Bilirubin is a well-known neurotoxin in newborn infants; however, current evidence has shown that a higher serum bilirubin concentration in physiological ranges is associated with a lower risk for ...the development and progression of both chronic kidney disease (CKD) and cardiovascular disease (CVD) in adults. The protective mechanisms of bilirubin in CVD, CKD, and associated mortality may be ascribed to its antioxidant and anti-inflammatory properties. Bilirubin further improves insulin sensitivity, reduces low-density lipoprotein cholesterol levels and inhibits platelet activation in at-risk individuals. These effects are expected to maintain normal vascular homeostasis and thus reduce the incidence of CKD and the risks of cardiovascular complications and death. In this review, we highlight the recent advances in the biological actions of bilirubin in the pathogenesis of CVD and CKD progression, and further propose that targeting bilirubin metabolism could be a potential approach to ameliorate morbidity and mortality in CKD patients.
Mounting evidence indicates that an increase in histone deacetylation contributes to renal fibrosis. Although inhibition of histone deacetylase (HDAC) can reduce the extent of fibrosis, whether HDAC ...inhibitors exert the antifibrotic effect through modulating the phenotypes of macrophages, the key regulator of renal fibrosis, remains unknown. Moreover, the functional roles of the M2 macrophage subpopulation in fibrotic kidney diseases remain incompletely understood. Herein, we investigated the role of HDAC inhibitors on renal fibrogenesis and macrophage plasticity. We found that HDAC inhibition by trichostatin A (TSA) reduced the accumulation of interstitial macrophages, suppressed the activation of myofibroblasts and attenuated the extent of fibrosis in obstructive nephropathy. Moreover, TSA inhibited M1 macrophages and augmented M2 macrophage infiltration in fibrotic kidney tissue. Interestingly, TSA preferentially upregulated M2c macrophages and suppressed M2a macrophages in the obstructed kidneys, which was correlated with a reduction of interstitial fibrosis. TSA also repressed the expression of proinflammatory and profibrotic molecules in cultured M2a macrophages and inhibited the activation of renal myofibroblasts. In conclusion, our study was the first to show that HDAC inhibition by TSA alleviates renal fibrosis in obstructed kidneys through facilitating an M1 to M2c macrophage transition.
Abstract
Patients with systemic lupus erythematosus (SLE) have a higher risk of vascular complications. This retrospective cohort study aimed to analyze the differences in the risk of arteriovenous ...fistula or graft (AVF/AVG) dysfunction in hemodialysis patients with and without SLE from Taiwan’s National Health Insurance Database over a 10-year period. AVF/AVG dysfunction is defined as the occurrence of the first episode of intervention after vascular access creation. A total of 1366 HD patients with SLE had higher incidence rates of AVF/AVG dysfunction than 4098 non-SLE HD patients in the following 4 periods: (1) after 1 year (incidence rates = 15.21% and 13.01%, respectively; subdistribution hazard ratio (SHR) = 1.16; P = 0.007), (2) 1st-to-10th-year period (15.36% and 13.25%; SHR = 1.16; P = 0.007), (3) 5th-to-10th-year period (11.91% and 8.1%; SHR = 1.42; P = 0.003), and (4) overall period (23.53% and 21.66%; SHR = 1.09; P = 0.027). In conclusion, there were significantly higher incidence rates of AVF/AVG dysfunction in SLE patients during the long-term follow-up period. Vascular access function should be monitored regularly by clinical examinations, especially after 1 year and during 5 to 10 years, to improve AVF/AVG patency and dialysis adequacy in SLE patients undergoing maintenance hemodialysis.
In 1996, the National Health Insurance Administration of Taiwan applied a restrictive reimbursement criteria for erythropoiesis-stimulating agents (ESAs) use in patients with chronic kidney disease. ...The maximal ESAs dosage allowed by insurance is capped at 20,000 U of epoetin per month. Nephrologists avoided the use of high ESA dosages to achieve a hemoglobin level of 10-11 g/dL using iron supplementation. We assessed the association of anemia and iron parameters with mortality among peritoneal dialysis (AIM-PD) patients. A retrospective cohort study was conducted based on the Taiwan Renal Registry Data System. From January 1, 2000 to December 31, 2008, we enrolled 4356 well-nourished PD patients who were older than 20 years and had been receiving PD for more than 12 months. All patients were divided into subgroups according to different hemoglobin, ferritin and transferrin saturation (TSAT) values. Patients were followed until death or December 31, 2008. In a median 2.9-year study period, 694 (15.9%) patients died. By multivariate adjustment, a hemoglobin level lower than 10 g/dL was significantly associated with a higher risk for all-cause and cardiovascular deaths. Moreover, a serum ferritin level higher than 800 ng/mL was associated with a higher risk for all-cause deaths, and a TSAT value between 20 and 50% was associated with the lowest all-cause mortality. In conclusions, we recommend avoiding a low hemoglobin level and a serum ferritin level of more than 800 ng/mL and maintaining a TSAT value between 20 and 50%, as these conditions were associated with lower risks of all-cause mortality in the AIM-PD study.
Background The Taiwan Health Insurance Bureau has conducted a bundled payment system for hemodialysis reimbursement since 1995. The maximum dose of erythropoiesis-stimulating agents allowed by ...insurance is capped at 20 000 U of epoetin or 100 μg of darbepoetin alfa per month. Nephrologists have avoided the use of high dosages of erythropoiesis-stimulating agents to achieve a hemoglobin level of 10 to 11 g/dL by iron supplementation. The clinical impact of these policies on patients' outcomes is unknown. The authors aimed to assess the AIM-HD (Association of Anemia, Iron parameters, and Mortality among the prevalent Hemodialysis patients) Study in Taiwan. Methods and Results The AIM-HD study was conducted based on the Taiwan Renal Registry Data System. From 2001 to 2008, the authors enrolled 42 230 patients undergoing hemodialysis who were older than 20 years and had received hemodialysis for more than 12 months. Patient follow-ups occurred until death or December 31, 2008. During a study period of 8 years, 12 653 (30.0%) patients died. After multivariate adjustment, the authors found that a hemoglobin level <10 g/dL was significantly associated with higher risk for all-cause and cardiovascular deaths. Moreover, a serum ferritin level between 300 and 800 ng/mL and transferrin saturation value between 30% and 50% were associated with the lowest all-cause mortality. Conclusions The authors recommend avoiding a low hemoglobin level and maintaining serum ferritin between 300 and 800 ng/mL and transferrin saturation between 30% and 50%, which were associated with lower risks of all-cause mortality among patients undergoing hemodialysis receiving the restricted erythropoiesis-stimulating agent doses but prompt intravenous iron supplementation in Taiwan.
Objective Diabetic nephropathy (DN), also known as diabetic kidney disease (DKD), is a major chronic complication of diabetes and is the most frequent cause of kidney failure globally. A better ...understanding of the pathophysiology of DN would lead to the development of novel therapeutic options. Acrolein, an α,β-unsaturated aldehyde, is a common dietary and environmental pollutant. Design The role of acrolein and the potential protective action of acrolein scavengers in DN were investigated using high-fat diet/ streptozotocin-induced DN mice and in vitro DN cellular models. Methods Acrolein-protein conjugates (Acr-PCs) in kidney tissues were examined using immunohistochemistry. Renin–angiotensin system (RAS) and downstream signaling pathways were analyzed using quantitative RT-PCR and Western blot analyses. Acr-PCs in DN patients were analyzed using an established Acr-PC ELISA system. Results We found an increase in Acr-PCs in kidney cells using in vivo and in vitro DN models. Hyperglycemia activated the RAS and downstream MAPK pathways, increasing inflammatory cytokines and cellular apoptosis in two human kidney cell lines (HK2 and HEK293). A similar effect was induced by acrolein. Furthermore, acrolein scavengers such as N-acetylcysteine, hydralazine, and carnosine could ameliorate diabetes-induced kidney injury. Clinically, we also found increased Acr-PCs in serum samples or kidney tissues of DKD patients compared to normal volunteers, and the Acr-PCs were negatively correlated with kidney function. Conclusions These results together suggest that acrolein plays a role in the pathogenesis of DN and could be a diagnostic marker and effective therapeutic target to ameliorate the development of DN.
To evaluate the risk and protective factors of serious infection (SI) in patients with systemic lupus erythematosus (SLE) within 180 days of rituximab (RTX) treatment.
Patients with SLE treated with ...RTX were analyzed. SI was defined as any infectious disease requiring hospitalization. The clinical characteristics, laboratory profiles, medications, and incidence rate (IR) are presented. Multivariate Cox proportional hazards models and Kaplan-Meier analysis for risk factors of SI were performed.
A total of 174 patients with SLE receiving RTX treatment were enrolled. The overall IR of SIs was 51.0/100 patient-years (PYs). Pneumonia (30.4/100 PYs), followed by soft tissue infections, intra-abdominal infections, and
pneumonia (all 6.1/100 PYs) were the leading types of SIs. Twelve patients died during the 180-day follow-up (crude mortality rate: 14.6/100 PYs). Chronic kidney disease (CKD), defined as an estimated glomerular filtration rate < 60 mL/min/1.73 m
(hazard ratio HR 2.88, 95% CI 1.30-6.38), and a background prednisolone (PSL) equivalent dosage ≥ 15 mg/day (HR 3.50, 95% CI 1.57-7.78) were risk factors for SIs among all patients with SLE. Kaplan-Meier analysis confirmed the risk of SI for patients with SLE with CKD and a background PSL equivalent dosage ≥ 15 mg/day (log-rank
= 0.001 and 0.02, respectively). Hydroxychloroquine (HCQ) reduced the risk of SIs in patients with SLE (HR 0.35, 95% CI 0.15-0.82; log-rank
= 0.003).
SI was prevalent in patients with SLE after RTX treatment. Patients with SLE with CKD and high-dose glucocorticoid use required constant vigilance. HCQ may reduce the risk of SI among patients with SLE administered RTX.
Background Acute kidney injury (AKI) is an emerging global healthcare issue without effective therapy yet. Autophagy recycles damaged organelles and helps maintain tissue homeostasis in acute renal ...ischemia-reperfusion (I/R) injury. Hypoxic mesenchymal stem cells (HMSCs) represent an innovative cell-based therapy in AKI. Moreover, the conditioned medium of HMSCs (HMSC-CM) rich in beneficial trophic factors may serve as a cell-free alternative therapy. Nonetheless, whether HMSCs or HMSC-CM mitigate renal I/R injury via modulating tubular autophagy remains unclear. Methods Renal I/R injury was induced by clamping of the left renal artery with right nephrectomy in male Sprague-Dawley rats. The rats were injected with either PBS, HMSCs, or HMSC-CM immediately after the surgery and sacrificed 48 h later. Renal tubular NRK-52E cells subjected to hypoxia-reoxygenation (H/R) injury were co-cultured with HMSCs or treated with HMSC-CM to assess the regulatory effects of HSMCs on tubular autophagy and apoptosis. The association of tubular autophagy gene expression and renal recovery was also investigated in patients with ischemic AKI. Result HMSCs had a superior anti-oxidative effect in I/R-injured rat kidneys as compared to normoxia-cultured mesenchymal stem cells. HMSCs further attenuated renal macrophage infiltration and inflammation, reduced tubular apoptosis, enhanced tubular proliferation, and improved kidney function decline in rats with renal I/R injury. Moreover, HMSCs suppressed superoxide formation, reduced DNA damage and lipid peroxidation, and increased anti-oxidants expression in renal tubular epithelial cells during I/R injury. Co-culture of HMSCs with H/R-injured NRK-52E cells also lessened tubular cell death. Mechanistically, HMSCs downregulated the expression of pro-inflammatory interleukin-1beta, proapoptotic Bax, and caspase 3. Notably, HMSCs also upregulated the expression of autophagy-related LC3B, Atg5 and Beclin 1 in renal tubular cells both in vivo and in vitro. Addition of 3-methyladenine suppressed the activity of autophagy and abrogated the renoprotective effects of HMSCs. The renoprotective effect of tubular autophagy was further validated in patients with ischemic AKI. AKI patients with higher renal LC3B expression were associated with better renal recovery. Conclusion The present study describes that the enhancing effect of MSCs, and especially of HMCSs, on tissue autophagy can be applied to suppress renal tubular apoptosis and attenuate renal impairment during renal I/R injury in the rat. Our findings provide further mechanistic support to HMSCs therapy and its investigation in clinical trials of ischemic AKI. Keywords: Acute kidney injury, Autophagy, Hypoxic mesenchymal stem cells, Ischemia-reperfusion injury
Hemodialysis (HD) patients are particularly vulnerable to severe coronavirus disease 2019 (COVID-19) due to their immunocompromised state and comorbid conditions. Timely vaccination could be the most ...effective strategy to reduce morbidity and mortality. However, data on the survival benefit of the COVID-19 vaccine against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and death among HD patients are limited, especially during the Omicron-dominant period.
In this prospective hospital-based cohort study, we identified HD patients from July 1, 2021, to April 29, 2022. The patients were divided into fully vaccinated and partially vaccinated groups. We compared the humoral response, risk of developing SARS-CoV-2 infection, and all-cause mortality between the two groups.
Among the 440 HD patients included, 152 patients were fully vaccinated, and 288 patients were partially vaccinated. Patients in the fully vaccinated group exhibited higher anti-spike protein receptor-binding domain (S protein RBD) antibody levels and lower risks of all-cause mortality (adjusted hazard ratio, 0.35; 95% confidence interval, 0.17–0.73; p = 0.005) than the partially vaccinated group. However, the risk for SARS-CoV-2 infection did not significantly differ between the two groups. Irrespective of the number of vaccinations, the risk of all-cause mortality was lower in patients with anti-S protein RBD antibody levels in the higher tertile.
A third dose of the COVID-19 vaccine was associated with a decreased risk of all-cause mortality among HD patients during the Omicron-dominant period. A higher post-vaccination anti-S protein RBD antibody level was also associated with a lower risk of mortality.
Background
The link between elevated serum uric acid (SUA) levels and cardiovascular disease (CVD)–related mortality in the elderly population remains inconclusive. Nutritional status influences both ...SUA and CVD outcomes. Therefore, we investigated whether SUA‐predicted mortality and the effect‐modifying roles of malnourishment in older people.
Methods and Results
A longitudinal Taiwanese cohort including 127 771 adults 65 years and older participating in the Taipei City Elderly Health Examination Program from 2001 to 2010 were stratified by 1‐mg/dL increment of SUA. Low SUA (<4 mg/dL) strata was categorized by malnourishment status defined as Geriatric Nutritional Risk Index <98, serum albumin <38 g/L, or body mass index <22 kg/m2. Study outcomes were all‐cause and CVD‐related mortality. Cox models were used to estimate hazard ratios (HRs) of mortality, after adjusting for 20 demographic and comorbid covariates. Over a median follow‐up of 5.8 years, there were 16 439 all‐cause and 3877 CVD‐related deaths. Compared with the reference SUA strata of 4 to <5 mg/dL, all‐cause mortality was significantly higher at SUA <4 mg/dL (HR, 1.16; 95% confidence interval, 1.07–1.25) and ≥8 mg/dL (HR, 1.13; confidence interval, 1.06–1.21), with progressively elevated risks at both extremes. Similarly, increasingly higher CVD‐related mortality was found at the SUA level <4 mg/dL (HR, 1.19; confidence interval, 1.00–1.40) and ≥7 mg/dL (HR, 1.17; confidence interval, 1.04–1.32). Remarkably, among the low SUA (<4 mg/dL) strata, only malnourished participants had greater all‐cause and CVD‐related mortality. This modifying effect of malnourishment remained consistent across subgroups.
Conclusions
SUA ≥8 or <4 mg/dL independently predicts higher all‐cause and CVD‐related mortality in the elderly, particularly in those with malnourishment.
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