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Biochemical Assessment of Nutrition Status – Protein Assessment

August 2, 2016 Clinical Skills, Critical Care, Medical Nutrition No comments , , , , , , , , , , , , , , , , ,

Protein Assessment

Protein's unique function in supporting cellular growth and development elevates its significance in nutrition assessment. Even though a large amout of protein is stored in muscle and viscera, the body strives to protect it from being used as an energy source. Under healthy conditions or normal energy deficits, additional energy is drawn from fat and glycogen stores. But when the body is under metabolic stress, it draws protein from the muscles to meet its needs. No specific laboratory value can determine the precise protein status of an individual. Each test has its own limitations. Therefore, a comprehensive nutrition assessment must use a battery of tests in order to delineate the changes that mark the development of a nutrient deficiency.

Historically, protein assessment has focused on evaluation of two compartments: somatic and visceral. Somatic protein refers to skeletal muscle. Visceral protein refers to nonmuscular protein making up the organs, structrual components, erythrocytes, granulocytes, and lymphocytes, as well as other proteins found in the blood.

Somatic Protein Assessment

In addition to using anthropometric measures such as midarm muscle area, midarm circumference, and overall body weight and subjective global assessment, biochemical tests such as creatinine height index and nitrogen balance can be used to more specifically analyze somatic protein status.

Screen Shot 2016-08-01 at 2.59.17 PMNutrition Care Indicator: Creatinine Hight Index Creatinine is formed at a constant daily rate from muscle creatine phosphate. Creatine phosphate group, which is stored in muscle, provides the phosphate group needed to regenerate ATP during high-intensity exercise. Creatinine is not stored in muscle but is cleared and excreted by the kidney. Daily urine output of creatinine can be correlated with total muscle mass.

For Creatinine Height Index, a 24-hour urine collection is performed and the total amount of creatinine excreted in that 24-hour period is compared with either a standard based on height or (as a percentage) to a standard excretion for a particular reference individual of a specific height, gender, and age.

In Table 3.8, expected creatinine excretion is shown for various heights. Creatinine height index (CHI) is usually expressed as a percentage of a standard value and is calculated with the following equation:

CHI = 24-hour urine creatinine (mg) / expected 24-hour urine creatinine (mg) x 100

A value calculated to be 60%-80% of the standard suggests mild skeletal muscle depletion, 40%-59% suggests moderate skeletal muscle depletion, and <40% is considered to be a severe loss of skeletal muscle.

One limitation of this measurement is that its accuracy depends on a complete collection of urine for 24 hours, which is a common source of error and makes the test more difficult to conduct. Interpretation of this test must also take into accouont the fact that creatinine excretion can be either higher or lower than the standard depending on certain clinical conditions. Creatinine excretion is increased by meat consumption, sepsis, trauma, fever, and strenuous exercise, and during the second half of the menstrual cycle. Creatinine excretion is decreased with compromised renal function, low urine output, aging, and muscle atrophy unrelated to malnutrition. Furthermore, standards that are used do not account for creatinine excretion changes with age, disease, physical training, frame size, or weight status.

Nutrition Care Indicator: Nitrogen Balance In healthy individuals, nitrogen excretion should be equal to nitrogen intake – thus indicating a state of nitrogen balance. A negative nitrogen balance develops when nitrogen excretion is greater than nitrogen intake, indicating catabolism or inadequate nitrogen intake, whereas a positive nitrogen blance occurs when nitrogen intake is greater than excretion. Measuring nitrogen balance assesses overall protein status. Additionally, it can serve as a metod of assessing the effectiveness of a nutrition intervention. Nitrogen balance is not routinely used for all acute-care patients but is more common in critical care, with nutrition support, and in research settings.

In order to measure nitrogen balance, the dietary intake of protein for a 24-hour period is estiamted while a 24-hour urine collection is gathered to measure total excretion of nitrogen. Nitrogen loss through other routes such as fecal excretion, normal skin breakdown, wound drainage, and nonurea nitrogen is estimated using a constant value of either 3 or 4. The following equation is used for calculation (6.25 g protein = 1 g nitrogen):

N2 balance = dietary protein intake / 6.25 – urine urea nitrogen – 4

Limitations of measuring nitrogen balance include the inherent error of 24-hour urine collection, failure to account for renal impairment, and inability to measure nitrogen losses from some wounds, burns, diarrhea, and vomiting. Nitrogen intake may also pose difficulties. Oral protein intake may be difficult to measure consistently and accurately except when the pateint is exclusively on enteral or parenteral nutrition support.

Visceral Protein Assessment

As stated previously, visceral protein refers to nonskeletal protein making up the organs, structrual components, erythrocytes, granulocytes, and lymphocytes, as well as other proteins found in the blood. Thus, visceral protein assessment indirectly measures these protein stores by assessing proteins made by these organs (primarily the liver) and present in blood or lymph fluid. Theoretically, serum protein measurement is affected by a change in the amount of amino acids needed for protein synthesis by the liver. Thus, a change in serum protein levels would be consistent with changes in visceral protein status. However, the synthesis rate of these transport proteins can be affected by factors other than protein intake or protein requirements. In general, transport protein synthesis is inhibited when the acute-phase protein synthesis rate is increased in response to inflammation, stress, or trauma. In the acute care setting where most patients are affected by these conditions, using transport proteins to measure protein status becomes difficult. The sensitivity and specificity of these assessment measures are often determined by the "half-life" of the protein. Half-life, in this clinical situation, means the amount of time it takes for half of the protein to be either eliminated or broken down by the body. Therefore, actual changes in serum levels will be reflected mroe quickly in proteins with a shorter half-life than in those with a longer half-life.

Acute-phase proteins are defined as "those whose plasma concentration increases (positive acute-phase proteins) or decreases (negative acute-phase proteins) by at least 25%" during inflammation, illness, and/or metabolic stress. C-reactive protein (CRP) is a common indicator for inflammation that has also been correlated with visceral protein markers. Increasing levels of CRP, indicating acute inflammation, are consistent with lower visceral protein markers as well as poor outcomes for the individual.

Nutrition Care Indicator: Albumin Albumin is probably the most well-known measure of visceral protein status even though it is not the best. It is also the most abundant serum protein. Approximately 60% of the albumin in the body is found in extravascular spaces – in skin, muscle, and organs. The remaining albumin is found within the vascular space, which allows for its measurement. Normal serum levels of albumin are >=3.5 g/dL. Synthesized by the liver (120-170 mg/kg/day), albumin serves many significant functions within the body, most commonly as a transport protein and as a component of vascular fluid and electrolyte balance. Decreases in serum albumin occur due to a decreased synthesis rate, an increased degradation rate, or a change in fluid distribution (either total volume or between compartments). Using albumin as a nutritional assessment marker in acute care is complicated by the fact that most patients are experiencing at least one of these factors; thus, albumin changes often reflect illness and not necessarily nutritional status.

Albumin has been the subject of significant nutrition research and thus serves as a good prognostic screening tool, though it is not as reliable in the acute care setting as an overall indicator of protein and nutritional status due to the effects of disease, inflammation, hydration, and numerous other factors. Still, because it is easily measured and has an abundant body pool, albumin is readily available in the lab reports at the acute care setting. Decreased albumin levels have been correlated with increased morbidity, mortality, and length of hospital stay.

Some of the same factors contribute to its limitations as well. 1)Albumin has a long half-life (approximately 20 days), which decreases its sensitivity to short-term changes in protein status or to short-term interventions to improve protein status. 2)Albumin synthesis is also affected by acute stress and the inflammation response. 3)Albumin loss occurs with burn injuries, nephrotic syndrome, protein-losing enteropathy, and cirrhosis. 4)Other medical conditions that may result in hypoalbuminemia include infection, multiple myeloma, acute or chronic inflammation, and rheumatoid arthritis. 5)Levels also decrease with aging. On the other hand, 6)albumin levels will be higher with dehydration and when individuals are prescribed anabolic hormones and corticosteroids. Albumin levels must be interpreted carefully – the levels are a better indicator of stress and inflammation than of overall protein nutrition, even though they historically have been widely used for that purpose.

Nutrition Care Indicator: Transferrin Synthesized by the liver, transferrin serves as a transporter for iron throughout the body. It can also serve as an indicator of protein status because it has a shorter half-life (8-10 days) and thus is sensitive to acute changes in protein intake or requirments. Normal serum levels are 215-380 mg/dL. Transferrin can be measured directly or calculated from total iron binding capacity (TIBC) with the use of the following equation: Transferrin saturation (%) = (Serum iron level X 100%) / TIBC.

Transferrin's primary limitation is that its concentration is directly affected by iron status. When iron stores are decreased, transferrin levels will increase to accommodate the need for increased levels of transport. Other disease states such as hepatic and renal disease, inflammation, and congestive heart failure can also affect transferrin levels.

Nutrition Care Indicator: Prealbumin (Thyroxine-Binding Prealbumin or Transthyretin) Prealbumin is another example of an acute-phase transport protein synthesized by the liver. Prealbumin is responsible for transport of thyroxine and is associated with retinol-binding protein.

Research has shown that because of its very short half-life (2 days), prealbumin levels respond to short-term modifications in nutritional intake and interventions. Prealbumin is a more expensive test than albumin, but research has indicated that if it were used routinely during admission screening, approximately 44% more hospitalized patients would be identified as being at nutritional risk. The clinician evaluating prealbumin should recognize that levels are inceased with renal disease and Hodgkin's disease, and decreased with liver disorders such as hepatitis or cirrhosis, malabsorption, and hyperthyroidism. Furthermore, like albumin, prealbumin levels may decrease as a result of illness and inflammation and not necessarily malnutrition.

PS: 1/5-life of nutrition care indicators, albumin 193 hrs; transferrin 70 hrs; prealbumin 15 hrs; RBP 4 hrs.

Nutrition Care Indicator: Retinol-Binding Protein (RBP) Retinol-binding protein, synthesized by the liver, is an acute-phase respondent and serves as the transport molecule for vitamin A (retinol). RBP has the smallest body pool and shortest half-life (12 hours) of the serum proteins.

RBP is considered to be one of the more sensitive indicators of protein status in the non-critical ill. Theoretically, it should reflect short-term changes and responses to nutrition support interventions. Lee and Nieman note that it is most likely a better measure of recent dietary intake than an indicator of overall nutrition status. The literature does not support its use preferentially over other measures of serum proteins. Note that RBP levels are elevated with renal failure and decreased with hyperthyroidism, liver failure, vitamin A deficiency, zinc deficiency, and metabolic stress.

Nutrition Care Indicator: C-Reactive Protein (CRP) C-reactive protein is a positive acute-phase protein that is released during periods of inflammation and infection. As the levels of acute-phase protein increase, hepatic reprioritization decreases synthesis of other transport proteins, such as prealbumin or albumin. Increasingly, CRP is being used to investigate the contribution of inflammation to malnutrition syndromes. Since albumin and prealbumin levels may be reduced by the inflammatory process, they are not reliable prognostic indicators during periods of inflammation and infection; in these situations, the CRP level becomes a component of nutrition assessment. Higher CRP levels are assocaited with increased nutritional risk during stress, illness, and trauma.

Renal Potassium Reabsorption and Secretion

July 24, 2016 Cardiology, Critical Care, Nephrology, Physiology and Pathophysiology No comments , , , , , , , , , , ,

Percentage of fitered load transported at different locations depending on diet

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The Importance of Potassium Balance

The vast majority of body potassium is freely dissolved in the cytosol of tissue cells and constitutes the major osmotic component of the intracellular fluid (ICF). Only about 2% of total-body potassium is in the extracellular fluid (ECF). This small fraction, however, is absolutely crucial for body function, and the concentration of potassium in the ECF is a closely regulated quantitiy. Major increases and decreases (called hyperkalemia and hypokalemia) in plasma values are cause for medical intervention. The importance of maintaining this concentration stems primarily from the role of potassium in the excitability of nerve and muscle, especially the heart.

The ratio of the intracellular to extracellular concentration of potassium is the major determinant of the resting membrane potential in these cells. A significant rise in the extracellular potassium concentration causes a sustained depolarization. Low extracellular potassium may hyperpolarize or depolarize depending on how changes in extracellular potassium affect membrane permeability. Both conditions lead to muscle and cardiac disturbances.


Potassium Movement Between the ICF and ECF

Given that the vast majority of body potassium is contained within cells, the extracellular potassium concentration is cruically dependent on 1).the total amount of potassium in the body and 2).the distribution of this potassium between the extracellular and intracellular fluid compartments. Total-body potassium is determined by the balance between potassium intake and excretion. Healthy individuals remain in potassium balance, as they do in sodium balance, by excreting potassium in response to dietary loads and withholdin g excretion when body potassium is depleted. The urine is the major route of potassium excretion, although some is lost in the feces and sweat. Normally the losses via sweat and the gastrointestinal tract are small, but large quantities can be the lost from digestive tract during vomiting or diarrhea. The control of renal potassium transport is the major mechanism by which total-body potassium is maintained in balance.

The high level of potassium within cells is maintained by the collective operation of the Na-K-ATPase plasma membrane pumps, which actively transport potassium into cells. Because the total amount of potassium in the extracellular compartment is so small (40-60 mEq total), even very slight shifts of potassium into or out of cells produce large changes in extracellular potassium concentration. Similarly, a meal rich in potassium (e.g., steak, potato, and spinach) could easily double the extracellular concentration of potassium if most of that potassium were not transferred from the blood to the intracellular compartment. It is crucial, therefore, that dietary loads be taken up into the intracellular compartment rapidly to prevent major changes in plasma potassium concentration.

The tissue contributing most to the sequestration of potassium is skeletal muscle, simply because muscle cells collectively contain the largest intracellular volume. Muscle effectively buffers extracellular potassium by taking up or releasing it to keep the plasma potassium concentration close to normal. On a moment-to-moment basis, this is what protects the ECF from large swings in potassium concentration. Major factors involved in these homeostatic processes include insulin and epinephrine, both of which cause increased potassium uptake by muscle and certain other cells through stimulation of plasma membrane Na-K-ATPases. Another influence is the gastrointestinal tract, which contains an elaborate neural network (the "gut brain") that sends signals to the central nervous system. It also contains a complement of enteroendocrine cells that release an array of peptide hormones. Together these neural and hormonal signals affect many target organs, including the kidneys in response to dietary input.

The increase in plasma insulin concentration after a meal is a crucial factor in moving potassium absorbed from the GI tract into cells rather than allowing to accumulate in the ECF. This newly ingested potassium then slowly comes out of cells between meals to be excreted in the urine. Moreover, a large increase in plasma potassium concentration facilitates insulin secretion at any time, and the additional insulin induces greater potassium uptake by the cells.

The effect of epinephrine on cellular potassium uptake is probably of greatest physiological importance during exercise when potassium moves out of muscle cells that are rapidly firing action potentials. In fact, very intense intermittent exercises such as wind sprints can actually double plasma potassium for a brief period. However, at the same time, exercise increases adrenal secretion of epinephrine, which stimulates potassium uptake bu the Na-K-ATPase in muscle and other cells and transiently high potassium levels are restored to normal with a few minutes of rest. Similarly, trauma causes of loss of potassium from damaged cells and epinephrine released due to stress stimulates other cells to take up plasma potassium.

Another influence on the distribution of potassium between the ICF and ECF is the ECF hydrogen ion concentration: An increase in ECF hydrogen ion concentration is often associated with net potassium movement out of cells, whereas a decrease in ECF hydrogen ion concentration causes net potassium movement into them. It is as though potassium and hydrogen ions were exchanging across plasma membranes.


Renal Potassium Handling

Althgouh skeletal msucle and other tissues play an important role in the moment-to-moment control of plasma potassium concentration, in the final analysis, the kidney determines total-body potassium content. It is helpful to keep in mind several major differences between teh renal handling of sodium and potassium.

  • The filtered load of sodium is 30 to 40 times greater than the filtered load of potassium and the tubules always have to recover the majority of filtered sodium. This is not the case for potassium.
  • Sodium is only reabsorbed, never sereted. In contrast, potassium is both reabsorbed and secreted, ant its regulation is primarily focused on secretion.
  • The renal handling of sodium has a much greater effect on potassium than vice versa, which is a major feature of control.

Potassium is freely filtered into Bowman's space. Under all conditions, almost all the filtered load (~90%) is reabsorbed by the proximal tubule and thick ascending limb of the loop of Henle. Then, if the body is conserving potassium, most of the rest is reabsorbed in the distal nephron and medullary collecting ducts, leaving almost none in the urine. In contrast, if the body is ridding itself of potassium, a large amount is secreted in the distal nephron, resulting in a substantial excretion, of which the amount excreted may exceed the filtered load when secretion occurs at high rates.

PS: Proximal tubule reabsorption percentage: 65%; thick ascending limb of the loop of Henle reabsorption percentage: 25%

Proximal tubule

In the proximal tubule about 65% of the filtered load is reabsorbed, mostly via the paracellular route. The flux is driven by the concentration gradient set up when water is reabsorbed, which concentrates potassium and other solutes remaining in the tubular lumen. This flux is essentially unregulated and varies mostly with how much sodium, and therefore water, is reabsorbed.

The active transport of potassium is always coupled to the active transport of another solute, either sodium or hydrogen. In the proximal tubule the efflux of sodium by the Na-K-ATPase is very vigorous, requiring a high rate of potassium uptake from the interstitium. Since we know that there is net potassium transport into the interstitium, this pumped potassium must therefore recycle right back by passive flux through channels in the basolateral membrane. In some regions influx of potassium across apical membranes occurs via H-K antiporters that are simultaneously secreting protons.

The loop of Henle

The loop of Henle continues the reabsorption of potassium. The major events take place in the thick ascending limb, where the Na-K-2Cl multiporter in the apical membrane of the tubular cells takes up potassium. The interaction with sodium in these cells is even more complicated than in the proximal tubule because potassium is transported into the bubular cells both from the lumen with sodium via Na-K-2Cl symporters and from the interstitium via the Na-K-ATPase. The tubule contains far less potassium than sodium, but the Na-K-2Cl transporter moves equal amounts of each one. Therefore to supply enough potassium to accompany the large amount of sodium being reabsorbed by the symporter, potassium must recycle back to the lumen by passive channel flux. If this did not happen then sodium reabsorption would be limited only to the amount of potassium present in the tubular fluid.

Some potassium entering from the lumen does move through the cells and exit across the basolateral membrane along with the potassium entering via the Na-K-ATPase. It exits by a combination of passive flux through channels and through K-Cl symporters with chloride, thus yielding net transcellular reabsorption. Some potassium is also reabsorbed by the paracellular route in this segment, driven by a lumen-positive voltage.

The distal nephron

The distal convoluted tubule and connecting tubule stand out as being particularly imporant in potassium handling because of their rich complement of transport elements and their location prior to segments where most of water is absorbed. These regions play a major role in potassium secretion when total body potassium is high (high potassium diet). The distal nephron expresses both reabsorptive and secretory mechanisms, and it is the quantitative amount of each that determines net potassium excretion. There are several cell types in the epithelium of the connecting tubule and cortical collecting duct. Principal cells (approximately 70% of the cells) and intercalated cells. The intercalcated cells are further subdivided into type A (more numerous), type B (sparse) and a third type called non-A non-B cells. Potassium secretion occurs in principal cells, whereas the type A intercalated cells reabsorb potassium. The mechanisms of both secretion and reabsorption are straightforward. Secretion of potassium by principal cells involves the uptake of potassium from the interstitium via the Na-K-ATPase and secretion into the tubular lumen through channels. Type A intercalated cells reabsorb potassium via the H-K-ATPase in the apical membrane, which actively takes up potassium from the lumen. They then allow potassium to enter the interstitium across the basolateral membrane via potassium channels.

Finally, the medullary collecting ducts reabsorb small amounts of potassium under all conditions. When the sum of upstream processes has already reabsorbed almost all the potassium, the medullary collecting ducts bring the final urine excretion down to a few percent of the filtered load, for an excretion of about 10 to 15 mEq/day. On the other hand, if upstream segments are secreting avidly, the modest reabsorption in the medullary collecting ducts does little to prevent an excretion that can reach 1000 mEq/day.


Regulation of Potassium Excretion

The mechanisms regulating potassium excretion are as complex, and perhaps more so, than those regulating sodium excretion. And as pointed out earlier, active potassium trasnport is intertwined with sodium and hydrogen transport. But within the complexity one thing is abundantly clear – the healthy kidneys do a remarkable job of integrating signals to increase potassium excretion in response to high dietary loads and reduce excretion in the face of restricted diets.

The key regulated variable is potassium secretion by principal cells in the distal nephron. There are 3 transport processes in these cells that determine the amount of secretion: potassium influx by the Na-K-ATPase, potassium efflux into the lumen, and potassium efflux back into the interstitium (recycling). Much of the control is exerted on the activity of potassium channels. The kidneys and other body organs express numerous potassium channel species; for simplicity we do not usually differentiate between types. However in the apical membrane of principal cells in the distal nephrone, 2 types of channels stand out as being those that secrete potassium in a regulated manner: ROMK and BK. Although ROMK and BK channels are both permeable to potassium, they play different mechanisms. At very low dietary loads of potassium, there is virtually no secretion by either kind of channel. ROMK channels are sequestered in intracellular vesicles and BK channels are closed. At normal potassium loads, ROMK channels are moved to the apical membrane and secrete potassium at a modest rate. BK channels are still closed, held in reserve and ready to respond to appropriate signals when needed. At high excretion rates, both types of channel are present in the luminal membrane and avidly secreting potassium being pumped in by the Na-K-ATPase.

Plasma potassium

First, the filtered load is directly proportional to plasma concentration. Second, the environment of the principal cells that secrete potassium, that is, the cortical interstitium, has a potassium concentration that is nearly the same as in plasma. The Na-K-ATPase that takes up potassium is highly sensitive to the potassium concentration in this space, and varies its pump rate up and down when potassium levels in the plasma vary up and down. Thus plasma potassium concentration exerts an influence on potassium excretion, but is not the dominant factor under normal conditions.

Dietary potassium

Dietary potassium must be matched by renal excretion. The healthy kidneys do this very well by increasing and decreasing potassium excretion in parallel with dietary load. Just how the kidneys "know" about dietary input is still somewhat mysterious. Although very large potassium loads can increase plasma potassium somewhat, the changes in excretion assocaited wtih ordinary fluctuations in dietary input do not seem to be accounted for on the basis of either changes in plasma potassium or the other identified factors. One factor known to exert an influence, but not the major one, is the previously mentioned gastrointestinal peptide hormones released in response to ingested potassium. They influence not only the cellular uptake of potassium absorbed from the GI tract, but also the renal handling ot potassium, and seem to be one of the links between dietary load and excretion.

A manifestation of changing dietary loads over time is to regulate the distribution of ROMK channels between the apical membrane and intracellular storage, that is, high-potassium diets lead to insertion of apical channels and therefore highest potassium secretion. In contrast, during periods of prolonged low potassium ingestion, there are few ROMK channels in the apical membrane. Yet another adaptation to prolonged periods of low potassium ingestion is an increase in H-K-ATPase activity in intercalated cells, resulting in even more efficient reabsortpion of filtered potassium.

Aldosterone

A stimulator of aldosterone secretion by the adrenal cortex, in addition to AII, is an increase in plasma potassium concentration. This is a direct action of potassium and does not involve the renin-angiotensin system. If anything, high levels of potassium decrease the formation of AII. Aldosterone, as well as increasing expression of the Na-K-ATPase and ENaC sodium channels, also stimulates the activity of ROMK channels in principal cells of the distal nephron. Both actions have the effect of increasing potassium secretion. Greater pumping by the Na-K-ATPase supplies more potassium from the interstitium to the cytosol of the principal cells, and more functioning ROMK channels provide more pathways for secretion. Conversely, low levels of aldosterone deter potassium secretion.

Angiotensin II

AII is an inhibitor of potassium secretion. Its mechanism of action is to decrease the activity of ROMK channels in principal cells and distal convoluted cells, thereby limiting the potassium flux from cell to lumen. Thus AII and aldosterone exert influences on potassium excretion in opposite directions.

Delivery of sodium to principal cells

Sodium delivery to principal cells in the connecting tubule and cortical collecting duct is a major regulator. High sodium delivery stimulates potassium secretion. It does so in 2 ways. First, sodium entry via sodium channels (ENaC?) in principal cells depolarizes the apical membrane and thereby increases the electrochemical gradient driving the outward flow of potassium through channels. Second, more sodium delivered means more sodium taken up, and therefore more sodium pumped out by the Na-K-ATPase, in turn causing more potassium to be pumped in. Sodium delivery to principal cells, and hence potassium secretion, is strongly affected by the amount of sodium reabsorption in prior segments.