Urine Metabolite Levels, Adverse Kidney Outcomes, and Mortality in CKD Patients: A Metabolome-wide Association Study

Steinbrenner, Inga; Kotsis, Fruzsina; Schlosser, Pascal; Stockmann, Helena; Mohney, Robert P.; Schmid, Matthias; Oefner, Peter J.; Eckardt, Kai‐Uwe; Köttgen, Anna; Sekula, Peggy; Meiselbach, Heike; Schneider, Markus P.; Schiffer, Mario; Prokosch, Hans‐Ulrich; Bärthlein, Barbara; Beck, Andreas; Reis, André; Ekici, Arif B.; Becker, Susanne; Becker-Grosspitsch, Dinah; Alberth-Schmidt, Ulrike; Hausknecht, Birgit; Weigel, Anke; Walz, Gerd; Schultheiß, Ulla T.; Meder, Simone; Mitsch, Erna; Reinhard, Ursula; Floege, Jürgen; Schaeffner, Elke; Baid-Agrawal, Seema; Theisen, Kerstin; Haller, Hermann; Menne, Jan; Zeier, Martin; Sommerer, Claudia; Theilinger, Johanna; Wolf, G; Busch, Martin; Paul, Rainer; Sitter, Thomas; Wanner, Christoph; Krane, Vera; Börner-Klein, Antje; Bauer, Britta; Kronenberg, Florian; Raschenberger, Julia; Kollerits, Barbara; Forer, Lukas; Schönherr, Sebastian; Weißensteiner, Hansi; Gronwald, Wolfram; Nadal, Jennifer

doi:10.1053/j.ajkd.2021.01.018

Cited by 27 publications

(23 citation statements)

References 37 publications

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“…We focused on plasma because of our extensive experience with this biofluid, opportunities for replication with other blood-based data sets, and challenges in metabolite measurement across the wide range of urine dilution. Nevertheless, urine is an attractive biofluid for CKD risk assessment and other groups have demonstrated its promise for metabolomic discovery (40)(41)(42). We have highlighted the increased confidence drawn from replication across two distinct LC-MS platforms, but also acknowledge that neither platform-and indeed no available platform-provides comprehensive coverage of the metabolome.…”

Section: Discussionmentioning

confidence: 94%

Metabolite profiling of CKD progression in the chronic renal insufficiency cohort study

Wen¹,

Zheng²,

Surapaneni³

et al. 2022

JCI Insight

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Background: Metabolomic profiling in individuals with chronic kidney disease (CKD) has the potential to identify novel biomarkers and provide insight into disease pathogenesis. Methods: We 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 1773 participants of the Chronic Renal Insufficiency Cohort (CRIC) study, 962 participants of the African American Study of Kidney Disease and Hypertension (AASK), and 5305 participants of the Atherosclerosis Risk in Communities (ARIC) study. Results:In CRIC, more than half of 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 fullyadjusted models in CRIC; three 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 nominate N-acetylserine as a potential marker of kidney tubular function, with significant associations with CKD progression observed in CRIC and ARIC. Conclusion:Together, our findings demonstrate the application of metabolomics to identify potential biomarkers and causal pathways in CKD progression.

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Section: Discussionmentioning

confidence: 94%

Metabolite profiling of CKD progression in the chronic renal insufficiency cohort study

Wen¹,

Zheng²,

Surapaneni³

et al. 2022

JCI Insight

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“…The roles of other diacylphospholipids in the pathogenesis of AKI have not been reported. Regarding the modulations of urinary diacylphospholipids in humans, a recent study showed that urinary PC levels might be associated with adverse outcomes and mortality in patients with chronic kidney diseases [60]; however, their associations with human AKI are not well known at present.…”

Section: Introductionmentioning

confidence: 99%

Dynamic modulations of urinary sphingolipid and glycerophospholipid levels in COVID-19 and correlations with COVID-19-associated kidney injuries

et al. 2022

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Background Among various complications of coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), renal complications, namely COVID-19-associated kidney injuries, are related to the mortality of COVID-19. Methods In this retrospective cross-sectional study, we measured the sphingolipids and glycerophospholipids, which have been shown to possess potent biological properties, using liquid chromatography-mass spectrometry in 272 urine samples collected longitudinally from 91 COVID-19 subjects and 95 control subjects without infectious diseases, to elucidate the pathogenesis of COVID-19-associated kidney injuries. Results The urinary levels of C18:0, C18:1, C22:0, and C24:0 ceramides, sphingosine, dihydrosphingosine, phosphatidylcholine, lysophosphatidylcholine, lysophosphatidic acid, and phosphatidylglycerol decreased, while those of phosphatidylserine, lysophosphatidylserine, phosphatidylethanolamine, and lysophosphatidylethanolamine increased in patients with mild COVID-19, especially during the early phase (day 1–3), suggesting that these modulations might reflect the direct effects of infection with SARS-CoV-2. Generally, the urinary levels of sphingomyelin, ceramides, sphingosine, dihydrosphingosine, dihydrosphingosine l-phosphate, phosphatidylcholine, lysophosphatidic acid, phosphatidylserine, lysophosphatidylserine, phosphatidylethanolamine, lysophosphatidylethanolamine, phosphatidylglycerol, lysophosphatidylglycerol, phosphatidylinositol, and lysophosphatidylinositol increased, especially in patients with severe COVID-19 during the later phase, suggesting that their modulations might result from kidney injuries accompanying severe COVID-19. Conclusions Considering the biological properties of sphingolipids and glycerophospholipids, an understanding of their urinary modulations in COVID-19 will help us to understand the mechanisms causing COVID-19-associated kidney injuries as well as general acute kidney injuries and may prompt researchers to develop laboratory tests for predicting maximum severity and/or novel reagents to suppress the renal complications of COVID-19.

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“…Urine metabolites profiling allows to capture molecules released into the tubular lumen potentially reflecting kidney pathological processes (20)(21)(22). We performed a targeted metabolomic profiling of 498 urine samples from 272 kidney transplant recipients (KTR) collected 3 and 12 months after transplantation.…”

Section: Higher Urinary Long Chain Fatty Acids Levels In Kidney Allog...mentioning

confidence: 99%

Impaired fatty acid metabolism perpetuates lipotoxicity along the transition to chronic kidney injury

Rinaldi¹,

Lazareth²,

Poindessous³

et al. 2022

JCI Insight

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Energy metabolism failure in proximal tubule cells (PTC) is a hallmark of chronic kidney injury.We combined transcriptomic, metabolomic and lipidomic approaches in experimental models and patient cohorts to investigate the molecular bases of the progression to chronic kidney allograft injury initiated by ischemia-reperfusion injury (IRI). The urinary metabolome of kidney transplant recipients with chronic allograft injury and who experienced severe IRI was significantly enriched with long chain fatty acids (FA). We identified a renal FA-related gene signature with low levels of Cpt2 and Acsm5 and high levels of Acsl4 and Acsm5 associated with IRI, transition to chronic injury, and established CKD in mouse models and kidney transplant recipients. The findings were consistent with the presence of Cpt2 -, Acsl4 + , Acsl5 + , Acsm5 -PTC failing to recover from IRI as identified by snRNAseq. In vitro experiments indicated that endoplasmic reticulum (ER) stress contributes to CPT2 repression, which, in turn, promotes lipids accumulation, drives profibrogenic epithelial phenotypic changes, and activates the unfolded protein response. ER stress through CPT2 inhibition and lipid accumulation, engages an auto-amplification loop leading to lipotoxicity and self-sustained cellular stress. Thus, IRI imprints a persistent FA metabolism disturbance in the proximal tubule sustaining the progression to chronic kidney allograft injury.

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Urine Metabolite Levels, Adverse Kidney Outcomes, and Mortality in CKD Patients: A Metabolome-wide Association Study

Cited by 27 publications

References 37 publications

Metabolite profiling of CKD progression in the chronic renal insufficiency cohort study

Metabolite profiling of CKD progression in the chronic renal insufficiency cohort study

Dynamic modulations of urinary sphingolipid and glycerophospholipid levels in COVID-19 and correlations with COVID-19-associated kidney injuries

Impaired fatty acid metabolism perpetuates lipotoxicity along the transition to chronic kidney injury

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