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Rationale & Objective: Hemoglobin A 1c (HbA 1c ) is widely used to estimate glycemia, yet it is less reliable in patients with chronic kidney disease (CKD). There is growing interest in the complementary use of glycated albumin (GA) to improve glycemic monitoring and risk stratification. However, whether GA associates with clinical outcomes in a non-dialysis-dependent CKD population remains unknown., Study Design: Prospective cohort study., Setting & Participants: 3,110 participants with CKD from the Chronic Renal Insufficiency Cohort study., Exposure: Baseline GA levels., Outcome: Incident end-stage kidney disease (ESKD), cardiovascular disease (CVD) events, and all-cause mortality., Analytical Approach: Cox proportional hazards regression., Results: Participant characteristics included mean age 59.0±10.8 SD years; 1,357 (43.6%) female; and 1,550 (49.8%) with diabetes. The median GA was 18.7% (IQR, 15.8%-23.3%). During an average 7.9-year follow-up, there were 980 ESKD events, 968 CVD events, and 1,084 deaths. Higher GA levels were associated with greater risks of all outcomes, regardless of diabetes status: hazard ratios for ESKD, CVD, and death among participants with the highest quartile compared with quartile 2 (reference) were 1.42 (95% CI, 1.19-1.69), 1.67 (95% CI, 1.39-2.01), and 1.63 (95% CI, 1.37-1.94), respectively. The associations with CVD and death appeared J-shaped, with increased risk also seen at the lowest GA levels. Among patients with coexisting CKD and diabetes, the associations of GA with outcomes remained significant even after adjusting for HbA 1c . For each outcome, we observed a significant increase in the fraction of new prognostic information when both GA and HbA 1c were added to models., Limitations: Lack of longitudinal GA measurements; and HbA 1c measurements were largely unavailable in participants without diabetes., Conclusions: Among patients with CKD, GA levels were independently associated with risks of ESKD, CVD, and mortality, regardless of diabetes status. GA added prognostic value to HbA 1c among patients with coexisting CKD and diabetes., Plain-Language Summary: Hemoglobin A 1c (HbA 1c ) is widely used to estimate glycemia, yet it is less reliable in patients with chronic kidney disease (CKD). There is growing interest in the complementary use of glycated albumin (GA) to improve glycemic monitoring and risk stratification. However, whether GA associates with clinical outcomes in a non-dialysis-dependent CKD population remains unknown. In this cohort study of 3,110 individuals with non-dialysis-dependent CKD, GA levels were independently associated with risks of end-stage kidney disease, cardiovascular disease (CVD), and mortality. The associations with CVD and mortality appeared to be J-shaped. Among patients with coexisting CKD and diabetes, GA added prognostic value to HbA 1c. Thus, GA may be a valuable complementary test to HbA 1c in patients with CKD., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Patients with chronic kidney disease (CKD) are at an increased cardiovascular risk compared with the general population, which is driven, at least in part, by mechanisms that are uniquely associated with kidney disease. In CKD, increased levels of oxidative stress and uraemic retention solutes, including urea and advanced glycation end products, enhance non-enzymatic post-translational modification events, such as protein oxidation, glycation, carbamylation and guanidinylation. Alterations in enzymatic post-translational modifications such as glycosylation, ubiquitination, acetylation and methylation are also detected in CKD. Post-translational modifications can alter the structure and function of proteins and lipoprotein particles, thereby affecting cellular processes. In CKD, evidence suggests that post-translationally modified proteins can contribute to inflammation, oxidative stress and fibrosis, and induce vascular damage or prothrombotic effects, which might contribute to CKD progression and/or increase cardiovascular risk in patients with CKD. Consequently, post-translational protein modifications prevalent in CKD might be useful as diagnostic biomarkers and indicators of disease activity that could be used to guide and evaluate therapeutic interventions, in addition to providing potential novel therapeutic targets., (© 2024. Springer Nature Limited.)

Rationale & Objective: The toxins that contribute to uremic symptoms in patients with chronic kidney disease (CKD) are unknown. We sought to apply complementary statistical modeling approaches to data from untargeted plasma metabolomic profiling to identify solutes associated with uremic symptoms in patients with CKD., Study Design: Cross-sectional., Setting & Participants: 1,761 Chronic Renal Insufficiency Cohort (CRIC) participants with CKD not treated with dialysis., Predictors: Measurement of 448 known plasma metabolites., Outcomes: The uremic symptoms of fatigue, anorexia, pruritus, nausea, paresthesia, and pain were assessed by single items on the Kidney Disease Quality of Life-36 instrument., Analytical Approach: Multivariable adjusted linear regression, least absolute shrinkage and selection operator linear regression, and random forest models were used to identify metabolites associated with symptom severity. After adjustment for multiple comparisons, metabolites selected in at least 2 of the 3 modeling approaches were deemed "overall significant.", Results: Participant mean estimated glomerular filtration rate was 43mL/min/1.73m 2 , with 44% self-identifying as female and 41% as non-Hispanic Black. The prevalence of uremic symptoms ranged from 22% to 55%. We identified 17 metabolites for which a higher level was associated with greater severity of at least one uremic symptom and 9 metabolites inversely associated with uremic symptom severity. Many of these metabolites exhibited at least a moderate correlation with estimated glomerular filtration rate (Pearson's r≥0.5), and some were also associated with the risk of developing kidney failure or death in multivariable adjusted Cox regression models., Limitations: Lack of a second independent cohort for external validation of our findings., Conclusions: Metabolomic profiling was used to identify multiple solutes associated with uremic symptoms in adults with CKD, but future validation and mechanistic studies are needed., Plain-Language Summary: Individuals living with chronic kidney disease (CKD) often experience symptoms related to CKD, traditionally called uremic symptoms. It is likely that CKD results in alterations in the levels of numerous circulating substances that, in turn, cause uremic symptoms; however, the identity of these solutes is not known. In this study, we used metabolomic profiling in patients with CKD to gain insights into the pathophysiology of uremic symptoms. We identified 26 metabolites whose levels were significantly associated with at least one of the symptoms of fatigue, anorexia, itchiness, nausea, paresthesia, and pain. The results of this study lay the groundwork for future research into the biological causes of symptoms in patients with CKD., (Copyright © 2024 National Kidney Foundation, Inc. All rights reserved.)

Background: Protein carbamylation, a post-translational protein modification primarily driven by urea, independently associates with adverse clinical outcomes in patients with CKD. Biomarkers used to quantify carbamylation burden have mainly included carbamylated albumin (C-Alb) and homocitrulline (HCit, carbamylated lysine). In this study, we aimed to compare the prognostic utility of these two markers in order to facilitate comparisons of existing studies employing either marker alone, and to inform future carbamylation studies., Methods: Both serum C-Alb and free HCit levels were assayed from the same timepoint in 1632 individuals with CKD stages 2-4 enrolled in the prospective Chronic Renal Insufficiency Cohort (CRIC) study. Adjusted Cox proportional hazard models were used to assess risks for the outcomes of death (primary) and end stage kidney disease (ESKD) using each marker. C-statistics, net reclassification improvement, and integrated discrimination improvement were used to compare the prognostic value of each marker., Results: Participant demographics included mean (SD) age 59 (11) years; 702 (43%) females; 700 (43%) white. C-Alb and HCit levels were positively correlated with one another (Pearson correlation coefficient 0.64). Higher C-Alb and HCit levels showed similar increased risk of death (e.g., the adjusted hazard ratio [HR] for death in the 4th carbamylation quartile compared to the 1st was 1.90 (95% confidence interval [CI] 1.35-2.66) for C-Alb, and 1.89 [1.27-2.81] for HCit; and on a continuous scale, the adjusted HR for death using C-Alb was 1.24 [1.11 to 1.39] per standard deviation increase, and 1.27 [1.10-1.46] using HCit). Both biomarkers also had similar HRs for ESKD. The C-statistics were similar when adding each carbamylation biomarker to base models (e.g., for mortality models, the C-statistic was 0.725 [0.707-0.743] with C-Alb and 0.725 [0.707-0.743] with HCit, both compared to a base model 0.723). Similarities were also observed for the net reclassification improvement and integrated discrimination improvement metrics., Conclusions: C-Alb and HCit had similar performance across multiple prognostic assessments. The markers appear readily comparable in CKD epidemiological studies., (© 2024. The Author(s).)

Significance Statement: Protein carbamylation, a nonenzymatic post-translational protein modification partially driven by elevated blood urea levels, associates with mortality and adverse outcomes in patients with ESKD on dialysis. However, little is known about carbamylation's relationship to clinical outcomes in the much larger population of patients with earlier stages of CKD. In this prospective observational cohort study of 3111 individuals with CKD stages 2-4, higher levels of carbamylated albumin (a marker of protein carbamylation burden) were associated with a greater risk of developing ESKD and other significant adverse clinical outcomes. These findings indicate that protein carbamylation is an independent risk factor for CKD progression. They suggest that further study of therapeutic interventions to prevent or reduce carbamylation is warranted., Background: Protein carbamylation, a post-translational protein modification partially driven by elevated blood urea levels, associates with adverse outcomes in ESKD. However, little is known about protein carbamylation's relationship to clinical outcomes in the much larger population of patients with earlier stages of CKD., Methods: To test associations between protein carbamylation and the primary outcome of progression to ESKD, we measured baseline serum carbamylated albumin (C-Alb) in 3111 patients with CKD stages 2-4 enrolled in the prospective observational Chronic Renal Insufficiency Cohort study., Results: The mean age of study participants was 59 years (SD 10.8); 1358 (43.7%) were female, and 1334 (42.9%) were White. The mean eGFR at the time of C-Alb assessment was 41.8 (16.4) ml/minute per 1.73 m 2 , and the median C-Alb value was 7.8 mmol/mol (interquartile range, 5.8-10.7). During an average of 7.9 (4.1) years of follow-up, 981 (31.5%) individuals developed ESKD. In multivariable adjusted Cox models, higher C-Alb (continuous or quartiles) independently associated with an increased risk of ESKD. For example, compared with quartile 1 (C-Alb ≤5.80 mmol/mol), those in quartile 4 (C-Alb >10.71 mmol/mol) had a greater risk for ESKD (adjusted hazard ratio, 2.29; 95% confidence interval, 1.75 to 2.99), and the ESKD incidence rate per 1000 patient-years increased from 15.7 to 88.5 from quartile 1 to quartile 4. The results remained significant across numerous subgroup analyses, when treating death as a competing event, and using different assessments of eGFR., Conclusions: Having a higher level of protein carbamylation as measured by circulating C-Alb is an independent risk factor for ESKD in individuals with CKD stages 2-4., Podcast: This article contains a podcast at https://dts.podtrac.com/redirect.mp3/www.asn-online.org/media/podcast/JASN/2023_04_24_JSN_URE_EP22_042423.mp3., (Copyright © 2023 by the American Society of Nephrology.)

Importance: Calciphylaxis is a rare disease with high mortality mainly involving patients with chronic kidney disease (CKD). Sodium thiosulphate (STS) has been used as an off-label therapeutic in calciphylaxis, but there is a lack of clinical trials and studies that demonstrate its effect compared with those without STS treatment., Objective: To perform a meta-analysis of the cohort studies that provided data comparing outcomes among patients with calciphylaxis treated with and without intravenous STS., Data Sources: PubMed, Embase, Cochrane Library, Web of Science, and ClinicalTrials.gov were searched using relevant terms and synonyms including sodium thiosulphate and calci* without language restriction., Study Selection: The initial search was for cohort studies published before August 31, 2021, that included adult patients diagnosed with CKD experiencing calciphylaxis and could provide a comparison between patients treated with and without intravenous STS. Studies were excluded if they reported outcomes only from nonintravenous administration of STS or if the outcomes for CKD patients were not provided., Data Extraction and Synthesis: Random-effects models were performed. The Egger test was used to measure publication bias. Heterogeneity was assessed using the I2 test., Main Outcomes and Measures: Skin lesion improvement and survival, synthesized as ratio data by a random-effects empirical Bayes model., Results: Among the 5601 publications retrieved from the targeted databases, 19 retrospective cohort studies including 422 patients (mean age, 57 years; 37.3% male) met the eligibility criteria. No difference was observed in skin lesion improvement (12 studies with 110 patients; risk ratio, 1.23; 95% CI, 0.85-1.78) between the STS and the comparator groups. No difference was noted for the risk of death (15 studies with 158 patients; risk ratio, 0.88; 95% CI, 0.70-1.10) and overall survival using time-to-event data (3 studies with 269 participants; hazard ratio, 0.82; 95% CI, 0.57-1.18). In meta-regression, lesion improvement associated with STS negatively correlated with publication year, implying that recent studies are more likely to report a null association compared with past studies (coefficient = -0.14; P = .008)., Conclusions and Relevance: Intravenous STS was not associated with skin lesion improvement or survival benefit in patients with CKD experiencing calciphylaxis. Future investigations are warranted to examine the efficacy and safety of therapies for patients with calciphylaxis.

Background: Vascular calcification (VC) is a common comorbidity among patients with chronic kidney disease (CKD), indicating major cardiovascular events. This study aimed to evaluate the effects and safety of intravenous sodium thiosulphate (STS) for VC in CKD patients., Methods: Electronic databases were searched for clinical trials that provided data comparing outcomes among patients treated with and without STS. The PRISMA guidelines were followed. Efficacy was assessed using calcification scores and arterial stiffness. Safety was examined by analyzing adverse symptoms, electrolytes and bone mineral density (BMD). Random-effects models were performed. Meta-regression and sensitivity analysis were done. The risk of bias was assessed using the Cochrane tools., Results: Among the 5601 publications, 6 studies involving 305 participants (mean age: 56 years, male: 56.6%) with all participants on maintenance hemodialysis met eligibility criteria. For efficacy, the progression in Agatston scores in the coronary arteries [107 patients, mean difference (MD): -241.27, 95% confidence interval (95% CI): -421.50 to -61.03] and iliac arteries (55 patients, MD: -382.00, 95% CI: -751.07 to -12.93) was lower in the STS treated group compared with controls. The increase in pulse wave velocity was lower in the STS group (104 patients, MD: -1.29 m/s, 95% CI: -2.24 to -0.34 m/s). No association was found between the change in calcification scores and STS regimen. For safety, gastrointestinal symptoms (e.g. nausea) and increased anion gap acidosis were noted. No reduction in BMD by STS was observed., Conclusions: Intravenous STS may attenuate the progression of VC and arterial stiffness in hemodialysis patients. Large and well-designed randomized controlled trials are warranted., (© The Author(s) 2022. Published by Oxford University Press on behalf of the ERA.)

Background: Pruritus is a common symptom experienced by patients with nondialysis CKD, but risk factors for incident pruritus in this patient population have not been evaluated., Methods: We identified 1951 participants with CKD in the Chronic Renal Insufficiency Cohort Study without pruritus at the baseline assessment. Pruritus was assessed by the Kidney Disease Quality of Life-36 (KDQOL-36) instrument, and moderate-to-severe pruritus was defined as a response of 3 or higher on a Likert scale of 1-5. We used time-updated multivariable joint models to evaluate the association of patient clinical characteristics, eGFR, and laboratory parameters with incident pruritus., Results: Over a median follow-up of 6 years, 660 (34%) participants developed incident moderate-to-severe pruritus, with a higher incidence rate observed among participants with more advanced CKD. In multivariable models, the hazard ratio (95% confidence interval [CI]) for pruritus associated with a 10 ml/min per 1.73 m 2 lower eGFR was 1.16 (95% CI, 1.10 to 1.23). Older age (≥65 years), higher body mass index, diabetes, current smoking, opioid use, depressive symptoms, and serum parathyroid hormone were also associated with a higher risk of incident pruritus, whereas low serum calcium (<9 mg/dl) was associated with a lower risk (all P <0.05). Serum phosphate was not associated with incident pruritus in the primary analysis., Conclusions: A substantial proportion of patients with nondialysis CKD develop moderate-to-severe pruritus. Although lower eGFR is associated with the risk of pruritus, other comorbidities, particularly depressive symptoms, were potential risk factors., Podcast: This article contains a podcast at https://www.asn-online.org/media/podcast/CJASN/2023&#95;02&#95;08&#95;CJN09480822.mp3., (Copyright © 2022 by the American Society of Nephrology.)

Objective: Glycated hemoglobin (HbA1c) can predict risk for microvascular complications in patients with diabetes. However, HbA1c's reliability in chronic kidney disease (CKD) has been questioned, with concerns including competition from another posttranslational protein modification, carbamylation, acting on the same amino groups as glycation, and anemia with reduced erythrocyte lifespans leading to altered glycation accumulation. We investigated whether carbamylation and anemia modify the impact of HbA1c on renal outcomes in patients with diabetes and CKD., Research Design and Methods: In 1,516 participants from the Chronic Renal Insufficiency Cohort study with diabetes and CKD, Cox regression models were applied to evaluate the association between HbA1c and CKD progression (composite of end-stage kidney disease or 50% decline in estimated glomerular filtration rate [eGFR]), stratified by carbamylated albumin (C-Alb) quartiles and anemia., Results: The mean eGFR was 38.1 mL/min/1.73 m2, mean HbA1c was 7.5% (58 mmol/mol), and median C-Alb was 8.4 mmol/mol. HbA1c was lower in the higher C-Alb quartiles. During a median follow-up of 6.9 years, 763 participants experienced CKD progression. Overall, higher HbA1c was associated with an increased risk of CKD progression (adjusted hazard ratio 1.07 [95% CI 1.02-1.13]). However, using stratified analyses, HbA1c was no longer associated with CKD progression in the highest C-Alb quartile, but did show a monotonic increase in CKD progression risk across each lower C-Alb quartile (P-interaction = 0.022). Anemia also modified the association between HbA1c and CKD progression (P-interaction = 0.025)., Conclusions: In patients with coexisting diabetes and CKD, the association between HbA1c and CKD progression is modified by carbamylation and anemia., (© 2022 by the American Diabetes Association.)

BACKGROUNDMetabolomic profiling in individuals with chronic kidney disease (CKD) has the potential to identify novel biomarkers and provide insight into disease pathogenesis.METHODSWe examined the association between blood metabolites and CKD progression, defined as the subsequent development of end-stage renal disease (ESRD) or estimated glomerular filtrate rate (eGFR) halving, in 1,773 participants of the Chronic Renal Insufficiency Cohort (CRIC) study, 962 participants of the African-American Study of Kidney Disease and Hypertension (AASK), and 5,305 participants of the Atherosclerosis Risk in Communities (ARIC) study.RESULTSIn CRIC, more than half of the measured metabolites were associated with CKD progression in minimally adjusted Cox proportional hazards models, but the number and strength of associations were markedly attenuated by serial adjustment for covariates, particularly eGFR. Ten metabolites were significantly associated with CKD progression in fully adjusted models in CRIC; 3 of these metabolites were also significant in fully adjusted models in AASK and ARIC, highlighting potential markers of glomerular filtration (pseudouridine), histamine metabolism (methylimidazoleacetate), and azotemia (homocitrulline). Our findings also highlight N-acetylserine as a potential marker of kidney tubular function, with significant associations with CKD progression observed in CRIC and ARIC.CONCLUSIONOur findings demonstrate the application of metabolomics to identify potential biomarkers and causal pathways in CKD progression.FUNDINGThis study was supported by the NIH (U01 DK106981, U01 DK106982, U01 DK085689, R01 DK108803, and R01 DK124399).

Non-enzymatic post-translational modifications (nPTMs) of proteins have emerged as novel risk factors for the genesis and progression of various diseases. We now have a variety of experimental and established therapeutic strategies to target harmful nPTMs and potentially improve clinical outcomes. Protein carbamylation and glycation are two common and representative nPTMs that have gained considerable attention lately as favorable therapeutic targets with emerging clinical evidence. Protein carbamylation is associated with the occurrence of cardiovascular disease (CVD) and mortality in patients with chronic kidney disease (CKD); and advanced glycation end products (AGEs), a heterogeneous group of molecules produced in a series of glycation reactions, have been linked to various diabetic complications. Therefore, reducing the burden of protein carbamylation and AGEs is an appealing and promising therapeutic approach. This review chapter summarizes potential anti-nPTM therapy options in CKD, CVD, and diabetes along with clinical implications. Using two prime examples-protein carbamylation and AGEs-we discuss the varied preventative and therapeutic options to mitigate these pathologic nPTMs in detail. We provide in-depth case studies on carbamylation in the setting of kidney disease and AGEs in metabolic disorders, with an emphasis on the relevance to reducing adverse clinical outcomes such as CKD progression, cardiovascular events, and mortality. Overall, whether specific efforts to lower carbamylation and AGE burden will yield definitive clinical improvement in humans remains largely to be seen. However, the scientific rationale for such pursuits is demonstrated herein., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Background: Fibroblast growth factor 23 (FGF23) is a bone-derived phosphatonin that is elevated in chronic kidney disease (CKD) and has been implicated in the development of cardiovascular disease. It is unknown whether elevated FGF23 in CKD is associated with impaired cardiovascular functional capacity, as assessed by maximum exercise oxygen consumption (VO 2 Max). We sought to determine whether FGF23 is associated with cardiovascular functional capacity in patients with advanced CKD and after improvement of VO 2 Max by kidney transplantation., Methods: We performed secondary analysis of 235 patients from the Cardiopulmonary Exercise Testing in Renal Failure and After Kidney Transplantation (CAPER) cohort, which recruited patients with stage 5 CKD who underwent kidney transplantation or were waitlisted and hypertensive controls. All patients underwent cardiopulmonary exercise testing (CPET) and echocardiography and were followed longitudinally for 1 year after study enrollment., Results: Patients across FGF23 quartiles differed in BMI ( P =0.004) and mean arterial pressure ( P <0.001) but did not significantly differ in sex ( P =0.5) or age ( P =0.08) compared with patients with lower levels of FGF23. Patients with higher FGF23 levels had impaired VO 2 Max (Q1: 24.2±4.8 ml/min per kilogram; Q4: 18.6±5.2 ml/min per kilogram; P <0.001), greater left ventricular mass index (LVMI; P <0.001), reduced HR at peak exercise ( P <0.001), and maximal workload ( P <0.001). Kidney transplantation conferred a significant decline in FGF23 at 2 months ( P <0.001) before improvement in VO 2 Max at 1 year ( P =0.008). Multivariable regression modeling revealed that changes in FGF23 was significantly associated with VO 2 Max in advanced CKD ( P <0.001) and after improvement after kidney transplantation ( P =0.006). FGF23 was associated with LVMI before kidney transplantation ( P =0.003), however this association was lost after adjustment for dialysis status ( P =0.4). FGF23 was not associated with LVMI after kidney transplantation in all models., Conclusions: FGF23 levels are associated with alterations in cardiovascular functional capacity in advanced CKD and after kidney transplantation. FGF23 is only associated with structural cardiac adaptations in advanced CKD but this was modified by dialysis status, and was not associated after kidney transplantation., Competing Interests: A. Halim reports ownership interest in OVIBIO Corp. T.F. Hiemstra reports being an employee of GlaxoSmithKline; ownership interest in GlaxoSmithKline, Kodika Corp., and OVIBIO Corp.; research funding from UNION Therapeutics; and an advisory or leadership role for the International Clinical Trial Centre Network (SAB member) and the PHOSPHATE Trial (steering board member). S. Kalim reports participation in a speakers’ bureau for Fresenius Kabi. X. Li reports an advisory or leadership role for Health Services and Outcomes Research Methodology (member of editorial board 2014–present) and Circulation: Cardiovascular Quality and Outcomes (associated statistical editor 2016–present). K. Lim reports consultancy for Ambassadors Corp., MBX Biosciences, and OVIBIO Corp.; ownership interest in Ambassadors Corp., MBX Biosciences, and OVIBIO Corp.; and an advisory or leadership role for Ambassadors Corp. T. Lu reports consultancy for OVIBIO Corp. and ownership interest in OVIBIO Corp. S. Moe reports consultancy for Amgen, Ardelyx, and Sanifit; ownership interest in Eli Lilly (stock); research funding from Chugai (research grant), Keryx (research grant), and the National Institutes of Health (research grant); honoraria from Amgen, Ardelyx, and Sanifit; and an advisory or leadership role for the American Journal of Nephrology and the American Journal of Nutrition (editorial board). A.M. Siedlecki reports research funding from Alexion, and an advisory or leadership role for Alexion. R. Thadhani reports consultancy for Alnylum, Bayer, the US Food and Drug Administration, Fresenius Medical Care North America, Kaneka, and Thermo Fisher Scientific; ownership interest in Aggamin LLC, Comanche Pharma, Hero Health, and Tvardi; research funding from Thermo Fisher Scientific; honoraria from Alnylum, Bayer, and Thermo Fisher Scientific; patents or royalties from Gravidas Diagnostics, Thermo Fisher Scientific, and UpToDate; and an advisory or leadership role for Aggamin LLC and Vifor Pharma. D. Zehnder reports research funding for Abbott Laboratories and Amgen, and honoraria from Abbott Laboratories and Amgen. All remaining authors have nothing to disclose., (Copyright © 2022 by the American Society of Nephrology.)

Background and Objectives: Uremic symptoms, including fatigue, anorexia, pruritus, nausea, paresthesia, and pain, are attributed to the accumulation of organic waste products normally cleared by the kidneys, but whether kidney function is the primary driver of changes in symptom severity over time is not known. The goal of our study was to evaluate the association between eGFR and uremic symptom severity score in patients with CKD., Design, Setting, Participants, and Measurements: We identified 3685 participants with CKD not on dialysis in the prospective, observational Chronic Renal Insufficiency Cohort (CRIC) Study with baseline assessment of eGFR and uremic symptom severity. Symptoms were assessed by separate questions on the Kidney Disease Quality of Life-36 instrument (zero- to 100-point scale). The longitudinal association between eGFR and uremic symptom severity score was examined with multivariable adjusted linear mixed-effects models with random intercepts and random slopes., Results: The mean±SD eGFR at baseline was 44±15 ml/min per 1.73 m 2 , and participants had a median of six (interquartile range 3-11) simultaneous assessments of eGFR and uremic symptoms over the duration of follow-up. The most prevalent symptoms at baseline were pain (57%), fatigue (52%), paresthesia (45%), and pruritus (42%). In adjusted models, a decrease in eGFR of 5 ml/min per 1.73 m 2 was associated with a worsening of the symptom severity score by two points or less for each uremic symptom ( P <0.01; zero- to 100-point scale). The association between eGFR and uremic symptom severity score was nonlinear. When starting from a lower initial eGFR, a 5 ml/min per 1.73 m 2 decrease in eGFR was associated with a greater magnitude of uremic symptom worsening., Conclusions: The prevalence of uremic symptoms in CKD is high, with significant variability in patient symptom change over time. Declines in eGFR were associated with worsening of uremic symptom severity, but the magnitude of these changes is small and of uncertain clinical significance., (Copyright © 2022 by the American Society of Nephrology.)

Background The myocardial cytoskeleton functions as the fundamental framework critical for organelle function, bioenergetics and myocardial remodeling. To date, impairment of the myocardial cytoskeleton occurring in the failing heart in patients with advanced chronic kidney disease has been largely undescribed. Methods and Results We conducted a 3-arm cross-sectional cohort study of explanted human heart tissues from patients who are dependent on hemodialysis (n=19), hypertension (n=10) with preserved renal function, and healthy controls (n=21). Left ventricular tissues were subjected to pathologic examination and next-generation RNA sequencing. Mechanistic and interference RNA studies utilizing in vitro human cardiac fibroblast models were performed. Left ventricular tissues from patients undergoing hemodialysis exhibited increased myocardial wall thickness and significantly greater fibrosis compared with hypertension patients ( P <0.05) and control ( P <0.01). Transcriptomic analysis revealed that the focal adhesion pathway was significantly enriched in hearts from patients undergoing hemodialysis. Hearts from patients undergoing hemodialysis exhibited dysregulated components of the focal adhesion pathway including reduced β-actin ( P <0.01), β-tubulin ( P <0.01), vimentin ( P <0.05), and increased expression of vinculin ( P <0.05) compared with controls. Cytoskeletal adaptations in hearts from the hemodialysis group were associated with impaired mitochondrial bioenergetics, including dysregulated mitochondrial dynamics and fusion, and loss of cell survival pathways. Mechanistic studies revealed that cytoskeletal changes can be driven by uremic and metabolic abnormalities of chronic kidney disease, in vitro. Furthermore, focal adhesion kinase silencing via interference RNA suppressed major cytoskeletal proteins synergistically with mineral stressors found in chronic kidney disease in vitro. Conclusions Myocardial failure in advanced chronic kidney disease is characterized by impairment of the cytoskeleton involving disruption of the focal adhesion pathway, mitochondrial failure, and loss of cell survival pathways.

Background: Olfactory and gustatory changes may contribute to poor appetite and food aversion in chronic kidney disease (CKD), though the prevalence of olfactory and gustatory dysfunction is not known in the CKD population., Methods: We conducted a cross-sectional study among 3527 US adults aged ≥40 years old in the National Health and Nutrition Examination Survey (NHANES) between 2013 and 2014. We measured the prevalence of olfactory and gustatory dysfunction among patients with CKD defined as eGFR < 60 ml/min/1.73m 2 using the "scratch and sniff" NHANES Pocket Smell Test and quinine whole-mouth test. We also examined the association between CKD and olfactory/gustatory dysfunction, and nutritional markers., Results: The prevalence of olfactory dysfunction was 30% among CKD and 15% among non-CKD (p < 0.001). The prevalence of gustatory dysfunction was 13% among CKD and 17% among non-CKD (p = 0.10). After adjusting for confounders, CKD was significantly associated with olfactory dysfunction (OR = 1.47, 95% CI [1.07, 2.01]; p = 0.02) but not gustatory dysfunction (OR = 1.76, 95%CI [0.99, 3.11]; p = 0.05). Among the CKD population, the odds of olfactory dysfunction was 72% higher for every 10 kg decrease in grip strength (OR = 1.72, 95% CI [1.39, 2.13]; adjusted p = 0.005)., Conclusion: CKD was associated with higher odds of olfactory but not gustatory dysfunction. Olfactory dysfunction was associated with lower grip strength among those with CKD. Screening and early intervening on olfactory dysfunction among CKD may preserve muscle strength and improve nutritional status in this vulnerable population., (© 2022. The Author(s).)

Background: Protein carbamylation is a post-translational protein modification caused, in part, by exposure to urea's dissociation product cyanate. Carbamylation is linked to cardiovascular outcomes and mortality in dialysis-dependent end-stage kidney disease (ESKD), but its effects in earlier pre-dialysis stages of chronic kidney disease (CKD) are not established., Methods: We conducted two nested case-control studies within the Chronic Renal Insufficiency Cohort Study. First, we matched 75 cases demonstrating CKD progression [50% estimated glomerular filtration rate (eGFR) reduction or reaching ESKD] to 75 controls (matched on baseline eGFR, 24-h proteinuria, age, sex and race). In the second study, we similarly matched 75 subjects who died during follow-up (cases) to 75 surviving controls. Baseline carbamylated albumin levels (C-Alb, a validated carbamylation assay) were compared between cases and controls in each study., Results: At baseline, in the CKD progression study, other than blood urea nitrogen (BUN) and smoking status, there were no significant differences in any matched or other parameter. In the mortality group, the only baseline difference was smoking status. Adjusting for baseline differences, the top tertile of C-Alb was associated with an increased risk of CKD progression [odds ratio (OR) = 7.9; 95% confidence interval (CI) 1.9-32.8; P = 0.004] and mortality (OR = 3.4; 95% CI 1.0-11.4; P = 0.05) when compared with the bottom tertile. C-Alb correlated with eGFR but was more strongly correlated with BUN., Conclusions: Our data suggest that protein carbamylation is a predictor of CKD progression, beyond traditional risks including eGFR and proteinuria. Carbamylation's association with mortality was smaller in this limited sample size., (© The Author(s) 2020. Published by Oxford University Press on behalf of ERA-EDTA. All rights reserved.)

Background: Chronic prolonged hyponatremia (CPH) is a risk factor for hip fracture in the general population. Whether CPH increases hip fracture risk in chronic kidney disease (CKD) patients is unknown., Methods: Case-control study in patients over 60 years of age with stage 3 or greater CKD. Patients who had a hip fracture were referred to as cases (n = 1236) and controls had no hip fracture (n = 4515). Patients were classified as having CPH if serum sodium was <135 mEq/L on at least two occasions separated by a minimum of 90 days prior to the diagnosis of hip fracture (cases) or at any time during the study period (controls). Conditional logistic regression models were used to test the association between CPH and hip fracture. Analyses were conducted for patients with and without osteoporosis and falls and for patients with age >70 years versus ≤70 years., Results: CPH was present in 21% of cases and 10% of controls (p < 0.001; sodium level: 131-134 mEq/L). In univariate logistic regression analysis, CPH was associated with higher odds of hip fracture (odds ratio [OR] 2.44, (95% [CI] 2.07-2.89). In a multivariate model adjusted for comorbidities, medications and laboratory parameters CPH association with higher odds of Hip fracture was attenuated but remained significant (OR 1.36, 95% CI 1.04-1.78). The association between CPH and risk of hip fracture was consistent in patients with or without osteoporosis and falls and across the age strata., Conclusion: Chronic prolonged hyponatremia is a risk factor for hip fracture in CKD patients older than 60 years of age., (Copyright © 2019. Published by Elsevier Inc.)

Background and Objectives: The association between gut dysbiosis, high intestinal permeability, and endotoxemia-mediated inflammation is well established in CKD. However, changes in the circulating microbiome in patients with CKD have not been studied. In this pilot study, we compare the blood microbiome profile between patients with CKD and healthy controls using 16S ribosomal DNA sequencing., Design, Setting, Participants, & Measurements: Blood bacterial DNA was studied in buffy coat samples quantitatively by 16S PCR and qualitatively by 16S targeted metagenomic sequencing using a molecular pipeline specifically optimized for blood samples in a cross-sectional study comparing 20 nondiabetic patients with CKD and 20 healthy controls., Results: There were 22 operational taxonomic units significantly different between the two groups. 16S metagenomic sequencing revealed a significant reduction in α diversity (Chao1 index) in the CKD group compared with healthy controls (127±18 versus 145±31; P =0.04). Proteobacteria phylum, Gammaproteobacteria class, and Enterobacteriaceae and Pseudomonadaceae families were more abundant in the CKD group compared with healthy controls. Median 16S ribosomal DNA levels did not significantly differ between CKD and healthy groups (117 versus 122 copies/ng DNA; P =0.38). GFR correlated inversely with the proportion of Proteobacteria ( r =-0.54; P ≤0.01)., Conclusions: Our pilot study demonstrates qualitative differences in the circulating microbiome profile with lower α diversity and significant taxonomic variations in the blood microbiome in patients with CKD compared with healthy controls., (Copyright © 2019 by the American Society of Nephrology.)

Background and Objectives: In-center, extended duration nocturnal hemodialysis has been associated with variable clinical benefits, but the effect of extended duration hemodialysis on many established uremic solutes and other components of the metabolome is unknown. We determined the magnitude of change in metabolite profiles for patients on extended duration nocturnal hemodialysis., Design, Setting, Participants, & Measurements: In a 52-week prospective, observational study, we followed 33 patients receiving conventional thrice weekly hemodialysis who converted to nocturnal hemodialysis (7-8 hours per session, three times per week). A separate group of 20 patients who remained on conventional hemodialysis (3-4 hours per session, three times per week) served as a control group. For both groups, we applied liquid chromatography-mass spectrometry-based metabolite profiling on stored plasma samples collected from all participants at baseline and after 1 year. We examined longitudinal changes in 164 metabolites among those who remained on conventional hemodialysis and those who converted to nocturnal hemodialysis using Wilcoxon rank sum tests adjusted for multiple comparisons (false discovery rate <0.05)., Results: On average, the nocturnal group had 9.6 hours more dialysis per week than the conventional group. Among 164 metabolites, none changed significantly from baseline to study end in the conventional group. Twenty-nine metabolites changed in the nocturnal group, 21 of which increased from baseline to study end (including all branched-chain amino acids). Eight metabolites decreased after conversion to nocturnal dialysis, including l-carnitine and acetylcarnitine. By contrast, several established uremic retention solutes, including p -cresol sulfate, indoxyl sulfate, and trimethylamine N -oxide, did not change with extended dialysis., Conclusions: Across a wide array of metabolites examined, extended duration hemodialysis was associated with modest changes in the plasma metabolome, with most differences relating to metabolite increases, despite increased dialysis time. Few metabolites showed reduction with more dialysis, and no change in several established uremic toxins was observed., (Copyright © 2018 by the American Society of Nephrology.)

Patients with CKD suffer from food aversion, anorexia, and malnutrition. Although olfaction has a significant role in determining food flavor, our understanding of olfactory impairment and of the olfaction-nutrition axis in patients with kidney disease is limited. We quantified odor identification, odor threshold, and subjective odor perception in a cohort ( n =161) comprising 36 participants with CKD, 100 participants with ESRD, and 25 controls. We investigated olfaction-nutrition associations in these participants and examined a novel intervention to improve olfaction in ESRD. The mean odor identification score was lower in patients with CKD (75.6%±13.1%; P =0.02) and ESRD (66.8%±15.1%; P <0.001) than in controls (83.6%±11.4%). Patients with ESRD exhibited higher odor threshold than the remaining participants exhibited. All groups had similar scores for subjective smell assessment. In multivariable adjusted analyses, kidney disease associated with increased odds of odor identification deficits (odds ratio, 4.80; 95% confidence interval, 1.94 to 11.89). A reduction in odor identification score was associated with higher subjective global assessment score and lower serum total cholesterol, LDL cholesterol, and albumin concentrations. We found no associations between odor threshold and nutritional parameters. In a proof of concept, 6-week, open-label clinical trial, intranasal theophylline (an epithelial membrane transport and proton secretion activator) increased odor identification score in five out of seven (71%) patients with ESRD. In conclusion, patients with kidney disease have olfactory deficits that may influence their nutritional status. Our preliminary results regarding olfactory improvement using intranasal theophylline warrant confirmation in a randomized controlled trial., (Copyright © 2017 by the American Society of Nephrology.)

The high-throughput, high-resolution phenotyping enabled by metabolomics has been applied increasingly to a variety of questions in nephrology research. This article provides an overview of current metabolomics methodologies and nomenclature, citing specific considerations in sample preparation, metabolite measurement, and data analysis that investigators should understand when examining the literature or designing a study. Furthermore, we review several notable findings that have emerged in the literature that both highlight some of the limitations of current profiling approaches, as well as outline specific strengths unique to metabolomics. More specifically, we review data on the following: (i) tryptophan metabolites and chronic kidney disease onset, illustrating the interpretation of metabolite data in the context of established biochemical pathways; (ii) trimethylamine-N-oxide and cardiovascular disease in chronic kidney disease, illustrating the integration of exogenous and endogenous inputs to the blood metabolome; and (iii) renal mitochondrial function in diabetic kidney disease and acute kidney injury, illustrating the potential for rapid translation of metabolite data for diagnostic or therapeutic aims. Finally, we review future directions, including the need to better characterize interperson and intraperson variation in the metabolome, pool existing data sets to identify the most robust signals, and capitalize on the discovery potential of emerging nontargeted methods., (Copyright © 2016 International Society of Nephrology. Published by Elsevier Inc. All rights reserved.)