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AHA24 Screening for Kidney Disease to Reduce CVD Risk: uACR and eGFR

Screening for Kidney Disease to Reduce CVD Risk uACR and eGFR testing are the first step. A Toolkit for Health Care Professionals This toolkit is sponsored by Bayer. Digital copy

Publisher’s Note This Toolkit for Health Care Professionals is published by Ascend Media. 401 SW Ward Road, Suite 210, Lee’s Summit, MO 64081 © 2024 American Heart Association, Inc., a 501(c)(3) not-for-profit. All rights reserved. Unauthorized use prohibited. All references and data are as of August 2024.

3 A Toolkit for Health Care Professionals Screening for Kidney Disease to Reduce CVD Risk Contents 4 Contributing Authors 6 Introduction 8 Causation 8 Pathophysiology and Outcomes 10 Prevalence and Incidence of Undetected CKD 11 Individuals With CVD 11 Individuals With Diabetes and Others at Risk For CVD 12 Early Testing Can Improve Clinical Outcomes 14 Undetected CVD in Those With Known CKD 15 People Living With Diabetes 16 Use Guideline-Directed Medical Therapy and Shared Decision-Making to Improve Outcome 17 Barriers to Guideline-Directed Medical Therapy 18 Screening and Staging CKM 19 Act Now 20 Key Takeaways 21 Key for Toolkit Terms

4 Contributing Authors Bige Ozkan, MD, ScM Carolyn M. Reilly, PhD, RN, CNE, FAHA, FAAN Andrew M. South, MD, MS Telisa Spikes, PhD, RN Katherine R. Tuttle, MD, FASN, FACP, FNKF Relationship disclosures within the past 24 months: The American Heart Association (AHA) is committed to ensuring balance, independence, objectivity and scientific rigor in its certified educational activities. All faculty, planners and contributors in a position to control the content for an AHA-sponsored activity are required to disclose to the activity audience any financial relationships regardless of the amount during the prior 24 months with (1) the manufacturer(s) of any ineligible company product(s) and/or interest(s) of ineligible companies regardless of relation to the content of the activity and (2) any ineligible company supporters of the activity. When an unlabeled use of a commercial product or an investigational use not yet approved for any purpose is discussed during an educational activity, the faculty must disclose that the product is not labeled for the use under discussion or that the product is still investigational. Bige Ozkan, MD, ScM, is an internal medicine resident in the Johns Hopkins Osler Medical Residency Program. She previously obtained a master’s degree in cardiovascular epidemiology from the Johns Hopkins Bloomberg School of Public Health and completed postdoctoral research training at Johns Hopkins Division of Cardiology, funded by the American Heart Association’s Cardiometabolic Health Research Network. Her research focuses on exploring the links between various cardiometabolic risk factors, kidney disease and adverse cardiovascular outcomes, as well as leveraging both established and novel biomarkers to improve cardiovascular risk prediction. Disclosures: Employment: Johns Hopkins Medicine, Johns Hopkins Bloomberg School of Public Health Professional services and activities: Nothing to disclose Carolyn M. Reilly, PhD, RN, CNE, FAHA, FAAN, is an experienced critical care clinician, researcher and master teacher, bringing to Berry College core values of caring and creativity. It is through these lenses that she is leading the division of nursing to grow the program to meet the pressing need for excellent Professional Nurses. Disclosures: Employment: Berry College Professional services and activities: Nothing to disclose

5 A Toolkit for Health Care Professionals Screening for Kidney Disease to Reduce CVD Risk Andrew M. South, MD, MS, is a pediatric nephrologist and director of the Youth-Onset Hypertension Program at Atrium Health Levine Children’s Brenner Children’s Hospital. He is the PI of Collaborative Research (COACH) Catalyst©, whose mission is to better understand the development and progression of kidney disease, hypertension and cardiovascular disease across the life course to support innovative preventive and treatment interventions. Disclosures: Employment: Wake Forest University School of Medicine Independent contractor: Eunice Kennedy Shriver National Institute of Child Health and Human Development (grant), National Heart, Lung, and Blood Institute (grant) Professional services and activities: Conjupro Biotherapeutics, Inc. Telisa Spikes, PhD, RN, is a tenure-track assistant professor in the Nell Hodgson Woodruff School of Nursing at Emory University. Dr. Spikes’ research interest focuses on chronic stressors derived from the social environment and the impact of their embodiment on physiological aging and cardiovascular disease (CVD) risk in early midlife adult African American women. She has published on psychosocial stressors, hypertension medication adherence and blood pressure reactivity in Black women as well as socioeconomic status and arterial stiffness in Black adults using community-based cohorts and a large epidemiological cohort, Atherosclerosis Risk in Communities (ARIC) study, published in highimpact clinical journals. Disclosures: Employment: Emory University, Nell Hodgson Woodruff School of Nursing Professional services and activities: Nothing to disclose Katherine R. Tuttle, MD, FASN, FACP, FNKF, is executive director for research at Providence Inland Northwest Health and professor of medicine at the University of Washington. Dr. Tuttle’s collective body of work has shaped the “pillars of therapy“ approach to chronic kidney disease and cardiovascular disease in a fundamental manner across the spectrum of scientific discovery, clinical trials and population level implementation. She is chair of the Diabetic Kidney Disease Collaborative for the American Society of Nephrology and a member of the Cardio-KidneyMetabolic working group for the American Heart Association. Disclosures: Employment: Providence, University of Washington Independent contractor: Travere Therapeutics, Inc. Professional services and activities: AstraZeneca, Bayer, Boehringer Ingelheim, Eli Lilly and Company, Novo Nordisk, ProKidney

6 Introduction Chronic kidney disease (CKD) is a common and potentially deadly condition that is universally underrecognized as it can progress silently and unpredictably. And while symptoms may not appear until the disease is well-advanced, impaired kidney function can increase the risk of cardiovascular disease (CVD) two- to fourfold.1 Impaired kidney function is an independent risk factor for developing multiple forms of CVD, including: • heart failure • atrial fibrillation • stroke • coronary heart disease • peripheral artery disease • sudden cardiac death1-Results The relationship between CVD and CKD is bidirectional, with each condition increasing the incidence and progression of the other. Early testing and diagnosis of CKD is critical to improving health outcomes, using early treatment to prevent progression of both CVD and CKD. Because early-stage CKD often has few overt symptoms and is seldom recognized, early screening for CKD in both children and adults with diabetes, hypertension and metabolic syndrome using eGFR and uACR is encouraged to reduce the risk of CVD.2-Top 10 Highlights The interplay between CVD and CKD is detailed in Cardiovascular-Kidney-Metabolic Health: A Presidential Advisory from the American Heart Association.2 Both cardioprotective and kidney protective treatments are available and may be prescribed as appropriate.3-Novel Therapeutic Approaches, 4-Figure 3 CKM syndrome The link between CVD and CKD has been recognized since the 1830s.1-Results CVD and CKD are mutually reinforcing co-contributors to excess morbidity and mortality, an association now recognized as cardiovascular-kidney-metabolic (CKM) syndrome. This bidirectional association between heart and kidneys links disorder in either organ with disorder in the other.2-Introduction There is an exponential increase in absolute risk for all-cause and cardiovascular mortality with decreasing kidney function even after adjusting for other established risk factors.3-Epidemiology and prognosis CKD can be assessed using two common laboratory tests widely available in primary care and other settings: • estimated glomerular filtration rate (eGFR) • urinary albumin-to-creatinine ration (uACR).

7 A Toolkit for Health Care Professionals Screening for Kidney Disease to Reduce CVD Risk CKM syndrome is the pathophysiologic interplay between metabolic risk factors such as excess or dysfunctional adipose tissue, CKD and the cardiovascular system that leads to multiorgan dysfunction and a high rate of adverse cardiovascular outcomes.4-The current understanding of CKM syndrome CKM syndrome affects nearly all organ systems and has a particularly powerful impact on the risk and incidence of CVD.2-Summary 2x-4x Impaired kidney function can increase the risk of CVD two- to fourfold. 1-Results Consequently, the most common causes of death for people with diabetes and CKD are heart failure (HF) and atherosclerotic CVD (ASCVD), and only ≈10% of patients with CKD even survive to reach kidney failure. Conversely, the presense of CVD is associated with the development of CKD. 4-The current scientific understanding of CKM syndrome Screening Poor CKM health is a major contributor to morbidity and mortality that requires comprehensive approaches from childhood through old age. And because there are few, if any, symptoms in the early stages of CKD, broad-based screening may be the only viable approach to early detection and management.4-Evidence supporting CKM-related screening Comprehensive CKM screening that includes two common kidney parameters—estimated glomerular filtration rate (eGFR) and albuminuria as measured by urine albumin-creatinine ratio (uACR)—improves the potential to predict and prevent clinically relevant kidney and cardiovascular outcomes.3-Evidence supporting CKM-related screening If CKM is identified, clinicians have an expanding toolkit of therapeutic approaches to prevent or mitigate metabolic risk factors, to delay the progression of kidney disease and to reduce the associated CVD risk. A growing number of therapeutic agents include: • angiotensin-converting enzyme inhibitors/angiotensin II receptor blockers (ACEi/ARB) • sodium-glucose transporter-2 inhibitors (SGLT2i) • a non-steroidal mineralocorticoid antagonist (nsMRA), (finerenone) • glucagon-like peptide-1 receptor agonists (GLP1-RA) • other incretin analogues4-Figure 3 These provide beneficial metabolic effects, kidney effects, or both, while also improving CVD outcomes which can improve CKM health.4-introduction

8 Pathophysiology and Outcomes CKM syndrome is a multidimensional pathophysiology leading to increased morbidity and mortality that goes well beyond the sum of its individual components.4-The current scientific understanding of CKM Syndrome Dysfunctional adiposity, particularly visceral adipose tissue, secretes proinflammatory and prooxidative products that damage arterial, heart and kidney tissues. Inflammatory processes reduce sensitivity to insulin, resulting in impaired glucose tolerance affecting multiple organs and tissues. Metabolic dysfunction-associated steatotic liver disease (MASLD), previously called nonalcoholic steatohepatitis, or NASH, amplifies systemic inflammation and insulin resistance. MASLD has become the leading cause of liver failure and need for liver transplantation.4-The current scientific understanding of CKM Syndrome, Fig. 1 Proinflammatory and prooxidative mediators released into circulation exacerbate pathophysiologic processes involved in atherosclerosis and myocardial injury, glomerulosclerosis, kidney tubular inflammation, kidney fibrosis and the development of additional metabolic risk factors.3-The current scientific understanding of CKM Syndrome, Fig. 1 Ectopic fat may also produce local dysfunctional mediators and can cause compressive organ damage. When deposited in the epicardium, ectopic fat can promote arrhythmogenesis myocardial dysfunction and coronary atherosclerosis. When deposited “within” and around the kidney, ectopic fat can contribute to hypertension and abnormal variation in blood pressure.4-The current scientific understanding of CKM Syndrome, Fig. 1 The constellation of risk factors that make up metabolic syndrome (MetS), including abdominal obesity, dysglycemia, atherogenic dyslipidemia and hypertension, has multiple pathophysiologic consequences. MetS contributes to endothelial dysfunction, atherogenesis, thrombosis, myocardial injury, fibrosis and cardiac remodeling. Adipose Tissue ADIPONECTIN Causation CKM syndrome most commonly originates from excess or dysfunctional adipose tissue or both.Adiposity can lead to inflammation, insulin resistance and the emergence of myriad metabolic risk factors and systemic effects, including increased CVD risk. Metabolic abnormalities play key pathophysiologic roles in bi-directional cardiovascular-kidney interactions with kidney dysfunction a key mediator between metabolic risk factors and CVD in the CKM syndrome.

9 A Toolkit for Health Care Professionals Screening for Kidney Disease to Reduce CVD Risk These factors contribute to coronary heart disease, cerebrovascular disease, peripheral artery disease (PAD), cardiac arrhythmia and HF. MetS commonly progresses to type 2 diabetes (T2D) due to beta cell dysfunction in the setting of chronic insulin resistance. T2D markedly increases risk for both vascular and kidney disease.4-The current scientific understanding of CKM Syndrome, Fig. 1 The vascular, heart and kidney injuries associated with these processes stem from hemodynamic, metabolic, inflammatory and fibrotic mechanisms. Hyperglycemia induces glomerular hyperfiltration and hypertension, hemodynamic mechanisms long recognized as initiating and propagating kidney damage. Endothelial damage contributes to atherosclerosis and to glomerulosclerosis. Hypertension and obesity underly the development of left ventricular hypertrophy and HF.4-The current scientific understanding of CKM Syndrome Hyperglycemia in T2D promotes kidney and vascular damage through inflammation and fibrosis. Altered glucose metabolism generates advanced glycation end products and reactive oxygen species. Activation of protein kinase C, Janus kinase signaling and other intracellular signaling pathways lead to the ongoing release of proinflammatory mediators, profibrotic factors and immune cell recruitment. These metabolic disturbance pathways may become selfperpetuating despite intensive control of hyperglycemia later in the course of T2D.4-The current scientific understanding of CKM Syndrome CKD, detected or undetected, is a major amplifier of cardiovascular risk. Albuminuria and low glomerular filtration rate (GFR) are both hallmarks of CKD and associated with progressive risk of major atherosclerotic vascular and HF events and with cardiovascular death.4-The current scientific understanding of CKM Syndrome MetS and diabetes predisposes individuals to CKD. 3/4 of kidney failure cases in the United States are attributed to diabetes and hypertension. And while the prevalence of many diabetes complications has fallen in recent years, the number of individuals living with diabetes who develop kidney failure is progressively rising.4-The current scientific understanding of CKM Syndrome CKD, particularly in the presence of diabetes, is a proinflammatory state with elevated markers of systemic inflammation associated with high cardiovascular risk. Vascular calcification is a common complication of CKD and associated with ischemic complications, including myocardial infarction and PAD. CKD + diabetes is more likely to precipitate PAD below the knee, which can be more difficult to treat with revascularization and is linked to greater ischemic injury.4The current scientific understanding of CKM Syndrome CKD can also lead to anemia and bone and mineral disorders, exacerbating CVD.4-The current scientific understanding of CKM Syndrome Conversely, CVD, particularly HF, is associated with the development of CKD. HF may reduce GFR while low eGFR can exacerbate fluid retention and increase vascular congestion in a downward spiral of interlocking organ failure.4-The current scientific understanding of CKM Syndrome CVD, especially HF, can trigger or exacerbate CKD. HF can reduce GFR, and low eGFR can contribute to fluid retention, which can increase vascular congestion, leading to a downward spiral of linked organ failure.4-The current scientific understanding of CKM Syndrome

albumin-creatine ratio (uACR) >30mg/g < 60 GFR mL/min/1.73 m2 Prevalence and Incidence of Undetected CKD CKD is characterized by kidney damage, which can be defined as albuminuria (typically a urinary albuminto-creatinine ratio (uACR) >30 mg/g) or a glomerular filtration rate (GFR) <60 mL/min/1.73 m², that is present for more than three months.3-Epidemiology and prognosis, Fig 3 CKD affects 8% to 16% of the global population. The average annual decline in GFR across the general U.S. population is approximately 1 mL/min/1.73 m2, which carries >50% lifetime risk of GFR<60 mL/ min/1.73m2.5-Review, Chronic kidney disease Due to the lack of symptoms in the early stages, testing may be the only way to know if a patient has kidney disease. 10 The hallmarks of CKD, albuminuria and low GFR, are associated with progressive increases in the risk of major atherosclerotic cardiovascular and HF events and with cardiovascular death.4-The current scientific understanding of CKM syndrome The Kidney Disease Improving Global Outcomes (KDIGO) CKD staging system uses eGFR and albuminuria to assess risk for CKD progression, CVD events and overall mortality.4-Evidence supporting CKM-related screening In clinical practice, CKD is typically evaluated using two lab tests widely available, eGFR and uACR.7-Fig3, Practice Point 1.1.1.1 CKD is present when reduced eGFR or increased uACR is confirmed on two or more occasions at least three months apart.1-Results Higher levels of albuminuria indicate increased risk for mortality independent of eGFR.3Epidemiology and prognosis

A Toolkit for Health Care Professionals Screening for Kidney Disease to Reduce CVD Risk Individuals With CVD CKD often coexists with CVD and often goes undetected. Those with CKD are at increased risk for CVD events. Cardiovascular-associated mortality accounts for up to 50% in advanced and kidney failure versus 26% in individuals with normal kidney function. Patients with CKD are at increased risk for CVD even after adjusting for familiar CVD risk factors such as hypertension, diabetes and dyslipidemia. Even in early-stage CKD, patients carry an increased risk for CVD. Patients with CKD are more likely to die from cardiovascular events than to progress to kidney failure and the need for kidney replacement therapy.5-Introduction and Background Although CKD and CVD have often been treated as separate health entities, growing recognition that these conditions are closely linked by shared biological and social risk factors necessitates reconsideration. Most specialty organizations support the importance of identifying CKD and including kidney parameters as part of comprehensive CKM screening to better predict and prevent clinically relevant events.4Evidence supporting CKM-related screening Hyperglycemia is strongly associated with the development of both CKD and CVD.3-Traditional Risk Factors of Vascular Disease in CKD-Diabetes KDIGO consortium recommends routine CKD assessments, including eGFR and albuminuria, to provide prognostic information for both kidney and cardiovascular risks. Assessment of eGFR and uACR has the greatest utility in those with CKD and established metabolic risk factors such as diabetes. Individuals with moderate CKD risk, including excess weight or prior gestational diabetes, can also benefit from CKM screening. Otherwise healthy adults can benefit from less frequent but routine screening for CKM risk.4-Gaps in Screening for Metabolic Risk Factors and CKD in Adulthood The American Diabetes Association and KDIGO recommend annual screening of individuals with diabetes for CKD. Screening should begin at diagnosis for those with T2D because CKD is often already present. For type 1 diabetes (T1D), screening should begin five years after diagnosis.7-Screening and Prevention Individuals With Diabetes and Others at Risk for CVD 11

12 Early Testing Can Improve Clinical Outcomes CKD is an insidious disease, typically silent and unnoticed until it progresses to advanced stages.9-Introduction There are recommendations for at-risk population screening for CKD.7 The elements of CKD screening, eGFR and uACR, are widely available and used in both primary and specialty care,6-pg 2, 1-Results but seldom used in combination to screen for CKD.10-Who should be screened for CKD? Asymptomatic and unrecognized CKD can only be diagnosed and staged using both eGFR and uACR. Find it early and treat it early.11-Testing and Treatment But there is no consensus around CKD screening in patients with risk factors. Despite significant prevalence among Americans, there are no federal government screening recommendations for CKD, which could increase testing and diagnosis and potentially allow for earlier treatment intervention. Although studies recommend screening individuals with diabetes and hypertension at high risk for CVD, data on the potential benefits of general population screening are conflicting. Fortunately, the CKD treatment landscape has changed. Unlike 2012, clinicians have growing numbers of effective agents to save kidneys, hearts and lives.10-Why screen for CKD? Multiple classes of medications have demonstrated benefit in slowing the progression of CKD, including ACE inhibitors/ ARBs, SGLT2 inhibitors, GLP-1 receptor agonists and nsMRA (finerenone).4-Evidence supporting CKM-related screening, 9-Introduction, 10-Why screen for CKD? Emerging therapies , such as GLP-1 receptor agonists and aldosterone synthase inhibitors, are being investigated for their potential role in CKD management. The kidney benefits of these medication classes far exceed the benefits expected from improved blood pressure and glycemic control, including reductions of cardiovascular death and heart failure.9Introduction, 10, 14-Conclusion 7, 18-introduction, 20-Gaps Between Knowledge and Implementation in Kidney Care By 2021, more than 850 million people globally suffered from kidney disease, about double the number who live with diabetes and 20 times the global prevalence of cancer or AIDS/HIV.7-The global burden of CKD In the United States alone, about 16% of the adult population is affected by CKD. Ninety percent of these individuals are unaware they have CKD.9-Introduction Screening is an obvious approach to raising awareness of CKD status and promoting effective treatment. Screening is the detection of previously unrecognized, subclinical disease in asymptomatic individuals to facilitate early intervention to reduce morbidity and mortality.9-Introduction Between 1990 and 2019, the global CKD incidence more than doubled.10-Why Screen for CKD?

A Toolkit for Health Care Professionals Screening for Kidney Disease to Reduce CVD Risk 13 There are currently no general practice guidelines recommending CKD screening for the entire population. However, the KDIGO guidelines recommend screening using uACR and eGFR for people at risk for CKD.7, 10-Who should be screened for CKD? The AHA Cardio-Kidney-Metabolic Initiative includes eGFR and uACR in the recent PREVENT equation, underscoring the role CKD plays in atherosclerotic CVD and heart failure.12-Introduction In practice, uACR and other albuminuria testing are not commonly performed, even in those living with diabetes. Many other individuals at elevated risk for CKD, including those with a family history of kidney disease, hypertension, excess adiposity and other CKD/CVD risk factors, or CVD, too often go unscreened.10-Who should be screened for CKD? A 2014 systematic review of cost-effectiveness analyses of CKD screening strategies concluded that screening high-risk individuals is cost-effective in any scenario. General population screening could be costeffective if medication intervention could be considered highly effective for both kidney and cardiovascular risk reduction.13-Discussion, Conclusion A decade later, SGLT2 inhibitors, GLP-1 receptor agonists, nsMRA (finerenone) and other medication classes are highly effective for both kidney and cardiovascular risk reduction. A cost-effectiveness analysis concluded population-wide screening for albuminuria followed by treatment with SGLT2 inhibitors in addition to ACE inhibitors/ARB treatment may be cost-effective in the general U.S. population aged 35 years and older.10-Discussion, Conclusion The benefits of population-wide screening were published before the confirmation of combined kidney and cardiovascular benefits of GLP-1 receptor agonists and a nsMRA.10-How and When Should CKD Screening Be Performed? It is reasonable to follow a similar path as novel classes of agents are confirmed to benefit kidneys, hearts and lives. The optimal frequency of screening varies by age, reflecting the epidemiology of CKD over the lifetime. For 35- to 45-year-olds, screening every 10 years is costeffective. Because the prevalence of CKD increases with age, screening every five years, starting at age 55 may be reasonable.10-Discussion CKD patients, advocacy groups and others argue strongly in favor of early screening, diagnosis, risk stratification and intervention, particularly for individuals with hypertension, diabetes or CVD. Effective screening and risk stratification must include both eGFR and uACR.14-Introduction, Table 1 Point-of-care (POC) testing is recommended if laboratory access is limited or when POC testing can facilitate clinical intervention.10-Recommendation 1.4.1

CVD is the leading cause of death in patients with established CKD. Kidney-specific practice guidelines recommend that all patients with CKD be evaluated for CVD regardless of the presence or absence of CVD symptoms.8-Introduction Just as screening asymptomatic patients without CKD for CVD can lead to early interventions and improved outcomes, some experts suggest screening asymptomatic patients with CKD can be expected to produce similar benefits. The same atherosclerotic CVD risk calculator is used to assess risk in individuals with or without.8-Use of ASCVD Risk Calculator It is important to diagnose CVD early to intervene early and modify risk factors to improve clinical outcomes.8-Conclusion Undetected CVD in Those With Known CKD CKD risk factors include: † existing hypertension, diabetes or CVD (including HF) or prior acute kidney injury/diseases † residence in geographic areas with high prevalence of CKD associated with environmental factors, high prevalence of APOL1 genetic variants or endemic CKD † genitourinary disorders, multisystem diseases or chronic inflammatory conditions, including systemic lupus erythematosus, vasculitis and HIV † iatrogenic exposures including drug-induced nephrotoxicity and radiation nephritis † family history or known genetic variant associated with CKD † gestational conditions including preterm birth, small gestational size or preeclampsia/eclampsia † occupational exposures including cadmium, lead, mercury, polycyclic hydrocarbons or presticides7-Table5 as well as obesity and age.14-Figure 2 Risk Stratification in CKD Using eGFR and uACR Screening must include both eGFR and uACR measures.7Figure 3 Risk should be stratified using eGFR and uACR. CKD is staged using the KDIGO heat map, which is based on clinical outcomes: † All-cause mortality † Cardiovascular mortality † Myocardial infarction † Stroke † Heart failure † Atrial fibrillation † Peripheral artery disease † Kidney failure with replacement therapy † Acute kidney injury † Hospitalization7-Figure 5 The KDIGO risk class directs the need for treatment and/or specialty consultation.14-Figure 2 14

A Toolkit for Health Care Professionals Screening for Kidney Disease to Reduce CVD Risk People Living With Diabetes CKD in people with any type of diabetes is prevalent, morbid and costly. About 537 million people worldwide were living with diabetes in 2021, a number expected to increase to 783 million by 2045, according to the International Diabetes Federation. As the prevalence of diabetes grows, so does the prevalence of CKD attributed to diabetes.15-Background Recognizing both the growing prevalence, morbidity and mortality associated with CKD in diabetes and the rapidly expanding treatment landscape, the American Diabetes Association (ADA)16 and KDIGO17 have both updated standards of care for those living with diabetes and CKD. The two organizations have also published a consensus statement outlining their broad areas of agreement in screening, diagnosis, risk stratification and management.15 Diabetes is now the leading cause of kidney failure requiring transplantation or dialysis worldwide. In the U.S., increasing prevalence of diabetes is fueling an increase in kidney failure. Diabetes is now responsible for half of all new cases of kidney failure.15-Background At the same time, CKD dramatically increases the risks of ASCVD, HF, cardiovascular death and all-cause mortality among people living with diabetes.15-Background The prevalence of CKD among people with diabetes is >25%, and about 40% of people with diabetes are estimated to develop CKD during their lifetime. >25% 40% Awareness of diabetes and CKD is dismal. One of every five adults with diabetes in the U.S. does not know it. Among those with CKD, up to 90% do not know it, including 40% of those with severe CKD. CKD is a silent disease, particularly in the earlier stages, and can be detected only through screening. Both the ADA and KDIGO recommend annual CKD screening for anyone living with diabetes.15-Screening and diagnosis CKD typically presents five to 15 years after diagnosis of T1D but may be present at diagnosis in T2D.16-Epidemiology of Diabetes and Chronic Kidney Disease CKD screening using uACR and eGFR should begin five years after diagnosis for those with T1D and beginning at diagnosis for those with T2D.16-Recommendation 11.1a If CKD is present, uACR and eGFR should be monitored one to four times per year, depending on the stage of kidney disease.16Recommendation 11.1b, Figure 11.1 5YEARS 15

16 Use Guideline-Directed Medical Therapy and Shared Decision-Making to Improve Outcomes CKD in the advanced stages is largely irreversible, but progression can be halted, even reversed, in earlier stages. Early detection through screening of at-risk individuals who may be asymptomatic, followed by early intervention using guideline-directed medical therapy (GDMT), are critical steps in reducing CKD progression and CKD-associated morbidity and mortality.18-introduction Lifestyle intervention, including weight control, physical activity, appropriate eating patterns and tobacco avoidance, is the basis of good CKM health. Clinicians have a substantial and growing collection of therapeutic options for those with disease already, not at risk for CVD or CKD. They can prevent adverse outcomes, such as kidney failure, particularly when used early in the course of disease. Just as risk reduction and therapeutic approaches to HF are based on Pillars of Therapy, so too are CKD and CKM health. Renin-angiotensin system (RAS) blockade using ACE inhibitors or ARBS emerged as the first pillar for CKD in the 1990s. More recent evidence has established SGLT2 inhibitors, a nsMRA and GLP-1 receptor agonists as additional pillars of treatment for CKD, intially in individuals with diabetes and increasingly in those without diabetes.19-Article highlights, 20-Gaps Between Knowledge and Implementation in Kidney Care, 21-Introduction Practice guidelines for CKD are clear, but application of GDMT is poor.20- Gaps Between Knowledge and Implementation in Kidney Care More than 15 years after the most recent CKD and T2D approvals of ACE inhibitors/ARBs in the United States, realworld data from electronic health records suggest uptake is about 40% after 90 days.20-Gaps Between Knowledge and Implementation in Kidney Care. Pg. 408 SGLT2 inhibitors can reduce risk of substantial decline in eGFR, kidney failure and death in individuals with CKD, HF and CVD by about 40%. These benefits are additive to risk reductions seen with RAS blockade, yet uptake of SGLT2 inhibitors is only about 6% after 90 days. Uptake of GLP1 receptor agonists is similarly low.20- Gaps Between Knowledge and Implementation in Kidney Care First-line GDMT focuses on blood pressure, glucose and lipid management22-First-line GDMT, 7- Chapter3 including RAS blockade plus SGLG2 inhibition for individuals with or without diabetes.7-Figure 18, 3.7 Either an ACE inhibitor or ARB at maximum tolerated dose are appropriate RAS inhibitors.7-Figure 18, 3.6 Target blood pressure for most patients is <120 mm Hg or <130 mm Hg systolic depending on risks of CVD and CKD and overall health status.7-Figure 18, 3.4, 20-Figure 3 Treating CKD is more successful with a holistic approach that includes risk modification and GDMT.7-Figure 18 Healthy lifestyle interventions are the foundation for GDMT, including healthy diet, physical activity, weight management and cessation of tobacco use. The same interventions are also recommended to reduce CVD risk.22-Foundation: healthy lifestyle and management of traditional risk factors

17 A Toolkit for Health Care Professionals Screening for Kidney Disease to Reduce CVD Risk Treatment In adults aged 18–49 years with CKD but not treated with chronic dialysis or kidney transplantation, we suggest statin treatment in people with one or more of the following: • known coronary disease (myocardial infarction or coronary revascularization) • diabetes mellitus • prior ischemic stroke • estimated 10-year incidence of coronary death or nonfatal myocardial infarction >10%..7-Figure 18, 3.15, 20-Figure 3 In individuals without CKD, statin therapy is first-line treatment for primary prevention of ASCVD in patients with elevated low-density lipoprotein cholesterol levels (≥190 mg/dL), those with diabetes mellitus, who are 40 to 75 years of age, and those determined to be at sufficient ASCVD risk after a clinician– patient risk discussion. Targeted therapies for complications include management of hyperglycemia per the KDIGO 2022 guidelines for diabetes management in CKD7 summary of recommendation statements and practice points and include the use of a GLP-1 receptor agonist,7-3.9 nsMRA in those with T2D7-3.8 or dihydropyridine CCB and/ or diuretic if needed to achieve blood pressure goal, followed by steroidal MRA if needed for resistant hypertension if eGFR ≥45. ASCVD risk should be managed using ezetimibe and a PCSK9 inhibitor based on risk levels and lipids. Use the same principles employed to diagnose and manage ASCVD and atrial fibrillation as in those without CKD. For individuals living with T1D and CKD, current GDMT is RAS blockade using ACE inhibitor or ARB, statin and insulin.17-Figure 1, 1.1 Safety and efficacy of SGLT2 inhibition in T1D have not been established.17-Recommendation 1.3.1 Barriers to GDMT Low rates of screening are early barriers to the implementation of kidney and heart protective GDMT. Limited health care professional awareness of subspecialties may contribute to low prescription rates for GDMT therapies shown to protect kidneys and hearts. Inconsistencies across professional society guidelines may add to provider confusion and uncertainty. High rates of discontinuation of kidney and heart protective drugs are another barrier to GDMT. Multiple factors are related to adherence and discontinuation, including side effects, cost, access, insurance plan coverage, health inequities related to social determinants of health (SDOH) and more. Practical strategies that are patient-centered and leverage multidisciplinary expertise are needed.24-Challenges in the Implementation of Kidney Protective and Cardioprotective Therapies, Strategies to Improve the Implementation of Kidney Protective and Cardioprotective Therapies

Screening and Staging CKM Historically, there is about a 17-year gap between evidence of clinical benefit from a new treatment and adoption into routine clinical practice. The millions of people at increasing risk of death from CKM syndrome progression to CKD and/or CVD cannot wait.20- Gaps Between Knowledge and Implementation in Kidney Care The CKM staging path is bidirectional. The absolute risk of both ASCVD and HF increase with progression from Stage 0 to more advanced stages. Individuals can also regress toward, or to, Stage 0 with the appropriate targeted interventions. The clinical conundrum is accurately assessing and predicting CKM risk to best match the type and intensity of intervention with the predicted risk to reduce morbidity and mortality.12-Introduction 18 Reducing that 17-year gap starts with appropriate screening, risk prediction and risk stratification. CKM syndrome is a five-stage spectrum with stepwise increases in absolute CVD risk. STAGE 0 represents no CKM risk factors.4 STAGE 1 is excess or dysfunctional adiposity. STAGE 2 includes metabolic risk factors of moderate to high risk of CKD. STAGE 3 Subclinical CVD in CKM or the risk equivalents of subclinical CVD, either highrisk CKD or high predicted risk of CVD. STAGE 4 Clinical CVD with CKM risk factors. CVD risk equations have long omitted the welldocumented recognized associations between obesity, diabetes, CKD and CVD morbidity and mortality. These four factors are interrelated, mutually reinforcing and disproportionately affect disenfranchised populations, e.g., underrepresented racial and ethnic groups.12-Introduction Multiple new risk equations are being developed to better assess CKM, CVD and CKD risk in different populations with and without diabetes. These equations include familiar risk factors such as blood pressure, lipids and BMI, and add measures such as eGFR, uACR and SDOH to more accurately predict risk of CKM, CKD and CVD over different time periods.12, 18, 23, 25, 26, 29 The PREVENT equation, developed by the AHA, provides sex-specific and race-free estimates of 10- and 30year for total CVD, a composite of ASCVD and HF, among adults 30 to 79 years of age. The central model includes eGFR and adjusts for competing risks of non-CVD death. Additional models enhance predictive utility by adding uACR, A1C or SDOH measures when available. Growing evidence supports observations that declining kidney health is associated with worse CVD outcomes. Kidney-protective therapies improve CVD outcomes.12Predicting Adverse Kidney Outcomes to Optimize Prevention of CVD PREVENT can be applied in a broad range of clinical and community settings using readily available clinical factors plus additional factors as available. The equation can be implemented by any clinician caring for adult patients, including primary care, obstetrics and gynecology, cardiology, nephology and endocrinology.12-Conclusions Clinical practice guidelines from cardiovascular, nephrology and diabetes organizations recommend the four pillars approach, but translating guidelines into clinical practice can be slow.19 Clinicians typically add each successive therapy in the order in which evidence was generated, first RAS blockade, followed by SGLT2 inhibition, nsMRA (finerenone) and GLP-1 receptor agonist.21

19 A Toolkit for Health Care Professionals Screening for Kidney Disease to Reduce CVD Risk KDIGO heat map detailing the prognosis of CKD based upon GFR and albuminuria category [7]. Abbreviations: Kidney Disease: Improving Global Outcomes (KDIGO); GFR-glomerular filtration rate. This traditional approach may not fully address patients’ elevated early CVD risk, particularly the risk for HF, as it can result in treatment delays. Following some current guidelines could delay full treatment >18 months. And spacing multiple medication adjustments and additions over many months substantially increases the risk for therapeutic inertia and further delay.21 The rapid sequence approach used in HF, acute myocardial infarction and HIV is a viable alternative. Rather than adjusting medications in a slow, stepwise fashion, introduce them simultaneously or within a very short period based on GDMT. This rapid approach reduces therapeutic inertia and increases potential benefits.21 It is also appropriate to use an externally validated risk equation to assess the absolute risk of kidney failure and adjust GDMT by risk stratification. The KDIGO heat map and Kidney Failure Risk Equation are the most commonly used risk assessments in practice21 and other equations are in various stages of development and validation.23, 25, 26, 27 Act Now New and continuing therapeutic advances offer genuine hope that many people with CKD can survive without progression to kidney failure and death. The time is now to implement broad-based screening using eGFR and uACR, both common and readily accessible in primary and specialty care. The time is now to spur the adoption of GDMT to ensure that all who might benefit from CKD treatment can receive it and do receive it. Healthy hearts and healthy kidneys will become a reality only when we narrow the gap between what we know about protecting CKM health and what we do to protect it. 20-Call to action Persistent Albuminuria Categories Description and Range GFR categories (ml/min/1.73 m2) Description and range A1 G1 ≥90 G2 60–89 G3a 45–59 G3b 30–44 G4 15–29 G5 <15 Kidney failure Severely decreased Moderately to severely decreased Mildly to moderately decreased Mildly decreased Normal or high A2 A3 Normal to mildly increased Moderately increased Severely increased <30 mg/g <3 mg/mmol 30–300 mg/g 3–30 mg/mmol >300 mg/g >30 mg/mmol KDIGO: Prognosis of CKD by GFR and Albuminuria Categories Green: low risk (if no other markers of kidney disease, no CKD);Yellow: moderately increased risk; Orange: high risk; Red: very high risk.

20 Key Takeaways CKD is emerging as a key and almost universally unrecognized risk factor for CVD. The prevalence of CKD may be as high as 15% of all adults in the United States7-Fast Facts and up to 16% of the global population,5-Review affecting about 35.5 million people in the U.S. and 1.3 billion individuals around the world. Even in its earliest stages, CKD can lead to hypertension and potentiate CVD. Impaired kidney function is an independent risk factor for the development of CVD and may increase CVD risk more than traditional risk factors such as diabetes mellitus or hypertension. Impaired kidney function alone can increase the risk of CVD two- to fourfold.1-Results CKD develops and progresses silently and unpredictably with symptoms that may not appear until the late stages.1-Results As many as 90% of all individuals with CKD are unaware they have impaired kidney function and about 33% with severe CKD do not know it.6-Fast Facts, 28 All individuals, children and adults at risk should be screened for CKD using a combination of two standard laboratory tests widely available in primary and specialty care, eGFR and uACR. Because CKD has few, if any, symptoms in the early stages, broad-based screening is the only viable approach to early detection and management of CKD and the associated CVD risk.4-Evidence supporting CKM-related screening If CKD is identified, clinicians have an expanding toolkit of therapeutic approaches to prevent or mitigate metabolic risk factors, to delay the progression of kidney disease, and to reduce the associated CVD risk. Multiple therapeutic agents, including ACEi/ ARB, SGLT2 inhibitors, a nsMRA (finerenone), GLP1-RAs and other incretin analogues,3Figure 3 offer beneficial metabolic effects, kidney effects, cardiovascular effects or all three to improve CVD and kidney health.4-introduction These agents are effective only if they are used. We know how to prevent or delay the onset and progression of kidney disease; we have clear clinical practice guidelines for CKD and CVD. Adherence to evidence-based GDMT is suboptimal.20-Gaps Between Knowledge and Implementation in Kidney Care The time is now to implement broad-based screening of children and adults at high risk for CKD using eGFR and uACR to diagnose asymptomatic and unrecognized CKD. The time is now to implement appropriate heart protective and kidney protective treatments and new agents as they become available. The time is now to spur the adoption of GDMT to ensure that all who might benefit from CKD treatment can receive it and do receive it. Healthy hearts and healthy kidneys will become a reality only when we narrow the gap between what we know about protecting CKM health and what we do to protect it.20-Call to action 1 2 3 4 5 6 7 8 9 10

21 A Toolkit for Health Care Professionals Screening for Kidney Disease to Reduce CVD Risk Notes: Key for toolkit terms ACEi/ARB: angiotensin-converting enzyme inhibitors/angiotensin II receptor blockers ACE inhibitors: angiotensin-converting enzyme ADA: American Diabetes Association AHA: American Heart Association CKD: chronic kidney disease CKM: cardiovascular-kidney-metabolic CVD: cardiovascular disease GFR: glomerular filtration rate eGFR: estimated glomerular filtration rate GDMT: guideline-directed medical therapy GLP1-RA: glucagon-like peptide-1 receptor agonists HF: heart failure MASLD: metabolic dysfunction-associated steatotic liver disease MetS: metabolic syndrome nsMRA: non-steroidal mineralocorticoid antagonists (finerenone) PAD: Peripheral artery disease SDOH: social determinants of health SGLT2i: sodium-glucose transporter-2 inhibitors T1D: type 1 diabetes T2D: type 2 diabetes uACR: urine albumin-creatinine ratio

22 References 1. Said S, Hernandez GT. The link between chronic kidney disease and cardiovascular disease. J Nephropathol. 2014 Jul;3(3):99-104. doi: 10.12860/ jnp.2014.19. Epub 2014 Jul 1. PMID: 25093157; PMCID: PMC4119330. 2. Ndumele CE, Rangaswami J, Chow SL, Neeland IJ, Tuttle KR, Khan SS, Coresh J, Mathew RO, Baker-Smith CM, Carnethon MR, Despres JP, Ho JE, Joseph JJ, Kernan WN, Khera A, Kosiborod MN, Lekavich CL, Lewis EF, Lo KB, Ozkan B, Palaniappan LP, Patel SS, Pencina MJ, Powell-Wiley TM, Sperling LS, Virani SS, Wright JT, Rajgopal Singh R, Elkind MSV; American Heart Association. Cardiovascular-Kidney-Metabolic Health: A Presidential Advisory From the American Heart Association. Circulation. 2023 Nov 14;148(20):1606-1635. doi: 10.1161/CIR.0000000000001184. Epub 2023 Oct 9. Erratum in: Circulation. 2024 Mar 26;149(13):e1023. doi: 10.1161/ CIR.0000000000001241. PMID: 37807924 3. Jankowski J, Floege J, Fliser D, Böhm M, Marx N. Cardiovascular Disease in Chronic Kidney Disease: Pathophysiological Insights and Therapeutic Options. Circulation. 2021 Mar 16;143(11):1157-1172. doi: 10.1161/ CIRCULATIONAHA.120.050686. Epub 2021 Mar 15. PMID: 33720773; PMCID: PMC7969169. 4. Ndumele CE, Neeland IJ, Tuttle KR, Chow SL, Mathew RO, Khan SS, Coresh J, Baker-Smith CM, Carnethon MR, Després JP, Ho JE, Joseph JJ, Kernan WN, Khera A, Kosiborod MN, Lekavich CL, Lewis EF, Lo KB, Ozkan B, Palaniappan LP, Patel SS, Pencina MJ, Powell-Wiley TM, Sperling LS, Virani SS, Wright JT, Rajgopal Singh R, Elkind MSV, Rangaswami J; American Heart Association. A Synopsis of the Evidence for the Science and Clinical Management of CardiovascularKidney-Metabolic (CKM) Syndrome: A Scientific Statement From the American Heart Association. Circulation. 2023 Nov 14;148(20):1636-1664. doi: 10.1161/ CIR.0000000000001186. Epub 2023 Oct 9. PMID: 37807920. 5. Saeed D, Reza T, Shahzad MW, Karim Mandokhail A, Bakht D, Qizilbash FH, Silloca-Cabana EO, Ramadhan A, Bokhari SFH. Navigating the Crossroads: Understanding the Link Between Chronic Kidney Disease and Cardiovascular Health. Cureus. 2023 Dec 30;15(12):e51362. doi: 10.7759/ cureus.51362. PMID: 38292979; PMCID: PMC10825078. 6. National Kidney Foundation. 30 East 33rd Street, New York, NY 10016 © 2023 National Kidney Foundation Inc. https:// www.kidney.org/atoz/content/knowyour-kidney-numbers-two-simple-tests. 7. Kidney Disease: Improving Global Outcomes (KDIGO) CKD Work Group (2024). KDIGO 2024 Clinical Practice Guideline for the Evaluation and Management of Chronic Kidney Disease. Kidney international, 105(4S), S117—S314. https://doi.org/10.1016/j. kint.2023.10.018 8. Jain N, McAdams M, Hedayati SS. Screening for Cardiovascular Disease in CKD: PRO. Kidney360. 2022 Feb 28;3(11):1831-1835. doi: 10.34067/ KID.0005012021. PMID: 36514398; PMCID: PMC9717623. 9. Marika M. Cusick, Rebecca L. Tisdale, Glenn M. Chertow, et al. PopulationWide Screening for Chronic Kidney Disease: A Cost-Effectiveness Analysis. Ann Intern Med. 2023;176:788-797. [Epub 23 May 2023]. doi:10.7326/M22-3228 10. Tuttle KR. CKD screening for better kidney health: Why? Who? How? When? Nephrol Dial Transplant. 2024 Feb 29:gfae055. doi: 10.1093/ndt/gfae055. Epub ahead of print. PMID: 38425029. 11. Centers for Disease Control and Prevention. Chronic Kidney Disease in the United States, 2023. Atlanta, GA: US Department of Health and Human Services, Centers for Disease Control and Prevention; 2023. 12. Khan SS, Coresh J, Pencina MJ, Ndumele CE, Rangaswami J, Chow SL, Palaniappan LP, Sperling LS, Virani SS, Ho JE, Neeland IJ, Tuttle KR, Rajgopal Singh R, Elkind MSV, Lloyd-Jones DM; American Heart Association. Novel Prediction Equations for Absolute Risk Assessment of Total Cardiovascular Disease Incorporating Cardiovascular-KidneyMetabolic Health: A Scientific Statement From the American Heart Association. Circulation. 2023 Dec 12;148(24):19822004. doi: 10.1161/CIR.0000000000001191. Epub 2023 Nov 10. PMID: 37947094. 13. Komenda, P., Ferguson, T. W., Macdonald, K., Rigatto, C., Koolage, C., Sood, M. M., & Tangri, N. (2014). Cost-effectiveness of primary screening for CKD: a systematic review. American journal of kidney diseases: the official journal of the National Kidney Foundation, 63(5), 789–797. https://doi. org/10.1053/j.ajkd.2013.12.012

23 A Toolkit for Health Care Professionals Screening for Kidney Disease to Reduce CVD Risk 14. Shlipak, M. G., Tummalapalli, S. L., Boulware, L. E., Grams, M. E., Ix, J. H., Jha, V., Kengne, A. P., Madero, M., Mihaylova, B., Tangri, N., Cheung, M., Jadoul, M., Winkelmayer, W. C., Zoungas, S., & Conference Participants (2021). The case for early identification and intervention of chronic kidney disease: conclusions from a Kidney Disease: Improving Global Outcomes (KDIGO) Controversies Conference. Kidney international, 99(1), 34–47. https://doi.org/10.1016/j.kint.2020.10.012 15. de Boer IH, Khunti K, Sadusky T, Tuttle KR, Neumiller JJ, Rhee CM, Rosas SE, Rossing P, Bakris G. Diabetes Management in Chronic Kidney Disease: A Consensus Report by the American Diabetes Association (ADA) and Kidney Disease: Improving Global Outcomes (KDIGO). Diabetes Care. 2022 Dec 1;45(12):3075-3090. doi: 10.2337/ dci22-0027. PMID: 36189689; PMCID: PMC9870667. 16. American Diabetes Association Professional Practice Committee. 11. Chronic Kidney Disease and Risk Management: Standards of Care in Diabetes-2024. Diabetes Care. 2024 Jan 1;47(Suppl 1):S219-S230. doi: 10.2337/ dc24-S011. PMID: 38078574; PMCID: PMC10725805. 17. Kidney Disease: Improving Global Outcomes (KDIGO) Diabetes Work Group. KDIGO 2022 Clinical Practice Guideline for Diabetes Management in Chronic Kidney Disease. Kidney Int. 2022 Nov;102(5S):S1-S127. doi: 10.1016/j. kint.2022.06.008. PMID: 36272764. 18. Grams ME, Brunskill NJ, Ballew SH, et al. Development and Validation of Prediction Models of Adverse Kidney Outcomes in the Population With and Without Diabetes. Diabetes Care. Sep 1 2022;45(9):2055-2063. doi:10.2337/dc220698 19. Naaman SC, Bakris GL. Diabetic Nephropathy: Update of Pillars of Therapy Slowing Progression. Diabetes Care 2023;46(9):1574–1586 | https://doi. org/10.2337/dci23-0030 20. Luyckx VA, Tuttle KR, Abdellatif D, Correa-Rotter R, Fung WWS, Haris A, Hsiao LL, Khalife M, Kumaraswami LA, Loud F, Raghavan V, Roumeliotis S, Sierra M, Ulasi I, Wang B, Lui SF, Liakopoulos V, Balducci A; World Kidney Day Joint Steering Committee. Mind the gap in kidney care: translating what we know into what we do. Kidney Int. 2024 Mar;105(3):406-417. doi: 10.1016/j. kint.2023.12.003. PMID: 38375622. 21. Neuen BL, Tuttle KR, Vaduganathan M. Accelerated Risk-Based Implementation of Guideline-Directed Medical Therapy for Type 2 Diabetes and Chronic Kidney Disease. Circulation. 2024 Apr 16;149(16):1238-1240. doi: 10.1161/ CIRCULATIONAHA.123.068524. Epub 2024 Apr 15. PMID: 3862008 22. Neumiller JJ, Alicic RZ, Tuttle KR. Optimization of guideline-directed medical therapies in patients with diabetes and chronic kidney disease. Clin Kidney J. 2023 Nov 16;17(1):sfad285. doi: 10.1093/ckj/sfad285. PMID: 38213492; PMCID: PMC10783256. 23. Limonte CP, Lamprea-Montealegre JA, Tuttle KR. Challenges and Strategies in Implementing Novel Kidney Protective and Cardioprotective Therapies in Patients With Diabetes and Kidney Disease. Semin Nephrol. 2024 May 4:151520. doi: 10.1016/j. semnephrol.2024.151520. Epub ahead of print. PMID: 38705774. 24. Zacharias HU, Altenbuchinger M, Schultheiss UT, et al. A Predictive Model for Progression of CKD to Kidney Failure Based on Routine Laboratory Tests. Am J Kidney Dis. Feb 2022;79(2):217-230.e1. doi:10.1053/j.ajkd.2021.05.018 25. Lam D, Nadkarni GN, Mosoyan G, et al. Clinical Utility of KidneyIntelX in Early Stages of Diabetic Kidney Disease in the CANVAS Trial. Am J Nephrol. 2022;53(1):21-31. doi:10.1159/000519920 26. Tangri N, Grams ME, Levey AS, et al. Multinational Assessment of Accuracy of Equations for Predicting Risk of Kidney Failure: A Meta-analysis. Jama. Jan 12 2016;315(2):164-74. doi:10.1001/ jama.2015.18202 27. Nelson RG, Grams ME, Ballew SH, et al. Development of Risk Prediction Equations for Incident Chronic Kidney Disease. Jama. Dec 3 2019;322(21):21042114. doi:10.1001/jama.2019.17379 28. Centers for Disease Control and Prevention. https://www.cdc.gov/kidneydisease/media/pdfs/CKD-Factsheet-H. pdf. 29. Edward P. Havranek, MD, FAHA, Mahasin S. Mujahid, PhD, MS, et al. Social Determinants of Risk and Outcomes for Cardiovascular Disease. Circulation. Aug. 3, 2015. https://doi.org/10.1161/ CIR.0000000000000228

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