Glycated Albumin and Adverse Clinical Outcomes in Patients With CKD: A Prospective Cohort Study.

RATIONALE & OBJECTIVE: Hemoglobin A1c (HbA1c) 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 HbA1c. For each outcome, we observed a significant increase in the fraction of new prognostic information when both GA and HbA1c were added to models. LIMITATIONS: Lack of longitudinal GA measurements; and HbA1c 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 HbA1c among patients with coexisting CKD and diabetes. PLAIN-LANGUAGE SUMMARY: Hemoglobin A1c (HbA1c) 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 HbA1c. Thus, GA may be a valuable complementary test to HbA1c in patients with CKD.

Metabolites Associated With Uremic Symptoms in Patients With CKD: Findings From the Chronic Renal Insufficiency Cohort (CRIC) Study.

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/1.73m2, 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.

Healthcare Resource Utilization and Goals of Care Discussions in Patients with Cirrhosis and Acute Kidney Injury.

BACKGROUND: Patients with cirrhosis and acute kidney injury (AKI) are critically ill and have high health care resource utilization (HCRU). The impact and timing of goals of care discussions on HCRU are not well described. METHODS: 221 patients enrolled in a prospective cohort study of patients admitted with AKI and cirrhosis were reviewed. Documentation and timing of a goals of care discussions were analyzed as predictors of HCRU, defined as a composite outcome of intubation, initiation of renal replacement therapy, and/or admission to the intensive care unit. RESULTS: Median MELD score was 26 [IQR 19, 33]. 29% patients were listed for liver transplant. 90-day mortality was 61%. 51% patients had at least one HCRU episode. Code status changed from admission to discharge from 91%/7%/0% to 68%/14%18% (full code/do not resuscitate/comfort measures, p < 0.001). 28% patients underwent goals of care discussions, with change in code status at a median of 16 [9, 22] days into admission. Only 18% of discussions were within 7 days of admission and all were after an HCRU event. Being listed for liver transplant was not associated with whether goals of care discussions occurred (23% listed vs. 31% non-listed, p = 0.24) but was associated with higher HCRU (69% vs. 43%; p < 0.001). CONCLUSION: Goals of care discussions occurred late into the hospital course, after episodes of HCRU. Efforts should be made to engage in these discussions earlier in the hospital stay, which may decrease HCRU rates in this critically ill population and align with patients' goals of care.

Comparative CKD risk prediction using homocitrulline and carbamylated albumin: two circulating markers of protein carbamylation.

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.

Protein Carbamylation and the Risk of ESKD in Patients with CKD.

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.

Intravenous sodium thiosulphate for vascular calcification of hemodialysis patients-a systematic review and meta-analysis.

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 association between olfactory and gustatory dysfunction and chronic kidney disease.

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/1.73m2 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.

Protein carbamylation and chronic kidney disease progression in the Chronic Renal Insufficiency Cohort Study.

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.

Kidney Function Decline among Black Patients with Sickle Cell Trait and Sickle Cell Disease: An Observational Cohort Study.

BACKGROUND: Sickle cell trait and sickle cell disease are thought to be independent risk factors for CKD, but the trajectory and predictors of kidney function decline in patients with these phenotypes are not well understood. METHODS: Our multicenter, observational study used registry data (collected January 2005 through June 2018) and included adult black patients with sickle cell trait or disease (exposures) or normal hemoglobin phenotype (reference) status (ascertained by electrophoresis) and at least 1 year of follow-up and three eGFR values. We used linear mixed models to evaluate the difference in the mean change in eGFR per year. RESULTS: We identified 1251 patients with sickle cell trait, 230 with sickle cell disease, and 8729 reference patients, with a median follow-up of 8 years. After adjustment, eGFR declined significantly faster in patients with sickle cell trait or sickle cell disease compared with reference patients; it also declined significantly faster in patients with sickle cell disease than in patients with sickle cell trait. Male sex, diabetes mellitus, and baseline eGFR ≥90 ml/min per 1.73 m2 were associated with faster eGFR decline for both phenotypes. In sickle cell trait, low hemoglobin S and elevated hemoglobin A were associated with faster eGFR decline, but elevated hemoglobins F and A2 were renoprotective. CONCLUSIONS: Sickle cell trait and disease are associated with faster eGFR decline in black patients, with faster decline in sickle cell disease. Low hemoglobin S was associated with faster eGFR decline in sickle cell trait but may be confounded by concurrent hemoglobinopathies. Prospective and mechanistic studies are needed to develop best practices to attenuate eGFR decline in such patients.

Serum Angiopoietin-2 Predicts Mortality and Kidney Outcomes in Decompensated Cirrhosis.

Acute kidney injury in decompensated cirrhosis has limited therapeutic options, and novel mechanistic targets are urgently needed. Angiopoietin-2 is a context-specific antagonist of Tie2, a receptor that signals vascular quiescence. Considering the prominence of vascular destabilization in decompensated cirrhosis, we evaluated Angiopoietin-2 to predict clinical outcomes. Serum Angiopoietin-2 was measured serially in a prospective cohort of hospitalized patients with decompensated cirrhosis and acute kidney injury. Clinical characteristics and outcomes were examined over a 90-day period and analyzed according to Angiopoietin-2 levels. Primary outcome was 90-day mortality. Our study included 191 inpatients (median Angiopoietin-2 level 18.2 [interquartile range 11.8, 26.5] ng/mL). Median Model for End-Stage Liver Disease (MELD) score was 23 [17, 30] and 90-day mortality was 41%. Increased Angiopoietin-2 levels were associated with increased mortality (died 21.9 [13.9, 30.3] ng/mL vs. alive 15.2 [9.8, 23.0] ng/mL; P < 0.001), higher Acute Kidney Injury Network stage (stage I 13.4 [9.8, 20.1] ng/mL vs. stage II 20.0 [14.1, 26.2] ng/mL vs. stage III 21.9 [13.0, 29.5] ng/mL; P = 0.002), and need for renal replacement therapy (16.5 [11.3, 23.6] ng/mL vs. 25.1 [13.3, 30.3] ng/mL; P = 0.005). The association between Angiopoietin-2 and mortality was significant in unadjusted and adjusted Cox regression models (P ≤ 0.001 for all models), and improved discrimination for mortality when added to MELD score (integrated discrimination increment 0.067; P = 0.001). Conclusion: Angiopoietin-2 was associated with mortality and other clinically relevant outcomes in a cohort of patients with decompensated cirrhosis with acute kidney injury. Further experimental study of Angiopoietin/Tie2 signaling is warranted to explore its potential mechanistic and therapeutic role in this population.

Protein carbamylation in end stage renal disease: is there a mortality effect?

PURPOSE OF REVIEW: Protein carbamylation is a posttranslational protein modification caused, in part, by exposure to urea's dissociation product cyanate. Additional modulators of protein carbamylation include circulating free amino acid levels, inflammation, diet, smoking, and environmental pollution exposures. Carbamylation reactions can modify protein charge, structure, and function, leading to adverse molecular and cellular responses. These changes have been linked to several pathologic biochemical pathways relevant to patients with end stage renal disease (ESRD) such as accelerated atherosclerosis and dysfunctional erythropoiesis, among others. This review examines the consequences of human protein carbamylation and the clinical impact this is thought to have in patients with ESRD. RECENT FINDINGS: Recent well-conducted studies across diverse cohorts of patients have independently associated elevations in protein carbamylation to mortality and morbidity in patients with ESRD. Studies are now examining the best strategies to reduce carbamylation load, including interventions aimed at lowering urea levels and restoring amino acid balance. Whether such carbamylation lowering strategies yield clinical improvements remain to be determined. SUMMARY: Numerous fundamental studies provide plausible mechanisms for the observed association between protein carbamylation burden and adverse clinical outcomes in ESRD. Studies employing nutritional and dialytic interventions to lower carbamylation may mitigate this risk but the net clinical benefit has not been established.

Pulmonary Hypertension, Mortality, and Cardiovascular Disease in CKD and ESRD Patients: A Systematic Review and Meta-analysis.

BACKGROUND: Pulmonary hypertension is common in patients with chronic kidney disease (CKD) and end-stage renal disease (ESRD) and may be associated with poor outcomes. The magnitude of the association between pulmonary hypertension and mortality is uncertain due to the small size and variable findings of observational studies. STUDY DESIGN: Systematic review and meta-analysis of observational studies using subgroup analyses and metaregression. SETTING & POPULATION: Patients with ESRD or earlier stages of CKD. SELECTION CRITERIA FOR STUDIES: Observational studies reporting clinical outcomes in patients with co-existing pulmonary hypertension and CKD or ESRD identified using a systematic search of PubMed and Embase. PREDICTOR: Pulmonary hypertension diagnosed by Doppler echocardiography. OUTCOMES: All-cause mortality, cardiovascular mortality, and cardiovascular events. RESULTS: 16 studies, with 7,112 patients with an overall pulmonary hypertension prevalence of 23%, were included. Pulmonary hypertension was associated with increased risk for all-cause mortality among patients with CKD (relative risk [RR], 1.44; 95% CI, 1.17-1.76), with ESRD receiving maintenance dialysis (RR, 2.32; 95% CI, 1.91-2.83), and with a functioning kidney transplant (RR, 2.08; 95% CI, 1.35-3.20). Pulmonary hypertension was associated with increased risk for cardiovascular events in patients with CKD (RR, 1.67; 95% CI, 1.07-2.60) and ESRD receiving dialysis (RR, 2.33; 95% CI, 1.76-3.08). There was an association between pulmonary hypertension and increased risk for cardiovascular mortality in patients with CKD or ESRD (RR, 2.20; 95% CI, 1.53-3.15). LIMITATIONS: Heterogeneity of included studies, possibility of residual confounding, unavailability of individual patient-level data, and possibility of outcome reporting bias. CONCLUSIONS: Pulmonary hypertension is associated with a substantially increased risk for death and cardiovascular events in patients with CKD and ESRD. Risk is higher in patients with ESRD receiving dialysis compared with patients with CKD stages 1 to 5. Understanding the effect of interventions to lower pulmonary artery pressure on the survival of these patents awaits their evaluation in randomized controlled trials.

Characterization and Correction of Olfactory Deficits in Kidney Disease.

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.

An overview of renal metabolomics.

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.

Siglec-7 as a Novel Biomarker to Predict Mortality in Decompensated Cirrhosis and Acute Kidney Injury.

BACKGROUND: Patients with decompensated cirrhosis have high morbidity and are commonly hospitalized with acute kidney injury. AIMS: We examined serum levels of Siglec-7, a transmembrane receptor that regulates immune activity, as a biomarker for mortality in patients with cirrhosis and acute kidney injury. METHODS: Serum Siglec-7 was measured in hospitalized patients with cirrhosis and acute kidney injury, as well as in reference groups with acute liver injury/acute kidney injury, cirrhosis without acute kidney injury, and sepsis without liver disease. Clinical characteristics and subsequent outcomes were examined using univariate and multivariable analyses according to initial Siglec-7 levels. Primary outcome was death by 90 days. RESULTS: One hundred twenty-eight subjects were included, 92 of which had cirrhosis and acute kidney injury and were used in the primary analysis. Average Model for End-Stage Liver Disease (MELD) score was 24 [95 % CI 23, 26], and serum creatinine was 2.5 [2.2, 2.8] mg/dL at the time Siglec-7 was measured. After adjusting for age and MELD score, high serum Siglec-7 level predicted mortality with a hazard ratio of 1.96 [1.04, 3.69; p = 0.04]. There was no difference in Siglec-7 levels by etiology of AKI (p = 0.24). Addition of serum Siglec-7 to MELD score improved discrimination for 90-day mortality [category-free net reclassification index = 0.38 (p = 0.04); integrated discrimination increment = 0.043 (p = 0.04)]. CONCLUSION: Serum Siglec-7 was associated with increased mortality among hospitalized patients with cirrhosis and acute kidney injury. Addition of Siglec-7 to MELD score may increase discrimination to predict 90-day mortality.

Protein carbamylation is associated with heart failure and mortality in diabetic patients with end-stage renal disease.

Serum carbamylated albumin (C-Alb) levels are associated with excess mortality in patients with diabetic end-stage renal disease. To gain insight into the pathophysiology of carbamylation, we determined associations between C-Alb and causes of death in patients on chronic hemodialysis. The Die Deutsche Diabetes Dialyse Studie (4D study) was a randomized controlled trial testing the effects of atorvastatin on survival in diabetic patients on dialysis during a median follow-up of 4 years. We stratified 1161 patients by C-Alb to see whether differences in carbamylation altered the effects of atorvastatin on survival. Baseline C-Alb significantly correlated with serum cardiac stress markers troponin T and N-terminal pro-B-type-natriuretic peptide and was associated with a history of heart failure and arrhythmia. C-Alb was strongly associated with 1-year adjusted risk of cardiovascular mortality, sudden cardiac death, and the 4-year risk of death from congestive heart failure (hazard ratios of 3.06, 3.78, and 4.64, respectively) but not with myocardial infarction or stroke. Patients with low C-Alb, treated with atorvastatin, experienced a significant improvement in their 4-year survival (hazard ratio 0.692). High C-Alb levels are associated with ongoing cardiac damage, risk of congestive heart failure, and sudden cardiac death. Thus, carbamylation and uremic cardiomyopathy are associated in patients with diabetes mellitus and kidney disease. In addition, statins were specifically beneficial to hemodialysis patients with low C-Alb.