Browsing by Author "Thadhani, Ravi"

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    A Metabolomics Approach to Identify Metabolites Associated With Mortality in Patients Receiving Maintenance Hemodialysis
    (Elsevier, 2024-06-29) Al Awadhi, Solaf; Myint, Leslie; Guallar, Eliseo; Clish, Clary B.; Wulczyn, Kendra E.; Kalim, Sahir; Thadhani, Ravi; Segev, Dorry L.; McAdams DeMarco, Mara; Moe, Sharon M.; Moorthi, Ranjani N.; Hostetter, Thomas H.; Himmelfarb, Jonathan; Meyer, Timothy W.; Powe, Neil R.; Tonelli, Marcello; Rhee, Eugene P.; Shafi, Tariq; Medicine, School of Medicine
    Introduction: Uremic 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. Methods: We 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. Results: The 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. Conclusion: Quinolinate 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.
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    FGF23 and Cardiovascular Structure and Function in Advanced Chronic Kidney Disease
    (Wolters Kluwer, 2022-07-05) Halim, Arvin; Burney, Heather N.; Li, Xiaochun; Li, Yang; Tomkins, Claudia; Siedlecki, Andrew M.; Lu, Tzong-shi; Kalim, Sahir; Thadhani, Ravi; Moe, Sharon; Ting, Stephen M.S.; Zehnder, Daniel; Hiemstra, Thomas F.; Lim, Kenneth; Medicine, School of Medicine
    Background: Fibroblast growth factor 23 (FGF23) is a bone-derived phosphatonin that is elevated in chronic kidney disease (CKD) and has been implicated in the development of cardiovascular disease. It is unknown whether elevated FGF23 in CKD is associated with impaired cardiovascular functional capacity, as assessed by maximum exercise oxygen consumption (VO2Max). We sought to determine whether FGF23 is associated with cardiovascular functional capacity in patients with advanced CKD and after improvement of VO2Max by kidney transplantation. Methods: We performed secondary analysis of 235 patients from the Cardiopulmonary Exercise Testing in Renal Failure and After Kidney Transplantation (CAPER) cohort, which recruited patients with stage 5 CKD who underwent kidney transplantation or were waitlisted and hypertensive controls. All patients underwent cardiopulmonary exercise testing (CPET) and echocardiography and were followed longitudinally for 1 year after study enrollment. Results: Patients across FGF23 quartiles differed in BMI (P=0.004) and mean arterial pressure (P<0.001) but did not significantly differ in sex (P=0.5) or age (P=0.08) compared with patients with lower levels of FGF23. Patients with higher FGF23 levels had impaired VO2Max (Q1: 24.2±4.8 ml/min per kilogram; Q4: 18.6±5.2 ml/min per kilogram; P<0.001), greater left ventricular mass index (LVMI; P<0.001), reduced HR at peak exercise (P<0.001), and maximal workload (P<0.001). Kidney transplantation conferred a significant decline in FGF23 at 2 months (P<0.001) before improvement in VO2Max at 1 year (P=0.008). Multivariable regression modeling revealed that changes in FGF23 was significantly associated with VO2Max in advanced CKD (P<0.001) and after improvement after kidney transplantation (P=0.006). FGF23 was associated with LVMI before kidney transplantation (P=0.003), however this association was lost after adjustment for dialysis status (P=0.4). FGF23 was not associated with LVMI after kidney transplantation in all models. Conclusions: FGF23 levels are associated with alterations in cardiovascular functional capacity in advanced CKD and after kidney transplantation. FGF23 is only associated with structural cardiac adaptations in advanced CKD but this was modified by dialysis status, and was not associated after kidney transplantation.
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    Myocardial Cytoskeletal Adaptations in Advanced Kidney Disease
    (American Heart Association, 2022) Halim, Arvin; Narayanan, Gayatri; Hato, Takashi; Ho, Lilun; Wan, Douglas; Siedlecki, Andrew M.; Rhee, Eugene P.; Allegretti, Andrew S.; Nigwekar, Sagar U.; Zehnder, Daniel; Hiemstra, Thomas F.; Bonventre, Joseph V.; Charytan, David M.; Kalim, Sahir; Thadhani, Ravi; Lu, Tzongshi; Lim, Kenneth; Medicine, School of Medicine
    Background: The myocardial cytoskeleton functions as the fundamental framework critical for organelle function, bioenergetics and myocardial remodeling. To date, impairment of the myocardial cytoskeleton occurring in the failing heart in patients with advanced chronic kidney disease has been largely undescribed. Methods and Results: We conducted a 3‐arm cross‐sectional cohort study of explanted human heart tissues from patients who are dependent on hemodialysis (n=19), hypertension (n=10) with preserved renal function, and healthy controls (n=21). Left ventricular tissues were subjected to pathologic examination and next‐generation RNA sequencing. Mechanistic and interference RNA studies utilizing in vitro human cardiac fibroblast models were performed. Left ventricular tissues from patients undergoing hemodialysis exhibited increased myocardial wall thickness and significantly greater fibrosis compared with hypertension patients (P<0.05) and control (P<0.01). Transcriptomic analysis revealed that the focal adhesion pathway was significantly enriched in hearts from patients undergoing hemodialysis. Hearts from patients undergoing hemodialysis exhibited dysregulated components of the focal adhesion pathway including reduced β‐actin (P<0.01), β‐tubulin (P<0.01), vimentin (P<0.05), and increased expression of vinculin (P<0.05) compared with controls. Cytoskeletal adaptations in hearts from the hemodialysis group were associated with impaired mitochondrial bioenergetics, including dysregulated mitochondrial dynamics and fusion, and loss of cell survival pathways. Mechanistic studies revealed that cytoskeletal changes can be driven by uremic and metabolic abnormalities of chronic kidney disease, in vitro. Furthermore, focal adhesion kinase silencing via interference RNA suppressed major cytoskeletal proteins synergistically with mineral stressors found in chronic kidney disease in vitro. Conclusions: Myocardial failure in advanced chronic kidney disease is characterized by impairment of the cytoskeleton involving disruption of the focal adhesion pathway, mitochondrial failure, and loss of cell survival pathways.
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    Plasma metabolites and physical function in patients undergoing hemodialysis
    (Springer Nature, 2024-04-10) Moorthi, Ranjani N.; Moe, Sharon M.; O’Connell, Thomas; Dickinson, Stephanie; Kalim, Sahir; Thadhani, Ravi; Clish, Clary B.; Shafi, Tariq; Rhee, Eugene P.; Avin, Keith G.; Medicine, School of Medicine
    Impaired physical function contributes to falls, fractures, and mortality among patients undergoing dialysis. Using a metabolomic approach, we identified metabolite alterations and effect size-based composite scores for constructs of impaired gait speed and grip strength. 108 participants incident to dialysis had targeted plasma metabolomics via liquid chromatography-mass spectrometry and physical function assessed (i.e., 4 m walk, handgrip strength). Physical function measures were categorized as above/ below median, with grip utilizing sex-based medians. To develop composite scores, metabolites were identified via Wilcoxon uncorrected p < 0.05 and effect size > 0.40. Receiver operating characteristic analyses tested whether scores differentiated between above/below function groups. Participants were 54% male, 77% Black and 53 ± 14 y with dialysis vintage of 101 ± 50 days. Median (IQR) grip strength was 35.5 (11.1) kg (males) and 20 (8.4) kg (females); median gait speed was 0.82 (0.34) m/s. Of 246 measured metabolites, composite scores were composed of 22 and 12 metabolites for grip strength and gait speed, respectively. Area under the curve for metabolite composite was 0.88 (gait) and 0.911 (grip). Composite scores of physical function performed better than clinical parameters alone in patients on dialysis. These results provide potential pathways for interventions and needed validation in an independent cohort.
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    Serum phospholipid fraction of polyunsaturated fatty acids is the preferred indicator for nutrition and health status in hemodialysis patients
    (Elsevier, 2016-12) Watkins, Bruce A.; Kim, Jeffrey; Tamez, Hector; Wenger, Julia; Thadhani, Ravi; Friedman, Allon N.; Department of Medicine, IU School of Medicine
    Long chain (LC) polyunsaturated fatty acids (PUFA) are major components of cell membrane phospholipids (PL) and serve as precursors for numerous bioactive lipid derivatives. Fatty acids (FA) are routinely analyzed in biological samples to assess composition of tissues, cells, and lipid fractions. In human studies, serum or plasma is often used because of their easy procurement. However, the lipid pool in serum and plasma is a mixture of triacylglycerol (TG), PL, cholesterol and its esters, and other components. Herein, we report findings from a serum FA analysis after fractionation of polar and neutral lipids by solid phase extraction in a large cohort of 400 hemodialysis patients. LC PUFA were found concentrated in the polar fraction compared to the total or the neutral lipid fraction. When correlated with clinical markers of disease, a greater number of significant correlations were found for PUFA in polar compared to total or the neutral fraction. We also observed that polar lipids are a reliable reflection of LC PUFA status compared to the total or neutral fractions because the latter are diluted by non-essential FA. The relative amounts of LC PUFA in the total and neutral fractions reflect the contribution of TG in blood that varies with diet, age, and physiologic state. Our data indicate that LC PUFA in the polar fraction are superior indicators of bioactive FA-status than in the total or the neutral fraction and should be used to establish important links between PUFA status, their bioactive substrates in hemodialysis patients.
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    What have we learned about chronic kidney disease-mineral bone disorder from the EVOLVE and PRIMO trials?
    (Wolters Kluwer, 2014-11) Moe, Sharon M.; Thadhani, Ravi; Medicine, School of Medicine
    PURPOSE OF REVIEW: The treatment of chronic kidney disease-mineral bone disorder (CKD-MBD) has traditionally focused on improvement in biochemical parameters of the disease. However, studies evaluating hard clinical end points or surrogate end points are limited. RECENT FINDINGS: Two randomized controlled trials have recently been published. In the EVOLVE study (Evaluation of Cinacalcet Hydrochloride Therapy to Lower Cardiovascular Events), cinacalcet was compared with placebo in 3883 haemodialysis patients with secondary hyperparathyroidism. The primary end point (death, myocardial infarction, unstable angina, heart failure or peripheral vascular disease) in an unadjusted intention-to-treat analysis was not significant [hazard ratio 0.93; 95% confidence interval (CI) 0.85-1.02, P=0.11]. However, the pre-specified secondary end points of an adjusted intention-to-treat analysis (hazard ratio 0.88; 95% CI 0.79-0.97, P=0.008) were significant. In the PRIMO (Paricalcitol Capsule Benefits in Renal Failure Induced Cardiac Morbidity) trial, 227 patients with CKD stage 3-4 and left ventricular hypertrophy by echocardiography were randomized to paricalcitol or placebo. The primary end point of change in left ventricular mass index by MRI after 12 months was not different between the two groups, but the prespecified end point of cardiovascular-related hospitalizations was reduced in the paricalcitol-treated group (P=0.04). SUMMARY: The results of these two randomized controlled trials have negative primary end points but significant secondary end points and thus require physicians to individualize therapies for the treatment of secondary hyperparathyroidism.