Preventing chronic kidney disease and maintaining kidney health: conclusions from a Kidney Disease: Improving Global Outcomes (KDIGO) Controversies Conference

Abstract

To date, the primary focus of chronic kidney disease (CKD) care has been on managing disease progression, complications, and kidney failure. In contrast, maintaining kidney health and preventing CKD have received limited attention, despite their potential to save millions of lives, reduce health care costs, and lessen environmental burdens. The cardiovascular-kidney-metabolic (CKM) concept frames CKD as part of a complex, high-risk syndrome requiring global risk assessment and multifactorial intervention. CKD incidence along with CKM risk factors may be reduced by a healthy diet, physical activity, and a supportive environment. However, risk for CKD does extend beyond the cardiovascular-metabolic component, and residual risk persists despite healthy lifestyles and treatment of risk factors. Post hoc analyses of clinical trials suggest pharmacological interventions, such as sodium-glucose cotransporter-2 inhibitors and glucagon-like peptide-1 receptor agonists, may help to prevent or regress CKD in individuals with type 2 diabetes or obesity. Clinical trials are needed to validate these findings in broader high-risk populations. Personalized strategies to improve kidney health should include CKD risk prediction via targeted testing, genetic or biomarker assessments, shared decision-making, cost considerations, selection of therapeutics, and the potential for adverse effects. The overall goals of CKD prevention should prioritize a lifespan approach to risk evaluation along with safe, efficacious, and accessible interventions to maintain kidney health.

Keywords: CKD prevention; case finding; interventions; screening.

Figure 1 ∣. The blind spot issue was addressed for diabetes by creating the concept of prediabetes.

The current diagnostic criteria for chronic kidney disease (CKD) may identify CKD only after years or decades from the initiation of kidney injury, delaying specific therapy for CKD. (a) The CKD blind spot refers to the years or decades in which kidney function is not evaluated, monitored, or managed therapeutically. Defining and naming this preclinical condition that refers to high risk of CKD may facilitate understanding and uptake of the concept by diverse health care workers and specialties, akin to the coining of the term prediabetes. However, the precise biomarker(s) and cutoffs used to define such a condition have yet to be determined. (b) The existence of the prediabetes concept allows diagnosis of a treatable condition years before diabetes develops, enabling primary prevention. Panel (a) was adapted from Sanchez-Niño et al. Diabetes and prediabetes diagnosis criteria of the American Diabetes Association. eGFR, estimated glomerular filtration rate; UACR, urinary albumin-to-creatinine ratio.

Figure 2 ∣. A conceptual framework summarizing the trends for kidney health during the life course.

Adapted from Xie et al. CKD, chronic kidney disease.

Figure 3 ∣. Despite large reductions in relative risk of kidney events, the absolute residual risk remains high in patients with chronic kidney disease (CKD) treated with current kidney-protective therapy.

Sodium-glucose cotransporter-2 inhibitors (SGLT2i) are examples where post hoc analyses have described participants in cardiovascular outcomes trials (CVOTs) at high risk of CKD (type 2 diabetes mellitus [T2DM] plus high cardiovascular disease risk) but with no CKD, as defined by estimated glomerular filtration rate (eGFR) >60 ml/min per 1.73 m² and urinary albumin-to-creatinine ratio < 30 mg/g (3 mg/mmol). (a) Mean hazard ratios for kidney disease progression for dapagliflozin and empagliflozin CVOTs in T2DM plus high cardiovascular disease risk (Dapagliflozin Effect on Cardiovascular Events–Thrombolysis in Myocardial Infarction 58 [DECLARE-TIMI 58] and Empagliflozin Cardiovascular Outcome Event Trial in Type 2 Diabetes Mellitus Patients [EMPA-REG Outcome]) and in CKD trials (Dapagliflozin and Prevention of Adverse Outcomes in Chronic Kidney Disease [DAPA-CKD] and Study of Heart and Kidney Protection with Empagliflozin [EMPA-KIDNEY]). Relative risk reduction is observed across all categories tested for a CKD progression endpoint (kidney failure, kidney death, or persistent reduction in eGFR). Note that DAPA-CKD and EMPA-KIDNEY enrolled patients with and without T2DM and other inclusion/exclusion criteria may differ across trials. Results obtained in CANagliflozin cardioVascular Assessment Study (CANVAS) (CVOT in T2DM plus high cardiovascular disease risk) and Canagliflozin and Renal Events in Diabetes with Established Nephropathy Clinical Evaluation (CREDENCE) (CKD T2DM) testing canagliflozin were aligned with those for dapagliflozin and empagliflozin but percentage of patients with events were not reported for Kidney Disease: Improving Global Outcomes (KDIGO) risk categories. Available results for CANVAS and KDIGO risk categories, expressed as events per 100 patient-years, are shown in Supplementary Table S1. (b) Residual risk expressed as percentage of participants with kidney disease progression events is shown in blue for participants on SGLT2i in trials from panel (a). For comparison, percentage of participants with events while taking placebo are shown in red. The proportion with CKD progression is nearly 9-fold higher when therapy is started with severe CKD rather than treating to prevent CKD (14.15% vs. 1.6%). (c) Median chronic eGFR slopes for canagliflozin, dapagliflozin, and empagliflozin CVOTs (T2DM plus high cardiovascular disease risk: CANVAS, DECLARE-TIMI 58, and EMPA-REG Outcome) and for CKD trials (CREDENCE, DAPA-CKD, and EMPA-KIDNEY). Note that for the duration of the trials, the median eGFR slopes across trials for participants with no CKD or mild CKD were neutral. The expected age-associated eGFR loss of −1 ml/min per 1.73 m² in people with no CKD is indicated. Note that this was the eGFR slope observed in participants on placebo with no CKD. Data are from Neuen et al., Perkovic et al., Mosenzon et al., Heerspink et al., Levin et al., and Herrington et al. Mild, moderate, and severe CKD is based on European Society of Cardiology terminology for KDIGO risk categories of moderate, high, and very high risk. The reason for using this simplified nomenclature is that it may facilitate implementation by non-nephrologists. The number (percentage) of participants with no CKD was 5876 (58%) in CANVAS, 10,958 (64%) in DECLARE-TIMI 58, and 3322 (48%) in EMPA-REG Outcome for a total of 20,156 participants with no CKD among the 3 trials

Figure 4 ∣. Shifting the paradigm from treatment to prevention of kidney disease.

CKD, chronic kidney disease; eGFR, estimated glomerular filtration rate; GLP-1RA, glucagon-like peptide 1 receptor agonists; nsMRA, non-steroidal mineralocorticoid receptor antagonists; RASi, renin-angiotensin system inhibitors; SGLT2i, sodium-glucose cotransporters-2 inhibitors.

Figure 5 ∣. Incorporation of strategies to assess actionable risk of incident chronic kidney disease (CKD) into the overall management of CKD burden with the aim of preserving kidney health.

(a) Conditions that are risk factors for CKD, such as type 2 diabetes mellitus (T2DM) or hypertension, are treated, but even in patients with high risk of CKD, treatment is not specifically tailored to prevent progression of kidney disease until after CKD has developed. (b) Future management of CKD calls for a novel actionable category of very high risk of incident CKD that mirrors concepts from other noncommunicable diseases (NCDs). The interventions aligned to a diagnosis of very high risk of CKD would be pharmacological, as in both examples from other NCDs, as well as a healthy lifestyle. CVOT, cardiovascular outcomes trial; eGFR, estimated glomerular filtration rate; HICs, high-income countries; UACR, urinary albumin-to-creatinine ratio.