The Four Pillars (ACEIs & ARBs, SGLT-2, MRAs, GLP-1) of Diabetic Kidney Disease (DKD)

Comprehensive Approach to Diabetic Kidney Disease (DKD) Management: The Four Pillars

Diabetic Kidney Disease (DKD) is a leading cause of chronic kidney disease (CKD) and end-stage renal disease (ESRD) worldwide. As internal medicine residents, understanding the pathophysiology, progression, and treatment of DKD is crucial for providing high-quality care to diabetic patients. DKD management hinges on addressing hyperglycemia, hypertension, inflammation, and fibrosis within the kidneys. Recent advancements have provided robust evidence that a combination of therapies, targeting different pathways, offers the best chance to slow the progression of the disease.

The four pillars of DKD treatment – Renin-Angiotensin System (RAS) Blockers, Sodium-Glucose Cotransporter 2 (SGLT2) Inhibitors, Nonsteroidal Mineralocorticoid Receptor Antagonists (MRAs), and Glucagon-Like Peptide 1 Receptor Agonists (GLP1RAs) – are integral to managing this complex condition. This approach aligns with guidelines from the Kidney Disease: Improving Global Outcomes (KDIGO) and provides a multi-targeted strategy to address the progression of DKD.

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1. Renin-Angiotensin System (RAS) Blockers

ACE inhibitors (ACEIs) and Angiotensin II receptor blockers (ARBs) remain foundational therapies in the treatment of DKD, particularly for patients with albuminuria and hypertension. These agents reduce intraglomerular pressure, proteinuria, and slow kidney disease progression.

Mechanism of Action:

• Angiotensin II promotes vasoconstriction, sodium retention, and inflammation within the kidney. Blocking this pathway with ACEIs or ARBs helps reduce these harmful effects, preserving kidney function.

Indications:

• Patients with DKD, particularly those with albuminuria (urine albumin-to-creatinine ratio > 30 mg/g).

• Hypertension with or without albuminuria in diabetic patients.

Dosage:

• Lisinopril: 10–40 mg/day orally.

• Ramipril: 2.5–20 mg/day orally.

• Losartan: 50–100 mg/day orally.

• Irbesartan: 150–300 mg/day orally.

Key Points:

• Initiation and Monitoring: Start at a low dose and titrate to the maximum tolerated dose. Monitor serum potassium and renal function (creatinine, eGFR) 1–2 weeks after starting or adjusting therapy.

• Avoidance: Avoid combining ACE inhibitors and ARBs due to increased risks of hyperkalemia and kidney injury.

KDIGO Guidance:

• KDIGO recommends ACEIs or ARBs for diabetic patients with CKD, particularly if albuminuria exceeds 300 mg/day.

  
  

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2. Sodium-Glucose Cotransporter 2 (SGLT2) Inhibitors

SGLT2 inhibitors have revolutionized DKD management, offering kidney protection beyond glucose control. These agents reduce hyperfiltration, lower intraglomerular pressure, and mitigate inflammation and fibrosis.

Mechanism of Action:

• By inhibiting the reabsorption of glucose in the proximal tubule, SGLT2 inhibitors promote glycosuria and natriuresis, thereby reducing glomerular hypertension and oxidative stress within the kidneys.

Indications:

• Type 2 diabetes mellitus (T2DM) with DKD (eGFR ≥ 25 mL/min/1.73 m²) and albuminuria.

• Patients with cardiovascular risk factors.

Dosage:

• Empagliflozin: 10–25 mg/day orally.

• Dapagliflozin: 10 mg/day orally.

• Canagliflozin: 100–300 mg/day orally.

Key Points:

• When to Start: Initiate when eGFR is ≥ 25 mL/min/1.73 m². Early initiation is crucial for maximal benefit in reducing DKD progression.

• Adverse Effects: Monitor for volume depletion, hypotension, and urinary tract infections. Ensure patients maintain adequate hydration.

KDIGO Guidance:

• KDIGO strongly recommends SGLT2 inhibitors for T2DM patients with CKD and albuminuria.

  
  

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3. Nonsteroidal Mineralocorticoid Receptor Antagonists (MRAs)

Nonsteroidal MRAs, such as Finerenone, offer significant benefits in reducing kidney disease progression by targeting inflammation and fibrosis. These agents are particularly beneficial in patients with persistent albuminuria despite optimal RAS blockade.

Mechanism of Action:

• By blocking mineralocorticoid receptors, MRAs reduce aldosterone-mediated sodium retention and inflammation, thus reducing fibrosis and preserving kidney function.

Indications:

• DKD with albuminuria, especially in patients who remain at high risk despite optimal RAS inhibition.

Dosage:

• Finerenone: 10–20 mg/day orally.

Key Points:

• Monitoring: Regularly monitor serum potassium, as MRAs can cause hyperkalemia, especially when used with RAS blockers.

• Initiation: Initiate in patients with an eGFR ≥ 25 mL/min/1.73 m² and adjust based on serum potassium and kidney function.

KDIGO Guidance:

• KDIGO recommends consideration of MRAs in patients with CKD and persistent albuminuria who are already on ACEIs or ARBs.

  
  

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4. Glucagon-Like Peptide 1 Receptor Agonists (GLP1RAs)

GLP1RAs, initially developed for glycemic control, have shown benefits in cardiovascular protection and potential renal benefits in patients with T2DM and DKD.

Mechanism of Action:

• GLP1RAs improve glycemic control by enhancing insulin secretion and reducing glucagon release, while also promoting weight loss and lowering blood pressure, thus reducing kidney stress.

Indications:

• T2DM patients with cardiovascular risk and DKD who need additional glycemic control or cardiovascular risk reduction.

Dosage:

• Liraglutide: Start with 0.6 mg subcutaneously daily, titrate to 1.2–1.8 mg/day.

• Semaglutide: Start with 0.25 mg subcutaneously once weekly, titrate to 0.5–1 mg weekly.

Key Points:

• Benefits: GLP1RAs provide cardiovascular protection and may reduce albuminuria in patients with DKD.

• Adverse Effects: Nausea and vomiting are common during dose titration. Watch for signs of pancreatitis.

KDIGO Guidance:

• KDIGO suggests using GLP1RAs in patients with T2DM and CKD who require improved glycemic control and are at high cardiovascular risk.

  
  

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Multifaceted Benefits of the Four-Pillar Approach

1. Targeting Multiple Pathways: The combination of these four drug classes addresses different mechanisms contributing to DKD progression, including hyperglycemia, hypertension, inflammation, and fibrosis.

2. Reducing Disease Progression: By addressing hyperfiltration, albuminuria, and oxidative stress, this approach slows down the natural progression of DKD, reducing the risk of ESRD.

3. Safety and Tolerability: Combining medications that have complementary effects, such as SGLT2 inhibitors (which reduce hyperkalemia risk) with RAS blockers (which may cause hyperkalemia), improves the overall safety profile.

4. Reduced Treatment Duration and Hospitalizations: Early initiation of this pillar-based approach can prevent complications, leading to fewer hospitalizations, and delays the need for dialysis or kidney transplantation.

5. Improved Patient Outcomes: Cardiovascular and renal protection provided by these medications improves patient quality of life, reduces morbidity, and extends survival.

   
   

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Conclusion

The four-pillar approach to DKD treatment is a powerful strategy that internal medicine residents should adopt for managing diabetic patients at risk of CKD progression. By using a combination of RAS blockers, SGLT2 inhibitors, MRAs, and GLP1RAs, residents can tackle multiple aspects of the disease simultaneously, improving long-term renal outcomes and patient survival. Familiarity with the KDIGO guidelines is essential for staying up-to-date with the latest evidence-based recommendations for DKD management.