The role of urea-induced osmotic diuresis and hypernatremia in a critically ill patient: case report and literature review / O papel da diurese osmótica induzida por ureia na geração de hipernatremia no paciente crítico: relato de caso e revisão da literatura

Abstract Hypernatremia is a common electrolyte problem at the intensive care setting, with a prevalence that can reach up to 25%. It is associated with a longer hospital stay and is an independent risk factor for mortality. We report a case of hypernatremia of multifactorial origin in the intensive care setting, emphasizing the role of osmotic diuresis due to excessive urea generation, an underdiagnosed and a not well-known cause of hypernatremia. This scenario may occur in patients using high doses of corticosteroids, with gastrointestinal bleeding, under diets and hyperprotein supplements, and with hypercatabolism, especially during the recovery phase of renal injury. Through the present teaching case, we discuss a clinical approach to the diagnosis of urea-induced osmotic diuresis and hypernatremia, highlighting the utility of the electrolyte-free water clearance concept in understanding the development of hypernatremia.

Resumo A hipernatremia é um distúrbio eletrolítico comum no ambiente de terapia intensiva, com uma prevalência que pode chegar a 25%. Está associada a maior tempo de internação hospitalar e é um fator de risco independente para a mortalidade. Este relato ilustra um caso de hipernatremia de origem multifatorial no ambiente de terapia intensiva. Destacaremos o papel da diurese osmótica por geração excessiva de ureia, uma causa de hipernatremia pouco conhecida e subdiagnosticada. Este cenário pode estar presente em pacientes em uso de elevadas doses de corticoides, com sangramento gastrointestinal, em uso de dietas e suplementos hiperproteicos e estado de hipercatabolismo, especialmente durante a fase de recuperação de injúria renal. A seguir, discutiremos uma abordagem clínica para o diagnóstico da hipernatremia secundária à diurese osmótica induzida por ureia, destacando a importância do conceito de clearance de água livre de eletrólitos nesse contexto.

Low-protein diet does not alter reproductive, biochemical, and hematological parameters in pregnant Wistar rats

The aim of this study was to investigate the reproductive, biochemical, and hematological outcomes of pregnant rats exposed to protein restriction. Wistar rat dams were fed a control normal-protein (NP, 17% protein, n=8) or a low-protein (LP, 8% protein, n=14) diet from the 1st to the 20th day of pregnancy. On the 20th day, the clinical signs of toxicity were evaluated. The pregnant rats were then anesthetized and blood samples were collected for biochemical-hematological analyses, and laparotomy was performed to evaluate reproductive parameters. No sign of toxicity, or differences (P>0.05) in body weight gain and biochemical parameters (urea, creatinine, albumin, globulin, and total protein) between NP and LP pregnant dams were observed. Similarly, hematological data, including red blood cell count, white blood cell count, hemoglobin, hematocrit, red blood cell distribution width (coefficient of variation), mean corpuscular volume, mean corpuscular hemoglobin, mean corpuscular hemoglobin concentration, % lymphocytes, absolute lymphocyte count, platelet count, and mean platelet volume were similar (P>0.05) at the end of pregnancy. Reproductive parameters (the dam-offspring relationship, ovary mass, placenta mass, number of corpora lutea, implantation index, resorption index, and the pre- and post-implantation loss rates) were also not different (P>0.05) between NP and LP pregnant dams. The present data showed that a protein-restricted diet during pregnancy did not alter reproductive, biochemical, and hematological parameters and seems not to have any toxic effect on pregnant Wistar rats.

Desnutrição materna durante a lactação em ratos Wistar: efeitos sobre as fibras elásticas da matriz extracelular na traqueia dos filhotes / Maternal malnutrition during lactation in Wistar rats: effects on elastic fibers of the extracellular matrix in the trachea of offspring

OBJETIVO: Investigar os efeitos da desnutrição proteica materna durante a lactação sobre as fibras elásticas da traqueia de filhotes de ratos Wistar. MÉTODOS: Ao nascimento, 12 filhotes machos de duas ratas Wistar foram igualmente divididos em dois grupos: grupo controle, cuja mãe recebeu água e dieta padrão de laboratório ad libitum durante a lactação, e grupo restrição proteica (RP), cuja mãe recebeu água ad libitum e dieta isoenergética com RP (8% de proteína). Aos 21 dias de vida, os filhotes foram sacrificados, e suas traqueias foram ressecadas. As fibras elásticas foram coradas pelo método de resorcina-fucsina de Weigert (precedido de oxidação) e avaliadas sob microscopia óptica. As determinações morfométricas foram feitas por estereologia, utilizando o método de contagem de pontos, e expressas em densidade volumétrica. RESULTADOS: As fibras elásticas foram identificadas abaixo da mucosa traqueal, sendo a maioria em distribuição longitudinal. Além disso, camadas circulares bem definidas de fibras elásticas envolviam as superfícies interna e externa do anel cartilaginoso. Não houve diferenças entre os grupos quanto à organização e distribuição das fibras elásticas. A densidade volumétrica das fibras elásticas dos filhotes nos grupos controle e RP foi de, respectivamente, 2,46 ± 0,99% e 3,25 ± 1,13% (p < 0,01). CONCLUSÕES: Nossos resultados sugerem que a densidade volumétrica de fibras elásticas é maior em filhotes de ratos alimentados por fêmeas submetidas a dieta com RP do que naqueles de mães recebendo dieta normal.

OBJECTIVE: To investigate the effects of maternal protein malnutrition during lactation on the elastic fibers in the tracheas of Wistar rat pups. METHODS: At delivery, 12 male pups of two Wistar rat dams were equally divided into two groups: control, in which the dam received water and standard rat chow ad libitum during lactation; and protein-restricted (PR), in which the dam received water ad libitum and an isoenergetic PR diet (8% protein). At 21 days of age, the pups were killed and their tracheas were excised. The elastic fibers were stained with Weigert's resorcin-fuchsin (after oxidation) and evaluated under light microscopy. Morphometric determinations were performed by stereology, with the point-counting method, and expressed as volumetric densities. RESULTS: Elastic fibers, most having a longitudinal distribution, were identified beneath the tracheal mucosa. In addition, well-defined circular layers of elastic fibers were found around the inner and outer surfaces of the cartilaginous ring. There were no differences between the groups regarding the organization and distribution of the elastic fibers. The volumetric density of the elastic fibers of the pups in the control and PR groups was 2.46 ± 0.99% and 3.25 ± 1.13%, respectively (p < 0.01). CONCLUSIONS: The volumetric density of elastic fibers appears to be greater in rat pups breastfed by dams receiving a PR diet than in those breastfed by dams receiving a normal diet.

Restrição proteica materna e alteração do desenvolvimento das artérias coronárias em camundongos / Maternal protein restriction and alteration of the development of coronary arteries in mice

O desenvolvimento da programação fetal é considerado um importante fator de risco para doenças não-transmissíveis da vida adulta, incluindo doença cardíaca coronariana. Com o objetivo de investigar a associação entre nutrição materna e o desenvolvimento das artérias coronárias (AC) em embriões de camundongos estadiados; embriões de camundongos C57BL/6 nos estádios de 16-23 foram retirados de mães alimentadas com dietas de proteína normal (NP) ou de baixa proteína (LP), e as AC foram estudadas. Embora os embriões LP possuam massa corporal menor, entretanto tinham taxas de crescimento cardíaco maior, quando comparados com os embriões NP. O Plexo subepicárdico foi observado no início do período pós-somítico (estádio 16) em embriões NP, enquanto que nos embriões LP apenas no estádio 17 (P <0,01), persistindo até o estádio 18 (P <0,01). As artérias coronárias foram detectadas inicialmente no estádio 18 dos embrioes NP, já nos embriões LP foram encontradas a partir do estádio 19 (P <0,01). Núcleos apoptóticos foram observados em torno do anel aórtico peritruncal no estádio 18 em embriões NP e LP. Células FLK1+ (Fetal Liver Kinase 1 = VEGFr2 = Vascular Endothelial Growth Factor Receptor 2) apresentaram uma distribuição homogênea nos embriões NP já no estádio 18, enquanto uma distribuição semelhante nos embriões LP foi visto apenas nos estádios 22 e 23. A restrição proteica materna em camundongos leva a um atraso no crescimento do coração no período embrionário modificando o desenvolvimento do plexo peritruncal subepicárdica e diminuindo a taxa de apoptose na região do futuro orifício coronariano

Programming of fetal development is considered to be an important risk factor for non-communicable diseases of adulthood, including coronary heart disease (CHD). Aiming to investigate the association between maternal nutrition and the development of the coronary arteries (CA) in staged mice embryos, C57BL/6 mice embryos from stages 16 to 23 were taken from mothers fed a normal protein (NP) or low protein (LP) diet, and the CA were studied. Although the LP embryos had lower masses, they had faster heart growth rates when compared to the NP embryos. The subepicardial plexuses were observed earlier in the NP embryos (stage 20) than in the LP ones (stage 22) (P<0.01). Apoptotic nuclei were seen around the aortic peritruncal ring beginning at stage 18 in the NP and LP embryos. FLK1+ (fetal liver kinase 1 = VEGFr2 or vascular endothelial growth factor receptor 2) cells had a homogeneous distribution in the NP embryos as early as stage 18, whereas a similar distribution in the LP embryos was only seen at stages 22 and 23. Maternal protein restriction in mice leads to a delay in the growth of the heart in the embryonic period modifying the development of the subepicardial peritruncal plexus and the apoptosis in the future coronary orifice region

Avaliação da composição corporal e homeostase glicêmica e papel da sinalização de leptina em ratos programados pela restrição proteíca materna na lactação / Evaluation of body composition and glucose homeostasis and role of leptin signaling in mice programmed by maternal protein restriction in lactation

A restrição protéica neonatal causa baixo peso corporal, hipertireoidismo, hipoinsulinemia, aumento de glicocorticóides e de catecolaminas nos animais aos 180 dias. Assim, estudamos nestes animais durante o seu desenvolvimento, a composição corporal, lipídeos e proteínas no soro, além de alguns hormônios relacionados à homeostase glicêmica. Ao nascimento, dividimos as ratas lactantes em: controle (C) - alimentadas com ração comercial (23% de proteína) e RP - alimentadas com dieta hipoprotéica (8% de proteína). Após o desmame, os filhotes receberam dieta comercial. Os animais foram sacrificados em idades distintas (21, 90 e 80 dias). Os animais RP apresentaram baixa massa corporal desde a lactação até 180 dias, menor massa de gordura visceral e total (90 e 180 dias); menor conteúdo corporal de proteína e maior água corporal aos 21 dias. A morfologia dos adipócitos viscerais e subcutâneos aos 180 dias mostrou menor área e perímetro. Observamos menor massa, comprimento e diâmetro do fêmur em todas as idades estudadas. Detectamos maior conteúdo de glicogênio hepático (21 dias) e muscular (180 dias). Aos 21 dias, a insulinemia foi menor e a adiponectinemia foi maior. Aos 180 dias, detectamos menor insulina sérica e glicemia. Em relação à função adrenal, verificamos maior concentração de corticosterona sérica, maior conteúdo intra-adrenal e secreção in vitro de catecolaminas aos 180 dias. A prole RP apresentou: menores concentrações de proteínas totais e frações (21 dias), menor concentração de colesterol total (180 dias), maior concentração de LDL-c (21 dias), menores concentrações de VLDL-c e triglicerídeos (21 e 90 dias). Quanto à sinalização da leptina, observamos menor conteúdo de STAT3 no hipotálamo aos 180 dias. Na tireóide, estes animais apresentaram menor conteúdo de Ob-Rb (21 dias) e a expressão de JAK2 foi maior aos 21 dias e menor aos 180 dias de idade. Assim, a RP materna na lactação induz a uma desnutrição energético-protéica...

Neonatal protein restriction (PR) causes lower body weight, hyperthyroidism, hypoinsulinaemia, higher glucocorticoids and catecholamines in the adult rat offspring. In this model, we studied the body composition, serum lipids and proteins, as well as, some hormones related to glucose homeostasis in the offspring during development. At birth, lactating rats were divided into: control (C) - fed a normal diet (23% protein) and PR - fed a diet with 8% protein. After weaning, pups received normal diet. They were killed at distinct ages until the 21, 90 and 180 days-old. PR rats presented lower body weight since weaning until 180 days-old, lower visceral and fat mass (90th and 180th day), lower body protein and higher body water (21st day: +3%). At 180 days-old, the visceral and subcutaneous adipocytes morphology showed lower area and perimeter. Concerning the femur, we observed lower weight, length and width at all analized periods. We detected higher liver (21 days-old) and muscle glycogen content (180 days-old). At 21st day, insulinaemia was lower and adiponectinaemia was higher. At 180th day, we detected lower insulinaemia and glycaemia. Concerning adrenal function, we verified higher serum corticosterone, adrenal catecholamines content and in vitro secretion. PR offspring showed the following serum parameters: lower total protein serum and fractions (21st day), lower total serum cholesterol (180th day), higher serum LDL-c (21st day), lower serum VLDL-c and triglycerides (21st and 90st day). Regardind the leptin signaling, we observed lower hipothalamic STAT3 content at 180th day. In thyroid, these animals presented lower Ob-Rb content (21st day); JAK2 content was higher at 21st day and lower at 180th day. Thus, maternal PR during lactation induces an energy-protein malnutrition, characterized by an impairment of the pup's protein anabolism, and after weaning, the offspring showed lower central and total adiposity, suggesting a higher lipolitic activity...

Metabolismo mitocondrial y ultraestructura de músculo esquelético de ratón con restricción calórico proteica / Mitochondrial metabolism and ultrastructure of mice's skeletal muscle with caloric proteic restriction

Para estudiar el metabolismo mitocondrial en este trabajo se utilizó el método de permeabilización del tejido muscular mediante saponina, la cual destruye el sarcolema, manteniendo las mitocondrias "in situ". Para crear un modelo de patología mitocondrial se produjo restricción calórico-proteica (RCP) en ratones adultos con un 50 por ciento de la dieta de los ratones alimentados "ad libitum" durante un período de 15 días. Se efectuaron estudios del consumo de oxígeno, relación ADP/O, así como la actividad enzimática de los Complejos I y II de la cadena respiratoria y la determinación de proteínas. Para evaluar el efecto de la saponina sobre el tejido muscular en presencia y ausencia de restricción calórica-proteica se observaron muestras del mismo al microscopio electrónico de transmisión. Los resultados revelaron en los animales una pérdida de peso, disminución en el consumo de oxígeno y de la relación ADP/O en presencia de glutamato y de succinato, por otra parte se obtuvo una disminución evidente de la actividad del Complejo I, sin modificación del Complejo II. Las observaciones obtenidas con el microscopio electrónico demuestran que la RCP en ratas tiene efecto directo sobre el aparato contráctil de las fibras musculares, produciendo desorganización de las estructuras sarcoméricas y reducción importante de los miofilamentos. La saponina, por otra parte afecta todo el sistema de citomembranas.

In this work, the method of permeabilization of muscular tissue with saponin was employed, which destroyed the sarcolemma but maintained the mitochondria "in situ". To create a model of mitochondrial pathology, a caloric-protein restriction (CPR) was produced in adult mice by reducing 50 percent the diet to fed animals for 15 days. Determinations of oxygen consumption, ADP/O ratio, total proteins, as well as enzymatic activities of respiratory chain Complexes I and II were performed. To evaluate the effect of saponin on muscular tissues under normal or CPR conditions, electron microscopy observations were done. Results of the study showed that the animals in CPR group had loss of weight, reduced total proteins, diminished oxygen consumption, lower ADP/O ratio in the presence of glutamate and succinate, and a notable decrement in the activity of Complex I but without modifications of that of Complex II. Electron microscopic observations demonstrates directs effects of CPR over the contractile apparatus of muscle fibers, such as, disorganization of sarcomeric structures and an important reduction of the myofilaments. On the other hand, saponin affected all cytomembranous systems.

The time has come: a new scene for PKU treatment

Phenylketonuria (PKU) is one of the few genetic diseases in which mental retardation can be prevented. Hence, diagnosis and treatment must be established early. PKU treatment consists of a phenylalanine-restricted diet supplemented with a phenylalanine-free mixture of amino acids. However, it is difficult to adhere to this diet. In the last decade, a better comprehension of the biochemistry, genetics and molecular basis of the disease, as well as the need for easier treatment, led to the development of several new therapeutic strategies for PKU. In the present study, we evaluated these new therapeutic options in terms of theoretical basis, methodologies, efficacy, and costs.

Regulação da expressão gênica das UCP2 e UCP3 pela restrição energética, jejum e exercício físico / UCP2 and UCP3 genic expression: regulation by food restriction, fasting and physical exercise

O tecido adiposo marrom, onde se localiza a proteína desacopladora 1 (UCP1 - uncoupling protein 1), é um tecido termogênico presente somente nos pequenos mamíferos e neonatos, com função de manter temperatura e peso corporal estáveis quando da exposição ao frio ou consumo de dietas hipercalóricas. Como a UCP1 está localizada exclusivamente no tecido adiposo marrom, tecido pouco expressado em adultos, os estudos dão ênfase às proteínas desacopladoras 2 e 3 (UCP2 e UCP3), proteínas homólogas à UCP1, expressas em múltiplos tecidos e nos músculos esqueléticos, respectivamente. A atividade física provoca aumento do RNAm da UCP2 e UCP3, questiona-se, porém, se este aumento é devido a mudanças no metabolismo de gordura ou a mudanças no metabolismo energético. Durante a restrição energética ou jejum, há depleção de gordura corporal e aumento da concentração plasmática de ácidos graxos livres, com regulação positiva da UCP2 e da UCP3 no músculo e aumento da oxidação lipídica. A concentração elevada de ácidos graxos representa sinal intracelular importante na indução da expressão das UCP no músculo, o que pode estar ligado à sua utilização como combustível até que ocorra aumento da demanda do organismo para dissipação da energia. No entanto, discute-se se a UCP2 e a UCP3 no músculo esquelético têm como função mediar a termogênese ou regular a oxidação de lipídios.

Efeito da temperatura ambiente e da restrição alimentar protéica ou energética sobre o ganho de peso e crescimento ósseo de frangos de corte / Effect of environmental temperature and protein or energy restriction on body weight gain and broiler chicken bone growth

Avaliou-se o efeito da restrição alimentar qualitativa, protéica ou energética sobre o ganho de peso e desenvolvimento ósseo de frangos criados em diferentes temperaturas ambientes. O delineamento experimental foi inteiramente ao acaso, com os tratamentos em um esquema fatorial 3 3, com os fatores: restrição alimentar (R0 = ad libitum; R1 = restrição energética; R2 = restrição protéica) e temperatura ambiente (T1 = 18ºC; T2 = 25ºC; T3 = 33º C). Do 8º ao 14º dia, os frangos foram submetidos à restrição energética (2565kcal de EM/kg e 20 por cento de proteína bruta) ou protéica (2850kcal de EM/kg e 15 por cento de proteína bruta), sendo, posteriormente, alimentados à vontade. A restrição protéica resultou em menor ganho de peso e menor diâmetro do fêmur no 14º dia de idade. Não foram observadas diferenças nessas características a partir do 21º dia de idade. O ganho de peso e o crescimento do fêmur não foram influenciados pela restrição energética. A alta temperatura ambiente (33ºC) influenciou negativamente o ganho de peso e o diâmetro do fêmur, a partir do 21º dia, e o comprimento do fêmur, no 42º dia de idade. Tanto a restrição protéica, na segunda semana, quanto a alta temperatura ambiente, a partir do 21º dia de idade, reduziram o ganho de peso e o crescimento do fêmur de frangos.

Nutrition in the management of hepatic encephalopathy.

Nutritional factors play a major role both in the pathogenesis as well as management of hepatic encephalopathy (HE). Physicians treating patients with chronic liver disease often restrict the intake of dietary protein to prevent a rise in blood ammonia levels. The role of protein restriction in patients with chronic hepatic encephalopathy (CHE) has been questioned recently as the efficacy of protein withdrawal in patients with CHE has never been subjected to a controlled trial. Evidence suggests that protein intake plays only a limited role in precipitating encephalopathy. In fact, measures taken to suppress endogenous protein breakdown are more effective than dietary restrictions in reducing the load of amino acids on the decompensated liver. A protein intake of less than 40 g per day, as has been indicated, contributes to a negative nitrogen balance, which along with increased endogenous protein breakdown, worsens encephalopathy. A positive nitrogen balance may have positive effects on encephalopathy. Rather, depressed plasma branched-chain amino acid (BCAA) levels, implicated in the pathogenesis of HE, also supervene in cirrhosis only when malnutrition is present as well. Therefore, the emphasis in the nutritional management of patients with HE should not be on the reduction of protein intake. Instead, the goal should be to promote synthesis by making available ample amounts of amino acids, while instituting other measures to reverse the ongoing catabolism. Different protein sources have varying effects on HE and efforts should be made to identify the most tolerated protein source to prevent malnutrition and maintain these patients on a long-term basis.

Practical aspects of managing low protein diets.

Many inborn errors of metabolism can be successfully managed by restriction of natural protein intake, with or without special supplements. In some cases, there is a need for clear advice on management during metabolic crisis brought about by illness. Even when medical facilities and ongoing support are on hand, and special products are available and affordable, management of such conditions is challenging to families. Tailoring diet instruction to the needs and capabilities of the family is most likely to achieve success. Many Australian families cope better with simple guidelines aimed at reducing protein intake within the needs for growth and development and this style of management is also more likely to be successful in countries in which support is limited. Simple guidelines can take the form of increasing intake of certain types of foods and limiting others. Assessment of vitamin and mineral intake is however essential. Breastfeeding will provide less protein than standard infant formula, as well as immune protection, and needs to be encouraged and supported. Restricting meat and other high protein foods with increased intake of cereal and vegetable protein will still substantially decrease protein intake. Increasing intake of low protein vegetable sources or special low protein foods will also by default decrease protein intake. Families need specific guidelines for the care of their child when metabolic decompensation is a risk, with the aim of maintaining adequate energy intake, in forms that the child can eat or drink. A specialist pediatric dietitian can provide the expertise in formulating management plans appropriate for the family and facilities, with ongoing local management. The support of other families dealing with similar conditions can also be invaluable.

Effect of long-term intake of Asian food with different glycemic indices on diabetic control and protein conservation in type 2 diabetic patients.

The study was carried out in 10 females with type 2 diabetes aged 32-60 yrs. All of them were receiving weight-maintaining diets composed of 12 per cent protein, 30 per cent fat and 58 per cent carbohydrate. The only difference among all study-diets was the types of complex carbohydrate used. High-glycemic diet (HG) or low glycemic diet (LG) consisted mainly of glutinous rice or mungbean noodles and the intermediate-glycemic diet (DM) was solely white rice. After the metabolic evaluation of the baseline diet (BL), each subject was placed on DM and followed randomly by HG and LG or vice versa for 4 weeks each. The diurnal plasma glucose levels tended to be lowest after LG. The integrated plasma glucose levels among all diets were not different. The integrated insulin levels after DM and LG did not differ but they were lower than HG and BL. Long-term ingestion of all test-diets spilt less urinary glucose than BL, the lowest was LG. HbA1 levels and nitrogen balance after all diets were better than BL, the best was LG. It was concluded that in addition to strict dietary control, ingestion of mungbean noodles (a low glycemic diet) without increasing fiber intake, can improve diabetic control and protein conservation in type 2 diabetes.

The role of dietary protein restriction in Indian patients with chronic renal failure.

OBJECTIVE: To determine dietary protein intake in Indian patients with chronic renal failure and the impact of prescribing protein restricted diets to these patients. METHODS: Baseline dietary protein intake was estimated in forty five patients with chronic renal failure on an unrestricted diet. Of these 45 patients, 27 were vegetarian and 18 were non-vegetarian. Then the patients were divided into 2 comparable groups. Twenty group I patients were allowed to continue unrestricted diet while 25 group II patients were advised 0.6 g/kg/day (50% high biological value) protein. Protein intake was estimated at 1 and 2 month follow up. RESULTS: The baseline dietary protein intake in 45 patients was 0.65 +/- 0.15 (mean +/- 1 SD) g/kg/day. There was no significant difference in protein intake of group I and group II patients at 1 and 2 month follow up. Also, the protein intake in group II patients was not different at 1 and 2 month follow up compared to baseline value. CONCLUSION: Protein intake of Indian patients with CRF is usually low even on an unrestricted diet. The usual practice of advising dietary protein restriction has no significant impact on the protein intake.