Nutritional Support in Acute Renal Failure

Wilfred Druml

Previously, acute kidney injury (AKI) was regarded in terms of “simple” organ dysfunction, which is easily supported by modern renal replacement therapies (RRT). Currently, AKI is recognized as a systemic inflammatory syndrome, a pro-oxidative, proinflammatory, and hypermetabolic state exerting a profound impact on the course of the disease that is associated with AKI. Despite modern dialytic techniques, AKI is still associated with a high mortality.

Because dialysis does not provide a cure, the nutritional and metabolic management must present a cornerstone in the care of these patients. Nutrition support now provides much more than a merely quantitative approach to providing energy and nitrogen and, instead, is a more qualitative type of metabolic intervention aimed at modulating the inflammatory state, correcting the oxygen radical scavenger system, and promoting immunocompetence. The goals of nutritional therapy are not only to replace the macro- and micronutrient requirements but also to take advantage of specific pharmacologic effects of various nutrients. Similar considerations are applicable in the prevention and treatment of AKI.

In patients with AKI, the metabolic environment is complex; it is not only affected by the acutely uremic condition per se but also by the underlying disease process(es) with the associated complications. The type and intensity of RRT must also be considered. Depending on the severity of associated illnesses, nutrient requirements can differ widely among individual patients and during the course of disease. A nutritional program for a patient with AKI is not fundamentally different from the regimens proposed for other critically ill patients, but it is more complicated because the regimen must be devised in the context of the complex alterations in metabolism and nutrient balances that occur with acute loss of kidney function. In addition, the nutritional program has to be coordinated with RRT. Patients with AKI are extremely prone to developing metabolic complications during nutritional support. A major problem is a patient’s lack of tolerance to administering fluids and electrolytes because of impaired excretory function and because metabolic processing of nutrients is altered. Clearly, nutritional therapy for patients with AKI must be more closely monitored than patients with other acute disease states.

For many years, parenteral nutrition was the preferred route for supporting nutritional demands of patients with AKI. This is now changed as enteral nutrition has become the preferred principal route for nutritional support of these patients. It is important to recognize, however, that enteral and parenteral nutrition should not be viewed as opposed therapies but rather as complementary methods of nutritional support. Since meeting
the nutritional requirements by the enteral route alone is often not possible, supplementary parenteral nutrition is necessary but the benefits of enteral nutrition are not lost.

METABOLIC ALTERATIONS CHANGE NUTRITIONAL REQUIREMENTS IN ACUTE KIDNEY INJURY

Rarely is AKI an isolated disease process; instead, it often complicates sepsis, trauma or conditions leading to multiple-organ failure. In short, the metabolic responses of critically ill patients with AKI are determined not only by impaired kidney function but also by the underlying disease process and complications, including severe infections and multiple organ dysfunction. The type and intensity of RRT can exert a profound effect on metabolism and nutrient balances. It is clear that AKI by itself induces and/or augments a systemic inflammatory response with multiple downstream consequences, including decreased immunocompetence. In short, the acute loss of kidney function not only affects water, electrolyte, and acid-base metabolism, but also it can induce important changes in the “milieu interieur” (Table 5-1).

Protein and Amino Acid Metabolism and their Requirements in Acute Kidney Injury

The hallmark of metabolic alterations in AKI is the activation of protein catabolism, which releases excessive amounts of amino acids from skeletal muscle thereby increasing hepatic gluconeogenesis and ureagenesis. This results in sustained negative nitrogen balance and, hence, loss of somatic protein stores. Besides accelerated protein breakdown, the utilization of amino acids in the processes of protein synthesis is defective. For example, in the liver, the synthesis and secretion of acute phase proteins are stimulated. These processes can lead to imbalances in the pools of amino acids in both the plasma and the intracellular fluid of muscle. In addition, the clearance of most amino acids that support gluconeogenesis is enhanced by AKI. Finally, several amino acids (e.g., arginine or tyrosine), conventionally considered as nonessential amino acids, become “conditionally indispensable” when their metabolism is altered by AKI.

Table 5-1. Important metabolic abnormalities induced by acute kidney injury

•	Induction of a proinflammatory state
•	Activation of protein catabolism
•	Peripheral glucose intolerance / increased gluconeogenesis
•	Inhibition of lipolysis and altered fat clearance
•	Oxidative Stress
	•	Activation of ROS
	•	Depletion of the antioxidant system
•	Impairment of immunocompetence
•	Endocrine abnormalities: hyperparathyroidism, insulin resistance, EPO resistance, resistance to growth factors, anabolic hormones
EPO, erythropoietin; ROS, reactive oxygen species.

Table 5-2. Protein catabolism in acute kidney injury: contributing factors

Impairment of metabolic functions by uremic toxins
Endocrine factors
	Insulin resistance
	Increased secretion of catabolic hormones (catecholamines, glucagon, glucocorticoids)
	Hyperparathyroidism
	Suppression of release / resistance to growth factors
Acidosis
Acute phase reaction—Systemic inflammatory response syndrome (activation of cytokine network)
Release of proteases
Inadequate supply of nutritional substrates
Renal replacement therapy
	Loss of nutritional substrates
	Activation of protein catabolism

The etiology of hypercatabolism in AKI is complex; in addition to the loss of kidney function, the induction of an inflammatory state, the stresses of concurrent illnesses, and the type and intensity of RRT all contribute to the process (Table 5-2). A major stimulus of the acceleration of muscle protein catabolism by AKI is the development of insulin resistance. Interestingly, AKI glucose formation is not suppressed by excessive substrate as occurs in healthy subjects or patients with chronic kidney disease (CKD). When insulin resistance develops, there is depressed protein synthesis and increased protein degradation. Consequently, providing insulin to maintain normoglycemia can be beneficial to patients with AKI by acting to suppress excessive muscle protein catabolism, although this potential benefit of intensive glucose control has recently been questioned in large studies.

Acidosis is another important factor that stimulates muscle protein breakdown. The accumulation of acid activates the catabolism of protein and the oxidation of amino acids in muscle, independently of azotemia. In patients with CKD, there is evidence that correcting the degree of acidosis can eliminate the increase in muscle protein degradation to improve nitrogen balance. Clinical experience suggests that correcting acidosis is associated with improved nitrogen balance in patients with AKI.

Additional catabolic factors causing loss of protein stores include the release of inflammatory mediators, such as tumor necrosis factor-α (TNF-α) and interleukin-1 and -6, which are associated with hypercatabolism in many animal models and human disease states. In addition, secretion of hormones with catabolic properties such as catecholamines, glucagon, and glucocorticoids; development of hyperparathyroidism; suppression of and decreased sensitivity to growth factors; and the release of proteases from activated leukocytes can separately (or together) stimulate protein breakdown. Finally, the type and frequency of RRT can
affect protein balance (Table 5-3). During hemodialysis, protein catabolism is accelerated, a process mediated in part by the loss of nutritional substrates plus the activation of catabolic pathways mentioned above (see Chapter 11).

Table 5-3. Metabolic effects renal replacement therapy in acute kidney injury

Intermittent hemodialysis
	Loss of water soluble molecules
		Amino acids
		Water soluble vitamins
		L-carnitine
	Activation of protein catabolism:
	Impairment of insulin/IGF-1 signalling leading to activation of muscle protein degradation
	Loss of amino acids, protein and blood inducing release of proinflammatory cytokines (IL-1, IL-6, and TNF-α)
	Inhibition of protein synthesis
	Increase in ROS production
		Loss of antioxidants
		Stimulation of ROS formation through bioincompatibility
Continuous renal replacement therapy (CRRT)
	Heat loss
	Excessive load of substrates (lactate, citrate, glucose)
	Loss of nutrients (amino acids, vitamins, selenium etc.)
	Loss of electrolytes (phosphate, magnesium)
	Elimination of (short-chain) proteins (hormones, mediators?, but also albumin)
	Metabolic consequences of bio incompatibility (induction/activation of mediator-cascades, of an inflammatory reaction, stimulation of protein catabolism)
IGF-1, insulin-like growth factor-I; IL-1, interleukin-1; IL-6, interleukin-6; ROS, reactive oxygen species; TNF-α, tumor necrosis factor-α.

Last but not least, inadequate nutritional support can contribute to the loss of protein mass in patients with AKI. In experimental animals, starvation aggravates the catabolic response to AKI, and clinical experience suggests that pre-existing malnutrition is a major determinant of complications and mortality in patients with AKI.

AMINO ACID AND PROTEIN REQUIREMENTS IN PATIENTS WITH ACUTE RENAL FAILURE

Despite the well-established highly protein catabolic state of AKI, few studies have attempted to define the optimal requirements for protein or amino acids in these patients. In noncomplicated, nonhypercatabolic patients with AKI, a protein intake of 0.97 to 1.3 g/kg b.w./day was shown to lead to a positive nitrogen balance during the polyuric phase of AKI. It should be pointed out, however, that measuring nitrogen balance in patients who are experiencing rapid changes in accumulated nitrogen waste products is difficult and subject to considerable error.

In complicated critically ill patients with AKI, especially in
ones who are treated with continuous renal replacement therapy (CRRT), the estimated protein catabolic rate is reportedly at 1.4 to 1.75 g/kg b.w./day. There also appears to be an inverse relation between protein and energy provision and protein catabolic rate. On the basis of these measurements, an amino acid/protein intake of about 1.5 g/kg b.w./day is recommended. It also recommended that amino acid/protein intake should not exceed 1.7 g/kg b.w./day. Higher amino acid or protein intakes (e.g., 2.5 g/kg b.w./day) have been suggested, but there is no convincing evidence that the higher intakes are beneficial. In addition, excessive intake of amino acids/proteins will definitely increase the accumulation of unexcreted waste products. This in turn, will induce adverse metabolic complications such as hyperammoniemia while aggravating uremic complications and increasing the need for dialysis by stimulating muscle protein degradation. Unfortunately, the dialysis procedure itself is catabolic, and therefore, providing amounts of amino acid/protein above 1.5 g/kg b.w./day and increasing the frequency of dialysis could be counterproductive. In short, hypercatabolism cannot be overcome by simply increasing protein or amino acid intake; even in patients with normal kidney function who have sepsis or burns, providing more than 1.5 g protein (or amino acids)/kg b.w./d does not improve catabolism.

It is recommended that unless AKI will be brief and there are no associated catabolic illnesses, the intake of protein or amino acids should not be less than 0.8 g/kg b.w./day. But when patients with AKI are catabolic, they should receive approximately 1.2 g to 1.5 g protein (or amino acids)/kg b.w./day. This recommendation is in accordance with those for critically ill patients. The recommended level of amino acid/protein intake includes the amount needed for the amino acid and protein losses that occur with hemodialysis, CRRT, or peritoneal dialysis.

POTENTIAL METABOLIC INTERVENTIONS OF CONTROLLING CATABOLISM

Unfortunately, no effective methods have been identified that will reduce or stop the hypercatabolism associated with AKI. Consequently, “upstream” therapeutic interventions aimed at mitigating underlying metabolic abnormalities, especially inflammation, have been attempted.

Nutritional substrates: It is not possible to reverse hypercatabolism and the hepatic gluconeogenesis that is stimulated by AKI simply by providing conventional nutritional substrates (see subsequent sections for details on nutritional supplementation in AKI). It is speculated that novel substrates (e.g., glutamine, leucine or its keto-acid, or structured triglycerides) might exert a more pronounced anti-inflammatory, hence anticatabolic response.
Endocrine: Experimentally, therapy with anabolic hormones (insulin, insulin-like growth factor-I [IGF-I], recombinant human growth hormone [rHGH]) or hormone antagonists (antiglucocorticoids) can be partially effective in suppressing hypercatabolism in critical illness. But clinical results with the administration of IGF-I and rHGH (described later in this chapter) have been rather disappointing and in certain circumstances
deleterious (e.g., the increased mortality of critically ill patients treated with rHGH).
Anti-inflammatory interventions: Proinflammatory cytokines such as IL-1, IL-6, and TNF-α can cause excessive release of amino acids from skeletal muscle while activating hepatic amino acid uptake and gluconeogenesis. Various nutritional supplements such as specific amino acids (glutamine, glycine, arginine), omega-3-fatty acids, or antioxidants can modify the inflammatory response in animal models, but they have not been tested clinically in critically ill patients with AKI. The same is true for proinflammatory cytokine antagonists (IL-1 receptor, IL-6, and TNF-α receptor antagonists).
Interventions to block catabolic pathways: Correcting acidosis is simple and clearly can suppress muscle protein catabolism by blocking the ubiquitin-proteasome proteolytic system.

Energy Metabolism and Energy Requirements

In patients with uncomplicated AKI, oxygen consumption is similar to that in healthy subjects. In patients with AKI with sepsis or the multiple-organ dysfunction syndrome, however, oxygen consumption increases to 20% to 30% above the calculated basal energy expenditure (BEE). In short, energy expenditure in patients with AKI is determined by the underlying disease and its associated complications rather than by the acute loss of kidney function.

Previously, energy requirements for patients with AKI were grossly overestimated, and excessive energy intakes were advocated. The adverse effects of an exaggerated nutrient intake are now established. The energy supply should never exceed actual energy requirements; complications from slightly “underfeeding” calories are less deleterious than those caused by overfeeding calories. Increasing energy intake of patients with AKI from 30 kcal/kg b.w./day to 40 kcal/kg b.w./day merely increases the frequency of metabolic complications such as hyperglycermia and hypertriglyceridemia.

Unfortunately, direct measurements of energy requirements of individual patients with AKI is generally unavailable, so energy requirements are calculated using a standard formula based on the BEE from the Benedict-Harrison equation multiplied by a “stress factor.” On average, patients with AKI should receive 20 to 30 kcal/kg b.w./day; even when they are in a hypermetabolic state because of other underlying diseases (i.e., sepsis or multipleorgan failure), the energy expenditure rarely exceeds 130% of calculated BEE, and we recommend that the energy intake should not exceed 30 kcal/kg b.w./day in any patient with AKI.

CARBOHYDRATE METABOLISM

Frequently, AKI is associated with hyperglycemia because of insulin resistance of stress, which is further exacerbated as a complication of the loss of kidney function. The condition is recognized if there is a high plasma insulin concentration, a 50% decrease in the maximal insulin-stimulated glucose uptake by skeletal muscle and impaired glycogen synthesis in muscle. AKI-induced abnormalities in glucose metabolism also include accelerated hepatic gluconeogenesis because of excessive conversion from
amino acids released during protein catabolism. Notably, hepatic gluconeogenesis in patients with AKI cannot be suppressed by exogenous glucose infusion. Besides resistance to the hypoglycemic effects of insulin, the rate of endogenous insulin secretion in patients with AKI is low in the basal state and during glucose infusion. Because the kidney is the main organ of insulin disposal, insulin degradation is decreased in AKI. Surprisingly, insulin catabolism in the liver is also consistently reduced in AKI, which may simply be a response to nonphysiologic hyperglycemia.

The importance of insulin resistance in AKI is further emphasized by studies showing improved patient and kidney survival in critically patients with strict normalization of blood glucose levels (80 to 110 mg/dL [4.4 to 6.1 mmol per liter]) versus conventional therapy (insulin administered when the blood glucose level exceeded 215 mg/dL [12 mmol per liter], with the infusion tapered when the level fell below 180 mg/dL [10 mmol per liter]). Because nutritional supplementation is a critical determinant of plasma glucose concentrations, appropriate therapy is important. Most recent studies also indicate a significant increase in hypoglycemic episodes in critically ill patients receiving strict blood glucose control regimens, adding some controversy to the subject. For these reasons, we recommend that while normoglycemia should be the goal during nutritional support of patients with AKI, the target glucose concentrations to be considered as “normoglycemia” must be adjusted according to the risk/benefit profile of the patient with particular attention to prevention of hypoglycemic events.

LIPID METABOLISM

There are also profound alterations of lipid metabolism in patients with AKI. The triglyceride content of plasma lipoproteins, especially very low-density lipoproteins (VLDL) and low-density lipoproteins (LDL) are increased; total cholesterol and HDLcholesterol in particular, are decreased. The major cause of lipid abnormalities in AKI is impaired lipolysis because the activities of the lipolytic systems, peripheral lipoprotein lipase, and hepatic triglyceride lipase are decreased to values 50% below normal values. These changes contrast with those in most other acute disease states, which are usually associated with enhanced lipolysis. Metabolic acidosis can contribute to the impairment of lipolysis in AKI by inhibiting lipoprotein lipase. Notably, artificial lipid emulsions provided in parenteral nutritional solutions are degraded similar to endogenous VLDL. Thus, the impaired lipolysis of AKI leads to a delay in eliminating intravenously infused lipid emulsions: the elimination half-life is doubled and the clearance of fat emulsions is reduced by more than 50%. Finally, intestinal lipid absorption is delayed, complicating the responses to enteral nutrition.

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