Year : 2010 | Volume
: 21 | Issue : 3 | Page : 526--530
ANCA-Positive Pauci-Immune rapidly progressive glomerulonephritis and the nephrotic syndrome
Wael Latif Jabur, Hareth M Saeed
New Medical Center Specialty Hospital, Dubai, United Arab Emirates
Wael Latif Jabur
Specialist Nephrologist, New Medical Center Specialty Hospital, P.O. Box 7832, Dubai
United Arab Emirates
We herewith report a case of biopsy proven crescentic glomerulonephritis (GN) due to vasculitis, whose sole presentation was the nephrotic syndrome. Our case raises the possibility of whether the disease initially was a primary GN, upon which crescentic GN was superimposed, or was it vasculitis from initial stages with an atypical presentation. The various points for both these possibilities are discussed.
|How to cite this article:|
Jabur WL, Saeed HM. ANCA-Positive Pauci-Immune rapidly progressive glomerulonephritis and the nephrotic syndrome.Saudi J Kidney Dis Transpl 2010;21:526-530
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Jabur WL, Saeed HM. ANCA-Positive Pauci-Immune rapidly progressive glomerulonephritis and the nephrotic syndrome. Saudi J Kidney Dis Transpl [serial online] 2010 [cited 2020 Jul 11 ];21:526-530
Available from: http://www.sjkdt.org/text.asp?2010/21/3/526/62704
Atypical presentation of a rare disease can pose diagnostic difficulties. Renal vasculitis characteristically presents with acute crescentic glomerulonephritis and the nephrotic syndrome is often manifested in severe cases. In the patient we are reporting in this paper, the sole presentation of vasculitis was the nephrotic syndrome, which has not been reported previously, to our best knowledge. This presentation raises the possibility of whether the disease, at its outset, was a primary glomerulonephritis (GN) that later evolved to systemic vasculitis in the form of ANCA-positive necrotizing crescentic glomerulonephritis (NCGN), with its clinical corollary of rapidly progressive renal failure (RPRF). Thus, did our patient have an unusual presentation of vasculitis, or were there two distinct disease entities. We attempt at emphasizing the significant clinical, histopathological and electron microscopic (EM) findings of each possibility, in order to hypothesize the most probable diagnosis.
A 55-year-old male patient of Arabic origin presented with a history of high grade intermittent fever and profuse sweating of three weeks duration. Past medical history was remarkable for bronchial asthma for many years, chronic sinusitis and significant weight loss over the last six months. Clinical examination revealed a febrile, emaciated, middle-aged male, with anemia and bilateral ankle edema. Chest examination revealed bilateral expiratory rhonchi and prolonged expiratory phase. The remaining physical examination was unremarkable. Blood tests revealed normochromic normocytic anemia of 6.5 gm/dL and eosinophilic leukocytosis (WBC count of 18000 cells per mL and 30% eosinophils); other cells were normal. The serum albumin was 2.7 gm/dL, 24-hours urinary protein was 3.7 gm and the urine sediment was benign. Urine for Bence Jones protein was negative. Blood and urine cultures were negative as also serology screening and cultures for probable bacterial infections. MRI of the abdomen was normal and CT scan of the chest showed a non-specific pulmonary lesion, which was proved to be eosinophilic infiltrate by bronchoscopy.
Screening for connective tissue disease as well as virology screening was negative. The serum complement level was normal. Screening for ANCA was positive for anti-myeloperoxidase antibodies (MPO) of 174 unit/titer; the anti-proteinase-three antibody (PR3) titer was normal. Bone marrow biopsy was normal. During the follow-up period, the patient's renal function was found to deteriorate rapidly over one month, with the last serum creatinine being 3.2 mg/dL with a glomerular filtration rate (GFR) of 22 mL/min.
Kidney biopsy was performed and it revealed the presence of necrotic glomerulonephritis and severe extra-capillary proliferative lesions in more then 50% of the glomeruli, in the form of cellular crescents [Figure 1]. The renal arterioles showed fibrinoid necrosis and immunofluorescence study was negative. There were no electron-dense deposits but, there was diffuse foot process effacement on electron microscopy.
A diagnosis of vasculitic syndrome was made. Immunosuppression therapy with methylprednisolone 1 gm/day pulses for three days followed by oral prednisolone 60 mg/day and oral cyclophosphamide 2 mg/kg body weight/day was initiated immediately. After two months, the general condition of the patient had improved, and the nephrotic syndrome had remitted completely, but the renal function had improved only partially with the latest serum creatinine being 1.7 mg/dL, and GFR being 42 mL/min, and he continued to be significantly anemic. A trial to taper the immunosuppressive drugs was associated with a relapse of the vasculitic process in form of acute rise in CRP to 22.2 from a baseline of 7, and of creatinine to 2.2 mg/dL, which remitted again with dosage re-adjustment.
The primary glomerular diseases usually present with the nephrotic syndrome; they include membranoproliferative glomerulonephritis,  IgA nephropathy,  and membranous nephropathy;  it has often been reported that these glomerular diseases might transform into ANCA-positive NCGN. However, the significance of ANCA in the context of these diseases is still debatable.  The secondary glomerular diseases that might manifest as the nephrotic syndrome and progress into ANCA-positive NCGN are SLE, mixed essential cryoglobulinemia and other autoimmune diseases.  The histopathological lesion of vascular necrosis and NCGN include the following: on light microscopy, the capillaries and glomerular configuration in the nonnecrotic glomeruli are normal. On immunoflourescence study, no immune deposits are found. On electron microscopy, there is absence of dense deposits, both in the necrotic and the normal glomeruli. All these would highlight the diagnosis of pauci-immune RPGN and would contest the aforementioned suggestions of underlying immune-complex disease.
Despite the absence of clinical manifestations of systemic vasculitis, the presence of necrotic glomerulonephritis and the presence of antibodies against specific components of the neutrophilic cytoplasm, would have suggested a vasculitic process, in the form of ANCA-positive pauci-immune RPGN. Based on the ChapelHill Consensus Conference (CHCC) classification of vasculitis,  our patient might be considered as having ANCA-associated small vessel vasculitis. However, the assumed disease process is not always amenable for categorization. Such drastic presentation of vasculitis, which would fall in the European Vasculitis Study (EUVAS)  Stage-3 is a recognizable feature in Wegners Granulomatosis, which usually presents as the acute nephritic syndrome associated with RPRF occurring over days, weeks, or months. However, in such cases, the ANCA antibodies are usually of the anti-proteinase-3 type.  Nevertheless, there are reported cases of significant discordance between renal histopathologic involvement and the classical mentioned presentation, especially for renal failure and proteinuria.  Also, interstitial granuloma is the most specific finding for Wegners Granulomatosis,  which was not present in our patient. The presence of significant eosinophilia and the history of asthma makes the Churg Strauss Syndrome (CSS) a possibility, according to the American Association of Rheumatology criteria.  Also, there was partial response to treatment, although with residual chronic renal impairment (stage-3 CRF).  Also, there was the perinuclear pattern of ANCA which was of the neutrophilic myeloperoxidase enzyme variety (although the specificity of ANCA-MPO in CSS is only 80%). However, renal involvement is not a prominent feature of the CSS and neither eosinophilia nor worsening of asthma is seen during relapse.  Additionally, our patient did not have cardiac or peripheral nerve involvement, which are common presenting manifestations in CSS.  Nevertheless, we are more inclined to the diagnosis of CSS than Wegners Granulomatosis.
This clinical scenario of our patient had two intriguing aspects. Firstly, there was the nephrotic phase followed by the phase of RPRF, both associated with eosinophilia which is a feature of the CSS.  Also, the widespread tissue and vascular eosinophilic infiltration, the acute eosinophilic interstitial nephritis  with eosinophiluria,  that is often encountered in CSS, point to a probable role of eosinophilia in CSS. A definite link is still unproven.
The renal involvement in CSS is notably more of subtle presentation, mainly as chronic renal failure and the commonest histopathologic corollary is focal and segmental glomerulosclerosis (FSGS).  This lesion is not specific and usually encountered secondary to glomerular injury of any nature,  with variable crescents, which are again non-specific lesions encountered with any severe glomerular inflammation.
The suggestion of renal vasculitis from the onset would be tempered by the fact that the initial clinical presentation would be RPGN, which was not the case in our patient. Some authors have reported the occurrence of crescentic GN without concurrent fibrinoid necrosis, which seems somewhat contradictory to the commonly held view that necrosis is the earliest glomerular sign in crescentic GN. 
The other important feature that might highlight the probable etiology in our patient is that, despite the initial presentation, the recurrence of the vasculitic process shortly after the tapering of prednisolone without associated relapse of the nephrotic syndrome; might mean that we are facing two different disease processes. Also, the activity of the vasculitic process does not seem temporally related to the nephrotic syndrome. One is steroid responsive glomerular disease and the other is ANCA positive NCGN. Considering the whole picture of full blown nephrotic syndrome, absence of hematuria, response to steroids, negative immunofluorescence study and diffuse foot process effacement in the normal glomeruli, we believe that the nephrotic syndrome was due to minimal change disease (MCD) at the outset. This was later superimposed by the ANCApositive pauci-immune RPGN. This proposition might have been helped by repeating the biopsy during the remission phase of the nephrotic syndrome which would have disclosed normalization of the epithelial foot process configuration in the non-necrotic glomeruli. This association of MCD and CSS has not been reported before, to our best knowledge.
In order to propose a common tenet that might explain the link between MCD and CSS, we endeavor to find out tangible mutual factors implicated in the pathogenesis and the disease history of both as follows:
Both are idiopathic diseases.The disease process is associated with systemic inflammation in both, and the pivotal role of systemic inflammatory factors in vasculitis, such as TNF-alpha, IL-1, and IL-8, is widely recognized as the priming factors that up-regulate and re-localize the neutrophilic antigens to their surface membrane and up-regulate the expression of endothelial adhesion molecules. The inflammatory process is addressed on the other side by IL-18, IL-12 and recently hemopexin (which is an acute phase reactant), which are widely blamed as the front players in initiating the disease process in MCD. , The evidence for the involvement of the immune system is sizeable and cellular immunity is supposed to orchestrate the disease process in both.Atopy and allergic reactions are prominent promoters of relapse of the disease process in both, and higher serum level of IgE immunoglobulin, soluble IgE-receptors and eosinophilia are frequently reported.The lack of deposition of immune complexes or complement components demonstrable by immunofluorescence study is common for both; likewise, the absence of dense deposits is against involvement of the complement system or distinctive antigenantibody reaction.Both the diseases are reportedly encountered with the use of certain drugs, which is probably a sort of allergic reaction.Acute renal failure secondary to acute interstitial nephritis, which is the harbinger of drug induced MCD, is an often reported event in the context of both diseases.  Infections such as Chlamydia and Staph aureus in vasculitis and Mycoplasma in MCD are often notable as potential provocative factors in both disease processes.  Whether these two diseases are genetically similar needs further clarification.Nevertheless, there are anecdotal reports of association of MCD and atopy with HLA-B12. 
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