LUPUS NEPHRITIS

1. LUPUS NEPHRITIS;
The Full Story!!

2. Objectives
 Types of renal diseases in lupus patients.
 Review the WHO classification of lupus
nephritis.
 Rules of treatment.
 The role of Mycophenolate in DPGN.

3. Types of renal disease
 Glomerular disease
 Tubulo-interstitial
disease
 Vascular
 Drug induced

5. Quiz
What is the hallmark of DPGN?
 Subepithelial deposits
 Subendothelial deposits
Mesangeal proliferation
 Inflammatory cell infiltarte

12. WHO CLASSIFICATION of LN
Class I: normal glomeruli
Class II: Purely mesangial disease
a. normocellular mesangium by LM;
mesangial deposits by IF &/or EM
b. mesangial hypercellularity with mesangial
deposits by IF &/or EM
Class III: Focal proliferative GN
Class IV: Diffuse proliferative GN
Class V: Membranous GN
a. pure membranous
b. with lesions of II (a or b)
Class VI: Chronic sclerosing GN

13. Focal Vs Diffuse..!!
 Only difference between focal & proliferative
GN/LN is amount of endocapillary
hypercellularity (proliferative lesions):
 focal < 50% glomeruli affected
 diffuse> 50% glomeruli affected

14. WHO Morphological Classification
Revised 1995
I. Normal glomeruli
a. normal by all techniques
b. normal on LM but deposits seen on IF or EM
II. Pure Mesangial Disease
a. Mesangial widening, mild hypercellularity, or both
b. Moderate hypercellularity

15. WHO Morphological Classification
Revised 1995
III. Focal Segmental Glomerulonephritis (GN)
(associated with mild or moderate mesangial alterations)
a. Active necrotizing lesions
b. Active & sclerosing lesions
c. Sclerosing lesions
IV. Diffuse GN (severe mesangial, endocapillary, or mesangiocapillary
proliferation, &/or extensive subendothelial deposits. Mesangial deposits
invariably present & subepithelial deposits often & may be numerous
a. Without segmental lesions
b. With active necrotizing lesions
c. With active & sclerosing lesions
d. With sclerosing lesions

16. WHO Morphological Classification
Revised 1995
V. Diffuse Membranous GN
a. Pure membranous GN
b. Associated with lesions of category II (a or B) IV
VI. Advanced Sclerosing GN
NOTE: Lupus renal lesions can change WHO classes over time (either develop a new
form of LN after treatment of previous LN or change -------usually progress----to a
worse class of LN)

17. NIH Histologic Scoring System for Activity &
Chronicity in LN
Activity Index Chronicity Index
Glomerular Endocapillary hypercellularity
Leukocyte infiltration
Fibrinoidnecrosis,
karyorrhexis
Cellular crescents
Hyaline deposits, wire loops
Glomerular sclerosis
Fibrous crescents
Tubulointerstitial Mononuclear cell infiltration
Maximal score 24 12

20. Rules of Treatment

21. Treatment of DPGN
 Induction therapy
Maintenace of remission

22. First rule: Kidney Biopsy.
 Is it for diagnosis or prognosis?
Why not just start treatment empirically and
follow the patient clinically?
 Is the kidney biopsy accurate all the time?

23. First rule: Kidney biopsy
 Delaying therapy, because of presumably mild
disease, is often associated with increased
glomerular injury and fibrosis and therefore a
lesser response to immunosuppressive drugs.
The benefit of early treatment with immunosuppressive agents in lupus
nephritis, Esdaile JM et al, J Rheum 1994, 21(11)

24. First rule: Kidney biopsy
 Glomerular hyperfiltration can initially maintain
the glomerular filtration rate despite marked
nephron loss.
Outcome of the acute glomerular injury in proliferative lupus nephritis.
Chagnac A et al; J Clin Invest 1989 Sep;84(3):922-30

25. Quiz

26. What are the clinical risk
factors for progressive
lupus nephritis?

27. Answer
Clinical risk factors for progression include:
 Elevated plasma creatinine concentration at
the time of renal biopsy,
 Nephrotic-range proteinuria,
 Anemia with a hematocrit below 26 percent,
 Black race.

29. Second rule:
No place for prednisone only!
 111 patients with active GN randomized to
receive IV Cyc, oral Cyc, imuran + Cyc had
significantly better preservation of renal
function compared to a group received only
high dose prednisone. Stienberg AD, A & R,34(8):945-
50,1991

30. Second rule:
No place for prednisone only!
 Therapy of lupus nephritis. Controlled trial of
prednisone and cytotoxic drugs. Austin HA et
al, N Engl J Med 1986 Mar 6;314(10):614-9
 Treatment of diffuse proliferative lupus
nephritis with prednisone and combined
prednisone and cyclophosphamide. Donadio
JV et al, N Engl J Med 1978 Nov
23;299(21):1151-5.

31. Second rule:
No place for prednisone only!
 The number of lupus nephritis patients one
needs to treat with prednisone and
immunosuppressive drugs compared to
prednisone alone is 7.6 to prevent one death
and 7.8 to prevent one end-stage renal
disease.
Bansal et al, Am J Kid Dis, 1997; 29.

32. Third rule:
IV monthly pulses of MP and CYC
 A land mark controlled study by NIH of pulse methylprednisolone
versus two regimens of pulse cyclophosphamide in severe lupus
nephritis.
Boumpas DT et al, Lancet 1992, 26;340(8822):741-5

33. MP
monthly
pulses
CYC
monthly
CYC
monthly
with
Q3/12
CYC
more effective than 6
months of pulse
methylprednisolone in
preserving renal function
reduces the rate
of exacerbations
Boumpas DT et al, Lancet 1992,
26;340(8822):741-5

35. Third rule:
IV monthly pulses of MP and CYC
Comments:
 Another report from the NIH compared one year of
monthly pulse MP (1 g/m2 body surface area) to monthly
pulse CYC (0.5 to 1.0 g/m2 body surface area for six
months and then quarterly) to combination therapy
(pulse MP plus pulse CYC).
 Again after 5 years of follow up, CYC alone and
combination therapy were better than MP alone.
Gourley MF et al, Ann Intern Med 1996 Oct 1;125(7):549-57.

36. MP
monthly
for 1Y
CYC
monthly,
then
Q3/12
MP+ CYC
monthly then
Q3/12
5 years
follow up
CYC alone and
combination
therapy were
better than MP
alone
Gourley MF et al, Ann Intern Med 1996 Oct
1;125(7):549-57

38. Extended report
 After 11 years of follow up, the proportion of patients who had
doubling of serum creatinine concentration was significantly lower in
the combination group than in the CYC group.
 Both groups were superior to MP alone.
 Combination therapy and CYC therapy alone did not differ
statistically in terms of effectiveness or adverse events.
 Combination therapy with pulse CYC plus pulse MP improves long-term
renal outcome without adding toxicity in patients with lupus
nephritis.
llei GG et al, Ann Intern Med 2001 Aug 21;135(4):248-57

40. Fourth rule:
CYC is the best!
 A meta-analysis concluded that until future RCTs of
newer agents are completed, the current use of
cyclophosphamide combined with steroids remains the
best option to preserve renal function in patients with
DPLN. The smallest effective dose and shortest duration of treatment
should be used to minimize gonadal toxicity without compromising efficacy.
Treatment of diffuse proliferative lupus nephritis: a meta-analysis of randomized
controlled trials. Flanc RS et al, Am J Kidney Dis 2004 Feb;43(2):197-208
Treatment for lupus nephritis. Cochrane Database Syst Rev 2004;
(1):CD002922.

41. Fourth rule:
CYC is the best!
 NNT with pulse IV CYC to prevent one death
as compared to prednisone alone is 5, and to
prevent end-stage renal disease is 6.2.
Bansal et al, Am J Kid Dis, 1997; 29.

42. Fifth rule:
Maintenance regimen.
 A study by Contreras et al. assessed the role of MMF, AZA and
quarterly intravenous CYC as maintenance therapy in three
groups of lupus nephritis patients (mainly classes III and IV) who
all received induction therapy with monthly intravenous.

43. Induction
therapy with
IV CYC
+
Corticosteroids
CYC IV 0.5-1
gm/m Q3/12
Azathioprine
1-3mg/kg
Mycophenolate
0.5-3 gm/day
hospitalization,
amenorrhoea,
infections and
gastrointestinal side-effects
The cumulative
probability of
remaining relapse-free
was higher in the
MMF (78%) and AZA
(58%) groups
compared to the CYC
group (43%) after a
median treatment
duration of 29, 30
and 25 months,
respectively.
Contreras G et al. Sequential therapies for proliferative
lupus nephritis. N. Engl. J. Med. 2004; 350

44. Is this the full story??

45. Interesting issues:
 High versus low dose CYC.
 The role of Mycophenolate as a remission
inducing agent.

46. High vs Low dose
Cyclophospahamide
The Euro-Lupus Nephritis Trial, Houssiau FA
et al, A & R 2002, 46(8):
 A prospective clinical trail.
 To evaluate the efficacy and toxicity of low-dose
IV CYC as a remission-inducing
treatment, followed by AZA as a remission-maintaining
treatment

47. High doses IV CYC
(6 monthly pulses+ 2
pulses Q3/12)
Fixed doses of IV
CYC at 500mg
(6 monthly pulses)
AZA
2mg/kg/day
41.3 months
Comparable
clinical results
Low Infective complications but no
statistical significance
Houssiau FA et al. Arthritis Rheum. 2002; 46

48. High vs Low dose
Cyclophospahamide
 Similar results were obtained with an
extended observation of the cohort for a
further 2 years.
Houssiau FA et al. Early response to immunosuppressive therapy predicts
good renal outcome in lupus nephritis: Lessons from the long-term follow-up
of the Euro-Lupus Nephritis Trial. Arthritis Rheum 2004;50.

49. What about Mycophenolate?
 It is used first in lupus nephritis patients in resistant disease.
 Randomized control trials:
1. Chan TM et al, N. Engl. J. Med. 2000;343
2. Chan TM et al, J. Am. Soc. Nephrol. 2001; 12
3. Hu W et al, Chin. Med. J. 2002; 115
4. Ginzler EM, Aranow C, Merrill JT, Orloff K, Henry D. Toxicity
and tolerability of mycophenolate mofetil vs intravenous
cyclophosphamide in a multicenter trial as induction therapy for
lupus nephritis. Arthritis Rheum. 2003; 48 (9 Suppl.): S647

50. Is this the full story??

51. The other face of the coin!!
 The cumulative relapse rate could be up to 44% at
5 years with intravenous CYC therapy. (Ciruelo et al,
A&R,1996; 39, Illei GG et al, A&R, 2002; 46, Mok CC et al, A&R, 2004; 50)
 Approximately 5-15% of patients with SLE-related
diffuse proliferative glomerulonephritis were
refractory to CYC. (Valeri A et al, Clin. Nephrol. 1994; 42, Mok CC
et al, Am. J. Kidney Dis. 2001; 38)
 30-50% still developed doubling of plasma
creatinine or end-stage renal disease after 5 years.
(Sesso R et al, Lupus 1994; 3, Belmont HM et al, Lupus 1995; 4)

52. Take home messages
 Consider kidney biopsy for abnormal urinary
sediment, protienuria, and/or elevated creatinine.
 No place for prednisone alone in lupus nephritis.
 IV MP + IV CYC for severe lupus nephritis.
 AZA and MMF are effective agents for maintenance
of remission.
 You may use low doses of CYC as a remission
inducing agent.
 MMF soon will be a valid option for inducing
remission.

53. New therapies for lupus
nephritis
 Blockade of costimulatory molecules;
biological agents such as CTLA4-Ig and anti-
CD40L monoclonal antibodies used to block
the interaction between T cells and B cells.
 LJP 394 tolerizes B cells by cross-linking
anti-dsDNA surface immunoglobulin receptor
on the B cell and triggering the signal
transduction pathways that lead to B cell
anergy or apoptosis.

54. New research findings
 Hydroxychloroquine is an Independent Predictor of Complete
Renal Remission to Initial Mycophenolate Mofetil Therapy in
Membranous Lupus Nephritis
Nuntana Kasitanon1, Derek Fine1, Mark Haas1, Laurence
Magder2, Michelle Petri1. 1Johns Hopkins University, Baltimore,
MD; 2University of Maryland, Baltimore, MD
 Methylprednisolone and Cyclophosphamide, Alone or in
Combination in Patients with Very Early Lupus Nephritis: A
Randomized Controled Trial. Author(s):Juan Antonio Avina-
Zubieta1, Griselda Galindo-Rodriguez2, Azucena Ramos3,
Reyna Bustamante4, Argelia Perez4, Consuelo Calleja5,
Carmen Sanchez6, Carlos Lavalle7 (Combination therapy with
IVCy plus IVMP is more effective to achieve and sustain renal
remissions )

55.  Cyclophosphamide Therapy for Renal Involvement in SLE: When to
Discontinue in Responders? When to Consider it has Failed?
Category:27. SLE — treatment and gene therapyAuthor(s):Panayiotis
G. Vlachoyiannopoulos1, Michael Samarkos1, Maria Fotia1, Elias
Zintzaras2, John Boletis1, Haralampos M. Moutsopoulos1. 1University
of Athens, Athens, Greece; 2University of Thessaly, Larissa, Greece
Lupus nephritis occurs relatively early following diagnosis of SLE.
Approximately 60% of patients achieve CR with IVCY therapy. More than
half of them do so within the first 12 months while CR is unlikely after
the 13th CY pulse.
 Mycophenolate Mofetil as the Primary Treatment of Membranous Lupus
NephritisCategory:27. SLE — treatment and gene
therapyAuthor(s):Nuntana Kasitanon1, Michelle Petri1, Mark Haas1,
Laurence Magder2, Derek Fine1. 1Johns Hopkins University, Baltimore,
MD; 2University of Maryland, Baltimore, MD

56.  Safety and Efficacy of Leflunomide in the
Treatment of Lupus Nephritis Refractory to
Traditional Immunosuppressive Therapy: An
Open-Label TrialCategory:26. SLE —
clinical aspectsAuthor(s):Lai-Shan Tam,
Edmund K. Li, Chun-Kwok Wong,
Christopher W. Lam, Cheuk-Chun Szeto.
Chinese University of Hong Kong, Hong
Kong, Hong Kong Special Administrative
Region of China Presentation Number:444

57.  TNF-Alfa and TNF-Receptors in Biopsy-Verified Lupus
NephritisCategory:28. SLE — human etiology and
pathogenesisAuthor(s):Iva Gunnarsson, Gouzhong Fei, Stefan
H. Jacobson, Johan Frostegård. Department of Medicine;
Karolinska Institutet, Stockholm, Sweden
 Infliximab Treatment in SLE: Despite Transient Autoantibody
Increase Transient Remission of Arthritis and Long-Term
Reduction in ProteinuriaCategory:27. SLE — treatment and
gene therapyAuthor(s):Martin Aringer, Winfried B. Graninger,
Gunter Steiner, Josef S. Smolen. Medical University of Vienna,
Austria, Vienna, Austria

58. Quiz

59. What is the defenition
of remission?

60. Answer:
 Proteinuria < 500 mg/24h (rarely some recent
studies uses < 1gm/24h)
 RBC in urine < 5/HPF
 No RBC casts
 Normal serum creatinine and estimated GFR
or…..

61. Is there a relationship
between risk of kidney
disease/flare and ANA?

62. Is there…AntidsDNA
level?

63. Answer:
 Progressive Reduction in Risk of Renal Flare
in SLE Patients is Associated with Improved
Long-Term Control of Anti-dsDNA Antibody
LevelsCategory:27. SLE — treatment and
gene therapyAuthor(s):Matthew D. Linnik,
Tenshang Joh. La Jolla Pharmaceutical
Company, San Diego, CA

64. Thank you