Systemic lupus nephritis or Lupus Nephritis.pptx

SLE nephritis

1. Lupus Nephritis February 29, 2024

2. Epidemiology Lupus nephritis (LN) more common in children (~60%) v/s adults (~40%) with systemic lupus erythematosus (SLE) Presents early in course of SLE ~85% in first year Significant cause of morbidity and mortality ~20-50% progresses to end stage kidney disease (ESKD)

3. Pathogenesis Complement activation Reduced DNAse1 production Activation of pDCs leading to Type 1 INF-alpha production Defects in pathways related to apoptosis and clearance of apoptotic debris Autoreactive Abs bind to exposed chromatin in apoptotic renal cells (INTRA-RENAL ICs) Inflammation and tissue damage Impaired apoptosis Increased immune activation in local milieu

4. Classification International Society of Nephrology/Renal Pathology Society (ISN/RPS) classification 2003 Based on renal biopsy findings- LM/IF/EM ‘Full-house’ immune deposits (all of IgG, IgM, IgA, C3, C1q, kappa and lambda light chain) If LN suspected but no ‘full-house’- reconsider diagnosis Non LN causes of ‘full-house’- Idiopathic Secondary (membranous nephropathy, IgA nephropathy, PIGN, MPGN, diffuse proliferative GN, amyloidosis, C1q nephropathy etc.)

5. 2003 ISN/RPS Classification of LN Class LM IF/EM I Minimal mesangial Normal Mesangial immune deposits II Mesangial proliferative Mesangial hypercellularity Mesangial matrix expansion Mesangial immune deposits Isolated subepithelial/ subendothelial deposits Class II

6. III Focal proliferative <50% of all glomeruli involved Lesions can be active/chronic/mixed Segmental/global Focal subendothelial immune deposits +- mesangial deposits

7. IV Diffuse proliferative >=50% of all glomeruli involved Lesions can be active/chronic/mixed Segmental/global Diffuse wire loop deposits Diffuse subendothelial immune deposits +- mesangial deposits

8. V Membranous Thickened basement membranes ‘Spikes’ in-between subepithelial immune deposits Global/segmental Can be combined with class III or IV Subepithelial immune deposits +- mesangial alterations

9. VI Advanced scelrotic >=90% of glomeruli sclerosed without residual activity

10. International nephron-pathology working group 2018 update to ISN/RPS 2003 classification Meeting held in 2016 Recommendations published in 2018 Mesangial hypercellularity- >=4 cells fully surrounded by matrix (excluding hilar region) Endocapillary hypercellularity ( endocapillary proliferation ) Clearer definition of crescents Elimination of segmental and global sub-divisions of class IV LN Modified National Institute of Health (NIH) activity and chronicity system to be used Future prospects Index for scoring severity of tubulointerstitial involvement Grading system for vascular lesions Bajema IM et al. Revision of the International Society of Nephrology/Renal Pathology Society classification for lupus nephritis: clarification of definitions, and modified National Institutes of Health activity and chronicity indices. Kidney International. 2018.

11. International nephron-pathology working group 2018 update to ISN/RPS 2003 classification Meeting held in 2016 Recommendations published in 2018 Mesangial hypercellularity- >=4 cells fully surrounded by matrix (excluding hilar region) Endocapillary hypercellularity ( endocapillary proliferation ) Clearer definition of crescents Elimination of segmental and global sub-divisions of class IV LN Modified National Institute of Health (NIH) activity and chronicity system to be used Future prospects Index for scoring severity of tubulointerstitial involvement Grading system for vascular lesions Bajema IM et al. Revision of the International Society of Nephrology/Renal Pathology Society classification for lupus nephritis: clarification of definitions, and modified National Institutes of Health activity and chronicity indices. Kidney International. 2018.

12. Interstitial inflammation, interstitial fibrosis and tubular atrophy (IFTA)- independently affect renal outcomes and survival Unit increase in interstitial inflammation grade/IFTA category= 1.5 to 2 x increase in risk of death d/t renal causes ISN/RPS limitation More glomerular oriented Does not reflect impact of tubulointerstitial lesions to the extent necessary Wilson PC. Interstitial inflammation and interstitial fibrosis and tubular atrophy predict renal survival in lupus nephritis. Clinical Kidney Journal. 2018 Apr 1;11(2):207–18. Tubulointerstitial involvement

13. Wilson PC et al. Interstitial inflammation and interstitial fibrosis and tubular atrophy predict renal survival in lupus nephritis. Clinical Kidney Journal. 2018 Apr.

14. Clinical features Syndrome Clinical features Expected pathological findings Isolated asymptomatic hematuria and/or non-nephrotic proteinuria >= 5 RBC/ hpf ( gross hematuria not characteristic of LN ) Spot U p :U c b/w 0.2-2 24 hr urine protein b/w 4-40 mg/m 2 /hr Class II Others if post treatment biopsy Acute nephritic syndrome Hypertension ( if present indicates severe disease ) Hematuria (usually microscopic) Variable proteinuria Cellular casts (active sediment) Class IV Class III

15. Syndrome Clinical features Expected pathological findings Nephrotic syndrome Spot U p :U c > 2 or 24 hr urine protein > 40 mg/m 2 /hr Hyperlipidemia Hypoalbuminemia, edema +- nephritic features Class V Class IV Class III Chronic kidney disease Persistently high creatinine/ low GFR Sequelae of CKD Prolonged proliferative LN Class V

16. Quantifying proteinuria ‘Given the cumbersome nature of 24-hour urine collection, and the possible unreliability in young or noncontinent children, spot urine protein/creatinine (or urine albumin/creatinine) determination greater than 0.2 mg/mg creatinine in a first-morning urine collection is a convenient and reliable method for evaluating and following LN in children. It also shows good correlation with 24-hour urine collection.’ ( Cassidy textbook) Matar HE et al. Correlation of 24-hour urinary protein quantification with spot urine protein:creatinine ratio in lupus nephritis. Lupus. 2012 Jul.

17. Real world experience Study Hematuria Proteinuria Hyper-tension Nephritic syndrome Nephrotic syndrome Deranged renal function PGIMER, 2015 (55/122 cSLE had renal involvement) 53 (43.4%) 55 (47.5%) 27 (22.1%) - - 15 (12.3%) NEIGRIHMS, 2023 (53 biopsy proven LN) 23 (43.3%) 31 (58.49%) 20 (37.7%) 25 (47.1%) INSPIRE cohort 2022 (288 cSLE ) 102 (35.41%) SGPGI, 2015 (134 LN, 92 biopsy proven) 55% 93% 32% 30% 18% AIIMS, 2009 (54 biopsy proven LN) 31 (57.4%) 52 (96.3%) 30 (55.6%) Pediatric Nephrology Centre, Hong Kong 2023 (92 biopsy proven LN) 23 (25%) 37 (40.2%) 25 (27.1%) Italian collaboration 2013 (161 biopsy proven LN) 52 (32.2%) 60 (40.3%) 44 (27.3%)

18. Diagnosis Renal biopsy in cSLE Absolute indications Relative indications Biopsy NOT indicated Nephrotic syndrome Acute nephritic syndrome Persistently deranged RFTs w/o alternative cause Urine casts Persistent proteinuria ( U p :U c > 0.2) Persistent microscopic hematuria (>5 RBCs/ hpf ) Urine testing not done before starting tx Newly diagnosed cSLE who is treatment naïve does not have abnormalities on urine routine and has normal S. creatinine

19. Groot Net al. SHARE initiative. Ann Rheum Dis. 2017 Dec. SHARE 2017

20. KDIGO 2024

21. KDIGO 2024 treatment of LN For all SLE patients (with or w/o LN): Hydroxychloroquine (HCQ) 5 mg/kg/d Benefits of HCQ 1 : Reduced flares Better rate of treatment response Slowed progression of kidney disease Improvement in lipid profile Increase in bone mass Adjunctive therapies for all patients Reduce complications related to disease itself or therapy 1. Dima A et al. Hydroxychloroquine in systemic lupus erythematosus: overview of current knowledge. Therapeutic Advances in Musculoskeletal. 2022 Jan.

22. Treatment of Class I/II LN (KDIGO 2024) In class I/II magnitude of proteinuria decides treatment If non nephrotic- treat based on extra-renal manifestations Nephrotic range proteinuria with Class I/II histology- Diffuse podocyte effacement on EM- lupus podocytopathy Treatment similar to Minimal Change Disease (MCD) Glucorticoids (GCs) till remission followed by maintenance with low dose GCs plus MMF/Azathioprine/CNIs Limited evidence wrt choice and duration of regimen

23. Treatment of Class I/II LN (SHARE 2017) Class I Class II Isolated class I LN- low dose oral GCs Class I LN with extra-renal manifestations- treatment decided based on the severity of extra renal manifestations Low dose oral GCs Start at 0.25-0.5 mg/kg/d (max 30 mg) Taper over 3 to 6 months If proteinuria persists at 3 months of tx or steroid dependent state Relook at renal biopsy slide by expert Can consider adding another DMARD ( Mtx /Aza/MMF/CNI/Cyc)

24. Treatment of proliferative LN

25. Induction therapy for Class III/IV LN

26. KDIGO 2024

27. CARRA 2012

28. EULAR recommendations 2023 induction therapy For active proliferative LN, acceptable regimens: GC (pulse f/b low dose oral) + Low dose CYC GC + MMF GC + MMF/CYC + Belimumab GC+ MMF + CNI (tac/ voclosporin ) Consider high dose CYC + MP pulse in patients at high risk of renal failure Reduced GFR Cellular crescents Fibrinoid necrosis Severe interstitial inflammation

29. Cochrane review 2018 on treatment of proliferative LN Compared newer regimes to CYC+GCs Primary outcomes Induction phase- death, progression to ESKD, complete renal remission (return to baseline S. creat , 24 hr urine protein <0.5g, no active sediment) Maintenance phase- risk of relapse Adverse effects of therapies compared

30. MMF vs CYC Outcome Relative effect (95% CI) Death 1.12 (0.61-2.06) ESKD 0.71 (0.27-1.84) Complete renal remission 1.17 (0.97-1.42) Alopecia 0.29 (0.19-0.46) Major infection 1.02 (0.67-1.54) Diarrhoea 2.42 (1.64-3.58) MMF+Tacrolimus vs CYC Outcome Relative effect (95% CI) Complete renal remission 2.38 (1.07-5.30)

31. Low vs high dose CYC Outcome Relative effect (95% CI) Complete renal remission 1.09 (0.63-1.86) ESKD 0.49 (0.05-5.2) Ovarian failure 1.73 (0.7-4.31) Major infection 1.44 (0.83-2.49) Leucopenia 0.82 (0.13-5.15)

32. Standard vs low dose GCs Outcome Relative effect (95% CI) Death 4.65 (0.23-93.95) Complete renal remission 0.93 (0.39-2.23) Major infection 4.64 (0.57-38)

33. Rituximab Outcome Relative effect (95% CI) Rtx+MMF vs MMF + placebo (LUNAR 2012) Rtx+CYC vs Rtx alone Death 5 (0.24-102.35) - Complete renal remission 0.86 (0.51-1.45) 0.9 (0.16-5.13) Major infection 1 (0.48-2.08) 0.9 (0.07-12.38) Leucopenia 3 (0.85-10.63) -

34. Recombinant human monoclonal Ab inhibiting B-cell activating factor (BAFF) FDA approved in Dec 2019 for treatment of cSLE aged 5 years and above Belimumab

35. Biopsy proven LN > 18 years of age Belimumab added to Standard of care (GC + CYC-Aza or GC + MMF) Received belimumab (10 mg/kg) or placebo on D1, D15, D29 and then q 4 weekly till wk 100 Excluded those with eGFR < 30 or history of dialysis in preceding year Primary efficacy renal response (PERR)- U p :U c < 0.7 eGFR within 20% of patient’s baseline and not less than 60 No use of rescue therapy for treatment failure BLISS LN trial

36. 2 year 6 month follow up Reduced flares Better preserved kidney function Most of the improvement restricted to Patients on MMF+GC backbone therapy Patients with non-nephrotic range proteinuria Outcome Belimumab (%) Placebo (%) Odds ratio (95% CI) P-value PERR @ wk 52 104 (47%) 79 (35%) 1.6 (1.1-2.4) 0.02 PERR @ wk 104 96 (43%) 72 (32%) 1.6 (1-2.3) 0.03 Complete renal response @ wk 104 67 (30%) 44 (20%) 1.7 (1.1-2.7) 0.02

37. CNIs have dual benefit in LN- Inhibit T cell activation and IL 2 release Stabilise podocyte cytoskeleton and reduce proteinuria Calcineurin inhibitors MMF vs Tacrolimus (Cochrane review 2018) Outcome Relative effect (95% CI) Death 1.10 (0.44-2.77) Complete renal remission 1.02 (0.83-1.26) ESKD 1.22 (0.51-2.91)

38. Compared to older CNIs More potent Consistent pharmaco-kinetics Therapeutic drug monitoring may not be necessary USFDA approval for treatment of adults with LN in February 2021 (with eGFR >= 45 mL/min/1.73 m 2 ) Voclosporin

39. RCT comparing Voclosporin to placebo over and above standard of care (SoC) regimen SoC regimen: MMF (target 2 g/d) and GC (2 MP pulses 500 mg f/b 20-25 mg prednisolone tapered to 2.5 mg by wk 16) Primary endpoint (measured at wk 24 and wk 52 respectively in AURA LV and AURORA 1) : Renal response ( U p :U c <= 0.5) GFR >= 60 or within 20% of baseline Prednisolone dose < 10 mg/d for at least 8 weeks prior to endpoint measurement AURORA trial

40. Voclosporin vs Placebo Outcome Odds ratio (95% CI) Complete renal response Month 12 2.30 (1.30-4.05) Month 24 1.81 (1.04-3.16) Month 36 1.74 (1-3.03) Renal flare 0.85 (0.42-1.73)

41. Maintenance therapy for Class III/IV LN

42. KDIGO 2024

43. Cochrane review 2018 on maintenance treatment of proliferative LN AZA + GC vs MMF + GC Outcome Relative effect (95% CI) Death 1.15 (0.34-3.87) Renal relapse 1.75 (1.20-2.55) ESKD 1.70 (0.52-5.54) Doubling of S. creatinine 2.19 (1.03-4.66) Major infection 1.08 (0.60-1.96) Leucopenia 5.61 (1.68-18.72) GI side effects Nausea 1.08 (0.65-1.80) Diarrhoea 0.74 (0.31-1.73) Vomiting 0.81 (0.18-3.62)

44. Few RCTs about treatment of isolated class V LN If coexisting class III/IV LN- treat as per proliferative LN protocol If isolated class V- severity of proteinuria decides treatment Treatment of Class V LN KDIGO 2024

45. KDIGO 2024

46. Induction- Low dose GC (0.5 mg/kg/d) + MMF Maintenance- MMF/AZA Non-responders- consider CNIs/CYC/ Rtx Treatment of Class V LN SHARE 2017

47. In trial set-up response often analysed by 6-12 mo In real world practice May take 3-6 mo for complete renal response Trend more important than absolute value and single cut off time point ALMS trial- favourable renal outcomes if at wk 8 Normalisation of complement levels 25% or more fall in proteinuria Clinical response not always = cessation of intra-renal activity (?role of repeat biopsy) Assessing response to therapy

48. Always rule out non-compliance to treatment Non-compliance rates ~ 60% in SLE Consider switch from oral to i/v For drugs like MMF/Tac Variable bioavailability Check trough levels Effect of switching from MMF to CYC or vice-versa not investigated Can consider Rtx Extended CYC pulses Unsatisfactory response to therapy

49. LN relapse If complete remission initially- relapse in 39% If only partial response- relapse in 64% As per CARRA 2012 Renal flare Proteinuric flare (nephrotic) Non- proteinuric flare (nephritic) Repeated U p :U c values > 0.5 (if baseline is complete remission) Doubling of U p :U c to > 1 (if baseline is partial remission) Increase or recurrence of active urinary sediment ( hematuria /casts) +- increase in proteinuria

50. Increase in proteinuria can be d/t- flare of ds v/s progression to CKD Points in favour of increased disease activity Associated hematuria /sediments Sudden, rapid increase in proteinuria Disease activity markers (hypocomplementemia, high anti dsDNA) If uncertainty persists consider repeat renal biopsy Investigations for renal flare

51. KDIGO 2024 SHARE 2017 No major diff b/w tx of initial episode and flare Can consider tx same as initial episode or alternative first line tx For repeat CYC calculate lifetime exposure @ >= 8 g/m 2 50% pts develop ovarian failure @>= 36g increased risk of malignancy Restart or increase GC dose (can consider pulse MP) Can consider switching to alternative regimen Consider adding Rtx Treatment of renal flare

52. 2018 study by Yap et al, Hong Kong Biopsy proven LN pts from June 1993 to May 2015 records screened for ‘asymptomatic serological reactivation’ (ASR) absence of renal or systemic manifestations of active SLE with dsDNA change from negative to positive or doubling of positive titres Some pts with ASR, based on physician discretion received pre-emptive immunosuppression Oral GC increased to 0.4-0.5 mg/kg/d and then tapered slowly MMF increased to 1.2-1.5 g/d or AZA increased to 100 mg/d for min 12 wks and then tapered Pre-emptive treatment

53. Indications of repeat renal biopsy (Cassidy’s)- Persistent/increasing proteinuria Worsening RFTs New development of active urine sediment Poor response to tx ?Flare ?Decision on stopping immunosuppression post remission Clinical and histological remissions (activity index 0) can be discordant Time frame for histological remission- variable for different lesions Persistent activity on histology- maybe associated with higher relapse risk Whether to intensify treatment based on repeat biopsy- ongoing ReBIOLUP trial Rodriguez-Ramirez S et al Kidney Biopsy in Management of Lupus Nephritis: A Case-Based Narrative Review. Kidney Medicine [Internet]. 2024 Feb 1. Repeat renal biopsy

54. Indications of repeat renal biopsy (Cassidy’s)- Persistent/increasing proteinuria Worsening RFTs New development of active urine sediment Poor response to tx ?Flare ?Decision on stopping immunosuppression post remission Clinical and histological remissions (activity index 0) can be discordant Time frame for histological remission- variable for different lesions Persistent activity on histology- maybe associated with higher relapse risk Whether to intensify treatment based on repeat biopsy- ongoing ReBIOLUP trial Rodriguez-Ramirez S et al Kidney Biopsy in Management of Lupus Nephritis: A Case-Based Narrative Review. Kidney Medicine [Internet]. 2024 Feb 1. Repeat renal biopsy

55. Prognosis Adult data Response rate at end of induction= 50% Response during maintenance= 60-90% Relapse in 40% (median 32-79 mo ) Pediatric Risk of CKD 23% @ 5 yr and 36% @ 10 yr 5 year survival ~ 90% ESKD- RRT (HD/transplant) Post transplant recurrence in 2-30% Leading cause of death in LN Infectious Cardiovascular complications

56. Poor prognostic factors African-American race GFR < 60 mL/min/m2 at presentation Nephrotic range proteinuria Hypertension Delayed diagnosis Higher chronicity index Interstitial inflammation Interstitial fibrosis and tubular atrophy (IFTA) Lack of response to 6 mo of induction therapy

57. PGIMER study 2015

58. “ What is man, when you come to think upon him, but a minutely set, ingenious machine for turning with infinite artfulness, the red wine of Shiraz into urine?”