Acute Kidney

Injury
Acute Kidney Injury
Sudden impairment of kidney function resulting in the
retention of nitrogenous and other waste products
Diagnostic features:
Increase in Blood Urea Nitrogen (BUN) conc.
Increase in Plasma or Serum Creatinine (SCr)
Can range from asymptomatic and transient changes in
laboratory parameters of GFR to overwhelming and
rapidly fatal derangements in effective circulating
volume regulation and electrolyte and acid-base
composition of the plasma
Acute Kidney Injury - Epidemiology
Complicates 5-7% acute care hospital admissions and up to 30% of
admissions to the ICU (diarrheal illnesses, infectious diseases
[malaria and leptospirosis] and natural disasters
Increases the risk for CKD
Patients who survive severe AKI has increased risk for dialysis-
requiring end-stage kidney disease
Causes of community acquired AKI: volume depletion, adverse
effects of medications
Hospital-acquired AKI: sepsis, major surgical procedures,
critical illness (heart or liver failure), IV iodinated contrast
administration and nephrotoxic medication
Etiology and Pathophysiology
Prerenal Azotemia
Intrinsic Renal Parenchyma
Disease
Postrenal Obstruction
Prerenal Azotemia
Most common form of AKI
Rise in SCr or BUN concentration due to inadequate
renal plasma flow and intraglomerular
hydrostatic pressure to support normal glomerular
filtration
Most common clinical conditions:
Hypovolemia
Decreased cardiac output
Decreased effective circulating volume
Prerenal Azotemia
May lead to ischemic injury Acute Tubular Necrosis
Involves no parenchymal damage the kidney
Rapidly reversible once intraglomerular
hemodynamics are restored
 Renal efferent
Hypovolemia and vasoconstriction Glomerular
reduced cardiac and salt and filtration is
output water maintained
reabsorption
Prerenal Azotemia
In addition, a myogenic reflex within the afferent
arteriole leads to dilation in the setting of low
perfusion pressure, thereby maintaining glomerular
perfusion
Intrarenal biosynthesis of vasodilator
prostaglandins, kallikrein and kinins and NO
increase
Dilation of the juxtaposed afferent arteriole in order
to maintain glomerular perfusion, a mechanism
mediated, in part by NO
Risks
Atherosclerosis
Long-standing hypertension
Older age
Intrinsic AKI
Most common causes: sepsis, ischemia and
nephrotoxins
Pathophysiology: acute tubular necrosis,
inflammation, apoptosis and altered regional
perfusion
Sepsis-Associated AKI
AKI complicates more than 50% of cases of severe
sepsis and greatly increases the risk of death
AKI typically occur in the setting of hemodynamic
collapse requiring vasopressor support
Associated with tubular injury, inflammation,
mitochondrial dysfunction, and interstitial
edema
Sepsis

Generalized arterial vasodilation (mediated by

cytokines that upregulate the expression of NO
synthase)

Excessive efferent arteriole vasodilation or Renal

vasoconstriction from activation of SNS, RAAS,
vasopressin and endothelin

Reduction in GFR
Sepsis-Associated AKI
Sepsismay lead to endothelial damage, which results
in microvascular thrombosis, activation of reactive
oxygen species and leukocyte adhesion and
migration may injure renal tubular cells
Ischemia-Associated AKI
Outer medulla vulnerable to ischemic damage
because of the architecture of the blood vessels that
supply oxygen and nutrients to the tubules
AKI more commonly develops when ischemia occurs
in the context of limited renal reserve (CKD or
older age) or coexisting insults such as sepsis,
vasoactive or nephrotoxic drugs,
rhabdomyolysis or the systemic inflammatory
states
Ischemia-Associated AKI
Postoperative AKI
Burns and Acute Pancreatitis
Diseases of the Microvasculature Leading to Ischemia
Postoperative AKI
Ischemia-associated AKI is a serious complication in
the postoperative period (operations involving
significant blood loss and intraoperative hypotension)
Surgery: cardiac surgery with cardiopulmonary
bypass, vascular procedures with aortic cross
clamping and intraperitoneal procedures
Risk factors: underlying CKD, older age, DM, CHF and
emergency procedures
Postoperative AKI
Cardiopulmonary bypass characterized by
nonpulsatile flow and exposure of the circulation to
extracorporeal circuits
May cause AKI through
Extracorporeal circuit activation of leukocytes and
inflammatory processes
Hemolysis with resultant pigment nephropathy
Aortic injury with resultant atheroemboli
Due to cholesterol crystal embolization resulting in partial or total
occlusion of multiple small arteries within the kidney
Postoperative AKI
Over time, a foreign body reaction can result in
intimal proliferation, giant cell formation and further
narrowing of the vascular lumen subacute decline in
the renal function
Burns and Acute Pancreatitis
Extensive fluid losses into the extravascular compartments
of the body
Causes hypovolemia which results to decreased cardiac
output and increased neurohormonal activation,
dysregulated inflammation and an increased risk of
sepsis and acute lung injury - AKI
Massive fluid resuscitation - can develop abdominal
compartment syndrome marked elevation of
intraabdominal pressures, usually higher than 20 mmHg,
lead to renal vein compression and reduced GFR
Diseases of the Microvasculature
Leading to Ischemia
Thrombotic Microangiopathies (Antiphospholipid
syndrome, radiation nephritis, malignant
nephrosclerosis, and thrombotic thromobocytopenic
purpura/HUS)
Scleroderma and atheroembolic disease
Large vessel diseasess: renal artery dissection,
thromoembolism, thrombosis and renal vein
compression or thrombosis
Nephrotoxin-Associated AKI
Contrast Agents
Antibiotics
Chemotherapeutic agents
Toxic Ingestions
Endogenous toxins
Allergic Acute Tubulointerstitial Disease and Other Causes of
Intrinsic AKI

Risk
Factors: old age, CKD, prerenal azotemia and
hypoalbuminemia
Contrast Agents
Iodinated contrast agents used for CV and CT
imaging are a leading cause of AKI
Contrast nephropathy increased markedly in the
setting of CKD (diabetic nephropathy)
Clinical course:
Rise in SCr beginning 24-48 h after exposure
Peak: 3-5 days
Resolution: within 1 week
Contrast Nephropathy
Pathophysiology
Hypoxia in the renal outer medulla due to perturbations
in renal microcirculation and occlusion of small vessels
Cytotoxic damage to the tubules directly or via the
generation of oxygen free radicals
Transient tubule obstruction with precipitated contrast
material
Antibiotics
Aminoglycosides freely filtered across the glomerulus and then
accumulate within the renal cortex
AKI typically manifests after 5-7 days of therapy and can present even after
the drug has been discontinued
Hypomagnesemia common finding
Amphotericin B causes renal vasoconstriction from an increase
tubuloglomerular feedback as well as direct tubular toxicity mediated
by reactive oxygen species
Binds to tubular membrane cholesterol and introduces pores
Nephrotoxicity dose and duration dependent
Clinical features: polyuria, hypomagnesemia, hypocalcemia and nongap
metabolic acidosis
Antibiotics
Vancomycin
Acyclovir
Foscarnet, pentamidine, tenofovir and cidofovir
Penicillins, cephalosporins, quinolones, sulfonamides
and rifampin
Chemotherapeutic Agents
Cisplatin and Carboplatin accumulated by proximal
tubular cells and cause necrosis and apoptosis
Ifosfamide may cause hemorrhagic cystitis and
tubular toxicity (type II renal tubular acidosis, polyuria,
hypokalemia and decline in GFR)
Bevacizumab can cause proteinuria and hypertension
via injury to the glomerular microvasculature
Mitomycin C and gemcitabine may cause
thrombotic microangiopathy with resultant AKI
Toxic Ingestions
Ethylene glycol metabolized to oxalic acid,
glycoaldehyde and glyoxylate AKI through direct
tubular injury
Diethylene glycol 2-hydroxyethoxyacetic acid (HEAA)
cause tubular toxicity
Melamine nephrolithiasis and AKI through intratubular
obstruction or possibly direct tubular toxicity
Aristolochic acid Chinese herb nephropathy and
Balkan nephropathy
Endogenous Toxins
Myoglobin, hemoglobin, uric acid and myeloma
light chains
Rhabdomyolsis may result from traumatic crush
injuries, muscle ischemia during vascular or
orthopedic surgery, compression during coma or
immobilization, prolonged seizure activity, excessive
exercise, heat stroke or malignant hyperthermia
Endogenous Toxins
Pathogenic Factors:
Intrarenal vasoconstriction
Direct proximal tubular toxicity
Mechanical obstruction of the distal nephron lumen when
myoglobin or hemoglobin preciptates with Tamm-Horsfall
protein
Tumor lysis syndrome patients with lymphoma and
lymphoblastic leukemia
Massive release of uric acid in the renal tubules and lead to AKI
Endogenous Toxins
Myeloma light chains direct tubular toxicity and
binding to Tamm-Horsfall protein to form obstructing
intratubular casts
Hypercalcemia may cause AKI by intense renal
vasoconstriction and volume depletion
Allergic Acute Tubulointerstitial Disease
and Other Causes of Intrinsic AKI
AllergicAcute Tubulointerstitial Disease -
Characterized by inflammatory infiltrate and often
peripheral and urinary eosinophilia
Severe infections and infiltrative diseases
Diseases of the glomeruli or vasculature
compromised blood flow
Glomerulonephritis and vasculitis
Postrenal Acute Kidney Injury
Postrenal Acute Kidney Injury
Bladder neck obstruction prostate disease,
neurogenic bladder, or therapy with anticholinergic
drugs
Obstructed Foley catheters
Blood clots, calculi and urethral strictures
Postrenal Acute Kidney Injury
Pathophysiology
Hemodynamic alterations triggered by an abrupt
increase in intratubular pressures
(1) Hyperemia from afferent arteriolar dilation
(2) Intrarenal vasoconstriction (angiotensin II,
thromboxane A2 and vasopressin, and reduction in NO
production)
Reduced GFR changes in glomerular ultrafiltration
coefficient