Grazoprevir/Elbasvir Treatment in Liver or Kidney Transplant Recipients with Genotype 1b Hepatitis C Virus Infection.

More options regarding the choice of direct-acting antivirals (DAAs) are helpful for avoiding individual limitations in treating hepatitis C virus (HCV) infection. We aimed to assess the efficacy and tolerability of grazoprevir (GZR)/elbasvir (EBR) treatment in genotype-1b (GT-1b) HCV-infected liver or kidney transplant recipients. In this phase 4, single-arm, open-label, multicenter trial, patients received GZR 100 mg/EBR 50 mg daily for 12 weeks. Patients with any HCV infection other than GT-1b, liver decompensation, human immunodeficiency virus, or hepatitis B virus co-infection, a history of NS5A inhibitor exposure, or any severe drug-drug interactions (DDIs), was excluded. The primary endpoint was sustained virologic response at 12 weeks posttreatment (SVR12). Of the 14 patients (10 kidney and 4 liver transplant subjects) enrolled in this study, 9 (64%) were females; the median age was 64.0 (range: 43-73) years. The regularly used immunosuppressants were tacrolimus (93%), everolimus (29%), and sirolimus (7%), with patient blood levels easily managed and generally stable (all P > 0.05 in quantile regression analysis). The rate of SVR12 was 100% in intent-to-treat analysis. Only one patient discontinued GZR/EBR therapy at 6 weeks posttreatment, due to a treatment-unrelated adverse event (AE); however, this patient remained, achieving SVR12. Most AEs were mild in severity and deemed to be not treatment-related. No organ rejection episodes or deaths occurred during the study period. The single-tablet regimen of GZR/EBR for 12 weeks is highly effective and well tolerated in GT-1b HCV-infected liver or kidney transplant recipients, and its DDIs are generally easy to manage. (This study has been registered at ClinicalTrials.gov under identifier NCT03723824.).

Risks of central nervous system infections and related mortality in patients undergoing dialysis.

INTRODUCTION: This study aimed to investigate the risks of central nervous system (CNS) infections and related mortality in patients with end-stage renal disease (ESRD) undergoing dialysis. METHODS: Incident dialysis patients were identified from 2000 to 2013. The risks of CNS infection and related mortality were analyzed. RESULTS: The adjusted hazard ratio (HR) of CNS infection in the ESRD group compared with the control group was 3.46 (95% confidence interval [CI] 2.75-4.35). The adjusted odds ratio (OR) of 90-day mortality following CNS infections in the ESRD group in comparison with the control group was 5.99 (95% CI 2.78-12.9). The adjusted HR of overall CNS infection for the peritoneal dialysis (PD) group in comparison with the hemodialysis (HD) group was 1.07 (95% CI 0.63-1.82). Influenza vaccination was associated with a lower risks of CNS infection in dialysis patients (adjusted HR: 0.38, 95% CI 0.30-0.48). The adjusted OR of 90-day mortality following CNS infection for the PD group in comparison with the HD group was 1.01 (95% CI 0.55-1.87). CONCLUSIONS: The risks of CNS infections and related mortality were remarkably high in dialysis patients with no significant difference between patients with ESRD under HD and PD treatment.

The impact of multidisciplinary pre-dialysis care on the outcomes of incident peritoneal dialysis patients.

BACKGROUND: This study aims to evaluate the impact of multidisciplinary pre-dialysis care (MDPC) on the risks of peritonitis, technique failure and mortality in peritoneal dialysis (PD) patients. METHODS: Incident end-stage kidney disease patients who received peritoneal dialysis (PD) for more than 90 days were recruited in this study from 1 January 1, 2007 to December 31, 2018. Patients were classified into two groups, the MDPC group and the control group, that received the usual care by nephrologists. Risks of the first episode of peritonitis, technique failure and mortality were compared between the two groups. RESULTS: There were 126 patients under the usual care and 546 patients under the MDPC. Patients in the MDPC group initiated dialysis earlier than those in the non-MDPC group. There was no significant difference between these two groups in time to the first episode of peritonitis. Compared to the non-MDPC group, the MDPC group was at similar risks of technique failure (adjusted HR = 0.85, 95% CI = 0.64-1.15) and mortality (adjusted HR = 0.66, 95% CI = 0.42-1.02). Among patients with diabetes, the risk of mortality was significantly reduced in the MDPC group with an adjusted HR of 0.45 (95% CI = 0.25-0.80). CONCLUSIONS: There was no significant difference in time to develop the first episode of peritonitis, and risks of technique failure and mortality between these two groups. Diabetic PD patients under MDPC had a lower risk of mortality than those under the usual care.

Necroptosis: A Pathogenic Negotiator in Human Diseases.

Over the past few decades, mechanisms of programmed cell death have attracted the scientific community because they are involved in diverse human diseases. Initially, apoptosis was considered as a crucial mechanistic pathway for programmed cell death; recently, an alternative regulated mode of cell death was identified, mimicking the features of both apoptosis and necrosis. Several lines of evidence have revealed that dysregulation of necroptosis leads to pathological diseases such as cancer, cardiovascular, lung, renal, hepatic, neurodegenerative, and inflammatory diseases. Regulated forms of necrosis are executed by death receptor ligands through the activation of receptor-interacting protein kinase (RIPK)-1/3 and mixed-lineage kinase domain-like (MLKL), resulting in the formation of a necrosome complex. Many papers based on genetic and pharmacological studies have shown that RIPKs and MLKL are the key regulatory effectors during the progression of multiple pathological diseases. This review focused on illuminating the mechanisms underlying necroptosis, the functions of necroptosis-associated proteins, and their influences on disease progression. We also discuss numerous natural and chemical compounds and novel targeted therapies that elicit beneficial roles of necroptotic cell death in malignant cells to bypass apoptosis and drug resistance and to provide suggestions for further research in this field.

Gender Differences in microRNA Expressions as Related to Long-Term Graft Function in Kidney Transplant Patients.

In recent studies, much has been discussed about biomarkers used in the evaluation of the transplanted graft function. However, there remains a lack of research regarding the long-term effects of microRNAs (miRNAs) on the different genders for kidney transplant (KTx) patients. In this study, we aim to assess the functions of miRNAs on long term outcomes of KTx patients by extracting differently expressed miRNAs between patients of normal graft function and graft dysfunction, while further analyzing their impact on the different genders. We analyzed the data of 40 patients who had received KTx for a period of more than ten years and included data regarding renal function, immuno-related markers and plasma miRNAs. Data were classified by gender for further studies. Twelve out of 17 females and 8 out of 23 males had undergone graft dysfunction. Renal function analysis showed significantly worse outcomes in the female patients. There were five differently expressed miRNAs between the female control group and female dysfunction group: miR-128-3p, miR-21-5p, miR-150-5p, miR-92a-3p and miR-15a-5p, and five between the male control group and male dysfunction group: miR-23a-3p, miR-126-3p, miR-142-3p, miR-223-3p and miR-26a-5p. Gender differences exist in incidences of kidney graft dysfunction, with male patients displaying better preservation in graft functions. Overall, these differently expressed miRNAs either enhance or suppress host immune responses. They can be predictive markers for graft survival and can also be important factors that lead to worse long term kidney graft function in females when compared to males.

A Fatal Case of Chlorfenapyr Poisoning and the Therapeutic Implications of Serum Chlorfenapyr and Tralopyril Levels.

Chlorfenapyr is a new contact and stomach insecticide derived from natural pyrroles secreted by Streptomyces spp. It is a pro-insecticide and acts after metabolic transformation to its active metabolite tralopyril. Tralopyril is an uncoupler of oxidative phosphorylation in the mitochondria of the target insects and of experiment animals, leading to the disruption of adenosine triphosphate synthesis and death. Several fatal human poisonings had been reported and no blood chlorfenapyr or tralopyril measurements were available. The treatment remains supportive. A 32-year-old healthy man ingested 200 mL of 10% chlorfenapyr as a suicide attempt. Unfortunately, he succumbed at 157 h post-ingestion, shortly after having fever and seizures. His serum level of chlorfenapyr at 4 h post-exposure was 77.4 ng/mL, and was undetectable at 113 and 156 h, respectively. The serum levels of tralopyril were 723.6, 14,179, and 9654.2 ng/mL at 4, 113, and 156 h post-ingestion, respectively. The delay in the rise of serum tralopyril levels was noticeable, which seems to correlate with the patient's signs and symptoms. The information may have therapeutic implications in the management of this deadly poisoning.

Human antigen R regulates hypoxia-induced mitophagy in renal tubular cells through PARKIN/BNIP3L expressions.

Mitochondrial dysfunction contributes to the pathophysiology of acute kidney injury (AKI). Mitophagy selectively degrades damaged mitochondria and thereby regulates cellular homeostasis. RNA-binding proteins (RBPs) regulate RNA processing at multiple levels and thereby control cellular function. In this study, we aimed to understand the role of human antigen R (HuR) in hypoxia-induced mitophagy process in the renal tubular cells. Mitophagy marker expressions (PARKIN, p-PARKIN, PINK1, BNIP3L, BNIP3, LC3) were determined by western blot analysis. Immunofluorescence studies were performed to analyze mitophagosome, mitolysosome, co-localization of p-PARKIN/TOMM20 and BNIP3L/TOMM20. HuR-mediated regulation of PARKIN/BNIP3L expressions was determined by RNA-immunoprecipitation analysis and RNA stability experiments. Hypoxia induced mitochondrial dysfunction by increased ROS, decline in membrane potential and activated mitophagy through up-regulated PARKIN, PINK1, BNIP3 and BNIP3L expressions. HuR knockdown studies revealed that HuR regulates hypoxia-induced mitophagosome and mitolysosome formation. HuR was significantly bound to PARKIN and BNIP3L mRNA under hypoxia and thereby up-regulated their expressions through mRNA stability. Altogether, our data highlight the importance of HuR in mitophagy regulation through up-regulating PARKIN/BNIP3L expressions in renal tubular cells.

Increased risk of pulmonary and extrapulmonary tuberculosis infection in patients with polycystic kidney disease: a nationwide population-based study with propensity score-matching analysis.

BACKGROUND: Polycystic kidney disease (PKD) is a common renal disorder affecting approximately 1 in 1000 live births. Tuberculosis (TB) is an infectious disease worldwide. This study investigated the risk of TB infection in patients with PKD. METHODS: A nationwide population-based cohort study was performed using Taiwan's National Health Insurance Research Database. We used patients' hospitalization files for the entire analysis during 2000-2012. As per diagnosis, we divided patients into PKD and non-PKD cohorts and the major outcome was TB infection. RESULTS: A total of 13,540 participants with 6770 patients in each cohort were enrolled. The PKD cohort had a higher risk of TB infection than did the non-PKD cohort after adjusting for age, sex, and comorbidities (adjusted hazard ratio (aHR) = 1.91, 95% confidence interval [CI] = 1.51-2.43). When classifying by sites of pulmonary TB (PTB) and extrapulmonary TB (EPTB), the PKD cohort demonstrated a significantly higher risk of EPTB (aHR = 2.44, 95% CI = 1.46-4.08) as well as a risk of PTB (aHR = 1.69, 95% CI = 1.29-2.22). When stratified by the presence or absence of a comorbidity, high TB infection risk was noted in the PKD patients without any comorbidity (HR = 2.69, 95% CI = 1.69-4.30). CONCLUSIONS: Taken together, our findings suggest that PKD is associated with a 1.91-fold increased risk of TB infection. Medical professionls should maintain a high index of suspicion in daily practice for patients with PKD, particularly those with EPTB infection.

Pneumococcal pneumonia in adult hospitalised solid organ transplant recipients: Nationwide, population-based surveillance.

BACKGROUND: Pneumococcal disease poses a burden to the community in high risk population. Most early studies focused on invasive pneumococcal disease. However, the epidemiology of pneumococcal pneumonia (PP) requiring hospitalisation in solid organ transplant recipients (SOTRs) is poorly defined. METHODS: We conducted a retrospective cohort study (January 1, 2000 and December 31, 2012) to evaluate the risk of PP requiring hospitalisation in SOTRs. SOTRs and non-SOT cohorts, propensity score-matched at a 1:1 ratio for age, sex, index date and underlying comorbidities, were identified from the National Health Insurance Research Database. RESULTS: Each cohort consisted of 7507 patients. In the SOT cohort, 26 episodes of PP requiring hospitalisation were identified (incidence rate of 52.4 per 100,000 person-years). The risk of PP requiring hospitalisation in the SOT cohort was 1.50 times greater than in the non-SOT cohort [adjusted hazard ratio: 1.50, 95% confidence interval = 1.31-1.71, P < .001]. The nested case control study identified older age, kidney transplant, and concomitant chronic obstructive pulmonary disease, chronic kidney disease and heart failure as predictors of PP requiring hospitalisation in the SOT cohort. The highest risk period for PP requiring hospitalisation occurred within the first year of transplantation (36.47 per 1000 patients). Amongst kidney transplant recipients, patients with PP requiring hospitalisation exhibited higher cumulative incidences of graft failure than those without PP (log-rank test: P value = .004). CONCLUSIONS: SOTRs are at risk of PP requiring hospitalisation with its attendant morbidity. Strategies to reduce risk of PP requiring hospitalisation using preventive vaccinations warrant further study.

Risk of severe herpes zoster infection in patients with polycystic kidney disease: A nation-wide cohort study with propensity score matching analysis.

BACKGROUND: Polycystic kidney disease (PKD) is suggested to be likely associated with underlying immunological dysregulation. This lymphopenia poses a risk of viral infection. Data to elucidate the herpes virus infection risk in patients with PKD are lacking; therefore, we conducted a national-wide population-based cohort study to investigate the herpes virus risk in PKD patients. METHODS: From the Taiwan National Health Insurance Research Database (NHIRD), patients who were hospitalised with a diagnosis of polycystic kidney disease were defined as case group of PKD patients; patients without any diagnosis of PKD during the study period were grouped into the non-PKD cohort. The index date was set as the date when the patients were newly diagnosed with PKD. All study patients were followed up until the occurrence of herpes zoster infection, death, withdrawal from the NHIRD for other reasons, or until December 31, 2013. RESULTS: We included 4366 PKD patients and 4366 non-PKD patients. The incidence rate and the risk of developing herpes zoster infection were estimated using multivariate stratified analyses. PKD patients had a 1.97-fold risk of herpes zoster virus infection (aHR = 1.97, 95% CI 1.17-3.31) compared with the non-PKD cohort. On multilayer stratification, PKD patients without any comorbidities had a significantly increased risk of herpes zoster infection (aHR = 3.10, 95% CI 1.37-7.00). CONCLUSION: This is the first study to reveal a high risk of severe herpes zoster infection in patients with PKD. High index suspicion of severe herpes zoster infection should be maintained in clinical professionals.

The functional interplay of lncRNA EGOT and HuR regulates hypoxia-induced autophagy in renal tubular cells.

Autophagy, an important cellular homeostatic mechanism regulates cell survival under stress and protects against acute kidney injury. However, the role of long noncoding RNA (lncRNA) in autophagy regulation in renal tubular cells (HK-2) is unclear. The study was aimed to understand the importance of lncRNA in hypoxia-induced autophagy in HK-2 cells. LncRNA eosinophil granule ontogeny transcript (EGOT) was identified as autophagy-associated lncRNA under hypoxia. The lncRNA EGOT expression was significantly downregulated in renal tubular cells during hypoxia-induced autophagy. Gain- and loss-of-EGOT functional studies revealed that EGOT overexpression reduced autophagy by downregulation of ATG7, ATG16L1, LC3II expressions and LC 3 puncta while EGOT knockdown reversed the suppression of autophagy. Importantly, RNA-binding protein, (ELAVL1)/Hu antigen R (HuR) binds and stabilizes the EGOT expression under normoxia and ATG7/16L1 expressions under hypoxia. Furthermore, HuR mediated stabilization of ATG7/16L1 expressions under hypoxia causes a decline in EGOT levels and thereby promotes autophagy. Altogether, the study first reveals the functional interplay of lncRNA EGOT and HuR on the posttranscriptional regulation of the ATG7/16L1 expressions. Thus, the HuR/EGOT/ATG7/16L1 axis is crucial for hypoxia-induced autophagy in renal tubular cells.

Ongoing donor-transmitted diabetic kidney disease in kidney transplant recipients with fair sugar control: a single center retrospective study.

BACKGROUND: Transplantation with a diabetic donor kidney may have some benefits compared to remaining on the waitlist for selected patients. However, we found that some kidney transplant recipients have ongoing donor-transmitted diabetic kidney disease (DT-DKD) despite fair blood sugar control. This study aimed to survey the incidence and clinical pattern of DT-DKD in kidney transplant recipients. METHODS: We retrospectively reviewed the medical records of kidney transplantations in our hospital. We found 357 kidney transplantations from February 2006 to April 2018. Among these, 23 (6.4%) diabetic donor kidney transplantations were done in the study period. RESULTS: Among the 23 recipients, 6 (26.1%) displayed biopsy-proven DKD. Recipients with biopsy-proven DKD had longer dialysis vintage, higher proteinuria amount, lower last estimated glomerular filtration rate (eGFR), and a more rapid decline in the eGFR. The median fasting blood sugar level in the biopsy-proven DKD group was unexpectedly lower than the non-DKD group. Most of the pre-implantation frozen sections in biopsy-proven DKD group showed diabetic lesions worse than diabetic nephropathy (DN) class IIa. In the biopsy-proven DKD group, 5 recipients had no history of diabetes before or after transplantation. Among the 23 recipients, 5 (21.7%) were diagnosed with DT-DKD. Serial post-transplant biopsies showed the histological progression of allograft DN. CONCLUSIONS: To the best of our knowledge, this is the first study to report the phenomenon of ongoing DT-DKD in kidney transplant recipients with fair blood sugar control. The zero-time pre-transplant kidney biopsy may be an important examination before the allocation of diabetic donor kidneys. Further study is needed to elucidate the possible mechanism of ongoing DT-DKD in non-diabetic recipients with fair blood sugar control as well as the impaction of pre-implantation diabetic lesion on the graft outcome.

Is combined peritoneal dialysis and hemodialysis redundant? A nationwide study from Taiwan.

BACKGROUND: Combined peritoneal dialysis (PD) and hemodialysis (HD) therapy (combined therapy) has numerous clinical benefits and should be emphasized for PD patients encountering technique failure. METHODS: This 12-year nationwide retrospective study was conducted to compare long-term outcomes (including admission and mortality risks) between combined therapy patients (combined group) and patients directly transferred from PD to HD (transfer group). RESULTS: All 12,407 incidental PD patients from 2000 to 2010 were enrolled and followed up until the end of 2011. A total of 688 patients in the combined group and 688 patients in the transfer group were selected after 1:1 frequency matching based on age, sex, and PD duration. The overall admission and mortality risks of the two groups were comparable in a Cox proportional hazards model (adjusted hazard ratio [HR] = 1.06 [95% confidence interval (CI) = 0.95-1.19] and 1.02 [95% CI = 0.80-1.30]), respectively). Compared with the transfer group, combined group patients with recent peritonitis or frequent hemodialysis (four HD sessions per month) had significantly higher risk of admission while combined group patients without peritonitis had significantly lower risk. The number of incidents in the combined group increased over time. On average, patients stayed on combined therapy for 2 years. CONCLUSIONS: Combined therapy (two HD sessions per month) is not redundant but a rational and cost-effective treatment, particularly for patients without recent peritonitis. Dialysis staff should be familiar with the advantages and disadvantages of combined therapy and consider it an essential part of integrated dialysis care.

Treatment of chronic active antibody-mediated rejection in renal transplant recipients - a single center retrospective study.

BACKGROUND: Chronic active antibody-mediated rejection is a major etiology of graft loss in renal transplant recipients. However, there is no consensus on the optimal treatment strategies. METHODS: Computerized records from Taichung Veterans General Hospital were collected to identify renal transplant biopsies performed in the past 7 years with a diagnosis of chronic active antibody-mediated rejection. The patients were divided into two groups according to treatment strategy: Group 1 received aggressive treatment (double filtration plasmapheresis and one of the followings: rituximab, intravenous immunoglobulin, antithymogycte globulin, bortezomib, or methylprednisolone pulse therapy); and group 2 received supportive treatment. RESULTS: From February 2009 to December 2017, a total of 82 patients with biopsy-proven chronic antibody mediated rejection were identified. Kaplan-Meier analysis of death-censored graft survival showed a worse survival in group 2 (P = 0.015 by log-rank test). Adverse event-free survival was lower in group 1, whereas patient survival was not significantly different. Proteinuria and supportive treatment were independent risk factors for graft loss in multivariate analysis. CONCLUSIONS: Aggressive treatment was associated with better graft outcome. However, higher incidence of adverse events merit personalized treatment, especially for those with higher risk of infection. Appropriate prophylactic antibiotics are recommended for patients undergoing aggressive treatment.

RNA-binding protein, human antigen R regulates hypoxia-induced autophagy by targeting ATG7/ATG16L1 expressions and autophagosome formation.

Autophagy, a prosurvival mechanism offers a protective role during acute kidney injury. We show novel findings on the functional role of RNA binding protein, HuR during hypoxia-induced autophagy in renal proximal tubular cells-2 (HK-2). HK-2 cells showed upregulated expressions of HuR and autophagy-related proteins such as autophagy related 7 (ATG7), autophagy related 16 like 1 (ATG16L1), and LC3II under hypoxia. Increased autophagosome formation was visualized as LC3 puncta in hypoxic cells. Further, short hairpin-RNA-mediated loss of HuR function in HK-2 cells significantly decreased ATG7 and ATG16L1 protein expressions. Bioinformatics prediction revealed HuR motif binding on the coding region of ATG7 and AU-rich element at 3'UTR ATG16L1 messnger RNA (mRNA). The RNA immunoprecipitation study showed that HuR was predominantly associated with ATG7 and ATG16L1 mRNAs under hypoxia. In addition, HuR enhanced autophagosome formation by regulating LC3II expressions. These results show that HuR regulates ATG7 and ATG16L1 expressions and thereby mediate autophagy in HK-2 cells. Importantly, HuR knockdown cells underwent apoptosis during hypoxia as observed through the terminal deoxynucleotidyl transferase dUTP nick end labeling assay. Collectively, these findings show the crucial role of HuR under hypoxia by regulating autophagy and suppressing apoptosis in renal tubular cells.

Risk of cancer in patients with polycystic kidney disease: a propensity-score matched analysis of a nationwide, population-based cohort study.

BACKGROUND: Data for the risk of any solid cancer in patients with polycystic kidney disease are scarce. Therefore, we did a nationwide cohort study in Taiwan to establish the risk of cancer in patients with polycystic kidney disease without either chronic kidney disease or end-stage renal disease. METHODS: From inpatient claims of the Taiwan National Health Insurance Research Database, we included patients aged 20 years and older and diagnosed with polycystic kidney disease between January, 1998 and December, 2010, in the polycystic kidney disease cohort. Patients with a history of cancer, a history of chronic kidney disease or of end-stage renal disease (recorded from the Registry of Catastrophic Illness Patient Database) were excluded. For each patient with polycystic kidney disease, one patient aged older than 20 years with no history of polycystic kidney disease or cancer was randomly selected from the National Health Insurance Research Database, matched 1:1 on the basis of the propensity score calculated by logistic regression, and was included in the control non-polycystic kidney disease cohort. The follow-up period for each patient was estimated from the index date to the date of diagnosis of cancer, or the patient was censored due to withdrawal from the insurance programme (eg, death, immigration, or imprisonment) or on Dec 31, 2011. The primary outcome of interest was a diagnosis of cancer during a 14-year follow-up period. The risk of cancer was represented as a hazard ratio (HR) calculated in Cox proportional hazard regression models. FINDINGS: 4346 patients with polycystic kidney disease and 4346 without were enrolled in the study. The median follow-up period in the polycystic kidney disease cohort was 3·72 years (IQR 1·25-7·31) and in the non-polycystic kidney disease cohort was 4·96 years (2·29-8·38). The overall incidence of cancer was higher in the polycystic kidney disease cohort than in the control cohort (20·1 [95% CI 18·3-21·9] per 1000 person-years vs 10·9 [10·1-11·8] per 1000 person-years; crude hazard ratio (HR) 1·77 [95% CI 1·52-2·07]; HR adjusted for age, sex, frequency of medical visits, and comorbidities was 1·83 [1·57-2·15]). The specific risks (adjusted subhazard ratios) were significantly higher in the polycystic kidney disease cohort than that in the non-polycystic kidney disease cohort for liver cancer (1·49 [95% CI 1·04-2·13]; p=0·030), colon cancer (1·63 [1·15-2·30]; p=0·006), and kidney cancer (2·45 [1·29-4·65]; p=0·006). INTERPRETATION: To our knowledge, this is the first report of the association of polycystic kidney disease without end-stage renal disease with the risk of liver, colon, and kidney cancer. Health-care professionals should be aware of this risk, when treating patients with polycystic kidney disease. FUNDING: Taiwan Ministry of Health and Welfare Clinical Trial and Research Center of Excellence, Academia Sinica Taiwan Biobank, Stroke Biosignature Project, NRPB Stroke Clinical Trial Consortium, Tseng-Lien Lin Foundation, Taiwan Brain Disease Foundation, Katsuzo and Kiyo Aoshima Memorial Funds, China Medical University Hospital, and Taiwan Ministry of Education.

The impact of icodextrin on the outcomes of incident peritoneal dialysis patients.

OBJECTIVE: The aim of the study is to investigate the effects of icodextrin on the risks of death, technique failure and the first episode of peritonitis in peritoneal dialysis (PD) patients. METHODS: From medical records of a medical center in Taiwan, a total of 725 newly diagnosed end-stage kidney disease patients receiving PD for at least 90 days from January 1, 2007 to December 31, 2018 were identified. These patients were grouped as 190 icodextrin users and 535 non-users. Users were defined as utilization of icodextrin for ≥ 50% of their PD duration. The use of icodextrin was considered a time-varying exposure in the Cox proportional hazard model. The risks of death, technique failure and the first episode of peritonitis were compared between two cohorts by the end of 2018. RESULTS: Compared to the non-users, the icodextrin users had significant lower risks of mortality (6.5 vs.7.2 per 100 person-years; adjusted HR = 0.62, 95% CI = 0.42-0.91) and technique failure (12.7 vs. 15.2 per 100 person-years; adjusted HR = 0.61, 95% CI = 0.47-0.81), and the first peritonitis episode (5.0 vs. 17.0 per 100 person-years; adjusted HR = 0.22, 95% CI = 0.14-0.35). The risk of peritonitis reduced further in icodextrin users with diabetes and with cardiovascular disease. CONCLUSION: Icodextrin was associated with lower risks of mortality, technique failure, and the first episode of peritonitis.

Risk of Diabetic Retinopathy in Patients With Type 2 Diabetes After SGLT-2 Inhibitors: A Nationwide Population Cohort Study.

Diabetic retinopathy (DR) accounts for 80% of cases of vision loss in patients with type 2 diabetes mellitus (T2DM). Interventional treatments are only indicated in advanced DR and are ineffective in some patients. Sodium-glucose cotransporter 2 inhibitors (SGLT2is) are used to attenuate T2DM-associated cardiovascular complications. We conducted the cohort study to investigate the effect of SGLT2is on DR development. Data (May 2016-December 2018) obtained from the Taiwan National Health Insurance Research Database were analyzed in this nationwide retrospective cohort study. After propensity score matching, a total of 31,764 patients receiving SGLT2is and another 31,764 patients receiving dipeptidyl peptidase 4 inhibitors (DPP4is) were included in this study. Multiple Cox proportional-hazards regression models were used to evaluate DR risk. Overall DR incidence among SGLT2i or DPP4i users was 10.9 or 15.6 per 10,000 patient-years, respectively. After covariate adjustment, DR (both early and late stage) risk was substantially lower in SGLT2i users (adjusted hazard ratio: 0.68, 95% confidence interval: 0.6-0.78) than in DPP4i users. DR risk appears to be considerably lower in SGLT2i users than in DPP4i users. Glycemic control measurement with HbA1C level was unavailable in this claim database.

Expression of hypoxia-inducible factor-1α (HIF-1α) in infiltrating inflammatory cells is associated with chronic allograft dysfunction and predicts long-term graft survival.

BACKGROUND: In chronic kidney failure, a hypoxic state, infiltrating inflammatory cells play a crucial role in the progression to end-stage renal disease. No studies have evaluated the influence of hypoxia and infiltrating inflammatory cells on chronic allograft dysfunction. METHODS: Renal transplant recipients who underwent renal allograft biopsy with interstitial fibrosis/tubular atrophy (IF/TA) were enrolled and renal allograft tissue sections were processed for immunohistochemical staining including hypoxia-inducible factor-1α (HIF-1α), nitrotyrosine, α-smooth muscle actin and e-cadherin. Patients with total renal tissue HIF score ≥1 were defined as positive for HIF-1α. To assess the phenotype of the infiltrating cells, dual staining of HIF-1α with CD45, CD68 and CD3 was performed. The correlation between HIF-1α score and Banff's score was analysed. Clinical parameters including renal survival among patients with or without an expression of HIF-1α were compared. RESULTS: Out of 55 patients enrolled, 23 patients (41.8%) had an HIF-1α score ≥1 (Group B). Compared with Group A (total renal HIF score <1), Group B had a significantly higher Banff score of interstitial infiltrates (i) (P = 0.029), vascular fibrous intimal thickening (cv) (P = 0.007) and arteriolar hyaline thickening (ah) (P = 0.026). Clinically, patients with an HIF-1α score were associated with a poor graft survival. Significantly inferior allograft survival was noted in Group B. HIF scores had an adjusted hazard ratio of 3.25 (95% confidence inteval: 1.71-6.16, P = 0.0003) in allograft failure. CONCLUSIONS: We first demonstrated the expression of HIF-1α protein among infiltrating inflammatory cells in areas with IF/TA in patients with chronic allograft dysfunction.