Acute Tubular NecrosisAcute Tubular Necrosis

Resident’s conference

Presented by Dr Gagandeep K Heer, MD

(PGY-2)

BackgroundBackground

DefinitionDefinition:: ARF is defined as an abrupt or ARF is defined as an abrupt or rapid decline in the renal function.rapid decline in the renal function.

A rise in serum BUN or creatinine A rise in serum BUN or creatinine concentration, with or without decrease in concentration, with or without decrease in urine output, usually is evidence of ARF.urine output, usually is evidence of ARF.

ARF is often transient and completely ARF is often transient and completely reversible.reversible.

Background Background The causes of ARF are divided into 3 categories: The causes of ARF are divided into 3 categories: PPrerenalrerenal Renal Renal PostrenalPostrenal ATNATN is the most common cause of ARF in the is the most common cause of ARF in the renalrenal category.category. ATN is the 2ATN is the 2ndnd most common cause of all categories of ARF in most common cause of all categories of ARF in

hospitalizedhospitalized patients, with only prerenal azotemia occurring patients, with only prerenal azotemia occurring more frequently.more frequently.

In outpatients, obstruction (ureteric, bladder neck or urethral) is In outpatients, obstruction (ureteric, bladder neck or urethral) is the 2the 2ndnd most common cause of ARF after prerenal azotemia. most common cause of ARF after prerenal azotemia.

Other causes of ARF include acute interstitial nephritis, acute Other causes of ARF include acute interstitial nephritis, acute glumerulonephtitis, vasculitis, HUS, TTP, DIC, accelerated HTN, glumerulonephtitis, vasculitis, HUS, TTP, DIC, accelerated HTN, radiation nephritis, acute on chronic renal failure, renovascular radiation nephritis, acute on chronic renal failure, renovascular obstruction (bilateral or unilateral in the setting of single obstruction (bilateral or unilateral in the setting of single functioning kidney), renal allograft rejection, intratubular functioning kidney), renal allograft rejection, intratubular deposition and obstruction (myeloma proteins, urate, oxalate deposition and obstruction (myeloma proteins, urate, oxalate crystals, etc.)crystals, etc.)

PathophysiologyPathophysiology ATN usually occurs after an acute ischemic or ATN usually occurs after an acute ischemic or

toxic event, and it has a well-defined sequence of toxic event, and it has a well-defined sequence of events. events.

Initiation phaseInitiation phase characterized by acute decrease characterized by acute decrease in GFR to very low levels, with a sudden increase in GFR to very low levels, with a sudden increase in serum Cr and BUN concentrations. in serum Cr and BUN concentrations.

Maintenance phaseMaintenance phase is characterized by sustained is characterized by sustained severe reduction in GFR and the BUN and Cr severe reduction in GFR and the BUN and Cr continue to rise.continue to rise.

Recovery phaseRecovery phase, in which the tubular function is , in which the tubular function is restored, is characterized by an increase in urine restored, is characterized by an increase in urine volume (if oliguria was present) and gradual volume (if oliguria was present) and gradual decrease in Cr and BUN to their pre-injury level.decrease in Cr and BUN to their pre-injury level.

Ischemic ATNIschemic ATN Ischemic ATN is often described as a continuum of prerenal Ischemic ATN is often described as a continuum of prerenal

azotemia. Response to fluid repletion can help distinguish azotemia. Response to fluid repletion can help distinguish between the two: return of renal function within 24-72 between the two: return of renal function within 24-72 hours usually indicate prerenal disease although short-lived hours usually indicate prerenal disease although short-lived ATN can recover within similar timeframe (e.g. self limited ATN can recover within similar timeframe (e.g. self limited insult such as transient aortic clamping during suprarenal insult such as transient aortic clamping during suprarenal aortic aneurysm surgery).aortic aneurysm surgery).

Initiation phaseInitiation phase:: Hypoperfusion initiates cell injury that Hypoperfusion initiates cell injury that often leads to cell death. It is most prominent in straight often leads to cell death. It is most prominent in straight portion of the proximal tubules and thick ascending limb of portion of the proximal tubules and thick ascending limb of loop of Henle. The reduction in the GFR occurs not only loop of Henle. The reduction in the GFR occurs not only from from reduced filtrationreduced filtration due to hypoperfusion but also from due to hypoperfusion but also from casts and debris casts and debris obstructingobstructing the lumen, causing back leak the lumen, causing back leak of filtrate through the damaged epithelium (of filtrate through the damaged epithelium (ineffective ineffective filtrationfiltration). In addition, ischemia leads to decreased ). In addition, ischemia leads to decreased production of vasodilators (i.e. nitric oxide, prostacyclin) by production of vasodilators (i.e. nitric oxide, prostacyclin) by tubular epithelial cells, leading to further vasoconstriction tubular epithelial cells, leading to further vasoconstriction and hypoperfusion.and hypoperfusion.

Ischemic ATNIschemic ATN Maintenance phaseMaintenance phase is characterized by stabilization of is characterized by stabilization of

GFR at a very low level, and it typically lasts 1-2 weeks. GFR at a very low level, and it typically lasts 1-2 weeks. Uremic complications typically develop during this Uremic complications typically develop during this phase. In addition to the above mentioned mechanism of phase. In addition to the above mentioned mechanism of injury, tubulo-glomerular feedback also plays a role by injury, tubulo-glomerular feedback also plays a role by causing constriction of afferent arterioles by the macula causing constriction of afferent arterioles by the macula densa cells, which detect and increased salt load in the densa cells, which detect and increased salt load in the distal tubules.distal tubules.

During During Recovery phaseRecovery phase, there is regeneration of tubular , there is regeneration of tubular epithelial cells. An abnormal diuresis sometimes occurs, epithelial cells. An abnormal diuresis sometimes occurs, causing salt and water loss and volume depletion. The causing salt and water loss and volume depletion. The mechanism of the diuresis is not completely understood, mechanism of the diuresis is not completely understood, but it may in part be due to delayed recovery of tubular but it may in part be due to delayed recovery of tubular cell function in the setting of increased glomerular cell function in the setting of increased glomerular filtration. In addition, continued use of diuretics (often filtration. In addition, continued use of diuretics (often administered during initiation and maintenance phases) administered during initiation and maintenance phases) may also add to the problem.may also add to the problem.

Nephrotoxic ATNNephrotoxic ATN

Most of the pathophysiological features of Most of the pathophysiological features of ischemic ATN are shared by the ischemic ATN are shared by the nephrotoxic forms and it has the same nephrotoxic forms and it has the same three phases.three phases.

Nephrotoxic injury to tubular cells occurs Nephrotoxic injury to tubular cells occurs by multiple mechanisms including direct by multiple mechanisms including direct toxicity, intrarenal vasoconstriction, and toxicity, intrarenal vasoconstriction, and intratubular obstruction.intratubular obstruction.

At cellular level…At cellular level… Ischemic ATNIschemic ATN:: Cellular ischemia results in series of alterations in energetics, Cellular ischemia results in series of alterations in energetics,

ion transport and membrane integrity that ultimately leads to cell ion transport and membrane integrity that ultimately leads to cell injury or necrosis. These changes include depletion of ATP, injury or necrosis. These changes include depletion of ATP, inhibition of active sodium transport and transport of other inhibition of active sodium transport and transport of other solutes, impairment of cell volume regulation, cytoskeletal solutes, impairment of cell volume regulation, cytoskeletal disruption and loss of cell polarity, cell-cell and cell-matrix disruption and loss of cell polarity, cell-cell and cell-matrix attachment, accumulation of intracellular calcium, altered attachment, accumulation of intracellular calcium, altered phospholipid metabolism, oxygen free radical formation and phospholipid metabolism, oxygen free radical formation and peroxidation of membrane lipids. peroxidation of membrane lipids.

A characteristic feature of ischemic ATN is the absence of A characteristic feature of ischemic ATN is the absence of widespread necrosis of tubular epithelial cells. Necrosis is more widespread necrosis of tubular epithelial cells. Necrosis is more subtle and is reflected in individual necrotic cells within some subtle and is reflected in individual necrotic cells within some proximal or distal tubules. These single cells shed into tubular proximal or distal tubules. These single cells shed into tubular lumen, with resulting focal denudation of the tubular basement lumen, with resulting focal denudation of the tubular basement membrane. Interstitial edema is common.membrane. Interstitial edema is common.

Ischemic ATNIschemic ATN

Histology (continued…)Histology (continued…) Toxic ATNToxic ATN:: The morphology differs from ischemic The morphology differs from ischemic

ATN in that the former is characterized by more ATN in that the former is characterized by more extensive necrosis of the tubular epithelium. In extensive necrosis of the tubular epithelium. In most cases, however, the necrosis is limited to most cases, however, the necrosis is limited to certain segments that are most sensitive to the certain segments that are most sensitive to the toxin. ATN caused by hemoglobin or myoglobin toxin. ATN caused by hemoglobin or myoglobin has added feature of numerous red-brown tubular has added feature of numerous red-brown tubular casts, colored by heme pigments.casts, colored by heme pigments.

During the During the recovery phase recovery phase of ATN, the tubular of ATN, the tubular epithelium regenerates, leading to the epithelium regenerates, leading to the appearance of mitoses, increased size of cells and appearance of mitoses, increased size of cells and nuclei, and cell crowding. Survivors eventually nuclei, and cell crowding. Survivors eventually display complete restoration of normal renal display complete restoration of normal renal architecture.architecture.

Nephrotoxic ATNNephrotoxic ATN

FrequencyFrequency

In the US: ARF is seen in 5% of all hospital In the US: ARF is seen in 5% of all hospital admissions and upto 30% of patients admissions and upto 30% of patients admitted to the ICU. Prerenal causes admitted to the ICU. Prerenal causes account for about half of all cases. account for about half of all cases.

ATN is most common cause out of the ATN is most common cause out of the intrinsic renal diseases.intrinsic renal diseases.

HistoryHistory A good history is very important in diagnosis of A good history is very important in diagnosis of

ATN. ATN. Find out about: Find out about: Recent hypotensionRecent hypotension SepsisSepsis Muscle necrosis (e.g. h/o seizure, cocaine use)Muscle necrosis (e.g. h/o seizure, cocaine use) Exposure to contrast or nephrotoxic medicationsExposure to contrast or nephrotoxic medications HypovolumiaHypovolumia Other risk factors for development of ATN like Other risk factors for development of ATN like

underlying renal disease from DM, HTN, etc.underlying renal disease from DM, HTN, etc.

Physical ExamPhysical Exam Physical exam may be unremarkable because Physical exam may be unremarkable because

ARF is often found incidentally during routine ARF is often found incidentally during routine laboratory studies (i.e. elevated BUN and Cr).laboratory studies (i.e. elevated BUN and Cr).

Look for pericardial friction rub (pt may have Look for pericardial friction rub (pt may have pericarditis), asterixis and/or excoriation marks pericarditis), asterixis and/or excoriation marks related to uremic pruritis.related to uremic pruritis.

Hypertension or edema may be noted.Hypertension or edema may be noted. Physical findings related to the underlying Physical findings related to the underlying

disease.disease.

Causes of ATNCauses of ATN

ATN is usually caused by an acute event, ATN is usually caused by an acute event, either ischemic or toxic. either ischemic or toxic.

Causes of Ischemic ATNCauses of Ischemic ATN

It may be considered part of the spectrum It may be considered part of the spectrum of prerenal azotemia and they have the of prerenal azotemia and they have the same causes and risk factorssame causes and risk factors

• Hypovolumic states – hemorrhage, volume Hypovolumic states – hemorrhage, volume depletion from GI or renal losses, burns, depletion from GI or renal losses, burns, fluid sequestration.fluid sequestration.

• Low cardiac output states – CHF and other Low cardiac output states – CHF and other diseases of the myocardium, valvulopathy, diseases of the myocardium, valvulopathy, arrhythmia, pericardial diseases, arrhythmia, pericardial diseases, tamponade.tamponade.

Causes of Ischemic ATNCauses of Ischemic ATN

• Systemic vasodilation – sepsis, Systemic vasodilation – sepsis, anaphylaxisanaphylaxis

• DICDIC• Renal vasoconstriction – cyclosporine, Renal vasoconstriction – cyclosporine,

norepinephrine, epinephrine, amphotericin norepinephrine, epinephrine, amphotericin B, etcB, etc

• Hyperviscosity syndromeHyperviscosity syndrome• Impaired renal autoregulatory responses – Impaired renal autoregulatory responses –

cyclooxygenase inhibitorscyclooxygenase inhibitors

Causes of Nephrotoxic ATNCauses of Nephrotoxic ATN

The kidney is a good target for toxins. Not The kidney is a good target for toxins. Not only does it have a rich blood supply, only does it have a rich blood supply, receiving 25% of CO, but it also helps in receiving 25% of CO, but it also helps in the excretion of these toxins by the excretion of these toxins by glomerular filtration and tubular secretion.glomerular filtration and tubular secretion.

Exogenous toxinsExogenous toxins

Aminoglycosides:Aminoglycosides:• 10-30% of patients getting aminoglycosides 10-30% of patients getting aminoglycosides

develop ATN. develop ATN. • Risk factors include preexisting liver disease, Risk factors include preexisting liver disease,

renal disease, concomitant use of other renal disease, concomitant use of other nephrotoxins, advanced age, shock, female sex nephrotoxins, advanced age, shock, female sex and a higher level 1 hr after the dose.and a higher level 1 hr after the dose.

• Toxicity presumably more common with 3 Toxicity presumably more common with 3 doses/day than a single daily dose (as the drug doses/day than a single daily dose (as the drug uptake by tubules is saturable phenomenon).uptake by tubules is saturable phenomenon).

Amphotericin B:Amphotericin B: The likelihood of toxicity is in direct The likelihood of toxicity is in direct proportion to the total dose administered and is proportion to the total dose administered and is more common if > 3 grams is administered.more common if > 3 grams is administered.

Exogenous ToxinsExogenous Toxins

Radiocontrast media:Radiocontrast media:• Contrast-induced nephropathy has become a frequent Contrast-induced nephropathy has become a frequent

occurrence with increased number of studies requiring occurrence with increased number of studies requiring contrast media like angiography, CT scan, etccontrast media like angiography, CT scan, etc

• Iodinated contrast media causes vasoconstriction as well as Iodinated contrast media causes vasoconstriction as well as a direct toxic effects on tubular cells.a direct toxic effects on tubular cells.

• Patients at increased risk include diabetes, baseline renal Patients at increased risk include diabetes, baseline renal insufficiency, large contrast load, history of HTN, older age insufficiency, large contrast load, history of HTN, older age and presence of proteinuria.and presence of proteinuria.

Cyclosporine and tacrolimus:Cyclosporine and tacrolimus: Can cause ARF as well as chronic Can cause ARF as well as chronic interstitial nephritis.interstitial nephritis.

Sulfa drugsSulfa drugs, , acycloviracyclovir and and indinavirindinavir cause ARF by tubular cause ARF by tubular obstruction due to crystal formation in the tubular lumenobstruction due to crystal formation in the tubular lumen

Others:Others: Cisplatin, methotrexate and foscarnet, etc. Cisplatin, methotrexate and foscarnet, etc.

Endogenous toxinsEndogenous toxinsMyoglobinuriaMyoglobinuria• The breakdown of muscle (rhabdomyolysis), leading to The breakdown of muscle (rhabdomyolysis), leading to

myoglobinuria, occurs in many clinical settings like crush injuries, myoglobinuria, occurs in many clinical settings like crush injuries, viral illness, cocaine, heavy exercise, alcoholism, seizures and viral illness, cocaine, heavy exercise, alcoholism, seizures and certain medications. ATN can develop in small proportion of these certain medications. ATN can develop in small proportion of these patients.patients.

• The exact mechanism of renal failure is not clearly understood, The exact mechanism of renal failure is not clearly understood, but several theories include direct toxic injury, development of but several theories include direct toxic injury, development of DIC, mechanical tubular obstruction by the pigment and intrarenal DIC, mechanical tubular obstruction by the pigment and intrarenal ischemia from vasomediator release.ischemia from vasomediator release.

• Factors that increase the risk of ATN in this setting include Factors that increase the risk of ATN in this setting include extracellular fluid volume depletion, liver dysfunction and extracellular fluid volume depletion, liver dysfunction and hypotension.hypotension.

HemoglobinuriaHemoglobinuria ARF is a rare complication of hemolysis and hemoglobinuria and is ARF is a rare complication of hemolysis and hemoglobinuria and is

most often associated with transfusion reactions. Hemoglobin has most often associated with transfusion reactions. Hemoglobin has no apparent direct toxicity on the cells and the renal failure in this no apparent direct toxicity on the cells and the renal failure in this setting is probably related to hypotension and decrease renal setting is probably related to hypotension and decrease renal perfusion.perfusion.

Endogenous ToxinsEndogenous Toxins

Crystals: Crystals: Acute crystal-induced nephropathy is encountered in Acute crystal-induced nephropathy is encountered in

conditions where crystals are produced endogenously due conditions where crystals are produced endogenously due to high cellular turnover (i.e. uric acid, calcium phosphate), to high cellular turnover (i.e. uric acid, calcium phosphate), as seen in certain malignancies or the treatment of these as seen in certain malignancies or the treatment of these malignancies (tumor lysis syndrome). However, this malignancies (tumor lysis syndrome). However, this condition is also associated with ingestion of certain toxic condition is also associated with ingestion of certain toxic substances, such as ethylene glycol. substances, such as ethylene glycol.

Multiple myeloma:Multiple myeloma: This condition causes renal failure by several mechanisms, This condition causes renal failure by several mechanisms,

such as prerenal azotemia due to volume contraction, cast such as prerenal azotemia due to volume contraction, cast nephropathy due to increased light chain proteins nephropathy due to increased light chain proteins precipitated into the tubular lumen, hypercalcemia and uric precipitated into the tubular lumen, hypercalcemia and uric acid nephropathy.acid nephropathy.

WorkupWorkup

Lab studiesLab studies• Serum chemistries: By definition, BUN and serum Cr Serum chemistries: By definition, BUN and serum Cr

concentrations are increased. In addition, hyponatremia, concentrations are increased. In addition, hyponatremia, hyperkalemia, hypermagnesemia, hypocalcemia, hyperkalemia, hypermagnesemia, hypocalcemia, hyperphosphatemia and metabolic acidosis may be hyperphosphatemia and metabolic acidosis may be present. present. Remember that hypercalcemia and hyperuricemia Remember that hypercalcemia and hyperuricemia may suggest a malignant condition as a cause.may suggest a malignant condition as a cause.

• CBC: Pt may be anemic. Not only is erythropoietin CBC: Pt may be anemic. Not only is erythropoietin production decreased but platelet dysfunction from uremia production decreased but platelet dysfunction from uremia also makes bleeding more likely.also makes bleeding more likely.

• Urinalysis: May reveal muddy brown, granular casts and Urinalysis: May reveal muddy brown, granular casts and epithelial cell casts. In addition, checking urine lytes may epithelial cell casts. In addition, checking urine lytes may also help differentiate ATN from prerenal azotemia. also help differentiate ATN from prerenal azotemia.

Laboratory Findings Used to Laboratory Findings Used to Differentiate Prerenal Azotemia Differentiate Prerenal Azotemia

from ATNfrom ATN

FindingFinding Prerenal Prerenal AzotemiaAzotemia

ATNATN

Urine osmolarity Urine osmolarity (mOsm/kg)(mOsm/kg)

>500>500 <350 <350

Urine sodium Urine sodium (mmol/d)(mmol/d)

<20<20 >40>40

Fraction excretion Fraction excretion of sodium(%)of sodium(%)

<1<1 >2>2

Fraction excretion Fraction excretion of Urea(%)of Urea(%)

<35<35 >50>50

Plasma BUN/Cr Plasma BUN/Cr ratioratio

>20>20 <10-15<10-15

Urine Cr/Plasma Cr Urine Cr/Plasma Cr ratioratio

>40>40 <20<20

Urine sedimentUrine sediment Bland and/or Bland and/or nonspecificnonspecific

May show muddy May show muddy brown granular brown granular

castscasts

Lab (continued…)Lab (continued…)

Loss of concentrating ability is an early and Loss of concentrating ability is an early and almost universal finding in ATN.almost universal finding in ATN.

None of the above criteria for the diagnosis of None of the above criteria for the diagnosis of prerenal disease may be present in a patient with prerenal disease may be present in a patient with underlying renal disease. Hence, a cautious trial underlying renal disease. Hence, a cautious trial of fluids may be given.of fluids may be given.

Imaging StudiesImaging Studies

Abdominal radiograph is of limited benefit Abdominal radiograph is of limited benefit in ARF except in diagnosing (or excluding) in ARF except in diagnosing (or excluding) nephrolithiasis.nephrolithiasis.

UltrasoundUltrasound,, CT scan CT scan, or, or MRI MRI very useful, very useful, both to exclude obstructive uropathy and both to exclude obstructive uropathy and measure renal size and cortical thickness. measure renal size and cortical thickness.

Renal USRenal US is a simple, relatively is a simple, relatively inexpensive and non-invasive imaging inexpensive and non-invasive imaging modality and should be done in all modality and should be done in all patients presenting with ARF.patients presenting with ARF.

Renal biopsyRenal biopsy Biopsy is rarely necessary. It should only be performed when the Biopsy is rarely necessary. It should only be performed when the

exact renal cause of ARF is unclear, the course is protracted and exact renal cause of ARF is unclear, the course is protracted and knowing the exact cause is possibly knowing the exact cause is possibly going to change the going to change the management.management.

Needless to say, prerenal and postrenal causes must be ruled out Needless to say, prerenal and postrenal causes must be ruled out before subjecting a patient to this invasive procedure. The before subjecting a patient to this invasive procedure. The diagnosis of ATN is made on a clinical basis, i.e. with the help of diagnosis of ATN is made on a clinical basis, i.e. with the help of detailed and accurate history, thorough physical exam, and detailed and accurate history, thorough physical exam, and pertinent lab tests and imaging studies. pertinent lab tests and imaging studies.

A more urgent indication for renal biopsy is in the setting of A more urgent indication for renal biopsy is in the setting of clinical and urinary findings suggestive of clinical and urinary findings suggestive of renal vasculitisrenal vasculitis rather rather than ATN and the diagnosis needs to be established quickly so than ATN and the diagnosis needs to be established quickly so that appropriate immunomodulatory therapy can be initiated. that appropriate immunomodulatory therapy can be initiated.

Biopsy may also be more critically important in a Biopsy may also be more critically important in a renal transplant renal transplant patient to rule out rejection.patient to rule out rejection.

Other indications for biopsy include suspected Other indications for biopsy include suspected glomerulonephritisglomerulonephritis, , HUSHUS, , TTPTTP and and acute interstitial nephritisacute interstitial nephritis..

The biopsy is performed under ultrasound or CT guidance after The biopsy is performed under ultrasound or CT guidance after ascertaining the safety of the procedure.ascertaining the safety of the procedure.

ComplicationsComplications Patients with ATN can have several complications.Patients with ATN can have several complications. Electrolyte abnormalitiesElectrolyte abnormalities

• Hyperkalemia: Higher levels are associated with ECG Hyperkalemia: Higher levels are associated with ECG abnormalities (e.g. peaked T waves, prolonged PR interval, P abnormalities (e.g. peaked T waves, prolonged PR interval, P wave flattening, widened QRS) and risk of developing life-wave flattening, widened QRS) and risk of developing life-threatening arrhythmias (e.g. ventricular tachycardia or threatening arrhythmias (e.g. ventricular tachycardia or fibrillation, complete heart block, bradycardia, asystole). fibrillation, complete heart block, bradycardia, asystole). Arrhythmias have been reported in up to 30% of patients. In Arrhythmias have been reported in up to 30% of patients. In addition to these worrisome cardiac effects, hyperkalemia can addition to these worrisome cardiac effects, hyperkalemia can also lead to neuromuscular dysfunction and, potentially, also lead to neuromuscular dysfunction and, potentially, respiratory failure.respiratory failure.

• HyponatremiaHyponatremia• HyperphosphatemiaHyperphosphatemia• HypermagnesemiaHypermagnesemia• Hypocalcemia: Hypocalcemia may be secondary to both Hypocalcemia: Hypocalcemia may be secondary to both

deposition of calcium phosphate and reduced levels of 1,25 deposition of calcium phosphate and reduced levels of 1,25 dihydroxyvitamin D. It is usually asymptomatic, but hypocalcemia dihydroxyvitamin D. It is usually asymptomatic, but hypocalcemia may result in nonspecific ECG changes, muscle cramps, or may result in nonspecific ECG changes, muscle cramps, or seizures.seizures.

• Metabolic acidosisMetabolic acidosis

Complications Complications IntravascularIntravascular volume overload:volume overload: It is characterized by weight gain, raised It is characterized by weight gain, raised

jugular venous pressure and dependent edema. In its most severe jugular venous pressure and dependent edema. In its most severe manifestation, this may lead to respiratory failure from pulmonary manifestation, this may lead to respiratory failure from pulmonary edema.edema.

Hypertension:Hypertension: Hypertension is suspected to mainly be due to salt and Hypertension is suspected to mainly be due to salt and water retention. About 25% of patients with ARF develop some water retention. About 25% of patients with ARF develop some hypertension. hypertension.

Uremic syndrome/Uremia:Uremic syndrome/Uremia: Uremia results from the accumulation of Uremia results from the accumulation of nitrogenous waste. It is a potentially life-threatening complication nitrogenous waste. It is a potentially life-threatening complication associated with ARF. associated with ARF. • Platelet dysfunction is common and can lead to life-threatening Platelet dysfunction is common and can lead to life-threatening

hemorrhage.hemorrhage.• This may manifest as pericardial disease (uremic pericarditis…listen This may manifest as pericardial disease (uremic pericarditis…listen

for a rub on exam)for a rub on exam)• GI symptoms (i.e. nausea, vomiting, cramping)GI symptoms (i.e. nausea, vomiting, cramping)• Neurological symptoms (i.e. lethargy, confusion, asterixis, seizures). Neurological symptoms (i.e. lethargy, confusion, asterixis, seizures).

Anemia:Anemia: Anemia may develop from many possible causes. Anemia may develop from many possible causes. Erythropoiesis is reduced in ARF, but platelet dysfunction is also Erythropoiesis is reduced in ARF, but platelet dysfunction is also observed in the setting of uremia, which may predispose to hemorrhage. observed in the setting of uremia, which may predispose to hemorrhage. In addition, volume overload may lead to hemodilution, and red cell In addition, volume overload may lead to hemodilution, and red cell survival time may be decreased. survival time may be decreased.

Complications Complications Polyuric phase of ATN:Polyuric phase of ATN: This complication can lead This complication can lead

to hypovolemia and create a setting for prerenal to hypovolemia and create a setting for prerenal azotemia and perpetuation of ATN. azotemia and perpetuation of ATN.

Infections:Infections: Infections is the leading cause of Infections is the leading cause of morbidity and mortality and can occur in 30-70% morbidity and mortality and can occur in 30-70% of patients with ARF. Infections are more likely in of patients with ARF. Infections are more likely in these patients because of an impaired immune these patients because of an impaired immune system and because of increased use of system and because of increased use of indwelling catheters and intravenous needles.indwelling catheters and intravenous needles.

PreventionPrevention

Ischemic ATNIschemic ATN:: Be attentive to optimizing Be attentive to optimizing cardiovascular function as well as maintaining cardiovascular function as well as maintaining intravascular volume, especially in patients intravascular volume, especially in patients with preexisting risk factors or those taking with preexisting risk factors or those taking nephrotoxic medications. Medicines that nephrotoxic medications. Medicines that reduce systemic resistance (e.g. afterload reduce systemic resistance (e.g. afterload reducers) may cause renal vasoconstriction or reducers) may cause renal vasoconstriction or affect the kidney’s autoregulatory response affect the kidney’s autoregulatory response (e.g. ACE inhibitors, cyclooxygenase inhibitors) (e.g. ACE inhibitors, cyclooxygenase inhibitors) and also should be used with caution.and also should be used with caution.

Dopamine, mannitol and furosemide, etc have Dopamine, mannitol and furosemide, etc have been tried within 24 hrs of ischemic insult to been tried within 24 hrs of ischemic insult to prevent progression to ATN, but have no prevent progression to ATN, but have no proven benefit.proven benefit.

PreventionPrevention

• Nephrotoxic ATNNephrotoxic ATN AminoglycosidesAminoglycosides: Once daily dosing of : Once daily dosing of

aminoglycosides decreases the aminoglycosides decreases the incidence of nephrotoxicity. incidence of nephrotoxicity.

Amphotericin BAmphotericin B: Minimize the use of : Minimize the use of this drug and assure that ECF volume this drug and assure that ECF volume is adequate. is adequate.

Cyclosporin and tacrolimusCyclosporin and tacrolimus: Regular : Regular monitoring of blood levels. monitoring of blood levels.

Alkalinization of the urine should be Alkalinization of the urine should be tried in patients with marked tried in patients with marked myoglobinuria and hemoglobinuria.myoglobinuria and hemoglobinuria.

PreventionPrevention Radiocontrast dyeRadiocontrast dye: Out of all the agents/modalities that : Out of all the agents/modalities that

have been investigated for prevention of CIN, only the have been investigated for prevention of CIN, only the following have been shown to be of some benefit:following have been shown to be of some benefit:

11..HydrationHydration with isotonic saline infusion has proven benefits in with isotonic saline infusion has proven benefits in prevention of contrast-induced nephropathy. Typically, half prevention of contrast-induced nephropathy. Typically, half isotonic sodium chloride solution (0.45%) administered at a isotonic sodium chloride solution (0.45%) administered at a rate of 50-100 mL/h 12 hours before and 12 hours after the rate of 50-100 mL/h 12 hours before and 12 hours after the administration of the dye load is most effective, especially in administration of the dye load is most effective, especially in the setting of prior renal insufficiency and diabetes mellitus.the setting of prior renal insufficiency and diabetes mellitus.

2. 2. Low osmolal and iso-osmolalLow osmolal and iso-osmolal nonionic contrastnonionic contrast media are media are also associated with lower incidence of CIN. also associated with lower incidence of CIN.

3. 3. NN-acetylcysteine-acetylcysteine has been used with success in high-risk has been used with success in high-risk patients to prevent contrast-induced nephrotoxicity. patients to prevent contrast-induced nephrotoxicity.

4. Using 4. Using lower doses of contrast medialower doses of contrast media, , avoiding volume avoiding volume depletion and NSAIDsdepletion and NSAIDs,, both of which can cause renal both of which can cause renal vasoconstriction are some other useful measures. vasoconstriction are some other useful measures.

5. A new modality recently investigated is use of 5. A new modality recently investigated is use of prophylacticprophylactic hemofiltrationhemofiltration in patients who need contrast and have in patients who need contrast and have baseline renal insufficiency.baseline renal insufficiency.

The Prevention of Radiocontrast-Agent–Induced Nephropathy by Hemofiltration Giancarlo Marenzi, M.D., et al. NEJM October 2nd, 2003. 114 consecutive patients with chronic renal failure (serum creatinineconcentration, >2 mg/dl, who were undergoing coronary interventions, wereRandomly assigned to either hemofiltration in an intensive care unit (ICU) orisotonic-saline hydration at a rate of 1 ml per kilogram of body weight perhour given in a step-down unit. Hemofiltration and saline hydration wereinitiated 4 to 8 hours before the coronary intervention and were continued for18 to 24 hours after the procedure was completed. Results: Compared with intravenous saline, hemofiltration was associatedwith the following significant benefits  1. A lesser likelihood of an increase in the serum creatinine concentration of

greater than 25 percent from baseline values (5 versus 50 percent) 2. A lesser likelihood of requirement for temporary renal replacement

therapy (3 versus 25 percent) 3. A reduction in both in-house mortality (2 versus 14 percent) and one-year

mortality (10 versus 30 percent). 4. Greatest benefit was seen in patients with higher Cr (>4 mg/dl).

Until additional data are available, routine use of hemofiltration for prevention ofCIN is not recommended. However, consideration should be given to the use ofhemofiltration (in combination with other preventive measures) among patients at highestrisk of contrast nephropathy, particularly the diabetic patient with a baseline serumcreatinine concentration of 4 mg/dL or greater.

TreatmentTreatment General treatmentGeneral treatment

The main goal of treatment is to prevent further injury to The main goal of treatment is to prevent further injury to the kidney. ECF volume should be assessed promptly, the kidney. ECF volume should be assessed promptly, either on clinical grounds or by invasive means (Swan-Ganz either on clinical grounds or by invasive means (Swan-Ganz catheter), and repletion of any deficit should be initiated catheter), and repletion of any deficit should be initiated promptly. A renal ultrasound should be performed to promptly. A renal ultrasound should be performed to exclude obstruction. exclude obstruction.

All possible nephrotoxic drugs should be stopped. All possible nephrotoxic drugs should be stopped. In general, an attempt is made to increase the urine output In general, an attempt is made to increase the urine output

if oliguria is present, by using loop diuretics, although there if oliguria is present, by using loop diuretics, although there is some controversy about this in the literature. One is some controversy about this in the literature. One retrospective study showed that diuretics may even retrospective study showed that diuretics may even increase the risk of death and non-recovery of renal increase the risk of death and non-recovery of renal function. function. OnlyOnly use diuretics use diuretics ifif ECF volume and cardiac ECF volume and cardiac function are first carefully assessed and found adequate.function are first carefully assessed and found adequate.

The only true The only true indicationindication for diuretic use is for diuretic use is volume overloadvolume overload. . Furosemide and bumetanide are the commonly used Furosemide and bumetanide are the commonly used diuretics. diuretics.

Treatment Treatment Aggressively treat any complications that develop. Aggressively treat any complications that develop.

Remember that sepsis is a common cause of death Remember that sepsis is a common cause of death with severe ARF, so aggressive treatment of with severe ARF, so aggressive treatment of infections is prudent. However, prophylactic antibiotic infections is prudent. However, prophylactic antibiotic has not been proven to be of any benefit.has not been proven to be of any benefit.

Also, adjust doses of all medications if the kidney Also, adjust doses of all medications if the kidney eliminates them.eliminates them.

Various agents have been studied for their possible Various agents have been studied for their possible role in hastening tubular regeneration and functional role in hastening tubular regeneration and functional recovery in ATN including growth factors (IGF-I), low recovery in ATN including growth factors (IGF-I), low dose DA, combination of DA and ANP and anaritide (a dose DA, combination of DA and ANP and anaritide (a synthetic form of ANP) but have shown no benefit in synthetic form of ANP) but have shown no benefit in recovery or survival.recovery or survival.

Treatment Treatment Dialysis treatmentDialysis treatment

In general, no clear consensus is established on when or In general, no clear consensus is established on when or how often to perform hemodialysis in the setting of ARF. how often to perform hemodialysis in the setting of ARF. Some studies have suggested that early initiation may be Some studies have suggested that early initiation may be beneficial, but, in one prospective trial, aggressive dialysis beneficial, but, in one prospective trial, aggressive dialysis did not improve recovery or survival rates. However, did not improve recovery or survival rates. However, hemodialysis is still considered standard therapy in severe hemodialysis is still considered standard therapy in severe ARF. In addition, continuous hemodialysis (continuous ARF. In addition, continuous hemodialysis (continuous venovenous hemofiltration [CVVHD] and continuous venovenous hemofiltration [CVVHD] and continuous arteriovenous hemofiltration with dialysis (CAVHD) and arteriovenous hemofiltration with dialysis (CAVHD) and peritoneal dialysis are also available. No compelling peritoneal dialysis are also available. No compelling studies suggest that one mode is better than another. In studies suggest that one mode is better than another. In general, patients with multiorgan failure and general, patients with multiorgan failure and hemodynamic instability may benefit from a continuous hemodynamic instability may benefit from a continuous mode because it is typically less taxing on the mode because it is typically less taxing on the hemodynamics. hemodynamics.

Indications for dialysisIndications for dialysis: Clinical evidence of uremia, : Clinical evidence of uremia, intractable intravascular volume overload, hyperkalemia intractable intravascular volume overload, hyperkalemia or severe acidosis resistant to conservative measures.or severe acidosis resistant to conservative measures.

Treatment of ComplicationsTreatment of Complications Volume overload:Volume overload: Salt and water restriction, diuretics. Salt and water restriction, diuretics.

Dialysis for refractory cases.Dialysis for refractory cases. Hyperkalemia:Hyperkalemia: Restrict potassium intake, glucose and Restrict potassium intake, glucose and

insulin, sodium bicarbonate, kayexalate, calcium gluconate, insulin, sodium bicarbonate, kayexalate, calcium gluconate, dialysis.dialysis.

Metabolic acidosis:Metabolic acidosis: Sodium bicarb (only if HCO3 <15mmol/L Sodium bicarb (only if HCO3 <15mmol/L or pH<7.2) or dialysis.or pH<7.2) or dialysis.

Hypocalcemia:Hypocalcemia: Calcium carbonate, calcium gluconate. Calcium carbonate, calcium gluconate. Infections:Infections: Antibiotics, assess the IV sites. Antibiotics, assess the IV sites. Hyponatremia:Hyponatremia: Free water restriction. Free water restriction. Hyperphosphatemia:Hyperphosphatemia: Restrict phosphate intake, phosphate Restrict phosphate intake, phosphate

binding agents.binding agents. Hypermagnesemia:Hypermagnesemia: Avoid Mg containing antacids. Avoid Mg containing antacids. Anemia:Anemia: Blood transfusion may be required. Blood transfusion may be required.

NutritionNutrition Clearly, the maintenance of fluid and electrolyte Clearly, the maintenance of fluid and electrolyte

balance is critical. Aggressive and early balance is critical. Aggressive and early nutritional support also improves survival rates. nutritional support also improves survival rates. Adequate caloric intake is essential to avoid Adequate caloric intake is essential to avoid catabolism and starvation ketoacidosis, while catabolism and starvation ketoacidosis, while minimizing production of nitrogenous waste. This minimizing production of nitrogenous waste. This is best achieved by restricting dietary protein to is best achieved by restricting dietary protein to approximately 0.6g/kg/day of protein of high approximately 0.6g/kg/day of protein of high biologic value (rich in essential amino acids) and biologic value (rich in essential amino acids) and provide most calories as carbohydrate provide most calories as carbohydrate (approximately 100 g/day). (approximately 100 g/day).

Enteral hyperalimentation or parenteral nutrition Enteral hyperalimentation or parenteral nutrition if recovery prolonged or if patient very catabolic.if recovery prolonged or if patient very catabolic.

Mortality and MorbidityMortality and Morbidity The The in-hospitalin-hospital survival rate of patients with ATN survival rate of patients with ATN

is about is about 50%50%, with , with 30%30% surviving for surviving for 1 year1 year. . Factors associated with increased mortalityFactors associated with increased mortality

include:include: poor nutrition status, male sex, the poor nutrition status, male sex, the presence of oliguria, need for mechanical presence of oliguria, need for mechanical ventilation, chronic immunosuppression, acute ventilation, chronic immunosuppression, acute MI, stroke or seizures.MI, stroke or seizures.

The presence of renal failure itself seems to be a The presence of renal failure itself seems to be a prognostic factor in survival since it weakens prognostic factor in survival since it weakens immune system and impairs platelet function immune system and impairs platelet function thus predisposing the patient to sepsis and thus predisposing the patient to sepsis and bleeding.bleeding.

Mortality and MorbidityMortality and Morbidity Infections remain the leading cause of death.Infections remain the leading cause of death. For ARF the mortality rate is For ARF the mortality rate is 20-50%20-50% in patients with in patients with

underlying underlying medical illnessesmedical illnesses, but the mortality rate is as , but the mortality rate is as high as high as 60-70%60-70% with patients in a with patients in a surgical settingsurgical setting or with or with severe trauma. severe trauma. If If multiorgan failuremultiorgan failure is present, especially is present, especially severe hypotension or acute respiratory distress syndrome, severe hypotension or acute respiratory distress syndrome, the mortality rate ranges from the mortality rate ranges from 50-80%50-80%. .

With dialysis intervention, the frequency of uremia, With dialysis intervention, the frequency of uremia, hyperkalemia, and volume overload as causes of death hyperkalemia, and volume overload as causes of death have decreased. have decreased. The most common causes of death now The most common causes of death now are sepsis, cardiovascular and pulmonary dysfunction, and are sepsis, cardiovascular and pulmonary dysfunction, and withdrawal of life support. withdrawal of life support.

The type of dialysis membrane utilized during HD may also The type of dialysis membrane utilized during HD may also affect prognosis.affect prognosis.

PrognosisPrognosis

Patients with Patients with oliguric ATNoliguric ATN have a have a worse prognosisworse prognosis than patients with nonoliguric ATN. This probably than patients with nonoliguric ATN. This probably is related to more severe necrosis and more is related to more severe necrosis and more significant disturbances in electrolyte balance.significant disturbances in electrolyte balance.

Rapid increase in serum creatinineRapid increase in serum creatinine (i.e. >3 mg/dL) (i.e. >3 mg/dL) probably also indicates a probably also indicates a poorer prognosispoorer prognosis. Again, . Again, this probably reflects more serious underlying this probably reflects more serious underlying disease.disease.

Of the survivors of ATN, approximately Of the survivors of ATN, approximately 50% have 50% have residual subclinical impairment of renal functionresidual subclinical impairment of renal function, , aboutabout 5% 5% continue to undergo a decline in renal continue to undergo a decline in renal function function following an initialfollowing an initial recovery phase and recovery phase and about about 5%5% never recover never recover kidney function and kidney function and require dialysisrequire dialysis..