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Ammonium, stemming from renal ammoniagenesis, is a major urinary proton buffer and is excreted along the collecting duct. This process depends on the concomitant secretion of ammonia by the ammonia channel RhCG and of protons by the vacuolar-type proton-ATPase pump. Thus, urinary ammonium content and urinary acidification are tightly linked. However, mice lacking Rhcg excrete more alkaline urine despite lower urinary ammonium, suggesting an unexpected role of Rhcg in urinary acidification. RhCG and the B1 and B2 proton-ATPase subunits could be co-immunoprecipitated from kidney. In ex vivo microperfused cortical collecting ducts (CCD) proton-ATPase activity was drastically reduced in the absence of Rhcg. Conversely, overexpression of RhCG in HEK293 cells resulted in higher proton secretion rates and increased B1 proton-ATPase mRNA expression. However, in kidneys from Rhcg -/- mice the expression of only B1 and B2 subunits was altered. Immunolocalization of proton-ATPase subunits together with immuno-gold detection of the A proton-ATPase subunit showed similar localization and density of staining in kidneys from Rhcg +/+ and Rhcg -/- mice. In order to test for a reciprocal effect of intercalated cell proton-ATPases on Rhcg activity, we assessed Rhcg and proton-ATPase activities in microperfused CCD from Atp6v1b1 -/- mice and showed reduced proton-ATPase activity without altering Rhcg activity. Thus, RhCG and proton-ATPase are located within the same cellular protein complex. RhCG may modulate proton-ATPase function and urinary acidification, whereas proton-ATPase activity does not affect RhCG function. This mechanism may help to coordinate ammonia and proton secretion beyond physicochemical driving forces.

Zusammenfassung Hintergrund Die Mangelernährung ist ein zentrales Problem im Spitalalltag und korreliert mit Komplikationen, längeren Spitalaufenthalten und schlechteren Outcomes. Viele der hospitalisierten, internistischen Patienten sind polymorbide. Bisherige klinische Leitlinien für Ernährungstherapie befassen sich meist nur mit Einzelerkrankungen ohne Berücksichtigung der Polymorbidität. Ziel der ESPEN-Arbeitsgruppe war das Erstellen von Leitlinien zur Ernährungstherapie bei polymorbiden, hospitalisierten Patienten. Methode Die Arbeitsgruppe formulierte Schlüsselfragen zu folgenden Aspekten der Ernährungstherapie: Indikation, Weg der Nahrungszufuhr, Energie- und Proteinbedarf, Mikronährstoffe, krankheitsspezifische Nährstoffe, Überwachung, zeitliche sowie prozedurale Aspekte. Es erfolgte eine systematische Literatursuche in 3 Datenbanken (Medline, Embase und Cochrane Library) sowie in sekundären Quellen (z. B. publizierte Guidelines). Darauf basierend wurden Empfehlungen formuliert. Die hier vorgestellte Arbeit ist eine deutsche Übersetzung der kürzlich publizierten ESPEN-Leitlinien. Ergebnisse Bei polymorbiden, hospitalisierten Patienten sollte ein einfaches, standardisiertes Mangelernährungs-Screening innerhalb 48 Stunden nach Spitaleintritt durchgeführt werden. Der totale tägliche Energiebedarf kann bei polymorbiden Patienten > 65 Jahren mittels gewichtsbasierter Formel „27 – 30 kcal/kg Körpergewicht (KG)“ geschätzt werden. Der tägliche Proteinbedarf kann mit „≥ 1,0 g/kg KG“ geschätzt werden. Primär sollte eine orale Ernährung angestrebt werden, welche bei Bedarfsabdeckung Schlussfolgerungen Trotz methodischen Herausforderungen aufgrund der heterogenen Patientenpopulation und dem Fehlen großer Interventionsstudien ist es der Arbeitsgruppe gelungen, evidenzbasierte Empfehlungen zur nicht-krankheitsspezifischen Ernährungstherapie bei polymorbiden Patienten zu erarbeiten. Als Resultat sind 22 praktische Empfehlungen und 4 Stellungnahmen entstanden, welche im klinischen Alltag im Umgang mit mangelernährten, hospitalisierten, polymorbiden Patienten genutzt werden können. Einige Fragen bleiben bei mangelnder oder fehlender Evidenz offen und benötigen noch weiterer Untersuchungen.

This systematic review and meta-analysis assesses whether nutritional support is associated with better clinical outcomes in medical inpatients who are malnourished or at nutritional risk., Key Points Question What is the association of nutritional support with clinical outcomes in medical inpatients who are malnourished or at nutritional risk? Findings In this updated systematic review and meta-analysis of 27 trials including 6803 patients, nutritional support provided during hospitalization was associated with significantly lower rates of mortality and nonelective hospital readmissions, as well as higher energy and protein intake and weight increase. Meaning This study’s findings suggest that nutritional support in hospitalized patients who are malnourished or at nutritional risk is associated with improved nutritional and clinical outcomes and should be considered when treating this population., Importance Malnutrition affects a considerable proportion of the medical inpatient population. There is uncertainty regarding whether use of nutritional support during hospitalization in these patients positively alters their clinical outcomes. Objective To assess the association of nutritional support with clinical outcomes in medical inpatients who are malnourished or at nutritional risk. Data Sources For this updated systematic review and meta-analysis, a search of the Cochrane Library, MEDLINE, and Embase was conducted from January 1, 2015, to April 30, 2019; the included studies were published between 1982 and 2019. Study Selection A prespecified Cochrane protocol was followed to identify trials comparing oral and enteral nutritional support interventions with usual care and the association of these treatments with clinical outcomes in non–critically ill medical inpatients who were malnourished. Data Extraction and Synthesis Two reviewers independently extracted data and assessed risk of bias; data were pooled using a random-effects model. Main Outcomes and Measures The primary outcome was mortality. The secondary outcomes included nonelective hospital readmissions, length of hospital stay, infections, functional outcome, daily caloric and protein intake, and weight change. Results A total of 27 trials (n = 6803 patients) were included, of which 5 (n = 3067 patients) were published between 2015 and 2019. Patients receiving nutritional support compared with patients in the control group had significantly lower rates of mortality (230 of 2758 [8.3%] vs 307 of 2787 [11.0%]; odds ratio [OR], 0.73; 95% CI, 0.56-0.97). A sensitivity analysis suggested a more pronounced reduction in the risk of mortality in recent trials (2015 or later) (OR, 0.47; 95% CI, 0.28-0.79) compared with that in older studies (OR, 0.94; 95% CI, 0.72-1.22), in patients with established malnutrition (OR, 0.52; 95% CI, 0.34-0.80) compared with that in patients at nutritional risk (OR, 0.85; 95% CI, 0.62-1.18), and in trials with high protocol adherence (OR, 0.67; 95% CI, 0.54-0.84) compared with that in trials with low protocol adherence (OR, 0.88; 95% CI, 0.44-1.76). Nutritional support was also associated with a reduction in nonelective hospital readmissions (14.7% vs 18.0%; risk ratio, 0.76; 95% CI, 0.60-0.96), higher energy intake (mean difference, 365 kcal; 95% CI, 272-458 kcal) and protein intake (mean difference, 17.7 g; 95% CI, 12.1-23.3 g), and weight increase (0.73 kg; 95% CI, 0.32-1.13 kg). No significant differences were observed in rates of infections (OR, 0.86; 95% CI, 0.64-1.16), functional outcome (mean difference, 0.32; 95% CI, −0.51 to 1.15), and length of hospital stay (mean difference, −0.24; 95% CI, −0.58 to 0.09). Conclusions and Relevance This study’s findings suggest that despite heterogeneity and varying methodological quality among trials, nutritional support was associated with improved survival and nonelective hospital readmission rates among medical inpatients who were malnourished and should therefore be considered when treating this population.

La malnutrition proteino-energetique correspond a un desequilibre entre les apports nutritionnels et les besoins nutritionnels, et elle affecte souvent les patients de medecine interne hospitalises. La prevalence de la malnutrition chez les patients hospitalises est tres elevee, de l’ordre de 40–50% [1, 2]. La malnutrition est associee a une mortalite et morbidite elevees, a des taux de complications accrus, a un allongement de la duree d’hospitalisation, ainsi qu’a une augmentation des couts de sante. Par le biais d’un traitement nutritionnel, les apports en proteines et calories peuvent etre augmentes et l’etat nutritionnel peut etre ameliore [3]. Selon des estimations, plus de 70% des patients de medecine interne hospitalises sont polymorbides et souffrent d’au moins deux affections chroniques concomitantes [4]. Toutefois, les lignes directrices jusqu’alors disponibles concernant les traitements nutritionnels portaient uniquement sur des maladies isolees, sans tenir compte de la polymorbidite (par ex. lignes directrices relatives a la nutrition des patients cancereux). La question de savoir si l’approche de depistage, d’evaluation et de traitement de la malnutrition chez les patients polymorbides devrait differer de celle chez les patients souffrant d’une affection unique reste ouverte. Sur cette base, un groupe de travail de la Societe europeenne de nutrition clinique et metabolisme («European Society for Clinical Nutrition and Metabolism» [ESPEN]) a elabore de nouvelles lignes directrices relatives au traitement nutritionnel chez les patients polymorbides hospitalises [5], qui sont egalement publiees et soutenues par la Societe allemande de nutrition clinique («Deutsche Gesellschaft fur klinische Ernahrung» [DGEM]) [6]. Par ailleurs, un groupe de travail suisse a mis au point en 2016, a l’occasion d’une conference de consensus, des recommandations sous forme d’algorithme pratique concernant le traitement nutritionnel chez les patients de medecine interne hospitalises, en s’appuyant sur les lignes directrices deja existantes [7]. Dans cet article, nous souhaitons resumer le contenu de ces deux lignes directrices relatives au traitement nutritionnel chez les patients polymorbides hospitalises souffrant de malnutrition, en les completant par d’autres sources de la litterature lorsque cela s’avere judicieux. Le tableau 1 fournit un apercu des nouvelles recommandations de l’ESPEN [5]; la figure 1 (p. 259) presente un algorithme pratique concernant le traitement nutritionnel chez les patients polymorbides hospitalises, adapte d’apres les lignes directrices consensuelles suisses [7, 8].

Reason for withdrawal from publication This protocol has been withdrawn from the Cochrane Library because there is an overlap with the published Cochrane Review on "Nutrition support in hospitalised adults at nutritional risk".

Background & Aims: Polymorbidity (also known as multimorbidity) - defined as the co-occurrence of at least two chronic health conditions - is highly prevalent, particularly in the hospitalized population. Nonetheless, clinical guidelines largely address individual diseases and rarely account for polymorbidity. The aim of this project was to develop guidelines on nutritional support for polymorbid patients hospitalized in medical wards. Methods: The methodology used for the development of the current project follows the standard operating procedures for ESPEN guidelines. It started with an initial meeting of the Working Group in January 2015, where twelve key clinical questions were developed that encompassed different aspects of nutritional support: indication, route of feeding, energy and protein requirements, micronutrient requirements, disease-specific nutrients, timing, monitoring and procedure of intervention. Systematic literature searches were conducted in three different databases (Medline, Embase and the Cochrane Library), as well as in secondary sources (e.g. published guidelines), until April 2016. Retrieved abstracts were screened to identify relevant studies that were used to develop recommendations, which was followed by submission to Delphi voting rounds. Results: From a total of 4532 retrieved abstracts, 38 relevant studies were analyzed and used to generate a guideline draft that proposed 22 recommendations and four statements. The results of the first online voting showed a strong consensus (agreement of >90%) in 68% of recommendations and 75% of statements, and consensus (agreement of >75-90%) in 32% of recommendations and 25% of statements. At the final consensus conference, a consensus greater than 89% was reached for all of the recommendations. Conclusions: Despite the methodological difficulties in creating non-disease specific guidelines, the evidence behind several important aspects of nutritional support for polymorbid medical inpatients was reviewed and summarized into practical clinical recommendations. Use of these guidelines offer an evidence-based nutritional approach to the polymorbid medical inpatients and may improve their outcomes.

High dietary protein imposes a metabolic acid load requiring excretion and buffering by the kidney. Impaired acid excretion in CKD, with potential metabolic acidosis, may contribute to the progression of CKD. Here, we investigated the renal adaptive response of acid excretory pathways in mice to high-protein diets containing normal or low amounts of acid-producing sulfur amino acids (SAA) and examined how this adaption requires the RhCG ammonia transporter. Diets rich in SAA stimulated expression of enzymes and transporters involved in mediating NH4 (+) reabsorption in the thick ascending limb of the loop of Henle. The SAA-rich diet increased diuresis paralleled by downregulation of aquaporin-2 (AQP2) water channels. The absence of Rhcg transiently reduced NH4 (+) excretion, stimulated the ammoniagenic pathway more strongly, and further enhanced diuresis by exacerbating the downregulation of the Na(+)/K(+)/2Cl(-) cotransporter (NKCC2) and AQP2, with less phosphorylation of AQP2 at serine 256. The high protein acid load affected bone turnover, as indicated by higher Ca(2+) and deoxypyridinoline excretion, phenomena exaggerated in the absence of Rhcg. In animals receiving a high-protein diet with low SAA content, the kidney excreted alkaline urine, with low levels of NH4 (+) and no change in bone metabolism. Thus, the acid load associated with high-protein diets causes a concerted response of various nephron segments to excrete acid, mostly in the form of NH4 (+), that requires Rhcg. Furthermore, bone metabolism is altered by a high-protein acidogenic diet, presumably to buffer the acid load.

Ammonia secretion by the collecting duct (CD) is critical for acid-base homeostasis and, when defective, causes distal renal tubular acidosis (dRTA). The Rhesus protein RhCG mediates NH3 transport as evident from cell-free and cellular models as well as from Rhcg-null mice. Here, we investigated in a Rhcg mouse model the metabolic effects of Rhcg haploinsufficiency, the role of Rhcg in basolateral NH3 transport, and the mechanisms of adaptation to the lack of Rhcg. Both Rhcg+/+ and Rhcg+/− mice were able to handle an acute acid load, whereas Rhcg−/− mice developed severe metabolic acidosis with reduced ammonuria and high mortality. However, chronic acid loading revealed that Rhcg+/− mice did not fully recover, showing lower blood HCO3− concentration and more alkaline urine. Microperfusion studies demonstrated that transepithelial NH3 permeability was reduced by 80 and 40%, respectively, in CDs from Rhcg−/− and Rhcg+/− mice compared with controls. Basolateral membrane permeability to NH3 was reduced in CDs from Rhcg−/− mice consistent with basolateral Rhcg localization. Rhcg−/− responded to acid loading with normal expression of enzymes and transporters involved in proximal tubular ammoniagenesis but reduced abundance of the NKCC2 transporter responsible for medullary accumulation of ammonium. Consequently, tissue ammonium content was decreased. These data demonstrate a role for apical and basolateral Rhcg in transepithelial NH3 transport and uncover an incomplete dRTA phenotype in Rhcg+/− mice. Haploinsufficiency or reduced expression of RhCG may underlie human forms of (in)complete dRTA.

In 2009, the American Society of Parenteral and Enteral Nutrition and its European counterpart (Euopean Society for Parenteral and Enteral Nutrition) published guidelines regarding nutritional support of patients with hematologic stem cell transplantation. Our aim was to do an up-to-date literature review regarding benefit of nutritional interventions and treatment recommendations. We searched MEDLINE, EMBASE and Cochrane Library for interventional and observational clinical studies. We extracted data based on a predefined case report form and assessed bias. Out of 459 potential abstracts, 13 studies of mostly moderate quality with a total of 18 167 patients were included. Two very large trials reported negative associations of malnutrition and survival, transplant-related mortality and relapse risk. Some trials found enteral nutrition (EN) to be as effective as parenteral nutrition (PN) with lower complication rates. In addition, EN was associated with better survival, less acute GvHD and faster neutrophil recovery. A neutropenic diet was not superior regarding overall survival, but in contrast resulted in higher infection risk. Current moderate quality studies show negative associations of malnutrition and clinical outcomes, with EN being superior to PN. There was no benefit of neutropenic diets. Large, randomized controlled studies are needed to better understand optimal nutritional support in this patient population.

Objective Despite the high prevalence of malnutrition in the general inpatient population, there is a lack of knowledge in regard to detecting disease-related malnutrition and implementing nutritional support. Our aim was to suggest practical procedures for screening and treating malnourished or at-risk patients hospitalized in medical wards, thereby fostering a straightforward implementation of nutritional therapy independent of the underlying disease and comorbidities. Methods A working group of experts in clinical nutrition selected and analyzed published disease-specific European Society for Clinical Nutrition and Metabolism (ESPEN) guidelines relevant for our aim. Eight questions in population, intervention, control, outcome format were defined to cover topics such as screening, nutritional targets, and routes of feeding. Individual studies were extracted from the guidelines by applying inclusion and exclusion criteria targeting the heterogeneous population of medical inpatients with or at-risk of disease-related malnutrition. We used those studies as evidence, as well as recommendations from the selected ESPEN guidelines, to formulate answers to the questions. Final agreement with the statement was obtained by consensus of the whole working group. Results Procedures on how to provide integrated nutritional therapy (oral, enteral, and parenteral) to a heterogeneous patient population were suggested, including how to identify malnourished or at-risk patients, nutrient targets, choice of feeding route, monitoring, and assessment of patients. We also developed a simple algorithm to facilitate the implementation of a nutritional care plan for the general medical inpatient population. Conclusion By compiling evidence and recommendations from disease-specific guidelines, we were able to suggest a nutritional strategy applicable to large and heterogeneous group of malnourished or at-risk patients admitted to hospitals. A large randomized controlled trial is currently investigating whether this strategy improves clinical outcomes of patients.

Importance During acute illness, nutritional therapy is widely used for medical inpatients with malnutrition or at risk for malnutrition. Yet, to our knowledge, no comprehensive trial has demonstrated that this approach is effective and beneficial for patients. Objective To assess the effects of nutritional support on outcomes of medical inpatients with malnutrition or at risk for malnutrition in a systematic review of randomized clinical trials (RCTs). Data Sources The Cochrane Library, MEDLINE, and EMBASE. The study dates were October 5, 1982, to April 30, 2014, in various (mostly European) countries. The dates of our analysis were March 10, 2015, to September 16, 2015. Study Selection Based on a prespecified Cochrane protocol, we systematically searched RCTs investigating the effects of nutritional support (including counseling and oral and enteral feeding) in medical inpatients compared with a control group. Data Extraction Two reviewers extracted data on study characteristics, methods, and outcomes. Disagreement was resolved by consensus. Main Outcomes and Measures The primary study outcome was mortality. Secondary outcomes included hospital-acquired infections, nonelective readmissions, functional outcome, length of hospital stay, daily caloric and protein intake, and weight change. Results We included 22 RCTs with a total of 3736 participants. Heterogeneity across RCTs was high, with overall low study quality and mostly unclear risk of bias. Intervention group patients significantly increased their weight (mean difference, 0.72 kg; 95% CI, 0.23-1.21 kg), caloric intake (mean difference, 397 kcal; 95% CI, 279-515 kcal), and protein intake (mean difference, 20.0 g/d; 95% CI, 12.5-27.1 g/d) compared with control group patients. No differences between intervention group patients and control group patients were found with respect to mortality (9.8% vs 10.3%; odds ratio [OR], 0.96; 95% CI, 0.72-1.27), hospital-acquired infections (overall, 6.0% vs 7.6%; OR, 0.75; 95% CI, 0.50-1.11), functional outcome (mean Barthel index difference, 0.33 point; 95% CI, −0.88 to 1.55 points), or length of hospital stay (mean difference, −0.42 days; 95% CI, −1.09 to 0.24 days). Nonelective readmissions were significantly decreased by the intervention (20.5% vs 29.6%; risk ratio, 0.71; 95% CI, 0.57-0.87). Conclusions and Relevance In medical inpatients, nutritional support increases caloric and protein intake and body weight. However, there is little effect on clinical outcomes overall except for nonelective readmissions. High-quality RCTs are needed to fill this gap.