Sepsis (and the kidney): what’s new? What’s hot?

Vincenzo Cantaluppi

SCDU Nefrologia e Trapianto Renale,

Dipartimento di Medicina Traslazionale,Università del Piemonte Orientale,

AOU Maggiore della Carità,Novara

University of Eastern Piedmont- Center for Experimental

UPO Medical Research-UNITO

EUROPE400 cases of sepsis per 100,000 habitants annually

ITALYIn Italy there are

about 60,000 deaths due to sepsis every year

Sepsis, Septic Shock, Refractory Septic Shock(different severity = different outcomes)

Insult

Acute Renal Failure and Sepsis

Robert W. Schrier, M.D., and Wei Wang, M.D 1999

Acute renal failure occurs in approximately 19 percent of patients with

moderate sepsis, 23 percent with severe sepsis, and 51 percent with

septic shock when blood cultures are positive

Sepsis Septic ShockHealthy individual

Insult

Mort

alit

y

Refractory Septic Shock

NEP+EP requirement≥ 0.25 μg/kg/min

Refractory Septic Shock

Sepsis Septic ShockHealthy

Mo

rtality

Refractory Septic Shock

NEP+EP ≥ 0.25 mcg/kg/min

Three cornerstones of Sepsis Therapy

• Antibiotics and

Source Control

• Supportive Therapy

• Specific Therapy

– Immuno-modulation

Hemodynamic monitoring and support for prevention

and management of AKI

In patients in the ICU, use of either 4

percent albumin or normal saline for

fluid resuscitation results in similar

outcomes at 28 days.

Il primo grande studio randomizzato effettuato su pazienti settici e stato condotto

confrontando HES 200/0.60 a 0,66 con una gelatina e ha dimostrato una maggiore

incidenza di AKI.

Punti critici dello studio: SCr basale piu elevata nel gruppo HES, piccola dimensione

campionaria, breve durata del follow-up (34 giorni).

Kidney Liver

Bone marrow

84 studi inclusi

37 studi sull’uomo (tot 635 pz)

11 studi su animali

Storage occurrs within 30 min of infusion

HES deposits may last 8-10 ys (skin, kidney)

• Children with

severe febrile

illness and

impaired perfusion

20-40 ml/kg

of 5%

Albumin

0.9% saline

No bolus

• Primary endpoint

was 48h mortality

• Secondary

endpoints:

pulmonary edema,

increased

intracranial

pressure, and

mortality or

neurologic

sequelae at 4

weeks

Mortality (%) 10.6 vs 10.5 vs 7.3

Multicenter RCT, double-blind, placebo-

controlled trial

•251 patients to receive 50 mg of intravenous

hydrocortisone

Or

•248 patients to receive placebo every 6

hours for 5 days

A genomic storm: Refining the immune, inflammatory paradigm in trauma.

Immunosupression in Sepsis and Impaired Immunity

No New Genes or Pathways Activated

Sepsis is considered to induce immune

suppression, leading to increased susceptibility to

secondary infections with associated late

mortality

ICU–acquired infections occurred more

commonly in patients with sepsis with higher

disease severity, but such infections contributed

only modestly to overall mortality.

The genomic response of patients with sepsis

was consistent with immune suppression at the

onset of secondary infection.

Presepsin levels may have useful prognostic information for patients with severe sepsis

or septic shock.

Circulating sCD40L levels are increased in septic patients and are independently

associated with mortality

Numerous promising therapies targeting the maladaptive host immune response to sepsis are under investigation.

Importantly, these potential treatments can have an effect on the three different levels we have discussed earlier: the

number of immune cells; the proportion of cell subtypes with the modification of the leucocyte surface markers

expression; and the cell expression and function.

Multistep evaluation of immune cell activation, suppression, and homeostasis.

Endotoxin is an important mediator of septic shock and supports efforts to develop anti-endotoxin

therapies for treating patients with this disease.

ROS + RNS

Role of endotoxin in septic shock

LPS neutralization failed to save

patients with sepsis

Patients early severe sepsis or septic shock2:1 eritoran:placebo ratio

Eritoran is synthetic analog of lipid A/inhibits lipid A binding toMD2

Implications of lower mortality

• As long as lower mortality has been detected in

control arms of studies addressing new therapies in

sepsis, much larger sample size will be needed

• If sepsis associated mortality decreases because of

better standard of care, increase the likelihood that

therapies aimed to modulate innate immune

response result less effective

Compartmentalization of the inflammatory response in

sepsis and SIRS Cavaillon JM et al.

AKI Etiology

From an international study including >29,000 critically ill patients

48%

34%

27% 26%

19%

6%3%

12%

0

10

20

30

40

50

Sep

tic S

hock

Major

Sur

gery

Car

dioge

nic Sho

ck

Hyp

ovo

lemia

Dru

g-induc

ed

Hep

atore

nal S

yndro

me

Obs

truc

tive Uro

pathy

Oth

er

Uchino S, et al. JAMA. 2005;294:813-818.

% o

f P

ati

en

tsUchino S et al.

San Giovanni Battista Molinette Hospital Turin: AKI in ICU

RIFLE

Mortality (day 28)

TOTAL

1584 PATIENTS

13210 RRT

AKI 11,3%

Liver Tx (151/1335)

AKI 25% Lung Tx (22/88)

AKI 26,2 % Heart Tx (60/229)

Main cause of AKI in solid organ transplant recipients : sepsis (43,6%)

AKI in solid organ transplantation (liver, lung and heart)

SEPSIS AND AKI: THE “ENTANGLEMENT” QUESTION

Entanglement is a physical phenomenon that occurs when pairs or groups of particles are generated or interact in ways such that the quantum state of each particle cannot be described independently.

First defined by Erwin Schrodinger in

1935 as “something that can not be

separated”……..

AKI

SEPSI AND AKI: ENTANGLEMENT

AKI

1

2

AKI

SEPSIS: FREQUENT AFTER AKI

INCREASE MORTALITY AND HOSPITALIZATION

(PICARD STUDY)

PREDOMINANT PARADIGM

Septic AKI is associated with

reduced renal perfusion

-) loss of GFR by ischemia

-) Tubular ischemic injury

-) Acute tubular necrosis

… the hemodynamic hallmark of sepsis is generalized arterial

vasodilatation

E coli bolus E coli bolus

LA VASODILATAZIONE DELLA

ARTERIOLA EFFERENTE CAUSA

PERDITA DEL GFR.

PRESENZA DI SHUNT.

DISSOCIAZIONE FLUSSO – FUNZIONE RENALE IN CORSO DI SEPSI

Insufficienza renale acuta può complicare la sepsi anche in presenza di una

flusso renale normale, se non addirittura aumentato

Ang II riduce flusso renale

Migliora la funzione renale

Angiotensin II: effective

rescue vasopressor

agent in patients with

distributive shock

requiring multiple

vasopressors.

The initiation of an ATII

infusion in patients

receiving norepinephrine

for septic shock resulted

in a marked decrease

in norepinephrine doses.

ATII may be effective as a

novel pressor agent in

the treatment of high-

output shock.

Initial dosing ranges:

between 2 and 10

ng/kg/min. In the pilot

study, the drug appears

to be welltolerated.

No significant difference in the rate of death between

patients with shock who were treated with dopamine

or norepinephrine as the first-line vasopressor agent,

the use of dopamine was associated with a greater

number of adverse events such as arrhythmias.

Vasopressor therapy is safe and probably beneficial from a renal,

and probably general, point of view.

In hypotensive vasodilated patients with AKI, restoration of blood

pressure within autoregulatory values should occur promptly with

noradrenaline and be sustained until such vasodilatation dissipates.

The addition of vasopressin may be helpful in individual patients,

but widespread use is not supported by evidence.

Alpha-dose dopamine has no advantages over noradrenaline and is

not as reliably effective in restoring blood pressure and urine

output. Its widespread use cannot be supported in patients with

vasodilatation and acute kidney injury.

Terlipressin: useful in patients with AKI secondary to hepatorenal

syndrome.

An increasing body of evidence suggests that AKI can occur in the

absence of hypoperfusion.

Sepsis induces profound alterations in microcirculatory flow in the

entire organism, and the kidney is not the exception

Sepsis is associated with the release of damage and pathogen

associated molecular patterns (DAMPs and PAMPs) into the

circulation.

Circulating plasma factors induce tubular and glomerular

alterations in septic burns patientsFilippo Mariano,# Vincenzo Cantaluppi,# Maurizio Stella, Giuseppe Mauriello Romanazzi, Barbara

Assenzio, Monica Cairo, Luigi Biancone, Giorgio Triolo, V Marco Ranieri, and Giovanni Camussi

CIRCULATING ENDOTOXINS REDUCE RENAL OXYGENATION AND MODULATE MITOCHONDRIAL FUNCTION.

PGC-1 alpha REPRESENTS ONE OF THE MAIN REGULATORS OF MYTOCHONDRIAL BIOGENESIS AND ITS

EXPRESSION IS SUPPRESSED IN PROPORTION WITH RENAL FUNCTION IMPAIRMENT.

PGC-1 alpha LEVELS ARE ALSO REDUCED IN RELATIONSHIP WITH TNF-alpha ACTIVITY

Cell polarity/ tight junction dysfunction in MOF

Fink MP et al. RL.Epithelial barrier

dysfunction: a unifying theme to

explain the pathogenesis of multiple

organ dysfunction at the cellular

level.

Crit Care Clin. 2005 Apr;21(2):177-96.

Sepsis: tight junction injury

in lung, liver and bowel

epithelium. control sepsis

Sepsis modulates the tubular regulation of ion, glucose,

urea and water transport and acid–base homeostasis in the

kidney.

Recent discoveries on changes in epithelial transport under

septic and endotoxemic conditions as well as the

mechanisms that link inflammation with impaired tubular

membrane transport.

Tubular dysfunction that is mediated by inflammation in

sepsis ultimately leads to increased sodium and chloride

delivery to the distal tubule and macula densa, contributing

to tubuloglomerular feedback and GFR decrease.

Systemic inflammation is known to

target tubular epithelial cells (TECs),

leading to acute kidney injury.

Tubular cells have been implicated in

the response to inflammatory

mediators in

ischaemic and septic renal damage.

Loss of tubular cells by apoptosis or

epithelial-to-mesenchymal transition

may ingenerate conditions that lead

to progression towards

chronic kidney disease.

TECs may actively contribute to the

production of inflammatory

mediators that may propagate the

injury locally or in distant organs.

Prof. Peter Higgs

The Higgs’ boson or “the God’s particle”

AKI

What’s new in the

STANDARD MODEL?

PRODUCTION OF MICROVESICLES

Shedding vesicles are usually larger than exosomes with sizeranging from 100nm to 1mm.

Formation of shedding vesicles takes place from the buddingof small cytoplasmic protrusions followed by their detachmentfrom the cell surface dependent on calcium influx, calpain andcytoskeleton reorganization.

The intra-cellular levels of calcium ions modify the asymmetricphospholipids distribution of plasmamembranes by specificenzymes named flippase, floppase and scramblase.

The increase of calcium ions inhibits translocase and inducesactivation of scramblase that translocates phosphatydilserinefrom the inner leaflet of the cell membrane bilayer to theouter with changes in curvature-mediated lateralredistribution of membrane components with the formationof membrane nanodomains.

Calcium ions by activation of calpain which cleaves tallin andactivin, and of gelsolin which cleaves actin-capping proteinsalso favor the reorganization of cytoskeleton.

MICROVESICLES

James E. Rothman Randy W. Schekman Thomas C. Südhof

A mechanism of cell-to-cell communication…….

MICROVESCICOLE:L’ULTIMA FRONTIERA

Camussi G, Cantaluppi V et al Kidney Int 2010

Bioanalyzer RNA

profilingSmall RNAs

MicroRNAs

(RT-PCR)

FACS

Healthy Septic

0

1

2

3

4

5

6

7

8

9

10

1 2 3 4 5 6

Nr.

of

faile

d o

rgan

sNr. of failed organs

MICROVESICLES IN EXPERIMENTAL MODELS OF SEPSIS

i.p.LPS injection

Cecal ligation

and puncture

0

1

2

3

4

5

6

7

8

9

Control LPS CLP

MV

/ml

(10^

8)

Tubular epithelial

cells

Recently, two small phase II clinical trials

demonstrated beneficial renal effects of

bovine-derived alkaline phosphatase

administration in critically ill patients with

sepsis-associated AKI.

Rationale: related to dephosphorylation and

thereby detoxification of detrimental

molecules involved in the pathogenesis of

sepsis-associated AKI.

Potential target of alkaline phosphatase:

adenosine triphosphate, (proinflammatory

mediator released during cellular stress) and

endotoxin (LPS)

recAP can attenuate LPS-induced cytokine

production in a human renal cell line,

whereas recAP improves renal blood flow

and vascular resistance and inhibits various

parameters of renal inflammation and tissue

damage during AKI induced by ischemia-

reperfusion or by LPS injection in vivo.

Interestingly, recAP tends to also exert renal

protective effects during cisplatin- or

gentamicin-induced AKI, which may indicate

a broader use for recAP treatment than

sepsis-associated AKI alone (fig. 1

To evaluate whether

alkaline phosphatase (AP)

treatment improves renal

function in sepsis-induced

AKI, a prospective,

double-blind, randomized,

placebo-controlled study

in critically ill patients

with severe sepsis or

septic shock with evidence

of AKI was performed

The improvements in

renal function suggest

alkaline phosphatase is a

promising new treatment

for patients with severe

sepsis or septic shock with

AKI.

Start extracorporeal therapies?

MODALITY OF RRT

Renal replacement therapy for acute kidney injury: let's follow the

evidence.Ronco C.

LA DOSE DIALITICA

OTTIMALE PER AKI E’

CONTROVERSA

NON SI OTTIENE BENEFICIO

DA DOSI DIALITICHE MOLTO

ALTE

The dilemma of whether and

when to start RRT among

critically ill patients with AKI

in the absence of conventional

indications has long been a

vexing challenge for

clinicians.

Recently, two randomized

trials (ELAIN and AKIKI)

reported specifically on the

issue of the timing of initiation

of RRT in critically ill patients

with AKI

Their fundamental differences

in trial design, sample size,

and widely discrepant findings

are considered in context.

While both trials are

important contributions

towards

informing practice on this

issue, additional evidence from

large multicenter randomized

trials is needed.

Possible biological effects of different drugs and of extracorporeal blood purification

therapies on immune system activation, suppression,

and homeostasis

According to II law od

thermodynamics, spontaneous

chemical and biological reactions are

always accompained by a decrease in

free energy.

Natural course of entropy is distrupted

by the effects of kidney disease and

uremia

Polymyxin B hemoperfusion added to conventional therapy

significantly improved hemodynamics and organ

dysfunction and reduced 28-day mortality in a targeted

population with severe sepsis and/or septic shock from

intra-abdominal gram-negative infections.

Evaluating the Use of PMX-B Hemoperfusion in a Randomized controlled trial of Adults Treated for

Endotoxemia and Septic Shock

Severe sepsis and septic shock

(14000 pts/year Italy)

Endotoxins

septic shock

(9000 pts/year )

EUPHAS patients

What makes EUPHRATES unique?

Biomarkers and AKI: personalized

therapies

Septic AKI

-AKI to CKD-MOF

-Death

Kidney regenerationFunctional improvement -Wrong therapy

-Wrong timing

CRRT

M.O.S.T

Multiple Organ Support therapy

Ronco C et al, Blood Purification, 2005

UF systems

VAD

MARS

Prometheus BAL

CO2 removal

Islet encapsulation

Artifical pancreas

The “entanglement” between sepsis and AKI…..

Grazie

vincenzo.cantaluppi@med.uniupo.it

University of Eastern Piedmont- Center for Experimental

UPO Medical Research-UNITO