Figure 57.1. Autoregulation of Glomerular Filtration. (A) The glomerular filtration rate (GFR) for each glomerulus is determined by glomerular capillary pressure (P) and is represented by the open arrow. Total GFR is the sum of all individual glomeruli. The magnitude of blood entering the glomerulus through the afferent arteriole is shown by size of solid black arrow. With a drop in renal blood flow, GFR is preserved by afferent vasodilation (mediated by prostaglandins) and efferent vasoconstriction (mediated by angiotensin II). In the presence of angiotensin blockade, efferent vasoconstriction is inhibited, and GFR falls due to the decrease in PGC. (B) The changes in GFR from baseline as a function of mean arterial pressure (MAP). Open circles are control conditions. Black squares are in the presence of an angiotensin-converting enzyme inhibitor. SOURCE: Bradley Denker, MD

MECHANISMS OF REDUCED GLOMERULAR FILTRATION

POSTRENAL

Urinary outflow obstruction is a reversible cause of AKI that must be excluded early in the evaluation of AKI. Finding an obstruction by ultrasound not only identifies the cause of AKI, it also may reveal the anatomic etiology for the obstruction. This allows the management of the patient to be directed toward relief of the obstruction. However, the renal ultrasound may not reveal a dilated collecting system early in the course of obstruction, and with bulky pelvic tumors the compression of the ureters may prevent dilation. Therefore, it is important to have a high index of suspicion for obstruction in these clinical scenarios even in the absence of hydronephrosis on ultrasound. In addition, obstruction in a single kidney (such as from a kidney stone) will not result in a significant change in GFR due to compensation from the remaining kidney. The finding of a severe reduction in GFR from obstruction must involve the outflow tract (such as prostate hypertrophy) or a bilateral process.

PRERENAL

The definition of prerenal AKI is any etiology of reduced renal perfusion resulting in a decreased GFR without intrinsic renal damage. By definition, prerenal AKI will resolve when adequate renal perfusion has been restored. The etiologies of prerenal AKI can be broadly divided into volume depletion, peripheral vasodilation, decreased cardiac output, intrarenal vasoconstriction, and impaired autoregulatory responses (material summarized in box 57.1). In clinical practice there are often multiple prerenal mechanisms contributing to the decreased GFR. For example, volume depletion in addition to decreased cardiac output or impaired autoregulatory response due to medications is a common combination of factors. In all causes of prerenal AKI, the renal compensatory mechanisms discussed above (afferent vasodilation and efferent vasoconstriction) are preserved, and GFR will be protected until compensatory mechanisms are overwhelmed.

    Volume depletion is a common cause of prerenal AKI and can be seen with any fluid loss. These include blood loss from any site, or protracted vomiting or diarrhea. Bleeding from the gastrointestinal tract or other locations can lead to prerenal AKI after approximately 5% of blood volume loss or after mean arterial pressure falls below 80 mm Hg. Other causes of volume depletion include severe insensible losses that occur with systemic skin reactions or burns, and renal etiologies from the overuse of diuretics, uncontrolled hyperglycemia (osmotic diuresis), or with adrenal insufficiency.

Box 57.1 PRERENAL MECHANISMS OF AKI

    Peripheral vasodilation leads to shunting of blood away from the renal circulation and contributes to decreased renal perfusion. This commonly occurs with certain medications (anesthetics, vasodilators) and is also a major feature of both the hepatorenal and sepsis syndromes. Other mechanisms of decreased renal perfusion can be seen with intrinsic cardiac disease (acute myocardial infarction, decompensated congestive heart failure, valvular abnormalities, arrhythmias), pulmonary processes (pulmonary emboli or pulmonary hypertension), or from renal artery stenosis (either when bilateral or occurring in a single kidney). Intrarenal vasoconstriction, especially on the afferent arteriole, also contributes to decreased perfusion and GFR in the sepsis and hepatorenal syndromes. Intrarenal vasoconstriction is also seen with the use of certain medications and hypercalcemia (see box 57.1).

    Finally, hemodynamic AKI can result from impairment of the autoregulatory mechanisms. Nonsteroidal antiinflammatory drugs (NSAIDs) inhibit prostaglandins and prevent compensatory vasodilation of the afferent arteriole (Figure 57.1). ACE inhibitors and ARBs prevent angiotensin II actions on the efferent arteriole and block compensatory vasoconstriction necessary for maintaining GFR with reduced perfusion (Figure 57.1). These are commonly used medications and are often taken simultaneously. Nevertheless, most patients will not suffer hemodynamic AKI until there is another perturbation of the system (i.e., mild volume depletion from a gastrointestinal source or more aggressive diuresis). As discussed above, inhibiting either the afferent or efferent compensation will make patients more susceptible to hemodynamic mechanisms of AKI, and inhibiting both afferent and efferent mechanisms further increases the risk.

INTRINSIC CAUSES OF AKI

The three anatomic structures that can be injured with intrinsic kidney injury are the renal tubules, the glomeruli, and blood vessels (table 57.1). Of these, the renal tubules are the most susceptible to acute injury. Although kidneys receive 25% of cardiac output, the enormous metabolic activity within the tubules renders the environment quite hypoxic. In the renal cortex, arterial oxygen tension is approximately 50 mm Hg, but it rapidly falls to 10 mm Hg in the medulla. This normally hypoxic environment renders the renal tubules uniquely susceptible to any disruption in oxygen delivery.

TUBULAR ETIOLOGIES OF AKI

Any etiology of prerenal AKI can lead to acute tubular injury, commonly referred to as ATN (acute tubular necrosis). The factors that determine whether the reduced GFR is prerenal or has produced tubular damage relate to the severity and duration of the injury. As discussed above, the response of the kidneys to restoration of perfusion is the most important consideration in distinguishing these possibilities. Volume-depleted patients must receive adequate volume resuscitation, but knowing whether intrinsic damage has occurred is important for anticipating the clinical course and prognosis of patients with acute renal failure. Numerous criteria can be utilized to help distinguish prerenal AKI from ATN, and these are summarized in table 57.2. All of these biochemical indicators reveal whether tubular function is intact (i.e., without injury). The appropriate renal response to volume depletion is to preserve sodium (by catecholamine and angiotensin II stimulation of sodium reabsorption in the proximal tubule) leading to concentrated urine with very low sodium (see table 57.2). In addition, filtered urea nitrogen is reabsorbed in the proximal tubule along with sodium. As a result, blood urea nitrogen (BUN) rises disproportionately to the rise in serum creatinine (creatinine is not reabsorbed but, rather, secreted), and the BUN/creatinine ratio often exceeds 20:1 with volume depletion. Although the BUN/creatinine ratio and the urine findings in table 57.2 are helpful for distinguishing prerenal AKI from ATN, they are often indeterminate.

    Finally, the urinalysis can be helpful. With prerenal AKI, the urinary sediment is bland and may only reveal hyaline casts characteristic of concentrated urine, whereas ATN (tubular injury) is often associated with muddy brown casts (~85% of ATN presentations) and renal tubular epithelial cells reflecting dead/necrotic cells shed into the urine.

    In addition to hemodynamic insults resulting in ATN, the renal tubules are also susceptible to toxic injuries (see table 57.1). Again, this reflects the hypoxic metabolic environment and renal clearance for many of these compounds. Many etiologies of toxic ATN result from administered agents, but endogenous compounds liberated into the circulation, such as myoglobin with rhabdomyolysis and free hemoglobin, can also cause tubular injury. The clinical presentation and biochemical findings of toxin tubular injury are similar to what is described above for hemodynamic etiologies. However, a urinalysis showing strongly positive blood by dipstick and only a few red blood cells should prompt an investigation for myoglobin or free hemoglobin in the blood and urine (as seen with rhabdomyolysis and hemolysis, respectively).

    Two other mechanisms of tubular injury are important causes of AKI. Interstitial nephritis (common) and intratubular obstruction (less common) must be considered in the evaluation of patients with AKI (table 57.1). Interstitial nephritis is most commonly allergic in origin, has been reported with virtually every category of medication, and may not be associated with systemic manifestations (rash, eosinophilia). The kidneys can also be affected by interstitial infiltrates in infectious disorders, malignancy (lymphoma, leukemia), and autoimmune disorders (sarcoid, rheumatologic diseases). With allergic interstitial nephritis the cellular infiltrate is often mononuclear and not eosinophilic. As a result, a negative urine eosinophil count does not exclude drug-induced interstitial nephritis. With all etiologies of interstitial nephritis, the urinalysis will often have white blood cells, red blood cells, and may have white blood cell and red blood cell casts. Even in the absence of systemic manifestations, the clinical scenario will often suggest the diagnosis of interstitial nephritis (e.g., initiation of a new medication with development of AKI and abnormal urinalysis).

    Another important mechanism of AKI results when crystals, drugs, or proteins precipitate within the renal tubules resulting in intratubular obstruction. Often the patients at risk develop this complication in the setting of volume depletion and a concentrated urine. The hemodynamic consequences on GFR are identical to those of urinary obstruction at more distal sites, but intratubular obstruction will not be associated with hydronephrosis. Uric acid and oxalates are the most common crystals that precipitate within the tubules. Uric acid may precipitate in the tumor lysis syndrome, and likewise oxalates may precipitate with primary hyperoxalosis or ethylene glycol ingestion. Certain drugs (e.g., acyclovir, indinavir, methotrexate, sulfonamides) may precipitate if overdosed or administered to a volume-depleted patient, especially in the setting of preexisting renal insufficiency. Occasionally the drug crystals can be identified on the urinalysis. Finally, paraproteins can precipitate within renal tubules, and this is most commonly seen in patients with multiple myeloma and Bence-Jones proteinuria.

GLOMERULAR ETIOLOGIES OF AKI

Acute glomerulonephritis is a rare cause of acute kidney injury (table 57.1), but rapid diagnosis and treatment can prevent the development of end-stage renal disease. An overview of glomerular disease can found in chapter 62, and here the focus will be on disorders associated with AKI. Glomerular disease can be broadly divided into the nephrotic syndrome (>3.5 g of proteinuria/day, hypoalbuminemia, edema, hypercholesterolemia) and nephritic syndrome (hypertension, edema, azotemia, active urinary sediment with red blood cells, white blood cells, and cellular casts). Nephrotic syndrome is not usually associated with acute reductions in GFR. However, there are three clinical syndromes to consider in patients presenting with nephrotic syndrome and AKI. First, minimal change disease (normal glomeruli but podocyte foot process effacement on renal biopsy) in elderly or volume-depleted patients can have coexisting ATN. Second, collapsing glomerulopathy (focal and segmental glomerulosclerosis with collapsed glomeruli on kidney biopsy) is associated with rapid declines in GFR and can lead to end-stage disease within months. This syndrome is often seen in HIV-positive patients, but it can also be seen in the absence of HIV disease. Finally, allergic reactions to NSAIDs are commonly associated with minimal change or membranous patterns of injury in addition to classical findings of allergic interstitial nephritis. As a result, these patients will often have AKI and a picture of allergic interstitial nephritis and nephrotic syndrome.

    Acute glomerulonephritis or rapidly progressive glomerulonephritis (RPGN) can present as part of a systemic disease or may be renal-limited. The presentation usually includes hypertension, AKI, and active urinary sediment. The hallmark of an active urinary sediment in acute glomerulonephritis is the presence of dysmorphic red blood cells and red blood cell casts. Red blood cell casts are not always visualized, but hematuria of renal origin (dysmorphic red blood cells) is nearly universal. Other cells and casts, especially those of white blood cells, can also be present. RPGN can develop through three major mechanisms. (1) Antiglomerular basement membrane antibody disease (GBM), also known as Goodpasture syndrome, may be associated with pulmonary hemorrhage. Rapid diagnosis and treatment with plasmapheresis and cytotoxic agents is imperative, because renal recovery is rare when the creatinine reaches 5.8 mg/dL. (2) Pauci-immune etiologies of glomerulonephritis do not reveal immune complex staining or deposits on kidney biopsy and are often associated with antineutrophil cytoplasmic antibodies (ANCA). These disorders typically include Wegener granulomatosis (also known as granulomatosis with polyangiitis), Churg-Strauss syndrome (also known as eosinophilic granulomatosis with polyangiitis), and microscopic polyarteritis. (3) Immune complex diseases are typically divided into those with normal complement levels and those with hypocomplementemia. Systemic lupus erythematosus, postinfectious causes (streptococcal [group A] pharyngitis and subacute bacterial endocarditis are most common), and cryoglobulinemia are the most common etiologies of acute glomerulonephritis associated with low complement levels. These disorders are discussed in more detail in chapter 62. Other glomerular diseases that can present with AKI and do not include complement deposition are IgA nephropathy, the most common etiology of glomerulonephritis worldwide; Henoch-Schönlein purpura (HSP); and a less common deposition disease known as fibrillary or immunotactoid glomerulonephritis. Table 57.1 summarizes these disorders.

VASCULAR ETIOLOGIES OF AKI

Damage to the renal microcirculation can mimic acute glomerulonephritis, although the pathologic pattern is distinct from other etiologies of acute glomerulonephritis. The glomerular capillary is uniquely susceptible to injury and is frequently a target of pathology even when other capillary beds are spared. Glomerular endothelial cells are disproportionately affected in systemic microangiopathies such as thrombotic thrombocytopenic purpura (TTP) and hemolytic uremic syndrome (HUS). In addition to systemic thrombocytopenia and evidence for intravascular hemolysis, these disorders are characterized by platelet microthrombi in glomerular capillary loops and thickened glomerular basement membranes. The occlusion of blood flow in the renal microcirculation leads to shearing of red blood cells and loss of GFR. Both TTP and HUS can present as primary diseases (such as diarrhea-associated Escherichia coli O157 toxin–mediated), as a paraneoplastic syndrome in malignancy, or as complications of therapy with medications including cyclosporine, chemotherapy agents, or radiation therapy. Endothelial damage with a thrombotic microangiopathy is also seen in malignant hypertension, scleroderma crisis, and disseminated intravascular coagulation. Thrombotic microangiopathy can also be seen with antiphospholipid antibody syndrome associated with systemic lupus and as a complication of pregnancy. In all of these conditions the underlying renal pathophysiology is identical and therefore not distinguishable by kidney biopsy.

    Vasculitis (table 57.1) of small arterioles can result in acute glomerulonephritis as described above. These are often ANCA-associated and usually associated with Churg Strauss syndrome (asthma, eosinophilia), Wegener granulomatosis (pulmonary or ENT involvement common), microscopic polyarteritis (similar to polyarteritis nodosa [PAN]), hypersensitivity (drug related), cryoglobulinemia (often seen with hepatitis B or C or paraprotein disease), or HSP. Vasculitis of medium-sized arteries as seen with PAN can result in AKI, but vasculitis of large arteries (giant cell and Takayasu arteritis) rarely results in renal failure.

COMMON SCENARIOS OF AKI IN HOSPITALIZED PATIENTS

AKI in hospitalized patients is often associated with complications of procedures performed in the course of evaluation and treatment of other disease processes. AKI that develops during a hospital course can often be anticipated. The two most common scenarios are postoperative AKI and radiologic imaging/intervention injuries.

POSTOPERATIVE AKI

There are numerous variables that increase the risk for AKI in patients undergoing surgical procedures. Any patient with preexisting chronic renal disease is at higher risk, and the more severe the chronic kidney disease the greater the risk for procedure-related AKI. Virtually all patients will have anesthesia-induced drops in blood pressure due to the vasodilatory action of anesthetic agents. This alone will not cause AKI in most settings, but if there is significant blood loss or larger drops in blood pressure for a prolonged interval, this can result in AKI. Certain medications taken prior to surgery including NSAIDs and ACE inhibitors or ARBs may interfere with normal renal autoregulatory mechanisms (as described above) and, when combined with anesthesia- induced drop in blood pressure, may lead to AKI. Other risk factors include the length of the procedure and the type of operation. Vascular and cardiac surgeries pose a higher risk, and large blood loss or the use of cardiopulmonary bypass also increases the risk of AKI. Finally, it is important to identify additional potential nephrotoxins administered during the surgery including antibiotics or irrigants (many of which are highly nephrotoxic if absorbed).

POST–INTRAVENOUS CONTRAST AND ANGIOGRAPHIC PROCEDURE AKI

There are two common mechanisms of AKI in the setting of intravenous contrast (see table 57.3). One results from renal toxicity related to contrast exposure (contrast nephropathy), and the other is atheroembolic syndrome resulting from mechanical disruption of cholesterol plaque during an angiographic procedure. Atheroemboli to the renal arteries can occur spontaneously, but they are usually associated with angiographic procedures through the femoral artery. The atheroembolic syndrome is often associated with a diffuse systemic reaction that can mimic an acute autoimmune disease and may include livedo reticularis, fever, eosinophilia, hypocomplementemia, and AKI. On renal biopsy, cholesterol emboli may be visualized in the small intrarenal arteries. The course and prognosis of renal atheroembolic disease are variable. Some patients will recover, but others will progress to end-stage disease requiring renal replacement over the course of days to weeks because many of these patients had existing chronic kidney disease prior to the procedure. Some patients exhibit a waxing and waning course in which GFR will worsen and improve over several weeks to months before stabilizing with reduced GFR.

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