Evolution of Mineralocorticoid Receptor Antagonists in the Treatment of Chronic Kidney Disease Associated with Type 2 Diabetes Mellitus.

Chronic kidney disease (CKD) is one of the most frequent complications associated with type 2 diabetes mellitus (T2DM) and is also an independent risk factor for cardiovascular disease. The mineralocorticoid receptor (MR) is a nuclear receptor expressed in many tissue types, including kidney and heart. Aberrant and long-term activation of MR by aldosterone in patients with T2DM triggers detrimental effects (eg, inflammation and fibrosis) in these tissues. The suppression of aldosterone at the early stage of T2DM has been a therapeutic strategy for patients with T2DM-associated CKD. Although patients have been treated with renin-angiotensin system (RAS) blockers for decades, RAS blockers alone are not sufficient to prevent CKD progression. Steroidal MR antagonists (MRAs) have been used in combination with RAS blockers; however, undesired adverse effects have restricted their usage, prompting the development of nonsteroidal MRAs with better target specificity and safety profiles. Recently conducted studies, Finerenone in Reducing Kidney Failure and Disease Progression in Diabetic Kidney Disease (FIDELIO-DKD) and Finerenone in Reducing Cardiovascular Mortality and Morbidity in Diabetic Kidney Disease (FIGARO-DKD), have reported that finerenone, a nonsteroidal MRA, improves both renal and cardiovascular outcomes compared with placebo. In this article, we review the history of MRA development and discuss the possibility of its combination with other treatment options, such as sodium-glucose cotransporter 2 inhibitors, glucagon-like peptide-1 receptor agonists, and potassium binders for patients with T2DM-associated CKD.

Kidney disease and congenital heart disease: Partnership for life.

The literature on the relationship between kidney and cardiovascular diseases is continuously expanding. Scientists have elucidated many of the neurohormonal and hemodynamic pathways involved in cardiorenal disease. However, little is known about kidney disease in patients with congenital heart disease. Given advances in the medical and surgical care of this highly complex patient population, survival rates have dramatically improved leading to a higher percentage of adults living with congenital heart disease. Accordingly, a noticeable increase in the prevalence of kidney disease is appreciated in these patients. Some of the main risk factors for developing chronic kidney disease in the adult congenital heart disease population include chronic hypoxia, neurohormonal derangements, intraglomerular hemodynamic changes, prior cardiac surgeries from minimally invasive to open heart surgeries with ischemia, and nephrotoxins. Unfortunately, data regarding the prevalence, pathophysiology, and prognosis of chronic kidney disease in the adult congenital heart disease population remain scarce. This has led to a lack of clear recommendations for evaluating and managing kidney disease in these patients. In this review, we discuss contemporary data on kidney disease in adults with congenital heart disease in addition to some of the gaps in knowledge we face. The article highlights the delicate interaction between disease of the heart and kidneys in these patients, and offers the practitioner tools to more effectively manage this vulnerable population.

Past, Present, and Future of Phosphate Management.

Cardiovascular (CV) disease (CVD) accounts for >50% of deaths with known causes in patients on dialysis. Elevated serum phosphorus levels are an important nontraditional risk factor for bone mineral disease and CVD in patients with chronic kidney disease (CKD). Given that phosphorus concentrations drive other disorders associated with increased CV risk (e.g., endothelial dysfunction, vascular calcification, fibroblast growth factor-23, parathyroid hormone), phosphate is a logical target to improve CV health. Phosphate binders are the only pharmacologic treatment approved for hyperphosphatemia. Although their safety has improved since inception, the mechanism of action leads to characteristics that make ingestion difficult and unpleasant; large pill size, objectionable taste, and multiple pills required for each meal and snack make phosphate binders a burden. Side effects, especially those affecting the gastrointestinal (GI) system, are common with binders, often leading to treatment discontinuation. The presence of "hidden" phosphates in processed foods and certain medications makes phosphate management even more challenging. Owing to these significant issues, most patients on dialysis are not consistently achieving and maintaining target phosphorus concentrations of <5.5 mg/dl, let alone more normal levels of <4.5 mg/dl, indicating novel approaches to improve phosphate management and CV health are needed. Several new nonbinder therapies that target intestinal phosphate absorption pathways have been developed. These include EOS789, which acts on the transcellular pathway, and tenapanor, which targets the dominant paracellular pathway. As observational evidence has established a strong association between phosphorus concentration and clinical outcomes, such as mortality, phosphate is an important target for improving the health of patients with CKD and end-stage kidney disease (ESKD).

Patient and Care Partner Burden in CKD Patients With and Without Anemia: A US-Based Survey.

Rationale & Objective: Chronic kidney disease (CKD) has a far-reaching impact on both patients and care partners, which can be further compounded by frequent complications such as anemia. This study assessed the burden experienced by patients with CKD and the care partners of patients with CKD, with and without anemia. Study Design: Online survey. Setting & Participants: Adult patients with CKD and the care partners of adult patients with CKD living in the United States were recruited through the American Association of Kidney Patients and a third-party online panel (January 9, 2020-March 12, 2020). Outcomes: Patient and care partner characteristics, care received or provided; health-related quality of life, and work productivity. Analytical Approach: Descriptive statistics were reported separately based on the presence or absence of anemia. Results: In total, 410 patients (anemia: n=190, no anemia: n=220) and 258 care partners (anemia: n=110, no anemia: n=148) completed the survey. Most patients reported receiving paid or unpaid care because of their health condition (anemia: 58.9%, no anemia: 50.9%), with an overall average of 14.2 and 11.3 h/wk among the anemia and no anemia patients, respectively. The care partners also reported providing numerous hours of care (anemia: 33.6 h/wk, no anemia: 38.0 h/wk), especially care partners living with their care recipient (anemia: 52.6 h/wk, no anemia: 42.8 h/wk). Among the patients, those with anemia reported a numerically lower average health-related quality of life (Functional Assessment of Cancer Therapy-Anemia score, anemia: 110.1; no anemia: 121.6). Most care partners reported a severe or very severe burden (Burden Scale for Family Caregivers-Short Version score≥15, anemia: 69.1%; no anemia: 58.8%). The work productivity impairment was substantial among employed patients (anemia: 44.9%, no anemia: 35.4%) and employed care partners (anemia: 47.9%, no anemia: 40.7%). Limitations: The survey results may have been subject to selection and recall biases; moreover, the observational nature of the study does not allow for causal inferences. Conclusions: Patients with CKD and the care partners of patients with CKD experience a considerable burden, especially when anemia is present.

Recent and Emerging Therapies for Iron Deficiency in Anemia of CKD: A Review.

Iron deficiency commonly contributes to the anemia affecting individuals with chronic kidney disease. This review describes diagnostic criteria for iron deficiency in chronic kidney disease, as well as mechanisms of functional and absolute iron deficiency and general treatment principles as delineated in the KDIGO (Kidney Disease: Improving Global Outcomes) guideline. Repletion of absolute iron deficits has progressed over time with the addition of better tolerated, more effective oral agents, including ferric citrate, ferric maltol, and sucrosomial iron. This article examines the structural characteristics and trial data enabling regulatory approval of these novel oral agents. Newer intravenous iron therapies, including ferric carboxymaltose and ferric derisomaltose, allow for fewer infusions and decreased risk of serious hypersensitivity reactions. Concerns about adverse effects such as cardiovascular events and infections are discussed. The potential risk of 6H syndrome (high FGF-23, hypophosphatemia, hyperphosphaturia, hypovitaminosis D, hypocalcemia, and secondary hyperparathyroidism) due to these intravenous agents is emphasized. The proposed pathophysiology of 6H syndrome and hypophosphatemia is described. Ferric pyrophosphate citrate enables administration of iron for repletion through dialysate. Relative merits, costs, and risks of various iron agents such as hypersensitivity and 6H syndrome/hypophosphatemia are summarized.

Iron Deficiency in CKD Without Concomitant Anemia.

The physiological role of iron extends well beyond hematopoiesis. Likewise, the pathophysiological effects of iron deficiency (ID) extend beyond anemia. Although inextricably interrelated, ID and anemia of chronic kidney disease (CKD) are distinct clinical entities. For more than 3 decades, however, nephrologists have focused primarily on the correction of anemia. The achievement of target hemoglobin (Hgb) concentrations is prioritized over repletion of iron stores, and iron status is generally a secondary consideration only assessed in those patients with anemia. Historically, the correction of ID independent of anemia has not been a primary focus in the management of CKD. In contrast, ID is a key therapeutic target in the setting of heart failure (HF) with reduced ejection fraction (HFrEF); correction of ID in this population improves functional status and quality of life and may improve cardiovascular (CV) outcomes. Given the strong interrelationships between HF and CKD, it is reasonable to consider whether iron therapy alone may benefit those with CKD and evidence of ID irrespective of Hgb concentration. In this review, we differentiate anemia from ID by considering both epidemiologic and pathophysiological perspectives and by reviewing the evidence linking correction of ID to outcomes in patients with HF and/or CKD. Furthermore, we discuss existing gaps in evidence and provide proposals for future research and practical considerations for clinicians.

Treatment of Anemia in Kidney Disease: Beyond Erythropoietin.

Anemia is common in patients with chronic kidney disease. Treatment with erythropoiesis-stimulating agents has decreased transfusion rates, but has not been consistently shown to improve cardiovascular outcomes or quality of life. Moreover, treatment to hemoglobin levels normal for the general population (13-14 g/dL) has resulted in increased cardiovascular morbidity and mortality versus lower hemoglobin targets, and some patients with chronic kidney disease do not reach these lower hemoglobin targets despite escalating doses of erythropoiesis-stimulating agents. The pathophysiology of anemia in patients with chronic kidney disease has been informed by the discovery of hypoxia-inducible factor and hepcidin pathways. Recent innovations in anemia treatment leverage knowledge of these pathways to effectively raise hemoglobin levels independent of erythropoiesis-stimulating agent administration. Several agents that stabilize hypoxia-inducible factor are undergoing or have completed phase 3 clinical trials. These agents appear to have equal efficacy as erythropoiesis-stimulating agents in raising hemoglobin levels and have not been associated with major safety signals to date. Because of the potential for off-target effects from non-anemia-related gene transcription by hypoxia-inducible factor stabilization, longer-term follow-up studies and registries will be needed to ensure safety. Agents that modulate hepcidin have undergone early clinical trials with mixed results regarding safety and efficacy in increasing hemoglobin levels. Sodium-glucose cotransporter 2 inhibitors, which also decrease hepcidin levels, have been associated with increased hemoglobin levels among patients with chronic kidney disease in clinical trials exploring proteinuria and kidney disease progression.

Hypoxia-Inducible Factor Stabilization as an Emerging Therapy for CKD-Related Anemia: Report From a Scientific Workshop Sponsored by the National Kidney Foundation.

The National Kidney Foundation convened an interdisciplinary international workshop in March 2019 to discuss the potential role of a new class of agents for the treatment of anemia in patients with chronic kidney disease (CKD): the hypoxia-inducible factor prolyl hydroxylase inhibitors (HIF-PHIs). International experts with expertise in physiology, biochemistry, structural chemistry, translational medicine, and clinical management of anemia participated. Participants reviewed the unmet needs of current anemia treatment, the biology of hypoxia-inducible factor, the pharmacology of prolyl hydroxylase inhibitors, and the results of phase 2 clinical trials of HIF-PHIs among patients with CKD, both those treated by dialysis and those not receiving kidney replacement therapy. The results of key phase 3 clinical trials of HIF-PHIs available as of the time of writing are also included in this report, although they appeared after the workshop was completed. Participants in the workshop developed a number of recommendations for further examination of HIF-PHIs, which are summarized in this report and include long-term safety issues, potential benefits, and practical considerations for implementation including patient and provider education.

Strategies to Reduce Rehospitalization in Patients with CKD and Kidney Failure.

Readmissions in patients with nondialysis-dependent CKD and kidney failure are common and are associated with significant morbidity, mortality, and economic consequences. In 2013, the Centers for Medicare and Medicaid Services implemented the Hospital Readmissions Reduction Program in an attempt to reduce high hospitalization-associated costs. Up to 50% of all readmissions are deemed avoidable and present an opportunity for intervention. We describe factors that are specific to the patient, the index hospitalization, and underlying conditions that help identify the "high-risk" patient. Early follow-up care, developing volume management strategies, optimizing nutrition, obtaining palliative care consultations for seriously ill patients during hospitalization and conducting goals-of-care discussions with them, instituting systematic advance care planning during outpatient visits to avoid unwanted hospitalizations and intensive treatment at the end of life, and developing protocols for patients with incident or prevalent cardiovascular conditions may help prevent avoidable readmissions in patients with kidney disease.

Iron Administration, Infection, and Anemia Management in CKD: Untangling the Effects of Intravenous Iron Therapy on Immunity and Infection Risk.

Patients with chronic kidney disease (CKD) are at increased risk for infection, attributable to immune dysfunction, increased exposure to infectious agents, loss of cutaneous barriers, comorbid conditions, and treatment-related factors (eg, hemodialysis and immunosuppressant therapy). Because iron plays a vital role in pathogen reproduction and host immunity, it is biologically plausible that intravenous iron therapy and/or iron deficiency influence infection risk in CKD. Available data from preclinical experiments, observational studies, and randomized controlled trials are summarized to explore the interplay between intravenous iron and infection risk among patients with CKD, particularly those receiving maintenance hemodialysis. The current evidence base, including data from a recent randomized controlled trial, suggests that proactive judicious use of intravenous iron (in a manner that minimizes the accumulation of non-transferrin-bound iron) beneficially replaces iron stores while avoiding a clinically relevant effect on infection risk. In the absence of an urgent clinical need, intravenous iron therapy should be avoided in patients with active infection. Although serum ferritin concentration and transferrin saturation can help guide clinical decision making about intravenous iron therapy, definition of an optimal iron status and its precise determination in individual patients remain clinically challenging in CKD and warrant additional study.