By Naheed Ansari, MD FASN

1. Lupus and Kidney
Naheed Ansari, MD FASN
10/15/12

2. Systemic Lupus Erythematosis
• The term “Lupus Erythematosis” was introduced in
19th century to describe skin lesions
• 100 years later, it was realized that it is a systemic
disease and it is causes by some aberrant
autoimmunity
• Prevalence- 1 case per 2000 population
• Currently, US 322,000 have SLE
• Incidence higher in African Americans,Hispanics,
and Asian ancestry
• 4 year survival rate- 50% in 1950s
• 15 year survival rate- 80% in 2012

3. Lupus Nephritis
• Multisystem involvement
• Lupus patients are more at risk for development of
kidney disease than people who do not have lupus
• Kidney involvement can occur in upto 50% of patients
with SLE. It usually occurs within first 5 years of
diagnosis of SLE.
• Renal involvement can occur before ACR criterion for
SLE is made
• Patients with SLE can also develop kidney disease due
to other medical problems like Diabetes Mellitus

4. Lupus Nephritis
• Defined as presence of abnormal elements in
the urine of patients with SLE
• red blood cells, white blood cells
• Red blood cell casts in urine
• Presence of protein >0.5gm/Day
• Elevated serum creatinine reflecting kidney
damage
• occurs both in children and
• adults
4

5. Lupus Nephritis
Cameron et al:JASN 1999
5

6. Lupus Nephritis- Clinical
Features
• History:
• Patients usually experience other symptoms of active
SLE like rash, fatique, arthritis,serositis or clinical CNS
disease
• Some patients are asymptomatic usually with
mesangial/membranous lupus nephritis.
• Some patients experience swelling of the body due to
proteinuria. Some are hypertensive along with
proteinuria.
• Some have symptoms associated with hypertension like
dizziness,headaches and heart failure

7. Lupus Nephritis- Clinical
Features
• Physical Examination:
• Evidence of rash, oral or nasal ulcers, joint swelling,
brown or foamy urine and changes in amount of
urine
• Patients with active lupus nephritis have
hypertension, peripheral edema, and occasionally
heart failure
• With membranous nephropathy, signs of nephrotic
syndrome( peripheral edema, ascites, pericardial
effusion and pleural effusions can be seen.

8. Diagnosis of Lupus Nephritis
• Blood tests
» BUN
» Serum Creatinine
» Laboratory tests for lupus disease activity like complement
level, antibodies to DNA, ESR,CRP etc
• Urine tests
» Urinalysis- presence of blood or protein in the urine as well
as presence of red blood cell casts
» Spot urine for protein/creatinine ratio
» 24 hour urine for creatinine clearance and protein
• Kidney biopsy

9. International Society of Nephrology/Renal
Pathology Society (ISN/RPS) 2003 classification of
lupus nephritis
• Class I Minimal mesangial lupus nephritis
• Normal glomeruli by light microscopy, but mesangial immune deposits by immunofluorescence
• Class II Mesangial proliferative lupus nephritis
• Purely mesangial hypercellularity of any degree or mesangial matrix expansion by light microscopy, with mesangial
immune deposits
• Class III Focal lupus nephritis
• Active or inactive focal, segmental or global endo- or extracapillary glomerulonephritis involving <50% of all
glomeruli, typically with focal subendothelial immune deposits, with or without mesangial alterations
– A=active lesions, C=chronic lesions
• Class IV Diffuse lupus nephritis
• Active or inactive diffuse, segmental or global endo- or extracapillary glomerulonephritis involving >50% of all
glomeruli, typically with diffuse subendothelial immune deposits, with or without mesangial alterations.
– This class is divided into diffuse segmental(IV-S) lupus nephritis when 50% of the involved glomeruli have segmental lesions, and diffuse
global (IV-G) lupus nephritis when 50% of the involved glomeruli have global lesions.
– A=active lesions, C=chronic lesions
• Class V Membranous lupus nephritis
• Global or segmental subepithelial immune deposits or their morphologic sequelae by light microscopy and by
immunofluorescence or electron microscopy, with or without mesangial alterations
– Class V lupus nephritis may occur in combination with class III or IV in which case both will be diagnosed

10. Lupus Nephritis- Biopsy
Findings
Mesangioproliferative Lupus Nephritis
Norma Kidney- Light Micro

11. Lupus Nephritis( Biopsy
Findings)
Proliferative GN with
necrosis Cellular Crescent

12. Lupus Nephritis
Lupus Membranous- LM Lupus Membranous- EM

13. Lupus Nephritis
Lupus Podocytopathy-LM Lupus Podocytopathy- EM

14. IF staining for IgG
IgG-TBM deposits IgG vessel wall deposits

15. US NIH renal Pathology System for Lupus
Nephritis

16. Treatment of Lupus Nephritis
• Depends upon class of LN diagnosed on kidney biopsy along with
presence of extra-renal manifestations of SLE
• Goal of treatment is to normalize kidney function, reduce
proteinuria, and prevent progressive loss of kidney function.
• Conservative (Non-immunomodulatory) treatment is appropriate for
Class I and II LN
• RAAS Blockade with ACE/ARB delays progression of Lupus Nephritis
• (Durán-Barragán S et al. Rheumatology 2008;47:1093-1096)
• Spironolactone significantly reduces proteinuria and lowers levels of
anti ds DNA and anti ss DNA
• (Role of aldosterone blockade in murine lupus nephritis Arthritis Res Ther 2008;10:R5)

17. Kaplan–Meier survival curve for the development of renal involvement as a function of the use of
ACE inhibitors.
Durán-Barragán S et al. Rheumatology 2008;47:1093-1096

18. Treatment of Lupus Nephritis
• Patients with proliferative classes of lupus
nephritis need immunomodulatory treatment
to turn off the immune system.
• Induction: usually Corticosteroids with either
Cyclophosphamide or Mycophenalate are used for first
six months
• Maintenance: usually with lowest and best
tolerated immunosuppressive medication. Azathioprine
or Mycophenalate are used based on recent clinical
trials

19. Induction Treatment
• It is initial intense treatment given to induce
remission of active disease
• Corticosteroids
» PO or IV
» 3 day Pulse( 7mg/kg/day) followed by 1mg/kg/day ( not
exceeding 60mg/day) for 8 weeks and then taper
» Glucocorticoids alone is significantly less effective
• Immunosuppressive agents
» Cyclophosphamide (Cytoxan) given IV
» Mycophenalate Mofetil (cellcept) administered orally
» Azathioprine( Imuran)

20. Cyclophosphamide
• Efficacious when used in conjunction with
glucocorticoids
• can be used intravenously or orally
• Used in dose of 0.5- 1.0gm/m2 monthly for six
months and then quarterly for at least two
years
• Can be given in biweekly doses of 500mg/m2
• Toxicity remains an issue

21. Standard “NIH protocol” dosing
Methylprednisolone and cyclophosphamide Alone or in Combination in
Patients w LN
• Randomized Controlled Trial in 85 Pts
• Treatment Remission
• IV Cyt x 6 mo + q 3rd mo 13/21 62%
• Methylpred 1 g/m2 x 1yr 7/24 29%
• Combined Therapy 17/20 85%
• Gourly MF, et al. Ann Int Med. 125:549, 1996

22. Kaplan-Meier Analysis of Failure of Therapy
Illei GG, et al. Ann Intern Med. 2 001
1.0 Cy + MP
Cy alone
0.9 MP alone
0.8
Probability That Therapy
0.7
Would Not Fail
0.6
0.5
0.4
Patients at Risk
0.3 27 25 25 24 23 22 18 18 17 11 7 Cy
0.2
28 27 27 26 23 23 20 20 17 15 12 Cy + MP
27 23 23 19 17 13 11 10 10 8 6 MP
0 24 48 72 96 120
Months From Study Entry

23. Long-term Follow-up of Protocol Completers in
WHO Class IV LN
50 Dialysis
Doubling SCr
40 50% Rise SCr
Patients (%)
30
20
10
0
MP alone CY alone MP + CY
(n = 24*) (n = 21) (n = 20)
*14 of 24 patients received CY after study completion
Illei GG, et al. Ann Intern Med. 2001;135:248-257.

24. • Multicenter Prospective Clinical trial
• Enrolled 90 patients from September 1996 – 2000 in 19
European centers
• Objective: To evaluate efficacy and safety of low dose
IV CYC for remission induction followed by AZA

25. Euro Lupus Trial- Study Design
90 Patients with LN Class
III-V
Low Dose IV CYC
High Dose IV CYC 44
46 (6 pulses of 500mg
(6 monthly pulses and 2 q2wks)
quaterly pulses)
40 Remained in the study 38 Remained in the study

26. Euro Lupus Trial Treatment failure
100
90 LD
Free of Failure (%)
80
HD
70
60
50 HD
LD
0
0 12 24 36 48 60
Follow-up (months)
Houssiau et al., Arthritis Rheum, 2002

27. Mycophenalate Mofetil-
Cellcept

28. Efficacy of MMF vs sequential PO CYT-AZA in 42
patients with DPLN
Group 1: MMF
(2 g x 6 mo,
then 1 g x 6 mo)
+ prednisone
(0.8 mg/kg)
Group 2: POCY
(2.5 mg/kg/d
x 6 mo), then
AZA (1.5-2.0
mg/kg/d) +
prednisone
Pts (%)
Chan TM et al. New Engl J Med 2000; 343:1156-62.

29. Multicenter Trial of MMF vs IV CTX for
Induction Therapy of Severe LN
• Multicenter, randomized, non-blinded trial of
induction RX for severe active LN
• Designed as equivalence trial
• Calculated sample size: 64/ Rx arm
• Hypothesis: MMF has equivalent efficacy with
superior toxicity/tolerability profile vs. IVC
•
• Ginzler et al. N Eng J Med 2005

30. Baseline Patient Characteristics
MMF (n=71) IVC (n=69)
Age ( yrs) 32.5 ± 10.0 31.0 ± 9.0
Female 61 (86%) 65 (94%)
Black 43 (61%) 36 (52%)
Duration of SLE, mo. 43.72 ± 66.88 58.70 ± 80.64
Screatinine, mg/dL 1.06 ± 0.52 1.08 ± 0.49
Urine protein, g/24 hr 4.06 ± 3.14 4.41 ± 3.51
Urine sediment
RBC/hpf 24.1 ± 50.3 33.2 ± 115.5
WBC/hpf 12.6 ± 23.5 10.3 ± 17.3
Salbumin, g/L 2.81 ± 0.95 2.69 ± 0.56

31. Remission Rates: MMF vs. IVC
Intent to treat analysis
P=0.009
Percent Responding
P=0.005 P=NS

32. • Multinational, Prospective, Randomized, Open label trial
comparing MMF to IV Cyclophosphamide
• Background: Smaller studies have shown that MMF may offer
advantages over IV Cyclophosphamide for treatment of Lupus
Nephritis but there is no large International Randomized control
trial
• Objective: To assess the efficacy and safety of MMF as Induction
therapy in Lupus Nephritis
• Hypothesis: More patents with Lupus Nephritis would respond to
MMF than IV Cyclophosphamide during 24 weeks

33. ALMS TRIAL – RCT MMF vs IVC in Severe LN
Appel , Contreras, Dooley et al JASN 2009
Randomized (n = 370)
MMF Open-label treatment IVC
Allocated to MMF Allocated to IVC
(n = 185) (n = 185)
Received MMF (n = 184) Received IVC (n = 180)
Withdrawals (n = 35) Withdrawals (n = 29)
Due to adverse event (n = 24)
Consent withdrawn (n = 6) Due to adverse event (n = 13)
Other reason (n = 5) Consent withdrawn (n = 5)
Other reason (n = 11)
Primary endpoint: responders in randomized population (n = 370)
Responders
Maintenance phase
Double-blind re-randomization to corticosteroids plus MMF or azathioprine for up to 3 years

34. Figure 2. Response rates of study population and by racial group
Appel, G. B. et al. J Am Soc Nephrol 2009;20:1103-1112

35. Summary – Induction Phase
Therapy for Class III or IV LN
• Multiple options
– Standard, NIH protocol IV CTX
• 0.75-1.0 g/m2 IV q4 weeks for 6 doses
– Eurolupus IV CTX
• 500 mg IV q2 weeks for 6 doses
– MMF
• 2000-3000 mg/day for 6 months
• All should be given alongside standard steroid
regimen
– 3 days pulse (7 mg/kg) followed by PO steroids at 1
mg/kg/day (not exceeding 60 mg) for 8 weeks, then taper

36. Treatment of Resistant LN
• Some patients are challenging for induction
• Plasmaphresis may be beneficial in some cases although randomized
controlled trials showed no benefit
• Tacrolimus can by used
• 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
• LUNAR study showed that induction of complete or partial remission
is higher with rituximab as compared to placebo
Rovin et al LUNAR study Arth Rheu 2012
Lewis et al NEJM 1992
Euler et al Arth Rheum 1994

37. Maintenance Therapy for
Proliferative LN
• Up to 50% of patients with LN relapse during reduction in or cessation of
immunosuppressive therapy
• Relapse rate is 5-15 per 100 patient years with an average of 8 per 100 patient years
for first 5 years of follow up.
• Treatment is usually continued for 24 months to prevent progressive kidney disease
• Usually treatment with cellcept or azathioprine is continued to keep patient in
remission and prevent relapses
• Cyclosporine is not used due to high risk of relapse upon withdrawl of drug
• Low dose oral prednisone is continued in most patients receiving maintenance
therapy with goal to prevent extrarenal symptoms. Usually a dose of 0.05 to
0.2mg/kg/day is used
Houssiau et al Maintain Trial 2010
Chan et al JASN 2005
Contreras et al NEJM 2004

38. Treatment of LN- Membranous
Nephropathy
• Treatment with immunosuppressive drugs is indicated in patients
» Severe symptomatic nephrotic syndrome
» Rising serum creatinine
» Mixed membranous and proliferative lesions on renal biospy
» Non immunosuppressive treatment is continued in these patients along with
immunosuppressive drugs
• Various drugs can be used in patients with class V lupus nephritis,
usually Mycophenalate is used for remission of nephrotic syndrome
because of its safety and better tolerance.
•
• IV cyclophosphamide and cyclosporine can be used as alternative
when MMF cannot be used.
• Non immunosuppressive agents include use of ACEI, statins, aspirin,
non dihydropyridine calcium channel blockers

39. Partial and Complete Remission Rates
Membranous LN
Radhakrishnan J, Moutzouris D, Ginzler E, and Appel GB
Kidney Int 77:152-160, 2009.

40. Prognostic Features- Lupus
Nephritis
• End Stage Renal Disease can occur in some patients with lupus
• Histological Predictors
• Class IV (diffuse proliferative LN)
• High activity and chronicity on Biopsy
• Crescents
• Interstitial fibrosis
• Segmental necrotizing lesions
• Clinical Predictors
• Hypertension
• Anemia
• High baseline serum creatinine
• Higher baseline proteinuria
• Delay in therapy
• Epidemiologic Predictors
• African American Race
• Low socioeconomic status

41. Treatment of LN- ESRD
• Survival rate for individuals with LN after 10 years of diagnosis
of SLE is reduced to 88%.
• This survival rate is further reduced in African Americans
• 15-20% of patients with lupus nephritis start renal replacement
therapy if End Stage Renal Disease occurs
• USRDS data shows that 1.4% of ESRD due to LN
» Hemodialysis
» Peritoneal Dialysis
» Kidney Transplantation
Appel et al: AJKD 1987: 83-877
Ortega LM et al: Lupus 2010: 19-557

42. Hemodialysis
• Patient survival with either hemodialysis or CAPD appears to be similar in
patients with ESRD ( 5 year survival rate is 90%)
• Most lupus nephritis patients with end-stage renal disease opt for
hemodialysis therapy(82%)
• Increased risk of death during the first three months of dialysis due to sepsis
and other complications of high dose of steroids.
Cheigh et al AJKD 1993: 21:2
Devlin et al Arth Care & Resear 2011

43. Peritoneal Dialysis
• Peritoneal dialysis and kidney transplantations lower among African-
Americans, uninsured, and unemployed
• Only 12.2% of LN patients started PD between 1995-2006
• Patients on PD do better than HD after kidney transplantation
• There may be high risk of peritonitis and non catheter related Infections in
PD.
Huang et al PDI 2001 21:143
Siu YP et al NDT 2005 20:2797
Kasiske et al J Transp 2001

44. Kidney Transplantation
• Under utilized in patients with LN
• Only 3% of LN patients undergo renal transplantation
• Graft survival rates at 5 and 10 years in patients with lupus are similar to those in
patients with other diseases.
• Rate of recurrent disease is low ( 2-9% in LN patients)
• Patients with rapidly progressive renal disease
• Should undergo dialysis before kidney transplant
• Measurement of serologic marker such as titres of
• DNA and complement levels do not help predict
• disease recurrence
• Kidney transplant recipients with lupus and
• Antiphospholipid antibodies are at increased
• Risk for thrombotic events.
Stone et al Semin Arth Rheu 1997
Choy et al Am J Transplant 2006

45. Thank You