Rethinking Kidney Health: Advancing Combination Therapy in CKD

CKD affects approximately 1 in 7 adults in the United States. Modern lifestyle factors, including lower levels of physical activity, higher intake of ultraprocessed foods, and inadequate sleep, have driven an increased prevalence of dysfunctional visceral adiposity, which in turn promotes microinflammation and oxidative stress, contributing to a mosaic of chronic diseases: CKD,  heart failure, diabetes, obesity, hypertension, atherosclerotic cardiovascular disease (ASCVD) and metabolic liver disease that collectively characterize the cardiovascular-kidney-metabolic (CKM) syndrome.

Building on a foundation of lifestyle modification, evidence continues to support earlier and more intensive use of therapies such as:

• Renin-angiotensin system (RAS) inhibitors

• Sodium-glucose cotransporter-2 (SGLT2) inhibitors

• Nonsteroidal mineralocorticoid receptor antagonists (nsMRAs)

• Glucagon-like peptide-1 receptor agonists (GLP-1 RAs)

As a result, healthcare professionals are asking an important question: How should these therapies be combined in real-world care?

The modern CKD treatment landscape has evolved rapidly over the past decade. Clinical trials such as CONFIDENCE, CREDENCE, DAPA-CKD, EMPA-KIDNEY, FIDELIO-DKD, FINE-ONE, FLOW, and SURPASS-CVOT (kidney outcomes analysis[JAV1] ) have demonstrated that multiple therapies can independently reduce CKD progression, cardiovascular (CV) events, and mortality risk.^1–8 At the same time, emerging evidence suggests that combining these therapies may provide even greater benefits.

A recent cross-trial analysis estimated the lifetime cardiovascular, kidney, and survival benefits of combining therapies in patients with type 2 diabetes and albuminuria. Compared with conventional care (i.e., RAS blockade and traditional risk factor control), adding the combination of SGLT2 inhibitor, GLP-1 RA, and nsMRA was associated with a 58% reduction in CKD progression compared with 37%, 23%, or 14% when adding an SGLT2 inhibitor, nsMRA, or GLP-1 RA, respectively.⁹ These findings reinforce the emerging concept of “four-pillar” CKM therapy – combining RAS blockade, SGLT2 inhibition, GLP-1 receptor agonism, and nsMRA therapy to address overlapping kidney, CV, and metabolic risk factors in high-risk patient populations.^10–12

However, translating this evidence into routine practice remains challenging. Clinicians are often left navigating difficult practical questions.

• Which therapies should be prioritized first?
• Should medications be initiated simultaneously or sequentially?
• How does side effect risk influence therapy selection?
• Which patients are most likely to benefit from combination therapy?
• What is the best way to match a patient’s kidney and cardiovascular risks with the intensity of lifestyle and pharmacologic interventions?
• How should treatment decisions change based on kidney function, cardiovascular risk, or patient preferences?
• What interventions will promote long-term durability of the pillars of therapy, such as pharmacist-led interventions, implementation of sick day rules, and remote monitoring interventions?

These questions can become even more complicated when patients receive care from multiple specialists. Without coordinated communication and accountability, treatment recommendations may become fragmented or even conflicting, contributing to therapeutic inertia, patient confusion, and missed opportunities for risk reduction.

The NKF workshop brought together experts across nephrology, cardiology, endocrinology, primary care, pharmacy, and implementation science, alongside patient advocates and other healthcare stakeholders. The goal was not only to review the evolving science behind combination therapy but also to discuss the operational and patient-centered realities of implementing these strategies in everyday practice.

Importantly, the workshop emphasized that evidence alone is not enough. Successful implementation also depends on workflow design, referral coordination, medication access, patient education, and shared decision-making.

Participants explored several core questions, including:

• Should therapies be initiated all at once or added stepwise over time?

• Which patient-specific factors should guide sequencing decisions?

• How can interdisciplinary collaboration be improved when multiple specialists are involved?

• What barriers prevent optimal implementation of guideline-directed therapies?

• How should healthcare systems measure quality of CKD care and identify gaps?

• What research priorities remain unanswered?

Another major focus involved risk prediction and stratification. Existing calculators can help estimate outcomes such as progression to kidney failure or cardiovascular events, but they do not always accurately predict risk at the individual patient level. Workshop discussions highlighted the growing need for more precise and equitable risk assessment tools that better support individualized treatment decisions.

The workshop also reflects NKF’s longstanding leadership in advancing integrated kidney and cardiovascular care. Through initiatives such as KDOQI and CKDintercept, NKF has consistently emphasized the interconnected nature of kidney disease, cardiovascular disease, diabetes, and other CKM conditions, making the population health approach especially impactful.

This scientific workshop represents a natural progression of that work: creating a collaborative forum where experts across specialties can identify barriers, align practical solutions, and define future research priorities. By convening multidisciplinary voices, including patients, NKF continues to help shape the national conversation around evidence-based, coordinated CKM care.

Workshop leaders are currently synthesizing the discussions, feedback, and consensus-building activities into a comprehensive report to inform future clinical guidance, educational initiatives, and research priorities.

As evidence supporting combination therapy in CKM continues to grow, healthcare professionals increasingly need practical guidance to integrate these therapies efficiently while considering safety, efficacy, and equity in real-world patient care. Workshop findings are expected to provide practical insights into how clinicians can move from isolated disease management to integrated, patient-centered approaches that improve kidney health, cardiovascular outcomes, and overall quality of life.