Diagnosis and management of pruritus associated with chronic kidney disease in hemodialyzed patients / Diagnostic et prise en charge du prurit associé à la maladie rénale chronique chez les patients hémodialysés

Chronic kidney disease-associated pruritus (CKD-aP) is a disabling symptom which is frequent and often underestimated. Pa-MRC has a negative impact on quality of life, and is frequently accompanied by sleep disorders and depression. The approval of difelikefalin ­ a kappa opioid receptor agonist ­ in this indication requires updated recommendations. As a first step, secondary causes of pruritus without skin lesions must be ruled out, and general measures taken (emollients, psychological support, optimization of dialysis, normalization of serum calcium, phosphate and PTH in the range proposed by the KGIDO guidelines, treatment of iron deficiency). A therapeutic test with a non-sedating oral antihistamine may be proposed. If this test is negative, Pa-MRC must be strongly suspected, and its intensity (WI-NRS scale) and impact on quality of life assessed. In the case of mild Pa-MRC (WI-NRS ≤ 3), only general measures are implemented. If Pa-MRC is moderate to severe (WI-NRS ≥ 4), specific treatment with difelikefaline can be initiated for 6 months in addition to general measures. At 3 months, if the response is complete (WI-NRS score ≤ 1) or partial (decline ≥ 3 points), treatment is continued. At 6 months, if the response is complete, treatment may be discontinued with the patient's agreement; treatment is maintained if the response is partial. At 3 or 6 months, if response is insufficient (decline < 3 points) and/or in the event of intolerance, treatment is discontinued and an alternative treatment (e.g., gabapentinoids, UVB) may be considered after dermatological consultation.

Le prurit associé à la maladie rénale chronique (Pa-MRC) est un symptôme invalidant qui est fréquent et souvent sous-estimé. Le Pa-MRC a des conséquences négatives sur la qualité de vie et s'accompagne fréquemment de troubles du sommeil et de dépression. L'approbation de la difélikéfaline ­ agoniste des récepteurs opioïdes kappa ­ dans cette indication nécessite l'actualisation des recommandations. Les causes secondaires de prurit sans lésions cutanées doivent être exclues et des mesures générales doivent être prises (émollients, aide psychologique, optimisation de la dialyse, équilibre phosphocalcique avec parathormone [PTH] dans la cible KDIGO [Kidney Disease: Improving Global Outcomes], traitement de la carence martiale). Une épreuve thérapeutique avec un antihistaminique oral non sédatif peut être proposée. En cas de test négatif, il faut fortement suspecter un Pa-MRC et évaluer son intensité (échelle WI-NRS [Worst Itch Numeric Rating Scale]) et son impact sur la qualité de vie. En cas de Pa-MRC léger (WI-NRS ≤ 3), seules les mesures générales sont mises en œuvre. Si le Pa-MRC est modéré à sévère (WI-NRS ≥ 4), un traitement spécifique par difélikéfaline peut être instauré pour 6 mois en plus des mesures générales. À 3 mois, si la réponse est complète (score WI-NRS ≤ 1) ou partielle (baisse ≥ 3 points), le traitement est poursuivi. À 6 mois, si la réponse est complète, l'arrêt du traitement peut être envisagé avec l'accord du patient ; il est maintenu en cas de réponse partielle. À 3 ou 6 mois, en cas de réponse insuffisante (baisse < 3 points) et/ou d'intolérance, le traitement est interrompu et un autre traitement (par exemple, gabapentinoïdes, ultraviolet de type B [UVB]) peut être envisagé après avis dermatologique.

Pruritus associated with chronic kidney disease in hemodialysis patients: a survey in French nephrologists / Prurit associé à la maladie rénale chronique chez les patients hémodialysés : une enquête auprès des néphrologues français

Background: Chronic kidney disease-associated pruritus (CKD-aP) is common in hemodialysis patients and severely impairs their quality of life, but the practices of nephrologists remain poorly known. Methods: The objective of this on-line survey was to describe the management of CKD-aP in French nephrologists affiliated with the French-speaking Society of Nephrology, Dialysis and Transplantation (SFNDT) and involved in hemodialysis. Results: In total, 122 questionnaires were completed and 100 were usable. Nephrologists reported they personally managed a median of 52 patients; they estimated that the CKD-aP prevalence in their hemodialysis patients was a median of 10% (IQR, 6.3-17.2); 6% of nephrologists reported not following any patient with CKD-aP. In case of CKD-aP, the first-intention intervention was the evaluation of phosphocalcic metabolism (53.5%) and verification of dialysis adequacy (52%). For moderate-to-severe CKD-aP, the first-line prescription was topical therapy (71.3%), antihistamine (23.2%) and membrane change (15.9%). Patients were referred to a dermatologist mainly in case of treatment failure (86.9%) or scratching lesions (40.4%). Available treatments were considered ineffective for 50.5% of nephrologists, partially effective for 45.5% and effective for only 4%. Conclusion: These results show that according to the opinion of nephrologists, the pruritus prevalence is low in dialysis patients. This is inconsistent with studies based on systematic patient interviews, thus suggesting that pruritus is a symptom overlooked by nephrologists. In the context of the arrival of a new drug for pruritus, patients should be more questioned about this symptom in order to propose this treatment.

Introduction: Le prurit associé à l'insuffisance rénale chronique (Pa-IRC) est fréquent chez les patients hémodialysés et altère gravement leur qualité de vie, mais les pratiques des néphrologues restent mal connues. Méthodes: L'objectif de cette enquête en ligne était de décrire la prise en charge du Pa-IRC par les néphrologues français hémodialyseurs affiliés à la Société francophone de néphrologie, dialyse et transplantation (SFNDT). Résultats: Au total, 122 questionnaires ont été remplis et 100 étaient utilisables. Les néphrologues suivaient personnellement 52 patients (médiane). Ils estimaient que la prévalence du Pa-IRC chez ces patients était de 10 % (médiane ; écart interquartile : 6,3-17,2) ; 6 % des néphrologues ont déclaré ne suivre aucun patient atteint de Pa-IRC. En cas de Pa-IRC, l'intervention de première intention était l'évaluation du métabolisme phosphocalcique (53,5 %) et la vérification de la qualité de dialyse (52 %). Pour le Pa-IRC modéré à sévère, la prescription de première intention était un traitement topique (71,3 %), un antihistaminique (23,2 %) et un changement de membrane (15,9 %). Les traitements disponibles étaient considérés comme inefficaces pour 50,5 % des néphrologues, partiellement efficaces pour 45,5 % et efficaces pour seulement 4 %. Conclusion: Ces résultats montrent que selon l'opinion des néphrologues, la prévalence du prurit est faible chez les patients dialysés. Ceci est en contradiction avec les études basées sur des entretiens systématiques avec les patients, suggérant ainsi que le prurit est un symptôme sous-estimé par les néphrologues. Dans le contexte de l'arrivée d'un nouveau médicament pour le prurit, les patients devraient être davantage interrogés sur ce symptôme afin de proposer ce traitement.

Moderate-to-severe pruritus in untreated or non-responsive hemodialysis patients: results of the French prospective multicenter observational study Pruripreva.

Background: Chronic kidney disease-associated pruritus (CKD-aP) is a common condition in patients treated with hemodialysis, and has a negative impact on quality of life (QoL). Due to the lack of standardized diagnostic tools and frequent underreporting, pruritus prevalence remains poorly documented. Methods: Pruripreva was a prospective multicenter observational study that aimed to evaluate the prevalence of moderate to severe pruritus in a cohort of French hemodialysis patients. The primary endpoint was the rate of patients with mean Worst Itch Numerical Rating Scale (WI-NRS) score ≥4 calculated over 7 days (moderate pruritus, 4-6; severe, 7-8; very severe, 9-10). Impact of CKD-aP on QoL was analyzed according to its severity (WI-NRS), using 5-D Itch scale, EQ-5D and Short Form (SF)-12. Results: Mean WI-NRS was ≥4 in 306 patients (mean age, 66.6 years; male, 57.6%) out of 1304 and prevalence of moderate to very severe pruritus was 23.5% (95% confidence interval 21.2-25.9). Pruritus was unknown prior to the systematic screening in 37.6% of patients, and 56.4% of those affected were treated for this condition. The more severe the pruritus, the poorer the QoL according to the 5-D Itch scale, EQ-5D and SF-12. Conclusion: Moderate to very severe pruritus was reported in 23.5% of hemodialysis patients. CKD-aP was underrated although it is associated with a negative impact on QoL. These data confirm that pruritus in this setting is an underdiagnosed and underreported condition. There is an urgent demand for new therapies to treat chronic pruritus associated with CKD in hemodialysis patients.

Risks and Benefits of Different Dietary Patterns in CKD.

Food has the potential to cause and exacerbate many lifestyle diseases. Or it can be used to prevent and treat illnesses like primary hypertension, the metabolic syndrome, and insulin resistance. In parallel, there is also a growing body of evidence of the role of diet in the treatment of kidney disease and its ensuing complications. Popular diets for this purpose have included low-carbohydrate diets, including the ketogenic diet, and higher carbohydrate diets like Mediterranean diets and other plant-based dietary patterns. Low-carbohydrate diets have not shown harm in patients with kidney disease and may benefit a select few. Mediterranean diets have an established record of cardioprotective benefits but also may be beneficial for the kidney. Intermittent fasting has benefits for metabolic health, but limited research exists on the risk or benefit for patients with kidney disease. Plant-based diets, especially those that are lower in protein, may slow kidney disease progression, mitigate uremia, and delay dialysis initiation. Although each dietary pattern has its unique pros and cons, most healthful dietary patterns favor the inclusion of whole, unprocessed foods, preferably from plant-based sources. In this perspective, we discuss the risks and benefits of major popular diets to help guide health care professionals in treating patients with kidney disease.

Whole-bowel irrigation in cases of poisoning: A retrospective multicentre study of feasibility, tolerability, and effectiveness.

BACKGROUND: Whole-bowel irrigation (WBI) is a strategy of gastrointestinal decontamination, recommended by several European and American learned societies, which may be used in the management of the poisoned patients. OBJECTIVES: The objectives of this study were to describe the feasibility and tolerability of this technique and to compare the clinical outcome of a group of poisoned patients treated with WBI versus that of an untreated group. METHODS: This was a retrospective and observational study of data recorded by the Angers Poison Control Centre (PCC) between 2012 and 2018. All cases for which the PCC advised WBI were included. The association between outcomes (clinical deterioration after WBI advised by a PCC, length of hospitalisation), WBI treatment, and relevant associated risk factors was determined using univariate and multivariate logistic regression. RESULTS: A total of 257 patients were included. One hundred forty-one patients were treated with WBI with clearly successful induction of diarrhoea in 47 cases (31%). WBI was not initiated in 89 patients. WBI was initiated but unsuccessful (no diarrhoea) in nine cases. The median age is 46 years (interquartile range: 32-55 years), with a sex ratio (M/F) of 1.3. A total of 27 of 150 patients (18%) who underwent WBI had adverse effects possibly linked to WBI, mainly vomiting (n=23). The patients with clinical deterioration (n=49) were irrigated significantly less often (95% confidence interval: 0.13-0.52; p<0.001). After adjustment for sex, age, time to implementation of WBI, type of substance ingested, and admission to intensive care, patients who were treated with WBI were less likely to deteriorate clinically than patients who were not treated with WBI (p<0.001). CONCLUSION: Despite a low rate of completion of this procedure, WBI appeared to provide clinical benefits in patients treated in comparison of an untreated group and is associated with an acceptably low risk of direct complications.

Mediterranean Diet for Cardiovascular Risk Reduction in Chronic Kidney Disease.

The Mediterranean diet is a plant-based healthy diet similar to the vegetarian and the Dietary Approaches to Stop Hypertension diets. Unlike vegetarian and Dietary Approaches to Stop Hypertension diets, the Mediterranean diet encourages a lifestyle associated with physical activity, and social connections. In addition, the Mediterranean diet is not based on restriction of nutrients but does limit intake of processed foods. Prospective studies have confirmed that the Mediterranean diet confers primary and secondary cardiovascular disease prevention in the general population. The benefits of the Mediterranean diet lifestyle include reducing the risk of diabetes mellitus, dyslipidemia, and lowers blood pressure. In adults with CKD, adherence to the Mediterranean diet is associated with a lower risk of CKD progression and its complications such as hyperphosphatemia and metabolic acidosis, and reduces production of uremic toxins and inflammatory mediators when compared to omnivore dietary patterns. Nevertheless, prospective studies are needed to confirm the cardiovascular disease prevention with the Mediterranean diet in adults with CKD. Medical nutrition therapy remains a cornerstone of CKD management, and the Mediterranean diet could be utilized to slow CKD progression and complications.

"I did it without hesitation. Am I the bad guy?" Online conversations in response to controversial in-game violence.

Video game content has evolved over the last six decades, from a basic focus on challenge and competition to include more serious and introspective narratives capable of encouraging critical contemplation within gamers. The "No Russian" mission from Call of Duty: Modern Warfare 2 casts players as terrorists responsible for the murder of innocent bystanders, sparking debate around how players engage and react to wanton violence in modern video games. Through thematic analysis of 649 Reddit posts discussing the mission, 10 themes emerged representing complexity in player experiences. Those themes were grouped into categories representing (descending order), (1) rote gameplay experiences, (2) dark humor, (3) comparing the mission to other games and real-world events, and (4) self-reflective eudaimonic reactions to the mission. Although less common, the presence of eudaimonic media effects (in at least 15% of posts) holds promise for the use of video games as reflective spaces for violence prevention.

Patient-reported outcome measures in hemodialysis patients: results of the first multicenter cross-sectional ePROMs study in France.

BACKGROUND: Kidney failure with replacement therapy and hemodialysis are associated with a decrease in quality of life (QOL). Self-reported QOL symptoms are not always prioritized by the medical team, potentially leading to conflicting priorities with patients. Electronic patient-reported outcome measures (ePROMs) allow physicians to better identify these symptoms. The objective was to describe the prevalence of symptoms self-reported by hemodialysis (HD) patients. METHODS: A multicenter cross-sectional study was conducted in three HD centers. Patients were included if they were 18 years old or over treated with HD for at least 3 months in a center. Data were collected by the patient via a self-administered ePROMs questionnaire. Data included patient characteristics, post-dialysis fatigue and intensity, recovery time after a session, perceived stress, impaired sleep the day before the dialysis session, current state of health and the change from the past year. A multivariate analysis was conducted to identify relations between symptoms. RESULTS: In total, we included 173 patients with a mean age of 66.2 years, a mean ± SD hemodialysis duration of 48.9 ± 58.02 months. The prevalence of fatigue was 72%. 66% had a high level of stress (level B or C). Recovery time was more than 6 h after a HD session for 25% of patients and 78% declared they had a better or unchanged health status than the previous year. Sleep disturbance was associated with cardiovascular comorbidities (OR 5.08 [95% CI, 1.56 to 16.59], p = 0.007). CONCLUSIONS: Fatigue and stress were the main symptoms reported by HD patients. The patient's care teams should better consider these symptoms.

VITADIAL "Does correction of 25 OH-VITAmin D with cholecalciferol supplementation increase muscle strength in hemoDIALysis patients?": study protocol for a randomized controlled trial.

BACKGROUND: Muscle strength decreases as kidney failure progresses. Low muscle strength affects more than 50% of hemodialysis patients and leads to daily life activities impairment. In the general population, numerous studies have linked low 25OH-vitamin D (25OHD) concentrations to the loss of the muscle strength and low physical performances. Data on native vitamin D and muscle function are scarce in the chronic kidney disease (CKD) population, but low 25OHD levels have been associated with poor muscle strength. We present in this article the protocol of an ongoing study named VITADIAL testing if cholecalciferol supplementation in hemodialysis patients with low 25OHD improves their muscle strength. METHODS/DESIGN: VITADIAL is a prospective open randomized French multicenter study. All patients will have 25OHD levels ≤50nmol/L at randomization. One group will receive 100,000 UI cholecalciferol once a month during 6 months; the other group will receive no treatment during 6 months. In order to randomize patients with 25OHD ≤50nmol/L, supplemented patients will undergo a 3 months wash-out period renewable 3 times (maximum of 12 months wash-out) until 25OHD reaches a level ≤50nmol/L. The main objective of this study is to analyze if a 6-month period of oral cholecalciferol (i.e., native vitamin D) supplementation improves muscle strength of hemodialysis patients with low 25OHD vitamin D levels. Muscle strength will be assessed at 0, 3, and 6 months, by handgrip strength measured with a quantitative dynamometer. Secondary objectives are (1) to analyze 25OHD plasma levels after vitamin D wash-out and/or supplementation, as well as factors associated with 25OHD lowering speed during wash-out, and (2) to analyze if this supplementation improves patient's autonomy, reduces frailty risk, and improves quality of life. Fifty-four patients are needed in each group to meet our main objective. DISCUSSION: In the general population, around 30 randomized studies analyzed the effects of vitamin D supplementation on muscle strength. These studies had very different designs, sizes, and studied population. Globally, these studies and the meta-analysis of studies favor a beneficial effect of vitamin D supplementation on muscle strength, but this effect is mainly found in the subgroup of aged patients and those with the lowest 25OHD concentrations at inclusion. We reported a positive independent association between 25OHD and handgrip strength in a population of 130 hemodialysis patients in a dose-dependent manner. In our cohort, a plateau effect was observed above 75 nmol/L. Only two randomized studies analyzed the effect of native vitamin D supplementation on muscle strength in hemodialysis patients, but unfortunately, these two studies were underpowered. VITADIAL is a trial specifically designed to assess whether cholecalciferol might benefit to hemodialysis patient's muscle strength. TRIAL REGISTRATION: ClinicalTrials.gov NCT04262934 . Registered on 10 February 2020 - Retrospectively registered.

[Psychological impact of lockdown and the COVID-19 epidemic on haemodialysis patients and carers in France]. / Répercussions psychologiques du confinement et de l'épidémie à COVID-19 chez les patients et soignants en hémodialyse en France.

INTRODUCTION: The health crisis linked to the COVID-19 epidemic has required lockdown measures in France and changes in practices in dialysis centers. The objective was to assess the depressive and anxiety symptoms during lockdown in hemodialysis patients and their caregivers. METHODS: We sent, during lockdown period, between April and May 2020, self-questionnaires to voluntary subjects (patients and caregivers), treated by hemodialysis or who worked in hemodialysis in one of the 14 participating centers in France. We analyzed their perception of dialysis sessions (beneficial or worrying), their stress level (VAS rated from 0 to 10), their anxiety and depressive symptoms (Hospital anxiety and depression scale). Factors associated with stress, anxiety and depression were analyzed with multiple linear regression models. RESULTS: 669 patients and 325 caregivers agreed to participate. 70 % of participants found it beneficial to come to dialysis during confinement. The proportions of subjects with a stress level ≥ 6 linked to the epidemic, confinement, fear of contracting COVID-19 and fear of infecting a loved one were respectively 23.9%, 26.2%, 33.4% and 42%. 39.2% presented with certain (13.7%) or doubtful (19.2%) anxious symptoms. 21.2% presented a certain (7.9%) or doubtful (13.3%) depressive symptomatology. Age, gender, history of psychological disorders and perception of dialysis sessions were associated with levels of stress, anxiety and depression. CONCLUSION: During the lockdown period, in France, the majority of hemodialysis patients and caregivers found it beneficial to come to dialysis. One in three subjects had anxiety symptoms and one in five subjects had depressive symptoms.

Nomenclature in nephrology: preserving 'renal' and 'nephro' in the glossary of kidney health and disease.

A recently published nomenclature by a "Kidney Disease Improving Global Outcomes" (KDIGO) Consensus Conference suggested that the word "kidney" should be used in medical writings instead of "renal" or "nephro" when referring to kidney disease and kidney health. Whereas the decade-old move to use "kidney" more frequently should be supported when communicating with the public-at-large, such as the World Kidney Day, or in English speaking countries in communications with patients, care-partners, and non-medical persons, our point of view is that "renal" or "nephro" should not be removed from scientific and technical writings. Instead, the terms can coexist and be used in their relevant contexts. Cardiologists use "heart" and "cardio" as appropriate such as "heart failure" and "cardiac care units" and have not replaced "cardiovascular" with "heartvessel", for instance. Likewise, in nephrology, we consider that "chronic kidney disease" and "continuous renal replacement therapy" should coexist. We suggest that in scientific writings and technical communications, the words "renal" and "nephro" and their derivatives are more appropriate and should be freely used without any pressure by medical journals to compel patients, care-partners, healthcare providers, researchers and other stakeholders to change their selected words and terminologies. We call to embrace the terms "kidney", "renal" and "nephro" as they are used in different contexts and ask that scientific and medical journals not impose terminology restrictions for kidney disease and kidney health. The choice should be at the discretion of the authors, in the different contexts including in scientific journals.

Evolution of body composition following successful kidney transplantation is strongly influenced by physical activity: results of the CORPOS study.

BACKGROUND: Weight gain (mainly gain of fat mass) occurs quickly after successful kidney transplantation and is associated with metabolic complications (alterations of glycaemic control, hyperlipidaemia). Determinants of weight gain are multifactorial and are mainly related to the transplant procedure itself (glucocorticoid use, increased appetite). In the modern era of transplantation, one challenge is to limit these metabolic alterations by promoting gain of muscle mass rather than fat mass. This prospective study was performed to assess determinants of fat mass, fat-free mass and body cell mass changes after kidney transplantation with a focus on physical activity and nutritional behaviour before and after transplantation. METHODS: Patients were included at the time of listing for deceased donor kidney transplantation. Body composition was determined using dual X-ray absorptiometry and bioimpedance spectroscopy to assess fat mass, fat-free mass and body cell mass (= fat-free mass - extracellular water) at the time of inclusion, 12 months later, and 1, 6, 12 and 24 months after transplantation. Recall dietary data and physical activity level were also collected. RESULTS: Eighty patients were included between 2007 and 2010. Sixty-five had a complete 24-month follow-up after kidney transplantation. Fat mass, fat-free mass and body cell mass decreased during the waiting period and early after kidney transplantation. The nadirs of body cell mass and fat-free mass occurred at 1 month and the nadir for fat mass occurred at 6 months. Maximum levels of all parameters of body composition were seen at 12 months, after which body cell mass and fat-free mass decreased, while fat mass remained stable. In multivariate analysis, male recipients, higher physical activity level and lower corticosteroid dose were significantly associated with better body cell mass recovery after kidney transplantation. CONCLUSIONS: Lifestyle factors, such as physical activity level, together with low dose of corticosteroids seem to influence body composition evolution following kidney transplantation with recovery of body cell mass. Specific strategies to promote physical activity in kidney transplant recipients should be provided before and after kidney transplantation.

Myostatin and muscle atrophy during chronic kidney disease.

Chronic kidney disease (CKD) patients often exhibit a low muscle mass and strength, leading to physical impairment and an increased mortality. Two major signalling pathways control protein synthesis, the insulin-like growth factor-1/Akt (IGF-1/Akt) pathway, acting as a positive regulator, and the myostatin (Mstn) pathway, acting as a negative regulator. Mstn, also known as the growth development factor-8 (GDF-8), is a member of the transforming growth factor-ß superfamily, which is secreted by mature muscle cells. Mstn inhibits satellite muscle cell proliferation and differentiation and induces a proteolytic phenotype of muscle cells by activating the ubiquitin-proteasome system. Recent advances have been made in the comprehension of the Mstn pathway disturbance and its role in muscle wasting during CKD. Most studies report higher Mstn concentrations in CKD and dialysis patients than in healthy subjects. Several factors increase Mstn production in uraemic conditions: low physical activity, chronic or acute inflammation and oxidative stress, uraemic toxins, angiotensin II, metabolic acidosis and glucocorticoids. Mstn seems to be only scarcely removed during haemodialysis or peritoneal dialysis, maybe because of its large molecule size in plasma where it is linked to its prodomain. In dialysis patients, Mstn has been proposed as a biomarker of muscle mass, muscle strength or physical performances, but more studies are needed in this field. This review outlines the interconnection between Mstn activation, muscle dysfunction and CKD. We discuss mechanisms of action and efficacy of pharmacological Mstn pathway inhibition that represents a promising treatment approach of striated muscle dysfunction. Many approaches and molecules are in development but until now, no study has proved a benefit in CKD.

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.