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1. Acute Tubular NecrosisAcute Tubular Necrosis
Resident’s conference
Presented by Dr Gagandeep K Heer, MD
(PGY-2)

2. BackgroundBackground
 DefinitionDefinition:: ARF is defined as an abrupt orARF is defined as an abrupt or
rapid decline in the renal function.rapid decline in the renal function.
 A rise in serum BUN or creatinineA rise in serum BUN or creatinine
concentration, with or without decrease inconcentration, with or without decrease in
urine output, usually is evidence of ARF.urine output, usually is evidence of ARF.
 ARF is often transient and completelyARF is often transient and completely
reversible.reversible.

3. BackgroundBackground
 The causes of ARF are divided into 3 categories:The causes of ARF are divided into 3 categories:
PPrerenalrerenal
RenalRenal
PostrenalPostrenal
 ATNATN is the most common cause of ARF in theis 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 inmost common cause of all categories of ARF in
hospitalizedhospitalized patients, with only prerenal azotemia occurringpatients, with only prerenal azotemia occurring
more frequently.more frequently.
 In outpatients, obstruction (ureteric, bladder neck or urethral)In outpatients, obstruction (ureteric, bladder neck or urethral)
is the 2is the 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, acuteOther 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, renovascularradiation nephritis, acute on chronic renal failure, renovascular
obstruction (bilateral or unilateral in the setting of singleobstruction (bilateral or unilateral in the setting of single
functioning kidney), renal allograft rejection, intratubularfunctioning kidney), renal allograft rejection, intratubular
deposition and obstruction (myeloma proteins, urate, oxalatedeposition and obstruction (myeloma proteins, urate, oxalate
crystals, etc.)crystals, etc.)

4. PathophysiologyPathophysiology
 ATN usually occurs after an acute ischemic orATN usually occurs after an acute ischemic or
toxic event, and it has a well-defined sequence oftoxic event, and it has a well-defined sequence of
events.events.
 Initiation phaseInitiation phase characterized by acute decreasecharacterized by acute decrease
in GFR to very low levels, with a sudden increasein 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 sustainedis characterized by sustained
severe reduction in GFR and the BUN and Crsevere 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 urinerestored, is characterized by an increase in urine
volume (if oliguria was present) and gradualvolume (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.

5. Ischemic ATNIschemic ATN
 Ischemic ATN is often described as a continuum of prerenalIschemic ATN is often described as a continuum of prerenal
azotemia. Response to fluid repletion can help distinguishazotemia. Response to fluid repletion can help distinguish
between the two: return of renal function within 24-72between the two: return of renal function within 24-72
hours usually indicate prerenal disease although short-livedhours usually indicate prerenal disease although short-lived
ATN can recover within similar timeframe (e.g. self limitedATN can recover within similar timeframe (e.g. self limited
insult such as transient aortic clamping during suprarenalinsult such as transient aortic clamping during suprarenal
aortic aneurysm surgery).aortic aneurysm surgery).
 Initiation phaseInitiation phase:: Hypoperfusion initiates cell injury thatHypoperfusion initiates cell injury that
often leads to cell death. It is most prominent in straightoften leads to cell death. It is most prominent in straight
portion of the proximal tubules and thick ascending limb ofportion of the proximal tubules and thick ascending limb of
loop of Henle. The reduction in the GFR occurs not onlyloop of Henle. The reduction in the GFR occurs not only
fromfrom reduced filtrationreduced filtration due to hypoperfusion but also fromdue to hypoperfusion but also from
casts and debriscasts and debris obstructingobstructing the lumen, causing back leakthe lumen, causing back leak
of filtrate through the damaged epithelium (of filtrate through the damaged epithelium (ineffectiveineffective
filtrationfiltration). In addition, ischemia leads to decreased). In addition, ischemia leads to decreased
production of vasodilators (i.e. nitric oxide, prostacyclin) byproduction of vasodilators (i.e. nitric oxide, prostacyclin) by
tubular epithelial cells, leading to further vasoconstrictiontubular epithelial cells, leading to further vasoconstriction
and hypoperfusion.and hypoperfusion.

6. Ischemic ATNIschemic ATN
 Maintenance phaseMaintenance phase is characterized by stabilization ofis 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 phase.Uremic complications typically develop during this phase.
In addition to the above mentioned mechanism of injury,In addition to the above mentioned mechanism of injury,
tubulo-glomerular feedback also plays a role by causingtubulo-glomerular feedback also plays a role by causing
constriction of afferent arterioles by the macula densaconstriction of afferent arterioles by the macula densa
cells, which detect and increased salt load in the distalcells, which detect and increased salt load in the distal
tubules.tubules.
 DuringDuring 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. Thecausing 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 tubularbut it may in part be due to delayed recovery of tubular
cell function in the setting of increased glomerularcell function in the setting of increased glomerular
filtration. In addition, continued use of diuretics (oftenfiltration. 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.

7. Nephrotoxic ATNNephrotoxic ATN
 Most of the pathophysiological features ofMost of the pathophysiological features of
ischemic ATN are shared by theischemic ATN are shared by the
nephrotoxic forms and it has the samenephrotoxic forms and it has the same
three phases.three phases.
 Nephrotoxic injury to tubular cells occursNephrotoxic injury to tubular cells occurs
by multiple mechanisms including directby multiple mechanisms including direct
toxicity, intrarenal vasoconstriction, andtoxicity, intrarenal vasoconstriction, and
intratubular obstruction.intratubular obstruction.

9. 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 cellion 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 otherinhibition of active sodium transport and transport of other
solutes, impairment of cell volume regulation, cytoskeletalsolutes, impairment of cell volume regulation, cytoskeletal
disruption and loss of cell polarity, cell-cell and cell-matrixdisruption and loss of cell polarity, cell-cell and cell-matrix
attachment, accumulation of intracellular calcium, alteredattachment, accumulation of intracellular calcium, altered
phospholipid metabolism, oxygen free radical formation andphospholipid metabolism, oxygen free radical formation and
peroxidation of membrane lipids.peroxidation of membrane lipids.
A characteristic feature of ischemic ATN is the absence ofA characteristic feature of ischemic ATN is the absence of
widespread necrosis of tubular epithelial cells. Necrosis is morewidespread necrosis of tubular epithelial cells. Necrosis is more
subtle and is reflected in individual necrotic cells within somesubtle and is reflected in individual necrotic cells within some
proximal or distal tubules. These single cells shed into tubularproximal or distal tubules. These single cells shed into tubular
lumen, with resulting focal denudation of the tubular basementlumen, with resulting focal denudation of the tubular basement
membrane. Interstitial edema is common.membrane. Interstitial edema is common.

10. Ischemic ATNIschemic ATN

11. Histology (continued…)Histology (continued…)
 Toxic ATNToxic ATN:: The morphology differs from ischemicThe morphology differs from ischemic
ATN in that the former is characterized by moreATN in that the former is characterized by more
extensive necrosis of the tubular epithelium. Inextensive necrosis of the tubular epithelium. In
most cases, however, the necrosis is limited tomost cases, however, the necrosis is limited to
certain segments that are most sensitive to thecertain segments that are most sensitive to the
toxin. ATN caused by hemoglobin or myoglobintoxin. ATN caused by hemoglobin or myoglobin
has added feature of numerous red-brownhas added feature of numerous red-brown
tubular casts, colored by heme pigments.tubular casts, colored by heme pigments.
 During theDuring the recovery phaserecovery phase of ATN, the tubularof ATN, the tubular
epithelium regenerates, leading to theepithelium regenerates, leading to the
appearance of mitoses, increased size of cells andappearance of mitoses, increased size of cells and
nuclei, and cell crowding. Survivors eventuallynuclei, and cell crowding. Survivors eventually
display complete restoration of normal renaldisplay complete restoration of normal renal
architecture.architecture.

12. Nephrotoxic ATNNephrotoxic ATN

13. FrequencyFrequency
 In the US: ARF is seen in 5% of allIn the US: ARF is seen in 5% of all
hospital admissions and upto 30% ofhospital admissions and upto 30% of
patients admitted to the ICU. Prerenalpatients admitted to the ICU. Prerenal
causes account for about half of all cases.causes account for about half of all cases.
 ATN is most common cause out of theATN is most common cause out of the
intrinsic renal diseases.intrinsic renal diseases.

14. HistoryHistory
 A good history is very important in diagnosis ofA 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 likeOther risk factors for development of ATN like
underlying renal disease from DM, HTN, etc.underlying renal disease from DM, HTN, etc.

15. Physical ExamPhysical Exam
 Physical exam may be unremarkable because ARFPhysical exam may be unremarkable because ARF
is often found incidentally during routineis 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 haveLook for pericardial friction rub (pt may have
pericarditis), asterixis and/or excoriation markspericarditis), 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 underlyingPhysical findings related to the underlying
disease.disease.

16. 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.

17. Causes of Ischemic ATNCauses of Ischemic ATN
It may be considered part of the spectrumIt may be considered part of the spectrum
of prerenal azotemia and they have theof prerenal azotemia and they have the
same causes and risk factorssame causes and risk factors
• Hypovolumic states – hemorrhage, volumeHypovolumic 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 otherLow cardiac output states – CHF and other
diseases of the myocardium, valvulopathy,diseases of the myocardium, valvulopathy,
arrhythmia, pericardial diseases,arrhythmia, pericardial diseases,
tamponade.tamponade.

18. Causes of Ischemic ATNCauses of Ischemic ATN
• Systemic vasodilation – sepsis,Systemic vasodilation – sepsis,
anaphylaxisanaphylaxis
• DICDIC
• Renal vasoconstriction – cyclosporine,Renal vasoconstriction – cyclosporine,
norepinephrine, epinephrine, amphotericinnorepinephrine, epinephrine, amphotericin
B, etcB, etc
• Hyperviscosity syndromeHyperviscosity syndrome
• Impaired renal autoregulatory responses –Impaired renal autoregulatory responses –
cyclooxygenase inhibitorscyclooxygenase inhibitors

19. Causes of Nephrotoxic ATNCauses of Nephrotoxic ATN
The kidney is a good target for toxins. NotThe 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 inreceiving 25% of CO, but it also helps in
the excretion of these toxins bythe excretion of these toxins by
glomerular filtration and tubular secretion.glomerular filtration and tubular secretion.

20. Exogenous toxinsExogenous toxins
Aminoglycosides:Aminoglycosides:
• 10-30% of patients getting aminoglycosides10-30% 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 otherrenal disease, concomitant use of other
nephrotoxins, advanced age, shock, female sexnephrotoxins, 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 3Toxicity presumably more common with 3
doses/day than a single daily dose (as the drugdoses/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 directThe likelihood of toxicity is in direct
proportion to the total dose administered and isproportion to the total dose administered and is
more common if > 3 grams is administered.more common if > 3 grams is administered.

21. Exogenous ToxinsExogenous Toxins
Radiocontrast media:Radiocontrast media:
• Contrast-induced nephropathy has become a frequentContrast-induced nephropathy has become a frequent
occurrence with increased number of studies requiringoccurrence 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 asIodinated 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 renalPatients at increased risk include diabetes, baseline renal
insufficiency, large contrast load, history of HTN, older ageinsufficiency, 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 chronicCan cause ARF as well as chronic
interstitial nephritis.interstitial nephritis.
Sulfa drugsSulfa drugs,, acycloviracyclovir andand indinavirindinavir cause ARF by tubularcause 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.

22. Endogenous toxinsEndogenous toxins
MyoglobinuriaMyoglobinuria
• The breakdown of muscle (rhabdomyolysis), leading toThe 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 andviral illness, cocaine, heavy exercise, alcoholism, seizures and
certain medications. ATN can develop in small proportion of thesecertain 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 ofbut several theories include direct toxic injury, development of
DIC, mechanical tubular obstruction by the pigment and intrarenalDIC, 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 includeFactors that increase the risk of ATN in this setting include
extracellular fluid volume depletion, liver dysfunction andextracellular fluid volume depletion, liver dysfunction and
hypotension.hypotension.
HemoglobinuriaHemoglobinuria
ARF is a rare complication of hemolysis and hemoglobinuria and isARF is a rare complication of hemolysis and hemoglobinuria and is
most often associated with transfusion reactions. Hemoglobin hasmost often associated with transfusion reactions. Hemoglobin has
no apparent direct toxicity on the cells and the renal failure in thisno apparent direct toxicity on the cells and the renal failure in this
setting is probably related to hypotension and decrease renalsetting is probably related to hypotension and decrease renal
perfusion.perfusion.

23. Endogenous ToxinsEndogenous Toxins
Crystals:Crystals:
Acute crystal-induced nephropathy is encountered inAcute crystal-induced nephropathy is encountered in
conditions where crystals are produced endogenously dueconditions 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 theseas seen in certain malignancies or the treatment of these
malignancies (tumor lysis syndrome). However, thismalignancies (tumor lysis syndrome). However, this
condition is also associated with ingestion of certain toxiccondition 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, castsuch as prerenal azotemia due to volume contraction, cast
nephropathy due to increased light chain proteinsnephropathy due to increased light chain proteins
precipitated into the tubular lumen, hypercalcemia and uricprecipitated into the tubular lumen, hypercalcemia and uric
acid nephropathy.acid nephropathy.

24. WorkupWorkup
Lab studiesLab studies
• Serum chemistries: By definition, BUN and serum CrSerum 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 present.hyperphosphatemia and metabolic acidosis may be present.
Remember that hypercalcemia and hyperuricemia mayRemember that hypercalcemia and hyperuricemia may
suggest a malignant condition as a cause.suggest a malignant condition as a cause.
• CBC: Pt may be anemic. Not only is erythropoietinCBC: Pt may be anemic. Not only is erythropoietin
production decreased but platelet dysfunction from uremiaproduction decreased but platelet dysfunction from uremia
also makes bleeding more likely.also makes bleeding more likely.
• Urinalysis: May reveal muddy brown, granular casts andUrinalysis: May reveal muddy brown, granular casts and
epithelial cell casts. In addition, checking urine lytes mayepithelial cell casts. In addition, checking urine lytes may
also help differentiate ATN from prerenal azotemia.also help differentiate ATN from prerenal azotemia.

27. Laboratory Findings Used toLaboratory Findings Used to
Differentiate Prerenal AzotemiaDifferentiate Prerenal Azotemia
from ATNfrom ATN

28. FindingFinding PrerenalPrerenal
AzotemiaAzotemia
ATNATN
Urine osmolarityUrine osmolarity
(mOsm/kg)(mOsm/kg)
>500>500 <350<350
Urine sodiumUrine sodium
(mmol/d)(mmol/d)
<20<20 >40>40
Fraction excretionFraction excretion
of sodium(%)of sodium(%)
<1<1 >2>2
Fraction excretionFraction excretion
of Urea(%)of Urea(%)
<35<35 >50>50
Plasma BUN/CrPlasma BUN/Cr
ratioratio
>20>20 <10-15<10-15
Urine Cr/Plasma CrUrine Cr/Plasma Cr
ratioratio
>40>40 <20<20
Urine sedimentUrine sediment Bland and/orBland and/or
nonspecificnonspecific
May show muddyMay show muddy
brown granularbrown granular
castscasts

29. Lab (continued…)Lab (continued…)
 Loss of concentrating ability is an early andLoss 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 ofNone of the above criteria for the diagnosis of
prerenal disease may be present in a patient withprerenal disease may be present in a patient with
underlying renal disease. Hence, a cautious trialunderlying renal disease. Hence, a cautious trial
of fluids may be given.of fluids may be given.

30. Imaging StudiesImaging Studies
 Abdominal radiograph is of limited benefitAbdominal radiograph is of limited benefit
in ARF except in diagnosing (or excluding)in ARF except in diagnosing (or excluding)
nephrolithiasis.nephrolithiasis.
 UltrasoundUltrasound,, CT scanCT scan, or, or MRIMRI very useful,very useful,
both to exclude obstructive uropathy andboth to exclude obstructive uropathy and
measure renal size and cortical thickness.measure renal size and cortical thickness.
 Renal USRenal US is a simple, relativelyis a simple, relatively
inexpensive and non-invasive imaginginexpensive and non-invasive imaging
modality and should be done in all patientsmodality and should be done in all patients
presenting with ARF.presenting with ARF.

31. Renal biopsyRenal biopsy
 Biopsy is rarely necessary. It should only be performed when theBiopsy is rarely necessary. It should only be performed when the
exact renal cause of ARF is unclear, the course is protracted andexact renal cause of ARF is unclear, the course is protracted and
knowing the exact cause is possiblyknowing the exact cause is possibly going to change thegoing to change the
management.management.
 Needless to say, prerenal and postrenal causes must be ruled outNeedless to say, prerenal and postrenal causes must be ruled out
before subjecting a patient to this invasive procedure. Thebefore subjecting a patient to this invasive procedure. The
diagnosis of ATN is made on a clinical basis, i.e. with the help ofdiagnosis of ATN is made on a clinical basis, i.e. with the help of
detailed and accurate history, thorough physical exam, anddetailed 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 ofA more urgent indication for renal biopsy is in the setting of
clinical and urinary findings suggestive ofclinical and urinary findings suggestive of renal vasculitisrenal vasculitis ratherrather
than ATN and the diagnosis needs to be established quickly sothan 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 aBiopsy may also be more critically important in a renal transplantrenal transplant
patient to rule out rejection.patient to rule out rejection.
 Other indications for biopsy include suspectedOther indications for biopsy include suspected glomerulonephritisglomerulonephritis,,
HUSHUS,, TTPTTP andand acute interstitial nephritisacute interstitial nephritis..
 The biopsy is performed under ultrasound or CT guidance afterThe biopsy is performed under ultrasound or CT guidance after
ascertaining the safety of the procedure.ascertaining the safety of the procedure.

32. ComplicationsComplications
Patients with ATN can have several complications.Patients with ATN can have several complications.
 Electrolyte abnormalitiesElectrolyte abnormalities
• Hyperkalemia: Higher levels are associated with ECGHyperkalemia: Higher levels are associated with ECG
abnormalities (e.g. peaked T waves, prolonged PR interval, Pabnormalities (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 orthreatening 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. InArrhythmias have been reported in up to 30% of patients. In
addition to these worrisome cardiac effects, hyperkalemia canaddition 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 bothHypocalcemia: Hypocalcemia may be secondary to both
deposition of calcium phosphate and reduced levels of 1,25deposition of calcium phosphate and reduced levels of 1,25
dihydroxyvitamin D. It is usually asymptomatic, butdihydroxyvitamin D. It is usually asymptomatic, but
hypocalcemia may result in nonspecific ECG changes, musclehypocalcemia may result in nonspecific ECG changes, muscle
cramps, or seizures.cramps, or seizures.
• Metabolic acidosisMetabolic acidosis

33. ComplicationsComplications
 IntravascularIntravascular volume overload:volume overload: It is characterized by weight gain,It is characterized by weight gain,
raised jugular venous pressure and dependent edema. In its mostraised jugular venous pressure and dependent edema. In its most
severe manifestation, this may lead to respiratory failure fromsevere manifestation, this may lead to respiratory failure from
pulmonary edema.pulmonary edema.
 Hypertension:Hypertension: Hypertension is suspected to mainly be due to saltHypertension is suspected to mainly be due to salt
and water retention. About 25% of patients with ARF developand water retention. About 25% of patients with ARF develop
some hypertension.some hypertension.
 Uremic syndrome/Uremia:Uremic syndrome/Uremia: Uremia results from the accumulationUremia results from the accumulation
of nitrogenous waste. It is a potentially life-threateningof nitrogenous waste. It is a potentially life-threatening
complication associated with ARF.complication associated with ARF.
• Platelet dysfunction is common and can lead to life-threateningPlatelet dysfunction is common and can lead to life-threatening
hemorrhage.hemorrhage.
• This may manifest as pericardial disease (uremic pericarditis…This may manifest as pericardial disease (uremic pericarditis…
listen for a rub on exam)listen 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,Neurological symptoms (i.e. lethargy, confusion, asterixis,
seizures).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 alsoErythropoiesis is reduced in ARF, but platelet dysfunction is also
observed in the setting of uremia, which may predispose toobserved in the setting of uremia, which may predispose to
hemorrhage. In addition, volume overload may lead tohemorrhage. In addition, volume overload may lead to
hemodilution, and red cell survival time may be decreased.hemodilution, and red cell survival time may be decreased.

34. ComplicationsComplications
 Polyuric phase of ATN:Polyuric phase of ATN: This complication can leadThis complication can lead
to hypovolemia and create a setting for prerenalto hypovolemia and create a setting for prerenal
azotemia and perpetuation of ATN.azotemia and perpetuation of ATN.
 Infections:Infections: Infections is the leading cause ofInfections 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 inof patients with ARF. Infections are more likely in
these patients because of an impaired immunethese patients because of an impaired immune
system and because of increased use ofsystem and because of increased use of
indwelling catheters and intravenous needles.indwelling catheters and intravenous needles.

35. PreventionPrevention
 Ischemic ATNIschemic ATN:: Be attentive to optimizingBe attentive to optimizing
cardiovascular function as well as maintainingcardiovascular function as well as maintaining
intravascular volume, especially in patientsintravascular volume, especially in patients
with preexisting risk factors or those takingwith preexisting risk factors or those taking
nephrotoxic medications. Medicines that reducenephrotoxic medications. Medicines that reduce
systemic resistance (e.g. afterload reducers)systemic resistance (e.g. afterload reducers)
may cause renal vasoconstriction or affect themay cause renal vasoconstriction or affect the
kidney’s autoregulatory response (e.g. ACEkidney’s autoregulatory response (e.g. ACE
inhibitors, cyclooxygenase inhibitors) and alsoinhibitors, cyclooxygenase inhibitors) and also
should be used with caution.should be used with caution.
 Dopamine, mannitol and furosemide, etc haveDopamine, mannitol and furosemide, etc have
been tried within 24 hrs of ischemic insult tobeen tried within 24 hrs of ischemic insult to
prevent progression to ATN, but have noprevent progression to ATN, but have no
proven benefit.proven benefit.

36. PreventionPrevention
• Nephrotoxic ATNNephrotoxic ATN
 AminoglycosidesAminoglycosides: Once daily dosing of: Once daily dosing of
aminoglycosides decreases theaminoglycosides 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 volumethis 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 beAlkalinization of the urine should be
tried in patients with markedtried in patients with marked
myoglobinuria and hemoglobinuria.myoglobinuria and hemoglobinuria.

37. PreventionPrevention
 Radiocontrast dyeRadiocontrast dye: Out of all the agents/modalities: Out of all the agents/modalities
that have been investigated for prevention of CIN, onlythat have been investigated for prevention of CIN, only
the following have been shown to be of some benefit:the following have been shown to be of some benefit:
11..HydrationHydration with isotonic saline infusion has provenwith isotonic saline infusion has proven
benefits in prevention of contrast-induced nephropathy.benefits in prevention of contrast-induced nephropathy.
Typically, half isotonic sodium chloride solutionTypically, half isotonic sodium chloride solution
(0.45%) administered at a rate of 50-100 mL/h 12(0.45%) administered at a rate of 50-100 mL/h 12
hours before and 12 hours after the administration ofhours before and 12 hours after the administration of
the dye load is most effective, especially in the settingthe dye load is most effective, especially in the setting
of prior renal insufficiency and diabetes mellitus.of prior renal insufficiency and diabetes mellitus.
2.2. Low osmolal and iso-osmolalLow osmolal and iso-osmolal nonionic contrastnonionic contrast mediamedia
are also associated with lower incidence of CIN.are also associated with lower incidence of CIN.
3.3. NN-acetylcysteine-acetylcysteine has been used with success in high-has been used with success in high-
risk patients to prevent contrast-inducedrisk patients to prevent contrast-induced
nephrotoxicity.nephrotoxicity.
4. Using4. Using lower doses of contrast medialower doses of contrast media,, avoiding volumeavoiding volume
depletion and NSAIDsdepletion and NSAIDs,, both of which can cause renalboth 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 of5. A new modality recently investigated is use of
prophylacticprophylactic hemofiltrationhemofiltration in patients who needin patients who need
contrast and have baseline renal insufficiency.contrast and have baseline renal insufficiency.

38. 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 creatinine
concentration, >2 mg/dl, who were undergoing coronary interventions, were
Randomly assigned to either hemofiltration in an intensive care unit (ICU) or
isotonic-saline hydration at a rate of 1 ml per kilogram of body weight per
hour given in a step-down unit. Hemofiltration and saline hydration were
initiated 4 to 8 hours before the coronary intervention and were continued for
18 to 24 hours after the procedure was completed.
Results: Compared with intravenous saline, hemofiltration was associated
with 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 of
CIN is not recommended. However, consideration should be given to the use of
hemofiltration (in combination with other preventive measures) among patients at highest
risk of contrast nephropathy, particularly the diabetic patient with a baseline serum
creatinine concentration of 4 mg/dL or greater.

39. TreatmentTreatment
 General treatmentGeneral treatment
 The main goal of treatment is to prevent further injury toThe 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-either on clinical grounds or by invasive means (Swan-
Ganz catheter), and repletion of any deficit should beGanz catheter), and repletion of any deficit should be
initiated promptly. A renal ultrasound should be performedinitiated promptly. A renal ultrasound should be performed
to exclude obstruction.to 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 outputIn general, an attempt is made to increase the urine output
if oliguria is present, by using loop diuretics, although thereif oliguria is present, by using loop diuretics, although there
is some controversy about this in the literature. Oneis some controversy about this in the literature. One
retrospective study showed that diuretics may evenretrospective study showed that diuretics may even
increase the risk of death and non-recovery of renalincrease the risk of death and non-recovery of renal
function.function. OnlyOnly use diureticsuse diuretics ifif ECF volume and cardiacECF volume and cardiac
function are first carefully assessed and found adequate.function are first carefully assessed and found adequate.
 The only trueThe only true indicationindication for diuretic use isfor diuretic use is volume overloadvolume overload..
Furosemide and bumetanide are the commonly usedFurosemide and bumetanide are the commonly used
diuretics.diuretics.

40. TreatmentTreatment
 Aggressively treat any complications that develop.Aggressively treat any complications that develop.
Remember that sepsis is a common cause of deathRemember that sepsis is a common cause of death
with severe ARF, so aggressive treatment ofwith severe ARF, so aggressive treatment of
infections is prudent. However, prophylactic antibioticinfections 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 kidneyAlso, adjust doses of all medications if the kidney
eliminates them.eliminates them.
 Various agents have been studied for their possibleVarious agents have been studied for their possible
role in hastening tubular regeneration and functionalrole in hastening tubular regeneration and functional
recovery in ATN including growth factors (IGF-I), lowrecovery in ATN including growth factors (IGF-I), low
dose DA, combination of DA and ANP and anaritide (adose DA, combination of DA and ANP and anaritide (a
synthetic form of ANP) but have shown no benefit insynthetic form of ANP) but have shown no benefit in
recovery or survival.recovery or survival.

41. TreatmentTreatment
 Dialysis treatmentDialysis treatment
 In general, no clear consensus is established onIn general, no clear consensus is established on
when or how often to perform hemodialysis in thewhen or how often to perform hemodialysis in the
setting of ARF. Some studies have suggested thatsetting of ARF. Some studies have suggested that
early initiation may be beneficial, but, in oneearly initiation may be beneficial, but, in one
prospective trial, aggressive dialysis did not improveprospective trial, aggressive dialysis did not improve
recovery or survival rates. However, hemodialysis isrecovery or survival rates. However, hemodialysis is
still considered standard therapy in severe ARF. Instill considered standard therapy in severe ARF. In
addition, continuous hemodialysis (continuousaddition, continuous hemodialysis (continuous
venovenous hemofiltration [CVVHD] and continuousvenovenous hemofiltration [CVVHD] and continuous
arteriovenous hemofiltration with dialysis (CAVHD)arteriovenous hemofiltration with dialysis (CAVHD)
and peritoneal dialysis are also available. Noand peritoneal dialysis are also available. No
compelling studies suggest that one mode is bettercompelling studies suggest that one mode is better
than another. In general, patients with multiorganthan another. In general, patients with multiorgan
failure and hemodynamic instability may benefit fromfailure and hemodynamic instability may benefit from
a continuous mode because it is typically less taxinga continuous mode because it is typically less taxing
on the hemodynamics.on the hemodynamics.
 Indications for dialysisIndications for dialysis: Clinical evidence of uremia,: Clinical evidence of uremia,
intractable intravascular volume overload,intractable intravascular volume overload,
hyperkalemia or severe acidosis resistant tohyperkalemia or severe acidosis resistant to
conservative measures.conservative measures.

42. 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 andRestrict 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 HCO3Sodium bicarb (only if HCO3
<15mmol/L or pH<7.2) or dialysis.<15mmol/L 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, phosphateRestrict 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.

43. NutritionNutrition
 Clearly, the maintenance of fluid and electrolyteClearly, the maintenance of fluid and electrolyte
balance is critical. Aggressive and earlybalance is critical. Aggressive and early
nutritional support also improves survival rates.nutritional support also improves survival rates.
Adequate caloric intake is essential to avoidAdequate caloric intake is essential to avoid
catabolism and starvation ketoacidosis, whilecatabolism and starvation ketoacidosis, while
minimizing production of nitrogenous waste. Thisminimizing production of nitrogenous waste. This
is best achieved by restricting dietary protein tois best achieved by restricting dietary protein to
approximately 0.6g/kg/day of protein of highapproximately 0.6g/kg/day of protein of high
biologic value (rich in essential amino acids) andbiologic value (rich in essential amino acids) and
provide most calories as carbohydrateprovide most calories as carbohydrate
(approximately 100 g/day).(approximately 100 g/day).
 Enteral hyperalimentation or parenteral nutritionEnteral hyperalimentation or parenteral nutrition
if recovery prolonged or if patient very catabolic.if recovery prolonged or if patient very catabolic.

44. Mortality and MorbidityMortality and Morbidity
 TheThe in-hospitalin-hospital survival rate of patients with ATNsurvival rate of patients with ATN
is aboutis about 50%50%, with, with 30%30% surviving forsurviving for 1 year1 year..
 Factors associated with increased mortalityFactors associated with increased mortality
include:include: poor nutrition status, male sex, thepoor nutrition status, male sex, the
presence of oliguria, need for mechanicalpresence of oliguria, need for mechanical
ventilation, chronic immunosuppression, acuteventilation, chronic immunosuppression, acute
MI, stroke or seizures.MI, stroke or seizures.
 The presence of renal failure itself seems to be aThe presence of renal failure itself seems to be a
prognostic factor in survival since it weakensprognostic factor in survival since it weakens
immune system and impairs platelet functionimmune system and impairs platelet function
thus predisposing the patient to sepsis andthus predisposing the patient to sepsis and
bleeding.bleeding.

45. Mortality and MorbidityMortality and Morbidity
 Infections remain the leading cause of death.Infections remain the leading cause of death.
 For ARF the mortality rate isFor ARF the mortality rate is 20-50%20-50% in patients within patients with
underlyingunderlying medical illnessesmedical illnesses, but the mortality rate is as, but the mortality rate is as
high ashigh as 60-70%60-70% with patients in awith patients in a surgical settingsurgical setting or withor with
severe trauma.severe trauma. IfIf multiorgan failuremultiorgan failure is present, especiallyis present, especially
severe hypotension or acute respiratory distress syndrome,severe hypotension or acute respiratory distress syndrome,
the mortality rate ranges fromthe 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 deathhyperkalemia, and volume overload as causes of death
have decreased.have decreased. The most common causes of death nowThe most common causes of death now
are sepsis, cardiovascular and pulmonary dysfunction, andare sepsis, cardiovascular and pulmonary dysfunction, and
withdrawal of life support.withdrawal of life support.
 The type of dialysis membrane utilized during HD may alsoThe type of dialysis membrane utilized during HD may also
affect prognosis.affect prognosis.

46. PrognosisPrognosis
 Patients withPatients with oliguric ATNoliguric ATN have ahave a worse prognosisworse prognosis
than patients with nonoliguric ATN. This probablythan patients with nonoliguric ATN. This probably
is related to more severe necrosis and moreis 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(i.e. >3
mg/dL) probably also indicates amg/dL) probably also indicates a poorerpoorer
prognosisprognosis. Again, this probably reflects more. Again, this probably reflects more
serious underlying disease.serious underlying disease.
 Of the survivors of ATN, approximatelyOf the survivors of ATN, approximately 50% have50% have
residual subclinical impairment of renal functionresidual subclinical impairment of renal function,,
aboutabout 5%5% continue to undergo a decline in renalcontinue to undergo a decline in renal
functionfunction following an initialfollowing an initial recovery phase andrecovery phase and
aboutabout 5%5% never recovernever recover kidney function andkidney function and
require dialysisrequire dialysis..