Crit Care Clin 21 (2005) 251 260

Physiologic Consequences of Acute Renal Failure on the Critically Ill

Eric A.J. Hoste, MD*, Jan J. De Waele, MD
Intensive Care Unit, Ghent University Hospital, De Pintelaan 185, Ghent 9000, Belgium

In most diseases, a description of the physiologic consequences includes a summary of all the symptoms that occur after the onset of the disease. In community-acquired pneumonia, for instance, there is an acute event: infection of the lungs with bacteria. All symptoms and alterations in organ function that occur after this event, such as hypotension, altered liver function, or thrombocytopenia, are very likely related to the disease. The predominate etiologies of acute renal failure (ARF) in critically ill patients are inflammatory, ischemic, or toxic in nature (see the articles by Lameire and by Klenzak and Himmelfarb elsewhere in this issue). ARF is predominantly caused by other diseases. It may be difficult to distinguish the physiologic consequences of ARF from the physiologic consequences secondary to the cause of ARF. When a patient with pneumonia develops respiratory insufficiency, shock, and ARF, the first two symptoms are related to the infection. It is very likely, however, that ARF also plays a role in the development of shock and respiratory insufficiency. To delineate the physiologic consequences of ARF one has to look for the physiologic consequences caused by decreased kidney function. The kidneys fulfill important roles in many physiologic processes: the maintenance of salt, water, and acid-base homeostasis; excretion of waste products; and production of metabolites, such as erythropoietin. Many of these functions are compromised in patients with ARF, and ARF has many direct and indirect consequences for normal body homeostasis and functioning of different organ systems. The physiologic consequences of ARF can be divided in two main categories: direct consequences and indirect consequences (Box 1).

* Corresponding author. E-mail address: eric.hoste@ugent.be (E.A.J. Hoste). 0749-0704/05/$ see front matter D 2005 Elsevier Inc. All rights reserved. doi:10.1016/j.ccc.2005.01.003 criticalcare.theclinics.com

252

hoste

&

de waele

Box 1. Causes of physiologic changes in ICU patients with ARF Related to retention of compounds Organic compounds = uremic toxicity Inorganic compounds: water and electrolytes Related to decreased production of metabolites (ie, erythropoietin) Side effects of therapy for acute renal failure Side effects of drug therapy Side effects of renal replacement therapy Adverse drug reactions Direct consequences are related to the decreased production of erythropoietin and the retention of compounds that are normally excreted by the kidneys. Retention compounds can be inorganic (ie, water and electrolytes) or organic. Indirect consequences are caused by the therapy applied to patients with ARF. Impaired kidney function and the uremic state have their effects on pharmacokinetics and pharmacodynamics of drugs used for the treatment of ICU patients. Adequate dosing of drugs is a challenge. Underdosing of drugs makes therapy less effective or even ineffective. Overdosing of drugs can occur when dosing regimens are not adapted to the decreased renal excretion. Overdosing may result in unwanted side effects and have its effects on the physiologic function of organs. In addition, renal replacement therapy has important effects on physiology. The indirect consequences of physiologic changes are, however, beyond the scope of this article and are not discussed here.

Effects of decreased kidney function Volume overload Even early in the course of ARF, salt and water retention result in volume overload [1,2]. Depending on the definition of ARF used, between 30% and 70% of the ARF patients in the ICU are oliguric [3,4]. Approximately 70% of ARF patients in the Beginning and Ending Supportive Therapy (B.E.S.T.) Kidney trial were treated with diuretics, again suggesting that volume overload is a frequent finding in ARF patients [5]. In addition to that, volume overload and oliguria are important reasons for starting renal replacement therapy in critically ill patients with ARF [4]. Patients with volume overload are at greater risk for complications and worse outcome. This has been convincingly demonstrated in patients who underwent colorectal surgery and who were randomized to a restrictive or a standard perioperative fluid regimen [6]. Patients in the restrictive fluid arm had significantly fewer complications compared with those randomized to the standard fluid regimen, and patients who had more volume administered had more complica-

arf in the critically ill

253

tions. In addition, observational data demonstrated that ARF patients who are responsive to diuretics have a better outcome compared with those who have a limited urine output [7]. These data suggest, in an indirect way, that volume overload has a negative impact on outcome. Finally, in children with ARF treated with continuous renal replacement therapy, nonsurvivors had more volume overload compared with patients who survived to hospital discharge [8], again suggesting that volume overload may contribute to worse outcome. Electrolyte disorders Hyponatremia is a common finding in ARF patients. The most important cause of hyponatremia in ARF patients is dilutional hyponatremia caused by impaired free water clearance [9]. Hyponatremia causes cell swelling, because the osmotic gradient between the intracellular and extracellular compartments causes a shift of water from extracellular to intracellular. Symptoms are mainly neurologic, and contain a wide spectrum of symptoms from headache to coma [10]. The more acute the onset of hyponatremia, the higher the likelihood of symptoms [11]. Hyperkalemia is another common condition in ARF. Excretion of potassium from the body relies for the greater part on the kidneys. Failure to excrete potassium results in hyperkalemia. Other causes of hyperkalemia may be shift from the intracellular compartment as in acidosis, rhabdomyolysis, or hemolysis, or as a side effect of certain drugs (eg, co-trimoxazole [12]; angiotensin blockers [13,14]; or calcineurin inhibitors, such as cyclosporine or tacrolimus) [15]. Acidosis The kidneys play an important role in preservation of the acid-base homeostasis. When renal function is decreased, there is accumulation of organic anions (eg, phosphate) and other unmeasured anions [16]. Furthermore, there is decreased production of bicarbonate by the decreased proximal tubular reabsorption and regeneration. Another factor that is important in the pathogenesis of metabolic acidosis is the decreased buffering capacity, secondary to hypoalbuminemia [16]. Many patients also have nonrenal reasons for acidosis leading to mixed disorders in acid-base balance. Examples of nonrenal etiologies of acidosis are lactic acidosis, respiratory acidosis induced by permissive hypercapnia ventilation strategies, or less frequently ketoacidosis. Mild-moderate metabolic acidosis is a common finding in patients with ARF [9,16]. Retention of organic compounds: uremia Retention of organic compounds has been well described in chronic renal failure and is called uremic toxicity or uremia after the surrogate serum marker of renal function, urea [17]. The term uremia is probably not aptly chosen: uremic toxicity may occur irrespective of the level of serum urea or blood

254

hoste

&

de waele

urea nitrogen. It is disputable whether urea itself causes toxicity. Chronic hemodialysis treatment with urea added to the dialysate compartment increased urea levels, but had no impact on toxicity [18]. Serum urea level is probably a marker for retention of other compounds that may cause toxicity. Organic retention solutes can be of low molecular weight (b 500 d) or middle molecules, and protein-bound or water-soluble. An encyclopedic list of 90 welldocumented uremic toxins in chronic renal failure has been published by the European Uremic Toxin Work Group [19]. There are only very limited data on uremic toxicity in the setting of ARF. The time course of retention of uremic retention compounds in ARF is completely different compared with that in patients with chronic renal failure. Instead of accumulation of retention compounds over months or even years, exposure to retention compounds in ARF patients only lasts for a period of days or weeks. Uremic toxicity in chronic renal failure patients can probably not be completely extrapolated to patients with ARF. Increased inflammation and decreased immunity Increased inflammation The normal inflammatory reaction seems dysregulated in ARF patients [20], and this seems to play an important role in subsequent development of multiple organ dysfunction [21]. Proinflammatory mediators, such as tumor necrosis factor and interleukin-1b, -6, and -8, have increased levels in ARF patients compared with patients with end-stage renal disease or normal subjects. In addition, the level of the anti-inflammatory mediator interleukin-10 is also increased, suggesting a compensatory anti-inflammatory response syndrome. It has also been demonstrated that there is increased oxidative stress in ARF patients [22]. Finally, ARF leads to dysfunction of other organs, as has been demonstrated in the lungs. After ischemia-reperfusion injury of the kidneys there is dysregulation of the salt and water channels and increased vascular permeability in the lungs leading to interstitial edema [23,24]. The etiology for this dysregulated inflammatory response is not entirely clear. Dysregulation of the lung salt and water channels is related to the severity of ARF, suggesting that uremia may be responsible [23]. Increased cytokine levels and oxidative stress in patients with end-stage renal disease also suggests that uremia may play a role in the cause of dysregulated inflammation [2527]. In addition, there is much evidence that ARF itself is caused, at least in part, by an inflammatory cascade of events [2832]. The inflammatory response seldom is localized to one organ system, but also has consequences for other organ systems. It is likely that this response also causes generalized inflammation and organ dysfunction. Acidosis may also contribute to the inflammatory status of ARF patients. The effects on inflammation seem to vary according to the type of acidosis: respiratory versus metabolic, and hyperchloremic versus lactic. Hyperchloremic acidosis is more proinflammatory compared with lactic acidosis. In vitro experi-

arf in the critically ill

255

ments demonstrated that hyperchloremic acidosis increased the interleukin-6 interleukin-10 ratio and also increased NF-kB DNA binding [33]. In vivo, acidosis leads to increased nitric oxide levels and lower blood pressure or shock [34]. It also increases lung and intestinal injury and decreases gut barrier function [3538]. Decreased immunity There is much evidence for an immune depressed state caused by uremia in chronic renal failure patients. ARF patients also experience uremia; hence, immune suppression seems plausible in these patients [27,39]. Several uremic retention compounds, such as leptin [40], advanced glycation end-products [41], guanidine [42], and P-cresol [4345], interfere with normal white blood cell function, phagocytosis, or endothelial function and also with normal immunity. Other factors that are believed to contribute to these effects in chronic uremia are malnutrition, iron overload, anemia, and bioincompatibility of dialyzer membranes. These factors are also present in patients with ARF. Finally, acidosis may also impair immune function by depressant effects on polymorphonuclear and lymphocyte function [46,47].

Clinical symptoms of decreased kidney function in patients with acute renal failure To get a more comprehensive overview of the consequences of ARF the major clinical symptoms and the effects of altered renal physiology on different organ systems are now summarized. Cardiovascular consequences Hypertension may occur as a consequence of volume overload and increased intravascular volume. Hypotension and shock are more common in critically ill patients with ARF. Several physiologic consequences contribute to the development of shock in ARF patients (Fig. 1). Volume overload may cause congestive heart failure and hypotension. Formation of ascites and retroperitoneal tissue edema may increase intraabdominal pressure, and cause intra-abdominal hypertension or even an intraabdominal compartment syndrome [48]. Intra-abdominal hypertension has many diverse and untoward effects on hemodynamics (compression of the inferior vena cava causing decreased preload and cardiac output); lung function (decreased functional residual capacity by upward shift of the diaphragm); and perfusion of intra-abdominal organs, causing ileus and decreased liver and kidney function [49,50]. Acidosis also contributes to hypotension. Moderate hyperchloremic acidosis increases nitric oxide levels and inducible nitric oxide synthase leading to vasodilation and lower blood pressure [34]. Acidosis may also impair cardiac output

256

hoste

&

de waele

ARF

Uremia

Acidosis

Volume overload

Inflammation Immunity

Infection

Vasodilation

Heart failure

IAH

Shock
Fig. 1. Mechanisms contributing to the development of shock in patients with ARF. ARF, acute renal failure; IAH, intra-abdominal hypertension.

and decrease liver and kidney perfusion [51], probably by down-regulation of the b2 receptors [52,53]. Other conditions that may contribute to the development of hypotension and shock are anemia, particularly in patients with pre-existing coronary artery disease, and hyperkalemia, which may cause cardiac arrhythmia. Finally, the dysregulated inflammatory state and decreased immunity may cause infection, and contribute to multiple organ dysfunction and shock. Pulmonary function Volume overload may cause pulmonary congestion, pleural effusions, or intraabdominal hypertension, leading to decreased gas exchange. ARF patients may also experience interstitial edema by dysregulation of the inflammatory cascade and increased vascular permeability [23,24,36]. Decreased immune function and all of the previously mentioned factors may lead to infection or pneumonia. Loss of muscle mass and oversedation by retention of sedatives may prolong the duration of mechanical ventilation, which in itself is also a risk factor for other complications. Anemia ARF patients experience decreased synthesis and increased breakdown of red blood cells. Decreased erythropoietin levels or erythropoietin resistance, secondary to infection, are responsible for decreased bone marrow synthesis [5456]. Uremia also causes increased fragility of the membrane of the red blood cells and hence decreases half-life [56]. In addition, uremic coagulopathy interferes with coagulation and also leads to increased blood loss [57,58]. Espe-

arf in the critically ill

257

cially in patients with coronary artery disease, anemia may have severe hemodynamic consequences. Neuromuscular disease ARF patients experience increased muscle breakdown and decreased protein metabolism, leading to decreased muscle mass. Uremia and acidosis are both important etiologic factors in these processes [59,60]. Furthermore, polyneuropathy is a frequent finding in chronic renal failure patients and also in critically ill patients with ARF [61,62]. Decreased muscle mass and nerve conducting disturbances play an important role in the weaning of mechanical ventilation, and contribute to a prolongation of the length of ICU stay. Central nervous system function Hyponatremia and acidosis may contribute to impaired consciousness, seizures, and eventually coma by cell swelling and interference with metabolism of the central nervous system [10,63]. Infection ARF patients are at increased risk for infection after cardiac surgery and have an almost threefold greater incidence of bloodstream infection in the ICU [64,65]. Furthermore, infection was attributed as the cause of death in 40% of the ICU patients with ARF [66]. The increased incidence of infection can be explained by decreased immunity and dysregulation of inflammation, and possibly by altered glucose metabolism. Acidosis has untoward effects on glucose metabolism. Acidosis causes induction of insulin resistance and inhibition of anaerobic glycolysis [67]. Hyperglycemia is associated with immune dysfunction and increased susceptibility to infection [68], probably by proinflammatory effects and decreased phagocytosis [69]. Hyperglycemia is now recognized as an important risk factor for multiple organ dysfunction and death in critically ill patients, and tight glucose control improves outcome [7072]. Tissue edema may negatively influence wound healing [6], and this increases the length of stay, and puts the patient at greater risk for infection and other complications. Finally, increased length of stay in the ICU, and increased length of mechanical ventilation caused by loss of muscle mass and prolongation of multiple organ dysfunction also increases the risk for nosocomial infection.

Summary Retention of uremic toxins and acidosis in patients with ARF leads to dysregulation of the inflammatory response, decreased immunity, and impaired hemodynamics. This causes multiple adverse effects, including increased risk for

258

hoste

&

de waele

infection and multiple organ dysfunction. The combination and interaction of the different pathophysiologic processes produce an even greater net effect on organ function. ARF is not only a consequence of multiple organ dysfunction, but is also an important etiologic factor for multiple organ dysfunction.

References
[1] Baek SM, Makabali GG, Brown RS, et al. Free-water clearance patterns as predictors and therapeutic guides in acute renal failure. Surgery 1975;77:632 40. [2] Hoste EA, Lameire NH, Vanholder RC, et al. Acute renal failure in patients with sepsis in a surgical ICU: predictive factors, incidence, comorbidity, and outcome. J Am Soc Nephrol 2003; 14:1022 30. [3] Mehta RL, Pascual MT, Soroko S, et al. Spectrum of acute renal failure in the intensive care unit: The PICARD experience. Kidney Int 2004;66:1613 21. [4] Silvester W, Bellomo R, Cole L. Epidemiology, management, and outcome of severe acute renal failure of critical illness in Australia. Crit Care Med 2001;29:1910 5. [5] Uchino S, Doig GS, Bellomo R, et al. Diuretics and mortality in acute renal failure. Crit Care Med 2004;32:1669 77. [6] Brandstrup B, Tonnesen H, Beier-Holgersen R, et al. Effects of intravenous fluid restriction on postoperative complications: comparison of two perioperative fluid regimens: a randomized assessor-blinded multicenter trial. Ann Surg 2003;238:641 8. [7] Mehta RL, Pascual MT, Soroko S, et al. Diuretics, mortality, and nonrecovery of renal function in acute renal failure. JAMA 2002;288:2547 53. [8] Foland JA, Fortenberry JD, Warshaw BL, et al. Fluid overload before continuous hemofiltration and survival in critically ill children: a retrospective analysis. Crit Care Med 2004;32:1771 6. [9] Dolson GM. Electrolyte abnormalities before and after the onset of acute renal failure. Miner Electrolyte Metab 1991;17:133 40. [10] Adrogue HJ, Madias NE. Hyponatremia. N Engl J Med 2000;342:1581 9. [11] Rose BD, Post TW. Hyperosmolar states-hyponatremia. In: Post TW, editor. Clinical physiology of acid-base and electrolyte disorders. 5th edition. New York7 McGraw-Hill; 2001. p. 696 745. [12] Hsu I, Wordell CJ. Hyperkalemia and high-dose trimethoprim/sulfamethoxazole. Ann Pharmacother 1995;29:427 9. [13] Schepkens H, Vanholder R, Billiouw JM, et al. Life-threatening hyperkalemia during combined therapy with angiotensin-converting enzyme inhibitors and spironolactone: an analysis of 25 cases. Am J Med 2001;110:438 41. [14] Wrenger E, Muller R, Moesenthin M, et al. Interaction of spironolactone with ACE inhibitors or angiotensin receptor blockers: analysis of 44 cases. BMJ 2003;327:147 9. [15] Kahan BD. Cyclosporine nephrotoxicity: pathogenesis, prophylaxis, therapy, and prognosis. Am J Kidney Dis 1986;8:323 31. [16] Rocktaeschel J, Morimatsu H, Uchino S, et al. Acid-base status of critically ill patients with acute renal failure: analysis based on Stewart-Figge methodology. Crit Care 2003;7:R606. [17] Vanholder R, Argiles A, Baurmeister U, et al. Uremic toxicity: present state of the art. Int J Artif Organs 2001;24:695 725. [18] Johnson WJ, Hagge WW, Wagoner RD, et al. Effects of urea loading in patients with faradvanced renal failure. Mayo Clin Proc 1972;47:21 9. [19] Vanholder R, De Smet R, Glorieux G, et al. Review on uremic toxins: classification, concentration, and interindividual variability. Kidney Int 2003;63:1934 43. [20] Simmons EM, Himmelfarb J, Sezer MT, et al. Plasma cytokine levels predict mortality in patients with acute renal failure. Kidney Int 2004;65:1357 65. [21] Hotchkiss RS, Karl IE. The pathophysiology and treatment of sepsis. N Engl J Med 2003; 348:138 50.

arf in the critically ill

259

[22] Himmelfarb J, McMonagle E, Freedman S, et al. Oxidative stress is increased in critically ill patients with acute renal failure. J Am Soc Nephrol 2004;15:2449 56. [23] Rabb H, Wang Z, Nemoto T, et al. Acute renal failure leads to dysregulation of lung salt and water channels. Kidney Int 2003;63:600 6. [24] Kramer AA, Postler G, Salhab KF, et al. Renal ischemia/reperfusion leads to macrophagemediated increase in pulmonary vascular permeability. Kidney Int 1999;55:2362 7. [25] Vaziri ND. Oxidative stress in uremia: nature, mechanisms, and potential consequences. Semin Nephrol 2004;24:469 73. [26] Glorieux G, Vanholder R, Lameire N. Uraemic retention and apoptosis: what is the balance for the inflammatory status in uraemia? Eur J Clin Invest 2003;33:631 4. [27] Vanholder R, De Smet R. Pathophysiologic effects of uremic retention solutes. J Am Soc Nephrol 1999;10:1815 23. [28] Donnahoo KK, Shames BD, Harken AH, et al. Review article: the role of tumor necrosis factor in renal ischemia-reperfusion injury. J Urol 1999;162:196 203. [29] Donnahoo KK, Meldrum DR, Shenkar R, et al. Early renal ischemia, with or without reperfusion, activates NFkappaB and increases TNF-alpha bioactivity in the kidney. J Urol 2000;163: 1328 32. [30] Donnahoo KK, Meng X, Ayala A, et al. Early kidney TNF-alpha expression mediates neutrophil infiltration and injury after renal ischemia-reperfusion. Am J Physiol 1999;277:R9229. [31] Bonventre JV, Zuk A. Ischemic acute renal failure: an inflammatory disease? Kidney Int 2004; 66:480 5. [32] Ramesh G, Reeves WB. Inflammatory cytokines in acute renal failure. Kidney Int 2004;66: S5661. [33] Kellum JA, Song M, Li J. Lactic and hydrochloric acids induce different patterns of inflammatory response in LPS-stimulated RAW 264.7 cells. Am J Physiol Regul Integr Comp Physiol 2004;286:R68692. [34] Kellum JA, Song M, Venkataraman R. Effects of hyperchloremic acidosis on arterial pressure and circulating inflammatory molecules in experimental sepsis. Chest 2004;125:243 8. [35] Pedoto A, Nandi J, Oler A, et al. Role of nitric oxide in acidosis-induced intestinal injury in anesthetized rats. J Lab Clin Med 2001;138:270 6. [36] Pedoto A, Caruso JE, Nandi J, et al. Acidosis stimulates nitric oxide production and lung damage in rats. Am J Respir Crit Care Med 1999;159:397 402. [37] Salzman AL, Wang H, Wollert PS, et al. Endotoxin-induced ileal mucosal hyperpermeability in pigs: role of tissue acidosis. Am J Physiol 1994;266:G63346. [38] Unno N, Hodin RA, Fink MP. Acidic conditions exacerbate interferon-gamma-induced intestinal epithelial hyperpermeability: role of peroxynitrous acid. Crit Care Med 1999;27:1429 36. [39] Vanholder R, Van Biesen W. Incidence of infectious morbidity and mortality in dialysis patients. Blood Purif 2002;20:477 80. [40] Ottonello L, Gnerre P, Bertolotto M, et al. Leptin as a uremic toxin interferes with neutrophil chemotaxis. J Am Soc Nephrol 2004;15:2366 72. [41] Glorieux G, Helling R, Henle T, et al. In vitro evidence for immune activating effect of specific AGE structures retained in uremia. Kidney Int 2004;66:1873 80. [42] Glorieux GL, Dhondt AW, Jacobs P, et al. In vitro study of the potential role of guanidines in leukocyte functions related to atherogenesis and infection. Kidney Int 2004;65:2184 92. [43] Cerini C, Dou L, Anfosso F, et al. P-cresol, a uremic retention solute, alters the endothelial barrier function in vitro. Thromb Haemost 2004;92:140 50. [44] Dou L, Cerini C, Brunet P, et al. P-cresol, a uremic toxin, decreases endothelial cell response to inflammatory cytokines. Kidney Int 2002;62:1999 2009. [45] Vanholder R, De Smet R, Waterloos MA, et al. Mechanisms of uremic inhibition of phagocyte reactive species production: characterization of the role of p-cresol. Kidney Int 1995;47: 510 7. [46] Lardner A. The effects of extracellular pH on immune function. J Leukoc Biol 2001;69:522 30. [47] Kellum JA, Song M, Li J. Science review: extracellular acidosis and the immune response. Clinical and physiologic implications. Crit Care 2004;8:331 6.

260

hoste

&

de waele

[48] Malbrain ML, Chiumello D, Pelosi P, et al. Prevalence of intra-abdominal hypertension in critically ill patients: a multicentre epidemiological study. Intensive Care Med 2004;30:822 9. [49] Moore AF, Hargest R, Martin M, et al. Intra-abdominal hypertension and the abdominal compartment syndrome. Br J Surg 2004;91:1102 10. [50] De Waele JJ, Benoit D, Hoste E, et al. A role for muscle relaxation in patients with abdominal compartment syndrome? Intensive Care Med 2003;29:332. [51] Bersentes TJ, Simmons DH. Effects of acute acidosis on renal hemodynamics. Am J Physiol 1967;212:633 40. [52] Marsh JD, Margolis TI, Kim D. Mechanism of diminished contractile response to catecholamines during acidosis. Am J Physiol 1988;254:H207. [53] Weil MH, Houle DB, Brown Jr EB, et al. Vasopressor agents; influence of acidosis on cardiac and vascular responsiveness. Calif Med 1958;88:437 40. [54] Lipkin GW, Kendall R, Haggett P, et al. Erythropoietin in acute renal failure. Lancet 1989; 1:1029. [55] Lipkin GW, Kendall RG, Russon LJ, et al. Erythropoietin deficiency in acute renal failure. Nephrol Dial Transplant 1990;5:920 2. [56] Nagano N, Koumegawa J, Arai H, et al. Effect of recombinant human erythropoietin on new anaemic model rats induced by gentamicin. J Pharm Pharmacol 1990;42:758 62. [57] Eknoyan G, Wacksman SJ, Glueck HI, et al. Platelet function in renal failure. N Engl J Med 1969;280:677 81. [58] Weigert AL, Schafer AI. Uremic bleeding: pathogenesis and therapy. Am J Med Sci 1998;316: 94 104. [59] Mitch WE. Mechanisms causing loss of muscle in acute uremia. Ren Fail 1996;18:389 94. [60] Bailey JL, Mitch WE. Metabolic acidosis as a uremic toxin. Semin Nephrol 1996;16:160 6. [61] Tegner R, Brismar T. Experimental uremic neuropathy. Part 1. Decreased nerve conduction velocity in rats. J Neurol Sci 1984;65:29 36. [62] Palmer CA. Neurologic manifestations of renal disease. Neurol Clin 2002;20:23 34. [63] Adrogue HJ, Madias NE. Management of life-threatening acid-base disorders: first of two parts. N Engl J Med 1998;338:26 34. [64] Thakar CV, Yared JP, Worley S, et al. Renal dysfunction and serious infections after open-heart surgery. Kidney Int 2003;64:239 46. [65] Hoste EA, Blot SI, Lameire NH, et al. Effect of nosocomial bloodstream infection on the outcome of critically ill patients with acute renal failure treated with renal replacement therapy. J Am Soc Nephrol 2004;15:454 62. [66] Lian o F, Junco E, Pascual J, et al. The spectrum of acute renal failure in the intensive care unit compared to that seen in other settings. Kidney Int 1998;53(Suppl 66):S1624. [67] DeFronzo RA, Beckles AD. Glucose intolerance following chronic metabolic acidosis in man. Am J Physiol 1979;236:E32834. [68] Zerr KJ, Furnary AP, Grunkemeier GL, et al. Glucose control lowers the risk of wound infection in diabetics after open heart operations. Ann Thorac Surg 1997;63:356 61. [69] Weekers F, Giulietti AP, Michalaki M, et al. Metabolic, endocrine, and immune effects of stress hyperglycemia in a rabbit model of prolonged critical illness. Endocrinology 2003;144: 5329 38. [70] Van den Berghe G, Wouters P, Weekers F, et al. Intensive insulin therapy in critically ill patients. N Engl J Med 2001;345:1359 67. [71] Finney SJ, Zekveld C, Elia A, et al. Glucose control and mortality in critically ill patients. JAMA 2003;290:2041 7. [72] Pittas AG, Siegel RD, Lau J. Insulin therapy for critically ill hospitalized patients: a metaanalysis of randomized controlled trials. Arch Intern Med 2004;164:2005 11.