Dataset Information

Serum Metabolomic Alterations Associated with Proteinuria in CKD.

ABSTRACT:

Background and objectives

Data are scarce on blood metabolite associations with proteinuria, a strong risk factor for adverse kidney outcomes. We sought to investigate associations of proteinuria with serum metabolites identified using untargeted profiling in populations with CKD.

Design, setting, participants, & measurements

Using stored serum samples from the African American Study of Kidney Disease and Hypertension (AASK; n=962) and the Modification of Diet in Renal Disease (MDRD) study (n=620), two rigorously conducted clinical trials with per-protocol measures of 24-hour proteinuria and GFR, we evaluated cross-sectional associations between urine protein-to-creatinine ratio and 637 known, nondrug metabolites, adjusting for key clinical covariables. Metabolites significantly associated with proteinuria were tested for associations with CKD progression.

Results

In the AASK and the MDRD study, respectively, the median urine protein-to-creatinine ratio was 80 (interquartile range [IQR], 28-359) and 188 (IQR, 54-894) mg/g, mean age was 56 and 52 years, 39% and 38% were women, 100% and 7% were black, and median measured GFR was 48 (IQR, 35-57) and 28 (IQR, 18-39) ml/min per 1.73 m². Linear regression identified 66 serum metabolites associated with proteinuria in one or both studies after Bonferroni correction (P<7.8×10^-5), 58 of which were statistically significant in a meta-analysis (P<7.8×10^-4). The metabolites with the lowest P values (P<10^-27) were 4-hydroxychlorthalonil and 1,5-anhydroglucitol; all six quantified metabolites in the phosphatidylethanolamine pathway were also significant. Of the 58 metabolites associated with proteinuria, four were associated with ESKD in both the AASK and the MDRD study.

Conclusions

We identified 58 serum metabolites with cross-sectional associations with proteinuria, some of which were also associated with CKD progression.

Podcast

This article contains a podcast at https://www.asn-online.org/media/podcast/CJASN/2019_02_07_CJASNPodcast_19_03_.mp3.

SUBMITTER: Luo S

PROVIDER: S-EPMC6419293 | biostudies-literature | 2019 Mar

REPOSITORIES: biostudies-literature

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Serum Metabolomic Alterations Associated with Proteinuria in CKD.

Luo Shengyuan S Coresh Josef J Tin Adrienne A Rebholz Casey M CM Appel Lawrence J LJ Chen Jingsha J Vasan Ramachandran S RS Anderson Amanda H AH Feldman Harold I HI Kimmel Paul L PL Waikar Sushrut S SS Köttgen Anna A Evans Anne M AM Levey Andrew S AS Inker Lesley A LA Sarnak Mark J MJ Grams Morgan Erika ME

Clinical journal of the American Society of Nephrology : CJASN 20190207 3

<h4>Background and objectives</h4>Data are scarce on blood metabolite associations with proteinuria, a strong risk factor for adverse kidney outcomes. We sought to investigate associations of proteinuria with serum metabolites identified using untargeted profiling in populations with CKD.<h4>Design, setting, participants, & measurements</h4>Using stored serum samples from the African American Study of Kidney Disease and Hypertension (AASK; <i>n</i>=962) and the Modification of Diet in Renal Dise ...[more]

PMID: 30733224

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Project description:Background and objectivesCauses of CKD differ in prognosis and treatment. Metabolomic indicators of CKD cause may provide clues regarding the different physiologic processes underlying CKD development and progression.Design, setting, participants & measurementsMetabolites were quantified from serum samples of participants in the Modification of Diet in Renal Disease (MDRD) Study, a randomized controlled trial of dietary protein restriction and BP control, using untargeted reverse phase ultraperformance liquid chromatography tandem mass spectrometry quantification. Known, nondrug metabolites (n=687) were log-transformed and analyzed to discover associations with CKD cause (polycystic kidney disease, glomerular disease, and other cause). Discovery was performed in Study B, a substudy of MDRD with low GFR (n=166), and replication was performed in Study A, a substudy of MDRD with higher GFR (n=423).ResultsOverall in MDRD, average participant age was 51 years and 61% were men. In the discovery study (Study B), 29% of participants had polycystic kidney disease, 28% had glomerular disease, and 43% had CKD of another cause; in the replication study (Study A), the percentages were 28%, 24%, and 48%, respectively. In the discovery analysis, adjusted for demographics, randomization group, body mass index, hypertensive medications, measured GFR, log-transformed proteinuria, and estimated protein intake, seven metabolites (16-hydroxypalmitate, kynurenate, homovanillate sulfate, N2,N2-dimethylguanosine, hippurate, homocitrulline, and 1,5-anhydroglucitol) were associated with CKD cause after correction for multiple comparisons (P<0.0008). Five of these metabolite associations (16-hydroxypalmitate, kynurenate, homovanillate sulfate, N2,N2-dimethylguanosine, and hippurate) were replicated in Study A (P<0.007), with all replicated metabolites exhibiting higher levels in polycystic kidney disease and lower levels in glomerular disease compared with CKD of other causes.ConclusionsMetabolomic profiling identified several metabolites strongly associated with cause of CKD.

Project description:Background and objectivesNovel biomarkers that more accurately reflect kidney function and predict future CKD are needed. The human metabolome is the product of multiple physiologic or pathophysiologic processes and may provide novel insight into disease etiology and progression. This study investigated whether estimated kidney function would be associated with multiple metabolites and whether selected metabolomic factors would be independent risk factors for incident CKD.Design, setting, participants, & measurementsIn total, 1921 African Americans free of CKD with a median of 19.6 years follow-up among the Atherosclerosis Risk in Communities Study were included. A total of 204 serum metabolites quantified by untargeted gas chromatography-mass spectrometry and liquid chromatography-mass spectrometry was analyzed by both linear regression for the cross-sectional associations with eGFR (specified by the Chronic Kidney Disease Epidemiology Collaboration equation) and Cox proportional hazards model for the longitudinal associations with incident CKD.ResultsForty named and 34 unnamed metabolites were found to be associated with eGFR specified by the Chronic Kidney Disease Epidemiology Collaboration equation with creatine and 3-indoxyl sulfate showing the strongest positive (2.8 ml/min per 1.73 m(2) per +1 SD; 95% confidence interval, 2.1 to 3.5) and negative association (-14.2 ml/min per 1.73 m(2) per +1 SD; 95% confidence interval, -17.0 to -11.3), respectively. Two hundred four incident CKD events with a median follow-up time of 19.6 years were included in the survival analyses. Higher levels of 5-oxoproline (hazard ratio, 0.70; 95% confidence interval, 0.60 to 0.82) and 1,5-anhydroglucitol (hazard ratio, 0.68; 95% confidence interval, 0.58 to 0.80) were significantly related to lower risk of incident CKD, and the associations did not appreciably change when mutually adjusted.ConclusionsThese data identify a large number of metabolites associated with kidney function as well as two metabolites that are candidate risk factors for CKD and may provide new insights into CKD biomarker identification.

Project description:BackgroundA multidrug treatment strategy that targets urinary proteins with an angiotensin-converting enzyme (ACE) inhibitor and angiotensin receptor blocker (ARB) up-titrated to the respective maximum tolerated dose combined with intensified blood pressure (BP) control has been found to prevent renal function loss in adults with proteinuric nephropathies. Herein, we investigated the effects of this treatment protocol in the pediatric patient population.MethodsFrom May 2002 to September 2014 we included in this observational, longitudinal, cohort study 20 consecutive children with chronic nephropathies and 24-h proteinuria of >200 mg who had received ramipril and losartan up-titrated to the respective maximum approved and tolerated doses [mean (standard deviation) dose:2.48 (1.37) mg/m2 and 0.61 (0.46) mg/kg daily, respectively]. The primary efficacy endpoint was a >50 % reduction in 24-h proteinuria to <200 mg (remission). Secondary outcomes included changes in proteinuria, serum albumin, BP, and glomerular filtration rate (GFR).ResultsMean (± standard deviation) patient age at inclusion was 13.8 ± 2.8 years, and the median [interquartile range (IQR)] serum creatinine level and proteinuria were 0.7 (0.6-1.0) mg/dl and 690 (379-1270) mg/24 h or 435 (252-711) mg/m2/24 h, respectively. Proteinuria significantly decreased by month 6 of follow-up, and serum albumin levels increased over a median follow-up period of 78 (IQR 39-105) months. In the nine children who achieved remission, proteinuria reduction persisted throughout the whole follow-up without rebounds. The GFR improved in those children who achieved remission and worsened in those who did not. The mean GFR slopes differed significantly between these two groups (p < 0.05), being positive in those children with remission and negative in those without remission (+0.023 ± 0.15 vs.-0.014 ± 0.23 ml/min/1.73 m2/month, respectively), whereas BP control was similar between the two groups. Hyperkalemia was observed in two children.ConclusionsCombination therapy with maximum approved doses of ACE inhibitors and ARBs is a safe strategy which may achieve proteinuria remission with kidney function stabilization or even improvement in a substantial proportion of children with proteinuric nephropathies.

Project description:BackgroundProteinuria is commonly measured to assess the renal status of chronic kidney disease (CKD) patients before the 20th week of gestation during pregnancy. High levels of proteiuria have been associated with adverse pregnancy outcomes. However, researchers have not clearly determined what baseline proteinuria levels would be associated with adverse pregnancy outcomes. This study aimed to analyse associations between proteinuria levels and adverse pregnancy outcomes among CKD patients treated with or without steroids/immunosuppressive therapy in early pregnancy.MethodsThis retrospective study included the clinical information of 557 pregnant patients with CKD from 1 January 2009 to 31 December 2021. A multivariable logistic regression analysis was conducted to evaluate the risk of adverse pregnancy outcomes across various proteinuria ranges, which were further stratified by whether the patients were receiving steroids/immunosuppressive therapy.Results(i) Proteinuria was assessed on 24-h urine collection. The median (quartile) baseline proteinuria levels were 0.83 g (0.20, 1.92) and 0.25 g (0.06, 0.80) in the steroids/immunosuppressive therapy and therapy-free groups, respectively. (ii) CKD patients with adverse pregnancy outcomes had significantly higher proteinuria levels in the first trimester than patients without adverse pregnancy outcomes. (iii) The risk of adverse pregnancy outcomes increased with increasing baseline proteinuria levels (P < .001). (iv) In the early-pregnancy steroids/immunosuppressive therapy group, the risk of severe preeclampsia was higher in patients with higher baseline proteinuria levels (P < .007) [odds ratio (OR) 30.86 for proteinuria ≥5.00 g/24 h]; in the therapy-free group, the risks of severe preeclampsia, very-low-birth-weight infants, early preterm birth and foetal-neonatal death were higher in patients with higher baseline proteinuria levels (OR 53.16 for proteinuria ≥5.00 g/24 h; OR 37.83 for proteinuria ≥5.00 g/24 h; OR 15.30 for proteinuria ≥5.00 g/24 h; and OR 18.83 for proteinuria ≥5.00 g/24 h, respectively; P < .001, P < .001, P < .001 and P = .006, respectively).ConclusionsAs shown in the present study, a baseline 24-h proteinuria level >1.00 g was associated with adverse maternal outcomes. Furthermore, a 24-h proteinuria level >2.00 g increased the incidence of adverse foetal events among CKD patients.

Dataset Information

Serum Metabolomic Alterations Associated with Proteinuria in CKD.

Background and objectives

Design, setting, participants, & measurements

Results

Conclusions

Podcast

Publications

Serum Metabolomic Alterations Associated with Proteinuria in CKD.

Similar Datasets

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