Prerenal Acute Renal Failure
Prerenal azotemia is the most common cause of ARF in hospitalized patients. The main feature of prerenal ARF is the presence of intact renal parenchymal tissue and the rapid correction of GFR with restoration of renal perfusion. Uncorrected prerenal azotemia predisposes to the development of ATN. Prerenal ARF is caused by any condition leading to renal hypoperfusion, including systemic hypoperfusion with hypovolemia, cardiac failure, or vasodilatory shock, and/or regional hypoperfusion caused by renal vasoconstriction (Table 75-1; see Chap. 21).
Table 75–1. Causes of Acute Renal Failure |Favorite Table|Download (.pdf)
Table 75–1. Causes of Acute Renal Failure
|Volume depletion: Gastrointestinal fluid loss or hemorrhage; renal losses (diuretics or glucosuria, salt-wasting nephropathy, diabetes insipidus, or adrenal insufficiency); cutaneous losses (burns, desquamation)|
|Volume redistribution: Peripheral vasodilation (sepsis or antihypertensives), peritonitis, burns, pancreatitis, hypoalbuminemia (nephrotic syndrome or hepatic disease)|
|Cardiac dysfunction: Pericardial tamponade, complications of myocardial infarction, acute or chronic valvular disease, cardiomyopathies, arrythmias|
|Vasodilatory shock: Sepsis, liver failure, postcardiotomy, anaphylaxis, or antihypertensives|
|Renal vasoconstriction: Cirrhosis, sepsis, hypercalcemia, drugs (cyclosporine, tacrolimus, nonsteroidal anti-inflammatory drugs, or pressors)|
|Ischemia: Trauma, surgery, sepsis, pigment nephropathy (hemolysis or rhabdomyolysis), cardiac or aortic hemorrhage|
|Nephrotoxic: Radiocontrast, antibiotics (aminoglycosides or amphotericin), nonsteroidal anti-inflammatory drugs, carbon tetrachloride, ethylene glycol, heavy metals (lead, mercury, arsenic, cadmium, or uranium), pesticides, fungicides, cyclosporine, or tacrolimus|
|Disorders of glomeruli and blood vessels: Poststreptococcal glomerulonephritis, infective endocarditis, systemic lupus erythematosus, Goodpasture's syndrome, microscopic polyarteritis, Wegener's granulomatosis, Henoch-Schöunlein purpura, idiopathic rapidly progressive glomerulonephritis, polyarteritis nodosa, malignant hypertension, thrombotic microangiopathies (hemolytic uremic syndrome, thrombotic thrombocytopenic purpura, postpartum renal failure, or antiphospholipid syndrome), renal artery embolism, renal artery dissection, bilateral renal vein thrombosis, or abdominal compartment syndrome|
|Acute interstitial nephritis:|
|Allergic: Semisynthetic penicillin analogues (e.g., methicillin, ampicillin, or nafcillin), cephalosporins, rifampin, ciprofloxacin, cotrimoxazole, sulfonamides, thiazides, furosemide, allopurinol, phenytoin, tetracyclines, or warfarin|
|Infectious: Streptococcal, staphylococcal, leptospirosis, infectious mononucleosis, diphtheria, brucellosis, Legionnaire's disease, toxoplasmosis, or cytomegalovirus|
|Infiltrative: Sarcoidosis, lymphoma, leukemia|
|Autoimmune/alloimmune: Systemic lupus erythematosus or renal transplant rejection|
|Malignancy: Lymphoma, renal adenocarcinoma, bladder ureteral carcinoma, gynecologic cancers, prostate cancer, other pelvic tumors, or metastatic disease|
|Inflammatory processes: Tuberculosis, inflammatory bowel disease, retroperitoneal abscess or fibrosis, postradiation therapy|
|Vascular diseases: Aortic aneurysm, renal artery aneurysm|
|Papillary necrosis: Diabetes mellitus, sickle hemoglobinopathy, analgesic abuse, prostaglandin inhibition, or hepatic cirrhosis|
|Intratubular: Uric acid, calcium phosphate, Bence Jones proteins, methotrexate, acyclovir, sulfonamide antibiotics, or indinavir|
|Miscellaneous: Nephrolithiasis, ureteral ligation, retrograde pyelography with ureteral edema, neurogenic bladder, neuropathic ureteral dysfunction, or obstructed urinary catheter
Renal blood flow and GFR are relatively maintained during mild hypoperfusion, due to compensatory mechanisms.11 Renal perfusion is largely preserved within a range of mean arterial pressure (MAP) between 80 to 180 mm Hg, if cardiac output is adequate. As MAP falls below 80 mm Hg there is a precipitous fall in renal blood flow and GFR.12 There are two major mechanisms of renal blood flow autoregulation: a myogenic reflex and tubuloglomerular (TG) feedback. The myogenic reflex is mediated by stretch receptors in the afferent arterioles, which detect a decrease in perfusion pressure, leading to autoregulatory relaxation of afferent arterioles and vasodilation. TG feedback defends renal perfusion as follows: chloride concentration is continuously sensed in the tubular lumen by the macula densa, just distal to the thick ascending loop of Henle. When luminal chloride decreases (presumably reflecting decreased renal blood flow, GFR, intravascular volume, or a combination of these), a vasodilatory signal is transduced to the corresponding afferent arteriole (and vice versa if flow increases). Together these mechanisms autoregulate renal blood flow in the face of hypotension or hypertension. A third mechanism additionally helps autoregulate GFR. Increased renin secretion stimulated by hypotension/hypovolemia sensed in the afferent arteriole helps maintain GFR (but not renal blood flow) during hypotension, through the efferent arteriolar action of angiotensin II (discussed further below).
Of course, in addition to local autoregulation, systemic neurohumoral influences also play a prominent role in determining the renal response to shock. Systemic hypoperfusion activates the sympathetic nervous system and renin-angiotensin-aldosterone axis. Norepinephrine and angiotensin II are systemic vasoconstrictors, and tend to increase renal blood flow by preserving renal perfusion pressure. On the other hand, both hormones are renal vasoconstrictors, though they differ in their glomerular hemodynamic effects. Angiotensin II preferentially constricts efferent arterioles, and helps preserve glomerular filtration, increasing filtration fraction (the ratio of GFR to renal plasma flow) by creating “back-pressure” to augment net filtration pressure in the glomerular capillary. Norepinephrine causes balanced afferent and efferent arteriolar constriction, similarly increasing filtration fraction in the face of decreased renal blood flow, but to a lesser extent than angiotensin II. Both angiotensin II and norepinephrine stimulate intrarenal vasodilator prostaglandin production, thus attenuating their simultaneous effect of afferent arteriolar vasoconstriction and helping preserve renal perfusion.
Drugs may unfavorably alter the glomerular hemodynamic response to renal hypoperfusion. Nonsteroidal anti-inflammatory drug (NSAIDs) administration to patients with decreased effective arterial blood volume (due to hypovolemia or congestive heart failure) or renal vasoconstriction (due to cirrhosis) leads to a decline in renal blood flow and GFR. These patients are dependent on vasodilator prostaglandins to maintain renal perfusion, so NSAIDs leave renal vasoconstrictor influences unopposed. Angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin receptor blockers (ARBs) can lead to prerenal azotemia in patients who are dependent on angiotensin II for maintenance of GFR. This phenomenon is most commonly seen in patients receiving ACEIs or ARBs in the presence of hypovolemia, bilateral renal artery stenosis, or unilateral renal artery stenosis with a solitary kidney.
Prerenal azotemia also leads to avid renal tubular sodium and water reabsorption throughout the nephron. Catecholamines and angiotensin II directly increase sodium transport and reabsorption in the proximal and distal nephron. Efferent arteriolar constriction by angiotensin II and increased filtration fraction simultaneously lead to decreased peritubular capillary hydraulic pressure and increased peritubular capillary oncotic pressure. The combination of high oncotic pressure and low hydraulic pressure in peritubular capillaries increases sodium and water absorption in the proximal tubule, a process termed glomerulotubular balance. Angiotensin II also leads to downstream production of aldosterone, another salt-retaining influence. Severe hypovolemia/ hypotension (>10% to 15% decrease in MAP or blood volume) leads to nonosmotic vasopressin secretion, and avid water reabsorption in the collecting duct, along with systemic vasoconstriction. Finally, in hypovolemic patients decreased atrial stretch downregulates production of atrial natriuretic peptide, also favoring sodium retention (the opposite is true if renal hypoperfusion is caused by congestive heart failure). Thus the combination of glomerulotubular balance and the tubular effects of catecholamines, angiotensin II, aldosterone, and vasopressin mediate the salt and water retention which is the hallmark of prerenal azotemia. Accordingly, patients with prerenal azotemia tend to have oliguria, low urine sodium, and concentrated urine with a urine osmolality exceeding 500 mOsm/kg. Low urine sodium (and fractional excretion of sodium; see below) and increased urine osmolality (with a high urine:plasma creatinine ratio) are not seen in patients who have prerenal ARF due to renal losses (ongoing diuretic therapy, salt-wasting nephropathies, osmotic diuresis, adrenal insufficiency, and central or nephrogenic diabetes insipidus). Other common laboratory features of prerenal ARF are increased serum BUN:creatinine ratio (caused by low tubular flow and increased urea reabsorption), decreased fractional excretion of urea (see below), polycythemia/high serum albumin (hemoconcentration), mild hypercalcemia, hyperuricemia, and acid-base abnormalities (metabolic acidosis from diarrhea or shock or lactic acidosis; metabolic alkalosis from diuretics or vomiting). Hyponatremia may also be present, depending on abnormalities in water balance (see Chap. 76). The renal response to volume challenge or vasoactive drug initiation may also be used to determine the presence or absence of a reversible, “prerenal” etiology of ARF.
Postrenal Acute Renal Failure
Postrenal ARF (often called obstructive uropathy) accounts for 5% of all cases of ARF, and is more common in the elderly. Unilateral obstruction is not sufficient alone to cause ARF. Renal insufficiency due to obstruction occurs only when the obstruction involves a site that affects both kidneys, or a single functioning kidney. The most common cause of postrenal obstruction is bladder neck obstruction (prostatic hypertrophy, prostate cancer, and neurogenic bladder). Postrenal obstruction is also caused by bilateral ureteral obstruction or unilateral obstruction in patients with solitary kidney (stones, clots, sloughed renal papillae, retroperitoneal fibrosis, or retroperitoneal masses). Intratubular obstruction can be caused by crystals like uric acid, calcium oxalate, calcium phosphate, acyclovir, sulfadiazine, indinavir, methotrexate, or by paraprotein (myeloma cast nephropathy). Volume expansion, sometimes with urinary alkalinization (uric acid, methotrexate, or myeloma), is the primary treatment for these causes of intratubular obstruction.
Obstruction to urine flow by increased tubular hydrostatic pressure is only partly responsible for the reduced GFR of obstructive uropathy. ARF is also caused and sustained by renal vasoconstriction that occurs in response to ureteral obstruction, mediated by thromboxanes. Obstruction should be suspected in patients with recurrent urinary tract infections, nephrolithiasis, prostate disease, or pelvic tumor. Causes of obstructive uropathy are listed in Table 75-1. These patients usually have a preceding history of obstructive symptoms followed by sudden onset of anuria or oliguria. Polyuria and nocturia due to renal concentrating defect may be seen in patients with partial or intermittent obstruction. Other features of ARF secondary to obstruction are increased BUN:creatinine ratio, hyperkalemia, and defective urinary acidification with metabolic acidosis.
The two most important diagnostic tests when obstruction is suspected are bladder catheterization and renal ultrasonography. If urinary tract obstruction is strongly suspected, but ultrasound results are equivocal, then a “stone protocol” noninfused computed tomography (CT) scan should be performed. In some cases where false-negative ultrasound or CT scan results are suspected, cystoscopy and retrograde pyelograms may be required to definitively exclude the diagnosis of obstructive uropathy. For example, we would request retrograde pyelograms despite normal ultrasound images in a patient with anuric, hyperkalemic ARF and extensive pelvic tumor, potentially encasing the ureters and preventing dilation and hydronephrosis. Retroperitoneal fibrosis can similarly cause obstructive ARF without hydronephrosis. Early diagnosis is essential, as the extent of parenchymal damage is dependent on the duration of obstruction; complete recovery is possible up until 10 to 14 days of obstruction.
Intrinsic Acute Renal Failure
Intrinsic acute renal failure can be categorized anatomically, according to the site of the lesion: vascular, glomerular, or tubulointerstitial. We will discuss tubular and interstitial causes first, because they are far more common in hospitalized patients.
The most common cause of intrinsic ARF in hospitalized patients is acute tubular necrosis (ATN). ATN is caused by ischemia, nephrotoxins, or a combination of both, and accounts for approximately 85% to 90% of intrinsic ARF cases.2,13 Ischemic ATN is commonly seen in patients with sepsis or severe cardiac failure, or postoperative patients, particularly after cardiac and aortic surgeries. Massive trauma or cardiac arrest are other causes of ATN. Prerenal failure can result in ischemic ATN if renal hypoperfusion is severe and not reversed by timely therapy. Although improving renal perfusion may reverse prerenal ARF (by definition), and diminish ischemic contributions to the pathogenesis of ATN, it is quite conceivable that in many cases ATN develops despite appropriate resuscitation and adequate renal perfusion. Zager has shown in an endotoxemic rat model of septic ARF that paired combinations of insults (renal cross clamp, systemic endotoxin, aminoglycoside, and temperature elevation) cause azotemia and renal pathologic findings of ATN, but these insults individually cause no renal dysfunction or injury.13 We suspect that this synergistic injury model accurately reflects the pathogenesis of much ARF in the ICU. Positive pressure mechanical ventilation alters renal perfusion and function through a variety of mechanisms, both hemodynamic and inflammatory.14 Other experimental data have shown that endotoxin, tumor necrosis factor, and numerous other inflammatory mediators are directly cytotoxic to renal endothelial and tubular cells.15
The diagnosis of ATN is usually made by clinical exclusion of alternative diagnoses such as obstruction or prerenal azotemia, and a lack of features suggestive of other intrinsic renal lesions. Characteristic urinalysis and urine chemistry findings frequently support the clinical diagnosis (see below). Ischemic ATN is usually reversible by tubular regeneration in surviving patients with previously normal renal function. Failure to recover prompts consideration of a differential diagnostic list including bilateral cortical necrosis, renal atheroembolism, renal artery stenosis/thrombosis/dissection, and severe forms of other intrinsic lesions such as rapidly progressive glomerulonephritis (GN). Bilateral cortical necrosis causes irreversible renal failure and is associated with profound shock with disseminated intravascular coagulation, obstetric complications, hemolytic uremic syndrome, or snake bites.16
Cellular mediators that play a role in the pathogenesis of ATN include calcium, reactive oxygen species, phospholipases, proteases, adhesion molecules, and nitric oxide (NO).17 ATN has several phases: prerenal, initiation, extension, maintenance, and repair.18 It is not intuitive that renal tubular injury should cause decreased glomerular filtration and ARF. A decrease in glomerular ultrafiltration coefficient has been shown in several animal models of ARF, but this is a minor contributor to the observed decrement in GFR.19,20 The pathophysiologic mechanisms that explain the reduction of GFR in ATN are hemodynamic abnormalities, tubular obstruction, and tubular backleakage of glomerular filtrate (Fig. 75-1).21 Renal vasoconstriction is seen in ARF,21,22 caused by activation of tubuloglomerular feedback; increased distal chloride delivery past injured tubular segments is sensed by the macula densa, causing vasoconstriction of the corresponding afferent arteriole. This reversible, functional mechanism seems to be the major cause of decreased GFR in ATN, and is in part protective. Severe hypovolemia would rapidly result if injured tubules failed to reabsorb the bulk of filtered sodium and water; thus the term “acute renal success” has been used to describe the development of decreased GFR (“acute renal failure”) in the presence of tubular necrosis.22 Furthermore, reabsorption of filtered sodium accounts for the bulk of renal oxygen consumption; continued glomerular filtration of sodium in ATN may aggravate hypoxic damage to sublethally injured tubules. The phenomenon of medullary hypoxia plays an important role in the pathogenesis of ATN. Low medullary blood flow is required for urinary concentration.23 Reabsorption of sodium chloride by the medullary thick ascending limb of the loop of Henle (mTAL) is the major determinant of medullary oxygen consumption, resulting in a hypoxic environment under normal circumstances.23,24 mTAL is vulnerable to ischemic injury if increased oxygen requirement is associated with decreased oxygen delivery. In addition, the inflammatory mechanisms that dominate as ATN progresses from initiation to extension and maintenance phases of ATN result in medullary congestion and hypoperfusion.18
Pathophysiologic mechanisms of acute renal failure. Tubular damage by ischemia, nephrotoxins, or both, leads to decreased GFR by a combination of mechanisms. (1) Renal vasoconstriction via activation of tubuloglomerular feedback, and decreased vasodilator substances (PGI2, prostacyclin; NO, nitric oxide) is a prominent functional mechanism of decreased GFR in ATN. (2) Backpressure from tubular obstruction by casts directly decreases GFR. (3) Backleakage of glomerular filtrate into peritubular capillaries decreases the efficiency of glomerular filtration, effectively decreasing GFR. (4) There is increasing evidence for a role of interstitial inflammation in the extension phase of ATN. (5) Direct glomerular effects (mesangial contraction, decreased filtration surface area) may also play a role in decreasing GFR in the presence of ATN. (Reproduced with permission from Lameire et al.21)
The tubular factors that are also involved in the reduction of GFR in ARF are tubular obstruction and tubular backleakage. Necrotic cell debris incorporated into casts causes obstruction of proximal and distal tubules and has been shown to play a significant role in experimental ARF.25,26 Backleakage of tubular fluid across denuded basement membranes and injured proximal tubule cells has been demonstrated in several experimental models of ARF.27 Subsequently it has been shown that tubular backleakage and intratubular obstruction are important factors contributing to the reduction of GFR in human ischemic ARF.28,29
Nephrotoxic injury is the second major cause of ATN. Nephrotoxic ATN is caused by drugs (aminoglycosides, cisplatin, amphotericin, and chemotherapy), radiocontrast agents, heme pigments (myoglobin and hemoglobin), and myeloma light chain proteins. ARF due to aminoglycosides and radiocontrast agents accounts for most cases of nephrotoxic ATN. Nephrotoxicity of cancer chemotherapy is discussed in Chap. 74; malignancy and ARF are further discussed below. Three nephrotoxic ARF syndromes will be further discussed here: aminoglycoside nephrotoxicity, radiocontrast nephropathy, and ARF caused by nonsteroidal anti-inflammatory drugs (NSAIDs).
Aminoglycosides like tobramicin, gentamicin, amikacin, and netilmicin are widely used for the treatment of gram-negative infections. Although they are effective antibiotics, therapy with aminoglycosides is complicated by nephrotoxicity in 10% to 20% of patients.30 Aminoglycosides are excreted by glomerular filtration and are reabsorbed by proximal tubular cells. The mechanism of aminoglycoside-induced renal injury is not well understood. Accumulation of aminoglycosides in the proximal tubules in high concentration results in disruption of a variety of intracellular processes. Aminoglycosides are tubular toxins, and the earliest morphologic changes consist of vacuolization of proximal tubules, loss of brush border, and the presence of myeloid bodies within proximal tubule cells. Clinical evidence also attests to the tubular toxicity of aminoglycosides; maximum urine osmolality falls, and renal wasting of Mg2 + and K+ ensues. The relationship between this tubule damage and reduced GFR remains unclear, although in experimental models using high doses of aminoglycosides, tubule obstruction and backleakage can be demonstrated. In experimental models of aminoglycoside nephrotoxicity, relatively small doses decrease glomerular permeability, while larger doses cause renal vasoconstriction. The relevance of these hemodynamic changes to human aminoglycoside nephrotoxicity is not known.
ARF generally develops 7 to 10 days after aminoglycoside therapy is started. Aminoglycoside nephrotoxicity is associated with nonoliguric ARF, due to a concentrating defect caused by tubular injury. Aminoglycoside nephrotoxicity is also accompanied by potassium and magnesium wasting. Risk factors for aminoglycoside nephrotoxicity are summarized in Table 75-2. In patients with preexisting renal insufficiency the dosing interval should be adjusted and levels monitored to minimize the risk of ototoxicity and nephrotoxicity. Once-daily dosing of aminoglycosides decreases nephrotoxicity with no apparent loss of effectiveness.31–33 In patients with acutely deteriorating renal function who require aminoglycoside therapy, monitoring may be very difficult and require frequent reassessment. Aminoglycosides should be discontinued whenever renal dysfunction develops; increasing trough levels and decreased calculated aminoglycoside clearance may signal decreased GFR before serum creatinine increases. Recovery of renal function is expected in most cases when nephrotoxicity is recognized early and aminoglycosides held, but may be delayed for days to weeks.
Table 75–2. Risk Factors for Aminoglycoside Nephrotoxicity |Favorite Table|Download (.pdf)
Table 75–2. Risk Factors for Aminoglycoside Nephrotoxicity
|Preexisting renal disease|
ARF due to radiocontrast agents occurs within 24 to 48 hours of intravenous radiocontrast administration, and is termed radiocontrast nephropathy. Vasoconstriction and direct tubular toxicity due to generation of oxygen free radicals are thought to be the pathogenetic mechanisms of radiocontrast nephrotoxicity. In most cases the ARF is mild and recovery typically begins with stabilization of serum creatinine at 3 to 5 days postcontrast.34 Renal failure is usually nonoliguric. However, in patients with preexisting severe chronic renal failure radiocontrast nephropathy may be severe, irreversible, and require chronic dialysis.
The risk of nephrotoxicity due to contrast agents varies with the type and dose of agent. Low- or iso-osmolal agents are less nephrotoxic than ionic high-osmolal agents.35,36 The incidence of ARF due to radiocontrast agents is less than 2% in patients with normal renal function, but is inversely related to GFR in patients with chronic renal insufficiency; in high-risk patients the incidence is as high as 60%.37 There are several important risk factors for radiocontrast nephropathy, including chronic renal insufficiency, diabetic nephropathy, severe congestive heart failure, intravascular volume depletion, high contrast dose, and multiple myeloma (Table 75-3). Of note, the risk of radiocontrast nephropathy at any GFR level of chronic renal impairment is approximately double in diabetics compared to nondiabetics. The group at risk for radiocontrast nephropathy can be reliably identified, and a variety of prophylactic strategies have been used, several successfully.
Table 75–3. Risk Factors for Radiocontrast Nephrotoxicity |Favorite Table|Download (.pdf)
Table 75–3. Risk Factors for Radiocontrast Nephrotoxicity
|Preexisting renal failure|
|Previous contrast nephropathy|
|Multiple contrast procedures|
|High contrast dose (>2 mL/kg)|
|Congestive heart failure|
A number of measures are used for prevention of radiocontrast nephropathy. Alternative imaging approaches (ultrasound, noninfused CT, or gadolinium-enhanced magnetic resonance angiography) are preferred to radiocontrast studies in patients with a high risk of radiocontrast nephropathy. Nonionic low-osmolal agents35 and nonionic iso-osmolol agents36 are less nephrotoxic, and these agents are used to decrease the incidence of ARF due to radiocontrast agents. Standard recommendations suggest that IV hydration with 0.45% saline is beneficial in reducing the incidence and severity of radiocontrast nephropathy,38 but recently normal saline (1 mL/kg per hour for 12 hours pre- and postcontrast) was demonstrated superior for this purpose.39 Most recently, Merten and colleagues showed that administration of an equimolar sodium bicarbonate solution was superior to normal saline for radiocontrast nephropathy prophylaxis, infused as 3 mL/kg per hour for 1 hour precontrast, then 1 mL/kg per hour for 6 hours.40 In some studies the administration of acetylcysteine, a thiol-containing antioxidant, in combination with saline hydration has been shown to be beneficial in reducing the incidence of contrast nephropathy when administered in various oral regimens (1200 mg once or 600 mg every 12 hours before and after radiocontrast).41–43 One successful study used intravenous acetylcysteine for radiocontrast nephropathy prophylaxis.44 Although other studies did not show any benefit,45,46 a recent meta-analysis of eight randomized controlled trials involving 855 patients reported that the use of acetylcysteine reduced the risk of radiocontrast by 59%.46 However, further doubt has been cast over these inconsistent findings by emerging experimental data that suggest that the apparent efficacy of acetylcysteine in these studies may have been artifactual. Specifically, acetylcysteine causes a decrement in serum creatinine (but not cystatin C) by a GFR-independent mechanism,47 perhaps by inhibiting creatinine phosphokinase function.48 Nevertheless, given the available data, oral administration of acetylcysteine to patients at high risk of developing contrast nephropathy appears warranted, and should do no harm in combination with adequate volume expansion. Other approaches such as vasodilation with dopamine49 or fenoldopam50 failed to prevent radiocontrast nephropathy, and mannitol and furosemide appeared to increase the rate of ARF postcontrast in one study.38 Prophylactic hemodialyis has not been shown to be beneficial in the prevention of contrast nephropathy.51 More recently, Marenzi and colleagues compared the effectiveness of hemofiltration with intravenous isotonic saline administration in patients with chronic renal insufficiency undergoing coronary interventions.52 BUN and serum creatinine were measured at baseline, immediately before the procedure, and then daily for the following 3 days and at hospital discharge. In this study there was less likelihood of an increase in serum creatinine (the primary end point), less likelihood of requiring emergent hemodialysis, and less in-hospital and 1-year mortality in the hemofiltration group.52 Adulteration of the primary end point by hemofiltration of creatinine in one arm is a fatal flaw of this study. Other flaws include an unbalanced level of care between the groups (floor vs. hemofiltration in the ICU), and more regulation of fluid balance in the hemofiltration group (and more pulmonary edema in the fluids-alone arm). Since hemofiltration is also expensive, associated with a variety of risks, and a limited resource, we do not recommend this approach to radiocontrast nephropathy prevention unless confirmed by additional prospective controlled studies.
Nonsteroidal Anti-Inflammatory Drugs and Acute Renal Failure
NSAIDs can cause hemodynamically mediated ARF. Vasodilatory prostaglandins (prostacyclin and prostaglandin E2 [PGE2]) are essential for the maintenance of renal blood flow and GFR in states of effective volume depletion, such as congestive heart failure, cirrhosis of the liver, nephrotic syndrome, and in states of true volume depletion.53 Prostaglandins counterbalance the effects of vasoconstrictors such as angiotensin II and catecholamines. NSAIDs inhibit prostaglandins and thus would lead to unopposed effect of angiotensin II and catecholamines, leading to reduced GFR. Hyperkalemia may be prominent because NSAIDs impair renin secretion. Patients with chronic renal insufficiency are similarly at risk for NSAID-induced ARF, because vasodilator prostaglandins maintain hyperfiltration in remnant nephrons. Hemodynamically-mediated ARF is seen within days of taking NSAIDs in high-risk patients. Cyclooxygenase-2 (COX-2) selective drugs have the same renal effects as nonselective NSAIDs, because COX-2 is constitutively expressed and physiologically active in the kidney.54 The second type of acute renal injury is allergic interstitial nephritis, as discussed below. Chronic NSAID use is also associated with papillary necrosis and is thought to occur in patients who are taking multiple analgesics.
Acute Tubulointerstitial Nephritis
ARF due to acute interstitial nephritis (AIN) is most often caused by allergic reaction to various drugs (allergic AIN), but there are also a variety of infectious (Legionnaire's disease, cytomegalovirus, and Hantavirus), autoimmune (lupus), alloimmune (renal transplant rejection), and infiltrative (sarcoidosis, leukemia, and lymphoma) disorders that can cause AIN (see Table 75-1). The most common drugs that cause allergic AIN are penicillins, cephalosporins, ciprofloxacin, rifampin, sulfonamides (furosemide, thiazide diuretics, and trimethoprim-sulfamethoxazole), cimetidine, allopurinol and NSAIDs.
Patients with AIN classically present with ARF temporally related to drug therapy or infection, associated with a triad of fever, rash, and eosinophilia.55 Urinalysis findings include leukocyturia with eosinophiluria, leukocyte casts, and low-grade proteinuria. Although all these signs are present in the majority of patients with AIN, absence of these does not exclude the diagnosis of AIN. In particular, these findings are usually absent in NSAID-induced AIN. Proteinuria is mild to moderate except in NSAID-induced AIN, in which nephrotic syndrome caused by a minimal change lesion has been described. Tubular dysfunction (e.g., Fanconi's syndrome, distal renal tubular acidosis, or hyperkalemia) occurs in the majority of patients with AIN.
AIN is usually suspected from the history and laboratory findings. In the absence of urinary tract infection, detection of large numbers of urinary eosinophils (>5%) strongly suggests the diagnosis of drug-induced tubulointerstitial nephropathy (TIN). Hansel's stain of the urine is more sensitive than Wright's stain for the detection of urinary eosinophils.56 The Hansel method correctly identified 10 of 11 patients with TIN, as opposed to only 2 of 11 correctly classified using Wright's stain. False-positive results with the Hansel technique are most commonly caused by rapidly progressive GN or acute prostatitis. Diagnosis can be confirmed by renal biopsy if ARF is progressive and treatment of an alternative diagnosis is considered (e.g., rapidly progressive GN), or if there is no recovery of renal function after discontinuation of the medication suspected to have caused AIN.
No therapy is recommended in patients with mild renal insufficiency, and in patients who respond after discontinuation of the offending medication. AIN is usually reversible after withdrawal of the offending agent and treatment of underlying disease; corticosteroid therapy is unproven, and generally recommended only in patients with biopsy-confirmed acute allergic interstitial nephritis who do not respond to conservative management, and have no contraindication to immunosuppression.
Rapidly Progressive Glomerulonephritis
Glomerulonephritis such as postinfectious glomerulonephritis, lupus nephritis, and Goodpasture's syndrome can cause acute or subacute renal failure (see Table 75-1). Rapidly progressive glomerulonephritis (RPGN) causing ARF is an emergency. The combination of ARF with an “active” urine sediment (heavy proteinuria, hematuria, leukocyturia, and erythrocyte/leukocyte/mixed cellular casts) should prompt urgent evaluation with renal biopsy and serologies. The underlying pathologic lesion is classically necrotizing crescentic glomerulonephritis, treated with high-dose pulse corticosteroid therapy to stabilize renal function, followed by intensive immunosuppression (with or without plasmapheresis). Causes include inflammatory disorders with immune complex deposition (lupus, postinfectious, or cryoglobulinemia), anti–glomerular basement membrane antibodies (Goodpasture's syndrome, when associated with pulmonary hemorrhage), and pauci-immune glomerulonephritis (usually with small-vessel vasculitis; see below). Associated clinical features such as pulmonary hemorrhage, sinus involvement, leukocytoclastic vasculitis, neuropathy, or other stigmata of autoimmune disease may increase the index of suspicion for this diagnosis, but it must be emphasized that a skilled urinalysis demonstrating an “active” sediment in a patient with ARF may make this diagnosis alone. In fact the presence of erythrocyte casts is pathognomonic of GN; associated with ARF, this is essentially diagnostic of RPGN.
Vascular Causes of Acute Renal Failure
Vascular causes of ARF are categorized into small-vessel diseases and large-vessel diseases (see Table 75-1). Diseases involving small vessels include microscopic polyarteritis (vasculitis in polyarteritis nodosa and Kawasaki's disease involves medium-sized vessels), Wegener's granulomatosis, mixed cryoglobulinemia, and conditions that are categorized as thrombotic microangiopathies, including thrombotic thrombocytopenic purpura, hemolytic uremic syndrome, scleroderma renal crisis, malignant hypertension, and antiphospholipid antibody syndrome. Large-vessel renal vascular diseases include thromboembolic diseases and renal vein thrombosis. Atheroembolic disease should be considered in patients who develop ARF after instrumentation of the aorta, particularly in patients with known atherosclerotic disease.57 Renal vein thrombosis is usually a complication of nephrotic syndrome, and if bilateral can cause ARF. Abdominal compartment syndrome (see Chap. 42) is present when the intra-abdominal pressure (IAP) reaches 20 to 25 cm H2O, and unless decompressed, irreversible organ failure may result.58 The pathogenesis of oliguria and ARF in abdominal compartment syndrome involves venous compression (decreased venous return and renal vein compression), ureteral compression with obstructive uropathy, and possibly changes in renovascular resistance and intrarenal blood flow distribution. Regardless of the underlying cause, a reduction in urine output with or without azotemia in the presence of a measured intra-abdominal pressure over 15 cm H2O is cause for concern and should prompt intervention.