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Membranous and crescentic glomerulonephritis in a patient with anti-nuclear and anti-neutrophil cytoplasmic antibodies
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Membranous and crescentic glomerulonephritis in a patient with anti-nuclear and anti-neutrophil cytoplasmic antibodies A Chang1, O Aneziokoro2, SM Meehan1 and RJ Quigg2 1
Department of Pathology, University of Chicago, Chicago, Illinois, USA and 2Department of Medicine, University of Chicago, Chicago, Illinois, USA
CASE PRESENTATION A 49-year-old African-American female presented with acute renal failure. Her serum creatinine had increased from 0.8 to 2.8 mg/dl over 11 weeks. She had a 1-month history of anorexia, 20 lb weight loss, nausea, and vague abdominal discomfort. An outpatient evaluation included a renal ultrasound and magnetic resonance imaging of the abdomen, which were normal. Her past medical history was significant for a 12-year history of hypertension. There was no recent non-steroidal anti-inflammatory drug usage or radiocontrast study. Her medications included losartan 100 mg daily, amlodipine 2.5 mg daily, hydrochlorothiazide 25 mg daily, and potassium chloride 20 mEq daily. On physical examination, the patient appeared normal. She was afebrile with a blood pressure of 168/98 mm Hg. Her physical and neurologic exam was unremarkable. There were no rashes, edema, or joint abnormalities. Laboratory evaluation showed a total leukocyte count of 7500/mm3 (normal range, 3500–11 000/mm3) with a normal differential, hemoglobin 9.1 g/dl (normal range, 11.5–15.5 g/dl), reticulocytes 1.1% of total erythrocytes (normal range, 0.5–1.5%), platelet count 419 000/mm3 (normal range, 150 000–450 000/mm3), serum sodium 140 mmol/l (normal range, 134–149 mmol/l), serum potassium 4.0 mmol/l (normal range, 3.5–5.2 mmol/l), serum chloride 103 mmol/l (normal range, 95–108 mmol/l), serum bicarbonate 29 mmol/l (normal range, 23–30 mmol/ l), total serum calcium 8.7 mg/dl (2.2 mmol/l) (normal range, 8.4–10.2 mg/dl (2.1–2.8 mmol/l)), serum albumin 3.2 g/dl (normal range, 3.5–5.0 g/dl), and cholesterol
Correspondence: A Chang, Department of Pathology, University of Chicago, 5841 S. Maryland Avenue, Room S-628 (MC6101), Chicago, Illinois 60637, USA. E-mail: [email protected] Kidney International (2007) 71, 360–365. doi:10.1038/sj.ki.5001957; published online 11 October 2006
Received 14 July 2006; revised 6 September 2006; accepted 12 September 2006; published online 11 October 2006 360
216 mg/dl (normal range, 120–199 mg/dl). Liver function tests were normal. Serologic evaluation revealed an anti-nuclear antibody (ANA) titer of 1:2560 with a homogenous staining pattern, and the presence of perinuclear-staining anti-neutrophil cytoplasmic antibodies (ANCAs), which were specific for myeloperoxidase (MPO) (22 U/ml, normal o20 U/ml). Complement C3 and C4 levels were normal. Cryoglobulins, rheumatoid factor, hepatitis B antigen, and antibodies to double-stranded DNA, extractable nuclear antigens (Smith and ribonucleoprotein), histones, SS-A, SS-B, proteinase 3, glomerular basement membrane (GBM), and hepatitis C were not detectable. Urinalysis showed 3 þ protein and 4 þ blood, with greater than 20 red blood cells (normal less than 3) and white blood cells (normal less than 5) per high-power field. There were granular casts but no apparent cellular casts. There was 4470 mg of protein (87% albumin, 7% polyclonal gamma globulin) in a 24 h urine collection. In the first week of hospitalization, her serum creatinine rose to 3.5 mg/dl. A diagnostic renal biopsy was performed.
RENAL BIOPSY FINDINGS
The renal biopsy contained up to 16 glomeruli for light microscopic evaluation, of which four were globally sclerotic. Cellular to fibrocellular crescents (Figure 1a) with frequent disruption of Bowman’s capsules and segmental fibrinoid necrosis of a few capillaries were identified in nine glomeruli. One glomerulus contained a fibrous crescent. The GBM showed marked thickening and subepithelial ‘spike’ formation without significant mesangial or endocapillary proliferation as seen with the Jones methenamine silver stain (Figure 1b). Diffuse and prominent interstitial inflammation consisted of numerous plasma cells and lymphocytes and demonstrated focal tubulitis. There was patchy interstitial fibrosis and tubular atrophy involving up to 20% of the biopsy. The sampled arteries and arterioles were without evidence of vasculitis or significant sclerosis. Kidney International (2007) 71, 360–365
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A Chang et al.: ANA- and ANCA-associated crescentic GN
Immunofluorescence (IF) microscopic evaluation of four glomeruli revealed granular staining of primarily the capillary walls and some mesangial areas for immunoglobulin (Ig)G (3 þ , Figure 1c), IgA (trace), IgM (trace), C3 (3 þ ), C1q (trace), and kappa (3 þ ) and lambda light chains (1 þ ). There was no significant staining of the tubular basement membranes or interstitium. Electron microscopy of one glomerulus demonstrated numerous immune-type electron-dense deposits in primarily subepithelial locations (Figure 1d). There was basement membrane material or ‘spike’ formation between these electron-dense deposits. Significant deposits were not present in mesangial or subendothelial regions. The podocyte foot processes demonstrated extensive effacement. Endothelial tubuloreticular inclusions or extraglomerular electron-dense deposits were not identified.
Differential diagnosis
The diagnosis of membranous nephropathy (MN) can be easily established in this patient. There is strong granular IF staining of the capillary walls for IgG, C3, and kappa and lambda light chains, which corresponds to the presence of numerous subepithelial immune-type electron-dense deposits seen by electron microscopy. The additional IF staining for IgA, IgM, and C1q satisfies a ‘full-house’ pattern that is most suggestive of lupus nephritis. Although the presence of renal disease and a positive ANA were the only major American Rheumatism Association criteria for systemic lupus erythematosus (SLE) in this patient, this is not an uncommon occurrence in patients with lupus MN.1 Not infrequently, MN is the first clinical manifestation of lupus. Particularly in these instances, the distinction between idiopathic and lupus MN can be difficult. Clues to the diagnosis of lupus MN
a
b
c
d
Figure 1 | Renal biopsy findings. (a) Fibrocellular crescent occupies Bowman’s space with focal rupture of Bowman’s capsule. The glomerular tufts uninvolved by crescent formation do not reveal significant mesangial or endocapillary hypercellularity. The interstitium shows a prominent inflammatory mononuclear cell infiltrate (periodic acid-Schiff, high power). (b) The GBMs are thickened with diffuse subepithelial ‘spike’ formation, whereas the adjacent glomerular tufts lack significant mesangial or endocapillary hypercellularity (Jones methenamine silver, high power). (c) IF microscopy demonstrates strong granular staining of the capillary walls and some mesangial areas for IgG. C3, and kappa and lambda light chains revealed a similar glomerular IF staining pattern (data not shown). (d) Electron microscopy highlights several subepithelial immune-type electron-dense deposits (arrowheads) with basement membrane material (or ‘spikes’) between the deposits. The overlying podocyte foot processes show extensive effacement (original magnification 9800). Kidney International (2007) 71, 360–365
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include its appearance in young women in whom lupus is more common than idiopathic MN, and a ‘full-house’ IF staining pattern, the presence of tubuloreticular inclusions, and/or coexisting immune deposits in various anatomic locations outside the subepithelial space in the biopsy specimen. The main pathologic differential diagnosis includes diffuse proliferative (class IV) and membranous (class V) lupus nephritis or an ANCA-associated crescentic glomerulonephritis superimposed on lupus MN. The absence of linear GBM IF staining for IgG excludes anti-GBM disease. In conjunction with the presence of ANCA and normal serum complement levels, the absence of both significant subendothelial or mesangial immune complex deposition, or mesangial or endocapillary proliferation is most consistent with a pauci-immune ANCA-associated crescentic glomerulonephritis in the setting of lupus MN. Although the clinical diagnosis of SLE is not firmly established, the ensuing discussion will be based on a presumptive pathologic diagnosis of lupus MN. CLINICAL FOLLOW-UP
Owing to the clinical features of rapidly progressive glomerulonephritis, the patient was empirically given 1 g of IV methylprednisolone, which was repeated for a total of three daily doses when the initial histological diagnosis of crescentic glomerulonephritis was obtained. She was also given 1.6 g of IV cyclophosphamide (0.8 g/m2), which was well tolerated. Oral iron and darbepoetin alfa were started for anemia. Her hypertension was difficult to control initially, yet later in the hospital course was controlled with losartan and verapamil, which she continued as an outpatient. On hospital day 11, her serum creatinine was 2.2 mg/dl (194 mmol/l), which further decreased to 1.3 mg/dl (146 mmol/l) 2 weeks later. Because of persistently active urinary sediment and a transient rise in serum creatinine to 2.4 mg/dl (270 mmol/l) 2 months after hospitalization, she received escalating monthly doses of intravenous cyclophosphamide to a maximum of 2.0 g (1.0 g/m2), together with 1 g intravenous methylprednisolone for a total of six doses, after which she was maintained on 3.0 g/d mycophenolate mofetil. Three months after her hospitalization, her serum creatinine was 1.0 mg/dl (88 mmol/ l) and urinary protein/creatinine 1.0 (normal 0–0.15). For the ensuing year, she did well with repeated serum creatinine
measurements between 1.0–1.1 mg/dl, urinary protein/creatinine less than 1.7, and resolution of anemia. At the 1-year period, her ANA titer was 1:640 and ANCA was undetectable. DISCUSSION
Crescentic glomerulonephritis represents a severe form of glomerular injury that is characterized by disruption of the GBM leading to cellular proliferation within Bowman’s space, often accompanied by fibrinoid necrosis. Crescentic glomerulonephritis is classified into three main immunopathologic categories: (1) anti-GBM disease; (2) immune complex-mediated glomerulonephritis; and (3) pauci-immune (ANCA-associated) glomerulonephritis. In the setting of SLE, crescentic glomerulonephritis is usually associated with prominent immune complex deposition in subendothelial regions, which often correlates with the histologic finding of endocapillary proliferation, ‘wire-loop’ deposits, or cellular crescent formation. However, in the absence of significant mesangial and subendothelial immune complex deposition and glomerular endocapillary hypercellularity, a pauciimmune (ANCA-associated) glomerular injury process should be a diagnostic consideration as the underlying cause of the crescentic glomerulonephritis. Lupus glomerular lesions are categorized according to the 2003 International Society of Nephrology/Renal Pathology Society revised lupus nephritis classification. In addition, renal biopsies of SLE patients have revealed a spectrum of diseases that are not considered within the lupus nephritis classification scheme, including thin GBM disease, focal segmental glomerulosclerosis, amyloidosis, IgM nephropathy, IgA nephropathy, sarcoidosis, and hypertensive nephrosclerosis.2–5 Lupus nephritis occurring concurrently with another renal injury process has been reported with minimal change disease (podocytopathy).6,7 Of particular relevance to the current report, there are five cases (Table 1) of lupus nephritis with pauci-immune crescentic glomerulonephritis in the literature of which two cases demonstrated class V lupus MN.8–10 Schwartz et al.11 and Ferrario et al.12 report an additional 13 SLE cases with similar histopathologic findings, although ANCA serologies were not available and there was limited IF and no electron microscopy was performed in the latter study. Analogous to the notion that not all ANAs are equal, ANCAs also represent a heterogenous group of antibodies with variable degrees of specificity or avidity, as illustrated by
Table 1 | Renal biopsies of lupus nephritis and pauci-immune GN Case 1 2 3 4 5 6
Age (years)/sex 17/F 40/F 55/M 37/F 50/F 49/F
Renal biopsy findings
ANCA (ELISA)
Clinical outcome
Reference
Class Class Class Class Class Class
Negative Negative pANCA (ND) pANCA (MPO) pANCA (MPO) pANCA (MPO)
Methylprednisone+IV CYC with good recovery Prednisone+CYC; follow-up N/A Died 1.5 months after biopsy Prednisone+IV CYC with creatinine of 1.3 mg/dl Prednisone+IV CYC with good recovery Methylprednisolone+IV CYC with good recovery
Akhtar et al.8 Akhtar et al.8 Marshall et al.9 Marshall et al.9 Masani et al.10 Current case
III LN+focal necrotizing GN IV LN+crescentic GN V LN+crescentic GN V LN+crescentic GN III LN+crescentic GN V LN+crescentic GN
ANCA, anti-neutrophil cytoplasmic antibody; CYC, cyclophosphamide; ELISA, enzyme linked immunosorbent assay; F, female; GN, glomerulonephritis; LN, lupus nephritis; M, male; MPO, myeloperoxidase; N/A, not available; ND, not done; pANCA, perinuclear ANCA.
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A Chang et al.: ANA- and ANCA-associated crescentic GN
Table 2 | Serologic detection of ANCA in SLE patients with lupus nephritis Number of patients
pANCA+ (%)
MPO+ (%)
LF+ (%)
79
20.2
5.1
39.2
Sinico et al.17 Schnabel et al.18 Spronk et al.19 Nishiya et al.20 Zhao et al.22
70 120 84 31 95
ND 25 9.5 42 18.9
ND 0 8.3 16.1 0
15–20 10 15.5 32.2 8.4
Chin et al.23 Manolova et al.21 Pradhan et al.24
51 55 59
31.4 27.3 33.9
2.4 10.9 20.3
30.2 18.2 16.9
Caccavo et al.25
97
ND
ND
54.6
Study 16
Lee et al.
Conclusions No correlation with anti-LF Abs and lupus nephritis. Among class IV lesions, 3 of 4 patients with anti-LF Abs and 1 of 8 without anti-LF-Abs contained crescents No correlation with anti-LF Abs and lupus nephritis No correlation with ANCA and lupus nephritis No correlation with ANCA and lupus nephritis No correlation with ANCA and lupus nephritis or proteinuria 62% of all samples (86% of ANCA+ samples) recognized cathepsin G. Anti-cathepsin G Abs but not anti-LF Abs correlate with lupus nephritis Positive ANCA associated with lupus nephritis No correlation with ANCA and lupus nephritis ANCA titers correlated and were higher in patients with lupus nephritis Anti-LF Ab titers correlate with lupus nephritis
Abs, antibodies; ANCA, anti-neutrophil cytoplasmic antibody; LF, lactoferrin; MPO, myeloperoxidase; ND, not done; pANCA, perinuclear ANCA; SLE, systemic lupus erythematosus.
their different targets, which include MPO, proteinase 3, lysozyme, lactoferrin, cathepsin G, and elastase to name a few.13 Just like with the suggestions that anti-double-stranded DNA antibodies may play a pathogenic role in lupus nephritis, recent data implicate ANCA as an important pathogenic factor. Xiao et al.14 demonstrated that the administration of IgG antibodies specific for MPO alone in RAG2-knockout mice could lead to vasculitis and crescentic glomerulonephritis. One case of transplacental transmission of MPO-ANCA causing rapidly progressive glomerulonephritis in a newborn has been reported, although this was not confirmed with a renal biopsy.15 The proposed mechanism of injury by ANCAs begins with the activation of neutrophils and monocytes, which leads to formation of reactive oxygen species and subsequent damage to the endothelial cells and basement membranes that can result in rupture and subsequent glomerular crescent formation. Approximately 15–20% of SLE patients have detectable ANCA (Table 2). The majority of these have a perinuclear staining pattern by indirect IF, which typically is attributable to reactivity to either MPO (as in our patient) or lactoferrin. Cytoplasmic ANCA staining and/or reactivity to proteinase 3 are seen in a minority of patients (approximately 2%). A number of studies have attempted to correlate ANCA seropositivity with various clinical manifestations of SLE including renal disease with mixed results (reviewed by Sen and Isenberg13). Thus, there are studies that show no association of anti-MPO or anti-lactoferrin ANCA with lupus nephritis16–21 and those that do suggest the two are linked22–25 (Table 2). In these studies, the descriptions of renal histopathologic findings were limited. As such, overall it is difficult to arrive at generalizations regarding ANCA in lupus nephritis. There have been a few studies that have focused specifically on the histopathologic features of lupus nephritis. Using the revised 2003 International Society of Nephrology/ Renal Pathology Society lupus classification, Hill et al.26 found that diffuse segmental proliferative (class IV-S) lupus Kidney International (2007) 71, 360–365
nephritis had fewer immune deposits and more fibrinoid necrosis when compared to diffuse global proliferative (class IV-G) lupus nephritis, which behaved as an immune complex-mediated disease process. Mittal et al.27 observed similar findings, but they did not find the difference between classes IV-G and IV-S lesions to be statistically significant. Hill et al.26 suggested the possibility that an alternate pathogenic mechanism, such as an ANCA-mediated process, may be the cause of the class IV-S lesions, but unfortunately ANCA titers were not available in either study. It does seem clear that a limited subset of patients with lupus nephritis can have concomitant pauci-immune crescentic glomerulonephritis associated with ANCA (Table 1). Although ANCA-related vasculitis is autoimmune in nature, in this instance whether it is an extension of the underlying autoimmune disease in SLE, or alternatively is a separate phenomenon, remains to be established. Lupus MN occurs in up to 20% of lupus nephritis patients.1 The pathogenesis of both idiopathic and lupus MN remains unclear. In MN, there is the uniform presence of subepithelial immune deposits and complement components together with ultrastructural evidence for podocyte damage. The latter can account for proteinuria, given the key role for podocytes to maintain the normal glomerular permselectivity barrier to protein passage. The weight of experimental evidence supports that complement activation results in C5b9-mediated injury of podocytes, but no chemoattractantmediated influx of inflammatory cells owing to the separation of the subepithelial and vascular spaces by the GBM.28 Work in the Heymann nephritis model in rats has shown that antibodies to podocyte antigens can form subepithelial immune complexes in situ. Recently, this mechanism has been shown to be operative in neonatal MN owing to passively transferred maternal antibodies to podocyte neutral endopeptidase.29 This is an uncommon form of MN, and other podocyte target antigens have been elusive. It is likely that autoantibodies binding to intrinsic podocyte antigens is not the exclusive mechanism for subepithelial immune 363
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deposit formation in idiopathic or lupus MN, with other possible mechanisms including antibody binding to extrinsic antigens in the subepithelial region and extrinsic immune complexes traversing the GBM. Given the diversity of autoantibodies in lupus, it seems likely that any or all of these could be operative in lupus MN. The pathologic distinction between coexisting diffuse proliferative lupus nephritis and lupus MN from a pauciimmune, ANCA-associated crescentic glomerulonephritis on a background of lupus MN can be problematic. One could argue the distinction is not crucial, given that the current therapeutic regimens available for both consist of intensive, but nonspecific immunosuppression. Once the clinical diagnosis of rapidly progressive glomerulonephritis is made, treatment with high-dose pulse intravenous corticosteroids is widely used and can be considered standard-of-care. Thereafter, induction therapy with oral or intravenous cyclophosphamide is often used. Intravenous cyclophosphamide has the advantage of a lower cumulative dose and the relative success of prophylaxis against hemorrhagic cystitis; this regimen has been shown to be effective in diffuse proliferative lupus nephritis, whereas only suggested to be effective in lupus MN and in ANCA-associated diseases.30,31 The clear role for daily oral cyclophosphamide in the latter has been proven, and remains the mainstay of therapy until supplanted by more directed forms of treatment.32 Our use of ‘pulse’ intravenous cyclophosphamide was a conscious decision based upon the presumption that it is active against both ANCA-associated glomerulonephritis and lupus MN, as well as it is generally being well-tolerated. Thereafter, the use of daily oral mycophenolate mofetil for maintenance therapy was based on its effectiveness in diffuse proliferative lupus nephritis and that it is also well-tolerated, but with no proof of efficacy for the two diseases present. Despite the potential pathogenic role of ANCAs and ANAs, the precise role for plasmapheresis in patients with lupus nephritis or ANCA-associated glomerulonephritis remains to be established. The most convincing evidence for a possible role for plasma exchange is in those patients with ANCA-associated glomerulonephritis with severe enough disease to require renal replacement therapy.33 Our patient did not receive plasma exchange, and she had a dramatic response to pulse intravenous corticosteroids and cyclophosphamide, as her serum creatinine went from 3.5 to 1.3 mg/dl in 3 weeks. Thereafter, she did well with 6 months of this therapy followed by 6 months of daily oral mycophenolate mofetil. Unfortunately, we cannot make generalizations to use this type of therapeutic regimen in patients with a similar presentation, given the anecdotal nature of this case. Proof continues to await definitive clinical studies on these established and newer therapies. REFERENCES 1. Austin HA, Illei GG. Membranous lupus nephritis. Lupus 2005; 14: 65–71. 2. Baranowska-Daca E, Choi YJ, Barrios R et al. Nonlupus nephritides in patients with systemic lupus erythematosus: a comprehensive clinicopathologic study and review of the literature. Hum Pathol 2001; 32: 1125–1135.
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Membranous and crescentic glomerulonephritis in a patient with anti-nuclear and anti-neutrophil cytoplasmic antibodies A Chang1, O Aneziokoro2, SM Meehan1 and RJ Quigg2 1
Department of Pathology, University of Chicago, Chicago, Illinois, USA and 2Department of Medicine, University of Chicago, Chicago, Illinois, USA
CASE PRESENTATION A 49-year-old African-American female presented with acute renal failure. Her serum creatinine had increased from 0.8 to 2.8 mg/dl over 11 weeks. She had a 1-month history of anorexia, 20 lb weight loss, nausea, and vague abdominal discomfort. An outpatient evaluation included a renal ultrasound and magnetic resonance imaging of the abdomen, which were normal. Her past medical history was significant for a 12-year history of hypertension. There was no recent non-steroidal anti-inflammatory drug usage or radiocontrast study. Her medications included losartan 100 mg daily, amlodipine 2.5 mg daily, hydrochlorothiazide 25 mg daily, and potassium chloride 20 mEq daily. On physical examination, the patient appeared normal. She was afebrile with a blood pressure of 168/98 mm Hg. Her physical and neurologic exam was unremarkable. There were no rashes, edema, or joint abnormalities. Laboratory evaluation showed a total leukocyte count of 7500/mm3 (normal range, 3500–11 000/mm3) with a normal differential, hemoglobin 9.1 g/dl (normal range, 11.5–15.5 g/dl), reticulocytes 1.1% of total erythrocytes (normal range, 0.5–1.5%), platelet count 419 000/mm3 (normal range, 150 000–450 000/mm3), serum sodium 140 mmol/l (normal range, 134–149 mmol/l), serum potassium 4.0 mmol/l (normal range, 3.5–5.2 mmol/l), serum chloride 103 mmol/l (normal range, 95–108 mmol/l), serum bicarbonate 29 mmol/l (normal range, 23–30 mmol/ l), total serum calcium 8.7 mg/dl (2.2 mmol/l) (normal range, 8.4–10.2 mg/dl (2.1–2.8 mmol/l)), serum albumin 3.2 g/dl (normal range, 3.5–5.0 g/dl), and cholesterol
Correspondence: A Chang, Department of Pathology, University of Chicago, 5841 S. Maryland Avenue, Room S-628 (MC6101), Chicago, Illinois 60637, USA. E-mail: [email protected] Kidney International (2007) 71, 360–365. doi:10.1038/sj.ki.5001957; published online 11 October 2006
Received 14 July 2006; revised 6 September 2006; accepted 12 September 2006; published online 11 October 2006 360
216 mg/dl (normal range, 120–199 mg/dl). Liver function tests were normal. Serologic evaluation revealed an anti-nuclear antibody (ANA) titer of 1:2560 with a homogenous staining pattern, and the presence of perinuclear-staining anti-neutrophil cytoplasmic antibodies (ANCAs), which were specific for myeloperoxidase (MPO) (22 U/ml, normal o20 U/ml). Complement C3 and C4 levels were normal. Cryoglobulins, rheumatoid factor, hepatitis B antigen, and antibodies to double-stranded DNA, extractable nuclear antigens (Smith and ribonucleoprotein), histones, SS-A, SS-B, proteinase 3, glomerular basement membrane (GBM), and hepatitis C were not detectable. Urinalysis showed 3 þ protein and 4 þ blood, with greater than 20 red blood cells (normal less than 3) and white blood cells (normal less than 5) per high-power field. There were granular casts but no apparent cellular casts. There was 4470 mg of protein (87% albumin, 7% polyclonal gamma globulin) in a 24 h urine collection. In the first week of hospitalization, her serum creatinine rose to 3.5 mg/dl. A diagnostic renal biopsy was performed.
RENAL BIOPSY FINDINGS
The renal biopsy contained up to 16 glomeruli for light microscopic evaluation, of which four were globally sclerotic. Cellular to fibrocellular crescents (Figure 1a) with frequent disruption of Bowman’s capsules and segmental fibrinoid necrosis of a few capillaries were identified in nine glomeruli. One glomerulus contained a fibrous crescent. The GBM showed marked thickening and subepithelial ‘spike’ formation without significant mesangial or endocapillary proliferation as seen with the Jones methenamine silver stain (Figure 1b). Diffuse and prominent interstitial inflammation consisted of numerous plasma cells and lymphocytes and demonstrated focal tubulitis. There was patchy interstitial fibrosis and tubular atrophy involving up to 20% of the biopsy. The sampled arteries and arterioles were without evidence of vasculitis or significant sclerosis. Kidney International (2007) 71, 360–365
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Immunofluorescence (IF) microscopic evaluation of four glomeruli revealed granular staining of primarily the capillary walls and some mesangial areas for immunoglobulin (Ig)G (3 þ , Figure 1c), IgA (trace), IgM (trace), C3 (3 þ ), C1q (trace), and kappa (3 þ ) and lambda light chains (1 þ ). There was no significant staining of the tubular basement membranes or interstitium. Electron microscopy of one glomerulus demonstrated numerous immune-type electron-dense deposits in primarily subepithelial locations (Figure 1d). There was basement membrane material or ‘spike’ formation between these electron-dense deposits. Significant deposits were not present in mesangial or subendothelial regions. The podocyte foot processes demonstrated extensive effacement. Endothelial tubuloreticular inclusions or extraglomerular electron-dense deposits were not identified.
Differential diagnosis
The diagnosis of membranous nephropathy (MN) can be easily established in this patient. There is strong granular IF staining of the capillary walls for IgG, C3, and kappa and lambda light chains, which corresponds to the presence of numerous subepithelial immune-type electron-dense deposits seen by electron microscopy. The additional IF staining for IgA, IgM, and C1q satisfies a ‘full-house’ pattern that is most suggestive of lupus nephritis. Although the presence of renal disease and a positive ANA were the only major American Rheumatism Association criteria for systemic lupus erythematosus (SLE) in this patient, this is not an uncommon occurrence in patients with lupus MN.1 Not infrequently, MN is the first clinical manifestation of lupus. Particularly in these instances, the distinction between idiopathic and lupus MN can be difficult. Clues to the diagnosis of lupus MN
a
b
c
d
Figure 1 | Renal biopsy findings. (a) Fibrocellular crescent occupies Bowman’s space with focal rupture of Bowman’s capsule. The glomerular tufts uninvolved by crescent formation do not reveal significant mesangial or endocapillary hypercellularity. The interstitium shows a prominent inflammatory mononuclear cell infiltrate (periodic acid-Schiff, high power). (b) The GBMs are thickened with diffuse subepithelial ‘spike’ formation, whereas the adjacent glomerular tufts lack significant mesangial or endocapillary hypercellularity (Jones methenamine silver, high power). (c) IF microscopy demonstrates strong granular staining of the capillary walls and some mesangial areas for IgG. C3, and kappa and lambda light chains revealed a similar glomerular IF staining pattern (data not shown). (d) Electron microscopy highlights several subepithelial immune-type electron-dense deposits (arrowheads) with basement membrane material (or ‘spikes’) between the deposits. The overlying podocyte foot processes show extensive effacement (original magnification 9800). Kidney International (2007) 71, 360–365
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include its appearance in young women in whom lupus is more common than idiopathic MN, and a ‘full-house’ IF staining pattern, the presence of tubuloreticular inclusions, and/or coexisting immune deposits in various anatomic locations outside the subepithelial space in the biopsy specimen. The main pathologic differential diagnosis includes diffuse proliferative (class IV) and membranous (class V) lupus nephritis or an ANCA-associated crescentic glomerulonephritis superimposed on lupus MN. The absence of linear GBM IF staining for IgG excludes anti-GBM disease. In conjunction with the presence of ANCA and normal serum complement levels, the absence of both significant subendothelial or mesangial immune complex deposition, or mesangial or endocapillary proliferation is most consistent with a pauci-immune ANCA-associated crescentic glomerulonephritis in the setting of lupus MN. Although the clinical diagnosis of SLE is not firmly established, the ensuing discussion will be based on a presumptive pathologic diagnosis of lupus MN. CLINICAL FOLLOW-UP
Owing to the clinical features of rapidly progressive glomerulonephritis, the patient was empirically given 1 g of IV methylprednisolone, which was repeated for a total of three daily doses when the initial histological diagnosis of crescentic glomerulonephritis was obtained. She was also given 1.6 g of IV cyclophosphamide (0.8 g/m2), which was well tolerated. Oral iron and darbepoetin alfa were started for anemia. Her hypertension was difficult to control initially, yet later in the hospital course was controlled with losartan and verapamil, which she continued as an outpatient. On hospital day 11, her serum creatinine was 2.2 mg/dl (194 mmol/l), which further decreased to 1.3 mg/dl (146 mmol/l) 2 weeks later. Because of persistently active urinary sediment and a transient rise in serum creatinine to 2.4 mg/dl (270 mmol/l) 2 months after hospitalization, she received escalating monthly doses of intravenous cyclophosphamide to a maximum of 2.0 g (1.0 g/m2), together with 1 g intravenous methylprednisolone for a total of six doses, after which she was maintained on 3.0 g/d mycophenolate mofetil. Three months after her hospitalization, her serum creatinine was 1.0 mg/dl (88 mmol/ l) and urinary protein/creatinine 1.0 (normal 0–0.15). For the ensuing year, she did well with repeated serum creatinine
measurements between 1.0–1.1 mg/dl, urinary protein/creatinine less than 1.7, and resolution of anemia. At the 1-year period, her ANA titer was 1:640 and ANCA was undetectable. DISCUSSION
Crescentic glomerulonephritis represents a severe form of glomerular injury that is characterized by disruption of the GBM leading to cellular proliferation within Bowman’s space, often accompanied by fibrinoid necrosis. Crescentic glomerulonephritis is classified into three main immunopathologic categories: (1) anti-GBM disease; (2) immune complex-mediated glomerulonephritis; and (3) pauci-immune (ANCA-associated) glomerulonephritis. In the setting of SLE, crescentic glomerulonephritis is usually associated with prominent immune complex deposition in subendothelial regions, which often correlates with the histologic finding of endocapillary proliferation, ‘wire-loop’ deposits, or cellular crescent formation. However, in the absence of significant mesangial and subendothelial immune complex deposition and glomerular endocapillary hypercellularity, a pauciimmune (ANCA-associated) glomerular injury process should be a diagnostic consideration as the underlying cause of the crescentic glomerulonephritis. Lupus glomerular lesions are categorized according to the 2003 International Society of Nephrology/Renal Pathology Society revised lupus nephritis classification. In addition, renal biopsies of SLE patients have revealed a spectrum of diseases that are not considered within the lupus nephritis classification scheme, including thin GBM disease, focal segmental glomerulosclerosis, amyloidosis, IgM nephropathy, IgA nephropathy, sarcoidosis, and hypertensive nephrosclerosis.2–5 Lupus nephritis occurring concurrently with another renal injury process has been reported with minimal change disease (podocytopathy).6,7 Of particular relevance to the current report, there are five cases (Table 1) of lupus nephritis with pauci-immune crescentic glomerulonephritis in the literature of which two cases demonstrated class V lupus MN.8–10 Schwartz et al.11 and Ferrario et al.12 report an additional 13 SLE cases with similar histopathologic findings, although ANCA serologies were not available and there was limited IF and no electron microscopy was performed in the latter study. Analogous to the notion that not all ANAs are equal, ANCAs also represent a heterogenous group of antibodies with variable degrees of specificity or avidity, as illustrated by
Table 1 | Renal biopsies of lupus nephritis and pauci-immune GN Case 1 2 3 4 5 6
Age (years)/sex 17/F 40/F 55/M 37/F 50/F 49/F
Renal biopsy findings
ANCA (ELISA)
Clinical outcome
Reference
Class Class Class Class Class Class
Negative Negative pANCA (ND) pANCA (MPO) pANCA (MPO) pANCA (MPO)
Methylprednisone+IV CYC with good recovery Prednisone+CYC; follow-up N/A Died 1.5 months after biopsy Prednisone+IV CYC with creatinine of 1.3 mg/dl Prednisone+IV CYC with good recovery Methylprednisolone+IV CYC with good recovery
Akhtar et al.8 Akhtar et al.8 Marshall et al.9 Marshall et al.9 Masani et al.10 Current case
III LN+focal necrotizing GN IV LN+crescentic GN V LN+crescentic GN V LN+crescentic GN III LN+crescentic GN V LN+crescentic GN
ANCA, anti-neutrophil cytoplasmic antibody; CYC, cyclophosphamide; ELISA, enzyme linked immunosorbent assay; F, female; GN, glomerulonephritis; LN, lupus nephritis; M, male; MPO, myeloperoxidase; N/A, not available; ND, not done; pANCA, perinuclear ANCA.
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Table 2 | Serologic detection of ANCA in SLE patients with lupus nephritis Number of patients
pANCA+ (%)
MPO+ (%)
LF+ (%)
79
20.2
5.1
39.2
Sinico et al.17 Schnabel et al.18 Spronk et al.19 Nishiya et al.20 Zhao et al.22
70 120 84 31 95
ND 25 9.5 42 18.9
ND 0 8.3 16.1 0
15–20 10 15.5 32.2 8.4
Chin et al.23 Manolova et al.21 Pradhan et al.24
51 55 59
31.4 27.3 33.9
2.4 10.9 20.3
30.2 18.2 16.9
Caccavo et al.25
97
ND
ND
54.6
Study 16
Lee et al.
Conclusions No correlation with anti-LF Abs and lupus nephritis. Among class IV lesions, 3 of 4 patients with anti-LF Abs and 1 of 8 without anti-LF-Abs contained crescents No correlation with anti-LF Abs and lupus nephritis No correlation with ANCA and lupus nephritis No correlation with ANCA and lupus nephritis No correlation with ANCA and lupus nephritis or proteinuria 62% of all samples (86% of ANCA+ samples) recognized cathepsin G. Anti-cathepsin G Abs but not anti-LF Abs correlate with lupus nephritis Positive ANCA associated with lupus nephritis No correlation with ANCA and lupus nephritis ANCA titers correlated and were higher in patients with lupus nephritis Anti-LF Ab titers correlate with lupus nephritis
Abs, antibodies; ANCA, anti-neutrophil cytoplasmic antibody; LF, lactoferrin; MPO, myeloperoxidase; ND, not done; pANCA, perinuclear ANCA; SLE, systemic lupus erythematosus.
their different targets, which include MPO, proteinase 3, lysozyme, lactoferrin, cathepsin G, and elastase to name a few.13 Just like with the suggestions that anti-double-stranded DNA antibodies may play a pathogenic role in lupus nephritis, recent data implicate ANCA as an important pathogenic factor. Xiao et al.14 demonstrated that the administration of IgG antibodies specific for MPO alone in RAG2-knockout mice could lead to vasculitis and crescentic glomerulonephritis. One case of transplacental transmission of MPO-ANCA causing rapidly progressive glomerulonephritis in a newborn has been reported, although this was not confirmed with a renal biopsy.15 The proposed mechanism of injury by ANCAs begins with the activation of neutrophils and monocytes, which leads to formation of reactive oxygen species and subsequent damage to the endothelial cells and basement membranes that can result in rupture and subsequent glomerular crescent formation. Approximately 15–20% of SLE patients have detectable ANCA (Table 2). The majority of these have a perinuclear staining pattern by indirect IF, which typically is attributable to reactivity to either MPO (as in our patient) or lactoferrin. Cytoplasmic ANCA staining and/or reactivity to proteinase 3 are seen in a minority of patients (approximately 2%). A number of studies have attempted to correlate ANCA seropositivity with various clinical manifestations of SLE including renal disease with mixed results (reviewed by Sen and Isenberg13). Thus, there are studies that show no association of anti-MPO or anti-lactoferrin ANCA with lupus nephritis16–21 and those that do suggest the two are linked22–25 (Table 2). In these studies, the descriptions of renal histopathologic findings were limited. As such, overall it is difficult to arrive at generalizations regarding ANCA in lupus nephritis. There have been a few studies that have focused specifically on the histopathologic features of lupus nephritis. Using the revised 2003 International Society of Nephrology/ Renal Pathology Society lupus classification, Hill et al.26 found that diffuse segmental proliferative (class IV-S) lupus Kidney International (2007) 71, 360–365
nephritis had fewer immune deposits and more fibrinoid necrosis when compared to diffuse global proliferative (class IV-G) lupus nephritis, which behaved as an immune complex-mediated disease process. Mittal et al.27 observed similar findings, but they did not find the difference between classes IV-G and IV-S lesions to be statistically significant. Hill et al.26 suggested the possibility that an alternate pathogenic mechanism, such as an ANCA-mediated process, may be the cause of the class IV-S lesions, but unfortunately ANCA titers were not available in either study. It does seem clear that a limited subset of patients with lupus nephritis can have concomitant pauci-immune crescentic glomerulonephritis associated with ANCA (Table 1). Although ANCA-related vasculitis is autoimmune in nature, in this instance whether it is an extension of the underlying autoimmune disease in SLE, or alternatively is a separate phenomenon, remains to be established. Lupus MN occurs in up to 20% of lupus nephritis patients.1 The pathogenesis of both idiopathic and lupus MN remains unclear. In MN, there is the uniform presence of subepithelial immune deposits and complement components together with ultrastructural evidence for podocyte damage. The latter can account for proteinuria, given the key role for podocytes to maintain the normal glomerular permselectivity barrier to protein passage. The weight of experimental evidence supports that complement activation results in C5b9-mediated injury of podocytes, but no chemoattractantmediated influx of inflammatory cells owing to the separation of the subepithelial and vascular spaces by the GBM.28 Work in the Heymann nephritis model in rats has shown that antibodies to podocyte antigens can form subepithelial immune complexes in situ. Recently, this mechanism has been shown to be operative in neonatal MN owing to passively transferred maternal antibodies to podocyte neutral endopeptidase.29 This is an uncommon form of MN, and other podocyte target antigens have been elusive. It is likely that autoantibodies binding to intrinsic podocyte antigens is not the exclusive mechanism for subepithelial immune 363
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deposit formation in idiopathic or lupus MN, with other possible mechanisms including antibody binding to extrinsic antigens in the subepithelial region and extrinsic immune complexes traversing the GBM. Given the diversity of autoantibodies in lupus, it seems likely that any or all of these could be operative in lupus MN. The pathologic distinction between coexisting diffuse proliferative lupus nephritis and lupus MN from a pauciimmune, ANCA-associated crescentic glomerulonephritis on a background of lupus MN can be problematic. One could argue the distinction is not crucial, given that the current therapeutic regimens available for both consist of intensive, but nonspecific immunosuppression. Once the clinical diagnosis of rapidly progressive glomerulonephritis is made, treatment with high-dose pulse intravenous corticosteroids is widely used and can be considered standard-of-care. Thereafter, induction therapy with oral or intravenous cyclophosphamide is often used. Intravenous cyclophosphamide has the advantage of a lower cumulative dose and the relative success of prophylaxis against hemorrhagic cystitis; this regimen has been shown to be effective in diffuse proliferative lupus nephritis, whereas only suggested to be effective in lupus MN and in ANCA-associated diseases.30,31 The clear role for daily oral cyclophosphamide in the latter has been proven, and remains the mainstay of therapy until supplanted by more directed forms of treatment.32 Our use of ‘pulse’ intravenous cyclophosphamide was a conscious decision based upon the presumption that it is active against both ANCA-associated glomerulonephritis and lupus MN, as well as it is generally being well-tolerated. Thereafter, the use of daily oral mycophenolate mofetil for maintenance therapy was based on its effectiveness in diffuse proliferative lupus nephritis and that it is also well-tolerated, but with no proof of efficacy for the two diseases present. Despite the potential pathogenic role of ANCAs and ANAs, the precise role for plasmapheresis in patients with lupus nephritis or ANCA-associated glomerulonephritis remains to be established. The most convincing evidence for a possible role for plasma exchange is in those patients with ANCA-associated glomerulonephritis with severe enough disease to require renal replacement therapy.33 Our patient did not receive plasma exchange, and she had a dramatic response to pulse intravenous corticosteroids and cyclophosphamide, as her serum creatinine went from 3.5 to 1.3 mg/dl in 3 weeks. Thereafter, she did well with 6 months of this therapy followed by 6 months of daily oral mycophenolate mofetil. Unfortunately, we cannot make generalizations to use this type of therapeutic regimen in patients with a similar presentation, given the anecdotal nature of this case. Proof continues to await definitive clinical studies on these established and newer therapies. REFERENCES 1. Austin HA, Illei GG. Membranous lupus nephritis. Lupus 2005; 14: 65–71. 2. Baranowska-Daca E, Choi YJ, Barrios R et al. Nonlupus nephritides in patients with systemic lupus erythematosus: a comprehensive clinicopathologic study and review of the literature. Hum Pathol 2001; 32: 1125–1135.
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