Acute Kidney Injury RenalResp REM

Acute Kidney Injury (AKI)

Subcategory of AKD

Definition: sudden loss (occurring over 7 days or less) of kidney function resulting in accumulation of metabolic waste products

The term AKI encompasses a wide spectrum of kidney injury, not just failure (mild cellular injury → necrosis)

Epidemiology

May occur in the setting of no prior kidney disease or in association with chronic kidney disease (CKD)

May occur in the hospital or community setting

13-18% among hospitalized patients

8-24% among newborns

Acute Kidney Disease (AKD)

Functional and/or structural kidney abnormalities with implications for health

The injury or damage to the kidneys occurred suddenly, is short lived (< 3 months) and reversible

May occur in the setting of no prior kidney disease or in association with chronic kidney disease (CKD)

May occur in the hospital or community setting

AKI Onset, Common Causes, Reversibility, and Duration

Rapid Onset (hours to days)

Caused by Sepsis, dehydration, ischemia, obstruction, medications

Often reversable with prompt interventions

Duration: Up to 7 days

AKD Onset, Common Causes, Reversibility, and Duration

Subacute (days to weeks)

Caused by Prolonged AKI, unresolved AKI, persistent injury, medications

Potentially reversable but with risk for progression

Duration: 7 to 90 days

Chronic Kidney Disease CKD Onset, Common Causes, Reversibility, and Duration

Gradual Onset (months to years)

Caused by Diabetes, hypertension, glomerulonephritis, polycystic kidney disease, tubulointerstitial disease

Irreversible, progressive decline

Duration: > 90 days

Kidneys Are Vulnerable To Injury Due To

High renal blood flow requirements: ~20-25% of resting cardiac output

Large vascular surface area

High energy requirements of tubular cells (e.g. loop of Henle)

Proximal tubule uptake of toxins

Intrarenal drug metabolism can lead to toxicity if metabolism results in a nephrotoxic metabolite or prolonged exposure

AKI Exposure Risk Factors

Exposure Risks - Triggers or direct insults

Sepsis (life-threatening infection)

Critical illness

Circulatory shock

Burns

Trauma

Cardiac surgery

Major noncardiac surgery

Nephrotoxic medications

Radiocontrast agents

AKI Susceptibilities

(Think of these as underlying vulnerabilities)

Dehydration or volume depletion

Advanced age

Neonates: premature birth, very low birth weight

Chronic diseases (heart, lung, liver, kidneys)

Diabetes mellitus

Cancer

Anemia

Complications of AKI

Fluid and electrolyte imbalances - Hypervolemia or Hypovolemia, Acid/base and electrolyte disturbances (e.g. acidosis, hyponatremia, hyperkalemia, hyperphosphatemia, hypocalcemia)

Systemic Effects: Bleedings, cardiovascular complications, infection risk, malnutrition, toxin accumulation

Long term complications: Risk for developing CKD and progression to end stage kidney disease

AKI Mortality

independent risk factor for mortality

Mortality: ~15-80%

10% mortality with uncomplicated AKI

High risk of death if AKI + CKD

> 50% mortality rate in patients with AKI and multi-organ failure

Up to 80% mortality rate in patients who require renal replacement therapy

AKI Detection

mostly based on monitoring serum creatinine ± urine output

The different AKI classification systems are generally similar with some differences in Scr and urine output criteria

AKI classification systems help predict patient outcomes

Considerations With Urine Output As A Marker of AKI Among Certain Populations

Weight and urine output is a non-linear relationship

Overweight/obese patients may be misclassified as having AKI when they have normal urine output if using a weight-based urine output criterion

Urine output criterion will not be reliable if patients are receiving diuretic therapy

Pediatric Considerations with Scr as an AKI Biomarker

Small Scr Change --> Major GFR Change

Example: 5-month-old (full term)

Length: 60 cm

Scr: 0.2 mg/dL, GFR 135 mL/min/1.73m2

Scr: 0.4 mg/dL, GFR ~68 mL/min/1.73m2

Recommendations For Using Scr to Screen for AKI

Rather than using one isolated value for determining AKI, look at trends

Determining baseline Scr - Use the lowest Scr value within the past 6 months, The lowest Scr during hospitalization may also be considered as equal to or higher than the patient’s true baseline value, Consider population-based normative values for the patient’s baseline Scr

Estimate GFR

Cystatin-C for Detecting AKI

More accurate than Scr for most patient populations

Detects AKI up to 48 hours earlier than Scr

Limited availability, lack of assay standardization, higher cost

Lack of clear guidance on its role and application for AKI screening and management

Stage 1 Improving Global Outcomes (KDIGO)

Scr: 1.5 – 1.9 times the baseline or > 0.3 mg/dl increase

Urine Output: <0.5 ml/kg/hr for 6-12 hours

Stage 2 Improving Global Outcomes (KDIGO)

Scr: 2.0 – 2.9 times baseline

Urine Output: <0.5 ml/kg/hr for > 12 hours

Stage 3 Improving Global Outcomes (KDIGO)

3 times baseline or > 4.0 mg/dl increase or Initiation of renal replacement therapy Or In patients < 18 years-old, decrease in eGFR to < 35 ml/min/1.73m2

Urine output: <0.3 ml/kg/hr for > 24 hours Or Anuria > 12 hours

Decreased Perfusion: True Volume Depletion

Dehydration due to poor fluid intake, vomiting, diarrhea

Diabetes insipidus

Glucosuria

Overly aggressive diuresis

Hemorrhage

Increased insensible losses

Decreased Perfusion: Effective Volume Depletion

Decreased volume of blood perceived by baroreceptors

Decreased cardiac output

Due to certain disease states (sepsis, CHF, liver disease)

Diseases that cause hypoalbuminemia (e.g. nephrotic syndrome) or third-spacing

Medications: e.g. NSAIDs, ACEI, overly aggressive treatment with anti-hypertensive medications

Clinical Findings Associated With Pre-renal Azotemia

Elevated BUN:Scr ratio > 20

Oliguria

Concentrated urine

Types of Intrinsic Azotemia Based On Affected Structure

Structural damage within the kidney

Blood vessels – damage to renal vasculature (vasculitis, emboli, malignant hypertension, glomerulonephritis)

Interstitium (space between nephrons and blood vessels) – interstitial nephritis

Renal tubules – acute tubular necrosis (ATN)

Most commonly caused by prolonged ischemia, nephrotoxins, or sepsis

Acute Interstitial Nephritis (AIN)

Sudden inflammation of the kidney’s interstitium

Medications are the most common cause

Medications Associated with Acute Interstitial Nephritis (AIN)

Analgesics - Aspirin, NSAIDs: ibuprofen, ketoprofen, naproxen

Anticonvulsants: carbamazepine, phenytoin, valproate sodium

Antimicrobials:

Beta lactams: penicillin, ampicillin, methicillin, cephalosporins

Rifampin, Sulfonamides

Anti-neoplastic agents: adriamycin, carboplatin, gemcitabine

Diuretics: furosemide, chlorthalidone, hydrochlorothiazide

Other: allopurinol, cimetidine, omeprazole, contrast dye, ACEIs

AIN Presentation

Renal Manifestations: Elevated blood urea nitrogen and Scr, ± Oliguria, Sterile pyuria with leukocyte casts, Microscopic hematuria, Non-nephrotic range proteinuria

Nonspecific Symptoms: Fever, rash, and eosinophilia, May present with generalized hypersensitivity reactions, Malaise, Anorexia, Weight loss, Nausea and vomiting

Pathophysiology of ATN - Acute Tubular Necrosis

Common cause of AKI in hospitalized patients

Accounts for 85% of all cases of intrinsic AKI

Prolonged and/or severe ischemia leading to renal tubular injury

Inflammation and microvascular compromise result in histologic changes

Necrosis, shedding of epithelial cells and denuding of the basement membrane in the proximal tubule

Distal tubule obstruction by sloughed cells

ATN Clinical Findings

Patient history

Prolonged and/or severe pre-renal azotemia (hypovolemia, CHF, sepsis, etc)

Exposure to nephrotoxic medications (e.g. aminoglycosides, sucrose containing IV immunoglobulin, synthetic cannabanoids)

Nephrotoxic procedures

Rhabdomyolysis

Laboratory Assessment For ATN

Rapid decline in GFR

Oliguria - Decreased urine output leading to fluid and electrolyte abnormalities

Loss of urine concentrating ability (develops early and is almost a universal finding in ATN)

Urine is dark colored with presence of casts (cellular debris)

Post-Renal Azotemia

Renal injury is caused by inadequate urine drainage

Obstruction of urine flow downstream from the kidney to the ureter, bladder outlet, or urethra leading to increased retrograde hydrostatic pressure and interference with glomerular filtration

Causes of Post-renal Azotemia

Nephrolithiasis (i.e. kidney stones)

Cystinosis

Anatomical defects (e.g. posterior urethral valves, vesicoureteral reflux)

Strictures

Benign prostatic hypertrophy

Neurogenic bladder

Improper catheter placement

Infections

Cancer

Medications: e.g. anticholinergic agents

Clinical Findings Associated With Post-renal Azotemia

Patient history

Decreased urine stream/output

History of kidney stones, prostate disease, obstructed bladder, etc

Medications history: anticholinergic agents

No specific findings other than AKI

May have pyuria (white blood cells in the urine) or hematuria (red blood cells in the urine)

Medication-Related Causes of Post-Renal Azotemia

Medications that crystallize in the renal tubules - Acyclovir (crystal precipitation in tubules with high doses), Methotrexate (Leucovorin is used to mitigate toxic effects of high dose methotrexate), Triamterene (Dyrenium, Maxzide, Dyazide), Indinavir (Crixivan)

Medications that cause ureteral or bladder obstruction - Anticholinergic medications (antihistamines, tricyclic antidepressants, anti-emetics)

Cyclophosphamide & Ifosfamide both may cause hemorrhagic cystitis (Mesna is used to prevent hemorrhagic cystitis)

Summary of Renal Assessment by AKI Etiology

Prerenal: BUN:SCr > 20, FeNa (%) - <1%

Intrinsic: UA - casts, cellular debris, blood

Post renal: UA - Cellular debris, crystals or normal

Assess, Prevent, and Detect AKI

Ongoing assessment to identify patients at risk for AKI and correct factors when possible

Use a tracking system to permit early recognition of patients have high-risk for AKI

Patients should receive nephrotoxic medications only if needed for as long as needed

Administer IV hydration if appropriate to optimize hemodynamic status

Nephrotoxic Injury Negated Just-in-time Action (NINJA)

Screen hospitalized patients for AKI risk factors

High nephrotoxic medication exposure: Over three (3) nephrotoxic medications on the same day or Aminoglycoside or Vancomycin monotherapy for more than three (3) consecutive days

Daily Scr, weight, strict intake and output monitoring while exposed

Adjust medications if clinically appropriate

General AKI Management

Treat or remove AKI cause

Provide supportive care (correct fluid and electrolyte imbalances)

Use loop diuretics only treat fluid overload

AIN: initiate corticosteroids

Avoid routine use of loop diuretics to “force” urine output

Low-dose dopamine has no proven renal protective effects and may cause potential harm

Mechanism of NSAID Injury

Hemodynamic injury due to disruption of normal autoregulation of intraglomerular capillary hydrostatic pressure

Inhibit prostaglandin E2 which is responsible for vasodilating afferent arteriole

Risks and Prevention in NSAIDs

Risks - Concomitant administration with angiotensin-converting enzyme inhibitors (ACEI) angiotensin II receptor blockers (ARB)

Atherosclerotic CV disease

Diuretic therapy

Polypharmacy

Dehydration

Prevention and Managemen - Use alternative analgesics, Optimize volume status and avoid dehydration

Mechanism of ACEI/ARB Injury

Hemodynamic injury due to disruption of normal autoregulation of intraglomerular capillary hydrostatic pressure

Presentation of ACEI/ARB Injury

Up to 30% ↑ in Scr during first 3 weeks may be expected with these agents

Reversible upon discontinuation; If rise in Scr persists for more than 4 months at the lowest dose then may need to discontinue

ACEI/ARB Risks

Concomitant administration with NSAIDs

Co-administration of ACEI and ARB

Bilateral renal artery stenosis or severe atherosclerotic disease

CKD - diabetic nephropathy

Risks with Dual ACEI and ARB Therapy

Rationale for dual therapy - Incomplete elimination of angiotensin II by ACEI; ARB offer additional reduction in angiotensin II activity

Despite greater reductions in proteinuria, dual therapy is not recommended due to higher rates of renal dysfunction and hyperkalemia

Prevention of ACEI/ARB Injuries

Initiation of ACEI/ARB at low doses

Close monitoring of renal function and serum potassium on initiation - Inpatients: daily; Outpatients: 2-3 days after starting new therapy or dose adjustments

Avoid using in combination with other drugs that may also affect renal blood flow such as NSAIDs or diuretics (if possible)

If clinically appropriate, hold one or both medications 12-24 hours prior to procedures that may affect hemodynamic status (e.g. surgery) for patients who are on ACEI or ARB with diuretics

Avoid dehydration

Treatment ACEI/ARB Injuries

May require discontinuation of ACEI/ARB

Consider alternative antihypertensive agents if appropriate

Manage hyperkalemia

Fluid replacement if needed - Optimize volume status, Maintain BP

Mechanism of Aminoglycoside Injury

Aminoglycosides are cations which readily binds to anion phospholipids within proximal tubular epithelial cell membranes

They undergo intracellular transport and concentration in lysosomes ultimately result in cellular dysfunction and release of lysosomal enzymes

This results in cellular damage to proximal tubular epithelial cells

This damage leads to obstruction of the tubular lumen and back-leakage of the glomerular filtrate across the damaged tubular epithelium

Presentation of Aminoglycoside Injury

Gradual ↑ in Scr and ↓ in GFR after 5–10 days of therapy

Can be nonoliguric renal failure

Electrolyte abnormalities can occur but are rare (e.g. ↓Mg, ↓K, ↓Ca, ↓Phos)

Usually reversible because the proximal tubules can regenerate. (Up to 3 weeks for Scr to return to baseline)

Aminoglycoside Injury Risks

Large cumulative dose

Prolonged duration of therapy - At least 5-7 days of therapy in patients with normal hemodynamic status

Frequency of dosing

Repeated courses of aminoglycoside therapy because of aminoglycoside sequestration in the renal cortex

Relative affinity of an aminoglycoside for proximal tubule cell plasma membrane

Troughs > 2 mg/L

Mg, K deficiencies prior to therapy

Prevention and Treatment Aminoglycoside Injury

Maintain adequate urine production (1 mL/kg/h)

Monitor Scr every 1-2 days during therapy

Use alternative antibiotics if appropriate

Use extended interval dosing (i.e. once daily dosing of aminoglycosides)

Limit duration of therapy if appropriate

Appropriate pharmacokinetic drug monitoring

Mechanism of Amphotericin B Injury

Direct tubular epithelial cell toxicity

↑ Tubular permeability and necrosis

Arterial vasoconstriction and ischemia

Ultimately this results in tubular cell damage

↑ Cell energy and oxygen requirements leading to medullary tubular epithelial cell necrosis and renal failure

Amphotericin B Injury Clinical Presentation

K, Mg, Na wasting

Inability to concentrate urine

Distal renal tubular acidosis

Amphotericin B Injury Risks

High daily doses (cumulative doses of conventional amphotericin B > 2-3 g)

Concomitant use of diuretics or nephrotoxins

Rapid infusions

Amphotericin B Injury Prevention and Treatment

If clinically appropriate, consider alternative antifungals

Limit cumulative amphotericin B dose if clinically appropriate

Use liposomal formulation (AmBisome, Abelcet, Amphotec)

Maintain adequate hydration

Adults - 1000 mL IV NS immediately before amphotericin infusion or 500 ml IV NS over 30 min before and after infusion

Children: 10-15 mL/kg IV NS

Maintain adequate urine production to 1 mL/kg/h

Mechanism of Vancomycin Injury

Various mechanisms

Acute tubular necrosis, acute tubulointerstitial nephritis, inratubular crystal obstruction

Vancomycin binds to uromodulin to form obstructive tubular casts

High doses may be associated with oxidative stress that leads to apoptosis

Vancomycin Injury Risks

Higher trough concentrations > 20 mcg/mL

Prolonged duration of therapy > 7 days

Significantly higher risk of injury with concurrent vancomycin and aminoglycosides

Exposure to other nephrotoxic medications

Critically ill patients

Presence of sepsis

Vancomycin Injury Prevention and Treatment

Most cases of kidney injury are reversible following discontinuation

Maintain adequate urine production (1 mL/kg/h)

Monitor Scr every 1-2 days during therapy

Avoid trough concentrations > 20 mcg/mL

Use alternative antibiotics if appropriate

Appropriate pharmacokinetic drug monitoring

Mechanism of Radiographic Contrast Media Injury

Direct tubular toxicity; Renal ischemia

Initial transient osmotic diuresis followed by tubular proteinuria and enzymuria

Proteinuria directly damages cells

Systemic hypotension occurs secondary to osmotic diuresis

Renal ischemia occurs secondary to vasoconstriction and diuresis

RCIN Presentation

Usually reversible and nonoliguric

Definition: ↑ Scr > 0.5 mg/dL at 2-7 days after IV contrast

Can see ↑ of 0.5 – 3.0 mg/dL

↑SCr with peak 1-5 days after exposure

Recovery in 10-14 days after exposure

General Prevention Strategies RCIN Injury

Alternative imaging for high risk patients

Avoid high osmolar agents

Give the smallest possible dose

Use iso or low osmolality agents

Hold or discontinue nephrotoxic medications (NSAID, ACEI, diuretics) 24-48 hours before contrast in high risk patients

Hydration in RCIN Injury

NS hydration 1 mL/kg/h (up to 150ml/h) 6–12 hours pre-procedure, intra-procedure, and 6–12 hours post-procedure OR

Isotonic sodium bicarbonate added to IV fluid (154 mEq/L) to maintain urinary pH > 6.5 as an alternative to NS

Begin 1 hour prior to procedure - 3 mL/kg/h

Continue 6 hours post procedure - 1 mL/kg/h

Mechanism of Sucrose Containing IVIG Injury

Osmotic nephropathy: sucrose has the highest osmotic activity of all stabilizers used in IVIG

Sucrose is metabolized by sucrase which is found only in the intestines

The kidneys are unable to metabolize sucrose leading to accumulation within phagolysosomes of proximal tubules

Sucrose accumulation inside the proximal tubule cells create an osmotic concentration gradient that draws water into the cells

Cell swelling, lysosomal dysfunction, and occlusion of the tubules leads to cellular damage

Sucrose Containing IVIG Injury Prevention

Use sucrose-free IVIG formulations for patients who are at risk for kidney injury

All other IVIG stabilizers are metabolized by the liver