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
University of Eastern Piedmont- Center for Experimental
UPO Medical Research-UNITO