What is the most effective strategy to reduce the risk of Chronic Kidney Disease (CKD) in patients with Hypertension (high blood pressure), Diabetes Mellitus (DM), or a family history of kidney disease?

What Reduces the Risk of CKD the Most

SGLT2 inhibitors combined with RAS inhibition (ACE inhibitors or ARBs) represent the most effective pharmacological strategy to reduce CKD risk in patients with hypertension, diabetes, or family history of kidney disease, alongside blood pressure control targeting <130/80 mmHg in those with albuminuria. 1

First-Line Pharmacological Interventions

The 2024 KDIGO guidelines establish SGLT2 inhibitors as first-line therapy for most patients at risk of CKD, continued until dialysis or transplantation. 1 This represents a paradigm shift from previous guidelines that prioritized only RAS inhibition.

For Patients with Albuminuria ≥300 mg/24h:

• ACE inhibitors or ARBs are mandatory as they consistently reduce proteinuria and slow progression in both diabetic and non-diabetic nephropathy 1, 2
• These agents should be titrated to maximum tolerated doses 1
• Add SGLT2 inhibitors when eGFR ≥20 mL/min/1.73 m² 1, 3

For Patients with Albuminuria 30-299 mg/24h:

• ACE inhibitors or ARBs are recommended to slow CKD progression 3
• SGLT2 inhibitors should be added for diabetic patients 1, 3

For Patients without Albuminuria (<30 mg/24h):

• SGLT2 inhibitors remain first-line for diabetic patients 1
• Blood pressure control with any antihypertensive class is acceptable, though dihydropyridine calcium channel blockers or diuretics may be preferred initially 1

Blood Pressure Targets: The Critical Differentiator

Blood pressure control is the predominant mechanism for kidney protection, and targets must be stratified by albuminuria status. 1

Aggressive BP Targets for Albuminuria ≥30 mg/24h:

• Target BP ≤130/80 mmHg 1, 4, 3
• This lower target is essential as proteinuric patients derive greater benefit from intensive BP control 1

Standard BP Targets for Albuminuria <30 mg/24h:

• Target BP ≤140/90 mmHg 1, 4
• More aggressive targets in this population lack evidence of additional benefit 1

Achieving BP Targets:

• Most patients require 3 or more antihypertensive agents 1
• Add dihydropyridine calcium channel blockers and/or diuretics as second and third agents 1
• Monitor for postural hypotension regularly 4

Lifestyle Modifications: Quantifiable Impact

Lifestyle interventions provide additive benefit to pharmacotherapy and should be implemented simultaneously, not sequentially. 1

Physical Activity:

• Prescribe moderate-intensity exercise for at least 150 minutes per week 1, 4
• This reduces CKD progression risk independent of weight loss 5
• Advise patients to avoid sedentary behavior entirely 1, 4

Dietary Sodium Restriction:

• Limit sodium intake to <2 g per day 1, 2, 3
• This intervention is critical to optimize effectiveness of RAS inhibitors and achieve BP targets 1
• Sodium restriction reduces proteinuria independent of BP effects 2

Protein Intake:

• Restrict protein to 0.8 g/kg body weight/day for CKD stages 3-5 4, 3
• Avoid high protein intake (>1.3 g/kg/day) as it accelerates progression 4
• Do not restrict protein in malnourished, sarcopenic, or cachectic patients 1

Weight Management:

• Encourage weight loss for patients with obesity (BMI >25 kg/m²) 1
• Target BMI of 20-25 kg/m² 1

Smoking Cessation:

• Tobacco use accelerates CKD progression and must be stopped 1, 4
• Referral to cessation programs should be offered 1

Glycemic Control in Diabetic Patients

Target HbA1c of approximately 7% to reduce CKD risk and slow progression. 1, 3

Medication Hierarchy:

• Metformin as first-line when eGFR ≥30 mL/min/1.73 m² 4, 3
• Add SGLT2 inhibitors when eGFR ≥20 mL/min/1.73 m² 1, 4, 3
• Consider GLP-1 receptor agonists for additional cardiovascular and renal protection 1, 6

Important caveat: Strict glycemic control prevents CKD progression in non-albuminuric diabetics but shows no benefit in those with baseline albuminuria >300 mg/g. 1 This underscores the primacy of RAS inhibition and BP control over glycemic control in advanced diabetic kidney disease.

Cardiovascular Risk Reduction

Statins are mandatory for all CKD patients ≥50 years regardless of lipid levels or GFR category. 1, 4, 3

Statin Therapy:

• Prescribe moderate- to high-intensity statins 1
• For patients 18-49 years, use statins if coronary disease, diabetes, prior stroke, or 10-year coronary event risk >10% 4, 3
• Add ezetimibe based on ASCVD risk and lipid levels 1

Antiplatelet Therapy:

• Reserve for patients with established clinical ASCVD 1
• The risks of aspirin may equal benefits in non-dialysis CKD patients without established cardiovascular disease 1

Monitoring Strategy

Reassess risk factors every 3-6 months to detect progression early and adjust therapy. 1

Essential Monitoring:

• Measure eGFR and urine albumin-to-creatinine ratio at each visit 4, 7
• For severely increased albuminuria (≥300 mg/g), target a 30% or greater reduction in urinary albumin 3
• Monitor serum potassium within 4 weeks when initiating or titrating RAS inhibitors 1
• Check for postural hypotension at each visit 4

Common Pitfalls to Avoid

Do not combine ACE inhibitors with ARBs—this increases adverse events without additional kidney protection. 1 The 2024 KDIGO guidelines explicitly moved away from dual RAS blockade after trials showed harm.

Do not withhold RAS inhibitors due to small increases in creatinine (<30% rise). 1 Acute eGFR declines up to 30% are expected and acceptable when initiating these agents.

Do not restrict protein in children with CKD due to risk of growth impairment. 4

Do not assume lipid-lowering therapy benefits dialysis-dependent patients—statins improve outcomes in non-dialysis CKD but not in dialysis-dependent patients. 1

Hierarchical Summary: Most to Least Impactful

1. SGLT2 inhibitors (for diabetic patients with eGFR ≥20) 1
2. RAS inhibition with ACE inhibitors or ARBs (especially with albuminuria ≥300 mg/24h) 1, 2
3. Blood pressure control to target (<130/80 if albuminuria ≥30 mg/24h) 1, 3
4. Sodium restriction to <2 g/day 1, 2
5. Statin therapy 1, 3
6. Glycemic control (HbA1c ~7%) 1, 3
7. Physical activity (≥150 min/week) 1, 4
8. Weight loss (if BMI >25) 1
9. Smoking cessation 1, 4
10. Protein restriction (0.8 g/kg/day for stages 3-5) 4, 3