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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.