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
 Sepsis may 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
 Allergic Acute 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