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      Cardiovascular Functional Reserve Before and After Kidney Transplant

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          Abstract

          This cohort study assesses cardiovascular functional reserve before and after kidney transplant in patients with end-stage renal disease. How is kidney transplant associated with cardiovascular functional reserve? In this cohort study of 166 patients with stage 5 chronic kidney disease and 87 patients with hypertension only to assess change to cardiovascular functional reserve after improving the uremic milieu through a kidney transplant using state-of-the-art cardiopulmonary exercise testing, improved cardiovascular functional reserve was seen 1 year after kidney transplant in the absence of significant alterations in left ventricular morphologic findings. Improved cardiovascular reserve after kidney transplant may be associated with ultrastructural and functional alterations to the cardiovascular system and may not be associated with a change in left ventricular muscle mass. Restitution of kidney function by transplant confers a survival benefit in patients with end-stage renal disease. Investigations of mechanisms involved in improved cardiovascular survival have relied heavily on static measures from echocardiography or cardiac magnetic resonance imaging and have provided conflicting results to date. To evaluate cardiovascular functional reserve in patients with end-stage renal disease before and after kidney transplant and to assess functional and morphologic alterations of structural-functional dynamics in this population. This prospective, nonrandomized, single-center, 3-arm, controlled cohort study, the Cardiopulmonary Exercise Testing in Renal Failure and After Kidney Transplantation (CAPER) study, included patients with stage 5 chronic kidney disease (CKD) who underwent kidney transplant (KTR group), patients with stage 5 CKD who were wait-listed and had not undergone transplant (NTWC group), and patients with hypertension only (HTC group) seen at a single center from April 1, 2010, to January 1, 2013. Patients were followed up longitudinally for up to 1 year after kidney transplant. Clinical data collection was completed February 2014. Data analysis was performed from June 1, 2014, to March 5, 2015. Further analysis on baseline and prospective data was performed from June 1, 2017, to July 31, 2019. Cardiovascular functional reserve was objectively quantified using state-of-the-art cardiopulmonary exercise testing in parallel with transthoracic echocardiography. Of the 253 study participants (mean [SD] age, 48.5 [12.7] years; 141 [55.7%] male), 81 were in the KTR group, 85 in the NTWC group, and 87 in the HTC group. At baseline, mean (SD) maximum oxygen consumption (V̇ O 2 max) was significantly lower in the CKD groups (KTR, 20.7 [5.8] mL · min −1 · kg −1 ; NTWC, 18.9 [4.7] mL · min −1 · kg −1 ) compared with the HTC group (24.9 [7.1] mL · min −1 · kg −1 ) ( P  < .001). Mean (SD) cardiac left ventricular mass index was higher in patients with CKD (KTR group, 104.9 [36.1] g/m 2 ; NTWC group, 113.8 [37.7] g/m 2 ) compared with the HTC group (87.8 [16.9] g/m 2 ), ( P  < .001). Mean (SD) left ventricular ejection fraction was significantly lower in the patients with CKD (KTR group, 60.1% [8.6%]; NTWC group, 61.4% [8.9%]) compared with the HTC group (66.1% [5.9%]) ( P  < .001). Kidney transplant was associated with a significant improvement in V̇O 2 max in the KTR group at 12 months (22.5 [6.3] mL · min −1 · kg −1 ; P  < .001), but the value did not reach the V̇O 2 max in the HTC group (26.0 [7.1] mL · min −1 · kg −1 ) at 12 months. V̇O 2 max decreased in the NTWC group at 12 months compared with baseline (17.7 [4.1] mL · min −1 · kg −1 , P  < .001). Compared with the KTR group (63.2% [6.8%], P  = .02) or the NTWC group (59.3% [7.6%], P  = .003) at baseline, transplant was significantly associated with improved left ventricular ejection fraction at 12 months but not with left ventricular mass index. The findings suggest that kidney transplant is associated with improved cardiovascular functional reserve after 1 year. In addition, cardiopulmonary exercise testing was sensitive enough to detect a decline in cardiovascular functional reserve in wait-listed patients with CKD. Improved V̇O 2 max may in part be independent from structural alterations of the heart and depend more on ultrastructural changes after reversal of uremia.

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          Value of peak exercise oxygen consumption for optimal timing of cardiac transplantation in ambulatory patients with heart failure.

          Optimal timing of cardiac transplantation in ambulatory patients with severe left ventricular dysfunction is often difficult. To determine whether measurement of peak oxygen consumption (VO2) during maximal exercise testing can be used to identify patients in whom transplantation can be safely deferred, we prospectively performed exercise testing on all ambulatory patients referred for transplant between October 1986 and December 1989. Patients were assigned into one of three groups on the basis of exercise data: Group 1 (n = 35) comprised patients accepted for transplant (VO2 less than or equal to 14 ml/kg/min); group 2 (n = 52) comprised patients considered too well for transplant (VO2 greater than 14 ml/kg/min); and group 3 (n = 27) comprised patients with low VO2 rejected for transplant due to noncardiac problems. All three groups were comparable in New York Heart Association functional class, ejection fraction, and cardiac index (p = NS). Pulmonary capillary wedge pressure was significantly lower in group 2 than in either group 1 or 3 (p less than 0.05), although there was wide overlap. Patients with preserved exercise capacity (group 2) had cumulative 1- and 2-year survival rates of 94% and 84%, which are equal to survival levels after transplantation. In contrast, patients rejected for transplant (group 3) had survival rates of only 47% at 1 year and 32% at 2 years, whereas patients awaiting transplantation (group 1) had a survival rate of 70% at 1 year (both p less than 0.005 versus patients with VO2 greater than 14 ml/kg/min). All deaths in group 2 were sudden. By univariate and multivariate analyses, peak VO2 was the best predictor of survival, with only pulmonary capillary wedge pressure providing additional prognostic information. These data suggest that cardiac transplantation can be safely deferred in ambulatory patients with severe left ventricular dysfunction and peak exercise VO2 of more than 14 ml/min/kg.
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            Cross talk between the renin-angiotensin-aldosterone system and vitamin D-FGF-23-klotho in chronic kidney disease.

            There is increasingly evidence that the interactions between vitamin D, fibroblast growth factor 23 (FGF-23), and klotho form an endocrine axis for calcium and phosphate metabolism, and derangement of this axis contributes to the progression of renal disease. Several recent studies also demonstrate negative regulation of the renin gene by vitamin D. In chronic kidney disease (CKD), low levels of calcitriol, due to the loss of 1-alpha hydroxylase, increase renal renin production. Activation of the renin-angiotensin-aldosterone system (RAAS), in turn, reduces renal expression of klotho, a crucial factor for proper FGF-23 signaling. The resulting high FGF-23 levels suppress 1-alpha hydroxylase, further lowering calcitriol. This feedback loop results in vitamin D deficiency, RAAS activation, high FGF-23 levels, and renal klotho deficiency, all of which associate with progression of renal damage. Here we examine current evidence for an interaction between the RAAS and the vitamin D-FGF-23-klotho axis as well as its possible implications for progression of CKD.
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              α-Klotho Expression in Human Tissues

              Context: α-Klotho has emerged as a powerful regulator of the aging process. To date, the expression profile of α-Klotho in human tissues is unknown, and its existence in some human tissue types is subject to much controversy. Objective: This is the first study to characterize systemwide tissue expression of transmembrane α-Klotho in humans. We have employed next-generation targeted proteomic analysis using parallel reaction monitoring in parallel with conventional antibody-based methods to determine the expression and spatial distribution of human α-Klotho expression in health. Results: The distribution of α-Klotho in human tissues from various organ systems, including arterial, epithelial, endocrine, reproductive, and neuronal tissues, was first identified by immunohistochemistry. Kidney tissues showed strong α-Klotho expression, whereas liver did not reveal a detectable signal. These results were next confirmed by Western blotting of both whole tissues and primary cells. To validate our antibody-based results, α-Klotho-expressing tissues were subjected to parallel reaction monitoring mass spectrometry (data deposited at ProteomeXchange, PXD002775) identifying peptides specific for the full-length, transmembrane α-Klotho isoform. Conclusions: The data presented confirm α-Klotho expression in the kidney tubule and in the artery and provide evidence of α-Klotho expression across organ systems and cell types that has not previously been described in humans.
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                Author and article information

                Journal
                JAMA Cardiology
                JAMA Cardiol
                American Medical Association (AMA)
                2380-6583
                April 01 2020
                April 01 2020
                : 5
                : 4
                : 420
                Affiliations
                [1 ]Division of Nephrology, Department of Medicine, Massachusetts General Hospital and Harvard Medical School, Boston
                [2 ]Department of Medicine, University Hospitals Birmingham National Health Service Foundation Trust, Birmingham, United Kingdom
                [3 ]Pragmatic Clinical Trials Unit, Centre for Primary Care and Public Health, Queen Mary, University of London, London, United Kingdom
                [4 ]Department of Nephrology, University Hospital Coventry and Warwickshire National Health Service Trust, Coventry, United Kingdom
                [5 ]Department of Cardiology, University Hospital Coventry and Warwickshire National Health Service Trust, Coventry, United Kingdom
                [6 ]Research Institutes of Sports and Exercise Sciences, Liverpool John Moores University, Liverpool, United Kingdom
                [7 ]Department of Pathology Service, University Hospital Coventry and Warwickshire National Health Service Trust, Coventry, United Kingdom
                [8 ]Division of Cardiology, Department of Medicine, Massachusetts General Hospital and Harvard Medical School, Boston
                [9 ]Division of Biomedical Sciences, University of Warwick, Coventry, United Kingdom
                [10 ]Centre for Innovative Research Across the Life Course, Coventry University, Coventry, United Kingdom
                [11 ]Department of Nephrology, North Cumbria University Hospital National Health Service Trust, Carlisle, United Kingdom
                [12 ]Department of Acute Medicine, North Cumbria University Hospital National Health Service Trust, Carlisle, United Kingdom
                [13 ]Cambridge Clinical Trials Unit and School of Clinical Medicine, University of Cambridge, Cambridge, United Kingdom
                Article
                10.1001/jamacardio.2019.5738
                7042833
                32022839
                c2e16d63-1514-4c6d-a2ed-e0bd5f73264b
                © 2020
                History

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