Evaluation of the effect of sodium zirconium cyclosilicate on arrhythmia-related cardiovascular outcomes in patients receiving chronic haemodialysis with hyperkalaemia: protocol for the multicentre, randomised, controlled DIALIZE-Outcomes study.

INTRODUCTION: Patients with kidney failure receiving chronic haemodialysis have elevated risk of arrhythmias potentially increasing the likelihood of sudden cardiac death, stroke and hospitalisation. The DIALIZE study (NCT03303521) demonstrated that sodium zirconium cyclosilicate (SZC) was an efficacious and well-tolerated treatment for predialysis hyperkalaemia in patients undergoing haemodialysis. The DIALIZE-Outcomes study evaluates the effect of SZC on sudden cardiac death and arrhythmia-related cardiovascular outcomes in patients receiving chronic haemodialysis with recurrent hyperkalaemia. METHODS AND ANALYSIS: International, multicentre, randomised, double-blind, placebo-controlled study conducted at 357 study sites across 25 countries. Adults (≥18 years) receiving chronic haemodialysis three times per week with recurrent predialysis serum potassium (K+) ≥5.5 mmol/L post long interdialytic interval (LIDI) are eligible. Patients (~2800) will be randomised 1:1 to SZC or placebo, starting at 5 g orally once daily on non-dialysis days and titrated weekly in 5 g increments (maximum 15 g) to target predialysis serum K+ 4.0-5.0 mmol/L post LIDI. The primary objective is to evaluate efficacy of SZC versus placebo in reducing occurrence of the primary composite endpoint of sudden cardiac death, stroke or arrhythmia-related hospitalisation, intervention or emergency department visit. Secondary endpoints include efficacy of SZC versus placebo in maintaining normokalaemia (serum K+ 4.0-5.5 mmol/L post LIDI) at the 12-month visit, preventing severe hyperkalaemia (serum K+ ≥6.5 mmol/L post LIDI) at the 12-month visit and reducing the incidence of individual cardiovascular outcomes. Safety of SZC will be evaluated. The study is event driven, with participants remaining in the study until 770 primary endpoint events have occurred. Average time in the study is expected to be ~25 months. ETHICS AND DISSEMINATION: Approval was obtained from the relevant institutional review board/independent ethics committee from each participating site (approving bodies in supplementary information). The results will be submitted to a peer-reviewed journal. TRIAL REGISTRATION NUMBERS: EudraCT 2020-005561-14 and clinicaltrials.gov identifier NCT04847232.

Management of Heart Failure Patient with CKD.

CKD is common in patients with heart failure, associated with high mortality and morbidity, which is even higher in people undergoing long-term dialysis. Despite increasing use of evidence-based drug and device therapy in patients with heart failure in the general population, patients with CKD have not benefitted. This review discusses prevalence and evidence of kidney replacement, device, and drug therapies for heart failure in CKD. Evidence for treatment with ß-blockers, angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, angiotensin receptor neprilysin inhibitors, and sodium-glucose cotransporter inhibitors in mild-to-moderate CKD has emerged from general population studies in patients with heart failure with reduced ejection fraction (HFrEF). ß-Blockers have been shown to improve outcomes in patients with HFrEF in all stages of CKD, including patients on dialysis. However, studies of HFrEF selected patients with creatinine <2.5 mg/dl for ACE inhibitors, <3.0 mg/dl for angiotensin-receptor blockers, and <2.5 mg/dl for mineralocorticoid receptor antagonists, excluding patients with severe CKD. Angiotensin receptor neprilysin inhibitor therapy was successfully used in randomized trials in patients with eGFR as low as 20 ml/min per 1.73 m2 Hence, the benefits of renin-angiotensin-aldosterone axis inhibitor therapy in patients with mild-to-moderate CKD have been demonstrated, yet such therapy is not used in all suitable patients because of fear of hyperkalemia and worsening kidney function. Sodium-glucose cotransporter inhibitor therapy improved mortality and hospitalization in patients with HFrEF and CKD stages 3 and 4 (eGFR>20 ml/min per 1.73 m2). High-dose and combination diuretic therapy, often necessary, may be complicated with worsening kidney function and electrolyte imbalances, but has been used successfully in patients with CKD stages 3 and 4. Intravenous iron improved symptoms in patients with heart failure and CKD stage 3; and high-dose iron reduced heart failure hospitalizations by 44% in patients on dialysis. Cardiac resynchronization therapy reduced death and hospitalizations in patients with heart failure and CKD stage 3. Peritoneal dialysis in patients with symptomatic fluid overload improved symptoms and prevented hospital admissions. Evidence suggests that combined cardiology-nephrology clinics may help improve management of patients with HFrEF and CKD. A multidisciplinary approach may be necessary for implementation of evidence-based therapy.

Diagnosis, Evaluation, Prevention, and Treatment of Chronic Kidney Disease-Mineral and Bone Disorder: Synopsis of the Kidney Disease: Improving Global Outcomes 2017 Clinical Practice Guideline Update.

Description: The Kidney Disease: Improving Global Outcomes (KDIGO) 2017 Clinical Practice Guideline Update for the Diagnosis, Evaluation, Prevention, and Treatment of Chronic Kidney Disease-Mineral and Bone Disorder (CKD-MBD) is a selective update of the prior CKD-MBD guideline published in 2009. The guideline update and the original publication are intended to assist practitioners caring for adults with CKD and those receiving long-term dialysis. Methods: Development of the guideline update followed an explicit process of evidence review and appraisal. The approach adopted by the Work Group and the evidence review team was based on systematic reviews of relevant trials, appraisal of the quality of the evidence, and rating of the strength of recommendations according to the GRADE (Grading of Recommendations Assessment, Development and Evaluation) approach. Searches of the English-language literature were conducted through September 2015 and were supplemented with targeted searches through February 2017. Final modification of the guidelines was informed by a public review process involving numerous stakeholders, including patients, subject matter experts, and industry and national organizations. Recommendations: The update process resulted in the revision of 15 recommendations. This synopsis focuses primarily on recommendations for diagnosis of and testing for CKD-MBD and treatment of CKD-MBD that emphasizes decreasing phosphate levels, maintaining calcium levels, and addressing elevated parathyroid hormone levels in adults with CKD stage G3a to G5 and those receiving dialysis. Key elements include basing treatment on trends in laboratory values rather than a single abnormal result and being cautious to avoid hypercalcemia when treating secondary hyperparathyroidism.

Oral Anticoagulants to Prevent Stroke in Nonvalvular Atrial Fibrillation in Patients With CKD Stage 5D: An NKF-KDOQI Controversies Report.

Stroke risk may be more than 3-fold higher among patients with chronic kidney disease stage 5D (CKD-5D) compared to the general population, with the highest stroke rates noted among those 85 years and older. Atrial fibrillation (AF), a strong risk factor for stroke, is the most common arrhythmia and affects >7% of the population with CKD-5D. Warfarin use is widely acknowledged as an important intervention for stroke prevention with nonvalvular AF in the general population. However, use of oral anticoagulants for stroke prevention in patients with CKD-5D and nonvalvular AF continues to be debated by the nephrology community. In this National Kidney Foundation-Kidney Disease Outcomes Quality Initiative (NKF-KDOQI) controversies report, we discuss the existing observational studies that examine warfarin use and associated stroke and bleeding risks in adults with CKD-5D and AF. Non-vitamin K-dependent oral anticoagulants and their potential use for stroke prevention in patients with CKD-5D and nonvalvular AF are also discussed. Data from randomized clinical trials are urgently needed to determine the benefits and risks of oral anticoagulant use for stroke prevention in the setting of AF among patients with CKD-5D.

Executive summary of the 2017 KDIGO Chronic Kidney Disease-Mineral and Bone Disorder (CKD-MBD) Guideline Update: what's changed and why it matters.

The KDIGO 2017 Clinical Practice Guideline Update for the Diagnosis, Evaluation, Prevention, and Treatment of CKD-MBD represents a selective update of the prior CKD-MBD Guideline published in 2009. This update, along with the 2009 publication, is intended to assist the practitioner caring for adults and children with chronic kidney disease (CKD), those on chronic dialysis therapy, or individuals with a kidney transplant. This review highlights key aspects of the 2017 CKD-MBD Guideline Update, with an emphasis on the rationale for the changes made to the original guideline document. Topic areas encompassing updated recommendations include diagnosis of bone abnormalities in CKD-mineral and bone disorder (MBD), treatment of CKD-MBD by targeting phosphate lowering and calcium maintenance, treatment of abnormalities in parathyroid hormone in CKD-MBD, treatment of bone abnormalities by antiresorptives and other osteoporosis therapies, and evaluation and treatment of kidney transplant bone disease.

Acute and chronic cardiovascular effects of hyperkalemia: new insights into prevention and clinical management.

The plasma pool of potassium is a partial reflection of the overall body, transient cellular shifts, and potassium elimination regulated by the kidneys. Potassium concentrations elevating above the upper limit of normal (> 5.0 mEq/L) have become more common in cardiovascular practice due to the growing population of patients with chronic kidney disease and the broad applications of drugs that modulate potassium excretion by either reducing production of angiotensin II (angiotensin-converting enzyme inhibitors, direct renin inhibitors, beta-adrenergic receptor antagonists), blocking angiotensin II receptors (angiotensin receptor blockers), or antagonizing the action of aldosterone on mineralocorticoid receptors (mineralocorticoid receptor antagonists). In addition, acute kidney injury, critical illness, crush injuries, and massive red blood cell transfusions can result in hyperkalemia. Progressively more severe elevations in potassium are responsible for abnormalities in cardiac depolarization and repolarization and contractility. Untreated severe hyperkalemia results in sudden cardiac death. Traditional management steps have included reducing dietary potassium and discontinuing potassium supplements; withdrawal of exacerbating drugs; acute treatment with intravenous calcium gluconate, insulin, and glucose; nebulized albuterol; correction of acidosis with sodium bicarbonate for short-term shifts out of the plasma pool; and, finally, gastrointestinal ion exchange with oral sodium polystyrene sulfonate in sorbitol, which is mainly used in the hospital and is poorly tolerated due to gastrointestinal adverse effects. This review explores hyperkalemia as a complication in cardiovascular patients and highlights new acute, chronic, and preventative oral therapies (patiromer calcium, cross-linked polyelectrolyte, ZS-9) that could potentially create a greater margin of safety for vulnerable patients with combined heart and kidney disease.

Serum phosphorus levels associate with coronary atherosclerosis in young adults.

Phosphorus levels correlate with atherosclerosis in both animal models and humans with advanced chronic kidney disease, but whether this relationship exists among individuals with normal kidney function is unknown. This study aimed to determine whether an association exists between phosphorus levels and coronary artery calcium levels in a community-based cohort of 3015 healthy young adults in the prospective Coronary Artery Risk Development in Young Adults (CARDIA) study. Phosphorus levels were measured at baseline, and presence of coronary artery calcium was assessed by computed tomography 15 yr later. Mean age at study inception was 25.2 yr, and the mean levels of phosphorus and calcium were 3.6 and 9.5 mg/dl, respectively. Only 0.2% of participants had estimated GFR <60 ml/min per 1.73 m(2). Phosphorus levels were associated with coronary artery calcium in unadjusted models. In multivariate models, however, phosphorus levels were significantly associated with the category of coronary artery calcium level. In conclusion, higher serum phosphorus levels, even within the normal range, may be a risk factor for coronary artery atherosclerosis in healthy young adults.

Phosphorus levels are associated with subclinical atherosclerosis in the general population.

BACKGROUND: Elevated serum phosphorus has been linked to mortality among patients with renal failure and in one study in the general population. The aim of our study was to examine the association of serum phosphorus level with carotid atherosclerosis in the general population. METHODS: We determined the association of serum phosphorus levels with carotid intima-media thickness (cIMT) in 13,340 subjects 45-64 years old without known coronary heart disease, stroke, or renal disease from the Atherosclerosis Risk in Communities (ARIC) study. RESULTS: Phosphorus levels were significantly associated with age, female gender, diabetes mellitus, hypertension, hypercholesterolemia and fibrinogen levels (p < 0.0001 for each), but not with estimated glomerular filtration rate (eGFR). Age- and sex-adjusted mean cIMT ranged from 0.718 to 0.736 mm for the lowest to the highest quintile of serum phosphorus (p-value for trend < 0.0001). This relationship was attenuated but remained statistically significant after adjustment for atherosclerotic risk factors and eGFR (trend p < 0.0001) in men but not in women. In a multivariable model, a one standard deviation increase in baseline serum phosphorus (0.48 mg/dL) was associated with a 0.012 mm increase in mean cIMT (p < 0.007) in men. CONCLUSION: In a population-based cohort of subjects free of overt cardiovascular and renal disease serum phosphorus was positively associated with cIMT independent of traditional risk factors for atherosclerosis and eGFR in men but not in women.