What is the recommended management plan for patients with Diabetic Kidney Disease (DKD), including early detection and treatment with Renin-Angiotensin System inhibitors (RASi), Sodium-Glucose Cotransporter 2 inhibitors (SGLT2i), and non-steroidal Mineralocorticoid Receptor Antagonists (nsMRA)?

Comprehensive Management of Diabetic Kidney Disease (DKD)

The optimal management of diabetic kidney disease requires a triple therapy approach with RAS inhibitors, SGLT2 inhibitors, and non-steroidal MRAs initiated within 3 months of diagnosis, with early detection of albuminuria and integration of GLP-1 receptor agonists to maximize kidney protection and reduce mortality.

Early Detection and Screening

• Annual screening for DKD is essential using spot urine albumin/creatinine ratio (UACR) testing, with diagnosis confirmed by repeated elevation in urinary albumin excretion 1
• DKD is defined as persistent albuminuria (UACR >30 mg/g [3 mg/mmol]), persistently reduced eGFR (<60 ml/min/1.73 m²), or both, for greater than 3 months 2
• Early detection is critical as DKD is associated with poor quality of life, increased risk of cardiovascular disease, and premature death 2
• CKD classification should be based on cause, GFR, and albuminuria categories to guide treatment and referral decisions 2

Core Treatment Strategy: Triple Therapy

1. RAS Inhibition (First-line)

• Initiate ACE inhibitor or ARB in patients with diabetes, hypertension, and albuminuria, titrated to the highest approved dose that is tolerated 2
• For patients with diabetes, albuminuria, and normal blood pressure, treatment with an ACEi or ARB may still be considered 2
• Monitor serum creatinine and potassium within 2-4 weeks after initiating or increasing the dose of RAS inhibitors 3
• Continue ACEi or ARB therapy unless serum creatinine rises by more than 30% within 4 weeks following initiation or dose increase 2

2. SGLT2 Inhibitors (First-line)

• Add SGLT2 inhibitor regardless of glycemic control for kidney and cardiovascular protection 2
• SGLT2 inhibitors can be initiated at eGFRs as low as 20 mL/min/1.73 m² 2
• Expect a modest decrease in eGFR (3-10%) upon initiation, which is hemodynamic and not associated with adverse kidney outcomes 2
• Do not discontinue SGLT2 inhibitor therapy prematurely due to this initial eGFR decline unless serious acute kidney injury is suspected 2

3. Non-steroidal MRAs (Add-on)

• Add non-steroidal MRA (e.g., finerenone) for patients with T2D, eGFR ≥25 ml/min/1.73 m², normal serum potassium, and persistent albuminuria despite maximum tolerated RAS inhibitor 2
• Non-steroidal MRAs can be added to the combination of RAS inhibitor and SGLT2 inhibitor for enhanced kidney protection 2
• Monitor serum potassium regularly after initiation to mitigate the risk of hyperkalemia 2
• The use of an SGLT2 inhibitor has been shown to lower risks of hyperkalemia related to MRA, facilitating combination therapy 2

"3-in-3" Proposal Implementation

• Implement all three core therapies (RAS inhibitor, SGLT2 inhibitor, and non-steroidal MRA) within the first 3 months after DKD diagnosis to maximize kidney protection 2
• This aggressive early intervention approach can delay kidney failure by up to 10 years based on the combined benefits of these therapies 2, 4
• Monitor disease progression with CKD biomarkers including albuminuria (UACR) and natriuretic peptides 2

Integration of GLP-1 Receptor Agonists

• Add GLP-1 receptor agonists for patients with T2D and DKD for additional kidney and cardiovascular protection 2, 5
• GLP-1 RAs demonstrate significant reduction in albuminuria and progression of nephropathy, complementing the effects of triple therapy 4, 6
• GLP-1 RAs have vasotropic actions that contribute to reducing the risk of DKD progression 4

Additional Management Considerations

• Optimize glycemic control targeting HbA1c <7.0% to decrease microvascular complications 5
• Target blood pressure <130/80 mmHg in patients with diabetes and kidney disease 5
• Initiate statin therapy for cardiovascular risk reduction 5
• Recommend smoking cessation for all patients with diabetes and CKD 2
• Implement dietary sodium restriction (<2.3 g/day) to optimize effectiveness of antihypertensive medications 5
• Refer patients to nephrology when they progress to stage 3 DKD or beyond 1

Monitoring and Follow-up

• Monitor HbA1c twice per year, or up to 4 times per year if glycemic target is not met or after changing glucose-lowering therapy 2
• Regular monitoring of kidney function, albuminuria, blood pressure, and serum potassium is essential, particularly after medication initiation or dose changes 5
• Be aware that HbA1c measurement accuracy declines with advanced CKD (G4-G5), particularly in patients on dialysis 2

Potential Pitfalls and Caveats

• Do not discontinue RAS inhibitors or SGLT2 inhibitors due to the expected initial decline in eGFR unless the decline exceeds 30% for RAS inhibitors or serious AKI is suspected 2
• When initiating SGLT2 inhibitors, implement sick day protocols and proper perioperative management to reduce the risk of diabetic ketoacidosis 2
• For patients with hyperkalemia on RAS inhibitors, consider measures to reduce serum potassium rather than immediately reducing the dose or stopping therapy 2
• Be aware that combining multiple kidney-protective medications may increase the risk of adverse effects, particularly hypotension and hyperkalemia, requiring careful monitoring 7, 6