Kidney disease associated with autoimmune disease

Transcription

1 Kidney disease associated with autoimmune disease Masaomi Nangaku Division of Nephrology and Endocrinology the University of Tokyo Graduate School of Medicine, Japan

2 M-type Phospholipase A2 Receptor as a pathogenic antigen in membranous nephropathy Beck et al. N Engl J Med 2009

3 Risk HLA-DQA1 and PLA2R1 Alleles in Idiopathic Membranous Nephropathy PLA2R1 HLA-DQA1 Stanescu et al. N Engl J Med 2011

4 PLA 2 R Ab level is an independent risk factor for not achieving remission after 12 months Hoxha E et al. JASN 2014

5 Autoantibody against thrombospondin type-1 domaincontaining 7A (THSD7A) in 10% of MN patients Tomas NM et al. N Engl J Med 2014

6 Lupus nephritis IgG4-related kidney disease Atypical HUS

7 Lupus nephritis

8 Association of Asian ethnicity with SLE activity an observational study from the Monash Lupus Clinic Golder et al. Lupus 2013

9 association between ACE I/D polymorphism and the presence of SLE disease and lupus nephritis The prevalence of DD genotype in SLE patients was lower than controls (OR 0.44 [95% CI ]) The prevalence of ID genotype was higher in LN patients compared to controls (OR 1.77 [95% CI ]) Pitipakorn et al. Int J Rheum Dis 2013

10 No association between ACE I/D polymorphism and SLE disease severity, either in patients with or without nephritis Pitipakorn et al. Int J Rheum Dis 2013

11 Weening et al. Kidney Int 2004 ISN/RPS 2003 classification of lupus nephritis Class I: minimal mesangial lupus nephritis Class II: mesangial proliferative lupus nephritis Class III: focal lupus nephritis Class IV: diffuse lupus nephritis Class V: membranous lupus nephritis Class VI: advanced sclerotic lupus nephritis

12 Weening et al. Kidney Int 2004

13 2015

14 Suggested treatment algorithm for resistant LN several therapeutic approaches may be tried, including prolonging the course of standard therapy, switching to MMF or intravenous cyclophosphamide, adding a CNI, using adjunctive plasmapheresis or immunoabsorption, and using B cell-targeted therapy with rituximab Kalloo et al. CJASN 2013

15 Monitoring activity of lupus nephritis Joint European League Against Rheumatism and European Renal Association European Dialysis and Transplant Association (EULAR/ERA-EDTA) recommendations Monitoring of egfr, proteinuria, urinary sediment, serum C3/C4, and serum antidsdna antibody levels are used to define activity although their individual predictive value for hard outcomes at particular time points is modest. Bertsias et al. Ann Rheum Dis 2012

16 Monitoring activity of lupus nephritis Joint European League Against Rheumatism and European Renal Association European Dialysis and Transplant Association (EULAR/ERA-EDTA) recommendations Although serum C3 has generally higher sensitivity than serum C4, both tests have modest specificity for active lupus nephritis. The diagnostic accuracy of serum antidsdna is also modest. Bertsias et al. Ann Rheum Dis 2012

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19 Common Treat proteinuria with RAAS (first) Treatment Class II Difference ACR: no immunosuppressive treatment EULAR/ERA-EDTA: proteinuria >1 g/day; low to moderate doses oral glucocorticoids alone or in combination with AZA KDIGO: proteinuria <1day; treat as dictated by extrarenal manifestations Proteinuria >3 g/day; corticosteroids or CNI GEAS: proteinuria >1~2 g/day and/or deteriorated renal function; steroids possibly plus AZA or MMF

20 Induction treatment Class III/IV without crescents Common Oral steroid with or without iv pulse methylprednisolone + ivcyc or MMF (induction) Difference Dosage and preferences for different severities and ethnic groups: Glucocorticoids: Tapering schedule: unclear ivcyc: In case of low-dose ivcyc, combine pulses MP

21 Induction treatment Class IV or IV/V with crescents Common No consensus Difference KDIGO, DWP, CARRA: same as without crescents ACR: ivcyc or MMF+ iv pulses MP + oral glucocorticoids; MMF and oral glucocorticoids at highest doses EULAR/ERA-EDTA: high dose ivcyc can also be prescribed GEAS: ivcyc + iv pulses MP

22 Common If nephroticrange proteinuria: oral steroid (0.5 mg/kg/d) combined with other immunosuppressants (except in GEAS) Induction treatment Class V Difference GEAS: also in patients with non-nephroticrange proteinuria; oral glucocorticoids up to 1 mg/kg/day (max 60 mg) combined with either ivcyc,mmf, AZA or CNIs Type of additional immunosuppressive medication: EULAR/ERA-EDTA: preferably MMF, alternatives; high-dose ivcyc, CNIs or rituximab ACR: MMF KDIGO: ivcyc, CNIs, MMF or AZA

23 CONSENSUS RECOMMENDATIONS FOR THE MANAGEMENT OF LUPUS NEPHRITIS IN ASIAN PATIENTS by Asian Lupus Nephritis Network (ALNN)

24 CONSENSUS RECOMMENDATIONS IN ASIAN PATIENTS: treatment of Class III or Class IV Induction treatment: combination immunosuppression comprising high-dose corticosteroids and an immunosuppressive agent (intravenous pulse CYC, MMF, or oral CYC) Intravenous pulse corticosteroid treatment should be administered to patients with crescentic involvement of 10% or more of the glomeruli on renal biopsy, or those with deteriorating renal function.

25 CONSENSUS RECOMMENDATIONS IN ASIAN PATIENTS treatment of Class III or Class IV Combination immunosuppression with corticosteroids and MMF is considered a standard-of-care treatment option. However, while the short-term efficacy was similar between MMF or CYC based induction treatment, CYC induction may be associated with more sustained remission and more favorable long-term renal outcome.

26 CONSENSUS RECOMMENDATIONS IN ASIAN PATIENTS treatment of Class III or Class IV The recommended target dose for MMF during the induction phase is g daily in Asian patients, and it is advisable not to reduce the daily dose of MMF to below 1.5 g within the first year, and not to go below 1 g daily within the second year in view of the reported association with increased risk of relapse.

27 CONSENSUS RECOMMENDATIONS IN ASIAN PATIENTS treatment of Class V The threshold for immunosuppressive treatment is proteinuria 2 g/day in patients with normal renal function and inactive lupus serology, while a lower threshold may apply in patients with deterioration in proteinuria or renal function or active lupus serology.

28 Lupus paradox: SLE in complement deficiency The classical pathway of complement is important for preventing SLE, but once the disease is established, complement may amplify the disease. Leffler et al. Ann Rheum Dis 2014

29 IgG4-related tubulointerstitial nephritis

30 IgG4-related tubulointerstitial nephritis 23 case:65-year-old in average sialadenitis in 80% of the patients autoimmune pancreatitis in 40% of the patients Sjögren s syndrome in 30% of the patients various renal functions (from normal to end-stage kidney failure) Saeki et al. Kidney Int 2010

31 Representative light microscopic histology Kawano et al. Clin Exp Nephrol 2011 a Dense lymphoplasmacytic infiltration with fibrosis in the interstitium with clear border between affected and unaffected areas

32 Representative light microscopic histology Kawano et al. Clin Exp Nephrol 2011 b Typical fibrosis c CD138 immunostain d IgG4 immunostain

33 (1)well-demarcated borders between involved and uninvolved areas (2)interstitial inflammatory cells comprising predominantly plasma cells and lymphocytes, with a high prevalence of IgG4-positive cells often admixed with fibrosis (3)peculiar features of interstitial fibrosis resembling a bird s-eye pattern (4)deposits visible by light and immunofluorescent microscopy in the tubular basement membrane, Bowman capsule, and interstitium Yamaguchi et al. Hum Pathol 2012

34 Characteristic CT imaging of IgG4-RKD Kawano et al. Clin Exp Nephrol 2011 a Multiple low-density lesions on enhanced CT. b Diffuse bilateral renal swelling.

35 Characteristic CT imaging of IgG4-RKD Kawano et al. Clin Exp Nephrol 2011 c A hypovascular solitary nodule. d Diffuse thickening of the renal pelvis wall with smooth intra-luminal surface

36 Proposed diagnostic criteria for IgG4-related tubulointerstitial nephritis Histology Plasma cell rich tubulointerstitial nephritis with >10 IgG4 + plasma cells/hpf field in the most concentrated field Tubular basement membrane immune complex deposits by immunofluorescence, immunohistochemistry, and/or electron microscopy Imaging Serology Other organ involvement Small peripheral low-attenuation cortical nodules, round or wedge-shaped lesions, or diffuse patchy involvement Diffuse marked enlargement of kidneys Elevated serum IgG4 or total IgG level Includes autoimmune panceatitis, sclerosing cholangitis, inflammatory masses in any organ, sialadenitis, inflammatory aortic aneurysm, lung involvement, retroperitoneal fibrosis Raissian et al. J Am Soc Nephrol 2011

37 Diagnostic algorithm for IgG4-related kidney disease Kawano et al. Clin Exp Nephrol 2011

38 atypical hemolytic uremic syndrome (atypical HUS)

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40 Definition of atypical HUS atypical HUS is a type of TMA that differs from STEC-HUS and TTP, with the latter being caused by markedly reduced ADAMTS13 activity. atypical HUS is a syndrome characterized by the triad of microangiopathic hemolytic anemia, thrombocytopenia, and AKI, which is similar to STEC-HUS.

41 secondary TMA

42 Clinical manifestations Factor H Factor I MCP C3 Factor B THBD Antifactor H prevalence 20-30% 4-10% 5-15% 2-10% 1-4% 3-5% 6% death or ESKD within 1 year after the onset 50-70% 50% 0-6% 60% 50% 50% 30-40% relapse 50% 10-30% 70-90% 50% 3/3 not in ESRD 30% 40-60% Relapse in the transplant 75-90% 45-80% < 20% 40-70% 100% 1 patient High titer Loirat & Frémeaux-Bacchi. Orphanet J Rare Dis 2011

43 Genetics and outcome of ahus: A nationwide French series Frémeaux-Bacchi et al. CJASN 2013

44 DEAP-HUS: Deficiency of CFHR and autoantibodypositive form of HUS Zipfel et al. Pediatric Nephrol 2010

45 Autoimmunity due to CFHR1 deficiency Bhattacharjee et al. J Biol Chem 2015

46 Plasma exchanges and immunosuppressive treatment improves the outcomes of anti-factor H Ab-associated HUS Sinha et al. Kidney Int 2014

47 2013

48 Kidney function Trial 1 Trial 2 Licht et al. Kidney Int 2015

49 2014

50 The prevalence of this mutation among the patients with PNH (3.2%) was similar to that among healthy Japanese persons (3.5%) Nishimura et al. N Engl J Med 2014

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52 Conclusion Inappropriate complement activation plays a crucial role in the pathogenesis of ahus. Because a number of complement regulatory proteins are involved, genetic analysis is often difficult and is inconclusive. Eculizumab is effective, and should be initiated early in the disease course.

53 Conclusion The markers of an active TMA (thrombocytopenia, anemia, elevated LDH) respond rapidly to treatment with eculizumab in virtually all patients with an underlying complement abnormality.

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