What is the recommended treatment for patients with Chronic Kidney Disease (CKD) and a Urine Albumin-to-Creatinine Ratio (UACR) of more than 24, indicating massive proteinuria?

Treatment for CKD with UACR >24 (Massive Proteinuria)

Start a renin-angiotensin system inhibitor (ACE inhibitor or ARB) immediately at the highest tolerated dose, as this is the cornerstone of therapy for patients with CKD and severely increased albuminuria (UACR >24 mg/mmol or >200 mg/g). 1

Primary Pharmacological Management

First-Line Therapy: RAS Inhibition

• Initiate either an ACE inhibitor OR an ARB (not both) for patients with CKD stages G1-G4 and severely increased albuminuria (A3 category, which includes UACR >24 mg/mmol) 1

• Use the highest approved dose that is tolerated, as clinical trial benefits were achieved at these doses 1

• For diabetic patients with CKD and UACR >24: ACE inhibitor or ARB is a Grade 1B recommendation 1

• For non-diabetic patients with CKD and UACR >24: ACE inhibitor or ARB is a Grade 1B recommendation 1

Second-Line Therapy: SGLT2 Inhibitors

• Add an SGLT2 inhibitor if eGFR ≥20 mL/min/1.73 m² and UACR ≥200 mg/g (≥20 mg/mmol), which is a Grade 1A recommendation 1

• SGLT2 inhibitors provide additional renoprotection beyond RAS inhibition and reduce cardiovascular events 1

• Continue SGLT2 inhibitor even if eGFR falls below 20 mL/min/1.73 m² unless not tolerated or kidney replacement therapy is initiated 1

Third-Line Therapy: Nonsteroidal MRA

• Consider adding a nonsteroidal mineralocorticoid receptor antagonist (such as finerenone) for patients with type 2 diabetes, eGFR >25 mL/min/1.73 m², normal potassium, and persistent albuminuria despite maximum tolerated RAS inhibitor 1

• This is a Grade 2A recommendation for high-risk patients with persistent proteinuria 1

• Nonsteroidal MRA can be added to both RAS inhibitor AND SGLT2 inhibitor for triple therapy in appropriate patients 1

Critical Monitoring Parameters

Initial Monitoring (Within 2-4 Weeks of Starting/Increasing RAS Inhibitor)

• Check serum creatinine, serum potassium, and blood pressure 1

• Continue therapy unless serum creatinine rises >30% within 4 weeks of initiation or dose increase 1

• Manage hyperkalemia with potassium-lowering measures rather than stopping RAS inhibitor when possible 1

Long-Term Management

• Continue RAS inhibitor even when eGFR falls below 30 mL/min/1.73 m², as cardiovascular and renal protection persists 1, 2, 3

• Only reduce dose or discontinue RAS inhibitor if symptomatic hypotension, uncontrolled hyperkalemia despite treatment, or need to reduce uremic symptoms in eGFR <15 mL/min/1.73 m² 1, 2

Blood Pressure Targets

• Target systolic blood pressure <120 mmHg when tolerated using standardized office measurement (Grade 2B recommendation) 1

• For patients with albuminuria ≥30 mg/24h (including UACR >24), older guidelines suggested <130/80 mmHg, though the 2024 KDIGO guideline emphasizes <120 mmHg systolic 1

Critical Contraindications and Pitfalls

Avoid Dual/Triple RAS Blockade

• Never combine ACE inhibitor + ARB + direct renin inhibitor (Grade 1B recommendation against this) 1

• Avoid ACE inhibitor + ARB combination therapy, as this increases hyperkalemia and acute kidney injury risk without additional benefit 1

• Research shows dual RAAS blockade does not reduce progression to ESRD, all-cause mortality, or cardiovascular mortality despite reducing proteinuria 4

Safety Considerations

• RAS inhibitors increase risk of hyperkalemia (RR 2.17) 5

• RAS inhibitors increase risk of acute kidney injury (RR 2.04) 5

• Non-selective aldosterone antagonists (spironolactone) increase risk of gynaecomastia (RR 5.14) 5

• Monitor potassium closely when using nonsteroidal MRA, selecting patients with consistently normal baseline potassium 1

Additional Considerations for Type 2 Diabetes

• Add GLP-1 receptor agonist if glycemic targets not achieved despite metformin and SGLT2 inhibitor, prioritizing agents with documented cardiovascular benefits (Grade 1B) 1

Evidence Quality Note

The 2024 KDIGO guidelines provide the most current and authoritative recommendations for this clinical scenario, with strong evidence (Grade 1A-1B) supporting RAS inhibition and SGLT2 inhibitor use in patients with massive proteinuria 1. The combination of RAS inhibitor plus SGLT2 inhibitor represents the current standard of care for reducing mortality, cardiovascular events, and CKD progression in this population.