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RATIONALE & OBJECTIVE: Patients with chronic kidney disease (CKD), hyperkalemia (serum potassium [sK+]>5.0 mEq/L), and hyperphosphatemia experience poor clinical outcomes. Patiromer, a potassium binder that uses calcium as the exchange ion, may also reduce serum phosphorus (sP). We characterized the effect of patiromer on sP in patients with CKD, hyperkalemia, and hyperphosphatemia. STUDY DESIGN: A post hoc pooled analysis of individual-level data from the AMETHYST-DN, OPAL-HK, and TOURMALINE trials of patiromer. SETTING & PARTICIPANTS: Patients with CKD and hyperkalemia. EXPOSURE: Patients treated with patiromer (8.4-33.6 g/day). OUTCOME: Mean changes from baseline in sP, sK+, serum calcium (sCa2+), and serum magnesium (sMg2+) after 2 and 4 weeks of treatment. ANALYTICAL APPROACH: Descriptive statistics to summarize pooled data on the study outcomes from the 3 studies. RESULTS: We included 578 patients in the analysis. Of these participants, 86 patients (14.9%) had baseline hyperphosphatemia of whom 75.6% (65 of 86) had CKD stage 4/5 and 31.1% (153 of 492) with sP≤4.5mg/dL had CKD stage 4/5. Among the patients with elevated sP and sK+at baseline, the mean±SD reduction in sP and sK+after 4 weeks of patiromer treatment was-0.62±1.09mg/dL and-0.71± 0.51 mEq/L, respectively. Additionally, the mean±SD reduction in sMg2+in these patients was -0.25±0.23mg/dL while sCa2+remained unchanged. Both sMg2+and sCa2+remained within the normal range. Patiromer was generally well tolerated, and no serious adverse events were considered related to patiromer. LIMITATIONS: These were post hoc analyses, no placebo comparison was performed due to the design of the original studies, and the follow-up period was limited to 4 weeks. CONCLUSIONS: Reductions in sP and sK+to the normal range were observed after 2 weeks of patiromer treatment, and the reduction was sustained during 4 weeks of treatment among patients with non-dialysis-dependent CKD, hyperkalemia, and hyperphosphatemia. Future controlled trials are needed to establish if patiromer is useful to reduce both sK+and sP in hyperkalemic patients with CKD and hyperphosphatemia.
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Hiperpotassemia , Hiperfosfatemia , Insuficiência Renal Crônica , Humanos , Hiperpotassemia/tratamento farmacológico , Hiperfosfatemia/tratamento farmacológico , Hiperfosfatemia/etiologia , Cálcio , Potássio , FósforoRESUMO
Mineralocorticoid receptor (MR) activation is involved in propagating kidney injury, inflammation, and fibrosis and in the progression of chronic kidney disease (CKD). Multiple clinical studies have defined the efficacy of MR antagonism in attenuating progressive kidney disease, and the US Food and Drug Administration recently approved the nonsteroidal mineralocorticoid receptor antagonist (MRA) finerenone for this indication. In this review, we consider the basic science and clinical applicability of MR antagonism. Because hyperkalemia constitutes a constraint to implementing evidence-based MR blockade, we review MRA-associated hyperkalemia in the context of finerenone and discuss evolving mitigation strategies to enhance the safety and efficacy of this treatment. Although the FIDELIO-DKD and FIGARO-DKD clinical trials focused solely on patients with type 2 diabetes mellitus, we propose that MR activation and the resulting inflammation and fibrosis act as a substantive pathogenetic mediator not only in people with diabetic CKD but also in those with CKD without diabetes. We close by briefly discussing both recently initiated and future clinical trials that focus on extending the attributes of MR antagonism to a wider array of nondiabetic kidney disorders, such as patients with nonalbuminuric CKD.
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Diabetes Mellitus Tipo 2 , Hiperpotassemia , Insuficiência Renal Crônica , Humanos , Antagonistas de Receptores de Mineralocorticoides/uso terapêutico , Receptores de Mineralocorticoides/uso terapêutico , Aldosterona , Diabetes Mellitus Tipo 2/complicações , Diabetes Mellitus Tipo 2/tratamento farmacológico , Hiperpotassemia/etiologia , Mineralocorticoides/uso terapêutico , Insuficiência Renal Crônica/complicações , Fibrose , InflamaçãoRESUMO
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.
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The classic focus on the mechanisms of action of aldosterone was directed primarily on its role in modulating renal excretory function and maintaining volume homeostasis. In contrast, many recent studies have demonstrated a much wider and expanded role for aldosterone and for the mineralocorticoid receptor (MR). Activation of the MR promotes inflammation, collagen formation, fibrosis, and necrosis with consequent renal injury. Increasing evidence has accrued that implicates the pathophysiological overactivation of the MR as a major determinant of progression of both diabetic and nondiabetic chronic kidney disease (CKD). By promoting cascades of injury encompassing inflammation and fibrosis, MR overactivation constitutes a pivotal determinant of CKD progression and consequently its associated morbidity and mortality. Based on this mechanism of action, blockade of the MR with the nonsteroidal MR antagonist finerenone is currently being investigated as a novel treatment regimen to slow the progression of CKD. The recently reported FIDELIO-DKD (FInerenone in reducing kiDnEy faiLure and dIsease prOgression in Diabetic Kidney Disease) study demonstrated that patients with CKD and type 2 diabetes (T2D) who were treated with finerenone manifested a lower risk of a composite primary outcome event compared with patients in the placebo arm (defined as kidney failure or a sustained decrease of ≥ 40% in the estimated glomerular filtration rate from baseline, or death from renal causes). In addition, patients in the finerenone group also manifested a lower risk of a key secondary outcome event (defined as death from cardiovascular causes, nonfatal myocardial infarction, nonfatal stroke, or hospitalization for heart failure). Based on the success of these major clinical trials, finerenone was approved by the FDA on 9 July 2021 as a novel treatment for retarding CKD progression in patients with T2D ( https://www.fda.gov/drugs/news-events-human-drugs/fda-approves-drug-reduce-risk-serious-kidney-and-heart-complications-adults-chronic-kidney-disease ). Podcast Video (MP4 258973 KB).
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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.
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Insuficiência Cardíaca , Antagonistas de Receptores de Mineralocorticoides , Insuficiência Cardíaca/tratamento farmacológico , Humanos , Antagonistas de Receptores de Mineralocorticoides/farmacologia , Antagonistas de Receptores de Mineralocorticoides/uso terapêutico , Volume Sistólico , Função Ventricular EsquerdaRESUMO
Chronic kidney disease affects approximately 10% of the population or 800 million people globally, with diabetes being the leading cause. The presence of chronic kidney disease with impaired kidney function or with albuminuria is associated with an increased risk of a progressive loss of renal function and increased risk of cardiovascular disease and excess mortality. Screening for chronic kidney disease is critically important because during the initial stages patients often have no symptoms and because we now have available recently approved multiple interventions that can reduce the high risks dramatically. Screening should be performed with regular measurement of albumin in the urine and creatinine or cystatin C in blood for estimation of kidney function. Regretfully recent data indicates that screening for albuminuria is conducted in only 20%-50% of people at risk depending on the setting. Clinicians need to perform regular screening and concomitant management of risk factors. Recent therapeutic options must be implemented to improve outcomes. Finally, a reduction in albuminuria after initiation of intervention constitutes a treatment target because it indicates improved prognosis.
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Doenças Cardiovasculares , Insuficiência Renal Crônica , Albuminúria/epidemiologia , Creatinina , Feminino , Humanos , Masculino , Insuficiência Renal Crônica/complicações , Insuficiência Renal Crônica/diagnóstico , Insuficiência Renal Crônica/epidemiologia , Fatores de RiscoRESUMO
The nexus of chronic kidney disease (CKD) and cardiovascular disease (CVD) amplifies the morbidity and mortality of CKD, emphasizing the need for defining and establishing therapeutic initiatives to modify and abrogate the progression of CKD and concomitant CV risks. In addition to the traditional CV risk factors, disturbances of mineral metabolism are specific risk factors that contribute to the excessive CV mortality in patients with CKD. These risk factors include dysregulations of circulating factors that modulate phosphate metabolism, including fibroblast growth factor 23 (FGF23) and soluble Klotho. Reduced circulating levels and suppressed renal Klotho expression may be associated with adverse outcomes in CKD patients. While elevated circulating concentrations or locally produced FGF23 in the strained heart exert prohypertrophic mechanisms on the myocardium, Klotho attenuates tissue fibrosis, progression of CKD, cardiomyopathy, endothelial dysfunction, vascular stiffness and vascular calcification. Mineralocorticoid receptor (MR) activation in nonclassical targets, mediated by aldosterone and other ligands, amplifies CVD in CKD. In concert, we detail how the interplay of elevated FGF23, activation of the MR and concomitant reductions of circulating Klotho in CKD may potentiate each other's deleterious effects on the kidney and heart, thereby contributing to the initiation and progression of kidney and cardiac functional deterioration, acting through multipronged, albeit complementary, mechanistic pathways.
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Doenças Cardiovasculares , Fatores de Crescimento de Fibroblastos , Proteínas Klotho , Receptores de Mineralocorticoides , Insuficiência Renal Crônica , Doenças Cardiovasculares/metabolismo , Fator de Crescimento de Fibroblastos 23 , Fatores de Crescimento de Fibroblastos/metabolismo , Glucuronidase/metabolismo , Humanos , Rim/metabolismo , Proteínas Klotho/metabolismo , Receptores de Mineralocorticoides/metabolismo , Insuficiência Renal Crônica/complicaçõesAssuntos
Hiperpotassemia , Insuficiência Renal Crônica , Inibidores da Enzima Conversora de Angiotensina , Feminino , Humanos , Hiperpotassemia/induzido quimicamente , Masculino , Antagonistas de Receptores de Mineralocorticoides/efeitos adversos , Insuficiência Renal Crônica/complicações , EspironolactonaRESUMO
BACKGROUND: A full understanding of the mechanisms of action of aldosterone and its interaction with the mineralocorticoid receptor (MR) allows a theoretical framework to predict the therapeutic potential of MR antagonists (MRAs) in CKD, and heart failure with reduced ejection fraction. SUMMARY: The initial focus on the mechanisms of action of aldosterone was directed primarily on its role in modulating renal excretory function. In contrast, many recent studies have demonstrated a wider and expanded role for aldosterone in modulating inflammation, collagen formation, fibrosis, and necrosis. Increasing evidence has accrued that implicates the pathophysiological overactivation of the MR as a major determinant of progression of CKD. By promoting inflammation and fibrosis, MR overactivation constitutes a pivotal determinant of CKD progression and its associated morbidity and mortality. In accord with this mechanism of action, blockade of the MR is currently being investigated as a novel treatment regimen to slow the progression of CKD. The recently reported FIDELIO-DKD (FInerenone in reducing kiDnEy faiLure and dIsease prOgression in Diabetic Kidney Disease) study demonstrated that patients with CKD and type 2 diabetes who were treated with finerenone (a novel nonsteroidal MRA) manifested a lower risk of a composite primary outcome event compared with patients in the placebo arm (defined as kidney failure, or a sustained decrease of ≥40% in the estimated glomerular filtration rate from baseline, or death from renal causes). In addition, patients in the finerenone group also manifested a lower risk of a key secondary outcome event (defined as death from cardiovascular causes, nonfatal myocardial infarction, nonfatal stroke, or hospitalization for heart failure). Key Messages: Based on the success of the FIDELIO-DKD study, future studies should be implemented testing the hypothesis that a wide array of nondiabetic CKD is modulated by overactivation of the MR, and consequently may be amenable to treatment with novel nonsteroidal MRAs. Future studies are encouraged to elucidate the clinical implications of the interplay of nonsteroidal MRAs and the components of the renin-angiotensin cascade. The unique and recently reported interrelationship of fibroblast growth factor (FGF23) and aldosterone may also constitute a propitious subject for future investigation.
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Aldosterona/fisiologia , Doenças Cardiovasculares/etiologia , Receptores de Mineralocorticoides/fisiologia , Insuficiência Renal Crônica/etiologia , Humanos , Antagonistas de Receptores de Mineralocorticoides/uso terapêutico , Naftiridinas/uso terapêutico , Insuficiência Renal Crônica/tratamento farmacológicoRESUMO
The hepatorenal syndrome (HRS), a progressive but potentially reversible deterioration of kidney function, constitutes a serious complication of hepatic decompensation. Coexistence of liver/kidney damage, mentioned in the dropsy literature, was highlighted by Richard Bright in 1827 and confirmed in 1840 by his contemporary nephrology pioneer Pierre Rayer. Cholemic nephrosis was described in 1861 by Friedrich Frerichs, and the renal tubular lesions of HRS by Austin Flint in 1863. The term "acute hepato-nephritis" was introduced in 1916 by Paul Merklen, and its chronic form was designated HRS by Marcel Dérot in 1930s. HRS then was applied to renal failure in biliary tract surgery and to cases of coexistent renal and hepatic failure of diverse etiology. The pathogenesis of HRS was elucidated during the 1950 studies of renal physiology. Notably, studies of salt retention in edema and its relation to regulating the circulating plasma volume by John Peters and subsequently Otto Gauer defined the concept of "effective blood volume" and the consequent elucidation of ascites formation in liver failure. Parallel studies of intrarenal hemodynamics demonstrated severe renal vasoconstriction and preferential cortical ischemia to account for the functional renal dysfunction of HRS. Dialysis and liver or combined liver-kidney transplantation transformed the fatal HRS of old into a treatable disorder by the 1970s. Elucidation of the pathogenetic mechanisms of renal injury and refinements in definition, classification, and diagnosis of HRS since then have allowed for earlier therapeutic intervention with combined i.v. albumin and vasoconstrictor therapy, enabling the continued improvement of patient outcomes.
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Síndrome Hepatorrenal , Transplante de Fígado , Síndrome Hepatorrenal/diagnóstico , Síndrome Hepatorrenal/etiologia , Humanos , Testes de Função Renal , Cirrose Hepática , Vasoconstritores/uso terapêuticoRESUMO
The current Coronavirus Disease 2019 (COVID-19) pandemic has exerted an unprecedented impact across the globe. As a consequence of this overwhelming catastrophe, long-established prevailing medical and scientific paradigms have been disrupted. The response of the scientific community, medical journals, media, and some politicians has been far from ideal. The present manuscript discusses the failure of the scientific enterprise in its initiatives to address the COVID-19 outbreak as a consequence of the disarray attributable to haste and urgency. To enhance conveying our message, this manuscript is organized into 3 interrelated sections: 1) the accelerated pace of publications coupled with a dysfunctional review process; 2) failure of the clinical trial enterprise; 3) propagation of misleading information by the media. In response we propose a template comprising a focus on randomized controlled clinical trials, and an insistence on responsible journal publication, and enumeration of policies to deal with social media-propagated news. We conclude with a reconsideration of the appropriate role of academic medicine and journals.