Chronic Kidney Disease (CKD) is a condition associated with high mortality rates, diminished quality of life, and substantial healthcare expenses. Therefore, interventions aimed at delaying the need for kidney replacement therapy are of paramount importance. Diet is a key component of care during chronic kidney disease (CKD). Nutritional interventions, and, specifically, a restricted protein diet has been under debate for decades. The current evidence suggests that KAs supplemented LPD diets should be included as part of the clinical recommendations for both the nutritional prevention and metabolic management of CKD. More research is needed to examine the effectiveness of KAs especially on uremic toxins.
The Role of Protein Intake in Kidney Function
Experimentally, it has been demonstrated that high protein intake induces marked kidney hypertrophy, leading to an increase in glomerular pressure and hyperfiltration, which negatively impacts kidney function. CKD is characterized by the accumulation of a number of organic solutes called uremic toxins. Many of these uremic toxins are produced by the degradation of dietary amino acids by intestinal microbiota and appears to accelerate CKD progression. Based on these observations, a reduction in protein intake can be expected to preserve renal function and reduce uremic toxicity. Dietitians provide patients with individualized medical nutrition therapy, working to find the appropriate balance of protein. Depending on the stage of CKD, individuals will have varying protein needs. Patient preference will also influence recommendations and compliance with nutritional goals.
Very-Low Protein Diets and Ketoacid Analogues
Different dietary protein regimens have been tested: low-protein diets (LPD, 0.6 g protein/kg/day) or very low-protein diets (VLPD: 0.3-0.4 g protein/kg/day) supplemented with essential amino acids (EAAs) or nitrogen-free ketoacid analogues (KAs). The main limitation of a restricted protein diet is the risk of malnutrition and cachexia.
Keto acid analogs are nitrogen-free essential amino acids used in conjunction with a very low-protein diet. KAs are precursors of corresponding amino acids since they can undergo a transamination, e.g., a chemical reaction that transfers an amino group to a ketoacid to form a new amino acid. Through this conversion, KAs can be utilized in place of their respective EAAs without providing nitrogen products while re-using available nitrogen already in excess during CKD. If a diet does not provide enough EAAs or calories, then the nitrogen balance can become negative and could partly induce cachexia. Therefore, administration of KAs has been proposed to improve protein status while limiting the nitrogen burden on the body. VLDP + KAs are likely also efficient because the calcium content of KA preparation could allow a better correction of mineral metabolism impairment. A diet lacking in nutrients, particularly calories or essential amino acids, can result in cachexia and a negative nitrogen load. The addition of KAAs can help improve deficiencies and nitrogen balance. Supplementation should support reaching the protein intake goal of the low-protein diet.
Review of Clinical and Experimental Studies
Great effort was undertaken to perform randomized controlled trials (RCTs). The aim of this review is to summarize the potential effects of this dietary therapy on renal function, uremic toxins levels, and nutritional and metabolic parameters and propose future directions. The purpose of this paper is also to select all experimental and randomized clinical studies (RCTs) that have compared VLDP + KA to normal diet or/and low protein diet (LPD). A literature search of trials in SCOPUS, WEB of SCIENCES, CENTRAL, and PUBMED databases from their inception to 1 January 2019 initially without a language restriction was performed. The search strategy used the terms renal or ESRD or end stage renal disease or kidney or CKD or chronic kidney disease and ketoacids or keto analogs or very low protein diet. Following duplicate removal and application of exclusion criteria, 23 RCTs and 12 experimental studies were included.
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Effects on Renal Function and Metabolic Parameters
New emerging studies suggest that restricted VLDP + KAs may improve renal function and nutritional status, while preventing hyperparathyroidism, insulin resistance, and accumulation of uremic retention solutes (URS).
Impact on Muscle Protein Metabolism
CKD is associated with muscular wasting and there are some concerns about potential catabolic and cachectic effects of LPD/VLPD. KAs in general and ketoleucine, in particular, have been shown to reduce muscle protein degradation. However, how muscle protein metabolism adapts to a LPD/VLPD + KAs in CKD is still an open question. Leucine kinetics studies have shown that adaptation to dietary protein restriction involves a reduction in leucine flux and oxidation, which leads to a more efficient use of dietary amino acids, and postprandial inhibition of protein degradation with a reduced ureagenesis. In addition, in animal models, KAs supplementation may play a protective role on muscle atrophy. In particular, in 5/6th nephrectomy rats, an LPD + KAs compared to an LPD alone was able to suppress ubiquitin-proteasome system activation and protected skeletal muscle from atrophy and from oxidative damage. LPD + KAs decreases autophagy markers in muscle, but there was no difference in inflammation in skeletal muscle. It should be noted that the anabolic effect of KAs can be partially explained by the reduction of acid load associated with the reduction in protein intake.
Reduction of Uremic Toxins
The uremic syndrome is attributed to the progressive retention of a large number of compounds called uremic retention solutes (URS). Protein bound uremic toxins derived from gut microbiota have emerged as a major class of URS. High levels of indoxyl sulfate (IS) (indol metabolites), p-cresyl sulfate (PCS) (p-cresol metabolite), and trimethylamine-N-oxide (TMAO) have been associated with an increase in cardiovascular risk and renal disease progression. One clinical trial reported that a VLPD + KAs reduced IS serum levels in non-dialyzed CKD patients. The reduction of URS may be explained by the reduction of protein intake and vegetarian diet since Marzocco et al. observed that the higher protein intake (observed during LPD compared to VLPD) was the major determinant of IS levels. Until now, no large RCT has been performed to test the effectiveness of KAs strategy at reducing URS and this is eagerly needed. One constant effect of VLPD/LPD + KAs treatment is the reduction of serum urea. Studies indicate that the reduction in net urea generation with LPD + KA is due to decreased amino acid degradation. At disease-relevant concentrations, urea induces reactive oxygen species (ROS) production and causes insulin resistance and beta-cell dysfunction by modifying insulin signaling molecules by O-linked β-N-acetylglucosamine.
Effects on Electrolyte Balance and Bone Parameters
All studies observed a reduction of acidosis, phosphorus, and possibly sodium intake, while still providing adequate calcium intake. The impact of this diet on carbohydrate and bone parameters are only preliminary and need to be confirmed with RCTs.
Clinical Trial Results and Meta-Analyses
The Modification of Diet in Renal Disease study, the largest RCTs, failed to demonstrate a benefit in the primary outcome of the decline rate for the glomerular filtration rate. However, the design of this study was challenged and data were subsequently reanalyzed. However, when adherent patients were selected, with a rapid rate of progression and a long-term follow up, more recent meta-analysis and RCTs suggest that these diets can reduce the loss of the glomerular filtration rate in addition to the beneficial effects of renin-angiotensin-aldosterone system (RAAS) inhibitors.
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Keto-analogues administration plays an important role in clinical chronic kidney disease (CKD) adjunctive therapy
In animal study, KA presented a protective effect on IR induced renal injury and fibrosis by attenuating inflammatory infiltration and apoptosis via inhibition of nuclear factor-kappa B (NF-κB) and mitogen-activated protein kinase (MAPK) pathways.
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