Deceased donor kidney function and branched chain amino acid metabolism during ex vivo normothermic perfusion.

Current kidney perfusion protocols are not optimized for addressing the ex vivo physiological and metabolic needs of the kidney. Ex vivo normothermic perfusion may be utilized to distinguish high-risk kidneys to determine suitability for transplantation. Here, we assessed the association of tissue metabolic changes with changes in a kidney injury biomarker and functional parameters in eight deceased donor kidneys deemed unsuitable for transplantation during a 12- hour ex vivo normothermic perfusion. The kidneys were grouped into good and poor performers based on blood flow and urine output. The mean age of the deceased kidney donors was 43 years with an average cold ischemia time of 37 hours. Urine output and creatinine clearance progressively increased and peaked at six hours post-perfusion among good performers. Poor performers had 71 ng/ml greater (95% confidence interval 1.5, 140) urinary neutrophil gelatinase-associated lipocalin at six hours compared to good performers corresponding to peak functional differences. Organ performance was distinguished by tissue metabolic differences in branched chain amino acid metabolism and that their tissue levels negatively correlated with urine output among all kidneys at six hours. Tissue lipid profiling showed poor performers were highlighted by the accumulation of membrane structure components including glycerolipids and sphingolipids at early perfusion time points. Thus, we showed that six hours is needed for kidney function recovery during ex vivo normothermic perfusion and that branched chain amino acid metabolism may be a major determinant of organ function and resilience.

Chronic Kidney Disease is Associated With Attenuated Plasma Metabolome Response to Oral Glucose Tolerance Testing.

OBJECTIVE: Chronic kidney disease (CKD) is associated with decreased anabolic response to insulin contributing to protein-energy wasting. Targeted metabolic profiling of oral glucose tolerance testing (OGTT) may help identify metabolic pathways contributing to disruptions to insulin response in CKD. METHODS: Using targeted metabolic profiling, we studied the plasma metabolome response in 41 moderate-to-severe nondiabetic CKD patients and 20 healthy controls at fasting and 2 hours after an oral glucose load. We used linear mixed modeling with random intercepts, adjusting for age, gender, race/ethnicity, body weight, and batch to assess heterogeneity in response to OGTT by CKD status. RESULTS: Mean estimated glomerular filtration rate among CKD participants was 38.9 ± 12.7 mL/min per 1.73 m2 compared to 87.2 ± 17.7 mL/min per 1.73 m2 among controls. Glucose ingestion induced an anabolic response resulting in increased glycolysis products and a reduction in a wide range of metabolites including amino acids, tricarboxylic acid cycle intermediates, and purine nucleotides compared to fasting. Participants with CKD demonstrated a blunted anabolic response to OGTT evidenced by significant changes in 13 metabolites compared to controls. The attenuated metabolome response predominant involved mitochondrial energy metabolism, vitamin B family, and purine nucleotides. Compared to controls, CKD participants had elevated lactate:pyruvate (L:P) ratio and decreased guanosine diphosphate:guanosine triphosphate ratio during OGTT. CONCLUSION: Metabolic profiling of OGTT response suggests a broad disruption of mitochondrial energy metabolism in CKD patients. These findings motivate further investigation into the impact of insulin sensitizers and mitochondrial targeted therapeutics on energy metabolism in patients with nondiabetic CKD.

Effects of caloric restriction and aerobic exercise on circulating cell-free mitochondrial DNA in patients with moderate to severe chronic kidney disease.

Circulating cell-free mitochondrial DNA (ccf-mtDNA) may induce systemic inflammation, a common condition in chronic kidney disease (CKD), by acting as a damage-associated molecular pattern. We hypothesized that in patients with moderate to severe CKD, aerobic exercise would reduce ccf-mtDNA levels. We performed a post hoc analysis of a multicenter randomized trial (NCT01150851) measuring plasma concentrations of ccf-mtDNA at baseline and 2 and 4 mo after aerobic exercise and caloric restriction. A total of 99 participants had baseline ccf-mtDNA, and 92 participants completed the study. The median age of the participants was 57 yr, 44% were female and 55% were male, 23% had diabetes, and 92% had hypertension. After adjusting for demographics, blood pressure, body mass index, diabetes, and estimated glomerular filtration rate, median ccf-mtDNA concentrations at baseline, 2 mo, and 4 mo were 3.62, 3.08, and 2.78 pM for the usual activity group and 2.01, 2.20, and 2.67 pM for the aerobic exercise group, respectively. A 16.1% greater increase per month in ccf-mtDNA was seen in aerobic exercise versus usual activity (P = 0.024), which was more pronounced with the combination of aerobic exercise and caloric restriction (29.5% greater increase per month). After 4 mo of intervention, ccf-mtDNA increased in the aerobic exercise group by 81.6% (95% confidence interval: 8.2-204.8, P = 0.024) compared with the usual activity group and was more marked in the aerobic exercise and caloric restriction group (181.7% increase, 95% confidence interval: 41.1-462.2, P = 0.003). There was no statistically significant correlation between markers of oxidative stress and inflammation with ccf-mtDNA. Our data indicate that aerobic exercise increased ccf-mtDNA levels in patients with moderate to severe CKD.NEW & NOTEWORTHY The effects of prolonged exercise on circulating cell-free mitochondrial DNA (ccf-mtDNA) have not been explored in patients with chronic kidney disease (CKD). We showed that 4-mo aerobic exercise is associated with an increase in plasma ccf-mtDNA levels in patients with stages 3 or 4 CKD. These changes were not associated with markers of systemic inflammation. Future studies should determine the mechanisms by which healthy lifestyle interventions influence biomarkers of inflammation and oxidative stress in patients with CKD.

Global Policy Barriers and Enablers to Exercise and Physical Activity in Kidney Care.

OBJECTIVE: Impairment in physical function and physical performance leads to decreased independence and health-related quality of life in people living with chronic kidney disease and end-stage kidney disease. Physical activity and exercise in kidney care are not priorities in policy development. We aimed to identify global policy-related enablers, barriers, and strategies to increase exercise participation and physical activity behavior for people living with kidney disease. DESIGN AND METHODS: Guided by the Behavior Change Wheel theoretical framework, 50 global renal exercise experts developed policy barriers and enablers to exercise program implementation and physical activity promotion in kidney care. The consensus process consisted of developing themes from renal experts from North America, South America, Continental Europe, United Kingdom, Asia, and Oceania. Strategies to address enablers and barriers were identified by the group, and consensus was achieved. RESULTS: We found that policies addressing funding, service provision, legislation, regulations, guidelines, the environment, communication, and marketing are required to support people with kidney disease to be physically active, participate in exercise, and improve health-related quality of life. We provide a global perspective and highlight Japanese, Canadian, and other regional examples where policies have been developed to increase renal physical activity and rehabilitation. We present recommendations targeting multiple stakeholders including nephrologists, nurses, allied health clinicians, organizations providing renal care and education, and renal program funders. CONCLUSIONS: We strongly recommend the nephrology community and people living with kidney disease take action to change policy now, rather than idly waiting for indisputable clinical trial evidence that increasing physical activity, strength, fitness, and function improves the lives of people living with kidney disease.

New insights into muscle function in chronic kidney disease and metabolic acidosis.

PURPOSE OF REVIEW: : Sarcopenia, defined as decreased muscle mass or function, is prevalent in chronic kidney disease (CKD) increasing the risk of mobility impairment and frailty. CKD leads to metabolic acidosis (MA) and retention of uremic toxins contributing to insulin resistance and impaired muscle mitochondrial energetics. Here we focus on the central role of muscle mitochondrial metabolism in muscle function. RECENT FINDINGS: : Mitochondrial dysfunction underlies muscle wasting and poor physical endurance in CKD. Uremic toxins accumulate in muscle disrupting mitochondrial respiration and enzymes. Changes in mitochondrial quantity, quality, and oxidative capacity contribute to mobility impairment in CKD. Major determinants of muscle mitochondrial function are kidney function, inflammation, and oxidative stress. In CKD, MA is the major determinant of muscle mitochondrial function. Metabolomics reveals defects in pathways linked to mitochondrial energy metabolism and acid-base homeostasis underlying insulin resistance in CKD. SUMMARY: : Decreased mitochondrial capacity and quality control can impair muscle function contributing to decreased physical endurance. MA augments insulin resistance perpetuating the catabolic state underlying muscle wasting in CKD. Further studies are needed to investigate if targeting of MA improves muscle mitochondrial function and insulin resistance translating into meaningful improvements in physical endurance.

Determinants of Health-Related Quality of Life and Physical Performance-Based Components of Frailty in Patients Undergoing Hemodialysis.

OBJECTIVES: Health-related quality of life (HRQoL) measures capture the patient's experience of the burden of chronic disease and are strongly associated with adverse health-related outcomes across multiple populations. The SF-36 score is the most widely used HRQoL measure among patients with end-stage renal disease. Current understanding of determinants of the physical component summary (PCS) and the mental component summary (MCS) and their association with objectively measured physical performance and activity is limited. METHODS: As an index of HRQoL, we prospectively examined the association of SF-36 and its component scores with physical function among 155 incident dialysis patients from the Hemodialysis Center. We investigated associations of HRQoL with the physical performance-based components of the frailty using multivariate linear and logistic regression after adjustment for confounders. Impaired physical performance was defined as having either slow usual gait speed or weak handgrip strength based on standardized and validated criteria derived from a large cohort study of older adults. RESULTS: The patients had a mean age of 65 ± 11 years, and 52.3% were male. After adjusting confounders, lower PCS was independently associated with decreased physical performance and reduced physical activity, but MCS was not associated. Among the PCS subscales, only physical functioning 10 (PF-10) was consistently associated with outcomes, and every 1 point increase in PF-10 score was associated with 4% lower odds of impaired physical performance (95% confidence interval 2-7, P = .01) after adjustment. CONCLUSIONS: SF-36, especially PF-10, is a valid surrogate that discriminates low physical performance and physical inactivity in the absence of formal physical function testing in patients on hemodialysis. The routine implementation of the PF-10 in clinical care has important clinical implications for medical management and therapeutic decision-making in patients undergoing hemodialysis.

Assessment of physical functioning in the clinical care of the patient with advanced kidney disease.

Maintenance of independent living is the top health priority among patients with advanced chronic kidney disease (CKD). Mobility limitation is often the first sign of functional limitation leading to loss of independence. Regular assessments of physical capacity can help provide kidney health providers identify patients at risk of frailty and other adverse health-related outcomes that contribute to the loss of functional independence. These physical capacities can be measured with commonly used self-reported measures of physical function or by objective physical performance testing. The current review describes commonly used assessments of self-reported physical function and physical performance. First, we describe the disablement process and how these assessments can be performed with commonly used quality of life instruments measuring self-reported physical function or objective physical performance tests. Second, we identify the determinants and correlates of self-reported physical function and physical performance and their contribution to the frailty phenotype. Third, we describe the association of physical capacities with clinical outcomes. We conclude with on possible approach to identifying and intervening on persons with CKD at high risk of functional decline.

Decline in the Functional Status and Mortality in Patients on Hemodialysis: Results from the Japan Dialysis Outcome and Practice Patterns Study.

OBJECTIVES: Patients with end-stage renal disease (ESRD) treated with hemodialysis suffer a high burden of poor functional status. Poor functional status is known as a strong, consistent predictor of mortality. However, little is known about the trajectory of functional status and its association with clinical outcomes in the ESRD population. We examined the association between a change in the functional status over time and all-cause mortality among patients on hemodialysis. DESIGN AND METHODS: This was a prospective cohort study of 817 patients with ESRD on hemodialysis with repeat measures of functional status, who enrolled in the Japan Dialysis Outcomes and Practice Patterns Study phase V. The functional status was assessed based on the Katz Index and Lawton-Brody instrumental activities of daily living scale, and the assessments were conducted twice over a median of 361 (range: 339-378) days between 2012 and 2013. We classified patients into 2 groups based on having or not having at least a 1-point decline in the functional status score. To evaluate the association between the decline in the functional status and all-cause mortality with adjustment for potential confounders, a Cox regression analysis was conducted. RESULTS: Over the study period, 19.9% of the patients showed a decline in the functional status score. During the follow-up period, 44 (5.4%) patients died. Using the Cox regression analysis and adjusting for potential confounders, it was determined that the decline in functional status score was significantly associated with higher mortality (incidence rate: 2.2 vs. 7.0 per 100 person-years; adjusted hazard ratio: 2.68; 95% confidence interval: 1.31-5.50). CONCLUSIONS: The present study provides evidence that ESRD patients on hemodialysis demonstrating a decline in the functional status are at elevated risk of mortality. Our findings strengthen the evidence underpinning the importance of interventions to maintain the functional status in this vulnerable population.

Physical Activity Dose for Hemodialysis Patients: Where to Begin? Results from a Prospective Cohort Study.

OBJECTIVE: Greater physical activity is associated with lower risk of mortality in persons with kidney disease; however, little is known about the appropriate dose of physical activity among hemodialysis patients. Here detected the minimum level of habitual physical activity to help inform interventions aimed at improving outcomes in the dialysis population. DESIGN: The design was prospective cohort study. SUBJECTS: Clinically stable outpatients in a hemodialysis unit from October 2002 to March 2014 were assessed for their eligibility to be included in this 7-year prospective cohort study. We used the Youden index to determine the optimal cutoff points for physical activity. The prognostic effect of physical activity on survival was estimated by Cox proportional hazards regression analysis. The number of steps per nondialysis day was recorded by accelerometer at study entry. MAIN OUTCOME MEASURE: The main outcome measure was all-cause mortality. RESULTS: There were 282 participants who had a mean age of 65 ± 11 years and 45% were female. A total of 56 deaths occurred during the follow-up period (56 months [interquartile range: 29-84 months]). The cutoff value for the physical activity discriminating those at high risk of mortality was 3,752 steps. After adjustment for the effect of confounders, the hazard ratio in the group of <4,000 steps was 2.37 (95% confidence interval: 1.22-4.60, P = .01) compared with the others. CONCLUSIONS: Engaging in physical activity is associated with decreased mortality risk among hemodialysis patients. Our findings of a substantial mortality benefit among those who engage in at least 4,000 steps provide a basis for as a minimum initial recommendation kidney health providers can provide for mobility disability-free hemodialysis patients.

Exercise and CKD: Skeletal Muscle Dysfunction and Practical Application of Exercise to Prevent and Treat Physical Impairments in CKD.

Patients with chronic kidney disease experience substantial loss of muscle mass, weakness, and poor physical performance. As kidney disease progresses, skeletal muscle dysfunction forms a common pathway for mobility limitation, loss of functional independence, and vulnerability to disease complications. Screening for those at high risk for mobility disability by self-reported and objective measures of function is an essential first step in developing an interdisciplinary approach to treatment that includes rehabilitative therapies and counseling on physical activity. Exercise has beneficial effects on systemic inflammation, muscle, and physical performance in chronic kidney disease. Kidney health providers need to identify patient and care delivery barriers to exercise in order to effectively counsel patients on physical activity. A thorough medical evaluation and assessment of baseline function using self-reported and objective function assessment is essential to guide an effective individualized exercise prescription to prevent function decline in persons with kidney disease. This review focuses on the impact of kidney disease on skeletal muscle dysfunction in the context of the disablement process and reviews screening and treatment strategies that kidney health professionals can use in clinical practice to prevent functional decline and disability.

Creatinine clearance, walking speed, and muscle atrophy: a cohort study.

BACKGROUND: Chronic kidney disease is associated with malnutrition and inflammation. These processes may lead to loss of skeletal muscle and reduced physical performance. Associations of kidney function with muscle composition and longitudinal measures of physical performance are unknown. STUDY DESIGN: Prospective cohort study. SETTING & PARTICIPANTS: We evaluated 826 community-dwelling older adults enrolled in the Invecchiare in Chianti (InCHIANTI) Study who were free of baseline stroke or activities of daily living disability. PREDICTOR: Baseline creatinine clearance (Clcr) based on 24-hour urine collection. OUTCOMES: Cross-sectional and longitudinal trajectories of physical performance measured by 7-m usual gait speed, 400-m fast gait speed, and knee extension strength using isometric dynamometry. Calf muscle composition assessed by quantitative computed tomography. RESULTS: Mean age of participants was 74 ± 7 (SD) years, with 183 having Clcr < 60 mL/min/1.73 m(2). After adjustment, each 10-mL/min/1.73 m(2) decrement in Clcr was associated with 0.01 (95% CI, 0.004-0.017) m/s slower 7-m usual walking speed and 0.008 (95% CI, 0.002-0.014) m/s slower 400-m walking speed. Each 10-mL/min/1.73 m(2) decrement in Clcr was associated with 28 (95% CI, 0.8-55) mm(2) lower muscle area and 0.15 (95% CI, 0.04-0.26) mg/cm(3) lower muscle density. After adjustment, lower Clcr was associated with slower mean 7-m (P=0.005) and 400-m (P=0.02) walk and knee extension strength (P=0.001) during the course of follow-up. During a mean follow-up of 7.1 ± 2.5 years, each 10-mL/min/1.73 m(2) lower baseline Clcr was associated with 0.024 (95% CI, 0.01-0.037) kg/y greater decline in knee strength. LIMITATIONS: Single baseline measurement of Clcr and 3-year interval between follow-up visits may lead to nondifferential misclassification and attenuation of estimates. CONCLUSIONS: Among older adults, lower Clcr is associated with muscle atrophy, reduced walking speed, and more rapid declines in lower-extremity strength over time.

Coenzyme Q10 dose-escalation study in hemodialysis patients: safety, tolerability, and effect on oxidative stress.

BACKGROUND: Coenzyme Q10 (CoQ10) supplementation improves mitochondrial coupling of respiration to oxidative phosphorylation, decreases superoxide production in endothelial cells, and may improve functional cardiac capacity in patients with congestive heart failure. There are no studies evaluating the safety, tolerability and efficacy of varying doses of CoQ10 in chronic hemodialysis patients, a population subject to increased oxidative stress. METHODS: We performed a dose escalation study to test the hypothesis that CoQ10 therapy is safe, well-tolerated, and improves biomarkers of oxidative stress in patients receiving hemodialysis therapy. Plasma concentrations of F2-isoprostanes and isofurans were measured to assess systemic oxidative stress and plasma CoQ10 concentrations were measured to determine dose, concentration and response relationships. RESULTS: Fifteen of the 20 subjects completed the entire dose escalation sequence. Mean CoQ10 levels increased in a linear fashion from 704 ± 286 ng/mL at baseline to 4033 ± 1637 ng/mL, and plasma isofuran concentrations decreased from 141 ± 67.5 pg/mL at baseline to 72.2 ± 37.5 pg/mL at the completion of the study (P = 0.003 vs. baseline and P < 0.001 for the effect of dose escalation on isofurans). Plasma F2-isoprostane concentrations did not change during the study. CONCLUSIONS: CoQ10 supplementation at doses as high as 1800 mg per day was safe in all subjects and well-tolerated in most. Short-term daily CoQ10 supplementation decreased plasma isofuran concentrations in a dose dependent manner. CoQ10 supplementation may improve mitochondrial function and decrease oxidative stress in patients receiving hemodialysis. TRIAL REGISTRATION: This clinical trial was registered on clinicaltrials.gov [NCT00908297] on May 21, 2009.

Association between physical performance and all-cause mortality in CKD.

In older adults, measurements of physical performance assess physical function and associate with mortality and disability. Muscle wasting and diminished physical performance often accompany CKD, resembling physiologic aging, but whether physical performance associates with clinical outcome in CKD is unknown. We evaluated 385 ambulatory, stroke-free participants with stage 2-4 CKD enrolled in clinic-based cohorts at the University of Washington and University of Maryland and Veterans Affairs Maryland Healthcare systems. We compared handgrip strength, usual gait speed, timed up and go (TUAG), and 6-minute walking distance with normative values and constructed Cox proportional hazards models and receiver operating characteristic curves to test associations with all-cause mortality. Mean age was 61 years and the mean estimated GFR was 41 ml/min per 1.73 m(2). Measures of lower extremity performance were at least 30% lower than predicted, but handgrip strength was relatively preserved. Fifty deaths occurred during the median 3-year follow-up period. After adjustment, each 0.1-m/s decrement in gait speed associated with a 26% higher risk for death, and each 1-second longer TUAG associated with an 8% higher risk for death. On the basis of the receiver operating characteristic analysis, gait speed and TUAG more strongly predicted 3-year mortality than kidney function or commonly measured serum biomarkers. Adding gait speed to a model that included estimated GFR significantly improved the prediction of 3-year mortality. In summary, impaired physical performance of the lower extremities is common in CKD and strongly associates with all-cause mortality.

The association of physical activity and physical function with clinical outcomes in adults with chronic kidney disease.

PURPOSE OF REVIEW: Despite guidelines supporting the regular assessment of physical functioning and encouragement of physical activity in management of the patient with chronic kidney disease (CKD), implementation has been undermined by a lack of understanding of the evidence for this recommendation. The purpose of this review is to present a summary of emerging data from larger epidemiologic cohorts that report associations between low levels of physical functioning and/or low physical activity and clinical outcomes in patients with CKD. RECENT FINDINGS: Low levels of physical activity and poor physical functioning are strongly associated with mortality and poor clinical outcomes in adult patients with CKD, regardless of treatment modality. Low physical performance and activity limitations are more prevalent in patients with CKD, regardless of age, compared to older community-dwelling adults. SUMMARY: The strength of the evidence presented should strongly motivate a focus of treatment on assessing and improving physical activity and physical function as part of routine patient-centered management of persons with CKD. Physical activity interventions are warranted because patients with CKD, regardless of age, have a high prevalence of low physical functioning and frailty that is similar to or higher than the general population of elderly adults; physical activity, physical function, and performance are strongly associated with all-cause mortality; and exercise training and exercise counseling have been shown to improve measures of physical functioning.

Assessment of physical activity in chronic kidney disease.

BACKGROUND: Physical inactivity plays an important role in the development of kidney disease and its complications; however, the validity of standard tools for measuring physical activity (PA) is not well understood. STUDY DESIGN: We investigated the performance of several readily available and widely used PA and physical function questionnaires, individually and in combination, against accelerometry among a cohort of chronic kidney disease (CKD) participants. SETTING AND PARTICIPANTS: Forty-six participants from the Seattle Kidney Study, an observational cohort study of persons with CKD, completed the Physical Activity Scale for the Elderly, Human Activity Profile (HAP), Medical Outcomes Study SF-36 questionnaire, and the Four-week Physical Activity History questionnaires. We simultaneously measured PA using an Actigraph GT3X accelerometer during a 14-day period. We estimated the validity of each instrument by testing its associations with log-transformed accelerometry counts. We used the Akaike information criterion to investigate the performance of combinations of questionnaires. RESULTS: All questionnaire scores were significantly associated with log-transformed accelerometry counts. The HAP correlated best with accelerometry counts (r(2) = 0.32) followed by SF-36 (r(2) = 0.23). Forty-three percent of the variability in accelerometry counts data was explained by a model that combined the HAP, SF-36, and Four-week Physical Activity History questionnaires. CONCLUSION: A combination of measurement tools can account for a modest component of PA in patients with CKD; however, a substantial proportion of PA is not captured by standard assessments.

Impaired incretin homeostasis in non-diabetic moderate-severe CKD.

Background: Incretins are regulators of insulin secretion and glucose homeostasis that are metabolized by dipeptidyl peptidase-4 (DPP-4). Moderate-severe CKD may modify incretin release, metabolism, or response. Methods: We performed 2-hour oral glucose tolerance testing (OGTT) in 59 people with non-diabetic CKD (eGFR<60 ml/min per 1.73 m2) and 39 matched controls. We measured total (tAUC) and incremental (iAUC) area under the curve of plasma total glucagon-like peptide-1 (GLP-1) and total glucose-dependent insulinotropic polypeptide (GIP). Fasting DPP-4 levels and activity were measured. Linear regression was used to adjust for demographic, body composition, and lifestyle factors. Results: Mean eGFR was 38 ±13 and 89 ±17ml/min per 1.73 m2 in CKD and controls. GLP-1 iAUC and GIP iAUC were higher in CKD than controls with a mean of 1531 ±1452 versus 1364 ±1484 pMxmin, and 62370 ±33453 versus 42365 ±25061 pgxmin/ml, respectively. After adjustment, CKD was associated with 15271 pMxmin/ml greater GIP iAUC (95% CI 387, 30154) compared to controls. Adjustment for covariates attenuated associations of CKD with higher GLP-1 iAUC (adjusted difference, 122, 95% CI -619, 864). Plasma glucagon levels were higher at 30 minutes (mean difference, 1.6, 95% CI 0.3, 2.8 mg/dl) and 120 minutes (mean difference, 0.84, 95% CI 0.2, 1.5 mg/dl) in CKD compared to controls. There were no differences in insulin levels or plasma DPP-4 activity or levels between groups. Conclusion: Incretin response to oral glucose is preserved or augmented in moderate-severe CKD, without apparent differences in circulating DPP-4 concentration or activity. However, neither insulin secretion nor glucagon suppression are enhanced.

Randomized crossover clinical trial of coenzyme Q10 and nicotinamide riboside in chronic kidney disease.

BackgroundCurrent studies suggest mitochondrial dysfunction is a major contributor to impaired physical performance and exercise intolerance in chronic kidney disease (CKD). We conducted a clinical trial of coenzyme Q10 (CoQ10) and nicotinamide riboside (NR) to determine their impact on exercise tolerance and metabolic profile in patients with CKD.MethodsWe conducted a randomized, placebo-controlled, double-blind, crossover trial comparing CoQ10, NR, and placebo in 25 patients with an estimated glomerular filtration rate (eGFR) of less than 60mL/min/1.73 m2. Participants received NR (1,000 mg/day), CoQ10 (1,200 mg/day), or placebo for 6 weeks each. The primary outcomes were aerobic capacity measured by peak rate of oxygen consumption (VO2 peak) and work efficiency measured using graded cycle ergometry testing. We performed semitargeted plasma metabolomics and lipidomics.ResultsParticipant mean age was 61.0 ± 11.6 years and mean eGFR was 36.9 ± 9.2 mL/min/1.73 m2. Compared with placebo, we found no differences in VO2 peak (P = 0.30, 0.17), total work (P = 0.47, 0.77), and total work efficiency (P = 0.46, 0.55) after NR or CoQ10 supplementation. NR decreased submaximal VO2 at 30 W (P = 0.03) and VO2 at 60 W (P = 0.07) compared with placebo. No changes in eGFR were observed after NR or CoQ10 treatment (P = 0.14, 0.88). CoQ10 increased free fatty acids and decreased complex medium- and long-chain triglycerides. NR supplementation significantly altered TCA cycle intermediates and glutamate that were involved in reactions that exclusively use NAD+ and NADP+ as cofactors. NR decreased a broad range of lipid groups including triglycerides and ceramides.ConclusionsSix weeks of treatment with NR or CoQ10 improved markers of systemic mitochondrial metabolism and lipid profiles but did not improve VO2 peak or total work efficiency.Trial registrationClinicalTrials.gov NCT03579693.FundingNational Institutes of Diabetes and Digestive and Kidney Diseases (grants R01 DK101509, R03 DK114502, R01 DK125794, and R01 DK101509).

A prospective study of frailty in nephrology-referred patients with CKD.

BACKGROUND: Frailty is a construct developed to characterize a state of reduced functional capacity in older adults. However, there are limited data describing the prevalence or consequences of frailty in middle-aged patients with chronic kidney disease (CKD). STUDY DESIGN: Observational study. SETTING & PARTICIPANTS: 336 non-dialysis-dependent patients with stages 1-4 CKD with estimated glomerular filtration rate (eGFR) <90 mL/min/1.73 m(2) (by the CKD-EPI [CKD Epidemiology Collaboration] serum creatinine-based equation) or evidence of microalbuminuria enrolled in the Seattle Kidney Study, a clinic-based cohort study. Findings were compared with community-dwelling older adults in the Cardiovascular Health Study. OUTCOME: Prevalence and determinants of frailty in addition to its association with the combined outcome of all-cause mortality or renal replacement therapy. MEASUREMENTS: We defined frailty according to established criteria as 3 or more of the following characteristics: slow gait, weakness, unintentional weight loss, exhaustion, and low physical activity. We estimated kidney function using serum cystatin C concentrations (eGFR(cys)) to minimize confounding due to relationships of serum creatinine levels with muscle mass and frailty. RESULTS: The mean age of the study population was 59 years and mean eGFR(cys) was 51 mL/min/1.73 m(2). The prevalence of frailty (14.0%) was twice that of the much older non-CKD reference population (P < 0.01). The most common frailty components were physical inactivity and exhaustion. After adjustment including diabetes, eGFR(cys) categories of <30 and 30-44 mL/min/1.73 m(2) were associated with a 2.8- (95% CI, 1.3-6.3) and 2.1 (95% CI, 1.0-4.7)-fold greater prevalence of frailty compared with GFR(cys) ≥60 mL/min/1.73 m(2). There were 63 events during a median 987 days of follow-up. After adjustment, the frailty phenotype was associated with an estimated 2.5 (95% CI, 1.4-4.4)-fold greater risk of death or dialysis therapy. LIMITATIONS: Cross-sectional study design obscures inference regarding temporal relationships between CKD and frailty. CONCLUSIONS: Frailty is relatively common in middle-aged patients with CKD and is associated with lower eGFR(cys) and increased risk of death or dialysis therapy.

GFR Estimation in Potential Living Kidney Donors: Race- and Nonrace-based Equations and Measured GFR.

Rationale & Objective: Recent studies evaluated and proposed new race-neutral, creatinine-based glomerular filtration rate (GFR) estimation equations. The performance of these equations in diverse potential living kidney donors requires study. Study Design: Cross-sectional study. Setting & Participants: 637 potential living kidney donors from one tertiary hospital with serum creatinine concentration measurement and GFR measurement by iohexol plasma clearance between October 2016 and December 2020. Exposure: Creatinine-based estimation of GFR by Chronic Kidney Disease Epidemiology Collaboration (2009, CKDEPI09; 2021, CKDEPI21) and Modification of Diet in Renal Disease equations with and without inclusion of race coefficient, where applicable. Outcomes: Equation bias, precision, accuracy, and accurate classification of GFR as equal to and above or below 80 mL/min/1.73 m2. Analytical Approach: GFR estimation equation performance compared to measured GFR (mGFR) by iohexol clearance. Results: The median bias of the CKDEPI21 equation underestimated mGFR by 2.8 mL/min/1.73 m2. The bias in the Black subgroup underestimated mGFR by 9.0 mL/min/1.73 m2. Compared to CKDEPI09 with and without race adjustment, the accuracy of CKDEPI21 increased across all subgroups. On average, 3.9% of individuals were misclassified by CKDEPI21 as having a GFR greater than, and 8.9% misclassified less than, 80 mL/min/1.73 m2, compared to 3.1% and 13.2% for CKDEPI09 with race adjustment, respectively. Total misclassification (either above or below 80 mL/min/1.73 m2) was 16.3% for CKDEPI21 and 16.0% for CKDEPI09 (with race adjustment). Limitations: Limited sample of individuals identifying as Black. Lack of cystatin C data. Conclusions: In our potential living donor sample, GFR estimation by creatinine-based CKDEPI21 is less biased and more accurate than previous creatinine-based estimated GFR equations. When evaluated by race, this summative improvement remains in individuals identifying as Asian, Hispanic, or White. More external validation is needed to assess whether the new equation is an improvement over the previous CKDEPI equation with a race coefficient.