IntroductionUremic toxins contributing to increased risk of death remain largely unknown. We used untargeted metabolomics to identify plasma metabolites associated with mortality in patients receiving maintenance hemodialysis.MethodsWe measured metabolites in serum samples from 522 Longitudinal US/Canada Incident Dialysis (LUCID) study participants. We assessed the association between metabolites and 1-year mortality, adjusting for age, sex, race, cardiovascular disease, diabetes, body mass index, serum albumin, Kt/Vurea, dialysis duration, and country. We modeled these associations using limma, a metabolite-wise linear model with empirical Bayesian inference, and 2 machine learning (ML) models: Least absolute shrinkage and selection operator (LASSO) and random forest (RF). We accounted for multiple testing using a false discovery rate (pFDR) adjustment. We defined significant mortality-metabolite associations as pFDR < 0.1 in the limma model and metabolites of at least medium importance in both ML models.ResultsThe mean age of the participants was 64 years, the mean dialysis duration was 35 days, and there were 44 deaths (8.4%) during a 1-year follow-up period. Two metabolites were significantly associated with 1-year mortality. Quinolinate levels (a kynurenine pathway metabolite) were 1.72-fold higher in patients who died within year 1 compared with those who did not (pFDR, 0.009), wheras mesaconate levels (an emerging immunometabolite) were 1.57-fold higher (pFDR, 0.002). An additional 42 metabolites had high importance as per LASSO, 46 per RF, and 9 per both ML models but were not significant per limma.ConclusionQuinolinate and mesaconate were significantly associated with a 1-year risk of death in incident patients receiving maintenance hemodialysis. External validation of our findings is needed.

Our study aimed to explore whether type 2 diabetes (T2DM) can affect arsenic metabolism in acute promyelocytic leukemia (APL) patients treated with arsenic trioxide. We found that compared with non-diabetic APL patients, the concentrations of arsenic metabolites in APL patients with T2DM increased significantly and positively correlated with blood glucose (P < 0.05). Meanwhile, APL patients with T2DM were more prone to liver injury and QTc interval prolongation due to altered arsenic methylation capacity. Then we cultured HEK293T cells at different glucose concentrations, and the results showed that the cells with high glucose had higher concentrations of arsenic metabolites compared to other cells. Meanwhile, the high glucose significantly increased the mRNA and protein expression levels of the arsenic uptake transporter AQP7 in HEK293T cells. Overall, our study demonstrated that T2DM can lead to elevated concentrations of arsenic metabolites in APL patients by increasing AQP7 expression.

1Journal of the American Society of Nephrology, Bernard, Maine 2University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 3Department of Medicine, University of California San Francisco at the Priscilla Chan and Mark Zuckerberg San Francisco General Hospital, San Francisco, California Correspondence: Josephine P. Briggs, PO Box 126, Bernard, ME 04612. Email: [email protected]

ABSTRACT Background Chronic kidney disease (CKD) is associated with atherosclerotic cardiovascular disease (ASCVD) risk, especially among those with diabetes. Altered metabolism of solutes that accumulate in CKD [asymmetric dimethylarginine (ADMA), symmetric dimethylarginine (SDMA) and trimethylamine N-oxide (TMAO)] may reflect pathways linking CKD with ASCVD. Methods This case–cohort study included Chronic Renal Insufficiency Cohort participants with baseline diabetes, estimated glomerular filtration rate <60 mL/min/1.73 m2, and without prior history for each outcome. The primary outcome was incident ASCVD (time to first myocardial infarction, stroke or peripheral artery disease event) and secondary outcome was incident heart failure. The subcohort comprised randomly selected participants meeting entry criteria. Plasma and urine ADMA, SDMA and TMAO concentrations were determined by liquid chromatography–tandem mass spectrometry. Associations of uremic solute plasma concentrations and urinary fractional excretions with outcomes were evaluated by weighted multivariable Cox regression models, adjusted for confounding covariables. Results Higher plasma ADMA concentrations (per standard deviation) were associated with ASCVD risk [hazard ratio (HR) 1.30, 95% confidence interval (CI) 1.01–1.68]. Lower fractional excretion of ADMA (per standard deviation) was associated with ASCVD risk (HR 1.42, 95% CI 1.07–1.89). The lowest quartile of ADMA fractional excretion was associated with greater ASCVD risk (HR 2.25, 95% CI 1.08–4.69) compared with the highest quartile. Plasma SDMA and TMAO concentration and fractional excretion were not associated with ASCVD. Neither plasma nor fractional excretion of ADMA, SDMA and TMAO were associated with incident heart failure. Conclusion These data suggest that decreased kidney excretion of ADMA leads to increased plasma concentrations and ASCVD risk.

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RATIONALE AND OBJECTIVE Cardiovascular disease (CVD) is a major cause of mortality among people with diabetic kidney disease (DKD). The pathophysiology is inadequately explained by traditional CVD risk factors. Three uremic solutes, trimethylamine-N-oxide (TMAO), asymmetric and symmetric dimethylarginine (ADMA, SDMA), have been linked to CVD in kidney failure with renal replacement therapy (KFRT), but data are limited in populations with diabetes and less severe kidney disease. STUDY DESIGN Observational cohort. SETTINGS AND PARTICIPANTS Random subcohort of 555 REGARDS Study participants with diabetes and eGFR <60 ml/min/1.73m2 at study entry. EXPOSURES ADMA, SDMA and TMAO were assayed by liquid chromatography-mass spectrometry in plasma and urine. OUTCOMES CV mortality (primary outcome), all-cause mortality and incident KFRT (secondary outcomes). ANALYTIC APPROACH Plasma and urine:plasma (U/P) ratios of ADMA, SDMA and TMAO were tested for association with outcomes. Adjusted Cox regression models were fitted and hazard ratios (HR) of outcomes presented per standard deviation, log2 increments and interquartile comparisons. RESULTS Mean baseline eGFR was 44 ml/min/1.73 m2. CV death, overall mortality and KFRT occurred in 120, 285 and 89 participants during mean 6.2 years follow-up. Higher plasma ADMA, and lower U/P ratios of ADMA, SDMA and TMAO were associated with CV mortality by interquartile (HR 1.9-3.9), log2 concentration comparisons (HR 1.4-2.1), and per standard deviation (HR 1.2). Higher plasma concentrations (HR 1.1-2.8) and lower U/P ratios (HR 1.3-2.3) of all three solutes were associated with all-cause mortality. Higher plasma SDMA was associated with incident KFRT (HR 1.2-3.0). LIMITATIONS Single cohort, restricted to diabetic patients with eGFR <60, potential residual confounding by GFR, no dietary information. CONCLUSIONS Higher plasma concentrations and lower U/P ratios of uremic solutes were independently associated with CV and all-cause mortality in DKD. Associations of U/P ratios with mortality suggest a connection between renal uremic solute clearance and CVD pathogenesis.

Introduction:Diuretic use may reduce volume-related complications in hemodialysis. We evaluated the efficacy, safety, and tolerability of furosemide in patients with hemodialysis-dependent kidney failure. Methods:We conducted an open label, single-arm, 18-week, dose titration pilot study of oral furosemide (maximum dose 320 mg/day) among patients receiving maintenance hemodialysis who reported at least 1 cup of urine output per day. The primary efficacy outcome was an increase from baseline to a specified threshold of 24-hour urine volume, with the threshold based on baseline urine volume (<200 ml/day vs. ≥200 ml/day). Safety outcomes included hypokalemia and hypomagnesemia, and tolerability was assessed by prespecified patient-reported symptoms. Results:Of the 39 participants, 28 (72%) received the expected furosemide dose, 3 (8%) underwent dose reduction, 5 (12%) discontinued furosemide without dose reduction, and 3 (8%) underwent dose reduction and subsequently discontinued furosemide. The median (quartile 1, quartile 3) baseline 24-hour urine volume was 290 ml (110, 740), and the maximum, average daily study furosemide dose ranged from 69 mg/day to 320 mg/d. The urine output efficacy outcome was met by 12 (33%), 11 (33%), and 7 (22%) participants at weeks 5, 12, and 18, respectively, in the intention-to-treat analysis, and by 12 (39%), 9 (35%), and 7 (28%) participants at weeks 5, 12, and 18, respectively, in the on-treatment analysis. There were no electrolyte, furosemide level, or patient-reported hearing change safety events. Conclusion:Furosemide was generally safe and well tolerated, but only one-third of participants met the efficacy definition at week 5. The clinical importance of the efficacy findings is uncertain.

1Department of Medicine, Veterans Affairs Palo Alto Health Care System, Palo Alto, California 2Department of Medicine, Stanford University, Palo Alto, California 3University of North Carolina Kidney Center, Division of Nephrology and Hypertension, Department of Medicine, University of North Carolina School of Medicine, Chapel Hill, North Carolina 4Cecil G. Sheps Center for Health Services Research, University of North Carolina, Chapel Hill, North Carolina Correspondence: Dr. Tammy L. Sirich, Veterans Affairs Palo Alto Healthcare, 111R Nephrology, 3801 Miranda Avenue, Palo Alto, CA 94304. Email: [email protected]

Background: Arsenic trioxide (ATO) was successfully applied to treat acute promyelocytic leukemia (APL).Methods: Inorganic arsenic (iAs), monomethylarsonic acid (MMAV) and dimethyarsinic acid (DMAV) in plasma of 143 APL patients with different renal function were determined. Arsenic methylation capacity was evaluated by iAs%, MMAV%, DMAV%, primary methylation index (PMI, MMAV/iAs), and secondary methylated index (SMI, DMAV/MMAV). Arsenic accumulation with administration frequency were explored. Moreover, safety assessments were performed.Results: Compared with normal renal function, MMAV and DMAV concentrations increased 1.5-4 fold in moderate and severe renal impairment groups, iAs increased 1.3-1.7 fold. APL patients with renal impairment showed lower iAs%, but higher DMAV% and PMI in plasma than those with normal renal function (P < 0.05). MMAV, DMAV, and tAs apparently accumulated with administration frequency in moderate and severe renal dysfunction groups. The incidence of QTc interval prolongation and liver injury increased with the increasing severity of renal impairment.Conclusion: Renal dysfunction may increase exposure to arsenic and arsenic accumulation and affect methylation capacity, then the clinical safety in APL patients treated with ATO. Arsenic-level monitoring and dosing regimen adjustment should be considered in APL patients with moderate and severe renal dysfunction.