A large body of evidence implicates the renin-angiotensin system in the pathogenesis of cardiovascular disease. However, not everyone understands that the magnitude of the risk reduction achieved in clinical trials with angiotensin-converting enzyme inhibitors and angiotensin receptor blockers is only a fraction of the residual risk for cardiovascular events and death. This paper addresses limitations of current therapeutic approaches based on renin-angiotensin system blockade for hypertension and cardiovascular disease by illustrating the complex biochemical physiology and mechanism of classical and alternate angiotensin peptide formation. Emerging evidence of alternate mechanisms that bypass both renin and angiotensin-converting enzyme to produce the angiotensins in tissues and cells is not currently universally recognized. Currently available treatment would benefit from further insights to help fully meet the aims of patient care, and the challenge is to delve more deeply into the renin-angiotensin system cascade, with the aim of enhancing therapeutics for renin-angiotensin system inhibition. This article provides a reappraisal of the renin-angiotensin-aldosterone cascade, highlighting newly elucidated intermediary components and interplay, and their consequent implications and relevance for understanding the long-term contribution of angiotensin II in cardiovascular diseases and their therapy.
The past 90 years have witnessed an extraordinary trajectory of scientific discovery relating to aldosterone and mineralocorticoid receptor (MR) activation, and a profound reappraisal of their physiological and pathophysiological roles. Although most reviews hark back to 1953 and the isolation of aldosterone by Simpson et al.,1,2 in truth we must revert to an earlier decade for a complete picture. Although many readers will date the birth of the discovery of aldosterone (initially called "electrocortin") to 1953, when Simpson et al.
Chronic kidney disease (CKD) in type 2 diabetes is a large and growing problem leading to end-stage kidney disease, atherosclerotic cardiovascular disease, and heart failure (HF). Aldosterone is a key risk factor in promoting inflammation and fibrosis, which causes cardiorenal failure. Treatment with angiotensin-converting enzyme inhibitors or angiotensin receptor blockers does not prevent overactivation of the mineralocorticoid receptor. Therapeutic options and challenges with blocking MR overactivation by aldosterone are reviewed herein. Whereas classic steroidal mineralocorticoid receptor antagonists (MRAs) reduced albuminuria in short-term studies of diabetic and nondiabetic CKD, long-term studies evaluating hard endpoints such as loss of kidney function were not conducted in CKD because of side effects (primarily hyperkalemia). Novel nonsteroidal MRAs reduce proteinuria and markers of HF, with lower risk of hyperkalemia and without renal impairment, in comparison to steroidal MRAs. Furthermore, recent clinical trials have demonstrated the efficacy of the novel, selective, nonsteroidal MRA finerenone to delay progression of kidney and cardiovascular disease, including HF, in patients with CKD and type 2 diabetes. Concomitantly, the safety profile of finerenone is good, with few patients discontinuing treatment because of hyperkalemia, even among study participants with a low estimated glomerular filtration rate (>25 ml/min per 1.73 m2). Novel nonsteroidal attractive addition to the treatment paradigm in the management of patients with CKD and type 2 diabetes, overactivation.
Aldosterone controls salt-water homeostasis by acting on the mineralocorticoid receptor (MR), a ligand-activated transcription factor, in kidney epithelial cells. However, it is now evident that the MR is expressed in multiple cell types and tissues, acting as a key driver of cardiovascular disease. MR antagonists have proven to be highly efficient in patients with heart failure and reduced ejection fraction, and they are a cornerstone of contemporary therapy. In the past decade, a series of experimental studies using models with cell type-specific MRs uncovered the cellular and molecular mechanisms underlying its detrimental effect on left ventricular remodeling. Based on these findings, the potential of MR antagonists has been evaluated in other cardiovascular diseases, including coronary artery disease, arterial hypertension, heart failure with preserved ejection fraction, pulmonary hypertension, atrial fibrillation, and heart valve disease. The present review summarizes the current knowledge on MR activation and antagonism in cardiovascular disease.
The recent successful demonstrations that the nonsteroidal mineralocorticoid receptor (MR) antagonist finerenone provides effective kidney and cardiovascular (CV) protection in patients with chronic kidney disease (CKD) and type 2 diabetes constitutes a platform for considering and implementing an array of future clinical trials in patients with nondiabetic CKD. Activation of the MR, with consequent inflammation and fibrosis, should be operative as a pathogenetic mediator not only in patients with diabetic CKD but also in those with nondiabetic kidney disease. Consequently, it is proposed that MR antagonism therapy will be equally efficacious in patients with nondiabetic CKD. Recently, a major new clinical trial has been initiated testing finerenone in patients with nondiabetic kidney disease (FIND-CKD; NCT05047263). A second clinical development program, FIONA, is dedicated to studies of finerenone in children with glomerular and nonglomerular CKD. Finally, the interrelationship of fibroblast growth factor 23 (FGF23), membrane αKlotho (hereafter called Klotho), and aldosterone may be a propitious subject for future investigation. The interplay and intersection of these seemingly disparate yet intricate relationships may unmask novel, and indeed compelling, opportunities for therapeutic interventions that are capable of interrupting the vicious cycle of excess aldosterone/MR activation and FGF23 secretion with concomitant Klotho insufficiency characteristically present in patients with CKD.
Chronic kidney disease is a major global health challenge, and mineralocorticoid receptor (MR) signaling is thought to play a role in disease progression. The classic role of the MR is the regulation of fluid and electrolyte homeostasis via differential gene expression, and recently its role in modulating inflammation and fibrosis has been identified. In addition to expression of the MR in renal epithelial cells, it is also found in nonepithelial cells, such as endothelial cells, vascular smooth muscle cells, podocytes, and fibroblasts. Targeting the MR in these cells may play a role in offering protection against inflammation and fibrosis in the kidneys and the cardiovascular system. Herein, data from preclinical cell-specific MR knockout mouse models and in vitro studies that help uncover the role of the MR in nonepithelial cells are presented. This review also discusses several potential targets that offer opportunities for the targeting of MR signaling in nonepithelial cells.
Chronic kidney disease is a progressive condition that affects >10% of the general population worldwide, amounting to >800 million individuals. Chronic kidney disease is more prevalent in older individuals, women, racial minorities, and in people experiencing diabetes mellitus and hypertension. Chronic kidney disease represents an especially large burden in low- and middleincome countries, which are least equipped to deal with its consequences. Chronic kidney disease has emerged as one of the leading causes of mortality worldwide, and it is one of a small number of non-communicable diseases that have shown an increase in associated deaths over the past 2 decades. The high number of affected individuals and the significant adverse impact of chronic kidney disease should prompt enhanced efforts for better prevention and treatment.
Chronic kidney disease is characterized by progressive scarring that results in loss of normal tissue in the kidney and eventually end-stage kidney disease. Interstitial fibrosis and tubular atrophy have been most closely correlated with decline in renal function. Potential mechanisms include profibrotic changes in tubules, influx of profibrotic rather than healing reparative macrophages, and an increase in activated myofibroblasts. Aldosterone activates the mineralocorticoid receptor in the collecting duct to increase sodium reabsorption, resulting in increased blood pressure. Aldosterone also promotes inflammation and fibrosis in the kidney by activating the mineralocorticoid receptor in other cellular compartments, including podocytes, mesangial cells, epithelial cells, and myeloid cells. Aldosterone also may act indirectly by stimulating factors in epithelial tissues that contribute to inflammatory macrophage polarization, myofibroblast differentiation, and progressive fibrosis. This review discusses the potential mechanisms by which aldosterone and mineralocorticoid receptor activation promotes inflammation and fibrosis via nonclassical pathways in the kidney.
The coronavirus disease 2019 (COVID-19) pandemic, causing considerable mortality and morbidity worldwide, has fully engaged the biomedical community in attempts to elucidate the pathophysiology of COVID-19 and develop robust therapeutic strategies. To this end, the predominant research focus has been on the adaptive immune response to COVID-19 infections stimulated by mRNA and protein vaccines and on the duration and persistence of immune protection. In contrast, the role of the innate immune response to the viral challenge has been underrepresented. This overview focuses on the innate immune response to COVID-19 infection, with an emphasis on the roles of extracellular proteases in the tissue microenvironment. Proteinase-mediated signaling caused by enzymes in the extracellular microenvironment occurs upstream of the increased production of inflammatory cytokines that mediate COVID-19 pathology. These enzymes include the coagulation cascade, kinin-generating plasma kallikrein, and the complement system, as well as angiotensin-generating proteinases of the renin-angiotensin system. Furthermore, in the context of several articles in this Supplement elucidating and detailing the trajectory of diverse profibrotic pathways, we extrapolate these insights to explore how fibrosis and profibrotic pathways participate importantly in the pathogenesis of COVID-19. We propose that the lessons garnered from understanding the roles of microenvironment proteinases in triggering the innate immune response to COVID-19 pathology will identify potential therapeutic targets and inform approaches to the clinical management of COVID-19. Furthermore, the information may also provide a template for understanding the determinants of COVID-19-induced tissue fibrosis that may follow resolution of acute infection (so-called "long COVID"), which represents a major new challenge to our healthcare systems.
Patients with end-stage kidney disease (ESKD) requiring kidney replacement therapy are often treated in conventional dialysis centers at substantial cost and patient inconvenience. The recent United States Executive Order on Advancing American Kidney Health, in addition to focusing on ESKD prevention and reforming the kidney transplantation system, focuses on providing financial incentives to promote a shift toward home dialysis. In accordance with this order, a goal was set to have 80% of incident dialysis patients receiving home dialysis or a kidney transplant by 2025. Compared with conventional in-center therapy, home dialysis modalities, including both home hemodialysis and peritoneal dialysis, appear to offer equivalent or improved mortality, clinical outcomes, hospitalization rates, and quality of life in patients with ESKD in addition to greater convenience, flexibility, and cost-effectiveness. Treatment of anemia, a common complication of chronic kidney disease, may be easier to manage at home with a new class of agents, hypoxia-inducible factor-prolyl hydroxylase inhibitors, which are orally administered in contrast to the current standard of care of i.v. iron and/or erythropoiesis-stimulating agents. This review evaluates the clinical, quality-of-life, economic, and social aspects of dialysis modalities in patients with ESKD, including during the coronavirus disease 2019 pandemic; explores new therapeutics for the management of anemia in chronic kidney disease; and highlights how the proposed changes in Advancing American Kidney Health provide an opportunity to improve kidney health in the United States.
The global health impacts of kidney disease are increasingly recognized because of the rising burden of disease and associated health consequences. According to the most recent estimates from the Global Burden of Disease study, chronic kidney disease (CKD) has become the 12th leading cause of death, up from the 17th position approximately 3 decades ago.1Bikbov B. Purcell C. Levey A. et al.Global, regional, and national burden of chronic kidney disease, 1990-2017: a systematic analysis for the Global Burden of Disease Study 2017.Lancet. 2020; 395: 709-733Abstract Full Text Full Text PDF PubMed Scopus (546) Google Scholar The number of patients with kidney failure receiving kidney replacement therapy (KRT; dialysis and transplantation) was estimated to be 2.62 million in 2010, and this figure is projected to double by 2030, affecting almost 5.44 million people worldwide and up to 14.5 million needing KRT by 2030.2Liyanage T. Ninomiya T. Jha V. et al.Worldwide access to treatment for end-stage kidney disease: a systematic review.Lancet. 2015; 385: 1975-1982Abstract Full Text Full Text PDF PubMed Scopus (794) Google Scholar This growth in the number of people requiring KRT has revealed significant disparities across nation states. For instance, treatment gaps between those who receive KRT and those who need it are quite high, particularly in low-income regions such as Asia and Africa, where 1.91 million and 0.43 million people, respectively, in 2010 were not receiving necessary KRT.2Liyanage T. Ninomiya T. Jha V. et al.Worldwide access to treatment for end-stage kidney disease: a systematic review.Lancet. 2015; 385: 1975-1982Abstract Full Text Full Text PDF PubMed Scopus (794) Google Scholar Various factors such as the public spending on health care, health system characteristics, and clinical practice culture contribute to treatment disparities. A country's capacity to provide optimal care for patients living with kidney failure largely depends on adequate funding, a workforce with sufficient capacity to meet demand, access to essential medicines, and appropriate infrastructure for care delivery. Differences in these factors across world regions and countries have not been studied systematically. The second iteration of the International Society of Nephrology's Global Kidney Health Atlas (ISN-GKHA) provides information on the organization and structures of kidney care programs worldwide. Subject matter experts from 160 countries representing 98% of the world's population participated in a survey in 2018, and the results were published in 2019. Methodological details have been described elsewhere.3Bello A.K. Levin A. Lunney M. et al.Status of care for end stage kidney disease in countries and regions worldwide: international cross sectional survey.BMJ. 2019; 367: l5873Crossref PubMed Scopus (51) Google Scholar The objective of the ISN-GKHA was to provide a snapshot of individual country and regional health system characteristics and specific elements relevant to the management of patients with kidney failure in terms of the World Health Organization health care building blocks. In this issue of Kidney International Supplements, country-specific data on kidney care are summarized and presented for each of the 10 ISN regions. Each manuscript presents data regarding characteristics of participating countries, the burden of CKD and kidney failure, health finance and service delivery, health care workforce capacity, access to essential medications and health products for kidney care, and registries and national health policies for countries in a particular region. The introduction to the regional papers (Bello et al.,4Bello A.K. Okpechi I.G. Jha V. et al.Understanding distribution and variability in care organization and services for the management of kidney care across world regions.Kidney Int Suppl. 2021; 11: e4-e10Google Scholar this issue) provides a broad overview of the overall data from a global perspective, with a special focus on regional differences in the availability and accessibility of KRT. Differences between the first and second iterations of the ISN-GKHA and some changes in the nomenclature of kidney disease used in the regional manuscripts are highlighted. A common theme that emerged from the regional papers was the lack of workforce capacity for kidney care. Shortages were particularly severe for nephrologists, with shortages reported for all countries in South Asia and Latin America, and most countries in Africa. Nephrologist shortage was less severe in Western European countries. A number of challenges specific for different regions were also noted. Oguejiofor et al. highlighted severe workforce shortages, limited government funding for KRT, and excessive out-of-pocket payments for kidney care services as major issues for optimal management of kidney failure in Africa and suggested an urgent need to develop and implement preventive strategies to reduce CKD burden.5Oguejiofor F. Kiggundu D.S. Bello A.K. et al.International Society of Nephrology Global Kidney Health Atlas: structures, organization, and services for the management of kidney failure in Africa.Kidney Int Suppl. 2021; 11: e11-e23Google Scholar Dębska-Ślizień et al. emphasized workforce shortages in Eastern and Central Europe and suggested that these challenges could be addressed by improving the organization of nephrological care in some countries in the region.6Dębska-Ślizień A. Bello A.K. Johnson D.W. et al.International Society of Nephrology Global Kidney Health Atlas: structures, organization, and services for the management of kidney failure in Eastern and Central Europe.Kidney Int Suppl. 2021; 11: e24-e34Google Scholar Wainstein et al. argue that the large variabilities in the availability, accessibility, and quality of care in Latin America and the Caribbean were related to individual countries' funding structures, under-reliance on peritoneal dialysis (a less expensive KRT modality), and limited CKD surveillance and management initiatives.7Wainstein M. Bello A.K. Jha V. et al.International Society of Nephrology Global Kidney Health Atlas: structures, organization, and services for the management of kidney failure in Latin America.Kidney Int Suppl. 2021; 11: e35-e46Google Scholar Amouzegar et al. reported that, although countries in the Middle East had an abundance of resources, the region still lacked reliable and cost-effective measures to improve kidney care.8Amouzegar A. Abu-Alfa A.K. Alrukhaimi M.N. et al.International Society of Nephrology Global Kidney Health Atlas: structures, organization, and services for the management of kidney failure in the Middle East.Kidney Int Suppl. 2021; 11: e47-e56Google Scholar In reporting data for the Newly Independent States and Russia, Zakharova et al. highlighted low reporting of KRT quality indicators, as well as funding issues for kidney care across the region.9Zakharova E. Gaipov A. Bello A.K. et al.International Society of Nephrology Global Kidney Health Atlas: structures, organization, and services for the management of kidney failure in Newly Independent States and Russia.Kidney Int Suppl. 2021; 11: e57-e65Google Scholar They indicated the need for strategic government intervention and support to enhance kidney care in the region. Bello et al. identified significant gaps between the 2 largest countries in North America and the Caribbean (i.e., the United States and Canada) and other smaller countries in the region, and suggested that augmenting the workforce, improving the monitoring and reporting of KRT indicators, and implementing noncommunicable disease policies would enhance care, especially in the less wealthy countries.10Bello A.K. McIsaac M. Okpechi I.G. et al.International Society of Nephrology Global Kidney Health Atlas: structures, organization, and services for the management of kidney failure in North America and the Caribbean.Kidney Int Suppl. 2021; 11: e66-e76Google Scholar Zhang et al. reported a high burden of kidney failure in North and East Asia due to the aging of the population and the high prevalence of diabetes, cardiovascular disease, and hypertension, and showed differences in the availability of KRT modalities across jurisdictions in the region.11Zhang L. Wang J. Yang C.-W. et al.International Society of Nephrology Global Kidney Health Atlas: structures, organization, and services for the management of kidney failure in North and East Asia.Kidney Int Suppl. 2021; 11: e77-e85Google Scholar Ethier et al. revealed that although availability, accessibility, and quality of KRT were generally high in Oceania and South East Asia, variability between countries was due to inequalities in the accessibility and affordability of KRT.12Ethier I. Johnson D.W. Bello A.K. et al.International Society of Nephrology Global Kidney Health Atlas: structures, organization, and services for the management of kidney failure in Oceania and South East Asia.Kidney Int Suppl. 2021; 11: e86-e96Google Scholar Divyaveer et al. highlighted the large, but poorly documented burden of CKD in the South Asia region, and reported suboptimal and variable quality of care.13Divyaveer S.S. Ramachandran R. Sahay M. et al.International Society of Nephrology Global Kidney Health Atlas: structures, organization, and services for the management of kidney failure in South Asia.Kidney Int Suppl. 2021; 11: e97-e105Google Scholar They suggested that sustainable strategies needed to be developed to address the growing burden of kidney disease in the region. Finally, Dearbhla et al. showed that although countries in Western Europe had uniform capacity to provide care, there was scope for improvement in disease prevention and management, exemplified by the variability in disease burden and transplantation rates in the region.14Kelly D.M. Anders H.-J. Bello A.K. et al.International Society of Nephrology Global Kidney Health Atlas: structures, organization, and services for the management of kidney failure in Western Europe.Kidney Int Suppl. 2021; 11: e106-e118Google Scholar This collection of manuscripts from the 10 ISN regions provides a robust description of the state of kidney care around the world by leveraging standard metrics across regions. The manuscripts identify important barriers and challenges that have important policy implications for how kidney care is structured and delivered. VJ reports grants from GlaxoSmithKline and Baxter Healthcare, provides scientific leadership to George Clinical, and consultancy fees for Biocon, Zudis Cadilla, and NephroPlus, all paid to his institution, outside the submitted work. DWJ reports grants and personal fees from Baxter Healthcare and Fresenius Medical Care, travel sponsorship from Amgen, personal fees from Astra Zeneca, AWAK, and Ono, and grants from National Health and Medical Research Council of Australia, outside the submitted work. All the other authors declared no competing interests. This article is published as part of a supplement supported by the International Society of Nephrology (ISN; grant RES0033080 to the University of Alberta). We thank Kara Stephenson Gehman in ISN–Global Kidney Health Atlas (GKHA) for carefully editing the English text of a draft of this manuscript. We thank Jo-Ann Donner, Coordinator at the ISN, for her prominent role and leadership in the manuscript management, editorial reviews, and submission process to Kidney International Supplements, Sandrine Damster, Senior Research Project Manager at the ISN, and Alberta Kidney Disease Network staff (Ghenette Houston, Sue Szigety, and Sophanny Tiv) for helping to organize and conduct the survey and for providing project management support. We also thank the ISN headquarters staff including the Executive Director, Charu Malik, and the Advocacy team. We also appreciate the support from the ISN's Executive Committee, regional leadership, and Affiliated Society leaders at the regional and country levels for their help with the ISN-GKA survey.
Hypoxia-inducible factor-prolyl hydroxylase domain inhibitors (HIF-PHIs) are a promising new class of orally administered drugs currently in late-stage global clinical development for the treatment of anemia of chronic kidney disease (CKD). HIF-PHIs activate the HIF oxygen-sensing pathway and are efficacious in correcting and maintaining hemoglobin levels in patients with non-dialysis- and dialysis-dependent CKD. In addition to promoting erythropoiesis through the increase in endogenous erythropoietin production, HIF-PHIs reduce hepcidin levels and modulate iron metabolism, providing increases in total iron binding capacity and transferrin levels, and potentially reducing the need for i.v. iron supplementation. Furthermore, HIF-activating drugs are predicted to have effects that extend beyond erythropoiesis. This review summarizes clinical data from current HIF-PHI trials in patients with anemia of CKD, discusses mechanisms of action and pharmacologic properties of HIF-PHIs, and deliberates over safety concerns and potential impact on anemia management in patients with CKD. Copyright (C) 2021, International Society of Nephrology. Published by Elsevier Inc. All rights reserved.
Anemia is common in patients with chronic kidney disease (CKD) and results from the dysregulation of iron metabolism and erythropoiesis. Hepcidin is a key regulator of iron availability and leads to iron sequestration during the state of iron repletion. Decreases in the level of hepcidin in the presence of hypoxia and/or iron limitation allow for greater iron availability for erythropoiesis. However, kidney excretion of hepcidin decreases as the severity of CKD increases, whereas production of hepcidin is increased under inflammatory conditions often present in patients with CKD, both of which contribute to anemia. Assessment of iron status is, therefore, essential in the treatment of anemia. However, current laboratory tests for the determination of the adequate supply of iron have many limitations, including diurnal variation in the levels of biomarkers, lack of standardized reference methods across laboratories, and confounding by the presence of inflammation. In addition, the current treatment paradigm for anemia of CKD can further disrupt iron homeostasis; for example, treatment with erythropoiesis-stimulating agents in the absence of supplemental iron can induce functional iron deficiency. Moreover, supplemental iron can further increase levels of hepcidin. Several novel therapies, including hypoxia-inducible factor prolyl hydroxylase inhibitors and hepcidin inhibitors/antagonists, have shown promise in attenuating the levels and/or activity of hepcidin in anemia of CKD, thus ensuring the availability of iron for erythropoiesis.
Information about disease burden and the available infrastructure and workforce to care for patients with kidney disease was collected for the second edition of the International Society of Nephrology Global Kidney Health Atlas. This paper presents findings for the 8 countries in the South Asia region. The World Bank categorizes Afghanistan and Nepal as low-income; Bangladesh, Bhutan, India, and Pakistan as lower middle-income; and Sri Lanka and the Maldives as upper-middle-income countries. The prevalence of chronic kidney disease (CKD) in South Asia ranged from 5.01% to 13.24%. Long-term hemodialysis and long-term peritoneal dialysis are available in all countries, but Afghanistan lacks peritoneal dialysis services. Kidney transplantation was available in all countries except Bhutan and Maldives. Hemodialysis was the dominant modality of long-term dialysis, peritoneal dialysis was more expensive than hemodialysis, and kidney transplantation overwhelmingly depended on living donors. Bhutan provided public funding for kidney replacement therapy (dialysis and transplantation); Sri Lanka, India, Pakistan, and Bangladesh had variable funding mechanisms; and Afghanistan relied solely on out-of-pocket expenditure. There were shortages of health care personnel across the entire region. Reporting was variable: Afghanistan and Sri Lanka have dialysis registries but publish no reports, whereas Bangladesh has a transplant registry. South Asia has a large, but poorly documented burden of CKD. Diabetes and hypertension are the major causes of CKD throughout the region with a higher prevalence of infectious causes in Afghanistan and a high burden of CKD of an unknown cause in Sri Lanka and parts of India. The extent and quality of care delivery is suboptimal and variable. Sustainable strategies need to be developed to address the growing burden of CKD in the region.
The articles in this edition of Kidney International Supplements timely focus on the rapidly evolving field of anemia management in patients with chronic kidney disease (CKD). The revolutionary introduction of recombinant human erythropoietin into the therapeutic arena in the 1980s profoundly changed the quality of life of most patients with end-stage kidney disease. However, it subsequently became clear that normalization of hemoglobin by erythropoiesis-stimulating agents (ESAs) was generally more harmful than beneficial, as demonstrated by several randomized controlled trials performed at the turn of the century.1Besarab A. Bolton W.K. Browne J.K. et al.The effects of normal as compared with low hematocrit values in patients with cardiac disease who are receiving hemodialysis and epoetin.N Engl J Med. 1998; 339: 584-590Crossref PubMed Scopus (1812) Google Scholar, 2Drueke T.B. Locatelli F. Clyne N. et al.Normalization of hemoglobin level in patients with chronic kidney disease and anemia.N Engl J Med. 2006; 355: 2071-2084Crossref PubMed Scopus (1715) Google Scholar, 3Singh A.K. Szczech L. Tang K.L. et al.Correction of anemia with epoetin alfa in chronic kidney disease.N Engl J Med. 2006; 355: 2085-2098Crossref PubMed Scopus (2178) Google Scholar, 4Pfeffer M.A. Burdmann E.A. Chen C.Y. et al.A trial of darbepoetin alfa in type 2 diabetes and chronic kidney disease.N Engl J Med. 2009; 361: 2019-2032Crossref PubMed Scopus (1557) Google Scholar Therefore, partial anemia correction has become the preferred treatment option in patients with CKD. Another important issue is the frequently observed state of absolute or functional iron deficiency requiring oral or i.v. iron supplementation. Because of poor absorption of iron from the gut due to high circulating hepcidin levels and poor gastrointestinal tolerance of most oral iron agents, the administration of i.v. iron has become routine practice in most patients with end-stage kidney disease. The recently published Proactive IV Iron Therapy in Haemodialysis Patients (PIVOTAL) trial, the first of its kind in a large-size hemodialysis patient population, provided an answer to the question whether relatively high i.v. iron sucrose doses are beneficial or harmful. The trial showed that monthly proactive administration of 400 mg i.v. iron with upper limits of serum ferritin of 700 μg/L and transferrin saturation of 40% not only decreased ESA use, but also lowered the risk of all-cause death, cardiovascular events, and infections compared with reactive low-dose i.v. iron.5Macdougall I.C. White C. Anker S.D. et al.Intravenous iron in patients undergoing maintenance hemodialysis.N Engl J Med. 2019; 380: 447-458Crossref PubMed Scopus (160) Google Scholar,6Macdougall I.C. Bhandari S. White C. et al.Intravenous iron dosing and infection risk in patients on hemodialysis: a prespecified secondary analysis of the PIVOTAL trial.J Am Soc Nephrol. 2020; 31: 1118-1127Crossref Scopus (27) Google Scholar Clearly, more randomized controlled trials are needed in patients with non–dialysis-dependent and dialysis-dependent CKD using different i.v. iron doses and brands in different patient populations, examining patient-centered outcomes. The development of a novel class of agents, the hypoxia-inducible factor–prolyl hydroxylase inhibitors (HIF-PHIs), represents an interesting alternative to correcting the anemia of patients with CKD,7Chen N. Hao C. Peng X. et al.Roxadustat for anemia in patients with kidney disease not receiving dialysis.N Engl J Med. 2019; 381: 1001-1010Crossref PubMed Scopus (207) Google Scholar,8Chen N. Hao C. Liu B.C. et al.Roxadustat treatment for anemia in patients undergoing long-term dialysis.N Engl J Med. 2019; 381: 1011-1022Crossref PubMed Scopus (209) Google Scholar with several possible advantages. HIF-PHIs are administered orally, in contrast to the parenteral administration of ESAs. HIF-PHIs are associated with much lower increases in circulating erythropoietin levels than treatment with traditional ESAs. Moreover, based on experimental evidence, PHIs are predicted to improve iron status by decreasing hepatic hepcidin production and to increase transcription of genes that promote iron availability.9Sanghani N.S. Haase V.H. Hypoxia-inducible factor activators in renal anemia: current clinical experience.Adv Chronic Kidney Dis. 2019; 26: 253-266Abstract Full Text Full Text PDF PubMed Scopus (67) Google Scholar However, clinical data on a possibly reduced need for i.v. iron supplementation as well as on global efficacy and cardiovascular safety are still too limited to allow definitive conclusions. Because HIFs regulate many genes in addition to erythropoietin, other actions could exert beneficial or harmful effects.9Sanghani N.S. Haase V.H. Hypoxia-inducible factor activators in renal anemia: current clinical experience.Adv Chronic Kidney Dis. 2019; 26: 253-266Abstract Full Text Full Text PDF PubMed Scopus (67) Google Scholar Thus, HIF-PHIs have been reported to reduce serum triglyceride, total cholesterol, and low-density lipoprotein levels, and to reduce blood pressure in animal models of CKD, an effect not observed in human patients. They could also exert anti-inflammatory effects, provide protection from ischemic injuries, and reduce CKD progression. Whether HIF-PHIs may offer an advantage over ESAs in treating the anemia of inflamed CKD patients remains to be seen. Potential concerns regarding HIF-PHIs include risk for enhanced tumor growth, pulmonary arterial hypertension, accelerated cyst growth in patients with polycystic kidney disease, proangiogenic effects in patients with vascular retinopathies, enhancement of vascular calcification, and risk for abnormal embryonic and fetal development. Therefore, despite reassuring, progressively accumulating evidence from phase 3 trials in patients with CKD, caution must be exercised regarding the benefit-to-risk ratio of HIF-PHIs in the long run compared with that of ESAs. The articles of the present supplement, which have been written by outstanding experts in the domain of CKD anemia, deal with these different aspects. They provide excellent updates in the field of interest, with particular focus on the novel treatment modality represented by HIF-PHIs. They allow the readers of Kidney International Supplements to gain a more complete picture of the current situation while clearly pointing out still open issues that need to be addressed. Finally, we would like to mention that yet other new anemia treatment strategies are in the pipeline. They include inhibitors of hepcidin production or action, and therapies either already in use or under investigation in other disease states, such as interleukin-6–specific antibodies, other anti-inflammatory agents, and activin receptor ligand traps.10Schmid H. Jelkmann W. Investigational therapies for renal disease-induced anemia.Expert Opin Investig Drugs. 2016; 25: 901-916Crossref Scopus (22) Google Scholar Time will tell which among these exciting novel approaches of anemia treatment in CKD will turn out to occupy a lasting place in clinical practice. ZAM reports having received grants for Chronic Kidney Disease–Renal Epidemiology and Information Network and other research projects from Amgen, Baxter, Fresenius Medical Care, Glaxo Smith Kline, Merck Sharp and Dohme-Chibret, Sanofi-Genzyme, Lilly, Otsuka, AstraZeneca, Vifor, and the French government, as well as fees and grants to charities from Amgen, Astellas, and Sanofi-Genzyme, outside the submitted work. TBD reports having received advisor, consultant, speaker, and/or travel fees from Akebia, Amgen, Astellas, Chugai, F. Hoffman-La Roche, FMC, Glaxo-Smith-Kline, Kyowa Hakko Kirin, and Vifor. This article is published as part of a supplement supported by AstraZeneca .
The management of anemia of chronic kidney disease (CKD) is often challenging. In particular, for patients with underlying inflammation, comorbid type 2 diabetes or cancer, those hospitalized, and recipients of a kidney transplant, the management of anemia may be suboptimal. Responsiveness to iron and/or erythropoiesis-stimulating agents, the mainstay of current therapy, may be reduced and the risk of adverse reactions to treatment is increased in these difficult-to-manage patients with anemia of CKD. This review discusses the unique patient and disease characteristics leading to complications and suboptimal treatment response. New treatment options in clinical development, such as hypoxia-inducible factor-prolyl hydroxylase (HIF-PH) inhibitors, may be particularly useful for difficult-to-treat patients. In clinical studies, HIF-PH inhibitors provided increased hemoglobin levels and improved iron utilization in anemic patients with non–dialysis-dependent and dialysis-dependent CKD, and preliminary data suggest that HIF-PH inhibitors may be equally effective in patients with or without underlying inflammation. The availability of new treatment options, including HIF-PH inhibitors, may improve treatment outcomes in difficult-to-manage patients with anemia of CKD.
Cardiorenal syndrome includes a spectrum of disorders of the kidneys and heart in which loss of function in one organ contributes to reduced function in the other organ. Cardiorenal syndrome is frequently complicated by comorbid anemia, which leads to reciprocal and progressive cardiac and renal deterioration. The triad of heart failure, chronic kidney disease (CKD), and anemia is termed cardiorenal anemia syndrome (CRAS). There are currently no evidence-based recommendations for managing patients with CRAS; however, the treatment of these patients is multifactorial. Not only must the anemia be controlled, but heart failure and kidney injury must be addressed, in addition to other comorbidities. Intravenous iron and erythropoiesis-stimulating agents are the mainstays of treatment for anemia of CKD, addressing both iron and erythropoiesis deficiencies. Since erythropoiesis-stimulating agent therapy can be associated with adverse outcomes at higher doses in patients with CKD and is not used in routine practice in patients with heart failure, treatment options for managing anemia in patients with CRAS are limited. Several new therapies, particularly the hypoxia-inducible factor-prolyl hydroxylase inhibitors, are currently under clinical development. The hypoxia-inducible factor-prolyl hydroxylase inhibitors have shown promising results for treating anemia of CKD in clinical trials and may confer benefits in patients with CRAS, potentially addressing some of the limitations of erythropoiesis-stimulating agents. Updated clinical practice guidelines for the screening and management of anemia in cardiorenal syndrome, in light of potential new therapies and clinical evidence, would improve the clinical outcomes of patients with this complex syndrome.
Prevention and early detection of kidney diseases in adults and children should be a priority for any government health department. This is particularly pertinent in the low-middle-income countries, mostly in Asia, Africa, Latin America, and the Caribbean, where up to 7 million people die because of lack of end-stage kidney disease treatment. The nephrology workforce (nurses, technicians, and doctors) is limited in these countries and expanding the size and expertise of the workforce is essential to permit expansion of treatment for both chronic kidney disease and end-stage kidney disease. To achieve this will require sustained action and commitment from governments, academic medical centers, local nephrology societies, and the international nephrology community.
