BSIM 2013 Workshop Nephrology Glomerulonephritis. K.M. Wissing MD PhD Department of Nephrology UZ Brussel

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1 BSIM 2013 Workshop Nephrology Glomerulonephritis K.M. Wissing MD PhD Department of Nephrology UZ Brussel

2 Case number 1 83-year old man Medical history Arterial hypertension Primary hyperparathyroidism with resection of an adenoma several years ago Surgical repair of inguinal hernia Treatment: Aprovel 150 mg/d, Aggrenox 200 mg/day and N- acethylcysteine. Infection of the upper respiratory tract in August 2011 with persistent cough and non-purulent sputum. No fever. Persisting in spite of cessation of smoking over the month. Loss of weight of 2 kg from 64 to 62.

3 Case history Pneumology consultation: 29/09/2011: only slight obstruction on LFT. 25/10/11: Hospitalisation in pneumology for intermittent fever, palpitations, anorexia, asthenia, weight loss) Physical examination relatively normal except for wasting (BMI 19), Extensive workup (CT thorax, MR abdomen, PET scan thorax, TEE, colonoscopy, temporal artery biopsy)

4 Laboratory analysis Biology 10/2011: Normal renal function (Urea 45, creatinine 1.0) Normocytic anemia (Hb 10.8) Inflammatory syndrome (CRP 150 mg/l) Hypoalbuminemia and low cholesterol No proteinuria Microscopic hematuria (97/µL)

5 Case 1 autoimmune tests baseline

6 Case presentation Important bilateral centrilobular emphysema on CT. Some small lymph nodes of moderate metabolic activity at the mediastinal and axillary level Atrial Flutter with anticoagulation. Villous adenoma of the colon with endoscopic resection Conclusion: Inflammatory syndrome, fever and alteration of the general condition probably due to ANCA vasculitis. Treatment: usual treatment + Trazodone + Fraxiparine

7 Case presentation 18/11/2011 Consultation of internal medicine: Sudden development of diplopia. Rest of clinical condition in status quo Ureum 42 mg/dl Creat 1.38 mg/dl Alb 2.7 g/dl CRP mg/dl Hb 8.9 g/dl Persistent microscopic hematuria. Proteinuria 0.48 g/l (0.4 g/g creat) Diagnosis of nervus abducens (VI) paresis on the left side.

8 How to proceed Additional work-up? Biopsy? Which organ to biopsy? Treatment? Which treatment regimen to chose?

9 Kidney biopsy Kidney biopsy 18/11/2013: 9 glomeruli (2 with complete sclerosis). Numerous red blood cells in the tubular cells. Interstitial inflammation and signs of tubulitis. 1 glomerulus with necrosis (presence of fibrin) with extracapillary proliferation of podocytes. Immunofluorescence negative.

10 Treatment of ANCA vasculitis KDIGO Guidelines June 2012 (kdigo.org)

11 NORAM Study Exlusion criteria: Organ or life-threatening manifestations: hemoptysis with lung infiltrates, cerebral infarction, progressive neuropathy Creat >150 µmol/l, Proteinuria >1g/day Treatment regimen: MTX (N=51): 15 mg/w increasing to mg/w. Stop by month 12 CYC (N=49): oral 2 mg/kg (max 150 mg); 1.5 mg/kg after remission. Stop month 12 Both groups: Pred: 1 mg/kg taper to 5 mg/d Stop month 12 De Groot et al. Arthritis Rheumatism 2005

12 NORAM Induction of remission Survival free of relapse 46.5% 69.5% Two deaths in both groups More leucopenia in CYC group more liver dysfunction in MTX group No difference in incidence of infections De Groot et al. Arthritis Rheumatism 2005

13 Treatment of ANCA vasculitis Ledertrexate 2.5mg: 1 x 6 tablets /week. Medrol 32mg: 1 x 2 tablets/day. Folavit 0.8 mg/day Pantoprazole eg 20mg: 1 x 1 /day Steovit forte 1000mg/800ie: 1 x 1 /day. Nobiten 5mg: 1 x 1 tablet/day. Fraxodi ie axa pe/0.6ml s.c.: 1 x /day. Pentamidine 300mg 1x/month D Cure 1/week

14 Evolution of ANCA and anti-pr3 antibodies 19/11/13 Ledertrexate 15 mg Medrol 64 mg 07/12/13 Medrol 32 mg/day 15/02/13 Medrol 24 mg/day 09/05/12 Medrol 12 mg /day 23/08/12 Medrol 6 mg/day 28/11/12 Medrol 4 mg/day 3/7/13 Stop Medrol March 2013 Ledertrexate 7.5 mg/week 4/12/13 Ledertrexate 5 mg/ week

15 Follow up 5/12/2011 (3 weeks after start of treatment): Slight pain at the right testis (at palpation and mobilization) with hard mass of about 5 cm diameter. Strong suspicion for a tumor at ultrasound examination. 6/3/2012: Hospitalization for pneumonia of the left lower lobe with good evolution under IV Amoxicilline Clavulanate therapy Normalization of microscopic hematuria and proteinuria from 02/2012. Normalization of CRP from March 2012 (after resolution of pneumonia). 21/3/2012: No more pain but persistent mass. Surgical removal to exclude tumor. Pathology ischemic necrosis with granuloma. Blood vessels with images of vasculitis and fibrinoid necrosis.

16 Necrotizing vasculitis of the testis Necrotizing vasculitis with granuloma formation compatible with granulomatous microscopic polyangitis of the testis

17 Case number 2 27 year-old women: 2006 microscopic hematuria. Sometimes macroscopic hematuria during infectious episodes. Biopsy in another hospital with mesangiocapillary glomerulonephritis and isolated deposits of C3. IgA negative (original and control staining) Proteinuria of about 4 grams with normal renal function. Treatment with ace inhibitors and reduction of proteinuria to about 1 gram/day. 17 titel

18 Case number 2 No more follow up between 2009 and /2011: Diagnosis of renal insufficiency during surgery for endometriosis 04/2012: Blood analysis by the general practitioner shows creatinine of 1.55 mg/dl and proteinuria of 5.4 g/24 h. 18 titel

19 Laboratory results 30/05/12 10/04/12 06/05/11 27/07/09 31/03/08 Urea mg/dl Creatinine mg/dl egfr ml/min 38. Hemoglobin g/dl Protein g/dl 6,7 6,1 Albumin g/dl /03/2008 C3: 0.71 g/l (N: ); C4: 0.2 (N: ) 30/05/2012 (UZ Brussel) IgA: 355 mg/dl; complement C3c: 84 mg/dl (N: mg/dl); complement C4: 27 mg/dl; hemolytic complement CH50: 422 U/ml ANA: neg; ANCA: neg; HBV neg, HCV neg 19 titel

20 Laboratory analysis 30/05/12 10/04/12 27/07/09 19/09/08 Volume ml/24 u sample sample Proteïnurie g/l g/g creat g/24 uur 5,44 8,1 2,86 7,3 5,4 0,34 0,5 0,6 0,99 1,13 MAU mg/g creat WBC/µl /µl 6 11 RBC/µl /µl Aerobe kweek kiemen/ml Neg Neg 20 titel

21 Evaluation of alternate complement pathway 21 titel

22 Differential diagnosis C3 glomerulopathy Inherited or acquired defect in control of activation of alternate complement pathway No effect of immunosuppressive treatment Recurrence on an eventual renal transplant IgA nephropathy Error in first biopsy Potential for immunosuppressive therapy Better prognosis in case of renal transplantation 22 titel

23 Additional workup Repeat kidney biopsy Kidney biopsy: mesangial expansion and increased mesangial cellularity. 3/10 glomeruli with sclerosis. Moderate tubular atrophy and significant tubular atrophy with thickened basal membranes. Fibrosis score 3/6 IF 3+ positive for IGA and 3+ for C3 Conclusion: IgA nephropathy. 23 titel

24 IgA nephropathy 24 titel

25 IgA Etiology and Pathogenesis Unknown: racial disparities familial aggregation suggest important genetic background Complex disease with gene-environment and immunological interactions. Hypothesis Environmental stimulus triggers IgA secretion Production of polymeric Gal-deficient IgA1 that form immune complexes Mesangial binding of macromolecular complexes triggering local inflammation Glomerulonephritis

26 IgA nephropathy IgA nephropathy (Gd-IgA1) GalNac: N-acethyl-galactosamine Gal: galactose NeuAc: sialyc acid Normal Beerman I et al. Nat Clin Pract Nephrol 2007; 3:325

27 Sporadic IgA nephropathy 78% of patients with sporadic IgAN had increased Gd-IgA1 25% of relatives (28% 1st degree, 17% 2d degree) with increased Gd-IgA1 Genetic model compatible with major dominant gene. Patients with low Gd- IgA1 also have relatives with low Gd-IgA1 Gharavi AG et al. J Am Soc Nephrol 19: 1008, 2008

28 Identification of B-cell clones producing glycan-specific anti-gd-iga1 antibodies 54 of 60 patients with binding above P95 of healthy controls Correlation of rigg levels with clinical severity Sensitivity 88% en specificity 95% as predictive test in ROC analysis Suzuki H et al. J Clin Invest 119:1668; 2009

29 Treatment of IgA Nephropathy KDIGO Guidelines June 2012 (kdigo.org) 29 titel

30 Immunosuppressive therapy in IgA nephropathy KDIGO Guidelines June 2012 (kdigo.org) 30 titel

31 Pozzi regimen Pozzi et al JASN titel

32 Manno Lv regimen Manno et al NDT 2009 Lv et al AJKD titel

33 Role of combination therapy in the treatment of IgA nephropathy Renal transplant patients Aggressive recurrence in exceptional although most of these patients had aggressive disease on their native kidneys Possibility to reduce the dose of steroids in order to improve the side effect profile Antibody-mediated disease. Potential for IS agents that reduce Ab production Problem of inadequate studies MMF monotherapy without effect AZA added to Pozzi regimen : no benefit 33 titel

34 KIDIGO guidelines 34 titel

35 Combination therapy in patients with aggressive IgA nephropathy Cyclophosphamide oral 1.5 mg/kg for 3M then AZA 1.5 mg/kg thereafter Pred 40 mg/day with progressive taper Control group with supportive care Balantine JASN titel

36 Combination therapy with AZA and steroids in children Yoshigawa CJASN titel

37 How to treat our patient? GFR <50ml/min High sclerosis score on biopsy No crescents on renal biopsy Reluctant to experience severe steroidmediated side effects Conservative care? High dose steroids for 6 months? (Cyc)-AZA in combination with lower dose of steroids although not recommended in guidelines? 37 titel

38 Combination therapy with Azathioprine and steroids Discussed extensively with the patient Physician and patient reluctant to use high dose long-term steroids Outside indications for CYC and risk for fertility in young woman Good results of proposed strategy in transplant recipients Good personal experience by doctor Not in accordance with current guidelines Low risk of serious adverse effects Medrol 32 mg (0.5 mg/kg) with rapid taper in combination with Imuran 100 mg (1.5 mg/kg) 38 titel

39 Evolution under combination therapy with AZA and low-dose steroids Immunosupp 8/11/13 28/06/13 25/03/13 23/01/13 7/12/ /10/12 13/09/12 7/08/12 11/07/12 Aza dose MPDS dose Proteinuria/ Hematuria Proteinuria g/l 0.5 negative negative Proteinuria g/g creat WBC /µl RBC /µl Urine Culture negative negative Lactobacill us species negative negative Lactobacill us species negative negative negative Creatinin slightly improved over last year: 1.55 mg last FU 39 titel

40 Case number 3 23 year-old women No significant medical history Hairdresser; non-smoker No medical therapy except hormonal contraception June 2011 sudden development of a nephrotic syndrome. 40 titel

41 Nephrotic syndrome Diffuse edema of the lower extremities en palpebral edema Weight increase from 51 to 56 kg 2-3 days. Laboratory analysis: Albumin 2 g/dl, Total Cholesterol 456 mg/dl; LDL cholesterol 283 mg/dl; Proteinuria 18 g/day (nonselective proteinuria) Normal kidney function and normal urinary sediment Normal ultrasound of the kidneys 41 titel

42 Differential Diagnosis?? Minimal change disease Focal Segmental glomerulosclerosis Membranous glomerulonephritis Amyloidosis (Diabetic nephropathy, renal vein thrombosis.) 42 titel

43 Additional Workup?? Kidney Biopsy Baseline Bone Mineral Density 43 titel

44 Minimal change disease 44 titel

45 Treatment KDIGO Guidelines June 2012 (kdigo.org) 45 titel

46 Treatment Date Medrol dose Proteinuria 30/6/11 48 mg 18 g/day Full remission in 2 weeks with weight loss of 5 kg. 46 titel

47 Steroid taper 47 titel

48 Recurrence of MCD 48 titel

49 What to do next? Iatrogenic Cushing Multiple striae on the back / Hirsutism Additional examinations? Repeat biopsy? Other? Therapy? Lumbar BMD (QCT) Date T-Score BMD 05/07/ mg/ml 29/10/ mg/ml 49 titel

50 What to do next? KDIGO Guidelines June 2012 (kdigo.org) 50 titel

51 What to do next? 25/12/12: Start Advagraf 3 mg/day with same dose of steroids 07/02/13: Proteinuria Neg - Stop steroids Complete remission with tacrolimus monotherapy and trough levels between 2 and 4 ng/ml Lumbar BMD (QCT) Date T-Score BMD 05/07/ mg/ml 29/10/ mg/ml 28/10/ mg/ml 51 titel