Interleukin-6-to-Albumin Ratio as a Superior Predictor of Mortality in End-Stage Kidney Disease Patients.

INTRODUCTION: In patients with chronic kidney disease (CKD), high interleukin-6 (IL-6) and low albumin circulating concentrations are associated with worse outcomes. We examined the IL-6-to-albumin ratio (IAR) as a predictor of risk of death in incident dialysis patients. METHODS: In 428 incident dialysis patients (median age 56 years, 62% men, 31% diabetes mellitus, 38% cardiovascular disease [CVD]), plasma IL-6 and albumin were measured at baseline to calculate IAR. We compared the discrimination of IAR with other risk factors for predicting 60-month mortality using receiver operating characteristic curve (ROC) and analyzed the association of IAR with mortality using Cox regression analysis. We divided patients into IAR tertiles and analyzed: (1) cumulative incidence of mortality and the association of IAR with mortality risk in Fine-Gray analysis, taking kidney transplantation as competing risk and (2) the restricted mean survival time (RMST) to 60-month mortality and differences of RMST (∆RMST) between IAR tertiles to describe quantitative differences of survival time. RESULTS: For all-cause mortality, the area under the ROC curve (AUC) for IAR was 0.700, which was greater than for IL-6 and albumin separately, while for CV mortality, the AUC for IAR (0.658) showed negligible improvement over IL-6 and albumin separately. In Cox regression analysis, IAR was significantly associated with all-cause mortality but not with CV mortality. Both high versus low and middle versus low tertiles of IAR associated with higher risk of all-cause mortality, subdistribution hazard ratio of 2.22 (95% CI 1.40-3.52) and 1.85 (95% CI 1.16-2.95), respectively, after adjusting for age, sex, diabetes mellitus, CVD, smoking, and estimated glomerular filtration rate. ∆RMST at 60 months showed significantly shorter survival time in middle and high IAR tertiles compared with low IAR tertile for all-cause mortality. CONCLUSIONS: Higher IAR was independently associated with significantly higher all-cause mortality risk in incident dialysis patients. These results suggest that IAR may provide useful prognostic information in patients with CKD.

Clinical and patient-reported trajectories at end-of-life in older patients with advanced CKD.

BACKGROUND: We explore longitudinal trajectories of clinical indicators, patient-reported outcomes, and hospitalizations, in the years preceding death in a population of older patients with advanced chronic kidney disease (CKD). METHODS: The EQUAL study is a European observational prospective cohort study with an incident eGFR <20 ml/min per 1.73 m2 and ≥65 years of age. The evolution of each clinical indicator was explored using generalized additive models during the 4 years preceding death. RESULTS: We included 661 decedents with a median time to death of 2.0 years (IQR 0.9-3.2). During the years preceding death, eGFR, Subjective Global Assessment score, and blood pressure declined, with accelerations seen at 6 months preceding death. Serum hemoglobin, hematocrit, cholesterol, calcium, albumin, and sodium values declined slowly during follow-up, with accelerations observed between 6 and 12 months preceding death. Physical and mental quality of life declined linearly throughout follow-up. The number of reported symptoms was stable up to 2 years prior to death, with an acceleration observed at 1 year prior to death. The rate of hospitalization was stable at around one hospitalization per person year, increasing exponentially at 6 months preceding death. CONCLUSIONS: We identified clinically relevant physiological accelerations in patient trajectories that began ∼6 to 12 months prior to death, which are likely multifactorial in nature, but correlate with a surge in hospitalizations. Further research should focus on how to effectively use this knowledge to inform patient and family expectations, to benefit the planning of (end-of-life) care, and to establish clinical alert systems.

Low-Plasma Insulin-Like Growth Factor-1 Associates With Increased Mortality in Chronic Kidney Disease Patients With Reduced Muscle Strength.

OBJECTIVES: Chronic kidney disease (CKD) leads to metabolic and nutritional abnormalities including resistance to insulin-like growth factor-1 (IGF-1) action, and reduced muscle mass and strength. Low IGF-1 as well as low hand-grip muscle strength (HGS) are independent predictors of increased mortality in CKD patients. METHODS: In 685 patients (CKD Stage 3-5, median age 58 years; 62% men), baseline measurements of IGF-1, HGS, subjective global assessment (SGA), lean body mass index (LBMI), and metabolic and inflammatory biomarkers potentially linked to IGF-1 were analyzed in relation to mortality during 5 years of follow-up. We compared survival in 4 groups with high or low (cut-offs defined by receiver operating characteristic curve analysis) levels of IGF-1 and HGS. RESULTS: Patients with low IGF-1 were older; had lower BMI, HGS, and LBMI, were more likely to have diabetes, cardiovascular disease (CVD), and malnutrition (SGA >1); and had high-sensitivity C-reactive protein levels. During 5 years of follow-up, 208 patients died. The mortality rate was highest among patients with Low IGF-1 + Low HGS. In competing-risk regression analysis, Low IGF-1 + Low HGS was independently associated with 2.8 times higher all-cause mortality risk than Low IGF-1 + High HGS, after adjusting for Framingham's CVD risk score, presence of CVD, SGA, dialysis status, high-sensitivity C-reactive protein, albumin, LBMI, and sample time in freezer. CONCLUSION: Low IGF-1 was associated with increased all-cause mortality in patients who also had low HGS but not in those with high HGS, suggesting that the association of IGF-1 with survival in CKD patients depends on nutritional status.

Converting from face-to-face to postal follow-up and its effects on participant retention, response rates and errors: lessons from the EQUAL study in the UK.

BACKGROUND: Prospective cohort studies are challenging to deliver, with one of the main difficulties lying in retention of participants. The need to socially distance during the COVID-19 pandemic has added to this challenge. The pre-COVID-19 adaptation of the European Quality (EQUAL) study in the UK to a remote form of follow-up for efficiency provides lessons for those who are considering changing their study design. METHODS: The EQUAL study is an international prospective cohort study of patients ≥65 years of age with advanced chronic kidney disease. Initially, patients were invited to complete a questionnaire (SF-36, Dialysis Symptom Index and Renal Treatment Satisfaction Questionnaire) at research clinics every 3-6 months, known as "traditional follow-up" (TFU). In 2018, all living patients were invited to switch to "efficient follow-up" (EFU), which used an abbreviated questionnaire consisting of SF-12 and Dialysis Symptom Index. These were administered centrally by post. Response rates were calculated using returned questionnaires as a proportion of surviving invitees, and error rates presented as the average percentage of unanswered questions or unclear answers, of total questions in returned questionnaires. Response and error rates were calculated 6-monthly in TFU to allow comparisons with EFU. RESULTS: Of the 504 patients initially recruited, 236 were still alive at the time of conversion to EFU; 111 of these (47%) consented to the change in follow-up. In those who consented, median TFU was 34 months, ranging from 0 to 42 months. Their response rates fell steadily from 88% (98/111) at month 0 of TFU, to 20% (3/15) at month 42. The response rate for the first EFU questionnaire was 60% (59/99) of those alive from TFU. With this improvement in response rates, the first EFU also lowered errors to baseline levels seen in early follow-up, after having almost trebled throughout traditional follow-up. CONCLUSIONS: Overall, this study demonstrates that administration of shorter follow-up questionnaires by post rather than in person does not negatively impact patient response or error rates. These results may be reassuring for researchers who are trying to limit face-to-face contact with patients during the COVID-19 pandemic.

Peritoneal dialysis patient selection from a comorbidity perspective.

Despite many medical and socioeconomic advantages, peritoneal dialysis (PD) is an underutilized dialysis modality that in most countries is used by only 5%-20% of dialysis patients, while the vast majority are treated with in-center hemodialysis. Several factors may explain this paradox, such as lack of experience and infrastructure for training and monitoring of PD patients, organizational issues, overcapacity of hemodialysis facilities, and lack of economic incentives for dialysis centers to use PD instead of HD. In addition, medical conditions that are perceived (rightly or wrongly) as contraindications to PD represent barriers for the use of PD because of their purported potential negative impact on clinical outcomes in patients starting PD. While there are few absolute contraindications to PD, high age, comorbidities such as diabetes mellitus, obesity, polycystic kidney disease, heart failure, and previous history of abdominal surgery and renal allograft failure, may be seen (rightly or wrongly) as relative contraindications and thus barriers to initiation of PD. In this brief review, we discuss how the presence of these conditions may influence the strategy of selecting patients for PD, focusing on measures that can be taken to overcome potential problems.

First-year mortality in incident dialysis patients: results of the Peridialysis study.

BACKGROUND: Controversy surrounds which factors are important for predicting early mortality after dialysis initiation (DI). We investigated associations of predialysis course and circumstances affecting planning and execution of DI with mortality following DI. METHODS: Among 1580 patients participating in the Peridialysis study, a study of causes and timing of DI, we registered features of predialysis course, clinical and biochemical data at DI, incidence of unplanned suboptimal DI, contraindications to peritoneal dialysis (PD) or hemodialysis (HD), and modality preference, actual choice, and cause of modality choice. Patients were followed for 12 months or until transplantation. A flexible parametric model was used to identify independent factors associated with all-cause mortality. RESULTS: First-year mortality was 19.33%. Independent factors predicting death were high age, comorbidity, clinical contraindications to PD or HD, suboptimal DI, high eGFR, low serum albumin, hyperphosphatemia, high C-reactive protein, signs of overhydration and cerebral symptoms at DI. Among 1061 (67.2%) patients who could select dialysis modality based on personal choice, 654 (61.6%) chose PD, 368 (34.7%) center HD and 39 (3.7%) home HD. The 12-months survival did not differ significantly between patients receiving PD and in-center HD. CONCLUSIONS: First-year mortality in incident dialysis patients was in addition to high age and comorbidity, associated with clinical contraindications to PD or HD, clinical symptoms, hyperphosphatemia, inflammation, and suboptimal DI. In patients with a "free" choice of dialysis modality based on their personal preferences, PD and in-center HD led to broadly similar short-term outcomes.

A genome-wide association study suggests correlations of common genetic variants with peritoneal solute transfer rates in patients with kidney failure receiving peritoneal dialysis.

Movement of solutes across the peritoneum allows for the use of peritoneal dialysis to treat kidney failure. However, there is a large inter-individual variability in the peritoneal solute transfer rate (PSTR). Here, we tested the hypothesis that common genetic variants are associated with variability in PSTR. Of the 3561 participants from 69 centers in six countries, 2850 with complete data were included in a genome-wide association study. PSTR was defined as the four-hour dialysate/plasma creatinine ratio from the first peritoneal equilibration test after starting PD. Heritability of PSTR was estimated using genomic-restricted maximum-likelihood analysis, and the association of PSTR with a genome-wide polygenic risk score was also tested. The mean four-hour dialysate/plasma creatinine ratio in participants was 0.70. In 2212 participants of European ancestry, no signal reached genome-wide significance but 23 single nucleotide variants at four loci demonstrated suggestive associations with PSTR. Meta-analysis of ancestry-stratified regressions in 2850 participants revealed five single-nucleotide variants at four loci with suggestive correlations with PSTR. Association across ancestry strata was consistent for rs28644184 at the KDM2B locus. The estimated heritability of PSTR was 19%, and a permuted model polygenic risk score was significantly associated with PSTR. Thus, this genome-wide association study of patients receiving peritoneal dialysis bolsters evidence for a genetic contribution to inter-individual variability in PSTR.

Sparing effect of peritoneal dialysis vs hemodialysis on BMD changes and its impact on mortality.

INTRODUCTION: Bone loss in end stage renal disease (ESRD) patients associates with fractures, vascular calcification, cardiovascular disease (CVD) and increased mortality. We investigated factors associated with changes of bone mineral density (ΔBMD) during the initial year on dialysis therapy and associations of ΔBMD with subsequent mortality in ESRD patients initiating dialysis. MATERIALS AND METHODS: In 242 ESRD patients (median age 55 years, 61% men) starting dialysis with peritoneal dialysis (PD; n = 138) or hemodialysis (HD; n = 104), whole-body dual-energy X-ray absorptiometry (DXA), body composition, nutritional status and circulating biomarkers were assessed at baseline and 1 year after dialysis start. We used multivariate linear regression analysis to determine factors associated with ΔBMD, and fine and gray competing risk analysis to determine associations of ΔBMD with subsequent mortality risk. RESULTS: BMD decreased significantly in HD patients (significant reductions of BMDtotal and BMDleg, trunk, rib, pelvis and spine) but not in PD patients. HD compared to PD therapy associated with negative changes in BMDtotal (ß=- 0.15), BMDhead (ß=- 0.14), BMDleg (ß=- 0.18) and BMDtrunk (ß=- 0.16). Better preservation of BMD associated with significantly lower all-cause mortality for ΔBMDtotal (sub-hazard ratio, sHR, 0.91), ΔBMDhead (sHR 0.91) and ΔBMDleg (sHR 0.92), while only ΔBMDhead (sHR 0.92) had a beneficial effect on CVD-mortality. CONCLUSIONS: PD had beneficial effect compared with HD on BMD changes during first year of dialysis therapy. Better preservation of BMD, especially in bone sites rich in cortical bone, associated with lower subsequent mortality. BMD in cortical bone may have stronger association with clinical outcome than BMD in trabecular bone.

Inverse J-shaped relation between coronary arterial calcium density and mortality in advanced chronic kidney disease.

BACKGROUND: The coronary artery calcium (CAC) score from cardiac computed tomography (CT) is a composite of CAC volume and CAC density. In the general population, CAC volume is positively and CAC density inversely associated with cardiovascular disease (CVD) events, implying that decreased CAC density reflects atherosclerotic plaque instability. We analysed associations of CAC indices with mortality risk in patients with end-stage renal disease [chronic kidney disease Stage 5 (CKD5)]. METHODS: In 296 CKD5 patients undergoing cardiac CT (median age 55 years, 67% male, 19% diabetes, 133 dialysed), the Framingham risk score (FRS), presence of CVD and protein-energy wasting (PEW; subjective global assessment) and high-sensitivity C-reactive protein (hsCRP) and interleukin-6 (IL-6) were determined at baseline. During follow-up for a median of 35 months, 51 patients died and 75 patients underwent renal transplantation. All-cause mortality risk was analysed with competing-risk regression models. Vascular calcification was analysed in biopsies of the arteria epigastrica inferior in 111 patients. RESULTS: Patients in the middle tertile of CAC density had the highest CAC score, CAC volume, age, CVD, PEW, FRS, hsCRP and IL-6. In competing risk analysis, the middle {subhazard ratio [sHR] 10.7 [95% confidence interval (CI) 2.0-57.3]} and high [sHR 8.9 (95% CI 1.5-51.8)] tertiles of CAC density associated with increased mortality, independent of CAC volume. The high tertile of CAC volume, independent of CAC density, associated with increased mortality [sHR 8.9 (95% CI 1.5-51.8)]. Arterial media calcification was prominent and associated with CAC volume and CAC density. CONCLUSIONS: In CKD5, mortality increased linearly with higher CAC score and CAC volume whereas for CAC density an inverse J-shaped pattern was observed, with the crude mortality rate being highest for the middle tertile of CAC density. CAC volume and CAC density were associated with the extent of arterial media calcification.

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.

Skin autofluorescence, arterial stiffness and Framingham risk score as predictors of clinical outcome in chronic kidney disease patients: a cohort study.

BACKGROUND: The risk of cardiovascular disease (CVD) is predicted by Framingham's CVD risk scores (FRS) but the high CVD-related mortality in patients with chronic kidney disease (CKD) is only partially explained by traditional CVD risk markers. Therefore, there is a need to explore whether other CVD risk markers may improve risk prediction. Although arterial stiffness measured by augmentation index (AIx) and tissue content of advanced glycation end-products (AGEs) measured by skin autofluorescence (SAF) are two biomarkers that associate with CVD and mortality in CKD, it is not known how they compare with FRS. We evaluated associations between SAF, AIx and FRS, and their associations with CVD and mortality in CKD patients. METHODS: SAF (AGE Reader) and AIx (SphygmoCor; adjusted for 75 heart beats per minute) were measured in 261 clinically stable and extensively phenotyped patients with CKD Stage 5 (median age 56 years, 66% male, 20% diabetes; 130 non-dialysed, 93 patients on peritoneal dialysis and 38 patients on haemodialysis). Multivariate receiver operator characteristics (ROC) curve analysis and multivariate Cox models followed by C-statistics were used to evaluate CVD-related and all-cause mortality risk associated with SAF, AIx and FRS during follow-up for median 25 months with 46 deaths. RESULTS: In multivariate regression analysis, SAF associated with FRS, haemoglobin, fat body mass index and CVD, and inversely with per cent handgrip strength (HGS). AIx associated with FRS, and inversely with per cent HGS. Associations of SAF and AIx with high-sensitivity C-reactive protein (hsCRP), serum albumin, statin therapy and renal replacement therapy were not statistically significant. In ROC analysis, area under the curve (AUC) for CVD mortality ranged from AUC = 0.72 (AIx and FRS, respectively) to AUC = 0.78 (FRS + AIx), and for all-cause mortality from AUC = 0.70 (AIx) to AUC = 0.79 (FRS + AIx). In multivariate Cox analysis, after adjusting for 1-standard deviation (1-SD) of FRS, 1-SD increase of SAF associated with all-cause mortality and 1-SD increase of AIx associated with CVD mortality and all-cause mortality. After further adjustments for hsCRP, albumin and presence of CVD, AIx (but not SAF) remained independently associated with CVD mortality, hazard ratio (HR) 2.14 [95% confidence interval (95% CI) 1.18-3.89] and all-cause mortality, HR 1.74 (95% CI 1.16-2.60). CONCLUSIONS: In patients with CKD Stage 5, SAF and aortic stiffness associated with mortality, independently of FRS. After adjusting for additional confounders including inflammation, aortic stiffness remained as an independent predictor of outcome. Since the contribution of SAF and aortic stiffness compared with FRS in ROC curve analysis was relatively modest, this underlines the importance of traditional CVD risk factors in CKD.

Uraemic symptom burden and clinical condition in women and men of ≥65 years of age with advanced chronic kidney disease: results from the EQUAL study.

BACKGROUND: The epidemiology and prognosis of chronic kidney disease (CKD) differ by sex. We aimed to compare symptom prevalence and the clinical state in women and men of ≥65 years of age with advanced CKD receiving routine nephrology care. METHODS: The European QUALity study on treatment in advanced chronic kidney disease (EQUAL) study follows patients from six European countries of ≥65 years of age years whose estimated glomerular filtration rate (eGFR) dropped to ≤20 mL/min/1.73 m2 for the first time during the last 6 months. The Dialysis Symptom Index was used to assess the prevalence and severity of 33 uraemic symptoms. Data on the clinical state at baseline were collected from medical records. Prevalence was standardized using the age distribution of women as the reference. RESULTS: The results in women (n = 512) and men (n = 967) did not differ with age (77.0 versus 75.7 years) or eGFR (19.0 versus 18.5). The median number of symptoms was 14 [interquartile range (IQR) 9-19] in women, and 11 (IQR 7-16) in men. Women most frequently reported fatigue {39% [95% confidence interval (CI) 34-45]} and bone/joint pain [37% (95% CI 32-42)] as severe symptoms, whereas more men reported difficulty in becoming sexually aroused [32% (95% CI 28-35)] and a decreased interest in sex [31% (95% CI 28-35)]. Anaemia [73% (95% CI 69-77) versus 85% (95% CI 82-87)] was less common in women than in men, as were smoking history and cardiovascular comorbidity. However, a diagnosis of liver disease other than cirrhosis, psychiatric disease and mild malnutrition were more common among women. CONCLUSIONS: Women in secondary care with an incident eGFR ≤20 mL/min/1.73 m2 reported a higher symptom burden, while their clinical state was considered similar or even more favourable as compared with men.

Differences in association of lower bone mineral density with higher coronary calcification in female and male end-stage renal disease patients.

BACKGROUND: Risk of cardiac events and cardiovascular disease (CVD) in end-stage renal disease (ESRD) patients are predicted by coronary artery calcification (CAC) independently. It is not clear to what extent low bone mineral density (BMD) is associated with higher risk of CAC and if sex interacts. We investigated the sex-specific associations of CAC score with total body BMD (tBMD) as well as with BMD of different skeletal sub-regions. METHODS: In 174 ESRD patients, median age 57 (10th-90th percentiles 29-75) years, 63% males, BMD (measured by dual-energy X-ray absorptiometry; DXA), CAC score (measured by cardiac CT) and circulating inflammatory biomarkers were analysed. RESULTS: A total of 104 (60%) patients with CAC > 100 AUs were older, had higher prevalence of both clinical CVD and diabetes, higher level of high sensitivity C-reactive protein, tumour necrosis factor, interleukin-6 and lower T-score of tBMD. Female patients had significantly lower tBMD and BMD of all skeletal sub-regions, except head, than male patients. Female patients with high CAC (> 100 AUs) had significantly decreased T-score of tBMD, and lower BMD of arms, legs than those low CAC (≤ 100 AUs); elevated CAC score were associated with tBMD, T-score, Z-score of tBMD and BMD of arms and legs, while no such differences was observed in males. Multivariate generalized linear model (GLM) analysis adjusted for age, diabetes and hsCRP showed that in females per SD higher CAC score (1057 AUs) was predicted by either per SD (0.13 g/cm2) lower tBMD or per SD (0.17 g/cm2) lower BMD at legs. No such associations were found in male ESRD patients. CONCLUSIONS: In female, but not male, lower BMD, in particular sub-regions of legs, was associated with higher CAC score independently. Low BMD has the potential to identify increased risk for high CAC score in ESRD patients.

Health-related quality of life as predictor of mortality in end-stage renal disease patients: an observational study.

BACKGROUND: Health-related quality of life (HRQoL) is an important component of patient-centered outcomes and a useful parameter for monitoring quality of care. We assessed HRQoL, its determinants, and associations with mortality in patients with end-stage renal disease (ESRD). METHODS: Short Form-36 was used to assess HRQoL, its domain components, and physical (PCS) and mental (MCS) composite summary scores in altogether 400 (338 incident and 62 prevalent) dialysis patients with median age 64 years, 37% women, 24% diabetes mellitus (DM), 49% cardiovascular disease (CVD), and median estimated glomerular filtration rate (eGFR) of 5.3 (3.0-9.4) ml/min/1.732. Results were analyzed separately for 338 incident patients starting on hemodialysis (HD; 68%) or peritoneal dialysis (PD; 32%), and 62 prevalent PD patients. Mortality risk was analyzed during up to 60 months (median 28 months). RESULTS: Linear multivariate regression analysis showed that in incident dialysis patients, 1-SD higher PCS associated negatively with 1-SD higher age, DM and CVD, and positively with 1-SD higher hemoglobin and sodium (adjusted r2 = 0.17). In 62 prevalent PD patients, 1-SD higher PCS was negatively associated with 1-SD higher age. MCS was not associated to any of the investigated factors. Multivariate Cox regression analysis showed that in incident dialysis patients, 1-SD increase of PCS associated with lower all-cause mortality, hazard ratio 0.65 (95% confidence interval 0.52-0.81), after adjustments for age, sex, DM, CVD, plasma albumin, C-reactive protein and eGFR whereas 1-SD lower MCS did not associate with mortality. In PD patients, neither PCS nor MCS associated with mortality. CONCLUSIONS: MCS did not associate with any of the investigated clinical factors, whereas lower PCS associated with higher age, CVD, DM, and lower hemoglobin and sodium levels. MCS was not associated with mortality, whereas lower PCS associated with increased mortality risk. These results suggest that HRQoL - in addition to its role as patient-centered outcome - matters also for hard clinical outcomes in ESRD patients. Our knowledge about factors influencing MCS in ESRD patients is limited and should motivate further studies.

Lung Dysfunction and Mortality in Patients with Chronic Kidney Disease.

BACKGROUND/AIMS: Lung dysfunction associates with increased mortality but the impact of chronic kidney disease (CKD) is less clear. We evaluated lung function and its association with mortality among individuals with normal to severely reduced glomerular filtration rate (GFR). METHODS: 404 individuals representing GFR category G1 (n=31; GFR >90 mL/min/1.73 m2), G2 (n=46), G3 (n=33), G4 (n=49) and G5 (n=245; GFR< 15 mL/min/1.73 m2) underwent spirometry yielding lung function indices forced vital capacity (FVC), forced expiratory volume in the first second (FEV1) and peak expiratory flow (PEF). Associations of lung function indices expressed as percentages of predicted values (%FEV1, %FVC and %PEF) with 5-year mortality were analyzed by competing-risk regression models. RESULTS: The prevalence of obstructive (6% in G1 and 11% in G5) and especially restrictive (9% in G1 to 36% in G5) lung dysfunction increased with declining GFR and with higher comorbidity burden. In patients (n=22) with protein-energy wasting, inflammation and cardiovascular disease, the prevalence of restrictive lung function was 64%. The highest tertiles of % FEV1 and %FVC associated with lower sub-hazard ratios (sHR) for all-cause mortality, 0.49 (95% CI, 0.27-0.88)) and 0.56 (95% CI, 0.32-0.98), and that of %FEV1 also with lower cardiovascular mortality risk (sHR 0.16; 95%CI 0.04-0.69) after adjusting for multiple confounders. Restrictive lung dysfunction (FEV1/FVC ≥ 0.70, and %FVC < 80) associated with increased mortality risk (sHR 1.80, 95%CI, 1.04-3.13) while the association with obstructive lung impairment was not statistically significant. CONCLUSION: Lung dysfunction and in particular restrictive lung dysfunction associates with degree of renal function impairment and presence of comorbidities, and is an independent predictor of increased mortality in CKD patients.

Do metabolic derangements in end-stage polycystic kidney disease differ versus other primary kidney diseases?

AIM: Autosomal dominant polycystic kidney disease (ADPKD), a systemic disorder caused by mutation in genes encoding polycystins, has been reported to lead to metabolic derangements including new-onset diabetes mellitus after kidney transplantation. We analyzed markers of insulin resistance (IR), inflammation, nutritional status and insulin-like growth factor-1 (IGF-1) in end-stage renal disease (ESRD) patients with ADPKD and ESRD patients with other primary kidney diseases. METHODS: In a post hoc cross-sectional analysis in 254 non-diabetic CKD 5 patients starting on dialysis, glucose metabolism (insulin, IGF-1, homeostasis model assessment of IR, HOMA-IR), inflammation (high sensitivity C-reactive protein, interleukin-6, and tumour necrosis factor), nutritional status, and bone mineral density (BMD), were assessed. Survival was recorded for median time of 28 months (IQR 15-48 months). RESULTS: Neither indices of IR, nor IGF-1, inflammatory status, nutritional status, or BMD were different in patients with ADPKD as compared to other aetiologies of ESRD. Kaplan-Meier curves showed better survival among the ADPKD group versus other aetiologies, even after an exclusion of diabetic patients. CONCLUSIONS: The ESRD phenotype did not differ in ADPKD versus other primary kidney diseases in terms of markers of IR, inflammation, and nutritional status. This argues against the proposition that ADPKD patients are more prone to develop metabolic derangements beyond those generally observed in advanced CKD. However, additional studies are warranted to further elucidate systemic metabolic aspects of ADPKD.

Does statins promote vascular calcification in chronic kidney disease?

BACKGROUND: In end-stage renal disease (ESRD), coronary artery calcification (CAC) and inflammation contribute to cardiovascular disease (CVD). Statins do not improve survival in patients with ESRD, and their effect on vascular calcification is unclear. We explored associations between CAC, inflammatory biomarkers, statins and mortality in ESRD. MATERIALS AND METHODS: In 240 patients with ESRD (63% males; median age 56 years) from cohorts including 86 recipients of living donor kidney transplant (LD-Rtx), 96 incident dialysis patients and 58 prevalent peritoneal dialysis patients, associations of CAC score (Agatston Units, AUs), interleukin-6 (IL-6) with high-sensitivity C-reactive protein (hsCRP), tumour necrosis factor (TNF), use of statins and all-cause mortality were analysed. Cardiac CT was repeated in 35 patients after 1·5 years of renal replacement therapy. In vitro, human vascular smooth muscle cells (hVSMCs) were used to measure vitamin K metabolism. RESULTS: Among 240 patients, 129 (53%) had a CAC score > 100 AUs. Multivariate analysis revealed that independent predictors of 1-SD higher CAC score were age, male gender, diabetes and use of statins. The association between CAC score and mortality remained significant after adjustment for age, gender, diabetes, CVD, use of statins, protein-energy wasting and inflammation. Repeated CAC imaging in 35 patients showed that statin therapy was associated with greater progression of CAC. In vitro synthesis of menaquinone-4 by hVSMCs was significantly impaired by statins. CONCLUSION: Elevated CAC score is a mortality risk factor in ESRD independent of inflammation. Future studies should resolve if statins promote vascular calcification and inhibition of vitamin K synthesis in the uremic milieu.

Plasma Beta-Trace Protein as a Marker of Residual Renal Function: The Effect of Different Hemodialysis Modalities and Intra-Individual Variability over Time.

BACKGROUND/AIMS: Beta-trace protein (BTP) is a low-molecular-weight molecule, which may be used to assess residual renal function (RRF) in dialysis patients. Here we evaluated the influence of hemodialysis (HD) and hemodiafiltration (HDF) on plasma BTP, and analyzed the inter- and intra-individual variability of plasma BTP over time in HD and peritoneal dialysis (PD) patients. METHODS: In 12 prevalent HD patients, the effect of a single session of low-flux HD, high-flux HD and HDF on plasma BTP was studied. Blood samples were taken at baseline, after 120 and 240 minutes, and at the start of the next dialysis session. In 13 HD patients and 10 PD patients, inter- and intra-individual variability over three months was studied (monthly and weekly, respectively). Plasma BTP was measured using a nephelometric method. RESULTS: No significant decrease in plasma BTP was seen following a session of low-flux HD. Both high-flux HD and HDF resulted in a significant decrease immediately after dialysis (22% and 61% median decrease, respectively). A significant reduction of the molecule persisted only in HDF and a significant decrease (-15%) was still found immediately before the start of the next dialysis session. In both HD and PD patients, the reproducibility over time was excellent with intra-class correlation coefficient of 0.96 (0.93-0.99) and 0.92 (0.86-0.99) respectively. In a small cohort of PD patients, fair agreement existed between mGFR (average of renal urea and creatinine clearance from a 24 hours urine collection) and the BTP-based GFR estimation. CONCLUSION: BTP is a stable marker and a promising tool for RRF estimations in PD and HD patients. In patients receiving HDF, plasma levels of BTP should be interpreted with caution.

Dialysis modality and nutritional status are associated with variability of inflammatory markers.

BACKGROUND: Inflammation is a common feature in dialysis patients and is associated with cardiovascular complications and poor outcome. Measuring the variability of inflammatory markers may help in understanding underlying factors triggering inflammation. Whether the inflammatory pattern in hemodialysis (HD) and peritoneal dialysis (PD) patients differs has scarcely been studied. Here we explored factors associated with the magnitude and variability of inflammation markers in HD and PD patients. METHODS: In two 3-month, prospective cohort studies comprising 228 prevalent HD and 80 prevalent PD patients, interleukin-6 (IL-6) and high-sensitivity C-reactive protein (CRP) were measured in blood samples drawn each month and every week, respectively. Information on comorbidity, protein-energy wasting (PEW) and medications was gathered at baseline, and information on symptoms potentially related to inflammation was gathered weekly. A mixed-effect model was used for multivariate analysis of factors linked to CRP and IL-6 variation. RESULTS: IL-6 and CRP levels were higher and showed higher variability in HD versus PD patients [median IL-6 8.3 (interquartile range, IQR, 5.3-14.5) versus 6.7 (IQR 4.2-10.0) pg/mL, P < 0.001 and median CRP 6.1 (IQR 2.5-14.0) versus 5.4 (IQR 1.6-9.0) mg/L, P < 0.001). PEW predicted increased inflammation variability after correcting for age, sex, dialysis vintage, modality and comorbidity. Increased comorbidity predicted IL-6, but not CRP, variability. CONCLUSIONS: Circulating concentrations as well as variability of IL-6 and CRP levels were higher in HD as compared with PD patients. In HD and PD patients, short-term variability of IL-6 and CRP levels associated strongly with PEW, while comorbidity was related to IL-6 but not to CRP variability.

Plasma S100A12 and soluble receptor of advanced glycation end product levels and mortality in chronic kidney disease Stage 5 patients.

BACKGROUND: Alterations in the advanced glycation end-products (AGE)-receptor of AGE (RAGE) system are linked to several chronic diseases, which may result from vascular damage. A high circulating level of the pro-inflammatory RAGE-ligand S100A12, also known as EN-RAGE, is thought to promote while a high level of soluble RAGE (sRAGE) is thought to protect against development of atherosclerotic cardiovascular disease (CVD). We evaluated circulating S100A12 and sRAGE in relation to clinical characteristics, nutritional status, inflammation and mortality risk in chronic kidney disease (CKD) Stage 5 patients starting on dialysis. METHODS: Plasma S100A12 and sRAGE, biomarkers of inflammation and nutritional status, and comorbidities were investigated in 200 CKD Stage 5 patients [median age of 56 years, 62% men and median glomerular filtration rate (GFR) of 6.2 mL/min/1.73 m(2)] in conjunction with initiation of dialysis therapy. Associations between mortality risk and S100A12 or sRAGE were assessed after a median follow-up period of 23 months. In addition, for comparative analyses, S100A12 and sRAGE levels were assessed also in 58 haemodialysis and 78 peritoneal dialysis patients after 1 year of dialysis, 56 CKD Stages 3-4 patients and 50 community-based control subjects. RESULTS: The median level of S100A12 was 4-fold higher, median sRAGE 2.4 higher and median ratio S100A12/sRAGE 2.27 times higher in CKD 5 patients than in controls. Similar alterations were observed in CKD 3-4 patients; however, CKD 5 patients had a higher median level of sRAGE than the CKD 3-4 patients. In the CKD 5 patients, S100A12 levels were higher in those with diabetes or CVD than in those without these comorbidities. Furthermore, S100A12 correlated with high-sensitivity C-reactive protein (hsCRP) levels (ρ = 0.53; P < 0.001) and a 1-SD higher level of S100A12 associated with increased all-cause mortality risk (hazard ratio 1.32, 95% confidence interval 1.01-1.73) after adjustment for age, sex, comorbidity, nutritional status and inflammation (hsCRP). In the CKD 5 patients, sRAGE correlated negatively with GFR (ρ = -0.26; P < 0.01) but sRAGE did not associate with hsCRP, comorbidities or mortality. CONCLUSIONS: Plasma concentrations of sRAGE, S100A12 and the ratio S100A12/sRAGE, are markedly elevated in CKD 5 patients starting on dialysis as well as in CKD 3-4 patients and prevalent dialysis patients suggesting that these alterations are typical for patients with moderate or severe CKD. In CKD 5 patients, an increased concentration of S100A12 are associated with inflammation, comorbidities and increased mortality risk whereas no such associations were observed for sRAGE. These results suggest that while high plasma S100A12 is an independent predictor of increased mortality risk, sRAGE does not seem to be a valid risk marker in this patient population.