Acute Kidney Injury (for Undergraduates)

CONTENTS
 Introduction
 Epidemiology
 Definition
 Pathophysiology
 Aetiology
 Symptoms & signs
 Differential diagnosis
 Investigations
 Management
 Complications
 Prognosis
 Prevention

 Acute kidney Injury, is a rapid loss of kidney function.
 Its causes are numerous and include low blood volume from
any cause, exposure to substances harmful to the kidney, and
obstruction of the urinary tract.
 AKI is diagnosed on the basis of characteristic laboratory
findings, such as elevated blood urea nitrogen and creatinine,
etc.
^ Webb S, Dobb G (December 2007). "ARF, ATN or AKI? It's now acute kidney injury". Anaesthesia and Intensive Care 35 (6): 843–4. PMID 18084974.

CONTD…
 AKI may lead to a number of complications,
including metabolic acidosis, high potassium levels, uremia,
changes in body fluid balance, and effects to other organ
systems.
 Management includes supportive care, such as renal
replacement therapy, as well as treatment of the underlying
disorder.
^ a b Dan Longo, Anthony Fauci, Dennis Kasper, Stephen Hauser, J. Jameson, Joseph Loscalzo (July 21, 2011).
Harrison's Principles of Internal Medicine, 18 edition. McGraw-Hill Professional.

 Recent studies have found an overall incidence of acute
kidney injury (AKI) of almost 500 per million per year.
 The incidence of AKI needing dialysis being more than 200
per million per year.
 Prerenal AKI and ischaemic acute tubular necrosis (ATN)
together account for 75% of the cases of AKI.
Lameire N, Van Biesen W, Vanholder R; Acute renal failure. Lancet. 2005 Jan 29-Feb 4;365(9457):417-30.

CONTD…
 Risk factors for AKI:
 Elderly
 Hypertension
 Vascular disease
 Pre-existing renal impairment
 Congestive cardiac failure
 Diabetes
 Myeloma
 Chronic infection
 Myeloproliferative disorder
Hilton R; Acute renal failure. BMJ. 2006 Oct 14;333(7572):786-90.

DEFINITION
 Acute kidney injury (AKI) (formerly acute renal
failure) is the syndrome arising from a rapid fall in
GFR (over hours to days).
 It is characterized by retention of both nitrogenous
(including Ur and Cr) and non-nitrogenous waste
products of metabolism, as well as disordered
electrolyte, acid –base, and fluid homeostasis.

 Acute renal failure (ARF) is characterized by azotmeia that
progresses over several hours or days, with or without
oliguria.
 Recently, the term acute kidney injury (AKI) has been
popularized to increase awareness of milder degrees of renal
impairment and to better describe the underlying pathobiology.
 Azotemia, on the other hand, signifies the accumulation of
nitrogenous waste (urea) and other solutes.
Bellomo R, Ronco C, Kellum JA, Mehta RL, Palevsky P. Acute renal failure—definition, outcome measures, animal models, fluid therapy and information
technology needs: the Second International Consensus Conference of the Acute Dialysis Quality Initiative (ADQI) Group. Crit Care. 2004, 8: (4): R204-12.

CONTD…
 A consensus classification for acute renal failure has been
proposed by The Acute Dialysis Quality Initiative (ADQI)
group to standardize the definition and severity categories of
AKI.
 The entry criteria for RIFLE (risk of renal dysfunction, injury to
the kidney, failure of kidney function, loss of kidney function,
and end-stage kidney disease) are based on changes in
serum creatinine or urine output

RIFLE CRITERIA
Category GFR Criteria Urine Output Criteria
Risk
Increased creatinine ×1.5
GFR decrease >25%
UO < 0.5 mL/kg/h × 6 hr
Injury
Increased creatinine ×2
GFR decrease >50%
UO < 0.5 mL/kg/h × 12 hr
Failure
Increase creatinine ×3
GFR decrease >75%
UO < 0.3 mL/kg/h × 24 hr
Anuria × 12 hr
Loss
Persistent ARF = complete
loss of kidney function >4
weeks
ESKD
End-stage kidney disease
(>3 months)

KDIGO AKI DEFINITION (2012)
 Increase in SCr by ≥ 26.5μmol/L ( ≥ 0.3mg/dL)
within 48h.
 Increase in SCr by ≥ 1.5 x baseline (known or
presumed to have occurred within prior 7d).
 Urine volume <0.5mL/kg/h for 6h.
(Only one criterion needs to be present to fulfill the definition.)

KDIGO CLASSIFICATION
Stage Serum creatinine Criteria Urine Output Criteria
1
1.5 – 1.9 times baseline OR
≥0.3mg/dL in ≤48h
<0.5mL/kg/h for 6 – 12h
2 2 – 2.9 times baseline <0.5mL/kg/h for ≥ 12h
3
≥ 3 times baseline OR
increase in SCr to ≥4.0mg/dL
OR initiation of RRT
<0.3mL/kg/h for ≥ 24h OR
anuria for ≥ 12h

 Once ARF is discovered, it is important to determine the
cause.

PRERENAL ACUTE RENAL FAILURE
 Prerenal ARF, caused by underperfusion of an otherwise
normal kidney, accounted for 21% of cases of ARF in a
multicenter study in Madrid.
 The hallmark of prerenal failure is that it is quickly reversible
with appropriate therapy, thus it can be thought of as “a good
kidney looking at a bad world.”
 Prerenal kidney failure can be a result of volume depletion
from renal or extrarenal losses, fluid sequestration in liver
failure or other edematous states, or inadequate perfusion
pressure caused by heart failure.
Liano F, Junco E, Pascual J, Madero R, Verde E. The spectrum of acute renal failure in the intensive care unit compared with that seen in other settings.
The Madrid Acute Renal Failure Study Group. Kidney Int Suppl. 1998, 66: S16-S24.

POSTRENAL ACUTE RENAL FAILURE
 Postrenal ARF, caused by obstruction of the urinary tract,
accounted for 10% of cases in the Madrid study.
 Urinary tract obstructions may be within the urinary tract (e.g.,
blood clots, stones, fungus balls), or extrinsic (e.g., tumors,
retroperitoneal fibrosis).
 Renal ultrasonography, when used to detect obstructions, has
a sensitivity and specificity of 90% to 95%.
 Unfortunately, it is also highly operator-dependent, so it should
be performed by a highly experienced radiologist.
Liano F, Junco E, Pascual J, Madero R, Verde E. The spectrum of acute renal failure in the intensive care unit compared with that seen in other settings.
The Madrid Acute Renal Failure Study Group. Kidney Int Suppl. 1998, 66: S16-S24.

INTRINSIC ACUTE RENAL FAILURE
 Once prerenal and postrenal causes are ruled out, intrinsic
renal failure is likely.
 Intrinsic ARF, caused by disease of the renal parenchyma,
accounted for 69% of cases in the Madrid study.
 Acute tubular necrosis (ATN), the most common type of
intrinsic ARF, accounted for 45% of all cases of ARF.
 ATN is most often caused by renal hypoperfusion and renal
ischemia.
 Other causes include various endogenous nephrotoxic
substances.
Glassock RJ MS, Massry SG, Humes HD. Diagnosis, clinical presentation and management. In: Glassock RJ, Massry SG (eds): Massry and Glassock's
Textbook in Nephrology. 4th ed. Baltimore: Lippincott Williams & Wilkins, 2001, pp 956-977.

PRERENAL
 Volume depletion:
 Haemorrhage
 Severe vomiting or diarrhoea
 Burns, inappropriate diuresis
 Oedematous states:
 Cardiac failure
 Cirrhosis, nephrotic syndrome
 Hypotension:
 Cardiogenic shock, sepsis, anaphylaxis.

CONTD…
 Cardiovascular:
 Severe cardiac failure
 Arrhythmias
 Renal hypoperfusion:
 Non-steroidal anti-inflammatory drugs (NSAIDs) or selective
cyclooxygenase-2 (COX-2) inhibitors, Angiotensin-converting
enzyme (ACE) inhibitors or angiotensin-II receptor antagonists
 Abdominal aortic aneurysm
 Renal artery stenosis or occlusion

INTRINSIC RENAL
 Glomerular disease:
 Glomerulonephritis
 Thrombosis
 Haemolytic uraemic syndrome
 Tubular injury:
 Acute tubular necrosis (ATN) following prolonged ischaemia
 Nephrotoxins (e.g, aminoglycosides, radiocontrast media,
myoglobin, cisplatin, heavy metals)
 Acute interstitial nephritis due to drugs (e.g, NSAIDs),
infection or autoimmune diseases

CONTD…
 Vascular disease:
 Vasculitis (usually associated with antineutrophil cytoplasmic
antibody)
 Cryoglobulinaemia
 Polyarteritis nodosa
 Thrombotic microangiopathy
 Cholesterol emboli
 Renal artery stenosis, Renal vein thrombosis
 Malignant hypertension
 Eclampsia

POSTRENAL
 Calculus
 Blood clot
 Papillary necrosis
 Urethral stricture
 Prostatic hypertrophy or malignancy
 Bladder tumour
 Radiation fibrosis
 Pelvic malignancy
 Retroperitoneal fibrosis

SYMPTOMS
 Fatigue
 Loss of appetite
 Headache
 Nausea and vomiting.
 Marked increases in the potassium level can lead
to irregularities in the heartbeat, which can be severe and life-
threatening.
 Fluid balance is frequently affected, though hypertension is
rare.
^ a b Tierney, Lawrence M.; Stephen J. McPhee and Maxine A. Papadakis (2004). "22". CURRENT Medical Diagnosis and Treatment 2005 (44 ed.).
McGraw-Hill. p. 871. ISBN 0-07-143692-8.

SIGNS
 Hypertension
 Abdomen: may reveal a large, painless bladder typical
of chronic urinary retention
 Dehydration with postural hypotension and no oedema
 Fluid overload with raised JVP, pulmonary
oedema and peripheral oedema
 Pallor, rash, bruising: petechiae, purpura, and nosebleeds
may suggest inflammatory or vascular disease, emboli
or disseminated intravascular coagulation, pericardial rub.
^ a b Tierney, Lawrence M.; Stephen J. McPhee and Maxine A. Papadakis (2004). "22". CURRENT Medical Diagnosis and Treatment 2005 (44 ed.).
McGraw-Hill. p. 871. ISBN 0-07-143692-8.

 Long duration of symptoms
 Nocturia, anemia
 Absence of acute illness
 Hyperphosphataemia, hypocalcaemia (but similar laboratory
findings may complicate acute kidney injury (AKI))
 Reduced renal size and cortical thickness on renal ultrasound
(but renal size is typically preserved in patients with diabetes
 Acute on chronic renal failure

URINALYSIS
 Urinalysis:
 Blood and/or protein suggests a renal inflammatory process;
microscopy for cells, casts, crystals; red cell casts diagnostic in
glomerulonephritis; tubular cells or casts suggest acute tubular
necrosis (ATN).
 Urine osmolality:
 Osmolality of urine is over 500 mmol/kg if the cause is pre-renal
and 300 mmol/kg or less if it is renal; patients with ATN lose the
ability to concentrate and dilute the urine and will pass a constant
volume with inappropriate osmolality.

BIOCHEMISTRY
 Serial urea, creatinine, electrolytes:
 Important metabolic consequences of AKI
include hyperkalaemia, metabolic acidosis, hypocalcaemia,
hyperphosphataemia.
 Serum creatinine:
 The level can remain within the normal range despite the loss of
over 50% of renal function.
 Creatine kinase, myoglobinuria:
 Markedly elevated creatine kinase and myoglobinuria
suggest rhabdomyolysis.

HAEMATOLOGY
 Full blood count, blood film:
 Eosinophilia may be present in acute interstitial nephritis,
cholesterol embolisation, or vasculitis.
 Thrombocytopenia and red cell fragments suggest thrombotic
microangiopathy.
 Coagulation studies:
 Disseminated intravascular coagulation associated with sepsis.

IMMUNOLOGY
 Cys-C:
 A stronger predictor than serum creatinine of risk of death and
cardiovascular events in older patients.
 C reactive protein:
 Nonspecific marker of infection or inflammation.
 Serum immunoglobulins, serum protein electrophoresis,
Bence Jones' proteinuria:
 Immune paresis, monoclonal band on serum protein
electrophoresis, and Bence Jones' proteinuria suggest myeloma.
Vaidya VS, Ferguson MA, Bonventre JV; Biomarkers of acute kidney injury. Annu Rev Pharmacol Toxicol. 2008;48:463-93.

CONTD…
 Antinuclear antibody (ANA):
 ANA positive in systemic lupus erythematosus (SLE) and other
autoimmune disorders.
 Anti-double stranded (anti-dsDNA) antibodies more specific for
SLE; anti-dsDNA antibodies; antineutrophil cytoplasmic antibody
(ANCA) (associated with systemic vasculitis; classical
antineutrophil cytoplasmic antibodies (c-ANCA) and antiproteinase
3 (anti-PR3) antibodies associated with Wegener's
granulomatosis.

CONTD…
 Complement concentrations:
 Low in SLE, acute post-infectious glomerulonephritis,
cryoglobulinaemia.
 Antiglomerular basement membrane (anti-GBM)
antibodies:
 Present in Goodpasture's disease.
 Antistreptolysin O and anti-DNAse B titres:
 High after streptococcal infection.

RADIOLOGY
 Renal ultrasonography:
 Renal size, symmetry, evidence of obstruction.
 Chest X-ray (pulmonary oedema):
 Abdominal X-ray if renal calculi are suspected.
 Doppler ultrasound of the renal artery and veins:
 Assessment of possible occlusion of the renal artery and veins.
 Magnetic resonance angiography:
 For more accurate assessment of renal vascular occlusion.

OTHERS
 Virology:
 Hepatitis B and C; HIV: important implications for infection control
within dialysis area.
 ECG:
 Recent myocardial infarction, tented T waves in hyperkalaemia.
 Renal biopsy:

INITIAL EVALUATION OF ACUTE RENAL FAILURE

 Critical measures include:
 Maintaining adequate intravascular volume and mean arterial
pressure
 Discontinuing all nephrotoxic drugs
 Electrolyte abnormalities must be corrected, and urine output
should be monitored closely.
 Pigment or uric acid exposure can be treated with alkaline
diuresis.
 Ethylene glycol or methanol poisoning should be treated with
an alcohol drip or with fomepizole (Antizol).
Fomepizole for the treatment of ethylene glycol poisoning. Methylpyr-azole for Toxic Alcohols Study Group. N Engl J Med 1999;340:832–8.

TREATING HYPERKALEMIA
 Hyperkalemia is a common complication of acute renal failure.
 Potassium levels below 6 mEq per L (6 mmol per L) usually can
be managed with dietary restriction and resin binders.
 Protein intake should be balanced to minimize nitrogenous waste
production while limiting starvation ketosis and subsequent
production of ketoacids.
 This balance is achieved best with a protein intake of 0.6 g per kg
per day.
Green GB, Coyne D. Renal disease. In: Green GB, Harris IS, Lin GA, Moylan KC, eds. The Washington manual of medical therapeutics. 31st
ed. Philadelphia: Lippincott Williams & Wilkins, 2004:252-71.

SUMMARY OF TREATMENT STRATEGIES IN
HYPERKALAEMIA
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2596697/table/tbl2/

SODIUM BICARBONATE THERAPY
 Sodium bicarbonate therapy should be reserved for the
treatment of severe metabolic acidosis (i.e, pH below 7.2 or a
bicarbonate level below 10 to 15 mEq per dL [10 to 15 mmol
per L]) with or without associated hyperkalemia.
 It is important to note that sodium bicarbonate and sodium
polystyrene sulfonate have a large sodium load and may
worsen fluid status in patients with acute renal failure.
 When hyperkalemia is severe and unresponsive to treatment,
kidney replacement therapy may be indicated.
Mehta RL, McDonald B, Gabbai FB, Pahl M, Pascual MT, Farkas A, et al.; Collaborative Group for Treatment of ARF in the ICU. A randomized
clinical trial of continuous versus intermittent dialysis for acute renal failure. Kidney Int 2001;60:1154-63.

DOPAMINE AND DIURETICS
 Low doses of dopamine (≤2 mcg/kg/min) increase renal blood
flow and might be expected to increase GFR.
 Loop diuretics may decrease tubular oxygen consumption by
reducing solute reabsorption.
 Despite most studies not showing improved patient outcomes
with its use, low-dose dopamine continues to be commonly
used.
 The risks associated with dopamine use (extravasation and
the potential for significant dosing errors) suggest that its use
should be avoided whenever possible.
Ronco C, Bellomo R. Prevention of ARF in the critically ill. Nephron Clin Pract 2003;93:c13-c20.

FENDOLPAM
 Fenoldopam mesylate is a selective dopamine A-1 receptor
agonist that increases blood flow to the renal cortex that has
been investigated for its ability to prevent the development of
ARF in many settings including contrast dye induced
nephropathy (CIN).
 A recent systematic review of randomized controlled trials of
critically ill patients or those undergoing major surgery,
revealed that fenoldopam significantly reduced the risk of
acute kidney injury and the need for renal replacement
therapy.
Stone GW, McCollough PA, Tumlin JA, et al. Fenoldopam mesylate for the prevention of contrast-induced nephropathy. JAMA 2003;290:2284–2292.

INDICATIONS FOR KIDNEY REPLACEMENT
THERAPY

DRUG DOSING CONSIDERATION IN
PATIENTS WITH ACUTE KIDNEY
DISEASE

DRUG DOSING IN AKD
 Dose recommendations are based on the severity of renal
impairment.
 This is expressed in terms of GFR.
 The serum creatinine concentration is sometimes used
instead as a measure of renal function but is only a rough
guide, even when corrected for age, weight, and sex.
 Nomograms should be used where accuracy is important.

MATHEMATICAL APPROACHES TO ESTIMATE
GFR THAT HAVE BEEN PROPOSED TO GUIDE
DRUG DOSAGE ADJUSTMENT
Matzke GR. Drug dosing in renal failure. In: DiPiro J, Talbert R, Yee G, Matzke GR, Wells B, Posey L (eds).Pharmacotherapy: A Pathophysiologic
Approach, 8th edn. McGraw-Hill: New York, NY, 2011.

STEPWISE APPROACH TO ADJUST DRUG
DOSAGE REGIMENS FOR PATIENTS WITH AKD
Levey AS, Stevens LA, Schmid CHet al.A new equation to estimate glomerular filtration rate.Ann Intern Med2009;150: 604–612.

DRUG DOSING CONSIDERATIONS FOR
PATIENTS WITH AKI
Thummel K, Shen D, Isoherranen Net al.Design and optimization of dosage regimens: pharmacokinetic data. In: Hardman J, Limbird L,
Goodman G (eds).Goodman and Gilman’s The Pharmacological Basis of Therapeutics, 11th edn. McGraw-Hill: New York, NY, 2006.

KEY MONITORING PARAMETERS FOR PATIENTS
WITH ESTABLISHED AKD

PRESCRIBING IN RENAL IMPAIRMENT
 For prescribing purposes renal impairment is usually divided
into three grades:
 Mild: GFR 20-50 ml/minute; serum creatinine approximately 150-
300 µmol/l.
 Moderate: GFR 10-20 ml/minute; serum creatinine approximately
300-700 µmol/L.
 Severe: GFR less than 10 ml/minute; serum creatinine >700
µmol/L.
 Patients with a GFR above 50 ml/min do not usually require
any dosage adjustment.
Joosten H, Drion I, Boogerd KJ, et al; Optimising drug prescribing and dispensing in subjects at risk for drug errors due to renal impairment: improving
drug safety in primary healthcare by low eGFR alerts. BMJ Open. 2013 Jan 24;3(1). pii: e002068. doi: 10.1136/bmjopen-2012-002068. Print 2013.

CONTD…
 The situation may change if a patient begins dialysis, since
some drugs will be removed by the dialysis.
 Drugs to which particular attention must be given include
many antibiotics, histamine H2-receptor antagonists,
digoxin, anticonvulsants and non-steroidal anti-
inflammatory drugs (NSAIDs).
 For many drugs with only minor or no dose-related side-
effects very precise modification of the dose regimen is
unnecessary and a simple scheme for dose reduction is
sufficient.

DRUGS CAUSING BIOCHEMICAL CHANGES
 Prescribing any drug that increases potassium levels is
potentially very dangerous e.g, potassium supplements and
potassium-sparing diuretics.
 Products with a high sodium content (e.g, some antacids) may
cause sodium and water retention in patients with renal
impairment.
 Excessive vitamin D replacement therapy can cause
hypercalcaemia that may precipitate or exacerbate renal
impairment.

NEPHROTOXIC DRUGS
 Nonsteroidal anti-inflammatory drugs (NSAIDs)
 Enflurane, Methoxyflurane
 Acyclovir, Aminoglycosides, Amphotericin B, Bacitracin
 Cephalosporins, Foscarnet, Leflunomide, Pentamidine
 Polymyxin, colistin, Sulfonamide, cotrimoxazole
 Tetracyclines, Vancomycin
 5-Azacitidine, Carboplatin, Cisplatin, Cyclosporine A and
tacrolimus
 Ifosfamide, Methotrexate, Mitomycin, Nitrosourea

Life-threatening complications include:
 Volume overload (severe pulmonary oedema)
 Hyperkalaemia
 Metabolic acidosis
 Spontaneous haemorrhage, e.g, Gastrointestinal

 When AKI is severe enough to need dialysis, in-hospital
mortality is around 50%, and it may exceed 75% in the context
of sepsis or in critically ill patients.
 The prognosis is closely related to the underlying cause.
 In prerenal failure, correction of volume depletion, using
central venous pressure monitoring when necessary, should
result in rapid recovery of renal function.
 However, once acute tubular necrosis (ATN) has developed,
and in other causes of acute kidney injury (AKI), the patient
will often be oliguric for several days or weeks.

CONTD…
 Prognosis is improved by rapid and aggressive treatment.
 This includes correcting prerenal causes like hypovolaemia or
inserting stents to bypass obstruction in postrenal causes.
 Patients who need dialysis have a higher mortality but this is a
reflection of the condition rather than a result of the treatment.
 Within an intensive care setting, mortality varies from 7.5% to
40% and outside of intensive care from zero to 17%.

CONTD…
 The Acute Physiology and Chronic Health Evaluation II
(APACHE II) scoring system indicates prognosis.
 In those who have a score between 10 and 19 the mortality
rate is 60% but with a score above 40 it approaches 100%.
 Indicators of poor prognosis include:
 Older age, multiple organ failure, oliguria,
 Hypotension, number of transfusions
 Acute on chronic renal failure.
Agraharkar M; Acute renal failure, eMedicine, Aug 2009.

 Identification of patients at risk.
 Maintain adequate blood pressure and volume status.
 Avoid potentially nephrotoxic agents, especially NSAIDs, ACE
inhibitors or Angiotensin-II receptor blockers.
 Acetylcysteine plus volume expansion may be used for
prevention of contrast nephropathy.
Lameire NH, De Vriese AS, Vanholder R; Prevention and nondialytic treatment of acute renal failure. Curr Opin Crit Care. 2003 Dec;9(6):481-90.

Acute Kidney Injury (for Undergraduates)

Acute Kidney Injury (for Undergraduates)

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