Acute Kidney Injury

Rapid deterioration in renal function manifested by reduction in GFR.

Occurs over hours to days
Loss of renal function leads to accumulation of nitrogenous wastes in the body.
Lab evidence of increased serum creatinine and BUN.
Oliguria may or may not be present

AKI is very common, occurs in 5% of all hospitalized patients.

AKI is associated with very high morbidity and mortality.
Definition
For the purposes of standardized definitions the Acute kidney injury network (AKIN) defines
AKI as an abrupt increase in serum creatinine of 0.3mg/dL or a 50% increase in serum creatinine,
or the development of oliguria (Urine output < 0.5mL/Kg/h for > 6 hours.
Causes of AKI
Pre renal
Reversible renal hypoperfusion due to:- true volume depletion (dehydration, diarrhea, diuretics, blood loss) or
- Poor effective renal blood flow (CHF, cirrhosis, hypoproteinemia)
Post renal
Caused by urinary tract obstruction leading to increased pressure in the bowmans space
-> reduced GFR.
Obstruction can be at multiple levels
- Urethra
- Bladder neck
- Ureteric bilateral. Unilateral obstruction usually does not lead to renal failure in the
presence of a functioning contra lateral
Intrinsic AKI
Characterized by injury to the renal parenchyma.
Can be a result of injury to:o Renal tubules
o Glomeruli
o Interstitium
o Renal arteries and veins
Causes of AKI
- Pre renal 60%
- ATN 25%
- All other intra renal disease 10%
- Obstruction 5%

Pre renal AKI

An adequate intra glomerular hydrostatic pressure and blood flow are essential to drive the
filtration of plasma water across the basement membrane into the Bowmans capsule (first step
in urine formation)
In pre renal AKI, blood pressure and /or intra renal blood flow is inadequate to sustain an
adequate intra glomerular hydrostatic pressure. As a result GFR falls.

In pre renal AKI, the renal parenchyma is UNINJURED. GFR can

return to normal if the pre renal state is rapidly corrected. If left
untreated, pre renal AKI can lead to ischemic ATN.
Causes of Pre renal AKI
Hypotension
An absolute reduction of total body volume
o Vomiting, diarrhea, excessive sweating
A reduction in effective intracellular volume where total body volume is usually
increased
o Congestive heart failure, cirrhosis, hypoproteinemia
Medication that alter intra renal hemodynamics
Nonsteroidal anti-inflammatory agents (NSAIDS)
Inhibitors of the renin angiotensin system
Angiotensin converting enzyme inhibitors (ACEs)
Angiotensin receptor blockers (ARBs)
Mechanism of NSAID and ACE induced AKI

GFR is driven by the high hydrostatic pressure

within the glomerular capillaries

o injury to the renal parenchyma

The afferent arterioles need to be adequately

dilated to allow renal flow and pressure to be
transmitted to the glomerular capillaries.
Prostaglandins play an important role in
maintaining
afferent
arteriolar
vasodilation and therefore GFR
Efferent arterioles need to be relatively constricted
to maintain a high hydrostatic pressure within
the glomerular capillaries
Angiotensin II plays an important role in
maintaining
efferent
arteriolar
constriction and therefore GFR

NSAIDs inhibit prostaglandin synthesis decreased vasodilatory prostaglandins

afferent arteriole constriction decreased GFR
ACE inhibitors decrease Angiotensin II levels efferent arteriole dilation decreased
GFR.
Administration of ACE inhibitors in the setting of volume depletion (low effective arterial
volume) leads to marked reduction in GFR because normally volume depletion stimulates the
renin-angiotensin system and Angiotensin II helps to maintain GFR by efferent arteriolar
constriction. ACE inhibitors will interfere with this compensatory mechanism.

ACE inhibitors must be discontinued in patients with volume depletion

Treatment of pre renal AKI

Diagnosis and treatment is urgent, since pre-renal AKI, if untreated, can lead to ischemic ATN
Treat the underlying cause:
Restore blood pressure in hypotensive patients
Administer appropriate fluids to volume-depleted patients
Treat CHF appropriately
Discontinue medications causing intra-renal vasoconstriction
If effective, treatment can result in the rapid return of urine flow and of GFR
Post renal AKI
Once urine exits the collecting duct and enters the calyces, renal function depends upon the
unhindered flow of urine along the entire urinary tract
Anatomical sites particularly at risk of obstruction are the:
Uretero-pelvic junction (often congenital)
Ureter
Uretero-vesical junction
Bladder neck (junction between bladder and urethra)
Urethra

In post-renal ARF the renal parenchyma itself is UNINJURED

GFR can return to normal if the cause of obstruction treated rapidly. However, if left
untreated, chronic obstruction can result in irreversible chronic kidney injury and CKD
Causes of Post Renal AKI
Bladder neck obstruction:
Women: Cancer of cervix
Men: Prostatic enlargement (benign or malignant)
Bilateral ureteral obstruction
Bilateral renal stones
Cancer (colon, uterine, cervical)
Retroperitoneal fibrosis

Clinical manifestation of urinary tract obstruction depend on the location of the obstruction
and time course within which it develops. In general, slowly developing obstructions are
asymptomatic while acute obstruction exhibits symptoms of pain, oliguria/anuria.
Prostatic hypertrophy symptoms such as urgency, frequency, hesitancy may herald
obstructive uropathy (BPH)
Diagnosis
History: - may have obstructive urinary symptoms, hematuria, and flank or suprapubic pain
depending on site of obstruction.
Physical exam: - may have palpable bladder as a suprapubic mass if obstruction is to the
bladder outlet
Laboratory:Elevated BUN/Creatinine
Urinalysis often unremarkable
Hematuria may be present when obstruction is due to stones, cancer
Imaging
Ultrasound is a quick and useful tool that will allow confirmation of the diagnosis of
obstruction.
Dilation of the renal pelvis (hydronephrosis) and ureter (hydroureter) may be seen.
Cystoscopy useful for evaluating bladder and prostate
CT and MRI can identify tumors, stones, adenopathy

Renal ultrasound showing a dilated pelvicaliceal system in hydronephrosis

Treatment: - relief of obstruction. If obstruction is due to BPH simple Foley catheter insertion
can relieve the obstruction while patient awaits definitive therapy for the prostate
enlargement.

Intrinsic AKI
AKI due to renal parenchymal disease
Acute tubular injury
- Ischemic (most common) due to prolonged pre renal state
- Nephrotoxic - Aminoglycosides, Amphotericin, NSAIDs, iodinated contrast, pigment
induced (hemoglobinuria, myoglobinuira)
Glomerulonephritis
Tubulointerstitial nephritis
Vascular vasculitis, thrombotic microangiopathy, renal artery stenosis/thrombosis, cholesterol
emboli
Acute tubular necrosis (ATN)
Acute tubular injury (ATI) is a better term because not all tubules are necrotic; apoptosis and
sub lethal injury are a major component of ATI.
ATI can be
- Ischemic - most common cause of ATI
Prolonged untreated pre renal state ischemic ATI
- Nephrotoxic e.g. Aminoglycoside , Amphotericin, Intravenous contrast , Rhabdomyolysis
Ischemic ATI
Several mechanisms are responsible for tubular injury following ischemia.
- Hemodynamic factors vasoconstriction, endothelial cell injury
- Intra renal inflammation

Role of medullary hypoxia in AKI

The medulla is supplied by via vasa rectae that originate in and return to the cortex.
Due to countercurrent loss of oxygen, O2 tension in the medulla falls progressively from outer
medulla to papilla. After an ischemic insult, the oxygen tension falls even further.

The renal outer medulla contains tubular segments that have high ongoing energy demand for
sodium transport.
- The third segment (S3) of the proximal tubule
- The medullary thick ascending limb (mTAL)
The combination of high energy needs for transport and the insufficient oxygen supply lead to
tubular cell injury and death of the tubular cells comprising both segments. This tubular cell
injury can persist long after the injury that precipitated the AKI has resolved.
Although the tubule is injured in ATI (not the glomerulus), the hallmark feature of ATI is
reduction in GFR. Mechanism of reduced GFR in tubular injury include
Tubuloglomerular feedback (TGF):- tubular damage results impaired proximal sodium
reabsorption which activates the TGF mechanisms leading to increased afferent vascular
resistance and a concomitant reduction in GFR. Adenosine, a potent renal vasoconstrictor is
thought to be the main mediator of TGF.

Tubular injury also leads to reduction in GFR by

- Back leak of glomerular filtrate
- Intratubular obstruction by cellular debris
and casts

Fate of ATI
In most cases, many tubular cells remain viable or are sublethally injured and are able to recover
functionally and structurally. It may take several days or weeks for full recovery to occur. Figure
below shows phases of ischemic ATI.
Phases of ischemic ATI

Treatment: - There is no proven treatment that will reverse ischemic ATI. Therapy is directed at
preventing further injury and allowing recovery to occur. If patients are volume depleted, restore
volume by administering IV fluids, remove offending agents e.g. NSAIDs.
Complications of ATI e.g. Volume overload may require therapy with diuretics, however the
injured tubules may not respond appropriately. Dialysis may be needed for management of
electrolyte abnormalities (e.g. hyperkalemia) and fluid overload. Dialysis is usually temporary

until tubules recover (as opposed to dialysis in advanced CKD where it is either lifelong or as a
bridge to kidney transplantation).
Sepsis and ATI
Sepsis is characterized by vasodilation, decrease in systemic blood pressure (septic shock) and
impaired renal perfusion. These hemodynamic effects contribute to AKI. In addition, sepsis
activates inflammatory cytokines and promotes microvascular injury. Treatment involves
management of sepsis (antibiotics) and hemodynamic support with intravenous fluids and
vasopressors as needed.

Contrast induced ATI

ATI is a common complication following exposure to iodinated contrast agents used for CT scan
and angiography. Mechanism of injury is thought to be a combination of direct vasoconstrictive
effects of the contrast agent with tubular toxicity mediated by generation of free radicals. Risk
factors for developing contrast nephropathy include existing renal disease, diabetic kidney
disease, advanced heart failure, volume depletion or any other cause of reduced effective arterial
volume. Higher osmolality and dose of contrast agent are associated with increased risk of
tubular injury.
Prevention of contrast induced nephropathy
- Hydration isotonic intravenous fluids normal saline or bicarbonate based
- Lower dose contrast
- Use of lower or iso osmolar agents
- Avoid NSAIDs and volume depletion
- N- Acetylcysteine is an anti-oxidant that has been used for prevention benefit is
controversial but used because it is harmless and may have some benefit.
Aminoglycoside induced ATI
The best understood nephrotoxic ATI is aminoglycoside induced ATI. Aminoglycosides are
concentrated in the proximal tubule by receptor mediated endocytosis and the concentration in
renal tubular epithelial cells is several fold higher than that of plasma. The accumulation persists
for as long as 4-6 weeks after therapy is discontinued. Aminoglycosides are though to increase
mitochondrial permeability resulting depletion of nucleotides that are necessary for oxidative
phosphorylation and generation of ATP.
Prevention monitoring drug levels, minimizing duration and frequency of drug therapy.
Rhabdomyolysis and ATI
Rhabdomyolysis (muscle necrosis) releases contents of muscle into the systemic circulation. The
cellular contents include myoglobin which is freely filtered in the glomerulus and causes direct
toxicity to tubular cells. Tubular obstruction by cellular debris is common. In addition to direct
toxicity, volume depletion (as fluid leaks from the injured muscle and is sequestered in the
extravascular space) and electrolyte disturbances (hyperkalemia and hyperphosphatemia as
cellular contents are released into the blood stream) are common in ATI caused by
rhabdomyolysis.
Causes of rhabdomyolysis include
- Crush injuries

Prolonged muscle ischemia from muscle compression e.g. alcohol abuses who fall and do
not move for prolonged periods
Illicit drug use cocaine
Tonic-clonic seizures
Severe electrolyte disturbances e.g. hypokalemia hypophosphatemia
Medication toxicity HMG CoA reductase inhibitors

Clinical features
- Disproportionate increase in serum creatinine, potassium, phosphorous and uric acid
relative to the degree of AKI (since there are released from injured muscle cells)
- Reddish brown urine
- FeNa < 1%
- Positive urinary dipstick for heme coupled with absence of RBCs on urine microscopy
- Increased muscle enzymes in the serum, Creatinine kinase
Treatment
- Aggressive hydration to correct volume contraction, increase renal perfusion and remove
tubular debris
- Alkalanization of urine by administering alkaline IV fluids (bicarbonate instead of saline)
to maintain urinary PH > 6.5 since tubular toxicity of myoglobin is reduced in alkaline
urine
- Correction of electrolyte abnormalities
Intravascular hemolysis with hemoglobinuria can cause AKI due to heme pigment mediated
injury to the renal tubules. Similar to myoglobin induced renal injury, urine dipstick tests +ve for
heme but no RBCs seen on microscopy.
Hepatorenal syndrome
An otherwise unexplained and progressive decline in renal function in a patient with advanced
hepatic disease.
In hepatic cirrhosis, marked splanchnic and systemic vasodilation leads intense intra renal
vasoconstriction.
Patients are typically oliguric and not responsive to fluid resuscitation although the main
underlying pathogenesis is due to depletion of effective circulating volume.
The kidneys are structurally normal and function can be restored if the patient received liver
transplantation.
Tumor lysis syndrome and AKI
Most commonly seen following treatment of hematologic malignancies of high cellular burden
e.g. Lymphoma and leukemia.
Rapid release of intracellular contents of tumor cells into the systemic circulation
Hyperuricemia, hyperkalemia, hyperphosphatemia, hypocalcemia.
AKI is primarily due to acute obstruction of urine flow by precipitated uric acid crystals within
the renal tubules
Treatment: - Aggressive hydration, uric acid lowering (allopurinol, rasburicase)

Acute interstitial nephritis (AIN)

One of the common causes of intrinsic AKI.
Causes: - Drug induced > 75% of all cases.
Infection bacterial or viral
Systemic diseases e.g. sarcoidosis, SLE
Drug induced interstitial nephritis is a hypersensitivity reaction that occurs within 2-15 days of
exposure to the offending agent.
Any medication can cause AIN, but drugs commonly associated with AIN are antibiotics
(penicillin, sulfonamides), NSAIDs, proton pump inhibitors. Pre exposure to the drug can
accelerate this process.
Clinical signs
- Elevated BUN/Creatinine
- Fever, rash, eosinophilia may be present.
Urine sediment white cells, WBC casts, and eosinophils may be present
Proteinuria if present is less than 1gram/day
Overt Nephrotic syndrome has been described with NSAID associated AIN. Biopsy shows
minimal change disease in addition to the tubulointerstitial nephritis.
Diagnosis: - renal biopsy is conclusive but not usually done.
Treatment: - most cases resolve with removal of the offending agent

Normal glomeruli. Interstitial nephritis comprising

Lymphocytes, plasma cells and eosinophils
Drug rush

Clinical approach to the patient with AKI

In all patients
- History
o Fluid loss (vomiting, diarrhea) , medications,
- Chart review
o Review blood pressure records, major surgery e.g. cardiac bypass, medications,
exposure to iodinated contrast
- Physical examination
o Blood pressure, orthostatic hypotension, mucus membranes, Jugular veins, lung:
rales, pleural effusion, heart: enlarged, s3, skin : rash, turgor, peripheral edema
- Routine blood tests
o BUN/Creatinine, electrolytes, CBC
- Urinalysis
o Dipstick
o Microscopy

Distinction between pre renal and intrinsic ATI

Muddy brown casts

FeNa not low exclusively in pre renal state. Intrinsic renal injury associated with low FeNa
include
- Contrast induced nephropathy
- Rhabdomyolysis
- Glomerulonephritis

Management of AKI
Depends on the cause but generally supportive.
Remove nephrotoxic agents.
Restore hemodynamics.
Indications of dialysis in patients with AKI include
- Hyperkalemia
- Pulmonary edema
- Pericarditis
- Severe metabolic acidosis
- CNS symptoms confusion, lethargy, seizures, coma