Acute Renal Failure

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, resulting instead from such sources as GI or mucosal bleeding, steroid use, or protein loading, so a careful inventory must be taken before determining if a kidney injury is present.



The RIFLE system

In 2004, the Acute Dialysis Quality Initiative work group set forth a definition and classification system for acute renal failure, described by the acronym RIFLE (Risk of renal dysfunction, Injury to the kidney, Failure or Loss of kidney function, and End-stage kidney disease; see Table, below).1 Investigators have since applied the RIFLE system to the clinical evaluation of AKI, although it was not originally intended for that purpose. AKI research increasingly uses RIFLE

Pathophysiology

AKI may be classified into 3 general categories, as follows:

Prerenal—as an adaptive response to severe volume depletion and hypotension, with structurally intact nephrons
Intrinsic—in response to cytotoxic, ischemic, or inflammatory insults to the kidney, with structural and functional damage
Postrenal—from obstruction to the passage of urine.
While this classification is 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. This lack of a uniform clinical presentation reflects 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, suggests 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), amphotericin, 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. In addition, the distal nephron may become obstructed 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 in distinguishing prerenal from intrinsic renal disease; in prerenal azotemia, urine osmolality is typically more than 500 mOsm/kg, whereas in intrinsic renal disease, urine osmolality is less than 300 mOsm/kg.

Glomerulonephritis can be a cause of AKI and usually falls into a class referred to as rapidly progressive glomerulonephritis (RPGN). Glomerular crescents (glomerular injury) are found in RPGN 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. AKI develops within 30 days postoperatively in approximately 1% of general surgery cases2 ; it develops in up to 67% of intensive care unit patients.3 Approximately 95% of consultations with nephrologists are related to AKI. Feest and colleagues calculated that the appropriate nephrologist referral rate is approximately 70 cases per million population.4
Mortality/Morbidity

The mortality rate estimates for AKI 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.

On long-term followup (1-10 years), approximately 12.5% of AKI survivors are dialysis-dependent (rates range widely, from 1%-64%, depending on the patient population) and 19-31% of them have chronic kidney disease.3
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 — fatigue, weight loss, anorexia, nocturia, and pruritus — suggests 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 acute urinary obstruction, acute and severe glomerulonephritis, or embolic 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
Petechiae, purpura, ecchymosis, and livedo reticularis provide clues to inflammatory and vascular causes of AK
Infectious diseases, thrombotic thrombocytopenic purpura (TTP), disseminated intravascular coagulation (DIC), and embolic phenomena can produce 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 on 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.
In hospitalized patients, 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.
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 – ACEIs or ARBs
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
Ischemic
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 (Sj ö gren 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)