Myoglobin showed to be a useful marker and a therapeutic guide in Mb-ARF

Need for HD increased considerably at blood levels 15-20 mg/l

High efficiency of Mb removal by HCO treatment was demonstrated

Rapid fall in serum Mb during HCO HDF was followed by a high rebound

A significant albumin loss into dialysate was observed, demanding substitution

Endogenous metabolic clearance of Mb was slow

Kinetics of Mb release and metabolism is still not well elucidated

HCO treatment might have prevented transition to anuria or shortened the

course of Mb-ARF in some patients; but its clinical benefits remain uncertain

High mortality rate was observed, extremely so in C-V surgery patients

H 1st lab

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Clinical consequences of rhabdomyolysis

• Local / systemic muscle fiber destruction

• Complications : AKI, DIC, etc.

• Systemic release of free iron, cytokines & oxygen radicals

• Secondary organ damage ?

• Persistent morbidity ?

• Increased mortality ?

Mb vs Hb : homology

Tomoki Nishiyama, Kazuo Hanaoka. Free hemoglobin concentrations in patients receiving massive blood transfusion during emergency surgery for trauma. Can J Anesth 2000; 47(9):881–885 Larsen R, Gozzelino R,Jeney V, et al. A central role for free heme in the pathogenesis of severe sepsis. Sci Transl Med 2010;2(51):51-71.

SYSTEMIC CONSEQUENCES OF RHABDOMYOLYSIS?

Hb

140 g/l ≈ 21.7 mmol/l

massive blood transfusion (5 l)

free Hb ≈ 4 μmol/l

(1mol Hb = 4 mol heme)

free heme ≈ 16 μmol/l

(Fe++/Fe+++)

Sickle cell crisis

free Hb to ≈ 25μmol/l

free heme ≈ 100 μmol/l

Mb

< 70 μg/l ≈ 4 nmol/l

rhabdomyolysis ↑ ↑ ↑ Mb

(70 mg/l = 1000 x)

free Mb ≈ 4 μmol/l

(1 mol Mb = 1 mol heme)

free heme ≈ 4 μmol/l

(Fe++/Fe+++)

Severe RML

Mb ≈ 200-700 mg/l

free heme ≈

12-40 μmol/l

Mark T. Gladwin, Tamir Kanias, Daniel B. Kim-Shapiro Hemolysis and cell-free hemoglobin drive an intrinsic mechanism for human disease. J Clin Invest. 2012; 122(4):1205–1208

Mb vs Hb : analogy ?

Flögel U, Merx MW, Gödecke A, Decking UK, Schrader J.

Myoglobin: A scavenger of bioactive NO.

Proc Natl Acad Sci USA. 2001; 98: 735-40.

SYSTEMIC CONSEQUENCES OF RHABDOMYOLYSIS?

Richard A Zager, Kirstin M Burkhart, Duane Scott Conrad and Dennis J Gmur. Iron, heme oxygenase, and glutathione: Effects on myohemoglobinuric proximal tubular injury.Kidney Int 1995; 48: 1624-1634; doi:10.1038/ki.1995.457 Zager RA: Heme protein-ischemic interactions at the vascular, intraluminal, and renal tubular cell levels: Implications for therapy of myoglobin-induced renal injury. Renal Failure 1992; 14:341–344 Zager RA, Foerder CA: Effects of inorganic iron and myoglobin on in vitro proximal tubular lipid peroxidation and cytotoxicity. J Clin Invest 1992; 89:989–995 Plotnikov EY, Chupyrkina AA. Pevzner IB, Isaev NK, Zorov DB. Myoglobin causes oxidative stress, increase of NO production and dysfunction of kidney's mitochondria. Biochim Biophys Acta 2009;1792(8):796-803. Epub 2009 Jun 21. Olivier Boutaud, L. Jackson Roberts Mechanism-based therapeutic approaches to rhabdomyolysis-induced renal failure . Free radical biology and Medicine 2011; 51(5):1062-1067. Translational aspects of free radical biology

Byrick RJ, Goldstein MB, Wong PY. Increased plasma tumor necrosis factor concentration in severe rhabdomyolysis is not reduced by continuous

arteriovenous hemodialysis. Crit Care Med, 1992; 20(10):1483-6.

SYSTEMIC CONSEQUENCES OF RHABDOMYOLYSIS?

Richard A Zager, Kirstin M Burkhart, Duane Scott Conrad and Dennis J Gmur. Iron, heme oxygenase, and glutathione: Effects on myohemoglobinuric proximal tubular injury.Kidney Int 1995; 48: 1624-1634; doi:10.1038/ki.1995.457 Zager RA: Heme protein-ischemic interactions at the vascular, intraluminal, and renal tubular cell levels: Implications for therapy of myoglobin-induced renal injury. Renal Failure 1992; 14:341–344 Zager RA, Foerder CA: Effects of inorganic iron and myoglobin on in vitro proximal tubular lipid peroxidation and cytotoxicity. J Clin Invest 1992; 89:989–995 Plotnikov EY, Chupyrkina AA. Pevzner IB, Isaev NK, Zorov DB. Myoglobin causes oxidative stress, increase of NO production and dysfunction of kidney's mitochondria. Biochim Biophys Acta 2009;1792(8):796-803. Epub 2009 Jun 21. Olivier Boutaud, L. Jackson Roberts Mechanism-based therapeutic approaches to rhabdomyolysis-induced renal failure . Free radical biology and Medicine 2011; 51(5):1062-1067. Translational aspects of free radical biology

Predlog SLO raziskave o sistemski toksičnosti rabdomiolize

Namen: ugotoviti lab (+ klinične?) znake sistemske toksičnosti RML

Bolniki z RML z Mb > 5.000 ug/l, verjetno povzročeno s statini, in +/- AOL

- brez akutnih / kroničnih hudih spremljajočih bolezni

(sepsa, AMI, CVI; kronični zapleti AS- IBS, PAOB; DM z zapleti; KOL/HD)

- brez znanih dejavnikov za hemolizo (AVR, hemolitične anemije,…)

Potrebno število vključenih ≈ 40-50, predviden čas ≈ 2-3 leta

Elektronski obrazec raziskave na spletu

Potrebni material

- klinični podatki o bolniku, čas od začetka simptomov, terapija RML +

ostala, Mbt0 in kreatinin, potek bolezni, ev. HD

- zamrznjen prvi vzorec plazme v običajni 7 ml epruveti za biokemijo

- ponovni vzorec naslednji dan in 5. dan

Vzorčenje: Mb, prosti Fe v serumu, prosti hem, hemopeksin, antioksidanti,

NO/NO2

Nove Th možnosti RML?

• ↓ lipidna peroksidacija : acetaminofen

• ↓ ROS (reaktivni kisikovi radikali): niacin, Hx

• Indukcija NO sintaze ↑NO : nitrit, arginin, glutamin,

• ↑ Hx (Hemopexin) = hem scavenger

• Indukcija HO-1: niacin

• Inhibicija adhezijskih molekul ICAM;VCAM

• ↑SOD : erythriol

Želimo vam lep adventni december, prijetne praznike…

In mnogo osebne sreče in delovnih uspehov

v Novem letu!!!