Characterizing cardiac involvement in chronic kidney disease using CMR—a systematic review

Purpose of Review: The aim of the review was to identify and describe recent advances (over the last 3 years) in cardiac magnetic resonance (CMR) imaging in patients with chronic kidney disease (CKD). We conducted a literature review in line with current guidelines. Recent Findings: The authors identified 22 studies. Patients with CKD had left ventricular global and regional dysfunction and adverse remodeling. Stress testing with CMR revealed a reduced stress-response in CKD patients. Native T1 relaxation times (as a surrogate markers of fibrosis) are elevated in CKD patients, proportional to disease duration. Patients with CKD have reduced strain magnitudes and reduced aortic distensibility. Summary: CMR has diagnostic utility to identify and characterize cardiac involvement in this patient group. A number of papers have described novel findings over the last 3 years, suggesting that CMR has potential to become more widely used in studies in this patient group

Pilot study protocol to inform a future longitudinal study of ageing using linked administrative data: Healthy AGeing in Scotland (HAGIS)

Introduction  Population ageing is a welcome testament to improvements in the social, economic and health circumstances over the life course. However, these successes necessitate that we understand more about the pathways of ageing to plan and cost our health and social care services, to support our ageing population to live healthier for longer and to make adequate provisions for retirement. Longitudinal studies of ageing facilitate such understanding in many countries around the world. Scotland presently does not have a longitudinal study of ageing, despite dramatic increases to its ageing population and its poor health record. Healthy AGeing in Scotland (HAGIS) constitutes the launch of Scotland’s first comprehensive longitudinal study of ageing.  Methods  A sample of 1000 people aged 50+ years will be invited to take part in a household social survey. The innovative sampling procedure used administrative data to identify eligible households. Anonymised survey responses will be linked to administrative data.  Ethics and dissemination  Ethics approval was obtained from the host institution for the study design and from the Public Benefits and Privacy Panel for administrative data linkage. Anonymised survey data will be deposited with the UK Data Service. A subset of survey data, harmonised with other global ageing studies, will be available via the Gateway to Global Aging platform. These data will enable powerful cross-country comparisons across the social, economic and health domains that will be relevant for national and international research.  Research publications from the HAGIS team will be disseminated through journal articles and national and international conferences. The findings will support current and future research and policy debate on ageing populations

Effect of left atrial and ventricular abnormalities on renal transplant recipient outcome—a single-center study

Background: Premature cardiovascular (CV) death is the commonest cause of death in renal transplant recipients. Abnormalities of left ventricular (LV) structure (collectively termed uremic cardiomyopathy) and left atrial (LA) dilation, a marker of fluid status and diastolic function, are risk factors for reduced survival in patients with end stage renal disease (ESRD). In the present analysis, we studied the impact of pre-transplant LA and LV abnormalities on survival after successful renal transplantation (RT).<p></p> Methods: One hundred nineteen renal transplant recipients (first transplant, deceased donors) underwent cardiovascular MRI (CMR) as part of CV screening prior to inclusion on the waiting list. Data regarding transplant function and patient survival after transplantation were collected.<p></p> Results: Median post-transplant follow-up was 4.3 years (interquartile range (IQR) 1.9, 6.2). During the post-transplant period, 13 patients returned to dialysis after graft failure and 23 patients died with a functioning graft. Survival analyses, censoring for patients returning to dialysis, showed that pre-transplant LV hypertrophy and elevated LA volume were significantly associated with reduced survival after transplantation. Multivariate Cox regression analyses demonstrated that longer waiting time, poorer transplant function, presence of LV hypertrophy and higher LA volume on screening CMR and female sex were independent predictors of death in patients with a functioning transplant.<p></p> Conclusions: Presence of LVH and higher LA volume are significant, independent predictors of death in patients who are wait-listed and proceed with renal transplantation.<p></p> METHODS: One hundred nineteen renal transplant recipients (first transplant, deceased donors) underwent cardiovascular MRI (CMR) as part of CV screening prior to inclusion on the waiting list. Data regarding transplant function and patient survival after transplantation were collected.<p></p> RESULTS: Median post-transplant follow-up was 4.3 years (interquartile range (IQR) 1.9, 6.2). During the post-transplant period, 13 patients returned to dialysis after graft failure and 23 patients died with a functioning graft. Survival analyses, censoring for patients returning to dialysis, showed that pre-transplant LV hypertrophy and elevated LA volume were significantly associated with reduced survival after transplantation. Multivariate Cox regression analyses demonstrated that longer waiting time, poorer transplant function, presence of LV hypertrophy and higher LA volume on screening CMR and female sex were independent predictors of death in patients with a functioning transplant.<p></p> CONCLUSIONS: Presence of LVH and higher LA volume are significant, independent predictors of death in patients who are wait-listed and proceed with renal transplantation

A Randomized Controlled Trial of the Effect of Allopurinol on Left Ventricular Mass Index in Hemodialysis Patients

Introduction: Increased left ventricular mass index (LVMI) is associated with mortality in end-stage renal disease. LVMI regression may improve outcomes. Allopurinol has reduced LVMI in randomized controlled trials in chronic kidney disease, diabetes, and ischemic heart disease. This study investigated whether allopurinol would regress LVMI in hemodialysis patients. Methods: This was a randomized placebo-controlled double-blind multicenter trial. A total of 80 patients undergoing regular maintenance hemodialysis were recruited from NHS Tayside, NHS Greater Glasgow and Clyde and NHS Ayrshire and Arran in Scotland, UK. Participants were randomly assigned on a 1:1 ratio to 12 months of therapy with allopurinol 300 mg or placebo after each dialysis session. The primary outcome was change in LVMI, as assessed by cardiac magnetic resonance imaging (MRI) at baseline and 12 months. Secondary outcomes were change in BP, flow-mediated dilation (FMD), augmentation indices (AIx), and pulse wave velocity (PWV). Results: A total of 53 patients, with a mean age of 58 years, completed the study and had MRI follow-up data for analysis. Allopurinol did not regress LVMI (change in LVMI: placebo +3.6 ± 10.4 g/m2; allopurinol: +1.6 ± 11 g/m2; P = 0.49). Allopurinol had no demonstrable effect on BP, FMD, AIx, or PWV. Conclusion: Compared with placebo, treatment with allopurinol did not regress LVMI in this trial

Left ventricular dysfunction with preserved ejection fraction: the most common left ventricular disorder in chronic kidney disease patients

Chronic kidney disease (CKD) is a risk factor for premature cardiovascular disease. As kidney function declines, the presence of left ventricular abnormalities increases such that by the time kidney replacement therapy is required with dialysis or kidney transplantation, more than two-thirds of patients have left ventricular hypertrophy. Historically, much research in nephrology has focussed on the structural and functional aspects of cardiac disease in CKD, particularly using echocardiography to describe these abnormalities. There is a need to translate knowledge around these imaging findings to clinical outcomes such as unplanned hospital admission with heart failure and premature cardiovascular death. Left ventricular hypertrophy and cardiac fibrosis, which are common in CKD, predispose to the clinical syndrome of heart failure with preserved left ventricular ejection fraction (HFpEF). There is a bidirectional relationship between CKD and HFpEF, whereby CKD is a risk factor for HFpEF and CKD impacts outcomes for patients with HFpEF. There have been major improvements in outcomes for patients with heart failure and reduced left ventricular ejection fraction as a result of several large randomized controlled trials. Finding therapy for HFpEF has been more elusive, although recent data suggest that sodium-glucose cotransporter 2 inhibition offers a novel evidence-based class of therapy that improves outcomes in HFpEF. These observations have emerged as this class of drugs has also become the standard of care for many patients with proteinuric CKD, suggesting that there is now hope for addressing the combination of HFpEF and CKD in parallel. In this review we summarize the epidemiology, pathophysiology, diagnostic strategies and treatment of HFpEF with a focus on patients with CKD

Differential associations of cystatin C versus creatinine‐based kidney function with risks of cardiovascular event and mortality among South Asian individuals in the UK Biobank

Background: South Asian individuals have increased cardiovascular disease and mortality risks. Reliance on creatinine‐ rather than cystatin C–based estimated glomerular filtration rate (eGFRcys) may underestimate the cardiovascular disease risk associated with chronic kidney disease. Methods and Results: Among 7738 South Asian UK BioBank participants without prevalent heart failure (HF) or atherosclerotic cardiovascular disease, we investigated associations of 4 eGFRcys and creatinine‐based estimated glomerular filtration rate categories (<45, 45–59, 60–89, and ≥90 mL/min per 1.73 m2) with risks of all‐cause mortality, incident HF, and incident atherosclerotic cardiovascular disease. The mean age was 53±8 years; 4085 (53%) were women. Compared with creatinine, cystatin C identified triple the number of participants with estimated glomerular filtration <45 (n=35 versus n=113) and 6 times the number with estimated glomerular filtration 45 to 59 (n=80 versus n=481). After multivariable adjustment, the eGFRcys 45 to 59 category was associated with higher risks of mortality (hazard ratio [HR], 2.38 [95% CI, 1.55–3.65]) and incident HF (sub‐HR [sHR], 1.87 [95% CI, 1.09–3.22]) versus the eGFRcys ≥90 category; the creatinine‐based estimated glomerular filtration rate 45 to 59 category had no significant associations with outcomes. Of the 7623 participants with creatinine‐based estimated glomerular filtration rate ≥60, 498 (6.5%) were reclassified into eGFRcys <60 categories. Participants who were reclassified as having eGFRcys <45 had higher risks of mortality (HR, 4.88 [95% CI, 2.56–9.31]), incident HF (sHR, 4.96 [95% CI, 2.21–11.16]), and incident atherosclerotic cardiovascular disease (sHR, 2.29 [95% CI, 1.14–4.61]) versus those with eGFRcys ≥90; those reclassified as having eGFRcys 45 to 59 had double the mortality risk (HR, 2.25 [95% CI, 1.45–3.51]). Conclusions: Among South Asian individuals, cystatin C identified a high‐risk chronic kidney disease population that was not detected by creatinine and enhanced estimated glomerular filtration rate–based risk stratification for mortality, incident HF, and incident atherosclerotic cardiovascular disease

Vitamin K supplementation to improve vascular stiffness in CKD:The K4Kidneys randomized controlled trial

BACKGROUND:Vascular calcification, a risk factor for cardiovascular disease, is common among patients with CKD and is an independent contributor to increased vascular stiffness and vascular risk in this patient group. Vitamin K is a cofactor for proteins involved in prevention of vascular calcification. Whether or not vitamin K supplementation could improve arterial stiffness in patients with CKD is unknown. METHODS:To determine if vitamin K supplementation might improve arterial stiffness in patients in CKD, we conducted a parallel-group, double-blind, randomized trial in participants aged 18 or older with CKD stage 3b or 4 (eGFR 15-45 ml/min per 1.73 m2). We randomly assigned participants to receive 400 μg oral vitamin K2 or matching placebo once daily for a year. The primary outcome was the adjusted between-group difference in carotid-femoral pulse wave velocity at 12 months. Secondary outcomes included augmentation index, abdominal aortic calcification, BP, physical function, and blood markers of mineral metabolism and vascular health. We also updated a recently published meta-analysis of trials to include the findings of this study. RESULTS:We included 159 randomized participants in the modified intention-to-treat analysis, with 80 allocated to receive vitamin K and 79 to receive placebo. Mean age was 66 years, 62 (39%) were female, and 87 (55%) had CKD stage 4. We found no differences in pulse wave velocity at 12 months, augmentation index at 12 months, BP, B-type natriuretic peptide, or physical function. The updated meta-analysis showed no effect of vitamin K supplementation on vascular stiffness or vascular calcification measures. CONCLUSIONS:Vitamin K2 supplementation did not improve vascular stiffness or other measures of vascular health in this trial involving individuals with CKD. CLINICAL TRIAL REGISTRY NAME AND REGISTRATION NUMBER:Vitamin K therapy to improve vascular health in patients with chronic kidney disease, ISRCTN21444964 (www.isrctn.com)

Native T1 mapping: inter-study, inter-observer and inter-center reproducibility in hemodialysis patients

Background Native T1 mapping is a cardiovascular magnetic resonance (CMR) technique that associates with markers of fibrosis and strain in hemodialysis patients. The reproducibility of T1 mapping in hemodialysis patients, prone to changes in fluid status, is unknown. Accurate quantification of myocardial fibrosis in this population has prognostic potential. Methods Using 3 Tesla CMR, we report the results of 1) the inter-study, inter-observer and intra-observer reproducibility of native T1 mapping in 10 hemodialysis patients; 2) inter-study reproducibility of left ventricular (LV) structure and function in 10 hemodialysis patients; 3) the agreement of native T1 map and native T1 phantom analyses between two centres in 20 hemodialysis patients; 4) the effect of changes in markers of fluid status on native T1 values in 10 hemodialysis patients. Results Inter-study, inter-observer and intra-observer variability of native T1 mapping were excellent with co-efficients of variation (CoV) of 0.7, 0.3 and 0.4% respectively. Inter-study CoV for LV structure and function were: LV mass = 1%; ejection fraction = 1.1%; LV end-diastolic volume = 5.2%; LV end-systolic volume = 5.6%. Inter-centre variability of analysis techniques were excellent with CoV for basal and mid-native T1 slices between 0.8–1.2%. Phantom analyses showed comparable native T1 times between centres, despite different scanners and acquisition sequences (centre 1: 1192.7 ± 7.5 ms, centre 2: 1205.5 ± 5 ms). For the 10 patients who underwent inter-study testing, change in body weight (Δweight) between scans correlated with change in LV end-diastolic volume (ΔLVEDV) (r = 0.682;P = 0.03) representing altered fluid status between scans. There were no correlations between change in native T1 between scans (ΔT1) and ΔLVEDV or Δweight (P > 0.6). Linear regression confirmed ΔT1 was unaffected by ΔLVEDV or Δweight (P > 0.59). Conclusions Myocardial native T1 is reproducible in HD patients and unaffected by changes in fluid status at the levels we observed. Native T1 mapping is a potential imaging biomarker for myocardial fibrosis in patients with end-stage renal disease

Assessment of Cystatin C level for risk stratification in adults with chronic kidney disease

Importance: Kidney function is usually estimated from serum creatinine level, whereas an alternative glomerular filtration marker (cystatin C level) associates more closely with future risk of cardiovascular disease (CVD) and mortality. Objectives: To evaluate whether testing concordance between estimated glomerular filtration rates based on cystatin C (eGFRcys) and creatinine (eGFRcr) levels would improve risk stratification for future outcomes and whether estimations differ by age. Design, Setting, and Participants: A prospective population-based cohort study (UK Biobank), with participants recruited between 2006-2010 with median follow-up of 11.5 (IQR, 10.8-12.2) years; data were collected until August 31, 2020. Participants had eGFRcr greater than or equal to 45 mL/min/1.73 m2, albuminuria (albumin <30 mg/g), and no preexisting CVD or kidney failure. Exposures: Chronic kidney disease status was categorized by concordance between eGFRcr and eGFRcys across the threshold for hronic kidney disease (CKD) diagnosis (60 mL/min/1.73 m2). Main Outcomes and Measures: Ten-year probabilities of CVD, mortality, and kidney failure were assessed according to CKD status. Multivariable-adjusted Cox proportional hazards models tested associations between CVD and mortality. Area under the receiving operating curve tested discrimination of eGFRcr and eGFRcys for CVD and mortality. The Net Reclassification Index assessed the usefulness of eGFRcr and eGFRcys for CVD risk stratification. Analyses were stratified by older (age 65-73 years) and younger (age <65 years) age. Results: There were 428 402 participants: median age was 57 (IQR, 50-63) years and 237 173 (55.4%) were women. Among 76 629 older participants, there were 9335 deaths and 5205 CVD events. Among 351 773 younger participants, there were 14 776 deaths and 9328 CVD events. The 10-year probability of kidney failure was less than 0.1%. Regardless of the eGFRcr, the 10-year probabilities of CVD and mortality were low when eGFRcys was greater than or equal to 60 mL/min/1.73 m2; conversely, with eGFRcys less than 60 mL/min/1.73 m2, 10-year risks were nearly doubled in older adults and more than doubled in younger adults. Use of eGFRcys better discriminated CVD and mortality risk than eGFRcr. Across a 7.5% 10-year risk threshold for CVD, eGFRcys improved case Net Reclassification Index by 0.7% (95% CI, 0.6%-0.8%) in older people and 0.7% (95% CI, 0.7%-0.8%) in younger people; eGFRcr did not add to CVD risk estimation. Conclusions and Relevance: The findings of this study suggest that eGFRcr 45 to 59 mL/min/1.73 m2 includes a proportion of individuals at low risk and fails to capture a substantial proportion of individuals at high-risk for CVD and mortality. The eGFRcys appears to be more sensitive and specific for CVD and mortality risks in mild CKD