Management of cardiovascular risk factors and other comorbidities in CKD

Introduction

Chronic kidney disease (CKD) affects over 650 million people and is the 12^th leading cause of death globally (1). CKD population have a higher comorbidity burden and sustain adverse outcomes at a higher rate. Hence, it is imperative to recognize and manage kidney disease progression and comorbid conditions that accompany CKD and complications that arise as kidney function declines. A multidisciplinary approach may improve care, quality of life, survival, and medical cost (2,3) for those with CKD as it encompasses management of comorbidities and adoption of lifestyle modifications. Cardiovascular (CV) disease continues to be the leading cause of death in patients with CKD (4) and are at higher risk of heart failure, pulmonary hypertension, and arrhythmias such as atrial fibrillation. Often, depression, pruritus, and impaired physical function are under recognized in clinical practice. In the current issue of Current Opinion in Nephrology and Hypertension, various articles address therapies for these complications and comorbidities that occur with CKD.

Cardiovascular disease management

LDL-c reduction

Patients with CKD and end-stage kidney disease (ESKD) are at higher risk for both atherosclerotic and non-atherosclerotic CV events. Low-density lipoprotein cholesterol (LDL-C) reduction is often targeted for lowering CV risk. Kidney Disease: Improving Global Outcomes (KDIGO) guidelines recommend initiation of statins or statin/ezetimibe (a cholesterol absorption inhibitor) combination for primary prevention of CV disease in patients > 50 years with estimated glomerular filtration rate (eGFR) <60 ml/min/1.73m², but not on dialysis (5). In patients between the ages of 18–49 with CKD (non-dialysis dependent), statin initiation is recommended for those with known CV disease or those at very high risk of CV events (5). If a targeted LDL-C level is not achieved with a statin or if eGFR<30 ml/min/1.73m², and there is a higher toxicity risk with high-intensity statins, others agents can be used to reduce LDL-C levels. Recent real-world data also support the safety and efficacy of using low-to-moderate dose statins in those with CKD (6). Goonasekera et al. (7) review the role of agents other than statins to lower LDL-c in the CKD population. Ezetimibe, monoclonal anti-proprotein convertase subtilisin kexin type-9 (PCSK9) antibodies, PCSK9 synthesis inhibitors, cholesterol synthesis inhibitors, and agents targeting apolipoprotein B (Apo-B) are various alternate options. While no dose adjustment is needed for patients with CKD on ezetimibe, recommended as a second-line agent, its interaction with cyclosporine should be considered. Fully humanized monoclonal anti-PCSK9 antibodies are third-line agents that have also been efficacious in reducing LDL-C levels in those with CV disease, CV equivalent risk factors, or those with primary hypercholesterolemia. No medication interaction or dose adjustment is needed with this agent in patients with CKD, but higher cost is a limiting factor. PCSK9 synthesis inhibitors are a promising class of drug to lower LDL-C levels that are currently undergoing phase-3 trial; however, the potential downside of these agents is that they are renally cleared. Cholesterol synthesis inhibitors may reduce LDL-C level by inhibiting ATP citrate lyase and restricting acetyl-CoA from mitochondrial citrate for cholesterol biosynthesis, but they are associated with increased blood urate level and an initial reduction in the eGFR.

Iron and Heart failure

Heart failure (HF) is the leading cause of hospitalization in those with CKD. Recent data highlight the impact of iron deficiency anemia in those with CKD (8). While iron deficiency is one of the most common causes of anemia in the CKD population, iron deficiency in patients with HF (even among those without CKD) is also increasing (9,10). The benefits of intravenous (IV) iron therapy in patients in both populations (HF with reduced ejection fraction and CKD) are summarized by Walther et al. (11). Agents like ferric carboxymaltose and iron sucrose may be used to manage patients with HF and potentially improve kidney function. IV ferric carboxymaltonse, an iron carbohydrate complex, has been associated with an improvement in symptoms of HF, anemia, and physical activity, and IV iron sucrose has been associated with improved systolic and diastolic dysfunction. Furthermore, in patients with CKD and ESKD, IV iron therapy has been associated with reduced risk of adverse events like myocardial infarction, cerebral vascular accident, hospitalizations related to CV events and mortality. Despite its advantages, current evidence suggests an association between IV iron therapy and iron overload and increased infectious risk. Ongoing trials would shed light on the long-term effects including the safety of IV iron therapy in those with HF.

Pulmonary hypertension

Pulmonary hypertension (PH) is common among patients with CKD and ESKD and is associated with an increased risk of mortality and cardiovascular events (12, 13). In CKD, underlying volume overload, left ventricular dysfunction, and the cardiovascular stress imposed by the arteriovenous (AV) dialysis access contribute to this higher burden. Edmonston et al. (14) comprehensively discuss the available therapeutic options to improve CKD associated PH. Therapy should be directed to improve volume status via optimizing medical management in CKD patients not on renal replacement therapy and increasing ultrafiltration during dialysis for patients on renal replacement therapy. Surgical ligation of a high flow AV fistula may also be considered in certain situations. Targeted medications are primarily approved for the management of class 1 PH or pulmonary arterial hypertension (13, 14). While the role of these agents in the CKD population is unclear, the pathogenesis of CKD associated pulmonary hypertension implies that these agents may be advantageous. Endothelin receptor agonists, phosphodiesterase 5 inhibitors, prostacyclin agonists and prostanoids, and peroxisome proliferator-activated receptor-gamma have been used to treat pulmonary arterial hypertension by affecting the pulmonary vascular tone and remodeling. Since they also regular the kidney vascular tone, promote vasodilation, and influence tubuloglomerular feedback, these agents may have a potential role in improving CKD associated PH.

Oral anticoagulants in CKD

Patients with CKD and ESKD are at high risk for thromboembolic events (15). While the use of vitamin K antagonists (VKAs) remain the first line, they are associated with an increased bleeding risk, warfarin associated calciphylaxis, and warfarin related nephropathy (16, 17, 18). Mavrakanas et al. (19) discuss the role of direct oral anticoagulants (DOACs) in patients with acute kidney injury, CKD, and ESKD. In patients with CKD Stage 3, available DOACs are non-inferior or superior to VKAs in reducing the risk of stroke or embolism. In patients with CKD Stage 4 or 5 (non-dialysis dependent), dose reduction for DOACs is recommended, but their role in decreasing stroke risk has not been firmly established. In patients with ESKD, oral anticoagulation may be used for stroke prevention; however, both VKAs and DOACs are associated with increased major bleeding risk. Further, the use of DOACs is dose-dependent, and the efficacy of low dose DOACs in the prevention of stroke or venous thromboembolism is indeterminate, which further limits its use. Prospective data on DOACs and VKAs suggest benefit in patients with acute kidney injury, but no randomized trials have been performed to support this.

Other comorbidity burden in CKD

Depression in CKD

Often overlooked, depression is highly prevalent among patients with CKD or ESKD (20). Diagnosing and treating patients with depression is critical, as depression is associated with increased mortality among those with CKD (21). Gregg et al. (22) provide an overview of pharmacologic therapy and cognitive-behavioral therapy (CBT) as treatment options for depression in the CKD or ESKD-hemodialysis dependent population. In the general population, a combination approach is often used to manage symptoms of depression. Antidepressants are usually selected as the initial therapeutic option, and selective serotonin reuptake inhibitors (SSRIs) are the most common class of antidepressants prescribed (23). Evidence on therapeutic options in the CKD or ESKD population for management of depression is limited. Sertraline, an SSRI, has been studied in randomized clinical trials (RCTs) for the management of patients with CKD and ESKD, but it has failed to be more effective than placebo in managing symptoms of depression (24). Further, adverse effects, including gastrointestinal side effects, neurologic side effects, and sexual dysfunction limit their use. CBT is an effective psychotherapy method employed for initial management of depression in the general population and a viable alternative option for patients with CKD or ESKD with evidence suggesting that it is associated with a higher quality of life (25, 26). However, limitations such as limited availability to attend these sessions for patients on thrice weekly dialysis have to be considered. Future research should focus on combination therapy for those on different dialysis modalities.

Exercise and physical activity in CKD

Physical inactivity is associated with poor quality of life and lower functional status, along with an increased risk of morbidity and mortality in CKD (27). The advantages of various exercise programs in this population are reviewed by Wilkinson et al. (28). While any form of exercise may enhance physical activity and improve muscle mass, a meta-analysis of 11 clinical trials for patients with CKD Stage 3 and 4, aerobic exercise improved eGFR and exercise tolerance (29). In the dialysis-dependent population, there is limited data supporting the use of various exercise protocols (including high-intensity interval training, virtual reality gaming, intradialytic yoga, electrical stimulation of muscles, blood flow restriction training, protocols that combine exercise and nutrition) to improve their physical activity. Very few studies have demonstrated the advantage of protocols combining aerobic and resistance exercises to improve physical activity and quality of life which could be focus of future studies.

Pruritus

Pruritus has been associated with poor quality of life, other mental disorders such as depression, and with mortality in those on dialysis. Recent reports also highlight that this is prevalent among 24% of dialysis population. In this issues, Trachtenberg and colleagues reviewed recent therapeutic options that are being examined in clinical trials including the recently reported KALM trial that studied the effects of difelikefalin, a peripherally restricted selective kappa opioid receptor agonist in hemodialysis population. (30, 31)

In summary, recent data have suggested the potential benefits of various therapeutic options to manage complications and comorbidities that are common but often under recognized in patients with CKD or ESKD. While these data are encouraging, additional larger clinical studies to firmly establish the benefits and safety of various agents tested in these studies are needed.