ABSTRACT
Taiwan renal care system is an evolving learning health‐care system. There are four facets of this system. From the early history of dialysis and Taiwan Renal Registry Data System, it ...facilitates the generation of data to knowledge. National multidisciplinary pre‐end‐stage renal disease care project and outcome enhances knowledge to practice. Early chronic kidney disease (CKD) programs and 2015 Taiwan CKD clinical guidelines implicate the practice to customer, and then explore the causes of CKD help to resume customer to data. A learning health‐care system allows better and safer care at lower cost, enhancement of public health and patient empowerment. The successful development of a learning health‐care system was to collect, accumulate and analyze data, interpret results, deliver tailored message and take action to change practice. Through the established database and data analysis, an integrated care system would be able to improve clinical outcomes and achieve the most cost‐effectiveness care. Acute kidney injury, CKD with unknown origin, palliative care and kidney transplant are our new focuses to struggle.
Summary at a Glance
Prevention of chronic kidney disease is an important public health issue in Taiwan. Through the four facets of this system, including data, knowledge, practice and customer, the experience of Taiwan Renal Data System is a success model of learning health‐care system.
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DOBA, FZAB, GIS, IJS, IZUM, KILJ, NLZOH, NUK, OILJ, PILJ, PNG, SAZU, SBCE, SBMB, UILJ, UKNU, UL, UM, UPUK
The association between incident chronic kidney disease (CKD) or end-stage renal disease (ESRD) and exposure to outdoor air pollution is under debate. We aimed to examine this relationship based on a ...systematic review with random-effects meta-analysis.
We screened the literature on long-term air pollution exposure assessment in the general population using an electronic search of PubMed, Medline, Embase, and Cochrane Library from inception to 20 October 2019. Observational studies investigating the association between long-term exposure to gaseous (CO, SO2, NO2, O3) or particulate (PM2.5 or PM10) outdoor air pollutants and CKD, ESRD, or renal dysfunction were included, and summary risks were estimated.
Of 4419 identified articles, 23 met our inclusion criteria after screening and 14 were included in the meta-analysis. Pooled effect estimates had the following summary risk ratios (RRs) for CKD: 1.10 (95% confidence intervals CI 1.00, 1.21; derived from four studies) per 10 μg/m3 increase in PM2.5 and 1.16 (95% CI 1.05, 1.29; derived from four studies) for PM10; 1.31 (95% CI 0.86, 2.00; derived from two studies) per 10 ppm increase in CO; and 1.11 (95% CI 1.09, 1.14; derived from three studies) per 10 ppb increase in NO2. For the pooled effect on eGFR, increases in PM10 and PM2.5 (of 10 μg/m3) were associated with eGFR decline by −0.83 (95% CI –1.54, −0.12; derived from two studies) and −4.11 (95% CI –12.64, 4.42; derived from two studies) mL/min/1.73 m2, respectively.
Air pollution was observed to be associated with CKD and renal function decline. Although more longitudinal studies are required, we argue that air pollution is pernicious to kidney health.
Forest plot and pooled estimates of the effect of air pollutants on the risk of chronic kidney disease.
(The size of the gray boxes for each point estimate represents the size of the included study.) Display omitted
•Long-term exposure to air pollutants, especially ambient PM and NO2, is associated with an increased risk of CKD.•PM2.5 substantially contributed to the global burden of CKD in 2016.•Considerable statistical heterogeneities were revealed in this meta-analysis.•An inverse relationship between the concentration of ambient air particulate matter and eGFR were identified.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Uremic toxins are considered to have a determinant pathological role in the progression of chronic kidney disease. The aim of this study was to define the putative pathological roles of the renal ...renin-angiotensin-aldosterone system (RAAS) and renal tubular epithelial-to-mesenchymal transition (EMT) in kidney fibrosis induced by (indoxyl sulfate) IS and (p-cresol sulfate) PCS.
Mouse proximal renal tubular cells (PKSV-PRs) treated with IS or PCS were used. Half-nephrectomized B-6 mice were treated with IS or PCS for 4 weeks. In the losartan treatment study, the study animal was administrated with IS+losartan or PCS+losartan for 4 weeks.
IS and PCS significantly activated the intrarenal RAAS by increasing renin, angiotensinogen, and angiotensin 1 (AT1) receptor expression, and decreasing AT2 receptor expression in vitro and in vivo. IS and PCS significantly increased transforming growth factor-β1 (TGF-β1) expression and activated the TGF-β pathway by increasing Smad2/Smad2-P, Smad3/Smad3-P, and Smad4 expression. The expression of the EMT-associated transcription factor Snail was increased by IS and PCS treatment. IS and PCS induced the phenotype of EMT-like transition in renal tubules by increasing the expression of fibronectin and α-smooth muscle actin and decreasing the expression of E-cadherin. Losartan significantly attenuated the expression of TGF-β1 and Snail, and decreased kidney fibrosis induced by IS and PCS in vivo.
Activating the renal RAAS/TGF-β pathway has an important pathological role in chronic kidney injury caused by IS and PCS. IS and PCS may increase Snail expression and induce EMT-like transition.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
The expression of the renoprotective antiaging gene Klotho is decreased in uremia. Recent studies suggest that Klotho may be a tumor suppressor, and its expression may be repressed by DNA ...hypermethylation in cancer cells. Here we investigated the effects and possible mechanisms by which Klotho expression is regulated during uremia in uninephrectomized B-6 mice given the uremic toxins indoxyl sulfate or p-cresyl sulfate. Cultured human renal tubular HK2 cells treated with these toxins were used as an in vitro model. Injections of indoxyl sulfate or p-cresyl sulfate increased their serum concentrations, kidney fibrosis, CpG hypermethylation of the Klotho gene, and decreased Klotho expression in renal tubules of these mice. The expression of DNA methyltransferases 1, 3a, and 3b isoforms in HK2 cells treated with indoxyl sulfate or p-cresyl sulfate was significantly increased. Specific inhibition of DNA methyltransferase isoform 1 by 5-aza-2′-deoxycytidine caused demethylation of the Klotho gene and increased Klotho expression in vitro. Thus, inhibition of Klotho gene expression by uremic toxins correlates with gene hypermethylation, suggesting that epigenetic modification of specific genes by uremic toxins may be an important pathological mechanism of disease.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
The kidney harbors one of the strongest circadian clocks in the body. Kidney failure has long been known to cause circadian sleep disturbances. Using an adenine-induced model of chronic kidney ...disease (CKD) in mice, we probe the possibility that such sleep disturbances originate from aberrant circadian rhythms in kidney. Under the CKD condition, mice developed unstable behavioral circadian rhythms. When observed in isolation in vitro, the pacing of the master clock, the suprachiasmatic nucleus (SCN), remained uncompromised, while the kidney clock became a less robust circadian oscillator with a longer period. We find this analogous to the silencing of a strong slave clock in the brain, the choroid plexus, which alters the pacing of the SCN. We propose that the kidney also contributes to overall circadian timekeeping at the whole-body level, through bottom-up feedback in the hierarchical structure of the mammalian circadian clocks.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
Left ventricular hypertrophy (LVH) is a common cardiovascular disorder and an independent risk factor for cardiovascular death in dialysis patients. Hyperphosphatemia is associated with LVH. Previous ...studies have shown that fibroblast growth factor 23 (FGF23), which has an important role in phosphate metabolism, is elevated in chronic hemodialysis patients.
The aim of this study is to determine the association of FGF23 and LVH and the prognostic value of FGF23 in chronic hemodialysis patients.
One hundred twenty-four end-stage renal disease patients were evaluated for LVH by echocardiography. Serum FGF23 levels were measured using a commercial enzyme-linked immunosorbent assay kit.
Patients with LVH were more likely to have poor urea clearance (Kt/V), higher systolic blood pressure, and comorbidity of diabetes mellitus and coronary artery disease. LVH was also associated with higher levels of FGF23. Multivariate analysis indicated that FGF23 level, systolic blood pressure, and comorbidity of diabetes mellitus and coronary artery disease remained correlated with LVH. This suggested that serum FGF23 level is independently associated with LVH in our hemodialysis patients. Cox analysis indicated no significant difference in risk of death for patients with elevated levels of FGF23.
LVH has a high prevalence in hemodialysis patients, and FGF23 is independently associated with LVH but is not a predictor for short-term prognosis (2-year follow-up).
Primary glomerulonephritis is a major global health concern and a disorder with significant heritable components. Rapid advances in sequencing technologies have led to genome‐wide, high‐throughput ...investigations of the genetic basis of complex human traits. Genetic studies have successfully mapped several susceptibility loci and disease‐causing genes for different subtypes of primary glomerulonephritis. These studies have revealed that IgA nephropathy–associated genes have a highly complex, polygenic and pleiotropic genetic architecture and that genetic susceptibility to membranous nephropathy may be driven by a few large‐effect loci. Furthermore, both susceptibility genes and high‐penetrant gene mutations reportedly contribute to the development of the most heterogeneous phenotype of focal segmental glomerulosclerosis. The genetic heterogeneity between each glomerular disease type and within different populations has indicated disease‐specific and ethnicity‐specific underlying molecular mechanisms for the disorders. The findings from genome‐wide association studies (GWAS) have mainly included variants on or near the major histocompatibility (MHC) loci, highlighting the molecular basis for the shared pathogenesis of the immune‐mediated disease. Recent studies with increased sample sizes and higher resolutions of genome‐wide imputation have provided novel insights into the pathogenesis of glomerular disorders. Further integration of results from genomic studies with functional genomics datasets can indicate novel targets for drug discovery as well as potential tools for patient diagnosis and stratification. However, larger GWASs and sequencing studies in independent cohorts and more standardized inclusion of phenotypes across studies are required for each subtype of glomerular disease.
Summary at a Glance
With the rapid advances in sequencing technologies, growing scale of genetics studies demonstrated novel insights into the pathogenesis of primary glomerulonephritis. The key findings can provide potential implications for drug discovery as well as patient diagnosis and stratification.
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DOBA, FZAB, GIS, IJS, IZUM, KILJ, NLZOH, NUK, OILJ, PILJ, PNG, SAZU, SBCE, SBMB, UILJ, UKNU, UL, UM, UPUK
Acute kidney disease (AKD) comprises acute kidney injury (AKI). However, whether the AKD staging system has prognostic values among AKI patients with different baseline estimated glomerular ...filtration (eGFR) remains a controversial issue. Algorithm-based approach was applied to identify AKI occurrence and to define different AKD stages. Risk ratio for major adverse kidney events (MAKE), including (1) eGFR decline > 35% from baseline, (2) initiation of dialysis, (3) in-hospital mortality of different AKD subgroups were identified by multivariable logistic regression. Among the 4741 AKI patients identified from January 2015 to December 2018, AKD stages 1-3 after AKI was common (53% in the lower baseline eGFR group and 51% in the higher baseline eGFR group). In the logistic regression model adjusted for demographics and comorbidities at 1-year follow-up, AKD stages 1/2/3 (AKD stage 0 as reference group) were associated with higher risks of MAKE (AKD stage: odds ratio, 95% confidence interval 95% CI, AKD 1: 1.85, 1.56-2.19; AKD 2: 3.43, 2.85-4.12; AKD 3: 10.41, 8.68-12.49). Regardless of baseline eGFR, staging criteria for AKD identified AKI patients who were at higher risk of kidney function decline, dialysis and mortality. Post-AKI AKD patients with severer stage need intensified care and timely intervention.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
Sepsis is a deadly disease that is widely attributed to endotoxin released by gram‐negative bacterial infections often plague emergency care facilities. Conventionally antibiotics and vasopressors ...are used to treat this disease. Recent treatment protocol shifted to a membrane to remove the offending endotoxin monomer. Despite this shift, membrane‐based devices are often extremely costly, hindering accessibility to this life saving medical device. In view of this challenges, we adopted the internally developed polysulfone (PSF) microtube array membrane alternating (MTAM‐A) for use in blood sepsis treatment. PSF MTAM‐A were with polymyxin B (PMB) molecules immobilized were assembled into an internally developed cartridge housing and subjected to endotoxin removal models with water and blood spiked with 100 EU/ml of endotoxin as the feed solution. Samples were derived at 15, 30, 60, and 120 min and endotoxin levels were determined with limulus amebocyte lysate assay and benchmarked against the commercially available Toraymyxin device. The PSF MTAM‐A with 2.3 times the surface area was successfully fabricated and with PMB molecules immobilized, and assembled into a hemoperfusion device. Dynamic endotoxin removal test revealed and overall endotoxin removal capacity of 90% and a superior endotoxin removal efficiency that was significantly higher than that of Toraymyxin (internally conducted and reported). The data suggested that PSF MTAM‐A PMB membranes could potentially be applied in future hemoperfusion devices which would be significantly more efficient, compact, and affordable; potentially making such a life‐saving medical device widely available to the general public.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
Identifying modifiable risk factors of peritoneal dialysis (PD)-related peritonitis is of clinical importance in patient care. Mineral bone disease (MBD) has been associated with mortality and ...morbidity in end-stage kidney disease (ESKD) patients. However, its influence on PD related peritonitis due to altered host immunity remains elusive. This study investigated whether abnormal biomarkers of MBD are associated with the development of peritonitis in patients undergoing maintenance PD. We conducted a retrospective observational cohort study, analysing data derived from a nationwide dialysis registry database in Taiwan, from 2005 to 2012. A total of 5750 ESKD patients commencing PD therapy during this period were enrolled and followed up to 60 months or by the end of the study period. The patients were stratified based on their baseline serum parathyroid hormone (PTH) levels, calcium (Ca) levels or phosphorus (P) levels, respectively or in combinations. The primary outcome was the occurrence of first episode of peritonitis, and patient outcomes such as deaths, transfer to haemodialysis or receiving renal transplantation were censored. Peritonitis-free survival and the influence of PTH, Ca, P (individual or in combination) on the peritonitis occurrence were analysed. A total of 5750 PD patients was enrolled. Of them, 1611 patients experienced their first episode of peritonitis during the study period. Patients with low PTH, high Ca or low P levels, respectively or in combination, had the lowest peritonitis-free survival. After adjusting for age, sex and serum albumin levels, we found that the combinations of low PTH levels with either high Ca levels or low/normal P levels were significant risk factors of developing peritonitis. Abnormal mineral bone metabolism in maintenance PD patients with low serum PTH levels, in combination with either high Ca levels or low/normal P levels, could be novel risk factors of PD-related peritonitis.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
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