What is the indication for ketoanalogue use in patients with chronic kidney disease (CKD) or those undergoing dialysis, particularly those with a history of metabolic acidosis or uremic symptoms?

Ketoanalogue Indication and Clinical Use

Ketoanalogues are indicated for patients with advanced CKD stages 3b-4 (eGFR 15-45 mL/min/1.73 m²) as an adjunctive nutritional intervention when implementing dietary protein restriction (0.3-0.6 g/kg/day) to delay dialysis initiation, slow CKD progression, and maintain nutritional status. 1

Primary Indications

Ketoanalogues serve as nitrogen-free precursors of essential amino acids that allow patients to follow very low-protein diets without developing malnutrition. The mechanism works by providing the carbon skeleton of essential amino acids while utilizing accumulated urea nitrogen for transamination, thereby reducing uremic toxin burden while preserving protein synthesis. 1, 2

Optimal Patient Selection

• CKD Stage 3b-4 patients (eGFR 15-45 mL/min/1.73 m²) represent the ideal candidates for ketoanalogue therapy, with earlier initiation at stage 3b (eGFR 30-45 mL/min/1.73 m²) potentially providing additional benefit in slowing progression. 1

• Diabetic patients show higher response rates to ketoanalogue supplementation and should be prioritized for this therapy. 1

• Patients with adequate baseline albumin levels (≥3.5 g/dL) predict better response to ketoanalogue therapy. 1

• Good nutritional status and demonstrated dietary compliance are prerequisites before initiating ketoanalogue therapy, as the treatment requires adherence to strict protein restriction. 3

Clinical Benefits and Outcomes

Delaying Dialysis Initiation

• Ketoanalogue-supplemented diets can delay dialysis initiation by approximately 1 year, with a 57% slower decline in renal function compared to conventional low-protein diet alone. 1, 2

• For stage 4 CKD patients, ketoanalogue therapy reduces short-term dialysis risk to 6.8% versus 10.4% at one year in those who discontinue therapy. 1, 4

• The number needed to treat (NNT) to avoid dialysis is 22.4 for patients with eGFR <30 mL/min/1.73 m², but decreases dramatically to 2.7 for patients with eGFR <20 mL/min/1.73 m², indicating greatest benefit in more advanced disease. 3

Metabolic and Nutritional Benefits

• Ketoanalogues reduce urea nitrogen levels by 6 months while preserving nutritional status, with no significant changes in BMI or albumin levels. 1

• Significant GFR improvement occurs between 3-12 months of therapy, with sustained reduction in plasma creatinine observed in the majority of patients. 1, 5

• Correction of metabolic acidosis and other uremic metabolic abnormalities occurs specifically with ketoanalogue therapy, not with conventional low-protein diet alone. 3

Mortality and Cardiovascular Benefits

• In diabetic kidney disease stage 5 patients not yet on dialysis, ketoanalogue use reduces 5-year all-cause mortality from 42.7% to 34.7% (adjusted HR: 0.73,95% CI: 0.66-0.82). 6

• The mortality benefit is particularly prominent in patients aged ≥70 years (adjusted HR: 0.65,95% CI: 0.56-0.76), despite this population having higher baseline mortality. 6

• Major adverse cardiovascular events (MACEs) are reduced with ketoanalogue supplementation (adjusted IRR: 0.76,95% CI: 0.67-0.86). 6

Dosing and Dietary Integration

Standard Regimen

• The standard dose is 1 tablet per 5 kg body weight (typically 9-14 tablets/day of Ketosteril®), combined with protein intake of 0.4-0.6 g/kg/day and caloric intake of 30-35 kcal/kg/day to prevent malnutrition. 1

• Very low-protein diet (0.3-0.4 g/kg/day) with ketoanalogue supplementation provides maximal benefit but requires intensive dietary counseling and monitoring. 2, 3

• Low-protein diet (0.6 g/kg/day) with ketoanalogue supplementation offers a more tolerable alternative with demonstrated efficacy in reducing dialysis risk. 4

Dietary Considerations

• Protein should be predominantly vegetarian sources to optimize metabolic benefits and reduce acid load. 3

• Adequate caloric intake (30-35 kcal/kg/day) is essential to prevent protein catabolism and maintain nutritional status. 1

Monitoring Requirements

Essential Parameters

• Nutritional status monitoring includes BMI and serum albumin every 3 months to ensure therapy is not causing malnutrition. 1

• Renal function monitoring includes eGFR, creatinine, and urea at 0,3,6,9, and 12 months to assess treatment response and progression. 1

• Metabolic parameters including serum potassium, phosphorus, and calcium require regular monitoring to detect and manage CKD-related complications. 1

• Monthly monitoring of serum bicarbonate is recommended to detect development of metabolic acidosis, which can occur despite ketoanalogue therapy. 1, 7

Integration with Standard CKD Management

Cardiovascular Medications

• Continue RAS inhibitors (ACE inhibitors or ARBs) at maximum tolerated dose in CKD patients with cardiovascular disease receiving ketoanalogue therapy. 1

• Add SGLT2 inhibitor if eGFR ≥20 mL/min/1.73 m² in CKD patients with cardiovascular disease receiving ketoanalogue therapy. 1

• Maintain statin therapy (moderate intensity for primary prevention, high intensity for established ASCVD) in CKD patients receiving ketoanalogue therapy. 1

• Consider nonsteroidal MRA (finerenone) if eGFR >25 mL/min/1.73 m² with persistent albuminuria in CKD patients receiving ketoanalogue therapy. 1

Conservative Management Context

Ketoanalogues represent a key therapeutic option for conservative management of patients choosing to delay dialysis, alongside low-protein diets, loop diuretics, and sodium polystyrene sulfonate to minimize uremic symptoms and maintain volume homeostasis. 1

When Ketoanalogues Are NOT Indicated

• Hospitalized CKD patients with acute illness or catabolic states should NOT continue dietary protein restriction or ketoanalogue therapy, as the pro-inflammatory and catabolic state requires increased protein intake (1.2-1.5 g/kg/day). 8, 7

• Patients with poor baseline nutritional status (albumin <3.5 g/dL) or inability to comply with dietary restrictions are not appropriate candidates. 1, 3

• Only 14% of screened CKD patients meet criteria for ketoanalogue therapy after assessment of nutritional status and dietary compliance, emphasizing the need for careful patient selection. 3

Common Pitfalls to Avoid

• Do not initiate ketoanalogues without first establishing dietary compliance during a run-in phase on conventional low-protein diet, as adherence is critical to success. 3

• Do not use ketoanalogues as a substitute for standard CKD management including blood pressure control, RAS inhibition, and treatment of metabolic complications. 1

• Do not continue protein restriction during acute hospitalization, as this worsens nitrogen balance without significantly affecting the need for kidney replacement therapy. 8, 7

• Avoid citrate-containing alkali in CKD patients exposed to aluminum when treating metabolic acidosis, as it increases aluminum absorption. 7