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REVISTA ROMN DE PEDIATRIE VOLUMUL LXI, NR. 4, AN 2012 349

Adresa de coresponden:Asist. Univ. Dr. Alexandru-Ioan Ulmeanu, Spitalul Clinic de Urgen pentru Copii Grigore Alexandrescu, Bd. Iancu de Hunedoara nr. 30-32, sector 1, Bucuretie-mail: [email protected]

NEFROPATIILE TOXICE LA COPILAsist. Univ. Dr. Alexandru-Ioan Ulmeanu, Prof. Dr. Coriolan Emil Ulmeanu

Spitalul Clinic de Urgen pentru Copii Grigore Alexandrescu, BucuretiCatedra Pediatrie, UMF Carol Davila, Bucureti

REZUMAT Nefropatiile toxice ale copilului reprezint entiti rare, dar important de recunoscut precoce datorit evoluiei severe i necesitii instituirii rapide a tratamentului. n faa unei insufi ciene renale acute toxice, obiectivul principal iniial este de a recunoate n primul rnd caracterul organic sau funcional al acesteia. Dei creatinina seric rmne principalul test de laborator pentru diagnosticul i urmrirea insufi cienei renale acute toxice, noi markeri poti fi utilizai pentru detecia rapid i precoce a injuriei renale. Autorii prezint implicarea renal n intoxicaiile acute ale copilului, clasifi carea i etiopatogenia nefropatiilor toxice, evaluarea nefrotoxicitii i principii de abordare practic ale acestora.

Cuvinte cheie: nefropatie toxic, insufi cien renal acut, nefrotoxicitate

REFERATE GENERALE 3

Nefropatiile acute toxice ale copilului sunt en-titi clinice difi cil de delimitat n cadrul afec trilor renale, cu evoluie acut sau mai ales supraacut. Numeroase substane toxice pot s determine o alterare major a funcionalitii glomerulare i/sau tubulare renale, inducnd o insufi cien renal acut (IRA), avnd caracter funcional sau organic. Efec-tele toxice instalate rapid pot determina o evoluie grav a intoxicaiei, care s necesite inclusiv folo-sirea mij loacelor de epurare extrarenal pentru a putea trata insufi ciena renal acut toxic.

n faa unei insufi ciene renale acute cu etiologie toxic, obiectivul principal iniial este de a preciza caracterul organic sau funcional, pentru care exa-menul de urin este determinant. Afectarea renal din intoxicaiile acute cuprinde (1):

1. Disfuncii renale toxice funcionale:acidoz tubular; sindrom de secreie inadecvat de hormon antidiuretic;diabetul insipid nefrogen.

Se va produce o insufi cien renal funcional nsoit de:

scderea debitului urinar; cresterea marcat a osmolaritii urinare peste 1.200 mOsm;creterea ureei sanguine; natriureza crescut.

2. Insufi ciena renal acut toxic poate realiza toate cele 3 forme, dar i combinaii diverse ale me-canismelor. Astfel, putem ntlni:

Insufi cien renal acut toxic:Prerenala. Postrenal prin: b. cristalurii toxice; retenie acut de urin prin disfuncie a vezicii urinare.Renal intrinsec prin:c. necroz tubular acut; nefrit interstiial acut; vasculit acut.

n insufi ciena renal organic de cauz toxic examenul de urin, esenial pentru diagnostic, ne va arta (2):

debit urinar variabil de la oligurie la anurie; osmolaritate urinar mic 300 mOsm; uree sanguin mare de peste 10 ori normalul

Disfunciile renale toxice funcionale din cla-sifi carea Goldfranks 2006 sunt caracterizate prin alterarea funciei renale, cu meninerea unei rate normale a ultrafi ltratului glomerular. Aceste tipuri de disfuncii renale funcionale sunt greu de diag-nosticat clinic, mai ales n pediatrie, ele necesitnd probe paraclinice multe i complexe pentru a de-monstra prezena izolat n context toxic a:

REVISTA ROMN DE PEDIATRIE VOLUMUL LXI, NR. 4, AN 2012350

acidozelor tubulare; sindromului de secreie inadecvat de ADH; diabetului insipid nefrogen.

Disfunciile renale toxice propriu-zise reprezint adevrata IRA toxic, caracterizat prin reducerea ratei fi ltratului glomerular i alterarea funcionalit-ii tubilor renali.

Nefropatiile toxice pot fi realizate prin ase ti-puri de mecanisme patogenice (1-3):

Toxicitate direct1. Toxicitate prin hemoliz2. Toxicitate prin rabdomioliz3. Toxicitate prin alterarea excreiei renale4. Toxicitate prin reacii imunologice5. Toxicitate prin insufi cien circulatorie acut 6. tip insufi cien renal prerenal

1. Toxicitatea direct la nivel renal realizeaz foarte multe toxice implicate n etiologia into xi-caiilor acute la copil, acestea putnd fi sintetizate ast fel:

metale: arsenic, bariu, bor, cadmiu, mercur, plumb, aurAINS: salicilai, ibuprofen, acetaminofen, gla feninantibiotice: cefalosporine, gentamicin, co- lis tin, neomicin, streptomicin, tetracicilinanestezice: metoxifl urani induc oxaloz etilenglicol: induce oxaloz tetraclorura de carbon: oxaloz i citoliz he- paticparacetamol: nefrit toxic asociat cu necroz hepaticprodui de contrast iodai: nefropatie grav prin toxicitate direct

2. Toxicitatea renal prin hemoliz se realizeaz prin precipitarea unei cantiti mici de hemoglobin la nivelul tubilor renali, unde se va produce cel mai frecvent necroza tubular acut. Exist 2 grupe de toxice ce pot produce hemolize masive:

Ageni methemoglobinizani: nitrii, nitrai, a. fenoli, anilin, toluen, benzaldehid, eti len-glicolHemolize alergice prin autoanticorpi: isonia-b. zid, clorpromazin, chinidin, penicilin

3. Toxicitatea renal prin rabdomioliz este frecvent diagnosticat n intoxicaiile severe la copil i apare din cauza cantitii mari de mioglo bin, pro-dus cu toxicitate renal remarcabil. Rabdo mioliza apare n urmtoarele tipuri de intoxicaii:

Opiacee, barbiturice, benzodiazepine induc come prelungite cu mioliz de compresieAntidepresive triciclice, carbamazepin, fenoli, raticide induc convulsii severe sub-intrante, prelungite

Neuroleptice majore induc hipertermie ma- lig nHeroin, cocain, ecstasy, fenotiazine to xi- citate muscular direct

4. Toxicitatea prin alterarea excreiei renale este prezent mai ales n intoxicaiile care altereaz funcionalitatea vezicii urinare, realiznd o insu-fi cien renal acut postrenal. Intoxicaiile cele mai frecvente, asociate cu acest tip de insufi cien renal sunt:

intoxicaia acut cu etilenglicol prin cristalu- ria cu acid oxalic;intoxicaiile acute cu antimitotice prin pre- cipitare de acid uric;intoxicaiile acute cu litiu i bismut; intoxicaiile acute cu diuretice osmotice; intoxicaiile acute cu clozapin n care apare diabet insipid nefrogen prin incapacitatea rinichiului de a rspunde la ADH;reteniile acute de urin pot s realizeze un tablou de anurie n cadrul intoxicaiilor acute cu anticolinergice, antihistaminice, an-ti depresoare triciclice, atropin i scopola-min.

5. Toxicitatea prin reacii imunologice se poate realiza n intoxicaiile cu phenindion i meticilin.

6. Toxicitatea ce induce IRA de tip prerenal: are ca prototip aciunea medicamentelor cu impact asu-pra vasomotricitii. Alterarea funciei renale are loc prin vasodilataia sistemic ce induce va sople-gie i sindromul de deshidratare acut, ce va scdea foarte rapid fl uxul sanguin renal. Produsele ce pot induce o astfel de toxicitate sunt reprezentate de: antidepresive triciclice, digitalice, colchicin, beta-blocante, barbiturice, carbamati, amanita pha llo-ides.

EVALUAREA NEFROTOXICITIIDiagnosticul nefrotoxicitii se bazeaz pe dou

elemente fundamentale: A. examenul clinic al pacientului; B. investigaiile paraclinice.

A. Examenul clinic presupune o anamnez ex-trem de minuioas care s evidenieze mai multe aspecte:

vrsta, greutatea obiceiurile alimentare i natura alimentelor consumate; antecedentele personale patologice; tratamentele efectuate, denumirea medicamentelor, posologia lor, durata i calea de administrare, asocierile medicamentoase;


dac a fost expus sau a venit n contact cu substane toxice; investigaiile radio-biologice efectuate i tolerana lor; dac a prezentat fenomene alergice sau dac a fcut vaccinri recente; dac este consumator de droguri i dac fo- losete substane de abuz; care sunt manifestrile clinice i modul lor de debut; dac a prezentat edeme sau hipotensiune arte- rial n perioada precedent.

Examenul fi zic al pacientului trebuie fcut sis-tematic, cu adresa special pentru aparatul reno-urinar.

B. Examene paraclinice Examenul de urin repetat n mod sistematic,

sumar i urin pe 24 de ore, este cel mai simplu de efectuat i ne poate evidenia primele semne de ne-frotoxicitate. Prezena unei proteinurii semni fi ca-tive este un marker important al nefrotoxicitii n evoluie, mai ales dac se cunoate c toxicul incri-minat are tropism renal.

Insufi ciena renal acut poate fi defi nit ca o de gradare rapid a funciei renale, cu sau/fr oli-gurie (mai puin 1 ml/kg/h). Criteriul paraclinic pen tru monitorizarea IRA este cel al creatininei serice; conform criteriilor RIFLE, o dublare a aces-teia semnaleaz injuria renal, iar triplarea acesteia faza de insufi cien renal. (4) Estimarea ratei fi l-trrii glomerulare (RFG) dup nivelul seric al crea-tininei nu este foarte util, deoarece n cadrul insufi -cienei renale acute, dei RFG este mult sczut, creatinina nu a avut destul timp s se acu muleze pentru a putea refl ecta cu adevrat funcia renal; creatinina seric ns, poate fi folosit pentru ur-mrirea evoluiei IRA. (6).

n cadrul examenului de urin trebuie evaluate: densitatea, Na urinar, osmolaritatea, creatinina uri-nar, proteinuria, hematuria, prezena cilindrilor granuloi i epiteliali i urocultura.

Alturi de acestea se recomand monitorizarea sistematic a ionogramei, n special nivelul pota-siului seric, a echilibrului acido-bazic, nivelul fos-fatemiei i al calcemiei.

Explorrile imagistice utile sunt:Ecografi e renal: dimensiuni, structur, sem-a. ne de obstrucie, evaluare fl ux sanguin renalRadiografi e toracic: semne de cardiomega-b. lie, edem pulmonarEKG:c. semne de hipertrofi e ventricular stng

semne de hiperkaliemie semne de hipocalcemie Ecocardiografi ed.

MARKERI BIOLOGICI NOI

S-a constatat ns c injuria toxic renal nu poate fi nici prevzut i nici cuantifi cat cores-punztor prin nivelul seric al creatininei. (5)

n diverse studii, cei mai promitori markeri pentru detecia precoce a injuriei renale, cuantifi ca-rea severitii afectrii renale, precum i pentru mo-ni torizarea rspunsului la terapie s-au dovedit a fi :

Cistatina C Lipocalina (pNGAL) KIM1 (kidney injury molecule 1) Interleukina 18 urinar

Cistatina CEste produs relativ constant n toate celulele

nucleate, puin infl uenat de modifi cri ale dietei i de masa muscular, este fi ltrat fr reabsorbie la nivel renal, ns metabolizat tubular.

Nivelurile cistatinei C se coreleaz mult mai fi -del cu rata fi ltrrii glomerulare fa de creatinin. Nivelurile cistatinei ncep s creasc la RFG = 90 ml /min, fa de RFG = 70 ml/min pentru creati nin.

Exist date ce sugereaz c evaluarea cistatinei ar prezenta multiple avantaje, mai ales la populaiile cu producie sczut de creatinin (copii, vrstnici, bolnavi cu ciroz hepatic). (7-9)

Lipocalina (pNGAL)Protein produs la nivel renal, cu rol n inhibiia

apoptozei locale i stimularea proliferrii celulelor tubulare. Crete semnifi cativ i precoce la pacienii cu insufi cien renal prin necroz tubular acut. (10,11,14)

KIM1 (kidney injury molecule 1)Este o glicoprotein transmembranar produs

la nivelul tubului contort proximal. Crete rapid i la niveluri mari la pacienii cu insufi cien renal prin necroz tubular acut, specifi citate i sensibi-litate foarte bun. Poate fi detectat n urin prin teste imunoenzimatice. (12)

Interleukina 18 urinarEste detectat precoce la pacienii cu necroz tu-

bular acut. (13)

Creatinina seric rmne testul de baz pentru diagnosticul insufi cienei renale acute, n practic


determinarea biomarkerilor este limitat n special de costul ridicat al reactivilor. Este nevoie de studii prospective importante pentru a determina cu pre-cizie momentul optim pentru dozarea acestor mar-keri, precum i pentru a demonstra dac detectarea precoce a acestora mbuntete prognosticul pa-cientului. (5)

Abordarea practic a IRA acute toxice are ca

obiective:Precizarea rapid a caracterului organic sau 1. funcional al IRA. Pentru orientare rapid, cel mai important este examenul de urin.Tratamentul de urgen al insufi cienei circu-2. latorii acute prin umplere vascular efi cient i substane vasoactive. Tratamentul hiperkaliemiei dac aceasta este 3. prezent.

Decizia rapid, dac IRA este instalat, dac 4. pacientul benefi ciaz de o terapie de epurare extrarenal i care este cea mai efi cient me-tod de substituie.

CONCLUZII

Insufi ciena renal toxic reprezint 15% din to-talul insufi cienelor renale ale copilului, iar din to-talul intoxicaiilor, nefropatiile toxice apar n mai puin de 1% din cazuri. Dei este o entitate rar ntlnit n cadrul intoxicaiilor acute la copil, po-tenialul evolutiv este sever, necesitnd tratament precoce mai ales prin tehnici de epurare extra-renal.

Toxic nephropathies in children

Alexandru-Ioan Ulmeanu, Coriolan Emil UlmeanuGrigore Alexandrescu Emergency Childrens Hospital, Bucharest

Pediatrics Department, Carol Davila University of Medicine and Pharmacy, Bucharest

ABSTRACT Toxic nephropathies in children are rare entities but important to diagnoze early due to severe evolution and the need for rapid treatment. In the face of toxic acute renal failure the primary objective is to specify whether the ARF is organic or functional. Although serum creatinine remains the main laboratory test for diagnosis and monitoring toxic acute renal failure, new markers can be used for rapid and early detection of renal injury. In this paper the authors present the renal involvement in acute poisoning in children, classifi cation and etiopathogenesis of toxic nephropathies, and practical approach in assessing nephrotoxicity.

Key words: toxic nephropathy, acute renal failure, nephrotoxicity

Acute toxic nephropathies are clinical entities that are hard to defi ne in the evolution of acute and rapidly progressive kidney injury. Many substances can cause a major alteration of glomerular and tu-bular function inducing organic or functional acute renal failure (ARF). Rapidly installed toxicity may cause severe evolution of the poisoining, requiring the use of extrarenal epuration methods for the treatment of acute renal failure.

In the face of toxic acute renal failure the prima-ry objective is to specify whether the ARF is orga-nic or functional, the examination of urine is deci-sive. Renal impairment in acute poisoning includes (1)

1. Toxic functional renal impairmenttubular acidosissyndrome of inappropriate antidiuretic hor-mone secretionnephrogenic diabetes insipidus

It will produce a functional renal insuffi ciency with:

Decreased urine outputUrinary osmolality increased markedly over 1,200m OsmIncreased BUNIncreased natriuresis

2. Renal toxicity, can present the 3 classic types of acute renal failure or various combinations of mechanisms. Thus we meet toxic ARF:


A. PrerenalB. Postrenal by:

toxic crystalluria acute urinary retention with bladder dysfunction

C. Intrinsic renal injury by:acute tubular necrosis acute interstitial nephritis acute vasculitis

In those with organic renal failure the urine ex-amination is essential for diagnosis and will show (2):

Variable urine output from oliguria to anuriaLower urinary osmolality 300 mOsmBUN greater than 10 times normal

Functional toxic renal dysfunction in Goldfranks classifi cation 2006 is characterized by impaired re-nal function while maintaining a normal rate of glomerular fi ltration. This type of functional renal failure is diffi cult to diagnose clinically, particular-ly in pediatrics, it requires multiple and complex laboratory tests to demonstrate the presence of to-xic context and isolated:

Tubular acidosis Syndrome of inappropriate secretion of ADH Nephrogenic diabetes insipidus

Organic kidney injury represents the true toxic ARF, characterized by reduction in glomerular fi l-tration rate and impaired functionality of the renal tubules.

Toxic nephropathies can be achieved through six types of pathogenic mechanisms (1-3):

1. Direct toxicity2. Toxicity by hemolysis3. Toxicity by rhabdomyolysis4. Toxicity by alterations in renal excretion5. Toxicity by immunological reactions6. Toxicity by acute circulatory failure- prerenal

type renal failure

1. Many toxic substances produce direct toxici-ty to the kidney, they can be summarized as:

Metals: Arsenic, Barium, Boron, Cadmium, Mercury, Lead, GoldNSAIDs: salicylates, ibuprofen, acetamino- phen, glaphenineAntibiotics: cephalosporins, gentamicin, co- listin, neomycin, streptomycin, tetracyclineAnesthetics: methoxyfl urane-induces oxalo- sisEthylene glycol: induces oxalosis Carbon tetrachloride: induces oxalosis and hepatic cytolysis

Paracetamol: toxic nephritis associated with hepatic necrosisIodinated contrast agents: severe nephropathy through direct toxicity

2. Renal toxicity by hemolysis is achieved by precipitation of a small amount of hemoglobin in the renal tubules where it will produce most frequently acute tubular necrosis. There are 2 gro-ups of toxic substances that can produce massive hemolysis:

Agents producing methemoglobinemia: ni-a. trates, nitrites, phenols, aniline, toluene, ben-zaldehyde, ethylene glycolAllergic hemolysis by autoantibodies: isoni-b. azid, chlorpromazine, quinidine, penicillin

3. Renal toxicity is frequently diagnosed with rhabdomyolysis in severe poisonings in children, and occurs due to the large amount of myoglobin, that produces important renal toxicity. Rhabdomyo-lysis occur during poisonings with:

Opioids, barbiturates, benzodiazepine- pro- longed coma can cause compression myoly-sisTricyclic antidepressants, carbamazepine, phenols, raticides can induce severe and prolonged seizures Major neuroleptics-can induce malignant hy- perthermiaHeroin, cocaine, ecstasy, phenothiazines- can induce direct muscle toxicity

4. Toxic alteration of renal excretion is present mainly in poisonings that alter bladder function, re-sulting in a postrenal acute renal failure. Poisonings that are frequently associated with this type of kid-ney failure are:

Acute poisoning with ethylene glycol by oxalic acid crystalluriaAcute poisoning with antimitotic agents by precipitation of uric acidAcute poisoning with lithium and bismuthAcute poisoning with osmotic diureticsAcute poisoning with clozapine: induces neph-rogenic diabetes insipidus Acute retention of urine can cause anuria in acute poisoning with anticholinergics, antihis-tamines, tricyclic antidepressants, atropine and scopolamine

5. Toxicity by immunological reactions occur in phenindione and meticillin poisonings

6. Prerenal ARF can be produced especially by drugs affecting vascular resistance. Impaired renal function is induced by systemic vasodilation with vasoplegia and acute dehydration syndrome with an important decrease in renal blood fl ow. Toxins


that can induce such toxicity are: tricyclic antide-pressants, digitalis, colchicine, beta-blockers, bar-biturates, carbamates, amanita phalloides

EVALUATION OF NEPHROTOXICITY

The diagnosis of nephrotoxicity is based on two fundamental elements:

A. clinical examination of the patientB. laboratory investigations.

A. The clinical examination requires a very me-ticulous history taking, highlighting several as-pects:

Age, weight Eating habits and nature of food consumed Past medical history Treatments performed, medication name, dosage, duration and route of administration, drug combinationToxic exposure Radiological investigations performed and their tolerancePresence of allergic phenomena , and recent immunizationsUse of drugs or substances of abuse Clinical manifestations and their onset History of edema or hypotension

Physical examination of the patient should be done systematically, with special attention for the genitourinary system.

B. Laboratory tests:Systematically repeated urinalysis, spot urine

and 24-hour urine, is the easiest to perform and may reveal the fi rst signs of nephrotoxicity. The presence of signifi cant proteinuria is an important marker of developing nephrotoxicity , especially if a poisoning with a nephrotoxic agent is suspected.

Acute renal failure can be defi ned as a rapid de-terioration of renal function, with or without oligu-ria (less 1ml/kg/h). Serum creatinine remains the test of choice for ARF monitoring, according to RIFLE criteria doubling of creatinine signals kid-ney injury and three time increase o its values sig-nals the development of acute renal failure. (4)

Estimation of glomerular fi ltration rate (GFR) by serum creatinine level is not very useful because although in acute renal failure GFR is greatly re-duced creatinine did not have enough time to ac-cumulate and truly refl ect renal function, serum creatinine, however, can be used to follow the evo-lution of ARF. (6).

Urinalysis should follow: density, urinary Na, osmolality, urinary creatinine, proteinuria, hematu-ria, presence of casts, and urine culture

Besides this, systematic monitoring of electro-lytes especially serum potassium, the acid-base balance, serum calcium and phosphate levels is rec-ommended.

Useful imaging tests are:Renala. ultrasound: evaluation of size, structure, signs of obstruction, renal blood fl ow assess-mentChestb. X-ray: evaluation of cardiomegaly, pul-monary edemaECGc. :Signs of left ventricular hypertrophySigns of hyperkalemiaSigns of hypocalcemiaEchocardiographyd.

Novel biomarkersIt was found, however, that toxic renal injury

can be neither foreseen nor properly measured by serum creatinine (5)

In various studies the most promising markers for early detection of kidney injury, quantifi cation of the severity of renal impairment and monitoring the response of therapy were found to be:

Cystatin C Lipocalin (pNGAL) KIM1 (kidney injury molecule 1) Urinary Interleukin 18

Cystatin CProduced in all nucleated cells relatively con-

stant, less infl uenced by changes in diet and muscle mass. Filtered without reabsorption in the kidney but metabolised at tubular level. Cystatin C levels correlate more closely with GFR than creatinine. Cystatin levels begin to rise at GFR = 90ml/min compared with GFR = 70ml/min creatinine

There are data suggesting that cystatin evalua-tion would present many advantages especially in populations with low production of creatinine (chil-dren, elderly, patients with hepatic cirrhosis) (7,8,9)

Lipocalin (pNGAL)Protein produced by the kidneys with a role in

inhibition of local apoptosis and stimulation of tu-bular cell proliferation. Increases signifi cantly in patients with early renal failure in acute tubular ne-crosis (10, 11, 14)

KIM1 (kidney injury molecule 1)Is a transmembrane glycoprotein produced in

the proximal convoluted tubule.


Has rapid growth and is found at high levels in patients with renal failure with acute tubular necrosis, has high specifi city and high sensitivity. Can be de-tected in urine by enzyme immunoassay tests (12)

Urinary interleukin 18Is detected early in patients with acute tubular

necrosis (13)Serum creatinine remains the test of choice for

the diagnosis of acute renal failure. In practice de-termining biomarkers is limited especially by the high cost of reagents. Important prospective clini-cal trials are needed to determine the optimal mo-ment for determining these markers and to show whether early detection improves prognosis for these patients (5)

Practical approach to acute toxic ARF consists of:

Rapid and accurate differentiation of organic 1. or functional nature of the ARF. Urinalysis can offer a rapid evaluation.

Emergency treatment of acute circulatory 2. failure with effi cient vascular fi lling and va-soactive agentsTreatment of hyperkalaemia 3. If ARF is present, determination of the pa-4. tient needs for extrarenal epuration therapy and determination of the most effective meth-od for renal substitution

CONCLUSIONS

Toxic renal failure represents 15% of all cases of renal failure in children and for acute poisonings, toxic nephropathies occurr in less than 1% of the cases. Although acute renal failure is a rare entity in acute poisoning in children, the evolution can be severe and usually requires early treatment, espe-cially renal replacement therapy.

Feinfeld D., Anthony V.1. Renal principles in Goldfranks Toxicology Emergencies a 8-a ed -Mc Graw- Hill, Med Publish Div 2006; 27:427-436Bismuth C., Baud F., Conso F., Dally S., Frjaville JP.., Garnier R., 2. Jaeger A. Toxicologie Clinique (Clinical Toxicology) Paris: Flammarion Mdecine-Sciences, (2000)Tarloff J., Lash L.3. Toxicology of the Kidney 3rd edition, CRC Press 2005Bellomo R., et al 4. Acute renal failure defi nition, outcome measures, animal models, fl uid therapy and information technology needs: the Second International Consensus Conference of the Acute Dialysis Quality Initiative (ADQI) GroupCrit Care 8(4):R204-12, 2004W. Stephen Waring, Alasdair Moonie 5. Earlier recognition of nephrotoxicity using novel biomarkers of acute kidney injury, Clinical Toxicology Oct 2011, Vol. 49, No. 8, Pages 720-728)Geary & Schaefer 6. Comprehensive Pediatric Nephrology, 1st ed.2008 MosbyKnight E.L., Verhave J.C., Spiegelman D., et al.7. Factors infl uencing serum cystatin C levels other than renal function and the impact on renal function measurement. Kidney Int 2004; 65:1416.Groesbeck D., Kttgen A., Parekh R., et al. 8. Age, gender, and race effects on cystatin C levels in US adolescents. Clin J Am Soc Nephrol 2008; 3:1777

Macdonald J., Marcora S., Jibani M., et al. 9. GFR estimation using cystatin C is not independent of body composition. Am J Kidney Dis 2006; 48:712Mishra J., Dent C., Tarabishi R., et al.10. Neutrophil gelatinase-associated lipocalin (NGAL) as a biomarker for acute renal injury after cardiac surgery. Lancet 2005; 365:1231Zappitelli M., Washburn K.K., Arikan A.A., et al.11. Urine neutrophil gelatinase-associated lipocalin is an early marker of acute kidney injury in critically ill children: a prospective cohort study. Crit Care 2007; 11:R84Bonventre J.12. Kidney injury molecule1: a urinary biomarker and much more. Neph Dial Trans 2009, 24:3265-3268Zhou H., Hewitt S.M., Yuen P.S., Star RA.13. Acute Kidney Injury Biomarkers - Needs, Present Status, and Future Promise. Nephrol Self Assess Program 2006; 5:63Di Grande A., Giuffrida C., Carpinteri G., Narbone G., Pirrone G., Di 14. Mauro A., Calandra S., Noto P., Le Moli C., Alongi B., Nigro F. Neutrophil gelatinase-associated lipocalin: a novel biomarker for the early diagnosis of acute kidney injury in the emergency department. Eur Rev Med Pharmacol Sci, 2009, 13:197-200

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