Managing Lupus Nephritis: Case Discussions Jai Radhakrishnan, MD, MS Professor of Medicine Columbia University
Objectives
Clinico-Pathological Correlations Current Treatment of Lupus Nephritis Induction Maintenance “Refractory” Lupus nephritis
Special Situations
CLINICOPATHOLOGIC CORRELATIONS
Case: ARS A 22-year-old female with known SLE for 2 years (hydroxychloroquine, intermittent steroids for rash , referred with proteinuria 3.8 g/day, 20-25 RBC/HPF and serum creatinine 1.3 mg/dL (baseline 0.7mg/dL), low complements, Positive anti DNA ab. ANCA negative. Hemogram is normal
What would you expect to find on the kidney biopsy? 1. Mesangial proliferation 2. Endocapillary proliferation
3. Epimembranous deposits without proliferation 4. Microthrombi in the glomerular vessels
Case:ARS Question RENAL BIOPSY • 75% of glomeruli involved • Endocapillary proliferation was present in 20-30% of the glomerular tuft in most involved glomeruli • 2 of 22 glomeruli with non circumferential crescents. • A few areas of fibrinoid necrosis • Immunofluorescence : “full house” staining with IgG, IgM, C3,C1q, kappa and lambda. • Infiltrate composed of lymphocytes and macrophages occupying 30% of the interstitium. No fibrosis What is her class of lupus nephritis? 1. Class II 2. Class III 3. Class IV S 4. Class IV G 5. Class V
Indications for Renal Biopsy in Lupus Patients Protein excretion greater than 500 mg/day.
An active urinary sediment with hematuria (five or more red blood cells per high-power field, most of which are dysmorphic) and cellular casts.
A rising serum creatinine that is not clearly attributable to another mechanism.
Arthritis Care Res (Hoboken). 2012 Jun;64(6):797-808.
Terminology Segmental< 50% of a Glomerulus
Focal Segmental
Diffuse Segmental Focal 50%)
Global > 50% of a Glomerulus
Diffuse Global Focal Global
ISN/RPS Classification of LN
Kidney Int. 2004 Feb;65(2):521-30.
Class I:
Minimal mesangial LN
Class II:
Mesangial proliferative LN
Class III:
Focal LN (50% of all glomeruli) (Diffuse Global or Segmental)
IV-S (A): Active lesions: diffuse segmental proliferative LN IV-G (A): Active lesions: diffuse global proliferative LN IV-S (A/C): Active and chronic lesions IV-G (A/C): Active and chronic lesions IV-S (C): Chronic inactive lesions with scars IV-G (C):Chronic inactive lesions with scars
Class V:
Membranous LN
Class VI:
Advanced sclerotic LN (90% sclerosed, no activity)
Figure 1
Segmental (LN IV-S) vs. global (LN IV-G)
Diffuse Segmental • More necrosis • Less immune complex • Lower response to IVC
Diffuse Global • More proliferation • More wire loops • Better response to IVC
Kidney International 2007 71, 491-495
ARS Case A 35-year-old woman with known SLE x 5 years on hydroxychlorquine, intermittent NSAID use is admitted with severe edema.
Physical exam: Normotensive. BP 110/70 Laboratory: Urine 4+ alb, 1+ heme, 3-4 RBC Serum: Creatinine 1.2mg/dL, Alb=2.0g/dL ANA 1:640, Anti DNA: moderate elev. C3, C4:normal
RENAL BIOPSY: LM: Mild mesangial proliferation, IF: IgG, IgM and IgA, C1q in the mesangium.
How would you treat her?
ARS Question 1. Diuretics and RAS inhibitors
2. Corticosteroids only 3. Mycophenolate and corticosteroids 4. Tacrolimus and corticosteroids 5. Rituximab and corticosteroids
Podocytopathy (“Minimal Change Disease”) in SLE
7 pts with SLE + MCD All pts with edema, sudden NS ( prot > 9 g/d ), hypoalbuminemia.
Biopsy: – diffuse foot process effacement – only mesangial EDD
Treatment: steroids rapid remit
Dube, Markowitz, Radhakrishnan, Appel, D’Agati Clin Neph 57:120-127, 2002.
Lupus Podocytopathy: A Distinct Entity Parameter
Features
Clinical
Diagnosis of SLE by ACR criteria; full nephrotic syndrome (i.e., nephrotic-range proteinuria, hypoalbuminemia, and edema)
Light microscopy
Normal glomeruli or FSGS; mesangial proliferation permitted [endocapillary proliferation, necrosis, and/or crescents not permitted]
Immunofluorescence microscopy
Deposits absent or confined to mesangium
Electron microscopy
Diffuse and severe foot process effacement (typically >70%); deposits absent or confined to mesangium
CJASN March 2016, doi: 10.2215/CJN.01880216
N=10 MPO ANCA =9 CYC+Steroids
3 deaths 5 remission 1 no response
Clin J Am Soc Nephrol. 2008 May;3(3):682-90
Crescentic Lupus Nephritis
Kidney Int. 2013 Apr;83(4):715-23
Renal Vascular Lesions Immune complex
Non inflammatory necrotizing vasculopathy
True vasculitis
Electron dense deposits
TMA
Atherosclerosis
Vasc Lesions & Renal Outcome
Interstitial Lesions and Outcome
Inflm.
IF
TA
Kidney Int. 2010 May;77(9):820-9
INITIAL THERAPY
12.1: Class I LN (minimal-mesangial LN) 12.1.1: We suggest that patients with class I LN be treated as dictated by the extrarenal clinical manifestations of lupus. (2D)
12.2: Class II LN (mesangial-proliferative LN) 12.2.1: Treat patients with class II LN and proteinuria 3 g/d be treated with corticosteroids or CNIs as described for MCD. (2D)
Case ARS A 22-year-old female with known SLE for 2 years (hydroxychloroquine, intermittent steroids for rash , referred with proteinuria 3.8 g/day, 20-25 RBC/HPF and serum creatinine 1.3 mg/dL (baseline 0.7mg/dL), low complements, Positive anti DNA ab. ANCA negative. Hemogram is normal
Renal biopsy shows Class IV-S(A) lupus nephritis. 30% interstitial inflammation
How would you treat her? 1.
Diuretics and RAS inhibitors for 3 months, then reevaluate with biopsy
2.
Corticosteroids only
3.
Mycophenolate and corticosteroids
4.
Tacrolimus and corticosteroids
5.
Rituximab and corticosteroids
Induction Protocols in Proliferative LN ACR- KDIGO Treatment guidelines – MMF + Glucocorticoids
CYC + Glucocorticoids
EURO LUPUS Low-dose CYC
6
months
Anti-MIF & LN Ad Board, July 13, 2011
or
NIH study Hi-dose CYC
6 months
KEY CLINICAL TRIAL
N Engl J Med 1986; 314: 614–619.
Patients Free of Failure (%)
ELNT:Low Dose vs Std Dose Cyclophosphamide
KEY CLINICAL TRIAL
100
Low dose High dose
90 80 70 60 50 0
0
12
24
36
48
60
Follow-up (months) Houssiau FA, et al. Arthritis Rheum. 2002;46:2121-2131.
Success of Induction Regimens: KEY CLINICAL TRIAL e.g. ALMS TRIAL
Proportion of patients reponding (%)
: ~ 50% Response at Month 6 100
80
60
56.2%
53.0%
40
20
MMF
IVC
0
J Am Soc Nephrol. 2009 May;20(5):1103-12.
Low-dose Intravenous Cyclophosphamide vs. Oral Mycophenolate Mofetil are Similar
Kidney Int. 2015 Oct 21. doi: 10.1038/ki.2015.318.
J Rheumatol. 2011 Jan;38(1):69-78
Rituximab: Anti-CD20 Monoclonal Antibody Rituximab - FDA approved for the treatment of relapsed or refractory, CD20-positive B-cell NH Lymphomas and Rheumatoid Arthritis
• Chimeric murine/human monoclonal antibody • Used in many glomerular diseases in uncontrolled trials
• Over 400 SLE pts treated in uncontrolled trials
31
Rituximab +MMF/Steroids (LUNAR): Week 52 Placebo (N=72)
Proportion of Patients
60
KEY CLINICAL TRIAL
Rituximab (N=72) 54.1
50
P=0.55*
40
30
30.6
30.6
26.4
20
43.0
15.3
10 0
Complete Renal Response (CRR)
Partial Renal Response (PRR)
No Response (NR)
Arthritis Rheum. 2012 Apr;64(4):1215-26 32
Multitarget Therapy ( MMF,Tacrolimus,Steroids ) vs IV Cyclophosphamide + Steroids for Induction Treatment of LN: A Randomized, Controlled Trial
Ann Intern Med. 2015 Jan 6;162(1):18-26.
Class III/class IV LN: Regimens for Initial Therapy (KDIGO)
• Oral prednisone, initial dose up to 0.5–1 mg/kg/d, tapering over 6–12 months according to clinical response. • IV methylprednisolone is sometimes added initially for severe disease. Kidney International Supple`ments (2012) 2, 221–232
Conclusions: Induction Therapy No difference between IVC and MMF as induction – MMF: Unknown long term outcome o MMF: Unknown response to severe/high risk lupus nephritis
oRituximab does not provide additive effects over MMF/steroids
oMultitargeted therapy may have a role in Class V + proliferative LN (earlier reduction of proteinuria)
MAINTENANCE THERAPY
ARS Case A 35-year-old woman with Class IV S (A) lupus nephritis was treated with pulse->tapering oral corticosteroids for six months. (currently prednisone 10mg, MMF 3g/day)
Baseline labs: Urine 4+ alb, 1+ heme, 3-4 RBC. UP/C 2 Serum: Creatinine 1.2mg/dL, Alb=2.0g/dL ANA 1:640, Anti DNA: moderate elev. C3, C4:normal
Month 6 Labs: Urine 1+ alb, Trace heme, 0-2 RBC. UP/C 0.6 Serum: Creatinine 0.8 mg/dL, Alb=3.5g/dL ANA 1:640, Anti DNA: moderate elev. C3, C4:normal
How would you treat her? 1. Continue MMF/prednisone at present doses 2. Switch to IV cyclophosphamide and increase prednisone 3. Reduce MMF to 1g bid, and taper prednisone 4. Add rituximab
KDIGO Definitions: Response to Therapy in LN Complete response: – Return of SCr to previous baseline, plus
– Decline in the uPCR to 3000 mg/g [>300 mg/mmol]), improvement requires a X>50% reduction in uPCR, and a uPCR of daily GC
6 months
MMF induction
Maintenance Therapy for WHO Class IV LN: Mycophenolate Mofetil vs. AZA vs. IVC.
KEY CLINICAL TRIAL
N = 59 (sig. Black and Hispanic pts) Monthly IV cyclophosphamide 0.5-1.0 g/M2 x 7
Q3 months IVC 1-3 years
AZA 1-3mg/kg/d MMF 500-3000mg/d
Contreras G, et al. N Engl J Med. 2004 Mar 4;350(10):971-80
MMF/AZA are Superior to 3-monthly IVC (Death or Renal Failure)
Contreras G, et Contreras, G. et al. N Engl J Med 2004;350:971-980
al. N Engl J Med. 2004 Mar 4;350(10):971-80
MAINTAIN Nephritis Trial
KEY CLINICAL TRIAL
All patients from D1 to W12 Euro-Lupus Regimen From W12 (whatever the response; randomization performed at baseline)
AZA
MMF
Houssiau et al., Ann Rheum Dis, 2010
42 42
MAINTAIN Nephritis Trial Primary endpoint: Time to renal flare Analysis by intention-to-treat
Houssiau et al., Ann Rheum Dis, 2010 43 43
ALMS Maintenance Trial
KEY CLINICAL TRIAL
20-40% relapse rate
44
12.4: Class III LN (focal LN) and class IV LN (diffuse LN)—maintenance therapy 12.4.1: We recommend that, after initial therapy is complete, patients with class III and IV LN receive maintenance therapy with azathioprine (1.5–2.5 mg/kg/d) or MMF (1–2 g/d in divided doses), and low-dose oral corticosteroids (IVC, IVC->MMF)
Non- responder add CNI
OR Add rituximab (1g q2weeks x 2 doses)
+ + IVIG
LUPUS MEMBRANOUS NEPHROPATHY
Case Presentation A 24 year old female presents to the ED with pleuritic chest pain and hemoptysis.
A CXR shows a R LL infiltrate She is diagnosed with pneumonia discharged home on antibiotics
Returns in 1 week with severe shortness of breath and LE edema
Laboratory Urine= 5RBC, 4+ protein UVPr= 8g/day Chol= 450mg/dl S Alb= 1.9g/L S Creat=1.0mg/dL
ANA= 1:360 ADNA= 108 CH50= Normal ACLAb=100
Case: ARS Unfractionated heparin is begun
How would you treat this patient? 1. Anticoagulation and RAS inhibitors for at least 3months 2. Corticosteroids only 3. Plasmapheresis 4. Tacrolimus and corticosteroids
Mycophenolate Mofetil and IV Cyclophosphamide are similar as Induction Therapy for Class V LN Reduction in Proteinuria was similar
Remission rates were similar
Radhakrishnan J. Kidney Int. 2009 Nov 4. 60
RCT of Prednisone, Cyclophosphamide, and Cyclosporine in Lupus MN. Probability of Remission
Austin HA 3rd . J Am Soc Nephrol. 2009 Apr;20(4):901-11.
61
RCT of Prednisone, Cyclophosphamide, and Cyclosporine in Lupus MN. Post Treatment Relapse
Austin HA 3rd . J Am Soc Nephrol. 2009 Apr;20(4):901-11.
62
12.5: Class V LN (membranous LN)
12.5.1: We recommend that patients with class V LN, normal kidney function, and non–nephrotic-range proteinuria be treated with antiproteinuric and antihypertensive medications, and only receive corticosteroids and immunosuppressives as dictated by the extrarenal manifestations of systemic lupus. (2D)
12.5.2: We suggest that patients with pure class V LN and persistent nephrotic proteinuria be treated with corticosteroids plus an additional immunosuppressive agent: cyclophosphamide (2C), or CNI (2C), or MMF (2D), or azathioprine (2D).
SPECIAL SITUATIONS
CASE: ARS 37 y.o. female referred for evaluation of abnormal U/A found on routine exam – 4 years ago during pregnancy had proteinuria that resolved
PMH – Remote history of low platelets that also resolved – No childhood illnesses, chronic illnesses or hospitalizations – No hypertension, diabetes or collagen vascular disease
Exam: normal BP, normal Labs: – U/A: 2+blood, 3+ protein; Micro 3-5 RBC – Uprotein: 1.1gm/day S Cr 1.4 – Serologies: ANA 1:2650, Anti ds DNA 26 (equivocal), Complements N
Global sclerosis (11/19 glomeruli)
Wrinkled GBMs
Mild mesangial hypercellularity
Segmental GBM duplication
Mesangial deposits
Focal cortical atrophy
Arteriosclerosis
Immunofluorescence Microscopy
IgG, IgG, C3, C1q
Mesangial electron dense deposits
Segmental GBM duplication Electron lucent “fluff”
CASE: ARS Your treatment recommendation: 1. MMF+steroids 2. Cyclophosphamide+steroids 3. Warfarin 4. Plasmapheresis
Path findings: summary Mesangial proliferative immune complex GN – With segmental MPGN features – EM findings c/w chronic TMA
Focal cortical atrophy
Moderate arteriosclerosis Final diagnosis: Antiphospholipid nephropathy and “lupus like” nephropathy – Anticardiolipin Ab • IgG (+>80): • IgM (inconclusive 12-19)
101 25
Renal disease in Primary APS How does it Present? ARF – – – – –
renal infarction renal vein thrombosis TMA Renal cortical necrosis CAPS
Chronic forms: – – – –
Often clinically silent Systemic hypertension *** Renal insufficiency Proteinuria/hematuria Nephrotic syndrome
Nephropathy of PAPS: Ensemble of renal lesions
Arteriosclerosis of interlobular artery thickened intima, cellular
Vascular Nephropathy – Vasoocclusive lesions of intrarenal vessels associating side- by-side – acute thromboses (TMA) & chronic vascular • lesions (FIH, arteriosclerosis) organized thromboses)
Thrombotic microangiopathy (TMA)
– Progression to fibrous occlusion of involved vessels
Fibrous intimal hyperplasia (FIH);
– Leads to development of zone of subcapsular ischemic cortical atrophy in regions supplied by vessels •
Focal cortical Atrophy
Systemic Lupus and Thrombotic Microangiopathy 12.10.1: We suggest that the antiphospholipid antibody syndrome (APS) involving the kidney in systemic lupus patients, with or without LN, be treated by anticoagulation (target international normalized ratio [INR] 2–3). (2D)
12.10.2: We suggest that patients with systemic lupus and thrombotic thrombocytopenic purpura (TTP) receive plasma exchange as for patients with TTP without systemic lupus. (2D)
Systemic lupus and pregnancy 12.11.1: We suggest that women be counseled to delay pregnancy until a complete remission of LN has been achieved. (2D)
12.11.2: We recommend that cyclophosphamide, MMF, ACE-I, and ARBs not be used during pregnancy. (1A)
12.11.3: We suggest that hydroxychloroquine be continued during pregnancy. (2B)
12.11.4: We recommend that LN patients who become pregnant while being treated with MMF be switched to azathioprine. (1B)
12.11.5: We recommend that, if LN patients relapse during pregnancy, they receive treatment with corticosteroids and, depending on the severity of the relapse, azathioprine. (1B)
Systemic lupus and pregnancy 12.11.6: If pregnant patients are receiving corticosteroids or azathioprine, we suggest that these drugs not be tapered during pregnancy or for at least 3 months after delivery. (2D)
12.11.7: We suggest administration of low-dose aspirin during pregnancy to decrease the risk of fetal loss. (2C)
12.12: LN in children 12.12.1: We suggest that children with LN receive the same therapies as adults with LN, with dosing based on patient size and GFR. (2D)
12.6: General treatment of LN 12.6.1: We suggest that all patients with LN of any class are treated with hydroxychloroquine (maximum daily dose of 6–6.5 mg/kg ideal body weight), unless they have a specific contraindication to this drug. (2C)
Hydroxychloroquine Prevent Flares/Renal Damage
Arthritis Rheum. 2009 Jun 15;61(6):830-9
Also…… BP control
RAAS inhibition Optimal lipid targets Bone health – BMD – Vitamin D/Calcium – Bisphosphonates
Timely evaluation for renal transplant
12.7: Class VI LN (advanced sclerosis LN) 12.7.1: We recommend that patients with class VI LN be treated with corticosteroids and immunosuppressives only as dictated by the extrarenal manifestations of systemic lupus. (2D)
Summary & Conclusions Initial therapy of LN – Short term: MMF = CYC • Long term: Unknown • Aggressive lesions: unknown
Resistant disease – Remission takes longer than 6 months – Rebiopsy if not sure/worsening – Options: switch to alternative regimen, rituximab, plasmapheresis, IVIg
Maintenance Therapy – – – –
MMF or AZA (MMF may be superior in pts who have remitted) 3-monthly IVC therapy is less effective Optimal duration/dose is unknown Continue hydroxychloroquine