5 - Acute Kidney Injury (AKI)

8 Questions

Acute Kidney Injury (AKI)?

Is an abrupt decrease in kidney filtration/excretory function identified by:

• Increase in serum creatinine and/or

• Decrease in urine output

What might an AKI reflect?

Impaired kidney function without structural injury

Structural kidney injury

or both

Consequences of AKI?

Accumulation of metabolic waste

Fluid, electrolyte and acid-base disturbances

Can mild AKI be asymptomatic?

Yes

It can be asymptomatic

Serum creatinine criteria for AKI?

Increase in serum creatinine of ≥ 0.3 mg/dL within 48 hours

or

Increase in serum creatinine ≥ 1.5-fold from baseline, which is known or presumed to have occurred within the prior 7 days

Urine output criteria for AKI?

Urine output of <0.5 ml/kg/hr for ≥ 6 hours

Patient susceptibility risk factors for AKI?

Chronic kidney disease

Older age

Diabetes

Hypertension / vascular disease

Heart failure or chronic liver disease

Acute illness or exposures risk factors for AKI?

Critical illness, sepsis, or shock

Hypovolemia / hemorrhage

Major surgery, trauma, or burns

Nephrotoxic or renal-hemodynamic medications

What are the 3 traditional categories of AKI?

Prerenal

Intrinsic

Postrenal

What is the other category of AKI?

Pseudo AKI

Prerenal AKI?

Reduced kidney perfusion without established parenchymal injury

Common causes of prerenal AKI?

Volume depletion → renal/GI losses, hemorrhage

Hypotension / Shock

Reduced effective renal perfusion → ex; HF

What has compensatory responses to reduced perfusion?

Sympathetic nervous system

RAAS

ADH + Thirst

Intrarenal autoregulation

Compensatory response of the sympathetic nervous system to reduced perfusion?

Supports blood pressure

Stimulates renin release

Compensatory response of the RAAS to reduced perfusion?

Helps maintain glomerular pressure

Increase Na+ and water retention

Compensatory response of the ADH + Thirst to reduced perfusion?

Conserve water / increase water intake

Compensatory response of the intrarenal autoregulation to reduced perfusion?

Adjusts arteriolar tone to help preserve GFR

What factors limit autoregulatory compensation?

Older age, atherosclerosis, long-standing hypertension

Chronic kidney disease

Medications → can interfere with compensatory arteriolar responses

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MOA of ACEI / ARBs?

Block angiotensin II mediated efferent constriction

Decrease intraglomerular pressure and GFR

What is expected after starting / increasing doses of ACEI/ARBs?

A small stable rise in SCr may occur

What is a concerning rise in SCr with ACEI/ARBs for Prerenal AKI?

>30% rise within 4 weeks

Evaluate for volume depletion, hypotension, NSAID use, or renal artery stenosis

Management of ACEI/ARBs if concerning rises in SCr for Prerenal AKI?

Correct reversible factors first

If kidney function does not improve → reduce/hold the ACEI/ARB

MOA of NSAIDs?

Inhibit vasodilatory prostaglandins → causing afferent arteriolar vasoconstriction

Decrease in intraglomerular pressure and GFR

Who is at higher risk of Prerenal AKI when using NSAIDs?

Reduced renal perfusion/volume depletion

CKD

Older age

Concurrent ACEI/ARB

Diuretic use

Prevention of AKI with NSAIDs?

Avoid or minimize NSAID use in high risk patients

Correct volume depletion when present

Management of NSAIDs with prerenal AKI?

Discontinue NSAID when possible

Correct the contributing volume depletion or hypotension

Clinical pearl with NSAIDs?

Can cause Acute interstitial nephritis (AIN) through a separate mechanism

MOA of calcineurin inhibitors?

Renal arteriolar vasoconstriction, particularly of the afferent arteriole

Decrease in renal blood flow and GFR

Ex → Tacrolimus, cyclosporine

Who is at higher risk of Prerenal AKI when using calcineurin inhibitors?

Higher CNI exposure

Volume depletion

Concurrent nephrotoxins

Prevention of Prerenal AKI with calcineurin inhibitors?

Monitor CNI exposure, volume depletion and concurrent nephrotoxins

Management of calcineurin inhibitors with Prerenal AKI?

Assess CNI concentration, volume status and interacting/nephrotoxic medications

Reduce CNI exposure when toxicity is suspected

When can compensatory responses fail to maintain GFR?

Severe or prolonged hypoperfusion → or medications that interfere with arteriolar responses

Early GFR changes may occur without tubular injury

Severe/prolonged ischemia → tubular injury → acute tubular necrosis (ATN)

What are the major causes of intrinsic AKI?

Tubular injury → Acute tubular necrosis (ATN), and Crystal induced nephropathy

Glomerular disease

Vascular injury/disease

Interstitial injury (AIN) → Drugs and infections

Acute tubular necrosis (ATN)?

Most common pattern of intrinsic AKI

Involves injury to renal tubular epithelial cells

What are common settings associated with tubular injury?

Sepsis

Ischemia

Nephrotoxins

How are prerenal AKI and ischemic ATN related?

They exist on a continuum of hypoperfusion

Severe or prolonged hypoperfusion can progress from prerenal AKI to ischemic ATN

How does myoglobin cause intrinsic AKI?

Endogenous nephrotoxin

Rhabdomyolysis → skeletal muscle breakdown → myoglobin release

Filtered myoglobin causes direct tubular injury and pigment-cast obstruction

Volume depletion and renal vasoconstriction further increase AKI ris

Aminoglycosides?

Exogenous nephrotoxin

Can cause ATN → intrinsic AKI

Presents as → Nonoliguric → urine output remains within a normal rang despite the kidneys being damaged/failing

Usually develops after several days of therapy

Mg2+ wasting and other tubular abnormalities may occur

Higher risk of ATN with aminoglycosides in intrinsic AKI?

Prolonged aminoglycoside therapy and concurrent nephrotoxins

Prevention of ATN and intrinsic AKI with aminoglycosides?

Use extended interval dosing when appropriate

Adjust dosing and monitor levels based on kidney function

Management of aminoglycosides for ATN and intrinsic AKI?

Discontinue when possible

Supportive care

Vancomycin?

Exogenous nephrotoxin

Can cause ATN → intrinsic AKI

MOA → Tubular cell injury; vancomycin-containing casts may contribute

Presents as → Rising SCr, usually after several days

High vancomycin concentrations may be a cause or consequence of AKI

Higher risk of ATN with vancomycin in intrinsic AKI?

Greater vancomycin exposure

Critical illness

Concurrent nephrotoxins

Prevention of ATN and intrinsic AKI with vancomycin?

Appropriate dosing and therapeutic drug monitoring

Minimize unnecessary nephrotoxins

Management of vancomycin for ATN and intrinsic AKI?

Reduce or discontinue when possible

Supportive care

Amphotericin B?

Exogenous nephrotoxin

Can cause ATN → intrinsic AKI

MOA → Direct tubular injury; renal vasoconstriction may also contribute

Presents as → Rising Scr with electrolyte wasting → K, Mg

Lipid formulations have less nephrotoxicity

Higher risk of ATN with Amphotericin B in intrinsic AKI?

Higher cumulative exposure

Dehydration

CKD

Prevention of ATN and intrinsic AKI with Amphotericin B?

Prefer lipid / liposomal formulations when clinically appropriate → IV isotonic crystalloid hydration

Management of vancomycin for ATN and intrinsic AKI?

Discontinue or change therapy when possible

Maintain hydration

Avoid other nephrotoxins

Tenofovir?

Exogenous nephrotoxin

Can cause ATN → intrinsic AKI

Presents as → AKI with phosphate wasting, glycosuria, proteinuria, or bicarbonate loss

Tubular dysfunction may occur before overt AKI

Higher risk of ATN with Tenofovir in intrinsic AKI?

Greater drug exposure

CKD

Concurrent nephrotoxins

Prevention of ATN and intrinsic AKI with Tenofovir?

Adjust TDR dosing for kidney function → monitor for tubular toxicity

Tenofovir alafenamide (TAF) → is less nephrotoxic than tenofovir disoproxil fumarate (TDF)

When is iodinated contrast used with?

IV contrast enhanced CT
Intra-arterial angiography

Contrast-associated AKI (CA-AKI)?

AKI occurring after contrast exposure

Regardless of cause

Contrast-induced AKI (CI-AKI)?

AKI actually caused by contrast

When contrast causes AKI → tubular injury and altered renal hemodynamics may contribute

What increases the risk of contrast-associated AKI?

AKI or advanced CKD

Volume depletion

Greater contrast exposure

Risk differs between routine IV CT and intra-arterial angiography.

How is contrast-associated AKI prevented and treated?

Prevention → Depends on patient risk and procedure

Treatment → Primarily supportive care once AKI develops

Crystal induced nephropathy?

Drugs or metabolites may precipitate when urinary concentrations exceed solubility

Tubular injury → Intrinsic AKI

What increases risk for crystal induced nephropathy?

Low urine flow / volume depletion

Greater drug exposure

CKD

How can drug crystals cause intrinsic AKI?

Urine pH affects drug crystallization risk differently depending on the drug

Crystals can cause → tubular injury, inflammation, and intratubular obstruction

How can acyclovir cause crystal-induced AKI, and how is it prevented?

Risk → Crystals form with high urinary concentrations

Prevention → Hydration, avoid rapid IV administration, and adjust dose for kidney function

How can high-dose methotrexate cause crystal-induced AKI, and how is it prevented?

Risk → Methotrexate is less soluble in acidic urine

Prevention → IV hydration and urine alkalinization

Clinical features of crystal-induced nephropathy?

May be asymptomatic except for increase in SCr

Possible symptoms → Hematuria, flank pain, or decreased urine output

Urinalysis may show → Drug-specific crystals or crystal-containing casts

Acute interstitial Nephritis (AIN)?

Immune-mediated inflammation of the tubulointerstitium

Medications are the most common cause

Intrinsic AKI

What drugs are common causes of AIN?

Antibiotics → especially Beta-lactams → penicillins, cephalosporins, sulfonamides, rifampin, and fluoroquinolones

NSAIDs

Proton pump inhibitors

Immune checkpoint inhibitors

How is acute interstitial nephritis (AIN) clinically recognized?

Classic triad → Rash, fever, eosinophilia → often absent

Urinalysis → Pyuria common; WBC casts uncommon

Urine eosinophils → Not reliable for diagnosis

If uncertain → Kidney biopsy may be needed

How is acute interstitial nephritis (AIN) prevented and treated?

Remove the cause → Stop the offending drug when possible

Glucocorticoids → May be considered in selected patients, evidence and optimal regimen are limited

Key point → Earlier recognition and treatment/removal of the cause may improve kidney recovery

Postrenal AKI?

Obstruction of urine flow

Lower tract → BPH, bladder dysfunction/urinary retention, urethral obstruction

Upper tract → Ureteral stones, tumors, retroperitoneal fibrosis

AKI usually requires bilateral obstruction or obstruction of a solitary functioning kidney

Hydronephrosis?

Dilation of the renal collection system

Often results from urinary tract obstruction

Is hydronephrosis synonymous with obstruction?

No

May occur without significant obstruction

Obstruction may occasionally occur without hydronephrosis

Pseudo-AKI?

Increased SCr without a true decrease in GFR

Causes of Pseudo-AKI?

Decreased creatinine secretion → trimethoprim, cimetidine, cobicistat

Increased creatinine production

Creatinine-assay interference

Increased SCr does not always mean decreased kidney filtration

What are the first questions to ask when evaluating AKI?

1. Is this AKI?

• Does the patient meet diagnostic criteria?

2. What was baseline kidney function?

• Prior SCr/eGFR, CKD history, urinalysis, and imaging when relevant

3. What is the likely cause?

• Hemodynamics/volume status, infection, obstruction, medications, or other exposures

Pharmacist role → Identify medication causes and adjust drugs requiring kidney-function-based dosing

What do SCr, eCrCl, and eGFR indicate during AKI?

SCr is an → indirect marker of filtration

eCrCl and eGFR are estimates

During rapidly changing kidney function, SCr lags behind GFR changes, making steady-state equations unreliable

How do kidney function estimates behave during AKI?

Worsening AKI → Estimates may overestimate current kidney function

Recovery → Estimates may underestimate current kidney function

What is Blood Urea Nitrogen (BUN), and why does it rise in AKI?

Urea is a product of protein metabolism

BUN rises as kidney clearance decreases

What does a BUN ratio greater than 20:1 suggest?

Low perfusion increases urea reabsorption

A ratio greater than 20:1 supports → prerenal AKI but is not diagnostic

What else may cause BUN to rise?

GI bleeding

Increased protein intake/nutrition

Catabolism

Glucocorticoids

What is oliguric AKI?

Markedly reduced urine output

Traditionally less than 400–500 mL/day in adults

What is anuria, and how is it related to oliguria?

Anuria is extreme oliguria

Approximately less than 100 mL/day

What do urine output patterns tell you?

Urine output patterns describe urine volume but do not establish the cause of AKI

Nonoliguric AKI?

AKI with relatively preserved urine output

Which urine microscopy findings support acute tubular necrosis (ATN)?

Renal tubular epithelial cells

Granular or muddy brown casts

What do WBC casts and RBC casts suggest?

WBC casts → Acute interstitial nephritis (AIN) or pyelonephritis

RBC casts → Glomerular disease

What do crystal-containing casts suggest in AKI?

Crystalline nephropathy

How is FENa interpreted in AKI?

FENa less than 1% → May support prerenal physiology (kidneys retain sodium)

FENa greater than 1% → May support tubular injury in the appropriate setting

When can FENa be misleading in AKI?

Diuretics

CKD

Sepsis

Glomerular disease

Obstruction

Is FEUrea a reliable substitute for FENa after diuretic use?

No

FEUrea is not reliably superior after diuretic exposure

Interpret both indices in the clinical context

What are FENa and FEUrea?

FENa → Fractional excretion of sodium — percentage of filtered sodium excreted in urine

FEUrea → Fractional excretion of urea — percentage of filtered urea excreted in urine

What biomarkers help assess kidney function or injury?

Cystatin C → Filtration marker that can complement SCr when estimating changes in filtration

NGAL and others → Kidney stress/injury markers that may detect tubular injury earlier in selected settings

What imaging is used when postrenal AKI or obstruction is suspected?

Bladder scan/postvoid residual

Renal ultrasound

CT → Used when clinically indicated.

Other urologic procedures → Depend on the suspected obstruction

When is kidney biopsy considered in AKI?

When intrinsic AKI remains unexplained

Most useful when results could change management

Major procedural risk → Bleeding

What are the general principles for preventing AKI?

Identify patients at increased risk

Correct volume depletion or hypotension

Avoid unnecessary nephrotoxic drugs and combinations

If nephrotoxic drugs are necessary → limit exposure and duration and monitor appropriately

Use drug-specific preventive measures when available

What is used for contrast-associated AKI prophylaxis?

IV isotonic saline to support hydration

Avoid volume expansion in patients who are hypervolemic

Who should receive prophylaxis before IV contrast for CT?

Ongoing AKI or eGFR less than <30 mL/min/1.73 m²

Consider prophylaxis at → eGFR 30–44 in selected high-risk patients

Who is high risk for AKI prophylaxis before intra-arterial angiography?

eGFR less than 30 mL/min/1.73 m²

eGFR less than 45 plus significant proteinuria and diabetes or another major comorbidity

What is the general treatment approach for AKI?

Identify and treat the cause

Stop or adjust contributing medications when possible

Maintain adequate blood pressure and kidney perfusion

Correct volume depletion; avoid excess fluid accumulation

Monitor recovery compared with baseline kidney function

How is prerenal AKI treated when volume depleted or hypotensive?

Volume depletion → IV isotonic crystalloid

Hypotension/shock → Treat the cause and support kidney perfusion

How is prerenal AKI treated with heart failure or medication-related causes?

Heart failure/congestion → Improve cardiac function and relieve venous congestion

Review medications contributing to hypotension or reduced GFR