DMGV Is a Rheostat of T Cell Survival and a Potential Therapeutic for Inflammatory Diseases and Cancers.

Activated effector T cells (Teff) and/or compromised regulatory T cells (Treg) underlie many chronic inflammatory diseases. We discovered a novel pathway to regulate survival and expansion of Teff without compromising Treg survival and a potential therapeutic to treat these diseases. We found dimethylguanidino valeric acid (DMGV) as a rheostat for Teff survival: while cell-intrinsic DMGV generated by Alanine-Glyoxylate Aminotransferase 2 (AGXT2) is essential for survival and expansion by inducing mitochondrial ROS and regulation of glycolysis, an excessive (or exogenous) DMGV level inhibits activated Teff survival, thereby the AGXT2-DMGV-ROS axis functioning as a switch to turn on and off Teff expansion. DMGV-induced ROS is essential for glycolysis in Teff, and paradoxically DMGV induces ROS only when glycolysis is active. Mechanistically, DMGV rapidly activates mitochondrial calcium uniporter (MCU), causing a surge in mitochondrial Ca2+ without provoking calcium influx to the cytosol. The mitochondrial Ca2+ surge in turn triggers the mitochondrial Na+/Ca2+ exchanger (NCLX) and the subsequent mitochondrial Na+ import induces ROS by uncoupling the Coenzyme Q cycle in Complex III of the electron transport chain. In preclinical studies, DMGV administration significantly diminished the number of inflammatory T cells, effectively suppressing chronic inflammation in mouse models of colitis and rheumatoid arthritis. DMGV also suppressed expansion of cancer cells in vitro and in a mouse T cell leukemic model by the same mechanism. Our data provide a new pathway regulating T cell survival and a novel mode to treat autoimmune diseases and cancers.

Supplemented Low-Protein Diet May Delay the Need for Preemptive Kidney Transplantation: A Nationwide Population-Based Cohort Study.

BACKGROUND: Although several studies suggest the benefit of a low-protein diet supplemented with amino acids and keto acids (sLPD) in delaying the initiation of hemodialysis, evidence on whether these nutritional approaches could delay the timing of preemptive transplantation is lacking. METHODS: Retrospective nationwide cohort study, from Taiwan's National Health Insurance Research Database. Patients having undergone a first preemptive kidney transplantation between 2001 and 2017 were identified and divided into two groups according to the presence of sLPD treatment or not. The primary outcome was the time between the diagnosis of advanced CKD and transplantation. Secondary outcomes were post-transplantation adverse events. RESULTS: A total of 245 patients who received their first preemptive kidney transplantation were identified from the nationwide database; 63 of them had been on an sLPD prior to transplantation (sLPD group). The duration between the day of advanced CKD diagnosis and the day of transplantation was significantly longer in the sLPD group compared with the non-sLPD group (median duration: 345 vs. 220 days, p = 0.001). The risk of post-transplantation adverse events did not differ between the two groups. CONCLUSIONS: Within the limits of its observational, retrospective design, this is the first study to suggest that nutritional management with sLPDs can safely delay the timing of preemptive kidney transplantation.

Anti-inflammatory and antioxidant activity of essential amino acid α-ketoacid analogues against renal ischemia-reperfusion damage in Wistar rats. / Actividad antiinflamatoria y antioxidante de los α-cetoanálogos de aminoácidos esenciales en un modelo de daño por isquemia-reperfusión en ratas Wistar

INTRODUCTION: Essential amino acid α-keto acid analogs are used in the treatment of chronic kidney disease to delay the symptoms of uremia. However, it is unknown whether essential amino acid α-keto acid analogs affect the oxidative stress and the inflammation in acute renal injury such as those produced by ischemia-reperfusion. OBJECTIVE: To evaluate the effect of essential amino acid α-keto acid analogs on renal ischemia-reperfusion injury in Wistar rats. MATERIALS AND METHODS: Rats were divided into 11 groups (n=6/group): Two groups received physiological saline with or without ischemia-reperfusion injury (45 min/24 h), six groups received essential amino acid α-keto acid analogs (400, 800, or 1,200 mg/kg/24 h/7d) with or without ischemia-reperfusion injury (essential amino acid α-keto acid analogs + ischemia-reperfusion), and two groups received allopurinol (50 mg/kg/24 h/7d) with or without ischemia-reperfusion injury. Biochemical markers included creatinine and blood urea nitrogen (BUN), proinflammatory cytokines (IL-1ß, IL-6, and TNF-α), renal damage markers (cystatin C, KIM-1, and NGAL), and markers of oxidative stress such as malondialdehyde (MDA) and total antioxidant activity. RESULTS: The essential amino acid α-keto acid analog- and allopurinol-treated groups had lower levels of creatinine, BUN, renal damage markers, proinflammatory cytokines, and MDA than their corresponding ischemia-reperfusion groups. These changes were related to the essential amino acid α-keto acid analogs dosage. Total antioxidant activity was lower in essential amino acid α-keto acid analog- and allopurinol-treated groups than in the corresponding ischemia-reperfusion groups. CONCLUSIONS: This is a new report on the nephroprotective effects of essential amino acid α-keto acid analogs against ischemia-reperfusion injury. Essential amino acid α-keto acid analogs decreased the levels of biochemical markers, kidney injury markers, proinflammatory cytokines, and MDA while minimizing total antioxidant consumption.

Introducción. Los α-cetoanálogos de aminoácidos esenciales se utilizan en el tratamiento de la enfermedad renal crónica para retrasar los síntomas de la uremia. Sin embargo, se desconoce si los α-cetoanálogos de aminoácidos esenciales afectan el estrés oxidativo y la inflamación en la lesión renal aguda tal como en la producida por la isquemia-reperfusión. Objetivo. Evaluar el efecto de las α-cetoanálogos de aminoácidos esenciales sobre la lesión renal por isquemia-reperfusión en ratas Wistar. Materiales y métodos. Se emplearon 11 grupos de ratas (n=6): dos grupos recibieron solución salina fisiológica con lesión isquemia-reperfusión o sin ella (45 min/24 h), seis grupos recibieron α-cetoanálogos de aminoácidos esenciales (400, 800 o 1.200 mg/kg/24 h/7d) con lesión isquemia-reperfusión o sin ella (α-cetoanálogos de aminoácidos esenciales + isquemia-reperfusión), y dos grupos recibieron (50 mg/kg/24 h/7d) con lesión isquemia-reperfusión o sin ella. Los marcadores bioquímicos incluyeron creatinina y nitrógeno ureico en sangre (BUN), citocinas proinflamatorias (IL-1ß, IL-6 y TNF-α), marcadores de daño renal (cistatina C, KIM-1 y NGAL) y marcadores del estrés oxidativo como el malondialdehído (MDA) y la actividad antioxidante total. Resultados. Los grupos tratados con α-cetoanálogos de aminoácidos esenciales y alopurinol tuvieron niveles inferiores de creatinina, BUN, marcadores de daño renal, citocinas proinflamatorias, actividad antioxidante total y MDA que los grupos isquemia-reperfusión correspondientes. Estos cambios se asociaron con la dosis. La actividad antioxidante total fue menor en los grupos tratados con α-cetoanálogos de aminoácidos esenciales que en los grupos isquemia-reperfusión correspondientes. Conclusiones. Este es un nuevo informe de los efectos nefroprotectores de las α-cetoanálogos de aminoácidos esenciales contra la lesión isquemia-reperfusión. Los α-cetoanálogos de aminoácidos esenciales disminuyeron los niveles de los marcadores bioquímicos, de los de lesión renal, de las citocinas proinflamatorias y el MDA, a la vez que minimizaron el consumo total de antioxidantes.

Effects of keto acid supplements on Chinese patients receiving maintenance hemodialysis: a prospective, randomized, controlled, single-center clinical study.

BACKGROUND: The effects of keto acid (KA) supplements on Chinese patients receiving maintenance hemodialysis (MHD) are unclear. This study aimed to evaluate the effects of KA supplementation on nutritional status, inflammatory markers, and bioelectric impedance analysis (BIA) parameters in a cohort of Chinese patients with MHD without malnutrition. METHODS: This was a prospective, randomized, controlled, single-center clinical study conducted in 2011 till 2014. Twenty-nine patients with MHD were randomly assigned to a control (n = 14) or a KA (n = 15) group. The control group maintained a dietary protein intake of 0.9 g/kg/day. The KA group received additional KA supplement (0.1 g/kg/day). BIA was used to determine the lean tissue mass, adipose tissue mass, and body cell mass. The patients' nutritional status, dialysis adequacy, and biochemical parameters were assessed at the ends of the third and sixth months with t test or Wilcoxon rank-sum test. RESULTS: The daily total energy intake for both groups was about 28 kcal/kg/day. After 6 months, the Kt/V (where K is the dialyzer clearance of urea, t is the dialysis time, and V is the volume of the distribution of urea) was 1.33 ±â€Š0.25 in KA group, and 1.34 ±â€Š0.25 in the control group. The median triceps skin-fold thickness in KA group was 12.00 and 9.00 mm in the control group. In addition, the median hand-grip strength in KA group was 21.10 and 25.65 kg in the control group. There were no significant differences between the groups with respect to the anthropometry parameters, dialysis adequacy, serum calcium and phosphorus levels, inflammatory markers, and amino-acid profiles, or in relation to the parameters determined by BIA. Both groups achieved dialysis adequacy and maintained nutritional status during the study. CONCLUSIONS: In this cohort of Chinese patients with MHD, the patients in the control group whose dietary protein intake was 0.9 g/kg/day and total energy intake was 28 kcal/kg/day, maintained well nutritional status during study period. The KA supplement (0.1 g/kg/day) did not improve the essential amino acid/non-essential amino acid ratio, nor did it change the patients' mineral metabolism, inflammatory parameters, or body compositions.

Ketoacid Analogues Supplementation in Chronic Kidney Disease and Future Perspectives.

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. In order to reduce the risk of nutritional disorders in very-low protein diets (VLDP), supplementation by nitrogen-free ketoacid analogues (KAs) have been proposed. 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). We reviewed the SCOPUS, WEB of SCIENCES, CENTRAL, and PUBMED databases from their inception to 1 January, 2019. Following duplicate removal and application of exclusion criteria, 23 RCTs and 12 experimental studies were included. LPD/VLPD + KAs appear nutritionally safe even if how muscle protein metabolism adapts to an LPD/VLPD + KAs is still largely unknown. VLPD + KAs seem to reduce uremic toxins production but the impact on intestinal microbiota remains unexplored. 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. 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. 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. A reflection about the dose and composition of the KAs supplement, the cost-effective features, and their indication to reduce the frequency of dialysis needs to be completed.

Compound α-keto acid tablet supplementation alleviates chronic kidney disease progression via inhibition of the NF-kB and MAPK pathways.

BACKGROUND: Keto-analogues administration plays an important role in clinical chronic kidney disease (CKD) adjunctive therapy, however previous studies on their reno-protective effect mainly focused on kidney pathological changes induced by nephrectomy. This study was designed to explore the currently understudied alternative mechanisms by which compound α-ketoacid tablets (KA) influenced ischemia-reperfusion (IR) induced murine renal injury, and to probe the current status of KA administration on staving CKD progression in Chinese CKD patients at different stages. METHODS: In animal experiment, IR surgery was performed to mimic progressive chronic kidney injury, while KA was administrated orally. For clinical research, a retrospective cohort study was conducted to delineate the usage and effects of KA on attenuating CKD exacerbation. End-point CKD event was defined as 50% reduction of initial estimated glomerular filtration rate (eGFR). Kaplan-Meier analysis and COX proportional hazard regression model were adopted to calculate the cumulative probability to reach the end-point and hazard ratio of renal function deterioration. RESULTS: 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. In clinical research, after adjusting basic demographic factors, patients at stages 4 and 5 in KA group presented a much delayed and slower incidence of eGFR decrease compared to those in No-KA group (hazard ratio (HR) = 0.115, 95% confidence interval (CI) 0.021-0.639, p = 0.0134), demonstrating a positive effect of KA on staving CKD progression. CONCLUSION: KA improved IR induced chronic renal injury and fibrosis, and seemed to be a prospective protective factor in end stage renal disease.

Cationized liposomal keto-mycolic acids isolated from Mycobacterium bovis bacillus Calmette-Guérin induce antitumor immunity in a syngeneic murine bladder cancer model.

Intravesical therapy using Mycobacterium bovis bacillus Calmette-Guérin (BCG) is the most established cancer immunotherapy for bladder cancer. However, its underlying mechanisms are unknown. Mycolic acid (MA), the most abundant lipid of the BCG cell wall, is suspected to be one of the essential active components of this immunogenicity. Here, we developed cationic liposomes incorporating three subclasses (α, keto, and methoxy) of MA purified separately from BCG, using the dendron-bearing lipid D22. The cationic liposomes using D22 were efficiently taken up by the murine bladder cancer cell line MB49 in vitro, but the non-cationic liposomes were not. Lip-kMA, a cationic liposome containing keto-MA, presented strong antitumor activity in two murine syngeneic graft models using the murine bladder cancer cell lines MB49 and MBT-2 in comparison to both Lip-aMA and Lip-mMA, which contained α-MA and methoxy-MA, respectively. Interestingly, Lip-kMA(D12), which was made of D12 instead of D22, did not exhibit antitumor activity in the murine syngeneic graft model using MB49 cells, although it was successfully taken up by MB49 cells in vitro. Histologically, compared to the number of infiltrating CD4 lymphocytes, the number of CD8 lymphocytes was higher in the tumors treated with Lip-kMA. Antitumor effects of Lip-kMA were not observed in nude mice, whereas weak but significant effects were observed in beige mice with natural killer activity deficiency. Thus, a cationized liposome containing keto-MA derived from BCG induced in vivo antitumor immunity. These findings will provide new insights into lipid immunogenicity and the underlying mechanisms of BCG immunotherapy.

Keto analogues and amino acid supplementation and its effects on ammonaemia during extenuating endurance exercise in ketogenic diet-fed rats.

Keto analogues and amino acids (KAAA) supplementation can reduce blood ammonia concentrations in athletes undergoing high-intensity exercise under both ketogenic and thermoneutral conditions. This study evaluated the acute effects of KAAA supplementation on ammonia metabolism during extenuating endurance exercise in rats fed a ketogenic diet. In all, eighty male Fischer rats at 90 d of age were divided into eight groups, and some were trained using a swimming endurance protocol. A ketogenic diet supplemented with keto analogues was administered for 10 d. Administration of the ketogenic diet ended 3 d before the exhaustion test (extenuating endurance exercise). A ketogenic diet plus KAAA supplementation and extenuating endurance exercise (trained ketogenic diet supplemented with KAAA (TKKa)) increased blood ammonia concentrations by approximately 50 % compared with the control diet (trained control diet supplemented with KAAA (TCKa)) and similar training (effect size=1·33; statistical power=0·50). The KAAA supplementation reduced blood urea concentrations by 4 and 18 % in the control and ketogenic diet groups, respectively, compared with the groups fed the same diets without supplementation. The trained groups had 60 % lower blood urate concentrations after TCKa treatment than after TKKa treatment. Our results suggest that KAAA supplementation can reduce blood ammonia concentrations after extenuating endurance exercise in rats fed a balanced diet but not in rats fed a ketogenic diet.

Dietary supplementation with ketoacids protects against CKD-induced oxidative damage and mitochondrial dysfunction in skeletal muscle of 5/6 nephrectomised rats.

BACKGROUND: A low-protein diet supplemented with ketoacids (LPD + KA) maintains the nutritional status of patients with chronic kidney disease (CKD). Oxidative damage and mitochondrial dysfunction associated with the upregulation of p66SHC and FoxO3a have been shown to contribute to muscle atrophy. This study aimed to determine whether LPD + KA improves muscle atrophy and attenuates the oxidative stress and mitochondrial damage observed in CKD rats. METHODS: 5/6 nephrectomy rats were randomly divided into three groups and fed with either 22% protein (normal-protein diet; NPD), 6% protein (low-protein diets; LPD) or 5% protein plus 1% ketoacids (LPD + KA) for 24 weeks. Sham-operated rats with NPD intake were used as the control. RESULTS: KA supplementation improved muscle atrophy and function in CKD + LPD rats. It also reduced the upregulation of genes related to the ubiquitin-proteasome system and 26S proteasome activity, as well as protein and mitochondrial oxidative damage in the muscles of CKD + LPD rats. Moreover, KA supplementation prevented the drastic decrease in activities of mitochondrial electron transport chain complexes, mitochondrial respiration, and content in the muscles of CKD + LPD rats. Furthermore, KA supplementation reversed the elevation in p66Shc and FoxO3a expression in the muscles of CKD + LPD rats. CONCLUSIONS: Our results showed that KA supplementation to be beneficial to muscle atrophy in CKD + LPD, which might be associated with improvement of oxidative damage and mitochondrial dysfunction through suppression of p66Shc and FoxO3a.

Effect of restricted protein diet supplemented with keto analogues in end-stage renal disease: a systematic review and meta-analysis.

AIM: To evaluate the efficacy and safety of the restricted protein diet supplemented with keto analogues when applied in end-stage renal disease (ESRD). METHODS: The Cochrane Library, PubMed, Embase, CBM and CENTRAL databases were searched and reviewed up to January 2017. Clinical trials were analyzed using RevMan 5.3 software. RESULTS: Five randomized controlled trials were selected and included in this study according to our inclusion and exclusion criteria. Changes in serum albumin, PTH, triglyceride, cholesterol, calcium, phosphorus, hemoglobin, Kt/v and CRP before and after treatment were analyzed. Meta-analysis results indicated that, compared with normal protein diet, low-protein diet (LPD) supplemented with keto analogues (sLPD) could improve serum albumin (P < 0.00001), hyperparathyroidism (P < 0.00001) and hyperphosphatemia (P = 0.008). No differences in triglyceride, cholesterol, hemoglobin, Kt/v and CRP were observed between different protein intake groups. CONCLUSION: Restricted protein diet supplemented with keto analogues (sLPD) may improve nutritional status and prevent hyperparathyroidism in ESRD patients. The current data were mainly obtained from short-term, single-center trails with small sample sizes and limited nutritional status indexes, indicating a need for further study.

Keto-analogues and essential aminoacids and other supplements in the conservative management of chronic kidney disease.

The manipulation of dietary protein intake is the mainstay of nutritional treatment of patients affected by chronic renal insufficiency, with the aim to reduce the burden of uremic toxins in order to decrease uremic toxicity and delay the need for dialysis. Consensus exists regarding the benefit of progressive protein restriction towards delaying the progression of renal failure and the need for dialysis, provided adequate energy supply. Although pivotal, protein restriction is only one aspect of the dietary management of chronic kidney disease (CKD) patients. Additional features, though strictly related to proteins, include modifications in sodium, phosphorus and energy intake, as well as in the source (animal or plant derived) of protein and lipids. In addition, supplements play an important role as a means to obtain both beneficial effects and nutritional safety in the renal patient. Essential amino acid and ketoacid mixtures are the most utilized types of supplementation in CKD patients on restricted protein regimens. The essential amino acids plus ketoacid supplementation is mandatory in conjunction with a very low-protein diet in order to assure an adequate essential amino acid supply. It is needed to safely implement a very low protein (and phosphorus) intake, so as to obtain the beneficial effect of a severe protein restriction while preventing malnutrition. Protein-free products and energy supplements are also crucial for the prevention of protein-energy wasting in CKD patients. Calcium, iron, native vitamin D and omega-3 PUFAs are other types of supplementation of potential benefits in the CKD patients on conservative management.

Low-protein diet supplemented with ketoacids ameliorates proteinuria in 3/4 nephrectomised rats by directly inhibiting the intrarenal renin-angiotensin system.

Low-protein diet plus ketoacids (LPD+KA) has been reported to decrease proteinuria in patients with chronic kidney diseases (CKD). However, the mechanisms have not been clarified. As over-activation of intrarenal renin-angiotensin system (RAS) has been shown to play a key role in the progression of CKD, the current study was performed to investigate the direct effects of LPD+KA on intrarenal RAS, independently of renal haemodynamics. In this study, 3/4 subtotal renal ablated rats were fed 18 % normal-protein diet (Nx-NPD), 6 % low-protein diet (Nx-LPD) or 5 % low-protein diet plus 1 % ketoacids (Nx-LPD+KA) for 12 weeks. Sham-operated rats fed NPD served as controls. The level of proteinuria and expression of renin, angiotensin II (AngII) and its type 1 receptors (AT1R) in the renal cortex were markedly higher in Nx-NPD group than in the sham group. LPD+KA significantly decreased the proteinuria and inhibited intrarenal RAS activation. To exclude renal haemodynamic impact on intrarenal RAS, the serum samples derived from the different groups were added to the culture medium of mesangial cells. It showed that the serum from Nx-NPD directly induced higher expression of AngII, AT1R, fibronectin and transforming growth factor-ß1 in the mesangial cells than in the control group. Nx-LPD+KA serum significantly inhibited these abnormalities. Then, proteomics and biochemical detection suggested that the mechanisms underlying these beneficial effects of LPD+KA might be amelioration of the nutritional metabolic disorders and oxidative stress. In conclusion, LPD+KA could directly inhibit the intrarenal RAS activation, independently of renal haemodynamics, thus attenuating the proteinuria in CKD rats.

Efficacy of the Essential Amino Acids and Keto-Analogues on the CKD progression rate in real practice in Russia - city nephrology registry data for outpatient clinic.

BACKGROUND: Renal replacement therapy (RRT) is growing by 10 % per year in Russia, but pre-dialysis care which can retard CKD progression and delay the start of RRT remains limited. We evaluate the effect of Essential Amino Acids and Keto-analogues (EAA/KA) on CKD progression. METHODS: The effect of low protein diet (LPD), supplemented by EAA/KA, on GFR slope changes between first and second treatment period (five sequential visits per period) in 96 patients withs CKD Stage 3B-5 was compared to GFR slope changes in the control group of 96 patients, randomly selected from matched (by gender, age, diagnosis and CKD Stage) cohort of 320 patients from the city Registry. The mean baseline eGFR was 23 ± 9 ml/min/1.73 m2; 29 % had CKD3B, 45 % - CKD4, 26 % - CKD5. RESULTS: The rate of eGFR decline changed from -2.71 ± 2.38 to -2.01 ± 2.26 ml/min/1.73 m2 per year in the treatment group and from -2.18 ± 2.01 to -2.04 ± 2.18 ml/min/1.73 m2 per year in the control group. Only in the treatment group the difference was significant (p = 0.04 and p = 0.6). Standardized effect size for intervention was significant in treatment group: -0.3 (of pooled SD), 95 % CI -0.58 ÷ -0.02 and non-significant in control group: -0.07 (-0.35 ÷ +0.22). The univariate and multivariate analysis of EAA/KA therapy effect demonstrated that it was probably more effective in patients of older age, with higher time-averaged proteinuria (PU), lower phosphate level, in patients with glomerular v. interstitial diseases, and in females. Only the latter factor was significant at pre-specified level (<0.05). CONCLUSIONS: LPD combined with EAA/KA supplementation lead to the decrease of the CKD progression both in well-designed clinical study and in real nephrology practice in wide variety diseases and settings. Registry data can be helpful to reveal patients with optimal chances for beneficial effect of LPD supplemented by EAA/KA. TRIAL REGISTRATION: ISRCTN28190556 06/05/2016.

Adherence to ketoacids/essential amino acids-supplemented low protein diets and new indications for patients with chronic kidney disease.

BACKGROUND: Low protein diets (LPD) have long been prescribed to chronic kidney disease patients with the goals of improving metabolic abnormalities and postpone the start of maintenance dialysis. METHODS: We reviewed the recent literature addressing low protein diets supplemented with ketoacids/essential aminoacids prescribed during chronic kidney disease and their effects on metabolic, nutritional and renal parameters since 2013. RESULTS: We show new information on how to improve adherence to these diets, on metabolic improvement and delay of the dialysis needs, and preliminary data in chronic kidney disease associated pregnancy. In addition, data on incremental dialysis have been reviewed, as well as potential strategies to reverse protein energy wasting in patients undergoing maintenance dialysis. CONCLUSION: These recent data help to better identify the use of low protein diets supplemented with ketoacids/essential aminoacids during chronic kidney disease.

Keto-supplemented Low Protein Diet: A Valid Therapeutic Approach for Patients with Steroid-resistant Proteinuria during Early-stage Chronic Kidney Disease.

BACKGROUND AND OBJECTIVES: Low protein diets supplemented with keto acid (sLPD) are recommended for patients with stage 3-5 chronic kidney disease (CKD). This study assessed whether sLPD is beneficial for patients with steroid-resistant proteinuria during early-stage CKD. DESIGN, SETTING, PARTICIPANTS, AND MEASUREMENTS: A 1-year randomized controlled trial was conducted from 2010 to 2012. In this study, 108 proteinuric patients who were steroid-resistant were assigned to a sLPD group (0.6 g/kg/d with 0.09 g/kg/d keto acids) or a normal protein diet group (NPD, 1.0 g/kg/d). Estimated dietary protein intake, urinary protein excretion, remission rate, renal function, nutritional status, and blood pressure were measured. RESULTS: Baseline characteristics were comparable between the sLPD group (47 patients) and the NPD group (49 patients). Urinary protein excretion significantly decreased in sLPD compared to NPD in months 6, 9, and 12 (P<0.05). Proteinuria reduction was higher in sLPD than in NPD (P<0.001) at the end of the study. Complete remission and partial remission rates were higher in sLPD than in NPD. Serum albumin and pre-albumin levels were higher in sLPD than in NPD in months 9 and 12 (P<0.05). Serum total cholesterol and triglyceride levels declined more significantly in sLPD than in NPD (P<0.01) at the end of the study. There were no differences in nutritional status, renal function, hemoglobin, or blood pressure between the two groups. CONCLUSIONS: sLPD is both nutritionally safe and beneficial, providing nephroprotective effects for early-stage CKD patients with steroid-resistant proteinuria.

Effect of a low-protein diet supplemented with keto-acids on autophagy and inflammation in 5/6 nephrectomized rats.

Ketoacids (KA) are known to preserve muscle mass among patients with chronic kidney disease (CKD) on a low-protein diet (LPD). The present study was to compare the effects of KA supplemented diet therapy in autophagy and inflammation in CKD rats' skeletal muscle. Rats with 5/6 nephrectomy were randomly divided into three groups and fed with either 11 g/kg/day protein [normal-protein diet (NPD)], 3 g/kg/day protein (LPD) or 3 g/kg/day protein which including 5% protein plus 1% KA (LPD + KA) for 24 weeks. Sham-operated rats with NPD intake were used as control. LPD could improve body weight, gastrocnemius muscle mass, as well as gastrocnemius muscle cross-sectional area, with the effect being more obvious in the LPD + KA group. The autophagy marker LC3 (microtubule-associated protein 1 light chain 3), p62, Parkin and PTEN induced putative kinase 1 (PINK1) were significantly attenuate in LPD + KA group than LPD group. LPD + KA group had the lower total mtDNA (mitochondiral DNA) and cytosol mtDNA, NACHT-PYD-containing protein 3 (NALP3) inflammasome than LPD group, but its reactive oxygen species (ROS), caspase-1 and apoptosis-associated speck-like protein containing a CARD (ASC) level was higher. Immunoblotting showed IL-1ß (interleukin-1-beta) was lower in LPD and LPD + KA group than the NPD group, but IL-18 showed no significant difference among control and CKD group; toll-like receptor signalling-dependent IL-6 was higher in LPD + KA group than LPD group, but tumor necrosis factor-α (TNF-α) was not significantly changed between LPD + KA and LPD group. Systematic changes of the four cytokines were different from that of the tissue. Although LPD + KA could further ameliorate-activated autophagy than LPD, its effect on the activated inflammation state in CKD was not distinctly. Further study is still required to explore the method of ameliorating inflammation to provide new therapeutic approaches for CKD protein energy wasting (PEW).

Is there a role for ketoacid supplements in the management of CKD?

Ketoacid (KA) analogues of essential amino acids (EAAs) provide several potential advantages for people with advanced chronic kidney disease (CKD). Because KAs lack the amino group bound to the α carbon of an amino acid, they can be converted to their respective amino acids without providing additional nitrogen. It has been well established that a diet with 0.3 to 0.4 g of protein per kilogram per day that is supplemented with KAs and EAAs reduces the generation of potentially toxic metabolic products, as well as the burden of potassium, phosphorus, and possibly sodium, while still providing calcium. These KA/EAA-supplemented very-low-protein diets (VLPDs) can maintain good nutrition, but the appropriate dose of the KA/EAA supplement has not been established. Thus, a KA/EAA dose-response study for good nutrition clearly is needed. Similarly, the composition of the KA/EAA supplement needs to be reexamined; for example, some KA/EAA preparations contain neither the EAA phenylalanine nor its analogue. Indications concerning when to inaugurate a KA/EAA-supplemented VLPD therapy also are unclear. Evidence strongly suggests that these diets can delay the need for maintenance dialysis therapy, but whether they slow the loss of glomerular filtration rate in patients with CKD is less clear, particularly in this era of more vigorous blood pressure control and use of angiotensin/aldosterone blockade. Some clinicians prescribe KA/EAA supplements for patients with CKD or treated with maintenance dialysis, but with diets that have much higher protein levels than the VLPDs in which these supplements have been studied. More research is needed to examine the effectiveness of KA/EAA supplements with higher protein intakes.

Supplementation of ketoacids contributes to the up-regulation of the Wnt7a/Akt/p70S6K pathway and the down-regulation of apoptotic and ubiquitin-proteasome systems in the muscle of 5/6 nephrectomised rats.

Ketoacids (KA) are known to improve muscle mass among patients with chronic kidney disease (CKD) on a low-protein diet (CKD-LPD), but the mechanism of its preventive effects on muscle atrophy still remains unclear. Since muscle atrophy in CKD may be attributable to the down-regulation of the Wnt7a/Akt/p70S6K pathway and the activation of the ubiquitin-proteasome system (UPS) and the apoptotic signalling pathway, a hypothesis can readily be drawn that KA supplementation improves muscle mass by up-regulating the Wnt7a/Akt/p70S6K pathway and counteracting the activation of the UPS and caspase-3-dependent apoptosis in the muscle of CKD-LPD rats. Rats with 5/6 nephrectomy were randomly divided into three groups, and fed with either 22 % protein (normal-protein diet; NPD), 6 % protein (LPD) or 5 % protein plus 1 % KA for 24 weeks. Sham-operated rats with NPD intake were used as the control. The results demonstrated that KA supplementation improved protein synthesis and increased related mediators such as Wnt7a, phosphorylated Akt and p70S6K in the muscle of CKD-LPD rats. It also inhibited protein degradation, withheld the increase in ubiquitin and its ligases MAFbx (muscle atrophy F-box) and MuRF1 (muscle ring finger-1) as well as attenuated proteasome activity in the muscle of CKD-LPD rats. Moreover, KA supplementation gave rise to a reduction in DNA fragment, cleaved caspase-3 and 14 kDa actin fragment via the down-regulation of the Bax:Bcl-2 ratio in the muscle of CKD-LPD rats. The beneficial effects unveiled herein further consolidate that KA may be a better therapeutic strategy for muscle atrophy in CKD-LPD.

Keto acid-supplemented low-protein diet for treatment of adult patients with hepatitis B virus infection and chronic glomerulonephritis.

OBJECTIVES: An open-label, randomized, controlled, single-centre clinical trial to evaluate the effects of low-protein intake, with or without keto acid supplementation, on nutritional status and proteinuria, in patients with hepatitis B virus (HBV) and early stage chronic glomerulonephritis. METHODS: Patients with chronic glomerulonephritis and HBV infection were randomized to receive a low-protein diet (0.6-0.8 g/kg ideal body weight [IBW] per day) either without (LP group) or with (sLP group) keto acid supplementation (0.1 g/kg IBW per day), for 12 months. Nutritional, clinical and safety parameters were recorded. RESULTS: The study included 17 patients (LP group n = 9; sLP group n = 8). Proteinuria and microalbuminuria were significantly lower in the sLP group at 6 and 12 months compared with baseline, and at 12 months compared with the LP group. There were no significant differences in serum creatinine level or estimated glomerular filtration rate. Nutritional parameters (serum albumin and prealbumin) were significantly improved at 12 months, compared with baseline, in the sLP group. CONCLUSIONS: Restriction of dietary protein intake to 0.6-0.8 g/kg IBW per day appears to have an acceptable safety profile. Supplementation with keto acids is associated with decreased urine protein excretion.

Protein-restricted diets plus keto/amino acids--a valid therapeutic approach for chronic kidney disease patients.

Chronic kidney disease (CKD) is increasingly common, and there is an increasing awareness that every strategy should be used to avoid complications of CKD. Restriction of dietary protein intake has been a relevant part of the management of CKD for more than 100 years, but even today, the principal goal of protein-restricted regimens is to decrease the accumulation of nitrogen waste products, hydrogen ions, phosphates, and inorganic ions while maintaining an adequate nutritional status to avoid secondary problems such as metabolic acidosis, bone disease, and insulin resistance, as well as proteinuria and deterioration of renal function. This supplement focuses on recent experimental and clinical findings related to an optimized dietary management of predialysis, dialysis, and transplanted patients as an important aspect of patient care. Nutritional treatment strategies are linked toward ameliorating metabolic and endocrine disturbances, improving/maintaining nutritional status, as well as delaying the renal replacement initiation and improving outcomes in CKD patients. A final consensus states that dietary manipulations should be considered as one of the main approaches in the management program of CKD patients and that a reasonable number of patients with moderate or severe CKD benefit from dietary protein/phosphorus restriction.