Abstract
Acute kidney injury (AKI) results in complex metabolic derangements driven by loss of kidney function and the injured kidney, the systemic response to illness, co-morbid illnesses, and the therapies used to treat this condition (e.g., renal replacement). In this chapter, we will detail the metabolic and nutritional abnormalities observed in patients with AKI, their potential contribution to morbidity and mortality, and the debates and current recommendations that surround nutritional and metabolic support for this growing population.
Keywords
acute kidney injury, acute renal failure, inflammation, insulin resistance, metabolism, nutrition, oxidative stress
Outline
Terminology, 698
Prevalence of Protein-Engery Wasting in Acute Kidney Injury, 698
Dysmetabolism of Acute Kidney Injury, 699
Nutritional Derangements in Acute Kidney Injury, 703
Carbohydrate Metabolism, 703
Protein Metabolism, 705
Causes of Enhanced Protein Catabolism in Acute Kidney Injury, 705
Inflammation, 705
Insulin Resistance, 705
Metabolic Acidosis, 707
Renal Replacement Therapy, 707
Lipid Metabolism, 707
The incidence of acute kidney injury (AKI) is growing and remains associated with increased mortality, cardiovascular disease, and long-term loss of kidney function. When severe, AKI presents a complicated array of metabolic challenges affected by the underlying precipitant, the systemic response to injury, and derangements resulting from the kidney injury itself and its subsequent therapies. The extent of these abnormalities and the processes that drive them adversely affect the nutritional and metabolic status of patients with AKI and contribute to the high mortality rates observed.
Although comorbidity burden and illness severity often are the main focus in determining prognosis, the nutritional status of patients with AKI is an overlooked but likely important determinant of morbidity and mortality. In addition to imbalances in electrolyte, acid-base, and volume status, AKI is associated with alterations in protein, carbohydrate, and lipid metabolism. This chapter details these complications and includes discussion of perturbations of substrate and energy metabolism, their underlying pathophysiological mechanisms, and the challenges of providing nutritional and metabolic support to this population.
Terminology
Different definitions have been applied to describe impaired nutritional status in acute and chronic kidney diseases, including uremic wasting, renal cachexia, malnutrition-inflammation complex, and protein-energy malnutrition. This variability has led to the potential for misinterpretation of terms and the available literature. For example, the term malnutrition refers specifically to a collection of findings resulting from inadequate nutrient and caloric intake that reverses upon adequate replenishment. It is well recognized, however, that although malnutrition shares some features with those seen in a variety of disease processes, differences in their timing of onset and tendency to persist despite nutritional supplementation makes them distinct from isolated malnutrition ( Table 46.1 ). For example, serum albumin, a classic biochemical marker of nutritional status, often remains relatively preserved during starvation until later stages, whereas decreases in levels during acute disease processes tend to occur earlier despite nutritional resuscitation. Among the factors that may explain these apparent defects in nutrient utilization and enhanced catabolic responses in patients with AKI include inflammation, oxidative stress, acidemia, uremic toxin accumulation, dialytic losses, and a variety of hormonal abnormalities including insulin resistance (IR) ( Fig. 46.1 ).
| Features | Malnutrition | Catabolic Disease State |
|---|---|---|
| Appetite | Starving | Anorectic |
| Metabolic rate | Decreases adaptively | Remains the same or increases |
| Principal substrate | Lipids/Fatty acids | Lean body mass/Muscle |
| Serum albumin | Preserved early | Depressed early |
| Response to nutrition | Effective | ???? |
In 2008 the International Society of Renal Nutrition and Metabolism proposed the consensus term protein-energy wasting (PEW) to characterize loss of lean body mass and energy reserves observed in kidney disease. Minimum requirements to meet this diagnosis include deficiencies in biochemical (albumin, prealbumin, or cholesterol) and anthropomorphic (body mass index [BMI] <23 kg/m 2 or unintentional weight loss) measures, quantified muscle mass (bioimpedence analysis [BIA]), or midarm muscle circumference), and low dietary protein/energy intake (e.g., <0.6 g/kg/day in patients with chronic kidney disease (CDK) stages 2 to 5) 10 ( Box 46.1 ). These criteria remain to be validated in AKI.
Criteria
Serum Chemistry
Serum albumin <3.8 g/100 mL (Bromcresol Green)
Serum prealbumin (transthyretin) <30 mg/100 mL (for maintenance dialysis patients only; levels may vary according to GFR level for patients with CKD stages 2–5) a
Not valid if low concentrations are due to abnormally great urinary or gastrointestinal protein losses, liver disease, or cholesterol-lowering medicines.
Serum cholesterol <100 mg/100 mL a
Body mass
BMI <23 kg/m 2 b
A lower BMI might be desirable for certain Asian populations; weight must be edema-free mass, for example, postdialysis dry weight. See text for the discussion about the BMI of the healthy population.
Unintentional weight loss over time: 5% over 3 mo or 10% over 6 mo
Total body fat percentage <10%
Muscle mass
Muscle wasting: reduced muscle mass 5% over 3 mo or 10% over 6 mo
Reduced midarm muscle circumference area c
Measurement must be performed by a trained anthropometrist.
(reduction >10% in relation to 50th percentile of reference population)
Creatinine appearance d
Creatinine appearance is influenced by both muscle mass and meat intake.
Dietary intake
Unintentional low DPI <0.80 g/kg/d for at least 2 mo e
Can be assessed by dietary diaries and interviews, or for protein intake by calculation of normalized protein equivalent of total nitrogen appearance (nPNA or nPCR) as determined by urea kinetic measurements.
for dialysis patients or <0.6 g/kg/d for patients with CKD stages 2–5
Unintentional low DEI <25 kcal kg/d for at least 2 mo e
AKI , Acute kidney injury; BMI , body mass index; CKD , chronic kidney disease; DEI , dietary energy intake; DPI , dietary protein intake; GFR , glomerular filtration rate; nPCR , normalized protein catabolic rate; nPNA , normalized protein nitrogen appearance; PEW , protein-energy wasting.
At least three of the four listed categories (and at least one test in each of the selected category) must be satisfied for the diagnosis of kidney disease–related PEW. Optimally, each criterion should be documented on at least three occasions, preferably 2–4 wk apart.
Prevalence of Protein-Engery Wasting in Acute Kidney Injury
Components of PEW are prevalent in patients with hospitalized AKI. Fiaccadori et al. observed severe preexisting malnutrition, as assessed by the Subjective Global Assessment (SGA), in 42% of 309 patients with AKI admitted to a renal intermediate care unit. Affected patients experienced a higher likelihood of in-hospital death and more intensive healthcare resource utilization. Another study of 100 retrospectively identified AKI patients demonstrated that hypoalbuminemia (<3.5 g/dL) and hypocholesterolemia (<150 mg/dL) on hospital admission were independently predictive of mortality. Another longitudinal study of prealbumin levels in 161 patients with AKI requiring renal consultation found that low serum prealbumin (<11 mg/dL) independently predicted in-hospital mortality after adjustment for illness severity and AKI stage. Further, every 5 mg/dL increase in prealbumin level was associated with an additional 29% decrease in hospital mortality (hazard ratio [HR], 0.71; 95% confidence interval [CI], 0.52 to 0.96), suggesting its potential as a prognostic marker. It is not clear whether prealbumin and other plasma nutritional markers reflect recent nutritional status or are influenced by the extent of underlying inflammation and illness severity. More importantly, whether treatment and/or prevention of PEW affects outcomes in AKI also remains poorly addressed.
Dysmetabolism of Acute Kidney Injury
Acute illness can affect a patient’s metabolic milieu, the effects of which can be further compounded by loss of kidney homeostatic function in patients who develop AKI. These derangements include dysregulation of the host inflammatory response as well as enhanced oxidative stress, which are implicated in the pathogenesis and outcomes in AKI and associated with abnormalities in carbohydrate, lipid, and protein metabolism ( Fig. 46.2 ).
Inflammation
As AKI rarely occurs in isolation, the inflammation associated with it often is described in the context of the acute physiological disturbance from which it stems. Severe illness of almost any etiology is accompanied by a generalized host inflammatory response, referred to as the systemic inflammatory response syndrome (SIRS). Key responses to tissue injury or infection include the elaboration of potent inflammatory mediators such as tumor necrosis factor (TNF)-α, interleukin (IL)-1, and IL-6, as well as compensatory antiinflammatory response (CARS) mediators such as IL-10 into the systemic circulation. Although critical to the modulation of immunity and cellular repair, imbalances of these responses have been postulated to disrupt capillary permeability, endothelial and vasomotor function, and coagulant and complement cascades. When sustained, these imbalances also adversely affect the prognosis of this patient population and possibly contribute to dysfunction in multiple organs.
Sepsis remains one of the most potent determinants of the onset and prognosis of AKI and a classic example of the kidney’s susceptibility to deranged inflammation. Infusion of TNF-α and IL-1 in animal models produce renal injury by promoting local neutrophil adhesion and activation as well as decrements in renal blood flow via effects on nitric oxide (NO) and prostaglandin synthesis. An abundance of evidence implicates a critical role for local inflammation and leukocyte infiltration in the pathogenesis of AKI during sepsis, ischemia-reperfusion, and nephrotoxic injury.
Several animal models have demonstrated systemic release of inflammatory markers including, but not limited to, TNF-α, IL-1β, C-reactive protein (CRP), and IL-12 after experimentally induced ischemia-reperfusion injury. Ischemia-induced AKI recently was shown to result in a rapid increase in serum CRP and granulocyte colony-stimulating factor levels as well as inflammatory and functional changes in the brain not seen with ischemic liver injury. Experimental studies also have found that AKI can induce inflammation in remote organs including the lungs and brain. Bilateral nephrectomy also has been used in animals as a model of acute renal loss not confounded by the systemic effects of ischemic injury. Hoke et al. demonstrated an increase in circulating levels of IL-6 and IL-1β after bilateral nephrectomy, which was independently associated with an pulmonary inflammation. Finally, a recent analysis of genomic changes in the kidney and lung after ischemic AKI detected similar upregulation in the transcription of several genes responsible for inflammation and innate immunity in both organs. Functional genomic analysis suggested that increased signaling at the level of IL-6 and IL-10 might be responsible for these remote effects.
The extension of these findings to humans have been described by repeated observations detailing how a proinflammatory phenotype confers high risk for the development of AKI. Chawla et al., for example, demonstrated an independent association between elevations in plasma IL-6 levels and the development of AKI in a cohort of critically ill patients with severe sepsis. Similarly, in examining the ability of inflammatory cytokines to predict AKI in 876 patients with acute respiratory distress syndrome, Liu et al. found elevations of IL-6, soluble TNF receptors, and plasminogen activator inhibitor-1 to be predictive of AKI even after adjusting for age, demographics, intervention, and severity of illness.
In addition to contributing toward the pathogenesis of AKI, the extent of dysregulated inflammation and immune responses also may affect the outcome of patients with established AKI. In a subset of patients from the multicenter PICARD (Program to Improve Care in Acute Renal Disease) study, the association between serum cytokine levels and outcome was compared in critically ill patients with established AKI at the time of nephrology consultation. Relative to healthy controls and patients on chronic hemodialysis, AKI patients experienced a 10- to 20-fold elevation in several proinflammatory cytokines including IL-6, IL-18, TNF-α, CRP, as well as the antiinflammatory cytokine IL-10 ( Fig. 46.3 ). Interestingly, these elevations were observed in AKI patients both with and without evidence of sepsis. Elevations of IL-6 and IL-8 also appeared to independently predict in-hospital mortality. The same group of investigators examined the effect of the systemic cytokine profile on immune function at the cellular level. Lipopolysaccharide stimulation of monocytes from AKI patients resulted in decreased production of inflammatory cytokines including IL-1β, TNF-α, and IL-6 compared with chronic kidney disease and end-stage renal disease patients. This suggests that imbalances in inflammation and immune responses in AKI represent a complex interplay at both a local and systemic level.
In summary, dysregulated expression of pro- and antiinflammatory mediators is central to both the development of AKI as well as its consequences at a local and systemic level. The biological effects of these mediators can be extensive, affecting both distant organ function as well as the capacity to effectively utilize nutritional substrates (see substrate metabolism).
Oxidative Stress
Under normal physiological conditions, cellular injury produces reactive oxygen species (ROS), primarily through mitochondrial oxidative phosphorylation. Detoxification and decomposition of ROS occurs via endogenous antioxidant compounds. Antioxidants are a varied group of molecules with diverse functions. These include enzymes with specific catalytic properties, water- and lipid-soluble chemical moieties with relatively nonspecific scavenging capacity, and metal chelating agents, which can inhibit oxidant production. As a rule, antioxidants control the prevailing relationship between reducing and oxidizing (redox) conditions and biological systems. Once regarded as virtually a medical curiosity, a large body of evidence now implicates ROS as important mediators of ischemic and toxic tissue injury.
In a number of pathological states, increased oxidative stress can occur when an imbalance develops between oxidant production and antioxidant defense. Considerable experimental data point to increased oxidative stress as a contributor to renal tubular epithelial cell injury and AKI. The dysregulated inflammatory response and uremia further potentiate oxidative stress in patients with AKI. Finally, increased systemic oxidative stress may contribute to the development and maintenance of the multiple organ dysfunction syndrome, potentially mediating adverse outcomes in critically ill patients with AKI.
What Is Oxidative Stress?
Oxidative stress often is defined as a disturbance in the balance between oxidant production and antioxidant defense. An imbalance in favor of prooxidants can lead to the oxidation of macromolecules and resultant tissue injury. Oxidative processes predominantly occur within the mitochondria, and the mitochondrial cytochrome oxidase enzyme complex accounts for the majority of metabolized oxygen. The mitochondrial cytochrome enzyme complex contains four redox centers, each of which stores a single electron. Mechanisms for the simultaneous reduction of the four redox centers resulting in the transfer of electrons results are evolutionarily conserved, and limit the production of ROS. Nonetheless, mitochondrial oxygen can leak through the electron transport chain, resulting in the formation of reactive oxygen intermediates and free radicals, which can diffuse out of mitochondria and be a source of oxidative stress.
An additional important in vivo source of excess oxidants occurs through the action of another enzyme complex, nicotinamide adenine dinucleotide phosphate (NADPH) oxidase. The NADPH oxidase system also is highly conserved, and is particularly important within the endothelium and in phagocytic cells for the generation of reactive oxygen intermediates. During an inflammatory response, phagocytes consume high levels of oxygen for the generation of reactive oxygen intermediates as part of the host defense against pathogens via the respiratory burst. Phagocytes contain other enzymes (including superoxide dismutase, nitric oxide synthase [NOS], and myeloperoxidase), which also contribute to the production of hydrogen peroxide, NO, peroxynitrite, and hypochlorous acid, respectively. Other enzyme systems, including xanthine oxidoreductase and uncoupled NOS, also may contribute to increased oxidative stress in the setting of AKI.
Animal Models of Oxidative Stress in Acute Kidney Injury
Sepsis and Endotoxemia: Sepsis is the most common etiology of AKI. Increased ROS production has been demonstrated to contribute to ischemic kidney injury in animal models, likely mediated through intense renal vasoconstriction. In the early phase of endotoxin-induced AKI, vasoconstriction may be mediated via activation of the sympathetic nerves and the renin-angiotensin system. The vasoconstriction can be counterbalanced through the vasodilatory effects of NO. However, increased oxidative stress results in an increase in superoxide anion production, causing NO to be scavenged, thus leading to an imbalance favoring vasoconstriction and ischemic AKI. Wang and colleagues demonstrated that during endotoxemia-related AKI in mice, several antioxidants exert a protective effect by potentiating NO function. Increased tissue levels of peroxynitrite, the end product of the reaction between superoxide anion and NO, have been detected in animal models of AKI.
Ischemic Acute Kidney Injury: The development of increased oxidative stress during acute renal ischemia-reperfusion has been reported in studies ranging over two decades. Furthermore the concept that damaged endothelium contributes to the pathogenesis of AKI in models of renal ischemia goes back several decades to the pioneering work of Alexander Leaf and colleagues. The injured endothelium may directly lead to oxidative and nitrosative stress through activation of endothelial NADPH oxidase, and conversion of xanthine reductase to an oxidase. Increased oxidative stress also may result when injured or activated endothelium promotes infiltration of phagocytic cells into the injured kidney. Overexpression of the cell adhesion molecule ICAM-1 by vascular endothelium is observed in ischemic models of AKI, and blockade of ICAM-1 receptors attenuates injury. A role for iron in mediating AKI through increased generation of oxygen-free radicals has been demonstrated in a number of studies. In a rat model of ischemia-reperfusion injury induced by clamping the renal artery, pretreatment with the iron chelator deferoxamine prevented AKI development. In this study, urinary-free iron concentration increased up to 20-fold during reperfusion. It has been found that labile or catalytic iron are elevated after cardiopulmonary bypass surgery and in critical illness in humans, and are associated with increased risk for AKI and death. Acute nitrosative stress also has been demonstrated to accompany increased oxidative stress in a rat model of acute kidney ischemia. In this model system, administration of Ebselen (a scavenger of peroxynitrite), before reperfusion, was able to ameliorate ischemic kidney injury and to reduce lipid peroxidation and DNA damage in ischemic kidneys.
Nephrotoxic AKI: Increased oxidative stress also is contributory to the pathogenesis of nephrotoxic AKI. Walker et al. demonstrated that increased oxidative stress also contributes to gentamicin-induced nephrotoxicity. Although the precise mechanisms of gentamicin nephrotoxicity remain unclear, gentamicin alters mitochondrial respiration and increases hydrogen peroxide generation. Gentamicin also has been demonstrated to induce superoxide anion and hydroxyl radical formation in renal cortical tissue. Gentamicin also may mobilize iron from mitochondria, and rats treated with deferoxamine had significantly lower blood urea nitrogen levels and improved histology than untreated rats. Human studies have demonstrated excess iron accumulation in proximal tubule lysosomes in biopsies of patients with AKI.
Injury from increased ROS production also has been demonstrated in models of cisplatin- and cyclosporine A-induced nephrotoxicity. In the glycerol model of myohemoglobinuric kidney injury, the resulting rhabdomyolysis and hemolysis led to the release and tubular cell absorption of heme proteins. Heme-loaded cells produce excess hydrogen peroxide, which can subsequently increase the release of iron from porphyrin compounds, thereby amplifying iron-dependent free radical generation. The resulting injury causes massive lipid peroxidation leading to cell death, a process that can be attenuated both in vitro and in vivo with the use of iron chelators such as deferoxamine.
Biomarkers of Oxidative Stress in Clinical Acute Kidney Injury
In vivo, oxygen intermediates are produced in minute quantities and have very short biological half-lives. The combination of low concentration and extreme reactivity make the in vivo detection of ROS extremely technically difficult. In response to these difficulties, the most effective strategy for understanding the underlying in vivo mechanisms of oxidative injury is to detect stable end products of redox chemistry reaction pathways. These biomarkers of increased oxidative stress measure the oxidation of important macromolecules, including lipids, carbohydrates, proteins, amino acids, and DNA. Elevations in these biomarkers (e.g., plasma protein thiol oxidation and carbonyl content, F2-isoprostanes and isofurans, and erythrocyte superoxide dismutase) provide supporting evidence for clinical AKI as a state of increased oxidative stress.
Pro- and Antioxidant Enzyme Gene Polymorphisms in Acute Kidney Injury
In clinical AKI, several gene polymorphisms have been described in key pro- and antioxidant enzymes that could potentially account for interindividual variability in the response to AKI. Perianayagam et al. examined gene polymorphisms associated with the NADPH oxidase enzyme and the antioxidant enzyme catalase (which metabolizes hydrogen peroxide) in a cohort of 200 patients with established AKI. A genotype-phenotype association was demonstrated between the NADPH oxidase genotype and plasma nitrotyrosine levels as a measure of increased oxidative and nitrosative stress. Furthermore, a genotype–phenotype association also was demonstrated between catalase genotypes and whole blood catalase activity. Of possible importance, the inheritance of an NADPH oxidase allele was associated with a 2.1-fold higher odds for dialysis requirement or hospital death. Polymorphisms in the gene encoding heme oxygenase-1, the rate-limiting enzyme in the degradation of heme, which has important antioxidant functions, have been shown to be associated with increased risk for AKI. These data suggest that propensity to increased oxidative stress may contribute to adverse outcomes in patients with established AKI. However, these results need to be confirmed in larger multicenter studies.
Nutritional Derangements in Acute Kidney Injury
A deeper understanding of how nutritional impairment in AKI may contribute toward poor outcomes requires a discussion of its effects on the metabolism of three principle substrates: carbohydrates, protein, and lipids.
Carbohydrate Metabolism
The Kidney and Glucose Metabolism
Glucose metabolism can be impaired by defects in insulin secretion or from defects in cellular sensitivity to insulin. The kidney plays an important role in glucose metabolism. Isotopic dilution studies have demonstrated that the renal cortex is responsible for between >25% of total body glucose appearance, whereas the more metabolically active medulla accounts for up to 20% of systemic glucose utilization. As renal function declines, diminished clearance of insulin coupled with decreased glucose utilization likely contribute to the IR observed in uremia. Animal studies have demonstrated that uremia is associated with both decreased hepatic and peripheral glucose uptake and IR.
In human studies, DeFronzo et al. used insulin clamp techniques in chronic hemodialysis patients to further characterize a diminished tissue sensitivity to insulin in advanced kidney disease. The site of this altered insulin sensitivity appears to be primarily a postreceptor defect of the phosphatidylinositol 3-kinase (PI3K)-Akt signaling, which is subject to influence from inflammation, oxidative stress, and the accumulation of “uremic toxins.”
Loss of Kidney Function Alters Insulin Dispersion
The kidney is a major site for the catabolism of plasma proteins with a molecular mass less than 50 kDa. Because most polypeptide hormones have molecular masses greater than 30 kDa, metabolism by the kidney is variable. Renal metabolism of polypeptide hormones after glomerular filtration often involves the binding of the hormone to specific receptors in the luminal membrane of tubular epithelia, which is followed by uptake and either reabsorption or catabolism. The rate of glomerular filtration of peptide hormones is variable and dependent on molecular mass, shape, charge, and the degree of protein binding.
The kidney and liver are the major sites of insulin degradation. In humans, less than 1% of the filtered insulin is freely excreted in the urine. Instead, catabolism of insulin in the kidney occurs after filtration-reabsorption and peritubular uptake. The kidney also catabolizes the insulin precursor proinsulin and C-peptide, with the kidney accounting for most of the catabolism of proinsulin. Renal extraction of each of these peptides is reported to be proportional to arterial concentration. In experimental studies, ligation of the renal pedicle results in a 75% increase in the levels of plasma insulin and a 300% increase in the levels of proinsulin and C-peptide. Conversely, the kidney accounts for only one-third of the metabolic clearance rate of insulin; with liver and muscle accounting for the majority of the dispersion of this peptide. The kidney also accounts for about one-third of the metabolic clearance of glucagon as a counterregulatory hormone.
Growth Hormone and Insulin-like Growth Factor I Axis
Growth hormone (GH; molecular mass, 21.5 kDa) has a somewhat restricted filtration rate of approximately 70% compared with the rate for insulin. However, the kidney accounts for approximately 40% to 70% of the metabolic clearance rate of GH in experimental animal studies; as a result, metabolic clearance is markedly decreased kidney failure. Similar to insulin, less than 1% of filtered hormone is excreted unchanged in the urine. Many of the GH biological effects are mediated by insulin-like growth factors (IGF)-I and IGF-II. GH stimulates the synthesis and release of IGFs, and circulating IGFs exert a negative effect on GH secretion, thereby forming a hormonal axis with negative feedback. Interestingly, the biological effects of IGF-I and IGF-II are blunted when assayed in the presence of uremic serum, suggesting that uremic factors interfere with biological activity.
Insulin Resistance in Critical Illness
Hyperglycemia, along with other aspects of IR, predicts death and morbidity in the critically ill and hallmarks the so-called “diabetes of injury.” Up to 75% of patients in the intensive care unit (ICU) may have detectable IR on admission as assessed by homeostasis model assessment (HOMA), with approximately two-thirds exhibiting overt hyperglycemia (serum glucose >7 mmol/L or 126 mg/dL). Traditionally, IR and hyperglycemia were considered to be a part of an overall adaptive response to increase substrate and energy availability during physiological stress. However, it has become clear that these responses are unregulated, maladaptive, and may contribute to organ dysfunction, infection, polyneuropathy of critical illness, and mortality.
Increased hepatic gluconeogenesis and glycogenolysis and decreased insulin-driven peripheral utilization are the main effectors of this phenomenon. Cellular uptake of glucose via the glucose transporter (GLUT) systems, a family of transport proteins distributed broadly among different cell types, are downregulated normally in response to hyperglycemia, presumably to avoid intracellular glucose overload. The GLUT-4 transporter is responsible for insulin-mediated glucose uptake in skeletal muscle, the main site of total body glucose disposal. The function of this transporter is often impaired in the setting of critical illness and hyperglycemia. In contrast, the GLUT-1, GLUT-2, and GLUT-3 transporters operate independently of insulin and appear on multiple cell types including neurons, hepatocytes, endothelial cells, gastrointestinal (GI) mucosa, and renal glomerular and tubular cells. Their upregulation during acute stress may partially account for the observed increase in total body glucose uptake despite frank hyperglycemia and IR in critical illness. Additional evidence suggests that intracellular accumulation of glucose has direct toxic effects on cellular function via enhanced generation of free radicals (oxidative stress) from increased uncoupling of oxidative phosphorylation. Furthermore, this process also appears to have deleterious effects on mitochondrial ultrastructure and function within hepatocytes of critically ill patients not receiving intensive insulin therapy.
The mechanisms by which IR ultimately leads to poor outcomes in critical illness are not fully established. As mitochondrial dysfunction and cellular energy depletion in critical illness have been implicated in the genesis of multiple organ failure, it may be that the benefit of avoiding excessive hyperglycemia is due to a reduction in the amount of circulating glucose available for noninsulin-mediated GLUT transport and subsequent cellular glucose toxicity. Indeed, one compelling finding from a post hoc analysis of intensive insulin therapy in the critically ill was a significant reduction in the occurrence of AKI. It also is known that hyperglycemia hampers the immune system, largely through the impairment of neutrophil and macrophage function. Insulin also is known to have an antiapoptotic role as well as antiinflammatory actions. Finally, as anabolic effects are known to extend beyond simple glucose metabolism, IR renders the body unable to effectively incorporate other nutrients.
Counterregulatory Hormones and Inflammation in the “Diabetes of Injury”
Although the mechanisms remain to be completely elucidated, it is clear that excessive counterregulatory hormone and cytokine elaboration often couple to alter glucose metabolism. Elevation of several classic “stress hormones” including glucagon, epi- and norepinephrine, cortisol, and GH oppose some of the normal actions of insulin. Early infusion studies using these hormones result in marked elevation in hepatic glucose production in humans. Epinephrine has been demonstrated to have multiple effects on glucose metabolism including impairment of insulin-mediated glucose uptake, increased glycogenolysis, and enhanced gluconeogenesis. Glucocorticoids are known to impair insulin-mediated uptake into skeletal muscle, likely via inhibition of GLUT-4 translocation to the plasma membrane. Finally, GH exerts its effect through IGF-1, which has insulin-like effects on cells. In excess, GH down-regulates expression of the insulin receptor and appears to increase gluconeogenesis.
As noted previously, severe illness often induces release of potent inflammatory mediators into the systemic circulation. Many of these mediators are involved in both the pathogenesis of AKI and IR. TNF-α, for example, has been associated with the development of IR in patients with renal impairment and those undergoing acute stress. In addition to secretion by macrophages, TNF-α also is found in skeletal muscle, where levels are known to inversely correlate with glucose disposal. Although the mechanism remains to be fully elucidated, one study demonstrated that infusion in humans induces directly suppresses phosphorylation of Akt substrate 160 leading to dysfunction of GLUT-4 translocation and glucose uptake. IL-6 has been shown to inhibit insulin receptor tyrosine phosphorylation and downstream signaling in hepatocytes as well in skeletal muscle in animal models. Elevated levels of IL-6 are also associated with IR in patients during cardiac surgery.
Insulin Resistance in Acute Kidney Injury
The high prevalence of AKI in the acutely ill and the known impairments of glucose metabolism resulting from loss of kidney function places AKI patients at high risk for IR. A large multicenter observational study of critically ill patients with established AKI recently demonstrated that hyperglycemia and IR are common and independently associated with poor outcomes. In this study, IR, defined by hyperglycemia in the setting of hyperinsulinemia, was associated with increased mortality rates. Moreover, glucose levels over a period of 5 weeks were significantly higher in nonsurvivors than in survivors, and insulin levels were higher in those who died, independent of demographics and severity of illness.
Whether or not hyperglycemia and/or hyperinsulinemia contribute directly to adverse events in patients with AKI or simply reflect the severity of metabolic injury has not been established. In addition to the potential glucotoxic mechanisms, IR may itself influence outcomes through alterations in the IGF-1 and IGF binding protein (bp) axis, a critical component for insulin action. For example, increased levels of IGFbp1, a major binding protein for IGF-1, suggest hepatic IR and appear to be higher in critically ill patients who die than in those who survive. IGFbp3, another binding protein for IGF-1, carries the majority (90% to 95%) of circulating IGF-1 in a ternary complex consisting of IGF-1, IGFbp3, and an acid-labile subunit. Timmins detected that a protease directed against IGFbp3 is induced in critically ill patients diminishing availability of IGF-1 and IGFbp3. In survivors, recovery is associated with decreased protease activity and subsequent levels of IGF-1 and IGFbp3. These findings also are consistent with the aforementioned observational study of AKI where IGFbp3 levels were lower and IGFbp1 levels were higher in those who died.
In summary, IR is a metabolic consequence of AKI with important implications on glucose and energy homeostasis as well as for the utilization of other substrates including protein and lipids. Furthermore, IR often occurs in concert with inflammation and oxidative stress to generate the deranged metabolic milieu in AKI and contribute to the poor outcomes observed.
Protein Metabolism
A key metabolic challenge facing recovery from illness is the restoration of cellular scaffolding and machinery, functions that are critically dependent on the proper synthesis and assembly of proteins. The substrate for these tasks is amino acids from both the intake of exogenous sources and the catabolism of endogenous ones. The normal adaptive response to dietary protein restriction is to limit oxidative degradation of proteins and essential amino acids. However, in AKI and other acute illness, enhanced protein catabolism often is observed and is marked by excess amino acid release from the skeletal muscle and negative nitrogen balance with protein catabolic rates of 1.4 to 1.8 g/kg/day reported in severe cases. Amino acid transport into skeletal muscle for protein synthesis also might be impaired, partly due to hepatic extraction to support gluconeogenesis and the synthesis of acute-phase proteins. The resulting imbalances in the utilization and clearance of both plasma and intracellular amino acid pools support are associated with poor prognosis in patients with AKI. Furthermore, deranged protein catabolism also might directly impair endothelial function, increase oxidative stress, and weaken the immune response.
Cellular protein homeostasis depends on the coordinated breakdown of proteins by a highly regulated system known as the ubiquitin-proteasome system ( Fig. 46.4 ). In muscle, for example, the enzyme caspase-3 first degrades myofibrillar proteins into component actin and myosin. These proteins are subsequently marked for degradation by covalent linkage to the protein factor ubiquitin by a series of conjugating enzymes. These reactions are repeated, forming a chain of several ubiquitin molecules sufficiently large enough to target the protein for degradation via a large proteolytic complex (the proteasome) into peptides and amino acids. The bulk of these amino acids are then recycled for use as an energy source or by the liver for gluconeogenesis. Several catabolic conditions including renal impairment (acute and chronic), sepsis, cancer, diabetes, AIDS, and Cushing syndrome have been associated with increased activation of the ubiquitin-proteasome proteolytic (UPP) system. In AKI, contributions from hormone imbalances, metabolic acidosis, the dialysis procedure itself, as well as underlying inflammation have been shown to enhance UPP activity and underlie the observed imbalance between protein accretion and breakdown in this disease.
Causes of Enhanced Protein Catabolism in Acute Kidney Injury
The mechanisms driving enhanced protein catabolism in AKI have not been well characterized, although several potential contributing factors have been identified.
Inflammation
Experimental infusion studies with TNF-α have demonstrated an enhanced proteolytic effect on muscle protein as well as a reduction in protein synthesis. Elevated IL-1 levels also appear to enhance muscle protein breakdown in animal models, which may improve with pharmacological blockade. It has been shown that IL-6 is associated with accelerated muscle atrophy, which may be through direct upregulation of the UPP system and attenuated by administration of IL-6 receptor antibody. Furthermore, in maintenance dialysis patients, IL-6 is elaborated from skeletal muscle during hemodialysis, which correlates with protein catabolism independent of amino acid availability. Similarly, IL-6 and CRP levels have been shown to predict decline in serum albumin in stable hemodialysis patients despite protein intake.
Although the exact mechanism by which inflammation affects protein degradation in AKI is not entirely clear, one possibility involves its effects on insulin signaling. We have previously discussed how TNF-α infusion in healthy humans induced IR by suppression of glucose uptake and metabolism in muscle. Inflammation also might contribute to the production of counterregulatory hormones, thereby affecting insulin signaling, which is a key modulator of the UPP system.
Insulin Resistance
Often overshadowed by its role in carbohydrate metabolism, insulin is the body’s principle protein anabolic hormone with effects including the suppression of protein breakdown and, to a lesser extent, promotion of amino acid uptake. Classic observations of insulinopenia in humans (i.e., uncontrolled type 1 diabetes mellitus [DM]) illustrated a condition highlighted by negative nitrogen balance, hyperaminoacidemia, and profound lean tissue atrophy, findings now known to be reversible upon the provision of insulin. The underlying mechanism appears to be suppression of insulin receptor substrate-1-associated PI3K activity resulting in stimulation of the UPP system via caspase-3. Investigations using tracer kinetic models and insulin clamp techniques have suggested that the blunting of proteolysis rather than enhanced protein synthesis promote the net protein anabolic effect of insulin in the postabsorptive state. The lack of effect on protein synthesis is probably due to the insulin-mediated decrease in amino acid release into the bloodstream. Biolo et al. examined protein metabolism in patients with insulin-dependent DM and healthy individuals and found no differences in protein turnover in the fasting or fed state between the two groups. However, other studies indicate that muscle protein synthesis is sensitive to both insulin and increases in amino acid concentrations administered by IV infusion.
Experimental studies suggest that enhanced protein catabolism not only applies to insulin-deficient states, but to insulin-resistant ones as well. Animal models of IR have demonstrated increased protein degradation in skeletal muscle via enhanced activation of caspase-3 and the UPP system, which are attenuated with the insulin-sensitizer rosiglitazone. In humans, Chevalier et al. demonstrated a greater degree of whole-body protein breakdown and a suppressed protein anabolic response to insulin in relatively healthy obese women compared with their lean counterparts using a hyperinsulinemic, euglycemic, isoaminoacidemic clamp technique. Dialysis patients with type 2 DM have been observed to have a marked increase in skeletal muscle protein breakdown compared with nondiabetic counterparts. As no significant difference in muscle protein synthesis was observed between the groups (at least in the fasting state), the net result was a significantly negative protein balance in the muscle compartment in the DM group. This finding was later supported by prospective data identifying diabetes as a potent independent predictor of loss of lean body mass in chronic hemodialysis patients. The role of IR in this process was examined further in a group of chronic hemodialysis patients without diabetes or severe obesity. Using stable tracer isotope methodology, a positive correlation was noted between the degree of IR as quantified by HOMA score, and the amount of skeletal muscle protein breakdown. An interesting finding from this study was that, although net balance trended toward being more negative in IR, HOMA score also correlated to a lesser degree with protein synthesis. This may reflect an imperfect adaptive mechanism to preserve protein stores in the face of increased substrate availability seen in diseases marked by enhanced catabolism such as AKI. In summary, multiple lines of evidence suggest that IR is evident in AKI, is associated with enhanced protein breakdown, and represents a potential target for metabolic intervention.
Metabolic Acidosis
Metabolic acidosis is a common complication of AKI/uremia and may represent another factor associated with increased protein degradation. Elegant studies in models of acute uremia have demonstrated that acidosis is associated with accelerated skeletal muscle proteolysis and is reversible with bicarbonate supplementation. Subsequent mechanistic studies in chronic dialysis patients using tracer isotopes have revealed enhanced whole-body protein degradation, which also was ameliorated upon correction of the acidosis. How exactly acidosis contributes to protein catabolism is not entirely clear; however, concomitant glucocorticoid presence may play a permissive role evidenced by their requirement to stimulate degradation in other models of sepsis and acidosis. Correction of acidosis with bicarbonate supplementation also has been demonstrated to improve IR. Mak demonstrated that 2 weeks of oral bicarbonate replacement significantly improved IR in eight chronic hemodialysis patients as measured by hyperinsulinemic euglycemic clamp. The mechanism remains unclear but may be mediated through upregulation of vitamin D 1,25(OH)2D3 levels via enhanced renal 1-α hydroxylase activity.
Renal Replacement Therapy
Renal replacement therapy (RRT) engenders negative nitrogen balance through the loss of amino acids and, to a lesser degree, plasma proteins incurred during treatments. A standard intermittent hemodialysis (IHD) run with current high-flux dialysis membranes can result in losses as high as 8 to 10 g of amino acids into the dialysate. Amino acid losses from continuous renal replacement therapy (CRRT) have generally been reported to be between 1.2 and 15 g/day, although as high as 20 to 30 g/day have been observed. Although heavily influenced by flow and filtration rates, convective clearance of amino acids may exceed that of dialysis by up to 30%. This also has direct implications for nutritional support as up to 17% of amino acids being received during the provision of total parenteral nutrition (PN) may be lost during treatment. Furthermore, studies in chronic hemodialysis patients have demonstrated markedly enhanced whole-body and skeletal muscle protein catabolism during the treatment itself, likely through the induction of inflammation and oxidative stress.
In summary, protein metabolism is a dynamic process involving a delicate balance between ongoing synthesis and catabolism. Dysregulation of this process in AKI is described by an imbalance toward the latter, often overriding attempts at increasing synthesis. The net result is ongoing negative nitrogen balance and loss of lean body mass with potential consequences for immune or organ function, liberation from mechanical ventilation, wound healing, and endothelial function. These effects combined with diminished clearance of solutes and nitrogenous wastes in AKI also have implications for the provision of nutritional support.
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