Lower serum potassium associated with increased mortality in dialysis patients: A nationwide prospective observational cohort study in Korea

Background: Abnormal serum potassium concentration has been suggested as a risk factor for mortality in patients undergoing dialysis patients. We investigated the impact of serum potassium levels on survival according to dialysis modality. Methods: A nationwide, prospective, observational cohort study for end stage renal disease patients has been ongoing in Korea since August 2008. Our analysis included patients whose records contained data regarding serum potassium levels. The relationship between serum potassium and mortality was analyzed using competing risk regression. Results: A total of 3,230 patients undergoing hemodialysis (HD, 64.3%) or peritoneal dialysis (PD, 35.7%) were included. The serum potassium level was significantly lower (P < 0.001) in PD (median, 4.5 mmol/L; interquartile range, 4.0-4.9 mmol/L) than in HD patients (median, 4.9 mmol/L; interquartile range, 4.5-5.4 mmol/L). During 4.4 ± 1.7 years of follow-up, 751 patients (23.3%) died, mainly from cardiovascular events (n = 179) and infection (n = 120). In overall, lower serum potassium level less than 4.5 mmol/L was an independent risk factor for mortality after adjusting for age, comorbidities, and nutritional status (sub-distribution hazard ratio, 1.30; 95% confidence interval 1.10-1.53; P = 0.002). HD patients showed a U-shaped survival pattern, suggesting that both lower and higher potassium levels were deleterious, although insignificant. However, in PD patients, only lower serum potassium level (<4.5 mmol/L) was an independent predictor of mortality (sub-distribution hazard ratio, 1.35; 95% confidence interval 1.00-1.80; P = 0.048). Conclusion: Lower serum potassium levels (<4.5 mmol/L) occur more commonly in PD than in HD patients. It represents an independent predictor of survival in overall dialysis, especially in PD patients. Therefore, management of dialysis patients should focus especially on reducing the risk of hypokalemia, not only that of hyperkalemia.ope

Prediction of the Mortality Risk in Peritoneal Dialysis Patients using Machine Learning Models: A Nation-wide Prospective Cohort in Korea

Herein, we aim to assess mortality risk prediction in peritoneal dialysis patients using machine-learning algorithms for proper prognosis prediction. A total of 1,730 peritoneal dialysis patients in the CRC for ESRD prospective cohort from 2008 to 2014 were enrolled in this study. Classification algorithms were used for prediction of N-year mortality including neural network. The survival hazard ratio was presented by machine-learning algorithms using survival statistics and was compared to conventional algorithms. A survival-tree algorithm presented the most accurate prediction model and outperformed a conventional method such as Cox regression (concordance index 0.769 vs 0.745). Among various survival decision-tree models, the modified Charlson Comorbidity index (mCCI) was selected as the best predictor of mortality. If peritoneal dialysis patients with high mCCI (>4) were aged ≥70.5 years old, the survival hazard ratio was predicted as 4.61 compared to the overall study population. Among the various algorithm using longitudinal data, the AUC value of logistic regression was augmented at 0.804. In addition, the deep neural network significantly improved performance to 0.841. We propose machine learning-based final model, mCCI and age were interrelated as notable risk factors for mortality in Korean peritoneal dialysis patients.ope

Low serum phosphate as an independent predictor of increased infection-related mortality in dialysis patients: A prospective multicenter cohort study

Background: The role of mineral metabolism in mortality among dialysis patients has received increased attention, but some aspects remain unclear. The aim of the present study was to investigate the prognostic value of serum calcium and phosphate levels for all-cause mortality and cause-specific mortality in dialysis patients. Methods: Patients on hemodialysis and peritoneal dialysis were enrolled from a multicenter prospective cohort study in Korea (NCT00931970). The patients were divided into low, normal, and high groups according to their baseline serum calcium or phosphate levels. Cox proportional analysis and a proportional hazards model for the subdistribution of a competing risk were used to calculate hazard ratios (HRs) for the association of serum calcium and phosphate levels with all-cause and cause-specific mortality. Time-dependent values of calcium and phosphate were also evaluated to assess the effect of longitudinal change in mineral metabolism parameters on mortality types. Results: A total of 3,226 dialysis patients were followed up for a mean of 19.8 ± 8.2 months. Infection was the most common cause of death. Low serum phosphate was significantly associated with all-cause and infection-related death using time-dependent values (HR, 1.43 [95% confidence interval (CI), 1.06-1.93], P = 0.02, and HR, 1.66 [95% CI, 1.02-2.70], P = 0.04, respectively). Low serum phosphate was associated with significantly higher infection-related mortality, especially in patients older than 65 years or on dialysis more than one year or with serum albumin lower than 3.9 g/dL (HR, 2.06 [95% CI, 1.13-3.75], P = 0.02, HR, 2.19 [95% CI, 1.20-4.01], P = 0.01, and HR, 1.77 [95% CI, 1.00-3.13], P = 0.05, respectively). Multinomial logistic regression analysis results suggested that low serum albumin, creatinine, and body mass index correlated with low serum phosphate. Conclusions: Low serum phosphate in dialysis patients was an independent risk factor for infection-related death, especially in elderly patients. Persistently low serum phosphate might be a nutritional biomarker to predict increased susceptibility to infection and in turn worse outcomes in dialysis patients.ope

Glomerular mRNAs in human type 1 diabetes: Biochemical evidence for microalbuminuria as a manifestation of diabetic nephropathy

Background In patients with type 1 diabetes, some consider microalbuminuria to be a predictor of diabetic nephropathy while others believe it is an early feature of diabetic nephropathy. Methods Levels of mRNAs that are of pathogenetic relevance in diabetic nephropathy were compared in glomeruli isolated from microalbuminuric and overtly proteinuric subjects and in control normoalbuminuric diabetic subjects and living renal transplant donors. Results In subjects with microalbuminuria and overt proteinuria, glomerular mRNAs were virtually identical and approximately twofold higher for connective tissue growth factor (CTGF; P < 0.01) and collagen alpha2(IV) (P < 0.03) compared to living renal donors and normoalbuminuric patients. Glomerular glyceraldehyde-3-phosphate dehydrogenase (GAPDH) levels were not significantly different among the groups (P = 0.4). Weak but statistically significant correlations were noted between CTGF mRNA and albuminuria (assessed by rank), fractional mesangial surface area, and a composite renal biopsy index. Glomerular CTGF mRNA correlated inversely with creatinine clearance. Glomerular collagen alpha2(IV) mRNA levels correlated with albuminuria (by rank) and less strongly with fractional mesangial area. Conclusion To our knowledge, these data provide the first biochemical evidence demonstrating that the glomeruli of microalbuminuric patients and those with overt proteinuria do not differ significantly. The data support the concept that microalbuminuria is not "predictive" of diabetic nephropathy, but rather is an earlier point in the spectrum of diabetic nephropathy.ope

Angiotensin II stimulates the synthesis of vascular endothelial growth factor through the p38 mitogen activated protein kinase pathway in cultured mouse podocytes

Angiotensin II (Ang-II) and vascular endothelial growth factor (VEGF) have an important role in the pathogenesis of diabetic nephropathy, but the signaling cascade of VEGF regulation in response to Ang-II in podocytes is largely unknown. In these experiments, we looked at the effect of Ang-II on the production of VEGF, and investigated whether VEGF production depends on the p38 mitogen activated protein kinase (MAPK) pathway in cultured mouse podocytes. Incubation of podocytes with Ang-II induced a rapid increase in VEGF mRNA expression and protein synthesis as well as its transcriptional activity in an Ang-II dose-dependent manner. To further define the role of angiotensin type 1 (AT1) and type 2 (AT2) receptors involved in Ang-II-mediated VEGF synthesis, the effects of selective AT1 and AT2 receptor antagonists were evaluated. Prior treatment with losartan significantly inhibited VEGF mRNA and protein synthesis induced by Ang-II, which suggests that the AT1 receptor is involved in Ang-II-mediated VEGF synthesis. Furthermore, stimulation of the cells with Ang-II increased both phosphorylation of p38 MAPK and MAP kinase kinase 3/6 (MKK3/6). Additionally, Ang-II enhanced the DNA binding activity to cAMP response element binding protein (CREB) and phosphorylation of CREB. In addition, to investigate the role of p38 MAPK in Ang-II-induced VEGF synthesis, podocytes were pretreated with or without the p38 MAPK inhibitor, SB203580 for 24 h to observe whether Ang-II-mediated VEGF synthesis was inhibited by blocking p38 MAPK. The addition of SB203580 led to a marked inhibition of the increased VEGF mRNA and protein production induced by Ang-II in a dose-dependent manner. Taken together, these results suggest that Ang-II stimulates the synthesis of VEGF in podocytes and the production of VEGF induced by Ang-II is mediated, in part, through the activation of the p38 MAPK pathway.ope

Risk of Stroke in Elderly Dialysis Patients

Despite the current knowledge about the risk of stroke and its related factors in general population, this issue in elderly patients receiving dialysis remains unresolved. Firstly, to compare the risk of stroke between hemodialysis (HD) and peritoneal dialysis (PD), data on 13,065 incident dialysis patients (aged ≥ 65 years; 10,675 in HD and 2,390 in PD) were retrieved from the Korean Health Insurance dataset. Secondly, to identify the risk factors of stroke amongst various clinical and laboratory parameters in HD, 980 elderly patients were retrospectively analyzed using an independent prospective cohort from 31 dialysis centers. For a mean duration of 1.8 years (maximum of 5 years), the risk of all cardiovascular diseases (ischemic heart disease and stroke) did not differ between HD and PD. However, when analyses were conducted separately by subtype, the risk of stroke, not ischemic heart disease, was significantly higher in HD patients than in PD patients. When the risk factors of stroke were probed after HD for a mean duration of 2.6 years (maximum of 7 years), the absolute dependence on social support, a previous history of cardiovascular disease, high levels of low-density lipoprotein cholesterol, and the use of a high number of anti-hypertensive drugs were identified as being significant. Based on the discrepancy of stroke risk between modalities and the HD-tailored risk factors of stroke, the monitoring and management of these factors may be a key strategy to reduce the risk of stroke in elderly patients receiving dialysis.ope

p38 MAPK and MAPK kinase 3/6 mRNA and activities are increased in early diabetic glomeruli.

Background The p38 mitogen-activated protein kinase (MAPK) pathway is activated by several stress factors, potentially leading to cellular apoptosis and growth. Little is known about the pattern of glomerular p38 MAPK pathway activation during the course of diabetic nephropathy (DN). We examined the activity and expression of the p38 MAPK pathway members, p38 MAPK, MKK3/6, cAMP-responsive element binding protein (CREB), and MAPK phosphatase-1 (MKP-1), in experimental DN in rats over the course of four months. Methods Control (C; N = 16) and diabetic (DM; N = 16) rats were studied. Four rats from each group were sacrificed monthly, and competitive reverse transcription-polymerase chain reaction and Western blot were performed with microdissected and sieved glomeruli, respectively. Results Glomerular p38 MAPK mRNA expression was significantly higher in DM than C (P < 0.01) throughout the four-month period. Western blot revealed an average 3.1-fold increase in p38 MAPK protein throughout the study period (P < 0.05). However, p38 MAPK activity was significantly increased only in one- and two-month diabetic glomeruli. Glomerular MKK3/6 and CREB mRNA as well as activity were significantly increased only in one- and two-month DM compared with C. MKP-1 mRNA showed a similar pattern. Conclusions Glomerular p38 MAPK activity was increased in early DN. Parallel to this, we also showed, to our knowledge for the first time, that there were increased MKK3/6 and CREB activities and mRNA expression. This activated p38 MAPK pathway in diabetic glomeruli may, in part, play a role in the pathogenesis of early hypertrophy and extracellular matrix accumulation.ope

Low parathyroid hormone level predicts infection-related mortality in incident dialysis patients: a prospective cohort study

Background/Aims: Parathyroid hormone (PTH) is an important factor influencing immunologic dysfunction, but the effect of PTH level on infection-related outcomes remains unclear in incident dialysis. Methods: We evaluated a multicenter prospective cohort study of 1,771 incident dialysis patients (1,260 hemodialysis and 511 peritoneal dialysis) in Korea. Patients were divided into three groups based on serum intact PTH (iPTH) level. The primary outcomes were all-cause and infection-related mortality and multivariate Cox regression analysis was performed to evaluate the role of iPTH in all-cause and infection-related mortality. Results: During the follow-up period of 27.3 months, 175 patients (9.9%) died, and infection-related death represented 20% of all-cause mortality. Both all-cause mortality and infection-related mortality rates (p < 0.001 and p = 0.003, by log-rank) were markedly higher in patients with serum iPTH < 1.50 pg/mL than in the other groups. Multivariate Cox regression analysis revealed that patients with serum iPTH < 150 pg/mL remained at higher risk for infection-related mortality than patients in the target range of 150 <= iPTH < 300 pg/mL, after adjusting for confounding variables (hazard ratio [HR], 2.52; 95% confidence interval, 1.06 to 5.99; p = 0.04). The HR of infection-related mortality in patients with serum iPTH < 150 pg/mL was significantly higher in patients with low serum phosphorus, low Ca x P product, low serum alkaline phosphatase and those older than 65 years. Conclusions: Low serum iPTH level is an independent predictor of infection-related mortality in incident dialysis patients.ope

The effects of vascular access types on the survival and quality of life and depression in the incident hemodialysis patients

Background Although arteriovenous fistula (AVF) is the preferred vascular access for hemodialysis (HD), the association between vascular access types and quality of life is not well-known. We investigated the relationships between HD vascular access types and all-cause mortality, health-related quality of life (HRQOL) and the degree of depression in a large prospective cohort. Methods A total of 1461 patients who newly initiated HD were included. The initial vascular access types were classified into AVF, arteriovenous graft (AVG), and central venous catheter (CVC). The primary outcomes were all-cause mortality and HRQOL and depression. The secondary outcome was all-cause hospitalization. Kidney Disease Quality of Life Short Form 36 (KDQOL-36) and Beck's depression inventory (BDI) scores were measured to assess HRQOL and depression. Results Among 1461 patients, we identified 314 patients who started HD via AVF, 76 via AVG, and 1071 via CVC. In the survival analysis, patients with AVF showed significantly better survival compared with patients with other accesses (p < .001). The AVF and AVG group had higher KDQOL-36 score and lower BDI score than CVC group at 3 months and 12 months after the initiation of HD. The frequency of hospitalization was higher in patients with AVG compared to those with AVF (AVF 0.7 vs. AVG 1.1 times per year) (p = .024). Conclusions The patients with AVF had better survival rate and low hospitalization rate, and the patients with AVF or AVG showed both higher HRQOL and lower depression scores than those with CVC.ope

Early dialysis initiation does not improve clinical outcomes in elderly end-stage renal disease patients: A multicenter prospective cohort study

Background: The optimal timing for initiating dialysis in end-stage renal disease (ESRD) is controversial, especially in the elderly. Methods: 665 patients ≥65 years old who began dialysis from August 2008 to February 2015 were prospectively enrolled in the Clinical Research Center for End-Stage Renal Disease cohort study. Participants were divided into 2 groups based on the median estimated glomerular filtration rate at the initiation of dialysis. Propensity score matching (PSM) was used to compare the overall survival rate, cardiovascular events, Kidney Disease Quality of Life Short Form 36 (KDQOL-36) results, Karnofsky performance scale values, Beck's depression inventory values, and subjective global assessments. Results: The mean patient age was 72.0 years, and 61.7% of the patients were male. Overall, the cumulative survival rates were lower in the early initiation group, although the difference was not significant after PSM. Additionally, the survival rates of the 2 groups did not differ after adjusting for age, sex, Charlson comorbidity index and hemoglobin, serum albumin, serum calcium and phosphorus levels. Although the early initiation group showed a lower physical component summary score on the KDQOL-36 3 months after dialysis, the difference in scores was not significant 12 months after dialysis. Furthermore, the difference was not significant after PSM. The Karnofsky performance scale, Beck's depression inventory, and subjective global assessments were not significantly different 3 and 12 months after dialysis initiation. Conclusions: The timing of dialysis initiation is not associated with clinical outcomes in elderly patients with ESRD.ope