Post on 21-Jan-2015
description
IM Morning ConferencesRenal Section
Antonio L. Diaz-Hernandez, MDPGY-5 Renal section
Reason for consult:
“Please evaluate pt with rhabdomyolysis related to statin/gemfibrozil combination”
History of present illnesso 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.
History of present illnesso 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.
Active medical problems
Active Medical Problems
o Hyperlipidemiao Hypertensiono Arthritiso BPH
Active medication
o Atenolol 50 mg dayo Gemfibrozil 600
mg BIDo Simvastatin 80
mg dayo ASA 81 mg dayo HCTZ12.5/ irbesartan150 mg
day
Past Medical Historyo Occupation - pensiono Habits
o Alcohol:1 liter of alcohol for 20 years, quit 18 years ago
o Tobacco: 40 packs/years, quit 18 years ago
o Drugs: marijuanao Family history
o Father: HBPo Allergies: NKAo Transfusions: denieso Travels: EEUU, Las Vegas, Oct 2007o Surgeries: tonsilectomy
Active Medications
o 0.9% sodium chloride inj, 150 ml/hr@0 IV
o sodium bicarbonate 150 meq in 5% dextrose/water 100 ml/hr@0 IV
o Ceftriaxone/azythromycin; suspected CAP
Physical exam:
o General: Alert and oriented times three. Free of chest pain, no in acute distress.
o HEENT: Atraumatic, No JVD at 45*, no carotid bruits.
o Heart: RRR, S4(-), S3(-) no murmur. o Chest/lungs: bilateral clean auscultation o Abd: Bowel sounds audible. Soft and
depressible, no rebound, no tenderness. o Extremities: +1 bilateral pitting edema no
cyanosis. Bilateral lower extremities pain to palpation, bilateral extremities weakness, more evident lower extremities.
Vital Signs: DATE/TIME TEMP PULSE RESP BP PAIN 8/30/08 @ 1528 98.6 82 20 110/75 0
Admission Labso CBC
o HGB 12.2o Htc 35.6 o WBC 15.5o Plat 253
o Serum Chemistry
o BUN 47o Creat 2.4
(1.1; 2007)o Na 140o K 5.2o Cl 103o HCO3 20o Glu 106o Ca 9.3 o PO4 XXo CPK >20,000
Admission Labso U/A
o Sg 1.015o Blood largeo pH 5.5o RBC 0-5o WBC 0-5o Protein 100 o Cast noneo Bacteria none
Initial Clinical Impression
oAKI
oRhabdomyolysis; statin induces
Rhabdomyolysis
Rhabdomyolysis
o Backgrounds:
oFirst describe 1940-1941 during WW IIoCommonly to the victims of crush injury
in London during blitzkrieg bombing raids
oBywaters and Beall describe pathologic change of four patient who die during blitz operations, change were similar to the previews describe in mismatch blood transfusion
Rhabdomyolysis
o Epidemiologyo World wide
o5-20% of AKIo United State
o8-15% of AKIoEstimated 2 cases per 10,000 person-
years 26,000 total cases per yearo 85% of patients with major traumatic
injuries will experience some degree of rhabdomyolysis
Rhabdomyolysiso Pathogenesis
o Three principal mechanism:
ATP demand that outstrip ATP supply
Sarcolema increase
permeability
Sustained increase in sarcoplasmatic calcium
concentration
Rhabdomyolysis
Na+
Na+
Na+
Na+
Na+
Na+
Na+
Na+
Na+
Na+
Na+
K+
Na+ K+
K+
K+
K+
K+
K+
K+
K+
K+
K+K+
K+
K+
K+
K+
K+
K+
K+
Ca+Ca+
Ca+
Ca+ Ca+
Ca+
Ca+
Ca+
Ca+
Ca+
ATPase
ATPase
Rhabdomyolysis
o ATP maintain [Ca+] byo Sequestration
sarcoplasmic reticulum
o Promote outflow to extracellular spaces
o ↓ATP
o Increase intracellular [Ca+]
o Activation proteolytic and cytotoxic enzymes
o Na+ with associate cellular swelling and injury
Rhabdomyolysis
Trauma or toxin
Sarcoplasmatic permeability
Swelling restricted by surrounding
fascia
compartment pressure
ischemia, necrosis and compartment syndrome
o Cell swelling
Hereditary Etiologieso Deficiencies of glyco(geno)lytic
enzymes o myophosphorylase (McArdle's disease)o phosphorylase kinaseo phosphofructokinase (Tarui's disease)o phosphoglycerate mutaseo phosphoglycerate kinase lo actate dehydrogenase
o Abnormal Lipid Metabolism o carnitine palmitoyltranferase deficiency I
and IIo carnitine deficiency
Acquires Etiologieso Excessive muscle exercise
o sports and military training o status epilepticus o status asthmaticus o prolonged myoclonus
o Metabolic disorderso diabetic ketoacidosis o nonketotic hyperosmolar
coma o hypothyroidismo hypophosphatemiao hyponatremiao hypokalemia
o Ischemic injury o compression o vascular occlusion o sickle cell trait
o Infections o bacterial o viral
o Heat-related syndromes o heat stroke
o Inflammatory myopathies o polymyositis o dermatomyositis
o Direct muscle injury o crush o burning/ freezing o electric shocko lightning stroke
Associate drugso Drug
o Barbiturateso Amphetamineso Heroin o Methadone o Phencyclidine
(PCP)o Phenylpropanolami
ne o Chlorpromazine o Morphine o Diazepam o Dihydrocodeineo LSDo Lithium
o Salicylates o Amoxapine o Clofibrate/Bezafibrateo Phenelzineo Isoniazido Loxapineo Antihistamineso Theophyllino Oxprenolol o Pentamidineo Ethanol o Vasopressin o Statins
Statin Induce Myopathies
o Presentationso Asymptomatic
CPK elevationso Myalgia with
normal CPKo Frank
rhabdomyolysis
o Muscle injury by o ↓sarcolema
cholesterol o ↓Ubiquinone
(coenzyme Q10)o Impairs oxidative
phosphorilation
Rhabdomyolysis
o Increase risk if:o Large doseo Kidney diseaseo Hepatic diseaseo Hypothyroidismo Amiodaroneo Gemfibrozilo Erythromycino Warfarino Cyclosporineo Itraconazole
Rhabdomyolysis
Rhabdomyolysiso Ethanol
o Direct myotoxicity
o Indirect effectoPoor caloric
intakeoMalnutritionoPotassium/
phosphate depletion
oHyperactivityoDeliriums
tremensoAssociate
traumaoMuscle
compression due to coma
o Cocaine
o Direct myotoxicity
o Indirect effectoVasoconstricti
onoSeizuresoAgitationoDeliriumoHyperthermiaoMuscle
compression in obtunded patient
Systemic Effects
Rhabdomyolysis
o Possible kidney manifestation
o Asymtomatic normal renal function with discrepancy of blood vs RBC presenceoEx: Blood= large/RBC=2-5
o Pigment nephropathyoATN
o Oliguric o Non oliguric
Kidney Vulnerability
Nitric oxide Heme proteins+ ↓[NO] ↓renal vasodilatatio
n
Heme proteins
production of vasoconstrictors
(endothelin, isoprostanes)
Glomerular filtration/
ultrafiltration
Concentrate and internalize heme proteins
Hydrogen peroxyde+urine heme proteinoxidizes
Increasing toxicity
Acidic urine pHdenaturate
heme
protein
interaction with Tamm-Horsfall protein
urine cast formation
Pigment Nephropathy
o Vasoconstriction
o Cytokines activity
o Heme toxic effect
o Cast formation
RhabdomyolysisDiagnosis
o Wide range of presentationoMuscle painoSwelling weaknessoBruisingoCompartment syndrome featuresoLargely asymtomatic with dark urine,
decrease urine output and abnormal electrolytes
RhabdomyolysisLaboratory evaluation
o MyoglobinuriaoDark urineo50% positive heme
proteins with 0-5 RBC/hpf
oAcidic urine pHoTubular epithelial cellsoGranular castoDark pigment castoProteinuria 50% case
o May reach nephrotic range
oMyoglobinuria; transitory finding
Rhabdomyolysiso Patient serum
o CPKoPeaks 48 hr after evento ½ life 48 hroRange could vary from 1,000 to 100,000
IU/LoFivefold greater than upper limits or >
500 IU/LoSecond wave elevation rise suspicious
of possible compartment syndrome
Rhabdomyolysiso Patient serum
o Hyperkalemiao Hyperphosphatemi
ao Hypocalemiao Hyperuricemiao Hypoalbuminemia?o Low
BUN/creatinine
Rhabdomyolysiso Treatment options:
o Crush syndrome: o1-1.5 L 0.9 NSS 1 Hro+/- 10 L first 24 Hr
o Non traumatic:oHigh rate 0.9 NSS infusionoCorrect intravascular volume depletion
Rhabdomyolysiso Treatment options:
o Urine alkalinization?oMay reduce risk of pigment
nephropathyo 1L 0.45 NSS + NaHCO3 75 mmol
oMannitol in isotonic solutiono 100 meqq NaHCO3 + mannitol 100mL(25%)
+ D5% 800 mL; 1 L in 4 Hr, if no improve in urinary output (< 20mL/Hr) stop treatment
oMay worse hypocalcemia
Rhabdomyolysiso Treatment
options:
oHemodialysis!
Be carful of simvastatin 80 mg! (and also from alcohol + exercise)
Clostridium septicum
o 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.
Pathogenesis of Pigment Nephropathy
Myoglobin Release
Intravascular volume
depletion
Systemic acidosis