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Chronic kidney disease (CKD) involves significant metabolic abnormalities and has a high mortality rate. Because the levels of serum metabolites in patients with CKD might provide insight into subclinical disease states and risk for future mortality, we determined which serum metabolites reproducibly associate with mortality in CKD using a discovery and replication design. Metabolite levels were quantified via untargeted liquid chromatography and mass spectroscopy from serum samples of 299 patients with CKD in the Modification of Diet in Renal Disease (MDRD) study as a discovery cohort. Six among 622 metabolites were significantly associated with mortality over a median follow-up of 17 years after adjustment for demographic and clinical covariates, including urine protein and measured glomerular filtration rate. We then replicated associations with mortality in 963 patients with CKD from the African American Study of Kidney Disease and Hypertension (AASK) cohort over a median follow-up of ten years. Three of the six metabolites identified in the MDRD cohort replicated in the AASK cohort: fumarate, allantoin, and ribonate, belonging to energy, nucleotide, and carbohydrate pathways, respectively. Point estimates were similar in both studies and in meta-analysis (adjusted hazard ratios 1.63, 1.59, and 1.61, respectively, per doubling of the metabolite). Thus, selected serum metabolites were reproducibly associated with long-term mortality in CKD beyond markers of kidney function in two well characterized cohorts, providing targets for investigation.
Copyright © 2018 International Society of Nephrology. Published by Elsevier Inc. All rights reserved.
BACKGROUND - Delayed-release dimethyl fumarate (DR-DMF) has cytoprotective and antiinflammatory properties and has recently been approved in the United States as an oral treatment for relapsing forms of multiple sclerosis. The most common adverse events associated with DR-DMF are flushing and gastrointestinal (GI) events, the incidences of which diminish over time.
OBJECTIVE - The purpose of this study was to evaluate the tolerability and pharmacokinetic (PK) profile of DR-DMF with or without concomitant acetylsalicylic acid (aspirin), a cyclooxygenase inhibitor.
METHODS - Healthy volunteers (N = 56) were randomized to receive different dosing regimens of DR-DMF or matching placebo with or without pretreatment with 325 mg aspirin for 4 days. Plasma levels of the active metabolite monomethyl fumarate were assessed on days 1 and 4. Flushing and GI events were assessed using patient-reported scales. Potential flushing mediators were explored.
RESULTS - DR-DMF showed a safety, tolerability, and PK profile consistent with previous clinical experience, with no evidence of accumulation. Pretreatment with aspirin had no effect on the primary PK parameters, AUC0-10h, or Cmax. Flushing severity, assessed by 2 subject-reported rating scales, was generally mild and was rated highest at the start of treatment. Pretreatment with aspirin reduced flushing incidence and intensity without affecting GI events or the PK profile of DR-DMF. In some DR-DMF-treated individuals, plasma concentrations of a prostaglandin D2 (PGD2) metabolite were increased.
CONCLUSIONS - In healthy volunteers, DR-DMF was well tolerated over 4 days of dosing, with a PK profile consistent with that previously reported and no evidence of accumulation. Aspirin pretreatment reduced the incidence and intensity of flushing without affecting GI events or the DR-DMF PK profile. Elevated levels of PGD2 in some DR-DMF-treated individuals suggest that flushing may be, at least in part, prostaglandin mediated. ClinicalTrials.gov identifier: ID: NCT01281111.
© 2013 The Authors. Published by Elsevier, Inc. All rights reserved.
Because MYC plays a causal role in many human cancers, including those with hypoxic and nutrient-poor tumor microenvironments, we have determined the metabolic responses of a MYC-inducible human Burkitt lymphoma model P493 cell line to aerobic and hypoxic conditions, and to glucose deprivation, using stable isotope-resolved metabolomics. Using [U-(13)C]-glucose as the tracer, both glucose consumption and lactate production were increased by MYC expression and hypoxia. Using [U-(13)C,(15)N]-glutamine as the tracer, glutamine import and metabolism through the TCA cycle persisted under hypoxia, and glutamine contributed significantly to citrate carbons. Under glucose deprivation, glutamine-derived fumarate, malate, and citrate were significantly increased. Their (13)C-labeling patterns demonstrate an alternative energy-generating glutaminolysis pathway involving a glucose-independent TCA cycle. The essential role of glutamine metabolism in cell survival and proliferation under hypoxia and glucose deficiency makes them susceptible to the glutaminase inhibitor BPTES and hence could be targeted for cancer therapy.
Copyright © 2012 Elsevier Inc. All rights reserved.
INTRODUCTION - Aldosterone blockade reduces albuminuria in diabetic patients with chronic kidney disease (CKD), and improves prognosis in chronic heart failure. This study assessed the effects of direct renin inhibition with aliskiren in combination with losartan and optimal antihypertensive therapy on urinary aldosterone, plasma renin activity (PRA) and plasma renin concentration (PRC).
MATERIALS AND METHODS - In the AVOID study, 599 patients with type 2 diabetes, hypertension and nephropathy received 6 months aliskiren (150 mg force titrated to 300 mg once daily after 3 months) or placebo added to losartan 100 mg and optimal antihypertensive therapy. Urinary aldosterone excretion, PRA and PRC were measured at baseline and after 24 weeks in a prespecified subset of 133 patients.
RESULTS - Aliskiren added to losartan provided reductions from baseline in urinary aldosterone compared with adding placebo (-24% vs. -4%, p = 0.017) at week 24. There was no significant difference between the aliskiren and placebo groups in the proportion of patients with aldosterone breakthrough (aliskiren 35%, placebo 46%, p = 0.199). Aliskiren treatment reduced PRA by 90% at 24 weeks and increased PRC by 328%.
CONCLUSIONS - Adding aliskiren to recommended renoprotective treatment with losartan and optimal antihypertensive therapy provided significant reductions in urinary aldosterone excretion which may attenuate decline in kidney function.
A major challenge in cancer biology is to monitor and understand cancer metabolism in vivo with the goal of improved diagnosis and perhaps therapy. Because of the complexity of biochemical pathways, tracer methods are required for detecting specific enzyme-catalyzed reactions. Stable isotopes such as (13)C or (15)N with detection by nuclear magnetic resonance provide the necessary information about tissue biochemistry, but the crucial metabolites are present in low concentration and therefore are beyond the detection threshold of traditional magnetic resonance methods. A solution is to improve sensitivity by a factor of 10,000 or more by temporarily redistributing the populations of nuclear spins in a magnetic field, a process termed hyperpolarization. Although this effect is short-lived, hyperpolarized molecules can be generated in an aqueous solution and infused in vivo where metabolism generates products that can be imaged. This discovery lifts the primary constraint on magnetic resonance imaging for monitoring metabolism-poor sensitivity-while preserving the advantage of biochemical information. The purpose of this report was to briefly summarize the known abnormalities in cancer metabolism, the value and limitations of current imaging methods for metabolism, and the principles of hyperpolarization. Recent preclinical applications are described. Hyperpolarization technology is still in its infancy, and current polarizer equipment and methods are suboptimal. Nevertheless, there are no fundamental barriers to rapid translation of this exciting technology to clinical research and perhaps clinical care.
BACKGROUND AND OBJECTIVES - Elevated BP contributes to development and progression of proteinuria and decline in renal function in patients with type 2 diabetes. Our post hoc analysis assessed the baseline BP influence on the antiproteinuric effect in the Aliskiren in the Evaluation of Proteinuria in Diabetes (AVOID) study.
DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS - In the AVOID study, 599 hypertensive type 2 diabetic patients with nephropathy received 6 months of aliskiren (150 mg force titrated to 300 mg daily after 3 months) or placebo added to losartan (100 mg) daily and optimal antihypertensive therapy. Changes in early morning urinary albumin:creatinine ratio and eGFR at week 24 were assessed by subgroups of baseline BP: Group A (prespecified target), <130/80 mmHg (n=159); Group B, <140/90 mmHg but ≥130/80 mmHg (n=189); and Group C (insufficient BP control), ≥140/90 mmHg (n=251).
RESULTS - Mean baseline BP (mmHg) levels for Groups A, B, and C were 120/71, 133/78, and 145/81, respectively. BP during the trial was nearly identical to baseline levels in all groups. The antiproteinuric effects of aliskiren were consistent across subgroups of baseline BP (19 to 22% reduction versus placebo). In Group C, the decline in eGFR was significantly lower with aliskiren than with placebo (P=0.013).
CONCLUSIONS - Aliskiren (300 mg) added to losartan (100 mg) plus optimal antihypertensive therapy provides antiproteinuric effects independent of BP in patients with type 2 diabetes and nephropathy. Renal function was better preserved with aliskiren in patients with insufficient BP control.
Copyright © 2011 by the American Society of Nephrology
Complex II superfamily members catalyze the kinetically difficult interconversion of succinate and fumarate. Due to the relative simplicity of complex II substrates and their similarity to other biologically abundant small molecules, substrate specificity presents a challenge in this system. In order to identify determinants for on-pathway catalysis, off-pathway catalysis, and enzyme inhibition, crystal structures of Escherichia coli menaquinol:fumarate reductase (QFR), a complex II superfamily member, were determined bound to the substrate, fumarate, and the inhibitors oxaloacetate, glutarate, and 3-nitropropionate. Optical difference spectroscopy and computational modeling support a model where QFR twists the dicarboxylate, activating it for catalysis. Orientation of the C2-C3 double bond of activated fumarate parallel to the C(4a)-N5 bond of FAD allows orbital overlap between the substrate and the cofactor, priming the substrate for nucleophilic attack. Off-pathway catalysis, such as the conversion of malate to oxaloacetate or the activation of the toxin 3-nitropropionate may occur when inhibitors bind with a similarly activated bond in the same position. Conversely, inhibitors that do not orient an activatable bond in this manner, such as glutarate and citrate, are excluded from catalysis and act as inhibitors of substrate binding. These results support a model where electronic interactions via geometric constraint and orbital steering underlie catalysis by QFR.
OBJECTIVE - Proteinuric diabetic patients with reduced glomerular filtration rate (GFR) are at high risk of renal and cardiovascular disease progression and treatment-related adverse events. This post hoc analysis assessed the efficacy and safety of aliskiren added to the maximal recommended dose of losartan according to baseline estimated GFR (eGFR) (stage 1-3 chronic kidney disease [CKD]).
RESEARCH DESIGN AND METHODS - In the Aliskiren in the Evaluation of Proteinuria in Diabetes (AVOID) study, 599 hypertensive patients with type 2 diabetes and nephropathy received 6 months of aliskiren (150 mg daily titrated to 300 mg daily after 3 months) or placebo added to 100 mg losartan and optimal antihypertensive therapy. Exclusion criteria included eGFR<30 ml/min per 1.73 m2 and serum potassium>5.1 mmol/l.
RESULTS - Baseline characteristics were similar between treatment groups in all CKD stages. The antiproteinuric effects of aliskiren were consistent across CKD stages (19, 22, and 18% reduction). In the stage 3 CKD group, baseline serum creatinine levels were equal, but renal dysfunction, prespecified as a postrandomization serum creatinine elevation>176.8 μmol/l (2.0 mg/dl) occurred more frequently in the placebo group (29.2 vs. 13.6%, P=0.032). Serum potassium elevations>5.5 mmol/l (based on a single measurement) were more frequent with aliskiren (22.5 vs. 13.6%) in stage 3 CKD. Adverse event rates were similar between treatments, irrespective of CKD stage.
CONCLUSIONS - Aliskiren added to losartan reduced albuminuria and renal dysfunction and was well tolerated, except for hyperkalemia (stage 3), independent of baseline CKD stage in patients with type 2 diabetes, hypertension, and nephropathy.
Here, we demonstrate the utility of low gamma nuclei for spin storage of hyperpolarization followed by proton detection, which theoretically can provide up to approximately (gamma[1H]/gamma[X])(2) gain in sensitivity in hyperpolarized biomedical MR. This is exemplified by hyperpolarized 1-(13)C sites of 2,2,3,3-tetrafluoropropyl 1-(13)C-propionate-d(3) (TFPP), (13)C T(1) = 67 s in D(2)O, and 1-(13)C-succinate-d(2), (13)C T(1) = 105 s in D(2)O, pH 11, using PASADENA. In a representative example, the spin polarization was stored on (13)C for 24 and 70 s, respectively, while the samples were transferred from a low magnetic field polarizer operating at 1.76 mT to a 4.7 T animal MR scanner. Following sample delivery, the refocused INEPT pulse sequence was used to transfer spin polarization from (13)C to protons with an efficiency of 50% for TFPP and 41% for 1-(13)C-succinate-d(2) increasing the overall NMR sensitivity by a factor of 7.9 and 6.5, respectively. The low gamma nuclei exemplified here by (13)C with a T(1) of tens of seconds acts as an efficient spin polarization storage, while J-coupled protons are better for NMR detection.
Angiotensin (Ang) II plays important roles in the development of hypertension and cardiovascular and renal injury. Pharmaceutical approaches to block its activity led to the development of angiotensin-converting enzyme inhibitors and angiotensin receptor blockers. Numerous trials have documented their efficacy in controlling blood pressure, minimising left ventricular remodelling, preventing progression to heart failure, ameliorating proteinuria and retarding renal disease progression. Although they are considered safe in general, there remain concerns about the potential for adverse events in certain target populations. Recently, several novel, low molecular weight renin inhibitors without the extended peptide-like backbone of previous renin inhibitors were developed with favourable pharmacokinetic properties. They have been shown to successfully reduce Ang II levels in normal volunteers and to lower blood pressure in patients with mild-to-moderate hypertension. In this review, the authors summarise current knowledge about these renin inhibitors.