Danno renale acuto Danno renale acuto in corso di sepsiin corso di sepsi
I Sessione:Meccanismi di Danno e Riparazione Tissutale
““DANNO RENALE ACUTO NEL PAZIENTE DANNO RENALE ACUTO NEL PAZIENTE POSTCHIRURGICO, CON TRAUMA E SEPSIPOSTCHIRURGICO, CON TRAUMA E SEPSI””
Danno dDanno d’’organo e riparazione tissutale:organo e riparazione tissutale:la clinica e la terapia sostitutivala clinica e la terapia sostitutiva
Giuseppe Stefano Netti, MD PhDUnit of Nephrology Dialysis and Renal Transplantation
Department of Biomedical Sciences
University of Foggia
AKI: A Common, Serious ProblemAKI: A Common, Serious Problem
• AKI is present in 5% of all hospitalized patients, and up to 30% of patients in Intensive Care Units (ICUs)
• The incidence is increasing at an alarming rate
• Mortality rate >50% in dialyzed ICU patients
• 25% of ICU dialysis survivors progress to end stage
renal disease within 3 yrs
% of all % of all ““discharged deaddischarged dead”” with a diagnosis of ARFwith a diagnosis of ARF1979: 1.5%1979: 1.5% 2002: 15.7%2002: 15.7%
The Sepsis ContinuumThe Sepsis Continuum
SIRS = systemic inflammatory response syndrome
SIRS with apresumedor confirmed infectiousprocess
SepsisSIRSSevere Sepsis
SepticShock
Sepsis with organ failure
Refractoryhypotension
A clinical response arising from a non‐specific insult, with ≥2 of the following:• T >38°C or <36°C• HR >90 beats/min• RR >20/min• WBC >12,000/mm3 or <4,000/mm3 or >10% bands
Modified from Bone RC et al, Chest 1992
EpidemiologyEpidemiology
• Current estimates suggest that over 1,000,000 cases of Sepsis are diagnosed annually in United States, resulting in more than 200,000 deaths.
• The incidence rate for Sepsis has been increasing over the past two decades, driving an increase in the number of deaths despite a decline in case‐fatality rates.
• Sepsis is the tenth leading cause of death in the United States and accounts for more than 17 billion dollars in direct healthcare expenditures.
• Risk factors include age >65 years, male, non‐whites.
• A primary site of infection cannot be established in 10% of patients with severe Sepsis/SIRS.
Hotchkiss RS et al, N Eng J Med 2003
A Theoretical Picture of SepsisA Theoretical Picture of SepsisInfectionInfection InflammationInflammation Cellular FailureCellular Failure Organ FailureOrgan Failure MODSMODS DeathDeath
Infection factors Infection factors
Cytokines Cytokines
Dysregulated Coagulation Dysregulated Coagulation
Apoptosis Apoptosis
Mitochondrial DysfunctionMitochondrial Dysfunction
Metabolic DerangementMetabolic Derangement
Poor Perfusion Poor Perfusion
Host factors Host factors
>83%
83%
69%
38%
22%
Organ Failure
The emerging problem with no solution in ICU
Every 24hMortality
Modified from Vincent JL, Crit Care Med 1998
Septic Shock and MODSSeptic Shock and MODS
Identifying Acute Organ Dysfunction as a Identifying Acute Organ Dysfunction as a Marker of Severe Sepsis: Marker of Severe Sepsis: the Kidneythe Kidney
TachycardiaHypotension
↑ CVP↑ PAOP
Altered ConsciousnessConfusionPsychosis
TachypneaPaO2 <70 mm Hg
SaO2 <90%PaO2/FiO2 ≤300
OliguriaOliguriaAnuriaAnuria
↑↑ CreatinineCreatinine
↓ Platelets↑ PT/APTT↓ Protein C↑ D‐dimer
Jaundice↑ Enzymes↓ Albumin
↑ PT
RIFLE criteria for diagnosing AKIRIFLE criteria for diagnosing AKI
Modified from Bellomo R, Crit Care 2004
Unfortunately, none of the large or small animal Unfortunately, none of the large or small animal species can completely reproduce the species can completely reproduce the pathophysiology, immunology, and consequences of pathophysiology, immunology, and consequences of human sepsis!human sepsis!
Phases of clinical biomarker evaluation and AKI studiesPhases of clinical biomarker evaluation and AKI studies
Siew ED et al, J Am Soc Nephrol 2011
Lameire NH, Vanholder RC and Van Biesen WA, Kidney Int 2011
Key pathogenic pathways involved in the Key pathogenic pathways involved in the clinical course of sepsis clinical course of sepsis
Zarjou A and Agarwal A, J Am Soc Nephrol 2011
Patogenesis of SepsisPatogenesis of Sepsis‐‐related AKIrelated AKI
Schrier RW et al, N Eng J Med 2004
Complement and Coagulation
MHC I and IIT cell
infiltration
Chemokines andAdhesion molecules
ROS
Apoptosis
NO
peroxynitrates
Monocytes and Granulocytesinfiltration
Injury
Immune Recognition
Inflammation
I/RObstToxin
From Acute to Chronic Damage: From Acute to Chronic Damage: tubular epithelialtubular epithelial‐‐mesenchymal transition (EMT)mesenchymal transition (EMT)
Quaggin SE and Kapus A, Kidney Int 2011
Loss of integrity of the barrier Loss of integrity of the barrier and increased permeabilityand increased permeability
Resistance to blood flowResistance to blood flow
Inflammation and fibrotic Inflammation and fibrotic process activationprocess activation
Coagulation activationCoagulation activation
Role of Endothelium in I/R injuryRole of Endothelium in I/R injury
Legrand M et al, Mol Med 2008
The role of the endothelium in sepsisThe role of the endothelium in sepsis
CirculatingEndothelial cells
Endothelium activation
Endothelialcell apoptosis
Increase in vascular permeability
TLR4LPS
platelets
vWF multimer
microparticles
vWF multimer
TF
PAR‐2PAR‐1
VIIa, Xa
Thrombin
Thrombin
APC
EPCR
Va+Xa
IL‐6TNF‐α
Thrombin
TAFI
TAFIa
C5a
TM
TFPIAT
PAI‐1tPA
monocyteIL‐6TNF‐α
TF+VIIa
Bacteria
TF
Schouten M, J Leuk Biol 2008
SacrificeSacrifice
Swine model of sepsisSwine model of sepsis
Control
LPS iv (300 μg/kg)
00 11 22 33 44 55 66 77 88 9h9h
Renal Biopsy
SacrificeSacrifice
Renal histology in a swine model of sepsisRenal histology in a swine model of sepsis
LPS iv (300 μg/kg)
00 11 22 33 44 55 66 77 88 9h9h
Normal Kidney Rare Glom Monocytes
Interstitial Edema
Diffuse Capillary Thrombosis
Rare Monocytes
Emerging therapeutic targets tested in animal modelsEmerging therapeutic targets tested in animal models
Clinical Trials Clinical Trials with rhAPCwith rhAPC
•• PROWESS (2001)PROWESS (2001)
•• RESOLVE (2005)RESOLVE (2005)
•• ADDRESS (2005)ADDRESS (2005)
•• ENHANCE (2005)ENHANCE (2005)
Sepsis corrupt the normal homeostatic balance Sepsis corrupt the normal homeostatic balance between procoagulant and anticoagulant mechanismsbetween procoagulant and anticoagulant mechanisms
Toussaint S et al, N Eng J Med 2009
Activated Protein C (APC) Activated Protein C (APC) counterbalances the counterbalances the procoagulant state in procoagulant state in patients with sepsispatients with sepsis
Take Home MessagesTake Home Messages
• Although sepsis is the most common cause of AKI in critical illness, there is limited information on sepsis‐induced AKI
• New insights into the pathogenesis of sepsis could indicate potential therapeutic targets in the future.
• Apart from activated protein C, there is no specific approved ancillary treatment for sepsis. There are certain key gaps in the field of sepsis induced AKI that require further research and investigation.
• Validation of novel biomarkers for early detection of sepsis‐induced AKI might open a window of opportunity for effective therapy of sepsis‐induced AKI
University of FoggiaUniversity of FoggiaInterdept. Research Center Interdept. Research Center ““BioAgroMedBioAgroMed””Clelia PrattichizzoClelia PrattichizzoNadia VarrasoNadia VarrasoMassimo PapaleMassimo PapaleMaria Teresa RocchettiMaria Teresa RocchettiElena RanieriElena Ranieri
Dept. Biomedical Sciences Dept. Biomedical Sciences ‐‐ Sect. of NephrologySect. of NephrologyAnna Maria Di PalmaAnna Maria Di PalmaGiuseppe GrandalianoGiuseppe Grandaliano
Dept. Surgical Sciences Dept. Surgical Sciences ‐‐ Sect. of UrologySect. of UrologyLuigi CormioLuigi CormioGiuseppe CarrieriGiuseppe Carrieri
University of BariUniversity of BariDept. Emergency and Organ TransplantationDept. Emergency and Organ TransplantationSect. of NephrologySect. of NephrologyGiuseppe CastellanoGiuseppe CastellanoLoreto GesualdoLoreto Gesualdo
Sect. of Veterinary SurgerySect. of Veterinary SurgeryFrancesco StaffieriFrancesco StaffieriAntonio CrovaceAntonio Crovace
Sect. of Anaesthesia and Intensive CareSect. of Anaesthesia and Intensive CareSalvatore GrassoSalvatore Grasso
BioAgroMed LabBioAgroMed Lab
This research program was founded by:
• Apulia Ministry of Budget Strategic Programs PSR_094 and PSR_144
• Italian Ministry of University and Research Grant PRIN 2008 2008M9WSJX
• European Community's 7° Framework Programme Grant Number: FP7/2007‐2013, HEALTH‐F5‐2008‐223007 STAR‐T REK
AcknowledgementsAcknowledgements