Introduction
Between 25% and 75% of critically ill patients are affected by acute kidney injury (AKI), and AKI is an independent risk factor for mortality in critically ill patients, including those with neurologic disorders such as traumatic brain injury (TBI) or subarachnoid hemorrhage (SAH). Even small changes in serum creatinine (SC) are associated with an increased risk of death. In addition, the incidence of end-stage renal disease (ESRD) is increasing. These patients, who have significant comorbidities, represent an important group of patients who require critical care. This chapter reviews renal physiology and AKI and its assessment, including consensus definitions (RIFLE: risk, injury, failure, loss, end-stage disease) from the Acute Kidney Network (AKIN). In addition, an approach to acid-base disorders is described. Assessment of volume status and sodium balance and its disorders are reviewed in Chapter 19 , Chapter 21 , respectively.
Normal Renal Physiology
The kidney maintains the extracellular environment by excreting the waste products of metabolism (urea, creatinine, and uric acid) while simultaneously regulating the excretion of water and solutes (Na + , K + , H + ) by causing changes in tubular reabsorption or secretion. The glomerular filtrate is more than 60 times the volume of plasma, thus almost all of this fluid must be returned to the systemic circulation by tubular reabsorption. Conversely, solutes move from the peritubular capillary through the cell and into the urine in a process called tubular secretion . Na + , Cl − , and H 2 O are reabsorbed, H + is secreted, K + and uric acid are both absorbed and secreted, and filtered creatinine is excreted virtually unchanged.
Hypovolemia is monitored by baroreceptors (located in the carotid sinuses and afferent arterioles of the glomerulus), and plasma volume is regulated by the resorption or excretion of sodium and water. The baroreceptors signal to increase intravascular volume by three mechanisms: (1) renin-angiotensin-aldosterone system (RAAS); (2) sympathetic activation with the nerves releasing epinephrine, norepinephrine, and dopamine; and (3) antidiuretic hormone (ADH). Techniques to monitor volume status are discussed in Chapter 19 .
Renin-Angiotensin-Aldosterone System
With hypovolemia, the juxtaglomerular apparatus releases renin that converts angiotensinogen from the liver to angiotensin I. Angiotensin I is converted to angiotensin II by angiotensin-converting enzyme (ACE), primarily in the lung ( Fig. 22.1 ). Angiotensin II is also produced by the zona glomerulosa of the adrenal gland in response to hypovolemia or hyperkalemia and has the following functions: (1) it increases Na + and water resorption in the kidney at the proximal convoluted tubule (PCT); (2) it increases the production and release of aldosterone from the adrenal gland that in turn causes an increase in Na + resorption in the collecting tubule; and (3) it is the most potent vasoconstrictor in the body and increases blood pressure through its direct vasoconstrictive effects.
Aldosterone acts on two types of cells in the collecting tubule—the principal cell and the intercalated cell. At the basolateral membrane of the principal cell, aldosterone increases the Na + -K + -adenosine triphosphate (ATPase) pump that creates a concentration gradient between the tubular lumen and the principal cell ( Fig. 22.2 ). This allows Na + to flow down the concentration gradient with the secretion of K + . The potassium-sparing diuretics, amiloride and triamterene, act by directly closing Na + channels, and spironolactone competes with aldosterone. At the level of the intercalated cell, aldosterone acts at the H + -ATPase pump to increase the secretion of H + into the tubule lumen ( Fig. 22.3 ). As H + is secreted into the lumen, HCO 3 − is formed inside the cell and then resorbed into the plasma. Thus an increase in aldosterone can result in a metabolic alkalosis and decreased activity results in type 4 renal tubular acidosis.
Sympathetic activity increases plasma volume by increasing Na + resorption in the PCT and by stimulating renin release.
Antidiuretic Hormone-Arginine Vasopressin
The hypothalamus regulates osmolality (water content) through the mechanisms of thirst and antidiuretic hormone (ADH). ADH is the generic name given to what is now known as arginine vasopressin that is synthesized in the supraoptic and paraventricular nuclei of the hypothalamus and stored in the posterior lobe of the pituitary ( Fig. 22.4 ). There are three stimuli for ADH secretion: (1) hyperosmolality—as little as a 1% increase in osmolality will stimulate ADH; (2) low circulating volume more than a 10% decrease in volume or more than 10 to 15 mm Hg decrease in blood pressure; and (3) inappropriate release (i.e., syndrome of inappropriate antidiuretic hormone [SIADH]) that is discussed further in Chapter 21 .
Plasma Osmolality
Plasma osmolality refers to the concentration of all the solutes (electrolytes and nonelectrolytes) in the plasma and is normally between 285 and 295 mmol/L. The kidney exerts control over osmolality at several locations. In the proximal convoluted tubule, sodium and water are resorbed in an isotonic manner, so the osmolality of the fluid leaving is isotonic. At the loop of Henle (LOH), Na + -K + -2 Cl − pumps remove electrolytes from the tubular fluid and in the process generate both a dilute urine and a hypertonic medullary interstitium. ADH inserts preformed water channels into the collecting tubule that allows water to be osmotically reabsorbed and to concentrate the urine ( Fig. 22.5 ). Osmolality is estimated by calculating the concentration of three solutes:
Osmolality = 2 × Na + (mmol/L) + Blood urea nitrogen (BUN) (mg/dL)/2.8 plus (glucose mg/dL)/18.
BUN and glucose are measured in mg/dL and must be converted to mmol/L. To convert mg to mmol, divide the mg by the MW (MW = mg/mmol). Thus the conversion of BUN:
BUN = 18 mg/dL
(18 mg/dL/(28 mg/mmol) × 10 dL/L = 6.4 mmol/L.
Similar osmolality calculations can be made for commonly infused intravenous (IV) solutions. D 5 W has:
5 g/100 mL (or 5000 mg/dL/180 mg/mmol) × 10 dL/L = 278 mmol/L.
Also:
0.9% normal saline (NS) = 0.9 g/dL = (900 mg/dL/58.5 mg/mmol) × 10 dL/L = 154 mmol/L.
This is balanced by an equal number of Cl − , so the osmolality is 154 mmol/L + 154 mmol/L = 308 mmol/L, that is, isotonic. The units of osmolality are expressed as either mOsm/kg in conventional units or mmol/L in SI units.
Because Mg + , Ca + , bilirubin, and albumin are not included in the calculation, there will always be a difference between the measured and calculated osmolality. This osmolar gap is less than 10 mmol/L, and a greater value indicates the accumulation of osmoles that are either endogenous (lactic acid, ketones) or exogenous (ethanol, methanol, ethylene glycol, isopropyl alcohol). In clinical practice it can be useful to know that ethanol has a molecular weight of 46, so a level of 230 mg/dL is 50 mmol/L (230 mg/dL/46 mg/mmol) ×10 dL/L = 50 mmol/L).
Urine concentration is measured by osmolality and by specific gravity. Osmolality is the number of particles per liter and is determined by freezing point depression. It is used in evaluation of hyponatremia and the investigation of polydipsia and polyuria. Specific gravity is the mass (in grams) of 1 mL of solution. Thus if there are particularly heavy particles such as glucose or radiocontrast dye, the specific gravity will overestimate the urine concentration compared with the osmolality. There are several circumstances in which the measurement of urine osmolality may be important :
- 1.
Distinguishing between prerenal AKI and acute tubular necrosis (ATN). A urine osmolality greater than 500 mosmol/kg suggests prerenal disease, in which lower values are not helpful.
- 2.
To distinguish between primary polydipsia and other causes of hyponatremia. A urine osmolality less than 100 mosmol/kg indicates normal suppression of ADH and therefore the presence of primary polydipsia. A higher urine osmolality suggests the presence of at least some ADH usually due to effective volume depletion or SIADH.
- 3.
A decreasing urinary osmolality suggests that a spontaneous water diuresis has begun to correct hyponatremia. This helps to avoid inadvertent overcorrection in hyponatremic patients with reversible causes of water retention such as volume depletion, pain, nausea, or drugs.
- 4.
Urine osmolality helps distinguish between primary polydipsia and diabetes insipidus (DI) as a cause of polyuria. After the plasma osmolality is increased by water restriction to stimulate ADH release, the urine becomes concentrated with primary polydipsia. The urinary osmolality remains relatively dilute with both forms of DI, though patients with central DI have some concentration after administration of desmopressin (DAVP).
- 5.
In patients who are hypernatremic, a urine osmolality less than plasma osmolality suggests the presence of DI.
AKI in the Intensive Care Unit
Overview
Acute renal failure is common in the intensive care unit (ICU), with a prevalence of up to 25% to 75%, and it is an independent risk factor for poor outcome with mortality rates from 28% to 90%. These wide ranges reflect that it is a complex, poorly understood process with more than 30 definitions in the literature. The following section provides a template for evaluation and management. A comprehensive review of therapy, however, is beyond the scope of this chapter, and the reader is referred to recent reviews on this topic for further information.
Epidemiology
Standardization of the definition of AKI has resulted in a better understanding of its incidence. Population-based studies suggest it is nearly as common as myocardial infarction. The causes of AKI are several. For example, Liano et al. collected data on 748 cases of AKI in a prospective, multicenter study from Madrid. The following causes were identified: ATN, 45%; prerenal, 21%; acute on chronic renal failure, 13%; urinary tract obstruction, 10%; glomerulonephritis or vasculitis, 4%; acute interstitial nephritis, 2%; and atheroemboli, 1%. In the United States, epidemiologic data from the Program to Improve Care in Acute Renal Disease (PICARD) examined the etiology of AKI in 618 patients from five medical centers. The most common causes were ischemic acute tubular necrosis (including sepsis and hypotension), prerenal disease (hypovolemia, hemorrhage), nephrotoxicity (radiocontrast media [RCM], rhabdomyolysis), AKI with cardiac disease (heart failure and shock), AKI with liver disease (hepatorenal syndrome, cirrhosis), and multifactorial etiologies. Multicenter epidemiologic studies suggest that overall sepsis is now the most common cause of AKI in the ICU.
Diagnosis
Conceptually AKI refers to the acute decline in glomerular and tubular function that results in azotemia (the accumulation of nitrogenous waste products), and the inability to maintain fluid and electrolyte homeostasis. The diagnosis of renal failure is based on a history and physical examination along with general supporting chemistries, the urinalysis, assessment of the glomerular filtration rate (GFR; primarily the BUN and SC), and urine output. However, not all elevations in BUN and creatinine indicate renal injury, and oliguria (<400 mL/24 hr) is not a universal finding ( Table 22.1 ).
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RIFLE and AKIN Criteria
The understanding of AKI has been hindered by the numerous definitions used in various studies, and an important contribution to conceptualization was the development of a consensus definition by the Acute Dialysis Quality Initiative (ADQI) in which they introduced the RIFLE criteria. This stratifies renal failure into:
R isk of renal dysfunction: a 1.5 times’ increase in SC; urine output less than 0.5 mL/kg/hr times 6 hours
(GFR decrease >25%)
I njury to the kidneys: twofold increase in SC; urine output less than 0.5 mL/kg/hr times 12 hours
(GFR decrease >50%)
F ailure of kidney function: threefold increase in SC; urine output less than 0.5 mL/kg/hr times 24 hours
(GFR decrease 75%)
L oss of kidney function: defined as the need for renal replacement therapy (RRT) for more than 4 weeks
E nd-stage kidney disease: need for dialysis for longer than 3 months
A modification of the RIFLE criteria was subsequently proposed by the AKIN, which included representatives from the ADQI group and from other nephrology and intensive care societies. Their proposal for kidney failure resulted in a three-stage classification that corresponds to risk (stage 1), injury (stage 2), and failure (stage 3) of the RIFLE criteria. Loss and ESRD are removed form the staging system and defined as outcomes.
Stage 1: Increase in SC of 0.3 mg/dL or an increase in 1.5 to 2 from baseline; urine output less than 0.5 mL/kg/hr for more than 6 hours
Stage 2: Increase in SC more than two- to threefold from baseline; urine output less than 0.5 mg/kg/hr for more than 12 hours
Stage 3: Increase in SC more than threefold from baseline or SC greater than or equal to 4 mg/dL with an acute increase of at least 0.5 mg/dL; urine output less than 0.5 mg/kg/hr for 24 hours or anuria for 12 hours
The addition of an absolute change in SC of more than or equal to 0.3 mL/kg/hr is based on data that show an 80% increase in mortality associated with changes in SC concentration of as little as 0.3 to 0.5 mL/kg/hr. The last two criteria are identical to the RIFLE risk criteria. The criteria should be applied after volume resuscitation and urinary tract obstruction excluded if oliguria is the sole diagnostic criterion. These criteria may have their greatest applicability in helping to standardize definitions in clinical studies. AKIN also recommended replacing the term acute renal failure with acute kidney injury to represent the entire spectrum of acute renal failure.
However, these modifications may still be misleading in assessing AKI. The SC does not accurately reflect the GFR in a patient who is not in steady state. Thus a patient may be developing AKI with a normal creatinine, and a rising creatinine may not imply ongoing kidney injury. Furthermore, creatinine is removed by dialysis, so it is not possible to assess kidney function by measuring it once dialysis is initiated. Moreover, AKI may exist despite a normal urine output. This has led to investigation into a number of biomarkers—N-acetyl-glucosaminidase (NAG), neutrophil gelatinase–associated lipocalin (NGAL), cystatin C, or kidney injury molecule 1 (KIM-1) among others—that may better indicate the state of kidney injury. Finally, RIFLE and AKIN criteria rely in large part on SC and measurement of urine output for the diagnosis of AKI. Changes in SC may be delayed and in most ICUs urine output is measured manually, so these measurements may be subject to human error. Newer techniques that provide continuous minute-to-minute monitoring of urine output may allow more accurate evaluation of urine output and hence early identification of AKI.
Classification of AKI
A standard strategy to classify AKI is to divide it into prerenal disease, postrenal disease, and intrinsic disease based on the primary site of injury—the tubules, glomerulus, interstitium, or vessels. Prerenal disease may progress to tubular injury, and ATN may result from ischemic or toxic causes. These categories may have some clinical utility in organizing thinking, but they imply an insight into pathophysiology (prerenal) or histology (ATN) that is either greatly simplified or misleading. A complementary approach is to examine the injury in different disease states. An integrative approach using both of these strategies is used in this outline.
Prerenal AKI and ATN
Prerenal AKI may result from intravascular volume depletion, an alteration of glomerular hemodynamics, or vascular compromise ( Table 22.2 ). Prerenal AKI may evolve into an entity traditionally referred to as ATN ; the distinctions based on urine chemistries are outlined in Table 22.3 . Physiologically, the reduction in blood pressure activates cardiac and arterial receptors that increases sympathetic neural tone (improving blood pressure but causing renal vasoconstriction), and releasing both renin, which leads to the production of angiotensin II, and ADH. Angiotensin II and adrenergic activation stimulate the proximal reabsorption of sodium, and aldosterone increases the sodium reabsorption in the distal tubule. This results in a urinary sodium concentration of less than 20 mEq/L. There is enhanced reabsorption of urea from the medullary collecting ducts, resulting in a disproportionate increase of BUN compared with creatinine with a BUN-to-SC ratio of greater than 10 : 1 to 15 : 1. As tubular function is preserved, there is a high urine osmolality, greater than 350 mOsm/L.
|
| Laboratory | Prerenal AKI | ATN |
|---|---|---|
| Urine specific gravity | >1.020 | ≈1.012 |
| Urine sodium, mEq/L | <20 | >30 |
| BUN/SC ratio | 20 | 10 |
| Urine osmolality | >350 | ≈300 |
| Urine/plasma osmolality | >1.5 | 1.0 |
| FENa | <1% | >1% |
| FE urea | <35% | >50% |
Of the tests available (see Table 22.3 ), the fractional excretion of sodium (FENa) may be the preferred screening test to differentiate between prerenal AKI and ATN ( Table 22.4 ).
FENa = ( urine Na × serum creatinine ) / ( serum Na × urine creatinine ) × 100
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Classically, a FENa less than 1% is characteristic of prerenal AKI, whereas a FENa greater than 1% to 2% signifies ATN. However, a low FENa is not unique to prerenal disease. It can occur in disorders associated with normal tubular function but a low GFR such as acute glomerulonephritis (GN), vasculitis, and acute urinary tract obstruction. It also can be seen when ATN is superimposed on a chronic sodium-retaining state as may occur with aminoglycoside therapy, congestive heart failure (CHF), or cirrhosis. The confounding effects of diuretics may be obviated by the use of the fractional excretion of urea, which when less than 35% accurately indicates prerenal azotemia.
The urinalysis in prerenal disease is normal (this may include granular casts), whereas ATN has muddy brown casts ( Fig. 22.6 ). Pathologically, tubular necrosis is usually not seen with ATN, and there is often limited histologic evidence of injury despite marked functional impairment. ATN may be induced by those factors that cause prerenal AKI as well as by drugs, rhabdomyolysis, tumor lysis, and vascular insults. Diuretics may convert ATN from an oliguric to a nonoliguric state and may be tried for volume control, but they have no effect on renal recovery or survival. Loop diuretics work by inhibition of a Na + −K + −2Cl − transporter in the loop of Henle. A secretory isoform of this transporter is present in the inner ear endolymph, and thus high-dose diuretics may lead to permanent hearing loss. Dopamine does not provide protection in early ATN and may cause harm by reducing renal blood flow in postischemic ATN. Prevention of ATN by optimizing volume status and avoiding nephrotoxic agents remain the mainstay of management.
Glomerular Disease in AKI
Acute glomerulonephritis may be the cause of AKI in the ICU due to bacterial endocarditis, staphylococcal sepsis, visceral abscesses, hepatitis B, systemic lupus erythematosus (SLE), Goodpasture syndrome, or rapidly progressive glomerulonephritis (RPGN). Red cells and red blood cell casts, and proteinuria are seen on urinalysis ( Fig. 22.7 ). An alteration of glomerular hemodynamics also may contribute to AKI. Afferent vasoconstriction may be seen in hepatorenal syndrome and efferent vasodilation from ACE inhibitors. Vasodilators such as nitroprusside and nifedipine may contribute to AKI by altering intrarenal hemodynamics without systemic hypotension.
Interstitial Disease in AKI
Drugs most often induce acute interstitial nephritis, but infections such as from Legionella, Leptospira, and streptococcal organisms, and autoimmune disorders may also be responsible. The most commonly implicated drugs are beta-lactam antibiotics, sulfonamides, rifampin, and nonsteroidal anti-inflammatory drugs (NSAIDs). The complete clinical spectrum presents as fever, rash, arthralgias, and eosinophilia, and a urine analysis shows sterile pyuria with white blood cell casts, and eosinophiluria (except NSAIDs). Hematuria and proteinuria also are common. The FENa usually is greater than 1%, indicating tubular damage, but lower values may be seen in mild disease.
AKI in Cirrhosis
Patients with cirrhosis or acute hepatitis can develop renal failure without proteinuria and with a reduced urinary sodium. The hallmark is intense renal vasoconstriction with peripheral vasodilation. The kidneys in patients with hepatorenal syndrome (HRS) are normal on autopsy and functioned normally when transplanted into patients without cirrhosis. Moreover, HRS can be reversed following liver transplantation. In 1996 the International Ascites Club published a consensus paper that subdivided HRS into two types. Type 1 HRS is characterized by a rapid decline in renal function with a doubling of SC to more than 2.5 mg/dL or having a creatinine clearance to less than 20 mL/min within 2 weeks. In type 2 HRS the presentation is of stable renal failure in a patient with refractory ascites in which the SC increases to more than 1.5 mg/dL or a creatinine clearance of less than 40 mL/min. Untreated type 1 has mortality as high as 80% in 2 weeks, whereas type 2 has a median survival of approximately 6 months.
The precipitating factors for HRS have been identified as bacterial infection (48%), gastrointestinal (GI) bleeding (33%), aggressive paracentesis (27%), and drugs (diuretics, aminoglycosides, nonsteroidal anti-inflammatory drugs [NSAIDs], and angiotensin-converting enzyme inhibitors [ACEIs]/angiotensin II receptor blockers [ARBs]). However, 24% develop type 1 HRS without an obvious precipitating factor. A high index of suspicion is needed to assess AKI in the context of advanced liver disease because reduction in muscle may render a SC within the normal range even in the context of a decreased GFR, and GI bleeding and the amount of protein in the diet may affect the BUN. Sepsis should be suspected in any cirrhotic patient with AKI even in the absence of leukocytosis and fever. Clinically the syndrome presents with prerenal physiology (i.e., oliguria, a benign urine sediment, and low urine sodium).
Treatment may include midodrine (an alpha agonist) and octreotide (a long-acting form of somatostatin that inhibits endogenous vasodilator release), with albumin, and terlipressin (a vasopressin analog used in Europe). Dialysis should be offered only if there is a chance for liver transplantation in the short term. Transjugular intrahepatic portosystemic shunt (TIPS) involves placing a stent between the hepatic vein and the intrahepatic portion of the portal vein. It is primarily designed to treat bleeding varices, but it has been used for HRS, though it may worsen encephalopathy. It may serve as a bridge to liver transplantation, which is the only effective treatment.
Vascular Diseases Causing AKI
A number of vascular disorders of both the large and small vessels may give a prerenal picture of AKI. Large vessel disease may arise from operative arterial cross-clamping, renal artery thrombosis or embolism, or renal artery stenosis. Renal infarction may present with fever, hematuria, acute flank pain, ileus, and leukocytosis that may mimic an acute abdomen. Hypertensive crises may disrupt the vascular endothelium and be associated with thrombocytopenia and microangiopathy, retinopathy, and AKI. Systemic vasculitis such as Wegener’s granulomatosis, polyarteritis nodosa, hypersensitivity vasculitis, and Henoch-Schönlein purpura often cause AKI.
Cholesterol emboli syndrome (CES) arises following aortic manipulation from percutaneous intervention, surgery, or systemic anticoagulation. The crystals incite an inflammatory reaction and adventitial fibrosis may obliterate the vessel lumen. Hypocomplementemia and eosinophilia are seen, and any organ may be affected including the kidney, the GI tract with bleeding from microinfarcts, the skin, and the central nervous system (CNS) with stroke. The cutaneous manifestations may include a blue toe or livedo reticularis that results from a superficial infarct and compensatory dilation of the surrounding vessels to give a livedo or “lacelike” pattern ( Fig. 22.8 ). Anticoagulation is dangerous in patients with CES but may be necessary in patients with a thrombotic event.
