1. Renal disease in SLE
R4 이설라/Prof.임천규

2. Introductions Renal involvement is common in idiopathic SLE
May eventually develop in up to 75 percent of cases of SLE
Progression to end stage renal disease can occur in up to 48% of those patients with renal involvement at 5 years
Onset of lupus nephritis directly increases the morbidity and mortality

4. Clinical feature Most frequently observed abnormality : proteinuria
Proliferative lupus glomerulonephritis
Hematuria, varying degrees of proteinuria, renal dysfunction
Membranous lupus glomerulonephritis
Nephrotic-range proteinuria generally predominates
In active lupus renal disease
serum levels of C3, C4,C1q are often depressed
In a small number of patients, renal disease may precede the onset of clinical SLE by months or years.
, both the
classic as well as the alternate pathways of the complement
cascade are activated, and

5. Clinical feature
Acta Reumatol Port Apr-Jun;33(2):157-69

6. Clinical associations of autoantibodies in SLE

7. Classification Minimal mesangial lupus nephritis (class I)
Without LM abnormalities
Mesangial immune deposits identified either by IF
Normal urinalysis and serum creatinine
Mesangial proliferative lupus nephritis (class II) 
Mesangial hypercellularity or mesangial matrix expansion by LM
A few subepithelial or subendothelial deposits by IF not LM
clinically by microscopic hematuria, proteinuria
The renal prognosis is excellent and no specific therapy

8. Minimal mesangial lupus nephritis (class I)
A, Glomerulus with mild focal mesangial hypercellularity (arrows) (periodic acid–Schiff, original magnification
400). B, Immunofluorescence microscopy showing 2 granular staining for immunoglobulin G (IgG) restricted to the mesangium (fluorescein
isothiocyanate anti-human IgG, original magnification 500). C, Electron micrograph of a glomerular mesangial area with finely granular, darkly
electron-dense deposits admixed with pale matrix and cells. Normal glomerular basement membrane reflected on the mesangium (arrows) (original
magnification ). D, Diagram of increased mesangial cells and deposits with focal distortion of foot processes.

9. Mesangial proliferative lupus nephritis (class II)
Immunofluorescence microscopy showing focal mesangial trace to 1 staining for immunoglobulin G (IgG) (C, Electron micrograph of glomerular capillary with normal basement membrane and
preserved foot processes showing small, granular mesangial deposits (arrows)

10. Focal lupus nephritis (class III)
Less than 50 percent of glomeruli being affected
Active or inactive segmental or global endocapillary or extracapillary glomerulonephritis
Focal subendothelial immune deposits
III (A): Active lesions: focal proliferative LN
III (A/C): Active and chronic lesions
: focal proliferative and sclerosing LN
III (C): Chronic inactive lesions with glomerular scars: focal sclerosing LN
Hematuria and proteinuria - almost all patients
Nephrotic syndrome, hypertension
Elevated serum Cr
Variable clinical presentation  percent of glomeruli involved

11. Focal lupus nephritis (class III)
Light micrograph of a mesangial glomerulonephritis showing segmental areas of increased mesangial matrix and cellularity (arrows). This finding alone can be seen in many diseases, including lupus nephritis and IgA nephropathy

12. Focal lupus nephritis (class III)
Segmental glomerular endocapillary proliferation and infiltration of inflammatory cells, covered by
a small cellular crescent (50% of glomeruli) with mild mesangial hypercellularity B, Class III–chronic. Segmental sclerosing lesions with capsular adhesions, mild mesangial changes, and a small fibrous crescent in one (arrow) (periodic
acid–Schiff, original magnification 400). C, Class III–active. Electron micrograph of a glomerular lobule showing endothelial swelling and an
influx of polymorphonuclear leukocytes and focal subendothelial electron-dense deposits (original magnification 6000). D, Diagram of focal
subendothelial deposits, mesangial deposits, and hypercellularity.

13. Diffuse lupus nephritis (class IV) More than 50 percent of glomeruli
Endo- or extracapillary glomerulonephritis
Diffuse subendothelial immune deposits
IV-S: involved glomeruli have segmental lesions
IV-G: involved glomeruli have global lesions
Hematuria and proteinuria are seen in nearly all patients
Nephrotic syndrome, HTN, renal insufficiency are all common.
Significant hypocomplementemia , elevated anti-DNA levels

14. Diffuse lupus nephritis (class IV-S)
Wire-loop
Cellular proliferation
Light micrograph sho wi n g a m em b r an o p r o li f e r a ti v e p a tt e r n I n lupus nephritis, characterized by areas of cellular proliferation (long arrows) and by thickening of the glomerular capillary wall (due to immune deposits) that may be prominent enough to form a "wire-loop" (short arrows). Although proliferative changes can be focal (affecting less than 50 percent of glomeruli), disease of this severity is usually diffu

15. Diffuse lupus nephritis (class IV) - subendothelial deposits
A, Lupus nephritis class IV–global-active. Electron micrograph (high magnification) of glomerular capillary basement membranes demonstrating
abundant subendothelial deposits (wire loop lesion) and small adjacent mesangial and scattered discrete subepithelial deposits. The
overlying epithelial foot processes are effaced with intact lamina densa (original magnification 7000). B, Diagram of extensive, large, subendothelial
deposits with small, scattered, subepithelial deposits. Varying mesangial hypercellularity and deposits are observed.

16. Membranous lupus nephritis (class V)
Diffuse thickening of the glomerular capillary wall on LM
Subepithelial immune deposits (either global or segmental involvement) on IF, EM
Advanced sclerosing lupus nephritis (class VI)
Global sclerosis of more than 90 percent of glomeruli
Slowly progressive renal dysfunction in association with proteinuria
Immunosuppressive therapy is unlikely to be beneficial.

17. Membranous lupus nephritis (class V)
Light micrograph of membranous lupus nephritis. The changes are similar to those in any form of membranous nephropathy with diffuse thickening of the glomerular capillary wall being the major abnormality (short arrows). Focal areas of mesangial expansion and hypercellularity (long arrows) are the only findings suggestive of an underlying disease such as lupus, although they can also be seen in idiopathic membranous nephropathy
Electron micrograph of membranous lupus nephritis. The subepithelial immune deposits (D) are characteristic of any form of membranous nephropathy, but the intraendothelial tubuloreticular structures (arrow) strongly suggest underlying lupus
intraendothelial tubuloreticular structures

18. Late-Onset Systemic Lupus Erythematosus

19. Late onset SLE : specific sub-group of the disorder, beginning above 50–65 years of age
Incidence :12–18%
Course of the disease is considered to be more benign
RF, anti-Ro and anti-La antibodies  higher rate of positive findings
Anti-RNP antibodies, hypocomplementaemia  lower occurrence

20. Skin manifestations, photosensitivity, arthritis, nephritis occur rarely
Serositis, lung involvement, Sjögren's syndrome were observed more often
Iinitial clinical manifestation : arthralgias, weakness, fatigue, myalgias, weight loss, pyrexia, loss of cognitive function

23. Therapy of diffuse or focal proliferative lupus nephritis

24. Non-immunosupressive therapies
Aggressive antihypertensive
Goal blood pressure is less than 130/80 mmHg
Antiproteinuric therapy with blockade of the renin-angiotensin system
Goal protein excretion is less than 500 to 1000 mg per day
Lipid lowering with statin therapy 

25. Immunosuppressive therapy - Induction
For patients with mild focal proliferative LN
less than 25 percent of the glomeruli affected on LM
No necrotizing lesions or crescent formation
normal BP and serum Cr and subnephrotic proteinuria
Glucocorticoids alone
60 mg/day for one week
 tapered to 30 mg every other day for 3 months
Goals of therapy - Loss of hematuria and proteinuria

26. Immunosuppressive therapy - Induction
Moderate to severe focal proliferative or diffuse proliferative LN
Glucocorticoids + either IV cyclophosphamide
or oral mycophenolate mofetil (MMF)
Choice between cyclophosphamide or MMF depends upon the clinical features
Cyclophosphamide infections and amenorrhea
recommend IV cyclophosphamide in patients with more severe disease (eg, substantial elevation in serum creatinine and/or crescents )

27. Immunosuppressive therapy - Induction
Severe active disease
Acute renal failure
Crescentic glomerulonephritis
Severe extrarenal disease
MPD : 500 ~1000 mg daily for three days
To induce rapid immunosuppressive effect
Response to IV cyclophosphamide is not seen for 10 to 14 days.

28. Immunosuppressive therapy - maintenance
Despite successful induction of proliferative GN, relapses are common, ranging from 10 to 65%
Maintenance immunosuppressive therapy for at least 18 to 24 months or longer
Azathioprine vs. MMF
The maintenance regimen depends upon the initial induction therapy:

29. Immunosuppressive therapy - maintenance
IV cyclophosphamide induction  azathioprine
starting WBC > cells/microL
Azathioprine is given at a dose of 2 mg/kg per day to a maximum of 150 to 200 mg/day
MMF as induction therapy  MMF at dose of 1000 to 2000 mg/day
Low-dose oral prednisone (0.05 to 0.20 mg/kg /d) is continued in all patients receiving maintenance therapy

31. Factors associated with poor renal outcomes
U nfavourable histological features
Diffuse proliferative glomerulonephritis, presence of cellular crescents, fibrinoid necrosis, tubular atrophy
Increased levels of serum creatinine and decreased eGFR
Presence of hypertension
Presence of nephrotic-range proteinuria
Lack of remission
Low levels of C3
Presence of anti-Ro antibodies

32. 치료에 대한 반응 및 재발의 예측인자 Active urine sediment (RBC or WBC cast)
Proteinuria
GFR
Serum complement
Anti-dsDNA titer