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Background and Aims Transferrin saturation (TSAT) is an indicator of iron deficiency or overload, but its relationship with mortality in patients with different stages of chronic kidney disease (CKD) is unclear. We investigated the association of TSAT with mortality in CKD patients. Method In 479 CKD patients (97 CKD3-4 patients, 298 CKD5 non-dialysis patients and 84 peritoneal dialysis patients; median age 58 years, 67% males, 33% cardiovascular disease, CVD, and 29% diabetes), biomarkers of iron status (plasma iron, TSAT, transferrin and ferritin), systemic inflammation (high sensitivity C-reactive protein, hsCRP, and interleukin-6, IL-6) and nutritional status were assessed. During median follow-up of 35.6 months, 139 (29%) patients died, and 176 (37%) patients underwent renal transplantation. Patients were stratified into low (n=157) and high (n=322) TSAT tertile groups. All-cause and CVD mortality risk were analyzed with competing risk regression with renal transplantation as competing risk. Results TSAT [median 23% (IQR 17-30%)] was negatively associated with presence of DM and CVD, body mass index, hsCRP, IL-6, Framingham´s CVD risk score (FRS), erythropoietin resistance index (ERI) and iron supplementation, and positively associated with hemoglobin, ferritin and s-albumin. In competing risk analysis, low tertile of TSAT was independently associated with increased all-cause mortality risk (sHR=1.50, 95%CI 1.05-2.14) after adjusting for CKD stages, 1-SD of FRS, 1-SD of hemoglobin, 1-SD of hsCRP, 1-SD of ESA dose and iron supplementation (Figure 1). Conclusion TSAT was inversely associated with mortality risk in CKD patients. When evaluating clinical outcomes of CKD patients, iron status using TSAT as a predictive marker, should be considered.

Background and Aims Major osteoporotic fractures (MOF) are associated with increased morbidity and mortality in ESRD patients. We investigated incidence, predictors and clinical outcomes associated with first MOF (MOFfirst) following kidney transplantation (KT). Method In Swedish Renal Registry of 3992 first KT recipients (2005 -2016) (age 53 years, 65% men), we identified all MOFfirst in hip, spine, humerus and forearm following KT. We estimated incidence rates and predictors of MOFfirst using flexible parametric hazard models and Fine-Gray analysis accounting for competing risk of death, and risk of all-cause mortality following MOFfirst using Cox proportional hazards models with fracture as time-varying exposure. Results During median follow-up of 4.8 years (IQR 2.2-7.9 years), there were 279 fractures of which 139 were forearm fractures. The crude incidence rate of MOFfirst (n=279) was 14/1000 patient-years and that of hip fractures (n=69) 3/1000 patient-years. The multivariate-adjusted fracture incidence rates were highest during the first 6 months following KT, and two-fold increased among women. High age, female sex, previous history of MOF, diabetes nephropathy, pretransplant dialysis therapy and acute rejection were associated with increased risk for MOFfirst, whereas pre-emptive KT was associated with lower risk of MOFfirst. Spline curves showed that impact of age in women on MOFfirst was markedly higher than in men. MOFfirst (including all cases) independently predicted increased all-cause mortality (hazard ratio, HR, 1.78(95%CI 1.35-2.36)). Among MOFfirst, hip fracture (HR, 4.68(95%CI 1.56-14.06)) and spine fracture (HR, 4.02(95%CI 1.19-13.54)) were significantly associated with increased all-cause mortality. Conclusion The initial six months following kidney transplantation is a high-risk period for major osteoporotic fractures, especially forearm fractures. MOFs, especially hip and spine fracture, are associated with increased mortality.

Background and Aims Vitamin K is a potential protective factor against premature vascular aging and vascular calcification (VC). Whether vitamin K supplement could halt VC progression in patients with end-stage renal disease (ESRD) is not clear, partially due to the heterogeneity of measurements of VC in different vascular sites. Here we investigated the associations between non-phosphorylated, uncarboxylated matrix-Gla protein (dp-ucMGP), a circulating marker of vitamin K insufficiency, and premature vascular aging phenotypes evaluated by coronary artery calcium (CAC) scoring, aortic valve calcium (AVC) scoring, and histology scoring of presence of media calcification in vascular biopsies in patients with ESRD. Method In this observational cohort study, 223 ESRD patients (median age 54 years, 68% males) comprising non-dialysis patients (n=109), prevalent peritoneal dialysis (PD, n=80, median dialysis vintage 11.6 months) and prevalent hemodialysis patients (HD, n=34, median dialysis vintage 12.0 months) underwent baseline measurements of plasma dp-ucMGP and scoring of CAC and AVC by computed tomography scan. Framingham risk score (FRS), inflammation and other relevant clinical and biochemical data were determined at baseline. In a sub-group of patients (n=94), scoring of media calcification by histology in epigastric artery biopsies was also performed. Results Plasma dp-ucMGP levels (median 1568 pmol/L) significantly correlated with age (rho=0.38), presence of cardiovascular disease (CVD, rho=0.16), triglycerides (rho=0.19), FRS (rho=0.33), high-sensitivity C-reactive protein (hsCRP; rho=0.35), CAC score (rho=0.30) and AVC score (rho=0.24) but did not differ with regards to treatment modality (i.e. non-dialysis, PD and HD). In multivariate regression analyses, with adjustment for presence of CVD, FRS, hsCRP and triglycerides, increased dp-ucMGP levels were independently associated with increased CAC score (coefficients 0.12, p=0.04), but not with AVC score nor presence of media calcification in epigastric arteries. Conclusion Our data suggest that vitamin K insufficiency as indicated by increased dp-ucMGP levels associates with premature vascular calcification evaluated by CAC but not with AVC or media calcification assessed by histology. This discrepancy warrants further studies to explore the pathophysiological background between vitamin K metabolism and susceptibility of calcification in different vascular sites as well as the pattern of VC (i.e. intima and media calcification) within sites.

Background and Aims The genome of every cell accumulates somatic mutations while aging. Somatic mutation data can be used to track a cell´s exposure to mutagens, thereby allowing the discovery of cell types that are more susceptible to mutate and become cancer and the underling mechanisms. Method To detect somatic mutations in healthy, human kidney, we set up a protocol for whole genome DNA sequencing of single non-cancer cells. The protocol requires in vitro clonal expansion prior to sequencing, a step that restricts the analysis to cells able to proliferate in vitro (progenitors), but allows a gene expression analysis in addition to genome sequencing. Cells were obtained from six living kidney donors undergoing surgery. In addition to the kidney cortex biopsy, multiple control tissues (skin, subcutaneous fata and visceral fat) were obtained from each donor, allowing a well-controlled comparison of mutation landscapes in different cell types. Donors´ age spanned from 30 to 69. Results Somatic mutation and gene expression data showed that we were able to culture two different populations of CD133/CD24 positive, tubular cells. One population showed a low amount of somatic mutations and a mutation profile similar to progenitors from other tissues (fat, skeletal muscle and blood), consistent with a lack of exposure to mutagens. Conversely, the other population showed high mutation burden and a unique mutation landscape, characterized by mutation enrichment in active chromatin, regulatory, and transcribed regions. Accumulation of potential, cancer-driver mutations was 6-fold faster in these compared to control cells. The mutation profile was similar to that of the most common kidney cancer subtypes (clear cell- and papillary cell-carcinoma) and indicated that these cells originated from the proximal tubule, in agreement with gene expression data. Conclusion Our somatic mutation data from single genomes support the existence of two different populations of proliferating tubule cells in healthy, human kidney. One is protected from mutagen exposure, similar to stem cells from other organs. The other population is derived from damaged proximal tubule cells and shows a high mutation rate between 30 and 70 years of age. Mutations are enriched in transcribed genes and regulatory regions, thus enhancing the chances of tumorigenic transformation and suggesting conditions that predispose to cancer in the kidney proximal tubule.

Background and Aims Bone loss is associated with progression of cardiac calcification and increased mortality in end stage renal disease (ESRD) patients but the relations and underlying causes are unclear. We investigated factors associated with changes of bone mineral density (BMD) during the first year after initiation of dialysis and the association between BMD changes and subsequent mortality in ESRD patients. Method In a prospective study of 242 ESRD patients (median age 55 years, 61% men) starting dialysis, total BMD and BMD at specific bone sites (including seven subregions: head, arms, legs, trunk, hip, pelvis and spine) was assessed by whole body dual-energy X-ray absorptiometry (DXA) at baseline and one year after dialysis start. Framingham cardiovascular disease (CVD) risk score, body composition, nutritional status, handgrip strength, various biochemical biomarkers (white blood cell, hemoglobin, albumin, creatinine, calcium, phosphate, intact parathyroid hormone, triglyceride, cholesterol, HDL cholesterol and high-sensitivity C-reactive protein) were recorded. We used multivariate linear regression analysis for BMD change analysis. We followed patients from 12 months after initiating of dialysis until renal transplantation, death or end of 60 months follow-up. During follow-up, 59 patients (24%) died due to CVD (n=33) or other causes (n=26) and 95 patients (39%) underwent renal transplantation. Fine and Gray competing risk analysis was used to ascertain associations of BMD changes with all-cause and CVD-related mortality. Results From baseline to one year after initiation of dialysis, there was a significant decrease of BMDtotal and BMDleg, trunk, rib, pelvis and spine in hemodialysis (HD) patients, whereas no difference was seen in peritoneal dialysis (PD) patients. In multivariate linear regression analysis adjusting for several confounders, HD therapy - compared to PD therapy - was significantly associated with negative changes in BMDtotal (β=-0.15), BMDhead (β=-0.14), BMDleg (β=-0.18) and BMDtrunk (β=-0.16). The direction and extent of changes in BMD, i.e. increase of BMD, associated with statistically significant lower all-cause mortality risk for BMDtotal (sHR, 0.91), BMDhead (sHR 0.91) and BMDleg (sHR 0.92), while for CVD-mortality a significant association with BMD changes was found only for changes in BMDhead (sHR 0.92). Conclusion In patients starting on dialysis, PD therapy appeared to have a beneficial effect on BMD changes as compared to HD during the first year of dialysis therapy. This difference may have implications for clinical outcomes as the degree of bone loss was associated with subsequent mortality. Changes towards increased BMDtotal, BMDhead and BMDleg associated with lower all-cause mortality. For head region – which is known as a cortical bone rich site – positive BMD change associated also with lower CVD mortality suggesting that increase or maintenance of BMD of cortical bone rich sites may have stronger association with clinical outcome in ESRD than BMD of trabecular bone.

Background and Aims Patients with chronic kidney disease (CKD) are at high risk of cardiovascular disease (CVD) due to complex processes in the uremic milieu linked to CKD - mineral and bone disorders (CKD-MBD). These processes alter structure and function of heart and vasculature e.g. by causing ectopic calcification that makes vessels stiffer thus affecting pulse (pressure) wave profiles. Our study aimed to derive patient-specific parameters using pulse wave propagation model including arterial stiffness and compare those parameters with cardiovascular status including biopsy proven severity of vascular calcification. Method In a group of 81 CKD (stage 5) patients undergoing living donor kidney transplantation, the degree of medial calcification in epigastric artery was histologically graded as 0 (n=22), 1 (n=31), 2 (n=21) and 3 (n=7) representing no, minimal, moderate and extensive signs of vascular calcification, respectively. Concomitantly 82 features were determined including demographic and anthropometric features, blood biomarkers related to CKD - MBD and other measurements. Pressure profiles (circles in Fig. 1) in radial artery were recorded using applanation tonometer (SphygmoCor, AtCor Medical, Australia) and used to derive patient-specific parameters from a mathematical model describing blood flow and pressure in 55 major arteries. Results The model was able to reproduce all recorded pressure profiles with high accuracy with average relative error less than 8% (compare solid line and circles in Fig. 1). Vascular stiffness, derived from the model, in arterial branches located in the area of artery for which calcification was histologically quantified, was significantly higher for higher calcification score (p-value < 0.001). The estimated stiffness correlated with the level of troponin T (rho=0.65**), advanced glycation end-products (by skin autofluorescence, rho=0.55*), osteoprotegerin (rho=0.44**), hepcidin 25 (rho=0.32*, interleukin 6 (rho=0.29*) and choline (rho=0.28**), (‘**’ and ‘*’ denote p-value < 0.01 and 0.05, respectively). Stiffer arteries were found in patients with diagnosed CVD (p-value < 0.01). Conclusion We demonstrate that a mathematical model based on a single peripheral recording of pulse pressure profile has the potential to provide information about cardiovascular status in the individual patient. Also, the estimated stiffness correlates well with several well-established CVD risk factors. Our mathematical model of the arterial tree, if validated in larger cohorts of patients, may be used as computational tool to predict vascular stiffness without need of arterial biopsy.

Background and Aims Vascular calcification (VC) is a consequence of ageing that confers development of future cardiovascular events. Accumulation of senescent cells can lead to structural and functional abnormalities in vessel wall towards increased stiffness, reduced compliance and impaired contractile and dilatory capacity. Thus, accumulation of senescent cells in the arterial wall could also contribute to the pathophysiology of VC. To test this hypothesis, the presence of cellular markers of senescence, p16, p21 and NRF2, was assessed in aorta from rat model of VC associated with chronic kidney disease (CKD). Method Six-week-old Sprague-Dawley rats underwent 5/6th subtotal nephrectomy (SNx, n=6) or no surgery (Control, n=1). After 8 weeks of renal failure, the regular chow was supplemented with high phosphate (1.2%) and vitamin D (1 µg/day, 5 days per week) for 1 or 4 weeks to initiate vascular calcification (SNx-VC group). At the end of the protocol (Figure 1), blood pressure was measured, and thoracic aorta was taken for determination of calcification by Von Kossa staining, and protein and gene expressions of p16, p21, and NRF2 by immunostaining and qPCR, respectively. Results After 4 weeks of dietary intervention, SNx rats showed an increase in pulse pressure (88±15mmHg vs 35 mmHg for the control). Marked VC was also observed in these animals, 17% of calcified area vs Conclusion This pilot study suggests that uraemia-induced cellular senescence accompanies VCs, as suggested by the modified expression of p16 or NRF2 genes. Our observations deserve exploration in larger studies using additional senescence markers for validation. If so, cellular senescence kinetics will be evaluated in order to test whether senolytics compounds could be a therapeutic option to arrest VC in CKD.

Background and Aims The incidence of fractures is markedly higher in dialysis patients than in pre-dialysis patients, but it is not clear to what extent the initiation of dialysis as such is associated with accelerated fracture incidence or if fracture rates are already increasing prior to dialysis start among incident dialysis patients. Here we investigated the temporal pattern of occurrence of a first major osteoporotic fracture (MOF) among incident dialysis patients in the pre-dialysis period and in the period following dialysis initiation. Method We analyzed data from Swedish Renal Registry (SRR) and identified 9041 incident dialysis patients (2005 -2015; age 67 years, 67% men). We identified all first MOF (MOFfirst) in hip, spine, humerus and forearm during 12 months before and after dialysis initiation. Using flexible parametric hazard models and Fine-Gray analysis accounting for competing risk of death and renal transplantation, we estimated adjusted fracture incidence rates and predictors of MOFfirst. Results During the whole follow-up period, there were 361 fractures including 196 hip fractures. The crude incidence rate of MOFfirst (n=157) before dialysis initiation was 17/1000 patient-years and after initiation of dialysis the incidence rate of MOFfirst increased to 24/1000 patient-years. Overall the adjusted MOFfirst incidence rates increased from 6 months before initiation of dialysis, fluctuated, and stabilized at a higher rate than that of the baseline rate after 12 months. The adjusted hip fracture rate rose steeply 3 months before dialysis initiation, declined 3 months after dialysis initiation, fluctuated, and then became stabilized. On the contrary, the adjusted incidence rates of other fractures, i.e., non-hip fractures, appeared to be stable all the time, before as well as after initiation of dialysis. Female gender, higher age and previous history of MOF had a negative impact on fracture incidence rates before and after dialysis initiation. Conclusion We conclude that the incidence of MOFfirst is increasing already from 6 months prior to dialysis initiation among incident dialysis patients, and that there is a further increase following dialysis initiation. For hip fracture, which was the most common MOF, the temporal pattern of incidence rates was compressed to a high risk period lasting from 3 months before to 3 months after dialysis initiation, underlining the need of increased attention to prevent hip fractures in incident dialysis patients during this critical period.

Background and Aims Preventing hyperkalemia - a potentially fatal complication in advanced CKD - by prescribing diets low in K (=limited intake of healthy components such as vegetables, fruits, whole grains and nuts) leads to poor dietary quality. K-restricted unhealthy diets may affect quality of life, patient satisfaction with treatment, achievement of nutritional targets, and increase risk of obstipation, gut dysbiosis and progression of CKD. We designed a feasibility study to test if a low-protein healthy K-rich diet with fruits, vegetables, whole grains and nuts with concomitant use of new potassium binder (SZC) can be safely prescribed to patients with CKD stages 4 and 5 with hyperkalemia. Method A feasibility descriptive single arm open-label interventional trial lasting 6 weeks will enroll 36 CKD patients at the outpatient clinic with: age 18 - 85 years; glomerular filtration rate < 29 ml/min/1.73 m2 and not on dialysis; serum K > 5.1 mmol/L or in previous use of sodium polystyrene sulfonate (SPS) to decrease serum K levels, and who develops hyperkalemia after SPS is ceased. Patients with serum K > 6.5 mmol/L and those likely to start dialysis within 2 months, with inflammatory bowel syndrome or with a history of hypokalemia ( Results NA Conclusion This interventional feasibility pilot study will test the hypothesis that - with precautions aiming at reducing risk of hyperkalemia - a K-rich healthy diet in patients with CKD stage 4 may improve patient satisfaction with treatment and patient symptoms. Depending on the results, a larger randomized controlled longitudinal trial will be considered to investigate if K-rich diet in CKD stage 4-5 patients is safe and beneficial.

Background and Aims Major osteoporotic fractures (MOF) are common in dialysis patients. We investigated incidence, predictors and clinical outcomes associated with first MOF occurring after initiation of dialysis (MOFfirst). Method In Swedish Renal Registry of 9714 incident (2005 -2016) dialysis patients (median age 68 years, 67% men), we identified all MOFfirst in hip, spine, humerus and forearm. Using flexible parametric hazard models and Fine-Gray analysis, we estimated incidence, mortality rates and predictors of MOFfirst, and, in time-dependent analysis, risk of all-cause and cardiovascular disease (CVD) mortality following MOFfirst. Results During median follow-up of 2.2 years, the crude incidence rate of MOFfirst (n=835) was 24/1000 patient-years (pt-yrs) and that of hip fractures (n=470) 13/1000 pt-yrs. The multivariate-adjusted fracture incidence rates increased gradually after dialysis initiation and were 47% higher among women. Female sex, higher age, presence of comorbidities, and previous history of MOF (MOFprevious) were associated with increased risk for MOFfirst, whereas peritoneal dialysis as compared to hemodialysis was associated with decreased fracture risk. The adjusted fracture incidence rate of MOFfirst during the first 90 days following dialysis initiation was higher in patients with MOFprevious than in those without MOFprevious. MOFfirst independently predicted increased all-cause mortality (sub-distribution hazard ratio, sHR, 1.67(95%CI 1.47-1.91) and CVD-related mortality (sHR 1.49 (95%CI 1.22-1.84). Adjusted mortality rate following hip fractures was higher than for other types of MOF. Spline curves showed that mortality following MOFfirst was highest during the first 6 months of follow-up. Conclusion Major osteoporotic fractures are common and associated with increased mortality in incident dialysis patients.

Background and Aims While chronological age associates with increased risk of death, there is a quest for markers of biological age in chronic kidney disease (CKD) that better reflect accumulation of tissue and cellular damage, which could contribute to shorter life span. Skin autofluorescence (SAF) is a biomarker for accumulation of advanced glycation end products in skin that associate with chronological age and with factors that may increase mortality risk. However, the predictive capacity of SAF for mortality has not been fully elucidated in CKD. We have investigated the relationship between biological age calculated by SAF, chronological age and all-cause mortality in patients with CKD stage 5. Method In a cohort of 199 CKD5 patients (non-dialysis CKD5, n=100, hemodialysis, n=27 and peritoneal dialysis, n=72; median age 66 years, 34% females, 21% diabetes (DM), 20% cardiovascular disease (CVD), and 34% malnourished), we calculated biological age by a formula based on SAF measurements using the AGE Reader. Framingham risk score, coronary artery calcium score, the heart rate-corrected augmentation index, body composition, nutritional status, handgrip strength, and various biochemical markers (hemoglobin, albumin, creatinine, intact-parathyroid hormone, triglyceride, cholesterol, HDL-cholesterol, high-sensitivity C-reactive protein (hsCRP), and interleukin (IL)-6) were recorded at baseline. During median follow-up of 38 months, 34 patients died, and 51 patients underwent renal transplantation. We analyzed spline curves showing sub-distribution hazard risk (sHR) for all-cause mortality with biological age calculated by SAF and chronological age by the Fine and Gray competing risk analysis. Results There was a significant association between biological age calculated by SAF and chronological age (rho=0.48; p Conclusion All-cause mortality risk increased linearly with higher chronological age and SAF-estimated biological age - and with similar magnitude of sHR for the two - suggesting that prediction of mortality risk based on SAF is not superior compared to chronological age in CKD. We conclude that biological age calculated by SAF and chronological age are equally robust predictors of clinical outcomes in CKD; however, both indices are influenced by the inflammatory status.

Background and Aims Ageing represents the greatest risk factor contributing to increased morbidity and mortality in most chronic diseases; it encompasses numerous biological changes resulting in declining physiological function and increasing burden of disease. Whether new biomarkers of ageing and risk scores for predicting physiological outcomes, including mortality, are applicable and more accurate than chronological age in patients with chronic kidney disease (CKD) is not clear. So far, the DNA methylation (DNAm) PhenoAge biomarker of ageing (Levine et al. Aging 2018) has not been tested in CKD. While we had no access to DNAm data, we applied the phenotypic age estimate proposed by Levine et al., which was included in their calculations of DNAm PhenoAge, and tested the relationship between estimated phenotypic age (ePhenoAge) and chronological age, respectively, with all-cause mortality in patients with CKD. Method In a cohort of 333 CKD patients (stage 1, n=78; stage 3-4, n=64; and stage 5, n=191) with median age 56 years, 43% females, 24% diabetes (DM), 25% cardiovascular disease (CVD), and 22% malnourished, we estimated age by ePhenoAge, using a formula with calculations based on nine biomarkers and chronological age, and compared this age index with chronological age. Framingham risk score, body composition, nutritional status, handgrip strength, and various biochemical markers (white blood cells, mean cell volume, hemoglobin, albumin, creatinine, glucose, calcium, alkaline phosphatase, intact-parathyroid hormone, triglyceride, cholesterol, HDL-cholesterol, high-sensitivity C-reactive protein (hsCRP), and interleukin (IL)-6) were recorded. During a median follow-up period of 52 months, 65 patients died, and 111 patients underwent renal transplantation. We used spline curve to illustrate sub-distribution hazard risk (sHR) for all-cause mortality versus increasing ePhenoAge and chronological age respectively as obtained by the Fine and Gray competing risk analysis. Results In univariate analyses, IL-6 (rho=0.49, p Conclusion All-cause mortality risk was associated with increasing chronological age in competing risk analysis with adjustments of confounders. A similar trend was observed for ePhenoAge, a finding which to a large extent may be explained by the inflammatory status of the study subjects. However, contrary to expectations, ePhenoAge was not as powerful as chronological age in predicting mortality, underlining that our knowledge about factors influencing phenotypic age in CKD patients is still limited. This should motivate further study of the potential role of other estimates of biological age in CKD.

Chocolate is a widely appreciated foodstuff with historical appreciation as a food from the gods. In addition to its highly palatable taste, it is a rich source of (poly)phenolics, which have several proposed salutogenic effects, including neuroprotective anti-inflammatory, anti-oxidant and cardioprotective capabilities. Despite the known benefits of this ancient foodstuff, there is a paucity of information on the effects of chocolate on in the context of chronic kidney disease (CKD). This review focusses on the potential salutogenic contribution of chocolate intake, to mitigate inflammatory and oxidative burden in CKD, its potential, for cardiovascular protection and on the maintenance of diversity in gut microbiota, as well as clinical perspectives, on regular chocolate intake by CKD patients.

Background: Transferrin saturation (TSAT) is an indicator of iron deficiency or overload, but its relationship with mortality in patients with different stages of chronic kidney disease (CKD) is unclear. We investigated the association of TSAT with mortality in CKD patients. Methods: In 479 CKD patients (97 CKD3-4 patients, 298 CKD5 non-dialysis patients and 84 peritoneal dialysis patients; median age 58 years, 67% males, 33% cardiovascular disease, CVD, and 29% diabetes), biomarkers of iron status (plasma iron, TSAT, transferrin and ferritin), systemic inflammation (high sensitivity C-reactive protein, hsCRP, and interleukin-6, IL-6) and nutritional status were assessed. During median follow-up of 35.6 months, 139 (29%) patients died, and 176 (37%) patients underwent renal transplantation. Patients were stratified into Low (n=157) and Middle and high (n=322) TSAT tertile groups. All-cause and CVD mortality risk were analyzed by competing risk regression with renal transplantation as competing risk. Results: TSAT (median 23%; interquartile range, 17-30%) was negatively associated with presence of diabetes and CVD, body mass index, hsCRP, IL-6, erythropoiesis stimulating agent (ESA) dose, erythropoietin resistance index (ERI) and iron supplementation, and positively associated with hemoglobin, ferritin and s-albumin. In competing risk analysis, low tertile of TSAT was independently associated with increased all-cause mortality risk (sHR=1.74, 95%CI 1.30-2.54) and CVD mortality risk (sHR=1.80, 95%CI 1.02-3.16) after fully adjusting for 1-standard deviation (SD) of age, sex, CKD stages, 1-SD of hemoglobin, 1-SD of ferritin, 1-SD of hsCRP, 1-SD of ESA dose and iron supplementation. Conclusions: Lower TSAT indicating iron deficiency was independently associated with increased mortality risk in CKD patients, underlining that iron status should be considered when evaluating clinical outcomes of CKD patients.

Background Major fractures (MF) are associated with increased mortality in the general population and represent an even higher risk in patients with chronic kidney disease. We investigated incidence, predictors and clinical outcomes associated with first MF (MFfirst) following kidney transplantation (KT). Methods We used the Swedish National Renal Registry of 3992 first KT recipients (2005–2016) (median age 53 years, 65% men) and identified all MFfirst in hip, spine, humerus and forearm following KT. We estimated incidence rates and predictors of MFfirst using flexible parametric hazard models and Fine-Gray analysis accounting for competing risk of death, and risk of all-cause mortality following MFfirst using Cox proportional hazards models with fracture as time-varying exposure. Results During median follow-up of 4.8 years (IQR 2.2–7.9 years), there were 279 fractures of which 139 were forearm fractures. The crude incidence rate of MFfirst (n = 279) was 13.5/1000 patient-years and that of hip fractures (n = 69) 3.4/1000 patient-years. The multivariate-adjusted fracture incidence rates were highest during the first 6 months following KT, and 86% higher in women than in men. High age, female sex, previous history of MF, diabetes nephropathy, pretransplant dialysis therapy and acute rejection were associated with increased risk for MFfirst, whereas pre-emptive KT was associated with lower risk of MFfirst. Spline curves showed markedly higher impact of higher age on risk of MFfirst in women than in men. MFfirst (n = 279) independently predicted increased all-cause mortality risk (hazard ratio, HR, 1.78(95%CI 1.35–2.36)). Among MFfirst, with humerus fracture as reference, hip fracture (HR, 4.68(95%CI 1.56–14.06)) and spine fracture (HR, 4.02(95%CI 1.19–13.54)), but not forearm fracture (HR, 1.17 (95%CI 0.38–3.53)), were associated with increased all-cause mortality risk. Conclusions The initial 6 months following kidney transplantation is a high-risk period for MF. Among MF, hip fracture and spine fracture associate with substantially increased all-cause mortality risk.

Summary 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-1β 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 NCT 03475017.

The underdeveloped opportunity to use the broad awareness of the diversity of animal life and comparative physiology (i.e. biomimetics) as nature´s own road map to provide novel insights and solutions from burden of lifestyle diseases has recently been discussed. Since human health, environmental changes and animal welfare are closely related (i.e. the 'one health' or 'planetary health' approach), such studies require close interdisciplinary collaboration including medical doctors, veterinarians, zoologists, climate researchers, ecologists, biologists and anthropologists. The ongoing coronavirus 2019 (COVID‐19) pandemic is a sobering example of the urgent need for global interdisciplinary collaboration, integrating human and animal health with environmental sustainability and ecosystem health. To begin with, it is worth noting that there is simply nothing uniquely Chinese about the COVID‐19 outbreak. The explanations for why so many epidemics seem to arise in China may not only be cultural, but also a matter of its current economic geography paired with the close interface between wildlife, livestock and humans. This is abundantly clear if we compare China to the United States, or Europe, when the latter were hubs of global production and mass industrial employment. The geography of blame, naming a germ after a country or ethnic group, has often been a symbol of helplessness during previous pandemics, detracting from the global aspect and unfairly labelling a country or ethnic group as being solely responsible. Ironically, the ‘Spanish flu’ pandemic of 1918 likely originated from a farm community in south‐western Kansas. Whilst previous pandemics were mainly linked to crises resulting from wars, the COVID‐19 pandemic is linked to a crisis based on environmental pollution, exploitation of the natural world, wildlife abuse and subsequent cumulative consequences on human health.

International audience; Inflammatory and innate immune responses triggered by pathogen-associated and other danger-associated signals emerging during infections, results in the activation of cytosolic inflammasomes. The nod-like receptor pyrin domain containing 3 (NLRP3) is one of the inflammasomes mediating such responses through the activation of caspase-1, which increases the production and release of pro-inflammatory cytokines, such as IL-1β and IL-18 and induces programmed cell death through pyroptosis. NLRP3 is thought to play a crucial role in the underlying inflammatory responses in many lifestyles related chronic diseases. Consequently, research on the NLRP3 inflammasome has expanded dramatically in recent years. Although several studies have investigated the role of NLRP3 activation in chronic kidney disease (CKD), few studies have evaluated strategies to modulate its activation by means of interventions using non-pharmacological strategies. This review discusses some nutritional strategies (bioactive compounds, probiotics and caloric restriction) that have been shown to influence NLRP3 in experimental models of renal disease, and in CKD. It discusses how nutritional interventions could potentially dampen NLRP3 associated inflammatory burden, as part of nutritional strategies to prevent and treat CKD and its complications.

Introduction Proteomic profiling of end-stage renal disease (ESRD) patients could lead to improved risk prediction and novel insights into cardiovascular disease mechanisms. Plasma levels of 92 cardiovascular disease-associated proteins were assessed by proximity extension assay (Proseek Multiplex CVD-1, Olink Bioscience, Uppsala, Sweden) in a discovery cohort of dialysis patients, the Mapping of Inflammatory Markers in Chronic Kidney disease cohort [MIMICK; n = 183, 55% women, mean age 63 years, 46 cardiovascular deaths during follow-up (mean 43 months)]. Significant results were replicated in the incident and prevalent hemodialysis arm of the Salford Kidney Study [SKS dialysis study, n = 186, 73% women, mean age 62 years, 45 cardiovascular deaths during follow-up (mean 12 months)], and in the CKD5-LD-RTxcohort with assessments of coronary artery calcium (CAC)-score by cardiac computed tomography (n = 89, 37% women, mean age 46 years). Results In age and sex-adjusted Cox regression in MIMICK, 11 plasma proteins were nominally associated with cardiovascular mortality (in order of significance: Kidney injury molecule-1 (KIM-1), Matrix metalloproteinase-7, Tumour necrosis factor receptor 2, Interleukin-6, Matrix metalloproteinase-1, Brain-natriuretic peptide, ST2 protein, Hepatocyte growth factor, TNF-related apoptosis inducing ligand receptor-2, Spondin-1, and Fibroblast growth factor 25). Only plasma KIM-1 was associated with cardiovascular mortality after correction for multiple testing, but also after adjustment for dialysis vintage, cardiovascular risk factors and inflammation (hazard ratio) per standard deviation (SD) increase 1.84, 95% CI 1.26–2.69, p = 0.002. Addition of KIM-1, or nine of the most informative proteins to an established risk-score (modified AROii CVM-score) improved discrimination of cardiovascular mortality risk from C = 0.777 to C = 0.799 and C = 0.823, respectively. In the SKS dialysis study, KIM-1 predicted cardiovascular mortality in age and sex adjusted models (hazard ratio per SD increase 1.45, 95% CI 1.03–2.05, p = 0.034) and higher KIM-1 was associated with higher CACscores in the CKD5-LD-RTx-cohort. Conclusions Our proteomics approach identified plasma KIM-1 as a risk marker for cardiovascular mortality and coronary artery calcification in three independent ESRD-cohorts. The improved risk prediction for cardiovascular mortality by plasma proteomics merit further studies. Electronic supplementary material The online version of this article (10.1007/s40620-018-0556-5) contains supplementary material, which is available to authorized users.

Under normal conditions, inflammation is a protective and physiological response to various harmful stimuli. However, in several chronic debilitating disorders, such as chronic kidney disease, inflammation becomes maladaptive, uncontrolled and persistent. Systemic persistent inflammation has, for almost 20 years, been recognized as a major contributor to the uraemic phenotype (such as cardiovascular disease, protein energy wasting, depression, osteoporosis and frailty), and a predictor of cardiovascular and total mortality. Since inflammation is mechanistically related to several ageing processes (inflammageing), it may be a major driver of a progeric phenotype in the uraemic milieu. Inflammation is likely the consequence of a multifactorial aetiology and interacts with a number of factors that emerge when uraemic toxins accumulate. Beside interventions aiming to decrease the production of inflammatory molecules in the uraemic milieu, novel strategies to increase the removal of large middle molecules, such as expanded haemodialysis, may be an opportunity to decrease the inflammatory allostatic load associated with retention of middle molecular weight uraemic toxins.

Background Dialysis patients have a high prevalence of cardiovascular mortality but also elevated cardiac troponins (cTns) even without signs of cardiac ischaemia. The study aims to assess variation and prognostic value of high-sensitivity cTnI and cTnT in prevalent dialysis patients. Methods In 198 prevalent haemodialysis (HD) and 78 peritoneal dialysis (PD) patients, 4-monthly serum troponin I and T measurements were obtained. Reference change values (RCVs) were used for variability assessment and competing-risk regression models for survival analyses; maximal follow-up was 50 months. Results HD and PD patients had similar troponin levels [median (interquartile range) troponin I: 25 ng/L (14–43) versus 21 ng/L (11–37), troponin T: 70 ng/L (44–129) versus 67 ng/L (43–123)]. Of troponin I and T levels, 42% versus 98% were above the decision level of myocardial infarction. RCVs were +68/−41% (troponin I) and +29/−23% (troponin T). Increased variability of troponins related to higher age, male sex, protein-energy wasting and congestive heart failure, but not ischaemic heart disease or dialysis form. Elevated troponin T, but not troponin I, predicted death after adjusting for confounders. Conclusions A large proportion of prevalent dialysis patients without current established or ongoing cardiac events have elevated levels of high-sensitivity cTns. Mortality risk was doubled in patients with persistently high troponin T levels. The large intraindividual variation of cTns suggests that serial measurements and reference change levels may be used to improve diagnostic utility. However, evidence-based recommendations require more data from large studies of dialysis patients with cardiac events.

Objective: HIV-1-infection infers an increased cardiovascular risk where gut dysbiosis and microbial translocation may contribute. We assessed TMAO, a microbial metabolite with atherosclerotic properties, in plasma of HIV-1-infected individuals at different clinical stages in relation to inflammatory markers, cardiovascular events and gut microbiota. Methods: Primary HIV-1-infected (n ¼ 17) and chronic HIV-1-infected individuals (n ¼ 22) were sampled before and after ART-initiation. In the chronic HIV-1-cohort, repeated faecal samples were analysed by 16SrRNA gene sequencing. HIV-1-infected individuals on longstanding ART (n ¼ 101) and healthy HIV-1-negative individuals (n ¼ 60), served as controls. TMAO and markers of immune activation were analysed by LC/MS/MS and immune assays, respectively. Results: TMAO levels were lower in untreated HIV-1-infected individuals, increased significantly after ART-initiation (P ¼ 0.040 and P < 0.001) but remained similar to healthy controls. TMAO levels were not affected by ART, immune status or degree of systemic inflammation. Higher TMAO in HIV-1-infected individuals on longstanding ART was not significantly associated with cardiovascular risk (P ¼ 0.38). Additionally, TMAO levels correlated inversely with Bacteroidetes (Rho: 0.62, P ¼ 0.002), and positively with Firmicutes (Rho: 0.65, P ¼ 0.001) but held no correlation to TMAproducing genera. Notably gut dysbiosis at follow-up was more pronounced in patients without increase in TMAO levels after ART characterized by loss of Bacteroidetes (P ¼ 0.023) and significantly elevated LPS levels (P ¼ 0.01). Conclusion: Our data does not support that TMAO is a significant link between gut dysbiosis and inflammation in HIV-1-infection. We propose that HIV-1, microbial composition and ART disparately confound TMAO levels, thus limiting its role as a cardiovascular risk marker in HIV-1-infected individuals.

Probiotics may mitigate the generation of uremic toxins and inflammatory biomarkers. The aim of this study was to evaluate the effects of probiotics on uremic toxins and inflammatory biomarkers in CKD. In this randomized, double-blind, placebo-controlled trial, 30 patients (63.8 ± 7.5 years, 14 men, mean BMI of 27.2 ± 3.8 kg/m2) were assigned to receive one of two treatments: probiotics (n = 15; Streptococcus thermophilus, Lactobacillus acidophilus and Bifidobacteria longum-90 billion CFU per day) or placebo (n = 15) daily for three months. Plasma uremic toxins were measured using reversed-phase liquid-chromatography (RP-HPLC); choline, betaine and trimethylamine-N-oxide (TMAO) were measured using liquid chromatography–mass spectrometry (LC-MS/MS); and inflammatory biomarkers were measured using ELISA. Uremic toxins were not influenced by the probiotics; however, IL-6 levels increased significantly from 15.6 (14.8–20.8) pg/mL to 23.0 (17.6–29.6) pg/mL, p = 0.01. There was a positive correlation between the levels of p-cresyl sulfate and urea (r = 0.55; p = 0.02) and between TMAO and CRP (r = 0.46; p = 0.05) at baseline. These data suggest that probiotic supplementation did not result in expected benefits for non-dialysis CKD patients.

Low serum albumin (S-Alb) is a frequent feature of end-stage renal disease (ESRD) that independently predicts mortality. Serum albumin has mainly been considered a biomarker of visceral protein and immunocompetence status, fundamental to nutritional assessment. However, low S-albumin level is associated with persistent systemic inflammation and many bodies of evidence show that S-Alb has a limited role as a marker of nutritional status. We reported that a low S-Alb concentration was an independent risk factor for poor outcome in ESRD only in the presence of systemic inflammation. Moreover, the relationships between inflammatory biomarkers and outcome are confounded also by alterations in body composition (such as obese sarcopenia) and oxidative stress. Taken together, S-Alb alone should not be used as a proxy of the nutritional status in a dialysis patient. Its association with dietary intake is poor and low S-Alb values are most often non-nutritional in origin. When analyzing S-Alb to predict mortality risk in ESRD, it should always be combined with measurement of hsCRP.

Açai (Euterpe oleracea Mart.) fruit from the Amazon region in Brazil contains bioactive compounds such as α-tocopherol, anthocyanins (cyanidin 3-glycoside and cyanidin 3-rutinoside), and other flavonoids with antioxidant and anti-inflammatory properties. Moreover, the prebiotic activity of anthocyanins in modulating the composition of gut microbiota has emerged as an additional mechanism by which anthocyanins exert health-promoting effects. Açai consumption may be a nutritional therapeutic strategy for chronic kidney disease (CKD) patients since these patients present with oxidative stress, inflammation, and dysbiosis. However, the ability of açai to modulate these conditions has not been studied in CKD, and this review presents recent information about açai and its possible therapeutic effects in CKD.

Components present in the diet, l-carnitine, choline, and betaine are metabolized by gut microbiota to produce metabolites such as trimethylamine-N-oxide (TMAO) that appear to promote cardiovascular disease in chronic kidney disease (CKD) patients. The objective of this pilot study was to evaluate the effects of probiotic supplementation for 3 months on plasma TMAO levels in CKD patients on hemodialysis (HD). A randomized, double-blind trial was performed in 21 patients [54.8 ± 10.4 years, nine men, BMI 26.1 ± 4.8 kg/m2, dialysis vintage 68.5 (34.2–120.7) months]. Ten patients were randomly allocated to the placebo group and 11 to the probiotic group [three capsules, totaling 9 × 1013 colony-forming units per day of Streptococcus thermophilus (KB19), Lactobacillus acidophilus (KB27), and Bifidobacteria longum (KB31). Plasma TMAO, choline, and betaine levels were measured by LC-MS/MS at baseline and after 3 months. While TMAO did not change after probiotic supplementation, there was a significant increase in betaine plasma levels. In contrast, the placebo group showed a significant decrease in plasma choline levels. Short-term probiotic supplementation does not appear to influence plasma TMAO levels in HD patients. Long-term studies are needed to determine whether probiotics may affect TMAO production in CKD patients.

Red meat is an important dietary source of high biological value protein and micronutrients such as vitamins, iron, and zinc that exert many beneficial functions. However, high consumption of animal protein sources, especially red meat, results in an increased intake of saturated fat, cholesterol, iron, and salt, as well as an excessive acid load. Red meat intake may lead to an elevated production of uremic toxins by the gut microbiota, such as trimethylamine n-oxide (TMAO), indoxyl sulfate, and p-cresyl sulfate. These uremic toxins are associated with increased risk for cardiovascular (CV) mortality. Limiting the intake of red meat in patients with chronic kidney disease (CKD) thus may be a good strategy to reduce CV risk, and may slow the progression of kidney disease. In the present review, we discuss the role of red meat in the diet of patients with CKD. Additionally, we report on a pilot study that focused on the effect of a low-protein diet on TMAO plasma levels in nondialysis CKD patients.

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.

Many of the >2 million animal species that inhabit Earth have developed survival mechanisms that aid in the prevention of obesity, kidney disease, starvation, dehydration and vascular ageing; however, some animals remain susceptible to these complications. Domestic and captive wild felids, for example, show susceptibility to chronic kidney disease (CKD), potentially linked to the high protein intake of these animals. By contrast, naked mole rats are a model of longevity and are protected from extreme environmental conditions through mechanisms that provide resistance to oxidative stress. Biomimetic studies suggest that the transcription factor nuclear factor erythroid 2-related factor 2 (NRF2) offers protection in extreme environmental conditions and promotes longevity in the animal kingdom. Similarly, during months of fasting, immobilization and anuria, hibernating bears are protected from muscle wasting, azotaemia, thrombotic complications, organ damage and osteoporosis - features that are often associated with CKD. Improved understanding of the susceptibility and protective mechanisms of these animals and others could provide insights into novel strategies to prevent and treat several human diseases, such as CKD and ageing-associated complications. An integrated collaboration between nephrologists and experts from other fields, such as veterinarians, zoologists, biologists, anthropologists and ecologists, could introduce a novel approach for improving human health and help nephrologists to find novel treatment strategies for CKD.

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 tumor 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 etiologies of ESRD. Kaplan-Meier curves showed better survival among ADPKD group versus other etiologies, 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. This article is protected by copyright. All rights reserved.

Background Declining trends of hip fracture incidence in dialysis patients were reported from USA and Japan while studies from Europe are lacking. We investigated trends in hip fracture incidence and subsequent mortality in Swedish dialysis patients, comparing with the Swedish general population. Methods We used the population-based Swedish national database of fractures and the Swedish National Renal Registry to retrieve data on hip fractures incidence and subsequent mortality for years 2007–2016. Trends for age-standardized hip fracture incidence rate (ASRhip fracture) and age-standardized 30-day (ASMR30day) and 180-day (ASMR180day) post-hip fracture mortality rate in Swedish general population were evaluated by joinpoint regression analysis. Standardized incidence ratios of hip fracture (SIR) and standardized mortality ratios (SMR) were calculated for Swedish dialysis patients. Results In the general population, ASRhip fracture declined significantly: in women from 2007 and in men from 2009. In dialysis patients, SIR was 3–5 times higher compared to the general population and declined over time in women but not in men. In general population, mortality (ASMR30day and ASMR180day) declined significantly in women and men. In dialysis patients, post-fracture mortality (SMR, mainly for 180-day mortality) remained two-fold higher than in general population with no consistent trend towards improvement. Conclusions Hip fracture incidence and subsequent mortality fell among women and men in the Swedish general population. In dialysis patients, hip fracture incidence declined in women but not in men while post-fracture mortality did not improve, and the incidence and subsequent mortality remained 3 to 5-fold and 2-fold higher than in the general population.

Systemic inflammation in end-stage renal disease is an established risk factor for mortality and a catalyst for other complications, which are related to a premature aging phenotype, including muscle wasting, vascular calcification, and other forms of premature vascular disease, depression, osteoporosis, and frailty. Uremic inflammation is also mechanistically related to mechanisms involved in the aging process, such as telomere shortening, mitochondrial dysfunction, and altered nutrient sensing, which can have a direct effect on cellular and tissue function. In addition to uremia-specific causes, such as abnormalities in the phosphate-Klotho axis, there are remarkable similarities between the pathophysiology of uremic inflammation and so-called “inflammaging” in the general population. Potentially relevant, but still somewhat unexplored in this respect, are abnormal or misplaced protein structures, as well as abnormalities in tissue homeostasis, which evoke danger signals through damage-associated molecular patterns, as well as the senescence-associated secretory phenotype. Systemic inflammation, in combination with the loss of kidney function, can impair the resilience of the body to external and internal stressors by reduced functional and structural tissue reserves, and by impairing normal organ crosstalk, thus providing an explanation for the greatly increased risk of homeostatic breakdown in this population. In this review, the relationship between uremic inflammation and a premature aging phenotype, as well as potential causes and consequences, are discussed.

Nuclear factor erythroid 2-related factor 2 (Nrf2) is a transcription factor with a high sensitivity to oxidative stress, which regulates the expression of detoxifying enzymes, besides that, can also control antioxidant and anti-inflammatory cellular responses. Therefore, the modulation of this transcription factor can be a new therapeutic approach to reduce complications in chronic kidney disease (CKD) patients, like oxidative stress and inflammation, which leads to increased risk of developing cardiovascular disease, the major cause of death in these patients. Recent studies have shown that nutritional components and physical exercises can regulate the activation of Nrf2; however, very few studies were performed in CKD patients. This review provides an overview about some of the nonpharmacologic strategies that may promote the activation of Nrf2, which may have impact on the human health, particularly in CKD, by preventing oxidative stress and maintaining cellular redox homeostasis.

An ability to separate natural ageing processes from processes specific to morbidities is required to understand the heterogeneity of age-related organ dysfunction. Mechanistic insight into how epigenetic factors regulate ageing throughout the life course, linked to a decline in renal function with ageing, is already proving to be of value in the analyses of clinical and epidemiological cohorts. Noncoding RNAs provide epigenetic regulatory circuits within the kidney, which reciprocally interact with DNA methylation processes, histone modification and chromatin. These interactions have been demonstrated to reflect the biological age and function of renal allografts. Epigenetic factors control gene expression and activity in response to environmental perturbations. They also have roles in highly conserved signalling pathways that modulate ageing, including the mTOR and insulin/insulin-like growth factor signalling pathways, and regulation of sirtuin activity. Nutrition, the gut microbiota, inflammation and environmental factors, including psychosocial and lifestyle stresses, provide potential mechanistic links between the epigenetic landscape of ageing and renal dysfunction. Approaches to modify the renal epigenome via nutritional intervention, targeting the methylome or targeting chromatin seem eminently feasible, although caution is merited owing to the potential for intergenerational and transgenerational effects.

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.

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.

Objective Muscle mass is a key element for the evaluation of nutritional disturbances in patients with chronic kidney disease (CKD). Low muscle mass is associated with increased morbidity and mortality. The assessment of muscle mass by computed tomography at the third lumbar vertebra region (CTMM-L3) is an accurate method not subject to errors from fluctuation in the hydration status. Therefore, we aimed at investigating whether CTMM-L3 was able to predict mortality in nondialyzed CKD 3-5 patients. Methods This is a prospective observational cohort study. We evaluated 223 nondialyzed CKD patients (60.3 ± 10.6 years; 64% men; 50% diabetics; glomerular filtration rate 20.7 ± 9.6 mLmin1.73 m2). Muscle mass was measured by CTMM-L3 using the Slice-O-Matic software and analyzed according to percentile adjusted by gender. Nutritional parameters, laboratory data, and comorbidities were evaluated, and mortality was followed up for 4 years. Results During the study period, 63 patients died, and the main cause of death was cardiovascular disease. Patients who died were older, had lower hemoglobin and albumin, as well as lower muscle markers. CTMM-L3 below the 25th percentile was associated with higher mortality according to the Kaplan-Meier curve (P = .017) and in Cox regression analysis (crude hazard ratio, 1.87 [95% confidence interval, 1.11-3.16]), also when adjusting for potential confounders (hazard ratio 1.83 [95% confidence interval 1.02-3.30]). Conclusion Low muscle mass measured by computed tomography at the third lumbar vertebra region is an independent predictor of increased mortality in nondialyzed CKD patients.

Under normal physiological conditions, free radical generation and antioxidant defences are balanced, and reactive oxygen species (ROS) usually act as secondary messengers in a plethora of biological processes. However, when this balance is impaired, oxidative stress develops due to imbalanced redox homeostasis resulting in cellular damage. Oxidative stress is now recognized as a trigger of cellular senescence, which is associated with multiple chronic 'burden of lifestyle' diseases, including atherosclerosis, type-2 diabetes, chronic kidney disease and vascular calcification; all of which possess signs of early vascular ageing.\ud \ud Nuclear factor erythroid 2-related factor 2 (Nrf2), termed the master regulator of antioxidant responses, is a transcription factor found to be frequently dysregulated in conditions characterized by oxidative stress and inflammation. Recent evidence suggests that activation of Nrf2 may be beneficial in protecting against vascular senescence and calcification. Both natural and synthetic Nrf2 agonists have been introduced as promising drug classes in different phases of clinical trials. However, overexpression of the Nrf2 pathway has also been linked to tumorigenesis, which highlights the requirement for further understanding of pathways involving Nrf2 activity, especially in the context of cellular senescence and vascular calcification.\ud \ud Therefore, comprehensive translational pre-clinical and clinical studies addressing the targeting capabilities of Nrf2 agonists are urgently required. The present review discusses the impact of Nrf2 in senescence and calcification in early vascular ageing, with focus on the potential clinical implications of Nrf2 agonists and non-pharmacological Nrf2 therapeutics.

Background Preterm delivery is an independent risk factor for maternal cardiovascular disease. Little is known about the association between preterm delivery and maternal renal function, and whether any association is independent of preeclampsia or intra-uterine growth restriction. This study aimed to examine the association between gestational age and long-term maternal chronic kidney disease (CKD) and end-stage kidney disease (ESKD). Methods Using data from the Swedish Medical Birth Register, singleton live births from 1973-2012 were identified and linked to data from the Swedish Renal Register and National Patient Register (up to 2013). Women with pre-pregnancy CKD/ESKD, cardiovascular disease, diabetes, hypertension, systemic lupus erythematosus were excluded. Gestational age at delivery was the main exposure, treated as a time-dependent variable. Primary outcomes were maternal CKD or ESKD. Cox regression was used, adjusting for maternal age, year of delivery, country of origin, education, parity, interpregnancy interval, smoking, BMI, gestational diabetes. Models were stratified by exposure to preeclampsia or small for gestational age (SGA). Results There were 3,847,694 pregnancies among 1,990,273 unique women. Nine percent of women (n = 172,915) had at least one preterm delivery ( Conclusions Women who gave birth at earlier gestation were at higher risk of later CKD and ESKD. This association persisted independently of preeclampsia and SGA. Key messages Preterm delivery is an independent predictor of long-term maternal renal disease. Obstetric history should be considered as part of overall risk stratification for chronic kidney disease in women.

Background Little is known about the long-term risk of renal disease following adverse pregnancy outcomes, such as hypertensive disorders of pregnancy (HDP), gestational diabetes (GDM) or preterm delivery. We aimed to investigate associations between adverse pregnancy outcomes and maternal chronic kidney disease (CKD) and end-stage kidney disease (ESKD), by synthesising results of relevant studies. Methods A systematic search of PubMed, EMBASE and Web of Science was done up to July 2018. Case-control and cohort studies were eligible for inclusion if they provided original effect estimates for associations between adverse pregnancy outcomes (HDP, GDM, preterm) and maternal renal disease (primary outcomes: CKD, ESKD; secondary outcomes: renal hospitalisation, renal mortality). Two independent reviewers extracted data and assessed risk of bias. Random effects meta-analyses were conducted to determine pooled adjusted odds ratio (AOR) and 95% confidence interval (95%CI) for each association. Results Of 5,120 studies retrieved, 21 studies met inclusion criteria (4,483,847 participants). HDP was associated with increased odds of ESKD (AOR 6.58, 95%CI 4.06-10.65), CKD (AOR 2.08, 95%CI 1.06-4.10), renal hospitalisation (AOR 2.29, 95%CI 1.42-3.71). The magnitude of association was dependent on HDP subtype: AOR for preeclampsia and ESKD was 4.87 (95%CI 3.01-7.87); gestational hypertension and ESKD was 3.65 (95%CI 2.34-5.67); other HDP (including chronic hypertension) and ESKD was 14.67 (95%CI 3.21-66.97). Preterm delivery was associated with increased odds of ESKD (AOR 2.16, 95%CI 1.64-2.85). GDM was associated with increased odds of CKD among black women (AOR 1.78, 95%CI 1.18-2.70), but not Caucasian women (AOR 0.81, 95%CI 0.58-1.13) Conclusions Women who experience adverse pregnancy outcomes have increased odds of renal disease, especially after HDP. Risk stratification and preventive interventions may be needed to reduce the risk of clinically significant renal disease in mothers. Key messages This is the first study to summarise the long-term risk of renal disease among women who experience a range of adverse pregnancy outcomes. Women who experience hypertensive disorders in pregnancy, preterm delivery, or gestational diabetes are at increased odds of renal disease.

Chronic non-communicable diseases have become a pandemic public problem in the 21st century, causing enormous burden on the economy, health and quality of life of societies. The role of a chronic inflammatory state in the pathogenesis of chronic disease has been more comprehensively recognized by recent findings. The new paradigm 'metaflammation' focuses on metabolism-induced (high fat or fructose-based diet or excessive calorie intake) chronic inflammation. There is a close correlation between the increased incidence of chronic kidney disease (CKD) and chronic heart failure with both increased inflammatory marker levels and western-type diet. In this review we describe the concept of metaflammation, its role in the development of CKD and chronic heart disease, the molecular and signalling pathways involved and the therapeutic consequences, Research by A.O. was funded by FIS ISCIII FEDER funds PI16/02057, ISCIII-RETIC REDinREN RD16/0009, EUTOX, Comunidad de Madrid en Biomedicina B2017/BMD-3686 CIFRA2-CM

Journal of nephrology : JN 33(4), 803-816 (2020). doi:10.1007/s40620-019-00686-z, Published by Springer, Milano