Acute kidney injury: definition, biomarkers, epidemiology, early

diagnosis.

Renal replacement therapy in children

Dmitry Zverev (Moscow, Russia)

Definition “Sudden loss of renal function resulting in the loss of the

kidneys’ ability to regulate electrolyte and fluid homeostasis”

Diagnostic criteria for AKI

urine output Serum creatinine levels

increase in serum creatinine (>50% above baseline level) and, in most cases, a concomitant reduction

in urine output (less than 0.5–1 ml/kg per hour)

Pediatric Modified RIFLE-definition

Ackan-Arikan et al: Kid Int 2007

Pediatric Modified RIFLE Criteria

CrCl Urine output

Risk GFR decrease by 25% <0.5ml/kg/hour for 8 hours

Injury

GFR decrease by 50%<0.5ml/kg/hour for 16 hours

Failure GFR decrease by 75% or GFR<35ml/min/1.73m2

<0.3 ml/kg/hour for 24 hours or anuric for 12 hours

Loss Persistent ARF > 4 weeks

End

stage End Stage Renal Disease (>3 months)

К - constantk = 0.33 premature neonatesk = 0.45 neonates and infants, under 1 y.o.k = 0.55 children, under 13 y.o.

and girls, over 13 y.ok = 0.70 boys, over 13 y.o.

• mg/dl х 88 = mkmol/l

• mkmol/l х 0,0113= mg/dl

GFR = height (cm) X К/sCr (mg/dl)

Calculating GFRusing Schwartz formula

GFR in childrenage GFR

1 - 2 days 20.8 ± 5.0

4 - 14 days 36.8 ± 7.2

15 – 19 days 46.9 ± 12.5

1 – 3 months 60.4 ± 17.4

4 – 6 months 87.4 ± 22.3

7 – 12 months 96.2 ± 12.2

1 – 2 years 105.2 ± 17.3

3 – 8 years 111.2 ± 18.5

9 – 12 years 116.6 ± 18.1

13 – 15 years 117.2 ± 16.1

G.Schwarts. Glomerular filtration rate measurement and estimation in kidney disease. Pediatric Nephrol (2007) 22:1839-1848

Creatinine disadvantages as AKI marker

Plasma Creatinine – measure of function (not injury)

More than 50% nephrons must be compromised for SCr level changes to be evident

Therefore, SCr is at best a late marker of significant renal dysfunction

Characteristics of an Ideal Biomarker

1. Biomarker have to be an active substance that is immediately excreted by the damaged cells of the kidneys2. Has a high sensitivity and specificity3. Be available for direct determination in urine or blood4. Have an acceptable "price - quality"

Biomarkers of AKI (Devarajan P: Emerging urinary biomarkers in the diagnosis of acute kidney injury. Expert Opin

Med Diagn 2008, 2:387-398.)

neutrophil gelatinase-associated lipocalin (NGAL) cystatin С (CysC) kidney injury molecule-1 (KIM-1) interleukin 18 (IL-18), liver-type fatty acid-binding protein(L-FABP)

NGAL(Neutrophil gelatinase-associated lipocalin)

a 25-kD protein of the lipocalin superfamily, is expressed by kidney tubules epithelium

First time as a marker of AKI was described in 2003 [Mishra J. et al]

The role of NGAL as a biomarker of kidney damage is confirmed by experimental studies on various models of critical states [Haase-Fielitz A., Bellomo R., Devarajanet P. 2009]

Critically ill patients in ICUs have NGAL level ≥155 nmol/l, indicating AKI (sensitivity 82%, specificity 97%) [Constantin J.M. et al.2010 De Geus H.R., 2011 . Haase-Fielitz 2009 ]

Cystatin C

Cystatin С (protease inhibitor) is filtrated in glomerulus in the kidneys, completely reabsorbed and isn’t secreted in the tubules Consequently it is a marker of glomerular filtration

rate (GFR) If kidney function and glomerular filtration rate decline, the

blood levels of cystatin C rise Cystatin C levels in AKI become higher on 24-48 hours

earlier than creatinine levels Disadvantages: high cost

Kidney injury molecule-1 (KIM-1)

Transmembrane protein Not detected in blood and urine normally Expression is markedly up-regulated in the damaged

proximal tubules Disadvantages:

• doesn’t make prediction • high cost

Interleukin 18 (IL-18)

Proinflammatory cytokine, produced by the distal tubules, collecting tubules of the kidneys

Urinary IL-18 is a useful biomarker of AKI IL-18 secretion distinctly increases in AKI Disadvantages:

• low sensitivity• low specificity

Nowadays biomarkers can’t provide the stratification of ungraded AKI

Validation of these biomarker studies needs to be performed in different critically ill populations

The incidence of AKI requiring RRT227 cases for 84-91 years (Yorkshire UK)

Adapted from Acute kidney injury in critically ill newborns: what do we know? What do we need to learn? Askenazi DJ, Goldstein SL. Pediatr Nephrol. 2009 Feb;24(2):265-74. Epub 2008 Dec 10.

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adults Children Newborns

1-4 years 5-15 years

Prerenal(renal hypoperfusion)

Renal (intrinsic) Postrenal

Low intravascular volume Hemorrhage/bleeding Severe dehydration Third-space losses Decreased effective circulating volume Cardiac dysfunction Renal artery obstruction Sepsis

Glomerulonephritis rapidly progressive, immune-mediated diseases HUS Cortical necrosis, renal vein/artery thrombosis,DIC Acute interstitial nephritis: Infection/pyelonephritis Acute tubular necrosis: hypoxic/ischemic injury, drug-induced Tumor lysis syndrome

Urethral obstruction:

posterior urethral

valves in neonates; Obstruction

kidney urinary tract:

(ureteral–pelvic unction,

ureteral stenosis,

uretero–vesical unction),

stones, mass

Etiology of AKI

Management of AKI should be monitoring and laboratory

controlling require special methods of intensive therapy

in the ICU an optimal microclimate around the child conducted simultaneously with the diagnostic

activities

At the beginning rapid volume replacement should be undertaken at the same time for final diagnosis (Crystalloid solution 20 ml/kg normal saline or 5% glucose for 20-30 minutes)

fresh frozen plasma could be used as a starting solution in sepsis, peritonitis and severe surgical pathology (it has a long-lasting effect on hemodynamics and stays in the circulatory longer)

Management of AKI

(attempt fast) improvement of renal perfusion (by dopamine, a rapid increase in blood volume, colloids transfusion) may lead to rupture of blood vessels in the germinal matrix and intraventricular hemorrhage development

Management of AKINo diuresis ensues after

fluid administra tion Normal cardiac output

(normal renal perfusion)

Renal intrinsic injury

Dialysis

AKI etiology in childrenand mortality

DGKB St.Vladimir (2002-12гг.)

AKI etiology Amount of children

n = 326

Mortalityn =53(16,3%)

HUS and TTP 219 (67,8%)

11(5%)

MODS 24(7,4%) 14 (58,3%)

GN, systemic diseases

25 2

AKI in newborns 38(12,7%) 23 (60%)

AKI of various etiology

19 3

AKI etiology in children

AKI etiology DGKB St.Vladimir Moscow hospitals

years 2002-10 2012 2012

Children with AKI

276 50 200

HUS 188(68%) 29(58%) 31(15,5%)

MODS, шок, sepsis,

cardiosurgery, HF

50 13 169

The main cause of AKI

Preschool age School age

HUS GN, shock, TTP

Hemolytic uremic syndrome

Is defined by a triad of symptoms:

- Hemolytic anemia- Thrombocytopenia

- Azotemia

Pathological basis of HUS - thrombotic microangiopathy affecting:

KIDNEYS brainlungsbowel

liverheart

Shiga like toxin, type 1

Shiga like toxin, type 2

Shiga-toxin, тип 1

Escherichia Coli

O157:H7O111:H8O103:H2

O121O145O26O113

Shigella dysenteria

Serotype 1

A

B

B

B

B

B

Typical HUS

Brooks J.T. et al., (2004) Sonntag A.K. et al., (2004)

Noris and Remuzzi,, JASN, 16:1035 (2005)

Infection sources Escherichia coli O157:H7

- meat

- dairy products

- fruit juices - potable water- pets

- water in open-air reservoirs and swimming pools

Typical HUS occurrence

North America 2-3 cases per 100000 children

under 5 years old,Argentina10 times higher

Moscow – 4 cases Moscow region 4-5 casesper 100000 children under 5 years old

Pediatric nephrology (2008)23:1749-1760

The earlier dialysis- the better prognosis of

HUS

HUS outcomes

Mortality during the acute phase2-6%

ESRF development 1-2%

Development ESRF during first 5 years5-7%

Development ESRF during 10-15 years10-15% more

Thrombotic thrombocytopenic purpura

TTP is characterized by microangiopathic hemolysis and platelet aggregation in hyaline thrombi, with no activation of the coagulation system

This leads to partial occlusion of blood vessels associated with excessive proliferation of endothelial cells

Kidney, brain, heart, pancreas, spleen, and adrenals endothelium are suffered

The reason of familial and aquired idiopatic TTP is insufficient destruction of unusually large multimers of von Willebrand factor, which are destroyed by metalloproteinase ADAMTS-13

lack of protease activity caused by either its serious shortage or production of autoantibodies

Thrombotic thrombocytopenic purpura

Management of TTP Plasmapheresis became the treatment of choice for

TTP in mid-80s

Supply of ADAMTS-13 and removal of anti-ADAMTS-13 autoantibodies and unusually large multimers of von Willebrand factor make provision the effect of plasmapheresis

Pulse therapy with Metipred

The mechanism of AKI in GN

Edema of interstitial tissue, increasing of hydrostatic pressure in the proximal tubule and the Bowman's capsule, which leads to reduction of filtrational pressure and glomerular filtration

protein mass and blood clots occlude tubules fast-growing proliferation of glomerular

capillary loops with compression and/or tubulointerstitial changes

vasoactive substances and cytokines release from monocytes and other cells

Management of GN with AKI

RRT when indicatedSymptomatic therapy (treatment of

neurological, cardiovascular and respiratory disorders)

Pathogenetic therapy of GN in the early stages of the disease (corticosteroids, alkylating agents, plasmapheresis)

Indications for emergency dialysis ANURIA > 1 day Complicated OLIGURIA:

• hyperhydration with pulmonary edema and/or respiratory failure, uncontrolled hypertension

• disorders of the central nervous system• heart failure• hyperkalaemia > 7.5 mmol/l• decompensated metabolic acidosis• increase of creatinine level > 120 mkmol/day• ensuring adequate child nutrition and infusion

therapy

HD? PD? CVVHDF?

3. A hemodialysis machine: volume control UF, a single needle connected option

4. Hemodiafiltration - option for maximum efficiency

1. Department of HD should be located in a children's hospital with multi-disciplinary experts available

2. Water quality: adequate biochemical composition, the absence of microbiological contamination

Hemodialysis in children(basic practical guidelines

European Pediatric Dialysis Working Group, 2005)

Hemodialysis

The high speed of purification and UFThe ability to adjust the composition of the dialysate

Advantages

Disadvantages• Difficulties of vascular access to ensure an adequate

blood flow in child weighing < 5 kg • Large extracorporeal volume• Hypotension episodes during UF• Cardiovascular insufficiency• Risk of bleeding assosiated with systemic anticoagulation• Fluid limitation between dialysis;• Disequilibrium syndrome

Peritoneal dialysis

Begins from 10 ml/kgExposition 0,5 – 1 hour

1. Dialysis solution2,3. Containersmeasuring cylinders4. Peritoneal catheter5. Container for the drained solution6. Clip

PD in infants with extremely low birth weight

Advantages of PD

Continuing process of blood purification and UF; Implantation of peritoneal catheter and PD conducting is a

simple procedure, possible in hospital PD does not have a marked influence on hemodynamics, it

can be used in patients with hypotension and even in patients with multiple organ failure

Isn’t required providing of vascular access, anticoagulation therapy

PD solution - a source of extra calories Low cost of treatment

low nitrogenous wastes, blood electrolytes clearance, small rate of UF

PD conducting is impossible in patients with purulent peritonitis, in the early postoperative period after laparotomy, with leaking abdominal

cautious and limited using of PD in patients with concomitant respiratory failure

Disadvantages of PD

Surgical complications during PD

1. Catheter setting and operation dialysate draining (14,1%), drainage disruption(4.5%), internal organs wounding, bleeding 2. InfectiousPeritonitis -80%, inflammation in the catheter area 3. Concomitant diseases of the abdominal cavity      (diaphragmatic, inguinal and umbilical hernia)

Continious methods of RRT

CVVHDF - extracorporeal blood purification techniquedue to convective transport of substances through the highly permeable membrane, with the replacement of UF with a special solution

Parametres of CVVHDFThe rate of blood flow 4-8 ml/kg/min

• Neonates - 20-40 ml/minInfants - 40-80 ml/min The volume of extra-Corporeal circuit 55-72ml Hemofilter membrane area – 0.2 м²

Substitution rate:35-50 ml/kg/hr

The flow rate of the dialysis solution:  equal to or greater than 1.5 times the rate of substitution

Heparinization:• Bolus -     20-30 U/kg• Continuous infusion -              10-30 U/kg/hr

Parametres of CVVHDF

Vascular access

Two way catheterunder 6 kg - 6,5 Frfrom 6 to 15 kg - 8 Frmore than 15 kg - 11 Fr

The implantation method puncture venesection

The puncture site

Subcutaneousvein Jugular vein

Femoral vein

Dynamics of blood creatinine in patients with AKI using

PD, HD and CVVHDF

100

150

200

250

300

350

400

450

500

550

600

0 1 2 3 4 5 6 7 8 9Сутки диализа

ГД

ПД

ПВВГДФ

mkmol/l

Creatinin

HD

PD

CVVGDF

The day of dialysis

Dynamics of blood urea in patients with AKIusing

PD, HD and CVVHDF

Ure

a, m

mol

/l

The day of dialysis

CVVHDF PD HD

Advantages of CVVHDF

provides continuous purification and UF; better control of azotemia does not require a large flow of blood little effect on hemodynamics can be used in critically ill patients with heart failure, severe

edema, cerebral edema; UF rate can be calculated, assigned and adjusted according

to the hourly needs of the patient; does not require water treatment and specially trained staff

Heparinization necessity Central venous catheterization Fairly sophisticated equipment High cost of the procedure The procedure is conducted by nondialysis staff who

has many other responsibilities

Disadvantages of CVVHDF

Factors affecting the type of the dialysis selection

age and anthropometric data hemodynamic the presence of respiratory failure degree of safety consciousness and the presence of

seizures the primary purpose of correction by the RRT the severity of fluid overload the severity of azotemia and electrolyte imbalance

The algorithm of RRT method selection in children with AKI

AKIHD PD

Age

Fluid overload

Hypertension

CV

VG

DF C

VV

GD

F

Hypotension

Neurological symptoms

Starting type of a dialysis in treatment of children with AKI

1991-2004 2006-09 2010-12HD 48.5% 15% 0,9%PD 51.5% 25% 19,6% CVVGDF - 60% 79,5%

The cost of consumables per 1 day of AKI treatment (USD)

Acute PD in childAcute PD in adultAcute HD

CVVGDF

CONCLUSIONS CRRT – a choice method at patients with sepsis,

the overhydratation, the expressed metabolic and electrolytic violations.

PD – a choice method at stable patients with AKI, at a hemorrhagic syndrome, impossibility of ensuring vascular access, and also basic therapy at long AKI

HD – a choice method at children of advanced age.