Acute kidney injury leading to CKD is associated with a persistence of metabolic dysfunction and hypertriglyceridemia

Harzandi, Azadeh; Lee, Sunjae; Bidkhori, Gholamreza; Saha, Sujit K; Hendry, Bruce M.; Mardinoğlu, Adil; Shoaie, Saeed; Sharpe, Claire C.

doi:10.1016/j.isci.2021.102046

Cited by 25 publications

(12 citation statements)

References 57 publications

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“…2OGDH is decreased in CKD induced by high-salt diet and aristocholic acid administration [ 22 , 115 ], as has been reported in non-diabetic CKD patients [ 42 ]. On the other hand, in RCC 2OGDH lower expression was associated with poor outcome [ 116 ].…”

Section: Succinyl-coamentioning

confidence: 91%

Involvement of Tricarboxylic Acid Cycle Metabolites in Kidney Diseases

et al. 2021

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Mitochondria are complex organelles that orchestrate several functions in the cell. The primary function recognized is energy production; however, other functions involve the communication with the rest of the cell through reactive oxygen species (ROS), calcium influx, mitochondrial DNA (mtDNA), adenosine triphosphate (ATP) levels, cytochrome c release, and also through tricarboxylic acid (TCA) metabolites. Kidney function highly depends on mitochondria; hence mitochondrial dysfunction is associated with kidney diseases. In addition to oxidative phosphorylation impairment, other mitochondrial abnormalities have been described in kidney diseases, such as induction of mitophagy, intrinsic pathway of apoptosis, and releasing molecules to communicate to the rest of the cell. The TCA cycle is a metabolic pathway whose primary function is to generate electrons to feed the electron transport system (ETS) to drives energy production. However, TCA cycle metabolites can also release from mitochondria or produced in the cytosol to exert different functions and modify cell behavior. Here we review the involvement of some of the functions of TCA metabolites in kidney diseases.

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Section: Succinyl-coamentioning

confidence: 91%

Involvement of Tricarboxylic Acid Cycle Metabolites in Kidney Diseases

et al. 2021

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“…Interestingly also in other types of organ fibrosis an increase in triglycerides was noted such as chronic kidney disease and fibrotic liver diseases ( Chen et al, 2017 ; Monteillet et al, 2018 ; Harzandi et al, 2021 ). In addition, an increase in triglycerides was also observed in several murine models of organ fibrosis ( Harzandi et al, 2021 ; Weckerle et al, 2021 ). In contrast, patients with cancer including lung malignancies show a down-regulation of triglycerides, which is associated with poor outcome ( Siemianowicz et al, 2000 ).…”

Section: Discussionmentioning

confidence: 94%

Changes in serum metabolomics in idiopathic pulmonary fibrosis and effect of approved antifibrotic medication

et al. 2022

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Idiopathic pulmonary fibrosis (IPF) is a progressive disease with significant mortality and morbidity. Approval of antifibrotic therapy has ameliorated disease progression, but therapy response is heterogeneous and to date, adequate biomarkers predicting therapy response are lacking. In recent years metabolomic technology has improved and is broadly applied in cancer research thus enabling its use in other fields. Recently both aberrant metabolic and lipidomic pathways have been described to influence profibrotic responses. We thus aimed to characterize the metabolomic and lipidomic changes between IPF and healthy volunteers (HV) and analyze metabolomic changes following treatment with nintedanib and pirfenidone. We collected serial serum samples from two IPF cohorts from Germany (n = 122) and Spain (n = 21) and additionally age-matched healthy volunteers (n = 16). Metabolomic analysis of 630 metabolites covering 14 small molecule and 12 different lipid classes was carried out using flow injection analysis tandem mass spectrometry for lipids and liquid chromatography tandem mass spectrometry for small molecules. Levels were correlated with survival and disease severity. We identified 109 deregulated analytes in IPF compared to HV in cohort 1 and 112 deregulated analytes in cohort 2. Metabolites which were up-regulated in both cohorts were mainly triglycerides while the main class of down-regulated metabolites were phosphatidylcholines. Only a minority of de-regulated analytes were small molecules. Triglyceride subclasses were inversely correlated with baseline disease severity (GAP-score) and a clinical compound endpoint of lung function decline or death. No changes in the metabolic profiles were observed following treatment with pirfenidone. Nintedanib treatment induced up-regulation of triglycerides and phosphatidylcholines. Patients in whom an increase in these metabolites was observed showed a trend towards better survival using the 2-years composite endpoint (HR 2.46, p = 0.06). In conclusion, we report major changes in metabolites in two independent cohorts testing a large number of patients. Specific lipidic metabolite signatures may serve as biomarkers for disease progression or favorable treatment response to nintedanib.

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“…In part, it can be explained by the involvement of the peroxisome proliferator receptors, that generate vasodilatory prostaglandins resulting in an increase in kidney blood filtration which increases serum creatinine and decreases GFR [44]. Moreover, emerging evidence, suggest that alterations in the PPAR pathway at the molecular level are both early and late events in CKD and CKD progression mouse models [45,46] and fenofibrate treatment exerts nephroprotective effects thought the attenuation of inflammatory and fibrotic pathways [41,47,48]. Enhancing binding at the PPARa receptor is a promising development, influencing downstream gene and physiological effects of PPRAa activation.…”

Section: Discussionmentioning

confidence: 99%

The Effect of Fibrates on Kidney Function and Chronic Kidney Disease Progression: A Systematic Review and Meta-Analysis of Randomised Studies

Hadjivasilis

Kouis

Kousios

et al. 2022

JCM

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Aim: Fibrates have proven efficacy in cardiovascular risk reduction and are commonly used, in addition to statins, to control hypertriglyceridaemia. Their use is often limited due to reduction in glomerular filtration rate at treatment initiation. However, recent studies suggest benign changes in kidney function and improvement of proteinuria, an established early marker of microvascular disease and kidney disease progression. We summarize the evidence from existing trials and provide a summary of effects of fibrates, alone or in combination, on kidney disease progression and proteinuria. Methods and Results: Systematic review and meta-analysis of randomized, controlled trials (PROSPERO CRD42020187764). Out of 12,243 potentially eligible studies, 29 were included in qualitative and quantitative analysis, with a total of 20,176 patients. Mean creatinine increased by 1.05 (95% CI (0.63 to 1.46)) units in patients receiving fibrates vs. comparator, and this was similar in all other subgroups. eGFR showed a bigger decrease in the fibrates arm (SMD −1.99; 95% CI (−3.49 to −0.48)) when all studies were pooled together. Notably, short-term serum creatinine and eGFR changes remained constant in the long-term. Pooled estimates show that fibrates improve albuminuria progression, RR 0.86; 95% CI (0.76 to 0.98); albuminuria regression, RR 1.19; 95% CI (1.08 to 1.310). Conclusions: Fibrates improve albuminuria in patients with and without diabetes when used to treat hyperlipidaemia. The modest creatinine increase should not be a limiting factor for fibrate initiation in people with preserved renal function or mild CKD. The long-term effects on kidney disease progression warrant further study.

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Acute kidney injury leading to CKD is associated with a persistence of metabolic dysfunction and hypertriglyceridemia

Cited by 25 publications

References 57 publications

Involvement of Tricarboxylic Acid Cycle Metabolites in Kidney Diseases

Involvement of Tricarboxylic Acid Cycle Metabolites in Kidney Diseases

Changes in serum metabolomics in idiopathic pulmonary fibrosis and effect of approved antifibrotic medication

The Effect of Fibrates on Kidney Function and Chronic Kidney Disease Progression: A Systematic Review and Meta-Analysis of Randomised Studies

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