1. IM Morning ConferencesRenal Section Antonio L. Diaz-Hernandez, MD PGY-5 Renal section

2. Reason for consult: “Please evaluate pt with rhabdomyolysis related to statin/gemfibrozil combination”

3. History of present illness Patient is a 72 year old man, with pertinent medical Hx of hypertension and hypercholeterolemia who was in his usual state of health consisting of free ambulation and self care until the day before admission when he was unable to even stand up. Patient was referring this progressive weakness since last April. He use to walk long distance from his home and had been felling more tired needing to take breaks every few blocks or so. The Monday before admission he started to have muscular pain in his extremities, more prominent in legs, and reproduce with palpation.

4. History of present illness The symptoms keep getting worse until yesterday when he felt extreme weakness. Patient also complains of tiredness and dizziness. As per interview reveals, signs and symptoms correlate in time with recent optimization of simvastatin treatment, form 40 mg to 80 mg day.

5. Active medical problems Active medication Atenolol 50 mg day Gemfibrozil 600 mg BID Simvastatin 80 mg day ASA 81 mg day HCTZ12.5/ irbesartan150 mg day Active Medical Problems Hyperlipidemia Hypertension Arthritis BPH

6. Past Medical History Occupation - pension Habits Alcohol:1 liter of alcohol for 20 years, quit 18 years ago Tobacco: 40 packs/years, quit 18 years ago Drugs: marijuana Family history Father: HBP Allergies: NKA Transfusions: denies Travels: EEUU, Las Vegas, Oct 2007 Surgeries: tonsilectomy

7. Active Medications 0.9% sodium chloride inj, 150 ml/hr@0 IV sodium bicarbonate 150 meq in 5% dextrose/water 100 ml/hr@0 IV Ceftriaxone/azythromycin; suspected CAP

8. Physical exam: Vital Signs: DATE/TIME TEMP PULSE RESP BP PAIN 8/30/08 @ 1528 98.6 82 20 110/75 0 General: Alert and oriented times three. Free of chest pain, no in acute distress. HEENT: Atraumatic, No JVD at 45*, no carotid bruits. Heart: RRR, S4(-), S3(-) no murmur. Chest/lungs: bilateral clean auscultation Abd: Bowel sounds audible. Soft and depressible, no rebound, no tenderness. Extremities: +1 bilateral pitting edema no cyanosis. Bilateral lower extremities pain to palpation, bilateral extremities weakness, more evident lower extremities.

9. Admission Labs CBC HGB 12.2 Htc 35.6 WBC 15.5 Plat 253 Serum Chemistry BUN 47 Creat2.4 (1.1; 2007) Na 140 K 5.2 Cl 103 HCO3 20 Glu 106 Ca 9.3 PO4 XX CPK >20,000

10. Admission Labs U/A Sg 1.015 Blood large pH 5.5 RBC 0-5 WBC 0-5 Protein 100 Cast none Bacteria none

11. Initial Clinical Impression AKI Rhabdomyolysis; statin induces

12. Rhabdomyolysis

13. Rhabdomyolysis Backgrounds: First describe 1940-1941 during WW II Commonly to the victims of crush injury in London during blitzkrieg bombing raids Bywaters and Beall describe pathologic change of four patient who die during blitz operations, change were similar to the previews describe in mismatch blood transfusion

14. Rhabdomyolysis Epidemiology World wide 5-20% of AKI United State 8-15% of AKI Estimated 2 cases per 10,000 person-years 26,000 total cases per year 85% of patients with major traumatic injuries will experience some degree of rhabdomyolysis

15. Rhabdomyolysis Pathogenesis Three principal mechanism: ATP demand that outstrip ATP supply Sustained increase in sarcoplasmatic calcium concentration Sarcolema increase permeability

16. Rhabdomyolysis Na+ Ca+ Ca+ Ca+ Na+ Ca+ Ca+ Ca+ Na+ Na+ Ca+ Na+ ATPase K+ K+ K+ Na+ Ca+ Na+ Na+ K+ K+ K+ K+ Na+ K+ K+ Ca+ K+ ATPase Na+ K+ K+ Na+ K+ K+ Na+ K+ K+ Ca+ K+ K+ K+

17. Rhabdomyolysis ↓ATP Increase intracellular [Ca+] Activation proteolytic and cytotoxic enzymes Na+ with associate cellular swelling and injury ATP maintain [Ca+] by Sequestration sarcoplasmic reticulum Promote outflow to extracellular spaces

19. Hereditary Etiologies Deficiencies of glyco(geno)lytic enzymes myophosphorylase (McArdle's disease) phosphorylasekinase phosphofructokinase (Tarui's disease) phosphoglyceratemutase phosphoglyceratekinase l actatedehydrogenase Abnormal Lipid Metabolism carnitinepalmitoyltranferase deficiency I and II carnitine deficiency

20. Acquires Etiologies Excessive muscle exercise sports and military training status epilepticus status asthmaticus prolonged myoclonus Metabolic disorders diabetic ketoacidosis nonketotichyperosmolar coma hypothyroidism hypophosphatemia hyponatremia hypokalemia Ischemic injury compression vascular occlusion sickle cell trait Infections bacterial viral Heat-related syndromes heat stroke Inflammatory myopathies polymyositis dermatomyositis Direct muscle injury crush burning/ freezing electric shock lightning stroke

21. Associate drugs Drug Barbiturates Amphetamines Heroin Methadone Phencyclidine (PCP) Phenylpropanolamine Chlorpromazine Morphine Diazepam Dihydrocodeine LSD Lithium Salicylates Amoxapine Clofibrate/Bezafibrate Phenelzine Isoniazid Loxapine Antihistamines Theophyllin Oxprenolol Pentamidine Ethanol Vasopressin Statins

22. Statin Induce Myopathies Muscle injury by ↓sarcolema cholesterol ↓Ubiquinone (coenzyme Q10) Impairs oxidative phosphorilation Presentations Asymptomatic CPK elevations Myalgia with normal CPK Frank rhabdomyolysis

23. Rhabdomyolysis Increase risk if: Large dose Kidney disease Hepatic disease Hypothyroidism Amiodarone Gemfibrozil Erythromycin Warfarin Cyclosporine Itraconazole

24. Rhabdomyolysis

25. Rhabdomyolysis Cocaine Direct myotoxicity Indirect effect Vasoconstriction Seizures Agitation Delirium Hyperthermia Muscle compression in obtunded patient Ethanol Direct myotoxicity Indirect effect Poor caloric intake Malnutrition Potassium/phosphate depletion Hyperactivity Deliriums tremens Associate trauma Muscle compression due to coma

26. Systemic Effects

27. Rhabdomyolysis Possible kidney manifestation Asymtomatic normal renal function with discrepancy of blood vs RBC presence Ex: Blood= large/RBC=2-5 Pigment nephropathy ATN Oliguric Non oliguric

28. Kidney Vulnerability ↓renal vasodilatation Nitric oxide Heme proteins ↓[NO] +  Heme proteins production of vasoconstrictors (endothelin, isoprostanes) Glomerular filtration/ ultrafiltration Concentrate and internalize heme proteins oxidizes Hydrogen peroxyde + urine heme protein Increasing toxicity denaturate heme protein Acidic urine pH interaction with Tamm-Horsfall protein  urine cast formation

29. Pigment Nephropathy Vasoconstriction Cytokines activity Heme toxic effect Cast formation

30. Rhabdomyolysis Diagnosis Wide range of presentation Muscle pain Swelling weakness Bruising Compartment syndrome features Largely asymtomatic with dark urine, decrease urine output and abnormal electrolytes

31. Rhabdomyolysis Laboratory evaluation Myoglobinuria Dark urine 50% positive heme proteins with 0-5 RBC/hpf Acidic urine pH Tubular epithelial cells Granular cast Dark pigment cast Proteinuria 50% case May reach nephrotic range Myoglobinuria; transitory finding

32. Rhabdomyolysis Patient serum CPK Peaks 48 hr after event ½ life 48 hr Range could vary from 1,000 to 100,000 IU/L Fivefold greater than upper limits or > 500 IU/L Second wave elevation rise suspicious of possible compartment syndrome

33. Rhabdomyolysis Patient serum Hyperkalemia Hyperphosphatemia Hypocalemia Hyperuricemia Hypoalbuminemia? Low BUN/creatinine

34. Rhabdomyolysis Treatment options: Crush syndrome: 1-1.5 L 0.9 NSS 1 Hr +/- 10 L first 24 Hr Non traumatic: High rate 0.9 NSS infusion Correct intravascular volume depletion

35. Rhabdomyolysis Treatment options: Urine alkalinization? May reduce risk of pigment nephropathy 1L 0.45 NSS + NaHCO3 75 mmol Mannitol in isotonic solution 100 meqq NaHCO3 + mannitol 100mL(25%) + D5% 800 mL; 1 L in 4 Hr, if no improve in urinary output (< 20mL/Hr) stop treatment May worse hypocalcemia

36. Rhabdomyolysis Treatment options: Hemodialysis!

37. Be carful of simvastatin 80 mg! (and also from alcohol + exercise)

38. Clostridium septicum

40. Human renal biopsy showing proximal tubule injury. This image is a representative sample of a kidney biopsy for ARF, kindly provided by Dr. James Hasbargen, following exercise-induced rhabdomyolysis. The biopsy, obtained within 24 hours of the event, revealed significant proximal tubule cell damage with intraluminal accumulation of apical membrane fragments and a detached cell (*), thinning of proximal tubular cells to maintain monolayer tubule integrity (arrowhead), and dividing cells and accumulation of white cells within the microvascular space in the peritubular area (arrow). The patient required renal replacement therapy but did regain complete renal function.

41. Pathogenesis of Pigment Nephropathy Myoglobin Release Intravascular volume depletion Systemic acidosis