Risk-Directed Management Key in Optimizing CKD Therapy

An arsenal of highly effective medications now represent pillars in the prevention of chronic kidney disease (CKD) progression, yet with the drugs under-utilized among patients who need them the most, better use of prognostic tools is recommended to help guide treatment, a new review reported.

“Leveraging prognostic estimates to guide therapy could help clinicians prescribe CKD-related therapies to those most likely to benefit from their use,” reported the authors of a review, published in Nature Reviews Nephrology.

“Risk-based CKD management thus aligns patient risk and care, allowing the prioritization of absolute benefit in determining therapeutic selection and timing.”

CKD, affecting 9.1% of the global population, is linked to an increased risk for cardiovascular disease (CVD), kidney failure, and death. While advances in medical therapy for CKD, particularly in the last decade, have gained high recognition for their efficacy and safety, the needed understanding of how and when to use them is lacking.

“Unfortunately, awareness of CKD and its related risks is low, both among patients and providers,” the authors, led by Morgan Grams, MD, of New York University Grossman School of Medicine, New York City, reported.

Notably, studies showed that while the standard assessment of estimated glomerular filtration rate (eGFR) is well-utilized, many patients never receive the also-needed assessment of albuminuria, which is necessary for determining optimal CKD management. Unlike GFR, albuminuria can be improved with medications.

Guidelines recommended annual albuminuria assessment for people with diabetes, CKD, hypertension, or CVD, however, one meta-analysis of studies involving the general population showed a urinary albumin-to-creatinine ratio screening rate of only 35.1% among people with diabetes and only 4.1% among those with hypertension.

Without the appropriate CKD assessment, timely treatment with neuroprotective medicines increasingly recognized as the pillars of CKD therapy — angiotensin-converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs), sodium-glucose cotransporter 2 (SGLT2) inhibitors, glucagon-like peptide 1 receptor agonists (GLP-1 RAs), and nonsteroidal mineralocorticoid receptor agonists (MRAs), is compromised.

“These medications remain underutilized, even in individuals at high risk,” the authors noted.

CKD Risk Assessment Tools

An overview of the key methods in the assessment of CKD risk that could help guide treatment decision-making includes the CKD heatmap, developed by the Kidney Disease Improving Global Outcomes (KDIGO) international guidelines organization, which provides eGFR as well as albuminuria staging.

Additional tools include absolute risk prediction with prognostic tools, which, in addition to having been shown to outperform physician and patient prognostication, also provide “important risk discrimination even within the categories of the KDIGO CKD heatmap,” the authors noted.

Four highly validated prognostic tools include the kidney failure risk equation (KFRE), risk for 40% GFR decline, predicting risk for CVD EVENTs (PREVENT), and the advanced CKD risk tool.

The KFRE, for instance, can be used to estimate the 2-year and 5-year risk for kidney failure among patients with an eGFR 2.

Meanwhile, the 40% decline in eGFR equation is designed to predict the risk for 40% decline in kidney function, developed for use in individuals in whom the KFRE might not adequately represent short-term risk.

The PREVENT tool adds to the previous pooled cohort equation tool, designed to estimate the 10-year risk of atherosclerotic CVD, with race-free risk prediction, prediction of CVD subtypes, 10-year and 30-year risk esti mates, and improved calibration.

And the advanced CKD risk tool, which applies to patients with an eGFR of 2, who have exceptionally high risks for CVD and death, uses a nine-variable model to predict the competing risks for kidney failure, CVD, and death after 2 years and 4 years among those patients.

Other CKD risk scores include genetic and disease-specific risk scores, such as the International immunoglobulin A (IgA) nephropathy prediction tool, which combines data about demographics, eGFR and albuminuria, and the Oxford MEST histology score, estimating the risk for 50% GFR decline or kidney failure in people with IgA nephropathy.

Use of Pillars of CKD Treatment

Importantly, the pillars of CKD therapy show benefit when used in combination, and that practice is rapidly becoming the standard of care, yet under-utilization is again an issue. When combination therapy is used, it often involves inappropriate prescribing, with the highest prescribing occurring among the lowest risk groups, when, conversely, the “largest absolute benefit of a therapy (and the lowest number needed to treat) is expected in people with the highest risk of adverse outcomes,” the authors explained.

For instance, US Renal Data System data shows that of Medicare fee-for-service recipients with diabetes and stage 3 CKD, more than one fifth of patients did not receive ACE inhibitors/ARBs in 2022, and the use was even lower among those with stage 4 and 5 CKD.

Overall, the use of SGLT2 inhibitors was under 15% even for beneficiaries with diabetes, CKD, or heart failure. Of note, among beneficiaries with stage 3 CKD, prescribing of GLP-1 RAs increased between 2012 and 2022 from 1.9% to 12.6%, and prescribing of SGLT2 inhibitors increased in the past 5 years.

The authors underscored that the systematic inclusion of risk tools in CKD management decisions could help improve treatment, particularly for the patients who could most benefit.

“For an individual with diabetes and high kidney or cardiovascular risk, rapid initiation of the four pillars supporting therapy — SGLT2 inhibitors, GLP1RAs, RAAS inhibition and MRAs, along with statins — could be prioritized,” they wrote.

An example of the benefits from a faster implementation of therapy can be seen in the heart failure literature and the STRONG-HF trial, which showed that rapid implementation of medical therapy after an admission for acute heart failure reduced heart failure readmission and mortality, in addition to heart failure symptoms compared with the usual care.

“A similar rapid sequence approach in CKD might provide similar benefits while avoiding some of the barriers to initiating and intensifying guideline-recommended medical therapy: Long wait times for nephrology clinics and the high risk of intervening hospitalizations and mortality,” the authors suggested.

More broadly, “by leveraging a framework of shared decision-making that incorporates patient preferences and clinician experience, risk-directed management offers the potential for profound improvements in the health of individuals with CKD,” the authors concluded.

Review co-author Brendon L. Neuen reported receiving fees for travel support, advisory boards, scientific presentations, and steering committee roles from AstraZeneca, Alexion, Bayer, Boehringer and Ingelheim, Janssen, Novo Nordisk, and Travere Therapeutics. The remaining authors had no disclosures to report.