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Diagnosticul si tratamentul nefropatiei lupice

Planul expunerii

• Manifestarile clinico-biologice in nefrita lupica

• Entitatile histologice in nefrita lupica

• Tratament

• Afectiune autoimuna, caracterizata printr-o varietate de anticorpi

directionati impotriva componentelor self
• Complexele Ag-Ac initiaza un raspuns inflamator “clasic”.

• Procesul inflamator afecteza diverse organe si sisteme =

Manifestarile renale in lupus

• 30-50% dintre pacientii cu LES prezinta initial sau la scurt timp dupa
diagnostic (6-36l) anomalii urinare sau o disfunctie renala
• Proportia creste in timp: >75%
• Debut tardiv (>50 ani) – prevalenta redusa
• Prevalenta reala (anomalii PBR): >90% cazuri
Manifestarile renale in lupus
• Proteinurie 100
• Proteinurie nefrotica 45-65
• Cilindri granulari 30
• Hematurie microscopica 80
• Hematurie macroscopica 1-2
• Cilindri hematici 10
• Retentie azotata 40-80
• IRA / retentie azotata progresiva 1-2 / 30
• Hipertensiune
Nefropatia lupica – criterii ACR 15-50
Proteinurie persistenta > 0,5 g/zi (+++) si/sau cilindrii celulari
• Acidoza
Raport proteinurietubulara hiperkaliemica
/ creatininurie > 0,5 si sediment urinar activ60-80
(>5 H/HPF, >5L/HPF in absenta
infectiei sau cilindri hematici, leucocitari)
PBR: CI – carcteristice NL
Manifestarile renale in lupus

Pacient cunoscut anterior cu LES Pacient admis pentru investigarea unui

sindrom glomerular
• Corelatii clinico-patologice PBR devine mandatorie
neconcludente / inselatoare

• Evolutia diferitelor forme histologice =

DIFERITA • Aceeasi entitate histologica este tratata
DIFERIT in LES fata de etiologia
• Stabileste prognosticul “idiopatic – primitiva”

• Influenteaza Tx initial
Manifestarile renale in LES

Afectarea glomerulara prin Afectarea non-glomerulara

complexe imune

• GN mezangiala
• Nefrita tubulo-interstitiala
• GN proliferativa focala (A, A/C, C)
• Vasculita
• GN proliferativa difuza (A, A/C, C)
• Microangiopatia trombotica – PTT
• GN membranoasa
• Scleroza difuza
Manifestarile renale in lupus
• Proteinurie 100
• Proteinurie nefrotica 45-65
• Cilindri granulari 30
• Hematurie microscopica 80
• Hematurie macroscopica 1-2
• Cilindri hematici 10
• Retentie azotata 40-80
• IRA / retentie azotata progresiva 1-2 / 30
• Hipertensiune
Nefropatia lupica – criterii ACR 15-50
Proteinurie persistenta > 0,5 g/zi (+++) si/sau cilindrii celulari
• Acidoza
Raport proteinurietubulara hiperkaliemica
/ creatininurie > 0,5 si sediment urinar activ60-80
(>5 H/HPF, >5L/HPF in absenta
infectiei sau cilindri hematici, leucocitari)
PBR: CI – carcteristice NL
Nefrita lupica mezangiala clasa I OMS:

MO: glomeruli optic normali

IF: depozite imune mesangiale
Nefrita lupica mezangiala
clasa II OMS

• 10-20% cazuri
• Forma cea mai precoce si benigna
• Manifestarile clinice pot fi absente
• Proteinurie modesta si/sau hematurie microscopica
• Retentia azotata este in general absenta
• Prognostic excelent in absenta transformarii
Nefrita lupica mezangiala - clasa II OMS
MO: cresterea matricei si/sau hipercelularitate mesangiala
Nefrita lupica proliferativa

Focala – clasa III Difuza – clasa IV

• 10-20% • 40-60%
• Proteinuria si hematuria prezente in • Proteinuria si hematuria prezente in
toate cazurile toate cazurile
• Sindromul nefrotic, HTA si retentia
• Sindromul nefrotic – manifestare a 1/4
azotata sunt comune si pot fi severe
cazuri • Manifestari extrarenale severe, C3,
• Insuficienta renala modesta, rara, antiADNds
caracteristica formei difuze • NETRATATA ENERGIC –
Nefrita lupica proliferativa focala – clasa III
MO: sub 50% din glomeruli, lez endo si/sau extracapilare, cu depozite imune subendoteliale
Nefrita lupica proliferativa focala – clasa III sau difuza – IV
Nefrita lupica proliferativa difuza – clasa IV
MO: peste 50% din glomeruli, proliferare endocapilara cu depozite imune subendoteliale
Nefrita lupica proliferativa difuza– clasa IV
Nefrita lupica membranoasa – clasa V OMS

• 10-20% cazuri

• Manifestarea caracteristica: sindromul nefrotic – 50% la debut,

100% in evolutie. Poate fi sever

• Hematuria microscopica si HTA relativ frecvente

• Retentia azotata de obicei absenta sau modesta

• Singura forma histologica la care manifestarile extrarenale sau

imunologice pot lipsi!!
Class V was subdivided into
• pure LMN (Va);
• LMN associated with mesangiopathy (Vb);
• LMN with signs of focal segmental glomerulonephritis (Vc)
• LMN associated with diffuse glomerulonephritis (Vd).
Nefrita lupica membranoasa – clasa V OMS
MO: proliferare mesangiala ades asociata
Nefrita lupica membranoasa – clasa V OMS
Scleroza difuza – clasa VI OMS
• Reprezinta de fapt calea comuna, finala de evolutie a leziunilor inflamatorii

• Sediment sarac

• HTA si retentie azotata severa si progresiva spre IRCT

Tratamentul nefropatiei lupice

• Obiectiv:
• Diminuarea productiei de autoAc de catre Ly B activate
• Diminuarea productiei de citokine proinflamatorii

• CORTICOIZII – Blocheaza la nivelul LyT (APC) activate de catre

autoAg, expresia genelor pentru citokinele proinflamatorii. Efect
imunosupresor non-specific de “liza” a inflamatiei – esential in Tx
formelor acute severe!

• CICLO, AZA, MMF, CB – Interfera sinteza si metabolismul ARN in

populatiile celulare cu rata de replicare maximala – LyB activate de
General measures
HCQ- Also as a general measure
Nefrita lupica mezangiala clasa II OMS

• Tratamentul patogenic = imunosupresor nu este necesar si nu previne “transformarea”

• Corticoterapia poate fi decisa de manifestarile extrarenale dar atentie la efectele


• Monitorizarea periodica este obligatorie

• Modificarea tabloului clinic in sensul aparitiei SN sau a retentiei azotate impune
Markeri histologici de activitate si de cronicitate 0-3

• Proliferarea celulara endocapilara • Scleroza glomerulara
• Proliferarea extracapilara (semilune) • Semiluni fibroase
• Trombi • Fibroza interstitiala
• Necroza fibrinoida
• Infiltrat inflamator glomerular sau

Class III&IV LN – no grading points

Decide a dose of steroids, divide it by 2
It still works!


Lower flare rate than AZA
Alternative in pregnancy
Furie R. et al, NEJM, 2020
Cost/year/patient for
Voclosporin is like the
cost of MMF/year, but
for 38 patients
Class III&IV LN: How long do we treat?
Nefrita lupica membranoasa – clasa V OMS
Nefrita lupica membranoasa – clasa VI OMS

• Nu necesita Tx patogenetic.
• Acesta poate fi indicat doar pentru manifestarile extrarenale

• Tx se suprapune cu cel al GNC – de limitare a ratei progresiei spre IRCT

Nefrita lupica si sarcina
RELAPSING LN: no new hope
SLE+ Antiphospholipid Syndrome
Nefrita lupica si IRCT
• 10-15% din cazurile de LES dezvolta IRCT
• LES = 2% populatia dialitica
• Imunosupresia poate fi oprita sau redusa – P
• Supravietuirea egala cu cea a NG primitive
• HD = DP
• Trombozele fistulei A-V mai frecvente
• Recurenta post-Tx rara
A 45-year-old female with no past history of note, was admitted to some other hospital with
generalized weakness and decreased appetite of 4 weeks.

She gave a vague history of nausea and occasional vomiting over the last 8 months.
She also - urine volume less than 250 ml/day.
In the past medical history, she had hypothyroidism and was on thyroxine replacement therapy
for the last 12 years, with recent thyroid stimulating hormone (TSH) level of 5.4 uIU/ml (Normal
range: 0.34 to 5.60 uIU/ml).

Family history was unsuggestive.

On general physical examination at arrival, she was stable vitally, with blood pressure of 120/80
mm of Hg. General and systemic examination revealed no abnormality except for 2+ oedema on
dependent parts.
• Initial laboratory results were as:
• haemoglobin, 11.5 g/dl; total leukocyte count (TLC), 9800; platelets,
• blood urea nitrogen, 187 mg/dl;
• creatinine, 14.15 mg/dl; sodium, 125 mEq/L; potassium, 4.2 mEq/l;
chloride, 86 mEq/l; bicarbonate, 17 mEq/l; calcium, 9.2 mg/dl;
phosphorus, 9.4 mg/dl; albumin, 2.4 g/dl; and alkaline phosphatase,
59 U/l.
• Urinalysis revealed: albumin, 3+; red blood cells (RBCs), numerous;
and white blood cells (WBCs), numerous.
• Chest roentgenogram was unremarkable.

• Abdominal sonography was unremarkable except for multiple, non-

obstructing gall stones. Both kidneys were of normal size.

• Renal biopsy done on the third day of admission comprised of cortex

only with up to 12 glomeruli
Rapidly progressive glomerulonephritis
• Definition:
• Clinical entity:
• A rapid loss of renal function (usually a 50 % decline in GFR)
within three months

• Pathological finding:
• Extensive crescent formation (usually involving over 50% of
the glomeruli)
• Crescents occur whenever breaks in glomerular capillaries
allow leakage of cells and plasma proteins into Bowman’s
• Infectious diseases • Drugs and toxic agents
• Poststreptococcal GN • Allopurinol
• Infectious endocarditis • D-Penicillamine
• Visceral sepsis • Hydralazine
• Hepatitis B or C infection with • Rifampicin
vasculitis and/or • Superimposed on primary glomerular
cryoimmunoglobulinemia disease
• Multisystemi diseases • Membranoproliferative GN (type I, II)
• Systemic lupus erythematosus • Membranous GN
• Goodpasture’s disease • IgA nephropathy
• Henoch-Schonlein purpura • Idiopathic
• Necrotizing vasculitis (including • Type I: Antiglomerular basement
Wegener’s gransulomatosis) membrane antibody disease
• Cryoimmunoglobinemia (hepatitis B • Type II: immune complex-mediated
or C related) disease
• Neoplasia • Type III: pauci-immune (ANCA-
• Relapsing polychondritis associated) disease
• Bechet’s disease • Type IV: mixed and anti-GBM and anti-
ANCA associated disease
• Clinical features common to the three forms of RPGN include
• Hematuria
• Proteinuria
• Decreased urine output
• Edema
• Hypertension
• The urinalysis typically reveals
• Hematuria, with dysmorphic red blood cells (RBC), RBC casts
• Variable degrees of proteinuria
Pathological finding

Bowman’s space Crescent

Crescent glomerulonephritis
(Histological classification)
• Type I: Anti-glomerular basement membrane (anti-GBM)
antibody-associated RPGN (95% crescents)
• Goodpasture’s syndrome
• Type II: Immune complex RPGN (20~50% crescents)
• Systemic lupus erythematosus
• IgA nephropathy (including Henoch-Schonlein purpura)
• Cryoglobulinemic vasculitis
• Type III: Pauci immune-associated glomerulonephritis
• Idiopathic crescentic GN
• Wegener’s granulomatosis GN
• Microscopic polyarteritis (polyangiitis) GN
Immunopathological findings
Pauci immune-
Anti-GBM antibody- Immune complex associated
associated RPGN RPGN glomerulonephritis

Linear deposits Granular deposits Scanty deposits

• Low salt diet
• Low potassium diet
• Low protein diet
• Hypertensive control: ACE inhibitor or Angiotensin II
receptor antagonist
• High dose steroid
• Immunocytotoxic agent (endoxan)
• Plasmaphresis
Evidence-Based Recommendations of
Treatment : Pauci-immune RPGN

• Recommendation 1.
• Initial steroid treatment is methylprednisolone 7 to 15
mg/kg/day to a maximum of 1 g/day three days, then
• Prednisone 1 mg/kg/day for one month, gradually tapered
over the next 6 to 12 months.
• Recommendation 2.
• Cyclophosphamide should be given either orally at a dose of 2
mg/kg/day adjusted to maintain the leukocyte count between 3
and 5 thousand/ml or intravenously starting at 0.5 g/m2/month
and increased monthly by 0.25 g to a maximum of 1 g/m2 per
• The dose should be adjusted to maintain a nadir of leukocyte
count two weeks post-treatment between 3 and 5 thousand/ml.
• Cyclophosphamide should be continued for 6 to 12 months.
• Treatment should be given even in advanced patients.
• Recommendation 3.
• Consider plasmapheresis in patients with lung hemorrhage and
those with severe disease and no response to conventional
• Recommendation 4.
• Monitoring for relapse with clinical follow-up, renal function
tests, and ANCA is recommended.
• Recommendation 5.
• Treatment of relapses should be similar to original treatment.
Indication of plasmapheresis in RPGN

• Anti-GBM associated RPGN

• Standard therapy and acceptable
• Pauci-immune RPGN
• Insufficient reported evidence
• Acceptable for dialysis-dependent patients or patients
with pulmonary hemorrhage
• Immune complex RPGN
• HUS-TTP: standard therapy and accept
• Insufficienct reported evidence: Multiple myeloma, lupus
nephritis, IgA nephropathy, Henoch-Sconlein purpura,
• Cryoglobulinemia: insufficient reported evidence;
acceptable for patients with acute active and severe
VASCULITELE - definitie
Inflamatie perete vascular (!) + stenoze / ocluzii  necroza
fibrinoida  granuloame
Localizarea preferentiala a vascularitelor
Clasificarea Chapel Hill ( JennetteJC ArthritisRheum1994)
• Variabila
• Boli rare…. dar uneori de o gravitate extrema
• Mai multe vasculite in anumite zone sau mai bine diagnosticate?
• Horton: 15 – 35 / 100 000 loc (tarile scandinave)
• Takayasu: 1 - 2 /1 000 000 loc (Japonia),
• PAN: 33 /1 000 000 (Norvegia)
• Wegener: 157 / 1 000 000 (Suedia)
• SCS: 13/ 1 000 000 (Norvegia)
• MPA: 66 / 1 000 000 (Suedia)
• Factorii genetici
• Factori infectiosi

• Infectia cu VHB
• Crioglobulinemia mixta
• Infectia cu parvovirus B19, HIV, EBV
• Infectia cu S.auriu

• Factori de mediu
• Siliciu
• Hidrocarburi
• Fumatul
• Infectii
• Medicamente (propiltiouracil, hidralazina, minociclina, alopurinol, penicilamina)
• Alergii
• Vaccinari si desensibilizari
Autoanticorpii ANCA

pANCA anti-MPO in MPA (45%) si in sindromul

cANCAanti-Pr3 in Wegener (90%) Churg-Strauss(40%)
Mecanism de actiune ANCA
Key message

• Grup heterogen

• Patogenie variabila

• Etiologie inca necunoscuta

• Epidemiologie ....
Vasculitele asociate cu ANCA

• Poliangeita microscopica

• Granulomatoza Wegener

• Sindromul Churg Strauss

Granulomatoza Wegener
• Definitie:
• Triada:
• Granuloame de cai aeriene superioare si / sau inferioare
• Vascularita necrozanta sau granulomatoasa artere calibru mic si
• GN necrozanta segmentara si focala + proliferare extracapilara
Granulomatoza Wegener



Granulomatoza Wegener Particularitati

• orice vârstă, în medie 40-45 ani

• B/F = 1,5/1
• Debut : afectare ORL sau pulmonară …. rezistentă la antibiotice
Patologie rino-sinusala

• Epistaxis
• Rinita crutoasa
• Perforare cloazon nazal
• Sinuzita acuta si cronica
Ulceratii palat / linguale
Granulomatoza Wegener
Manifestari clinice oftalmologice

• 29 - 58 %
• Oculare
• Vascularite: sclerite si atingeri vasculare retiniene

• Orbitare
• Granuloame inflamatorii (intraorbitar, glande lacrimale, intrasinusal):
exoftalmie, compresie de nerv optic, obstructie de cai lacrimale, keratite,
perforatii corneene
Granulomatoza Wegener
Manifestari clinice pulmonare
Granulomatoza Wegener
Manifestari renale
Alte manifestari in Wegener
Afectarea cutanată
• Purpură vasculară, ulceratii, noduli subcutanati, livedo, papule, vezicule, necroze
• Biopsia din piele: vasculită leucocitoclazică. Biopsia din noduli: granulom
Afectarea neurologică
• Periferică sau centrală
Afectarea articulară
Afectarea cardiacă

Altele: stenoze ureterale, orhită, prostatită, epididimită, ulceraţii rectale, colice sau
intestinale, hemoragii si perforaţii digestive, miozită
Granulomatoza Wegener
Explorări paraclinice

• Sdr. inflamator
• Proteinurie, hematurie
• Retentie azotata
• Ex. histologic: dg. de certitudine
Granulomatoza Wegener criterii de diagnostic
(ARA, 1990)

1. Inflamaţie orală sau nazală

2. Anomalii radiologice pulmonare
3. Anomalii sediment urinar
4. Inflamaţie granulomatoasă la biopsie

Prezenta a 2 criterii din 4

Sensibilitate 88,2% Specificitate 92%
Poliangeita microscopica -PAM
• vasculita de vase mici
• glomerulonefrita extracapilara
• si/sau hemoragia alveolara
• P ANCA (anti MPO) 75 – 80%
PAM: Manifestari clinice
• Semne generale
• Atingere renala (GNRP)
• Atingere pulmonara (HP)
• Manifestari cutanate (purpura)

• Alte manifestari: neuropatie periferica, atingere digestiva, etc

PAM: Manifestari paraclinice
• Sindrom inflamator
• Anemie
• Alterarea functiei renale
• p ANCA 75 – 80 %
• c ANCA sau c ANCA 5%
• Biopsia renala si cutanata
PAM: Evolutie si prognostic

• Remisiune completa

• Recadere

• Deces
• BVAS (Scor de activitate)
FFS (Five Factor Score)
• afectare cardiacă;
• afectare gastrointestinală (sângerare, perforaţie intestinală,
• creatinina > 1,58 mg/dl (141 µmol/l)
• proteinurie > 1g/4 ore;
• afectarea SNC.
• FFS - suma punctelor de la cele 5 scoruri.
• Scor minim: 0; Scor maxim: 5.
Scorul de activitate BVAS
• Semne generale: mialgii, artralgii/artrită, febră > 38°, scădere ponderală > 2 kg;
• Semne cutanate: infercte, purpură, ulcer, gangrena, alte semne de vasculită cutanată;
• Semne mucoase şi oculare: ulcere/granuloame orale, ulcere genitale, inflamaţia anexelor, proptosis,
episclerită, conjunctivită/blefarită/keratită, tulburări vizuale, pierderea bruscă a vederii, uveită,
vasculită/tromboze/exsudate retiniene, hemoragii retiniene ;
• Semne ORL : secreţie nazală sangvinolentă / cruste / ulcere / granuloame nazale, afectarea
sinusurilor paranazale, stenoză subglotică, surditate de conducţie, surditate senso-rineurală;
• Semne pulmonare: wheezing, noduli/caverne, revărsate pleurale, infiltrate, afectare endobronşică,
hemoptizii masive/hemoragii alveolare, insuficienţă respiratorie;
• Semne cardiovasculare: absenţa unor pulsuri periferice, valvulopatie, pericardită, angină pectorală,
cardiomiopatie, insuficienţă cardiacă;
• Semne abdominale: peritonită, diaree sangvinolentă, dureri abdominale ischemice;
• Semne renale: HTA, proteinurie > 1 + , hematurie > 10 H/HPF, creatininemie > 125-250 - 500 p.mol/1,
creşterea creatininemiei cu > 30%, scăderea Cer cu > 25% ;
• Semne neurologice: cefalee, meningită, sindrom confuzional organic, convulsii, AVC, leziuni
cordonale, pareze craniene, neuropatie senzorială periferică, mononeuritis multiplex.

• Scor minim: 0
• Scor maxim: 63
Tratamentul vasculitelor cu ANCA

• Terapia de inducţie a remisiunii

• Terapia de menţinere a remisiunii

• Remisiunea completă - BVAS = 0.

• Remisia renală - absenţa inflamaţiei active la nivel renal (absenţa hematuriei 0 – 3

H/HPF, absenţa cilindrilor hematici).

• Remisia parţială - persistenţa hematuriei cu sau fără cilindri hematici în ciuda

îmbunătăţirii sau stabilizării creatininemiei şi dispariţiei semnelor extrarenale de boală

Induction Therapy in newly dg ANCA

Prednisone 1mg/kg/d used in most RCTs
+ Rituximab

Non-life-threatening Consider MMF in

disease MPO-ANCA

Vital organ/life-threatening, Consider

Cr>5,7mg/dL plasmapheresis
Glucocorticoids – less is better?
A reduced regimen
of corticosteroids
non-inferior to
standard dose
- 704 ANCA-vasculitis patients
- eGFR<50mL/min/lung hemorrhage

Alternative to reduce glucocorticoids exposure:

C5a Receptor antagonist
Cyclophosphamide vs. Rituximab
AVA-COPING with vasculitis? A move forward?

r in
ri N
f e
n-in CTIO
Re r –
m Su
iss st
AVACOPA i o ai
n ne
BindsNto C5a d
Reduces inflammation
Reduces damage to blood
Safety profile – comparable to

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