ACUTE KIDNEY INJURY

KARUNAN PRAKASHAN KANNAMPOYILIL

RIFLE Until recently, a systematic definition of acute renal failure (ARF) was lacking, which led to significant confusion both clinically and in the medical literature.
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In 2004, the Acute Dialysis Quality Initiative

In 2004, the Acute Dialysis Quality Initiative (ADQI) group published the RIFLE classification of ARF, based on changes from the patient's baseline either in serum creatinine level or glomerular filtration rate (GFR) or urine output (UO). Acute kidney injury is generally defined as 'an abrupt and sustained decrease in kidney function'.
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RIFLE
Risk (R) - Increase in SCR level X 1.5 or decrease in GFR by 25%, or UO <0.5 mL/kg/h for 6 hours Injury (I) - Increase in SCR level X 2.0 or decrease in GFR by 50%, or UO <0.5 mL/kg/h for 12 hours Failure (F) - Increase in SCR level X 3.0, decrease in GFR by 75%, or serum creatinine level >4 mg/dL with acute increase of >0.5 mg/dL; UO <0.3 mL/kg/h for 24 hours, or anuria for 12 hours

Loss (L) - Persistent ARF, complete loss of kidney function >4 weeks End-stage kidney disease (E) - Loss of kidney function >3 months
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Pathophysiology
The driving force for glomerular filtration is the pressure gradient from the glomerulus to the Bowman space. Glomerular pressure is primarily dependent on renal blood flow (RBF) and is controlled by combined resistances of renal afferent and efferent arterioles. Regardless of the cause of acute renal failure (ARF), reductions in RBF represent a common pathologic pathway for decreasing GFR..
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The etiology of ARF comprises 3 main mechanisms

Prerenal,Intrinsic ,Postobstructive
PRARF defined by conditions with GFR is depressed by compromised renal perfusion. normal tubular and glomerular function; IRF includes diseases of the kidney itself, predominantly affecting the glomerulus or tubule, which are associated with release of renal afferent vasoconstrictors. IR injury is the most common cause of IRF. PORF initially causes an increase in tubular pressure, This pressure gradient soon equalizes, and maintenance of a depressed GFR is then dependent upon renal efferent vasoconstriction.
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decreasing the filtration driving force.

Depressed RBF leads to ischemia and cell death.

This may happen before frank systemic hypotension is present and is referred to as
Normotensive ischemic ARF.
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The initial ischemic insult triggers a cascade of events that includes production of oxygen free radicals, cytokines and enzymes, endothelial activation and leukocyte adhesion, activation of coagulation, and initiation of apoptosis.
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These events continue to cause cell injury even after restoration of RBF.

Tubular cellular damage results in disruption of tight junctions between cells, allowing back leak of glomerular filtrate and further depressing effective GFR.
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In addition,

Dying cells slough off into the tubules, forming obstructing casts, which further decrease GFR and lead toOLIGOANURIA.
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During this period of depressed RBF, the kidneys are particularly vulnerable to further insults. This is when iatrogenic renal injury is most common. The following are common iatrogenic combinations:
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Preexisting renal disease

(elderly, diabetic patients, jaundiced patients) with radiocontrast agents, aminoglycosides, atheroembolism, or cardiovascular surgery
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contd

Angiotensin-converting enzyme (ACE) inhibitors with diuretics, small- or large-vessel renal arterial disease
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contd

Nonsteroidal antiinflammatory drugs (NSAIDs) with congestive heart failure (CHF), hypertension (HTN), or renal artery stenosis
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 Hypovolemia with aminoglycosides, amphotericin, heme pigments, or radiologic contrast agents

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Recovery from ARF is first dependent upon restoration of RBF.

Early RBF normalization predicts better prognosis for recovery of renal function. In prerenal failure, restoration of circulating blood volume is usually sufficient. Rapid relief of urinary obstruction in postrenal failure results in a prompt decrease of vasoconstriction. With intrinsic renal failure, removal of tubular toxins and initiation of therapy for glomerular diseases decreases renal afferent vasoconstriction.
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Once RBF is restored,

the remaining functional nephrons increase their filtration and eventually hypertrophy. GFR recovery is dependent upon the size of this remnant nephron pool. If the number of remaining nephrons is below some critical value, continued hyperfiltration results in progressive glomerular sclerosis, eventually leading to increased nephron loss.
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A vicious cycle ensues

continued nephron loss causes more hyperfiltration until complete renal failure results. This has been termed the hyperfiltration theory of renal failure and explains the scenario in which progressive renal failure is frequently observed after apparent recovery from ARF.
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Frequency Mortality/Morbidity
Mortality rates for ARF have changed little since the advent of dialysis at 50%. RIFLE found in 9%, 5%, and 4% of hospital admissions,2 respectively, and in approximately 17%, 12%, and 7% of critical care admissions.3,4 ARF is not a benign disease. In a recent study, a 31% mortality rate was noted in patients with ARF not requiring dialysis, compared with a mortality rate of only 8% in matched patients without ARF. 70% DR MOD with ARF 90% mortality Mortality rates are generally lower for nonoliguric ARF (>400 mL/d) than for oliguric (<400 mL/d) ARF, reflecting the fact that nonoliguric ARF is usually caused by drug-induced nephrotoxicity and interstitial nephritis, which have few other systemic complications.

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Newborns and infants

The most common cause of ARF is prerenal etiologies. Prerenal ARF
Perinatal hemorrhage - Twin-twin transfusion, complications of amniocentesis, abruptio placenta, birth trauma Neonatal hemorrhage - Severe intraventricular hemorrhage, adrenal hemorrhage Perinatal asphyxia and hyaline membrane disease (newborn respiratory distress syndrome) both may result in preferential blood shunting away from the kidneys (ie, prerenal) to central circulation. Acute tubular necrosis (ATN) can occur in the setting of perinatal asphyxia. ATN also has been observed secondary to medications (eg, aminoglycosides, NSAIDs) given to the mother perinatally. ACE inhibitors can traverse placenta, resulting in a hemodynamically mediated form of ARF. Acute glomerulonephritis is rare and most commonly the result of maternal-fetal transfer of antibodies against the neonate's glomeruli or transfer of chronic infections (syphilis, cytomegalovirus) associated with acute glomerulonephritis.

Intrinsic ARF

Postrenal ARF: Congenital malformations of urinary collecting systems should be suspected.

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Children

The most common cause of ARF is prerenal etiologies. Prerenal ARF

The most common cause of hypovolemia in children is gastroenteritis. Congenital and acquired heart diseases are also important causes of decreased renal perfusion in this age group. Hemolytic uremic syndrome (HUS) often is cited as the most common cause of ARF in children. The most common form of the disease is associated with a diarrheal prodrome caused by Escherichia coli O157:H7. These children usually present with microangiopathic anemia, thrombocytopenia, colitis, mental status changes, and renal failure. Acute poststreptococcal glomerulonephritis should be considered in any child who presents with HTN, edema, hematuria, and renal failure.
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Intrinsic ARF

Adults
Acute renal failure (ARF) has a long differential diagnosis. History can help classify the pathophysiology of ARF as prerenal, intrinsic renal, or postrenal failure, and it may suggest some specific etiologies. Prerenal failure
Please remember that postobstructive ARF in elderly patients should never be overlooked in the ED.

Patients commonly present with symptoms related to hypovolemia, including thirst, decreased urine output, dizziness, and orthostatic hypotension. Elders with vague mental status change are commonly found to have prerenal or normotensive ischemic ARF. Ask about volume loss from vomiting, diarrhea, sweating, polyuria, or hemorrhage. Patients with advanced cardiac failure leading to depressed renal perfusion may present with orthopnea and paroxysmal nocturnal dyspnea. Insensible fluid losses can result in severe hypovolemia in patients with restricted fluid access and should be suspected in elderly patients and in comatose or sedated patients.
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Intrinsic renal failure

Patients can be divided into those with glomerular etiologies and those with tubular etiologies of ARF.
Glomerular diseases: Nephritic syndrome of hematuria, edema, and HTN indicates a glomerular etiology of ARF. Query about prior throat or skin infections. Tubular diseases: ATN should be suspected in any patient presenting after a period of hypotension secondary to cardiac arrest, hemorrhage, sepsis, drug overdose, or surgery.

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contd
A careful search for exposure to nephrotoxins should include a detailed list of all current medications and any recent radiologic examinations (ie, exposure to radiologic contrast agents). Pigment-induced ARF should be suspected in patients with possible rhabdomyolysis (muscular pain, recent coma, seizure, intoxication, excessive exercise, limb ischemia) or hemolysis (recent blood transfusion). Allergic interstitial nephritis should be suspected with fevers, rash, arthralgias, and exposure to certain medications including NSAIDs and antibiotics.
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Postrenal failure
Postrenal failure usually occurs in older men with prostatic obstruction and symptoms of urgency, frequency, and hesitancy. Patients may present with asymptomatic high-grade urinary obstruction because of chronicity of their symptoms.
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contd
History of prior gynecologic surgery or abdominopelvic malignancy often can be helpful in providing clues to the level of obstruction. Flank pain and hematuria should raise a concern about renal calculi or papillary necrosis as the source of urinary obstruction. Use of acyclovir, methotrexate, triamterene, indinavir, or sulfonamides implies the possibility of tubular obstruction by crystals of these medications.
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Physical

Hypotension and tachycardia are obvious clues to decreased renal perfusion. Evaluation for hypovolemia should include evaluations for orthostatic hypotension, mucosal membrane moisture, and tissue turgor.

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contd
Acute fluid overload may lead to compromise of a patient's ability to oxygenate and ventilate. Patients also may present hypovolemic, with increased risk for iatrogenic complications of their renal failure. Physical examination should include a search for the following signs:
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system
Skin
Livido reticularis, digital ischemia, butterfly rash, palpable purpura Systemic vasculitis Maculopapular rash - Allergic interstitial nephritis Track marks (ie, intravenous drug abuse) - Endocarditis Keratitis, iritis, uveitis, dry conjunctivae - Autoimmune vasculitis Jaundice - Liver diseases Band keratopathy (ie, hypercalcemia) - Multiple myeloma Signs of diabetes mellitus Signs of hypertension Atheroemboli (retinopathy)

Eyes

Ears

Hearing loss -Alport disease and aminoglycoside toxicity Mucosal or cartilage ulcerations -Wegener granulomatosis

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Cardiac PulmonaryAbdomen
Irregular rhythms (ie, atrial fibrillation) - Thromboemboli Murmurs - Endocarditis Increased jugulovenous distention, rales, S3 - Congestive heart failure (CHF) Rales -Goodpasture syndrome, Wegener granulomatosis Hemoptysis - Wegener granulomatosis Pulsatile mass or bruit - Atheroemboli Costovertebral angle tenderness - Nephrolithiasis, papillary necrosis Pelvic, rectal masses; prostatic hypertrophy; distended bladder Urinary obstruction Limb ischemia, edema - Rhabdomyolysis
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Pulmonary Abdomen

Urine output:
Changes in urine output generally are poorly correlated with changes in GFR. Approximately 50-60% of all causes of ARF are nonoliguric. However, categories of anuria, oliguria, and nonoliguria may be useful in differential diagnosis of ARF.

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 Anuria (<100 mL/d) - Urinary tract obstruction, renal artery obstruction, rapidly progressive glomerulonephritis, bilateral diffuse renal cortical necrosis Oliguria (100-400 mL/d) - Prerenal failure, hepatorenal syndrome Nonoliguria (>400 mL/d) - Acute interstitial nephritis, acute glomerulonephritis, partial obstructive nephropathy, nephrotoxic and ischemic ATN, radiocontrast-induced ARF, and rhabdomyolysis
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Prerenal failure - Diseases that compromise renal perfusion

Decreased effective arterial blood volume Hypovolemia, CHF, liver failure, sepsis Renal arterial disease - Renal arterial stenosis (atherosclerotic, fibromuscular dysplasia), embolic disease (septic, cholesterol)

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Intrinsic renal failure - Diseases of the renal parenchyma, specifically involving the renal tubules, glomeruli, interstitium

ATN, ischemia, toxins (eg, aminoglycosides, radiocontrast, heme pigments, cisplatin, myeloma light chains, ethylene glycol) Interstitial diseases - Acute interstitial nephritis, drug reactions, autoimmune diseases (eg, systemic lupus erythematosus [SLE]), infiltrative disease (sarcoidosis, lymphoma), infectious agents (Legionnaire disease, hantavirus) Acute glomerulonephritis Vascular diseases - Hypertensive crisis, polyarteritis nodosa, vasculitis
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Postrenal failure Diseases causing urinary obstruction

from the level of the renal tubules to the urethra

-Tubular obstruction from crystals (eg, uric acid, calcium oxalate, acyclovir, sulfonamide, methotrexate, myeloma light chains)
Ureteral obstruction - Retroperitoneal tumor, retroperitoneal fibrosis (methysergide, propranolol, hydralazine), urolithiasis, papillary necrosis Urethral obstruction - Benign prostatic hypertrophy; prostate, cervical, bladder, colorectal carcinoma; bladder hematoma; bladder stone; obstructed Foley catheter; neurogenic bladder; stricture
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Differential Diagnoses
Alcoholic Ketoacidosis Metabolic Acidosis Anemia, Sickle Cell Pediatrics, Dehydration Aneurysm, Abdominal Pediatrics, Diabetic Ketoacidosis Congestive Heart Failure and Pulmonary Edema Pediatrics, Inborn Errors of Metabolism Diabetic Ketoacidosis Pediatrics, Sickle Cell Disease
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DD
Glomerulonephritis, Acute Pediatrics, Urinary Tract Infections and Pyelonephritis Hemolytic Uremic Syndrome Renal Calculi Henoch-Schonlein Purpura Renal Failure, Chronic and Dialysis Complications Hyperkalemia Toxicity, Alcohols Hypermagnesemia Urinary Obstruction Hypernatremia Urinary Tract Infection, Female Hypertensive Emergencies Urinary Tract Infection, Male
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inv
Urinalysis: Microscopic examination of urine is essential in establishing differential diagnosis for acute renal failure (ARF).
Normal urinary sediment without hemoglobin, protein, cells, or casts generally consistent with prerenal and postrenal failure, HUS/thrombotic thrombocytopenic purpura (TTP), preglomerular vasculitis, or atheroembolism Granular casts - ATN, glomerulonephritis, interstitial nephritis RBC casts - Glomerulonephritis, malignant HTN WBC casts - Pyelonephritis Eosinophiluria - Acute allergic interstitial nephritis, atheroembolism Crystalluria - Acyclovir, sulfonamides, methotrexate, ethylene glycol toxicity, radiocontrast agents (Mild crystalluria can be a normal finding.)

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BUN: The urea concentration correlates poorly with the GFR. Because urea is highly permeable to renal tubules, urea clearance varies with urine flow rate.

Urea is filtered freely, but reabsorption along the tubule is a function of urine flow rate. During antidiuresis with urine flow rates less than 30 mL/h, urea clearance is as low as an estimated 30% of GFR. Under conditions of diuresis, with urine outputs greater than 100 mL/h, urea clearance can increase to 70-100% of GFR.

BUN concentration is dependent on nitrogen balance and renal function.

This information can be used clinically to help differentiate prerenal failure from other etiologies of ARF. In prerenal conditions, low urine flow rates favor BUN reabsorption out of proportion to decreases in GFR, resulting in a disproportionate rise of BUN relative to creatinine, creating a serum BUN-creatinine ratio >20 in prerenal failure. BUN concentration can rise significantly with no decrement in GFR by increases in urea production with steroids, trauma, or GI bleeding. Tetracycline increases BUN by decreasing tissue anabolic rates. Basal BUN concentration can be depressed severely by malnutrition or advanced liver disease. Always first estimate basal BUN concentration when attempting to correlate changes in BUN with GFR. For example, in a patient with cirrhosis and a BUN of 12 mg/dL, a GFR in the normal range may be assumed. Only with the knowledge of a baseline BUN of 4 mg/dL does the real decrease in GFR become apparent.

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 Creatinine: Serum creatinine measurement provides the ED physician with an accurate and consistent estimation of GFR. Correct interpretation of serum creatinine measurement extends beyond just knowing normal values for the specific laboratory.
Creatinine measuring methods
Serum creatinine level varies by method of measurement, either Jaffe or iminohydrolase. Upper limit of normal creatinine level can be 1.6-1.9 mg/dL or 1.2-1.4 mg/dL, respectively. This becomes important when patients present with changes in creatinine measured in different laboratories. Differing methods report markedly different results when interfacing with certain chemicals. Jaffe method of measuring creatinine reports falsely elevated serum creatinine in the presence of the following noncreatinine chromogens: glucose, fructose, uric acid, acetone, acetoacetate, protein, ascorbic acid, pyruvate, cephalosporin antibiotics. High levels of bilirubin cause reports of falsely low creatinine by the Jaffe method. Extremely high glucose levels and the antifungal agent flucytosine interfere with the iminohydrolase method.
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 Serum creatinine level is a reflection of creatinine clearance.

Serum creatinine level is a function of its production and excretion rates. Creatinine production is determined by muscle mass. Serum creatinine level must always be interpreted with respect to patient's weight, age, and sex. The GFR can be estimated by the following formulas: The ADQI consensus committee on ARF favors the Modification of Diet in Renal Disease (MDRD) equation to estimate GFR. Cockcroft-Gault equation: GFR mL/min = (140 - Age y)(Weight kg)(0.85 if female)/(72 X Serum Creatinine mol/L MDRD equation: GFR, in mL/min per 1.73 mm2 = 186.3 X ((Serum Creatinine) exp[-1.154]) X (Age exp[-0.203]) X (0.742 if female) X (1.21 if African American For example, GFR decreases by 1% per year after age 40 years, yet serum creatinine level generally remains stable. Balance is achieved via a decrease in muscle mass with age, which matches the fall in GF Men generally have a higher muscle mass per kilogram of body weight and thus a higher serum creatinine level than women.

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 An important consideration and limitation is that significant decrements in GFR can occur while creatinine levels remain in the normal range. Changes in serum creatinine level reflect changes in GFR. Rate of change in serum creatinine level is an important variable in estimating GFR. Stable changes in serum creatinine level correlate with changes in GFR by the following relationships:

If creatinine 1 mg/dL is baseline for a given patient with normal GFR Creatinine 2 mg/dL - 50% reduction in GFR Creatinine 4 mg/dL - 7085% reduction in GFR Creatinine 8 mg/dL - 9095% reduction in GFR As suggested by these data, knowledge of a patient's baseline creatinine level becomes very important. Small changes with low baseline levels of creatinine may be much more important clinically than large changes with high basal creatinine. Certain diseases and medications can interfere with the correlation of serum creatinine with GFR. Acute glomerulonephritis causes increased tubular secretion of creatinine, falsely depressing the rise in serum creatinine level when ARF occurs in acute glomerulonephritis. Trimethoprim and cimetidine cause decreased creatinine secretion and a falsely elevated creatinine with no change in GFR.

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Cystatin C is emerging as a superior biomarker for early kidney injury.

It is generated at a constant rate by all nucleated cells and is not secreted by the tubules or eliminated by other routes than renal excretion. It does not appear to be affected by body habitus, nutritional state, or comorbid illness. One of its principal advantages is that it identifies kidney injury while creatinine levels remain in the normal range.

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Complete blood cell count

Leukocytosis is common in ARF. Leukopenia and thrombocytopenia suggest SLE or TTP. Anemia and rouleaux formation suggest multiple myeloma. Microangiopathic anemia suggests DIC, TTP, or atheroemboli. Eosinophilia suggests allergic interstitial nephritis, polyarteritis nodosa, or atheroemboli. Coagulation disturbances indicate liver disease, DIC, TTP, or hepatorenal syndrome.
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Blood chemistry
Creatine phosphokinase (CPK) elevations are seen in rhabdomyolysis and myocardial infarction. Elevations in liver transaminase levels are seen in rapidly progressive liver failure and hepatorenal syndrome. Hypocalcemia (moderate) is common in ARF; marked hypocalcemia is more typical of chronic renal failure. Hyperkalemia is a common and important complication of ARF.
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Urine chemical indices

Differentiation of prerenal azotemia from ATN takes on a special importance in early management of these patients. Aggressive fluid resuscitation is appropriate in prerenal ARF. However, overly aggressive volume resuscitation in a patient with ATN who is unable to excrete the extra fluid can result in volume overload and respiratory embarrassment. To help with the differentiation of prerenal azotemia, analysis of urine may provide important clues. Diuretics interfere with some of these indices, so collect urine prior to any considered administration of diuretics. Urine indices that suggest prerenal ARF include the following:
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 Urine specific gravity >1.018 Urine osmolality (mOsm/kg H2 O) >500 Urine sodium (mEq/L) <15-20 Plasma BUN-creatinine ratio >20 Urine-plasma creatinine ratio >40

Urine indices that suggest ATN include the following:

Urine specific gravity <1.012 Urine osmolality (mOsm/kg H2 O) <500 Urine sodium (mEq/L) >40 Plasma BUN/creatinine ratio <10-15 Urine-plasma creatinine ratio <20
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inv
Calculation of fractional excretion of sodium (FeNa)
FeNa = (urine Na/plasma Na)/(urine creatinine/plasma creatinine) FeNa <1% suggests prerenal ARF FeNa >1% suggests ATN

Advantages of FeNa compared to other indices

Physiologic measure of sodium reabsorption Measured creatinine and sodium clearances, accounting for filtration and reabsorption of sodium FeNa increased before oliguric phase established and predictive of incipient ARF
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inv
Exceptions (intrinsic renal failure with FeNa <1%)
Acute glomerulonephritis Hepatorenal syndrome Radiologic contrastinduced ATN Myoglobinuric and hemoglobinuric ARF Renal allograft rejection Drug-related alterations in renal hemodynamics (eg, captopril, NSAIDs)
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Imaging studies in acute renal failure (ARF) are most important in the emergent workup of suspected postrenal azotemia. Please refer to Urinary Obstruction for a complete discussion of available imaging studies for this cause of ARF. Renal ultrasonography
Renal ultrasonography is the test of choice for urologic imaging in the setting of acute renal failure.6 It has excellent sensitivity and specificity for detecting hydronephrosis due to obstruction, and it can also give valuable information other than ruling obstruction in or out. Bipolar renal length is easy to assess, and kidneys smaller than 9 cm suggest chronic renal failure. Renal parenchyma should be isoechogenic or hypoechogenic when compared with that of the liver and spleen; hyperechogenicity indicates diffuse parenchymal disease. Color Doppler allows assessment of renal perfusion and can allow diagnosis of large-vessel etiologies of ARF. In critically ill patients, bedside sonography warrants special consideration as it can quickly diagnose treatable etiologies of the patients condition and give guidance for fluid resuscitation.

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 Chest radiography

Other Tests

Obtain chest radiographs on a routine basis to look for evidence of volume overload. Findings of lung infiltration can lead to pulmonary/renal syndromes, such as Wegener granulomatosis and Goodpasture syndrome, or evidence of pulmonary emboli from endocarditis or atheroembolic disease.

Electrocardiography: Obtain routine ECGs to look for manifestations of hyperkalemia and arrhythmias, ischemia, and infarction.
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Procedures

Renal biopsy
Renal biopsy is often helpful in finding specific cause of intrinsic renal failure; however, it is not an ED procedure. This is reserved for evaluation of ARF when the cause cannot be determined. Renal biopsy is especially important when glomerular causes of ARF are suspected. It is often helpful in finding a specific cause of renal failure.
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Severity of illness
The APACHE III [1] and the SOFA [2] scores were calculated based on the worst variables recorded during the first 24 hours of ICU admission. The nonrenal total SOFA score was calculated from the total SOFA score minus the points for kidney insufficiency.

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Abbreviations
APACHE III = Acute Physiology and Chronic Health Evaluation, version III; class F = failure, according to the RIFLE classification; class I = injury, according to the RIFLE classification; class R = risk, according to the RIFLE classification; CrMDRD = serum creatinine based upon the MDRD equation; ICU = intensive care unit; MDRD = Modification of Diet in Renal Disease; RIFLE = Risk, Injury, Failure, Loss, and End-stage Kidney; SOFA = Sequential Organ Failure Assessment score; SOFAnonrenal = SOFA score without points for renal insufficiency.
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PHASES OF ISCHEMIC ARF

Clinical Phases Prerenal azotemia Initiation Maintenance Recovery Cellular Phases Vascular and cellular adaptation ATP depletion, cell injury Repair, migration, apoptosis, proliferation Cellular differentiation

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ISCHEMIA INDUCED PROXIMAL TUBULE CELL ALTERATIONS

Surface Membrane Alterations 1. Microvilli fusion, internalization, fragmentation and luminal shedding resulting in loss of surface membrane area and tubular obstruction 2. Loss of surface membrane polarity for lipids and proteins 3. Junctional complex dissociation with unregulated paracellular permeability (backleak) 4. Reduced PTC vectorial transport
,
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Endothelial injury
In addition, endothelial injury results in cell swelling and enhancement of expression of cell adhesion molecules. This, together with leukocyte activation, leads to enhanced leukocyteendothelial interactions, which can promote injury and swelling of the endothelial cell, physically impede blood flow, contribute to the production of local factors promoting vasoconstriction, and add to the effects of vasoconstriction on local blood flow and tubule cell metabolism .
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Disorganization of the actin cytoskeleton

Disorganization of the actin cytoskeleton has been found to be present in the arteries, arterioles, and mural cells or pericytes of vasa recta of the kidney after an ischemic insult (9). It has been proposed that this change in the cytoskeleton may play an important role in the loss of autoregulation of renal blood flow and abnormal vascular reactivity, which is a characteristic of post-ischemic ARF (9).
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Vasoconstrictors
implicated in the regulation of post-ischemic vascular tone include

angiotensin II, thromboxane A2, leukotrienes C4 and D4, endothelin1, adenosine, endothelium-derived prostaglandin H2, and sympathetic nerve stimulation.
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Cell Death
Effects on the endothelium and smooth muscle determine the duration and distribution in the kidney of the further injury that occurs during the "extension" phase and contribute to the decrease of GFR subsequently during the "maintenance" phase
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Necrosis.
The severe ATP depletion that occurs during the initiation phase and in the most poorly reperfused areas during extension disrupts cellular Na+, K+, volume, and Ca2+ homeostasis (58), causes accumulation of phospholipid metabolites (58), and produces generalized protein dephosphorylation (59) and widespread protein redistribution (4) and aggregation (60). Cell death by necrosis, as seen most prominently in the proximal tubule, is usually considered the nonspecific outcome of the chaotic, confluence of these events. However, necrotic cell death can occur as the result of ATP depletion-induced opening of a plasma membrane "death channel" well before cell injury is particularly advanced or irreversible in other respects (61). This channel is normally kept closed in ischemic tissue by the presence of high levels of tissue glycine (62) and decreased pH (58). During extension, in areas that remain severely underperfused, necrosis will occur after periods of greater than several hours despite the presence of glycine and cellular acidosis. In reperfused areas, recovery of pH (63) and washout of glycine allow opening of the death channel in cells that are unable to recover ATP as a result of non-oxidant damage to mitochondrial oxidative phosphorylation mechanisms during ischemia (64) and oxidant damage to mitochondria during reperfusion (65). Oxidant generation and protease activation play major roles in continuing damage.

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Apoptosis.
On pathologic examination of the postischemic kidney, necrotic cell death of proximal tubules is initially more prominent than apoptotic cell death for several reasons.

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Apoptosis becomes increasingly important

Expression of pro-apoptotic members of the bcl2 family including bax, bak, and bad as well as caspases (84) increases. There is also increased expression of other components of both the intrinsic (85) and extrinsic pathways (86) for apoptosis. These pro-apoptotic factors are induced in response to a number of consequences of the primary insult, including DNA damage, production of ROS, and generation of ceramide .
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Sublethal Injury
Although cell killing is a prominent feature of experimental ischemic acute renal failure, much of the injury relevant to failure of organ function, particularly as expressed in biopsy material available for human acute renal failure, remains sublethal. During the past decade, there has been substantial progress in understanding some of the mechanisms that figure most prominently in this sublethal injury. Ischemia results in rapid loss of cytoskeletal integrity and cell polarity with mislocalization of adhesion molecules and other membrane proteins such as Na+K+ATPase Increases of paracellular permeability lead to backleak of glomerular filtrate . The apical actin network is disrupted very early after ischemia. The brush border disappears with shedding and internalization of apical membrane proteins and blebbing of apical membranes
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Repair

Proximal tubules are able to undergo repair after ischemic or nephrotoxic damage. While cell death itself is not a regenerative response, epithelial cells in the process of dying may generate signals that initiate the repair response. Cytokines may play a role in determining the fate of the epithelial cells, contribute to the generation of signals that result in neutrophil and monocyte infiltration into the tissue, and promote dedifferentiation and proliferation of epithelial cells. These cytokines may derive from the kidney tissue, epithelial and mesenchymal cells, or infiltrating cells, such as macrophages, as described previously in this review.
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Biomarkers
Clinical studies designed to test therapeutic agents to prevent or treat ARF have been severely compromised by the absence of reliable markers of early disease. As a result, therapeutic intervention is delayed and there are no sensitive markers for monitoring effectiveness. Serum creatinine is used as an overall marker for renal function but increases in this parameter often lag well behind the initiating event in ARF. There is no equivalent of troponin which can be used as an early marker for ischemia in the heart. Biomarkers for renal ischemic injury could be monitored in the blood or urine.

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CrCl
1.Cockcroft and Gault equation utilizing the adjusted body weight to calculate an estimated creatinine clearance. CrCl = [(140 - age) x AjBW] -------------------------------- (Scr x 72) Note: (Multiply result by 0.85 for females) K/DOQI Clinical Practice Guidelines for Chronic Kidney Disease: Evaluation, Classification, and Stratification

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