Acute Renal Failure * 3 categories based on the

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Acute Renal Failure
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• Definition and Classification
• Epidemiology
• Pathophysiology and Etiology
• Prerenal ARF
• Intrinisic ARF
• Postrenal ARF
• Pharmacologic Management of ARF
• RRT in ARF

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Definition
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• MDRD
• eGFR 186 x Screat ¹?¹54 X Age ?²³ X 1.21
  if black X o.74 if female
• Undersetimates GFR in healthy people (when GFR
  gt60 ml/min)
• Cockcroft-Gault formula
• (140-Age) X Mass (In KG) X o.85 if female/72 X
  Serum Creat
• The non-steady-state conditions that prevail in
  ARF preclude estimation of GFR using standard
  formulae derived from patients with chronic
  kidney disease.

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RR 2.4
RR 4.15
RR6.37
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Shortcomings

• The assignement of corresponding changes in serum
  creat and changes in urine output to the same
  strata is not based on evidence. The criteria
  that results in the least favorable rifle strata
  to be used.
• The patient would progress from "risk" on day one
  to "injury" on day two and "failure" on day
  three, even though the actual GFR has been lt10
  mL/min over the entire period.
• It is impossible to calculate the change in serum
  creatinine in patients who present with ARF but
  without a baseline measurement of the serum
  creat. The authors of the RIFLE criteria suggest
  back-calculating an estimated baseline creat
  using the four-variable MDRD equation, assuming a
  baseline GFR of 75 mL/min per 1.73 m2 .

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Diagnostic criteria

• Abrupt (within 48 hours) absolute increase in the
  serum creatinine concentration of 0.3 mg/dL
  (26.4 micromol/L) from baseline.
• Or a percentage increase in the serum creatinine
  concentration of 50 percent.
• Or oliguria of less than 0.5 mL/kg per hour for
  more than six hours.

• The diagnostic criteria could be applied only
  after volume status had been optimized
• Urinary tract obstruction needed to be excluded
  if oliguria was used as the sole diagnostic
  criteria

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Epidemiology of ARF
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• The observed incidence, etiology, and outcomes of
  ARF are highly dependent upon the populations
  studied and the definition of ARF employed.
• The absence of centralized registries to track
  the incidence and outcomes of patients with ARF
  has hindered our understanding of its
  epidemiology.

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The changing epidemiology of acute renal failure

• Nature Clinical Practice Nephrology (2006)
  2,364-377

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Non -ICU
ICU
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Key Points

• The absolute incidence of acute renal failure
  (ARF) has increased in the past two decades,
  while the mortality rate has remained relatively
  static
• The lack of a standard definition of ARF
  complicates the process of identifying the
  factors that underlie changes in epidemiology of
  this condition.
• Despite the use of different definitions in
  different studies, various factors that have
  contributed to altered epidemiology of ARF in the
  past few decades have been identified
• These factors include geographical site of
  disease onset (developed vs developing countries
  community vs hospital vs intensive care unit),
  patient age, infections (HIV, malaria,
  leptospirosis and hantavirus), concomitant
  illnesses (cardiopulmonary failure,
  hematooncological disease), and interventions
  (hematopoietic progenitor cell and solid organ
  transplantation)

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Prerenal Acute Renal Failure
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• GFR is reduced as a result of hemodynamic
  disturbances that decrease glomerular perfusion.
• The defining feature of prerenal ARF is the
  absence of cellular injury and the normalization
  of renal function with reversal of the altered
  hemodynamic factors.

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Pathophsiology

• Of Prerenal ARF

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Diagnosis of Prerenal ARF

• Hx
• P/E
• Urine sediment (usually normal, without cellular
  elements or abnormal casts, unless chronic kidney
  disease is present)
• UNalt 15 meq/L (gt20 in ATN)
• U/Pcreatgt 20 (lt15 in ATN)
• FeNa lt1 (gt1 in ATN)
• UNa/K lt1/4
• BUN/creat gt20

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• BUN/CREAT of gt20 is typical, BUT is not specific
  to prerenal ARF and may also be seen
• Obstructive uropathy
• Gastrointestinal bleeding
• Other states associated with increased urea
  production.

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FE Urea

• Patients on diuretics
• Prerenal azotemia due to vomiting on NG
  suctioning.
• FE Na may be low is sepsis, RCN, myoglobinuria,
  nonoliguric ATN, acute GN, urinary tract
  obstruction and renal allograft rejection

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Significance of the fractional
excretion of urea in thedifferential diagnosis
of acute renal failure

• 102 patients were divided into three groups
• Prerenal azotemia (N 50)
• Prerenal azotemia treated with diuretics (N 27)
• ATN (N 25)
• Kidney International, Vol. 62 (2002),
  pp. 22232229

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• FENa was low only in the patients with untreated
  plain prerenal azotemia while it was high in both
  the prerenal with diuretics and the ATN groups.
• FEUN was essentially identical in the two
  pre-renal groups (27.9 2.4 vs. 24.5 2.3), and
  very different from the FEUN found in ATN (58.6
  3.6, P lt 0.0001).
• 92 of the patients with prerenal azotemia had
  FENa lt1.
• 48 of those patients with prerenal and diuretic
  therapy had FENa lt1
• 89 of patients with prerenal azotemia and on
  diuretics had a FEUNlt 35.

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FE UREA

• Low FE urea lt35 is a more sensitive and
  specific index than FE Na in differentiating
  between ARF due to prerenal azotemia and that due
  to ATN, especially if diuretics have been
  administered.

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ARF Associated with ACE Inhibitors and
Angiotensin Receptor Blockers
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• Acute renal failure can develop acutely, when
  ACEI or ARB therapy is initiated, or in patients
  receiving chronic therapy, especially in patients
  with underlying CHF

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• Predisposing factors
• Advanced cardiac failure with low mean arterial
  pressure
• Volume depletion due to diuretic therapy
• The presence of renal vascular disease
• The concomitant use agents with vasoconstrictor
  effects (NSAIDs, cyclooxygenase-2 inhibitors,
  cyclosporine, and tacrolimus)
• CKD The risk of ARF is higher in patients with
  chronic kidney disease of any cause than in
  patients with normal renal function

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• Serum creatinine and electrolyte concentrations
  should be measured before and 1 wk after
  initiating or changing the dose of therapy
• An increase in serum creatinine of gt0.5 mg/dl if
  the initial serum creatinine is lt2.0 mg/dl, or a
  rise of gt1.0 mg/dl if the baseline serum
  creatinine is gt2.0 mg/dl, has been suggested as a
  threshold for discontinuation of therapy

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• The development of ARF should prompt an
  evaluation for cardiac failure, hypotension,
  volume depletion, use of a concomitant
  vasoconstrictive agent, or renovascular disease.

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Acute Renal Failure Associated with NSAIDS
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• Nonsteroidal anti-inflammatory drugs (NSAID)
  agents inhibit the synthesis of vasodilatory
  prostaglandins in the kidney.

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• Risk factors
• Severe CHF
• Advanced liver disease
• Severe atherosclerotic vascular disease
• CKD

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• Elderly patients are at increased risk due to the
  increased prevalence of cardiac dysfunction,
  occult renal vascular disease, and subclinical
  chronic kidney disease.

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Abdominal Compartment Syndrome
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• Unusual cause of decreased renal perfusion
  associated with increased intra-abdominal
  pressure
• Trauma patients who require massive volume
  resuscitation
• Mechanical limitations of the abdominal wall
  (tight surgical closures or scarring after burn
  injuries)
• Medical etiologies that are characterized by
  intraabdominal inflammation with fluid
  sequestration, such as bowel obstruction,
  pancreatitis, and peritonitis.

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Clinical manifestations

• Respiratory compromise
• Decreased cardiac output
• Intestinal ischemia
• Hepatic dysfunction
• Oliguric renal failure

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• The renal insufficiency results from decreased
  renal perfusion and correlates with the severity
  of the increased intraabdominal pressure.
• Oliguria develops when the intraabdominal
  pressure exceeds 15 mmHg, with anuria developing
  at pressures gt30 mmHg.

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Diagnosis

• The diagnosis should be suspected in patients
  with a tensely distended abdomen and progressive
  oliguria.
• Measurement of intraabdominal bladder pressure.
• Abdominal compartment syndrome can be excluded
  when the bladder pressure is lt10 mmHg and is
  virtually always present if the pressure is gt25
  mmHg.

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Treatment

• Abdominal decompression
• Paracentesis if massive ascites.
• Surgical decompression is required in the
  majority of patients.
• Renal failure usually recovers promptly after
  relief of the increased intraabdominal pressure

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Postrenal Acute Renal Failure
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Intrinsic
Extrinsic
Lower tract obstruction
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Urine output?

• The obstruction
• Complete Anuria

InComplete
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Pathophysiology

• After the acute onset of obstruction, GFR
  declines progressively, but it does not fall to
  zero.
• Factors that maintain GFR include continued salt
  and water reabsorption along the nephron,
  dilatation of the collecting system, and
  alterations in renal hemodynamics.
• Intratubular pressure rises acutely, but it
  begins to decline within the first 4 to 8 h,
  returning to nearly normal by 24 h.

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Complete obstruction

• Recovery after relief of obstruction depends on
• Severity
• Duration
• Less than 1 wk duration, recovery complete.
• Little or no recovery after 12 wk.

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Partial obstruction

• The course after relief of partial obstruction is
  less predictable
• Depends on
• Severity
• Duration
• Presence of infection or preexisting renal
  disease.

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• Relief of obstruction may be accompanied by a
  post-obstructive diuresis
• Excretion of salt and water retained during the
  obstruction.
• Persistent salt-wasting and impaired urinary
  concentrating ability .

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Diagnosis

• Elderly male patients
• Measurement of a post-voiding residual bladder
  volume, either by an bedside ultrasound bladder
  scan or by placement of an indwelling bladder
  catheter.

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Diagnosis

• Ultrasonography
• Sensitivity and specificity are high
• Non diagnostic
• Early in the course of postrenal ARF.
• Severe volume depletion.
• Obstruction is due to retroperitoneal disease
  (e.g., retroperitoneal fibrosis, tumors,
  adenopathy) encasing the ureter and preventing
  dilatation

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Diagnosis

• Computed tomography
• Non-contrasted CT scanning may be particularly
  useful for the identification of obstructing
  kidney stones

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Intrinsic ARF
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Etiology of Intrinsic ARF
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• atn

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• Acute tubular necrosis is the most common form of
  intrinsic ARF (85 )
• Tubular injury
• Nephrotoxic (35)
• Ischemic (50)
• Multifactorial.
• Profound ischemic injury may result in bilateral
  cortical necrosis.

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Nephrotoxic ATN
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Clinical course
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Pathogenesis of ATN
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Recovery from Ischemic Injury

• In contrast to the heart and brain, where
  ischemic injury results in permanent cell loss,
  the kidney is able to completely restore its
  structure and function after acute ischemic or
  toxic injury.
• The recovery from tubular necrosis involves the
  dedifferentiation and proliferation of remaining
  viable tubular epithelial cells followed by
  reestablishment of cellular polarity, normal
  histologic appearance, and physiologic function.

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• Under normal circumstances, renal tubular cells
  in vivo are quiescent and do not divide in
  response to growth factors.
• After ischemic or toxic injury, alterations in
  gene expression are observed that are similar to
  those induced in vitro by growth factors.
• Multiple growth factors, including (IGF-1),
  (EGF), and (HGF), and their receptors are
  upregulated during the regenerative process after
  renal injury
• Administration of exogenous IGF-1, EGF, or HGF to
  experimental animals after ischemic or toxic
  renal injury accelerates renal regeneration.
• Concern has been raised, that growth factors may
  also have a deleterious effect, augmenting
  tubulointerstitial injury and fibrosis.

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Short-term Outcomes

• The outcome of ATN is highly dependent on the
  severity of comorbid conditions.
• Uncomplicated ATN is associated with mortality
  rates of 7 to 23
• Mortality of ATN in postoperative or critically
  ill patients with multisystem organ failure is
  high as 50 to 80.
• Mortality rates increases with the number of
  failed organ systems

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Long-term Outcomes

• Long-term outcomes of patients who survive are
  good.
• Of a population of 979 critically ill patients
  with ARF who required RRT (predominately patients
  with ATN), in-hospital mortality was 69.
• Patients who survived to hospital discharge, 6-mo
  survival was 77, 1-yr survival was 69, and 5-yr
  survival was 50
• 59 of surviving patients had no residual renal
  insufficiency, and only 10 required chronic
  dialysis therapy.

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Radiocontratst Nephropathy
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• Contrast media induced nephropathy (CMIN) is the
  third highest cause of hospital-acquired acute
  renal failure.
• In nearly half of these patients, CMIN occurred
  during cardiac diagnostic or interventional
  procedures such as percutaneous coronary
  intervention.

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ARFincrease in serum creat ofgt50 above
baseline or gt1 mg/dl if baselinegt2 mg/dl

• Normal baseline creat negilgible risk
• Mild to moderate CKD 5-10 risk
• Mild to moderate CKD DM 10- 40
• Advanced renal insufficiency gt50 risk

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Pathogenesis

• Haemodynamic alterations and tubuloglomerular
  feedback
• The injection of CM induces early, rapid renal
  vasodilatation followed by prolonged
  vasoconstriction, with an increase in intrarenal
  vascular resistances, a reduction of total renal
  blood flow (RBF) and a decrease in glomerular
  filtration rate (GFR).
• Conversely, the effect on the extrarenal
  vasculature is transient vasoconstriction that
  precedes a stable decrease in vascular peripheral
  resistances.
• The resulting renal ischaemia due to these
  haemodynamic effects is, in part, responsible for
  nephropathy

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• Endothelial dysfunction
• Vasoactive mediators
• Free radicals and reperfusion damage
• Haemorheological factors
• Tubular toxicity and immunological mechanisms

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Treatment

• The best treatment of contrast-induced renal
  failure is prevention.
• The use, if clinically possible, of
  ultrasonography, magnetic resonance imaging or CT
  scanning without radiocontrast agents,
  particularly in high-risk patients.
• The use of lower doses of contrast and avoidance
  of repetitive studies that are closely spaced
  (within 48 to 72 hours).
• Avoidance of volume depletion or nonsteroidal
  antiinflammatory drugs, both of which can
  increase renal vasoconstriction.
• The use of low or iso-osmolal nonionic contrast
  agents.

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Treatment

• The administration of Intravenous Saline.
• Isotonic saline at a rate of 1 mL/kg per hour,
  begun at least two and preferably 6 to 12 hours
  prior to the procedure, and continuing for 6 to
  12 hours after contrast administration.
• The administration of the antioxidant
  Acetylcysteine.
• Dose of 600 to 1200 mg orally twice daily,
  administered the day before and the day of the
  procedure, based upon its potential for benefit
  and low toxicity and cost.

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Treatment

• Routine hemofiltration or hemodialysis for the
  prevention of contrast nephropathy in patients
  with stage 3 and 4 CKD is not recommended.
• More data are needed in stage 5 CKD
  (Prophylactic use of hemodialysis in patients
  with stage 5 CKD, can be considered,provided that
  a functioning access is already available)
• Extracorporeal blood purification therapies for
  prevention of radiocontrast-induced nephropathy
  a systematic review. Am J Kidney Dis 2006
  48361.
• Renal protection for coronary angiography in
  advanced renal failure patients by prophylactic
  hemodialysis. A randomized controlled trial. J Am
  Coll Cardiol 2007 501015.

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Treatment

• There is no indication for prophylactic dialysis
  for the prevention of volume overload in
  dialysis-dependent patients.

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Treatment

• Therapies with Limited Evidence
• Calcium Channel Blockers
• Diuretics
• Atrial Natriuretic Peptide (ANP)
• Endothelin (ET) Antagonists
• Prostaglandin E1
• ACE Inhibitors

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• The high-osmolal contrast media (osmolality
  15001800 mOsm/kg) are first generation agents.
• Low-osmolal contrast media still have an
  increased osmolality compared with plasma
  (600850 mOsm/kg),
• The newest nonionic radiocontrast agents have a
  lower osmolality, 290 mOsm/kg, iso-osmolal to
  plasma

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• In high-risk patient populations (patientswith
  underlying renal insufficiency and diabetes),
  both low-osmolar and iso-osmolar contrasts tend
  to reduce the risk of contrast nephropathy as
  compared to the high-osmolar compounds.

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• The volume of contrast administered to the patien
  also appears to correlate with the incidence of
  nephrotoxicity.
• In patients who undergo only diagnostic coronary
  procedures, the volume of dye (approximately 100
  mL) is considerably less than in patients who
  undergo interventional procedures (approximately
  250-300 mL).

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Heme pigment-induced acute tubular necrosis

• Myoglobinuria rhabdomyolysis.
• Hemoglobinuria intravascular hemolysis.

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Rhabdomyolysis

• The release of muscle cell contents as the result
  of traumatic or nontraumatic injury of skeletal
  muscle
• Physical findings may consist of
• Tender, doughy muscles
• Edema
• weakness
• Compartmental compression symptoms with signs and
  symptoms of neurovascular compromise may develop,
  necessitating the need for emergent fasciotomy.

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The majority of cases of rhabdomyolysis are
nontraumatic
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Hemolysis

• Transfusion reactions due to ABO incompatible
  blood are probably the most frequently
  encountered hemolytic processes that can lead to
  acute renal failure.
• Severe acute hemolytic episodes in patients with
  glucose-6-phosphate dehydrogenase deficiency.

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Laboratory abnormalities
Ph K CK SGOT Uric
acid LDH
CA
Hypovolemia and High AG acidosis
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• The urine may have a low FENa despite tubular
  injury.
• Positive dipstick test for heme pigment without
  red blood cells on microscopic exam should
  suggest myoglobinuria.
• Heme-pigmented granular casts.
• Plasma is normal color in myoglobinuria and red
  brown in hemoglobinuria

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Treatment

• IVF
• Isotonic saline at 1 to 2 liters per hour
• Fluids are titrated to maintain a urine output of
  200 to 300 mL/hour
• Continue until the urine discoloration clears,
  and plasma creatine kinase decreases to less than
  5,000 to 10,000 U/L (or there is cessation of
  hemolysis), or symptomatic fluid overload
  develops.

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Treatment

• Alkalinization.
• Mannitol diuresis.

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Acute Interstitial Nephritis

• Acute interstitial nephritis (AIN) is a syndrome
  of ARF associated with an inflammatory infiltrate
  involving the renal interstitium

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Drug hypersensitivity

• Penicillin
• Cephalosporin
• Sulfonamide
• Fluoroquinolone
• Rifampin

• NSAIDs
• Phenytoin
• Furosemide
• Thiazide diuretics
• Allopurinol
• Alpha interferon
• Cimetidine
• Omeprazole

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Others
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Methicillin induced AIN

• Renal symptoms typically develop 2 to 3 weeks
  after the initiation of treatment
• Hematuria
• Pyuria with white blood cell casts
• Proteinuria lt 1g/d (can be nephrotic with NSAIDs)
• Renal failure in 50 of patients
• Extrarenal manifestations
• Fever in 80
• Eosinophilia in 80
• Rash in 25

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Other kinetics

• Within 2 to 3 days after rechallenge with a drug
  with previous sensitisation
• De novo in response to a med previoulsy tolerated
  medication

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• Renal failure is the most prominent feature
• Develops within 3 wk of initiation of drug
  therapy in 80
• Hematuria and pyuria each are present in only 50
  of patients.
• Extrarenal manifestations, including fever,
  maculo-papular rash, arthralgias, and
  eosinophilia are each present in fewer than 50
• All of them together in lt5

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Eosinophiluria

• Diagnostic value is poor.
• Other conditions associated with Eosinophiluria
• Prostatitis
• RPGN
• Bladder Cancer
• Renal Atheroembolic disease

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Eosinophiluria

• PPV for AIN of only 50 .
• NPV of 90?
• Thus, the presence of eosinophiluria is not
  strongly predictive of a diagnosis of AIN
  however, its absence is useful in excluding the
  diagnosis.

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Renal biopsy

• Failure to improve after discontinuation of
  potential offending drug
• If the potential offending drug is critical for
  therapy
• If immunosupressive therapy is considered

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Treatment

• Supportive
• Dicontinue offending drug
• Prednisone 1mg/kg/d for 4 weeks
• Controversial
• Rcommended if biopsy proven AIN and who have
  persistent renal failure 1 week after DC the
  offending medication
• ?adjunct cyclophosphamide

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Hepatorenal syndrome

• ARF in HRS results from profound renal
  vasoconstriction in the setting of histologically
  normal kidneys.
• Although many of the features of HRS resemble
  prerenal azotemia, the defining feature is a lack
  of improvement in renal function with volume
  expansion.
• Recovery of renal function is usually observed
  after restoration of hepatic function after liver
  transplantation

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Diagnostic criteria

• Chronic or acute hepatic disease with advanced
  hepatic failure and portal hypertension
• A plasma creatinine concentration above 1.5 mg/dL
  (133 µmol/L) that progresses over days to weeks.
• The absence of any other apparent cause for the
  renal disease, including shock, ongoing bacterial
  infection, current or recent treatment with
  nephrotoxic drugs, and the absence of
  ultrasonographic evidence of obstruction or
  parenchymal renal disease.
• Urine red cell excretion of less than 50
  cells/HPF and protein excretion less than 500
  mg/day.
• Lack of improvement in renal function after
  volume expansion with intravenous albumin (1 g/kg
  of body weight per day up to 100 g/day) for at
  least two days and withdrawal of diuretics.
• Urine Nalt10

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Treatment

• Management of underlying cause
• Stop diuretics
• Low salt diet and free water restriction if
  hyponatremia
• Midodrine Octreotide Albumin
• Terlipressin Albumin
• RRT
• TIPS

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•  The management of patients with acute renal
  failure or acute kidney injury (AKI) is
  principally supportive, with renal replacement
  therapy (RRT) indicated in patients with severe
  kidney injury.

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Treatment of ARF
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Prevention

• Renal hypoperfusion is a predisposing factor to
  the development of renal failure.
• Optimizing vascular hemodynamics to ensure
  adequate renal perfusion is a fundamental
  principle in avoiding renal failure.
• Avoidance or discontinuation of drugs that
  increase renal vaso-constriction, such as NSAID
  and selective COX-2 inhibitors.
• Potentially nephrotoxic medications should be
  avoided, particularly in high-risk patients,
  whenever possible.
• Using alternative imaging techniques such as MRI
  scanning should be considered in patients at high
  risk for contrast .

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Pharmacologic Treatment of Acute Renal Failure

• Dopamine
• Loop diuretics
• ANP
• Thyroxine
• IGF-1

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Indications for RRT

• Refractory fluid overload
• Hyperkalemia (plasma potassium concentration gt6.5
  meq/L) or rapidly rising potassium levels
• Metabolic acidosis (pH less than 7.1)
• Signs of uremia, such as pericarditis,
  neuropathy, or an otherwise unexplained decline
  in mental status

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Timing of initiation of RRT

• It is not possible to specify a specific duration
  of renal injury or level of azotemia at which RRT
  should be optimally initiated.
• It is unproven whether initiation of earlier or
  prophylactic dialysis offers any clinical or
  survival benefit.

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• The optimal timing for initiation of RRT in
  patients with AKI will require an adequately
  powered prospective randomized trial.
• Adequate design of such a trial is limited by the
  current inability to quickly prospectively
  identify patients with early AKI who will have
  protracted renal injury and eventually require
  RRT.

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• Initiation of dialysis prior to the development
  of symptoms and signs of renal failure due to AKI
  is recommended.

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• Current data do not support the superiority of
  either CRRT or IHD.

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Learning objectives

• Understanding the limitations of serum creat
• Formulation of a DDx
• Understanding of the pathophysiology of ARF
• Prevention of ARF

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• Thank you