Introduction
Background
Acute renal failure (ARF) or acute kidney injury (AKI), as it is now referred to in the literature, is defined as an abrupt or rapid decline in renal filtration function. This condition is usually marked by a rise in serum creatinine concentration or azotemia (a rise in blood urea nitrogen [BUN] concentration). However, immediately after a kidney injury, BUN or creatinine levels may be normal, and the only sign of a kidney injury may be decreased urine production. A rise in the creatinine level can result from medications (eg, cimetidine, trimethoprim) that inhibit the kidney’s tubular secretion. A rise in the BUN level can occur without renal injury, such as in GI or mucosal bleeding, steroid use, or protein loading, so a careful inventory must be taken before determining if a kidney injury is present.
Pathophysiology
AKI may occur in 3 clinical patterns, including the following: (1) as an adaptive response to severe volume depletion and hypotension, with structurally intact nephrons; (2) in response to cytotoxic, ischemic, or inflammatory insults to the kidney, with structural and functional damage; and (3) with obstruction to the passage of urine. Therefore, in general terms, AKI may be classified as prerenal, intrinsic, and postrenal. While these classifications are useful in establishing a differential diagnosis, many pathophysiologic features are shared among the different categories.
Patients who develop AKI can be oliguric or nonoliguric, have a rapid or slow rise in creatinine levels, and may have qualitative differences in urine solute concentrations and cellular content. The reason for this lack of a uniform clinical presentation is a reflection of the variable nature of the injury. Classifying AKI as oliguric or nonoliguric based on daily urine excretion has prognostic value. Oliguria is defined as a daily urine volume of less than 400 mL/d and has a worse prognosis, except in prerenal failure. Anuria is defined as a urine output of less than 100 mL/d and, if abrupt in onset, is suggestive of bilateral obstruction or catastrophic injury to both kidneys. Stratification of renal failure along these lines helps in decision-making (eg, timing of dialysis) and can be an important criterion for patient response to therapy.
Pre renal AKI
Prerenal AKI represents the most common form of kidney injury and often leads to intrinsic AKI if it is not promptly corrected. Volume loss from GI, renal, cutaneous (eg, burns), and internal or external hemorrhage can result in this syndrome. Prerenal AKI can also result from decreased renal perfusion in patients with heart failure or shock (eg, sepsis, anaphylaxis). Special classes of medications that can induce prerenal AKI in volume-depleted states are angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin receptor blockers (ARBs), which are otherwise safely tolerated and beneficial in most patients with chronic kidney disease. Arteriolar vasoconstriction leading to prerenal AKI can occur in hypercalcemic states, with the use of radiocontrast agents, nonsteroidal anti-inflammatory drugs (NSAIDs), amphotereicin, calcineurin inhibitors, norepinephrine, and other pressor agents. The hepatorenal syndrome can also be considered a form of prerenal AKI because functional renal failure develops from diffuse vasoconstriction in vessels supplying the kidney.Intrinsic AKI
Structural injury in the kidney is the hallmark of intrinsic AKI, and the most common form is acute tubular injury (ATN), either ischemic or cytotoxic. Frank necrosis is not prominent in most human cases of ATN and tends to be patchy. Less obvious injury includes loss of brush borders, flattening of the epithelium, detachment of cells, formation of intratubular casts, and dilatation of the lumen. Although these changes are observed predominantly in proximal tubules, injury to the distal nephron can also be demonstrated. The distal nephron may also be subjected to obstruction by desquamated cells and cellular debris.
In contrast to necrosis, the principal site of apoptotic cell death is the distal nephron. During the initial phase of ischemic injury, loss of integrity of the actin cytoskeleton leads to flattening of the epithelium, with loss of the brush border, loss of focal cell contacts, and subsequent disengagement of the cell from the underlying substratum.
Many endogenous growth factors that participate in the process of regeneration have not been identified; however, administration of growth factors exogenously has been shown to ameliorate and hasten recovery from AKI. Depletion of neutrophils and blockage of neutrophil adhesion reduce renal injury following ischemia, indicating that the inflammatory response is responsible, in part, for some features of ATN, especially in postischemic injury after transplant.
Intrarenal vasoconstriction is the dominant mechanism for the reduced glomerular filtration rate (GFR) in patients with ATN. The mediators of this vasoconstriction are unknown, but tubular injury seems to be an important concomitant finding. Urine backflow and intratubular obstruction (from sloughed cells and debris) are causes of reduced net ultrafiltration. The importance of this mechanism is highlighted by the improvement in renal function that follows relief of such intratubular obstruction. In addition, when obstruction is prolonged, intrarenal vasoconstriction is prominent in part due to the tubuloglomerular feedback mechanism, which is thought to be mediated by adenosine and activated when there is proximal tubular damage and the macula densa is presented with increased chloride load.
Apart from the increase in basal renal vascular tone, the stressed renal microvasculature is more sensitive to potentially vasoconstrictive drugs and otherwise-tolerated changes in systemic blood pressure. The vasculature of the injured kidney has an impaired vasodilatory response and loses its autoregulatory behavior. This latter phenomenon has important clinical relevance because the frequent reduction in systemic pressure during intermittent hemodialysis may provoke additional damage that can delay recovery from ATN. Often, injury results in atubular glomeruli, where the glomerular function is preserved, but the lack of tubular outflow precludes its function.
A physiologic hallmark of ATN is a failure to maximally dilute or concentrate urine (isosthenuria). This defect is not responsive to pharmacologic doses of vasopressin. The injured kidney fails to generate and maintain a high medullary solute gradient because the accumulation of solute in the medulla depends on normal distal nephron function. Failure to excrete concentrated urine, even in the presence of oliguria, is a helpful diagnostic clue to distinguish prerenal from intrinsic renal disease, in which urine osmolality is less than 300 mOsm/kg. In prerenal azotemia, urine osmolality is typically more than 500 mOsm/kg.Glomerulonephritis can be a cause of AKI and usually falls into a class referred to as rapidly progressive glomerulonephritis (RPGN). The pathologic correlation of RPGN is the presence of glomerular crescents (glomerular injury) on biopsy; if more than 50% of glomeruli contain crescents, this usually results in a significant decline in renal function. Although comparatively rare, acute glomerulonephritides should be part of the diagnostic consideration in cases of AKI.
Postrenal AKI
Mechanical obstruction of the urinary collecting system, including the renal pelvis, ureters, bladder, or urethra, results in obstructive uropathy or postrenal AKI.
If the site of obstruction is unilateral, then a rise in the serum creatinine level may not be apparent due to contralateral renal function. Although the serum creatinine level may remain low with unilateral obstruction, a significant loss of GFR occurs, and patients with partial obstruction may develop progressive loss of GFR if the obstruction is not relieved. Causes of obstruction include stone disease; stricture; and intraluminal, extraluminal, or intramural tumors.
Bilateral obstruction is usually a result of prostate enlargement or tumors in men and urologic or gynecologic tumors in women.
Patients who develop anuria typically have obstruction at the level of the bladder or downstream to it.
Frequency
United States
Approximately 1% of patients admitted to hospitals have AKI at the time of admission, and the estimated incidence rate of AKI is 2-5% during hospitalization. Approximately 95% of consultations with nephrologists are related to AKI. Feest and colleagues calculated in their report that the appropriate nephrologist referral rate is approximately 70 cases per million population.1
Mortality/Morbidity
The mortality rate estimates vary from 25-90%. The in-hospital mortality rate is 40-50%; in intensive care settings, the rate is 70-80%. Increments of 0.3 mg/dL in serum creatinine have important prognostic significance.
Race
No racial predilection is recognized.
Clinical
History
A detailed and accurate history is crucial to aid in diagnosing the type of AKI and in determining its subsequent treatment. A detailed history and a physical examination in combination with routine laboratory tests are useful in making a correct diagnosis (see Lab Studies).
- Distinguishing AKI from chronic renal failure is important, yet making the distinction can be difficult. A history of chronic symptoms of fatigue, weight loss, anorexia, nocturia, and pruritus all suggest chronic renal failure.
- Take note of the following findings during the physical examination:
- Hypotension
- Volume contraction
- Congestive heart failure
- Nephrotoxic drug ingestion
- History of trauma or unaccustomed exertion
- Blood loss or transfusions
- Evidence of connective tissue disorders or autoimmune diseases
- Exposure to toxic substances, such as ethyl alcohol or ethylene glycol
- Exposure to mercury vapors, lead, cadmium, or other heavy metals, which can be encountered in welders and miners
- People with the following comorbid conditions are at a higher risk for developing AKI:
- Hypertension
- Congestive cardiac failure
- Diabetes
- Multiple myeloma
- Chronic infection
- Myeloproliferative disorder
- Urine output history can be useful. Oliguria generally favors AKI. Abrupt anuria suggests an acute obstruction, acute and severe glomerulonephritis, or an embolic event due to the renal artery occlusion. A gradually diminishing urine output may indicate a urethral stricture or bladder outlet obstruction due to prostate enlargement.
- Because of a decrease in functioning nephrons, even a trivial nephrotoxic insult may cause AKI to be superimposed on chronic renal insufficiency.
Physical
Obtaining a thorough physical examination is extremely important when collecting evidence about the etiology of AKI.
- Skin
- Examination of the skin for petechiae, purpura, ecchymosis, and livedo reticularis provides clues to inflammatory and vascular causes of AK
- Infectious diseases, thrombotic thrombocytopenic purpura (TTP), disseminated intravascular coagulation (DIC), and embolic phenomena can present with typical cutaneous changes.
- Eyes
- Evidence of uveitis may indicate interstitial nephritis and necrotizing vasculitis.
- Ocular palsy may indicate ethylene glycol poisoning or necrotizing vasculitis.
- Findings suggestive of severe hypertension, atheroembolic disease, and endocarditis may be observed after a careful examination of the eyes.
- Cardiovascular system
- The most important part of the physical examination is the assessment of cardiovascular and volume status.
- The physical examination must include pulse rate and blood pressure recordings measured in both the supine position and the standing position; close inspection of the jugular venous pulse; careful examination of the heart, lungs, skin turgor, and mucous membranes; and assessment for the presence of peripheral edema.
- Accurate daily records of fluid intake and urine output and daily measurements of patient weight are important.
- Blood pressure recordings can be important diagnostic tools.
- Hypovolemia leads to hypotension; however, hypotension may not necessarily indicate hypovolemia.
- Severe congestive cardiac failure (CHF) may also cause hypotension. Although patients with CHF may have low blood pressure, volume expansion is present and effective renal perfusion is poor, which can result in AKI.
- Severe hypertension with renal failure suggests renovascular disease, glomerulonephritis, vasculitis, or atheroembolic disease.
- Abdomen
- Abdominal examination findings can be useful to help detect obstruction at the bladder outlet as the cause of renal failure, which may be due to cancer or an enlarged prostate.
- The presence of an epigastric bruit suggests renal vascular hypertension.
Causes
The causes of AKI traditionally are divided into 3 main categories: prerenal, intrinsic, and postrenal. The 3 main categories are summarized below.
- Prerenal AKI
- Volume depletion
- Renal losses (diuretics, polyuria)
- GI losses (vomiting, diarrhea)
- Cutaneous losses (burns, Stevens-Johnson syndrome)
- Hemorrhage
- Pancreatitis
- Decreased cardiac output
- Heart failure
- Pulmonary embolus
- Acute myocardial infarction
- Severe valvular disease
- Abdominal compartment syndrome (tense ascites)
- Systemic vasodilation
- Sepsis
- Anaphylaxis
- Anesthetics
- Drug overdose
- Afferent arteriolar vasoconstriction
- Hypercalcemia
- Drugs (NSAIDs, amphotericin B, calcineurin inhibitors, norepinephrine, radiocontrast agents)
- Hepatorenal syndrome
- Efferent arteriolar vasodilation – ACEI or ARB
- Intrinsic AKI
- Vascular (large and small vessel)
- Renal artery obstruction (thrombosis, emboli, dissection, vasculitis)
- Renal vein obstruction (thrombosis)
- Microangiopathy (TTP, hemolytic uremic syndrome [HUS], DIC, preeclampsia)
- Malignant hypertension
- Scleroderma renal crisis
- Transplant rejection
- Atheroembolic disease
- Glomerular
- Anti–glomerular basement membrane (GBM) disease (Goodpasture syndrome)
- Anti–neutrophil cytoplasmic antibody-associated glomerulonephritis (ANCA-associated GN) (Wegener granulomatosis, Churg-Strauss syndrome, microscopic polyangiitis)
- Immune complex GN (lupus, postinfectious, cryoglobulinemia, primary membranoproliferative glomerulonephritis)
- Tubular
- Ischemi
- Cytotoxic
- Heme pigment (rhabdomyolysis, intravascular hemolysis)
- Crystals (tumor lysis syndrome, seizures, ethylene glycol poisoning, megadose vitamin C, acyclovir, indinavir, methotrexate)
- Drugs (aminoglycosides, lithium, amphotericin B, pentamidine, cisplatin, ifosfamide, radiocontrast agents)
- Interstitial
- Drugs (penicillins, cephalosporins, NSAIDs, proton-pump inhibitors, allopurinol, rifampin, indinavir, mesalamine, sulfonamides)
- Infection (pyelonephritis, viral nephritides)
- Systemic disease (Sjogren syndrome, sarcoid, lupus, lymphoma, leukemia, tubulonephritis, uveitis)
- Postrenal AKI
- Ureteric obstruction (stone disease, tumor, fibrosis, ligation during pelvic surgery)
- Bladder neck obstruction (benign prostatic hypertrophy [BPH], cancer of the prostate [CA prostate or prostatic CA], neurogenic bladder, tricyclic antidepressants, ganglion blockers, bladder tumor, stone disease, hemorrhage/clot)
- Urethral obstruction (strictures, tumor, phimosis)
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References
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Further Reading
Keywords
ARF, kidney failure, acute tubular necrosis, ATN, chronic renal failure, tumor lysis syndrome, ethylene glycol poisoning, vasculitis, intrinsic renal failure, interstitial renal disease, renal dysfunction, oliguria, anuria, hypotension, congestive heart failure, unaccustomed exertion, blood loss, blood transfusions, connective tissue disorders, exposure to ethyl alcohol, exposure to ethylene glycol, exposure to mercury vapors, exposure to lead, exposure to cadmium, exposure to heavy metals, hypertension, diabetes, myeloma, chronic infection, myeloproliferative disorder, acute glomerulonephritis, severe glomerulonephritis, renal artery occlusion, urethral stricture, bladder outlet obstruction, prostate enlargement, interstitial nephritis, necrotizing vasculitis, ocular palsy, atheroembolic disease, endocarditis, renovascular disease, bladder cancer, epigastric bruit, prerenal ARF, Addison disease, diabetic ketoacidosis, pancreatitis, hypercalcemia, prostaglandin inhibition, cocaine use, intrarenal ARF, scleroderma, malignant hypertension, thrombotic angiopathy, ischemic tubular necrosis, chinese herb nephropathy, crescentic glomerulonephritis, postinfective glomerulonephritis, lupus nephritis, hepatitis, vasculitis-associated glomerulonephritides, postrenal ARF, prostatic hypertrophy
