Refarat Acute Tubular Necrosis

8/4/2019 Refarat Acute Tubular Necrosis

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Furosemide may convert the oliguric ATN to a nonoliguric type, which is managed more

easily. In addition, ATN is frequently complicated by hyperphosphatemia and hypocalcemia,

which respond to calcium-containing oral phosphate binders.(7)



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THE RENAL TUBULES

The renal tubules, commencing in the renal corpuscles, present, during their course, manychanges in shape and direction, and are contained partly in the medullary and partly in the

cortical substance. At their junction with the glomerular capsule they exhibit a somewhat

constricted portion, which is termed the neck. Beyond this the tubule becomes convoluted, and

pursues a considerable course in the cortical substance constituting the proximal convoluted

tube. After a time the convolutions disappear, and the tube approaches the medullary substance

in a more or less spiral manner; this section of the tubule has been called the spiral

tube. Throughout this portion of their course the renal tubules are contained entirely in the

cortical substance, and present a fairly uniform caliber. They now enter the medullary substance,

suddenly become much smaller, quite straight in direction, and dip down for a variable depth

into the pyramids, constituting the descending limb of Henle’s loop. Bending on themselves,

they form what is termed the loop of Henle, and reascending, they become suddenly enlarged,

forming the ascending limb of Henle’s loop, and reenter the cortical substance. This portion of

the tubule ascends for a short distance, when it again becomes dilated, irregular, and angular.

This section is termed the zigzag tubule; it ends in a convoluted tube, which resembles the

proximal convoluted tubule, and is called the distal convoluted tubule. This again terminates in a

narrow junctional tube, which enters the straight or collecting tube.(1)

The straight or collecting tubes commence in the radiate part of the cortex, where they

receive the curved ends of the distal convoluted tubules. They unite at short intervals with one

another, the resulting tubes presenting a considerable increase in caliber, so that a series of

comparatively large tubes passes from the bases of the rays into the renal pyramids. In the

medulla the tubes of each pyramid converge to join a central tube (duct of Bellini) which finally

opens on the summit of one of the papilla; the contents of the tube are therefore discharged intoone of the calyces.

(1)

The renal tubules consist of a basement membrane lined with epithelium. The epithelium

varies considerably in different sections of the tubule. In the neck the epithelium is continuous

with that lining the glomerular capsule, and like it consists of flattened cells each containing an



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oval nucleus . The two convoluted tubules, the spiral and zigzag tubules and the ascending limb

of Henle’s loop, are lined by a type of epithelium which is histologically the same in all. The

cells are somewhat columnar in shape and dovetail into one another of their lateral aspect. Each

has a striated border next the lumen of the tube, its inner part is granular and its outer portion

vertically striated. The nucleus is spherical and situated about the center of the cell. In the

descending limb of Henle’s loop the epithelium resembles that found in the glomerular capsule

and the commencement of the tube, consisting of flat, clear epithelial plates, each with an oval

nucleus. The nuclei alternate on opposite surfaces of the tubule so that the lumen remains fairly

constant. In the straight tube the epithelium is clear and cubical: in its papillary portion the cells

are distinctly columnar and transparent.(1)

http://education.yahoo.com/reference/gray/illustrations/figure?id=1132






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TUBULAR FUNCTION

Water and electrolytes are freely filtered at the level of the glomerulus. Thus, the

electrolyte content of "ultrafiltrate" at the beginning of the proximal tubule is similar to that of

plasma. Carefully regulated processes of tubular reabsorption and/or tubular secretion determine

final water content and electrolyte composition of urine. As a general principle, "bulk"

movement of solute tends to occur in the proximal portions of the nephron, whereas fine

adjustments tend to occur distally. Modern advances in molecular biology have helped to

delineate the role of specific nephron segments in regulating ion and water transport and the

diseases that occur as a result of abnormalities in these processes.(2)

Sodium

Sodium is essential in maintaining extracellular fluid balance and, thus, volume status.

The kidney is capable of effecting large changes in sodium excretion in a variety of normal and

pathologic states. There are four main sites of sodium transport. Approximately 60% of sodium

is absorbed in the proximal tubule by coupled transport with glucose or amino acids, 25% in the

ascending loop of Henle (bumetanide-sensitive sodium-potassium 2 chloride transporter,

NKCC2), and 15% in the distal tubule (thiazide-sensitive sodium chloride cotransporter, NCCT)

and collecting tubule (epithelial sodium channel, ENaC). Under normal circumstances, the

urinary excretion of sodium approximates the sodium intake (80-250 mEq/24 hr for an adult who

consumes a typical American diet) minus 1-2 mEq/kg/24 hr required for normal metabolic

processes. However, in states of volume depletion (e.g., dehydration, blood loss) or decreased

effective circulating blood volume (e.g., septic shock, hypoalbuminemic states, or congestive

heart failure), there may be a dramatic decrease in urinary sodium excretion to as low as 1

mEq/L. Changes in volume status are detected by baroreceptors in the atria, afferent arteriole,

and the carotid sinus and by the macula densa, which detects changes in chloride delivery. The

major hormonal mechanisms mediating sodium balance include the renin-angiotensin-

aldosterone (RAA) axis, atrial natriuretic factor (ANF), and norepinephrine. Angiotensin II and

aldosterone increase sodium reabsorption in the proximal tubule and distal tubules, respectively.

Norepinephrine, released in response to volume depletion, does not directly act on tubular



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transport mechanisms but impacts on sodium balance by decreasing renal blood flow and thus

decreasing the filtered load of sodium, as well as stimulating renin release. With more severe

volume depletion antidiuretic hormone (ADH) is also released (see Chapter 522). Sodium

excretion is promoted by atrial natriuretic factor (ANF) and suppression of renin.(2)

Potassium

Extracellular potassium homeostasis is very tightly regulated, because small changes in

plasma potassium concentrations have dramatic effects on cardiac, neural, and neuromuscular

function. Essentially all filtered potassium is fully reabsorbed in the proximal tubule. Therefore,

urinary excretion of potassium is completely dependent on tubular secretion by potassium

channels present in the principal cells of the collecting tubule. Factors that promote potassium

secretion include aldosterone, increased sodium delivery to the distal nephron, and increased

urine flow rate.(2)

Calcium

A significant portion of filtered calcium (65%) is reabsorbed in the proximal tubule.

Additional calcium is reabsorbed in the ascending loop of Henle by passive movement between

cells (paracellular absorption) in a process driven by sodium chloride reabsorption and potassium

recycling into the lumen. Calcium uptake in this nephron segment is regulated by an extracellular

calcium receptor (CaR). Factors that promote calcium reabsorption include parathyroid hormone

(PTH, released in response to hypocalcemia), thiazide diuretics, and volume depletion. Factors

that promote calcium excretion include sodium intake (either orally or by infusion of sodium-

containing intravenous fluids) and loop diuretics such as furosemide.(2)

Phosphate

The majority of filtered phosphate is reabsorbed in the proximal tubule. Reabsorption is

increased by endogenous or exogenous calcitriol (1,25-dihydroxyvitamin D) and inhibited by

PTH.(2)



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Magnesium

About 25% of filtered magnesium is reabsorbed in the proximal tubule. Modulation of

renal magnesium excretion occurs primarily in the ascending loop of Henle, with some

contribution of the distal convoluted tubule. Although specific magnesium transporters have

been identified, the precise mechanisms by which they are regulated remain unclear.(2)



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ACUTE TUBULAR NECROSIS

PATHOPHYSIOLOGY

The current understanding of the pathophysiology of acute tubular necrosis (ATN) is the

result of intensive scientific studies performed over many decades. Despite the nomenclature,

frank necrosis of tubule cells is relatively inconspicuous in ischemic ATN, whereas it can be

more extensive in heavy metal – induced nephrotoxic ATN.(9)

The typical findings in humans include the following: (7)

Patchy loss of tubular epithelial cells with resultant gaps and exposure of denuded

basement membrane.

Diffuse effacement and loss of proximal tubule cell brush border.

Patchy necrosis, most typically in the outer medulla where the straight (S3) segment of

the proximal tubule and the medullary thick ascending limb (mTAL) of Henle loop.

Tubular dilatation and intraluminal casts in the distal nephron segments.

Evidence of cellular regeneration.

Regenerating cells are often detected in biopsies together with freshly damaged cells,

suggesting the occurrence of multiple cycles of injury and repair.

The clinical course of ATN may be divided into the following 3 phases(7)

Initiation

Maintenance

Recovery



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Initiation phase

The initiation phase corresponds to the period of exposure to ischemia or nephrotoxins.

Renal tubule cell damage begins to evolve (but is not yet established) during this phase. The

glomerular filtration rate (GFR) starts to fall, and urine output decreases.

(7)

Maintenance phase

During the maintenance phase, renal tubule injury is established, the GFR stabilizes at the

level well below normal, and the urine output is low or absent. Although oliguria (or anuria) is

one of the clinical landmarks of ATN, it is absent in a minority of patients with so-called

nonoliguric ATN. Acute kidney injury (AKI) due to nephrotoxins is typically nonoliguric. The

second phase of ATN usually lasts for 1-2 weeks but may extend to a few months.(7)

Recovery phase

The recovery phase of ATN is characterized by polyuria and gradual normalization of the

GFR. This phase involves the restitution of cell polarity and tight junction integrity in sublethally

injured cells, removal of dead cells by apoptosis, removal of intratubular casts by

reestablishment of tubular fluid flow, and regeneration of lost renal epithelial cells. (7)

In the absence of multiorgan failure, most patients with ATN regain most renal function.

However, when ATN occurs (as it often does) in the context of multiorgan dysfunction,

regeneration of renal tissue may be severely impaired and renal function may not return.

Morbidity and mortality in such situations remains dismally high despite significant scientific

and technological advances.(7)

Following ischemia-reperfusion, a marked up-regulation of numerous genes that play

important roles in renal tubule cell proliferation occurs, including epidermal growth factor

(EGF), insulin-like growth factor-1 (IGF-1), fibroblast growth factor (FGF), and hepatocyte

growth factor (HGF).(7)

In animals, exogenous administration of several of these growth factors has been shown

to accelerate recovery from ischemic AKI ; however, in a single human trial, IGF-1 did not prove



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to be beneficial when given to adults with AKI of various etiologies.

Additional human studies

with growth factors are currently under way.(7)

Heat shock proteins (HSPs) are a group of highly conserved proteins that are expressed

constitutively in normal cells and markedly induced in cells injured by heat, hypoxia, or toxins.They act as intracellular chaperones, allowing proper folding, targeting, and assembly of newly

synthesized and denatured proteins.(7)

At least 2 families of HSPs, namely HSP-70 and HSP-25, have been shown to be

overexpressed in renal tubule cells following ischemia - reperfusion injury in animals. HSP-70

may play a role in the restitution of cell polarity, and HSP-25 is an actin-capping protein that

may assist in the repair of actin microfilaments in sublethally injured cells. The role for HSPs in

human ATN remains to be elucidated.(7)



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ETIOLOGY

The following are prevalent causes of ATN in neonates : (10)

Ischemia : Perinatal asphyxia, respiratory distress syndrome, hemorrhage (eg,

maternal, twin-twin transfusion, intraventricular), congenital cyanotic heart disease,

shock/sepsis.

Exogenous toxins : Aminoglycosides, amphotericin B, maternal ingestion of

angiotensin-converting enzyme (ACE) inhibitors or nonsteroidal anti-inflammatory

drugs (NSAIDs).

Endogenous toxins : Hemoglobin following hemolysis, myoglobin following

seizures.

Kidney disease : Renal venous thrombosis, renal artery thrombosis, renal hypoplasia

and dysplasia, autosomal recessive polycystic kidney disease, bladder outlet

obstruction.

Causes of ATN in Older Children

The following are prevalent causes of ATN in older children : (7)

Ischemia - Severe dehydration, hemorrhage, shock/sepsis, burns, third-space losses in

major surgery, trauma, nephrotic syndrome, cold ischemia in cadaveric kidney

transplant, near drowning, severe cardiac or pulmonary disease.

Exogenous toxins - Drugs that impair autoregulation (eg, cyclosporine, tacrolimus,

ACE inhibitors, NSAIDs), direct nephrotoxins (eg, aminoglycosides, amphotericin B,

cisplatin, contrast agents, cyclosporine, tacrolimus).

Endogenous toxins - Hemoglobin release (eg, transfusion reactions, malaria, snake and

insect bites, glucose 6-phosphate dehydrogenase deficiency, extracorporeal circulation,

cardiac valvular prostheses), myoglobin release (eg, crush injuries, prolonged seizures,

malignant hyperthermia, snake and insect bites, myositis, hypokalemia,

hypophosphatemia, influenza).



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EPIDEMIOLOGY

Frequency varies widely, depending on the clinical context. ATN is the most frequent

cause of hospital acquired AKI. In adults, prevalence of ATN is approximately 1% at admission,

2-5% during hospitalization, and 4-15% after cardiopulmonary bypass. ATN occurs in

approximately 5-10% of newborn patients in the ICU and 2-3% of pediatric patients in the

ICU. Prevalence in children undergoing cardiac surgery is 5-8%. ATN is more common in

neonates than in other pediatric populations because of the high frequency of comorbid

conditions.(11)

PROGNOSIS

The prognosis for children with ATN from prerenal causes or in the absence of

significant comorbid conditions is usually quite good if appropriate therapy is instituted in a

timely fashion. Most patients recover adequate renal function to lead normal lives. Some are left

with permanent renal damage. In those left with mild-to-moderate renal damage, further

deterioration in kidney function may occur later in childhood; therefore, long-term follow-up is

required in these patients.(7)

Mortality rates widely vary according to the underlying cause and associated medical

condition. The most common causes of death are sepsis, cardiovascular and pulmonary

dysfunction, and withdrawal of life support measures.(7)

For patients with community-acquired ATN without other serious comorbid conditions,

mortality is approximately 5% and has decreased over the past decades because of the

availability of efficient renal replacement therapies.[25] Mortality jumps to 80% in patients in the

ICU with multiorgan failure, although death is almost never caused by renal failure.(7)

Despite significant advances in supportive care and renal replacement therapy, the high

mortality rates with multiorgan failure have not improved in the past few decades. Patients die

not because of renal failure but because of serious involvement of other systems during the

period of ATN.(7)



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HISTORY

Patients with hospital-acquired acute tubular necrosis (ATN) frequently have no specific

symptoms. The diagnosis is, at times, suspected when urine output diminishes and is usually

made by the documentation of successive elevations in blood urea nitrogen (BUN) and serum

creatinine levels. Careful evaluation of the hospital course usually reveals the cause of ATN. In

patients with community-acquired ATN, a thorough history and physical examination are

invaluable in pinpointing the etiology.(7)

In children, the most common form is ischemic ATN caused by severe hypovolemia,

shock, trauma, sepsis, burns, and major surgery. Nephrotoxic ATN is also common and is caused

by various drugs. Their deleterious effect is markedly enhanced by hypovolemia, renal ischemia,

or other renal insults.(7)

Conditions Resulting in Fluid Loss

Severe vomiting and/or diarrhea are common causes of renal hypoperfusion in children.

Significant fluid loss may also result from hemorrhage or burns. Loss of intravascular volume

into the interstitial compartment accompanies major surgery, shock syndromes, and the nephrotic

syndrome.(7)

Children with fluid losses may complain of thirst, dizziness, palpitations, and fatigue. A

history of acute weight loss and oliguria may be documented; however, ATN resulting from

nephrotoxic drugs and from perinatal events are frequently nonoliguric. Refer to the illustration

shown below.(7)

http://emedicine.medscape.com/article/928598-overview








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Medication use

In the presence of mild prerenal insufficiency, ingestion of seemingly innocuous

medications that impair renal autoregulation can precipitate oliguric ATN; for example,

nonsteroidal anti-inflammatory drugs (NSAIDs) inhibit the renal synthesis of vasodilator

prostaglandins and can precipitate ATN when administered to febrile children with intercurrent

dehydration.(7)

Cyclosporine, tacrolimus, and contrast agents are afferent arteriolar constrictors. Their

nephrotoxicity is potentiated by preexisting hypovolemia because they inhibit the myogenic

response of the afferent arteriole to renal hypoperfusion.(7)

Drugs that induce direct tubule cell damage include aminoglycosides, amphotericin B,

cyclosporine, tacrolimus, antineoplastic agents (eg, cisplatin, methotrexate), and contrast agents.

Acyclovir and sulfonamides can precipitate and obstruct the tubular lumens, especially in

children with diminished tubular fluid flow.(7)



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Conditions associated with release of endogenous tubular toxins

Myoglobinuric ATN may be encountered in various clinical situations, including muscle

trauma, prolonged seizures, malignant hyperthermia, snake and insect bites, myositis, severe

hypokalemia and hypophosphatemia, and infections such as severe influenza.

(7)

Hemoglobinuric ATN can accompany various states of hemolysis, including transfusion

reactions, malaria, snake and insect bites, glucose 6-phosphate dehydrogenase deficiency, and

mechanical causes such as extracorporeal circulation and cardiac valvular prostheses. (7)

Hyperuricosuric ATN is primarily observed during treatment of lymphoproliferative or

myeloproliferative malignancies and presents as tumor lysis syndrome.(7)

Hypoxia

In infants, ATN frequently complicates severe perinatal asphyxia, respiratory distress

syndrome, hemorrhage, and cyanotic congenital heart disease. Older children with severe

pulmonary or cardiac disease are also prone to ATN. (7)

PHYSICAL EXAMINATION

Signs of acute kidney injury (AKI) include hypertension, edema, anemia, and signs

of heart failure, such as hepatomegaly, gallop rhythm, and pulmonary edema. Signs of

intravascular volume depletion include tachycardia, orthostatic hypotension, decreased skin

turgor, dry mucous membranes, and changes in sensorium.(7)

DIFFERENTIAL DIAGNOSIS

Although oliguria is a criterion used to diagnose and stage acute kidney injury (AKI),

AKI can be present without oliguria, especially in patients with nephrotoxic kidney injury,

interstitial nephritis, or perinatal asphyxia. Oliguria may be defined as urine output less than 1

mL/kg/h in children and less than 400 mL/d in adults.(7)






http://www.medscape.com/resource/hypertension

http://www.medscape.com/resource/heartfailure

http://www.medscape.com/resource/heartfailure

http://www.medscape.com/resource/hypertension








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Differentials(7)

Dehydration

Oliguria

Renal Cortical Necrosis

Tumor Lysis Syndrome

LABORATORY FINDING

The following studies are indicated in patients with acute tubular necrosis (ATN):(7)

Urinalysis

Urinary indexes

Blood urea nitrogen (BUN) and serum creatinine

Serum electrolytes (sodium, potassium, phosphate, and calcium)

Arterial blood gases

Complete blood cell count

Although acute kidney injury (AKI) is usually secondary to ischemic or nephrotoxic injury, other

causes of intrinsic AKI should be kept in mind and excluded by history, physical examination,

and laboratory evaluation. Laboratory evaluation should include urine cultures and serologic

tests (including C3 and C4 in all patients) and lupus serologies and hepatitis profiles when

appropriate.(7)

Urinalysis

Careful examination of freshly voided urine is a rapid and inexpensive way of

distinguishing prerenal failure from ATN. In prerenal failure, a few hyaline and fine granular

casts may be observed with little protein, heme, or red blood cells (RBCs). Broad, brown

granular casts are typically found in ischemic or nephrotoxic ATN. Heme-positive urine in the

absence of erythrocytes in the sediment suggests ATN due to hemolysis or rhabdomyolysis.(7)











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Urinary Indices

Simultaneous measurement of urinary and serum sodium, creatinine, and osmolality can

help differentiate between prerenal azotemia (in which the reabsorptive capacity and

concentrating ability of the kidney are preserved or enhanced) and ATN (in which these

functions are impaired).(7)

In prerenal failure, urine specific gravity and the ratio of urine to plasma creatinine levels

are high, and the urinary sodium concentration is low (see Table, below). In contrast, the urine in

ATN is isosthenuric with a low urine-to-plasma creatinine ratio and high urine sodium

concentration.(7)

The fractional excretion of sodium (FENa) is the percentage of filtered sodium that is

excreted. It is easily calculated by the formula FENa (%) = ([U/P]Na)/([U/P]Cr) x 100, where Na

and Cr represent concentrations of sodium and creatinine in the urine (U) and plasma (P),

respectively. The FENa is typically more than 1% in ATN and less than 1% in prerenal azotemia.

Be alert to the fact that FENa may be low in intrinsic renal failure from glomerular diseases.(7)

Interpretation of urinary indexes requires caution. Collect blood and urine specimens

before the administration of fluids, mannitol, or diuretics. Urine should be free of glucose,

contrast material, or myoglobin. Urinary indexes suggestive of prerenal failure (FENa, < 1%)

may be observed in the ATN of contrast nephropathy and rhabdomyolysis (see Table, below). (7)

Table : Urinary Indexes in Acute Tubular Necrosis vs Prerenal Failure(7)

ATN Prerenal

Urine specific gravity 1010 >1020

Urine sodium (mEq/L) >40 < 10

Urine/plasma creatinine < 20 >40

FENa (%) >2 < 1



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Measurement of Blood Urea Nitrogen and Serum Creatinine Levels

The hallmark of established AKI is a daily increase in serum creatinine (by 0.5-1.5

mg/dL/d) and BUN (by 10-20 mg/dL/d) levels. In ATN, the BUN-to-creatinine ratio is usually

around 10, as opposed to a ratio of more than 20 that is commonly observed in prerenal failure

(due to enhanced proximal tubular reabsorption of urea). However, the BUN-to-creatinine ratio

may be misleading in patients whose conditions are wasting or in infants with physiologically

low muscle mass.(12)

Elevations of BUN can also result from steroid therapy, parenteral nutrition,

gastrointestinal (GI) bleeding, and catabolic states. A spurious elevation in serum creatinine may

be observed following the use of drugs that interfere with the tubular secretion of creatinine

(cimetidine, trimethoprim) or drugs that provide chromogenic substrates (cephalosporins) that

interfere with the Jaffe reaction for the determination of serum creatinine.(7)

Serum creatinine is the current criterion standard for the diagnosis of AKI. However,

important limitations have been noted, as follows:(7)

First, serum creatinine levels can widely vary with age, sex, lean muscle mass, muscle

metabolism, and hydration status.

Second, serum creatinine levels may not change until about 50% of kidney function has

been lost.

Third, at lower glomerular filtration rates (GFRs), the amount of tubular secretion of

creatinine results in overestimation of renal function.

Finally, during acute changes in glomerular filtration, serum creatinine does not

accurately depict kidney function until steady-state equilibrium has been reached, which

may require several days.

In the future, defining AKI by either a predictive biomarker of kidney damage or a sensitive

measure of decrease in kidney function may be appropriate. Fortunately, novel biomarkers are

currently undergoing evaluation and validation.(13,14)



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Determination of Serum Electrolyte Concentrations

Hyponatremia is a common finding in ATN and is usually dilutional secondary to fluid

retention and administration of hypotonic fluids.(7)

Hyperkalemia is a common and often serious complication of ATN. Contributing factors

include reduced GFR, reduced tubular secretion, metabolic acidosis (each 0.1 unit reduction in

arterial pH raises serum potassium by 0.3-0.4 mEq/L), and associated catabolic state.

Hyperkalemia is most pronounced in individuals with excessive endogenous potassium

production, such as in rhabdomyolysis, hemolysis, and tumor lysis syndrome. Symptoms are

nonspecific and may include malaise, nausea, and muscle weakness. Hyperkalemia represents a

life-threatening emergency that must be promptly and aggressively treated, primarily because of

its depolarizing effect on cardiac conduction pathways.(7)

Hyperphosphatemia and hypocalcemia frequently complicate ATN. The phosphate

excess is secondary to reduced renal excretion and can lead to hypocalcemia and calcium

phosphate deposition in various tissues.(7)

Hypocalcemia results predominantly from hyperphosphatemia and impaired absorption

of calcium from the GI tract because of inadequate 1,25-hydroxyvitamin D3 production by the

diseased kidneys. Severe hypocalcemia results in tetany, seizures, and cardiac arrhythmias. (7)

Determining ionized calcium concentration may be important because this unbound form

of serum calcium determines physiologic activity. Acidosis increases the fraction of serum

calcium that is in the ionized form, while correction of acidosis may decrease it; thus,

overzealous bicarbonate therapy can acutely decrease ionized calcium.(7)

Hypomagnesemia is a prominent finding in nephrotoxic ATN, particularly associated

with gentamicin, amphotericin B, cisplatinum, or pentamidine administration.(7)

Evaluation of Acid-Base Balance

The high anion gap metabolic acidosis of ATN is a consequence of impaired renal

excretion of nonvolatile acids. Decreased tubular reabsorption of bicarbonate further contributes







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to the metabolic acidosis. Severe acidosis can develop in children who are hypercatabolic (shock,

sepsis) or who have inadequate respiratory compensation.(7)

Complete Blood Cell Count

A mild-to-moderate anemia is commonly observed as a result of dilution and decreased

erythropoiesis. Severe anemia should prompt a search for hemolysis from a variety of causes,

because it can result in hemoglobinuric ATN. These patients usually display elevated serum

lactate dehydrogenase levels.(7)

Microangiopathic hemolytic anemia with schistocytes and thrombocytopenia are

indicative of possible hemolytic-uremic syndrome (HUS), which is an important cause of

intrinsic ARF in children. Prolonged ATN also can result in bleeding due to dysfunctional

platelets.(7)

Tests for Rhabdomyolysis and Tumor Lysis Syndrome

A suspicion of rhabdomyolysis may be confirmed by direct determination of urinary

myoglobin and elevation of serum creatine kinase (specifically the CK3 isoenzyme). Children

with rhabdomyolysis also usually display marked increases in serum potassium and phosphate.(7)

In the tumor lysis syndrome following cancer chemotherapy, a marked elevation in serum

uric acid occurs along with hyperkalemia and hyperphosphatemia.(7)

Determination of Serum Nephrotoxin levels

Serum levels of nephrotoxins should be determined and serially followed, particularly

when using gentamicin, vancomycin, cyclosporine, or tacrolimus.(7)



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Renal Ultrasonography

Ultrasonography of the kidneys and bladder with Doppler flow is essential in the workup

of ARF. Exceptions to this rule may include children with unmistakable prerenal failure from

well-documented dehydration who respond promptly to fluid therapy or children with renal

insufficiency secondary to obvious glomerular disease, hypoxia-ischemia, or exposure to

nephrotoxins.(7)

Ultrasonography provides important information regarding kidney size, contour,

echogenicity, corticomedullary differentiation, and blood flow. In ischemic or nephrotoxic ATN,

the kidneys are of normal size or slightly enlarged, with increased echogenicity. With prolonged

ATN, renal cortical necrosis may result in decreased kidney size. Bilateral small scarred kidneys

are indicative of chronic renal disease.(7)

Congenital disorders, such as polycystic kidney disease and multicystic dysplasia, are

easily detected, and calculi and tumors are also evident. Hydronephrosis is suggestive of urinary

tract obstruction, and accompanying hydroureter and a thickened bladder wall are consistent with

bladder outlet obstruction. A Doppler study is important in the evaluation of vascular

obstruction.(7)

Radionuclide Scanning

Radionuclide scans ( functional scans with mercaptotriglycylglycine [MAG-3] or

diethylenetriamine penta-acetic acid [DTPA] ) are useful in the assessment of obstruction and

may provide additional information regarding GFR, renal blood flow, and tubule function. Their

major clinical use in children with ATN is in the immediate post transplant period, when scans

can help differentiate between ATN and transplant rejection. (15)

Electrocardiography

Perform electrocardiography (ECG) if hyperkalemia is suspected or detected by laboratory

tests. The following are sequential ECG changes in hyperkalemia:(7)

Tall peaked T waves



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Prolongation of PR interval

Widening of QRS complex

ST segment changes

Ventricular tachycardia

Terminal ventricular fibrillation

Renal Biopsy

In general, a kidney biopsy is not necessary in the initial evaluation; however, if prerenal

and postrenal causes of ARF have been ruled out and an intrinsic renal disease other thanischemic ATN, nephrotoxic ATN, HUS, or postinfectious glomerulonephritis is a possibility,

renal biopsy findings may be valuable in establishing the diagnosis, guiding therapy, and

assessing prognosis. Renal biopsy findings may be also useful in the immediate post transplant

period for differentiating between ATN and acute rejection.(7)

Histologic Findings

Typical histologic findings in ATN include the following: (7)

Patchy loss of tubular epithelial cells with resultant gaps and exposure of denuded

basement membrane

Diffuse effacement and loss of proximal tubule cell brush border

Patchy necrosis, most typically in the outer medulla where the straight (S3) segment of

the proximal tubule and the medullary thick ascending limb (mTAL) of the loop of Henle

are located

Tubular dilatation and intraluminal casts in the distal nephron segments

Evidence of cellular regeneration

Regenerating cells are often detected in biopsies together with freshly damaged cells, suggesting

the occurrence of multiple cycles of injury and repair.



23

TREATMENT

Recognition of the circumstances that place children at risk for acute tubular necrosis

(ATN) and institution of corrective measures may prevent the development of this disorder.

Treatment of pediatric patients with ATN requires correction of imbalances in fluid volume,electrolytes, and acid-base balance. Children with ATN who are hemodynamically unstable or

require acute dialysis should be transferred to an intensive care unit (ICU).(7)

Fluid Management

The major goal of fluid management is to restore and maintain intravascular volume.

ATN may manifest itself with hypovolemia, euvolemia, or volume overload, and an estimation

of fluid status is a prerequisite for initial and ongoing therapy. This is accomplished by

measuring input and output, serial body weights, vital signs, skin turgor, capillary refill, serum

sodium, and fractional excretion of sodium (FENa).(7)

Children with intravascular volume depletion require prompt and vigorous fluid

resuscitation. Initial therapy includes normal saline or lactated Ringer solution at 20 mL/kg over

30 minutes. It can be repeated twice if necessary, after careful monitoring to avoid possible fluid

overload. Potassium administration is contraindicated until urine output is established. If anuria

persists after 3 fluid boluses (confirmed by bladder catheterization), central venous monitoring

may be required to guide further management.(7)

Oliguria in the presence of volume overload requires fluid restriction and possibly

intravenous administration of furosemide. Children with established ATN may not respond to

furosemide; in such cases, consider fluid removal by dialysis or hemofiltration, especially if signs

of pulmonary edema are evident.(7)

Input and output records, daily weights, physical examination, and serum sodium

concentration guide ongoing therapy. A bedside indicator of appropriate fluid therapy is a body

weight decrease of approximately 0.5% per day as a result of caloric deprivation; serum sodium

concentration should remain stable. A more rapid weight loss and increasing serum sodium

indicate inadequate fluid replacement. An absence of weight loss with decreasing serum sodium



24

suggests excess free water replacement. During the recovery phase, children develop significant

polyuria and natriuresis and may become dehydrated if appropriate adjustments in fluid

requirements are not made.(7)

Correction of Electrolyte Abnormalities and Acid-Base Imbalance

ATN may lead to hyperkalemia, hyponatremia, hyperphosphatemia, hypocalcemia, and

metabolic acidosis.(7)

Hyperkalemia

If serum potassium levels exceed 5.5-6.5 mEq/L, eliminate all sources of potassium from

the diet or intravenous fluids and administer a cation exchange resin such as sodium polystyrenesulfonate (Kayexalate). Kayexalate requires several hours of contact with the colonic mucosa to

be effective; the rectal route of administration is preferred. Complications of this therapy include

hypernatremia and constipation. An attempt can be made to lower serum potassium

concentration by increasing the dose of diuretics in those patients responding to them.(7)

When serum potassium exceeds 6.5 mEq/L or tall peaked T waves are evident on the

ECG, emergency treatment of hyperkalemia is indicated. In addition to Kayexalate, administer

intravenous sodium bicarbonate, which causes a rapid shift of potassium into cells. Themagnitude of the potassium intracellular shift is variable, and thus, bicarbonate is not reliable in

lowering the potassium level. Such therapy should be used with caution because it can

precipitate hypocalcemia and sodium overload.(7)

Sodium bicarbonate uptake of potassium by cells can also be stimulated by infusion of

glucose and insulin or by beta agonists (albuterol by nebulizer). The efficacy and convenience of

nebulized albuterol has been well described in chronic hemodialysis patients with hyperkalemia;

however, it can cause tachycardia, and the overall pediatric experience is limited.(7)

The presence of electrocardiographic (ECG) changes requires the immediate

administration of calcium gluconate (with continuous ECG monitoring) to counteract the effects

of hyperkalemia on the myocardium. This therapy may precipitate bradycardia and other cardiac

arrhythmias.(7)



26

severity of the abnormality to be corrected. Common indications for dialysis in ATN are as

follows:(16)

Fluid overload that is unresponsive to diuretics

Fluid overload that hinders adequate nutritional support

Hyperkalemia with oliguria

Symptomatic acid-base imbalances

Refractory hypertension

Symptomatic uremia ( pleuritis, pericarditis, CNS symptoms )

The choice between hemodialysis and peritoneal dialysis depends on the overall clinical

condition, availability of technique, etiology of the ATN, institutional preferences, and specificindications or contraindications. In general, peritoneal dialysis is a gentler and preferred method

in infants and younger children. Specific contraindications include abdominal wall defects,

bowel distention, perforation or adhesions, and communications between the abdominal and

chest cavities.(16)

Hemodialysis has the distinct advantage of rapid correction of fluid, electrolyte, and acid-

base imbalances, and it may be the treatment of choice in hemodynamically stable patients,

especially older children. Disadvantages include the requirement for vascular access, largeextracorporeal blood volume, heparinization, and skilled personnel.

(16)

An important advance has been the use of biocompatible synthetic dialysis membranes,

such as polysulfone. These membranes should minimize complement activation and neutrophil

infiltration into the kidney. Their use is generally recommended in children with AKI, although

not all studies have documented beneficial effects.(16)

Continuous venovenous hemofiltration (CVVH) has emerged as an alternative therapy

primarily for children with ATN who require fluid removal and are unstable or critically ill . The

major advantage of this technique lies in the ability to remove fluid in a hypotensive child in

whom hemodialysis may be relatively contraindicated and peritoneal dialysis inefficient. The

patient requires the continuous presence of trained personnel and specialized equipment that are

currently available only at select tertiary care centers. CVVH also can be modified easily to



27

allow for significant solute removal, and as experience accumulates, this continuous but gentle

modality may emerge as the dialytic therapy of choice for patients with ATN in the ICU.(16)

Some concern remains that dialysis may actually be detrimental to recovery of renal

function in ATN. Institution of dialysis may decrease any residual urine output (whichexacerbates intratubular obstruction), may induce episodes of hypotension (which further

compromises renal perfusion), and may activate complement (which increases neutrophil

infiltration into the kidney). Complement activation may be minimized by the use of

biocompatible membranes, and CVVH may allow for dialysis with better hemodynamic

control.(16)

Adjustment of Medications

Avoid nephrotoxic agents, as they may worsen the renal injury and delay recovery of

function. Such agents include contrast media, aminoglycosides, and nonsteroidal anti-

inflammatory drugs (NSAIDs).(7)

Prescribing medication in ATN requires knowledge of the route of elimination, and

modifications in dose or frequency should be made based on residual renal function. When

making these adjustments, patients in the early phase of ATN with a rising serum creatinine level

should be assumed to have a glomerular filtration rate (GFR) of less than 10 mL/min,

irrespective of the serum creatinine value.(7)

Administration of Calcium Channel Blockers

Calcium channel blockers (CCBs) have been shown to ameliorate ischemic renal injury

in various animal studies, although the mechanisms that confer the protection are unclear. They

may include an improvement in renal hemodynamics, a membrane stabilizing effect on tubule

epithelial cells, and a calmodulin antagonizing effect, in addition to the prevention of calcium

overloading of cells.(7)

CCBs have also yielded encouraging results in human ATN. Administration of CCBs to

both donors and recipients has been shown to reduce the prevalence of AKI following cadaveric



28

kidney transplants; however, the beneficial effect of CCBs in this setting may be because of their

ability to blunt the nephrotoxicity of the concomitantly administered cyclosporine.(7)

In addition, CCB administration prior to radio contrast materials confers protection

against nephrotoxicity. Therefore, the prophylactic use of CCBs prior to a potential renal insult,such as cold ischemia in cadaveric transplants or administration of contrast material, appears to

be beneficial; however, CCBs are unlikely to be effective in established ATN.(7)

Surgical Care

Patients with ATN secondary to obstruction frequently require urologic care. The site of

obstruction determines the therapy. In neonates, obstruction of the bladder neck caused byposterior urethral valves must be immediately relieved by gentle insertion of a fine urethral

catheter. The subsequent management of choice is endoscopic ablation of the valves. A

temporary cutaneous vesicostomy may be required in a small infant.(7)

Dietary Measures

Children with ATN are frequently in a highly catabolic state. Aggressive nutritional

support is important. Adequate calories to account for maintenance requirements and

supplements to combat excessive catabolism must be provided. Oral feeding is the preferred

route of administration. Children who are nauseous or anorexic may benefit from parenteral

feedings or intravenous hyperalimentation.(7)

Infants should receive a low-phosphorus diet (Similac PM 60/40), and older children

should be placed on a low-potassium, low-phosphorus diet. Additional calories may be supplied

by fortifying foods with Polycose and medium-chain triglyceride (MCT) oils. If adequate

nutrition cannot be achieved because of fluid restriction, consider early institution of

ultrafiltration or dialysis.(7)



29

Restriction of Activity

Children with ATN are usually hospitalized, and activity is restricted; however, strict bed

rest does not accelerate recovery.(7)

Consultations

Children with ATN are best treated in a tertiary care institution with pediatric nephrology

consultants.(7)

PREVENTION OF ACUTE TUBULAR NECROSIS

In clinical situations in which renal hypoperfusion or toxic injury is anticipated,

administration of fluids, diuretics, mannitol, and low-dose dopamine have been used to prevent

or reverse renal injury. Vigorous prophylactic fluid administration has been used successfully to

prevent ATN following cardiac surgery, cadaveric kidney transplantation, major trauma, burns,

hemoglobinuria, myoglobinuria, tumor lysis syndrome, radio contrast administration,

amphotericin B therapy, and cisplatin infusion.(17)

Ensuring adequate hydration prior to any of the above procedures is now an established

standard of care. However, the role of diuretics, mannitol, and low-dose dopamine is more

controversial. In one well-designed study using either low-dose dopamine or furosemide prior to

cardiac surgery in adults, no renoprotective effect could be documented. The prophylactic use of

diuretics or dopamine prior to the above procedures is not recommended at this time. (17)

Several studies, albeit uncontrolled, suggest that diuretics may be beneficial when

administered during the early phase of ATN. Although they do not appear to alter the course of

the acute kidney injury (AKI), they may convert an oliguric to a nonoliguric AKI, which is more

easily managed because it eliminates the need for fluid restriction and allows for maximal

nutritional support.(17)



30

The current recommendation is that a trial of intravenous furosemide should be attempted

in children with oliguria of less than 48 hours duration who have not responded to adequate

hydration. The dose of furosemide should be in the high range (2-5 mg/kg). Some evidence

suggests that in the prevention of crush syndrome, early administration of mannitol, before

muscle toxins and breakdown products are released into the circulation, may protect from the

development of ATN.(17)

MEDICATION

Diuretic treatment may convert oliguric acute tubular necrosis (ATN) to nonoliguric

ATN, although diuretics do not appear to alter the course of acute kidney injury (AKI).(7)

Hyperkalemia in ATN is a medical emergency that may be managed by shifting

potassium into cells with sodium bicarbonate, glucose/insulin infusion, or beta agonists; by

increasing potassium excretion with exchange resins (sodium polystyrene) or loop diuretics

(furosemide); or by dialysis. Protecting the myocardium from hyperkalemia is managed with

intravenous (IV) calcium.(7)

Hyperphosphatemia may be initially managed with oral calcium to bind dietary

phosphate. Oral citrate salts may be used to manage mild metabolic acidosis, whereas IV sodium

bicarbonate is needed for severe metabolic acidosis.(7)

Loop diuretics

In children with recent-onset oliguria from prerenal or toxic injury who are unresponsive

to hydration, a trial of furosemide may convert the oliguric ATN to a nonoliguric type, which ismanaged more easily. These agents have a direct vasodilatory action and additionally may

prevent tubular obstruction by increasing intratubular fluid flow.(7)



31

Furosemide (Lasix)

Furosemide increases excretion of water by interfering with the chloride-binding

cotransport system, which, in turn, inhibits sodium and chloride reabsorption in the ascending

loop of Henle and distal renal tubule. It is used for ATN prevention in children with oliguriaduration less than 48 hours who have not responded to adequate hydration. It may also be

considered for oliguria in the presence of volume overload. Furosemide is also used for

hyperkalemia to increase potassium excretion in the urine.(7)

Alkalizing agents

Intravenous sodium bicarbonate and oral sodium citrate are used as buffers that break

down to water and carbon dioxide after picking up free hydrogen ions, thus counteracting

acidosis by raising blood pH. IV sodium bicarbonate is also used to manage hyperkalemia.(7)

Sodium bicarbonate

Sodium bicarbonate is used to treat hyperkalemia. It causes a rapid shift of potassium into

cells. The magnitude of the potassium intracellular shift varies; thus, bicarbonate is not reliable

in lowering the potassium level by itself. It is also used emergently to manage severe metabolic

acidosis.(7)

Sodium citrate (Bicitra, Oracit)

Sodium citrate manages mild metabolic acidosis and is used as an alkalinizing agent

when long-term maintenance of an alkaline urine is desirable.(7)

Myocardium stabilizers

Intravenous calcium is primarily used to protect the myocardium from the deleterious

effects of hyperkalemia (ie, arrhythmias) by antagonizing the potassium actions on the

myocardial cell membrane. It does not lower serum potassium levels.(7)

http://reference.medscape.com/drug/lasix-furosemide-342423#1

http://reference.medscape.com/drug/sodium-bicarbonate-342305#1

http://reference.medscape.com/drug/albrights-solution-cytra-2-sodium-citrate-citric-acid-342854#1

http://reference.medscape.com/drug/albrights-solution-cytra-2-sodium-citrate-citric-acid-342854#1

http://reference.medscape.com/drug/sodium-bicarbonate-342305#1

http://reference.medscape.com/drug/lasix-furosemide-342423#1



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Calcium gluconate (Kalcinate)

Calcium gluconate is given intravenously to provide myocardial protection from

hyperkalemia. It is indicated if hyperkalemia is accompanied by ominous electrocardiographic

(ECG) changes beyond peaked T waves or if ECG changes persist after bicarbonate therapy.

(7)

Intracellular transporters

Insulin and glucose (dextrose) cause a transcellular shift of potassium into muscle cells,

thereby lowering (temporarily) potassium serum levels.(7)

Dextrose and insulin infusion

Dextrose and insulin infusion is used as an adjunct to bicarbonate therapy to promote

intracellular shift of potassium.(7)

Exchange resins

Sodium polystyrene sulfonate is an exchange resin that can be used to treat mild-to-

moderate hyperkalemia. Each 1 mEq of potassium is exchanged for 1 mEq of sodium.(7)

Sodium polystyrene sulfonate (Kayexalate)

Sodium polystyrene sulfonate is indicated in all cases of hyperkalemia because it is the

only modality (other than diuretics and dialysis) that actually removes excessive potassium from

the body. It exchanges sodium for potassium and binds it in the gut, primarily in the large

intestine, and decreases total body potassium. Its onset of action after oral administration ranges

from 2-12 hours and is longer when rectally administered. (7)

http://reference.medscape.com/drug/calcium-gluconate-344434#1

http://reference.medscape.com/drug/sps-kayexalate-sodium-polystyrene-sulfonate-342837#1

http://reference.medscape.com/drug/sps-kayexalate-sodium-polystyrene-sulfonate-342837#1

http://reference.medscape.com/drug/calcium-gluconate-344434#1



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Phosphate binders

ATN is frequently complicated by hyperphosphatemia and hypocalcemia, which respond

to calcium-containing oral phosphate binders.(7)

Calcium carbonate (Oystercal, Caltrate)

Calcium carbonate combines with dietary phosphate to form insoluble calcium

phosphate, which is excreted in feces.(7)

http://reference.medscape.com/drug/caltrate-600-os-cal-500-d-calcium-carbonate-341983#1

http://reference.medscape.com/drug/caltrate-600-os-cal-500-d-calcium-carbonate-341983#1



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