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Insufficienza renale acutaEnrico Fiaccadori
Unita’ di Fisiopatologia dell’Insufficienza renale Acuta e Cronica
Dipartimento di Medicina Clinica e Sperimentale
Universita’ degli Studi di ParmaUniversita’ degli Studi di Parma
Terapia Intensiva Nefrologica
Azienda Ospedaliera-Universitaria Parma
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AGENDA
• Epidemiology and outcome
Data and problems
• Pathogenetic mechanisms
- A new and more integrated view on AKI- A new and more integrated view on AKI
- Transition from AKI to CKD
• TreatmentThe need for a global approach
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- Neonates commonly have nonoliguric AKI,
making oliguria an insensitive marker
- After birth neonatal SCr reflects maternal levels
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ROC area 0.998 2-hr urine NGAL
ROC area 0.91 2-hr serum NGAL
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- Of 2,644,263 children, 10,322 children developed AKI (3.9/1000
admissions);
- In-hospital mortality among patients with AKI was 15.3%, but higher
among children <1 month old (31.3% versus 10.1%, P,0.001) and children among children <1 month old (31.3% versus 10.1%, P,0.001) and children
requiring critical care (32.8% versus 9.4%, P 0.001) or dialysis (27.1%
versus 14.2%, P 0.001);
- Shock, septicemia, intubation/mechanical ventilation, circulatory disease,
cardiac congenital anomalies, and extracorporeal support were
significantly associated with AKI
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Mortality and LOS associated with AKI
Mortality rates and length of stay are shown for patients with and without AKI,
AKI patients < 1and> 1 month of age, AKI patients who required and did not
require dialysis, and AKI patients who received and did not receive critical care.
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- Mortality risk increased by 3 to 6 times
- Lenght-of Hospital Stay increased
- 20% of patients leave the PICU with higher
than basal serum creatinine levels
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AGENDA
• Epidemiology and outcome
Data and problems
•• PathogeneticPathogenetic mechanismsmechanisms
-- A new and more A new and more integratedintegrated viewview on AKIon AKI-- A new and more A new and more integratedintegrated viewview on AKIon AKI
-- TransitionTransition from AKI to CKDfrom AKI to CKD
• TreatmentThe need for a global approach
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Peritu
bu
larm
icrocircu
lation
Tub
ule
Renal hypoperfusion/ ischemia Renal hypoperfusion/ ischemia Renal hypoperfusion/ ischemia Renal hypoperfusion/ ischemia ++++ direct nephrotoxicitydirect nephrotoxicitydirect nephrotoxicitydirect nephrotoxicity
Peritu
bu
larm
icrocircu
lation
Tub
ule
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AKI as an
immune-
inflammatory
syndrome
activated by activated by
ischemia-
reperfusion
injury
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AKI-induced distant organ effects:
The systemic complications of AKI as the consequence
of a “nephro-centric” inflammatory syndrome
Scheel PJ et al, Kidney Int 2008; 74:849-851
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Swaminathan S, Shah SV. Kidney Int 2011; 80:453-463
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Clinical course of AKI
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Nephrogenesis: key data
• Nephrogenesis in human begins around 6-week gestation age,
and is normally completed by 36 week gestation
• No evidence of active postnatal glomerulogenesis in at term
babiesbabies
• The number of nephrons formed within the kidney at
completion of of nephrogenesis influences lifetime renal
functional capacity and reserve � it is essential that adequate
nephrogenesis is achieved at the very beginning of life
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- In the kidneys of preterm neonates renal maturation accelerated after
preterm birth, with a decreased width of the nephrogenic zone
- Compared with gestational controls, preterm kidneys had a greater - Compared with gestational controls, preterm kidneys had a greater
percentage of morphologically abnormal glomeruli and a significantly
larger cross-sectional area of the renal corpuscle, suggestive of renal
hyperfiltration
- These observations suggest that the preterm kidney may have fewer
functional nephrons, thereby increasing vulnerability to impaired renal
function in both the early postnatal period and later in life.
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- 32 studies (46,249 patients), low birth weight defined
as birth weight between 1,500 and 2,500 g
- LBW associated with a 70% increase of risk of
developing CKD later in life (HR: 1.73, 95% CI: 1.44–
2.08) and with an 80% greater risk of developing
albuminuria (HR: 1.81, 95% CI: 1.19–2.77) compared
to normal birth weight infants
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- CKD incidence at 1-3 yrs 10.3% (17.1%
in patients with AKIN stage 3)in patients with AKIN stage 3)
- 46.8% of patients at risk for CKD
(hypertension, eGFR 60-90 ml/min/1.73
m2, proteinuria) and/or hyperfiltration
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Potential pathways by which ischemic AKI
may initiate progressive renal disease
Acetylation, methylation,
histone exchange
Nephrol Dial Transplant 2013; 28:1985-93
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According to
Brenner’s hypothesis,
reduced nephron
number
(oligonephropathy)
Mechanisms of vulnerability
to long-term renal disease in
prematurity and neonatal AKI
Neonatal
AKI
Prematurity
(oligonephropathy)
leads to
hyperfiltration,
hypertension, and
proteinuria, which
perpetuate renal
damage and lead to
glomerulosclerosis
and CKD
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AGENDA
• Epidemiology and outcome
Data and problems
• Pathogenetic mechanisms
- A new and more integrated view on AKI- A new and more integrated view on AKI
- Transition from AKI to CKD
•• TreatmentTreatmentThe The needneed for a global for a global approachapproach
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Treatment of pediatric AKI
• Specific therapy of the causal factor (for
example antibiotics, surgery etc.)
• General supportive therapy (fluids, vasoactive
agents, mechanical ventilation etc.)agents, mechanical ventilation etc.)
• Renal replacement therapy
• Nutritional supplementation
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Mortality in Mortality in
AKI is
increased
when FO
increases
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No single organ system
Why mortality
is increased
with FO?
is spared by the
pathological sequelae of
fluid overload (congestion)
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Inter-relationship between fluid overload and AKI:
FO may worsen AKI, and AKI may contribute to FO
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Renal replacement therapy
• Timing
• Dose
• Modality
• Anticoagulation
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- 15 percent or greater fluid overload
- Oliguria not responsive to diuretics
- Escalating ventilatory requirements, especially if related to volume
status (prior to intubation is preferred when possible)
- Need for adequate nutrition, especially when nutrition is
compromised by fluid restriction or electrolyte abnormalities
Indications to RRT start in pediatric AKI
compromised by fluid restriction or electrolyte abnormalities
- Need for provision of large volumes of medications or blood
products in a patient already >10 percent fluid overloaded
- BUN between 80 and 100 mg/dL
- Life-threatening metabolic derangements (eg, hyperkalemia) that
are refractory to medical management
UpToDate 2013
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RRT modalities
• Peritoneal dialysis
• Intermittent dialysis
• CRRT• CRRT
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From the patient To the patient
filter
Sustained, low-efficiency dialysis (SLED) with ACD-A
Blood flow200 ml/min
ACD-A (citrate 113 mmol/L), 200 ml/hour (target citrate in the circuit 2 mmol/L)
From the patient
Dialysis fluid out
Dialysisfluid in,
Ca 1.25 mmol/L
- Dialysis fluid rate 300 ml/min- Daily treatments, 8 to 12 hours- Standard dialysis machine- polisulfone filters, 1.7 m2, KUF 20 ml/mmHg/h
Monitoring: ACT by Hemochron
and Ca++
Target Ca++ of the patient > 0.9 mmoles/L
Citrate removal:
2/3 of the load
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In-hospital mortality
according to nutritional
status in 309 ICU pts
with AKI
Protein-energy wasting is associatedwith increased mortality risk in AKI
Nutritional status by SGA (Subjective Global Assessmentof nutritional status, Baker JP et al., NEJM 1982; 306:969-72)
A B C
Fiaccadori E et al., J Am Soc Nephrol 1999; 10:581-593
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Mechanisms of underfeeding in AKI
Fiaccadori E et al., Curr Opin Clin Nutr Metab Care 2013; 16:217-224
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800100012001400160018002000
kcal
Prescribed Engergy
Energy Received From Enteral Feed
Energy Debt
� Energy (and protein) debt
is associated with:
�↑ ICU LOS �↑ Days on MV
The concept of protein/energy debt in the ICU
and its negative impact on outcome
0200400600800
1 3 5 7 9 11 13 15 17 19 21
Days
�↑ Days on MV�↑ Complications� ↑ Mortality
Rubinson L et al., CCM 2004; 32:350-357
Villet S et al., Clin Nutr 2005; 24:502-509
Dvir D et al., Clin Nutr 2006; 25:37-44
Petros S et al., Clin Nutr 2006; 25:51-59
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- In patients with AKI the overall protein provision
(19% [0%–60%]) was lower than energy provision (55%
[22%–113%]) compared with estimated needs
(P,0.001)(P,0.001)
- Patients with AKI were more likely to be fasted versus
receiving enteral/parenteral nutrition, and to receive
less than 90% of BMR than no AKI patients
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Criteria for Selecting Patients That Would Benefit
the Most From Indirect Calorimetry in PICU
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Conclusion
- AKI in pediatric patients at risk is common, and is
associated with increased morbility and mortality
- AKI in now viewed as an inflammatory process
activated by ischemia-reperfusion injury
- AKI is associated with an increased risk for
progression to CKD
- An integrated therapeutic approach based on
supportive therapy, adequate nutrition and RRT is
needed
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The complex interactions between different
renal cells in the pathogenesis of ischemic AKI
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Preterm birth**
*IUGR : birth weight
and/or birth lenght
< 10° percentile for
gestational age,
4-10% of all term
pregnancies
**Preterm birth :
birth prior to 37
completed weeks
of gestation, 10-
16% of births
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Risk factors for AKI in neonates
• VLBW (500-1500 gr)
• Congenital heart disease
• ECMO• ECMO
• Perinatal depression
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Prematurity
• Worldwide almost 13 millions infants are born
prematurely each year
• About 80-90% of infants born 501 to 1500 g
survive to NICU dischargesurvive to NICU discharge
• 60% of survivors leave the NICU without any
major neonatal morbidity
Beck S et al., Bull World Health Organ 2010; 88:31-38
Horbar JD et al., Pediatrics 2012; 129:1019-26
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Follow up strategies for NICU survivors
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Pediatr Res 2007; 62: 307–312
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Prematurity and the kidney
The entity of preterm birth itself may result in
morphological and functional alterations associated
with negative long term renal outcomes:
• Reduced nephron numberReduced nephron number
• Reduced renal volume
• Hypertension
• Proteinuria
Shalloh C et al., Transl Res 2012; 159:80
Duncan AF et al., Ped Nephrol 2011; 26:1115
Kejzer-Veen MG et al., Ped Nephrol 2010; 25:499
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# Among the 29 patients assessed for long-term
sequelae at 3–5 years, 17/29 (59%) subjects had sequelae at 3–5 years, 17/29 (59%) subjects had
at least one sign of renal injury (microalbuminuria,
hyperfiltration, hypertension, decreased GFR)
# A pediatric nephrologist was involved in care of
only 6/17 (35%) with chronic renal injury
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The majority of pediatric patients with AKI are discharged
from the hospital with «normal» serum creatinine levels
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• Low birth weight
Developing nephrons are particularly
vulnerable to maldevelopment and
dysfunction in an ex-utero environment
• Low birth weight
• AKI in neonates
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Epidemiology of neonatal AKI
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Mandatory fluid
intake in the ICU
• Resuscitation fluids
• Blood products
Drug vehicles• Drug vehicles
• Enteral nutrition
• Parenteral nutrition
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Venous congestion reduces the glomerular net filtrationpressure � glomerular filtration rate is reduced
FO negatively affects GFR
and increase the risk of AKI
Jessup M et al., JACC 2009;53:597-599
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Endothelial activation, injury and
reduced microvascular flow in AKI
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The dose-response curve of fluids vs complications:two deadly extremes of the same problem
Hilton AK et al., MJA 2008; 189:509-513