Efficacy and safety of ketoanalogue supplementation combined with protein-restricted diets in advanced chronic kidney disease: a systematic review and meta-analysis

The benefits and harms of protein-restricted diets supplemented with ketoanalogues in patients with chronic kidney disease (CKD) remain uncertain. We aimed to evaluate the effects of ketoanalogues supplemented to protein-restricted diets in patients with advanced CKD.

We conducted systematic literature searches of PubMed, Embase, Scopus, and Cochrane Library up to June 3, 2024. Randomized controlled trials comparing ketoanalogue supplementation with a low- or very low-protein diet versus a low-protein diet alone in stages 3–5 CKD patients were selected. Outcomes included glomerular filtration rate (GFR), end-stage kidney disease (ESKD), all-cause mortality, and blood levels of urea nitrogen, calcium, phosphorus, and albumin. Triceps skin fold, mid-arm muscle circumference, lean body mass, and subjective global assessment were also evaluated. The protocol for this systematic review was registered in the International Prospective Register of Systematic Reviews (PROSPERO; registration number CRD42023465754).

A total of 16 trials comprising 1344 participants were identified, with a median follow-up of 13 months. Compared to a low-protein diet alone, ketoanalogues supplemented to a protein-restricted diet resulted in a significantly higher GFR, decreased levels of urea nitrogen and phosphorus, and increased levels of calcium. Furthermore, ketoanalogues combined with a protein-restricted diet showed a marginally lower risk of ESKD in participants without diabetes. No significant differences were observed in all-cause mortality, albumin, mid-arm muscle circumference, lean body mass, and subjective global assessment.

For stages 3–5 CKD patients, ketoanalogues combined with a protein-restricted diet may help postpone initiation of dialysis, improve calcium-phosphate homeostasis, and slow GFR decline, while maintaining a similar nutritional status and survival. Larger, long-term studies are needed to confirm these potential benefits, especially in CKD patients with diabetes.