Are ketoanalogues (ketone body analogs) effective for managing impaired renal function (increased creatinine levels)?

Ketoanalogues for Management of Increased Creatinine Levels

Ketoanalogues are not recommended as first-line therapy for managing increased creatinine levels or chronic kidney disease (CKD) according to current guidelines. Instead, evidence-based therapies such as SGLT2 inhibitors, RAS inhibitors, and nonsteroidal MRAs should be prioritized for slowing CKD progression and improving outcomes 1.

Evidence-Based Management of CKD and Elevated Creatinine

First-Line Therapies

• SGLT2 inhibitors are recommended for patients with CKD and eGFR ≥20 ml/min/1.73 m² with albuminuria ≥200 mg/g or heart failure 1
• RAS inhibitors (ACEi or ARB) are recommended for patients with albuminuria and hypertension, titrated to the highest tolerated dose 1
• Nonsteroidal mineralocorticoid receptor antagonists are suggested for adults with type 2 diabetes, eGFR >25 ml/min/1.73 m², normal potassium, and albuminuria despite maximum RAS inhibition 1
• GLP-1 receptor agonists are recommended for adults with type 2 diabetes and CKD who haven't achieved glycemic targets despite metformin and SGLT2i 1

Monitoring and Management

• Monitor serum creatinine and potassium within 2-4 weeks after starting or changing dose of RAS inhibitors 1
• Continue ACEi or ARB therapy unless serum creatinine rises by more than 30% within 4 weeks following initiation or dose increase 1
• Continue ACEi or ARB even when eGFR falls below 30 ml/min/1.73 m² 1
• Monitor both albuminuria and eGFR annually to enable timely diagnosis of CKD, monitor progression, and determine whether nephrology referral is needed 1

Role of Ketoanalogues in CKD Management

Limited Evidence for Ketoanalogues

• Ketoanalogues are not mentioned in current KDIGO guidelines for CKD management 1
• Some older, small studies suggest ketoanalogues combined with very low protein diets may slow progression in advanced CKD:
  • A 1987 study showed sustained reduction in plasma creatinine in 12 of 20 patients with advanced CKD on ketoanalogues with very low protein diet 2
  • A 1986 controlled study suggested better renal survival with ketoanalogues plus very low protein diet compared to standard low protein diet alone 3
  • A 2016 randomized controlled trial found ketoanalogue-supplemented vegetarian very low-protein diet deferred dialysis initiation in some patients with CKD, particularly those with eGFR <20 ml/min/1.73 m² 4

Practical Considerations

• Ketoanalogues are typically used as supplements to very low protein diets (0.3-0.4 g/kg/day) 5, 4
• The evidence suggests they may be most beneficial when started before end-stage renal failure 2
• Nutritional status must be carefully monitored when using ketoanalogues with protein restriction 5, 4

Clinical Decision Algorithm

1. First assess CKD stage and risk factors:

   • Measure eGFR and albuminuria 1
   • Evaluate for diabetes, hypertension, and cardiovascular disease 1

2. Implement evidence-based first-line therapies:

   • Start SGLT2i for eligible patients (eGFR ≥20 ml/min/1.73 m²) 1
   • Optimize RAS blockade with ACEi or ARB for patients with albuminuria 1
   • Consider nonsteroidal MRA for appropriate patients 1

3. Consider ketoanalogues only in specific scenarios:

   • Advanced CKD (eGFR <30 ml/min/1.73 m²) 2, 4
   • Patient is able to adhere to very low protein diet 5, 4
   • Good nutritional status at baseline 4
   • Goal is to delay dialysis initiation 4
   • Standard therapies have been optimized or are contraindicated 2, 4

Conclusion

While some limited evidence suggests ketoanalogues with very low protein diets may slow CKD progression in specific patients, they are not included in current guidelines as standard therapy for managing increased creatinine. The strongest evidence supports SGLT2 inhibitors, RAS inhibitors, and nonsteroidal MRAs as the cornerstone therapies for slowing CKD progression and improving outcomes.