«Syndrome  Pneumo-­‐rénal"    Bertrand  Souweine,  Clermont-­‐Ferrand  

Definition •  Diffuse alveolar hemorrhage (DAH) •  Rapid-progressive glomerulonephritis (RPGN)

Main causes of PRS •  ANCA-associated vascularitis •  Immune-complex glomerulonephritides •  Goodpasture syndrome

Characteristics in the ICU setting

Specific treatment

Pulmonary-renal syndrome (PRS)  

Combination of

•  Diffuse alveolar hemorrhage (DAH) •  Rapid-progressive glomerulonephritis (RPGN)

Pathology, systemic small vessel vasculitis

•  Inflammation and necrosis of small caliber blood vessels (arterioles, capillaries and venules)

•  Neutrophil ic inf i l trat ion through vascular endothelium results in alveolar and glomerular inflammation

Pulmonary-renal syndrome  

Schwartz MI, Chest 1998;113:1609-15

Diagnostic différentiel des hémorragies alvéolaires avec insuffisance rénale, selon l’atteinte rénale

Atteinte rénale Étiologie Lésions histologiques Syndrome clinico-biologique

Néphropathie vasculaire aiguë etmicroangiopathie thrombotique

PTT, crise rénale aiguësclérodermique, maladie desemboles de cholestérol, CAPS

Nécrose fibrinoïdeartériolo-capillaire, endartériteartériolaire avec rétrécissement enbulbe d’oignon, ± microthrombi

HTA sévère, hémolysemicroangiopathique, protéinurie ethématurie absentes ou faibles

Néphrite interstitielle aiguë Leptospirose, hantavirus, dengueet autres arboviroses, paludisme

Infiltrat inflammatoirecortico-médullaire et péritubulaire,œdème interstitiel

Leucocyturie (cylindres), protéinurie ethématurie absentes ou faibles

Nécrose tubulaire aiguë Pneumonie, choc septique, SDRA,embolie pulmonaire grave

Nécrose des cellules tubulaires Syndrome urinaire pauvre

Insuffisance rénale fonctionnelle OAP Pas de syndrome urinaire, fractiond’excrétion du sodium diminuée

Hié M, Rev Med Interne. 2013;34::679-86

Triad of symptoms that have to occur simultaneously

•  Hemoptysis ( < 200 mL), absent in 35% of cases •  Diffuse radiographic pulmonary infiltrates •  Anemia The clinical presentation is variable, slowly protracted courses through to fulminant organ failure

•  Acute- or subacute- onset cough •  Low grade fever •  Slight cough, progressive dyspnea •  Hypoxemic respiratory distress

Mainly caused by a pulmonary capillaritis

Diffuse alveolar hemorrhage

Zamora MR, Medicine (Baltimore) 1997;76:192–202.

DAH in pulmonary-renal syndrome  

Schwartz MI, Chest 1998;113:1609-15

Capillaritis characterized by the infiltration of alveolar septa by neutrophils, several of which are fragmented.

Capillaritis associated with marked DAH admixed with fibrin. The alveolar septum is thickened by homogenous material and infiltrating neutrophils

•  Diffuse bilateral infiltrates with air bronchogram •  Predominance in the lower parts of the lung •  Most common differential diagnosis is pneumonia and

pulmonary edema Naticchia A, G Ital Nefrol 2011; 28: 57–63.

Diffuse alveolar hemorrhage

•  Ground-glass opacities •  Interlobular septal thickening “crazy paving” pattern •  Ventrodorsal gradient

Diffuse alveolar hemorrhage

Balke L, Am J Respir Crit Care Med 2015

To rule out infection, microbiological testing

•  Gram’s staining of the aspirate •  Staining for acid-fast and modified acid-fast bacilli •  Testing for respiratory viruses •  Aspirate culture

Evaluate the presence of DAH

•  Serial BAL samples become bloodier •  Acute inflammation •  Haemosiderin-laden pulmonary macrophages

No malignant cells

Broncho-alveolar hemorrhage in DAH

1) Diffuse pulmonary infiltrates seen on thoracic imaging and either

2) Bronchoscopic documentation of progressively bloody BAL fluid and/or >20% hemosiderin-laden macrophages in the BAL cell differential count

Or lung biopsy showing alveolar hemorrhage and capillaritis

Diffuse alveolar hemorrhage

De Prost N, Respir Med 2012;106:1021-32 Cartin-Ceba R, Arthritis Rheum 2016;68:1467-76

Rapidly progressive glomerulonephritis (RPGN)

Characteristic feature

•  Leg edema, hematuria, acute renal failure Evidence of glomerular injury

•  Hematuria Upper tract origin Dysmorphic red cells of glomerular origin Red-cell casts in the sediment

•  Proteinuria, but rarely in the range of nephrotic syndrome

If left untreated, patients can progress to end-stage renal failure, requiring hemodialysis

Kidney biopsy (KB)

•  Provides definitive diagnosis •  Identifies the underlying cause •  Help to direct therapy •  Provides information on renal outcome

Sometimes contraindicated or not recommended

ICU patients are high-risk operative candidates for KB

•  The need for a KB must not delay to start specific treatment

•  Even if treatment is initiated, a KB can still be performed later

RPGN, diagnostic done by kidney biopsy

Necrotising glomerulonephritis

•  Fibrinoid necrosis and in-situ microangiopathy

•  Damage of the capillaries and basal membranes resulting in extracapillary cell proliferation (crescent formation )

Tubular involvement

•  Fibrosis and tubular atrophy, poor prognostic features

RPGN – Kidney biopsy – Light microscopy

Light microscopy

•  Glomerulonephritis with cellular crescents formation

Glassock RJ, N Engl J Med 2012;367:1540-1553 Foster MH, Matrix Biol 2016;1274:20

Glassock RJ, N Engl J Med 2012;367:1540-1553

Anti-IgG immunofluorescence of KB specimen

Linear staining of anti-GBM Abs against alpha3-NC1-collagen IV

Granular staining for IgG along the GBM

Foster MH, Matbio 2016

Pauci-immune

Hié M, Rev Med Interne. 2013;34::679-86

Glassock RJ, N Engl J Med 2012;367:1540-1553

Pneumo-renal syndrome

Other' includes SLE Cryoglobulinaemic vasculitis Henoch–Schönlein purpura CAPS Polyarteritis nodosa HIV-related vasculitis

Papiris SA, Crit Care. 2007; 11: 213.

Pourrat  et  al.,  Gallagher  et  al.,  Cruz  et  al.,  Bucciarrelli  et  al.  

C-ANCA P-ANCA

Bui VL, Jama 2016;316:983-5

ANCA-associated vaculitis Small vessel necrotizing vasculitis

Granulomatosis with polyangiitis (GPA) Microscopic polyangiitis (MPA) Eoosinophilic granulomatosis with polyangiitis (EGPA)

Semple D, Crit Care 2005; McCabe C, Respir Med 2011; Glassock RJ, N Engl J med 2012

ANCA-associated vasculitis GPA MPA EGPA Incidence cases/million 10-30 12-30 2 Caucasian predominance +++ +++ ++ Sinusitis +++ + +++ Asthma - - +++ SOB/Cough +++ + ++ Rash + + ++ Abdominal pain + + + Hypertension + + + Cardiac failure / pericarditis + + ++ Mononeuritis (multoiplex) + + ++ Pulmonary involvement (% of cases) >80 20-55 > 90 Renal involvement (% of cases) 70 80-100 25 Proteinuria / hematuria +++ +++ ++ Serum complement Normal Normal Normal Other laboratory tests Hypergammaglobulinemia

Eosinophilia (>1.5 × 109/l) Kidney lesions

Interstitial fibrosis ++ ++++ + Tubular atrophy +++ +++ ++

Granulomatous inflammation ++ 0 0

SOB, shortness of breath;

McCabe C, Respir Med 2011;105:1413-21

ANCA-associated vasculitis ( )

Granulomatosis with polyangiitis (Wegener’s) Microscopic Polyangiitis ChurgeStrauss syndrome

Renalpathology

Granulomatous inflammationwith extensive necrosis rarelyaccompanied by necrotising vasculitis

Necrotising vasculitis withfew or no immune depositson immunoflourescence(pauci-immune)

Eosinophil-rich granulomatousinfiltration.Vasculitis histologicallyindistinguishablefrom WG and MPA

Clinicalfeatures

ENT necrosis/collapse of nasalbridge cartilageConduction deafness e Eustachiantube damageOrbital scleritis, proptosis

PleurisyAsthmaHaemoptysis

Late onset asthmaSinusitis, rhinitisEosinophiliaGI disturbance e mesentericeosinophilic infiltrationMyositis (Cardiac failure)Skin nodules/purpura

Immunology PR3 ANCA positive 75e90% MPO-ANCA positive 45% MPO-ANCA positive in 35e70%Prognosis Mortality correlated to cANCA titre.

High relapse rateMortality highest in firstyear of diagnosis

Multisystem (renal, GI, Cardiac)carries worst prognosis

Obstructive AKI (granuloma) Drug induced AKI Sepsis-induced AKI

AKI not restricted to RGPM

Drug induced AKI Sepsis-induced AKI

Drug induced AKI Sepsis-induced AKI

Drug-associated ANCA vasculitis

Pauci-immune necrotizing and crescentic glomerulonephritis Clinical, serologic and pathologic features suggestive of MPA

•  High titer of P-ANCA / MPO-ANCA •  RGPM +++ •  IAH may complicate the course (pneumo-renal syndrome)

Allopurinol, hydralazine, propylthiouracil, penicillamine, sulfasalazine, cocaine, levamisole, TNF-α inhibitors, cephotaxime,

Choi HK, Arthritis Rheum 2000;43: 405–13.

Immune-complex glomerulonephritides  Hypo-

complementemic Normo-

complementemic

Low C3 levels Low C4 levels •  SLE •  Endocarditis •  Visceral abcesses •  Post-streptococcal GN •  Membranoproliferative GN •  Shunt nephritis

Cryoglobulinemia of any of the 3 types

•  IgA nephropathy •  Henoch–Schönlein

purpura •  Fibrillary GN

Kazzas M, Lupus Sci Med. 2015 Sep 23;2:e000117

SLE complicated by DAH: risk factors, therapy and survival. Table 1 Diffuse alveolar haemorrhage presentation

Active features Frequency Percentage

Dyspnoea 14/22 (64)Hypoxaemia* 12/22 (55)Cough (no haemoptysis) 9/22 (41)Haemoptysis 6/22 (27)BAL

Bloody return 8/14 (57)Haemosiderin-laden MΦ 2/14 (14)

SLEDAI-2K score† 11.4±7.3Any lupus rash 5/22 (23)Arthritis 4/22 (23)Serositis 7/22 (32)Nephritis 8/22 (36)Neuropsychiatric 2/22 (9)Leucopenia 5/21 (23)Haemolytic anaemia 2/22 (9)Thrombocytopenia 5/22 (23)Raynaud’s 2/22 (9)Hypocomplementemia 15/20 (75)

Down from baseline 12/16 (75)Elevated anti-dsDNA 14/18 (78)

Up from baseline 9/16 (56)*Nine patients required intubation.†Mean and SD are presented.BAL, bronchoalveolar lavage; dsDNA, double-stranded DNA; MΦ,macrophage; SLEDAI, systemic lupus erythematosus diseaseactivity index 2000.

When a multivariate model was constructed, only history of thrombocytopenia (OR=36) and history of low complement C3 (OR=19) were independent r isk factors.

Kazzas M, Lupus Sci Med. 2015 Sep 23;2:e000117

22 SLE with DAH in a 1000-patient US SLE cohort , and compare them to 66 controls from the same outpatient cohort.

Figure 1 Interval between lupus diagnosis and first episodeof diffuse alveolar haemorrhage (DAH).

All 22 patients survived their DAH episode and were discharged from the hospital

Rare disease, 0.1-1 per million per year

Organ-specific autoimmune disease mediated by autoantibodies directed against the glomerular/alveolar basement membrane.

Typically RGPM and DAH, but isolated RGPM in 40% of patients

Crescentic glomerulonephritis with linear immunofluorescent staining for IgG on the GBM.

In the absence of treatment Loss of kidney function in the vast majority of patients Life-threatening disease, especially in patients with DAH

Goodpasture syndrome

Goodpasture syndrome

Hudson BG, J Am Soc Nephrol . 2004;15:2014-27.

Men in late 20s (mainly Caucasian) •  Explosive sudden onset, sudden anemia •  Lung involvement more than in older age group,

dyspnea, hemoptysis – specially if smokers – •  RGPM, hematuria, proteinuria and rapid loss of GFR •  Better prognosis than older age group

Both sexes 60–70s •  Prolonged asymptomatic kidney injury Lung disease from dyspnea to severe DAH

No specific symptoms (malaise, weakness), no other, general vasculitic symptoms

Serology •  Anti-GBM antibody positive in 85-90% •  ANCA Abs against MPO (double positive patients) in 15%

Goodpasture syndrome

Bazari H, N Engl J Med 2012;366:2503-15

Urgent kidney biopsy a.s.a.p. when GPS or RPGN is suspected

•  In the absence of contraindications

•  Must not delay specific treatment

Sometimes mandatory for the diagnosis since anti-GBM Abs are sometimes absent

Goodpasture syndrome - Diagnosis

When the analysis was confined to patients who underwent renal biopsy (N = 27), the best model showed the percentage of crescents as the only independent predictor of dialysis dependence at 3 months (P = 0.03)

Alchi B, Nephrol Dial Transplant (2015) 30: 814–821

On dialysis(N = 30)a

Not on dialysis(N = 10)b

P-value

Age (years) 59 ± 15 37 ± 22 0.013Male (%) 11 (37) 7 (70) NSInitial creatinine>500 µmol/L (%)

25 (83) 3 (30) 0.003

Oligoanuria (%) 23 (77) 1 (10) 0.0003Glomerular crescent>75% (%)

15 (68) 0 (0) 0.01

Activity score 9 (2–12) 6 (4–10) NSChronicity score 2 (0–10) 3 (0–5) NS

Renal survival at 3 months according to initial clinical and pathologic data

Kaplan–Meier patient survival curves for anti-GBM disease

Alchi B, Nephrol Dial Transplant (2015) 30: 814–821

43 patients including nine with with dual anti-GBM and ANCA positivity

Overall, 1-year patient survival was 88% (95% CI, 78–98%)

Bilan paraclinique à réaliser devant une suscpicion de syndrome pneumo-rénal.

Bilan initialECBU avec recherche de cylindres hématiquesProtéinurie des 24 heures ou sur échantillon avec créatininurieNFS, bilan martial

Bilan immunologiqueANCAAc anti-MBGAc anti-nucléaires ± anti-ADN natifs et anti-ECT/ENACryoglobulinémieDosage du complément (C3, C4)Facteur rhumatoïdeÉlectrophorèse des protéines sériques et dosage pondéral des IgSérologie hépatite C

Diagnostic différentielRecherche de schizocytesHaptoglobine, bilirubine, LDHAc anti-phospholipides, anticoagulant circulant lupique, Ac anti-Scl70Prélèvements bactériologiques (hémocultures, LBA)Échographie cardiaque

Scanner thoracique sans injection

Fibroscopie bronchique avec LBA et score de Golde

Échographie rénale

Ponction-biopsie rénale en l’absence de contre-indication

Hié M, Rev Med Interne. 2013 Nov; 34(11):679-86

Hié M, Rev Med Interne. 2013 Nov; 34(11):679-86

Main etiologic diagnosis •  GPA >50%, MPA = 25% •  Newly or recently diagnosed

Reasons for ICU admission •  Disease exacerbation 50-70% (including DAH…) •  Sepsis 30-50% •  Respiratory failure +++

ICU mortality = in most reports 10% -20%;( à 50%)

Higher severity score and delay in specific treatment are reported to be associated with mortality

Causes of death •  Sepsis •  Disease flare

Papiris  SA  2007,  Khan  SA  2007,  Rabe  C  2010,    Befort  P  2013,  Dumas  G  2015;  Kimmoun  A  2016  

Pulmonary-renal syndrome in the ICU setting

Distinguishing vasculitis from infection in the ICU setting is essential

The risk of nosocomial infection in these patients is very high due to immune-suppression

Careful monitoring for bone marrow suppression and superadded infection is indicated

Patients with vasculitis frequently die of sepsis

Minimizing the risk of sepsis

Management of shock •  Hypotension may result from the combination of dehydration,

hemorrhage and systemic inflammatory response

Respiratory management •  Protective ventilation strategy •  Avoid exacerbation of pulmonary edema and hemorrhage

•  In GPA there may be subglottic stenosis which can result in difficult intubation.

Renal management •  Many patients develop severe AKI requiring RRT in ICU

ICU management of pulmonary-renal syndrome

Traitement d’attaque du syndrome pneumo-rénal après diagnostic étiologique.

Vascularites associéesaux ANCA

Créat < 500 �mol/L CT + CYC ou rituximabCréat > 500 �mol/L CT + EP + CYC

Syndrome de Goodpasture CT + CYC + EPLupus systémique CT + CYC + EP ± rituximabCryoglobulinémie mixte Rituximab + EP ± CT (+ antiviraux si hépatite C)

Créat : créatininémie ; CT : corticothérapie systémique ; EP : échanges plasmatiques ;CYC : cyclophosphamide.

Hié M. / La Revue de médecine interne 34 (2013) 679–686

PE is advocated in patients with AAV with either severe renal dysfunction or DAH Walsh M, Am J Kidney Dis. 2011;57:566–574

Plasma exchange was effective in patients with severe AKI secondary to vasculitis. Cochrane Database of Systematic Reviews 2015, Issue 9. Art. No.: CD003232.

PEXIVAS (Plasma Exchange and Glucocorticoids for Treatment of ANCA-Associated Vasculitis) plans to randomize 700 participants to either 7 plasma exchanges of 60 ml/kg within 14 days, in addition to standard care, or to standard care alone  

•  Pulmonary renal vasculitis is a clinical syndrome of diffuse alveolar hemorrhage and acute glomerulonephritis.

•  Infection and disease exacerbation are leading reasons for ICU admission

•  Diagnosis requires BAL, lung imaging, hemoglobin, creatininemia, urinary analyze and extensive serology tests

•  ANCA-associated vasculitis and Anti-GBM disease are the commonest causes.

•  Delayed immunosuppressant administration is associated with poor outcome

•  Patients should be managed in a specialist centre with appropriate experience.

Take-home messages

Lee RW, Autoimmunity 2010;9:657-60

• .

Walsh M, Kidney Int. 2013;84:397-402

Long-term follow-up of the MEPEX study

Kaplan–Meier curve Cumulative incidence curve

3.4 Twelve months 6 235 Risk Ratio (M-H, Random, 95% CI) 0.45 [0.29, 0.72]

Comparison 1. Plasma exchange as adjunctive therapy

Outcome or subgroup titleNo. of

studies

No. of

participants Statistical method Effect size

1 Death 7 Risk Ratio (M-H, Random, 95% CI) Subtotals only

1.1 Three months 2 169 Risk Ratio (M-H, Random, 95% CI) 1.02 [0.49, 2.15]

1.2 Six months 2 63 Risk Ratio (M-H, Random, 95% CI) 0.72 [0.08, 6.13]

1.3 One year 5 267 Risk Ratio (M-H, Random, 95% CI) 1.04 [0.57, 1.92]

1.4 Two years 4 120 Risk Ratio (M-H, Random, 95% CI) 1.29 [0.49, 3.38]

1.5 Five years 3 80 Risk Ratio (M-H, Random, 95% CI) 1.21 [0.71, 2.04]

1.6 Death at any time point 5 253 Risk Ratio (M-H, Random, 95% CI) 1.15 [0.71, 1.88]

2 Serum creatinine 5 Mean Difference (IV, Random, 95% CI) Subtotals only]

2.5 Twelve months 4 156 Mean Difference (IV, Random, 95% CI) 40.58 [-25.02, 106.

18]

3 Dialysis 7 Risk Ratio (M-H, Random, 95% CI) Subtotals only

y

4 Side effects 4 Risk Ratio (M-H, Random, 95% CI) Subtotals only

4.1 Serious infections 4 252 Risk Ratio (M-H, Random, 95% CI) 1.19 [0.76, 1.84]

4.2 Myocardial infarction 1 52 Risk Ratio (M-H, Random, 95% CI) 2.78 [0.31, 24.99]

4.3 Lung haemorrhage 1 52 Risk Ratio (M-H, Random, 95% CI) 0.62 [0.11, 3.39]

4.4 Subarachnoid

haemorrhage

1 52 Risk Ratio (M-H, Random, 95% CI) 0.31 [0.01, 7.26]

4.5 Gastrointestinal

haemorrhage

2 63 Risk Ratio (M-H, Random, 95% CI) 0.61 [0.08, 4.69]

Cochrane Database of Systematic Reviews 2015, Issue 9. Art. No.: CD003232.

Cartin-Ceba R, Arthritis Rheumatol. 2016;68:1467-76.

Efficacy of PE and of rituximab versus cyclophosphamide in 73 patients with DAH

secondary to AAV  

73 patients with ANCA-associated vasculitis and DAH GPA (N=44), 29 MPA (N=29), renal involvement (N=33) Propensity score, probability of receiving PE based on BVAS/WG score, respiratory failure, active renal disease, need for RRT, CRP levels

Complete remission at 6 months

Treatment OR [95% CI] P value PE 0.49 [0.12–1.95] 0.32 Rituximab 6.45 [1.78–29] <0.003

GPA (N=44), 29 MPA (N=29), renal involvement (N=33)