ENDO 12: Diabetic Nephropathy

Learning Objectives

1. Strategies to Delay Diabetic Nephropathy Progression

Glycemic Control

• Optimizing blood glucose levels reduces the risk of kidney damage.

• A1C target for diabetic CKD patients varies based on individual risk:

  • ≤6.5% for those at low risk of hypoglycemia.

  • ≤7.0% for most adults.

  • 7.1–8.5% for patients with high risk of hypoglycemia, frailty, or limited life expectancy.

• Relevant clinical trials:

  • DCCT, UKPDS-33, ADVANCE, ACCORD: Studied A1C control effects on CKD progression.

  • ACCORD trial found increased mortality with intensive glycemic control (A1C <6.3%).

Blood Pressure Control

• Hypertension accelerates kidney damage in diabetes.

• Target BP: <130/80 mmHg for CKD patients with diabetes.

• Studies:

  • UKPDS-38, HOT, ACCORD-BP: Lower BP reduced cardiovascular events and nephropathy progression.

  • BP lowering resulted in a 36% stroke reduction, 27% total mortality reduction, and 25% decrease in major cardiovascular events.

• Treatment algorithm:

  • First-line:

    • ACE inhibitors (ACEi) or

    • Angiotensin Receptor Blockers (ARB).

  • Second-line:

    • Dihydropyridine calcium channel blockers (DHP-CCB) or

    • Thiazide diuretics.

  • Monitor potassium and kidney function when using RAAS blockers.

Renin-Angiotensin-Aldosterone System (RAAS) Blockade

• ACEi/ARB are first-line therapies for diabetic nephropathy to reduce albuminuria and slow CKD progression.

• Combination of ACEi + ARB is NOT recommended due to risk of hyperkalemia and worsening kidney function.

• Key trials:

  • IDNT, RENAAL, IRMA-2, HOPE demonstrated renoprotective benefits.

  • RAAS inhibitors recommended for albuminuria ACR >3 mg/mmol.

Sodium-Glucose Cotransporter-2 Inhibitors (SGLT-2i)

• SGLT-2 inhibitors improve glycemic control while offering direct renal benefits.

• Recommended for all diabetic CKD patients unless contraindicated.

• Key trials:

  • CREDENCE, DAPA-CKD, EMPA-KIDNEY: Showed significant reductions in CKD progression, hospitalization, and mortality.

• Dosing considerations:

  • Effective in eGFR >20 mL/min but minimal glucose-lowering effect if eGFR <45 mL/min.

  • Avoid in severe CKD (eGFR <15 mL/min).

Glucagon-Like Peptide-1 Receptor Agonists (GLP-1 RA)

• Provide cardiovascular and renal benefits in diabetes and CKD.

• Key trials:

  • LEADER (liraglutide), REWIND (dulaglutide), SUSTAIN-6 (semaglutide) demonstrated reductions in albuminuria and cardiovascular risk.

• Recommended for patients with high CV risk and those requiring further glycemic control beyond SGLT-2i.

Non-Steroidal Mineralocorticoid Receptor Antagonist (NS-MRA) - Finerenone

• Reduces inflammation and fibrosis in diabetic nephropathy.

• FIDELIO-DKD trial: Showed kidney and CV benefits in diabetic CKD patients.

• Initiate in addition to RAAS blockade, monitor potassium.

2. Limitations of HbA1C & Glycemic Targets in CKD

• A1C can be misleading in CKD due to altered RBC lifespan and erythropoiesis.

• Increased risk of hypoglycemia due to:

  • Reduced insulin clearance.

  • Accumulation of insulin secretagogues (e.g., sulfonylureas).

• Monitor blood glucose closely rather than relying solely on A1C.

3. Antihyperglycemic Treatment Algorithm in Diabetic CKD

1. First-line: SGLT-2i for all eligible patients (unless contraindicated).

2. If additional control needed: Add GLP-1 RA (especially for CV risk patients).

3. If further control required: Consider insulin, DPP-4 inhibitors (linagliptin preferred in CKD), or metformin (if eGFR >30). metformin max = 500 mg if eGFR 15-29 but preferred to stop!

4. Avoid: Sulfonylureas and TZDs due to hypoglycemia and fluid retention risk.

4. Antihypertensive Treatment Algorithm in Diabetic CKD

1. First-line: ACEi or ARB (do not combine).

2. If BP >130/80 mmHg despite RAAS blockade:

   • Add DHP-CCB (e.g., amlodipine) or thiazide diuretic.

3. If resistant hypertension or proteinuria >30 mg/mmol:

   • Consider Finerenone (monitor potassium).

   • Multiple antihypertensives may be needed to reach target BP.

Case Applications

Case 1: 50 y/o female with diabetic nephropathy (G4A3)

• Optimal A1C target? ≤7.0% (Choice C)

• Optimal BP target? <130/80 mmHg (Choice B)

• Antihypertensive options? Add ACEi/ARB (Choice B or C, NOT both).

• Therapeutic options if K+ = 5.2 mmol/L? Avoid RAAS blockade; consider DHP-CCB.

• Antihyperglycemic options? Add SGLT-2i (Canagliflozin 100 mg) or GLP-1 RA.

Case 2: 68 y/o female with GFR 63 mL/min, ACR 4 mg/mmol

• Antihyperglycemic options? Consider adding Empagliflozin or GLP-1 RA.

• Antihypertensive options? If BP remains high, consider adding amlodipine or thiazide.

Key Takeaways for Success on the Exam

✅ Know A1C & BP targets in diabetic CKD. ✅ Understand how SGLT-2i, GLP-1 RA, and Finerenone improve kidney and CV outcomes. ✅ Be familiar with treatment algorithms for glycemic and BP control. ✅ Recognize when to avoid RAAS blockers (e.g., hyperkalemia, advanced CKD). ✅ Apply knowledge to patient cases!

✅ Screen annually unless there’s a reason to suspect non-diabetic kidney disease or temporary fluctuations.
✅ Start screening at 5 years for T1DM, immediately for T2DM.
✅ Use both ACR (urine test) + eGFR (blood test) for a full kidney function assessment.

• Diagnosis = ACR greater than or equal to 2 OR eGFR < 60