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.

Transcription factor NRF2 as potential therapeutic target for preventing muscle wasting in aging chronic kidney disease patients.

Increased muscle protein catabolism leading to muscle wasting is a prominent feature of the syndrome of protein-energy wasting (PEW) in patients with chronic kidney disease (CKD). PEW and muscle wasting are induced by factors such as inflammation, oxidative stress and metabolic acidosis that activate the ubiquitin-proteasome system, the main regulatory mechanism of skeletal muscle degradation. Whether deficiency of nuclear factor erythroid 2-related factor 2 (NRF2), which regulates expression of antioxidant proteins protecting against oxidative damage triggered by inflammation, may exacerbate PEW has yet to be examined in aging patients with CKD. This review focuses on the hypothesis that NRF2 is involved in the maintenance of muscle mass and explores whether sustained activation of NRF2 by non-pharmacological interventions using nutraceutical activators to improve redox homeostasis could be a plausible strategy to prevent skeletal muscle disorders, including muscle wasting, sarcopenia and frailty associated with PEW in aging CKD patients.

Resistant Starch Type-2 Supplementation Does Not Decrease Trimethylamine N-Oxide (TMAO) Plasma Level in Hemodialysis Patients.

Dysbiosis is recognized as a new cardiovascular disease (CVD) risk factor in hemodialysis (HD) patients because it is linked to increased generation in the gut of uremic toxins such as trimethylamine N-Oxide (TMAO) from dietary precursors (choline, betaine, or L-carnitine). Nutritional strategies have been proposed to modulate the gut microbiota and reduce the production of these toxins. This study aimed to evaluate the effect of amylose-resistant starch (RS) supplementation on TMAO plasma levels in HD patients.We conducted a randomized, double-blind, placebo-controlled trial (NCT02706808) with patients undergoing HD enrolled in a previous pilot study. The participants were allocated to RS or placebo groups to receive 16 g/d of RS or placebo for 4 weeks. Plasma TMAO, choline, and betaine levels were measured with LC-MS/MS. Fecal microbiome composition was evaluated by 16S ribosomal RNA sequencing, followed by a search for TMA-associated taxa. Anthropometric, routine biochemical parameters, and food intake were evaluated.Twenty-five participants finished the study, 13 in the RS group, and 12 in the placebo group. RS supplementation did not reduce TMAO plasma levels. Moreover, no significant alterations were observed in choline, betaine, anthropometric, biochemical parameters, or food intake in both groups. Likewise, RS was not found to exert any influence on the proportion of potential TMA-producing bacterial taxa in fecal matter.RS supplementation did not influence plasma TMAO, choline, betaine, or fecal taxa potentially linked to TMAO. Thus, RS does not seem to modify the TMA-associated bacterial taxa, precursors of TMAO.Supplemental data for this article is available online at https://doi.org/10.1080/07315724.2021.1967814 .

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.

Water removal during automated peritoneal dialysis assessed by remote patient monitoring and modelling of peritoneal tissue hydration.

Water removal which is a key treatment goal of automated peritoneal dialysis (APD) can be assessed cycle-by-cycle using remote patient monitoring (RPM). We analysed ultrafiltration patterns during night APD following a dry day (APDDD; no daytime fluid exchange) or wet day (APDWD; daytime exchange). Ultrafiltration for each APD exchange were recorded for 16 days using RPM in 14 patients. The distributed model of fluid and solute transport was applied to simulate APD and to explore the impact of changes in peritoneal tissue hydration on ultrafiltration. We found lower ultrafiltration (mL, median [first quartile, third quartile]) during first and second vs. consecutive exchanges in APDDD (-61 [-148, 27], 170 [78, 228] vs. 213 [126, 275] mL; p < 0.001), but not in APDWD (81 [-8, 176], 81 [-4, 192] vs. 115 [4, 219] mL; NS). Simulations in a virtual patient showed that lower ultrafiltration (by 114 mL) was related to increased peritoneal tissue hydration caused by inflow of 187 mL of water during the first APDDD exchange. The observed phenomenon of lower ultrafiltration during initial exchanges of dialysis fluid in patients undergoing APDDD appears to be due to water inflow into the peritoneal tissue, re-establishing a state of increased hydration typical for peritoneal dialysis.

Suboptimal dialysis initiation is associated with comorbidities and uraemia progression rate but not with estimated glomerular filtration rate.

BACKGROUND: Despite early referral of uraemic patients to nephrological care, suboptimal dialysis initiation (SDI) remains a common problem associated with increased morbimortality. We hypothesized that SDI is related to pre-dialysis care. METHODS: In the 'Peridialysis' study, time and reasons for dialysis initiation (DI), clinical and biochemical data and centre characteristics were registered during the pre- and peri-dialytic period for 1583 end-stage kidney disease patients starting dialysis over a 3-year period at 15 nephrology departments in the Nordic and Baltic countries to identify factors associated with SDI. RESULTS: SDI occurred in 42%. Risk factors for SDI were late referral, cachexia, comorbidity (particularly cardiovascular), hypoalbuminaemia and rapid uraemia progression. Patients with polycystic renal disease had a lower incidence of SDI. High urea and C-reactive protein levels, acidosis and other electrolyte disorders were markers of SDI, independently of estimated glomerular filtration rate (eGFR). SDI patients had higher eGFR than non-SDI patients during the pre-dialysis period, but lower eGFR at DI. eGFR as such did not predict SDI. Patients with comorbidities had higher eGFR at DI. Centre practice and policy did not associate with the incidence of SDI. CONCLUSIONS: SDI occurred in 42% of all DIs. SDI was associated with hypoalbuminaemia, comorbidity and rate of eGFR loss, but not with the degree of renal failure as assessed by eGFR.

Osteoprotegerin is a marker of cardiovascular mortality in patients with chronic kidney disease stages 3-5.

Cardiovascular disease (CVD) is the leading cause of death in patients with chronic kidney disease (CKD). Osteoprotegerin (OPG), known to regulate bone mass by inhibiting osteoclast differentiation and activation, might also play a role in vascular calcification. Increased circulating OPG levels in patients with CKD are associated with aortic calcification and increased mortality. We assessed the predictive role of OPG for all-cause and cardiovascular mortality in patients with CKD stages 3-5 over a 5-year follow-up period. We evaluated the relationship between OPG and all-cause and cardiovascular mortality in 145 CKD patients (stages 3-5) in a prospective observational follow-up study. Inflammation markers, including high-sensitivity C-reactive protein, standard echocardiography, and estimation of intima-media thickness in the common carotid artery, were assessed at baseline, and correlations with OPG levels were determined. The cutoff values for OPG were defined using ROC curves for cardiovascular mortality. Survival was assessed during follow up lasting for up to 5.5 years using Fine and Gray model. A total of 145 (89 men; age 58.9 ± 15.0 years) were followed up. The cutoff value for OPG determined using ROC was 10 pmol/L for general causes mortality and 10.08 pmol/L for CV causes mortality. Patients with higher serum OPG levels presented with higher mortality rates compared to patients with lower levels. Aalen-Johansen cumulative incidence curve analysis demonstrated significantly worse survival rates in individuals with higher baseline OPG levels for all-cause and cardiovascular mortality (p < 0.001). In multivariate analysis, OPG was a marker of general and cardiovascular mortality independent of sex, age, CVD, diabetes, and CRP levels. When CKD stages were included in the multivariate analysis, OPG was an independent marker of all-cause mortality but not cardiovascular mortality. Elevated serum OPG levels were associated with higher all-cause and cardiovascular mortality risk, independent of age, CVD, diabetes, and inflammatory markers, in patients with CKD.

Cruciferous vegetables: rationale for exploring potential salutary effects of sulforaphane-rich foods in patients with chronic kidney disease.

Sulforaphane (SFN) is a sulfur-containing isothiocyanate found in cruciferous vegetables (Brassicaceae) and a well-known activator of nuclear factor-erythroid 2-related factor 2 (Nrf2), considered a master regulator of cellular antioxidant responses. Patients with chronic diseases, such as diabetes, cardiovascular disease, cancer, and chronic kidney disease (CKD) present with high levels of oxidative stress and a massive inflammatory burden associated with diminished Nrf2 and elevated nuclear transcription factor-κB-κB expression. Because it is a common constituent of dietary vegetables, the salutogenic properties of sulforaphane, especially it's antioxidative and anti-inflammatory properties, have been explored as a nutritional intervention in a range of diseases of ageing, though data on CKD remain scarce. In this brief review, the effects of SFN as a senotherapeutic agent are described and a rationale is provided for studies that aim to explore the potential benefits of SFN-rich foods in patients with CKD.

Serum Lysyl Oxidase Is a Potential Diagnostic Biomarker for Kidney Fibrosis.

BACKGROUND: Kidney fibrosis is the ultimate consequence of advanced stages of chronic kidney disease (CKD); however, there are currently no reliable biomarkers or noninvasive diagnostic tests available for the detection of kidney fibrosis. Lysyl oxidase (LOX) promotes collagen cross-linking, and serum LOX levels have been shown to be elevated in patients with fibrosis of the heart, lungs, and liver. However, serum LOX levels have not been reported in patients with kidney fibrosis. We explored whether serum LOX levels are associated with kidney fibrosis. METHOD: Overall, 202 patients with kidney disease underwent renal biopsy, scoring of kidney fibrosis, and determination of the area of kidney fibrosis. LOX levels were measured in serum and in kidney tissues. We analyzed the association of circulating LOX and tissue LOX levels with the scores and areas of kidney fibrosis. LOX expression was also investigated with in vitro and in vivo kidney fibrosis models. RESULTS: Serum LOX levels were higher in patients with kidney fibrosis than in those without kidney fibrosis (p < 0.001) and higher in patients with moderate-severe kidney fibrosis than in patients with mild kidney fibrosis (p < 0.001). Both serum LOX and renal tissue LOX levels correlated with the area of kidney fibrosis (r = 0.748, p < 0.001; r = 0.899, p < 0.001, respectively). Receiver operating characteristic curve analysis of serum LOX levels showed an area under the curve of 0.80 (95% CI: 0.74-0.86). The optimal serum LOX level cutoff point was 253.34 pg/mL for the prediction of kidney fibrosis and 306.56 pg/mL for the prediction of moderate-severe kidney fibrosis. LOX expression levels were significantly upregulated (2.3-2.6 and 6-fold, respectively) in in vitro and in vivo interstitial fibrosis models. CONCLUSIONS: Both serum LOX and tissue LOX levels correlated with the presence and degree of kidney fibrosis in patients with CKD. These results suggest that serum LOX levels could potentially serve as a noninvasive diagnostic biomarker for kidney fibrosis and may further potentially serve as a stratified biomarker for the identification of mild and moderate-severe kidney fibrosis.

Plant-based diets, insulin sensitivity and inflammation in elderly men with chronic kidney disease.

BACKGROUND: In persons with CKD, adherence to plant-based diets is associated with lower risk of CKD progression and death, but underlying mechanisms are poorly characterized. We here explore associations between adherence to plant-based diets and measures of insulin sensitivity and inflammation in men with CKD stages 3-5. METHODS: Cross-sectional study including 418 men free from diabetes, aged 70-71 years and with cystatin-C estimated glomerular filtration rate (eGFR) <60 mL/min/1.73m2 and not receiving kidney-specific dietetic advice. Information from 7-day food records was used to evaluate the adherence to a plant-based diet index (PBDi), which scores positively the intake of plant-foods and negatively animal-foods. Insulin sensitivity and glucose disposal rate were assessed with the gold-standard hyperinsulinemic euglycemic glucose clamp technique. Inflammation was evaluated by serum concentrations of C-reactive protein (CRP) and interleukin (IL)-6. Associations were explored through linear regression and restricted cubic splines. RESULTS: The majority of men had CKD stage 3a. Hypertension and cardiovascular disease were the most common comorbidities. The median PBDi was 38 (range 14-55). Across higher quintiles of PBDi (i.e. higher adherence), participants were less often smokers, consumed less alcohol, had lower BMI and higher eGFR (P for trend <0.05 for all). Across higher PBDi quintiles, patients exhibited higher insulin sensitivity and lower inflammation (P for trend <0.05). After adjustment for eGFR, lifestyle factors, BMI, comorbidities and energy intake, a higher PBDi score remained associated with higher glucose disposal rate and insulin sensitivity as well as with lower levels of IL-6 and CRP. CONCLUSION: In elderly men with non-dialysis CKD stages 3-5, adherence to a plant-based diet was associated with higher insulin sensitivity and lower inflammation, supporting a possible role of plant-based diets in the prevention of metabolic complications of CKD.

Impact of curcumin supplementation on expression of inflammatory transcription factors in hemodialysis patients: A pilot randomized, double-blind, controlled study.

BACKGROUND & AIMS: Chronic kidney disease (CKD) patients have numerous complications associated with inflammation, which is a potential driver for cardiovascular disease. Curcumin, a compound of the curcuminoid class produced by the Curcuma longa, has been reported to activate nuclear factor erythroid factor 2-related (Nrf2) and inhibit nuclear factor kappa-B (NF-kB). Our aim was to evaluate the effects of curcumin juice on the expression of inflammatory transcription factors in hemodialysis (HD) patients. METHODS AND RESULTS: This double-blind randomized pilot study included 31 HD patients divided into two groups: curcumin group (receiving 100 mL of orange juice with 12 g of carrot and 2.5 g of turmeric after each dialysis session/week for 3 months) and control group (receiving the same juice without curcumin); 14 patients in each arm completed the study. The mRNA expression of Nrf2, NF-kB, NLRP3 inflammasome and IL-1ß in peripheral blood mononuclear cells (PBMC; using real-time quantitative polymerase chain reaction, qPCR) and routine biochemistries, food intake and anthropometrics were analyzed. After three months of supplementation, the curcumin group showed a significant decrease in NF-kB mRNA expression (AU) [from 1.08 (0.77-1.38) to 0.52 (0.32-0.95),p = 0.02] and in plasma high sensitivity C-reactive protein (hsCRP) levels [from 3.8 (2.5-6.8) to 2.0 (1.1-3.8) mg/L, p = 0.04]. There was no change in the other evaluated markers. CONCLUSION: Three months treatment with curcumin in CKD patients undergoing HD resulted in decreased markers of inflammation, NF-kB mRNA expression and hsCRP, suggesting that oral supplementation of curcumin may have an anti-inflammatory effect in this patient group. TRIAL REGISTRATION: Approved by the Ethics Committee of the Faculty of Medicine/UFF, number: 2.346.933. This study was registered within ClinicalTrials.gov under the number NCT03475017.

Serum 8-hydroxydeoxyguanosine, a marker of oxidative DNA damage, is associated with mortality independent of inflammation in chronic kidney disease.

BACKGROUND: Oxidative stress and low-grade systemic inflammation are common interrelated sequelae of chronic kidney disease (CKD) that associate with mortality. We investigated the association of serum 8-hydroxy-2'-deoxyguanosine (8-OHdG), a marker of oxidative DNA damage, with mortality in CKD individuals and analyzed whether inflammation modifies the association. METHODS: In 376 individuals with a wide range of estimated glomerular filtration rate (eGFR); >60 ml/min (n = 53), 15-60 ml/min (n = 60) and <15 ml/min (n = 263), cut-off values of serum 8-OHdG, high-sensitivity C-reactive protein (hsCRP), interleukin-6 (IL-6), and tumor necrosis factor (TNF) as predictors of mortality were determined by ROC curves. We analyzed associations of 8-OHdG with inflammation markers and the overlapping effect of hsCRP, IL-6 and TNF on the association between 8-OHdG and all-cause mortality by multivariate generalized linear models. RESULTS: In separate individual exposure analyses, higher 8-OHdG, hsCRP, and IL-6 (but not TNF) were each independently associated with increased risk of death in multivariate models adjusted for age, sex, diabetes mellitus, cardiovascular disease, protein-energy wasting, cohort calendar year, blood sample storage time and eGFR. For 8-OHdG, the multivariate relative risk ratio, RR8-OHdG (95% confidence interval) 1.17 (1.08-1.26), remained essentially unchanged when adjusting also for inflammation in three separate models including: hsCRP, RR8-OHdG = 1.15 (1.06-1.25); IL-6, RR8-OHdG = 1.15 (1.07-1.25); and TNF, RR8-OHdG = 1.16 (1.07-1.26). CONCLUSIONS: Serum 8-OHdG, a biomarker of oxidative DNA damage, is associated with increased all-cause mortality risk in individuals with a wide range of eGFR and this association is independent of inflammation.

Estimated Glomerular Filtration Rate and the Risk of Cancer.

BACKGROUND AND OBJECTIVES: Community-based reports regarding eGFR and the risk of cancer are conflicting. We here explore plausible links between kidney function and cancer incidence in a large Scandinavian population-based cohort. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: In the Stockholm Creatinine Measurements project, we quantified the associations of baseline eGFR with the incidence of cancer among 719,033 Swedes ages ≥40 years old with no prior history of cancer. Study outcomes were any type and site-specific cancer incidence rates on the basis of International Classification of Diseases-10 codes over a median follow-up of 5 years. To explore the possibility of detection bias and reverse causation, we divided the follow-up time into different time periods (≤12 and >12 months) and estimated risks for each of these intervals. RESULTS: In total, 64,319 cases of cancer (affecting 9% of participants) were detected throughout 3,338,226 person-years. The relationship between eGFR and cancer incidence was U shaped. Compared with eGFR of 90-104 ml/min, lower eGFR strata associated with higher cancer risk (adjusted hazard ratio, 1.08; 95% confidence interval, 1.05 to 1.11 for eGFR=30-59 ml/min and adjusted hazard ratio, 1.24; 95% confidence interval, 1.15 to 1.35 for eGFR<30 ml/min). Lower eGFR strata were significantly associated with higher risk of skin, urogenital, prostate, and hematologic cancers. Any cancer risk as well as skin (nonmelanoma) and urogenital cancer risks were significantly elevated throughout follow-up time, but they were higher in the first 12 months postregistration. Associations with hematologic and prostate cancers abrogated after the first 12 months of observation, suggesting the presence of detection bias and/or reverse causation. CONCLUSIONS: There is a modestly higher cancer risk in individuals with mild to severe CKD driven primarily by skin and urogenital cancers, and this is only partially explained by bias.

Dietary Components That May Influence the Disturbed Gut Microbiota in Chronic Kidney Disease.

Gut microbiota imbalance is common in patients with chronic kidney disease (CKD) and associates with factors such as increased circulating levels of gut-derived uremic toxins, inflammation, and oxidative stress, which are linked to cardiovascular disease and increased morbimortality. Different nutritional strategies have been proposed to modulate gut microbiota, and could potentially be used to reduce dysbiosis in CKD. Nutrients like proteins, fibers, probiotics, and synbiotics are important determinants of the composition of gut microbiota and specific bioactive compounds such as polyphenols present in nuts, berries. and fruits, and curcumin, may also play a key role in this regard. However, so far, there are few studies on dietary components influencing the gut microbiota in CKD, and it is therefore not possible to conclude which nutrients should be prioritized in the diet of patients with CKD. In this review, we discuss some nutrients, diet patterns and bioactive compounds that may be involved in the modulation of gut microbiota in CKD and provide the background and rationale for studies exploring whether nutritional interventions with these dietary components could be used to alleviate the gut dysbiosis in patients with CKD.

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.

Kidney Dysfunction and the Risk of Developing Aortic Stenosis.

BACKGROUND: Chronic kidney disease (CKD) and aortic stenosis (AS) share many risk factors. OBJECTIVES: This study sought to evaluate whether kidney dysfunction is associated with the development of AS in the community. METHODS: The study included 1,121,875 Stockholm citizens without a prior diagnosis of AS from the SCREAM (Stockholm CREAtinine Measurements) project. Estimated glomerular filtration rate (eGFR) (ml/min/1.73 m2) was calculated from serum creatinine. AS incidence during follow-up was ascertained by clinical diagnostic codes. The association between eGFR and AS incidence was estimated with multivariable Cox proportional hazards models. Sensitivity analyses included analysis of possible reverse causation bias by excluding the first 6 months to 2 years after enrollment and excluding individuals with comorbid heart failure. RESULTS: The median age was 50 years (interquartile range [IQR]: 36 to 64 years), and 54% of participants were women. Median eGFR was 96 ml/min/1.73 m2 (IQR: 82 to 109 ml/min/1.73 m2), and 66,949 (6.0%) participants had CKD (eGFR <60 ml/min/1.73 m2). During a median follow-up of 5.1 years (IQR: 3.3 to 6.1 years), 5,858 (0.5%) individuals developed AS (incidence rate [IR] 1.13/1,000 person-years). Compared with eGFR >90 (IR 0.34/1,000 person-years), lower eGFR strata were associated with higher hazards of AS: eGFR 60 to 90 ml/min/1.73 m2; IR: 1.88; hazard ratio (HR): 1.14; 95% confidence interval (CI): 1.05 to 1.25; eGFR 45 to 59 ml/min/1.73 m2; IR: 4.61; HR: 1.17; 95% CI: 1.05 to 1.30; eGFR 30 to 44 ml/min/1.73 m2; IR: 6.62; HR: 1.22; 95% CI: 1.07 to 1.39; and eGFR 30 ml/min/1.73 m2; IR: 8.27; HR: 1.56; 95% CI: 1.29 to 1.87. Sensitivity analysis attenuated only slightly the magnitude of the association; individuals with eGFR ≤44 ml/min/1.73 m2 remained at an approximate 20% risk of AS both when excluding events within the 2 years after baseline (HR: 1.22; 95% CI: 1.06 to 1.42) and when excluding participants with heart failure (HR: 1.20; 95% CI: 1.03 to 1.39). CONCLUSIONS: CKD, even in moderate to severe stages, is associated with an increased risk of AS.

Causes of death across categories of estimated glomerular filtration rate: The Stockholm CREAtinine Measurements (SCREAM) project.

INTRODUCTION: Reduced kidney function increases the risk of death, but there is limited information on causes of death across stages of chronic kidney disease (CKD). We aimed to identify leading causes of death in community-dwelling individuals with differing kidney function. METHODS: Observational analysis from SCREAM, a healthcare utilization cohort of Stockholm, Sweden. We included all individuals who died during 2006-2012 and had one serum creatinine measured in the year prior to death. Using the CKD-EPI formula, we calculated eGFR and stratified individuals according to CKD stages. Causes of death were classified as cardiovascular (CVD), cancer, infection and other, using ICD-10 codes. We compared age- and sex-adjusted differences in the proportions of deaths from each cause. RESULTS: Out of 89,117 registered deaths, 70,547 (79%) had a recent eGFR estimation and were included in this study. Individuals had a median age of 82 (IRE 62-93) years and 52% were women. The proportions of deaths from CVD increased with lower eGFR, along with the proportion of deaths from infections. Deaths due to diabetes and genito-urinary diseases increased. Deaths due to cancer decreased, but other death causes did not vary. Within CVD causes of death, the proportion of arrhythmias and heart failure increased, but ischemic heart disease and cerebrovascular disease remained stable. CONCLUSION: In a region-representative Swedish healthcare extraction, we observe differences regarding specific causes of death across different CKD stages. Increasing patient and provider awareness of this differential pattern of risk may have benefits for patient management, prevention strategies, and health service planning.

Association of Serum Sclerostin with Bone Sclerostin in Chronic Kidney Disease is Lost in Glucocorticoid Treated Patients.

The osteocytic protein sclerostin inhibits bone turnover. Serum sclerostin rises early in chronic kidney disease (CKD), but if this reflects osteocyte sclerostin production is unclear, since sclerostin is also expressed in extra-skeletal tissue. Glucocorticoid treatment impacts on serum sclerostin, but the effect on the association between serum and bone sclerostin is unknown. We sought to determine whether serum sclerostin reflects bone sclerostin in different CKD stages and how this association is influenced by glucocorticoid treatment. In a cross-sectional analysis, we investigated serum sclerostin, bone sclerostin by immunohistochemistry, and bone histomorphometry in iliac crest bone biopsies from 43 patients with CKD 3-5D, including 14 dialysis patients and 22 transplanted patients (18 kidney, 4 other). Thirty-one patients were on glucocorticoid treatment at time of biopsy. Patients with low bone turnover (bone formation rate < 97 µm²/mm²/day; N = 13) had higher median serum sclerostin levels (224.7 vs. 141.7 pg/ml; P = 0.004) and higher bone sclerostin, expressed as sclerostin positive osteocytes per bone area (12.1 vs. 5.0 Scl+ osteocytes/B.Ar; P = 0.008), than patients with non-low bone turnover (N = 28). In linear regression analyses, correcting for age, gender, dialysis status and PTH, serum sclerostin was only associated with bone sclerostin in patients not treated with glucocorticoids (r2 = 0.6, P = 0.018). For the first time, we describe that female CKD patients have higher median bone sclerostin than males (11.7 vs. 5.7 Scl+ osteocytes/B.Ar, P = 0.046), despite similar serum sclerostin levels and bone histo-morphometric parameters. We conclude that glucocorticoid treatment appears to disrupt the association of serum sclerostin with bone sclerostin in CKD.

Copeptin Plasma Levels are Associated with Decline of Renal Function in Patients with Type 2 Diabetes Mellitus.

BACKGROUND: Chronic kidney disease (CKD) is a leading complication of type 2 diabetes mellitus (T2DM) and is considered as a public health problem. Copeptin is a surrogate marker of arginine vasopressin (AVP) system and is proposed as a biomarker of decline renal function. OBJECTIVE: Evaluate whether plasma copeptin levels may be used as a biomarker of decline renal function in patients with T2DM. RESEARCH DESIGN AND METHODS: A total of 480 patients with T2DM and different stages of CKD were included. Plasma levels of copeptin, cystatin-C, and other biochemical parameters were measured. The correlation between copeptin and glomerular filtration rate (GFR), estimated based on plasma cystatin-C levels, was investigated. RESULTS: Plasma copeptin levels were gradually increased from the stage 1-5 of CKD in the patients with T2DM. In univariate linear regression analysis, high plasma levels of copeptin were associated with lower GFR (Standardized ß = -0.535, R2 = 0.287, p <0.0001). This association remained significant even after being adjusted for glucose levels and years of T2DM diagnosis, mean blood pressure, pharmacological treatment, gender, and age. CONCLUSIONS: The results show that high plasma copeptin levels are associated with the decline of renal function in patients with T2DM and, therefore, copeptin may be considered as a biomarker of renal function. Further evaluation of plasma copeptin levels to predict morbidity and mortality of T2DM patients, with or without CKD, has been taken into our consideration.

The higher mortality associated with low serum albumin is dependent on systemic inflammation in end-stage kidney disease.

BACKGROUND: The correlation of low serum albumin with mortality in patients with chronic kidney disease (CKD) is partly linked to its association with systemic inflammation. However, it is not clear to what extent albumin's correlation with mortality depends on concomitant systemic inflammation. Here we addressed this question in patients with CKD stage 5. METHODS: Serum albumin (S-Alb), systemic inflammation (high-sensitive C-reactive protein, hsCRP), cardiovascular disease (CVD) and nutritional status (subjective global assessment, SGA) were assessed at baseline in 822 patients: 523 incident dialysis patients, 212 prevalent hemodialysis (HD) and 87 prevalent peritoneal dialysis (PD) patients. Patients were divided into four groups according to hsCRP and S-Alb in each cohort: Group 1 -normal S-Alb and normal hsCRP (reference); Group 2 -low S-Alb and normal hsCRP; Group 3-normal S-Alb and high hsCRP; Group 4-low S-Alb and high hsCRP. Survival over 60 months was analyzed. RESULTS: In Cox analysis, Group 4 had an increased mortality risk (adjusted Hazard ratio (95% confidence interval): 1.62 (1.06-2.47); p = 0.02) whereas the augmented mortality risks for Groups 2 and 3 in univariate analyses were not significant after adjustments for age, gender, blood pressure, diabetes mellitus, smoking, SGA, renal function and renal replacement technique. CONCLUSIONS: Whereas mortality risk was increased in CKD stage 5 patients with low S-Alb and high CRP, it was not increased in patients with low S-Alb and normal CRP. Our observation suggests that inflammatory status should be taken into account when using S-albumin for risk assessment in CKD stage 5 patients.