LESO RENAL

AGUDA
Investigao Diagnstica:
Reviso e Perspectivas Futuras

Jos Lus Quesado

ndice de contedos

Contextualizao
Diagnstico de Leso Renal Aguda (LRA)
Limitaes do diagnstico baseado na [creatinina srica]
Limitaes do diagnstico baseado no dbito urinrio
Novos biomarcadores
Diagnstico de Doena Renal Aguda (DRA)
Estratgia diagnstica
Ferramentas futuras
Contextualizao

Sndrome caracterizada pela rpida deteriorao (horas a dias) da

funo renal.

Acumulao de resduos, electrlitos e fludos.

Reduo da imunidade, disfuno orgnica distncia (pulmo,
corao, fgado, Sistema Nervoso Central - SNC).
 Acute kidney injury (AKI) is a major contributor to
poor patient outcomes. AKI occurs in about 13
million people per year, () AKI is thought to
contribute to about 1-7 million deaths every year.

In Mehta RL, Cerda J, Burdmann EA, et al. International Society of Nephrologys 0by25 initiative for acute
kidney injury (zero preventable deaths by 2025): a human rights case for nephrology. Lancet. 2015;385:2616
Contextualizao

O impacto e o prognstico da LRA variam consideravelmente tendo em conta:

Gravidade
Quadro clnico
Comorbilidades
Localizao geogrfica

LRA est indelevelmente relacionada com:

Mortalidade e morbilidade acrescidas
Progresso para Doena Renal Crnica (DRC)
Altos custos para os sistemas de sade
Contextualizao

O diagnstico rpido e uma estratgia diagnstica

apropriada so essenciais no reconhecimento precoce das
possveis causas reversveis.
DIAGNSTICO DE
LRA
Critrios de diagnstico

2004 2007 2012

RIFLE AKIN KDIGO
(Kidney Disease
(Risk, Injury, Failure, (Acute Kidney Injury
Improving Global
Loss, End-Stage) Network)
Outcomes)
Critrios de diagnstico KDIGO
Kidney Disease Improving Global Outcomes

Aumento na creatinina srica 0.3mg/dl em 48 horas;

OU

Aumento da creatinina srica 1.5 vezes o valor basal

em 7 dias; OU

Volume de urina < 0.5ml/kg/h durante 6h.

Estadios de LRA KDIGO
Kidney Disease Improving Global Outcomes
Estadio de LRA Creatinina srica Dbito urinrio
Aumento na creatinina srica
0.3mg/dl
Dbito urinrio <0.5ml/kg/h por 6
Estadio I 12h
Aumento para 1.51.9 vezes o valor
basal

Aumento para 2.02.9 vezes o valor Dbito urinrio <0.5ml/kg/h por

Estadio II basal 12h

Aumento para 3.0 vezes o valor Dbito urinrio <0.3ml/kg/h por

basal 24h

Creatinina srica 4.0mg/dl

Estadio III
Dilise
Anria for 12h
Doentes <18anos, diminuio da TFG
para <35ml/min por 1.73m2
Limitaes do diagnstico
baseado na [creatinina srica]
Limitaes do diagnstico
baseado na [creatinina srica]
Frmacos que interferem na secreo tubular (p.e. cimetidina, trimetoprima)
Reduo da produo de creatinina (p.e. perda de massa muscular, doena
hepatica, spsis)
Ingesto de substncias que aumentam a produo de creatinina (p.e.
creatina, carnes vermelhas)
Aumento fisiolgico da TFG (p.e. gravidez)
Interferncia com os mtodos de quantificao (p.e. 5-fluorocitosina,
cefoxitina, bilirrubina)
Ressuscitao ou sobrecarga de fludos
DRC progressiva com aumento gradual da creatinina srica
Administrao de creatinina como tampo farmacolgico (p.e. dexametasona)
Limitaes do diagnstico
baseado no dbito urinrio
Obesidade
Aumento fisiolgico da TFG (p.e. gravidez)
Sobrecarga ou ressuscitao com fludos
Oliguria devido libertao aguda temporria de Hormona Anti-
Diurtica (p.e. ps-operatrio, nusea, dor, jejum, hipovolmia)
Cut-offs decididos por conveno, mais do que por evidncia cientfica
Estadios de LRA KDIGO
Kidney Disease Improving Global Outcomes
Estadio de LRA Creatinina srica Dbito urinrio
Aumento na creatinina srica
0.3mg/dl Dbito urinrio <0.5ml/kg/h
Estadio I
Aumento para 1.51.9 vezes por 612h
o valor basal
Aumento para 2.02.9 vezes Dbito urinrio <0.5ml/kg/h
Estadio II
o valor basal por 12h

Aumento para 3.0 vezes o Dbito urinrio <0.3ml/kg/h

valor basal por 24h

Creatinina srica 4.0mg/dl

Estadio III
Dilise
Anria for 12h
Doentes <18anos,
diminuio da TFG para
<35ml/min por 1.73m2
 FERRAMENTAS
COMPLEMENTARES DE
DIAGNSTICO
Novos Biomarcadores
Novos biomarcadores

Diagnosticar mais precocemente;

Informar sobre a etiologia subjacente.
Especfico do rim e que permita a distino entre
pr-renal, intrnseca e ps-renal.
Mensurvel de forma fcil, rpida, fivel e no-
invasiva.
Barato de aferir.
Novos biomarcadores

Filtrao glomerular
Cistatina C srica
Integridade glomerular
Albuminria e proteinria
Stress tubular
Insulin-like growth factor binding protein [IGFBP-7], tissue inhibitor
metalloproteinase 2 [TIMP2]
Dano tubular
Neutrophil gelatinase-associated lipocalin [NGAL], kidney injury molecule-1
[KIM-1], N-acetyl--D-glucosaminidase [NAG], liver fatty acid-binding
protein [L-FAB]
Inflamao intra-renal
Interleucina 18
Novos biomarcadores
 Novos biomarcadores
AKI biomarker:
Alanine aminopeptidase (AAP)
Alkaline phosphatase (ALP)
-Glutamyl transpeptidase (-GT)
Angiopoietin-1
Angiopoietin-2
Calprotectin
Chitinase 3-like protein 1
Cystatin C
Description Handling by the kidney Factors affecting biomarker levels
Enzymes located on the brush Released from tubular brush border
border villi of the proximal tubular after damage to proximal tubular
cells cells
57kDa endothelial growth factor Systemic inflammation
Upregulated in glomerular disease
secreted by endothelial cells, Diabetes
and sepsis
including renal endothelial cells Malignancy
Cytosolic calcium-binding complex Inflammatory bowel disease
of two proteins of the S100 group Urinary tract infection
Detectable in urine following
(S100A8/S100A9); derived from
intrinsic AKI
neutrophils and monocytes; CKD
activator of innate immune system
Inflammatory diseases
39kDa soluble intracellular protein
Glomerular filtration of serum Malignancy
of glycoside hydrolase family 18
concentrations; in addition: some COPD
expressed by chrondrocytes,
secretion by macrophages within
macrophages, endothelial cells, Liver cirrhosis
the kidneys upon renal stress or
neutrophils, smooth muscle, and Connective tissue disease
damage
cancer cells;
Cardiovascular disease
Systemic inflammation
Malignancy
Freely filtered in glomeruli and Thyroid disorders
13kDa cysteine protease inhibitor
completely absorbed and Glucocorticoid disorder
produced by all nucleated human
catabolized by proximal tubular
cells and released into the plasma Cigarette smoking
cells; no tubular resorption or
at a constant rate Hyperbilirubinaemia
secretion
Hypertriglyceridaemia
HIV disease
 Glutathione S-transferase (
GST)
Glutathione S-transferase (
GST)
Hepatocyte growth factor (HGF)
Hepcidin
Insulin-like growth factor binding
protein-7 (IGFBP-7), tissue
metalloproteinase-2 (TIMP-2)
Interleukin-18 (IL-18)
Kidney Injury Molecule-1 (KIM-1)
Liver-type fatty acid-binding
protein (L-FABP)
1Microglobulin
4751kDa cytoplasmic enzyme in Released into urine following
proximal tubule tubular injury
4751kDa cytoplasmic enzyme in Released into urine following
distal tubules tubular injury
Antifibrotic cytokine produced by Advanced heart failure
Released into urine following
mesenchymal cells and involved in Hypertension
tubular injury
tubular cell regeneration after AKI Bowel inflammation
2.78kDa peptide hormone Systemic inflammation
predominantly produced in
Freely filtered followed by tubular
hepatocytes but also in kidney,
uptake and catabolism Iron overload
brain, and heart; regulator of iron
metabolism
Metalloproteinases involved in cell Released into urine after tubular
cycle arrest cell stress
Released into urine by proximal Inflammation
18kDa pro-inflammatory cytokine tubular cells following tubular Sepsis
injury Heart failure
Transmembrane glycoprotein Renal cell carcinoma
Released into urine following Chronic proteinuria
produced by proximal tubular cells
ischaemic or nephrotoxic tubular
after ischaemic or nephrotoxic CKD
damage
injury Sickle cell nephropathy
Freely filtered in glomeruli and CKD
14kDa intracellular lipid Polycystic kidney disease
reabsorbed in proximal tubular
chaperone produced in proximal
cells; increased urinary excretion Liver disease
tubular cells and hepatocytes
after tubular cell damage Sepsis
Freely filtered by glomeruli;
Low molecular weight protein reabsorbed and catabolised by
Sepsis
produced in liver proximal tubular cells; urinary
excretion after tubular dysfunction
 12kDa light chain of major
histocompatibility class I expressed reabsorbed and catabolised by
2Microglobulin
on cell surface of every nucleated proximal tubular cells; urinary
cell
Endogenous single-stranded
MicroRNA molecules of non-coding
nucleotides
Monocyte chemoattractant Peptide expressed in renal
peptide-1 (MCP-1) mesangial cells and podocytes
>130kDa lysosomal enzyme;
N-acetyl--D-glucosaminidase
produced in proximal and distal
(NAG)
tubular cells and non-renal cells
At least three different types:
Monomeric 25kDa glycoprotein
produced by neutrophils and
Neutrophil gelatinase-associated epithelial tissues, including renal
lipocalin (NGAL) tubular cells
Homodimeric 45kDa protein
produced by neutrophils
Heterodimeric 135kDa protein
produced by renal tubular cells
5075kDa laminin-related
molecule, minimally expressed in
Netrin-1
proximal tubular epithelial cells of
normal kidneys
Endogenous polypeptide hormone
in adrenal medulla, nervous
Proenkephalin Cleared by glomerular filtration
system, immune system and renal
tissue
21kDa single-chain glycoprotein;
Retinol binding protein (RBP)
synthesized by liver
Freely filtered by glomeruli;
excretion after tubular dysfunction
Upregulated following tubular
injury and detectable in plasma Sepsis
and urine
Released into urine Variety of primary renal diseases
Too large to undergo glomerular
filtration; released into urine after Diabetic nephropathy
tubular damage
25kDa and 45kDa NGAL undergo Sepsis
glomerular filtration and Malignancy
reabsorption in healthy tubular
cells CKD
Urinary tract infection
Pancreatitis
25kDa and 135kDa NGAL are
COPD
released into urine following
tubular damage
Endometrial hyperplasia
Highly expressed in injured
proximal tubules and released into
urine
Systemic inflammation
Pain
Totally filtered by the glomeruli and Diabetes
reabsorbed but not secreted by Obesity
proximal tubules; released into
Acute critical illness
Novos biomarcadores
[Cistatina C] srica

Vantagens

Filtrada livremente no glomrulo.

Completamente absorvida a nvel tubular e
inactivada.
No secretada ou reabsorvida.
Menos dependente da idade, gnero, massa
muscular e funo heptica.
Novos biomarcadores
[Cistatina C] srica

Vantagens Desvantagens
Sofre alteraes com:
Cancro
Filtrada livremente no glomrulo.
Disfuno tireoideia
Completamente absorvida a nvel tubular e
inactivada. Terapia corticoesteride
No secretada ou reabsorvida. Fumadores
Menos dependente da idade, gnero, massa Hiperbilirrubinemia
muscular e funo heptica.
Hipertrigliceridemia
HIV
Novos biomarcadores
Neutrophil gelatinase-associated lipocalin
(NGAL)
Capaz de detectar LRA em doentes submetidos a cirurgia de bypass
cardiopulmonar.
O doseamento do Peptdeo Natriurtico do tipo B (BNP) e do NGAL so
fortes preditores de LRA em doentes com infeco do tracto
respiratrio inferior.
BNP > 267 pg/mL
NGAL > 231 ng/mL
O doseamento de NGAL talvez permita a distino entre Necrose
Tubular Aguda e LRA pr-renal.
DIAGNSTICO DE
DRA
Doena Renal Aguda
 LRA DRC
7 dias > 90 dias

DRC Doena Renal Crnica

 Doena Renal Aguda

LRA DRC
7 dias DRA > 90 dias

DRC Doena Renal Crnica

Doena Renal Aguda
Critrios de Diagnstico sob reviso
Leso Renal Aguda
TFG <60ml/min/1.73m2durante <3meses
Diminuio da TFG em 35% durante <3meses
Aumento da creatinina srica em >50% durante <3
meses
Evidncia de dano renal estrutural por <3 meses
 ESTRATGIA
DIAGNSTICA
Estratgia diagnstica
Identificar os doentes com risco acrescido de LRA:
Doena renal crnica
Diabetes
Insuficincia cardaca
Spsis
Hipovolmia
Idade 65 anos
Uso de frmacos com potencial nefrotxico (AINE, iECA)
Uso de contrastes iodados nos ltimos 7 dias
Oligria
Doena heptica
Acesso limitado a fludos
Sintomas ou histria de obstruo urolgica
Estratgia diagnstica
Estratgia diagnstica
Estratgia diagnstica
Estratgia diagnstica
Estratgia diagnstica

LRA
LRA
Funcional por dano
renal
 Estratgia diagnstica

In Murray PT, Mehta RL, Shaw A, et al. Current use of biomarkers in acute kidney injury: report and summary of
recommendations from the 10th Acute Dialysis Quality Initiative consensus conference. Kidney Int. 2014;85:51321
Estratgia diagnstica

Abordagem mnima:
Hemograma com contagem diferencial
Anlise de urina
Sedimento urinrio
Estudo ecogrfico
Clcio srico
Opcional:
Electrlitos urinrios
Ureia
cido rico
Osmolaridade
PERSPECTIVAS
FUTURAS
Perspectivas Futuras

Integrao dos biomarcadores nos novos critrios de diagnstico?

Novas tcnicas de imagem (microscopia de fluorescncia por
excitao de dois fotes)?
Avaliao de risco de LRA padronizada para triagem?
Visitas enfermaria de equipa da farmcia hospitalar para adequao
da prescrio para os doentes com LRA?
Referncias

Mehta RL, Cerda J, Burdmann EA, et al. International Society of Nephrologys 0by25 initiative for acute kidney injury
(zero preventable deaths by 2025): a human rights case for nephrology. Lancet. 2015;385:261643
Fliser D, Laville M, Covic A, et al. A European Renal Best Practice (ERBP) position statement on the Kidney Disease
Improving Global Outcomes (KDIGO) clinical practice guidelines on acute kidney injury: part 1: definitions, conservative
management and contrast-induced nephropathy. Nephrol Dial Transplant. 2012;27(12):426372
Ostermann M, Joannidis M. Acute kidney injury 2016: diagnosis and diagnosic workup. Critical Care. 2016;20:299
Acute kidney injury: prevention, detection and management Clinical guideline Published: 28 August 2013
nice.org.uk/guidance/cg169
Tuladhar SM, Pntmann VO, Soni M, Punjabi PP, Bogle RG. Rapid detection of acute kidney injury by plasma and urinary
neutrophil gelatinase-associated lipocalin after cardiopulmonary bypass. J Cardiovasc Pharmacol. 2009 Mar. 53(3):261-6
Breidthardt T, Christ-Crain M, Stolz D, et al. A combined cardiorenal assessment for the prediction of acute kidney injury
in lower respiratory tract infections. Am J Med. 2012 Feb. 125(2):168-75
Medscape: Novel Biomarkers of Renal Function. In http://emedicine.medscape.com/article/1925619-overview?
pa=SUAOTDNBU0vJTkD8MnnENAWQqGlOj97pHK63RlTgmXkj8YtJ9hCSQ3d7kmjz2ok4fYg00PkZWPhgqYzk2RwlQbOwhd8
Mdk7tVO%2FdkscsGC4%3D#showall
 LESO RENAL
AGUDA
Investigao Diagnstica:
Reviso e Perspectivas Futuras

Jos Lus Quesado