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Saudi Journal of Kidney Diseases and Transplantation
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CASE REPORT Table of Contents   
Year : 2010  |  Volume : 21  |  Issue : 3  |  Page : 526-530
ANCA-Positive Pauci-Immune rapidly progressive glomerulonephritis and the nephrotic syndrome

New Medical Center Specialty Hospital, Dubai, United Arab Emirates

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Date of Web Publication26-Apr-2010


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;21:526-30

How to cite this URL:
Jabur WL, Saeed HM. ANCA-Positive Pauci-Immune rapidly progressive glomerulonephritis and the nephrotic syndrome. Saudi J Kidney Dis Transpl [serial online] 2010 [cited 2022 Aug 10];21:526-30. Available from: https://www.sjkdt.org/text.asp?2010/21/3/526/62704

   Introduction Top

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.

   Case History Top

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.

   Discussion Top

The primary glomerular diseases usually pre­sent with the nephrotic syndrome; they include membranoproliferative glomerulonephritis, [1] IgA nephropathy, [2] and membranous nephropathy; [3] 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. [1] 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. [4] 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, [5] 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) [6] 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. [6] Nevertheless, there are reported cases of significant discordance between renal histopa­thologic involvement and the classical men­tioned presentation, especially for renal failure and proteinuria. [2] Also, interstitial granuloma is the most specific finding for Wegners Granu­lomatosis, [2] 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. [7] Also, there was partial response to treatment, although with residual chronic renal impairment (stage-3 CRF). [6] 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. [8] Additionally, our pa­tient did not have cardiac or peripheral nerve involvement, which are common presenting manifestations in CSS. [8] 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. [9] Also, the widespread tissue and vascular eosinophilic infiltration, the acute eosinophilic interstitial nephritis [10] with eosinophiluria, [11] 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,[6] mainly as chronic renal failure and the commonest histopatholo­gic corollary is focal and segmental glomeru­losclerosis (FSGS). [6] This lesion is not specific and usually encountered secondary to glome­rular injury of any nature, [12] 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. [2]

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.

   Highlights Top

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:

  1. Both are idiopathic diseases.
  2. 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. [12],[13]
  3. The evidence for the involvement of the immune system is sizeable and cellular im­munity is supposed to orchestrate the di­sease process in both.
  4. 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.
  5. 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.
  6. Both the diseases are reportedly encoun­tered with the use of certain drugs, which is probably a sort of allergic reaction.
  7. 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. [10]
  8. Infections such as Chlamydia and Staph aureus in vasculitis and Mycoplasma in MCD are often notable as potential provo­cative factors in both disease processes. [13]
  9. Whether these two diseases are genetically similar needs further clarification.
Nevertheless, there are anecdotal reports of association of MCD and atopy with HLA-B12. [13]

   References Top

1.Bonaci-Nicolic B, Nicolic MM, Andrejevic S, et al. (ANCA)-associated autoimmune diseases induced by anti-thyroid drugs: Comparison with idiopathic ANCA vasculitides. Arthritis Res Ther 2005;7:1072-81.  Back to cited text no. 1      
2.Aasarad K, Bostad L, Hammerstrem J, Jorstad S, Iversen BM. Renal histopathology and clin­ical course in 94 patients with Wegeners gra­nulomatosis. Nephrol Dial Transplant 2001;16: 953-60.  Back to cited text no. 2      
3.Nayak SG, Satish R. Crescentic transformation in primary membranous glomerulopathy: Asso­ciation with Anti-GBM antibody. Saudi J Kidney Dis Transpl 2007;18(4):599-602.  Back to cited text no. 3      
4.Lamprecht P, Schmitt WH, Gross WL. Mixed cryoglobulinaemia, glomerulonephritis, and ANCA: Essential cryoglobulinemic vasculitis or ANCA-associated vasculitis. Nephrol Dial Transplant 1998;13:213-21.  Back to cited text no. 4  [PUBMED]  [FULLTEXT]  
5.Deliyska B, Shurliev V. The efficacy of an individual treatment schedule in patients with vasculitis. Nephrol Dial Transplant 2003;18 (suppl 5):v13-5.  Back to cited text no. 5  [PUBMED]  [FULLTEXT]  
6.Tesar V, Rihova Z, Jancova E, Rysava R, Metra M. Current treatment in ANCA-positive renal vasculitis-lessons from European randomized trials. Nephrol Dial Transplant 2003;18(suppl 5):v2-4.  Back to cited text no. 6      
7.McAuley DF, McGovern V, Dick PT, Lawson JT, Macmahon J. Churge-Strauss syndrome asso­ciated with leukotriene receptor antagonists. Ulster Med J 2001;70(2):152-4.  Back to cited text no. 7      
8.Guillevin L, Cohen P, Gayraud M, et al. Churge Strauss syndrome: Clinical study and long term follow-up of 96 patients. Medicine 1999;78: 26-37.  Back to cited text no. 8  [PUBMED]  [FULLTEXT]  
9.Kumagai T, Hori Y, Kishida Y, et al. Acute re­nal failure and nephrotic syndrome associated with Zafirlukast therapy. Nephrol Dial Transplant 2003;18:2202-3.  Back to cited text no. 9  [PUBMED]  [FULLTEXT]  
10.Rychlik I, Tesar V, Stejskalova A, Stejskal J, Honsova E, Bartunkova J. ANCA-Positive Churge-Strauss syndrome with acute renal failure. Nephrol Dial Transplant 1997;12:837-8.  Back to cited text no. 10      
11.Ohsawa I, Ohi H, Takahashi K. Eosinophiluria in churge strauss syndrome. Nephrol Dial Transplant 2004;19:1333.  Back to cited text no. 11  [PUBMED]  [FULLTEXT]  
12.Jennette JC, Thomas DB. Crescentic glome­rulonephritis. Nephrol Dial Transplant 2001;16 (suppl 6):80-2.  Back to cited text no. 12  [PUBMED]    
13.Glassok RJ. Secondary minimal change di­sease. Nephrol Dial Transplant 2003;18(suppl 6):52-8.  Back to cited text no. 13      

Correspondence Address:
Wael Latif Jabur
Specialist Nephrologist, New Medical Center Specialty Hospital, P.O. Box 7832, Dubai
United Arab Emirates
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Source of Support: None, Conflict of Interest: None

PMID: 20427883

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