Anabolic response to amino acid supplementation in critical illness

Background: Critically ill patients suffer from protein catabolism with losses of skeletal muscle and whole-body proteins associated with morbidity and mortality. Catabolism is difficult to overcome, but nutritional supplementation with enteral protein or parenteral amino acids may limit protein losses. It is unknown which dose, mode, and timing of feeding is optimal for critically ill patients. Aim: The aim of this project was to evaluate a technique of quantifying the response of protein turnover to feeding, then apply it to study effects of protein or amino acid supplementation in critical illness. A main question was whether exogenous protein/amino acid is utilized for improved protein balance, or else consumed in catabolic pathways. Methods: In study 1, a previously characterized cohort of viscerally obese, insulin-resistant women was studied. Postprandial muscle and whole-body protein turnover were quantified by stable-isotope labeled phenylalanine tracers. In study 2, the whole-body technique was adapted to investigate the effects of early enteral feeding in critically ill patients. In study 3, the response of critically ill patients to a three-hour course of intravenous supplemental amino acids was studied. In study 4, the time course of uptake of stable-isotope-labeled phenylalanine from the intestine into arterial blood was studied in healthy subjects and critically ill patients during continuous enteral feeding. Results: In study 1, the technique was found workable to quantify postprandial protein metabolism, and it was found that viscerally obese women are resistant to postprandial stimulation of anabolism. In study 2, it was found in critically ill patients that enteral feeding of a small amount of protein yields a detectable gain in protein balance and no increase in amino acid oxidation. In study 3, an improvement in whole-body protein balance after three hours of intravenous amino acid supplementation was found in critically ill patients. In study 4, the uptake of dietary phenylalanine from continuous enteral feeding was found to reach a tentative steady state, but with high intra- and interindividual variability. Conclusion: Exogenous amino acids from enteral or intravenous nutrition improve protein balance in healthy subjects and critically ill patients, and are not predominantly consumed in catabolic pathways

Whole-body protein kinetics in critically ill patients during 50 or 100% energy provision by enteral nutrition: A randomized cross-over study.

BackgroundEnteral nutrition (EN) is a ubiquitous intervention in ICU patients but there is uncertainty regarding the optimal dose, timing and importance for patient-centered outcomes during critical illness. Our research group has previously found an improved protein balance during normocaloric versus hypocaloric parenteral nutrition in neurosurgical ICU patients. We now wanted to investigate if this could be demonstrated in a general ICU population with established enteral feeding, including patients on renal replacement therapy.MethodsPatients with EN >80% of energy target as determined by indirect calorimetry were randomized to or 50% or 100% of current EN rate. After 24 hours, whole-body protein kinetics were determined by enteral and parenteral stable isotope tracer infusions. Treatment allocation was then switched, and tracer investigations repeated 24 hours later in a crossover design with patients serving as their own controls.ResultsSix patients completed the full protocol. During feeding with 100% EN all patients received >1.2 g/kg/day of protein. Mean whole-body protein balance increased from -6.07 to 2.93 µmol phenylalanine/kg/h during 100% EN as compared to 50% (p = 0.044). The oxidation rate of phenylalanine was unaltered (p = 0.78).ConclusionsIt is possible to assess whole-body protein turnover using a stable isotope technique in critically ill patients during enteral feeding and renal replacement therapy. Our results also suggest a better whole-body protein balance during full dose as compared to half dose EN. As the sample size was smaller than anticipated, this finding should be confirmed in larger studies

High protein intake without concerns?

Abstract The high fashion in nutrition for the critically ill is to recommend a high protein intake. Several opinion leaders are surfing on this wave, expanding the suggested protein allowance upwards. At the same time, there is no new evidence supporting this change in recommendations. Observational data show that in clinical practice protein intake is most often far below current ESPEN recommendations of 1.2–1.5 g/kg/day. Therefore, it may be in the best interests of our patients just to adhere to that guideline, and not to stretch them upwards for protein intake? Here we give arguments to stay conservative

Effect of initiating enteral protein feeding on whole-body protein turnover in critically ill patients

Critically ill patients are susceptible to protein catabolism. Enteral feeding may ameliorate protein loss, but its effect is not well characterized in terms of protein kinetics

A supplemental intravenous amino acid infusion sustains a positive protein balance for 24 hours in critically ill patients

Abstract Background Providing supplemental amino acids to ICU patients during a 3-h period results in improved whole-body net protein balance, without an increase in amino acid oxidation. The primary objective was to investigate if a 24-h intravenous amino acid infusion in critically ill patients has a sustained effect on whole-body protein balance as was seen after 3 h. Secondary objectives were monitoring of amino acid oxidation rate, urea and free amino acid plasma concentrations. Methods An infusion of [1-13C]-phenylalanine was added to ongoing enteral nutrition to quantify the enteral uptake of amino acids. Primed intravenous infusions of [ring-2H5]-phenylalanine and [3,3-2H2]-tyrosine were used to assess whole-body protein synthesis and breakdown, to calculate net protein balance and to assess amino acid oxidation at baseline and at 3 and 24 hours. An intravenous amino acid infusion was added to nutrition at a rate of 1 g/kg/day and continued for 24 h. Results Eight patients were studied. The amino acid infusion resulted in improved net protein balance over time, from -1.6 ± 7.9 μmol phe/kg/h at 0 h to 6.0 ± 8.8 at 3 h and 7.5 ± 5.1 at 24 h (p = 0.0016). The sum of free amino acids in plasma increased from 3.1 ± 0.6 mmol/L at 0 h to 3.2 ± 0.3 at 3 h and 3.6 ± 0.5 at 24 h (p = 0.038). Amino acid oxidation and plasma urea were not altered significantly. Conclusion We demonstrated that the improvement in whole-body net protein balance from a supplemental intravenous amino acid infusion seen after 3 h was sustained after 24 h in critically ill patients. Trial registration This trial was prospectively registered at Australian New Zealand Clinical Trials Registry. ACTRN, 12615001314516. Registered on 1 December 2015

Altered molecular signatures during kidney development after intrauterine growth restriction of different origins

This study was performed to identify transcriptional alterations in male intrauterine growth restricted (IUGR) rats during and at the end of nephrogenesis in order to generate hypotheses which molecular mechanisms contribute to adverse kidney programming. IUGR was induced by low protein (LP) diet throughout pregnancy, bilateral uterine vessel ligation (LIG), or intrauterine stress (IUS) by sham operation. Offspring of unimpaired dams served as controls. Significant acute kidney damage was ruled out by negative results for proteins indicative of ER-stress, autophagy, apoptosis, or infiltration with macrophages. Renal gene expression was examined by transcriptome microarrays, demonstrating 53 (LP, n = 12; LIG, n = 32; IUS, n = 9) and 134 (LP, n = 10; LIG, n = 41; IUS, n = 83) differentially expressed transcripts on postnatal days (PND) 1 and 7, respectively. Reduced Pilra (all IUGR groups, PND 7), Nupr1 (LP and LIG, PND 7), and Kap (LIG, PND 1) as well as increased Ccl20, S100a8/a9 (LIG, PND 1), Ifna4, and Ltb4r2 (IUS, PND 7) indicated that inflammation-related molecular dysregulation could be a common feature after IUGR of different origins. Network analyses of transcripts and predicted upstream regulators hinted at proinflammatory adaptions mainly in LIG (arachidonic acid-binding, neutrophil aggregation, toll-like-receptor, NF-kappa B, and TNF signaling) and dysregulation of AMPK and PPAR signaling in LP pups. The latter may increase susceptibility towards obesity-associated kidney damage. Western blots of the most prominent predicted upstream regulators confirmed significant dysregulation of RICTOR in LP (PND 7) and LIG pups (PND 1), suggesting that mTOR-related processes could further modulate kidney programming in these groups of IUGR pups. Key messages Inflammation-related transcripts are dysregulated in neonatal IUGR rat kidneys. Upstream analyses indicate renal metabolic dysregulation after low protein diet. RICTOR is dysregulated after low protein diet and uterine vessel ligation

Kidney Cysts and Cystic Nephropathies in Children - A Consensus Guideline by 10 German Medical Societies

Zusammenfassung Die Leitlinie wurde im Konsens aller relevanten deutschen Fachgesellschaften zusammen mit Patientenvertretern erstellt. Standard der pra- und postnatalen Bildgebung von Nierenzysten ist die Sonografie, die auch im Abdomen und inneren Genitale extrarenale Manifestationen ausschlie ss en soll. Die MRT hat einzelne Indikationen. Bei Verdacht auf zystische Nierenerkrankungen ist eine kindernephrologische Vorstellung indiziert. Die pranatale Betreuung muss auf sehr unterschiedliche Schweregrade zugeschnitten werden. Bei renalem Oligohydramnion wird eine Entbindung in einem Perinatalzentrum der hochsten Stufe empfohlen. Neugeborenen sollte eine Nierenersatztherapie nicht allein aufgrund des Alters vorenthalten werden. Bei unilateraler multizystischer Nierendysplasie ist keine funktionelle Bildgebung oder Nephrektomie notwendig, aber (wie auch bei uni- oder bilateraler Nierenhypo-/dysplasie mit Zysten) eine langfristige nephrologische uberwachung. Bei der ARPKD (autosomal rezessive polyzystische Nierenerkrankung), Nephronophthise, Bardet-Biedl-Syndrom und HNF1B-Mutationen mussen extrarenale Manifestationen beachtet werden; eine genetische Testung ist hier sinnvoll. Kinder mit tuberoser Sklerose, Tumorpradispositionen (z.B. von Hippel Lindau Syndrom) oder hohem Risiko fur erworbene Nierenzysten sollten regelma ss ige Nierensonografien erhalten. Auch asymptomatische Kinder von Eltern mit ADPKD (aut. dominanter polyzystischer Nierenerkrankung) sollten regelma ss ig auf Hypertonie und Proteinurie untersucht werden. Eine prasymptomatische sonografische oder genetische Diagnostik dieser Minderjahrigen sollte nur nach ausfuhrlicher Aufklarung erwogen werden. Einfache (isolierte) Zysten sind bei Kindern sehr selten und eine ADPKD eines Elternteils sollte ausgeschlossen sein. Komplexe Nierenzysten bedurfen weiterer Abklarung. Abstract This consensus-based guideline was developed by all relevant German pediatric medical societies. Ultrasound is the standard imaging modality for pre- and postnatal kidney cysts and should also exclude extrarenal manifestations in the abdomen and internal genital organs. MRI has selected indications. Suspicion of a cystic kidney disease should prompt consultation of a pediatric nephrologist. Prenatal management must be tailored to very different degrees of disease severity. After renal oligohydramnios, we recommend delivery in a perinatal center. Neonates should not be denied renal replacement therapy solely because of their age. Children with unilateral multicystic dysplastic kidney do not require routine further imaging or nephrectomy, but long-term nephrology follow-up (as do children with uni- or bilateral kidney hypo-/dysplasia with cysts). ARPKD (autosomal recessive polycystic kidney disease), nephronophthisis, Bardet-Biedl syndrome and HNF1B mutations cause relevant extrarenal disease and genetic testing is advisable. Children with tuberous sclerosis complex, tumor predisposition (e.g. von Hippel Lindau syndrome) or high risk of acquired kidney cysts should have regular ultrasounds. Even asymptomatic children of parents with ADPKD (autosomal dominant PKD) should be monitored for hypertension and proteinuria. Presymptomatic diagnostic ultrasound or genetic examination for ADPKD in minors should only be done after thorough counselling. Simple cysts are very rare in children and ADPKD in a parent should be excluded. Complex renal cysts require further investigation

Early childhood height-adjusted total kidney volume as a risk marker of kidney survival in ARPKD

Autosomal recessive polycystic kidney disease (ARPKD) is characterized by bilateral fibrocystic changes resulting in pronounced kidney enlargement. Impairment of kidney function is highly variable and widely available prognostic markers are urgently needed as a base for clinical decision-making and future clinical trials. In this observational study we analyzed the longitudinal development of sonographic kidney measurements in a cohort of 456 ARPKD patients from the international registry study ARegPKD. We furthermore evaluated correlations of sonomorphometric findings and functional kidney disease with the aim to describe the natural disease course and to identify potential prognostic markers. Kidney pole-to-pole (PTP) length and estimated total kidney volume (eTKV) increase with growth throughout childhood and adolescence despite individual variability. Height-adjusted PTP length decreases over time, but such a trend cannot be seen for height-adjusted eTKV (haeTKV) where we even observed a slight mean linear increase of 4.5 ml/m per year during childhood and adolescence for the overall cohort. Patients with two null PKHD1 variants had larger first documented haeTKV values than children with missense variants (median (IQR) haeTKV 793 (450–1098) ml/m in Null/null, 403 (260–538) ml/m in Null/mis, 230 (169–357) ml/m in Mis/mis). In the overall cohort, estimated glomerular filtration rate decreases with increasing haeTKV (median (IQR) haeTKV 210 (150–267) ml/m in CKD stage 1, 472 (266–880) ml/m in stage 5 without kidney replacement therapy). Strikingly, there is a clear correlation between haeTKV in the first eighteen months of life and kidney survival in childhood and adolescence with ten-year kidney survival rates ranging from 20% in patients of the highest to 94% in the lowest quartile. Early childhood haeTKV may become an easily obtainable prognostic marker of kidney disease in ARPKD, e.g. for the identification of patients for clinical studies