ROLE OF RENAL BIOPSY IN SILENT LUPUS NEPHRITIS

M.E. Guerra1 , Y. Arce2, M.M Díaz3, P. Moya4. J. Ballarín3, F. Algaba5

1Department of Pathology. Central University Hospital of Asturias, Oviedo. Spain2Department of Pathology. Puigvert Foundation, Barcelona. Spain.

3Department of Nephrology. Puigvert Foundation, Barcelona. Spain4Department of Rheumatology. Sant Pau Hospital, Barcelona. Spain.

5Department of Pathology. Puigvert Foundation, Barcelona. Spain.

• Systemic Lupus Erythematosus (SLE) is a multisystem autoimmune disease primarily affecting women of reproductive age.

• Kidney disease develops up to 60% of patients with SLE:• 15-20% first clinical manifestation.• 25-50% had renal involvement at the time of lupus diagnosis.• Important cause of morbility, even mortality.

• Goals for managing patients with lupus nephritis (LN):• Early diagnosis• Proper and prompt therapy to prevent irreversible damage without

exposure of side effects of immunosupressors.

INTRODUCTION

• Renal Biopsy is essential to diagnose specific form of LN:

• Biological markers (serum levels C3, C4, anti-DNA): low sensitivity to predict activity disease and risk to develop new flares.

• Discrepancies between clinical presentation and pathologic findings.

• LN is not a static entity.

• Implies different prognosis and therapeutic approaches.

• Repeat biopsy in LN flares is a matter of controversy.

• Its role is still not defined after clinical remission.

• Daleboudt Gabrielle M. N. et al. Nephrol Dial Transplant (2009)• Hsieh YP. Clin Nephrol 2012; 77: 18-24..• Seshan S. Arch Pathol Lab Med. 2009;133:233–48.

INTRODUCTION

SILENT LUPUS NEPHRITIS (SLN)

• Zabaleta-Lanz M et al. Lupus 2003;12:26-30.• Zabaleta-Lanz M et al. Inmunol 2004; 23: 278-83.• Zabaleta-Lanz M et al. Lupus 2006; 15: 845-51.

• Moroni G. Am J Kidney Diseases.1999; 34:530–9.• Yoo CW. Nephrol Dial Transplant. 2000;15:1604–8. • Cavallo T. Am J Pathol1977;87:1–13• Ahmadian YS, Am J Dis Child 1972;123: 121 – 125.

OBJECTIVES

• Evaluate frequency of SLN in patients with at least one previous renal flare with histological confirmation, after induction/maintenance treatment, that achieved complete renal and clinical remission.

• Correlate complete renal remission with histological findings and compare them to those obseved in previous biopsy.

• Examine the influence of histological change in the therapeuthic decision.

• Prospective and descriptive study.

• Review of patients diagnosed of SLE , as defined by American Rheumatism Association, that had LN biopsy-proven.

• Selection of patients who fulfill complete remission (CR) criteria for at least 2 years. 2nd biopsy is performed at this moment

CR criteria:• Proteinuria < 50mg/mmol creatinine.• Normal renal function.• Inactive urine sediment.

• Biopsies were categorized according to ISN/RPS classification protocol.

• Activity and chronicity index were determined according to the scoring system of Pollack et al., as modified by Austin et al.

MATERIAL AND METHODS

• Weening JJ et al. J Am Soc Nephrol 2004; 15:241-250.• Weening JJ et al. Kidney Int 65 2004;15: 521-530.

• Prospective and descriptive study.

• Review of patients diagnosed of SLE , as defined by American Rheumatism Association, that had LN biopsy-proven.

• Selection of patients who fulfill complete remission (CR) criteria for at least 2 years. 2nd biopsy is performed at this moment

CR criteria:• Proteinuria < 50mg/mmol creatinine• Normal renal function.• Inactive urine sediment.

• Biopsies were categorized according to ISN/RPS classification protocol.

• Activity and chronicity index were determined according to the scoring system of Pollack et al., as modified by Austin et al.

MATERIAL AND METHODS

• Weening JJ et al. J Am Soc Nephrol 2004; 15:241-250.• Weening JJ et al. Kidney Int 65 2004;15: 521-530.

ACTIVITY AND CHRONICITY INDICES (NIH)Activity Index (0-24): - Endocapillary hypercellularity (0-3+) - Leucocyte infiltration (0-3+) - Subendothelial hyaline deposits (0-3+) - Fibrinoid necrosis / karyorrhexis: (0-3+) x 2 - Cellular crescents (0-3+) x 2 - Intersticial inflammation (0-3+)Chronicity Index (0-12): - Glomerular sclerosis (0-3+) - Fibrous crescents (0-3+) - Tubular atrophy (0-3+) - Intersticial fibrosis (0-3+)

0: Absent1+: <25 % glomeruli affected2+: 25-50 % glomeruli affected3+: > 50 % glomeruli affected

• Austin HA 3rd, Muenz LR, Joyce KM, Antonovych TA, Kullick ME, Klippel JH, Decker JL, Balow JE Kullick ME.. .Am J Med 1983 Sep;75(3):382-91.

• Austin HA 3rd, Muenz LR, Joyce KM, Antonovych TT, Balow JE. Kidney Int.1984 Apr;25(4):689-95

LUPUS NEPHRITIS CLASS I

LUPUS NEPHRITIS CLASS II

LUPUS NEPHRITIS CLASS III

LUPUS NEPHRITIS CLASS IV

LUPUS NEPHRITIS CLASS IV

LUPUS NEPHRITIS CLASS V

LUPUS NEPHRITIS CLASS VI

• Collecting data

• Demographic

• Clinical (SLEDAI)

• Analitical

• Renal histology:

• International Society of Nephrology/Renal Pathology Society Classification of Lupus Nephritis 2004 (ISN/RPS).

• Activity and Chronicity Index.

MATERIAL AND METHODS

RESULTS

1 2 3 4 5 6 7 8 9 10

Sex F F F F M F M F F F 8 F 2M

Age 46 16 24 22 15 32 24 25 18 51 27,3 ± 12,6

SLEDAI (initial)

6 10 19 8 16 26 17 25 14 16 15,7 ± 6,61

RENAL BIOPSY PRE-COMPLETE REMISSION1 2 3 4 5 6 7 8 9 10

Proteinuria (g/24h)

3,8 0,8 2,5 2,4 2,3 2,3 1,04 6,38 3,27 1,28 2,47 ± 1’66

Serum Creatinine (μmol/l)

84 52 107 81 53 88 54 70 79 45 71,3 ± 19,91

Serum (g/L) Albumine

22 21,6 20 44 39,1 40,6 39,7 20 27 41,5 31,5 ± 10,20

DNA + + + - - - + + + + 70% Positive

C3 /C4 ↓/↓ ↓/↓ ↓/↓ N/↓ N/↓ N/N N/N ↓/↓ N/↓ ↓/↓ 5 ↓/↓

Urine Sediment + + + + + + + + + + Positive

SLEDAI 9 14 19 8 11 4 16 25 14 16 13,6 ± 5,98

BIOPSY PRE-CRClass-Activity Index-Chronicity Index

III+V(A/C)

03

III+V(A/C)

24

IV (G/A)

130

II

12

V+II

00

III(A/C)

44

IV S(A/C)

50

IV G-A

90

IV

--

II

03

II: 2 III:1IV:4 III+V:2

3,41.6

INDUCTION TREATMENT CYC CYC CYC - - CYC CYC CYC CYC -

MANTEINANCE TREATMENT

MMFMMF

+TCR

MMF AZAMMF

+TCR

MMF MMF MMF MMF MMF

RESULTS

1 2 3 4 5 6 7 8 9 10Proteinuria (g/24h) 0,26 0,1 0,17 0,25 0,43 0,35 0,15 0,15 0,11 0,2 0,21 ± 0,1

Serum Creatinine (μmol/l) 67 60 68 88 68 83 58 54 49 57 65,2 ± 12,42

Serum Albumine (g/L) 48,3 42,5 43,2 46 43,5 38,9 40,8 45 42,7 43 43,4 ± 2,97

DNA - - + - - - - - + + 30% positive

C3 /C4 N/N N/N N/↓ N/N N/↓ N/N N/N N/↓ N/↓ N/N 6 N/N

Urine Sediment - - - - - - - - - - -

SLEDAI 0 0 6 0 0 0 0 2 4 2 1,4 ± 2,11

BIOPSY AFTER CR: Class

- Activity Index- Chronicity Index

V

03

V+II

23

V+II

01

II

02

V+II

11

II

20

II

00

II

01

II

00

II

02

II: 6 V: 4

0.51.3

RENAL BIOPSY AFTER COMPLETE REMISSION

RESULTS

1 2 3 4 5 6 7 8 9 10CLASS PRE-CR

- Activity Index- Chronicity Index

III+V

03

III+V

24

IV

130

II

12

V+II

00

III

44

IV

50

IV

90

IV

--

II

03

CLASS AFTER CR

- Activity Index- Chronicity Index

V

03

V+II

23

V+II

01

II

02

V+II

11

II

20

II

00

II

01

II

00

II

02

RESULTS

100% patients with SLN

1 2 3 4 5 6 7 8 9 10

V

II

III

IV

Biopsy Pre-CRClass III or IV

o

HISTOLOGICAL IMPROVEMENT 70%

Biopsy after CRClass II

NO HISTOLOGICAL CHANGE 30%

Biopsy Pre-CRClass II+V

Biopsy after CRClass II+V

RESULTS

Activity Index decreases

1 2 3 4 5 6 7 8 9 10

CLASS PRE-CR

-Activity Index- Chronicity Index

III+V

03

III+V

24

IV

130

II

12

V+II

00

III

44

IV

50

IV

90

IV

--

II

03

CLASS AFTER CR

--Activity Index- Chronicity Index

V

03

V+II

23

V+II

01

II

02

V+II

11

II

20

II

00

II

01

II

00

II

02

1 2 3 4 5 6 7 8 90

2

4

6

8

10

12

14

CI(CR)AICIAI(CR)

MANTEINANCE TREATMENT = = = ↓ = ↓ ↓ ↓ ↓ =

THERAPEUTIC OUTCOME

CLASS AFTER CR: - Activity Index-Chronicity Index

V03

V+II23

V+II01

II02

V+II11

II20

II00

II01

II00

II02

INDUCTION TREATMENT CYC CYC CYC - - CYC CYC CYC CYC -

MANTEINANCE TREATMENT

MMFMMF

+TCR

MMF AZAMMF

+TCR

MMF MMF MMF MMF MMF

1 2 3 4 5 6 7 8 9 10

CLASS PRE-CR

-Activity Index-Chronicity Index

III+V

03

III+V

24

IV

130

II

12

V+II

00

III

44

IV

50

IV

90

IV

--

II

03

• No patients achieve complete histological remission.

• Membranous pattern and mesangial proliferation remains, meanwhile

endocapillary proliferation dissapears.

• Activity Index decreases and Chronicity Index remains the same.

• Renal biopsy in Complete Remission implicates a change in therapeutic decision

in 50% of cases in our series.

CONCLUSION

Silent Lupus Nephritis is highly prevalent in patients with Systemic Lupus Erythematosus, being renal biopsy the gold standard for its diagnosis.

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