Epigenetic clocks indicate that kidney transplantation and not dialysis mitigate the effects of renal ageing.

BACKGROUND: Chronic kidney disease (CKD) is an age-related disease that displays multiple features of accelerated ageing. It is currently unclear whether the two treatment options for end-stage kidney disease (dialysis and kidney transplantation [KT]) ameliorate the accelerated uremic ageing process. METHODS: Data on clinical variables and blood DNA methylation (DNAm) from CKD stage G3-G5 patients were used to estimate biological age based on blood biomarkers (phenotypic age [PA], n = 333), skin autofluorescence (SAF age, n = 199) and DNAm (Horvath, Hannum and PhenoAge clocks, n = 47). In the DNAm cohort, we also measured the change in biological age 1 year after the KT or initiation of dialysis. Healthy subjects recruited from the general population were included as controls. RESULTS: All three DNAm clocks indicated an increased biological age in CKD G5. However, PA and SAF age tended to produce implausibly large estimates of biological age in CKD G5. By contrast, DNAm age was 4.9 years (p = 0.005) higher in the transplantation group and 5.9 years (p = 0.001) higher in the dialysis group compared to controls. This age acceleration was significantly reduced 1 year after KT, but not after 1 year of dialysis. CONCLUSIONS: Kidney failure patients displayed an increased biological age as estimated by DNAm clocks compared to population-based controls. Our results suggest that KT, but not dialysis, partially reduces the age acceleration.

Use of Analog and Human Insulin in a European Hemodialysis Cohort With Type 2 Diabetes: Associations With Mortality, Hospitalization, MACE, and Hypoglycemia.

RATIONALE & OBJECTIVE: Poor glycemic control may contribute to the high mortality rate in patients with type 2 diabetes receiving hemodialysis. Insulin type may influence glycemic control, and its choice may be an opportunity to improve outcomes. This study assessed whether treatment with analog insulin compared with human insulin is associated with different outcomes in people with type 2 diabetes and kidney failure receiving hemodialysis. STUDY DESIGN: Retrospective cohort study. SETTING & PARTICIPANTS: People in the Analyzing Data, Recognizing Excellence and Optimizing Outcomes (AROii) study with kidney failure commencing hemodialysis and type 2 diabetes being treated with insulin within 288 dialysis facilities between 2007 and 2009 across 7 European countries. Study participants were followed for 3 years. People with type 1 diabetes were excluded using an established administrative data algorithm. EXPOSURE: Treatment with an insulin analog or human insulin. OUTCOME: All-cause mortality, major adverse cardiovascular events (MACE), all-cause hospitalization, and confirmed hypoglycemia (blood glucose<3.0mmol/L sampled during hemodialysis). ANALYTICAL APPROACH: Inverse probability weighted Cox proportional hazards models to estimate hazard ratios for analog insulin compared with human insulin. RESULTS: There were 713 insulin analog and 733 human insulin users. Significant variation in insulin type by country was observed. Comparing analog with human insulin at 3 years, the percentage of patients experiencing end points and adjusted hazard ratios (AHR) were 22.0% versus 31.4% (AHR, 0.808 [95% CI, 0.66-0.99], P=0.04) for all-cause mortality, 26.8% versus 35.9% (AHR, 0.817 [95% CI, 0.68-0.98], P=0.03) for MACE, and 58.2% versus 75.0% (AHR, 0.757 [95% CI, 0.67-0.86], P<0.001) for hospitalization. Hypoglycemia was comparable between insulin types at 14.1% versus 15.0% (AHR, 1.169 [95% CI, 0.80-1.72], P=0.4). Consistent strength and direction of the associations were observed across sensitivity analyses. LIMITATIONS: Residual confounding, lack of more detailed glycemia data. CONCLUSIONS: In this large multinational cohort of people with type 2 diabetes and kidney failure receiving maintenance hemodialysis, treatment with analog insulins was associated with better clinical outcomes when compared with human insulin. PLAIN-LANGUAGE SUMMARY: People with diabetes who are receiving dialysis for kidney failure are at high risk of cardiovascular disease and death. This study uses information from 1,446 people with kidney failure from 7 European countries who are receiving dialysis, have type 2 diabetes, and are prescribed either insulin identical to that made in the body (human insulin) or insulins with engineered extra features (insulin analog). After 3 years, fewer participants receiving analog insulins had died, had been admitted to the hospital, or had a cardiovascular event (heart attack, stroke, heart failure, or peripheral vascular disease). These findings suggest that analog insulins should be further explored as a treatment leading to better outcomes for people with diabetes on dialysis.

The safety of a low protein diet in older adults with advanced chronic kidney disease.

BACKGROUND: A low protein diet (LPD) is recommended to patients with advanced chronic kidney disease (CKD), whereas geriatric guidelines recommend a higher amount of protein. The aim of this study was to evaluate the safety of LPD treatment in older adults with advanced CKD. METHODS: The EQUAL study is a prospective, observational study, including patients ≥65 years, incident estimated glomerular filtration rate <20 ml/min/1.73m², in six European countries with follow-up up till six years. Nutritional status was assessed by 7-point subjective global assessment (SGA) every 3-6 months. Prescribed diet (gram protein/kilogram/bodyweight) was recorded on every study visit; measured protein intake was available in three countries. Time to death and decline in nutritional status (SGA decrease by ≥2 points) were analysed using marginal structural models with dynamic inverse probability of treatment and censoring weights. RESULTS: Out of 1738 adults (631 prescribed LPD at any point during follow-up) there were 1319 with repeated SGA measurements of which 267 (20%) declined in SGA ≥ 2 points and 565 (32.5%) died. There was no difference in survival or decline in nutritional status for patients prescribed LPD ≤0.8 g/kg ideal bodyweight (Odds Ratio (OR) for mortality 1.15 (95% Confidence interval (CI) 0.86-1.55) and OR for decline in SGA 1.11 (95% CI 0.74-1.66) in the adjusted models. In patients prescribed LPD <0.6 g/kg ideal bodyweight, the results were similar. There was a significant interaction with LPD and higher age >75 years, lower SGA, and higher comorbidity burden for both mortality and nutritional status decline. CONCLUSIONS: In older adults with CKD approaching end-stage kidney disease, a traditional LPD prescribed and monitored according to routine clinical practice in Europe appears to be safe.

Identifying individuals at risk of needing CKD associated medications in a European kidney disease cohort.

BACKGROUND: The consequences of chronic kidney disease (CKD) can be addressed with a range of pharmacotherapies primarily prescribed by nephrologists. More accurate information regarding future CKD-related pharmacotherapy requirements could guide clinical decisions including follow-up frequency. METHODS: Following assignment to derivation and validation groups (2,1), variables predicting individually future use of vitamin D receptor agonists (VDRA), phosphate binders, erythropoiesis stimulating agents (ESAs) and iron were identified using logistic regression in a prospective cohort study containing demography, comorbidity, hospitalization, laboratory, and mortality data in patients with CKD stage G4/G5 across six European countries. Discriminative ability was measured using C-statistics, and predicted probability of medication use used to inform follow-up frequency. RESULTS: A total of 2196 patients were included in the analysis. During a median follow-up of 735 days 648 initiated hemodialysis and 1548 did not. Combinations of age, diabetes status and iPTH, calcium, hemoglobin and serum albumin levels predicted the use of ESA, iron, phosphate binder or VDRA, with C-statistics of 0.70, 0.64, 0.73 and 0.63 in derivation cohorts respectively. Model performance in validation cohorts were similar. Sixteen percent of patients were predicted to have a likelihood of receiving any of these medications of less than 20%. CONCLUSIONS: In a multi-country CKD cohort, prediction of ESA and phosphate binder use over a two-year period can be made based on patient characteristics with the potential to reduce frequency of follow-up in individuals with low risk for requiring these medications.

Chronic Kidney Disease and the Exposome of Ageing.

The gap between improvements in lifespan and age-related health is widening. Globally, the demographic of ageing is increasing and there has emerged a 'diseasome of ageing', typified by a range of non-communicable diseases which share a common underlying component of a dysregulated ageing process. Within this, chronic kidney disease is an emerging global epidemic.The extensive inter-individual variation displayed in how people age and how their diseasome manifests and progresses, has required a renewed focus on their life course exposures and the interplay between the environment and the (epi)genome. Termed the exposome, life course abiotic and biotic factors have a significant impact on renal health.We explore how the exposome of renal ageing can predispose and affect CKD progression. We discuss how the kidney can be used as a model to understand the impact of the exposome in health and chronic kidney disease and how this might be manipulated to improve health span.Notably, we discuss the manipulation of the foodome to mitigate acceleration of ageing processes by phosphate and to explore use of emerging senotherapies. A range of senotherapies, for removing senescent cells, diminishing inflammatory burden and either directly targeting Nrf2, or manipulating it indirectly via modification of the microbiome are discussed.

Unlocking the Potential of Brewers' Spent Grain: A Sustainable Model to Use Beer for Better Outcome in Chronic Kidney Disease.

The rising global incidence of chronic inflammatory diseases calls for innovative and sustainable medical solutions. Brewers' spent grain (BSG), a byproduct of beer production, presents a unique opportunity in this regard. This review explores the multifaceted health benefits of BSG, with a focus on managing chronic kidney disease (CKD). BSG is identified as a potent prebiotic with potential as a therapeutic agent in CKD. We emphasize the role of gut dysbiosis in CKD and discuss how BSG could help mitigate metabolic derangements resulting from dysbiosis and CKD. Fermentation of BSG further enhances its positive impact on gut health. Incorporating fermented BSG as a key component in preventive health care could promote a more sustainable and healthier future. By optimizing the use of this typically discarded byproduct, we can align proactive health-care strategies with responsible resource management, benefiting both people and the environment.

Increased risk for microvascular outcomes in NAFLD-A nationwide, population-based cohort study.

INTRODUCTION: Nonalcoholic fatty liver disease (NAFLD) is considered a multisystem disease, as it is bidirectionally linked to other cardiometabolic disorders, such as type 2 diabetes (T2D). However, the long-term risk for microvascular outcomes in NAFLD is unclear. METHODS: Using the outpatient part of the nationwide Swedish Patient Register in the time period between 01/01/2002 and 12/31/2019, we identified all individuals with a first NAFLD diagnosis (N = 6785) and matched these (age, sex, and municipality) with up to 10 reference individuals from the general population (N = 61,136). Using population-based registers, we ascertained the development of microvascular diseases. The primary outcome was defined as a composite outcome of any diagnosis representative of microvascular disease (chronic kidney disease, retinopathy, or neuropathy). As secondary outcomes, we separately examined the risk of each specific microvascular outcome. Hazard ratios (aHR, adjusted for cirrhosis and time-varying T2D, hypertension, and hyperlipidemia) for the outcomes were calculated by Cox proportional-hazards models. RESULTS: Median follow-up was 5.7 years. The incidence rate of microvascular diseases was >twofold higher in patients with NAFLD (10.8 per 1000 person-years [95% confidence interval (CI) = 9.9-11.8]) versus reference individuals (4.7 per 1000 person-years [95%CI = 4.5-4.9]). NAFLD was independently and positively associated with the development of microvascular diseases compared to non-NAFLD subjects (aHR = 1.45 [95%CI = 1.28-1.63]). When stratifying the analysis by follow-up time, sex, or age categories, results remain virtually unchanged. CONCLUSIONS: NAFLD is positively and independently associated with the development of microvascular diseases. The risk for development of microvascular diseases should be taken into account in the personalized risk assessment of individuals with NAFLD.

Urinary phosphate is associated with cardiovascular disease incidence.

INTRODUCTION: Elevated phosphate (P) in urine may reflect a high intake of inorganic P salts from food additives. Elevated P in plasma is linked to vascular dysfunction and calcification. OBJECTIVE: To explore associations between P in urine as well as in plasma and questionnaire-estimated P intake, and incidence of cardiovascular disease (CVD). METHODS: We used the Swedish Mammography Cohort-Clinical, a population-based cohort study. At baseline (2004-2009), P was measured in urine and plasma in 1625 women. Dietary P was estimated via a food-frequency questionnaire. Incident CVD was ascertained via register-linkage. Associations were assessed using Cox proportional hazards regression. RESULTS: After a median follow-up of 9.4 years, 164 composite CVD cases occurred (63 myocardial infarctions [MIs] and 101 strokes). Median P (percentiles 5-95) in urine and plasma were 2.4 (1.40-3.79) mmol/mmol creatinine and 1.13 (0.92-1.36) mmol/L, respectively, whereas dietary P intake was 1510 (1148-1918) mg/day. No correlations were observed between urinary and plasma P (r = -0.07) or dietary P (r = 0.10). Urinary P was associated with composite CVD and MI. The hazard ratio of CVD comparing extreme tertiles was 1.57 (95% confidence interval 1.05, 2.35; P trend 0.037)-independently of sodium excretion, the estimated glomerular filtration rate, both P and calcium in plasma, and diuretic use. Association with CVD for plasma P was 1.41 (0.96, 2.07; P trend 0.077). CONCLUSION: Higher level of urinary P, likely reflecting a high consumption of highly processed foods, was linked to CVD. Further investigation is needed to evaluate the potential cardiovascular toxicity associated with excessive intake of P beyond nutritional requirements.

Phenylacetylglutamine and trimethylamine N-oxide: Two uremic players, different actions.

BACKGROUND: Chronic kidney disease (CKD) patients exhibit a heightened cardiovascular (CV) risk which may be partially explained by increased medial vascular calcification. Although gut-derived uremic toxin trimethylamine N-oxide (TMAO) is associated with calcium-phosphate deposition, studies investigating phenylacetylglutamine's (PAG) pro-calcifying potential are missing. METHODS: The effect of TMAO and PAG in vascular calcification was investigated using 120 kidney failure patients undergoing living-donor kidney transplantation (LD-KTx), in an observational, cross-sectional manner. Uremic toxin concentrations were related to coronary artery calcification (CAC) score, epigastric artery calcification score, and markers of established non-traditional risk factors that constitute to the 'perfect storm' that drives early vascular aging in this patient population. Vascular smooth muscle cells were incubated with TMAO or PAG to determine their calcifying effects in vitro and analyse associated pathways by which these toxins may promote vascular calcification. RESULTS: TMAO, but not PAG, was independently associated with CAC score after adjustment for CKD-related risk factors in kidney failure patients. Neither toxin was associated with epigastric artery calcification score; however, PAG was independently, positively associated with 8-hydroxydeoxyguanosine. Similarly, TMAO, but not PAG, promoted calcium-phosphate deposition in vitro, while both uremic solutes induced oxidative stress. CONCLUSIONS: In conclusion, our translational data confirm TMAO's pro-calcifying effects, but both toxins induced free radical production detrimental to vascular maintenance. Our findings suggest these gut-derived uremic toxins have different actions on the vessel wall and therapeutically targeting TMAO may help reduce CV-related mortality in CKD.

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.

A normative microbiome is not restored following kidney transplantation.

Dialysis and kidney transplantation (Ktx) mitigate some of the physiological deficits in chronic kidney disease (CKD), but it remains to be determined if these mitigate microbial dysbiosis and the production of inflammatory microbial metabolites, which contribute significantly to the uraemic phenotype. We have investigated bacterial DNA signatures present in the circulation of CKD patients and those receiving a KTx. Our data are consistent with increasing dysbiosis as CKD progresses, with an accompanying increase in trimethylamine (TMA) producing pathobionts Pseudomonas and Bacillus. Notably, KTx patients displayed a significantly different microbiota compared with CKD5 patients, which surprisingly included further increase in TMA producing Bacillus and loss of salutogenic Lactobacilli. Only two genera (Viellonella and Saccharimonidales) showed significant differences in abundance following KTx that may reflect a reciprocal relationship between TMA producers and utilisers, which supersedes restoration of a normative microbiome. Our metadata analysis confirmed that TMA N-oxide (TMAO) along with one carbon metabolism had significant impact upon both inflammatory burden and the composition of the microbiome. This indicates that these metabolites are key to shaping the uraemic microbiome and might be exploited in the development of dietary intervention strategies to both mitigate the physiological deficits in CKD and enable the restoration of a more salutogenic microbiome.

Serum testosterone concentrations and outcomes in hemodialysis patients enrolled in the EVOLVE trial.

BACKGROUND: Hypogonadism is common in end-stage kidney disease and may contribute to morbidity and mortality. METHODS: Using data from the randomized controlled Evaluation of Cinacalcet Therapy to Lower Cardiovascular Events (EVOLVE) trial of cinacalcet, we analyzed the associations of total testosterone, free testosterone and sex hormone-binding globulin (SHBG) serum concentrations with mortality and major cardiovascular events in 1692 men and 1059 women receiving hemodialysis. We also describe the effect of cinacalcet treatment on serum concentrations of testosterone. RESULTS: Among men, lower serum free testosterone [odds ratio (OR) 0.18, 95% confidence interval (CI) 0.04-0.82, P = .026] and higher SHBG (OR 1.05 per 10 nmol/L, 95% CI 1.01-1.10, P = .012), but not total testosterone, were associated with higher risk of death or cardiovascular event. Only SHBG was associated with all-cause mortality (OR 1.07 per 10 nmol/L, 95% CI 1.02-1.12, P = .0073). Among women, neither total nor free testosterone, nor SHBG were associated with outcomes. We found no statistically significant effect of cinacalcet treatment on SHBG, free or total testosterone. CONCLUSIONS: Lower free testosterone and higher SHBG in serum are associated with higher risk of death or cardiovascular event in men undergoing chronic hemodialysis.

Association between CKD-MBD and mortality in older patients with advanced CKD-results from the EQUAL study.

BACKGROUND: Chronic kidney disease-mineral and bone disorder (CKD-MBD) is a common complication of CKD; it is associated with higher mortality in dialysis patients, while its impact in non-dialysis patients remains mostly unknown. We investigated the associations between parathyroid hormone (PTH), phosphate and calcium (and their interactions), and all-cause, cardiovascular (CV) and non-CV mortality in older non-dialysis patients with advanced CKD. METHODS: We used data from the European Quality study, which includes patients aged ≥65 years with estimated glomerular filtration rate ≤20 mL/min/1.73 m2 from six European countries. Sequentially adjusted Cox models were used to assess the association between baseline and time-dependent CKD-MBD biomarkers and all-cause, CV and non-CV mortality. Effect modification between biomarkers was also assessed. RESULTS: In 1294 patients, the prevalence of CKD-MBD at baseline was 94%. Both PTH [adjusted hazard ratio (aHR) 1.12, 95% confidence interval (CI) 1.03-1.23, P = .01] and phosphate (aHR 1.35, 95% CI 1.00-1.84, P = .05), but not calcium (aHR 1.11, 95% CI 0.57-2.17, P = .76), were associated with all-cause mortality. Calcium was not independently associated with mortality, but modified the effect of phosphate, with the highest mortality risk found in patients with both hypercalcemia and hyperphosphatemia. PTH level was associated with CV mortality, but not with non-CV mortality, whereas phosphate was associated with both CV and non-CV mortality in most models. CONCLUSIONS: CKD-MBD is very common in older non-dialysis patients with advanced CKD. PTH and phosphate are independently associated with all-cause mortality in this population. While PTH level is only associated with CV mortality, phosphate seems to be associated with both CV and non-CV mortality.

Proposal for a New Classification of Solutes of Interest in Uremia and Hemodialysis.

Uremic toxins contribute to clinical manifestations of kidney dysfunction. These toxins include organic and inorganic elements or compounds. While the kidney typically clears uremic toxins, gut dysbiosis, and tissue inflammation could lead to increased production of substances that can further the clinical manifestations of uremia. The uremic toxins are quantitatively measurable in biological fluids and have an established relationship with azotemia signs and symptoms. Their elimination is associated with mitigated uremic manifestations, while their administration to the uremic levels leads to uremic signs in animal or human models or in vitro studies. Besides, the uremic toxins have an established and plausible pathophysiologic relationship with uremic manifestations. The previous classification of uremic toxins was mainly focused on the physicochemical characteristics of these substances to divide them into three categories, (1) free water-soluble low-molecular-weight (<500 Da) solutes, (2) protein-bound, water-soluble, low molecular weight (<500 Da), (3) middle molecular weight (>500 Da and <12,000 Da), and (4) high molecular weight (>12,000 Da). Unfortunately, the classification named above was not centered around patient outcomes and quality of life among those with severe kidney failure. Therefore, a panel of experts convened virtually to provide additional insights into the current state and propose a new uremic toxin classification. This article describes the group's consensus recommendations regarding the new classification of uremic toxins into more clinically oriented categories.

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

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

Planetary Health, Nutrition, and Chronic Kidney Disease: Connecting the Dots for a Sustainable Future.

The increasing consumption of ultra-processed food (UPF) and the global chain of food production have a negative impact on human health and planetary health. These foods have been replacing the consumption of nonprocessed healthy foods. This shift has not only worsened human health by increasing the risk of the development of noncommunicable diseases, but also resulted in environmental perturbations. This review aims to bring awareness of the problems caused by the industrialized food production chain, addressing the negative effects it has on the environment and human health, with special reference to chronic kidney disease (CKD). We discuss possible solutions focusing on the benefits of adopting plant-based diets with low UPF content to promote a sustainable and healthy food production and diet for patients with CKD. For a sustainable future we need to "connect the dots" of planetary health, food production, and nutrition in the context of CKD.

Associations of Biopterins and ADMA with Vascular Function in Peripheral Microcirculation from Patients with Chronic Kidney Disease.

We hypothesized that patients with chronic kidney disease (CKD) display an altered plasma amino acid (AA) metabolomic profile that could contribute to abnormal vascular maintenance of peripheral circulation in uremia. The relationships between plasma AAs and endothelial and vascular smooth muscle function in the microcirculation of CKD patients are not well understood. The objective of this study is to investigate to what extent the levels of AAs and its metabolites are changed in CKD patients and to test their relationship with endothelial and vascular smooth muscle function. Patients with CKD stages 3 and 5 and non-CKD controls are included in this study. We report that there was a significant reduction of the biopterin (BH4/BH2) ratio, which was accompanied by increased plasma levels of BH2, asymmetric dimethylarginine (ADMA) and citrulline in patients with CKD-5 vs. CKD-3 vs. controls. In vivo augmentation index measurement showed a positive association with ADMA in all participants. The contribution of nitric oxide, assessed by ex vivo assay, showed a negative association with creatinine, ADMA and citrulline in all participants. In CKD-5, BH4 negatively correlated with ADMA and ornithine levels, and the ex vivo endothelium-mediated dilatation positively correlated with phenylalanine levels. In conclusion, uremia is associated with alterations in AA metabolism that may affect endothelium-dependent dilatation and vascular stiffness in microcirculation. Interventional strategies aiming to normalize the AA metabolism could be of interest as treatment options.

Indoxyl Sulphate Retention Is Associated with Microvascular Endothelial Dysfunction after Kidney Transplantation.

Kidney transplantation (KTx) is the preferred form of renal replacement therapy in chronic kidney disease (CKD) patients, owing to increased quality of life and reduced mortality when compared to chronic dialysis. Risk of cardiovascular disease is reduced after KTx; however, it is still a leading cause of death in this patient population. Thus, we aimed to investigate whether functional properties of the vasculature differed two years post-KTx (postKTx) compared to baseline (time of KTx). Using the EndoPAT device in 27 CKD patients undergoing living-donor KTx, we found that vessel stiffness significantly improved while endothelial function worsened postKTx vs. baseline. Furthermore, baseline serum indoxyl sulphate (IS), but not p-cresyl sulphate, was independently negatively associated with reactive hyperemia index, a marker of endothelial function, and independently positively associated with P-selectin postKTx. Finally, to better understand the functional effects of IS in vessels, we incubated human resistance arteries with IS overnight and performed wire myography experiments ex vivo. IS-incubated arteries showed reduced bradykinin-mediated endothelium-dependent relaxation compared to controls via reduced nitric oxide (NO) contribution. Endothelium-independent relaxation in response to NO donor sodium nitroprusside was similar between IS and control groups. Together, our data suggest that IS promotes worsened endothelial dysfunction postKTx, which may contribute to the sustained CVD risk.

Blood-Brain Barrier Biomarkers before and after Kidney Transplantation.

Kidney transplantation (KT) may improve the neurological status of chronic kidney disease (CKD) patients, reflected by the altered levels of circulating BBB-specific biomarkers. This study compares the levels of neuron specific enolase (NSE), brain-derived neurotrophic factor (BDNF), neurofilament light chain (NfL), and circulating plasma extracellular vesicles (EVs) in kidney-failure patients before KT and at a two-year follow up. Using ELISA, NSE, BDNF, and NfL levels were measured in the plasma of 74 living-donor KT patients. Plasma EVs were isolated with ultracentrifugation, and characterized for concentration/size and surface protein expression using flow cytometry from a subset of 25 patients. Lower NSE levels, and higher BDNF and NfL were observed at the two-year follow-up compared to the baseline (p < 0.05). Male patients had significantly higher BDNF levels compared to those of females. BBB biomarkers correlated with the baseline lipid profile and with glucose, vitamin D, and inflammation markers after KT. BBB surrogate marker changes in the microcirculation of early vascular aging phenotype patients with calcification and/or fibrosis were observed only in NSE and BDNF. CD31+ microparticles from endothelial cells expressing inflammatory markers such as CD40 and integrins were significantly reduced after KT. KT may, thus, improve the neurological status of CKD patients, as reflected by changes in BBB-specific biomarkers.

Lessons from evolution by natural selection: An unprecedented opportunity to use biomimetics to improve planetary health.

Planetary health embraces the concept that long-term human welfare depends on the well-being of its ecological systems. Current practices, however, have often ignored this concept and have led to an anthropocentric world, with the consequence of increased greenhouse gas emissions, heat stress, lack of clean water and pollution, that are threatening the environment as well as the health and life of Homo sapiens and many other species. One consequence of environmental stressors has been the stimulation of inflammatory and oxidative stress that may not only promote common lifestyle diseases, but the ageing process. Despite the harshness of the current reality, treatment opportunities may exist 'in our backyard'. Biomimicry is an emerging field of research that explores how nature is structured and aims to mimic ingenious solutions that have evolved in nature for different applications that benefit human life. As nature always counteracts excesses from within, biodiversity could be a source of solutions that have evolved through the natural selection of animal species that have survived polluted, warm, and arid environments - i.e. the same presumptive changes that now threaten human health. One example from the emerging science suggests that animals use the cytoprotective Nrf2 antioxidant pathway to combat environmental stress and this may be a case example that we can apply to better human health. Learning from nature may provide opportunities for environmental management and solutions to the most challenging issue that face the future of the planet.