# Rhabdomyolysis and Myoglobin-Induced AKI: Student Handout > **Updated March 2026 to reflect KDIGO 2026 draft guideline** ## Learning Objectives By the end of this handout, you should be able to: - Recognize clinical presentation and diagnostic criteria for rhabdomyolysis - Classify etiologies into traumatic, exertional, metabolic, and drug-induced categories - Understand the pathophysiology of myoglobin-induced acute kidney injury - Implement emergency management including aggressive IV crystalloid hydration - Identify high-risk populations and prevention strategies - Recognize genetic myopathies presenting as exercise-induced rhabdomyolysis ------------------------------------------------------------------------ ## Definition and Diagnostic Criteria **Rhabdomyolysis:** Breakdown of skeletal muscle with release of intracellular contents into systemic circulation. **Diagnostic Threshold:** - **Creatine kinase (CK) \>5× upper limit of normal** (typically \>1000 IU/L, often \>5000-10,000 IU/L in symptomatic cases) - Clinical symptoms: myalgia, weakness, dark urine (myoglobinuria) - May progress to life-threatening complications: AKI, electrolyte imbalances, DIC, compartment syndrome **Severity Spectrum:** - Mild: CK 1000-5000 IU/L; usually self-limited - Moderate: CK 5000-50,000 IU/L; high AKI risk - Severe: CK \>50,000 IU/L; almost always requires ICU management ------------------------------------------------------------------------ ## Classification of Etiologies ### 1. Traumatic Rhabdomyolysis **Mechanisms:** - Crush injuries from accidents, natural disasters, collapses - Prolonged immobilization (patient lying on limb for hours) - Compartment syndrome (external compression exceeds perfusion pressure) - Extensive surgical procedures (particularly lengthy lithotomy or lateral positioning) **Clinical Recognition:** - History of direct trauma or crush mechanism - Massive CK elevations (often \>100,000 IU/L) - Rapid AKI development within 24-48 hours - Gross myoglobinuria (cola-colored urine) **Prevention in Surgical Setting:** - Frequent position changes (if prolonged procedures) - Padding of pressure points - Early mobilization post-op - Adequate hydration peri-operatively ### 2. Exertional Rhabdomyolysis **Triggers:** - Unaccustomed intense exercise (military training, competitive athletics) - Prolonged exercise in hot conditions - Exercise combined with dehydration - Exercise combined with heat stress and high humidity **Classic Scenario:** - Young person (typically male) engages in unusual intense physical activity - Develops muscle pain, weakness, dark urine during or shortly after exercise - CK markedly elevated - Risk factors: dehydration, heat, lack of acclimatization **Underlying Factors Increasing Risk:** - Sickle cell disease (can precipitate rhabdo with exertion) - Unrecognized metabolic myopathy - Anticholinergic medications (impair sweating) - High environmental temperature + humidity **Prevention:** - Gradual acclimatization to exercise (5-14 day period) - Adequate hydration before, during, and after exercise - Recognition of warning signs (severe cramping, dark urine) - Cool-off periods in heat ### 3. Metabolic and Genetic Causes **Glycogen Storage Diseases:** - McArdle disease (GSD V): Muscle phosphorylase deficiency - Exercise-induced rhabdo - Characteristic “second wind” (symptoms improve 10-15 min into exercise as alternative fuels become available) - Tarui disease (GSD VII): Phosphofructokinase deficiency - Exercise intolerance, myoglobinuria - Associated hemolytic anemia (same enzyme deficiency in RBCs) **Fatty Acid Oxidation Defects:** - CPT II deficiency: Most common cause of **recurrent exertional rhabdomyolysis** in adults - Triggered by prolonged exercise, cold exposure, or fasting - Temperature-sensitive enzyme (cold worsens symptoms) - Multiple episodes over years **Mitochondrial Disorders:** - Impaired oxidative phosphorylation - Variable presentations - Exercise intolerance - May manifest with heat sensitivity **Ion Channel Disorders:** - RYR1 mutations: Can cause exercise/heat-induced rhabdomyolysis - Periodic paralyses: May present with rhabdo during attacks **Clinical Pearl:** Recurrent exertional rhabdo in young adults (especially triggered by specific conditions like cold or fasting) should prompt genetic evaluation. ### 4. Drug and Toxin-Induced **Statins:** - Most common medication cause - Risk increased with: higher doses, drug interactions (especially with CYP3A4 inhibitors), renal impairment - May occur weeks to months after initiation - Immune-mediated myopathy possible **Alcohols:** - Ethanol (direct myotoxicity + immobilization + electrolyte disturbances) - Methanol and ethylene glycol (toxic metabolites) **Stimulants and Drugs of Abuse:** - Cocaine (severe vasoconstriction compromising muscle perfusion) - Amphetamines (hyperthermia, agitation, muscle hyperactivity) - Heroin (immobilization, direct toxicity) - MDMA/Ecstasy (hyperthermia, exertion, dehydration) **Daptomycin (Antibiotic):** - Rare cause of drug-induced rhabdo - Risk increases with high doses, prolonged therapy, renal impairment - May cause creatine kinase elevation without overt rhabdo **Corticosteroids:** - Particularly with high doses or rapid escalation - Myopathy may be vacuolar (affects proximal muscles) - Distinguish from rhabdo per se (less severe CK elevation) **Hyperthermia-Inducing Agents:** - Anticholinergics (impair sweating) - Neuroleptic malignant syndrome (antipsychotics + dopamine antagonists) - Malignant hyperthermia (anesthetic-related) ------------------------------------------------------------------------ ## Pathophysiology of Myoglobin-Induced AKI ### The Myoglobin Cascade 1. **Muscle Injury** → Release of intracellular contents 2. **Myoglobin Release** → Large myoglobin molecules exceed renal threshold for reabsorption 3. **Myoglobinuria** → Dark (“cola” or “tea-colored”) urine 4. **Myoglobin Precipitation** → In acidic urine (pH \<5.6), myoglobin polymerizes 5. **Tubular Obstruction** → Precipitated myoglobin blocks tubular flow 6. **Tubular Injury** → Direct toxicity from oxidative stress, heme iron release 7. **Acute Tubular Necrosis** → Tubular epithelial cell necrosis 8. **Acute Kidney Injury** → Oliguria, rising creatinine ### Additional Contributing Factors **Hypovolemia:** - Myoglobin precipitation increases urine concentration - Volume depletion from third-spacing (rhabdo causes massive intracellular fluid sequestration, can lose 40% of body water) - Hypotension reduces renal perfusion **Electrolyte Disturbances:** - **Hyperkalemia:** From massive cell death - **Hyperphosphatemia:** From cell contents release - **Hypocalcemia (phase 1):** Calcium binds to damaged muscle - **Hypercalcemia (recovery phase):** Calcium mobilizes from injured muscle **DIC Risk:** - Tissue factor released from muscle - Can trigger disseminated intravascular coagulation - Associated with severe rhabdo and worst outcomes ------------------------------------------------------------------------ ## Clinical Recognition and Laboratory Diagnosis ### Clinical Presentation **Acute Phase (During/Immediately After Muscle Injury):** - Severe myalgia (muscle pain) - Muscle weakness or immobility - Dark/cola-colored urine (myoglobinuria) - Nausea, vomiting (from hyperkalemia or toxemia) - Oliguria or anuria **Later Manifestations:** - Rising creatinine (may lag CK peak by 24-48 hours) - Hyperkalemia symptoms: palpitations, weakness, cardiac arrhythmias - Hypocalcemia symptoms: tetany, paresthesias (if severe) - Edema and compartment syndrome (if localized crush injury) ### Laboratory Diagnosis **Gold Standard Marker:** - **Creatine kinase (CK)** — reflects muscle injury magnitude - Peak CK typically occurs 24-72 hours after injury - CK \>100,000 IU/L indicates severe injury with very high AKI risk - CK rise faster than creatinine rise (diagnostic timing advantage) **Pigment clue:** A urine dipstick reacts to heme. Heme-positive urine with few or no RBCs suggests myoglobin or hemoglobin; correlate with CK, the exposure history, and hemolysis assessment when appropriate. The dipstick does not identify the pigment by itself. **Additional Labs:** \| Test \| Finding \| Significance \| \|——\|———\|—\| \| Potassium \| Often \>5.5-7.0 mEq/L \| Life-threatening arrhythmia risk \| \| Phosphate \| Elevated \| Reflects massive cell death \| \| Calcium (acute) \| Low \| Binds to damaged muscle \| \| BUN/Creatinine \| Rising \| Indicates developing AKI \| \| LDH \| Markedly elevated \| Reflects muscle and hemolysis \| \| Uric acid \| Elevated \| From nucleic acid metabolism \| \| Creatinine \| Progressive rise \| Peak lags CK peak by 24-48 hrs \| **Urine Findings:** - Dark brown/cola color - Positive dipstick for blood without RBCs (myoglobin) - May have muddy brown casts (cellular debris) - pH typically \<6.0 (predisposes to myoglobin precipitation) ### Distinguishing Features from Other Hemoglobinurias | Source | Urine Color | Dipstick | RBCs on Microscopy | Clinical Clue | |----|----|----|----|----| | Myoglobin (rhabdo) | Dark cola-brown | Positive | NEGATIVE | History of muscle injury; very high CK | | Hemoglobin (hemolysis) | Tea-brown | Positive | NEGATIVE | Elevated indirect bilirubin, LDH; low haptoglobin | | Hematuria (blood) | Red/pink | Positive | POSITIVE | RBCs visualized on microscopy | ------------------------------------------------------------------------ ## Emergency Management ### Phase 1: Goal-Directed IV Crystalloid Resuscitation **KDIGO 2026 draft (PP 3.8.1):** IV crystalloids for volume expansion are the cornerstone of rhabdomyolysis management. No specific crystalloid type is preferred — both balanced crystalloids and normal saline are acceptable. **Goal:** Restore perfusion and support a safe urine response. AAST describes approximately 1–3 mL/kg/hour, up to 300 mL/hour, as a goal when achievable without overload; persistent anuria is a reason to reassess, not to force more fluid. [AAST consensus](https://pmc.ncbi.nlm.nih.gov/articles/PMC8804685/). **Method:** Establish appropriate IV access and assess perfusion, urine output, lungs, oxygen requirement, and cumulative fluid balance. Approximately 400 mL/hour is one suggested starting rate in an appropriate adult, then titrate to response and cardiac/kidney reserve. Do not prescribe a fixed first-day volume or insert a central line solely because the patient is anuric. Recheck electrolytes frequently, particularly potassium; persistent oliguria after resuscitation requires evaluation for evolving AKI, obstruction, or congestion. **Rationale:** - Dilutes myoglobin concentration in tubular fluid - Maintains glomerular filtration (reduces myoglobin precipitation risk) - Prevents hypovolemic shock from third-spacing **Complication Risk:** Fluid overload, pulmonary edema (especially if AKI develops). Balance between aggressive resuscitation and avoiding pulmonary edema requires careful monitoring. ### Phase 2: Urinary Alkalinization — NOT Supported by KDIGO 2026 draft **Historical rationale:** Myoglobin precipitates in acidic urine (pH \<5.6); alkaline urine was proposed to increase solubility. **KDIGO 2026 draft position:** Isotonic bicarbonate has been proposed for rhabdomyolysis-associated AKI, but **limited data does NOT support this practice.** The guideline does not endorse urinary alkalinization for rhabdomyolysis. **Why the evidence is insufficient:** - No high-quality RCTs demonstrate benefit of bicarbonate over crystalloid alone - Risk of metabolic alkalosis, worsened hypocalcemia (alkalosis increases calcium binding to albumin), and hypokalemia - Aggressive volume expansion alone achieves the primary goal of diluting tubular myoglobin **Clinical Pearl:** Use repeated physiologic assessment to guide fluids. More volume is not automatically better; bicarbonate does not prevent pigment AKI merely by raising urine pH. ### Mannitol and Loop Diuretics: Not for AKI Prevention **KDIGO 2026 draft position:** Do NOT use mannitol or loop diuretics to augment urine output in rhabdomyolysis. This practice is **not advised.** **Why not mannitol?** - Historically proposed to maintain tubular flow and prevent myoglobin cast formation - No controlled evidence of benefit - Risk of osmotic nephropathy, volume depletion, and worsened AKI - Can cause hyperosmolality in patients already at risk for electrolyte derangement **Why not loop diuretics?** - May cause intravascular volume depletion, counteracting the benefit of aggressive hydration - No evidence of improved outcomes in rhabdomyolysis-associated AKI - May worsen electrolyte abnormalities (hypokalemia, metabolic alkalosis) **Clinical distinction:** Do not use mannitol or loop diuretics to force urine production or prevent pigment AKI. A separate indication, such as volume overload, requires its own assessment. Bicarbonate may be considered for a separate acid–base indication, not routine urine alkalinization. ### Phase 3: Electrolyte Management **Hyperkalemia (Most Immediate Threat):** - **Monitor:** EKG for peaked T waves, prolonged PR - **Treat if symptomatic or K+ \>5.5-6.0 mEq/L:** - Calcium gluconate 10 mL of 10% IV (cardiac membrane stabilization) - Insulin + dextrose (shifts K+ intracellularly) - Albuterol nebulized (shifts K+ intracellularly) - Sodium polystyrene sulfonate or patiromer (potassium binding) - Renal replacement therapy if medical management fails **Hypocalcemia:** - Usually do NOT treat acute hypocalcemia (calcium binds to damaged muscle; treating may worsen outcomes during recovery phase) - May treat if symptomatic (tetany, seizures) with calcium gluconate - Monitor for hypercalcemia during recovery **Hyperphosphatemia:** - Usually self-limited - Monitor for secondary hyperparathyroidism during recovery ### Phase 4: Acute Kidney Injury Management **If AKI Develops Despite Fluid Resuscitation:** 1. **Renal replacement therapy indications:** - Oliguria refractory to fluid challenge - K+ \>6.0 mEq/L unresponsive to medical therapy - Pulmonary edema or fluid overload - Severe metabolic acidosis - Uremic symptoms 1. **Type of RRT:** Continuous modalities often preferred (gentler on hemodynamics, better electrolyte control) 2. **Dialysate:** Careful electrolyte composition (hyperkalemia, hypocalcemia risk) ------------------------------------------------------------------------ ## Long-Term Management and Prevention ### During Recovery Phase - Continue hydration, electrolyte monitoring - Monitor for **recovery phase hypercalcemia** (calcium mobilizes from muscle) - Gradual activity advancement as CK decreases - Repeat CK until normalized ### Prevention in At-Risk Populations **For Exertional Rhabdo Risk:** - Gradual acclimatization (5-14 day period) before intense exercise - Adequate hydration and electrolyte intake - Avoid combined heat/humidity/intensity extremes - Education on warning signs **For Genetic Myopathies:** - Genetic counseling and testing for familial recurrent rhabdo - Avoid specific triggers (cold, fasting, prolonged exercise) - Prophylactic measures (carbohydrate loading, frequent meals) **For Drug-Induced:** - Regular CK monitoring in patients on statins or other myotoxic agents - Educate about myalgia symptoms requiring CK check - Avoid drug combinations that increase statin myotoxicity ------------------------------------------------------------------------ ## Practice Questions **Question 1:** A 24-year-old military recruit develops severe bilateral calf pain and dark urine during a 10-mile run in 95°F heat on day 3 of basic training. CK is 48,000 IU/L. Urine dipstick: positive for blood. Urinalysis: no RBCs seen. Which is the most appropriate initial management? A) Start furosemide to increase urine output B) Goal-directed IV crystalloid with repeated perfusion, urine-output, and congestion assessment C) Observe; mild rhabdo is self-limited D) Electrophoresis to detect light chains **Answer:** B) Goal-directed IV crystalloid with repeated perfusion, urine-output, and congestion assessment. The exertional presentation, high CK, and heme-positive urine with no RBCs strongly support rhabdomyolysis with pigment injury risk. Restore demonstrated volume deficit while monitoring electrolytes and kidney function; do not chase a fixed urine target in anuria or overload. Routine bicarbonate, mannitol, or loop diuretics for AKI prevention are not recommended. [AAST consensus](https://pmc.ncbi.nlm.nih.gov/articles/PMC8804685/). ------------------------------------------------------------------------ **Question 2:** A 58-year-old with recurrent episodes of exercise-induced myoglobinuria every few years (triggered by prolonged exercise, especially in cold weather) is evaluated. CK elevations are moderate (8,000-15,000 IU/L). Which genetic defect should be highest on your differential? A) Dystrophinopathy (Duchenne muscular dystrophy) B) CPT II deficiency C) McArdle disease D) Statin myopathy **Answer:** B) CPT II deficiency. This patient’s presentation—recurrent exertional rhabdo in adulthood, triggered by **prolonged exercise and cold exposure**, with moderate (not massive) CK elevations—is classic for CPT II deficiency (carnitine palmitoyltransferase II). The adult form presents with exercise-induced symptoms, and the temperature sensitivity (cold worsens symptoms) is characteristic. McArdle disease (choice C) would present with shorter exercise triggers and the “second wind” phenomenon. ------------------------------------------------------------------------ Reassess volume status and complications; continue only the crystalloid needed for ongoing hypovolemia while arranging escalation for refractory complications **Answer: D) Reassess perfusion, urine output, electrolytes, and congestion and continue only the fluid still indicated.** A rising CK or creatinine alone is not an instruction to keep increasing fluid. Routine bicarbonate, mannitol, or loop diuretics do not prevent pigment AKI; refractory hyperkalemia, severe acidemia, pulmonary edema, or uremic complications may require KRT. [AAST consensus](https://pmc.ncbi.nlm.nih.gov/articles/PMC8804685/). ------------------------------------------------------------------------ ## Key Takeaways 1. **CK \>5× normal + dark urine = rhabdomyolysis diagnosis** 2. **Goal-directed crystalloid can restore perfusion** — titrate to urine response and congestion; do not force fluids in persistent anuria or overload 3. **Urine dipstick positive + NO RBCs = myoglobinuria** (classic discordance) 4. **Hyperkalemia is most immediately life-threatening** — EKG monitoring essential 5. **Urinary alkalinization, mannitol, and loop diuretics are NOT advised** (KDIGO 2026 draft) — crystalloid volume expansion alone is the treatment 6. **Recurrent exertional rhabdo** suggests genetic myopathy (CPT II, McArdle); genetic evaluation warranted 7. **Prevention** through acclimatization, hydration, recognition of warning signs is critical ------------------------------------------------------------------------ ## See Also ### Related Student Handouts - AKI Workup and Diagnostic Approach - ATN Management - Drug-Induced AKI - Acid-Base Disorders - Hyperkalemia Management ### Clinical Content (01-Clinical-Medicine/Nephrology) - AKI Hub - Full Clinical Reference - Essential Renal Laboratory Tests ### Atomic Notes (ZK) - CRRT Principles ### Butler-COM Resources - Butler COM - Nephrology Deep Dive ------------------------------------------------------------------------ ## Related Resources - AKI Workup and Differential - Comprehensive Rhabdomyolysis and Genetics - Renal Replacement Therapy Basics ------------------------------------------------------------------------ **Document Type:** Student Handout **Level:** PA/Medical Student **Created:** 2026-02-12 **Updated:** 2026-03-29 (KDIGO 2026 draft AKI/AKD guideline) **Source:** Rhabdomyolysis comprehensive clinical guide and literature, KDIGO 2026 draft AKI/AKD guideline --- [Website version](https://urinenephrology.org/student-resources/aki/rhabdomyolysis-student-handout.html) · Markdown synchronized October 3, 2026.