45 year old woman presents with a rash, hematuria and proteinuria

CLINICAL HISTORY

45 year old Caucasian female with past medical history significant for 10 years of hypertension presented 4 months prior to renal biopsy with a papular rash on her back that was biopsied and reported as being consistent with discoid lupus.  Shortly after this she developed a malar rash, a vasculitic rash on her thighs, arthralgias and pleuritis. Her primary physician performed basic laboratory testing and found her to have hemoglobin of 10.1, creatinine 0.8 mg/dL, and urine dipstick with 2+ blood and 2+ protein. Medications at that time were esomeprazole, hydrochlorothiazide and irbesartan. She was referred to a nephrologist who first saw her 2 months after her initial presentation with the rash. A serologic work-up showed +ANA (1:160), +dsDNA (>800), + SSA (>8), negative anti-cardiolipin antibodies and normal C3 and C4. Basic chemistries were repeated and creatinine had increased to 1.1 mg/dL. A 24 hour urine collection was performed, yielding 340 mg protein. The patient was started on Plaquenil and prednisone and the potential need for renal biopsy was discussed with the patient. The patient returned for follow-up and urinalysis performed in the office showed 3+ protein, 3+ blood, 10-20 RBCs/hpf, 2-5 WBC/hpf.  A renal biopsy was performed.

DIAGNOSIS:

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Lupus nephritis class IV-S with pauci-immune features. See note.
 
Note: While the patient has lupus and clearly has evidence of lupus nephritis (full-house, IgG dominant immune staining within glomerui), the amount of crescent formation and necrosis appears to be out of proportion to the immune complex deposition, which appears predominantly restricted to the mesangium.  Due to this discordance, ANCA testing was recommended.
 
Follow-up: Additional serologic testing showed a high titer P-ANCA (1:160).  In light of this information, it appears that the pathology present is best described as a combination of lupus nephritis, likely fairly mild given the degree of immune complex deposition, and a superimposed ANCA-mediated glomerulonephritis.
 
DISCUSSION:

Lupus nephritis is considered to be a classic example of immune complex mediated glomerular disease.  From a mechanistic perspective, immune complexes are deposited within glomeruli, the presence of these deposits results in complement activation, leukocyte infiltration, cytokine release, cellular proliferation and sometimes crescent formation and necrosis.  The pattern of glomerulonephritis reflects the distribution of immune deposits. Generally speaking, it is the amount of subendothelial immune complex deposition that correlates best with endocapillary proliferation and crescent formation. In the case presented above, crescents involved >50% of the glomeruli sampled but immune complexes appeared predominantly restricted to mesangial regions, with only focal peripheral capillary wall involvement.
 
In contrast to lupus nephritis, ANCA-mediated (pauci-immune) glomerulonephritis is thought to result when cytokine primed neutrophils express myeloperoxidase (MPO), proteinase 3 (PR3) and other antigens on the cell surface (as opposed to just in the neutrophil cytoplasm).  If this surface expression of MPO or PR3 occurs in the presence of anti-MPO or anti-PR3 antibodies neutrophil activation may occur, resulting in cytokine release, generation of toxic oxygen species, and release of proteases which all result in damage to endothelial surfaces and the glomerular basement membrane (GBM).  This injury to the endothelium and GBM may result in rupture of the GBM, crescent formation and necrosis.  In contrast to lupus nephritis, this is a pauci-immune process.  While trace immune complex formation may be seen by sensitive techniques like immunofluorescence and electron microscopy, in comparison to the glomerular damage present, immune complex deposition is minimal.
 
Given the serologic results and the histologic findings in this biopsy, this case most likely represents a relatively mild form of lupus nephritis (perhaps class II, as glomeruli that are not involved by crescents appear essentially normal, with only focal mild mesangial proliferation) with a superimposed P-ANCA mediated necrotizing and crescentic glomerulonephritis.  This case cannot be categorized as truly “pauci-immune” because the degree of immune complex deposition is greater than can be attributed to an entirely ANCA-driven process. Small series and case reports with cases similar to the one above have been previously published (see Nasr et al). Despite the observation that approximately 20% of SLE patients have evidence of ANCA seropositivity, the role of ANCA mediated glomerulonephritis in the SLE population has yet to be systematically studied.
 
Prior to the formulation of the ISN/RPS 2003 lupus classification, the lupus nephritis collaborative study group (see Najafi et.al.) released a study of patients with severe lupus nephritis, defined as the presence of proliferation and/or necrosis in ?50% of glomeruli sampled for biopsy. They further defined 3 morphologically distinct categories including 1) segmental active or necrotizing lesions in ?50%  of glomeruli (referred to as LN III?50%), 2) Diffuse proliferative glomerulonephritis in which the proliferative glomerular changes were global (as opposed to segmental) in nature, and 3) membranous changes superimposed on either of the above classes. The somewhat counterintuitive finding of this study was that the remission rate and renal survival was worse in the patients who had LNIII?50% (the segmentally active lesions) than it was in the patients who had the diffuse, globally proliferative lesions.  Futhermore, the patients with LNIII?50% showed more necrosis but less immune complex deposition than the group with diffuse and global proliferation. Based on these results the authors raise the possibility a mechanism similar to what is seen in pauci-immune systemic vasculitis may be at work in patients with “LNIII?50%” but no data regarding ANCA seropositivity was provided in the study.
 
 In the subsequent ISN/RPS 2003 lupus classification, class IV lupus nephritis (meaning endocapillary proliferation and/or crescent formation involving ?50% of glomeruli sampled in the biopsy specimen) was subdivided into class IV-S (S=segmental) and IV-G (G=global).  In this classification, IV-S lesions involve <50% of the glomerular tuft, but ?50% of total number of sampled glomeruli (as in the case presented here). Class IV-G shows the majority of glomeruli with ?50% (global) involvement of the glomerular tuft involved by an active proliferative lesion. This distinction was made in part to address the findings described by the lupus nephritis collaborative study group.  In the 2003 ISN/RPS classification, class IV-S was thought to be equivalent to the “LNIII?50%” category in the lupus nephritis collaborative study group.
 
What has been found since the introduction of the 2003 lupus classification? Five studies comparing clinical parameters and outcomes of IV-S and IV-G patients have been published. (see Mittal et.al., Yokoyama et.al., Hill et.al., Kim et.al. and Hiramatsu et.al.)  While findings vary somewhat from study to study, clinically, patients with IV-G tend to have greater proteinuria and renal insufficiency than their IV-S counterparts.  Histologically, IV-G patients showed greater immune complex deposition than IV-S patients, however fibrinoid necrosis was more frequently noted in IV-S patients.  Evaluation of outcome differences between the two groups have been inconclusive thus far.  Difficulty in analyzing outcome differences in part arises from different therapeutic regimens being used, in some cases IV-S patients are treated less aggressively than IV-G patients.  Keeping these limitations in mind, one study showed a better outcome in IV-G than IV-S (Kim et.al.), 1 study showed better outcome in IV-S than IV-G (Yokoyama et.al.) and 3 studies have shown similar outcomes between the 3 groups (Mittal et.al., Hill et.al. and Hiramatsu et.al.).
 
The question as to why we observe more necrosis in IV-S patients but fewer immune deposits raises the possibility of an additional pathologic process in some of these patients, such as an ANCA mediated GN.  Future studies of lupus nephritis with systematic testing for ANCA are needed.  Some cases, such as the one presented here, provide compelling evidence that both immune complex mediated and ANCA mediated damage can occur simultaneously.
 
REFERENCES:

Nasr SH, D’Agati VD, Park HR et.al. Necrotizing and crescentic lupus nephritis with antibeutriphil cytoplasmic antibody seropositivity. Clin J Am Soc Nephrol 3:682-90, 2008.
 
Najafi CC, Korbet SM, Lewis EJ et.al. Significance of histologic patterns of glomerular injury upon long-term prognosis in severe lupus glomerulonephritis. Kidney Int 59:2156-63, 2001.
 
Mittal B, Hurwitz S, Rennke H, Singh AK. New subcategories of class IV lupus nephritis: are there clinical, histology and outcome differences? Am J Kidney Dis 44:1050-1059, 2004.
 
Yokoyama H, Wada T, Hara A, et.al. The outcome and a new ISN/RPS 2003 classification of lupus nephritis in Japanese. Kidney Int 66:2382-2388, 2004.
 
Hill GS, Delahousse M, Nochy D et.al. Class IV-S versus class IV-G lupus nephritis: clinical and morphologic difference suggesting different pathogenesis. Kidney Int 68:2288-97, 2005.
 
Kim YG, kim HW, Cho YM et.al. The difference between lupus nephritis class IV-G and IV-S in Koreans: focus on the response to cyclophosphamide induction treatement. Rheumatol 47:311-14, 2008.
 
Hiramatsu N, Kuroiwa T, Ikeuchi H et.al. Revised classification of lupus nephritis is valuable in predicting renal outcome with an indication of the proportion of glomeruli affected by chronic lesions. Rheumatol 47:702-7, 2008.

CORRESPONDANCE

Leal C. Herlitz M.D.
Department of Pathology and Cell Biology, Columbia University Medical Center and the New York Presbyterian Hospital