Acute Tubular Necrosis

1
Acute Tubular Necrosis
Residents conference Presented by Dr Gagandeep K
Heer, MD (PGY-2)
2
Background

• Definition ARF is defined as an abrupt or rapid
  decline in the renal function.
• A rise in serum BUN or creatinine concentration,
  with or without decrease in urine output, usually
  is evidence of ARF.
• ARF is often transient and completely reversible.

3
Background

• The causes of ARF are divided into 3 categories
• Prerenal
• Renal
• Postrenal
• ATN is the most common cause of ARF in the renal
  category.
• ATN is the 2nd most common cause of all
  categories of ARF in hospitalized patients, with
  only prerenal azotemia occurring more frequently.
• In outpatients, obstruction (ureteric, bladder
  neck or urethral) is the 2nd most common cause of
  ARF after prerenal azotemia.
• Other causes of ARF include acute interstitial
  nephritis, acute glumerulonephtitis, vasculitis,
  HUS, TTP, DIC, accelerated HTN, radiation
  nephritis, acute on chronic renal failure,
  renovascular obstruction (bilateral or unilateral
  in the setting of single functioning kidney),
  renal allograft rejection, intratubular
  deposition and obstruction (myeloma proteins,
  urate, oxalate crystals, etc.)

4
Pathophysiology

• ATN usually occurs after an acute ischemic or
  toxic event, and it has a well-defined sequence
  of events.
• Initiation phase characterized by acute decrease
  in GFR to very low levels, with a sudden increase
  in serum Cr and BUN concentrations.
• Maintenance phase is characterized by sustained
  severe reduction in GFR and the BUN and Cr
  continue to rise.
• Recovery phase, in which the tubular function is
  restored, is characterized by an increase in
  urine volume (if oliguria was present) and
  gradual decrease in Cr and BUN to their
  pre-injury level.

5
Ischemic ATN

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

6
Ischemic ATN

• Maintenance phase is characterized by
  stabilization of GFR at a very low level, and it
  typically lasts 1-2 weeks. Uremic complications
  typically develop during this phase. In addition
  to the above mentioned mechanism of injury,
  tubulo-glomerular feedback also plays a role by
  causing constriction of afferent arterioles by
  the macula densa cells, which detect and
  increased salt load in the distal tubules.
• During Recovery phase, there is regeneration of
  tubular epithelial cells. An abnormal diuresis
  sometimes occurs, causing salt and water loss and
  volume depletion. The mechanism of the diuresis
  is not completely understood, but it may in part
  be due to delayed recovery of tubular cell
  function in the setting of increased glomerular
  filtration. In addition, continued use of
  diuretics (often administered during initiation
  and maintenance phases) may also add to the
  problem.

7
Nephrotoxic ATN

• Most of the pathophysiological features of
  ischemic ATN are shared by the nephrotoxic forms
  and it has the same three phases.
• Nephrotoxic injury to tubular cells occurs by
  multiple mechanisms including direct toxicity,
  intrarenal vasoconstriction, and intratubular
  obstruction.

8
(No Transcript)
9
At cellular level

• Ischemic ATN
• Cellular ischemia results in series of
  alterations in energetics, ion transport and
  membrane integrity that ultimately leads to cell
  injury or necrosis. These changes include
  depletion of ATP, inhibition of active sodium
  transport and transport of other solutes,
  impairment of cell volume regulation,
  cytoskeletal disruption and loss of cell
  polarity, cell-cell and cell-matrix attachment,
  accumulation of intracellular calcium, altered
  phospholipid metabolism, oxygen free radical
  formation and peroxidation of membrane lipids.
• A characteristic feature of ischemic ATN
  is the absence of widespread necrosis of tubular
  epithelial cells. Necrosis is more subtle and is
  reflected in individual necrotic cells within
  some proximal or distal tubules. These single
  cells shed into tubular lumen, with resulting
  focal denudation of the tubular basement
  membrane. Interstitial edema is common.

10
Ischemic ATN
11
Histology (continued)

• Toxic ATN The morphology differs from ischemic
  ATN in that the former is characterized by more
  extensive necrosis of the tubular epithelium. In
  most cases, however, the necrosis is limited to
  certain segments that are most sensitive to the
  toxin. ATN caused by hemoglobin or myoglobin has
  added feature of numerous red-brown tubular
  casts, colored by heme pigments.
• During the recovery phase of ATN, the tubular
  epithelium regenerates, leading to the appearance
  of mitoses, increased size of cells and nuclei,
  and cell crowding. Survivors eventually display
  complete restoration of normal renal architecture.

12
Nephrotoxic ATN
13
Frequency

• In the US ARF is seen in 5 of all hospital
  admissions and upto 30 of patients admitted to
  the ICU. Prerenal causes account for about half
  of all cases.
• ATN is most common cause out of the intrinsic
  renal diseases.

14
History

• A good history is very important in diagnosis of
  ATN.
• Find out about
• Recent hypotension
• Sepsis
• Muscle necrosis (e.g. h/o seizure, cocaine
  use)
• Exposure to contrast or nephrotoxic
  medications
• Hypovolumia
• Other risk factors for development of ATN
  like underlying renal disease from DM, HTN, etc.

15
Physical Exam

• Physical exam may be unremarkable because ARF is
  often found incidentally during routine
  laboratory studies (i.e. elevated BUN and Cr).
• Look for pericardial friction rub (pt may have
  pericarditis), asterixis and/or excoriation marks
  related to uremic pruritis.
• Hypertension or edema may be noted.
• Physical findings related to the underlying
  disease.

16
Causes of ATN

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

17
Causes of Ischemic ATN

• It may be considered part of the spectrum of
  prerenal azotemia and they have the same causes
  and risk factors
• Hypovolumic states hemorrhage, volume depletion
  from GI or renal losses, burns, fluid
  sequestration.
• Low cardiac output states CHF and other
  diseases of the myocardium, valvulopathy,
  arrhythmia, pericardial diseases, tamponade.

18
Causes of Ischemic ATN

• Systemic vasodilation sepsis, anaphylaxis
• DIC
• Renal vasoconstriction cyclosporine,
  norepinephrine, epinephrine, amphotericin B, etc
• Hyperviscosity syndrome
• Impaired renal autoregulatory responses
  cyclooxygenase inhibitors

19
Causes of Nephrotoxic ATN

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

20
Exogenous toxins

• Aminoglycosides
• 10-30 of patients getting aminoglycosides
  develop ATN.
• Risk factors include preexisting liver disease,
  renal disease, concomitant use of other
  nephrotoxins, advanced age, shock, female sex and
  a higher level 1 hr after the dose.
• Toxicity presumably more common with 3 doses/day
  than a single daily dose (as the drug uptake by
  tubules is saturable phenomenon).
• Amphotericin B The likelihood of toxicity is in
  direct proportion to the total dose administered
  and is more common if gt 3 grams is administered.

21
Exogenous Toxins

• Radiocontrast media
• Contrast-induced nephropathy has become a
  frequent occurrence with increased number of
  studies requiring contrast media like
  angiography, CT scan, etc
• Iodinated contrast media causes vasoconstriction
  as well as a direct toxic effects on tubular
  cells.
• Patients at increased risk include diabetes,
  baseline renal insufficiency, large contrast
  load, history of HTN, older age and presence of
  proteinuria.
• Cyclosporine and tacrolimus Can cause ARF as
  well as chronic interstitial nephritis.
• Sulfa drugs, acyclovir and indinavir cause ARF by
  tubular obstruction due to crystal formation in
  the tubular lumen
• Others Cisplatin, methotrexate and foscarnet,
  etc.

22
Endogenous toxins

• Myoglobinuria
• The breakdown of muscle (rhabdomyolysis), leading
  to myoglobinuria, occurs in many clinical
  settings like crush injuries, viral illness,
  cocaine, heavy exercise, alcoholism, seizures and
  certain medications. ATN can develop in small
  proportion of these patients.
• The exact mechanism of renal failure is not
  clearly understood, but several theories include
  direct toxic injury, development of DIC,
  mechanical tubular obstruction by the pigment and
  intrarenal ischemia from vasomediator release.
• Factors that increase the risk of ATN in this
  setting include extracellular fluid volume
  depletion, liver dysfunction and hypotension.
• Hemoglobinuria
• ARF is a rare complication of hemolysis and
  hemoglobinuria and is most often associated with
  transfusion reactions. Hemoglobin has no apparent
  direct toxicity on the cells and the renal
  failure in this setting is probably related to
  hypotension and decrease renal perfusion.

23
Endogenous Toxins

• Crystals
• Acute crystal-induced nephropathy is
  encountered in conditions where crystals are
  produced endogenously due to high cellular
  turnover (i.e. uric acid, calcium phosphate), as
  seen in certain malignancies or the treatment of
  these malignancies (tumor lysis syndrome).
  However, this condition is also associated with
  ingestion of certain toxic substances, such as
  ethylene glycol.
• Multiple myeloma
• This condition causes renal failure by
  several mechanisms, such as prerenal azotemia due
  to volume contraction, cast nephropathy due to
  increased light chain proteins precipitated into
  the tubular lumen, hypercalcemia and uric acid
  nephropathy.

24
Workup

• Lab studies
• Serum chemistries By definition, BUN and serum
  Cr concentrations are increased. In addition,
  hyponatremia, hyperkalemia, hypermagnesemia,
  hypocalcemia, hyperphosphatemia and metabolic
  acidosis may be present. Remember that
  hypercalcemia and hyperuricemia may suggest a
  malignant condition as a cause.
• CBC Pt may be anemic. Not only is erythropoietin
  production decreased but platelet dysfunction
  from uremia also makes bleeding more likely.
• Urinalysis May reveal muddy brown, granular
  casts and epithelial cell casts. In addition,
  checking urine lytes may also help differentiate
  ATN from prerenal azotemia.

25
(No Transcript)
26
(No Transcript)
27
Laboratory Findings Used to Differentiate
Prerenal Azotemia from ATN
28
Finding Prerenal Azotemia ATN
Urine osmolarity (mOsm/kg) gt500 lt350
Urine sodium (mmol/d) lt20 gt40
Fraction excretion of sodium() lt1 gt2
Fraction excretion of Urea() lt35 gt50
Plasma BUN/Cr ratio gt20 lt10-15
Urine Cr/Plasma Cr ratio gt40 lt20
Urine sediment Bland and/or nonspecific May show muddy brown granular casts
29
Lab (continued)

• Loss of concentrating ability is an early and
  almost universal finding in ATN.
• None of the above criteria for the diagnosis of
  prerenal disease may be present in a patient with
  underlying renal disease. Hence, a cautious trial
  of fluids may be given.

30
Imaging Studies

• Abdominal radiograph is of limited benefit in ARF
  except in diagnosing (or excluding)
  nephrolithiasis.
• Ultrasound, CT scan, or MRI very useful, both to
  exclude obstructive uropathy and measure renal
  size and cortical thickness.
• Renal US is a simple, relatively inexpensive and
  non-invasive imaging modality and should be done
  in all patients presenting with ARF.

31
Renal biopsy

• Biopsy is rarely necessary. It should only be
  performed when the exact renal cause of ARF is
  unclear, the course is protracted and knowing the
  exact cause is possibly going to change the
  management.
• Needless to say, prerenal and postrenal causes
  must be ruled out before subjecting a patient to
  this invasive procedure. The diagnosis of ATN is
  made on a clinical basis, i.e. with the help of
  detailed and accurate history, thorough physical
  exam, and pertinent lab tests and imaging
  studies.
• A more urgent indication for renal biopsy is in
  the setting of clinical and urinary findings
  suggestive of renal vasculitis rather than ATN
  and the diagnosis needs to be established quickly
  so that appropriate immunomodulatory therapy can
  be initiated.
• Biopsy may also be more critically important in a
  renal transplant patient to rule out rejection.
• Other indications for biopsy include suspected
  glomerulonephritis, HUS, TTP and acute
  interstitial nephritis.
• The biopsy is performed under ultrasound or CT
  guidance after ascertaining the safety of the
  procedure.

32
Complications

• Patients with ATN can have several
  complications.
• Electrolyte abnormalities
• Hyperkalemia Higher levels are associated with
  ECG abnormalities (e.g. peaked T waves, prolonged
  PR interval, P wave flattening, widened QRS) and
  risk of developing life-threatening arrhythmias
  (e.g. ventricular tachycardia or fibrillation,
  complete heart block, bradycardia, asystole).
  Arrhythmias have been reported in up to 30 of
  patients. In addition to these worrisome cardiac
  effects, hyperkalemia can also lead to
  neuromuscular dysfunction and, potentially,
  respiratory failure.
• Hyponatremia
• Hyperphosphatemia
• Hypermagnesemia
• Hypocalcemia Hypocalcemia may be secondary to
  both deposition of calcium phosphate and reduced
  levels of 1,25 dihydroxyvitamin D. It is usually
  asymptomatic, but hypocalcemia may result in
  nonspecific ECG changes, muscle cramps, or
  seizures.
• Metabolic acidosis

33
Complications

• Intravascular volume overload It is
  characterized by weight gain, raised jugular
  venous pressure and dependent edema. In its most
  severe manifestation, this may lead to
  respiratory failure from pulmonary edema.
• Hypertension Hypertension is suspected to mainly
  be due to salt and water retention. About 25 of
  patients with ARF develop some hypertension.
• Uremic syndrome/Uremia Uremia results from the
  accumulation of nitrogenous waste. It is a
  potentially life-threatening complication
  associated with ARF.
• Platelet dysfunction is common and can lead to
  life-threatening hemorrhage.
• This may manifest as pericardial disease (uremic
  pericarditislisten for a rub on exam)
• GI symptoms (i.e. nausea, vomiting, cramping)
• Neurological symptoms (i.e. lethargy, confusion,
  asterixis, seizures).
• Anemia Anemia may develop from many possible
  causes. Erythropoiesis is reduced in ARF, but
  platelet dysfunction is also observed in the
  setting of uremia, which may predispose to
  hemorrhage. In addition, volume overload may lead
  to hemodilution, and red cell survival time may
  be decreased.

34
Complications

• Polyuric phase of ATN This complication can lead
  to hypovolemia and create a setting for prerenal
  azotemia and perpetuation of ATN.
• Infections Infections is the leading cause of
  morbidity and mortality and can occur in 30-70
  of patients with ARF. Infections are more likely
  in these patients because of an impaired immune
  system and because of increased use of indwelling
  catheters and intravenous needles.

35
Prevention

• Ischemic ATN Be attentive to optimizing
  cardiovascular function as well as maintaining
  intravascular volume, especially in patients with
  preexisting risk factors or those taking
  nephrotoxic medications. Medicines that reduce
  systemic resistance (e.g. afterload reducers) may
  cause renal vasoconstriction or affect the
  kidneys autoregulatory response (e.g. ACE
  inhibitors, cyclooxygenase inhibitors) and also
  should be used with caution.
• Dopamine, mannitol and furosemide, etc have been
  tried within 24 hrs of ischemic insult to prevent
  progression to ATN, but have no proven benefit.

36
Prevention

• Nephrotoxic ATN
• Aminoglycosides Once daily dosing of
  aminoglycosides decreases the incidence of
  nephrotoxicity.
• Amphotericin B Minimize the use of this drug and
  assure that ECF volume is adequate.
• Cyclosporin and tacrolimus Regular monitoring of
  blood levels.
• Alkalinization of the urine should be tried in
  patients with marked myoglobinuria and
  hemoglobinuria.

37
Prevention

• Radiocontrast dye Out of all the
  agents/modalities that have been investigated for
  prevention of CIN, only the following have been
  shown to be of some benefit
• 1.Hydration with isotonic saline infusion has
  proven benefits in prevention of contrast-induced
  nephropathy. Typically, half isotonic sodium
  chloride solution (0.45) administered at a rate
  of 50-100 mL/h 12 hours before and 12 hours after
  the administration of the dye load is most
  effective, especially in the setting of prior
  renal insufficiency and diabetes mellitus.
• 2. Low osmolal and iso-osmolal nonionic contrast
  media are also associated with lower incidence of
  CIN.
• 3. N-acetylcysteine has been used with success in
  high-risk patients to prevent contrast-induced
  nephrotoxicity.
• 4. Using lower doses of contrast media, avoiding
  volume depletion and NSAIDs, both of which can
  cause renal vasoconstriction are some other
  useful measures.
• 5. A new modality recently investigated is use of
  prophylactic hemofiltration in patients who need
  contrast and have baseline renal insufficiency.

38
The Prevention of Radiocontrast-AgentInduced
Nephropathy by Hemofiltration
Giancarlo Marenzi, M.D., et al.
NEJM October 2nd,
2003. 114 consecutive patients with chronic
renal failure (serum creatinine concentration, gt2
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 (gt4 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
Treatment

• General treatment
• The main goal of treatment is to prevent further
  injury to the kidney. ECF volume should be
  assessed promptly, either on clinical grounds or
  by invasive means (Swan-Ganz catheter), and
  repletion of any deficit should be initiated
  promptly. A renal ultrasound should be performed
  to exclude obstruction.
• All possible nephrotoxic drugs should be stopped.
  
• In general, an attempt is made to increase the
  urine output if oliguria is present, by using
  loop diuretics, although there is some
  controversy about this in the literature. One
  retrospective study showed that diuretics may
  even increase the risk of death and non-recovery
  of renal function. Only use diuretics if ECF
  volume and cardiac function are first carefully
  assessed and found adequate.
• The only true indication for diuretic use is
  volume overload. Furosemide and bumetanide are
  the commonly used diuretics.

40
Treatment

• Aggressively treat any complications that
  develop. Remember that sepsis is a common cause
  of death with severe ARF, so aggressive treatment
  of infections is prudent. However, prophylactic
  antibiotic has not been proven to be of any
  benefit.
• Also, adjust doses of all medications if the
  kidney eliminates them.
• Various agents have been studied for their
  possible role in hastening tubular regeneration
  and functional recovery in ATN including growth
  factors (IGF-I), low dose DA, combination of DA
  and ANP and anaritide (a synthetic form of ANP)
  but have shown no benefit in recovery or
  survival.

41
Treatment

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

42
Treatment of Complications

• Volume overload Salt and water restriction,
  diuretics. Dialysis for refractory cases.
• Hyperkalemia Restrict potassium intake, glucose
  and insulin, sodium bicarbonate, kayexalate,
  calcium gluconate, dialysis.
• Metabolic acidosis Sodium bicarb (only if HCO3
  lt15mmol/L or pHlt7.2) or dialysis.
• Hypocalcemia Calcium carbonate, calcium
  gluconate.
• Infections Antibiotics, assess the IV sites.
• Hyponatremia Free water restriction.
• Hyperphosphatemia Restrict phosphate intake,
  phosphate binding agents.
• Hypermagnesemia Avoid Mg containing antacids.
• Anemia Blood transfusion may be required.

43
Nutrition

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

44
Mortality and Morbidity

• The in-hospital survival rate of patients with
  ATN is about 50, with 30 surviving for 1 year.
• Factors associated with increased mortality
  include poor nutrition status, male sex, the
  presence of oliguria, need for mechanical
  ventilation, chronic immunosuppression, acute MI,
  stroke or seizures.
• The presence of renal failure itself seems to be
  a prognostic factor in survival since it weakens
  immune system and impairs platelet function thus
  predisposing the patient to sepsis and bleeding.

45
Mortality and Morbidity

• Infections remain the leading cause of death.
• For ARF the mortality rate is 20-50 in patients
  with underlying medical illnesses, but the
  mortality rate is as high as 60-70 with patients
  in a surgical setting or with severe trauma. If
  multiorgan failure is present, especially severe
  hypotension or acute respiratory distress
  syndrome, the mortality rate ranges from 50-80.
• With dialysis intervention, the frequency of
  uremia, hyperkalemia, and volume overload as
  causes of death have decreased. The most common
  causes of death now are sepsis, cardiovascular
  and pulmonary dysfunction, and withdrawal of life
  support.
• The type of dialysis membrane utilized during HD
  may also affect prognosis.

46
Prognosis

• Patients with oliguric ATN have a worse prognosis
  than patients with nonoliguric ATN. This probably
  is related to more severe necrosis and more
  significant disturbances in electrolyte balance.
• Rapid increase in serum creatinine (i.e. gt3
  mg/dL) probably also indicates a poorer
  prognosis. Again, this probably reflects more
  serious underlying disease.
• Of the survivors of ATN, approximately 50 have
  residual subclinical impairment of renal
  function, about 5 continue to undergo a decline
  in renal function following an initial recovery
  phase and about 5 never recover kidney function
  and require dialysis.