CDKN2A/p16INK4a expression is associated with vascular progeria in chronic kidney disease

Patients with chronic kidney disease (CKD) display a progeric vascular phenotype linked to apoptosis, cellular senescence and osteogenic transformation. This has proven intractable to modelling appropriately in model organisms. We have therefore investigated this directly in man, using for the first time validated cellular biomarkers of ageing (CDKN2A/p16INK4a, SA-β-Gal) in arterial biopsies from 61 CKD patients undergoing living donor renal transplantation. We demonstrate that in the uremic milieu, increased arterial expression of CDKN2A/p16INK4a associated with vascular progeria in CKD, independently of chronological age. The arterial expression of CDKN2A/p16INK4a was significantly higher in patients with coronary calcification (p=0.01) and associated cardiovascular disease (CVD) (p=0.004). The correlation between CDKN2A/p16INK4a and media calcification was statistically significant (p=0.0003) after correction for chronological age. We further employed correlate expression of matrix Gla protein (MGP) and runt-related transcription factor 2 (RUNX2) as additional pathognomonic markers. Higher expression of CDKN2A/p16INK4a, RUNX2 and MGP were observed in arteries with severe media calcification. The number of p16INK4a and SA-β-Gal positive cells was higher in biopsies with severe media calcification. A strong inverse correlation was observed between CDKN2A/p16INK4a expression and carboxylated osteocalcin levels. Thus, impaired vitamin K mediated carboxylation may contribute to premature vascular senescence

Increased telomere attrition following renal transplantation: impact of anti-metabolite therapy

Background: The uremic milieu exposes chronic kidney disease (CKD) patients to premature ageing processes. The impact of renal replacement therapy (dialysis and renal transplantation [RTx]) or immunosuppressive treatment regimens on ageing biomarkers has scarcely been studied. Methods: In this study telomere length in whole blood cells was measured in 49 dialysis patients and 47 RTx patients close to therapy initiation and again after 12 months. Forty-three non-CKD patients were included as controls. Results: Non-CKD patients had significantly (P <= 0.01) longer telomeres than CKD patients. Telomere attrition after 12 months was significantly greater in RTx patients compared to dialysis patients (P = 0.008). RTx patients receiving mycophenolate mofetil (MMF) had a greater (P = 0.007) degree of telomere attrition compared to those treated with azathioprine. After 12 months, folate was significantly higher in RTx patients than in dialysis patients (P < 0.0001), whereas the opposite was true for homocysteine (P < 0.0001). The azathioprine group had lower levels of folate after 12 months than the MMF group (P = 0.003). Conclusions: The associations between immunosuppressive therapy, telomere attrition, and changes in folate indicate a link between methyl donor potential, immunosuppressive drugs, and biological ageing. The hypothesis that the increased telomere attrition, observed in the MMF group after RTx, is driven by the immunosuppressive treatment, deserves further attention

Elevated plasma phospholipid n-3 docosapentaenoic acid concentrations during hibernation

Factors for initiating hibernation are unknown, but the condition shares some metabolic similarities with consciousness/sleep, which has been associated with n-3 fatty acids in humans. We investigated plasma phospholipid fatty acid profiles during hibernation and summer in freeranging brown bears (Ursus arctos) and in captive garden dormice (Eliomys quercinus) contrasting in their hibernation patterns. The dormice received three different dietary fatty acid concentrations of linoleic acid (LA) (19%, 36% and 53%), with correspondingly decreased alphalinolenic acid (ALA) (32%, 17% and 1.4%). Saturated and monounsaturated fatty acids showed small differences between summer and hibernation in both species. The dormice diet influenced n-6 fatty acids and eicosapentaenoic acid (EPA) concentrations in plasma phospholipids. Consistent differences between summer and hibernation in bears and dormice were decreased ALA and EPA and marked increase of n-3 docosapentaenoic acid and a minor increase of docosahexaenoic acid in parallel with several hundred percent increase of the activity index of elongase ELOVL2 transforming C20-22 fatty acids. The highest LA supply was unexpectantly associated with the highest transformation of the n-3 fatty acids. Similar fatty acid patterns in two contrasting hibernating species indicates a link to the hibernation phenotype and requires further studies in relation to consciousness and metabolism

Elevated plasma phospholipid n-3 docosapentaenoic acid concentrations during hibernation

Factors for initiating hibernation are unknown, but the condition shares some metabolic similarities with consciousness/sleep, which has been associated with n-3 fatty acids in humans. We investigated plasma phospholipid fatty acid profiles during hibernation and summer in freeranging brown bears (Ursus arctos) and in captive garden dormice (Eliomys quercinus) contrasting in their hibernation patterns. The dormice received three different dietary fatty acid concentrations of linoleic acid (LA) (19%, 36% and 53%), with correspondingly decreased alphalinolenic acid (ALA) (32%, 17% and 1.4%). Saturated and monounsaturated fatty acids showed small differences between summer and hibernation in both species. The dormice diet influenced n-6 fatty acids and eicosapentaenoic acid (EPA) concentrations in plasma phospholipids. Consistent differences between summer and hibernation in bears and dormice were decreased ALA and EPA and marked increase of n-3 docosapentaenoic acid and a minor increase of docosahexaenoic acid in parallel with several hundred percent increase of the activity index of elongase ELOVL2 transforming C20-22 fatty acids. The highest LA supply was unexpectantly associated with the highest transformation of the n-3 fatty acids. Similar fatty acid patterns in two contrasting hibernating species indicates a link to the hibernation phenotype and requires further studies in relation to consciousness and metabolismpublishedVersio

Peritonitis: Episode Sequence, Microbiological Variation, Risk Factors and Clinical Outcomes in a North China Peritoneal Dialysis Center

Background/Aims: This study investigated peritonitis episodes with regard to time sequence, microbiological variation, factors associated with peritonitis and clinical outcomes in peritoneal dialysis (PD) patients. Methods: This single-center cohort study enrolled all incident patients who met the inclusion criteria at our center from June 1, 2012 to June 30, 2015 and who were followed until June, 2017. Clinical, biochemical characteristics and detailed data on peritonitis episodes, and hospitalizations were recorded. Results: A total of 218 episodes of peritonitis corresponding to a rate of 0.27 episode per patient-year were recorded. Gram positive bacteria, identified in 115 (52.8%) episodes, were the most common pathogens. The occurrence of enterococcus peritonitis increased from 15.1% of the first to 27.3% of the later episodes. Multivariate logistic regression showed that the presence of cardiovascular disease (CVD, odds ratio [OR] 2.177, 95% confidence interval [95%CI] 1.214–3.903, P=0.009), age≤ 55 (OR 2.282, 95%CI 1.062–4.906, P=0.035), non-independent operator (OR 0.440, 95%CI 0.206–0.938, P=0.034), lower values of potassium (OR=0.671,95%CI 0.472–0.954, P=0.026) and higher values of calcium-phosphate product (OR 1.410, 95%CI 1.065–1.868, P=0.017) were associated with peritonitis. Besides CVD (risk ratio [RR] 2.591, 95%CI 1.893–3.543, P< 0.001) and non-independent operator (RR 0.583, 95%CI 0.439–0.776, P< 0.001), a lower level of education (RR 0.641, 95%CI 0.487–0.842, P=0.001) was associated with higher peritonitis rates in log-linear analysis. Spearman analyses indicated that the time to the 1st episode was negatively related to the peritonitis rate (r=-0.291, P=0.001). Time-dependent Cox regression showed no association between the time to the 1st episode and patient survival (P=0.151). Patients with a high peritonitis rate (HPR) demonstrated worse technique survival (P< 0.001). Conclusion: The present study has revealed several center-based features and modifiable risk factors for peritonitis. The presence of CVD and the need for assistance with PD operation not only increased the odds of peritonitis but were also associated with more peritonitis episodes. Time to first peritonitis was related to the peritonitis rate but not associated with patient survival. Patients with HPR had worse technique survival

Study of the incidence of dialysis in São Paulo, the largest Brazilian city

OBJECTIVES: Chronic kidney disease is a major public health problem worldwide. In Brazil, approximately 100,000 patients (January 2012) receive renal replacement therapy. Nevertheless, data on dialysis incidence in the Brazilian population are scarce. This study aims to analyze the incidence of patients starting dialysis therapy in São Paulo City, the largest Brazilian metropolis. METHOD: This cohort study analyzed data from 9,994 patients starting hemodialysis or peritoneal dialysis funded by the Brazilian Public Health System during a 5-year period (2007-2011). Patient data for this study (recorded as electronic files) were obtained from the São Paulo City's Dialysis Regulatory Bureau, which regulates the allocation of patients requiring dialytic therapy. RESULTS: The dialysis incidence rates were 178, 174, 170, 185 and 188 per million population for the years 2007, 2008, 2009, 2010 and 2011, respectively. The incidence rates increased with age. Hypertension and diabetes were the main etiologies diagnosed. Hemodialysis was the chosen dialysis modality in the majority of patients (92.6%), whereas the percentage of patients referred for peritoneal dialysis decreased from 10.1% to 5.5%. CONCLUSION: The incidence of patients starting renal replacement therapy from 2007-2011 in São Paulo was stable but higher than the projected incidence for the entire country. The authors emphasize the need for further studies of the incidence of dialysis in the Brazilian population and for the creation of a Brazilian registry of dialysis patients, which would be a valuable tool for developing healthcare policies and renal replacement therapy strategies

Metabolic changes in summer active and anuric hibernating free-ranging brown bears (ursus arctos)

The brown bear (Ursus arctos) hibernates for 5 to 6 months each winter and during this time ingests no food or water and remains anuric and inactive. Despite these extreme conditions, bears do not develop azotemia and preserve their muscle and bone strength. To date most renal studies have been limited to small numbers of bears, often in captive environments. Sixteen free-ranging bears were darted and had blood drawn both during hibernation in winter and summer. Samples were collected for measurement of creatinine and urea, markers of inflammation, the calcium-phosphate axis, and nutritional parameters including amino acids. In winter the bear serum creatinine increased 2.5 fold despite a 2-fold decrease in urea, indicating a remarkable ability to recycle urea nitrogen during hibernation. During hibernation serum calcium remained constant despite a decrease in serum phosphate and a rise in FGF23 levels. Despite prolonged inactivity and reduced renal function, inflammation does not ensue and bears seem to have enhanced antioxidant defense mechanisms during hibernation. Nutrition parameters showed high fat stores, preserved amino acids and mild hyperglycemia during hibernation. While total, essential, non-essential and branched chain amino acids concentrations do not change during hibernation anorexia, changes in individual amino acids ornithine, citrulline and arginine indicate an active, although reduced urea cycle and nitrogen recycling to proteins. Serum uric acid and serum fructose levels were elevated in summer and changes between seasons were positively correlated. Further studies to understand how bears can prevent the development of uremia despite minimal renal function during hibernation could provide new therapeutic avenues for the treatment of human kidney disease

Body size and longitudinal body weight changes do not increase mortality in incident peritoneal dialysis patients of the Brazilian peritoneal dialysis multicenter study

OBJECTIVES: To determine the roles of body size and longitudinal body weight changes in the survival of incident peritoneal dialysis patients. PATIENTS AND METHODS: Patients (n = 1911) older than 18 years of age recruited from 114 dialysis centers (Dec/ 2004-Oct/2007) and participating in the Brazilian Peritoneal Dialysis Multicenter Cohort Study were included. Clinical and laboratory data were collected monthly (except if the patient received a transplant, recovered renal function, was transferred to hemodialysis, or died). RESULTS: Survival analyses were performed using Kaplan-Meier survival curves and Cox proportional hazards. Total follow-up was 34 months. The mean age was 59 years (54% female). The weight category percentages were as follows: underweight: 8%; normal: 51%; overweight: 29%; and obese 12%. The multivariate model showed a higher risk of death for a body mass index 30 kg/m2. Patients were divided into five categories according to quintiles of body weight changes during the first year of dialysis: +7.1%. Patients in the lowest quintile had significantly higher mortality, whereas no negative impact was observed in the other quintiles. CONCLUSION: These findings suggest that overweight/obesity and a positive body weight variation during the first year of peritoneal dialysis therapy do not increase mortality in incident dialysis patients in Brazil.

Copeptin is independently associated with vascular calcification in chronic kidney disease stage 5

Background: Vascular calcification (VC) is an independent predictor of cardiovascular disease (CVD) present in 30– 70% of patients with chronic kidney disease (CKD). Copeptin is a sensitive surrogate marker of arginine vasopressin (AVP), which is involved in many pathophysiologic processes in CKD. The aim of the present study was to explore the association of copeptin with VC in CKD stage 5. Methods: Copeptin was investigated in conjunction with living donor kidney transplantation in 149 clinically stable CKD stage 5 patients (CKD5), including 53 non-dialyzed (CKD5-ND) and 96 dialysis patients treated by peritoneal dialysis (PD) (n = 43) or hemodialysis (HD) (n = 53). We analyzed the association of copeptin with presence and extent of VC ascertained both histologically in biopsies from the inferior epigastric artery (n = 137) and by coronary artery calcification (CAC) score measured by computed tomography. Results: Patients with higher copeptin were older, had higher systolic blood pressure, higher prevalence of CVD and their preceding time on chronic dialysis was longer. In Spearman’s rank correlations (Rho), copeptin concentrations were significantly associated with CAC score (Rho = 0.27; p = 0.003) and presence of medial VC (Rho = 0.21; p = 0.016). Multivariate logistic regression analysis showed that 1-SD higher age, male gender, diabetes and 1-SD higher copeptin were significantly associated with the presence of moderate-extensive VC. Conclusions: High circulating levels of copeptin in CKD5 patients are independently associated with the degree of medial calcification ascertained by histology of arterial biopsies. Thus, plasma copeptin may serve as a marker of the uremic calcification process.Baxter HealthcareKarolinska Institutet Diabetes Theme CenterHeart and Lung FoundationNjurfondenWestmans FoundationEuropean Union’s Horizon 2020 research and innovation program, Marie Sklodowska-Curie (grant agreement No 722609)Publishe

Body size and longitudinal body weight changes do not increase mortality in incident peritoneal dialysis patients of the Brazilian peritoneal dialysis multicenter study

OBJECTIVES: To determine the roles of body size and longitudinal body weight changes in the survival of incident peritoneal dialysis patients. PATIENTS AND METHODS: Patients (n = 1911) older than 18 years of age recruited from 114 dialysis centers (Dec/ 2004-Oct/2007) and participating in the Brazilian Peritoneal Dialysis Multicenter Cohort Study were included. Clinical and laboratory data were collected monthly (except if the patient received a transplant, recovered renal function, was transferred to hemodialysis, or died). RESULTS: Survival analyses were performed using Kaplan-Meier survival curves and Cox proportional hazards. Total follow-up was 34 months. The mean age was 59 years (54% female). The weight category percentages were as follows: underweight: 8%; normal: 51%; overweight: 29%; and obese 12%. The multivariate model showed a higher risk of death for a body mass inde