NEFRITISINTERSTICIALAGUDA(NIA)

JavierReque SantivañezHo s p i t a l G e n e r a l U n i v e r s i t a r io d e C a s t e l l ó n

FRACASORENAL AGUDO

Prerenal Parenquimatoso Postrenal

Necrosistubularaguda Intersticial Glomerulonefritis aguda

85% 5 %10%

NEngl JMed1996;334:1448-1460

REGISTROESPAÑOLDEBIOPSIASSEN-MADRID2018

Biopsiasporfracasorenalagudo

18a45años

45a65años >65años

Haas M,SpargoBH,Wit EJ,MeehanSM:Etiologies andoutcome ofacute renalinsufficiency inolder adults:Arenal biopsy study of259cases.AmJKidney Dis 35:433–447,2000

ETIOLOGÍA

Fármacos E.Autoinmune

E.Sistémicas Infecciones SíndromeTINU

E.Autoinmune

E.Sistémicas

• Lupuseritematososistémico

• Sarcoidosis

• SíndromeSjögren

• EnfermedadIgG4(2003)• NTIHipocomplementémica(2001)

• Enfermedadporanticuerposantimembrana basaltubular

• Biopsy-proven acute interstitial nephritis,1993-2011:a case series.Muriithi AK,Leung N,Valeri AM,Cornell LD,Sethi S,FidlerME,Nasr SH AmJKidney Dis.2014;64(4):558.• Acute renalfailure ina64-year-oldwhiteman.Paueksakon P,ReveloM,LeeSM,Horn RG,FogoAB AmJKidney Dis.2000;36(3):669.

Infecciones

A S OC I A DA S C ON N I A

Legionella Poliomavirus

Leptospira Enterococus

Citomegalovirus (CMV) Escherichia coli

Streptococus Adenovirus

Micobacterium tuberculosis Espiroquetas (treponema)

Corinebacterium Diphteriae Hongos (histoplasmosis, coccidiodomicosis)

VirusdeEpstein Barr (EBV) Parásitos(Leishmania,Toxoplasma)

Yersinia

ETIOLOGÍA

Fármacos E.Autoinmune

E.Sistémicas Infecciones SíndromeTINU

70– 75% 10– 20% 4– 10% 5 – 7%

Fármacos

ASOC I ADOS C ON N I A

Antiinflamatoriosnoesteroideos(incluidosCOX-2)PenicilinasycefalosporinasRifampicinaSulfonamidasCiprofloxacinoDiuréticos(deasaytiazidas)CimetidinaAlopurinolInhibidoresdebomba deprotonesIndinavir5-aminosalicilatos (Ej.Mesalasina)Inmunomoduladores (iplimumab,nivolumab,pembrolizumab,atezolizumab)

• Drug-Induced Acute Interstitial Nephritis.Moledina DG, Perazella MA. Clin JAmSoc Nephrol. 2017Dec7;12(12):2046-2049• Managing toxicities associatedwithimmune checkpoint inhibitors:consensus recommendations fromtheSociety forImmunotherapy ofCancer (SITC)Toxicity ManagementWorking

Group.JImmunother Cancer. 2017Nov21;5(1):95

Nat Rev Nephrol. 2018Sep;14(9):571-588.Sury K, Perazella MA, Shirali AC.Cardiorenal complications of immune checkpoint inhibitors.

Patient Antibiotics PPIs NSAIDs Corticosteroids OtherMedications1 pantoprazole aspirin prednisone albuterol,fluticasone,oxycodone2 hydrocortisone levothyroxine,escitalopram,finesteride,

clonazepam3 linezolid metoprolol,zolpidem,docusate45 trimethoprim/sulfamethox

azolepantoprazole prednisone levothyroxine,enoxaparin

6 omeprazole hydrocortisone levothyroxine,pregabalin,sodiumbicarbonate,fexofenadine,oxycontin,androgel

7 pantoprazole levothyroxine,enoxaparin,maalox,ranitidine8 ibuprofen910 ursodiol,oxycodone, lorazepam,ondansetron1112 ciprofloxacin omeprazole phenazopyridine,quinapril,tramadol,

glucosamine chondroitin

13 omeprazole

Patogenia

Manifestacionesclínicas

Manifestacionesclínicas

• Renalfailure andinterstitial nephritis due topenicillin andmethicillin.BaldwinDS,Levine BB,McCluskey RT,GalloGR.NEngl JMed.1968Dec;279(23):1245-52.

Manifestacionesclínicas

• Fiebre,rash yeosinofilia.

• Acute interstitial nephritis.AUPragaM,GonzálezE Kidney Int.2010;77(11):956• Duration ofTreatmentwith Corticosteroids andRecovery ofKidney Function inAcute Interstitial Nephritis.Fernandez-Juarez G,Perez JV,SpanishGroup for the Study ofGlomerularDiseases

(GLOSEN).Clin JAmSoc Nephrol.2018Dec 7;13(12):1851-1858.

Manifestación Praga KI20101 Fernandez-JuarezCJASN20182

Fiebre 36% 18%

Rash Cutáneo 22% 8%

Eosinofilia (> 500/mm3) 35% 25%

Fiebre +Rash +Eosinofilia 10% 3%

Duration ofTreatmentwith Corticosteroids andRecovery ofKidney Function inAcute Interstitial Nephritis.Fernandez-Juarez G,Perez JV,Caravaca-Fontán F,QuintanaL,Shabaka A,RodriguezE,Gadola L,deLorenzoA,CoboMA,Oliet A,SierraM,Cobelo C,IglesiasE,BlascoM,GaleanoC,Cordon A,OlivaJ,PragaM;SpanishGroup for the Study ofGlomerularDiseases (GLOSEN).Clin JAmSoc Nephrol.2018Dec 7;13(12):1851-1858.

Nat Rev Nephrol. 2010Aug;6(8):461-70.Perazella MA1,Markowitz GS.Drug-induced acute interstitial nephritis.

(A) Nefritis intersticial inducida por Meticilina(B) Nefritis intersticial por otras drogas(C) Nefritis intersticial por AINEs

• Acute interstitial nephritis.AUPragaM,GonzálezE Kidney Int.2010;77(11):956.

ManifestacionesFracasorenalagudo 100%

Fracasorenalagudo (diálisis) 40 %

Artralgias 45%

Fiebre 36%

Rash cutáneo 22%

Eosinofilia 35%

Microhematuria 67%

Macrohematuria 5%

Leucocituria 82 %

Proteinurianonefrótica 93 %

Proteinurianefrótica 2,5%

Síndrome nefrótico 0,8%

¿Eosinofiluria?

Clin J Am Soc Nephrol 8: 1857–1862, 2013

Tiempodeinicio:

• 3a5días– Segundaexposiciónalfármaco

• Semanasameses- Primeraexposiciónalfármaco

BrJClinPharmacol.2007Dec;64(6):819–823.

Patología

Granuloma

Tratamiento

Tratamiento

•Discontinuacióndelfármaco

•Corticoides

•Otros

Tratamiento

Duration ofTreatmentwith Corticosteroids andRecovery ofKidney Function inAcute Interstitial Nephritis.Fernandez-Juarez G,Perez JV,SpanishGroup for the Study ofGlomerularDiseases(GLOSEN).Clin JAmSoc Nephrol.2018Dec 7;13(12):1851-1858.

• Lamayoríadeloscasosdenefritisintersticialsonreaccionesalérgicas:• Soninducidasporfármacos• No esfenómenodosisdependiente• Sólounpequeñoporcentajedelospacientesdesarrollalaenfermedad• Remisióntrasdiscontinuacióndelfármaco• Remiteconlareutilizacióndelmismofármacoyunosimilar

• LoslinfocitosTjueganunpapelfundamentalenlaetiopatogenia:• Tiempode10a14días(síndromesmediadosporcélulasT)• ElinfiltradointersticialestácompuestoporlinfocitosT• EltestdeestimulacióndelinfocitosTespositivoenlamayoríadelospacientes.

Drug-specificproliferationofpatientsPBMC

Pt 1.

Positive proliferative response of PBMC to flucloxacillin

Pt 2

PBMC proliferative response to penicillin G

Pt 3

PBMC proliferative response to disulfiram

Involvement of Drug-Specific T cells in Acute Drug-Induced Interstitial Nephritis Spanou et al, JASN, 17: 2919, 2006

#Even though there were multi drug exposure, each patient elicited proliferative response to only one drug

Duration ofTreatmentwith Corticosteroids andRecovery ofKidney Function inAcute Interstitial Nephritis.Fernandez-Juarez G,Perez JV,SpanishGroup for the Study ofGlomerularDiseases (GLOSEN).Clin JAmSoc Nephrol.2018Dec 7;13(12):1851-1858.

Parallevaracasa:• La N IA d eb e fo rma r p a r t e d e l d i a gn ó s t i co d i f e r en c i a l d e t od o pa c i e n t e con

f r a ca s o r en a l a gu d o .

• C u a l q u i e r f á rma co p u ed e ca u s a r N IA , d eb e p r e s t a r s e e s p e c i a l a t e n c i ó n a

a n t i b i ó t i co s , a n t i n f l ama t o r i o s n o e s t e r o i d eo s e i n h i b i d o r e s d e b omba d e

p r o t o n e s .

• La t r i a d a c l á s i c a ( f i e b r e , r a s h y e o s i n o f i l i a ) e s mu y i n f r e cu en t e

• E l t i empo d e s d e e l i n i c i o d e l f á rma co h a s t a e l i n i c i o d e l cu a d ro e s mu y va r i a b l e

• E l u s o d e co r t i co i d e s ( p r e co z ) s e a s o c i a a me j o r p r o n ó s t i co

• C o n l a e v i d en c i a q u e d i s p o n emo s a c t u a lmen t e :

• Lo s b o l o s p o d r í a n NO s e r n e ce s a r i o s

• E l t r a t am i en t o e s t e r o i d eo n o d eb e r í a d u r a r ma s d e 1 2 s eman a s .

Muchasgracias…

• PragaM,GonzálezE.Acuteinterstitialnephritis.Kidney Int2010;77:956.• MuriithiAK, LeungN,ValeriAM,etal.Biopsy-provenacuteinterstitialnephritis, 1993-2011:a case series.AmJKidney

Dis2014;64:558.• TorpeyN,BarkerT,RossC.Drug-induced tubulo-interstitialnephritis secondarytoprotonpump inhibitors: experience

fromasingleUKrenalunit.NephrolDialTransplant2004;19:1441.• PragaM,SevillanoA,Auñón P,GonzálezE.Changesintheaetiology, clinicalpresentationandmanagementofacute

interstitialnephritis, anincreasinglycommoncauseofacutekidneyinjury.NephrolDialTransplant2015;30:1472.• CortazarFB,MarroneKA,TroxellML,etal.Clinicopathological featuresofacutekidney injuryassociatedwithimmune

checkpointinhibitors.Kidney Int2016;90:638.• StoneJH,ZenY,DeshpandeV.IgG4-relateddisease.NEnglJMed2012;366:539.• Gupta A,JothyS,SomervilleP,ZaltzmanJS.Hypocomplementaemic immunecomplextubulointerstitialnephritis.NDT

Plus2010;3:78.• MuriithiAK, LeungN,ValeriAM,etal.Clinicalcharacteristics,causesandoutcomesofacuteinterstitialnephritis inthe

elderly.KidneyInt2015;87:458.• ClarksonMR,GiblinL,O'ConnellFP,etal.Acuteinterstitialnephritis: clinicalfeaturesandresponsetocorticosteroid

therapy.NephrolDialTransplant2004;19:2778.• GonzálezE,GutiérrezE,GaleanoC,etal.Earlysteroidtreatmentimproves therecoveryofrenalfunction inpatients

withdrug-induced acuteinterstitialnephritis.Kidney Int2008;73:940.• Duration ofTreatment with Corticosteroids andRecovery ofKidney Function inAcute Interstitial Nephritis.Fernandez-

Juarez G,Perez JV,Spanish Group for the Study ofGlomerularDiseases (GLOSEN).Clin JAmSoc Nephrol.2018Dec7;13(12):1851-1858.