Monitoring the GFR is important in both hospital and outpatient settings, and several different methodologies are available. GFR is the primary metric for kidney “function,” and its direct measurement involves administration of a radioactive isotope (such as inulin or iothalamate) that is filtered at the glomerulus into the urinary space but is neither reabsorbed nor secreted throughout the tubule. GFR—i.e., the clearance of inulin or iothalamate in milliliters per minute—is calculated from the rate of appearance of the isotope in the urine over several hours. In most clinical circumstances, direct GFR measurement is not feasible, and the plasma creatinine level is used as a surrogate to estimate GFR. Plasma creatinine (PCr) is the most widely used marker for GFR, which is related directly to urine creatinine (UCr) excretion and inversely to PCr. On the basis of this relationship (with some important caveats, as discussed below), GFR will fall in roughly inverse proportion to the rise in PCr. Failure to account for GFR reductions in drug dosing can lead to significant morbidity and death from drug toxicities (e.g., digoxin, imipenem). In the outpatient setting, PCr serves as an estimate for GFR (although much less accurate; see below). In patients with chronic progressive renal disease, there is an approximately linear relationship between 1/PCr (y axis) and time (x axis). The slope of that line will remain constant for an individual; when values deviate, an investigation for a superimposed acute process (e.g., volume depletion, drug reaction) should be initiated. Signs and symptoms of uremia, the clinical symptom complex associated with renal failure, develop at significantly different levels of PCr, depending on the patient (size, age, and sex), underlying renal disease, existence of concurrent diseases, and true GFR. Generally, patients do not develop symptomatic uremia until renal insufficiency is severe (GFR <15 mL/min).
Creatinine clearance (CrCl), an approximation of GFR, is measured from plasma and urinary creatinine excretion rates for a defined period (usually 24 h) and is expressed in milliliters per minute: CrCl = (Uvol × UCr)/(PCr × Tmin). The “adequacy” or “completeness” of the urinary collection is estimated by the urinary volume and creatinine content; creatinine is produced from muscle and excreted at a relatively constant rate. For a 20- to 50-year-old man, creatinine excretion should be 18.5–25.0 mg/kg body weight; for a woman of the same age, it should be 16.5–22.4 mg/kg body weight. For example, an 80-kg man should excrete between ~1500 and 2000 mg of creatinine in an “adequate” collection. Creatinine is useful for estimating GFR because it is a small, freely filtered solute that is not reabsorbed by the tubules. PCr levels can increase acutely from dietary ingestion of cooked meat, however, and creatinine can be secreted into the proximal tubule through an organic cation pathway (especially in advanced progressive chronic kidney disease), leading to overestimation of GFR. When a timed collection for CrCl is not available, decisions about drug dosing must be based on PCr alone. Two formulas are used widely to estimate kidney function from PCr: (1) Cockcroft-Gault and (2) four-variable MDRD (Modification of Diet in Renal Disease).
There are limitations to all creatinine-based estimates of GFR. Each equation, along with 24-h urine collection for measurement of creatinine clearance, is based on the assumption that the patient is in steady state, without daily increases or decreases in PCr as a result of rapidly changing GFR. The MDRD equation is better correlated with true GFR when the GFR is <60 mL/min per 1.73 m2. The gradual loss of muscle from chronic illness, chronic use of glucocorticoids, or malnutrition can mask significant changes in GFR with small or imperceptible changes in PCr. Cystatin C, a member of the cystatin superfamily of cysteine protease inhibitors, is produced at a relatively constant rate from all nucleated cells. Serum cystatin C has been proposed to be a more sensitive marker of early GFR decline than is PCr; however, like serum creatinine, cystatin C is influenced by the patient’s age, race, and sex and also is associated with diabetes, smoking, and markers of inflammation.
APPROACH TO THE PATIENT Azotemia
Once GFR reduction has been established, the physician must decide if it represents acute or chronic renal injury. The clinical situation, history, and laboratory data often make this an easy distinction. However, the laboratory abnormalities characteristic of chronic renal failure, including anemia, hypocalcemia, and hyperphosphatemia, are also often present in patients presenting with acute renal failure. Radiographic evidence of renal osteodystrophy (Chap. 305) can be seen only in chronic renal failure but is a very late finding, typically in patients with end-stage renal disease (ESRD) maintained on dialysis. The urinalysis and renal ultrasound can facilitate distinguishing acute from chronic renal failure. An approach to the evaluation of azotemic patients is shown in Fig. 48-1. Patients with advanced chronic renal insufficiency often have some proteinuria, nonconcentrated urine (isosthenuria; isosmotic with plasma), and small kidneys on ultrasound, characterized by increased echogenicity and cortical thinning. Treatment should be directed toward slowing the progression of renal disease and providing symptomatic relief for edema, acidosis, anemia, and hyperphosphatemia, as discussed in Chap. 305. Acute renal failure (Chap. 304) can result from processes that affect and blood flow and glomerular perfusion (prerenal azotemia), intrinsic renal diseases (affecting small vessels, glomeruli, or tubules), or postrenal processes (obstruction of urine flow in ureters, bladder, or urethra) (Chap. 313).
PRERENAL FAILURE Decreased renal perfusion accounts for 40–80% of cases of acute renal failure and, if appropriately treated, is readily reversible. The etiologies of prerenal azotemia include any cause of decreased circulating blood volume (gastrointestinal hemorrhage, burns, diarrhea, diuretics), volume sequestration (pancreatitis, peritonitis, rhabdomyolysis), or decreased effective arterial volume (cardiogenic shock, sepsis). Renal and glomerular perfusion also can be affected by reductions in cardiac output from peripheral vasodilation (sepsis, drugs) or profound renal vasoconstriction (severe heart failure, hepatorenal syndrome, agents such as nonsteroidal anti-inflammatory drugs [NSAIDs]). True or “effective” arterial hypovolemia leads to a fall in mean arterial pressure, which in turn triggers a series of neural and humoral responses, including activation of the sympathetic nervous and renin-angiotensin-aldosterone systems and vasopressin (AVP) release. GFR is maintained by prostaglandin-mediated dilatation of afferent arterioles and angiotensin II–mediated constriction of efferent arterioles. Once the mean arterial pressure falls below 80 mmHg, GFR declines steeply.
Blockade of prostaglandin production by NSAIDs can result in severe vasoconstriction and acute renal failure. Blocking angiotensin action with angiotensin-converting enzyme (ACE) inhibitors or angiotensin receptor blockers (ARBs) decreases efferent arteriolar tone and in turn decreases glomerular capillary perfusion pressure. Patients taking NSAIDs and/or ACE inhibitors/ARBs are most susceptible to hemodynamically mediated acute renal failure when blood volume or arterial perfusion pressure is reduced for any reason; under these circumstances, preservation of GFR is dependent on afferent vasodilation due to prostaglandins and efferent vasoconstriction due to angiotensin-II. Patients with bilateral renal artery stenosis (or stenosis in a solitary kidney) can also be dependent on efferent arteriolar vasoconstriction for maintenance of glomerular filtration pressure and are particularly susceptible to a precipitous decline in GFR when given ACE inhibitors or ARBs.
Prolonged renal hypoperfusion may lead to acute tubular necrosis (ATN), an intrinsic renal disease that is discussed below. The urinalysis and urinary electrolyte measurements can be useful in distinguishing prerenal azotemia from ATN (Table 48-2). The urine Na and osmolality of patients with prerenal azotemia can be predicted from the stimulatory actions of norepinephrine, angiotensin II, AVP, aldosterone, and low tubule fluid flow rate. In prerenal conditions, the tubules are intact, leading to a concentrated urine (>500 mosmol), avid Na retention (urine Na concentration, <20 mmol/L; fractional excretion of Na, <1%), and UCr/PCr >40 (Table 48-2). The FENa is typically >1% in ATN, but may be <1% in patients with milder, nonoliguric ATN (e.g., from rhabdomyolysis) and in pts with underlying “prerenal” disorders, such as congestive heart failure (CHF) or cirrhosis or hepatorenal syndrome. The prerenal urine sediment is usually normal or has hyaline and granular casts, whereas the sediment of ATN usually is filled with cellular debris, tubular epithelial casts, and dark (muddy brown) granular casts. The measurement of urinary biomarkers associated with tubular injury is a promising technique to detect subclinical ATN and/or help further diagnose the exact cause of acute renal failure.
POSTRENAL AZOTEMIA Urinary tract obstruction accounts for <5% of cases of acute renal failure but is usually reversible and must be ruled out early in the evaluation (Fig. 48-1). Since a single kidney is capable of adequate clearance, complete obstructive acute renal failure requires obstruction at the urethra or bladder outlet, bilateral ureteral obstruction, or unilateral obstruction in a patient with a single functioning kidney. Obstruction is usually diagnosed by the presence of ureteral and renal pelvic dilation on renal ultrasound. However, early in the course of obstruction or if the ureters are unable to dilate (e.g., encasement by pelvic or periureteral tumors or by retroperitoneal fibrosis), the ultrasound examination may be negative. Other imaging, such as a furosemide renogram (MAG3 nuclear medicine study), may be required to better define the presence or absence of obstructive uropathy. The specific urologic conditions that cause obstruction are discussed in Chap. 313.
INTRINSIC RENAL DISEASE When prerenal and postrenal azotemia have been excluded as etiologies of renal failure, an intrinsic parenchymal renal disease is present. Intrinsic renal disease can arise from processes involving large renal vessels, intrarenal microvasculature and glomeruli, or the tubulointerstitium. Ischemic and toxic ATN account for ~90% of cases of acute intrinsic renal failure. As outlined in Fig. 48-1, the clinical setting and urinalysis are helpful in separating the possible etiologies. Prerenal azotemia and ATN are part of a spectrum of renal hypoperfusion; evidence of structural tubule injury is present in ATN, whereas prompt reversibility occurs with prerenal azotemia upon restoration of adequate renal perfusion. Thus, ATN often can be distinguished from prerenal azotemia by urinalysis and urine electrolyte composition (Table 48-2 and Fig. 48-1). Ischemic ATN is observed most frequently in patients who have undergone major surgery, trauma, severe hypovolemia, overwhelming sepsis, or extensive burns. Nephrotoxic ATN complicates the administration of many common medications, usually by inducing a combination of intrarenal vasoconstriction, direct tubule toxicity, and/or tubular obstruction. The kidney is vulnerable to toxic injury by virtue of its rich blood supply (25% of cardiac output) and its ability to concentrate and metabolize toxins. A diligent search for hypotension and nephrotoxins usually uncovers the specific etiology of ATN. Discontinuation of nephrotoxins and stabilization of blood pressure often suffice without the need for dialysis, with ongoing regeneration of tubular cells. An extensive list of potential drugs and toxins implicated in ATN is found in Chap. 304.
Processes involving the tubules and interstitium can lead to acute kidney injury (AKI), a subtype of acute renal failure. These processes include drug-induced interstitial nephritis (especially by antibiotics, NSAIDs, and diuretics), severe infections (both bacterial and viral), systemic diseases (e.g., systemic lupus erythematosus), and systemic disorders (e.g., sarcoidosis, Sjögren’s syndrome, lymphoma, or leukemia). A list of drugs associated with allergic interstitial nephritis is found in Chap. 310. Urinalysis usually shows mild to moderate proteinuria, hematuria, and pyuria (~75% of cases) and occasionally WBC casts. The finding of RBC casts in interstitial nephritis has been reported but should prompt a search for glomerular diseases (Fig. 48-1). Occasionally, renal biopsy will be needed to distinguish among these possibilities. The classic sediment finding in allergic interstitial nephritis is a predominance (>10%) of urinary eosinophils with Wright’s or Hansel’s stain; however, urinary eosinophils can be increased in several other causes of AKI, such that measurement of urine eosinophils has no diagnostic utility in renal disease.
Occlusion of large renal vessels, including arteries and veins, is an uncommon cause of acute renal failure. A significant reduction in GFR by this mechanism suggests bilateral processes or, in a patient with a single functioning kidney, a unilateral process. In patients with preexisting renal artery stenosis, a substantial renal collateral circulation can develop over time and sustain renal perfusion—typically not enough to sustain glomerular filtration—in the event of total renal artery occlusion. Renal arteries can be occluded with atheroemboli, thromboemboli, in situ thrombosis, aortic dissection, or vasculitis. Atheroembolic renal failure can occur spontaneously but most often is associated with recent aortic instrumentation. The emboli are cholesterol-rich and lodge in medium and small renal arteries, with a consequent eosinophil-rich inflammatory reaction. Patients with atheroembolic acute renal failure often have a normal urinalysis, but the urine may contain eosinophils and casts. The diagnosis can be confirmed by renal biopsy, but this procedure is often unnecessary when other stigmata of atheroemboli are present (livedo reticularis, distal peripheral infarcts, eosinophilia). Renal artery thrombosis may lead to mild proteinuria and hematuria, whereas renal vein thrombosis typically occurs in the context of heavy proteinuria and hematuria. These vascular complications often require angiography for confirmation and are discussed in Chap. 311.
Diseases of the glomeruli (glomerulonephritis and vasculitis) and the renal microvasculature (hemolytic-uremic syndromes, thrombotic thrombocytopenic purpura, and malignant hypertension) usually present with various combinations of glomerular injury: proteinuria, hematuria, reduced GFR, and alterations of sodium excretion that lead to hypertension, edema, and circulatory congestion (acute nephritic syndrome). These findings may occur as primary renal diseases or as renal manifestations of systemic diseases. The clinical setting and other laboratory data help distinguish primary renal diseases from systemic diseases. The finding of RBC casts in the urine is an indication for early renal biopsy (Fig. 48-1), as the pathologic pattern has important implications for diagnosis, prognosis, and treatment. Hematuria without RBC casts can also be an indication of glomerular disease, since RBC casts are highly specific but very insensitive for glomerulonephritis. The specificity of urine microscopy can be enhanced by examining urine with a phase contrast microscope capable of detecting dysmorphic red cells (“acanthocytes”) that are associated with glomerular disease. This evaluation is summarized in Fig. 48-2. A detailed discussion of glomerulonephritis and diseases of the microvasculature is found in Chap. 310.
OLIGURIA AND ANURIA Oliguria refers to a 24-h urine output <400 mL, and anuria is the complete absence of urine formation (<100 mL). Anuria can be caused by complete bilateral urinary tract obstruction; a vascular catastrophe (dissection or arterial occlusion); renal vein thrombosis; acute cast nephropathy in myeloma; renal cortical necrosis; severe ATN; combined therapy with nonsteroidal anti-inflammatory drugs, ACE inhibitors, and/or ARBs; and hypovolemic, cardiogenic, or septic shock. Oliguria is never normal, since at least 400 mL of maximally concentrated urine must be produced to excrete the obligate daily osmolar load. Nonoliguria refers to urine output >400 mL/d in patients with acute or chronic azotemia. With nonoliguric ATN, disturbances of potassium and hydrogen balance are less severe than in oliguric patients, and recovery to normal renal function is usually more rapid.