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

Background: 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. Methods: 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). Results: 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. Conclusions: 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.