Personalized Low-Protein Diet Prescription in CKD Population: Merging Evidence From Randomized Trials With Observational Data.

Nutritional therapy is a cornerstone of the clinical management of chronic kidney disease (CKD). Nevertheless, randomized controlled trials often have failed to show a relevant benefit of low-protein diets in nonselected CKD populations in terms of slowing the progression of kidney disease and need for dialysis. The more the target population is selected, the less the results can be generalizable to implement in clinical practice. On the contrary, observational studies, especially if performed with patient-centered, flexible approaches, point toward an extensive implementation of dietary protein restriction in different and unselected CKD populations. The observational evidence cannot be disregarded anymore. The most recent guidelines advise implementing low-protein diets or even very-low-protein diets in all CKD patients as early as stage 3. However, the lack of data from large randomized controlled trials on unselected CKD populations as well as on specific subpopulations, such as diabetic or obese patients, which nowadays comprise the majority of CKD subjects, reduces the generalizability of the recommendations. For some patient populations, such as those encompassing very old, nephrotic, or pregnant patients, the literature is even more limited because of the lower prevalence of these conditions and diffused prejudices against reducing protein intake. This pragmatic review discusses the need for integrating information derived from randomized trials with evidence derived from observational studies to guide feasible strategies for more successful implementation of low-protein diets in the treatment of all segments of the CKD population.

In Vivo Metabolic Responses to Different Formulations of Amino Acid Mixtures for the Treatment of Phenylketonuria (PKU).

Phenylketonuria (PKU) is a rare autosomal recessive inborn error of metabolism where the mainstay of treatment is a Phe restricted diet consisting of a combination of limited amounts of natural protein with supplementation of Phe-free or low-Phe protein substitutes and special low protein foods. Suboptimal outcomes may be related to the different absorption kinetics of free AAs, which have lower biological efficacy than natural proteins. Physiomimic TechnologyTM is a technology engineered to prolong AA (AA-PT) release allowing physiological absorption and masking the odor and taste of free AAs. The aim of these studies was to assess the impact of AA-PT formulation on selected functional and metabolic parameters both in acute and long-term experimental studies. Adult rats in fasting conditions were randomized in different groups and treated by oral gavage. Acute AA-PT administration resulted in significantly lower BUN at 90 min versus baseline. Both BUN and glycemia were modulated in the same direction as intact casein protein. Long-term treatment with AA-PT significantly reduces the protein expression of the muscle degradation marker Bnip3L (-46%) while significantly increasing the proliferation of market myostatin (+58%). Animals dosed for 15 days with AA-PT had significantly stronger grip strength (+30%) versus baseline. In conclusion, the results suggest that the AA-PT formulation may have beneficial effects on both AA oxidation and catabolism with a direct impact on muscle as well as on other metabolic pathways.

Spontaneously Low Protein Intake in Elderly CKD Patients: Myth or Reality? Analysis of Baseline Protein Intake in a Large Cohort of Patients with Advanced CKD.

The recent guidelines on nutritional management of chronic kidney disease (CKD) advise a reduction in protein intake as early as CKD stage 3, regardless of age, to slow kidney function impairment. However, since elderly patients are usually considered as having a spontaneously reduced protein intake, nutritional interventions to reduce protein intake are often considered futile. This study aimed to assess the baseline protein intake of elderly CKD patients referred for nephrology care, and explore the need for dietary evaluations, focusing on the current recommendations for protein restriction in CKD. This is an observational study of CKD patients followed in the unit dedicated to advanced CKD patients in Le Mans, France. Patients with stages 3 to 5 not on dialysis were included. All patients were evaluated by an expert dietician to assess their baseline protein intake, whenever possible on the basis of a 7-days diet journal; when this was not available, dietary recall or analysis of delivered meals was employed. Demographic characteristics, underlying kidney disease, Charlson Comorbidity Index (CCI), Malnutrition-Inflammation Score (MIS), Subjective Global Assessment (SGA) and clinical and laboratory data were recorded. Between 15 November 2017 and 31 December 2020, 436 patients were evaluated in the unit. Their age distribution was as follows: "young": <60 (n = 62), "young-old": 60-69 (n = 74), "old": 70-79 (n = 108), "old-old": 80-89 (n = 140) and "oldest-old": ≥90 (n = 54). The prevalence of vascular nephropathies was higher in patients older than 70 years compared to younger ones, as did CCI and MIS (p < 0.001). Moderate nutritional impairment (SGA: B) was higher in elderly patients, reaching 53.7% at ≥90, while less than 3% of patients in the overall cohort were classified as SGA C (p < 0.001). The median protein intake was higher than the recommended one of 0.8 g/kg/day in all age groups; it was 1.2 g/kg/day in younger patients and 1.0 thereafter (p < 0.001). Patient survival depended significantly on age (p < 0.001) but not on baseline protein intake (p = 0.63), and younger patients were more likely to start dialysis during follow-up (p < 0.001). Over half of the patients, including the old-old and oldest-old, were still on follow-up two years after referral and it was found that survival was only significantly associated with age and comorbidity and was not affected by baseline protein intake. Our study shows that most elderly patients, including old-old and extremely old CKD patients, are spontaneously on diets whose protein content is higher than recommended, and indicates there is a need for nutritional care for this population.

Provision and Supervision of Food and Protein Substitute in School for Children with PKU: Parent Experiences.

Children spend a substantial part of their childhood in school, so provision of dietary care and inclusion of children with phenylketonuria (PKU) in this setting is essential. There are no reports describing the dietary support children with PKU receive whilst at school. The aim of this cross-sectional study was to explore the experiences of the dietary management of children with PKU in schools across the UK. Data was collected using an online survey completed by parents/caregivers of children with PKU. Of 159 questionnaire responses, 92% (n = 146) of children attended state school, 6% (n = 10) private school and 2% (n = 3) other. Fourteen per cent (n = 21/154) were at nursery/preschool, 51% (n = 79/154) primary and 35% (n = 54/154) secondary school. Sixty-one per cent (n = 97/159) said their child did not have school meals, with some catering services refusing to provide suitable food and some parents distrusting the school meals service. Sixty-one per cent of children had an individual health care plan (IHCP) (n = 95/155). Children were commonly unsupervised at lunchtime (40%, n = 63/159), with snacks (46%, n = 71/155) and protein substitute (30%, n = 47/157), with significantly less supervision in secondary than primary school (p < 0.001). An IHCP was significantly associated with improved supervision of food and protein substitute administration (p < 0.01), and better communication between parents/caregivers and the school team (p < 0.05). Children commonly accessed non-permitted foods in school. Therefore, parents/caregivers described important issues concerning the school provision of low phenylalanine food and protein substitute. Every child should have an IHCP which details their dietary needs and how these will be met safely and discreetly. It is imperative that children with PKU are supported in school.

Insulin/IGF-1 Signaling Is Downregulated in Barrett's Esophagus Patients Undergoing a Moderate Calorie and Protein Restriction Program: A Randomized 2-Year Trial.

Obesity and associated insulin resistance (Ins-R) have been identified as important risk factors for esophageal adenocarcinoma development. Elevated calories and protein consumption are also associated with Ins-R and glucose intolerance. We investigated the effect of a 24-month moderate calorie and protein restriction program on overweight or obese patients affected by Barrett's esophagus (BE), as no similar dietary approach has been attempted to date in this disease context. Anthropometric parameters, levels of serum analytes related to obesity and Ins-R, and the esophageal insulin/IGF-1 signaling pathway were analyzed. This study is registered with ClinicalTrials.gov, number NCT03813381. Insulin, C-peptide, IGF-1, IGF-binding protein 3 (IGFBP3), adipokines, and esophageal expression of the main proteins involved in insulin/IGF-1 signal transduction were quantified using Luminex-XMAP® technology in 46 patients who followed the restriction program (IA) and in 54 controls (CA). Body mass index and waist circumference significantly decreased in 76.1% of IA and 35.2% of CA. IGF-1 levels were reduced in 71.7% of IA and 51.8% of CA. The simultaneous reduction of glycaemia, IGF-1, the IGF-1/IGFBP3 ratio, and the improvement in weight loss-dependent insulin sensitivity, were associated with the downregulation of the insulin/IGF-1 signal on BE tissue. The proposed intervention program was an effective approach to counteract obesity-associated cancer risk factors. The improvement in metabolic condition resulted in a downregulation of the ERK-mediated mitogenic signal in 43.5% of patients, probably affecting the molecular mechanism driving adenocarcinoma development in BE lesions.

A low aromatic amino-acid diet improves renal function and prevent kidney fibrosis in mice with chronic kidney disease.

Despite decades of use of low protein diets (LPD) in the management of chronic kidney disease (CKD), their mechanisms of action are unclear. A reduced production of uremic toxins could contribute to the benefits of LPDs. Aromatic amino-acids (AA) are precursors of major uremic toxins such as p-cresyl sulfate (PCS) and indoxyl sulfate (IS). We hypothesize that a low aromatic amino acid diet (LA-AAD, namely a low intake of tyrosine, tryptophan and phenylalanine) while being normoproteic, could be as effective as a LPD, through the decreased production of uremic toxins. Kidney failure was chemically induced in mice with a diet containing 0.25% (w/w) of adenine. Mice received three different diets for six weeks: normoproteic diet (NPD: 14.7% proteins, aromatic AAs 0.019%), LPD (5% proteins, aromatic AAs 0.007%) and LA-AAD (14% proteins, aromatic AAs 0.007%). Both LPD and LA-AAD significantly reduced proteinuria, kidney fibrosis and inflammation. While LPD only slightly decreased plasma free PCS and free IS compared to NPD; free fractions of both compounds were significantly decreased by LA-AAD. These results suggest that a LA-AAD confers similar benefits of a LPD in delaying the progression of CKD through a reduction in some key uremic toxins production (such as PCS and IS), with a lower risk of malnutrition.

Metabolic Control of Patients with Phenylketonuria in a Portuguese Metabolic Centre Comparing Three Different Recommendations.

Blood phenylalanine (Phe) is used as the primary marker to evaluate metabolic control. Our study aimed to describe the metabolic control of patients with phenylketonuria (PKU) comparing three different treatment recommendations (European guidelines/US guidelines/Portuguese consensus). This was a retrospective, observational, single centre study in patients with PKU collecting data on blood Phe levels from 2017. Nutritional intake data and sapropterin (BH4) prescription were collected at the last appointment of 2017. The final sample studied included 87 patients (48% females) [13 hyperphenylalaninemia; 47 mild PKU; 27 classical PKU] with a median age of 18 y (range: 1-36 y). The median number of blood Phe measurements for patients was 21 (range: 6-89). In patients aged < 12 y, the median blood Phe level was 300 µmol/L (range 168-480) and 474 µmol/L (range 156-1194) for patients ≥ 12 y. Overall, a median of 83% of blood Phe levels were within the European PKU guidelines target range. In patients aged ≥ 12 years, there was a higher median % of blood Phe levels within the European PKU guidelines target range (≥12 y: 84% vs. <12 y: 56%). In children < 12 y with classical PKU (n = 2), only 34% of blood Phe levels were within target range for all 3 guidelines and 49% with mild PKU (n = 11). Girls had better control than boys (89% vs. 66% median Phe levels within European Guidelines). Although it is clear that 50% or more patients were unable to achieve acceptable metabolic control on current treatment options, a globally agreed upper Phe target associated with optimal outcomes for age groups is necessary. More studies need to examine how clinics with dissimilar resources, different therapeutic Phe targets and frequency of monitoring relate to metabolic control.

Quality of Life in CKD Patients on Low-Protein Diets in a Multiple-Choice Diet System. Comparison between a French and an Italian Experience.

Prescribing a low-protein diet (LPD) is part of the standard management of patients in advanced stages of chronic kidney disease (CKD). However, studies on the quality of life (QoL) of patients on LPDs are lacking, and the impact these diets have on their QoL is often given as a reason for not prescribing one. We, therefore, decided to assess the QoL in a cohort of CKD stage 3-5 patients followed up by a multiple-choice diet approach in an outpatient nephrology clinic in France. To do so, we used the short version of the World Health Organization's quality of life questionnaire and compared the results with a historical cohort of Italian patients. We enrolled 153 patients, managed with tailored protein restriction in Le Mans, and compared them with 128 patients on similar diets who had been followed in Turin (Italy). We found there were no significant differences in terms of age (median 73 vs. 74 years, respectively), gender, CKD stage, and comorbidities (Charlson's Comorbidity Index 7 vs. 6). French patients displayed a greater body mass index (29.0 vs. 25.4, p < 0.001) and prevalence of obesity (41.2 vs. 15.0%, p < 0.001). Baseline protein intake was over the target in France (1.2 g/kg of real body weight/day). In both cohorts, the burden of comorbidities was associated with poorer physical health perception while kidney function was inversely correlated to satisfaction with social life, independently of the type of diet. Our study suggests that the type of LPD they follow does not influence QoL in CKD patients and that a personalized approach towards protein restriction is feasible, even in elderly patients.

Nutrition in Chronic Kidney Disease-The Role of Proteins and Specific Diets.

Chronic kidney disease (CKD) is a global public health burden, needing comprehensive management for preventing and delaying the progression to advanced CKD. The role of nutritional therapy as a strategy to slow CKD progression and uremia has been recommended for more than a century. Although a consistent body of evidence suggest a benefit of protein restriction therapy, patients' adherence and compliance have to be considered when prescribing nutritional therapy in advanced CKD patients. Therefore, these prescriptions need to be individualized since some patients may prefer to enjoy their food without restriction, despite knowing the potential importance of dietary therapy in reducing uremic manifestations, maintaining protein-energy status.

The Effect of a Combined Gluten- and Casein-Free Diet on Children and Adolescents with Autism Spectrum Disorders: A Systematic Review and Meta-Analysis.

There has been a growing interest in the gastrointestinal system and its significance for autism spectrum disorder (ASD), including the significance of adopting a gluten-free and casein-free (GFCF) diet. The objective was to investigate beneficial and safety of a GFCF diet among children with a diagnosis of ASD. We performed a systematic literature search in Medline, Embase, Cinahl, and the Cochrane Library up to January 2020 for existing systematic reviews and individual randomized controlled trials (RCTs). Studies were included if they investigated a GFCF diet compared to a regular diet in children aged 3 to 17 years diagnosed with ASD, with or without comorbidities. The quality of the identified existing reviews was assessed using A Measurement Tool to Assess Systematic Reviews (AMSTAR). The risk of bias in RCTs was assessed using the Cochrane Risk of Bias Tool, and overall quality of evidence was evaluated using Grades of Recommendation, Assessment, Development, and Evaluation (GRADE). We identified six relevant RCTs, which included 143 participants. The results from a random effect model showed no effect of a GFCF diet on clinician-reported autism core symptoms (standardized mean difference (SMD) -0.31 (95% Cl. -0.89, 0.27)), parent-reported functional level (mean difference (MD) 0.61 (95% Cl -5.92, 7.14)) or behavioral difficulties (MD 0.80 (95% Cl -6.56, 10.16)). On the contrary, a GFCF diet might trigger gastrointestinal adverse effects (relative risk (RR) 2.33 (95% Cl 0.69, 7.90)). The quality of evidence ranged from low to very low due to serious risk of bias, serious risk of inconsistency, and serious risk of imprecision. Clinical implications of the present findings may be careful consideration of introducing a GFCF diet to children with ASD. However, the limitations of the current literature hinder the possibility of drawing any solid conclusion, and more high-quality RCTs are needed. The protocol is registered at the Danish Health Authority website.

Placental adaptations in a nonhuman primate model of gestational protein restriction.

We previously demonstrated decreased placental perfusion, reduced amniotic fluid protein content, and increased pregnancy loss in a nonhuman primate model of gestational protein restriction. Here, our objective was to link these detrimental findings with a functional placental assessment. As blood flow is critical to maternal-fetal exchange, we hypothesized that a protein-restricted diet would impair placental taurine uptake. Pregnant rhesus macaques were maintained on either control chow (CON, n = 5), a 33% protein-restricted diet (PR33, n = 5), or a 50% PR diet (PR50, n = 5) prior to and throughout pregnancy. Animals were delivered on gestational day 135 (G135; term is G168). Taurine activity was determined in fresh placental villous explants. Taurine transporter (TauT) protein expression, placental growth factor (PLGF), and insulin-like growth factor (IGF)-1 and IGF-2 protein concentrations were measured, and histological assessment was performed. Fetal body weights and placental weights were comparable between all three groups at G135. Placental taurine uptake was decreased in PR33- and PR50-fed animals compared to CON, yet TauT expression was unchanged across groups. PLGF was significantly increased in PR50 vs. CON, with no change in IGF-1 or IGF-2 expression in placental homogenate from PR-fed animals. Accelerated villous maturation was observed in all PR50 cases, three of five PR33, and was absent in CON. We demonstrate conserved fetal growth, despite a decrease in placental taurine uptake. Increased expression of PLGF and expansion of the syncytiotrophoblast surface area in the severely protein-restricted animals suggest a compensatory mechanism by the placenta to maintain fetal growth.

The impact of maternal protein restriction during perinatal life on the response to a septic insult in adult rats.

Although abundant evidence exists that adverse events during pregnancy lead to chronic conditions, there is limited information on the impact of acute insults such as sepsis. This study tested the hypothesis that impaired fetal development leads to altered organ responses to a septic insult in both male and female adult offspring. Fetal growth restricted (FGR) rats were generated using a maternal protein-restricted diet. Male and female FGR and control diet rats were housed until 150-160 d of age when they were exposed either a saline (control) or a fecal slurry intraperitoneal (Sepsis) injection. After 6 h, livers and lungs were analyzed for inflammation and, additionally, the amounts and function of pulmonary surfactant were measured. The results showed increases in the steady-state mRNA levels of inflammatory cytokines in the liver in response to the septic insult in both males and females; these responses were not different between FGR and control diet groups. In the lungs, cytokines were not detectable in any of the experimental groups. A significant decrease in the relative amount of surfactant was observed in male FGR offspring, but this was not observed in control males or in female animals. Overall, it is concluded that FGR induced by maternal protein restriction does not impact liver and lung inflammatory response to sepsis in either male or female adult rats. An altered septic response in male FGR offspring with respect to surfactant may imply a contribution to lung dysfunction.

Source and Composition in Amino Acid of Dietary Proteins in the Primary Prevention and Treatment of CKD.

Nutrition is a cornerstone in the management of chronic kidney disease (CKD). To limit urea generation and accumulation, a global reduction in protein intake is routinely proposed. However, recent evidence has accumulated on the benefits of plant-based diets and plant-derived proteins without a clear understanding of underlying mechanisms. Particularly the roles of some amino acids (AAs) appear to be either deleterious or beneficial on the progression of CKD and its complications. This review outlines recent data on the role of a low protein intake, the plant nature of proteins, and some specific AAs actions on kidney function and metabolic disorders. We will focus on renal hemodynamics, intestinal microbiota, and the production of uremic toxins. Overall, these mechanistic effects are still poorly understood but deserve special attention to understand why low-protein diets provide clinical benefits and to find potential new therapeutic targets in CKD.

Effects of High and Low Protein Diets on Inflammatory Profiles in People with Morbid Obesity: A 3-Week Intervention Study.

Nutritional interventions in morbidly obese individuals that effectively reverse a pro-inflammatory state and prevent obesity-associated medical complications are highly warranted. Our aim was to evaluate the effect of high (HP) or low (LP) protein diets on circulating immune-inflammatory biomarkers, including C-reactive protein (CRP), interleukin-6 (IL-6), tumor necrosis factor-alpha (TNF-a), interleukin-10 (IL-10), monocyte chemoattractant protein-1 (MCP-1), chemerin, omentin, leptin, total adiponectin, high molecular weight adiponectin, and fetuin-A. With this aim, 18 people with morbid obesity were matched into two hypocaloric groups: HP (30E% protein, n = 8) and LP (10E% protein, n = 10) for three weeks. Biomarkers were measured pre and post intervention and linear mixed-effects models were used to investigate differences. Consuming HP or LP diets resulted in reduced CRP (HP: -2.2 ± 1.0 mg/L, LP: -2.3 ± 0.9 mg/L) and chemerin (HP: -17.9 ± 8.6 ng/mL, LP: -20.0 ± 7.4 ng/mL), with no statistically significant differences by diet arm. Participants following the LP diet showed a more pronounced decrease in leptin (-19.2 ± 6.0 ng/mL) and IL-6 (-0.4 ± 0.1 pg/mL) and an increase in total adiponectin (1.6 ± 0.6 µg/mL). Changes were also observed for the remaining biomarkers to a smaller degree by the HP than the LP hypocaloric diet, suggesting that a LP hypocaloric diet modulates a wider range of immune inflammatory biomarkers in morbidly obese individuals.

Advanced Chronic Kidney Disease with Low and Very Low GFR: Can a Low-Protein Diet Supplemented with Ketoanalogues Delay Dialysis?

BACKGROUND: Previous studies have demonstrated that dietary therapy can delay the initiation of dialysis, but little research has investigated whether patients with very poor renal function would benefit from a dietary therapy. METHODS: This study was performed by using the Chang Gung Research Database (CGRD), which is based on the largest medical system in Taiwan. Patients with estimated glomerular filtration rates (eGFR) < 15 mL/min/1.73 m2 between 2001 and 2015 with more than 3 months of low-protein diet supplemented with ketoanalogues (sLPD) were extracted (Ketosteril group). We then assigned five patients without any sLPD to match one patient of the Ketosteril group (comparison group). Both groups were followed up for 1 year for the initiation of dialysis and rates of major adverse cardiac and cerebrovascular events (MACCEs). RESULTS: The Ketosteril group (n = 547), compared with the comparison group (n = 2735), exhibited a lower incidence of new-onset dialysis (40.2% vs. 44.4%, subdistribution hazard ratio (SHR): 0.80, 95% confidence interval (CI): 0.70-0.91) and MACCEs (3.7% vs. 5.9%, HR: 0.61, 95% CI: 0.38-0.97). The beneficial effect of an sLPD did not differ in patients with a baseline eGFR < 5 mL/min/1.73 m2. CONCLUSION: Even among patients with extremely low eGFR, sLPD treatment can safely delay the need for dialysis.

Ready to Change: Attitudes of an Elderly CKD Stage 3-5 Population towards Testing Protein-Free Food.

The recent Kidney Disease Outcomes Quality Initiative (K-DOQI) guidelines suggest an early start of protein restriction, raising issues on willingness to change dietary habits. The aim of this exploratory real-life study was to report on a test of dietary products (protein-free, not previously available in France) in a large, mainly elderly, chronic kidney disease (CKD) population (220 patients, median age: 77.5 years, Charlson comorbidity index (CCI): seven, malnutrition inflammation score (MIS): five, estimated glomerular filtration rate (eGFR): 26 mL/min), also as a means to tailor further implementation strategies. Forty-nine patients (22.28%) were considered to be poor candidates for the trial (metabolically unstable or with psychological, psychiatric or logistic barriers); of the remaining 171, 80.70% agreed to participate. Patients to whom the diet was not proposed had lower eGFR and higher comorbidity (eGFR 21 vs. 27 p = 0.021; MIS six vs. four p: <0.001). Patients who refused were 10 years older than those who accepted (83 vs. 73 years p < 0.001), with a higher CCI (eight vs. seven p = 0.008) and MIS (five vs. four p = 0.01). In the logistic regression, only age was significantly associated with refusal to participate (Odds ratio (OR): 5.408; 95% CI: 1.894 to 15.447). No difference was found according to low/intermediate/high frequency of weekly use of protein-free food. Our study suggests that most of the patients are ready to test new diet approaches. Only old age correlated with refusal, but frequency of implementation depended on individual preferences, underlying the importance of tailored approaches to improve adherence.

Protein Labelling Accuracy for UK Patients with PKU Following a Low Protein Diet.

A phenylalanine (protein)-restricted diet is the primary treatment for phenylketonuria (PKU). Patients are dependent on food protein labelling to successfully manage their condition. We evaluated the accuracy of protein labelling on packaged manufactured foods from supermarket websites for foods that may be eaten as part of a phenylalanine-restricted diet. Protein labelling information was evaluated for 462 food items ("free from", n = 159, regular, n = 303), divided into 16 food groups using supermarket website data. Data collection included protein content per portion/100 g when food was "as sold", "cooked" or "prepared"; cooking methods, and preparation instructions. Labelling errors affecting protein content were observed in every food group, with overall protein labelling unclear in 55% (n = 255/462) of foods. There was misleading, omitted, or erroneous (MOE) information in 43% (n = 68/159) of "free from" foods compared with 62% (n = 187/303) of regular foods, with fewer inaccuracies in "free from" food labelling (p = 0.007). Protein analysis was available for uncooked weight only but not cooked weight for 58% (n = 85/146) of foods; 4% (n = 17/462) had misleading protein content. There was a high rate of incomplete, misleading, or inaccurate data affecting the interpretation of the protein content of food items on supermarket websites. This could adversely affect metabolic control of patients with PKU and warrants serious consideration.

Nutrient Intake and Nutritional Status in Adult Patients with Inherited Metabolic Diseases Treated with Low-Protein Diets: A Review on Urea Cycle Disorders and Branched Chain Organic Acidemias.

Low-protein diets (LPDs) are the main treatment for urea cycle disorders (UCDs) and organic acidemias (OAs). In most cases, LPDs start in childhood and must be continued into adulthood. The improved life expectancy of patients with UCDs and OAs raises the question of their consequences on nutritional status in adult subjects. As this topic has so far received little attention, we conducted a review of scientific studies that investigated the nutrient intake and nutritional status in adult patients with UCDs and branched chain organic acidemias (BCOAs) on LPD. METHODS: The literature search was conducted in PubMed/MEDLINE, Scopus, EMBASE and Google Scholar from 1 January 2000 to 31 May 2020, focusing on nutrient intake and nutritional status in UCD and OA adult patients. RESULTS: Despite protein restriction is recommended as the main treatment for UCDs and OAs, in these patients, protein intake ranges widely, with many patients who do not reach safety levels. When evaluated, micronutrient intake resulted below recommended values in some patients. Lean body mass resulted in most cases lower than normal range while fat body mass (FM) was often found normal or higher than the controls or reference values. Protein intake correlated inversely with FM both in adult and pediatric UCD patients. CONCLUSIONS: The clinical management of adult patients with UCDs and BCOAs should include an accurate assessment of the nutritional status and body composition. However, as little data is still available on this topic, further studies are needed to better clarify the effects of LPDs on nutritional status in adult UCD and BCOA patients.

Nutritional Management and Biochemical Outcomes during the Immediate Phase after Liver Transplant for Methylmalonic Acidemia.

Methylmalonic acidemia (MMA) is caused by a deficiency of methyl-malonyl-CoA mutase. It is a multisystemic condition with poor clinical outcomes characterized by frequent metabolic decompensation with acidosis, hyperammonemia and encephalopathy. Restriction of intact protein and supplementation with amino acid-based formula play an important role in its management. Recently, liver transplant (LT) became a treatment option for MMA patients. However, there has been no current consensus on the post-operative nutrition management for MMA patients undergoing transplant, particularly during the initial phase of recovery period with catabolic stressors. We performed a retrospective analysis of clinical and nutritional management as well as biochemical profiles before and after LT in five patients with MMA. Through this study, we observed significant improvement of MMA-associated metabolites after LT. MMA patients were able to tolerate increased intact protein intake post-operatively. At least 1-1.5 g/kg/day of total protein during the acute phase after transplant may be tolerated without worsening of the metabolite levels. This information provides a guide in how to nutritionally manage MMA after LT.

Compositional and Functional Adaptations of Intestinal Microbiota and Related Metabolites in CKD Patients Receiving Dietary Protein Restriction.

The relationship between change of gut microbiota and host serum metabolomics associated with low protein diet (LPD) has been unraveled incompletely in CKD patients. Fecal 16S rRNA gene sequencing and serum metabolomics profiling were performed. We reported significant changes in the ß-diversity of gut microbiota in CKD patients having LPD (CKD-LPD, n = 16). We identified 19 genera and 12 species with significant differences in their relative abundance among CKD-LPD patients compared to patients receiving normal protein diet (CKD-NPD, n = 27) or non-CKD controls (n = 34), respectively. CKD-LPD had a significant decrease in the abundance of many butyrate-producing bacteria (family Lachnospiraceae and Bacteroidaceae) associated with enrichment of functional module of butanoate metabolism, leading to concomitant reduction in serum levels of SCFA (acetic, heptanoic and nonanoic acid). A secondary bile acid, glyco λ-muricholic acid, was significantly increased in CKD-LPD patients. Serum levels of indoxyl sulfate and p-cresyl sulfate did not differ among groups. The relationship between abundances of microbes and metabolites remained significant in subset of resampling subjects of comparable characteristics. Enrichment of bacterial gene markers related to D-alanine, ketone bodies and glutathione metabolism was noted in CKD-LPD patients. Our analyses reveal signatures and functions of gut microbiota to adapt dietary protein restriction in renal patients.