Histologic and immunologic markers to predict renal recurrence in IgA vasculitis nephritis - PowerPoint Presentation

1. Histologic and immunologic markers to predict renal recurrence in IgA vasculitis nephritisPreliminary resultsK Abukasm, AL Lapeyraque, H Mathieu, N Patey, A CambierKarma AbukasmPediatric Nephrology FellowCHU Sainte-JustineApril 25th, 2023

2. Introduction (1)IgA vasculitis (formerly Henoch-Schonlein Purpura, IgAV) is the most common vasculitis in children (incidence rate of 3 to 26.7 cases/100 000 children1)Diagnosis based on EULAR/PRINTO/PRES criteria2Renal involvement estimated in 30-50% of cases at 4-6 weeks following the initial presentation3 Chronic/end-stage kidney disease estimated in about 1-7% of casesSuggested poor outcome predictors of IgAV nephritis (IgAVN) 4 : older age, renal function impairment, nephrotic syndrome or mixed nephrotic/nephritic syndrome at presentation, presence of glomerular crescents1 Piram et Maher, 2013 ; 2 Ozen et al., 2010 ; 3 Narchi, 2005; 4 Shi et al., 2019

3. Introduction (2)Immunologic and pathologic similarities between IgAVN and IgA nephropathy (IgAN) 5,6,7,8 : Galactose deficient IgA1 (Gd-IgA1)IgG targeting Gd-IgA (anti-Gd-IgA1)Serum soluble CD89-IgA complex (sCD89-IgA)C5b9 membrane attack complex (MAC)Uncertain role of renal biopsy in the prognostic evaluation of patients with IgAVN (compared to IgAN) 95 Suzuki et al., 2009; 6 Vuong et al., 2010 ; 7 Dumont et al., 2020 ; 8 Cambier et al., 2022 ; 9 Tudorache et al., 2015

4. Main objectivesCompare clinical, biochemical and histological characteristics of three groups of patients with IgAVN classified based on their clinical course;Analyze and compare intrarenal immunological deposits (IgA, C3, C4d, CD89 et MAC) in histology samples in all three groups  ;Compare circulating immune complex levels (sCD89-IgA, Gd-IgA, IgG-IgA, sCD89) in plasma and renal biopsies in all three groups.Monophasic diseaseRenal relapsing disease (IgAN type)Renal and purpuric relapsing disease

5. MethodsRetrospective cohort study in pediatric patients diagnosed with IgAVN and followed-up in CHU Sainte-Justine nephrology clinic between July 2014 and February 2023Minimally one kidney biopsyIncomplete files excludedData collection through record reviewBiopsy samples reviewed with nephropathologist in order to complete missing data (Oxford scoring) and immunofluorescence stainingStatistical analysis completed with SPSS (p value < 0.05 considered statistically significant)Nominal data : Fisher’s Exact TestContinuous data : One-way ANOVA

6.  Monophasic diseaseRenal relapsing disease (IgAN type)Renal and purpuric relapsing disease p-valueFemale sex, n (%)9/24 (37.5)5/7 (71.4)4/5 (80.0) 0.158Age at IgAV diagnosis, mean (median)10.2 (8.1)9.3 (12.0)8.5 (9.2) 0.987†Involvement at initial presentation    Digestive, n (%)12/23 (52.2)6/7 (85.7)3/5 (60.0) 0.342Articular, n (%)20/23 (87.0)4/7 (57.1)2/5 (40.0) 0.360Renal, n (%)6/23 (26.1)3/7 (42.9)0/5 0.372Need for hospitalization at initial presentation, n (%)9/22 (40.9)3/7 (42.9)0/4 0.364Treatment received at initial presentation, n (%)12/17 (70.6)3/6 (50.0)1/2 (50.0) 0.528Corticosteroids, n (%)9/13 (69.2)3/3 (100.0)1/2 (50.0)NANSAID, n (%)10/12 (83.3)1/3 (33.3)0/1NAIVIg, n (%)1/12 (8.3)0/30/1NAACE inhibitors, n (%)0/121/3 (33.3)0/1NAMMF, n (%)1/12 (8.3)0/30/1NATable 1. Initial presentation of IgAV classified based on IgAVN clinical evolutionACE : Angiotensin-converting-enzyme ; IVIg : Intravenous immunoglobulin ; MMF : Mycophenolate Mofetil ;NSAID : Non-steroidal anti-inflammatory drugs† Fisher’s Exact TestResults

7.  Monophasic diseaseRenal relapsing disease (IgAN type)Renal and purpuric relapsing disease p-valueTime from initial IgAV presentation in days, mean (median)50.5 (22)483.5 (34)143.5 (139)Motive for referral 0.160Isolated proteinuria, n (%)9/24 (23.7)0/72/5 (40.0)Proteinuria and hematuria, n (%)10/24 (26.3)6/7 (85.7)3/5 (60.0)Gross hematuria, n (%)4/24 (10.5)0/70/5Microscopic hematuria, n (%)0/241/7 (14.3)0/5Nephrotic syndrome, n (%)0/240/70/5Nephritic syndrome, n (%)1/24 (2.6)0/70/5Acute kidney injury, n (%)0/240/70/5Hematuria at time of visit 1.000None, n (%)3/24 (12.5)0/70/5Gross, n (%)5/24 (20.8)2/7 (28.6)1/5 (20.0)Microscopic, n (%)15/24 (62.5)5/7 (71.4)4/5 (80.0)Presence of proteinuria on urinalysis, n (%)23/23 (100.0)6/7 (85.7)4/4 (100.0)0.324Nephrotic proteinuria on urinary spot (> 0.2 g/mmol)13/19 (68.4)1/6 (16.7)3/5 (60.0)0.178Proteinuria on 24-hour urine collection (g/day), mean (median)1.6 (1.3)1.4 (0.87)1.6 (1.6)Hypertension present at initial nephrology visit, n (%)4/24 (16.7)1/7 (14.3)0/40.307Bloodwork results   Urea, mean (median)4.7 (4.5)3.9 (3.8)4.1 (4.5)0.226†Creatinine, mean (median)53.5 (50.5)54.9 (55)51 (46)0.917†Albumin, mean (median)33.2 (33)34 (35)37.3 (37.5)0.460†Serum IgA, mean (median)2.6 (2.5)3.5 (3.6)2.95 (2.95)0.470†Table 2. Clinical and biochemical presentation at first nephrology visit for IgAVN classified based on IgAVN clinical evolution† Fisher’s Exact Test

8.  Monophasic diseaseRenal relapsing disease(IgAN type)Renal and purpuric relapsing disease p-valueNumber of biopsies performed, mean2.122.52.70.0701, n (%)20/24 (83.3)3/7 (42.9)1/5 (20.0) 2, n (%)3/24 (12.5)3/7 (42.9)2/5 (40.0) 3, n (%)1/24 (4.2)0/72/5 (40.0) 4, n (%)0/241/7 (14.3)0/5 Reason for renal biopsy   0.645Gross hematuria, n (%)2/24 (8.3)1/7 (14.3)0/5 Persistent proteinuria, n (%)18/24 (75.0)4/7 (57.1)5/5 (100.0) Nephrotic syndrome, n (%)1/24 (4.2)1/7 (14.3)0/5 Nephritic syndrome, n (%)2/24 (8.3)0/70/5 Nephrotic proteinuria recurrence, n (%)0/241/7 (14.3)0/5 Acute kidney injury, n (%)1/24 (4.2)0/70/5 Age at first kidney biopsy, mean (median)10.4 (8.3)10.9 (13.5)9.0 (9.4) Time from initial IgAV presentation in days, mean (median)80.0 (62.0)658.7 (150.0)192.2 (139.0)0.713† Presence of proteinuria on urinalysis, n (%)23/23 (100.0)6/6 (100.0)5/5 (100.0) 1.000Nephrotic proteinuria on urinary spot (> 0.2 g/mmol)12/18 (66.7)3/7 (42.9)2/5 (40.0)0.156Presence of hematuria, n (%)22/23 (95.7)6/6 (100.0)5/5 (100.0) 1.000Bloodwork results    Urea, mean (median)4.8 (4.6)3.8 (4.1)4.4 (4.5) 0.306†Creatinine, mean (median)54.8 (51.5)52.7 (56)50.4 (46)0.810†Albumin, mean (median)31.5 (33.0)33.7 (34)37 (39) 0.121†Serum IgA, mean (median)2.4 (2.4)2.27 (2.27)2.95 (2.95) NATable 3. Clinical and biochemical presentation at first renal biopsy classified based on IgAVN clinical evolution† Fisher’s Exact Test

9.  Monophasic diseaseRenal relapsing disease(IgAN type)Renal and purpuric relapsing disease p-valueM, mode1110.808 M0, n (%)9/24 (37.5)3/7 (42.9)2/4 (50.0) M1, n (%)15/24 (62.5)4/7 (57.1)2/4 (50.0) E, mode1010.322 E0, n (%)7/24 (29.2)5/7 (71.4)1/4 (25.0) E1, n (%)15/24 (62.5)2/7 (28.6)3/4 (75.0) S, mode001 1.000S0, n (%)15/24 (62.5)4/7 (57.1)2/4 (50.0) S1, n (%)9/24 (37.5)3/7 (42.9)2/4 (50.0) T, mode000 0.478T0, n (%)22/24 (91.7)6/7 (85.7)3/4 (75.0) T1, n (%)1/24 (4.2)1/7 (14.3)1/4 (25.0) T2, n (%)1/24 (4.2)0/70/4 C, mode011 0.164C0, n (%)10/23 (43.5)3/7 (42.9)0/4 C1, n (%)8/23 (34.8)4/7 (57.1)4/4 (100.0) C2, n (%)5/23 (21.7)0/70/4 Table 4. MEST-C score (Oxford score) on initial renal biopsy classified based on IgAVN clinical evolutionM : Mesangial score (M0, M1) ; E : endocapillary hypercellularity (E0, E1) ; S : segmental glomerulosclerosis (S0, S1) ; T : tubular atrophy (T0, T1, T2) ; C : cellular/fibrocellular crescents

10.  Monophasic diseaseRenal relapsing disease(IgAN type)Renal and purpuric relapsing disease p-valueIgA    1.000Negative, n (%)0/210/70/5 (+/-) , n (%)1/21 (4.8)0/70/5 Positive, n (%)20/21 (95.2)7/7 (100.0)5/5 (100.0) C3    0.804Negative, n (%)5/20 (25.0)1/7 (14.3)0/5 (+/-) , n (%)2/20 (10.0)1/7 (14.3)0/5 Positive, n (%)13/20 (65.0)5/7 (71.5)5/5 (100.0) MAC    0.642Negative, n (%)9/24 (37.5)2/7 (28.6)2/3 (66.7) (+/-) , n (%)5/24 (20.8)1/7 (14.3)1/3 (33.3) Positive, n (%)10/24 (41.7)4/7 (57.1)0/3 Presence of necrosis, n (%)3/22 (13.6)1/7 (14.3)1/5 (20.0) Table 5. Immunofluorescence staining on initial renal biopsy classified based on IgAVN clinical evolutionMAC : Macrophage activation complex

11.  Monophasic diseaseRenal relapsing disease (IgAN type)Renal and purpuric relapsing disease p-valueTreatment received, n (%)21/24 (87.5)6/7 (85.7)5/5 (100.0)1.000 Treatment choice     High dose corticosteroids (pulses), n (%)12/21 (57.1)6/6 (100.0)2/5 (40.0) 0.069Oral corticosteroids, n (%)18/21 (85.7)6/6 (100.0)4/5 (80.0) 0.778ACE inhibitor, n (%)16/21 (76.2)6/6 (100.0)5/5 (100.0) 0.475MMF, n (%)0/212/6 (33.3)0/5 0.050*Hydroxychloroquine, n (%)2/21 (9.5)3/6 (50.0)1/5 (20.0) 0.068Cyclophosphamide, n (%)2/21 (9.5)0/70/5 1.000Other**, n (%)2/21 (9.5)1/7 (14.3)2/5 (40.0) Table 6. Treatment throughout follow-up for IgAVN classified based on IgAVN clinical evolution **Other : Furosemide (1), amlodipine (1) Non renal indication : colchicine (2), IVIg (2), rituximab (1)ACE : Angiotensin-converting-enzyme ; MMF : Mycophenolate Mofetil

12. ConclusionInital presentation of IgAVFemale sex predominance in both renal (IgAN type) and renal/purpuric recurrent disease typeMore articular involvement in monophasic disease ; more digestive involvement in renal recurrent disease (IgAN type) More treatment at initial presentation in monophasic diseaseRenal presentationMore nephrotic proteinuria and lower serum albumin levels in monophasic diseaseSerum IgA levels elevated in most patients (19/25 ; 76%)Renal biopsy and pathologyMore renal biopsies performed in patients with recurrent diseaseNo difference on immunofluorescence staining and MEST-C scores between the three groupsTreatmentMost patients treated throughout disease courseMore aggressive treatment in renal recurrent disease (IgAN type) – more corticosteroid pulses (p = 0.069), hydroxychloroquine (p = 0.068) and MMF (p = 0.050)

13. Anticipated next steps… Extended intrarenal immune deposits analysis (C4d, CD89) and comparison of IgAVN findings to IgAN patientsAnalysis of circulating immune complex levels (sCD89-IgA, Gd-IgA, IgG-IgA, sCD89), which are likely involved in physiopathological processes of IgAVN (mirroring IgAN literature)Integration of clinical and immunopathological findings to inform decision making in regards to evolution and prognosis of IgAVN

14. Merci!karma.abukasm@umontreal.ca

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