In 1836, Sir Richard Bright, widely regarded as the founder of the field of nephrology, described the structural cardiac changes on autopsy seen in patients with “shrunk kidneys” who were secretors of albuminous urine (1). This report is perhaps the earliest description of the cardiorenal connection in contemporary literature of what is known today as CKD-associated cardiomyopathy. This connection is driven by shared risk factors, such as diabetes, hypertension, and obesity, as well as maladaptive cardiorenal crosstalk pathways resulting in bidirectional organ failure.
The Cardiorenal Link: A Historic Perspective
Notwithstanding major advances in the fields of cardiology and nephrology, clinical outcomes remain poor for patients with heart failure and CKD. With diabetes in particular, despite achieving guideline-directed treatment targets, there is a substantial unmet need for reducing the risks of heart failure and CKD. In fact, some earlier glucose-lowering therapies for diabetes, such as thiazolidinediones and sulfonylureas, are associated with higher cardiovascular disease risks (2). This prompted the Food and Drug Administration mandate in 2008 for the demonstration of cardiovascular safety before and after market approval for newer glucose-lowering agents (3). In this backdrop, sodium-glucose cotransporter-2 inhibitor (SGLT2i) serendipitously became a landmark cardiorenal-protective therapy when tested for cardiovascular safety as a treatment for hyperglycemia. In 2015, the first large randomized controlled trial (RCT) with the SGLT2i empagliflozin, EMPAREG-OUTCOME, showed significant reductions in risks for cardiovascular death, hospitalizations for heart failure, and progression of CKD. Several other RCTs with SGLT2i have since confirmed these benefits, including in patients without diabetes, transforming our capacity to save lives and reduce the burden of heart failure and CKD.
There is an urgent need to ensure equitable implementation of SGLT2i and other cardiorenal therapies, including glucagon-like peptide-1 receptor agonists and nonsteroidal mineralocorticoid receptor antagonists (MRAs), across populations. This requires the support of clinicians, scientists, professional organizations, patient advocacy groups, and industry stakeholders. To this end, a dialogue initiated by the Council on the Kidney in Cardiovascular Disease (KCVD) of the American Heart Association with their heart-kidney webinars has stimulated intense discussion between cardiologists and nephrologists to close gaps in the care of patients with heart and kidney diseases. Established in 1962, the mission of KCVD is to reduce cardiovascular disease–related disability and death through clinical, translational, and basic science research; communication; advocacy; and education relevant to the role of the kidneys in all phenotypes of cardiovascular disease. We hereby summarize some of the key conclusions generated from our cross-specialty collaboration, which offer perspective on current challenges and potential solutions for optimizing outcomes in patients with heart failure and CKD.
In 2004, Chertow et al. (4) described the phenomenon of “renalism,” referring to the systematic exclusion of patients with CKD from cardiovascular trials of medical therapies and procedures due to a misconception of futility and/or harm. For example, in a systematic review of 706 RCTs for therapies in heart failure with reduced ejection fraction between 2010 and 2020, over a third of the trials had no information reported on kidney function (5). The number of trials that included patients with CKD was inversely related to eGFR, and patients on maintenance dialysis and kidney transplant recipients were included in <60 trials. Ironically, renalism was propagated in clinical practice despite the recognition of CKD as an independent risk factor for all major phenotypes of cardiovascular diseases (6). It is gratifying to note that recent major trials with SGLT2i, such as EMPEROR, have included patients with eGFR as low as 20 ml/min per 1.73 m2 (7). Patients with moderate to advanced CKD are also well represented in recent kidney outcome trials such as CREDENCE and DAPA-CKD.
Structural racism is another driver of poor outcomes in patients with heart failure and CKD given the disproportionate burden of these conditions in Black, Hispanic or Latino/a, and indigenous patients. These patient populations still remain significantly under-represented in cardiovascular and kidney trials and are high-risk groups to prioritize for enrollment. The recent consensus statement by the American Society of Nephrology and the National Kidney Foundation on the removal of the race coefficient for eGFR is an important step in reducing race-based disparities (8), wherein Black patients are now less likely to be ineligible for therapies, such as SGLT2i (9), and will gain access to lifesaving therapies, such as kidney transplantation. Such developments will hopefully catalyze widespread implementation of the new, highly effective therapies in Black, Hispanic or Latino/a, and indigenous patients, groups that have traditionally been suboptimally treated, translating into better survival and quality of life with heart failure and CKD. It is important to note that access to these organ-saving therapies is highly variable given underlying structural disparities across demographics and insurance status. Involvement of specialty societies and public-private partnerships with the industry are important in ensuring accelerated access to generics for these newer therapies.
Therapeutic Inertia: Old Habits Die Hard
Much concern has been expressed about therapeutic inertia, with slower than expected uptake of newer therapies for heart failure and CKD, especially SGLT2i, reminiscent of several previous high-impact therapies, including statins. We must reverse this phenomenon given the mismatch between available effective therapies and the population at risk. Inertia results from barriers, including inadequate insurance coverage and high out-of-pocket costs; fragmented workflows between different specialties; and prioritizing “volume” over “value”-based care in the United States. Additionally, the inappropriate use of terms, such as “AKI,” to describe the functional decrease in eGFR due to therapeutic hemodynamic changes creates fear of harm, especially with the concomitant use of therapies such as renin-angiotensin system inhibitors, SGLT2i, and MRAs. To this end, improving affordability and access to SGLT2i with joint lobbying across specialty organizations and guidance from specialty societies on specific terminology to differentiate true kidney injury from benign fluctuations in kidney biomarkers, such as serum creatinine or cystatin C, would go far in effectively implementing these agents (10). Finally, educating patients and their caregivers about the benefits of SGLT2i that are incurred even within weeks of initiation is key to promoting adherence while actively engaging in strategies to reduce polypharmacy and deprescribing less effective agents.
Sodium-Glucose Cotransporter-2 Inhibitor in the Basic Translational Space
No single mechanism can fully explain the early separation of survival curves seen reproducibly across SGLT2i trials from low- to very high–risk populations, those with and without diabetes, across ejection fraction, and eGFR strata. Several unanswered questions remain from a mechanistic perspective. (1) Do changes in energy kinetics in the myocardium and proximal tubules contribute to the consistent benefits for heart failure and CKD? (2) Will SGLT2is have the potential to be deployed for primary prevention of heart failure and CKD if maladaptive neurohormonal and hemodynamic pathways can be attenuated before organ damage has occurred? (3) Although the clinical benefits with SGLT2i may partly be explained by metabolic and BP control, weight loss, uric acid excretion, and improvement in anemia, are there other mechanisms that are operative, akin to the pleiotropic effects with statins? (4) Do proximal tubular effects of SGLT2i complement pathways in the distal nephron to attenuate the hyperkalemia that often occurs with MRAs? There are many more translational questions that exist. However, the incomplete understanding of the precise mechanistic pathways for SGLT2i must not preclude rapid uptake of these agents in clinical practice. Additional deeper dives into these mechanisms will advance understanding of how far these agents can be extended therapeutically, including into primary prevention. The benefits noted with SGLT2i for heart failure and CKD draw parallels to the benefits that statins have shown for atherosclerotic cardiovascular disease and will go down in history as one of the most effective cardiorenal therapies of the twenty-first century.
The cardiology and nephrology communities are faced with a veritable embarrassment of riches with the advent of SGLT2i, nonsteroidal MRAs, glucagon-like peptide-1 receptor agonists, and more promising therapies in development. We have a moral and ethical obligation to ensure rapid, safe, and equitable implementation of these life- and organ-protecting therapies, as appropriately indicated. Although rapid uptake of these newer therapies is key, it is equally important to ensure that existing cardioprotective therapies in patients with CKD are effectively implemented. Disruptive models of care with emphasis on implementing high-quality and evidence-based therapies must be deployed to overcome barriers posed by current health care systems. Mirroring the RCTs where both major cardiovascular and kidney end points are prespecified in heart and kidney disease trials, we must share accountability for reducing cardiovascular and kidney disease burdens between cardiology and nephrology in clinical practice. A multidisciplinary approach in key areas for future research is critical toward advancing knowledge across several domains (Table 1). Finally, high-level engagement of patients, caregivers, industry stakeholders, and legislators is critical for ensuring that these remarkable innovations are delivered to patients effectively and equitably. By accomplishing these objectives, we will have come full circle from the early nineteenth century, using old wisdom on heart-kidney crosstalk to save lives and organs and improve quality of life.
Table 1. -
Key questions for future research in the cardiorenal space
|Key Questions for Future Research
|Can cardiac and kidney biomarkers guide a precision medicine–based approach to use guideline-directed medical therapies in patients with heart failure and kidney disease?
||Basic science/risk assessment/disease progression
|Can artificial intelligence complement precision medicine–based approaches to identifying patients for appropriate use of guideline-directed medical therapies in heart failure and kidney disease?
||Population health/risk assessment/health care delivery
|How can delivery of optimal guideline-directed medical therapies be achieved in the context of structural disparities in health care?
||Social determinants of health care
|How can an increasingly complex medication regimen with the advent of newer heart-kidney therapies be implemented in a patient-centric fashion with emphasis on quality of life, costs, pill burden, and side effects?
|How can the cardiology and nephrology communities leverage the support of key stakeholders to implement policy changes to ensure equitable access to lifesaving therapies in patients with heart failure and kidney disease?
||Health care policy/structural inequities
|Is there an opportunity to provide a unifying care platform spanning across primordial prevention, primary prevention, comprehensive lifestyle modification, and state-of-the-art therapies for patients with heart failure and kidney disease?
||Lifestyle/prevention/social determinants of care
|Can a cardiorenal care model for clinician practice and trainee education help with the seamless integration of evidence-based care pathways in patients with/at risk of heart failure and kidney disease?
||Quality of care/health care economics/medical education
V. Bhalla reports consultancy agreements with Bayer Pharmaceuticals, CareDx, Guidepoint LLC, LEK Consulting, Maxim Integrated, and Reata; reports ownership stock in Pyrames Health and Viscira LLC; reports honoraria from Bayer Pharmaceuticals; reports other interests or relationships as the immediate past-chair of the Kidney and Cardiovascular Disease Council of the American Heart Association (AHA) and as a member of the Hypertension Council of AHA and the American Medical Association Validated Device Listing–Blood Pressure Measurement Devices; and is a cosite investigator for the Controlling and Lowering Blood Pressure with MobiusHD 2 (CALM‐2) trial sponsored by Vascular Dynamics, Inc. V. Bhalla reports serving in an advisory or leadership role for American Journal of Physiology Renal Physiology (editorial board: July 2007 to present), European Journal of Clinical Investigation (scientific advisory board: February 2013 to present), Physiologic Reports (associate editor: April 2018 to present), the Pyrames Scientific Advisory Board, and the Relypsa Scientific Advisory Board. V. Bhalla’s spouse reports research funding from CareDx, honoraria from CareDx, serving on the CareDx Scientific Advisory Board, and serving on speakers bureau for CareDx. E. Braunwald reports consultancy agreements with Amgen, Boehringer-Ingelheim/Lilly, Bristol Myers Squibb (MyoKardia), Cardurion, Novo Nordisk, and Verve; research funding from AstraZeneca, Daiichi Sankyo, Merck, and Novartis (all through the author’s institution, Brigham and Women’s Hospital); and serving in an advisory or leadership role for Broadview Ventures (not for profit) and the Heart Failure Network (National Heart, Lung, and Blood Institute [NHLBI]; no compensation). G.M. Chertow reports consultancy agreements with Akebia, Amgen, Ardelyx, AstraZeneca, Baxter, Cricket, DiaMedica, Gilead, Miromatrix, Reata, Sanifit, Unicycive, and Vertex; reports ownership interest in Ardelyx, CloudCath, Durect, DxNow, Eliaz Therapeutics, Outset, Physiowave, and PuraCath; reports research funding from Amgen, the National Institute of Allergy and Infectious Diseases, and the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK); has received fees from AstraZeneca for the Dapagliflozin and Prevention of Adverse Outcomes in Chronic Kidney Disease (DAPA-CKD) trial steering committee; has received fees for advisory boards for Cricket, DiaMedica, and Reata; has received fees from Akebia, Sanifit, and Vertex for trial steering committees; reports serving in an advisory or leadership role as coeditor of Brenner & Rector’s The Kidney (Elsevier) and on the board of directors for Satellite Healthcare; and has received fees for DSMB service from Angion, Bayer, NIDDK, and ReCor. R.A. Harrington reports consultancy agreements with Atropos, Bitterroot, BMS, BridgeBio, Element Science, and WebMD; research funding from the Baim Institute (Data and Safety Monitoring Board [DSMB]), Commonwealth Serum Laboratories (Randomized Controlled Trial [RCT] executive committee), Janssen (RCT chair), NHLBI (RCT executive committee; DSMB chair), and Patient-Centered Outcomes Research Institute (RCT cochair); and serving on the board of directors for AHA. J. Rangaswami reports consultancy agreements with AstraZeneca, Boehringer-Lily, and Edwards LifeSciences; serves on the medical advisory board of Procyrion Inc. (Aortix); and is chair-elect of KCVD of the AHA. A. Staruschenko reports research funding from the Department of Veteran Affairs and the National Institutes of Health (NIH); serving as chair of the Kidney in Cardiovascular Disease of the AHA Council; serving as deputy editor of American Journal of Physiology Renal Physiology and associate editor for Frontiers in Physiology Renal and Epithelial Physiology; and serving on the editorial boards of American Journal of Physiology Cell Physiology, BMC Nephrology, Kidney360, and Scientific Reports. K. Tuttle reports consultancy agreements with AstraZeneca, Bayer, Boehringer Ingelheim, Eli Lilly and Company, Gilead, Goldfinch Bio, Janssen, Novo Nordisk, and Travere; reports research funding from Bayer, Goldfinch Bio, and Travere; is supported by a Centers for Disease Control and Prevention contract and six NIH grants; and reports honoraria from Bayer, Boehringer Ingelheim, Gilead, and Novo Nordisk.
This manuscript summarizes the salient content of the inaugural Heart-Kidney web-based symposium organized by KCVD of the American Heart Association. The opinions expressed in this article are not necessarily those of the American Heart Association.
The content of this article reflects the personal experience and views of the author(s) and should not be considered medical advice or recommendation. The content does not reflect the views or opinions of the American Society of Nephrology (ASN) or CJASN. The content of this publication do not necessarily reflect the views and policies of the American Heart Association. Responsibility for the information and views expressed herein lies entirely with the author(s).
V. Bhalla, J. Rangaswami, and A. Staruschenko conceptualized the study; K. Tuttle was responsible for visualization; J. Rangaswami wrote the original draft; and V. Bhalla, E. Braunwald, G.M. Chertow, R.A. Harrington, A. Staruschenko, and K. Tuttle reviewed and edited the manuscript.
1. Bright R: Cases and observations illustrative of renal disease accompanied by the secretion of albuminous urine. Med Chir Rev 25: 23–35, 1836
2. Azimova K, San Juan Z, Mukherjee D: Cardiovascular safety profile of currently available diabetic drugs. Ochsner J 14: 616–632, 2014
3. US Department of Health and Human Services, Food and Drug Administration, Center for Drug Evaluation and Research: Guidance for Industry: Diabetes Mellitus—
Evaluating Cardiovascular Risk in New Antidiabetic Therapies to Treat Type 2 Diabetes, 2008. Available at: https://www.fda.gov/media/71297/download
. Accessed January 28, 2022
4. Chertow GM, Normand SL, McNeil BJ: “Renalism”: Inappropriately low rates of coronary angiography in elderly individuals with renal insufficiency. J Am Soc Nephrol 15: 2462–2468, 2004
5. Lo KB, Essa H, Wattoo A, Gulab A, Akhtar H, Sudani HA, Angelim L, Helfman B, Peterson E, Brousas S, Whybrow-Huppatz I, Yazdanyar A, Sankaranarayanan R, Rangaswami J: Representation of chronic kidney disease in randomized controlled trials among patients with heart failure
with reduced ejection fraction: A systematic review. Curr Probl Cardiol 2021: 101047, 2021
6. Sarnak MJ, Levey AS, Schoolwerth AC, Coresh J, Culleton B, Hamm LL, McCullough PA, Kasiske BL, Kelepouris E, Klag MJ, Parfrey P, Pfeffer M, Raij L, Spinosa DJ, Wilson PW; American Heart Association Councils on Kidney in Cardiovascular Disease, High Blood Pressure Research, Clinical Cardiology, and Epidemiology and Prevention: Kidney disease as a risk factor for development of cardiovascular disease: A statement from the American Heart Association Councils on Kidney in Cardiovascular Disease, High Blood Pressure Research, Clinical Cardiology, and Epidemiology and Prevention. Circulation 108: 2154–2169, 2003
7. Packer M, Anker SD, Butler J, Filippatos G, Pocock SJ, Carson P, Januzzi J, Verma S, Tsutsui H, Brueckmann M, Jamal W, Kimura K, Schnee J, Zeller C, Cotton D, Bocchi E, Böhm M, Choi DJ, Chopra V, Chuquiure E, Giannetti N, Janssens S, Zhang J, Gonzalez Juanatey JR, Kaul S, Brunner-La Rocca HP, Merkely B, Nicholls SJ, Perrone S, Pina I, Ponikowski P, Sattar N, Senni M, Seronde MF, Spinar J, Squire I, Taddei S, Wanner C, Zannad F; EMPEROR-Reduced Trial Investigators: Cardiovascular and renal outcomes with empagliflozin in heart failure
. N Engl J Med 383: 1413–1424, 2020
8. Delgado C, Baweja M, Crews DC, Eneanya ND, Gadegbeku CA, Inker LA, Mendu ML, Miller WG, Moxey-Mims MM, Roberts GV, St Peter WL, Warfield C, Powe NR: A unifying approach for GFR estimation: Recommendations of the NKF-ASN Task Force on Reassessing the Inclusion of Race in Diagnosing Kidney Disease. J Am Soc Nephrol 32: 2994–3015, 2021
9. Rangaswami J, Lo KB, Vaduganathan M, Mathew RO: Eligibility for SGLT2 inhibitors in heart failure
without the race coefficient for kidney function estimation. J Am Coll Cardiol 78: 1669–1670, 2021
10. McCoy IE, Chertow GM: AKI: A relevant safety end point? Am J Kidney Dis 75: 508–512, 2020