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, 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. (See images below and Image 1.)
Photomicrograph of a renal biopsy specimen shows renal medulla, which is composed mainly of renal tubules. Patchy or diffuse denudation of the renal tubular cells is observed, suggesting acute tubular necrosis as the cause of acute renal failure.
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.
Table: RIFLE Classification System for Acute Kidney Injury
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Table
| Stage | GFR** Criteria | Urine Output Criteria | Probability |
| Risk | SCreat† increased × 1.5 or GFR decreased >25% | UO‡ <0.5 mL/kg/h × 6 h | High sensitivity (Risk >Injury >Failure) |
| Injury | SCreat increased × 2 or GFR decreased >50% | UO <0.5 mL/kg/h × 12 h | |
| Failure | SCreat increased × 3 or GFR decreased 75% or SCreat ≥4 mg/dL; acute rise ≥0.5 mg/dL | UO <0.3 mL/kg/h × 24 h (oliguria) or anuria × 12 h | |
| Loss | Persistent acute renal failure: complete loss of kidney function >4 wk | High specificity | |
| ESKD* | Complete loss of kidney function >3 mo | ||
| Stage | GFR** Criteria | Urine Output Criteria | Probability |
| Risk | SCreat† increased × 1.5 or GFR decreased >25% | UO‡ <0.5 mL/kg/h × 6 h | High sensitivity (Risk >Injury >Failure) |
| Injury | SCreat increased × 2 or GFR decreased >50% | UO <0.5 mL/kg/h × 12 h | |
| Failure | SCreat increased × 3 or GFR decreased 75% or SCreat ≥4 mg/dL; acute rise ≥0.5 mg/dL | UO <0.3 mL/kg/h × 24 h (oliguria) or anuria × 12 h | |
| Loss | Persistent acute renal failure: complete loss of kidney function >4 wk | High specificity | |
| ESKD* | Complete loss of kidney function >3 mo | ||
*ESKD—end-stage kidney disease; **GFR—glomerular filtration rate; †SCreat—serum creatinine; ‡UO—urine output
Note: Patients can be classified by GFR criteria and/or UO criteria. The criteria that support the most severe classification should be used. The superimposition of acute on chronic failure is indicated with the designation RIFLE-F C ; failure is present in such cases even if the increase in SCreat is less than 3-fold, provided that the new SCreat is greater than 4.0 mg/dL (350 μ mol/L) and results from an acute increase of at least 0.5 mg/dL (44 μ mol/L).
When the failure classification is achieved by UO criteria, the designation of RIFLE-F O is used to denote oliguria. The initial stage, risk, has high sensitivity; more patients will be classified in this mild category, including some who do not actually have renal failure. Progression through the increasingly severe stages of RIFLE is marked by decreasing sensitivity and increasing specificity.
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.
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. (See images below and Images 2-4.)
Flattening of the renal tubular cells due to tubular dilation.
Intratubular cast formation.
Intratubular obstruction due to the denuded epithelium and cellular debris. Note that the denuded tubular epithelial cells clump together because of rearrangement of intercellular adhesion molecules.
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)
More on Acute Renal Failure |
 Overview: Acute Renal Failure |
| Differential Diagnoses & Workup: Acute Renal Failure |
| Treatment & Medication: Acute Renal Failure |
| Follow-up: Acute Renal Failure |
| Multimedia: Acute Renal Failure |
| References |
| Further Reading |
| Next Page » |
References
Bellomo R, Ronco C, Kellum JA, Mehta RL, Palevsky P. Acute renal failure - definition, outcome measures, animal models, fluid therapy and information technology needs: the Second International Consensus Conference of the Acute Dialysis Quality Initiative (ADQI) Group. Crit Care. Aug 2004;8(4):R204-12. [Medline]. [Full Text].
[Best Evidence] Kheterpal S, Tremper KK, Heung M, Rosenberg AL, Englesbe M, Shanks AM, et al. Development and validation of an acute kidney injury risk index for patients undergoing general surgery: results from a national data set. Anesthesiology. Mar 2009;110(3):505-15. [Medline].
Goldberg R, Dennen P. Long-term outcomes of acute kidney injury. Adv Chronic Kidney Dis. Jul 2008;15(3):297-307. [Medline].
Feest TG, Mistry CD, Grimes DS, Mallick NP. Incidence of advanced chronic renal failure and the need for end stage renal replacement treatment. BMJ. Oct 20 1990;301(6757):897-900. [Medline]. [Full Text].
American College of Radiology. ACR Appropriateness Criteria® renal failure. National Guideline Clearinghouse. Available at http://www.guideline.gov/summary/summary.aspx?doc_id=8283&nbr=004615. Accessed May 20, 2009.
[Best Evidence] Ho KM, Morgan DJ. Meta-analysis of N-acetylcysteine to prevent acute renal failure after major surgery. Am J Kidney Dis. Jan 2009;53(1):33-40. [Medline].
[Best Evidence] Zacharias M, Conlon NP, Herbison GP, Sivalingam P, Walker RJ, Hovhannisyan K. Interventions for protecting renal function in the perioperative period. Cochrane Database Syst Rev. Oct 8 2008;CD003590. [Medline].
Agraharkar M, Safirstein RL. Pathophysiology of acute renal failure. In: Greenberg A, Coffman T, eds. Primer on Kidney Diseases. 3rd ed. San Diego, Calif: Academic Press; 2001:243-86.
Chertow GM, Christiansen CL, Cleary PD, et al. Prognostic stratification in critically ill patients with acute renal failure requiring dialysis. Arch Intern Med. Jul 24 1995;155(14):1505-11. [Medline].
Donohoe JF, Venkatachalam MA, Bernard DB, Levinsky NG. Tubular leakage and obstruction after renal ischemia: structural-functional correlations. Kidney Int. Mar 1978;13(3):208-22. [Medline].
[Best Evidence] Marenzi G, Assanelli E, Marana I, et al. N-acetylcysteine and contrast-induced nephropathy in primary angioplasty. N Engl J Med. Jun 29 2006;354(26):2773-82. [Medline].
Merten GJ, Burgess WP, Gray LV, et al. Prevention of contrast-induced nephropathy with sodium bicarbonate: a randomized controlled trial. JAMA. May 19 2004;291(19):2328-34. [Medline].
Mitch WE, Klahr S. Handbook of Nutrition and the Kidney. 4th ed. Philadelphia: Lippincott Williams & Wilkins.
Safirstein R, Bonventre JV. Molecular response to ischemic and nephrotoxic acute renal failure. In: Schlondorff D, Bonventre JV, eds. Molecular Nephrology. New York: Marcel Dekker; 1995:839-54.
Schrier RW, Wang W, Poole B, Mitra A. Acute renal failure: definitions, diagnosis, pathogenesis, and therapy. J Clin Invest. 114(1):5-14. [Medline].
Solomon R, Werner C, Mann D, et al. Effects of saline, mannitol, and furosemide to prevent acute decreases in renal function induced by radiocontrast agents. N Engl J Med. Nov 24 1994;331(21):1416-20. [Medline].
Thadhani R, Pascual M, Bonventre JV. Acute renal failure. N Engl J Med. May 30 1996;334(22):1448-60. [Medline].
Tonelli M, Manns B, Feller-Kopman D. Acute renal failure in the intensive care unit: a systematic review of the impact of dialytic modality on mortality and renal recovery. Am J Kidney Dis. Nov 2002;40(5):875-85. [Medline].
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Further Reading
Related eMedicine topics:
Acute Tubular Necrosis [Nephrology]
Acute Tubular Necrosis [Pediatrics: General Medicine]
Glomerulonephritis, Acute [Emergency Medicine]
Glomerulonephritis, Acute [Nephrology]
Glomerulonephritis, Rapidly Progressive
Hemolytic Uremic Syndrome [Emergency Medicine]
Hemolytic-Uremic Syndrome [Hematology]
Hemolytic Uremic Syndrome [Neurology]
Hemolytic-Uremic Syndrome [Pediatrics: General Medicine]
Renal Cortical Necrosis
Renal Failure, Acute
Clinical guidelines:
ACR Appropriateness Criteria® renal failure. American College of Radiology - Medical Specialty Society. 1995 (revised 2005). 8 pages. [NGC Update Pending] NGC:004615
Clinical practice guidelines for managing dyslipidemias in chronic kidney disease. National Kidney Foundation - Disease Specific Society. 2003 Apr. 91 pages. NGC:003133
Clinical trials:
A Dose Escalation and Safety Study of I5NP to Prevent AKI in Patients Undergoing Major Cardiovascular Surgery (QRK.002)
Cystatin C as a Marker for Detecting Early Renal Dysfunction in a Pediatric Emergency Department (CARING)
Phase I Study of Alpha-Melanocyte Stimulating Hormone in Patients With Acute Renal Failure
The Use of Nesiritide in Thoracic Aneurysm Repair to Prevent Acute Renal Failure
Use of Bicarbonate to Reduce the Incidence of Acute Renal Failure After Cardiac Surgery
Keywords
acute renal failure, kidney disease, renal failure, kidney failure, renal disease, acute renal, glomerulonephritis, dialysis renal, oliguria, anuria, hypotension, acute kidney failure, acute tubular necrosis, chronic renal failure, tumor lysis syndrome, ethylene glycol poisoning, vasculitis, intrinsic renal failure, interstitial renal disease, renal dysfunction, renal artery occlusion, urethral stricture, bladder outlet obstruction, prostate enlargement, interstitial nephritis, renovascular disease, bladder cancer, epigastric bruit, diabetic ketoacidosis, pancreatitis, hypercalcemia, prostaglandin inhibition, ischemic tubular necrosis, crescentic glomerulonephritis, postinfective glomerulonephritis, lupus nephritis, hepatitis, vasculitis-associated glomerulonephritides, prostatic hypertrophy
