Acute Kidney Injury and Chronic Kidney Disease Dorene M. Holcombe and Nancy Kern Feeley

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1 31 Acute Kidney Injury and Chronic Kidney Disease Dorene M. Holcombe and Nancy Kern Feeley Learning Objectives Based on the content in this chapter, the reader should be able to: 1. Explain the causes of acute kidney injury (AKI). 2. Identify interventions used to reduce the risk of contrast-induced nephropathy. 3. Differentiate between the three types of AKI based on history and physical examination, laboratory values, and diagnostic tests. 4. Discuss the major causes and the clinical stages of chronic kidney disease (CKD). 5. Explain factors that can contribute to the progression of CKD. 6. Discuss the clinical manifestations and management of renal failure. Acute Kidney Injury Acute kidney injury (AKI) occurs in up to 2% to 20% of non intensive care unit (ICU) hospitalized patients and in as many as 67% of patients treated in ICUs. 1 4 Regardless of the underlying etiology, AKI is associated with increased in-hospital morbidity, mortality, and costs as well as increased long-term mortality and morbidity. 1 6 Patients with AKI who are treated with renal replacement therapy (RRT) have a mortality rate between 40% and 70% despite advances in technology and RRT. 3,4,6 Evidence suggests that even in patients who survive AKI and approach normal kidney function by hospital discharge are at increased risk for later development of chronic kidney disease (CKD) and should have longitudinal monitoring of their kidney function. 5,7 AKI is a common clinical syndrome in which there is a sudden onset of reduced renal function that can result in derangements in fluid and electrolyte balance, acid base homeostasis, calcium and phosphate metabolism, blood pressure (BP) regulation, and erythropoiesis. The hallmark of AKI is a decreased glomerular filtration rate (GFR), reflected by an accumulation of blood urea nitrogen (BUN) and serum creatinine a condition termed azotemia. Serum creatinine is the better marker because increases in serum creatinine are relatively unaffected by metabolic factors. AKI was previously known as acute renal failure (ARF). More than 35 different definitions of ARF were contained in the medical literature. The lack of a standard definition resulted in variations in the reported incidence of ARF and conflicting reports regarding morbidity and mortality. This situation had an adverse effect on research studies. 1 Consequently, in 2004, a group of expert intensivists and nephrologists formed the Acute Dialysis Quality Initiative (ADQI) to develop a consensus definition for ARF/AKI. The consensus definition formulated by the ADQI is known as the Risk, Injury, Failure, Loss of kidney function, and End-stage kidney disease (RIFLE) classification. As defined by the RIFLE classification 1 (Table 31-1), there are three increasing grades of severity of AKI risk, injury, and failure based on a relative increase in serum creatinine or a period of decreased urine output. Also, two outcome criteria loss and end-stage kidney disease are defined by duration of loss of kidney function, 4 weeks and 3 months, respectively. 1 In 2007, the RIFLE criteria were modified by the Acute Kidney Injury Network (AKIN), which included the ADQI group as well as other representatives from nephrology and intensive care societies. The AKIN-proposed diagnostic criteria for AKI are an abrupt (within 48 hours) increase in the serum creatinine of 0.3 mg/dl or more from baseline, a percentage increase in the serum creatinine concentration of 50% or more, or a urine output of less than 0.5 ml/kg/h for more than 6 hours. 1 Most recently, the Kidney Disease/Improving Global Outcomes (KDIGO) Clinical Practice Guideline for Acute Kidney Injury further revised the definition of AKI. KDIGO is a nonprofit international foundation established in 2003 with the mission to develop global practice guidelines to improve kidney disease care and outcomes. The main change in the KDIGO definition is the extension of the timeframe for a 50% or more increase in serum creatinine to 7 days (see Table 31-1). 8 In the future, it is likely that functional markers of renal failure (urine output and serum creatinine) will be replaced or augmented by biologic injury markers, analogous to how troponin is now used to help diagnose an acute myocardial infarction (MI). It is hoped that such markers of kidney cellular injury will not only define AKI but will also offer the potential to diagnose the disorder before functional decline. Urine output patterns in AKI can manifest as oliguria (less than 500 ml/d), nonoliguria (greater than 500 ml/d), or anuria (less than 50 ml/d). Categorization of AKI as oliguric or nonoliguric is diagnostically significant because the oliguric form is associated with higher morbidity and mortality rates. This may be mediated in part by the more pronounced fluid retention in oliguric versus nonoliguric patients Anuria is rare and is most often seen in two conditions: shock and 584

2 Chapter 31 Acute Kidney Injury and Chronic Kidney Disease 585 Table 31-1 Acute Kidney Injury Staging Criteria Stage Creatinine Criteria Urine Output Criteria RIFLE Criteria Risk Creatinine increase of times baseline value <0.5 ml/kg/h 6 h Injury Creatinine increase of 2 3 times baseline value <0.5 ml/kg/h 12 h Failure Creatinine increase of 3 or more times baseline value or a creatinine value >4 mg/dl with an acute increase of 0.5 mg/dl or more <0.3 ml/kg/h 24 h or anuria 12 h Loss Persistent ARF for >4 wk End-stage kidney disease Persistent ARF for >3 mo AKIN Criteria* 1 Creatinine increase of 1/5 2 times baseline value or increases in creatinine of <0.5 ml/kg/h 6 h 0.3 or more mg/dl 2 Creatinine increase of 2 3 times baseline value <0.5 ml/kg/h 12 h 3 Creatinine increase of 3 or more times baseline value or a creatinine value >4 mg/dl with an acute increase of 0.5 mg/dl or more KDIGO Criteria 1 Creatinine increase of times baseline** or 0.3 mg/dl*** <0.5 ml/kg/h 6 h 2 Creatinine increase of times baseline <0.5 ml/kg/h 12 h 3 Creatinine increase of 3 or more times baseline or a creatine value of 4 mg/dl or initiation of RRT <0.3 ml/kg/h 24 h or anuria 12 h *Reduction in renal function must occur within 48 h. **Serum creatinine increase is known or presumed to have occurred within the prior 7 days. ***Serum creatinine increase within any 48-h period. complete bilateral urinary tract obstruction. Any sudden and complete cessation of urinary flow in a patient with a Foley catheter should alert the nurse to inspect, flush, or change the urinary catheter. Causes of Acute Kidney Injury Many pathophysiologic pathways may lead to the syndrome of AKI. To aid in establishing a diagnostic and management plan, AKI is organized into three general categories according to precipitating factors and the symptoms manifested (Box 31-1). Prerenal Acute Kidney Injury Prerenal AKI is characterized by any physiologic event that results in renal hypoperfusion. Most commonly, precipitating events include hypovolemia and cardiovascular failure; however, any other event that leads to an acute decrease in effective renal perfusion can fall into this category (see Box 31-1). For example, in sepsis, a systemic inflammatory response triggers a cascade of events that results in a vasodilated hypotensive state despite no net loss in body fluids. Intrarenal Acute Kidney Injury The intrarenal category of AKI is characterized by actual damage to the renal parenchyma, and has many possible associated causes. One way to categorize these causes is by anatomical compartment: glomerular, vascular, interstitial, and tubular. The glomerular etiologies, which result in acute glomerulonephritis, include immune complex mediated causes (eg, as seen with poststreptococcal glomerulonephritis) and diseases that cause vasculitis, such as Wegener granulomatosis and antiglomerular basement membrane disease. Interstitial causes include acute allergic interstitial nephritis, usually caused by pharmacologic agents, and infectious causes such as pyelonephritis. Vascular etiologies include malignant hypertension as well as microangiopathic processes, such as atheroembolic disease or hemolytic uremic syndrome (HUS) and thrombotic thrombocytopenic purpura (TTP). Finally, the tubules of the kidney can be primarily affected because of obstruction or acute tubular necrosis (ATN). Obstructive causes include multiple myeloma and acute urate nephropathy. A common cause of intrarenal hospital-acquired AKI is ATN. ATN results from either a prolonged prerenal condition (ischemic ATN) or the effects of toxins on the tubules (toxic ATN). Examples of potential toxins to the tubules include pharmacologic agents, such as aminoglycosides, amphotericin B, and chemotherapeutic agents; heavy metals; organic solvents; heme pigments (eg, myoglobin and hemoglobin); and radiocontrast media (Box 31-2). Postrenal Acute Kidney Injury Any obstruction in the flow of urine from the collecting ducts in the kidney to the external urethral orifice can result in postrenal AKI. Postrenal obstruction can result from ureteral blockage (as with bilateral renal stones), urethral blockage (as from stricture and benign prostatic hypertrophy), or an extrinsic source, such as a retroperitoneal tumor or fibrosis. Another source of postrenal AKI is a dysfunctional bladder (eg, as might be caused by ganglionic blocking agents that interrupt autonomic supply to the urinary system). Elderly men and the young are populations particularly susceptible to postrenal AKI. Children are at risk secondary to congenital anomalies, and elderly men are at risk because of the high prevalence of benign or malignant prostatic hypertrophy.

3 586 PART 7 Renal System BOX 31-1 Precipitating Causes of Acute Kidney Injury Prerenal Decreased intravascular volume Dehydration Hemorrhage Hypovolemic shock Hypovolemia (gastrointestinal losses, diuretics, diabetes insipidus) Third-spacing (burns, peritonitis) Cardiovascular failure Heart failure Myocardial infarction Cardiogenic shock Valvular heart disease Renal artery stenosis or thrombosis Drugs ACE inhibitors NSAIDs inhibit prostaglandin-mediated afferent arteriolar vasodilation Calcineurin inhibitors (eg, tacrolimus, cyclosporine) cause preglomerular vasoconstriction Decreased effective renal perfusion Sepsis Cirrhosis Neurogenic shock Intrarenal Acute glomerulonephritis Immune complex mediated (postinfectious, lupus nephritis, cryoglobulinemia, immunoglobulin A nephropathy) With vasculitis (Wegener s granulomatosis, antiglomerular basement membrane disease, polyarteritis nodosa) Vascular disease Malignant hypertension Microangiopathic HUS TTP Scleroderma Eclampsia Atheroembolic disease Acute cortical necrosis Acute interstitial disease Allergic interstitial nephritis Acute pyelonephritis Tubular obstruction Multiple myeloma Acute urate nephropathy Ethylene glycol or methanol toxicity Acute tubular necrosis Ischemia Nephrotoxins (contrast dye, drugs, heme pigments) Kidney transplant rejection Postrenal Ureteral obstruction Intrinsic (stones, transitional cell carcinoma of the ureter, blood clots, stricture) Extrinsic (ovarian cancer; lymphoma; metastatic cancer of the prostate, cervix, or colon; retroperitoneal fibrosis) Bladder problems Tumors Blood clots Neurogenic bladder (spinal cord injury, diabetes mellitus, ischemia, drugs) Stones Urethral obstruction Prostate cancer or benign prostatic hypertrophy Stones Stricture Blood clots Obstructed indwelling catheter BOX 31-2 Common Causes of Acute Tubular Necrosis Ischemic Causes Hemorrhagic hypotension Severe volume depletion Surgical aortic cross-clamping Cardiac surgery Defective cardiac output Septic shock Pancreatitis Immunosuppression (cyclosporine, tacrolimus) NSAIDs Nephrotoxic Causes Drugs, including antimicrobials (aminoglycosides, amphotericin), cyclosporine, anesthetics, chemotherapeutic agents Heavy metals (mercury, lead, cisplatinum, uranium, cadmium, bismuth, arsenic) Radiologic contrast agents Heme/pigments (myoglobin, hemoglobin) Organic solvents (carbon tetrachloride) Fungicides and pesticides Plant and animal substances (mushrooms, snake venom) Pathophysiology of Acute Kidney Injury Prerenal Acute Kidney Injury The pathophysiology of prerenal AKI is centered on the kidneys response to inadequate perfusion. A decrease in renal perfusion results in the release of the enzyme renin from juxtaglomerular cells in the walls of the afferent arterioles. This activates the renin angiotensin aldosterone cascade, the end result being the production of angiotensin II and the release of aldosterone from the adrenal cortex. Angiotensin II causes profound systemic vasoconstriction, and aldosterone induces sodium and water retention. These effects help the body preserve circulatory volume to maintain adequate blood flow to essential organs such as the heart and brain. In the kidneys, angiotensin II also helps maintain the GFR by increasing efferent arteriolar resistance and by stimulating intrarenal vasodilator prostaglandins (which dilate the afferent arteriole), increasing hydrostatic pressure in the glomeruli. 12 In this way, the kidneys can preserve the GFR over a wide range of mean arterial pressures. However, when renal

4 Chapter 31 Acute Kidney Injury and Chronic Kidney Disease 587 perfusion is severely compromised, the capacity for autoregulation is overwhelmed, and the GFR decreases. Even with moderate hypovolemia or congestive heart failure, certain drugs, such as angiotensin-converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs), and nonsteroidal anti-inflammatory drugs (NSAIDs), can overwhelm the kidney s ability to autoregulate. These drugs disrupt some of the autoregulatory mechanisms, such as prostaglandin-mediated afferent arterial vasodilation, in the case of NSAIDs, and increased efferent arteriolar resistance, in the case of ACE inhibitors and ARBs. Predisposing factors for NSAID- and ACE inhibitor induced prerenal failure are hypovolemia, baseline renal insufficiency, liver disease, heart failure, and diseases of the renal arteries. Concomitant use of diuretics, ACEI, or ARBS with NSAIDS may also increase the risk of NSAID-induced AKI, even in the absence of other risk factors. 12 In prerenal AKI, once autoregulatory capacity is overwhelmed and the GFR decreases, changes in urinary composition and volume occur in a predictable pattern. When the GFR decreases, the amount of tubular fluid is reduced, and the fluid travels through the tubule more slowly. This results in increased sodium and water reabsorption. Because of the reduced renal circulation, the solutes reabsorbed from the tubular fluid are removed more slowly than normal from the interstitium of the renal medulla. This results in increased medullary tonicity, further augmenting water reabsorption from the distal tubular fluid. As a result of these events, the urinary volume is reduced to less than 400 ml/d (less than 17 ml/h), the urine specific gravity is increased, and the urine sodium concentration is low (usually less than 5 meq/l; Fig. 31-1). Because of these characteristic changes associated with renal underperfusion, measurement of urinary volume, urinary sodium, and specific gravity is a simple method for determining the effect of management on renal perfusion. An increase in systemic BP does not necessarily imply improvement in renal perfusion. This may be especially evident when drugs such as norepinephrine are used to correct the hypotension associated with states of volume depletion. These drugs may be associated with further reduction in renal blood flow as a consequence of constriction of the renal arteries. This is manifested by a further fall in urinary volume and rise in specific gravity. In turn, if the hypoperfusion state is more appropriately and specifically treated by replacement of volume, improvement of cardiac output, correction of dysrhythmias, or a combination of these approaches, the improved renal perfusion is manifested as an increased urinary volume and urine sodium concentration and as a decreased specific gravity of the urine. This ability to reverse prerenal AKI is the key to its diagnosis. Intrarenal Acute Kidney Injury Just as there are many causes of intrarenal AKI, there are also many pathophysiologic mechanisms that lead to it (Fig. 31-2). Because ATN is the most common hospitalacquired form of intrarenal AKI, this discussion focuses on the pathophysiology of ATN, which is complex, but intense and ongoing research has increased understanding of the factors contributing to this condition. Ischemia and nephrotoxicity are two major underlying causes of ATN (Fig. 31-3). A. Normal perfusion Afferent arteriole Efferent arteriole B. Underperfusion Glomerulus Na H 2 O Na H 2 O Urine Volume: <17 ml/h Na: <5 meq/l OSM: 1,200 mosm Figure 31-1 Normal perfusion of the kidney compared with underperfusion as seen in prerenal AKI. Underperfusion of the kidney results in decreased renal blood flow and glomerular filtration, an increase in the fraction of filtrate reabsorbed in the proximal tubule, and low urine flow with low sodium (Na) content and increased concentration. H 2 O, water; OSM, osmolarity. Ischemic Acute Tubular Necrosis Na Na H 2 O Urea Urine Volume: 50 ml/h Na: meq/l OSM: 500 mosm H 2 O Urea Ischemic ATN results from prolonged hypoperfusion. Thus, prerenal AKI and ischemic ATN are actually a continuum, a fact that underscores the importance of prompt recognition and treatment of the prerenal state. When renal hypoperfusion persists for a sufficient time (the exact duration of which is unpredictable and varies with clinical circumstances), renal tubular epithelial cells become hypoxic and sustain damage to the point that restoration of renal perfusion no longer causes an improvement in glomerular filtration. Ischemia results in an inflammatory response and decreased adenosine triphosphate production in renal cell mitochondria. Inflammatory mediators produced by activated leukocytes and tubular epithelial cells promote inflammation in a positive feedback loop, causing further kidney injury. Decreased adenosine triphosphate production robs the cells of a needed energy supply. Part of this energy is used to keep the proper concentration of electrolytes in the cell through electrolyte exchange channels. Some of the cellular electrolyte disturbances from ischemia are decreased intracellular potassium, magnesium, and phosphate and increased intracellular sodium, chloride, and calcium. Increased intracellular calcium specifically has been shown to predispose the cells to injury and dysfunction. 13 During reperfusion, cellular insults also occur from the formation of oxygen free radicals. Eventually, these cellular

5 588 PART 7 Renal System A A B C Figure 31-2 Potential mechanisms of intrarenal AKI include decreased filtration pressure because of constriction in the renal arterioles (A), decreased glomerular capillary permeability (B), increased permeability of the proximal tubules with back leak of filtrate (C), obstruction of urine flow by necrotic tubular cells (D), and increased sodium delivery to the macula densa (E), which causes an increase in renin angiotensin production and vasoconstriction at the glomerular level. insults cause the tubular cells to swell and become necrotic. The necrotic cells then slough off and may obstruct the tubular lumen. These sloughed cells also allow back leak of tubular fluid because of altered function of their basement membrane, which contributes to the decreased GFR seen in this disorder. A final contributor to the pathophysiology of ischemic ATN is profound renal vasoconstriction and reduced renal blood flow. These hemodynamic disturbances further compromise renal oxygen delivery and add to the ischemic damage. Vasoconstrictors involved include norepinephrine from sympathetic nervous system activation, angiotensin II, thromboxane A 2, adenosine, leukotrienes C4 and D4, prostaglandin H 2, and endothelin. Release of endothelin, a powerful vasoconstrictor, by damaged vascular endothelial cells of the kidney results in profound reductions in GFR. Oxygen free radicals augment renal vasoconstrictor responses, and cellular swelling can further compromise renal blood flow. 13 Toxic Acute Tubular Necrosis The pathophysiology of toxic ATN begins with a concentration of a nephrotoxin in the renal tubular cells, which causes necrosis. These necrotic cells then slough off into the tubular lumen, possibly causing obstruction and impairing glomerular filtration in a manner similar to that of ischemic ATN. However, there are significant differences between toxic ATN and ischemic ATN. In toxic ATN, the basement membrane of the renal cells usually remains intact, and the injured necrotic areas are more localized. In addition, nonoliguria occurs more often with toxic ATN, and the healing process is often more rapid. Although the potential nephrotoxins in toxic ATN are many (see Box 31-2), aminoglycoside antibiotics and radiocontrast dye deserve special mention because of the frequency with which they are seen as causes of toxic ATN in hospitalized patients. Nephrotoxicity occurs in 10% to 25% of patients treated with aminoglycosides. 8,14,15 The onset of AKI secondary to aminoglycosides is usually delayed, often D E beginning 5 to 10 days after the onset of therapy. The toxicity of these agents is dose dependent, and because these agents are primarily eliminated by the kidneys, dosage must be adjusted in patients with preexisting renal impairment. To ensure that the correct therapeutic range is being achieved, blood is drawn frequently for peak and trough level analysis. Several studies have suggested that a single daily dose of an aminoglycoside may result in less nephrotoxicity than giving the same total amount of medication in three daily doses. 8,15,16 Accordingly, the KDIGO Practice Guideline for AKI recommends both once-daily dosing and close monitoring of drug levels. 8 Other risk factors for aminoglycoside toxicity are volume depletion, advanced age, diabetes, concurrent use of other nephrotoxic agents, and hepatic dysfunction. 14,15 If feasible, using alternative antibiotics with decreased associated nephrotoxicity is the best prevention of aminoglycoside-induced nephrotoxicity. Contrast-induced nephropathy (CIN), the sudden decline of renal function following intravascular injection of contrast media, accounts for a significant number of hospital-acquired cases of AKI. In critically ill patients, the frequency of CIN is 2% to 23%. 17,18 It usually begins within 24 to 48 hours of intravenous (IV) radiocontrast administration and peaks within 3 to 7 days. Typically, CIN is nonoliguric, transient, and reversible; however, in high-risk patients, dialysis may be required on an intermittent or permanent basis. Patients at greatest risk for CIN are those with diabetes and those with underlying renal impairment. In these patients, the incidence of CIN may be as high as 50%. 18 Other patients at risk are elderly patients; those with intravascular volume depletion, heart failure, therapy, or concomitant use of nephrotoxic drugs; and those who receive a large contrast load. 17 The only proven way to reduce the risk for CIN is by aggressive volume expansion with isotonic crystalloids (normal saline solution) before and after contrast agent administration. 5,19 Because CIN is believed to involve the production of oxygen free radicals, it is postulated that alkalinization of the urine with sodium bicarbonate may confer greater protection than IV fluids alone. However, multiple trials comparing the use of sodium bicarbonate with normal saline for prophylaxis have yielded inconsistent results, and metaanalyses have been inconclusive. 5,8,19 Accordingly, the KIDGO AKI Guideline recommends volume expansion with either isotonic sodium chloride or sodium bicarbonate solutions in patients with increased risk of CIN-AKI. Recently, there has been increased clinical trial activity revolving around the concept of forced diuresis (combining diuretics to augment urine output while given crystalloids to maintain euvolemia) for CIN prevention. 5,20,21 Although some studies have shown promise, further research is needed. Other interventions to reduce the incidence of CIN include using the minimal necessary dose of contrast media, using low or iso-osmolar nonionic contrast media instead of ionic hyperosmolar agents, stopping the intake of nephrotoxic drugs 24 hours before contrast media injection, and avoiding short intervals between contrast procedures. N-Acetylcysteine (NAC), an antioxidant and a potent vasodilator, is part of the protocol in many hospitals to prevent CIN based on clinical trials demonstrating its renoprotective effects in patients receiving IV contrast media. However, NAC has been the subject of many trials and meta-analyses, and overall there has been insufficient evidence to support

6 Chapter 31 Acute Kidney Injury and Chronic Kidney Disease 589 Ischemia or nephrotoxin Decreased renal blood flow Tubular cell damage Glomerular damage Decreased glomerular blood flow Increased NaCI delivery to macula densa Tubular obstruction Backleak of filtrate Decreased glomerular ultrafiltration Decreased glomerular filtration rate (GFR) Bowman capsule Proximal convoluted tubule Distal convoluted tubule Casts and cellular debris Necrosis Collecting duct Loop of Henle Acute tubular necrosis Figure 31-3 Ischemic ATN results from prolonged hypoperfusion. A sequence of pathophysiologic processes results in the sloughing off of necrotic cells that block the tubular lumen. Toxic ATN occurs when a nephrotoxin becomes concentrated in the renal tubular cells and causes necrosis. The necrotic cells slough off and obstruct the tubular lumen, similar to ischemic ATN. In toxic ATN, the basement membrane of the renal cells usually remains intact, and the necrotic areas are more localized. the use of NAC to prevent CIN. 5,18,22,23 However, despite lack of evidence of benefit, it remains a popular approach to CIN-AKI prevention, presumably owing to its low cost and negligible potential for harm. Studies have shown that other pharmacologic interventions, such as calcium-channel blockers, dopamine, mannitol, and atrial natriuretic peptide, do not consistently reduce the incidence of CIN and may even be harmful. Of course, avoiding any use of iodinated contrast media in high-risk patients is the best prevention; alternative studies, such as ultrasonography, computerized tomography (CT) scanning without contrast, and contrast-enhanced magnetic resonance imaging (MRI), should be considered. The MRI contrast agents in use are mostly chelates of gadolinium and are less nephrotoxic than iodinated radiocontrast, particularly when used in small doses. This has led to the use of gadolinium-based contrast agents (GB- CAs) as alternatives to iodinated contrast agents for digital subtraction angiography or interventional procedures, especially in patients with iodinated contrast allergies. However, one important caveat regarding the use of GBCA in patients with AKI or severe CKD (GFR <30 ml/min) is the rare but serious risk for developing nephrogenic systemic fibrosis (NSF). NSF, a fibrosing disorder seen only in patients with kidney disease, is characterized by thickening and hardening of the skin overlying the extremities and trunk. Occasionally, fibrosis of deeper structures (such as joints, muscles, the testes, dura, kidneys, and the heart) occurs as well. Because the condition can be devastating to a patient (resulting in significant loss of mobility and

7 590 PART 7 Renal System Table 31-2 ACR Classifications of GBCAs GBCA Trade Name Group I: Agents with greatest number of NSF cases Gadodiamide Omniscan Gadopentetate dimeglumine Magnevist Gadoversetamide OptiMARK Group II: Agents associated with few, if any, unconfounded cases of NSF Gadobenate dimeglumine MultiHance Gadoteridol ProHance Gadoteric acid Dotarem Gadobutrol Gadovist Group III: Agents that have only recently appeared on the market in the United States Gadofosveset Ablavar Gadoxetic acid Eovist even death), gadolinium agents should be avoided in patients with a GFR less than 30 ml/min If it is determined that a study using a GBCA must be performed, the American College of Radiology (ACR) recommends that the lowest possible dose of GBCA needed to conduct the study be used, and that there be allotted a sufficient period of time for elimination of the agent from the body before readministration. In addition, for patients receiving hemodialysis, prompt hemodialysis following GBCA administration is recommended to enhance elimination of the GBCA. Finally, the ACR has classified GBCA into three different groups based on their association with NSF cases, with group I agents associated with the highest rates (Table 31-2). All group I GBCAs are contraindicated in high-risk patients. 24,27,28 Postrenal Acute Kidney Injury Obstruction can occur at any point in the urinary tract. When urine cannot get around the obstruction, resulting congestion causes retrograde pressure through the collecting system and nephrons. This slows the rate of tubular fluid flow and lowers the GFR. As a result, the reabsorption of sodium, water, and urea is increased, leading to a lowered urine sodium concentration and increased urine osmolality and BUN. Serum creatinine levels also increase. With prolonged pressure from urinary obstruction, the entire collecting system dilates, compressing and damaging nephrons. This results in dysfunction of the concentrating and diluting mechanism, and the urine osmolality and urine sodium concentration become similar to that of plasma. This circumstance can be avoided by prompt removal of the obstruction. Because a single well-functioning kidney is adequate to maintain homeostasis, the development of AKI from obstruction requires blockage of both kidneys (ie, urethral or bladder neck obstruction or bilateral ureteral obstruction) or unilateral ureteral obstruction in patients with a single kidney. After relief of the obstruction, there is often a profound diuresis of greater than 4 L/d. Postobstructive diuresis in postrenal AKI ICU patients may be predictive of complete renal recovery. 29 However, if electrolytes and water are not replenished as needed, this diuresis can lead to hemodynamic compromise, dysrhythmias, and ATN. BOX 31-3 CONSIDERATIONS for the Older Patient Physiologic Changes Affecting the Renal System As the body ages, physiologic systemic and kidney-specific changes occur that are important to take into consideration when addressing the kidney. Vascular changes: At 30 years of age, arteriosclerosis starts to develop, including in the renal arteries; this can result in significant damage. Musculoskeletal changes: In elderly people, there is a decreased muscle mass and body weight. These changes must be kept in mind when assessing renal function because of the possibility of a consequent decreased baseline serum creatinine value. A minimum rise in serum creatinine value in elderly patients, which may be within normal limits for a young adult, may actually signify major renal impairment. Kidney-specific changes: With aging, there is a decrease in the total number of functioning glomeruli, a decrease in renal blood flow, and a decrease in GFR of about 0.75 ml/min/ 1.73 m 2 per year after 30 years of age. 24 In view of these systemic and kidney-specific changes, an accurate assessment of GFR using a 24-hour urine study or an isotopic study is essential. The Cockroft Gault formula or the Modification of Diet in Renal Disease (MDRD) formulas below, which take into account gender and age, can also be used. It is important to realize that these formulas are not extensively validated in patients older than 70 years. After true GFR is realized, therapy (eg, drug dosages) can be guided more safely. Cockcroft Gault Formula for Creatinine Clearance (ml/min) Men = (140 age) weight in kg/72 serum creatinine Women = 0.85 creatinine clearance for men MDRD Formula for GFR (adults; ml/min) 175 Serum creatinine concentration Age (if female) (if black) Websites are available to aid in the calculation of the GFR through these formulas. These include and Diagnosis of Acute Kidney Injury Diagnosis of AKI begins with a determination of whether the AKI is prerenal, intrarenal, or postrenal. The assessment tools used to make this determination include the history and physical examination, laboratory tests, and diagnostic studies. Special considerations for assessing renal function in older patients are given in Box History and Physical Examination Essential to any assessment is the health history and physical examination. By taking a detailed history, clues to the categorization and exact cause of the AKI can be obtained. Important indications in the history that suggest prerenal AKI include any event or condition that may have contributed to decreased renal perfusion (eg, acute MI, cardiovascular surgery, cardiac arrest, high fever, any shock state, and the use of certain drugs, such as NSAIDs). Also, a history of atherosclerotic disease may be a clue to renal artery stenosis, another precipitant of prerenal AKI. Clues to an intrarenal cause provided by the history include any prolonged prerenal event or condition as well as exposure to nephrotoxins, especially aminoglycoside antibiotics and radiocontrast media. It is

8 Chapter 31 Acute Kidney Injury and Chronic Kidney Disease 591 Table 31-3 Acute Kidney Injury: Comparison of Laboratory Findings in Prerenal Failure, Postrenal Failure, and Acute Tubular Necrosis Value Prerenal Postrenal Acute Tubular Necrosis Urine volume Oliguria May alternate between anuria and Anuria, oliguria, or nonoliguria polyuria Urine osmolality Increased (>500 mosm/kg H 2 O) Varies, increased, or equal to serum mosm/kg H 2 O Urine specific gravity Increased (>1.020) Varies Approximately Urine sodium <20 meq/l Varies >40 meq/l Urine sediment Normal, few casts Normal, may be crystals Granular casts, tubular epithelial cells FE Na <1% >1% >1% (often >3%) BUN:Cr >20:1 10:1 to 15:1 10:1 to 15:1 FE Na, fractional excretion of sodium; BUN:Cr, blood urea nitrogen/creatinine ratio. also important to collect information about systemic diseases such as lupus or vasculitis, recent streptococcal infections, and causes of heme pigment toxicity, such as rhabdomyolysis (eg, a history of trauma or a patient found unconscious for an unknown amount of time). In addition, a history of cardiac catheterization, anticoagulation, and thrombolytic therapy increases the possibility of atheroembolic intrarenal diseases. Findings that may point to postrenal AKI include any history of abdominal tumors or calculi, and especially a history of benign prostatic hypertrophy in elderly men. A family history of urolithiasis or benign prostatic hypertrophy may be contributory. The physical examination, particularly regarding fluid status, is critical to the diagnosis of AKI. In prerenal AKI, a state of decreased renal perfusion related to dehydration or hypovolemia is heralded by poor skin turgor, dry mucous membranes, weight loss, and reduced jugular venous distention. In contrast, when decreased perfusion is related to vasodilation, third spacing, cardiovascular disease (eg, heart failure), liver disease, or a combination of these factors, findings of increased extracellular fluid may be manifested by edema, ascites, and weight gain. For critical care patients, hemodynamic monitoring values help determine intravascular fluid status as well as cardiac functioning. Surveillance values include central venous pressure (CVP), pulmonary artery occlusion pressure (PAOP), and cardiac output (or cardiac index). By correlating physical examination findings with the history, hemodynamic values, and laboratory tests, potential prerenal etiologies can be narrowed down. Although no specific physical examination finding prompts consideration of intrarenal AKI, many examination findings are helpful clues to potential causes of intrarenal AKI. For example, signs of a streptococcal throat infection, lupus (eg, a butterfly mask rash), or embolic phenomena (eg, discolored toes and livedo reticularis, a semipermanent bluish mottling of the skin in the extremities) may all suggest an intrarenal cause. Again, correlation with the history and laboratory studies helps narrow the list of potential causes. Findings on physical examination that may suggest a postrenal cause include a distended bladder, an abdominal mass, an enlarged or nodular prostate gland, and, most obviously, a kinked or obstructed Foley catheter. Laboratory Studies Laboratory assessment, critical to the diagnosis and categorization of AKI, includes both serum and urinary values. For a basic comparison of laboratory values in prerenal AKI, postrenal AKI, and ATN, see Table In addition to helping differentiate between prerenal, intrarenal, and postrenal AKI, blood and urine tests are also helpful for diagnosing the underlying etiology of the AKI (Box 31-4). Urinary Values. Obtaining a urine specimen for diagnostic evaluations is invaluable in establishing the diagnosis and determining the type of AKI. The urine specimen should be obtained before a diagnostic challenge dose of BOX 31-4 Diagnostic Clues in Acute Kidney Injury Urine Urate crystals: Tumor lysis, especially lymphoma (urate nephropathy) Oxalate crystals: Ethylene glycol nephrotoxicity, methoxyflurane nephrotoxicity Eosinophils: Allergic interstitial nephritis, especially methicillin Positive peroxidase test without red blood cells: Hemoglobinuria or myoglobinuria Pigmented casts: Hemoglobinuria or myoglobinuria Massive proteinuria: Acute interstitial nephritis, thiazide diuretics, hemorrhagic fevers (eg, Korean, Scandinavian) Abnormal urine protein electrophoresis: Multiple myeloma Anuria: Renal cortical necrosis, bilateral obstruction, renal vascular catastrophe Plasma Marked hyperkalemia: Rhabdomyolysis, tissue necrosis, hemolysis Marked hypocalcemia: Rhabdomyolysis Hypercalcemia: Hypercalcemic nephropathy Hyperuricemia: Tumor lysis, rhabdomyolysis, toxin ingestion Marked acidosis: Ethylene glycol, methyl alcohol Elevated creatine kinase or myoglobin levels: Rhabdomyolysis Low complement levels: Systemic lupus erythematosus (SLE), postinfectious glomerulonephritis, subacute bacterial endocarditis Abnormal serum protein electrophoresis: Multiple myeloma Positive antibody/glomerular basement membrane ratio: Goodpasture s syndrome Positive antineutrophilic cytoplasmic antibody: Small vessel vasculitis (Wegener s granulomatosis or polyarteritis nodosa) Positive antinuclear antibody or antibody to double-stranded DNA: SLE Positive antibodies to streptolysin O: Poststreptococcal glomerulonephritis Elevated lactate dehydrogenase level, elevated serum bilirubin level, or decreased haptoglobin level: HUS or TTP

9 592 PART 7 Renal System diuretics is administered because these agents may alter the urine s chemical composition. The urine sodium concentration, osmolality, and specific gravity are especially helpful in distinguishing between prerenal AKI and ATN because these values reflect the concentrating ability of the kidney. In prerenal failure, the hypoperfused kidney actively reabsorbs sodium and water in an attempt to increase circulatory volume. Consequently, the urine sodium level and the fractional excretion of sodium (FE Na ) are low (less than 20 meq/l and less than 1%, respectively), whereas the urine osmolality and concentration of nonreabsorbable solutes are high. In contrast, in ATN in which parenchymal damage affects the kidney, the tubular cells can no longer effectively reabsorb sodium or concentrate the urine. As a result, the urine sodium concentration is often greater than 40 meq/l, the FE Na is greater than 1%, and the urine osmolality is close to that of plasma (isosthenuria). Unfortunately, there is a limit to the usefulness of these indices because of overlap in these values for prerenal AKI and ATN (ie, urine sodium concentration values in the 20 to 40 meq/l range). Values at the extremes are thus the most useful. The sediment in a urinalysis is also very helpful in diagnosing and distinguishing the types of AKI. In prerenal AKI, the urinary sediment is normal with only a few hyaline casts, whereas in ATN, coarse, muddy-brown granular casts and tubular epithelial cells are typically found. In postrenal AKI, the sediment is often normal but can be helpful in diagnosing kidney stones. Blood Urea Nitrogen and Creatinine Levels. Serum tests for BUN and creatinine are essential not only for diagnosing AKI but also for helping to distinguish between prerenal AKI and ATN or postrenal AKI. In prerenal AKI, the BUN-to-creatinine ratio is increased from the normal ratio of 10:1 to more than 20:1. This finding is caused by a state of dehydration and by the fact that, as the tubules become more permeable to sodium and water in prerenal AKI, urea is also passively reabsorbed. In ATN and postrenal AKI, when the concentrating ability of the kidneys is impaired, both the BUN and creatinine increase proportionally, maintaining the normal 10:1 ratio. Diagnostic Studies Renal ultrasonography, an important diagnostic test in the evaluation of AKI, is especially useful in ruling out an obstruction, and has the advantage of being noninvasive. With a high-grade obstruction, dilation of the urinary collecting system is detectable on ultrasonography within 1 to 2 days of the onset of the obstruction. Ultrasonography may also reveal proximal renal calculi as a cause of postrenal obstruction. In addition, it can be used to estimate renal size, which is helpful in distinguishing between AKI and advanced CKD. Often in advanced CKD, the kidneys are small (less than 9 cm) and echogenic. Other studies that may be useful in diagnosing AKI are CT and MRI to evaluate for masses, vascular disorders, and filling defects in the collecting system, and renal angiography to evaluate for renal artery stenosis. It is notable that the iodinated contrast media used in some studies are allergenic and nephrotoxic, and that GBCAs can cause NSF in patients with severe kidney disease (GFR < 30 ml/min). For any diagnostic test, the benefits of the study must be weighed against potential risks. If available, alternative technology, such as the use of carbon dioxide gas in digital subtraction angiography, should be considered for patients allergic to iodinated agents or with advanced kidney failure. 31,32 Finally, renal biopsy may be helpful in patients thought to have intrarenal AKI that is not ATN, especially if significant proteinuria or unexplained hematuria is revealed on urinalysis. In addition to having diagnostic value, the results of a biopsy may help determine prognosis and therapy. Chronic Kidney Disease CKD is a slow, progressive, irreversible deterioration in renal function that results in the kidney s inability to eliminate waste products and maintain fluid and electrolyte balance. Ultimately, it leads to end-stage renal disease (ESRD) and the need for RRT or renal transplantation to sustain life. Currently, there are more than 615,000 dialysis and renal transplant recipients in the United States, which is a 26% increase in prevalence since the year In 2011 alone, more than 115,000 patients were newly diagnosed with ESRD. Among ESRD patients, incidence rates are higher in men than in women and are higher with increasing age. The incidence rates in the African American population are 3.4 times greater than in the white population. Hispanics and Native Americans also have higher incidence rates than whites, but the difference in rates is not as dramatic. 33 These differences in incidence rates are important when considering patient risk factors and target populations for health education. Factors postulated to contribute to the increasing prevalence of ESRD include changes in the demographics of the population, differences in disease burden among racial groups, under-recognition and undertreatment of earlier stages of CKD, under-recognition of the risk factors for CKD, and increased survival of patients with ESRD. 33 Increasing evidence shows that early detection and treatment of CKD may prevent, or at least delay, progression to ESRD. 34,35 Consequently, it is important that opportunities to prevent and treat CKD are not lost secondary to underdiagnosis or undertreatment. Definition and Classification In an effort to address the growing public health problem of CKD, the National Kidney Foundation Kidney Disease Outcome Quality Initiative (NKF KDOQI) published clinical practice guidelines for CKD in The goals of the working group that developed these guidelines were to define CKD and classify its stages, to evaluate laboratory measurements for clinical assessment of kidney disease, to associate the level of kidney function with the complications of CKD, and to stratify risk for the loss of kidney function and the development of cardiovascular disease. 36 The KDOQI defines CKD as either kidney damage with or without decreased GFR for 3 or more months or a GFR of less than 60 ml/min/1.73 m 2 for greater than 3 months (Box 31-5). Markers of damage include abnormal findings in the blood or urine tests or imaging studies. Examples are proteinuria, abnormalities in the urine sediment, increased serum creatinine, and multiple renal cysts detected on ultrasound in a patient with a family history of polycystic kidney

10 Chapter 31 Acute Kidney Injury and Chronic Kidney Disease 593 BOX 31-5 disease (see Spotlight on Genetics 31-1). A GFR (considered to be the best overall measure of kidney function) of less than 60 ml/min/1.73 m 2 was chosen for two reasons: (1) it represents a loss of half or more of the adult level of normal kidney function, and (2) below this level, the prevalence of complications from CKD increases. Because predictable complications and management issues are based on the level of kidney dysfunction, regardless of the specific underlying etiology of CKD, the KDOQI working group also developed a classification system for CKD based on the measured GFR. This classification system had five stages based on GFR (Table 31-4). In 2013, KDIGO 2012 Clinical Practice Guideline for the Evaluation and Management of CKD was released, updating CKD staging. KDIGO recommended a classification based on cause of CKD, GFR category, and albumin category (referred to as CGA). Etiology of CKD was added because it provides important prognostic information and influences treatment decisions. The KDIGO Guideline recommends cause of CKD be based on the presence or absence of systemic disease, such as diabetes or lupus, and the anatomic location of the pathologic abnormality within the kidney. For GFR, KDIGO maintained the prior KDOQI stages, except that stage 3 was divided into 3a and 3b. This subdivision of stage 3 was in response to the great disparity in complications seen in patients in this stage. Lastly, KDIGO added the level of albuminuria in the staging. Albuminuria is assessed using the albumin-to-creatinine ratio (ACR) in an untimed spot urine. The threshold for an abnormally elevated ACR is 30 mg/g or greater. This addition was made in response to mounting evidence that there is an increase in mortality and progression of CKD to ESRD with higher levels of albuminuria, independent of GFR. 34 Consequently, patients now have a G-stage based on GFR and an albuminuria or A-stage, both identifying a patient s risk for CKD progression and complications (Fig. 31-4). This classification system provides a common language for practitioners and patients to improve communication, enhance education, and promote research. Most importantly, it also provides a framework for evaluation and development of a treatment plan for patients with various stages of CKD. G-Stages Definition of Chronic Kidney Disease 1. Kidney damage for greater than or equal to 3 months as defined by structural or functional abnormalities of the kidney, with or without decreased GFR, manifested by either: a. Pathologic abnormalities; or b. Markers of kidney damage, including abnormalities in the composition of the blood and urine, or abnormalities in imaging tests 2. GFR less than 60 ml/min/1.73 m 2, with or without kidney damage From National Kidney Foundation: K/DOQI clinical practice guidelines for chronic kidney disease: Evaluation, classification, and stratification. Am J Kidney Dis 39(2 Suppl 1):S1 S266, G1 is characterized by the lack of a clear filtration deficit and is defined as normal or increased kidney function (GFR 90 ml/min/1.73 m 2 ) in association with evidence of kidney damage. Polycystic Kidney Disease Polycystic kidney disease is one of the most common disorders caused by mutations in a single gene. It affects about 500,000 people in the United States. The autosomal-dominant form of the disease is much more common than the autosomal-recessive form. Autosomal-dominant polycystic kidney disease affects 1 in 500 to 1,000 people, while the autosomal-recessive type occurs in an estimated 1 in 20,000 to 40,000 people. Clusters of fluid-filled sacs, called cysts, develop in the kidneys and interfere with their ability to filter waste products from the blood. Mutations in the PKD1, PKD2, and PKHD1 genes cause polycystic kidney disease. Mutations in either the PKD1 or PKD2 gene can cause autosomal-dominant polycystic kidney disease. These genes provide instructions for making proteins whose functions are not fully understood. Researchers believe that they are involved in transmitting chemical signals from outside the cell to the cell s nucleus. The two proteins work together to promote normal kidney development, organization, and function. Mutations in the PKD1 or PKD2 gene lead to the formation of thousands of cysts, which disrupt the normal functions of the kidneys and other organs. Genetic tests for autosomal-dominant and autosomal-recessive type of polycystic kidney disease are available. G2 is defined as a mild reduction in kidney function (GFR 60 to 89 ml/min/1.73 m 2 ) that occurs in association with kidney damage. G3a is defined as mildly to moderately decreased kidney function (GFR 45 to 59 ml/min/1.73 m 2 ). G3b is defined as moderately to severely decreased kidney function (GFR 30 to 44 ml/min/1.73 m 2 ). G4 is defined as severely decreased kidney function (GFR 15 to 29 ml/min/1.73 m 2 ). G5 is defined as a GFR of less than 15 ml/min/1.73 m 2 or the need for dialysis therapy. The term ESRD, widely used in regulatory and administrative circles, correlates to G5 CKD and represents those patients receiving or eligible for RRT by dialysis or transplantation. Albuminuria A Stages A1 is defined as an ACR < 30 mg/g. A2 is defined as an ACR 30 to 299 mg/g. A3 is defined as an ACR 300 mg/g. Causes SPOTLIGHT ON GENETICS 31-1 Genetic Home Reference. Retrieved August 10, 2015, from Mochizuki T, Tsuchiya K, Nitta K: Autosomal dominant polycystic kidney disease: Recent advances in pathogenesis and potential therapies. Clin Exp Nephrol 17: , The causes of CKD are numerous (Box 31-6). By far, the two most common causes are diabetes mellitus and hypertension, which account for more than 44% and 28% of incident cases of ESRD, respectively. 33 Other causes include glomerulonephritis (both primary and secondary to systemic diseases),