Ambient temperature and the occurrence of intradialytic hypotension in patients receiving hemodialysis.

Background: Intradialytic hypotension (IDH) is a common hemodialysis complication causing adverse outcomes. Despite the well-documented associations of ambient temperatures with fluid removal and pre-dialysis blood pressure (BP), the relationship between ambient temperature and IDH has not been adequately studied. Methods: We conducted a cohort study at a tertiary hospital in southern Taiwan between 1 January 2016 and 31 October 2021. The 24-h pre-hemodialysis mean ambient temperature was determined using hourly readings from the weather station closest to each patient's residence. IDH was defined using Fall40 [systolic BP (SBP) drop of ≥40 mmHg] or Nadir90/100 (SBP <100 if pre-dialysis SBP was ≥160, or SBP <90 mmHg). Multivariate logistic regression with generalizing estimating equations and mediation analysis were utilized. Results: The study examined 110 400 hemodialysis sessions from 182 patients, finding an IDH prevalence of 11.8% and 10.4% as per the Fall40 and Nadir90/100 criteria, respectively. It revealed a reverse J-shaped relationship between ambient temperature and IDH, with a turning point around 27°C. For temperatures under 27°C, a 4°C drop significantly increased the odds ratio of IDH to 1.292 [95% confidence interval (CI) 1.228 to 1.358] and 1.207 (95% CI 1.149 to 1.268) under the Fall40 and Nadir90/100 definitions, respectively. Lower ambient temperatures correlated with higher ultrafiltration, accounting for about 23% of the increased IDH risk. Stratified seasonal analysis indicated that this relationship was consistent in spring, autumn and winter. Conclusion: Lower ambient temperature is significantly associated with an increased risk of IDH below the threshold of 27°C, irrespective of the IDH definition. This study provides further insight into environmental risk factors for IDH in patients undergoing hemodialysis.

YAP nuclear translocation induced by HIF-1α prevents DNA damage under hypoxic conditions.

Maladaptive repair of acute kidney injury (AKI) is associated with a high risk of developing chronic kidney disease deemed irremediable even in present days. When AKI arises from ischemia-reperfusion injury, hypoxia usually plays a major role. Although both hypoxia-inducible factor-1α (HIF-1α) and yes-associated protein (YAP) have been proven to promote renal cell survival under hypoxia, there is a lack of research that studies the crosstalk of the two and its effect on kidney repair. In studying the crosstalk, CoCl2 was used to create a mimetic hypoxic environment. Immunoprecipitation and proximity ligation assays were performed to verify protein interactions. The results show that HIF-1α interacts with YAP and promotes nuclear translocation of YAP at a high cell density under hypoxic conditions, suggesting HIF-1α serves as a direct carrier that enables YAP nuclear translocation. This is the first study to identify HIF-1α as a crucial pathway for YAP nuclear translocation under hypoxic conditions. Once translocated into a nucleus, YAP protects cells from DNA damage and apoptosis under hypoxic conditions. Since it is unlikely for YAP to translocate into a nucleus without HIF-1α, any treatment that fosters the crosstalk between the two holds the potential to improve cell recovery from hypoxic insults.

Deletion of NADPH oxidase 2 attenuates cisplatin-induced acute kidney injury through reducing ROS-induced proximal tubular cell injury and inflammation.

Backgrounds: Cisplatin is a commonly used chemotherapeutic agent in cancer treatment. However, its high nephrotoxicity limits its therapeutic application and efficacy. Cisplatin induces nephrotoxicity mainly through oxidative stress and inflammation. Reactive oxygen species (ROS) in the kidneys mainly arise from nicotinamide adenine dinucleotide phosphate (NADPH) oxidases 2 (NOX2), which is highly upregulated during ischemia-reperfusion injury and diabetes mellitus. However, its role in cisplatin-induced acute kidney injury (AKI) remains unknown. Methods: A 8-10-week-old NOX2 gene-knockout and wild-type mice were injected with 25 mg/kg cisplatin intraperitoneally for experiments. Results: We investigated the role of NOX2 in cisplatin-induced AKI and found that NOX2-mediated ROS production is a key inflammatory mediator of proximal tubular cell injury in cisplatin-induced AKI. NOX2 gene-knockout alleviated cisplatin-induced renal function decline, tubular injury score, kidney injury molecule-1(Kim-1) expression, and interleukin (IL)-6 and IL-1α levels with a reduction of ROS production. Moreover, in cisplatin-induced AKI, intercellular adhesion molecule 1 (ICAM-1) and the chemoattractant CXC ligand 1 (CXCL1) were highly expressed in association with neutrophil infiltration, which were all attenuated by deletion of NOX2. Conclusion: These data indicate that NOX2 aggravates cisplatin nephrotoxicity by promoting ROS-mediated tissue injury and neutrophil infiltration. Thus, appropriate targeting of NOX2/ROS pathway may minimize the risk of cisplatin-induced kidney injury in patients receiving cancer therapy.

NLRP3 inflammasome activation, metabolic danger signals, and protein binding partners.

The NOD-like receptor family pyrin domain-containing 3 (NLRP3) inflammasome is an oligomeric complex that assembles in response to exogenous signals of pathogen infection and endogenous danger signals of non-microbial origin. When NLRP3 inflammasome assembly activates caspase-1, it promotes the maturation and release of the inflammatory cytokines interleukin-1B and IL-18. Aberrant activation of the NLRP3 inflammasome has been implicated in various diseases, including chronic inflammatory, metabolic, and cardiovascular diseases. The NLRP3 inflammasome can be activated through several principal mechanisms, including K+ efflux, lysosomal damage, and the production of mitochondrial reactive oxygen species. Interestingly, metabolic danger signals activate the NLRP3 inflammasome to induce metabolic diseases. NLRP3 contains three crucial domains: an N-terminal pyrin domain, a central nucleotide-binding domain, and a C-terminal leucine-rich repeat domain. Protein-protein interactions act as a 'pedal or brake' to control the activation of the NLRP3 inflammasome. In this review, we present the mechanisms underlying NLRP3 inflammasome activation after induction by metabolic danger signals or via protein-protein interactions with NLRP3 that likely occur in metabolic diseases. Understanding these mechanisms will enable the development of specific inhibitors to treat NLRP3-related metabolic diseases.

Effect of dialysis modalities on risk of hospitalization for gastrointestinal bleeding.

Dialysis patients are at risk of both thromboembolic and bleeding events, while thromboembolism prevention and treatment may confer a risk of major bleeding. Gastrointestinal (GI) bleeding is a great concern which can result in high subsequent mortality rates. Our object was to clarify whether hemodialysis (HD) and peritoneal dialysis (PD) confer different incidence of GI bleeding, and further assist individualized decision-making on dialysis modalities. We conducted a population-based retrospective cohort study which included all incident dialysis patients above 18 years old derived from the National Health Insurance database from 1998 to 2013 in Taiwan. 6296 matched pairs of HD and PD patients were identified. A propensity score matching method was used to minimize the selection bias. The adjusted hazard ratio for GI bleeding was 1.13 times higher in the HD group than in the PD group, and data from the unmatched cohort and the stratified analysis led to similar results. Among subgroup analysis, we found that the use of anticoagulants will induce a much higher incidence of GI bleeding in HD patients as compared to in PD patients. We concluded that PD is associated with a lower GI bleeding risk than HD, and is especially preferred when anticoagulation is needed.

Nephrotoxins and acute kidney injury - The consensus of the Taiwan acute kidney injury Task Force.

The Taiwan Acute Kidney Injury (AKI) Task Force conducted a review of data and developed a consensus regarding nephrotoxins and AKI. This consensus covers: (1) contrast-associated AKI; (2) drug-induced nephrotoxicity; (3) prevention of drug-associated AKI; (4) follow up after AKI; (5) re-initiation of medication after AKI. Strategies for the avoidance of contrast media related AKI, including peri-procedural hydration, sodium bicarbonate solutions, oral N-acetylcysteine, and iso-osmolar/low-osmolar non-ionic iodinated contrast media have been recommended, given the respective evidence levels. Regarding anticoagulants, both warfarin and new oral anticoagulants have potential nephrotoxicity, and dosage should be reduced if renal pathology exam proves renal injury. Recommended strategies to prevent drug related AKI have included assessment of 5R/(6R) reactions - risk, recognition, response, renal support, rehabilitation and (research), use of AKI alert system and computerized decision support. In terms of antibiotics-associated AKI, avoiding concomitant administration of vancomycin and piperacillin-tazobactam, monitoring vancomycin trough level, switching from vancomycin to teicoplanin in high-risk patients, and replacing conventional amphotericin B with lipid-based amphotericin B have been shown to reduce drug related AKI. With respect to non-steroidal anti-inflammatory drug associated AKI, it is recommended to use these drugs cautiously in the elderly and in patients receiving renin-angiotensin-aldosterone system inhibitors/diuretics triple combinations.

Recovery of severe dialysis disequilibrium syndrome with uncal herniation following therapy with mannitol, hyperventilation and hypertonic saline.

Dialysis disequilibrium syndrome (DDS) is a rare complication of dialysis, especially with the general application of preventive strategies. Severe DDS with brain herniation is believed to be fatal. We present a patient presenting with bilateral uncal herniation after receiving two dialysis sessions with low-efficiency settings. Serial brain magnetic resonance imaging studies showed the temporal evolution of DDS-induced cerebral edema. With aggressive treatment of hypertonic saline and mannitol, the patient made a remarkable recovery. This case highlights that we should be cautious about this severe complication of dialysis even with preventive strategies, and recovery is possible with prompt recognition and treatment.

Healthcare utilization and expenditure among individuals with end-stage kidney disease in Taiwan.

BACKGROUND/PURPOSE: The prevalence of end-stage kidney disease (ESKD) in Taiwan has been increasing in recent decades. ESKD care and medical expenditures constitute an important part of the entire healthcare system. METHODS: This study analyzed data collected from the National Health Insurance (NHI) Research Database from 2010 to 2018. RESULTS: The annual medical cost increased by approximately 4% both in the entire Taiwanese population and in its ESKD population. The total medical expenditure in the ESKD population from 2010 to 2018 increased from 48.03 to 65.65 billion reimbursement points, with dialysis treatments costing higher than non-dialysis treatments. ESKD outpatient and inpatient costs accounted for 10.4%-11.1% and 4.8%-5.6% of the entire NHI expenditure, respectively. The leading cause of inpatient costs was circulatory diseases, accounting for 29.3% of the total ESKD inpatient costs in 2018. Furthermore, percutaneous coronary intervention had the highest cost followed by simple percutaneous transluminal angioplasty. In 2018, the hemodialysis population had the highest average monthly cost of 73 thousand points per person, while the kidney transplant population had the lowest average monthly cost of 39 thousand points per person. CONCLUSION: Medical expenditure, including both inpatient and outpatient costs, of the ESKD population continued to grow from 2010 to 2018. The non-dialysis cost in the ESKD population was mainly for cardiovascular disease management and vascular access care, for which prevention will always be challenging.

Development and validation of the dialysis dementia risk score: A retrospective, population-based, nested case-control study.

BACKGROUND: Dementia is prevalent and underdiagnosed in the dialysis population. We aimed to develop and validate a simple dialysis dementia scoring system to facilitate identification of individuals who are at high risk for dementia. METHODS: We applied a retrospective, nested case-control study design using a national dialysis cohort derived from the National Health Insurance Research Database in Taiwan. Patients aged between 40 and 80 years were included and 2940 patients with incident dementia were matched to 29,248 non-dementia controls. All subjects were randomly divided into the derivation and validation sets with a ratio of 4:1. Conditional logistic regression models were used to identify factors contributing to the risk score. The cutoff value of the risk score was determined by Youden's J statistic and the graphic method. RESULTS: The dialysis dementia risk score (DDRS) finally included age and 10 comorbidities as risk predictors. The C-statistic of the model was 0.71 (95% confidence interval [CI] 0.70-0.72). Calibration revealed a strong linear relationship between predicted and observed dementia risk (R2  = 0.99). At a cutoff value of 50 points, the high-risk patients had an approximately three-fold increased risk of having dementia compared to those with low risk (odds ratio [OR] 3.03, 95% CI 2.78-3.31). The DDRS performance, including discrimination (C-statistic 0.71, 95% CI 0.69-0.73) and calibration (p value of Hosmer-Lemeshow test for goodness of fit = 0.18), was acceptable during validation. The OR value (2.82, 95% CI 2.37-3.35) was similar to those in the derivation set. CONCLUSION: The DDRS system has the potential to serve as an easily accessible screening tool to determine the high-risk groups who deserve subsequent neurological evaluation in daily clinical practice.

Effects of helping relationships on health-promoting lifestyles among patients with chronic kidney disease: A randomized controlled trial.

BACKGROUND: Healthy behaviors can slow the progression of chronic kidney disease. Professional healthcare providers deliver education, physical exercise programs, motivation consultations, and stage-tailored strategies for improving health behaviors, but their effectiveness reported mixed. The helping relationships of significant others based on the transtheoretical model have been shown to be beneficial in facilitating and practicing health-promoting behaviors. However, few studies have examined the effects of helping relationships on health-promoting behaviors among patients with chronic kidney disease. OBJECTIVES: The aim of this study was to examine the effects of the intervention strategies of significant others in their helping relationships with patients to advance stages of exercise and diet behaviors, and to improve health-promoting lifestyles. DESIGN: A randomized controlled study. SETTINGS: Two outpatient nephrology clinics in southern Taiwan. PARTICIPANTS: Sixty participants in each of the two groups. METHODS: Patients were randomly assigned to either the intervention group (n = 60) whose significant others received strategies for helping relationships for 12 months, or the control group (n = 60). The Stage of Change of Exercise and Diet Behaviors, and Health Promoting Lifestyle Profile-II Chinese version were assessed at baseline and 3, 6, 9, and 12 months after receiving the helping relationship interventions tailored to stage of change from significant others. RESULTS: Generalized estimating equation analyzes revealed that the intervention group, when compared to the control group, had significantly advanced stages of change in exercise and diet, and improvement in health-promoting lifestyle over time. Adult children and spouses were the most common significant others to help patients practice healthy behaviors, compared to previous studies where professional healthcare providers were the significant others. CONCLUSIONS: Individualized plans for healthy behaviors should take into consideration patients' readiness for adopting stage-tailored strategies of helping relationships of significant others to adhere to the health-promoting lifestyle. To promote a healthier lifestyle, significant others, such as spouses and adult children, should be included in treatment programs.

Comparison of Immunogenicity and Safety between a Single Dose and One Booster Trivalent Inactivated Influenza Vaccination in Patients with Chronic Kidney Disease: A 20-Week, Open-Label Trial.

BACKGROUND: Non-dialysis-dependent chronic kidney disease (CKD-ND) patients are recommended to receive a one-dose influenza vaccination annually. However, studies investigating vaccine efficacy in the CKD-ND population are still lacking. In this study, we aimed to evaluate vaccine efficacy between the one-dose and two-dose regimen and among patients with different stages of CKD throughout a 20-week follow-up period. METHODS: We conducted a single-center, non-randomized, open-label, controlled trial among patients with all stages of CKD-ND. Subjects were classified as unvaccinated, one-dose, and two-dose groups (4 weeks apart) after enrollment. Serial changes in immunological parameters (0, 4, 8, and 20 weeks after enrollment), including seroprotection, geometric mean titer (GMT), GMT fold-increase, seroconversion, and seroresponse, were applied to evaluate vaccine efficacy. RESULTS: There were 43, 84, and 71 patients in the unvaccinated, one-dose, and two-dose vaccination groups, respectively. At 4-8 weeks after vaccination, seroprotection rates in the one- and two-dose group for H1N1, H3N2, and B ranged from 82.6-95.8%, 97.4-100%, and 73.9-100%, respectively. The concomitant seroconversion and GMT fold-increases nearly met the suggested criteria for vaccine efficacy for the elderly population. Although the seroprotection rates for all of the groups were adequate, the seroconversion and GMT fold-increase at 20 weeks after vaccination did not meet the criteria for vaccine efficacy. The two-dose regimen had a higher probability of achieving seroprotection for B strains (Odds ratio: 3.5, 95% confidence interval (1.30-9.40)). No significant differences in vaccine efficacy were found between early (stage 1-3) and late (stage 4-5) stage CKD. CONCLUSIONS: The standard one-dose vaccination can elicit sufficient protective antibodies. The two-dose regimen induced a better immune response when the baseline serum antibody titer was low. Monitoring change in antibody titers for a longer duration is warranted to further determine the current vaccine strategy in CKD-ND population.

PAX2 Mutation-Related Renal Hypodysplasia: Review of the Literature and Three Case Reports.

Paired box 2 (PAX2)-related disorder is an autosomal dominant genetic disorder associated with kidney and eye abnormalities and can result in end stage renal disease (ESRD). Despite reported low prevalence of PAX2 mutations, the prevalence of PAX2 related disorders may have been underestimated in past studies. With improved genetic sequencing techniques, more genetic abnormalities are being detected than ever before. Here, we report three patients from two families with PAX2 mutations identified within 1 year. Two patients were adults with chronic kidney disease and were followed for decades without correct diagnoses, including one with ESRD who had even undergone kidney transplant. The third patient was a neonate in whom PAX2-related disorder manifested as oligohydramnios, coloboma, and renal failure that progressed to ESRD within 1 year after birth. The phenotypes of PAX2 gene mutation were shown to be highly variable, even within the same family. Early detection promoted genetic counseling and guided clinical management. The appropriate time point for genetic study is an important issue. Clinicians must be more alert for PAX2 mutation when facing patients with congenital kidney and urinary tract anomalies, chronic kidney disease of unknown etiology, involvement of multiple systems, and/or a family history of renal disease.

Tailoring Health-promoting Programs for Patients with Chronic Kidney Disease: Randomized Controlled Trial.

Research on dietary and lifestyle modifications to decrease cardiovascular risk and slow disease progression has been limited to patients in the later stages of chronic kidney disease (CKD). Studies on the effectiveness of stage-of-change-tailored interventions on lifestyle modifications for individuals with early stage CKD are limited. Using random assignment, 60 patients with early stage CKD who received up to six tailored intervention visits over 30 months were compared to 60 usual care patients on physical indicators, lifestyle behaviors, and quality of life. Tailored interventions were consistent with the trans-theoretical Model of Change. Waist circumference, nutrition, and stress management improved over time in the intervention group. There was no difference or change in quality of life. To promote a healthier lifestyle, findings suggest that clinicians working with patients with CKD should consider patients' readiness to change their behaviors as well as implementation strategies tailored for different processes of change.

A comparison of the risk of acute myocardial infarction in patients receiving hemodialysis and peritoneal dialysis: A population-based, propensity score-matched cohort study.

BACKGROUND AND AIMS: Acute myocardial infarction (AMI) remains the major cause of morbidity and mortality in the dialysis population. Traditional cardiovascular (CV) risk factors are unable to fully account for the high incidence of AMI in the dialysis population. In this study, we investigated whether dialysis modalities could be one of the uremia-specific risk factors for AMI. METHODS: Using the National Health Insurance Research Database, we recruited all incident dialysis patients from the period January 1, 1998 to December 31, 2010. The propensity score matching method was applied to form the matched pairs of hemodialysis (HD) and peritoneal dialysis (PD) patients. Incidence rate (IR), cumulative incidence rate (CIR) and multivariable subdistribution hazards models were employed to compare the risk of AMI in the HD and PD groups. RESULTS: Of the 86,215 incident dialysis patients, 5,513 matched pairs of HD and PD patients were identified. The HD patients had a higher IR of AMI than the PD patients (9.71 vs. 8.35 per 1000 patient-years, respectively, p = 0.01). The CIR was also higher in the HD patients than in the PD patients (0.09 vs. 0.05), especially 4 years after dialysis therapy was initiated (p = 0.04). In the subdistribution hazards models, HD was still significantly associated with a higher risk of developing AMI (adjusted hazard ratio:1.30, 95% confidence interval:1.02-1.65). The results remained unchanged in various stratifications as well as in the analysis of the unmatched cohorts. CONCLUSIONS: Compared to PD, HD was significantly associated with higher risk of developing AMI, especially after 4 years since dialysis was initiated. Prevention and routine surveillance programs for AMI should be individualized according to dialysis modalities and vintage.

Loss of EGR-1 uncouples compensatory responses of pancreatic ß cells.

Rationale: Subjects unable to sustain ß-cell compensation develop type 2 diabetes. Early growth response-1 protein (EGR-1), implicated in the regulation of cell differentiation, proliferation, and apoptosis, is induced by diverse metabolic challenges, such as glucose or other nutrients. Therefore, we hypothesized that deficiency of EGR-1 might influence ß-cell compensation in response to metabolic overload. Methods: Mice deficient in EGR-1 (Egr1-/-) were used to investigate the in vivo roles of EGR-1 in regulation of glucose homeostasis and beta-cell compensatory responses. Results: In response to a high-fat diet, Egr1-/- mice failed to secrete sufficient insulin to clear glucose, which was associated with lower insulin content and attenuated hypertrophic response of islets. High-fat feeding caused a dramatic impairment in glucose-stimulated insulin secretion and downregulated the expression of genes encoding glucose sensing proteins. The cells co-expressing both insulin and glucagon were dramatically upregulated in islets of high-fat-fed Egr1-/- mice. EGR-1-deficient islets failed to maintain the transcriptional network for ß-cell compensatory response. In human pancreatic tissues, EGR1 expression correlated with the expression of ß-cell compensatory genes in the non-diabetic group, but not in the diabetic group. Conclusion: These results suggest that EGR-1 couples the transcriptional network to compensation for the loss of ß-cell function and identity. Thus, our study highlights the early stress coupler EGR-1 as a critical factor in the development of pancreatic islet failure.

A comparison of the risk of congestive heart failure-related hospitalizations in patients receiving hemodialysis and peritoneal dialysis - A retrospective propensity score-matched study.

INTRODUCTION: Congestive heart failure (CHF) is associated with high mortality and a heavy financial and healthcare burden in the dialysis population. Determining which dialysis modality is associated with a higher risk of developing CHF might facilitate clinical decision making and surveillance programs in the dialysis population. METHODS: Using the Taiwan National Health Insurance Database, we recruited all incident dialysis patients during the period from January 1, 1998 to December 31, 2010. The propensity score matching method was applied to establish the matched hemodialysis (HD) and peritoneal dialysis (PD) cohort. Incidence rates and cumulative incidence rates of CHF-related hospitalization were first compared for the HD and PD patients. Multivariable subdistribution hazards models were then constructed to control for potential confounders. RESULTS: Among a total of 65,899 enrolled dialysis patients, 4,754 matched pairs of HD and PD patients were identified. The incidence rates of CHF in the matched HD and PD patients were 25.98 and 19.71 per 1000 patient-years, respectively (P = 0.001). The cumulative incidence rate of CHF was also higher in the matched HD patients (0.16, 95% confidence interval (CI)(0.12-0.21)] than in the corresponding PD patients (0.09, 95% CI [0.08-0.11])(P<0.0001). HD was consistently associated with an increased subdistribution hazard ratio (HR) of CHF compared with PD in the matched cohort (HR: 1.45, 95% CI [1.23-1.7]). Similar phenomenons were observed in either the subgroup analysis stratified by selected confounders or in the HD and PD group without matching. CONCLUSIONS: HD is associated with a higher risk of developing CHF-related hospitalization than PD. The surveillance program for CHF should differ in patients receiving different dialysis modalities.

Male Patients on Peritoneal Dialysis Have a Higher Risk of Sleep Apnea.

STUDY OBJECTIVES: Peritoneal dialysis (PD) is a renal replacement therapy. One concern is whether patients on PD have a higher risk of sleep apnea (SA) due to intra-abdominal pressure increase and worsened ultrafiltration capacity. Despite this concern, to date, whether the risk of SA differs between PD, hemodialysis (HD), and groups without uremia is still uncertain. METHODS: In this retrospective cohort study, data were obtained from the National Health Insurance Research Database of Taiwan. This database enrolled almost all patients on dialysis in the country. A total of 7,645 incident patients on PD and 38,225 incident patients on HD were enrolled. In addition, 38,225 patients without uremia were selected as the comparison cohort. Individuals were monitored for the occurrence of SA until 2013. RESULTS: The results showed that patients on PD, regardless of sex, all had a higher risk of SA than non-dialysis groups. In contrast, the risk of SA in patients on HD was not significantly different from that of patients without uremia. We also compared the risk of SA between patients on PD and HD directly. The results showed that male patients on PD had a significantly higher risk of SA risk than male patients on HD. However, the risk of SA did not differ between female patients on PD and HD. CONCLUSIONS: Patients on PD should receive regular SA assessments and that an increased awareness and a higher index of suspicion for SA should be maintained in these patients, especially male patients.