No additional benefit of prescribing a very low-protein diet in patients with advanced chronic kidney disease under regular nephrology care: a pragmatic, randomized, controlled trial

Abstract

Background Whether very low-protein diet supplemented with ketoanalogs (sVLPD), compared to standard low-protein diet (LPD), improves outcomes in chronic kidney disease (CKD) patients under stable nephrology care is undefined. Objective To compare the effectiveness of sVLPD vs LPD in patients regularly seen in tertiary nephrology care. Methods Participants were CKD patients stage 4-5, followed for at least six months, randomized to receive sVLPD or LPD (0.35 or 0.60 g/kg Ideal Body Weight (IBW)/day, respectively), stratified by center and CKD stage. The primary outcome was time to renal death, defined as the first event between end-stage renal disease (ESRD) and all-cause mortality; secondary outcomes were the single components of the primary outcome, cardiovascular outcome, and nutritional status. Results We analysed 223 patients (sVLPD n = 107; LPD n = 116). Mean age was 64 years, 61% were male, 35% had diabetes. Median protein intake (PI), that was 0.8 g/kg IBW/day at baseline in both groups, was 0.83 and 0.60 g/kg IBW/day in LPD and sVLPD, respectively, during the trial with a large decrease only in sVLPD (P = 0.011). During a median of 74.2 months, we recorded 180 renal deaths (141 dialysis and 39 deaths before dialysis). Risk of renal death did not differ in sVLPD vs LPD (HR 1.17, 95%CI 0.88,1.57, P = 0.28). No difference was observed for ESRD (HR 1.12, 95% CI 0.81,1.56, P = 0.51), mortality (HR 0.95, 95%CI 0.62,1.45, P = 0.82) or time to fatal/non-fatal cardiovascular events (P-value log-rank test = 0.2). After 36 months, still active patients were 45 in sVLPD and 56 in LPD. No change of nutritional status emerged during the study in any arm. Conclusions This long-term pragmatic trial found that in CKD patients under stable nephrology care, adherence to protein restriction is low. Prescribing sVLPD versus standard LPD was safe but does not provide additional advantage to the kidney or patient survival.

Ketoanalogue Supplementation in Patients with Non-Dialysis Diabetic Kidney Disease: A Systematic Review and Meta-Analysis

“…In a further meta-analysis, a dietary protein intake <0.8 g protein/kg/day was found to have significant benefits on both GFR and proteinuria in early DKD [40]. Unfortunately, all the major RCTs on dietary protein intervention advanced CKD do not include diabetic patients [19]. This review provides some evidence that the decline in GFR may be attenuated in DKD patients who receive a KA-supplemented protein-restricted diet, as the meta-analysis showed a slight, nonsignificant increase in GFR.…”

“…Regarding mortality, Wang at al reported no difference between DKD patients who used KA and those who did not [29], and Chen et al showed a significantly lower all-cause mortality in KA users compared to non-users [26]. Whether LPD + KA in DKD patients does impact on mortality or not, as found in nondiabetic CKD [19,46], still needs to be explored. Overall, these differences were possibly due to major selection bias and highlight the need for RCT.…”

“…As DKD is characterized by increased systemic inflammation, insulin resistance, and hypercatabolism [2], protein-restricted diets might lead to essential amino acid (EAA) deficiency, low energy intake, and an increased risk of protein-energy wasting [2,8]. Current clinical practice guidelines for clinically stable, non-dialysis patients with DKD stages 3-5 are conflicting; the American Diabetic Association states that dietary protein intake should not be lower than 0.8 g/kg/day [9] because of the risk for malnutrition [10]; meanwhile, the National Nutrients 2022, 14, 441 2 of 19 Kidney Foundation (NKF) suggests a low protein diet (LPD) providing dietary protein of 0.6-0.8 g/kg/day coupled with adequate energy intake (25-35 kcal/kg/day) to preserve renal function and maintain nutritional status [6].…”

“…Indeed, the NKF guidelines strongly recommend KAsupplemented VLPD in metabolically stable nondiabetic CKD to improve outcomes [6]. The potential clinical benefits and harms of KA supplementation to protein-restricted diets in patients with non-dialysis DKD are less well characterized since the majority of the major trials did not include DKD patients, mostly because of the fear of malnutrition [19].…”

Ketoanalogues Supplemental Low Protein Diet Safely Decreases Short-Term Risk of Dialysis among CKD Stage 4 Patients

“…Indeed, one recent RCT performed by Bellizzi, V. et al, which enrolled patients with CKD stage 4 and stage 5, compared the long-term kidney and patient survival between patients that received sVLPDs and those that received LPD [ 18 ]. They found that the sVLPDs group did not have an additional advantage to the LPD group.…”