What improves all-cause mortality in patients with Chronic Kidney Disease (CKD)?

Improving All-Cause Mortality in Chronic Kidney Disease

Intensive blood pressure control targeting <130/80 mmHg and SGLT2 inhibitors provide the strongest evidence for reducing all-cause mortality in patients with chronic kidney disease. 1

Blood Pressure Management for Mortality Reduction

Target blood pressure <130/80 mmHg in all CKD patients to reduce all-cause mortality. 1

• In the SPRINT trial, CKD patients randomized to intensive antihypertensive therapy (SBP target <120 mmHg) achieved the same beneficial reduction in all-cause mortality as non-CKD patients 1
• This mortality benefit extended even to frail elderly patients ≥75 years of age with the slowest gait speed 1
• Initiate antihypertensive drug therapy at BP ≥130/80 mmHg, as the vast majority of CKD patients have 10-year ASCVD risk ≥10% 1

ACE Inhibitors or ARBs as Preferred Agents

• Use ACE inhibitors as first-line therapy for hypertension in CKD patients with albuminuria ≥300 mg/day 1
• ACE inhibitors demonstrated superior effects on all-cause mortality compared to other antihypertensive drugs in non-dialysis CKD stages 3-5 (OR 0.77,95% CI 0.66-0.91) 2
• ARBs are appropriate alternatives if ACE inhibitor intolerance occurs 1
• Avoid combining ACE inhibitors with ARBs due to demonstrated harms without additional mortality benefit 1
• Expect serum creatinine increases up to 30% when initiating these agents due to hemodynamic effects 1

SGLT2 Inhibitors for Mortality Reduction

Add SGLT2 inhibitors (canagliflozin, dapagliflozin, or empagliflozin) to reduce all-cause mortality across all CKD risk strata. 1, 3

Evidence for Mortality Benefit

• In the DAPA-CKD trial, dapagliflozin significantly reduced all-cause mortality (HR 0.52, P < 0.004) in patients with CKD (mean eGFR 43 mL/min/1.73 m²) 1
• For very high-risk CKD patients, SGLT2 inhibitors decrease all-cause mortality by 48 fewer deaths per 1000 patients (95% CI 84 fewer to 6 fewer) with high certainty evidence 1
• For moderate-risk CKD patients, SGLT2 inhibitors probably decrease all-cause mortality by 24 fewer deaths per 1000 patients (95% CI 41 fewer to 3 fewer) with moderate certainty 1
• The EMPA-KIDNEY trial demonstrated reduced risk of death from cardiovascular causes (HR 0.72,95% CI 0.64-0.82) in patients with eGFR 20-90 mL/min/1.73 m² 1

Initiation Criteria

• Initiate SGLT2 inhibitors in patients with eGFR ≥20 mL/min/1.73 m² 3, 4
• Use on background therapy with ACE inhibitor or ARB for optimal benefit 3, 4, 5
• Continue SGLT2 inhibitors even if eGFR falls below 25 mL/min/1.73 m² during treatment, until dialysis initiation 3
• Expect an initial reversible decline in eGFR of 3-5 mL/min/1.73 m² in the first 4 weeks, which does not require discontinuation 3, 4

Cardiovascular Mortality Benefits

• SGLT2 inhibitors reduce cardiovascular death by 31% in patients with advanced diabetic kidney disease (CREDENCE trial) 1
• Dapagliflozin reduced cardiovascular death or heart failure hospitalization by 29% (HR 0.79) in non-diabetic CKD patients 3
• These agents reduce heart failure hospitalization by 61% (HR 0.61,95% CI 0.47-0.80) 5

Additional Mortality-Reducing Interventions

Mineralocorticoid Receptor Antagonists

• Consider adding finerenone as second-line therapy if already on SGLT2 inhibitor and optimized RAAS inhibition with persistent albuminuria (UACR ≥30 mg/g) 4
• Finerenone reduced cardiovascular death, MI, stroke, or heart failure hospitalization by 13% (HR 0.87,95% CI 0.76-0.98) in the FIGARO-DKD trial 4
• Ensure serum potassium ≤4.8 mmol/L and eGFR ≥25 mL/min/1.73 m² before initiating 4
• Monitor potassium at 1 month, then periodically 4

Dialysis Population Considerations

• In hemodialysis patients, target predialysis blood pressure 140/90 mmHg to minimize left ventricular hypertrophy and death 1
• ACE inhibitor use has been associated with decreased mortality in observational studies of CKD Stage 5 patients 1

Critical Implementation Points

Monitor carefully during intensive BP lowering: electrolyte abnormalities and modest GFR reductions occur more frequently but are primarily hemodynamic and potentially reversible 1

Implement sick day protocols: hold SGLT2 inhibitors during acute illness to prevent complications 3

Avoid nephrotoxins: discontinue NSAIDs and adjust dosing of renally cleared medications to prevent accelerated mortality risk 6

The combination of intensive blood pressure control with ACE inhibitors/ARBs plus SGLT2 inhibitors represents the most evidence-based approach to reducing all-cause mortality in CKD patients, with benefits demonstrated across the spectrum of kidney function and regardless of diabetes status.