Abstract Chronic kidney disease (CKD) is a complex condition with a prevalence of 10–15% worldwide. An inverse-graded relationship exists between cardiovascular events and mortality with kidney function which is independent of age, sex, and other risk factors. The proportion of deaths due to heart failure and sudden cardiac death increase with progression of chronic kidney disease with relatively fewer deaths from atheromatous, vasculo-occlusive processes. This phenomenon can largely be explained by the increased prevalence of CKD-associated cardiomyopathy with worsening kidney function. The key features of CKD-associated cardiomyopathy are increased left ventricular mass and left ventricular hypertrophy, diastolic and systolic left ventricular dysfunction, and profound cardiac fibrosis on histology. While these features have predominantly been described in patients with advanced kidney disease on dialysis treatment, patients with only mild to moderate renal impairment already exhibit structural and functional changes consistent with CKD-associated cardiomyopathy. In this review we discuss the key drivers of CKD-associated cardiomyopathy and the key role of hypertension in its pathogenesis. We also evaluate existing, as well as developing therapies in the treatment of CKD-associated cardiomyopathy. 

https://www.nature.com/articles/s41371-022-00751-4.pdf

Hypertension and cardiomyopathy associated with chronic kidney disease: epidemiology, pathogenesis and treatment considerations

Kidney transplantation is considered the treatment of choice for end-stage kidney disease patients. However, the residual cardiovascular risk remains significantly higher in kidney transplant recipients (KTRs) than in the general population. Hypertension is highly prevalent in KTRs and represents a major modifiable risk factor associated with adverse cardiovascular outcomes and reduced patient and graft survival. Proper definition of hypertension and recognition of special phenotypes and abnormal diurnal blood pressure (BP) patterns is crucial for adequate BP control. Misclassification by office BP is commonly encountered in these patients, and a high proportion of masked and uncontrolled hypertension, as well as of white-coat hypertension, has been revealed in these patients with the use of ambulatory BP monitoring. The pathophysiology of hypertension in KTRs is multifactorial, involving traditional risk factors, factors related to chronic kidney disease and factors related to the transplantation procedure. In the absence of evidence from large-scale randomized controlled trials in this population, BP targets for hypertension management in KTR have been extrapolated from chronic kidney disease populations. The most recent Kidney Disease Improving Global Outcomes 2021 guidelines recommend lowering BP to less than 130/80 mmHg using standardized BP office measurements. Dihydropyridine calcium channel blockers and angiotensin-converting enzyme inhibitors/angiotensin-II receptor blockers have been established as the preferred first-line agents, on the basis of emphasis placed on their favorable outcomes on graft survival. The aim of this review is to provide previous and recent evidence on prevalence, accurate diagnosis, pathophysiology and treatment of hypertension in KTRs.

Hypertension in kidney transplant recipients

Cardiovascular events, including ischemic heart disease, heart failure, and arrhythmia, are common complications after kidney transplantation and continue to be leading causes of graft loss. Kidney transplant recipients have both traditional and transplant-specific risk factors for cardiovascular disease. In the general population, modification of cardiovascular risk factors is the best strategy to reduce cardiovascular events; however, studies evaluating the impact of risk modification strategies on cardiovascular outcomes among kidney transplant recipients are limited. Furthermore, there is only minimal guidance on appropriate cardiovascular screening and monitoring in this unique patient population. This review focuses on the limited scientific evidence that addresses cardiovascular events in kidney transplant recipients. Additionally, we focus on clinical management of specific cardiovascular entities that are more prevalent among kidney transplant recipients (ie, pulmonary hypertension, valvular diseases, diastolic dysfunction) and the use of newer evolving drug classes for treatment of heart failure within this cohort of patients. We note that there are no consensus documents describing optimal diagnostic, monitoring, or management strategies to reduce cardiovascular events after kidney transplantation; however, we outline quality initiatives and research recommendations for the assessment and management of cardiovascular-specific risk factors that could improve outcomes. 

New Approaches to Cardiovascular Disease and Its Management in Kidney Transplant Recipients

In Brief Visual Abstract Export 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. Key Points The highest fibroblast growth factor 23 (FGF23) quartile had impaired VO2Max and ventilatory exercise response patterns compared with the lowest FGF23 quartile. FGF23 was associated with changes in VO2Max in advanced CKD and after restitution of the failing kidney by transplantation. FGF23 was only associated with the progression of left ventricular mass index in patients with advanced CKD, however this association was lost after adjustment for dialysis status in the final model and was not associated after kidney transplantation in all models. 

FGF23 and Cardiovascular Structure and Function in Advanced Chronic Kidney Disease

Visual Abstract Key Points The highest fibroblast growth factor 23 (FGF23) quartile had impaired VO2Max and ventilatory exercise response patterns compared with the lowest FGF23 quartile. FGF23 was associated with changes in VO2Max in advanced CKD and after restitution of the failing kidney by transplantation. FGF23 was only associated with the progression of left ventricular mass index in patients with advanced CKD, however this association was lost after adjustment for dialysis status in the final model and was not associated after kidney transplantation in all models. 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.

AIMS This study aimed to examine if the cardiac changes associated with uraemic cardiomyopathy are reversed by renal transplantation. METHODS AND RESULTS MEDLINE, Embase, OpenGrey, and the Cochrane Library databases were searched from 1950 to March 2020. The primary outcome measure was left ventricular mass index. Secondary outcome measures included left ventricular dimensions and measures of diastolic and systolic function. Studies were included if they used any imaging modality both before and after successful renal transplantation. Data were analysed through meta-analysis approaches. Weight of evidence was assessed through the Grading of Recommendations Assessment, Development and Evaluation system. Twenty-three studies used echocardiography, and three used cardiac magnetic resonance imaging as their imaging modality. The methodological quality of the evidence was generally poor. Four studies followed up control groups, two using cardiac magnetic resonance imaging and two using echocardiography. Meta-analysis of these studies indicated that there was no difference in left ventricular mass index between groups following transplantation {standardized mean difference -0.07 [95% confidence interval (CI) -0.41 to 0.26]; P = 0.67}. There was also no difference observed in left ventricular ejection fraction [mean difference 0.39% (95% CI -4.09% to 4.87%); P = 0.86] or left ventricular end-diastolic volume [standardized mean difference -0.24 (95% CI -0.94 to 0.45); P = 0.49]. Inconsistent reporting of changes in diastolic dysfunction did not allow for any meaningful analysis or interpretation. CONCLUSIONS The evidence does not support the notion that uraemic cardiomyopathy is reversible by renal transplantation. However, the evidence is limited by methodological weaknesses, which should be considered when interpreting these findings.

https://onlinelibrary.wiley.com/doi/pdf/10.1002/ehf2.13283

Charalampos Loutradis

Papers

Changes in left ventricular structure and function associated with renal transplantation: a systematic review and meta-analysis.