Terapia non dialitica di AKI: nuove strategie di diagnosi e

trattamentoVincenzo 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

The global burden of acute kidney injury

AKI is associated with poor

patient outcomes

There is increased recognition

that AKI is encountered in

multiple settings and in all age

groups, and that its course and

outcomes are influenced by the

severity and duration of the

event.

The effect of AKI on an

individual patient and the

resulting societal burden that

ensues from the long-term

effects of the disease, including

development of CKD and

ESRD, is attracting increasing

scrutiny.

Urgent need for a global effort to

highlight that AKI is

preventable, its course is

modifiable, and its treatment can

improve outcomes.

AKI: progression toward CKD

AKI

NO AKI

Typical characteristics of acute kidney injury (AKI) in high-income and low-income countries

Estimated burden of AKI with progression to CKD and death across the world.

a) High-income (HI) countries.

b) Low- and middle-income

(LMI) countries.

The burden of cases of AKI,

deaths, and progression to CKD

in HI and LMI countries is

shown. In b, calculations were

made assuming a similar

incidence as in HI countries;

actual data are unavailable.

Fluid balance and acute kidney injuryProwle, J. R. et al. (2009)

Patient flow chart

The previously published “Dose

Response Multicentre International

Collaborative Initiative (DoReMi)”

study concluded that the high mortality

of critically ill patients with acute kidney

injury (AKI) was unlikely to be related

to an inadequate dose of renal

replacement therapy (RRT) and other

factors were contributing.

This follow-up study aimed to

investigate the impact of daily fluid

balance and fluid accumulation on

mortality of critically ill patients

without AKI (N-AKI), with AKI (AKI)

and with AKI on RRT (AKI-RRT)

receiving an adequate dose of RRT.

In critically ill patients, the severity and

speed of fluid accumulation are

independent risk factors for ICU

mortality.

Fluid balance abnormality precedes and

follows the diagnosis of AKI.

Thirty-day survival of N-AKI, AKI, and AKI-RRT patients.

The Kaplan-Meier analysis

including the first 30 days of

ICU stay indicated a

significant survival benefit for

patients without AKI (p <

0.0001).

The AKI-RRT group had the

lowest survival rate and AKI

patients who did not receive

RRT had intermediate survival

rates.

Fluid accumulation for N-AKI, AKI, AKI-RRT patients during the first 5 days following admission.

Looking at the first 5 days of

ICU stay, the cumulative fluids

differed significantly each day

among the three groups (N-AKI,

AKI and AKI-RRT). (p and p*

refer to the p values of the

Kruskal-Wallis

test and the correction for the

multiple test situation with the

Bonferroni test, respectively).

There was progressive fluid

accumulation in N-AKI and

AKI patients. AKI-RRT patients

accumulated a similar degree of

fluid, followed by a decrease.

Patients were daily assigned to

the corresponding group

(N-AKI, AKI and AKI-RRT).

Maximum fluid overload in survivors and non-survivors.

Maximum fluid overload

(MFO) was calculated for

survivors and non-survivors

among N-AKI, AKI and

AKI-RRT patients. In all

cohorts, non-survivors had

a higher MFO

Impact of maximum fluid overload.

The risk of death increased

exponentially with the

magnitude of maximum

fluid overload (MFO). In

this model, follow-up was

limited to the median time

in ICU (12 days).

Circles represent the

number of observations of

survivors and non-survivors

(at the bottom and at the

top respectively).

Every 1% increase of

MFO was associated

with an OR 1.075 for

mortality

Classificazione AKI – criteri RIFLE, AKIN e KDIGO

If RFR is intact, an

insult may remain

subclinical and never

displays a reduction in

GFR since baseline

GFR will not change.

In the setting of early acute kidney injury,

no test has been shown to definitively

predict the

progression to more severe stages.

Furosemide dose of 1.0 mg/kg.

Authors compared the UFR in response to

FST between those patients that progressed

and did not progress to AKIN stage III.

For each hourly interval, progressors had a

lower UFR response compared to non-

progressors (P <0.001).

The FST in subjects with early AKI serves

as a novel assessment of tubular function

with robust predictive capacity to identify

those patients with severe and progressive

AKI.

Urinary output in response to furosemide stress test.

1238 pianeti

extrasolari

Acute kidney injury often goes unrecognised in its early stages when eff ective treatment options might be available.

An electronic alert system for acute kidney injury did not improve clinical outcomes among patients in hospital.

This randomised, controlled study did not show a meaningful benefi t of an electronic alert system for acute kidney injury

in patients in hospital. Signals of more intense health care use, such as a possible increased rate of dialysis in the surgical

ward subgroup and during the fi rst half of the trial, should temper enthusiasm for the adoption of electronic alerts for

acute kidney injury in the absence of careful study of both their effi cacy and potential adverse eff ects.

Odds ratios of outcomes in acute kidney injury alert group compared with usual care group across the four study strata

Pathophysiological Features of AKI

Leading to CKD

The change in tissue architecture leads to altered

anatomical relationships between structures and a

tissue microenvironment that promotes additional

fibrosis and vascular dropout.

The inset shows renal tubular epithelial cells after an

episode of acute kidney injury. Representative

examples from various experimental studies in

animals are listed in the inset.

The fate of the cell, as well as the microenvironment

and organ, depends on the balance between the

results of repair and regenerative pathways,

including apoptosis, dedifferentiation, and

proinflammatory and antiinflammatory, epigenetic,

and profibrotic changes.

Specific macrophage and T-cell subsets, as well as

certain cytokines and immunoreactants, may be

associated with either injury or repair.

The chronic dysregulation of these factors over time

and their net interactions are likely to determine the

extent of fibrotic responses and organ function.

BMP-7 denotes bone morphogenetic protein 7, TGF-

β transforming growth factor β, and Tregs

regulatory T cells.

Consensus conference of AKI biomerkers

UN BIOMARKER DI AKI A BUON MERCATO…….

KIM-1: acute tubular injury marker

NGAL

• NGAL (neutrophil gelatinase associated

lipocalin) is a 25KDa soluble protein of

the lipocalin family

• Lipocalins are a family of proteins

characterized by a hydrophobic pocket

formed by antiparallel β sheets 7.

• This pocket has a high affinity for

siderophores, Fe2+ chelating with a low

MW.

• Siderophores are highly produced by

bacteria to sequester Fe2+. Recent

studies have demonstrated existence of

endogenous siderophores in different

animal species

NGAL

Plasma and urine NGAL pool

• NGAL is a 25 KDa soluble protein belonging to the lipocalin family

• Freely filtered by glomeruli, reabsorption and catabolism in the proximal tubular cells through the endocytic receptor megalin.

• Urine pool formed by non re-adsorbed NGAL and mostly by TAL production

Megalin

pNGAL

uNGAL

NGAL AND AKI

Several clinical studies on NGAL in AKI :• Cisplatin nephrotoxicity

• Drug interstitial disease

• Cyclosporine toxicity

• Diabetic nephropathy

• AKI after major surgery

• CKD

• CIN

• CAD/Cardiorenal syndrome

• Glomerulonephritis (Nephrotic syndrome,…)

• ……………

Cardiac-surgery associated NGAL score for acute kidney tubular damage

The expression pattern of acute tubular damage biomarkers such as neutrophil gelatinase–associated lipocalin

(NGAL) has been shown to precede functional AKI and, therefore, may be useful to identify very early tubular

damage.

The cardiac surgery–associated NGAL Score (CSA-NGAL score). The CSA-NGAL score might be the tool

needed to improve awareness and enable interventions to possibly modify these detrimental outcomes.

NGAL deficiency protects from the

progression toward CKD

Tubulo-interstitial fibrosis: EMT

Insulin-like growth factor-binding protein 7 (IGFBP7) e tissue

inhibitor of metalloproteinases-2 (TIMP-2) urinari sono

induttori di arresto del ciclo cellulare in G1, un meccanismo

chiave implicato in AKI.

[TIMP-2]·[IGFBP7] urinario risulta significativamente

superiore ai marcatori di AKI noti quali NGAL.

Urinary [TIMP-2]*[IGFBP7] represents a sensitive and specific biomarker to predict moderate to severe

AKI very early after CABG

URINARY/SERUM PANEL OF

AKI BIOMARKERS (like AMI):

a team work

The molecular microscope…..

Eineche et al. Am. J. Transplant.2010.

Non-dialytic preventive and therapeutic interventions in AKI

PRODOTTE DA: Italian Critical Care Nephrology Board (Commissione indipendente costituita dalla Società Italiana di

Nefrologia, Società Italiana Anestesia Analgesia Rianimazione e Terapia Intensiva, Società Italiana di Terapia Intensiva)

Presidente: Claudio Ronco

MEMBRI DELLA COMMISSIONE: Massimo Antonelli, Giovambattista Capasso, Raffaele De Gaudio, Enrico Fiaccadori, Luca

Lorini, Elena Mancini, Gianpaola Monti, Santo Morabito, Federico Nalesso, Pasquale Piccinni, Zaccaria Ricci, Stefano

Romagnoli, Antonio Santoro.

TEAM DI TRADUZIONE E RICERCA DELLA LETTERATURA: Stefania Aresu, Silvia De Rosa, Sara Samoni, Alessandra

Spinelli, Gianluca Villa

MEMBRI DEI GRUPPI DI LAVORO PER LA STESURA DELLE LINEE GUIDA: Massimo Antonelli, Stefania Aresu, Paolo

Armignacco, Carlo Basile, Gianni Biancofiore, Vincenzo Cantaluppi, Giovambattista Capasso, Stefania Cerutti, Raffaele De

Gaudio, Antonio De Pascalis, Silvia De Rosa, Enrico Fiaccadori, Roberto Fumagalli, Francesco Garzotto, Achille Gaspardone,

Simonetta Genovesi, Silvia Guggia, Paola Inguaggiato, Anna Lorenzin, Luca Lorini, Elena Mancini, Giancarlo Marenzi, Filippo

Mariano, Gianpaola Monti, Santo Morabito, Federico Nalesso, Mauro Neri, Antonello Pani, Giovanni Pertosa, Pasquale

Piccinni, Valentina Pistolesi, Zaccaria Ricci, Stefano Romagnoli, Sara Samoni, Antonio Santoro, Marco Sartori, Alessandra

Spinelli, Gianluca Villa

Use of diuretics in AKI

Poiche il sovraccarico di fluidi e

uno dei sintomi principali di AKI,

i diuretici sono spesso usati in

per facilitare la gestione dei

fluidi.

Recenti studi osservazionali

hanno mostrato che il 59-70%

dei pazienti con AKI sono stati

trattati con diuretici al momento

della consulenza nefrologica o

prima di iniziare una RRT.

Inoltre, l’AKI oligurica ha una

prognosi peggiore rispetto

all’AKI non oligurica.

I diuretici possono essere

dannosi, in quanto attraverso

una eccessiva riduzione del

volume circolante

aggiungerebbero un insulto pre-

renale peggiorando una AKI

preesistente.

Effetti della somministrazione di furosemide vs control sulla

mortalità da tutte le cause e su necessità di RRT: impatto non

significativo.

Cardiac surgery related acute

kidney injury (AKI) is a

common postoperative

complication

that greatly increases morbidity

and mortality.

There are currently no effective

interventions to prevent AKI

associated with cardiac surgery.

Experimental data have shown

that administration of the

mineralocorticoid receptor

blocker spironolactone prevents

renal injury induced by

ischemia-reperfusion in rats.

Spironolactone was not

protective for AKI associated

with cardiac surgery and there

may be a trend toward risk.

Surveys have documented

the continued popularity of

low-dose dopamine to

influence renal dysfunction

even though few data

support it and editorials and

reviews have discouraged

its use.

Low-dose dopamine offers

transient improvements in

renal physiology, but no

good evidence shows that it

offers important clinical

benefits to patients with or

at risk for acute renal

failure.

No impact of low-dose

dopamine on mortality and

RRT needing.

Effect on mortality and need of RRT

Among patients with acute kidney injury after cardiac surgery, fenoldopam infusion, compared with

placebo, did not reduce the need for renal replacement therapy or risk of 30-day mortality but was

associated with an increased rate of hypotension.

Vasodilatatore: agonista selettivo del recettore dopaminico post-sinaptico DA1

Levosimendan (Levo) reduced the incidence of AKI and need of RRT

Levosimendan, a novel calcium

sensitizer with inotropic and

vasodilatory effects, has been

found to increase renal blood flow

accompanied by improved cardiac

output in patients with low-output

heart failure

Levosimendan has been shown to

confer direct renoprotection in

renal endotoxemic and

ischemia-reperfusion injury and

could increase renal blood flow in

patients with low-cardiac-output

heart failure. Results from clinical

trials of levosimendan on AKI

following cardiac surgery

are controversial.

Perioperative administration of

levosimendan in patients

undergoing cardiac surgery may

reduce complications.

Administration of prophylactic glucocorticoids has been suggested as a strategy to reduce postoperative AKI and other adverse

events after cardiac surgery requiring cardiopulmonary bypass.

Compared with placebo, intraoperative dexamethasone appeared to reduce the incidence of severe AKI after cardiac surgery in

those with advanced CKD.

To test whether short-term

perioperative

administration of oral

atorvastatin could reduce

incidence of postoperative

AKI in cardiac surgical

patients.

Short-term perioperative

atorvastatin use was not

associated with a reduced

incidence of postoperative

AKI or smaller increases in

urinary NGAL.

Atorvastatin

Placebo

Atorvastatin

Placebo

α-MSH is an endogenous hormone that inhibits inflammatory, cytotoxic, and apoptotic pathways, thus preventing renal injury

caused by I/R-induced AKI. Additionally, α-MSH has direct protective effects on the kidney, which may result from stimulation of

the melanocortin receptors (MCRs) 1 and 3 in the outer renal medulla. ABT-719 (formerly AP214 acetate) is a novel synthetic

α-MSH.

Patients undergoing cardiac surgeries with cardiopulmonary bypass (on-pump) have a high risk for AKI. We tested ABT-719, a

novel alpha-melanocyte-stimulating hormone analog, for prevention of AKI in postoperative cardiac surgery patients

ABT-719 treatment did not lower AKI incidence using AKIN criteria, influence the elevations of novel biomarkers, or change 90-day

outcomes in patients after cardiac surgery.

Effect of ABT-719 treatment on AKI incidence

No interventions have yet been identified to

reduce the risk of AKI in the setting of

cardiac surgery.

Among high-risk patients undergoing

cardiac surgery, remote ischemic

preconditioning compared with no ischemic

preconditioning significantly reduced the

rate of AKI and use of RRT.

The observed reduction in the rate of AKI

and the need for RRT warrants further

investigation.

Surv

ival D

istr

ibution F

unction

0.00

0.25

0.50

0.75

1.00

Durata Follow-up Rene

0.0 2.5 5.0 7.5 10.0 12.5 15.0

STRATA: dgl_cl=0 Censored dgl_cl=0 dgl_cl=1 Censored dgl_cl=1

Graft survival - DGF

CM-48

No DGF DGF

1 anno 99.1 88.4

5 anni 94.5 76.9

10 anni 86.3 62.4

HR = 3.9 *

10 anni

Delayed graft function,

which is reported in up to

50% of kidney-transplant

recipients, is associated with

increased costs and

diminished long-term graft

function.

The effect that targeted mild

hypothermia in organ

donors before organ

recovery has on the rate of

delayed graft function is

unclear

Mild hypothermia, as

compared with

normothermia, in organ

donors after declaration

of death according to

neurologic criteria

significantly reduced the rate

of delayed

graft function among

recipients.

Static cold storage is generally used to preserve kidney allografts

from deceased donors.

Hypothermic machine perfusion may improve outcomes after

transplantation, but few sufficiently powered prospective studies

have addressed this possibility.

Hypothermic machine perfusion was associated with a reduced

risk of delayed graft function and improved graft survival in the

first year after transplantation

La creazione di un bio-graft

trapiantabile per sostituire

definitivamente la funzione renale

aiuterebbe a contenere l’importante

richiesta di organi e la morbidità

connessa con l’immunodepressione.

Tale innesto bioingegnerizzato deve

avere l'architettura del rene e

supportarne la funzione e la

perfusione, supportando inoltre le

funzioni basilari di filtrazione ,

secrezione , assorbimento e drenaggio

di urina.

I graft derivanti sono in grado in vitro

di produrre urina se ben perfusi

attraverso il loro letto vascolare.

Quando trapiantato in posizione

ortotopica nel ratto, il graft è perfuso

dalla circolazione del ricevente e

produce urina attraverso uretere in

vivo.

Targeting endogenous repair pathways after acute kidney injuryHumphreys B., Cantaluppi V, Ksingbarti K, Portilla D, Wu L, Rosner M, Okusa M, Ronco C, Kellum JA

AKI remains a highly prevalent disease associated with poor short- and long-term outcomes and high costs. Although significant

advances in our understanding of repair after AKI have been made over the last 5 years, this knowledge has not yet been translated

into new AKI therapies.

Suggested a research agenda to more efficiently bring new discoveries regarding repair after AKI to the clinic.

Autologous MSC in ESRD

patients undergoing living

donor kidney Tx

MSCs (1−2 x 106/kg) at Tx and

after 2 weeks;

53 pts. CNI standard vs.

52 pts. Reduced CNI (80%

standard);

51 pts. Anti-CD25 mAb and

standard CNI

Outcome I: AR incidence and

renal function (eGFR 1 year).

Outcome II: patient and graft

survival.

Conclusions: Compared to anti-

CD25 mAb, reduced incidence of

AR and infection, better renal

function (eGFR) at 1 year.

• ACT-AKI phase II clinical trial.

• 28 centers (USA, Canada)

• Analysis results ongoing

Allogenic MSC transplantation in patients

at high risk for AKI following major cardiac

surgery.

AC607 Proof of Concept Phase 2 Trial: ACT-AKI (NCT01602328)

Hauser et al. Am J Pathol 2010

Detection of MSCs at 24 hours (by FISH)

Detection of iron-labelled MSCs at 24 hours

Herrera et al. Kidney Int 2007

vehicle 5h 24h 48h

IVIS images of nude mice injected with 350000 MSCs

57

MSCs accelerate recovery in AKI

Mesenchymal Stem Cell-Derived Microvesicles Protect

Against Nephrotoxic AKI (glycerol injection)

MSC or MV

injection

Bruno et al. J Am Soc Nephrol 2009; 20:1053

AKI AKI+MV

AKI+RNaseMV AKI+MSC

MSC or MV

injection

*: 75,000 MSC or 15 mg of MVs

Mesenchymal Stem Cell-Derived MVs Localize within the Injured Kidney

for stem cells and

kidney regeneration

STARLIGHT, Muse 2006

Our hopes and expectations,

Black holes……

…and revelations.

CW

Administration of cell-free cord-blood mesenchymal stem cells derived extracellular vesicles (CF-CBMSCs-EVs) is safe and can ameliorate

the inflammatory immune reaction and improve the overall kidney function in grade III-IV CKD patients.

Grazie

vincenzo.cantaluppi@med.uniupo.it

University of Eastern Piedmont- Center for Experimental

UPO Medical Research-UNITO