Very Low Protein Diet Research Articles

#2380 A multicenter and randomized study of a VLPD supplemented with ketoanalogues in patients with advanced CKD in Spain. Adherence study

Abstract Background and Aims Clinical guidelines recommend a very low-protein diet (VLPD) supplemented with ketoanalogues (KAs) for patients with advanced chronic kidney disease (CKD) to reduce progression (evidence 1A) and improve the quality of life (evidence 1C). However, there is no prior experience with this nutritional intervention in Spain. Method A multicenter, randomized, and controlled study that evaluated adherence to a VLPD supplemented with KAs (Ernamin®) in non-dialysis dependent CKD patients, estimated using the Morisky scale. Secondary objectives included assessing the effect of VLPD + KAs on kidney function, urine protein, albumin levels and other metabolic and nutritional parameters, including changes in body composition stores, at months 0, 1, 3, 6, and 9. Results Preliminary data from 33 patients (67% men; mean age 68 ± 10; GFR 16.7 ± 3.9 ml/min/1.73 m2), randomized into 2 groups, are presented. The VLPD group showed good acceptance and tolerance of the diet and supplement, with medium or high adherence in 80% of patients from the first month, maintained throughout the study (Figure). The use of VLPD was associated with a decrease in phosphorus levels (−0.4 mg/dl VLPD vs. 0.09 mg/dl LPD, P = 0.027) and C-reactive protein (CRP) levels (−2 mg/dl VLPD vs. 0.33 mg/dl LPD), an increase in calcium levels (0.3 mg/dl VLPD vs. −0.2 mg/dl LPD, P = 0.015), and an increase in muscle mass (LTM) measured by bioimpedance (3.7 kg VLPD vs. −0.6 kg LPD, P = 0.03). Stability in weight, fat mass, extracellular volume, albumin levels, and MIS scale was observed during the follow-up. Estimated glomerular filtration rate, and urine protein remained unchanged in both groups. Conclusion Protein restriction associated with KAs shows good short-term tolerance and acceptance. This study confirms several effects associated with VLPD supplemented with KAs, including an anti-inflammatory effect, the preservation of nutritional status, and a better control of phosphate levels. These data suggest safe protein intake restriction with stabilization of protein stores.

#761 Effect of ketoanalogue-supplemented very low protein diet in the need to initiate renal replacement in chronic kidney disease patients

Abstract Background and Aims Chronic kidney disease (CKD) is a global concern, with increasing complications and potential end-stage renal disease. Protein intake restriction is crucial for conservative therapy. Investigators have theorized on the nephroprotective effect of either a very low-protein diet (VLPD) with ketoanalogues (KAA) or a low-protein diet (LPD); this was however not confirmed by the Modification of Diet in Renal Disease (MDRD) randomized clinical trial (RCT). This meta-analysis aims to evaluate the effect of VLPD supplemented with KAA on RRT need and disease progression among CKD patients. Method A systematic literature search was conducted up to January 3, 2024 for trials in the following databases: PUBMED/MEDLINE, Ovid MEDLINE, Google Scholar, Embase, Cochrane Central Register of Controlled Trials, Cochrane Database of Systematic Reviews, Web of Science and ClincalTrials.gov. Studies that compared VLPD supplemented with KAA to LPD in pre-dialysis CKD patients demonstrating outcomes such as the need for RRT, CKD progression, and all-cause mortality were included. A total of four studies were included in the final analysis. The number of individuals requiring and not requiring RRT on follow-up were computed and analyzed using fixed effects model; while CKD progression and mortality were analyzed using random effects models. Results Four studies (738 participants) investigated patients who needed RRT, CKD progression, and all-cause mortality on follow-up between those on VLPD with KAA and LPD. In Fig. 1, VLPD with KAA reduced the need of RRT by 36% (Odds Ratio 0.64, 95% CI: 0.45 to 0.93, P = 0.02), and decreased the incidence of CKD progression (Fig. 2) by 65% (Odds Ratio 0.35, 95% CI: 0.14 to 0.87, P = 0.02). Three studies (531 participants) reported on all-cause mortality (Fig. 3), and our analysis did not show a significant effect on all-cause mortality (OR 1.46, 95% CI: 0.72 to 2.96, P = 0.29). There was no significant heterogeneity among the studies. Conclusion The investigators conclude that the present meta-analysis of 4 RCTs demonstrates that the use of VLPD supplemented with KAA reduced the need for RRT initiation and progression of CKD among pre-dialysis CKD Stage 4-5 patients when compared to those on the conventional LPD regimen. Therefore, protein restriction diets especially VLPD with KAA should be considered and offered in eligible CKD patients as part of their supportive management.

#3008 Very low protein diet with ketoanalogues supplementation could start haemodialysis with AVF without additional CVCs insertion

Abstract Background and Aims Nutritional interventions and a low-protein diet (LPD) are a critical point in the management of chronic kidney disease (CKD). Several protein-restricted dietary regimens have been proposed in patients with end stage kidney disease: a typical LPD provides around 0.6–0.7 g·kg meanwhile a very low-protein diet (VLPD) provides around 0.3–0.4 g·kg and it is basically a vegetarian diet which has to be supplemented with essential amino acids (EAA) to satisfy the body nitrogen need and with nitrogen-free ketoanalogues (KA) to recirculate the endogenous urea, whose serum levels are elevated in patients with CKD. KA and EAA reduce the rate of progression of chronic kidney disease and improve the inflammatory state; they reduce the absorption of phosphates and can maintain a good state of nutrition even if associated with diets with very low protein content. On the contrary, an excessively restrictive and inadequate diet in terms of EAA or calorie intake induces a negative nitrogen balance, therefore cachexia. The recommended vascular access to start dialysis treatment is represented by the arteriovenous fistula (AVF). An early referral to the vascular surgeon for vascular access creation is pivotal for deciding on a patient-specific strategy for planning access. Guidelines advise referral at least 3–6 months before the expected start of HD, because time is needed for AVF maturation and possible repeat interventions when it is impaired. An early referral results in more autologous AVFs, which have a better long-term patency, whereas late referral, results in a greater risk of AVF non-maturation and failure and therefore the need for additional central venous catheters (CVCs) to initiate dialysis. Recent studies have shown that pre-dialysis patients who undergo a VLDP + KA require less emergency dialysis access and have better elasticity of the arterial wall, better maturation rates and duration of the AVF and sometimes a reduction in the uremic toxins responsible of endothelial dysfunction. The aim of the study was to evaluate if patients could start haemodialysis with fistula cannulation, without central venous catheter insertion. Method 10 patients, late referral end stage renal disease were enrolled in a prospective, single arm study starting very low protein diet supplemented with ketoanalogues after arteriovenous fistula creation; they were followed with periodically assessment of renal function, uremic toxin, and acid-base balance until they need to start haemodialysis. It was evaluated AVF maturation and needs to additional CVC insertion. Results Patients (3 females, 7 males) mean age was 71.2 years; before AVF creation, baseline mean value was: sCr: 6.46 mg/dl, sUrea: 150 mg/dl, phosphorus: 4.45 mg/dl, bicarbonates: 19.8 mmol/l, eGFR: 8,37 ml/min. After 3 months of VLPD supplemented with KA, eGFR and sCr was stable to 8.25 ml/min and 6.69 respectively, sUrea and phosphorus reduced to 115 mg/dl and 3.8 mg/dl, and bicarbonate increased to 22.4 mmol/l. All 10 patients achieved AVF maturation within 3 months, no one needed CVC insertion. Conclusion In this small group we see how late referral ESRD patients, undergone AVF surgery, after 3 months of VLPD supplemented with KA, had stability of renal function, with reduction of urea and phosphorus, improvement of acid-base balance and achievement of AVF maturation, without needing of CVC insertion. For these reasons VLPD + KA could be useful in delaying haemodialysis start in late referral ESRD patients who have created AVF, without emergency placement of a central venous catheter.

#1519 Nutritional impact of ketoanalogue supplementation with protein-restricted diets in advanced chronic kidney disease

Abstract Background and Aims The benefits and risks of a protein-restricted diet supplemented with ketoanalogues (KA) in patients with chronic kidney disease (CKD) are still being explored. Combining KA supplementation with a protein-restricted diet may potentially preserve the glomerular filtration rate (GFR) in CKD patients. However, concerns about protein-energy wasting and the nutritional benefits of KA supplementation remain uncertain. Previous systematic reviews have often included crossover or non-randomized studies and combined data from CKD and dialysis patients, potentially introducing heterogeneity when assessing the effects of KA supplementation in CKD patients. We aim to provide an updated and comprehensive assessment of the impact of combining KA supplementation with a protein-restricted diet on the nutritional status of advanced CKD patients compared to the effects of a protein-restricted diet alone. Method We conducted systematic literature searches of PubMed, Embase, Scopus, and Cochrane Library up to September 2023. We selected parallel-design randomized controlled trials comparing KA supplementation to a low- or very low-protein diet (VLPD) versus a low-protein diet (LPD) alone in adults with stages 3-5 CKD. Outcomes included serum albumin, triceps skinfold (TSF), and mid-arm muscle circumference (MAMC). Pooled estimates of effect measures were calculated using the random-effects model and presented as standardized mean differences (SMDs) with 95% confidence intervals (CIs). Given the variation in CKD stages among the included studies, subgroup analyses were conducted based on baseline renal function (GFR < 20 vs. ≥ 20 mL/min/1.73 m²). To assess the robustness of our meta-analyses, we conducted sensitivity analyses by excluding studies with an in-trial follow-up duration of less than one year. Results We identified 13 trials with 974 participants and a median follow-up of 12 months. KA supplementation combined with an LPD or a VLPD significantly increased TSF compared to an LPD alone (SMD, 0.25; 95% CI, 0.04, 0.45; P = 0.02; Fig. 1). No significant differences were observed in serum albumin (SMD, 0.28; 95% CI, -0.05, 0.61; P = 0.10; Fig.) and MAMC (SMD, 0.10; 95% CI, -0.12, 0.32; P = 0.37; Fig. 1). KA supplementation significantly increased serum albumin in patients with a baseline GFR ≥ 20 mL/min/1.73 m² (SMD 0.52; 95% CI, 0.20, 0.84; P = 0.001), but not in those with a baseline GFR < 20 mL/min/1.73 m² (SMD, -0.04; 95% CI, -0.41, 0.34; P = 0.85), and this difference between the subgroups was statistically significant (P = 0.03; Fig. 2). Sensitivity analysis that excluded studies with an in-trial follow-up duration of less than one year yielded results similar to the main analysis, except that the difference in TSF between the intervention and control arms became nonsignificant. Conclusion In patients with stages 3-5 CKD, KA supplementation with a protein-restricted diet did not adversely affect nutritional status. These findings remained consistent in sensitivity analyses of RCTs with a follow-up of more than one year and in subgroup analyses based on baseline GFR. The addition of KAs to protein-restricted diets improved serum albumin levels in patients with a baseline GFR of ≥ 20 mL/min/1.73 m². Our analyses confirmed the efficacy and safety of KA supplementation on nutritional status in advanced CKD patients over a one year follow-up period.

Economic Analysis of a Ketoanalogue-supplemented Very Low-protein Diet in Patients With Chronic Kidney Disease in Vietnam

The aim of this study was to estimate the cost-effectiveness of a very low-protein diet (VLPD) supplemented with ketoanalogues of essential amino acids compared with a conventional low-protein diet (LPD) in Vietnam. The study was conducted from payer (base case), patient, and societal perspectives. A Markov model simulated costs and quality-adjusted life-years (QALYs) for patients with chronic kidney disease stage 4 or 5 (CKD4+) who were followed up during their lifetimes. Patients received a VLPD (0.3- to 0.4-g/kg/d diet) supplemented with ketoanalogues (5 kg/d [1tablet]) versus LPD (0.6 g/kg/d, mixed proteins). In each model cycle, patient transitions among the health states-CKD4+ (nondialysis), dialysis, and death-were based on transition probabilities taken from the published literature. The time horizon covered the cohort's lifetime. Utilities and costs were estimated from literature review and projected for the lifespan considered in the model. Probabilistic and deterministic sensitivity analyses were performed. The ketoanalogue-supplemented VLPD increased survival and QALYs compared with the LPD. From a payer's perspective, total cost of care in Vietnam was ₫216,854,268 (€8684/$9242) per patient with LPD versus ₫200,928,819 (€8046/$8563) per patient with a supplemented VLPD (sVLPD) (difference, -₫15,925,449 [-€638/-$679]). From a patient's perspective, total cost of care in Vietnam was ₫217,872,043 (€8724/$9285) per patient with LPD versus ₫116,015,672 (€4646/$4944) per patient with sVLPD (difference, -₫101,856,371 [-€4,079/ -$4341]). From a societal perspective, total cost of care in Vietnam was ₫434,726,312 (€17,408/-$18,527) per patient with LPD versus ₫316,944,491 (€12,692/ $13,508) per patient with sVLPD (difference, -₫117,781,820 [-€4716 €/$5020). Ketoanalogue-supplemented VLPD lowered costs compared with LPD in all 3 perspectives considered.

Dietary Isoleucine and Valine: Effects on Lipid Metabolism and Ureagenesis in Pigs Fed with Protein Restricted Diets.

A mixture of valine (Val) and isoleucine (Ile) not only decreases the negative impact of very low protein (VLP) diets on the growth of pigs, but also influences the nitrogen (N) balance and lipid metabolism; however, the underlying pathways are not well understood. This study aimed to investigate the effect of dietary Val and Ile on lipogenesis, lipolysis, and ureagenesis under protein restriction. After one week of acclimation, forty three-week-old pigs were randomly assigned to following dietary treatments (n = 8/group) for 5 weeks: positive control (PC): normal protein diet; negative control (NC): VLP diet; HV: NC supplemented with Val; HI: NC supplemented with Ile; and HVI: NC supplemented with both Val and Ile. HVI partially improved the body weight and completely recovered the feed intake (FI) of pigs fed with NC. HVI increased thermal radiation and improved the glucose clearance. HVI had a lower blood triglyceride than PC and blood urea N than NC. NC and HV promoted lipogenesis by increasing the transcript of fatty acid synthase (FAS) in the liver and lipoprotein lipase (LPL) in adipose tissue but reducing hormone-sensitive lipase (HSL) in the liver. HVI reduced the increased rate of lipogenesis induced by the NC group through normalizing the mRNA abundance of hepatic FAS, sterol regulatory element binding transcription factor 1, and HSL and LPL in adipose tissue. NC, HV, HI, and HVI reduced the ureagenesis by decreasing the protein abundance of carbamoyl phosphate synthetase I, ornithine transcarboxylase, and arginosuccinate lyase in the liver. Overall, HVI improved the growth, FI, and glucose clearance, and decreased the rate of lipogenesis induced by VLP diets.

Effect of Isoleucine and Added Valine on Performance, Nutrients Digestibility and Gut Microbiota Composition of Pigs Fed with Very Low Protein Diets.

Little is known whether a combination Ile and added Val improves the growth of pigs offered very low protein (VLP) diets through changes in nutrients digestibility and gut microbiota. The objective of this study was to investigate the effect of a mixture of Val above and Ile at NRC levels on growth, nutrient digestibility and gut microbiota in pigs fed with VLP diets. Forty, weaned piglets were assigned to: positive control: normal-protein-diet; negative control (NC): VLP diet supplemented with first four limiting amino acids; VA: NC with Val above NRC; IL: NC with Ile at NRC level; VAIL: NC with Val above and Ile at NRC levels. While both VAIL and VA groups completely recovered the inhibitory effects of VLP diets on feed intake, only VAIL partially recovered the negative effects of VLP diets on growth performance. VAIL and VA increased the thermal radiation and decreased the digestibility of nitrogen. NC increased the relative abundance of Pasteurellaceae and Enterobacteriaceae in the colon. VAIL had a higher abundance of colonic Actinobacteria, Enterococcus, and Brevibacillus and the colon content of VA was more enriched with Mogibacterium. Overall, VAIL partially improved the growth performance which is likely linked with alterations in gut microbiota composition.

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

The effects of supplemental ketoanalogues (KA) in patients with diabetic kidney disease (DKD) are not well characterized. Several databases for peer-reviewed articles were systematically searched to identify studies reporting outcomes associated with the effects of a low-protein diet (LPD) or very-low protein diet (VLPD) in combination with supplemental KA in adults with DKD. Meta-analyses were conducted when feasible. Of 213 identified articles, 11 could be included in the systematic review. Meta-analyses for renal outcomes (4 studies examining glomerular filtration rate; 5 studies examining 24-h urinary protein excretion), metabolic outcomes (5 studies examining serum urea; 7 studies examining blood glucose), clinical outcomes (6 studies examining blood pressure; 4 studies examining hemoglobin), and nutritional outcomes (3 studies examining serum albumin; 4 studies examining body weight) were all in favor of KA use in DKD patients. Data from individual studies that examined other related parameters also tended to show favorable effects from KA-supplemented LPD/VLPD. The regimens were safe and well tolerated, with no evidence of adverse effects on nutritional status. In conclusion, LPD/VLPD supplemented with KA could be considered effective and safe for patients with non-dialysis dependent DKD. Larger studies are warranted to confirm these observations.

Ten-year experience of an outpatient clinic for CKD-5 patients with multidisciplinary team and educational support

PurposeTo analyze the results of an outpatient clinic with a multidisciplinary team and educational support for patients with late-stage CKD (lsCKD), to check its possible effect on their outcomes.MethodsLongitudinal cohort study on patients followed up in the MaReA (Malattia Renale Avanzata = CKD5) outpatient clinic at ASST Spedali Civili of Brescia from 2005 to 2015 for at least six months. Trajectory of renal function over time has been evaluated only in those patients with at least four estimations of eGFR before referring to MaReA.ResultsSeven hundred and six patients were enrolled, their mean age was 72 ± 14 years, 59% were males. At the end of the study, 147 (21%) were still on MaReA, 240 (34%) on dialysis, 92 (13%) on very low-protein diet (VLPDs), 13 (2%) on pre-hemodialysis clinic, 23 (3%) improved renal function, 10 (1%) transplanted, 62 (9%) transferred/lost to follow-up, and 119 (17%) died. Optimal dialysis start (defined as start with definitive dialysis access, as an out-patient and without lsCKD complications) occurred in 180/240 (75%) patients. The results showed a slower eGFR decrease during MaReA follow-up compared to previous renal follow-up: − 2.0 vs. − 4.0 mL/min/1.73 m2 BSA/year (p < 0.05), corresponding to a median delay of 17.7 months in dialysis start in reference to our policy in starting dialysis. The patient cumulative survival was 75% after 24 months and 25% after 70. Limitations: (1) lack of a control group, (2) one-center-study, (3) about all patients were Caucasians.ConclusionThe follow-up of lsCKD patients on MaReA is associated with an optimal and delayed initiation of dialysis.

Ketoanalogs' Effects on Intestinal Microbiota Modulation and Uremic Toxins Serum Levels in Chronic Kidney Disease (Medika2 Study).

Nutritional therapy (NT) is a therapeutic option in the conservative treatment of chronic kidney disease (CKD) patients to delay the start of dialysis. The aim of this study was to evaluate the specific effect of ketoanalogs (KA)-supplemented diets for gut microbiota modulation. In a previous study we observed that the Mediterranean diet (MD) and a KA-supplemented very-low-protein diet (VLPD) modulated beneficially gut microbiota, reducing indoxyl- and p-cresyl-sulfate (IS, PCS) serum levels, and ameliorating the intestinal permeability in CKD patients. In the current study, we added a third diet regimen consisting of KA-supplemented MD. Forty-three patients with CKD grades 3B–4 continuing the crossover clinical trial were assigned to six months of KA-supplemented MD (MD + KA). Compared to MD, KA-supplementation in MD + KA determined (i) a decrease of Clostridiaceae, Methanobacteriaceae, Prevotellaceae, and Lactobacillaceae while Bacteroidaceae and Lachnospiraceae increased; (ii) a reduction of total and free IS and PCS compared to a free diet (FD)—more than the MD, but not as effectively as the VLPD. These results further clarify the driving role of urea levels in regulating gut integrity status and demonstrating that the reduction of azotemia produced by KA-supplemented VLPD was more effective than KA-supplemented MD in gut microbiota modulation mainly due to the effect of the drastic reduction of protein intake rather than the effect of KA.

Protein-bound uremic toxin lowering strategies in chronic kidney disease: asystematic review and meta-analysis.

Accumulation of protein-bound uremic toxins, including indoxyl sulfate and p-cresyl sulfate, are associated with increased cardiovascular disease and mortality in chronic kidney disease (CKD). We performed a systematic review and meta-analysis to synthesize the available strategies for lowering protein-bound uremic toxin levels in CKD patients. We conducted a meta-analysis by searching the databases of MEDLINE, Scopus, and the Cochrane Central Register of Controlled Trials for observational studies and randomized controlled trials (RCTs) that examined the effect of dietary protein restrictions, biotic supplements (including prebiotics, probiotics, and synbiotics), AST-120, dialysis techniques, and the outcome of preservation of residual renal function (RRF) on indoxyl sulfate and p-cresyl sulfate levels. Random-effect model meta-analyses were used to compute changes in the outcomes of interest. A total of 38 articles (2,492 patients), comprising 28 RCTs, 8 single-arm or prospective cohort studies, and 2 cross-sectional studies were included in this meta-analysis. When compared with placebo, prebiotics, synbiotics, and AST-120 provided significantly lower levels of both serum indoxyl sulfate and p-cresyl sulfate. There were no significant reductions in serum indoxyl sulfate and p-cresyl sulfate levels in patients receiving probiotics. Preservation of RRF in dialysis patients resulted in lower levels of both of the protein-bound uremic toxins. When compared with conventional hemodialysis, hemodiafiltration significantly decreased serum p-cresyl sulfate alone, whereas a significant change in serum indoxyl sulfate levels was observed only in studies with long-term observation periods. Very low protein diet (VLPD) and other oral medications yielded insignificant differences in protein-bound uremic toxins. The present meta-analysis demonstrated that prebiotics, synbiotics, and AST-120 can effectively reduce both serum indoxyl sulfate and p-cresyl sulfate in CKD patients when compared with placebo. Preservation of RRF was associated with lower serum indoxyl sulfate and p-cresyl sulfate levels. The effect of biotic supplements was detected only in dialysis patients. For non-dialysis CKD patients, the results were limited due to the small number of studies. Further studies are needed to determine the efficacy in these populations.

Muscle protein turnover and low-protein diets in patients with chronic kidney disease.

Adaptation to a low-protein diet (LPD) involves a reduction in the rate of amino acid (AA) flux and oxidation, leading to more efficient use of dietary AA and reduced ureagenesis. Of note, the concept of 'adaptation' to low-protein intakes has been separated from the concept of 'accommodation', the latter term implying a decrease in protein synthesis, with development of wasting, when dietary protein intake becomes inadequate, i.e. beyond the limits of the adaptive mechanisms. Acidosis, insulin resistance and inflammation are recognized mechanisms that can increase protein degradation and can impair the ability to activate an adaptive response when an LPD is prescribed in a chronic kidney disease (CKD) patient. Current evidence shows that, in the short term, clinically stable patients with CKD Stages 3-5 can efficiently adapt their muscle protein turnover to an LPD containing 0.55-0.6 g protein/kg or a supplemented very-low-protein diet (VLPD) by decreasing muscle protein degradation and increasing the efficiency of muscle protein turnover. Recent long-term randomized clinical trials on supplemented VLPDs in patients with CKD have shown a very good safety profile, suggesting that observations shown by short-term studies on muscle protein turnover can be extrapolated to the long-term period.

The Effects of Restricted Protein Diet Supplemented With Ketoanalogue on Renal Function, Blood Pressure, Nutritional Status, and Chronic Kidney Disease-Mineral and Bone Disorder in Chronic Kidney Disease Patients: A Systematic Review and Meta-Analysis

To systemically review the meta-analysis exploring the effectiveness and safety of restricted protein diet supplemented with ketoanalogues (KAs) when compared with regular diet or low protein diet (LPD) without KAs in chronic kidney disease (CKD) patients. We conducted electronic searches in PubMed, Scopus, Cochrane Central Register of Controlled Trials, and ClinicalTrials.gov from January 1960 to May 2018 to identify randomized controlled clinical trials that explored the effects of restricted protein diet including vegetarian and mixed type of protein with KAs on kidney endpoints including the changes in estimated glomerular filtration rate (eGFR) and proteinuria, nutritional status, and CKD-mineral bone disorder. Seventeen RCTs with 1,459 participants were included in our meta-analysis. Restricted protein diet with KAs significantly preserved eGFR and reduced proteinuria, serum phosphate, parathyroid hormone (PTH) level, systolic blood pressure, diastolic blood pressure, and serum cholesterol. By subgroup analysis, very low protein diet (VLPD) with KAs was plausibly superior to LPD with KAs in slowing the decline in eGFR. Only VLPD with KAs significantly improved serum PTH, systolic blood pressure, and diastolic blood pressure while both regimens significantly decreased serum phosphate. Only LPD with KAs significantly raised serum albumin and serum calcium. Restricted protein diet supplemented with KAs could effectively improve kidney endpoints including preserving eGFR and diminishing proteinuria, blood pressure levels, and CKD-mineral bone disorder parameters without causing malnutrition. VLPD with KAs appears to provide more effectiveness in slowing the decline in eGFR, lowering blood pressure, reducing serum PTH, and less increasing serum calcium level.

Nutritional Therapy Modulates Intestinal Microbiota and Reduces Serum Levels of Total and Free Indoxyl Sulfate and P-Cresyl Sulfate in Chronic Kidney Disease (Medika Study).

In chronic kidney disease (CKD), the gut-microbiota metabolites indoxyl sulfate (IS) and p-cresyl sulfate (PCS) progressively accumulate due to their high albumin-binding capacity, leading to clinical complications. In a prospective crossover controlled trial, 60 patients with CKD grades 3B–4 (GFR = 21.6 ± 13.2 mL/min) were randomly assigned to two dietary regimens: (i) 3 months of free diet (FD) (FD is the diet usually used by the patient before being enrolled in the Medika study), 6 months of very low protein diet (VLPD), 3 months of FD and 6 months of Mediterranean diet (MD); (ii) 3 months of FD, 6 months of MD, 3 months of FD, and 6 months of VLPD. VLPD reduced inflammatory Proteobacteria and increased Actinobacteria phyla. MD and VLPD increased some butyrate-forming species of Lachnospiraceae, Ruminococcaceae, Prevotellaceae, Bifidobacteriaceae, and decrease the pathobionts Enterobacteriaceae. The increased level of potential anti-inflammatory Blautia and Faecalibacterium, as well as butyrate-forming Coprococcus and Roseburia species in VLPD was positively associated with dietary intakes and it was negatively correlated with IS and PCS. Compared to FD and MD, VLPD showed a lower amount of some Lactobacillus, Akkermansia, Streptococcus, and Escherichia species. MD and VLPD reduced both the total and free serum IS (MD −36%, −40% and VLPD −69%, −73%, respectively) and PCS (MD −38%, −44% and VLPD −58%, −71%, respectively) compared to FD. VLPD reduced serum D-lactate compared to MD and FD. MD and, to a greater extent, VLPD are effective in the beneficial modulation of gut microbiota, reducing IS and PCS serum levels, and restoring intestinal permeability in CKD patients.

Very Low Protein Diet for Patients with Chronic Kidney Disease: Recent Insights.

Use of nutritional therapy (NT) in chronic kidney disease (CKD) patients is still debated among nephrologists, but it represents a fundamental point in the conservative treatment of CKD. It has been used for years and it has new goals today, such as (1) the reduction of edema, diuretics, and blood pressure values with a low sodium-content diet; (2) the dose reduction of phosphate levels and phosphate binders; (3) the administration of bicarbonate with vegetables in order to correct metabolic acidosis and delay CKD progression; (4) the reduction of the number and the doses of drugs and chemical substances; and (5) the lowering of urea levels, the cure of intestinal microbioma, and the reduction of cyanates levels (such as indoxyl-sulphate and p-cresol sulphate), which are the most recent known advantages achievable with NT. In conclusion, NT and especially very low protein diet (VLPD) have several beneficial effects in CKD patients and slows the progression of CKD.

Very low protein diet plus ketoacid analogs of essential amino acids supplement to retard chronic kidney disease progression.

BackgroundA very low protein diet (VLPD) with ketoacid analogs of essential amino acids (KA/EAA) administration can remarkably influence protein synthesis and metabolic disturbances of patients with advanced chronic kidney disease (CKD), and may also slow the decline in renal function.MethodsA retrospective cohort study was carried out to monitor renal progression and metabolic and nutritional status among 140 patients with CKD stage III or IV. One group (n = 70) was on a low protein diet (LPD) with 0.6 g of protein intake, and another group (n = 70) was on a VLPD with 0.3 g of protein and KA/EAA supplementation of 100 mg/kg/day for 12 months.ResultsAt 12-month follow-up, estimated glomerular filtration rate (GFR) significantly decreased from 41.6 ± 10.2 to 36.4 ± 8.8 mL/min/1.73 m2 (P < 0.001) and urine protein increased from 0.6 ± 0.5 to 0.9 ± 1.1 g/day (P = 0.017) in the LPD group, but no significant changes in estimated GFR and urine protein were found in the VLPD plus KA/EAA group. A significant mean difference in rate of change in estimated GFR (−5.2 ± 3.6 mL/min/1.73 m2 per year; P < 0.001) was observed between the two groups. After Cox regression analysis, treatment with VLPD plus KA/EAA significantly protected against the incidence of declining GFR > 10% annually (adjusted hazard ratio, 0.42; 95% confidence interval, 0.23–0.79; P = 0.006) and significant correlations were found between using VLPD plus KA/EEA and increased GFR.ConclusionVLPD supplementation with KA/EAA is associated with delayed renal progression while preserving the nutritional status in the patients with CKD. Co-administration of VLPD and KA/EAA may prove an effective alternative to conservative management of CKD.

Cyclic and intermittent very low‐protein diet can have beneficial effects against advanced diabetic nephropathy in Wistar fatty (fa/fa) rats, an animal model of type 2 diabetes and obesity

A low-protein diet (LPD), particularly, very low-protein diet (VLPD) is expected for reno-protection in advanced chronic kidney disease, including diabetic nephropathy. We previously also demonstrated that a VLPD clearly improved advanced diabetic nephropathy in a type 2 diabetes and obesity rat. However, clinically, an everyday long-term VLPD contributes to poor adherence, which may be related to controvertial results of an LPD on the suppression for diabetic nephropathy, and has nutritional issues, such as sarcopenia or protein-energy wasting. The aim of this study is to elucidate the reno-protective effect of a cyclic and intermittent VLPD, not an everyday VLPD, against the advanced experimental diabetic nephropathy. Diabetic male Wistar fatty (fa/fa) rats (WFRs) were treated with a standard diet (STD; 23.84% protein) or a cyclic and intermittent VLPD (5.77% protein) consisting of an STD for 3 days and a VLPD for 4 days a week for 20 weeks beginning at 24 weeks of age. A cyclic and intermittent VLPD significantly improved renal hypertrophy, and significantly decreased urinary albumin and liver-type fatty acid binding protein (L-FABP) excretion without changes in body weight or exacerbation of HbA1c levels in diabetic rats. Additionally, diabetes-induced renal injuries including fibrosis, tubular cell damage and inflammation were significantly ameliorated by a cyclic and intermittent VLPD in diabetic rats. Thus, based on our experimental data, a cyclic and intermittent VLPD may be a dietary regimen that is easy to continue and has less risk of malnutrition, compared to an everyday long-term VLPD, against advanced diabetic nephropathy.

Nutritional therapy reduces protein carbamylation through urea lowering in chronic kidney disease.

Protein carbamylation is one of the non-enzymatic reactions involved in protein molecular ageing. We sought to investigate the relationship between urea levels and protein carbamylation, and whether a Mediterranean diet (MD) and a very low protein diet (VLPD) reduce protein carbamylation through reduction in urea levels in patients with chronic kidney disease (CKD). This is a prospective, randomized, crossover controlled trial that investigated 60 patients with CKD grades 3B-4 (46 males, mean age of 67 years). The enrolled CKD patients were randomly assigned (1:1) to two different nutritional treatment arms: (i) 3 months of free diet (FD), 6 months of VLPD, 3 months of FD and 6 months of MD; and (ii) 3 months of FD, 6 months of MD, 3 months of FD and 6 months of VLPD. Blood levels of lysine (Lys) and homocitrulline (Hcit) and their ratio were used as markers of cyanate levels. Due to a lack of pre-existing data on the potential effects of different dietary regimens and in light of the exploratory nature of the study, no formal sample size estimation was carried out. At study completion, lower diastolic blood pressure and decreased serum levels of urea, sodium, phosphorus and parathyroid hormone, but higher serum levels of bicarbonate and haemoglobin, were noted with MD and VLPD. When compared with FD, both MD and VLPD were also associated with a decrease in serum Hcit levels and Hcit/Lys ratios (P < 0.001). Notably, reductions in urea levels correlated with substantial reductions in Hcit levels (R2 = 0.16 and 0.17 for VLPD and MD, respectively). In conclusion, nutritional treatments that significantly decrease serum levels of urea are associated with reduced protein carbamylation.

Very Low-Protein Diet (VLPD) Reduces Metabolic Acidosis in Subjects with Chronic Kidney Disease: The "Nutritional Light Signal" of the Renal Acid Load.

Background: Metabolic acidosis is a common complication of chronic kidney disease; current guidelines recommend treatment with alkali if bicarbonate levels are lower than 22 mMol/L. In fact, recent studies have shown that an early administration of alkali reduces progression of CKD. The aim of the study is to evaluate the effect of fruit and vegetables to reduce the acid load in CKD. Methods: We conducted a case-control study in 146 patients who received sodium bicarbonate. Of these, 54 patients assumed very low-protein diet (VLPD) and 92 were controls (ratio 1:2). We calculated every three months the potential renal acid load (PRAL) and the net endogenous acid production (NEAP), inversely correlated with serum bicarbonate levels and representing the non-volatile acid load derived from nutrition. Un-paired T-test and Chi-square test were used to assess differences between study groups at baseline and study completion. Two-tailed probability values ≤0.05 were considered statistically significant. Results: At baseline, there were no statistical differences between the two groups regarding systolic blood pressure (SBP), diastolic blood pressure (DBP), protein and phosphate intake, urinary sodium, potassium, phosphate and urea nitrogen, NEAP, and PRAL. VLPD patients showed at 6 and 12 months a significant reduction of SBP (p < 0.0001), DBP (p < 0.001), plasma urea (p < 0.0001) protein intake (p < 0.0001), calcemia (p < 0.0001), phosphatemia (p < 0.0001), phosphate intake (p < 0.0001), urinary sodium (p < 0.0001), urinary potassium (p < 0.002), and urinary phosphate (p < 0.0001). NEAP and PRAL were significantly reduced in VLPD during follow-up. Conclusion: VLPD reduces intake of acids; nutritional therapy of CKD, that has always taken into consideration a lower protein, salt, and phosphate intake, should be adopted to correct metabolic acidosis, an important target in the treatment of CKD patients. We provide useful indications regarding acid load of food and drinks—the “acid load dietary traffic light”.

Very low protein diets supplemented with keto-analogues in ESRD predialysis patients and its effect on vascular stiffness and AVF Maturation.

BackgroundNative arteriovenous fistula (AVF) is the most appropriate type of vascular access for chronic dialysis. Its patency rates depend on vascular wall characteristics. Ketoacid analogues of essential amino acids (KA/EAA) are prescribed in end-stage renal disease (ESRD) pre-dialysis patients to lower toxic metabolic products generation and improve nutritional status. We hypothesized that very-low protein diet (VLPD) supplemented with KA/EAA may influence arterial wall stiffness and affect AVF maturation rates and duration in pre-dialysis ESRD patients.MethodsIn a prospective, cohort, 3 years study we enrolled 67 consecutive non-diabetic early referral ESRD patients that underwent AVF creation in our hospital. Patients were divided in two groups based on their regimen 12 months prior to surgery: a VLPD supplemented with KA/EAA study group versus a low protein diet non-KA/EAA-supplemented control group. For each patient we performed serum analysis for the parameters of bone mineral disease, inflammation and nutritional status, one pulse wave velocity (PWV) measurement and one Doppler ultrasound (US) determination prior the surgery, followed by consequent Doppler US assessments at 4, 6, 8 and 12 weeks after it. Rates and duration of mature AVF achievement were noted. We used logistic regression to analyze the association between AVF maturation and KA/EAA administration, by comparing rates and durations between groups, unadjusted and adjusted for systolic blood pressure, C-reactive protein, PWV, phosphorus values. All parameters in the logistic model were transformed in binary variables. A p-value < α = 0.05 was considered significant; data were processed using SPSS 16 software and Excel.ResultsIn the study group (n = 28, aged 57 ± 12.35, 13 females) we registered better serum phosphate (p = 0.022) and C-reactive protein control (p = 0.021), lower PWV (p = 0.007) and a higher percent of AVF creation success (33.3 % versus 17.8 %, p < 0.05). AVF maturation duration was lower in study group (5.91 versus 7.15 weeks, p < 0.001).ConclusionsVLPD supplemented with KA/EAA appear to improve the native AVF primary outcome, decreasing the initial vascular stiffness, possible by preserving vascular wall quality in CKD patients through a better serum phosphate levels control and the limitation of inflammatory response.