- Case report
- Open Access
- Open Peer Review
Fibrillary glomerulonephritis with small fibrils in a patient with the antiphospholipid antibody syndrome successfully treated with immunosuppressive therapy
- Muhammad M Javaid1,
- Helen Denley2 and
- Senyo Tagboto3Email author
https://doi.org/10.1186/1471-2369-8-7
© Javaid et al; licensee BioMed Central Ltd. 2007
- Received: 30 June 2006
- Accepted: 09 May 2007
- Published: 09 May 2007
Abstract
Background
Fibrillary glomerulonephritis is a rare cause of progressive renal dysfunction, often leading to the need for dialysis within a few years. The role of immunosuppressive treatment is still uncertain although this has been tried with variable success.
Case presentation
A 56 year old woman with the antiphospholipid antibody syndrome (IgM anticardiolipin antibodies) was seen in the nephrology clinic with haematuria, proteinuria, and worsening renal function. A renal biopsy demonstrated a mesangial proliferative glomerulonephritis on light microscopy and smaller fibrils (10.6–13.8 nm in diameter) than is usual for fibrillary glomerulonephritis (typically 18–22 nm) on electron microscopy. Amyloidosis was excluded following detailed evaluation. On account of rapidly worsening renal failure she was started on cyclophosphamide and prednisolone which led to the partial recovery and stabilization of her renal function.
Conclusion
This case highlights the need for routine electron microscopy in native renal biopsies, where the differential diagnosis is wide and varied and the light and immunofluorescence microscopic findings may be non specific.
Keywords
- Amyloidosis
- Perindopril
- Membranoproliferative Glomerulonephritis
- Serum Angiotensin Converting Enzyme
- Mesangial Proliferative Glomerulonephritis
Background
Classification and clinical features of fibrillary and immunotactoid glomerulopathies
Fibrillary glomerulonephritis | Immunotactoid glomerulopathy | |
---|---|---|
Composition | Fibrils | Microtubules |
Fibril or microtubule size | Average diameter 18–22 nm (usual range 12–30 nm) | Typically >30 nm (range 16–90 nm) |
Arrangement of fibrils or microtubules | Randomly arranged fibrils | Parallel arrays of microtubules |
Immunoglobulin type | Usually polyclonal (mostly IgG4 sometimes with IGg1) occasionally monoclonal (IgGκ) | Usually monoclonal IgGκ or IgGλ |
Light microscopy | Mesangial proliferation, membranoproliferative GN crescentic GN, sclerosing GN diffuse proliferative GN with endocapilliary exudation | Atypical membranous GN, diffuse proliferative GN membranoproliferative GN |
Association with lymphoproliferative disorder | Uncommon | Common (chronic lymphocytic leukaemia, nonHodgkin lymphoma) |
Renal presentation | Sub nephrotic or nephrotic range proteinuria + haematuria hypertension, rapidly progressive glomerulonephritis | Nephrotic syndrome with microhaematuria and hypertension |
Other manifestations (fibrillar deposits) | Pulmonary haemorrhage | Microtubular inclusions in leukaemic lymphocytes |
Treatment | Various immunosuppressive drugs tried with variable response (see table 1) | Treatment of the associated lymphoproliferative disorder |
Racial predilection | Predominantly Caucasian | Predominantly Caucasian |
Peak occurrence | 5th to 6th decades | Age 60 years |
Prognosis | Established renal failure in half of patients within 2–4 years | Probably better renal prognosis than fibrillary GN |
Frequency in renal biopsies | Approximately 1 % of renal biopsies | 0.06% of renal biopsies |
Light microscopy typically demonstrates a mesangioproliferative or a membranoproliferative glomerulonephritis. Glomerular crescents are present in about 25% of biopsies [1, 10]. Immunofluorescence may demonstrate IgG and C3, IgG4 being the predominant IgG subtype [5, 6]. IgA, IgM and C1q deposition are less commonly found.
We report a case of FibGN in a 56 year old woman. The size of her fibrils were rather small ranging between 10.6–13.8 nm. Further detailed evaluation did not demonstrate amyloid deposition. On account of rapidly worsening renal failure she was started on a trial of cyclophosphamide and prednisolone which led to the partial recovery and stabilization of her renal function.
Case Presentation
A 56 year old woman was referred to the nephrology outpatient clinic, in November 2004 with haematuria, proteinuria, and worsening renal function. Her only complaints were of intermittent macroscopic haematuria and right upper quadrant colicky abdominal pain.
Her past medical history included hypertension, hyperlipidaemia and psoriasis. Additionally, she had an appendicectomy aged 16 and a cholecystectomy in 1984. She had been diagnosed with the antiphospholipid antibody syndrome (IgM anticardiolipin antibodies) following an episode of branch retinal artery thrombosis in September 2003, and a transient ischaemic attack in January 2004.
Her medications included warfarin, atorvastatin and perindopril, although the latter had just been stopped by her General Practitioner.
At the time of her initial review in the renal out-patient clinic, her blood pressure was 164/90 mmHg. Her urine dipstick contained blood (+++) and protein quantified at 0.52 g in 24 hours. Serum albumin levels were low at 31 g/l. An ultrasound scan demonstrated normal kidneys with a small benign cyst on her left kidney. An IVU and cystoscopy were reported as normal. Her serum creatinine levels measured 84 μmol/l in July 2003, 150 μmol/l in November 2004, and 300 μmol/l in January 2005. Further investigations showed a haemoglobin level of 8 g/dl. Serum Folate levels were normal; however, B12 and Ferritin levels were low at 171 pg/ml and 33.7 ng/ml respectively. Gastric parietal cell antibodies and intrinsic factor antibodies were not detected.
ANA, ENA, ANCA and dsDNA antibodies, rheumatoid factor and cryoglobylins were not demonstrated. Serum angiotensin converting enzyme (ACE) levels and complement (C3 & C4) were within normal limits.
Serology for Hepatitis B and C was negative. C reactive protein levels were measured at 4 mg/l. Her ESR and plasma viscosity were elevated at 76 mm/hr and 1.98 mPas respectively. Serum electrophoresis revealed no abnormalities, and Bence-Jones proteins were not detected in a urine specimen.
Electron micrograph or kidney biopsy demonstrating fibrils ranging in size from 10.6 to 13.8 nm (original magnification × 64000).
Kidney biopsy showing possible early crescent (haematoxylin and eosin stain, original magnification × 100).
Kidney biopsy showing mesangial proliferative changes (haematoxylin and eosin stain, original magnification ×100).
Red cells and red cell cast in tubules (Masson trichrome stain, original magnification ×100).
Electron microscopy of a single glomerulus showed numerous fibrils with a diameter of 10.6–13.8 nm and within an expanded mesangial matrix. These findings suggested the diagnosis of FibGN although the small fibre size was somewhat suggestive of amyloid (FibGN typically has larger fibers, average diameter 20 nm).
She was referred to the National Amyloidosis Centre who also assessed her renal biopsy and did not find evidence of amyloid. They assessed her serum free light chains, demonstrating slightly increased kappa levels at 29.3 mg/l and lambda levels at 39.7 mg/l, probably the consequence of the decreased renal clearance of normal light chains in this patient. However, the κ/λ ratio was normal at 0.74 (range 0.26–1.65). Furthermore, serum amyloid P (SAP) scintigraphy did not reveal visceral amyloid deposition. A final diagnosis of FibGN was made.
Once her serum creatinine levels reached 300 μmol/l in January 2005, she was started on Prednisolone (40 mg daily) and cyclophosphamide (100 mg daily). In addition she received intravenous iron therapy, B12 injections and erythropoietin beta. Her blood pressure was treated with perindopril and amlodipine.
Changes in estimated GFR (abbreviated MDRD formula) with time (see text for details).
During the course of her illness, she had an episode of haematemisis and fresh bleeding per rectum. She also complained of easy skin bruising and had an episode of macroscopic haematuria. Upper gastrointestinal endoscopy and colonoscopy were normal. Unfortunately, a request, with the patient's permission to obtain biopsies at endoscopy to look for fibrils was inadvertently not carried out. A chest X-ray carried out to investigate a cough was reported as showing a bulky left hilum but a computed tomography scan of chest and upper abdomen was normal.
FibGN occurs in approximately 1% of renal biopsies [[8, 11] and [12]]. It is more common in Caucasians with a peak incidence between the fifth and the sixth decades of life [11].
Since the patient had been diagnosed with the antiphospholipid antibody syndrome, the presence of mesangioproliferative glomerulonephritis on light microscopy, initially suggested the diagnosis of lupus nephritis. However the presence of fibrils in the mesangium on electron microscopy and the negative staining for amyloid pointed to a diagnosis of FibGN, a condition with a relatively poor prognosis. It is quite possible that the diagnosis may be underreported where light microscopic findings are not routinely complemented by electron microscopy.
The fibrils in our patient were 10.6–13.8 nm in diameter. Fibrils of this size are possible in amyloidosis, which is characterized by the deposition of proteinaceous material in extracellular spaces, composed of a felt like array of 7.5–10 nm wide, linear, non branching fibrils of indefinite length [13]. In our patient, congo red staining, immunohistochemistry and SAP scintigraphy did not reveal amyloid.
Symptoms in FibGN are usually nonspecific and consist of proteinuria, haematuria, hypertension and renal insufficiency. Fibril deposition is predominantly confined to the kidneys. However, fibrillary deposits have been reported in the alveolar capillary membrane, producing a pulmonary-renal syndrome, and in the skin of a patient with leukocytoclastic skin vasculitis [7, 12, 14]. Whether the episodes skin bruising, haematemesis, and rectal bleeding in our patient was due to fibrillary deposition in these organs or not is not known. Our patient was understandably not keen to be subjected to further biopsies to confirm the deposition of fibrils elsewhere.
Key publications regarding the efficacy of immunosuppressive drugs in treating fibrillary glomerulonephritis
Treatment | Response | Authors |
---|---|---|
Methyprednisolone/Prednisolone | No response | Asaba et al., 2003 |
Prednisolone & Mycophenolate mofetil | Persistent haematuria and proteinuria, improvement in serum creatinine levels | Bijol et al., 2006 |
Prednisolone, Cyclophosphamide then Cyclosporin | Brief initial response with prednisolone then relapse. No response with cyclophosphamide resolution of nephrotic syndrome with cyclosporin | Bircan et al., 2004 |
Prednisolone & Cyclophosphamide | Marked improvement in renal function | Blume et al., 2002 |
Corticosteroids +/- Cyclophosphamide | No response in fibrillary glomerulonephritis. Variable response in immunotactoid glomerulopathy including melphalan, vincristine, doxorubicin, carmustine or chlorambucil in various combinations, remission or improvement in nephrotic syndrome in 10/12 patients, disappearance of deposits from the kidneys of 2 patients | Bridoux et al., 2002 |
Prednisolone & Cyclophosphamide then Azathioprine | Transient reduction in proteinuria | Chan han, 1998 |
Prednisolone | Resolution of nephrotic syndrome or reduction in proteinuria | Dickenmann et al., 2002 |
Prednisolone & Chlorambucil | Slight reduction in creatinine, reduction in proteinuria from 3 g to 1 g in 24 h. | Dussol et al., 1998 |
Prednisolone | No response | Gielen et al., 2006 |
Prednisolone & Cyclophosphamide then Azathioprine | No response | Hsu et al., 2001 |
Prednisolone & Cyclophosphamide | Recovery of renal function, discontinuation of dialysis | Mahajan et al., 2005 |
Prednisolone | Improvement in renal function, reduction in proteinuria | Moriyama et al., 2003 |
Prednisolone & Chloraminophen (Chlorambucil) | Reduction in creatinine levels, disappearance of proteinuria and haematuria | Nabarra et al., 2003 |
Prednisolone & Mycophenolate mofetil | Continued rapid deterioration in renal function | Ovuworie et al., 2000 |
Prednisolone, Cyclophosphamide, plasmapheresis & immunoglobulins | Fibrils in renal transplant patient, continued rapid deterioration in renal function | Palanichamy et al., 1998 |
Various combinations of Cyclosporin A | Biopsy proven recurrence of fibrillary glomerulopathy in 3 transplanted kidneys | Pronovost et al., 1996 |
Prednisolone, Azathioprine and ATG (in 1 patient) | Rate of decline in renal allografts slower than native kidneys suggesting either benefit of immunosuppressive therapy or spontaneous remission with time | |
20 treated patients out of 56 | No effect of immunosuppression on incidence of or time to end stage renal disease | Rosenstock et al., 2003 |
Steroids alone (16% of patients) | Variable response including improvement in renal function and reduction in proteinuria | |
Cyclophosphamide +/- steroids (14%) Cyclosporin (5%) | Poor response of patients with immunotactoid glomerulopathy to immunosuppression except one good responder to fludarabine with improvement in renal function and reduced proteinuria | |
Prednisolone & Cyclophosphamide | Recovery of renal function, discontinuation of dialysis, recovery from pulmonary haemorrhage | Rovin et al., 1993 |
Prednisolone & Chlorambucil | Reduction or stabilization in creatinine levels, reduction in proteinuria | Schneider et al., 1996 |
Conclusion
This case highlights the need for routine electron microscopy in native renal biopsies, where the differential diagnosis is wide and varied and the light and immunofluorescence microscopic findings may be non specific.
The diagnosis of FibGN cannot be made on the basis of the size of the fibrils alone. A therapeutic trial of cyclophosphamide and prednisolone in patients with progressive renal dysfunction who are able to tolerate the treatment, and who understand the risks is worthwhile. This may prevent or slow down the progression of renal failure.
Declarations
Acknowledgements
We thank Dr. Alan Curry, Consultant Clinical Scientist for the Electron micrographs. Written consent was obtained from the patient for publication of their medical history.
Authors’ Affiliations
References
- Brady HR: Fibrillary glomerulopathy. Kid Int. 1998, 53: 1421-1429. 10.1046/j.1523-1755.1998.t01-1-00094.x.View ArticleGoogle Scholar
- Rosenmann E, Eliakim M: Nephrotic Syndrome associated with amyloid like deposits. Nephron. 1977, 18: 301-308.View ArticlePubMedGoogle Scholar
- Alpers CE, Rennke HG, Hopper J, Biava CG: Fibrillary glomerulonephritis: an entity with unusual immunofluorescence features. Kid Int. 1987, 31: 781-789.View ArticleGoogle Scholar
- Adey DB, MacPherson BR, Groggel GC: Glomerulonephritis with associated hypocomplementemia and crescents: an unusual case of fibrillary glomerulonephritis. J Am Soc Nephrol. 1995, 6: 171-176.PubMedGoogle Scholar
- Fogo A, Qureshi N, Horn RG: Morphological and clinical features of fibrillary glomerulonephritis versus immunotactoid glomerulopathy. Am J Kidney Dis. 1993, 22: 367-377.View ArticlePubMedGoogle Scholar
- Ivanyi B, Degrell P: Fibrillary glomerulonephritis and immunotactoid glomerulopathy. Nephro Dial Transplantat. 2004, 19: 2166-2170. 10.1093/ndt/gfh376.View ArticleGoogle Scholar
- Ronco P, Aucouturier P, Moulin B: Renal amyloidosis and glomerular disease with monoclonal immunoglobulin deposit. Comprehensive Clinical Nephrology. Edited by: Johnson RJ, Feehally J. 2003, Spain, Elsevier Science, 398-400. 2Google Scholar
- Rosenstock JL, Markowitz GS, Valeri AM, Sacchi G, Appel GB, D'Agati VD: Fibrillary and immunotactoid glomerulonephritis: Distinct entities with different clinical and pathological features. Kidney Int. 2003, 63: 1450-1461. 10.1046/j.1523-1755.2003.00853.x.View ArticlePubMedGoogle Scholar
- Schwartz MM, Korbet SM, Lewis EJ: Immunotactoid glomerulopathy. J Am Soc Nephrol. 2002, 13: 1390-1397. 10.1097/01.ASN.0000013397.06964.19.View ArticlePubMedGoogle Scholar
- Guerra G, Narayan G, Rennke HG, Jaber BL: Crescentic fibrillary glomerulonephritis associated with hepatitis C viral infection. Clin Nephrol. 2003, 60: 364-368.View ArticlePubMedGoogle Scholar
- Iskandar SS, Falk RJ, Jennette JC: Clinical and pathologic features of fibrillary glomerulonephritis. Kidney Int. 1992, 42: 1401-1407.View ArticlePubMedGoogle Scholar
- Hvala A, Ferluga D, Vizjak A, Koselj-Kajtna M: Fibrillary noncongophilic renal and extrarenal deposits: a report of 10 cases. Ultrastruct Pathol. 2003, 27: 341-347.View ArticlePubMedGoogle Scholar
- Glenner GG: Amyloid deposits and amylodosis. The beta fibrilloses. N Eng J Med. 1980, 302: 1283-1292.View ArticleGoogle Scholar
- Masson RG, Rennke HG, Gottlieb MN: Pulmonary hemorrhage in a patient with fibrillary glomerulonephritis. N Eng J Med. 1992, 326: 36-39.View ArticleGoogle Scholar
- Hsu B, Chang C, Chiang S, Yang A: Fibrillary glomerulonephritis. Chin Med J (Tapei). 2001, 64: 419-452.Google Scholar
- Blume C, Ivens K, May P, Helmchen U, Jehle PM, Riedel M, Keller F, Grabensee B: Fibrillary glomerulonephritis associated with crescents as a therapeutic challenge. Am J Kid Dis. 2002, 40: 420-425. 10.1053/ajkd.2002.34548.View ArticlePubMedGoogle Scholar
- Rovin BH, Bou-Khalil P, Sedmak D: Pulmonary renal syndrome in a patient with fibrillary glomerulonephritis. Am J Kid Dis. 1993, 22: 713-716.View ArticlePubMedGoogle Scholar
- Asaba K, Tojo A, Lika M, Mimura ON, Kido M, Goto A, Endo H, Fujita T: Fibrillary glomerulonephritis associated with essential thrombocytosis. Clin Exp Nephrol. 2003, 7: 296-300. 10.1007/s10157-003-0250-2.View ArticlePubMedGoogle Scholar
- Bijol V, Agrawal N, Abernethy VE, Rifkin IR, Nosé V, Rennke HG: A 57-Year-Old Woman With Recently Diagnosed SLE, Proteinuria, and Microhematuria. Am J Kid Dis. 2006, 48: 1004-1008. 10.1053/j.ajkd.2006.09.012.View ArticlePubMedGoogle Scholar
- Bircan Z, Toprak D, Kilicalslan I, Solakoglu S, Uysal V, Ponard D, Turker G: Factor H deficiency and fibrillary glomerulopathy. Nephrol Dial Transplant. 2004, 19: 727-730. 10.1093/ndt/gfg605.View ArticlePubMedGoogle Scholar
- Bridoux F, Hugue V, Coldefy O, Goujon J, Bauwens M, Sechet A, Preud'homme J, Touchard G: Fibrillary glomerulonephritis and immunotactoid (microtubular) glomerulopathy are associated with distinct immunological features. Kidney Int. 2002, 62: 1764-1775. 10.1046/j.1523-1755.2002.00628.x.View ArticlePubMedGoogle Scholar
- Chan TM, Chan KW: Fibrillary glomerulonephritis in siblings. Am J Kid Dis. 1998, 31 (5): E4-View ArticlePubMedGoogle Scholar
- Dickenmann M, Schaub S, Nickeleit V, Mihatsch M, Steiger J, Brunner F: Fibrillary glomerulonephritis: early diagnosis associated with steroid responsiveness. Am J Kid Dis. 2002, 40 (3): E9-10.1053/ajkd.2002.34933.View ArticlePubMedGoogle Scholar
- Dussol B, Kaplanski G, Daniel L, Brunet P, Pellissier J, Berland Y: Simultaneous occurrence of fibrillary glomerulopathy and AL amyloid. Nephrol Dial Transplant. 1998, 13: 2630-2632. 10.1093/ndt/13.10.2630.View ArticlePubMedGoogle Scholar
- Gielen GAL, Wetzels JFM, Steenbergen EJ, Muddle AH: Fibrillary glomerulonephritis in a patient with type 2 diabetes mellitus. Neth J Med. 2006, 64 (4): 119-123.PubMedGoogle Scholar
- Mahajan S, Kalra V, Dinda AK, Tiwari SC, Agarwal SK, Bhowmik D, Dash SC: Fibrillary glomerulonephritis presenting as rapidly progressive renal failure in a young female: a case report. Int Uro Nephrol. 2005, 37: 561-4. 10.1007/s11255-004-4707-3.View ArticleGoogle Scholar
- Moriyama T, Honda K, Tsukada M, Koike M, Itoh K, Nitta K, Horita S, Yumura W, Nihei H: A case of immunotactoid glomerulopathy with IgA2, κ deposition ameliorated by steroid therapy. Nippon Jinzo Gakkai Shi. 2003, 45: 449-456.PubMedGoogle Scholar
- Nabarra B, Larquet E, Diemert M, Leblond V, Baumelou A, Beaufils H: Unusual IgM fibrillar deposits in glomerulonephritis: Ultrastructural and diffraction studies in a case report. Hum Pathol. 2003, 34: 1350-1354. 10.1016/j.humpath.2003.07.007.View ArticlePubMedGoogle Scholar
- Ovuworie C, Volmar K, Charney D, Kravet S, Racusen L: Rapidly progressive renal failure with nephrotic syndrome in a patient with type 2 diabetes mellitus: The differential of fibrillary deposits. Am J Kid Dis. 2000, 35: 173-177.View ArticlePubMedGoogle Scholar
- Palanichamy V, Saffarian N, Jones B, Nakhleh RE, Oh HK, Provenzano R, Tayeb JS: Fibrillary glomerulonephritis in a renal allograft. Am J Kid Dis. 1998, 32: E4-View ArticlePubMedGoogle Scholar
- Pronovost PH, Brady HR, Gunning ME, Espinoza O, Rennke HG: Clinical features, predictors of disease progression and results of renal transplantation in fibrillary/immunotactoid glomerulopathy. Nephrol Dial Transplant. 1996, 11: 837-842.View ArticlePubMedGoogle Scholar
- Schneider R, Lugassy G, Schlesinger M, Kopolovic J, Yagil Y: Fibrillar glomerulopathy associated with chronic lymphocytic leukaemia. Nephrol Dial Transplant. 1996, 11: 1352-1355.View ArticlePubMedGoogle Scholar
- The pre-publication history for this paper can be accessed here:http://www.biomedcentral.com/1471-2369/8/7/prepub
Pre-publication history
Copyright
This article is published under license to BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.