study, we performed whole exome sequencing (WES) to compare the genetic alterations between UC developed after kidney transplantation (UCKT) and UC from hemodialysis patients (UCHD). After mapping and variant calling, a total of 18,733 and 11,093 mutations were identified from UCKT and UCHD patients, respectively. We first excluded known SNPs and then retained genes that were annotated in Cosmic, Intogen, and TCGA bladder databases for onco-driver genes. Seventeen UCKT unique genes with recurrent SNPs in more than two patients were subjected for further analysis. IPA pathway analysis was used to explore the interconnections among these genes. Results: 17 novel mutations of BTK, CARD11, ELL, FNBP1, GNAQ, HOXD13, IKZF1, MAX, MLLT10, NTRK3, PAX5, SEPTIN6, SEPTIN9, SH3GL1, SLC34A2, TAL1 , and TRAF7 were identified UCKT groups, and none of the genes had been reported in the genomes of patients with UC. Among the affected genes, GNAQ, IKZF1, and NTRK3 were potentially involved in the signaling network of UCKT. Conclusion : Our findings provide information for understanding the mutational landscape of UC developed after kidney transplantation, and a gene list that may be of great importance in related molecular mechanisms. Genetic analysis in malignancy after transplantation may help to identify high risk patients in post-transplant care and also illuminate a fundamental aspect of the molecular pathogenesis of post-transplantation UC.

Kidney transplant recipients are a unique subgroup of chronic kidney disease patients due to their single functioning kidney, immunosuppressive agent usage, and long-term complications related to transplantation. Post-transplant diabetes mellitus (PTDM) has a significant adverse effect on renal outcomes in particular. As transplantations enable people to live longer, cardiovascular morbidity and mortality become more prevalent, and PTDM is a key risk factor for these complications. Although PTDM results from similar risk factors to those of type 2 diabetes, the conditions differ in their pathophysiology and clinical features. Transplantation itself is a risk factor for diabetes due to chronic exposure to immunosuppressive agents. Considering current evidence, this article describes the risk factors, pathogenesis, diagnostic criteria, prevention strategies, and management of PTDM. The therapeutic options are discussed regarding their safety and potential drug–drug interactions with immunosuppressive agents.

The introduction of mammalian target of rapamycin inhibitors (mTORi) as immunosuppressive agents has changed the landscape of calcineurin inhibitor-based immunosuppressive regimens. However, the timing of mTORi conversion and its associated outcomes in kidney transplantation have conflicting results. This study investigated the effect of early or late mTORi post-transplant initiation on major transplant outcomes, including post-transplant malignancy, in kidney transplant recipients in our center. We enrolled 201 kidney transplant recipients with surviving function grafts of >3 months between 1983 and 2016. Patients were divided into three groups: early mTORi (initiated within 6 months of kidney transplantation), late mTORi, (mTORi initiation >6 months after kidney transplantation) and no mTORi. The mean creatinine at conversion was 1.46 ± 0.48 mg/dL and 1.30 ± 0.53 mg/dL for the early and late mTORi groups, respectively. During the study period, 10.5% of mTORi users and 19.2% of mTORi nonusers developed malignancy, mainly urothelial carcinoma. After adjustment for confounding factors, mTORi users were found to have a lower incidence of post-transplant malignancy than did nonusers (adjusted OR: 0.28, P = 0.04). No significant difference was observed between early and late mTORi users. Our results verified the potential advantages of mTORi usage in reducing cancer incidence after kidney transplantation. However, no significant result was found related to the timing of mTORi introduction. Future studies should include a longer observation period with a larger cohort.

Digoxin is commonly prescribed for heart failure and atrial fibrillation, but there is limited data on its safety in patients with chronic kidney disease (CKD). We conducted a population-based cohort study using the pre-end stage renal disease (ESRD) care program registry and the National Health Insurance Research Database in Taiwan. Of advanced CKD patient cohort (N = 31,933), we identified the digoxin user group (N = 400) matched with age and sex non-user group (N = 2,220). Multivariable Cox proportional hazards and sub-distribution hazards models were used to evaluate the association between digoxin use and the risk of death, cardiovascular events (acute coronary syndrome, ischemic stroke, or hemorrhagic stroke) and renal outcomes (ESRD, rapid decline in estimated glomerular filtration rate—eGFR, or acute kidney injury). Results showed that all-cause mortality was higher in the digoxin user group than in the non-user group, after adjusting for covariates (adjusted hazard ratio, aHR 1.63; 95% CI 1.23–2.17). The risk for acute coronary syndrome (sub-distribution hazard ratio, sHR 1.18; 95% CI 0.75–1.86), ischemic stroke (sHR 1.42; 95% CI 0.85–2.37), and rapid eGFR decline (sHR 1.00 95% CI 0.78–1.27) was not significantly different between two groups. In conclusion, our study demonstrated that digoxin use was associated with increased mortality, but not cardiovascular events or renal function decline in advanced CKD patients. This finding warns the safety of prescribing digoxin in this population. Future prospective studies are needed to overcome the limitations of cohort study design.

Background Mammalian target of rapamycin inhibitors (mTORi) play an essential role as novel immunosuppressive agents in kidney transplantation (KT). Treatment cessation usually occurs after adverse effects occur. We investigated the risk factors associated with withdrawal of mTORi in KT recipients and evaluated the outcomes related to the withdrawal. Methods The study enrolled KT recipients being followed up in a medical center in southern Taiwan from January 1999 through December 2014. Results Risk factors associated with mTORi withdrawal were initial proteinuria level, higher initial serum creatinine level posttransplantation, and history of glomerulonephritis as the primary etiology of renal failure. mTORi withdrawal was associated with increased risk of graft failure (hazard ratio [HR], 9.97 [95% confidence interval (CI), 1.03–96.8]; P = .047). Higher body mass index (HR, 11.2 [95% CI, 1.63–76.6]; P = .01) and tacrolimus usage (HR, 8.30 [95% CI, 1.14–60.7]; P = .037) were associated with increased risk of new-onset diabetes after transplantation in mTORi withdrawal groups. Conclusions Proteinuria, poor graft function, and primary glomerulonephritis were associated with cessation of mTORi treatment. Earlier identification of these risk factors may prevent further adverse events and optimize transplantation outcomes after mTORi conversion.

Treatment with mammalian target of rapamycin inhibitors (mTORi) has been associated with an increased incidence of proteinuria after kidney transplantation as compared to other immunosuppressive agents. Proteinuria after mTORi use may occur in different clinical conditions and the precise mechanism remains unclear. The objective of this study was to investigate the related risk factors for proteinuria after mTORi treatment in kidney transplant recipients. This retrospective observational study population consisted of kidney transplant recipients followed up in a medical center in Southern Taiwan from January 1999 to April 2016. The baseline characteristics and transplantation-related profiles were collected at the time of enrollment. We examined risk factors for mTORi-associated proteinuria using a multivariate logistic regression analysis. P .05 was considered as statistically significant. Hyperlipidemia and obesity at the initiation of mTORi treatment were strong predictors for proteinuria. Earlier identification of these risk factors may assist physicians in deciding the best candidate for mTORi conversion in order to optimize transplantation outcomes.

Dipyridamole has been shown to decrease proteinuria and improve renal function progression especially in early chronic kidney disease (CKD) patients with glomerulonephropathy. A combination therapy of dipyridamole with aspirin could prevent second strokes in the general population. Whether these effects of dipyridamole are also true in advanced CKD patients and whether dipyridamole could improve renal outcomes or patient survival is unknown. We retrospectively analyzed an observational cohort of 3074 participants with CKD stage 3–5 from southern Taiwan, of whom 871 (28.3%) had received dipyridamole treatment ≥50 mg/d for ≥3 months and more than half of the observation period. The mean age was 63.6 ± 13.4 years and the mean estimated glomerular filtration rate (eGFR) was 25.5 mL/min/1.73 m2. After inverse probability of treatment weighted adjustment by propensity score, there were no differences between the dipyridamole-treated and untreated groups. Dipyridamole treatment was associated with decreased odds for rapid eGFR decline [odds ratio, 0.755; 95% confidence interval (CI), 0.595–0.958; p = 0.007] and progression of urine protein-to-creatinine ratio (odds ratio, 0.655; 95% CI, 0.517–0.832; p = 0.002). In survival analysis, the dipyridamole-treated group was also associated with a decreased risk for end-stage renal disease (hazard ratio, 0.847; 95% CI, 0.733–0.980; p = 0.011) and all-cause mortality (hazard ratio, 0.765; 95% CI, 0.606–0.971; p = 0.001) but not for cardiovascular events. Our findings demonstrate that dipyridamole treatment is significantly associated with better renal outcomes and patient survival in patients with CKD stage 3–5. Further investigations are warranted to confirm these independent positive effects.

Background/Aims: Gastrointestinal (GI) symptoms in renal transplant recipients may be caused due to mycophenolic acid (MPA) toxicity. Using small bowel capsule endoscopy (SBCE) we examined the impact of conversion from Mycophenolate Mofetil (MMF) to enteric-coated formulation of Mycophenolate Sodium (EC-MPS) given to treat GI mucosal lesions. Methods: Adult kidney-only recipients at least 30 days after transplant, presenting with GI symptoms while receiving MMF completed a Gastrointestinal Symptom Rating Scale (GSRS) questionnaire, underwent SBCE, and had MMF substituted by EC-MPS. After 30 days, GSRS and SBCE were repeated and findings were compared to baseline values. Patients who were still on EC-MPS 6-24 months post-conversion were contacted for completing a follow-up GSRS questionnaire and SBCE. Results: Eighteen out of 23 subjects completed the first part of the study. Subjects' median ages and post-transplant time were 47.5 years old and 4.5 months, respectively. Tacrolimus, MMF and prednisone was the main regimen (94%), with a median MMF dose of 750 mg BID. The average baseline GSRS was 2.99 ± 0.81; it significantly decreased to 2.19 ± 0.8 at 30 days post-conversion. At baseline, 50 had gastric and 89% had small bowel lesions. At 30 days, 29 and 62% of the SBCE were still showing gastric and small bowel lesions, respectively. Of 5 patients in the study extension, 4 had abnormal SBCE findings but have been reporting improvement in their symptoms. Conclusion: Stomach and small bowel mucosal lesions are common in kidney recipients with GI symptoms when treated with MMF. Conversion to EC-MPS for 30 days significantly alleviated the GI symptoms; however, no evident correlation with SBCE findings was found.

Angiopoietins (Angpt) and vascular endothelial growth factor (VEGF) have been associated with cardiovascular disease. The study enrolled 270 pre-dialysis stage 3–5 CKD patients to assess the link between circulating Angpt2, Angpt1 and VEGF-A and subclinical measures of cardiovascular structure and function. Serum markers of angiogenesis were measured using commercial enzyme-linked immunosorbent assays. Cardiac structure and function were examined by echocardiography. Brachial-ankle pulse wave velocity (baPWV) was measured by the ankle-brachial index. The adjusted mean of left ventricular mass index (LVMI) was 2.05 in patients of Angpt2 quartile 4 and 1.99 in those of Angpt2 quartile 1 (P = 0.04). Angpt2 was significantly associated with LV hypertrophy (LVH) (Angpt2 quartile 4 compared with Angpt2 quartile 1: adjusted OR: 2.68, 95% CI: 1.15–6.20). Angpt1 was negatively correlated with left atrial diameter (adjusted mean of LAD: 3.59 in Angpt1 quartile 4, 3.92 in Angpt1 quartile 1, P = 0.03). A positive and significant correlation was found between Angpt2 level and baPWV in spearman’s correlation, but not in adjusted model. In conclusion, high Angpt2 and low Angpt1 levels were positively associated with abnormal cardiac structure in stages 3–5 CKD patients, which is compatible with the viewpoint that angiopoietins participates in cardiovascular burdens.

BACKGROUND We aimed to investigate the impact of antibody induction on outcomes in human leukocyte antigen (HLA) 0-mismatched deceased donor kidney recipients. METHODS Using the Organ Procurement and Transplant Network/United Network of Organ Sharing database as of November 2009, we identified 44,008 adult deceased donor kidney recipients who received primary kidney transplants alone between 2003 and 2008 (HLA 0 mismatch, n = 6274; ≥ 1 mismatch, n=37,734; median follow-up: 834 days). The impact of induction (thymoglobulin, interleukin-2 receptor antagonists [IL-2RA], or alemtuzumab; vs. no induction) on rejection (initial hospitalization, 6 months, first year), death-censored graft failure, and mortality were analyzed using multivariate logistic and Cox regression in the two groups. The impact of individual agents on outcomes was further analyzed in 0-mismatch recipients. RESULTS There was a decreased risk of rejection over the first 6 months for HLA 0-mismatch recipients of antibody induction (adjusted odds ratio=0.71, P=0.003), but this effect was not observed at 1 year; in comparison, induction was associated with a reduced risk of rejection over the first year for HLA-mismatched recipients (0.87, P

The majority of kidney transplant recipients in the United States receive antibody induction, but its impact on outcomes in living donor transplant is not well-described. We used Organ Procurement and Transplant Network/United Network for Organ Sharing (OPTN/UNOS) data as of November 2009 to compare acute rejection (AR) and graft survival among all primary adult living donor kidney recipients of no antibody induction, antithymocyte globulin (ATG) and interleukin-2 receptor antagonists (IL-2RA) in an earlier era (1998-2002; n=21,919) and a later era (2003-2008, n=26,837). The incidence of AR in the overall cohort decreased from 18.5% in 1998 to 8% in 2008. From 1998 to 2002, antibody induction was associated with a decreased risk of acute rejection at six months (RR 0.67, 95% CI 0.62-0.72) and one yr (RR 0.71, 0.65-0.76), while in the recent era, induction was not associated with acute rejection at six months (RR 0.97, 0.88-1.07) or one yr (RR 1.01, 0.91-1.10). There was no difference in graft survival over five yr with antibody induction in either era. Although antibody induction was associated with a decreased risk of AR from 1998 to 2002, it was not associated with a decreased risk of acute rejection from 2003 to 2008, nor was it associated with a difference in graft survival in either era.

Pre-existing hepatitis B virus (HBV) infection has been associated in inferior renal transplant outcomes. We examined outcomes of HBV+ renal recipients in a more recent era with availability of oral anti-viral agents.Using the Organ Procurement Transplant Network/United Network for Organ Sharing database, we selected adult primary kidney recipients transplanted in the United States (2001 to 2007). The cohort was divided into HBV+ (surface antigen positive, n = 1346) and HBV- patients (surface antigen negative; n = 74,335). Five-year graft survival, patient survival, hepatic failure incidence, and associated adjusted risks were compared.HBV+ recipients were more frequently Asian, had a lower body mass index, and glomerulonephritis was more prevalent as the etiology of ESRD. HBV+ recipients had less pretransplant diabetes and cardiovascular disease, were less likely a living donor recipient, and were less likely to receive steroids at discharge. Five-year patient survival was 85.3% and 85.6% and graft survival was 74.9% and 75.1% for HBV+ and HBV-, respectively. HBV infection was not a risk factor for death or kidney failure, although 5-year cumulative incidence of hepatic failure was higher in HBV+ recipients (1.3% versus 0.2%; P0.001), and HBV+ was associated with 5.5- and 5.2-fold increased risk for hepatic failure in living and deceased donors, respectively, compared with HBV-.In a recent era (2001 to 2007), HBV-infected renal recipients were not at higher risk for kidney failure or death; however, they remain at higher risk of liver failure compared with HBV- recipients.

Summary Background and objectives The choice of induction agent in the elderly kidney transplant recipient is unclear. Design, setting, participants, & measurements The risks of rejection at 1 year, functional graft loss, and death by induction agent (IL2 receptor antibodies [IL2RA], alemtuzumab, and rabbit antithymocyte globulin [rATG]) were compared among five groups of elderly (60 years) deceased-donor kidney transplant recipients on the basis of recipient risk and donor risk using United Network of Organ Sharing data from 2003 to 2008. Results In high-risk recipients with high-risk donors there was a higher risk of rejection and functional graft loss with IL2RA versus rATG. Among low-risk recipients with low-risk donors there was no difference in outcomes between IL2RA and rATG. In the two groups in which donor or recipient was high risk, there was a higher risk of rejection but not functional graft loss with IL2RA. Among low-risk recipients with high-risk donors, there was a trend toward a higher risk of death with IL2RA. Conclusions rATG may be preferable in high-risk recipients with high-risk donors and possibly low-risk recipients with high-risk donors. In the remaining groups, although rATG is associated with a lower risk of acute rejection, long-term outcomes do not appear to differ. Prospective comparison of these agents in an elderly cohort is warranted to compare the efficacy and adverse consequences of these agents to refine the use of induction immunosuppressive therapy in the elderly population. Clin J Am Soc Nephrol 6: 1168–1178, 2011. doi: 10.2215/CJN.07540810

Ye X, Kuo H-T, Sampaio MS, Jiang Y, Bunnapradist S. Risk factors for development of new-onset diabetes mellitus after transplant in adult lung transplant recipients. Clin Transplant 2011: 25: 885–891. © 2010 John Wiley & Sons A/S. Abstract: The objectives of this study are to examine the incidence of new-onset diabetes mellitus after transplant (NODAT) and to identify its risk factors in adult lung transplant recipients using the Organ Procurement and Transplant Network/United Network of Organ Sharing database. Between July 2004 and December 2007, a total of 3540 adults (≥18 yr old) received their first single- or double-lung transplant alone and had at least one follow-up report of post-transplant diabetic status. Among these, 2991 recipients were identified as not having diabetes mellitus (DM) pre-transplant. Risk factors for NODAT were examined. DM was newly reported in 33.4% of the 2991 recipients over the median follow-up time of 670 d. Significant independent risk factors for the development of NODAT included male gender (HR = 1.15), recipient age ≥50 (1.46), African American (1.39), higher body mass index (1.51 for ≥30 vs. 18–25), cystic fibrosis (3.30), and tacrolimus use at discharge (1.67). NODAT occurred in a third of adult lung transplant recipients during the median follow-up period. Some of the risk factors for NODAT after lung transplant are similar to those reported in other solid-organ transplants. Cystic fibrosis is a strong risk factor for development of NODAT after lung transplant.

Background. The objectives of this study are to investigate the impact of cytomegalovirus (CMV) donor (D)/recipient (R) serostatus on kidney transplant outcomes in recipients who received CMV prophylaxis and to investigate the association of individual antiviral agents (acyclovir, ganciclovir, and valganciclovir) with outcomes in high-risk recipients (D+/R-). Methods. By using the Organ Procurement and Transplant Network/United Network for Organ Sharing database, 25,058 deceased donor kidney recipients (≥18 years, 2004-2008) who received CMV prophylaxis were stratified into four groups: D+/R+ (11,875), D-/R+ (6046), D+/R- (4555), and D-/R- (2582). The impact of CMV D/R serostatus on acute rejection (6 months and 1 year posttransplant) and long-term outcomes of death-censored graft failure and mortality were compared. The impact of the individual antiviral agent on long-term outcome was further evaluated in the high-risk group (D+/R-). Results. In multivariate analysis, CMV D/R status was not associated with acute rejection. Compared with D-/ R-, D+/R- was associated with an increased risk for death-censored graft failure (hazard ratio= 1.28, P=0.01), all-cause mortality(hazard ratio=1.36, P=0.003), and mortality because of viral infection (hazard ratio=8.36, P=0.04). In the D+/R- group, valganciclovir usage was associated with a decreased risk for death-censored graft failure (hazard ratio=0.65, P=0.007) and mortality because of viral infection (hazard ratio=0.22, P=0.03) compared with ganciclovir usage. Conclusions. CMV mismatch (D+/R-) was no longer a risk factor for acute rejection in kidney recipients who received antiviral prophylaxis but was still an independent risk factor for death-censored graft failure, all-cause mortality, and viral infection-related mortality.

Introduction Fluid overload is one of the major characteristics and complications in patients with chronic kidney disease (CKD). N-terminal pro-brain natriuretic peptide (NT-proBNP) is related to fluid status and fluid distribution. The aim of this study is to investigate the interaction between NT-proBNP and fluid status in adverse clinical outcomes of late stages of CKD. Methods We enrolled 239 patients with CKD stages 4–5 from January 2011 to December 2011 and followed up until June 2017. Fluid status was presented as hydration status (HS) value measured by body composition monitor, while HS>7% was defined as fluid overload. Clinical outcomes included renal outcomes (commencing dialysis and estimated glomerular filtration rate decline>3 ml/min/1.73 m2/year), all-cause mortality and major adverse cardiovascular events (MACEs). Results During a mean follow-up of 3.3±2.0 years, 129(54.7%) patients commenced dialysis, 88(37.3%) patients presented rapid renal function decline, and 48(20.3%) had MACEs or died. All patients were stratified by HS of 7% and the median of plasma NT-proBNP. The adjusted risks for commencing dialysis was significantly higher in patients with high plasma NT-proBNP and HS>7% compared to those with low plasma NT-proBNP and HS≦7%. There was a significant interaction between plasma NT-proBNP and HS in commencing dialysis (P-interaction = 0.047). Besides, patients with high plasma NT-proBNP and HS>7% had greater risks for MACEs or all-cause mortality than others with either high plasma NT-proBNP or HS>7%. Conclusion NT-proBNP and fluid overload might have a synergistic association of adverse clinical outcomes in patients with late stages of CKD.

We evaluated the effectiveness of induction therapy on transplant outcomes during 2004-2007 in the United States. We retrospectively reviewed OPTN/UNOS registry and selected kidney pediatric (

Background. Preexisting hepatitis C virus (HCV) infection is implicated in diminished patient and graft survivals in renal transplant recipients. The impact of HCV infection on patient and graft survival in simultaneous pancreas-kidney transplantations is unclear. We evaluated the effect of preexisting HCV infection on patient and graft survival in simultaneous pancreas-kidney transplant (SPKT) recipients in the United States. Methods. Using the Organ Procurement and Transplant Network/United Network for Organ Sharing database as of March 2009, adult primary SPKT recipients transplanted from 1995 to 2008 were studied. We stratified recipients based on pretransplant HCV status as HCV positive (HCV+) or HCV negative (HCV-). Overall kidney graft, pancreas graft, and patient survival were compared. Results. A total of 10,809 adults received primary SPKT, of which 350 (3.2%) were HCV+. Less than 2% of the HCV+ recipients received organs from HCV+ donors. There were no significant differences in baseline donor and recipient characteristics between groups. Rates of acute kidney rejection at 1 year were similar: 22.9% for HCV+ and 23.0% for HCV— recipients (P=0.49). There was no difference in serum creatinine between groups up to 3 years. After controlling for confounding factors, HCV positivity was not associated with worsened overall kidney graft (hazard ratio [HR] 0.80, 95% confidence interval [CI] 0.61-1.03), pancreas graft (HR 0.80, 95% CI 0.63-1.00), or patient survival (HR 0.78, 95% CI 0.56-1.08). Conclusions. Only 3.2% of SPKT recipients had preexisting HCV infection. Preexisting HCV infection had no significant impact on kidney graft, pancreas graft, or patient survival.

Background. The objectives of this study are to examine the incidence of new-onset diabetes mellitus (NODM) and to identify its risk factors in adult heart recipients using the Organ Procurement and Transplant Network/United Network of Organ Sharing database. Methods. Between July 2004 and December 2007, 4972 adults (aged 18 years or older) received their first heart transplant alone, and had at least one follow-up report of posttransplant diabetic status. Among these, 3763 recipients were identified as not having diabetes mellitus pretransplant. Risk factors for NODM were examined using multivariate Cox regression analysis using the time to NODM diagnosis as a time-varying endpoint. Results. NODM was reported in 1075 (28.6%) of the 3763 recipients without pretransplant diabetes (median follow-up time, 713 days). Independent risk factors for development of NODM included older age (hazard ratio= 1.20 for age ≥50 years vs.

BACKGROUND.: In kidney transplant, obesity was reported to be associated with increased posttransplant complications and worse survival outcomes. The impact of obesity in simultaneous pancreas-kidney (SPK) transplant is less known. METHODS.: Using Organ Procurement Transplantation Network/United Network for Organ Sharing data as of August 2008, we included all adults (>18 years) type 1 diabetic SPK recipients between years 2000 and 2007 with a pretransplant body mass index (BMI) of 18.5 to 40 kg/m. The cohort was divided in three groups: normal (BMI 18.5-24.9 kg/m, reference group), overweight (BMI 25-29.9 kg/m), and obese (BMI 30-40 kg/m). Covariate-adjusted relative risk of a combination of posttransplant complications and patient, pancreas and kidney allograft outcomes were evaluated. RESULTS.: Of 5725 recipients, 56%, 33%, and 11% were in normal, overweight, and obese groups, respectively. Overweight and obese recipients were older, had a higher percent of coronary artery disease, and private health insurance coverage. Overall posttransplant complications were higher in obese group (35.7% vs. 28.6%) when compared with normal BMI group. They were mainly due to increased delayed kidney graft function (11.8% vs. 7.4%), 1-year kidney acute rejection (17.0% vs. 12.1%), and pancreas graft thrombosis (2.6% vs. 1.3%). After adjusting for possible confounders, the odds ratios for overall transplant complications were 1.03 (95% confidence interval [CI]: 0.90-1.17) for overweight and 1.38 (95% CI: 1.15-1.68) for obese. Obesity, but not overweight, was associated with patient death (hazard ratio [HR]: 1.35; 95% CI: 1.00-1.81), pancreas graft loss (HR: 1.41; 95% CI: 1.17-1.69), and kidney graft loss (HR: 1.33; 95% CI: 1.05-1.67) at 3 years. The higher rates of death and graft failure in the first 30 days posttransplant mostly accounted for the 3-year survival differences. CONCLUSION.: Obesity in SPK recipients was associated with increased risk of posttransplant complications, pancreas and kidney graft loss, and patient death.

OBJECTIVE.: To analyze the risk factors for new-onset diabetes mellitus (NODM) in liver transplant recipients using the Organ Procurement and Transplant Network/United Network for Organ Sharing database. METHODS.: Among 20,172 primary liver recipients (ageor =18 years) transplanted between July 2004 and December 2008 in Organ Procurement and Transplant Network/United Network for Organ Sharing databases, 15,463 recipients without pretransplant diabetes were identified. Risk factors for NODM were examined using multivariate Cox regression analysis. RESULTS.: NODM was reported in 26.4% of recipients (median follow-up, 685 days). Independent predictors of NODM development included recipient age (or = 50 vs.50 years, hazard ratio [HR]=1.241), African American race (HR=1.147), body mass index (or = 25 vs.25, HR=1.186), hepatitis C (HR=1.155), recipient cirrhosis history (HR=1.107), donor age (or = 60 vs.60 year, HR=1.152), diabetic donor (HR=1.151), tacrolimus (tacrolimus vs. cyclosporine, HR=1.236), and steroid at discharge (HR=1.594). Living donor transplant (HR=0.628) and induction therapy (HR=0.816) were associated with a decreased risk of NODM. CONCLUSION.: The incidence of NODM was 26.4% in liver recipients with a median follow-up time of 685 days. Identified risk factors for NODM in liver transplantation were similar to that in kidney transplantation. Some of the identified factors are potentially modifiable, including obesity and the choice of immunosuppressive regimens.

The objective of this study was to identify the risk factors for new-onset diabetes mellitus (NODM) after kidney transplant in pediatric renal transplant recipients using Organ Procurement Transplant Network/United Network of Organ Sharing database.A total of 2726 nondiabetic primary kidney transplant recipients (age 2-20 years, transplanted between July 2004 and December 2007) in the Organ Procurement Transplant Network/United Network of Organ Sharing database as of August 2008 with at least one follow-up report were included. We examined the risk factors for NODM using multivariate Cox regression analysis using the time to NODM reported as a time-varying endpoint. In recipients with functional graft at 1 year after transplant, the graft survivals during subsequent 24 months were compared according to the presence of NODM within first year of transplant.NODM was reported in 4.6% (median follow-up time: 693 days). Independent risk factors for NODM included increased age (10 years vs.10 years, hazard ratio [HR]=2.143, P=0.015), abnormal body mass index percentile (5% or85% vs. 5%-85%, HR=1.697, P=0.01), and steroid use at discharge (yes vs. no, HR=3.573, P=0.03). Living donor transplant was associated with a decreased risk of NODM (living vs. deceased, HR=0.629, P=0.05). NODM within first year of transplant was not associated with inferior graft survival during subsequent 24 months.Some of the identified risk factors for NODM are potentially modifiable, including abnormal body mass index percentile and the use of steroid. Prospective clinical trials are needed to assess whether modifying these risk factors will prevent NODM.

Background. Chronic peritoneal dialysis (PD) is one of the major therapies for uremic patients. However, the peritoneal mesothelial cells (PMCs) are subject to the injury by bioincompatible dialysates. The aim of this study is to investigate the protective roles and mechanisms of heat shock response in PMCs. Methods. Primary cultured human PMCs (HPMCs) were subjected to commercial peritoneal dialysates. The cell viability was assayed by MTT test and Annexin V assay. The expression of HSPs was detected by Western blots analysis. Intracellular hydrogen peroxide and superoxide anion were detected using H2DCFDA and dHE probe, respectively, with flow cytometry. The mitochondrial membrane potential (�� m) of HPMCs was evaluated using JC1 probe with flow-cytometry. Results. Exposure of HPMCs to 1.5%, 2.5%, and 4.25% dextrose, and 7.5% icodextrin dialysates, respectively, for 60 min resulted in significantly accumulation of intracellular reactive oxygen species (ROS), �� m loss, and cell death in HPMCs. Amino acid dialysates exhibited no significant cytotoxicity. Adjusting the acidity in 1.5% dextrose and icodextrin dialysate significantly attenuated the dialysate-induced ROS generation and cell death in HPMCs. Heat pretreatment (41 ◦ C, 30 minutes), which induced HSP 27 and 72 syntheses, significantly attenuated the dialysate-induced intracellular ROS accumulation, Dym loss, and cell death in HPMCs. Conclusions. In conclusion, the acidic bioincompatible dialysates induce oxidative stress, �� m loss, and subsequent cell death in HPMCs. Amino acid dialysates is more biocompatible than glucose and icodextrin dialysates to HPMCs. Heat shock response protects HPMCs from the bioincompatible dialysates-induced cellular damage.

The present study was designed to investigate the proteomic alteration of hepatic mitochondria during sepsis and to explore the possible effects induced by heat shock treatment. Sepsis was induced by cecal ligation and puncture in Sprague-Dawley rats. Liver mitochondrial proteins were isolated and evaluated by 2-dimensional electrophoresis with broad pH-ranged (pH 3 - 10) immobile DryStrip and sodium dodecyl sulfate-polyacrylamide gel electrophoresis. The protein spots were visualized with silver stain and analyzed by Bio-2D software. Results showed that around 120 dominant spots could be separated and visualized distinctly by 2-dimensional electrophoresis analysis. Among them, three spots with the same molecular weight (56.4 kd), mitochondrial protein 1 (MP1), MP2, and MP3, were significantly altered in septic specimens. When analyzed by liquid chromatography-tandem mass spectrometry, the three spots all revealed to be an identical enzyme: aldehyde dehydrogenase 2 (ALDH2, EC 1.2.1.3). During sepsis, MP1 and MP2 were downregulated, whereas MP3 was upregulated concomitantly. Interestingly, heat shock treatment could reverse this phenomenon. Phosphoprotein staining showed that the degree of phosphorylation is higher in MP1 and MP2 than that in MP3. The enzyme activity assay showed that ALDH2 activity was downregulated in nonheated septic rats of 18 h after cecal ligation and puncture operation, and preserved in heated septic rats. The results of this study suggest that posttranslation modification, highly possible the phosphorylation, in ALDH2 may play a functional role in the pathogenesis of sepsis and provide a novel protective mechanism of heat shock treatment.

Disseminated intravascular coagulation (DIC) is a lethal situation in severe infections, characterized by the systemic formation of microthrombi complicated with bleeding tendency and organ dysfunction. Current clinical trials are not promising. In this study, we investigated the protective effect of curcumin in a lipopolysaccharide (LPS)-induced DIC model in rats. Experimental DIC was induced by sustained infusion of LPS (10 mg/kg body weight) for 4 h through the tail vein. Curcumin (60 mg/kg body weight) was given intraperitoneally 3 h before LPS infusion. Results showed that, in vivo, curcumin reduced the mortality rate of LPS-infused rats by decreasing the circulating TNF-α levels and the consumption of peripheral platelets and plasma fibrinogen. Furthermore, in vivo curcumin also has the effect of preventing the formation of fibrin deposition in the glomeruli of kidney. These results reveal the therapeutic potential of curcumin in infection-related coagulopathy of DIC.

The effects of diabetic status and acute rejection (AR) on liver transplant outcomes are largely unknown. We studied 13,736 liver recipients from the United Network for Organ Sharing/Organ Procurement Transplant Network database who underwent transplantation between 2004 and 2007 with a functioning graft for greater than 1 year. The association of pretransplant diabetes mellitus (PDM), new-onset diabetes after transplant (NODAT), and AR rates on allograft failure, all-cause mortality, and cardiovascular mortality were determined. To determine the differential and joint effects of diabetic status and AR on transplant outcomes, recipients were further stratified into 6 groups: neither (reference, n = 6600); NODAT alone (n = 2054); PDM alone (n = 2414); AR alone (n = 1448); NODAT and AR (n = 707); and PDM and AR (n = 513). An analysis with hepatitis C virus (HCV) serostatus was also performed (HCV recipients, n = 6384; and non-HCV recipient, n = 5934). The median follow-up was 2537 days. The prevalence of PDM was 21.3%. At 1 year after transplant, the rates of NODAT and AR were 25.5% and 19.4%, respectively. Overall, PDM, NODAT, and AR were associated with increased risks for graft failure (PDM, hazard ratio [HR] = 1.31, P < 0.01; NODAT, HR = 1.11, P = 0.02; AR, HR = 1.28, P < 0.01). A multivariate Cox regression analysis of the 6 recipient groups demonstrated that NODAT alone was not significantly associated with any study outcomes. The presence of PDM, AR, NODAT and AR, and PDM and AR were associated with higher overall graft failure risk and mortality risk. The presence of PDM was associated with higher cardiovascular mortality risk. The analyses in both HCV-positive and HCV-negative cohorts showed a similar trend as in the overall cohort. In conclusion, PDM and AR, but not NODAT, is associated with increased mortality and liver allograft failure. Liver Transplantation 22 796-804 2016 AASLD.

Background: Tubulointerstitial damage is a final common pathway of most renal diseases. Whether urinary neutrophil gelatinase-associated lipocalin (uNGAL), a biomarker for renal tubular damage, is of prognostic value for clinical outcomes in chronic kidney disease (CKD) patients has not been well investigated. Methods: The uNGAL and proteinuria levels were meas ured among a cohort of 473 advanced CKD patients of various etiologies recruited during 2002–2009. Results: The estimated glomerular filtration rate (eGFR) was 32.3 ± 22.0 mL/min/1.73 m 2 with a urine protein-to-creatinine ratio (UPCR) 680 (255–1248) mg/g and 132 (27.9%) participants had diabetes. The baseline uNGAL level was significantly associated with male gender, eGFR, UPCR, and hemoglobin. The hazard ratio (HR) of the highest uNGAL tertile for end-stage renal disease (ESRD) was 3.44 (95% CI 1.47–8.06, p = 0.004). With the adjustment of urine creatinine and urine protein, HR of the highest urine NGALto-creatinine ratio (UNCR) tertile and the highest urine NGAL-to-protein ratio (UNPR) tertile was 3.06 (95% CI 1.19– 7.90, p = 0.02) and 2.10 (95% CI 1.13–3.89, p = 0.02), respectively. UNPR increased the prediction of survival model for ESRD. HR of the highest UNCR tertile and UNPR tertile for cardiovascular (CV) events was 2.21 (95% CI 0.81–5.98, p = 0.08) and 2.79 (95% CI 1.25–6.26, p = 0.01), respectively. None of these were associated with all-cause mortality. Conclusions: Elevated uNGAL in CKD patients is associated with risks for ESRD and probably CV events. UNPR could improve the prediction for ESRD.

Results from animal experiments have suggested that reactive oxygen species (ROS) play an important role in tissue damage associated with diabetes. To determine whether ROS are involved in patients with diabetic nephropathy, we measured the plasma and urinary levels of malondialdehyde (MDA), an important marker of lipid peroxidation, and assessed the immunoreactivity of MDA and superoxide dismutase (SOD) in glomeruli of patients and experimental rats with diabetic nephropathy. Both plasma and urinary MDA levels were significantly higher in patients with diabetic glomerulosclerosis (DGS) than those of diabetic patients without proteinuria, proteinuric patients without diabetes, and normal controls. In DGS patients, the plasma MDA was significantly correlated with urinary MDA (p

This study elucidates the mechanism through which heat shock treatment influences the outcome of sepsis. Post-heat shock sepsis was induced in rats by CLP 24 h after whole-body hyperthermia. Liver cytosolic and nuclear fractions were collected and analyzed in early and late sepsis rats (sacrificed 9 and 18 h after CLP, respectively). During sepsis, levels of I-kappaB and nuclear factor-kappaB (NF-kappaB) declined in the cytosol of liver, whereas NF-kappaB increased in nucleus. NF-kappaB activity was significantly enhanced during sepsis, and the products of NF-kappaB target genes, such as TNF-alpha and inducible nitric oxide synthase (iNOS), were overexpressed. Heat shock treatment, inducing heat shock protein synthesis, prevented down-regulation of cytosolic I-kappaB and decreased translocation of NF-kappaB into the nucleus. Therefore, the sepsis-induced acceleration of NF-kappaB activation was inhibited. Expression of TNF-alpha and iNOS mRNA was also down-regulated. Coimmunoprecipitation with anti-NF-kappaB (p65) and anti-IkappaB antibodies verified an assembling phenomenon of heat shock protein (HSP) 72 with NF-kappaB and I-kappaB. We suggest that the mechanism preventing septic activation of NF-kappaB is that oversynthesized HSP72 forms a complex with NF-kappaB/I-kappaB, thus inhibiting nuclear translocation of NF-kappaB. HSP72 appears to play a crucial protective role in modulating the gene expression controlled by NF-kappaB in sepsis.

Adrenomedullin (AM) immunostaining and gene expression have seldom been measured in human kidneys. Because previous studies have shown that AM exerts antiproliferative effects on rat mesangial cells in vitro and that urine AM levels are decreased in patients with chronic glomerulonephritis, we measured glomerular AM and its gene expression in patients with primary IgA nephropathy (IgAN). Glomerular AM was measured by immunohistochemical staining, and glomerular AM mRNA was measured by in situ hybridization. Plasma and urine AM were measured by radioimmunoassay. The results showed that both the intensity of immunostaining for glomerular AM and the glomerular expression of AM mRNA were significantly decreased in IgAN patients compared with normal controls (both P.05). Similar results were not observed in patients with non-IgA MsPGN. Glomerular AM immunostaining and glomerular AM mRNA expression were significantly correlated ( P.001), and both were negatively correlated with the number of glomerular cells ( P.05 and.01, respectively). Both glomerular AM immunostaining and glomerular AM mRNA expression were correlated with urine AM levels (both P.001), but not with plasma AM levels. The urine AM level was significantly lower in IgAN patients than in normal controls ( P.01), whereas the plasma level was not different between the 2 groups. Our findings indicate that glomerular production of AM was decreased in patients with IgA nephropathy and that this lack of glomerular AM may be related to the pathogenesis of this mesangial disease.

To investigate the status and role of glutathione peroxidase (GPX) in diabetic nephropathy, we measured GPX in the plasma and urine of 14 patients with diabetic glomerulosclerosis (DGS) and measured glomerular GPX immunostaining in these patients and in rats with streptozotocin-induced diabetes of varying duration. Plasma GPX levels were significantly lower in DGS patients than in diabetic patients without nephropathy (P.05) or normal controls (P.01). Urinary GPX concentrations were also significantly lower in DGS patients than in diabetic patients without nephropathy or normal controls (both P.05). Immunostaining of glomerular GPX was significantly less in DGS patients than in normal controls (P.05) and was negatively correlated with the glomerular sclerosis score and the index of mesangial expansion. Serial examination of glomerular GPX in diabetic rats showed that immunostaining scores for glomerular GPX in rats were significantly lower than those in normal control rats after 1 and 3 months' duration of diabetes, and staining scores were also significantly lower in rats killed after 3 months of diabetes than in those killed after 1 week. In conclusion, our study demonstrates that GPX concentrations in plasma, urine, and glomeruli are decreased in individuals with DGS and that the immunostaining of glomerular GPX decreases progressively.

Liver function failure is one of the characteristics of critically ill, septic patients and is associated with worse outcome. Our previous studies have demonstrated that heat-shock response protects cells and tissue from subsequent insults and improves survival during sepsis. In this study, we have shown that mitochondrial cytochrome c oxidase (CCO) is one of the major sources of that protective effect. Experimental sepsis was induced by the cecal ligation and puncture (CLP) method. Heat-shock treatment was induced in rats by hyperthermia 24 h before CLP operation. The results showed that ATP content of the liver declined significantly, and the enzymatic activity of mitochondrial CCO was apparently suppressed during the late stages of sepsis. The mitochondrial ultrastructure of septic liver showed the deformity, mild swelling and inner membrane budding. Heat-shock treatment led to heat-shock protein 72 overexpression and prevented the downregulation of Grp75 during sepsis. On the contrary, the expression of the enzyme complex and its activity were preserved, associated with the minimization of ultrastructural deformities. In conclusion, the maintenance of mitochondrial function, especially the CCO, may be an important strategy in therapeutic interventions of a septic liver.

Dyslipoproteinemia is highly prevalent in diabetes, chronic kidney disease, and diabetic kidney disease (DKD). Both diabetes and chronic kidney disease (CKD) are associated with hypertriglyceridemia, lower high-density lipoprotein, and higher small, dense low-density lipoprotein. A number of observational studies have reported that dyslipidemia may be associated with albuminuria, renal function impairment, and end-stage renal disease (ESRD) in the general population, and especially in CKD and DKD patients. Diabetic glomerulopathy and the related albuminuria are the main manifestations of DKD. Numerous animal studies support the finding that glomerular atherosclerosis is the main mechanism of glomerulosclerosis in CKD and DKD. Some randomized, controlled trials suggest the use of statins for the prevention of albuminuria and renal function impairment in CKD and DKD patients. However, a large clinical study, the Study of Heart and Renal Protection (SHARP), does not support that statins could reduce ESRD in CKD. In this article, we analyze the complex association of dyslipoproteinemia with DKD and deduce its relevance from animal studies, observational studies, and clinical trials. We show that special subgroups could benefit from the statin treatment.

Clinical outcome of dialysis patients after eating star fruit ( Averrhoa carambola ) varies, but it may be fatal. In the past 10 years, 20 such patients were treated in our hospital when they developed clinical symptoms after eating the fruit or drinking star fruit juice. Their initial presentations included sudden-onset limb numbness, muscle weakness, intractable hiccups, consciousness disturbance of various degrees, and seizure. No other major events that might be responsible for these symptoms could be identified. Eight patients died, including one patient with a serum creatinine level of 6.4 mg/dL who had not yet begun dialysis. The clinical manifestations of the survivors were similar to those who died except for consciousness disturbance and seizure. Death occurred within 5 days despite emergent hemodialysis and intensive medical care. The survivors' symptoms usually became less severe after supportive treatment, and these patients subsequently recovered without obvious sequelae. The purpose of this article is to report that patients with renal failure who ingest star fruit may develop neurological symptoms and also run the risk for death in severe cases. Mortality may also occur in patients with chronic renal failure not yet undergoing dialysis.

Background Prior studies have indicated that type 1 diabetic (T1DM) recipients of a simultaneous pancreas-kidney (SPK) transplant have greater short-term mortality compared with living donor kidney (LDK) transplantation. Whether this association remains and how outcomes compare to deceased donor kidney (DDK) transplantation in the preemptive setting are unknown. Methods Using data on recipients transplanted between 2000 and 2010 from the Organ Procurement and Transplantation Network/United Network of Organ Sharing, patient and graft survival (calculated from the time of kidney transplant) of pancreas after preemptive LDK (PALK, n=389), preemptive LDK not receiving a pancreas transplant (LDK/noP, n=289), preemptive DDK (n=112), and preemptive SPK transplantations (n=1402) were compared. Results At 6 years, patient survival was excellent (PALK=89.4%, LDK/noP=84.9%, DDK=81.2%, and SPK=91.1%) and not different between PALK, LDK/noP, and SPK (P value vs. PALK: LDK/noP=0.08; SPK=0.85) but was lower with preemptive DDK versus preemptive PALK (P=0.03). When both LDK groups were considered together, there was higher mortality in the first 180 days after transplant with preemptive DDK (3.7% vs. 1.1%; P=0.03) and similar mortality with preemptive SPK (2.3%; P=0.07). After multivariate adjustment, there was a trend toward increased risk of death with preemptive DDK compared with preemptive PALK (hazard ratio: 1.91; 95% confidence interval: 0.95-3.84). Conclusions Patient survival associated with preemptive transplantation among T1DM recipients was excellent at 6 years, with the greatest survival favoring PALK, LDK/noP, and SPK rather than DDK. In contrast with prior studies reporting greater short-term mortality with SPK among the general T1DM population, short-term mortality after preemptive transplant is similar between LDK and SPK.

The majority of kidney transplant recipients in the United States receive antibody induction, but its impact on outcomes in living donor transplant is not well-described. We used Organ Procurement and Transplant Network/United Network for Organ Sharing (OPTN/UNOS) data as of November 2009 to compare acute rejection (AR) and graft survival among all primary adult living donor kidney recipients of no antibody induction, antithymocyte globulin (ATG) and interleukin-2 receptor antagonists (IL-2RA) in an earlier era (1998-2002; n=21,919) and a later era (2003-2008, n=26,837). The incidence of AR in the overall cohort decreased from 18.5% in 1998 to 8% in 2008. From 1998 to 2002, antibody induction was associated with a decreased risk of acute rejection at six months (RR 0.67, 95% CI 0.62-0.72) and one yr (RR 0.71, 0.65-0.76), while in the recent era, induction was not associated with acute rejection at six months (RR 0.97, 0.88-1.07) or one yr (RR 1.01, 0.91-1.10). There was no difference in graft survival over five yr with antibody induction in either era. Although antibody induction was associated with a decreased risk of AR from 1998 to 2002, it was not associated with a decreased risk of acute rejection from 2003 to 2008, nor was it associated with a difference in graft survival in either era.

The objectives of this study are to examine the incidence of new-onset diabetes mellitus after transplant (NODAT) and to identify its risk factors in adult lung transplant recipients using the Organ Procurement and Transplant Network/United Network of Organ Sharing database. Between July 2004 and December 2007, a total of 3540 adults (≥18 yr old) received their first single- or double-lung transplant alone and had at least one follow-up report of post-transplant diabetic status. Among these, 2991 recipients were identified as not having diabetes mellitus (DM) pre-transplant. Risk factors for NODAT were examined. DM was newly reported in 33.4% of the 2991 recipients over the median follow-up time of 670 d. Significant independent risk factors for the development of NODAT included male gender (HR = 1.15), recipient age ≥50 (1.46), African American (1.39), higher body mass index (1.51 for ≥30 vs. 18-25), cystic fibrosis (3.30), and tacrolimus use at discharge (1.67). NODAT occurred in a third of adult lung transplant recipients during the median follow-up period. Some of the risk factors for NODAT after lung transplant are similar to those reported in other solid-organ transplants. Cystic fibrosis is a strong risk factor for development of NODAT after lung transplant.

Our objectives are to examine the incidence of new-onset diabetes mellitus after transplant (NODAT) and to identify its risk factors in pediatric liver transplant recipients using the Organ Procurement and Transplant Network/United Network for Organ Sharing database. Between July 2004 and December 2008, a total of 1214 children (2-20 years old) received their first liver transplant alone, and had at least 1 follow-up report of posttransplant diabetic status. Among these, 1161 recipients were identified as not having diabetes mellitus before transplant. Risk factors for NODAT were examined using classification and regression tree and multivariate Cox regression analysis. Diabetes mellitus was newly reported in 10.1% of the 1161 recipients over the median follow-up time of 770 days. The cumulative incidences of NODAT at 1, 2, and 3 years after transplant were 5.9%, 8.3%, and 11.2%, respectively. More than 50% of recipients with cystic fibrosis developed NODAT. In recipients without cystic fibrosis, independent risk factors for NODAT included increased recipient age (compared to 2-5 years, hazard ratio = 3.09 for 5-13 years, p = 0.02; 7.14 for ≥13 years, p < 0.001), African American race (1.97, p = 0.003), and primary diagnosis of primary sclerosing cholangitis (2.24, p = 0.02) and acute hepatic necrosis (1.89, p = 0.04). In conclusion, NODAT occurred in one-tenth of pediatric liver transplant recipients in the United States during the median follow-up of 2 years. Some of the risk factors for NODAT in pediatric liver transplant recipients are similar to those reported in other solid organ transplants. Underlying liver disease of cystic fibrosis, primary sclerosing cholangitis, and acute hepatic necrosis are independent risk factors for NODAT in pediatric liver transplant recipients. Liver Transpl 16:1249-1256, 2010. © 2010 AASLD.

We evaluated the effectiveness of induction therapy on transplant outcomes during 2004-2007 in the United States. We retrospectively reviewed OPTN/UNOS registry and selected kidney pediatric (21-yr) recipients that received no induction (NoIND), IL-2RA, or rabbit anti-THY and were discharged with a triple drug immunosuppressive maintenance regimen, including steroids. Of 2932 recipients, 20%, 36%, and 43% were in NoIND, THY, and IL-2RA groups, respectively. The majority received tacrolimus (88%) and MMF (89%) at discharge. There was no association of induction with the risk of acute rejection even after adjusting for known cofounders. Compared to NoIND, IL2-RA, but not THY, had a modest decrease (3%) in absolute rate of graft loss and was associated with a risk reduction ratio of 0.51 (95% CI, 0.31-0.84) in one-yr graft loss. At three yr, no induction agent was associated with decreased graft loss. In conclusion, induction agents were used in 80% of pediatric kidney recipients discharged with a triple drug immunosuppressive maintenance regimen between 2004-2007 in the United States. Neither THY nor IL-2RA was associated with reduced rejection episodes. The use of induction therapy was not associated with improvement in three-yr graft survival.

Background Diabetes and acute rejection are major contributors to morbidity and mortality in kidney transplant recipients. Immunosuppressive medications decrease acute rejection, but increase the frequency of new-onset diabetes after transplant. Our objective was to investigate the joint associations of diabetes (pretransplant diabetes and new-onset diabetes after transplant) and acute rejection with transplant outcomes in a recent transplant cohort. Study Design Historical cohort study. Setting & Participants 37,448 recipients (age ≥18 years; 2004-2007) surviving with a functioning transplant for longer than 1 year were identified in the Organ Procurement and Transplant Network/United Network for Organ Sharing (OPTN/UNOS) database as of May 22, 2009. Predictors Recipients were stratified into 6 mutually exclusive groups according to status of diabetes and acute rejection at 1 year: group 1, neither (reference; n=20,964); group 2, new-onset diabetes alone (n = 2,140); group 3, pretransplant diabetes alone (n = 10,730); group 4, acute rejection alone (n = 2,282); group 5, new-onset diabetes and acute rejection (n = 361); and group 6, pretransplant diabetes and acute rejection (n = 1,061). Analyses were adjusted for other recipient, donor, and transplant characteristics. Outcomes Measurements Multivariate Cox regression analysis of time to transplant failure (overall and death censored) and mortality (all-cause and cardiovascular). Results Median follow-up after 1 year was 548 days (25th-75th percentiles, 334-752 days). During this time, there were 3,047 outcomes of overall transplant failure. New-onset diabetes alone (group 2) was not associated significantly with any study outcomes. Groups 3-6 were associated with higher overall transplant failure risk. However, only groups 4-6 were associated with higher death-censored transplant failure risk. Group 3, 4, and 6 were associated with higher all-cause mortality risk, whereas only groups 3 and 6 were associated with higher cardiovascular mortality risk. Limitations Potential information bias with exposure, covariable, or outcome misclassification; relatively short follow-up. Conclusions Pretransplant diabetes is the major predictor of all-cause and cardiovascular mortality, and acute rejection during the first year is the major predictor of death-censored transplant failure in kidney recipients surviving with a functioning transplant for at least 1 year. The influence of new-onset diabetes on long-term outcomes needs further observation.

Introduction: Bioincompatible peritoneal dialysate fluids (PDFs) may lead to peritoneal injury. The present study investigated the possible effects of N-acetylcysteine (NAC) during conventional PDF exposure for human peritoneal mesothelial cells (HPMCs). Methods: Cultured HPMCs were incubated with conventional 1.5% dextrose PDF for different time periods, and NAC was utilized as the antioxidant. The cell survival, superoxide accumulation, mitochondrial membrane potential (Δψm), expression of heat shock protein 72(HSP72), catalase, superoxide dismutase (SOD), and glutathione content of HPMCs were evaluated. Results: HPMC exposed to PDF resulted in a significant decrease in cell survival in a time-dependent manner, which was reversed by NAC. PDF exposure resulted in intracellular accumulation of superoxide in a time-dependent manner, with collapse of Δψm as well. The activity of enzymatic antioxidant, SOD and catalase remained the same in all groups. However, the reduced glutathione was significantly suppressed after PDF exposure. NAC treatment preserved the content of intracellular reduced glutathione, and also attenuated the PDF-induced superoxide accumulation and Δψm collapse. Moreover, the enhanced expression of HSP72 induced by PDF exposure was also reversed by NAC. Conclusion: Depletion of a nonenzymatic antioxidant, i.e. reduced glutathione, in HPMC is a crucial cause of PDF-induced oxidative stress. NAC protects HPMCs from PDF-induced cellular damage by preserving the reduced glutathione.

This study elucidates the mechanism through which heat shock treatment influences the outcome of sepsis. Post-heat shock sepsis was induced in rats by CLP 24 h after whole-body hyperthermia. Liver cytosolic and nuclear fractions were collected and analyzed in early and late sepsis rats (sacrificed 9 and 18 h after CLP, respectively). During sepsis, levels of I-kappaB and nuclear factor-kappaB (NF-kappaB) declined in the cytosol of liver, whereas NF-kappaB increased in nucleus. NF-kappaB activity was significantly enhanced during sepsis, and the products of NF-kappaB target genes, such as TNF-alpha and inducible nitric oxide synthase (iNOS), were overexpressed. Heat shock treatment, inducing heat shock protein synthesis, prevented down-regulation of cytosolic I-kappaB and decreased translocation of NF-kappaB into the nucleus. Therefore, the sepsis-induced acceleration of NF-kappaB activation was inhibited. Expression of TNF-alpha and iNOS mRNA was also down-regulated. Coimmunoprecipitation with anti-NF-kappaB (p65) and anti-IkappaB antibodies verified an assembling phenomenon of heat shock protein (HSP) 72 with NF-kappaB and I-kappaB. We suggest that the mechanism preventing septic activation of NF-kappaB is that oversynthesized HSP72 forms a complex with NF-kappaB/I-kappaB, thus inhibiting nuclear translocation of NF-kappaB. HSP72 appears to play a crucial protective role in modulating the gene expression controlled by NF-kappaB in sepsis.

Liver function failure is one of the characteristics of critically ill, septic patients and is associated with worse outcome. Our previous studies have demonstrated that heat-shock response protects cells and tissue from subsequent insults and improves survival during sepsis. In this study, we have shown that mitochondrial cytochrome c oxidase (CCO) is one of the major sources of that protective effect. Experimental sepsis was induced by the cecal ligation and puncture (CLP) method. Heat-shock treatment was induced in rats by hyperthermia 24 h before CLP operation. The results showed that ATP content of the liver declined significantly, and the enzymatic activity of mitochondrial CCO was apparently suppressed during the late stages of sepsis. The mitochondrial ultrastructure of septic liver showed the deformity, mild swelling and inner membrane budding. Heat-shock treatment led to heat-shock protein 72 overexpression and prevented the downregulation of Grp75 during sepsis. On the contrary, the expression of the enzyme complex and its activity were preserved, associated with the minimization of ultrastructural deformities. In conclusion, the maintenance of mitochondrial function, especially the CCO, may be an important strategy in therapeutic interventions of a septic liver.

Elevated plasma homocysteine, arterial stiffness, and increased pulse pressure (PP) are independently associated with higher cardiovascular risk in patients with end-stage renal disease. The aim of this study is to investigate the influence of plasma homocysteine on arterial stiffness and PP in hemodialysis (HD) patients. One hundred and nine HD patients were stratified into three groups by plasma homocysteine levels: low (11.2-20.8 micromol/L), middle (21.2-25.1 micromol/L), and high tertiles of plasma homocysteine (Hcy) group (25.2-43.9 micromol/L). Using a computerized oscillometry, we measured the arterial stiffness index (ASI) and blood pressure (BP) hemodynamic parameters in the brachial artery. The high Hcy group exhibited a higher ASI (110.4+/-129.5 versus 46.2+/-17.5, mean+/-S.E., P

The expression of inducible nitric oxide synthase (iNOS) expression and release of nitric oxide (NO) from macrophages are markedly increased in granulomatous infections. Activation of macrophages 1alpha-hydroxylase results in an increase of 1alpha,25-dihydroxyvitamin D(3) [1,25(OH)(2)D(3)]. However, the significance of this increased production is not completely understood. In this study, we analyzed 1,25(OH)(2)D(3) and NO production in patients with tuberculosis infection and hypercalcemia and used lipopolysaccharide (LPS) to stimulate RAW 264.7 cells in an attempt to assess iNOS expression and gaseous NO production regulated by 1,25(OH)(2)D(3). Peroxynitrite (OONO(-)) production and lactate dehydrogenase activity were also examined. Without additional stimulation, peripheral-blood mononuclear cells (PBMCs) from patients with tuberculosis converted more 25-hydroxyvitamin D(3) to 1,25(OH)(2)D(3) than did those from normal controls. These PBMCs released less NO than did those from control subjects, at baseline and in the stimulated state. We found that 1,25(OH)(2)D(3) dose-dependently inhibited iNOS messenger RNA expression of the LPS-stimulated RAW 264.7 cells and also significantly reduced the gaseous NO release and OONO(-) production. Paralleling the 1,25(OH)(2)D(3)-induced inhibition of NO release were reductions in OONO(-) and LDH production. In conclusion, 1,25(OH)(2)D(3) inhibited iNOS expression and reduced NO production by LPS-stimulated macrophages in the range of physiological doses. Inhibition of the NO surge was coupled with a reduction in OONO(-) and LDH production. Increased 1,25(OH)(2)D(3) production and decreased release of NO from the PBMCs of patients with tuberculosis and hypercalcemia were also noted. We propose that 1,25(OH)(2)D(3) production by macrophages may protect themselves against oxidative injuries caused by the NO burst. In the case of tuberculosis infection, increased 1,25(OH)(2)D(3) synthesis may further contribute to the development of an unwanted phenomenon-hypercalcemia.