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Saudi Journal of Kidney Diseases and Transplantation
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Year : 2017  |  Volume : 28  |  Issue : 6  |  Page : 1416-1420
Fibronectin glomerulopathy - A sporadic case with unusual clinical manifestation

1 Department of Nephrology, NH Malla Reddy Narayana Multispeciality Hospital, Telangana, Hyderabad, India
2 Department of Histopathology, Apollo Hospital, Telangana, Hyderabad, India
3 Laboratory of Immunology and Genetics of Transplantation and Rare Diseases IRCCS - “Mario Negri” Institute for Pharmacological Research Ranica, Bergamo, Italy
4 Department of Pathology, Apollo Hospital, Telangana, Hyderabad, India

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Date of Web Publication18-Dec-2017


A 22-year-old nondiabetic young Indian female presented with short history of dyspnea, anorexia, and bilateral leg swelling. Her laboratory evaluation showed severe anemia, serum creatinine of 11.89 mg/dL, nephrotic range proteinuria and microscopic hematuria with 6–8 red blood cell/high-power field. Renal biopsy showed brightly eosinophilic, periodic acid-Schiff (PAS) positive, silver negative, and fuschinophilic deposits in the mesangium extending around the capillary loops with thickening of the basement membrane. Immunohistochemistry was strongly positive for fibronectin (FN). There was no family history of renal disease. Genetic screening revealed absence of mutations in the FN1 gene. She was put on maintenance hemodialysis.

How to cite this article:
Mandal SN, Shrivastava S, Piras R, Gowrishankar S. Fibronectin glomerulopathy - A sporadic case with unusual clinical manifestation. Saudi J Kidney Dis Transpl 2017;28:1416-20

How to cite this URL:
Mandal SN, Shrivastava S, Piras R, Gowrishankar S. Fibronectin glomerulopathy - A sporadic case with unusual clinical manifestation. Saudi J Kidney Dis Transpl [serial online] 2017 [cited 2020 Sep 19];28:1416-20. Available from: http://www.sjkdt.org/text.asp?2017/28/6/1416/220860

   Introduction Top

Fibronectin (FN) Glomerulopathy is a rare hereditary disease which is transmitted as autosomal dominant. It has also been described as sporadic cases. Till now, 50 cases have been reported in the literature. It was first described by Mazzucco in 1992[1] Diagnosis of FN glomerulopathy is confirmed when the intense staining for the plasma isoform of FN is found in the mesangium and along the capillary walls.[2] On electron microscopy, it appears as an abnormal electron-dense finely granular or fibrillary substructure with randomly arranged, 12–16-nm fibrils deposits in the mesangium and subendothelial zone[3] There is no specific treatment for FN glomerulopathy.

   Case Report Top

A 22-year-old nondiabetic female presented with loss of appetite of one week, shortness of breath, and leg swelling from three days. She denied history of hair loss, alopecia, oral ulceration, oliguria, joint pain, rashes, and menstrual irregularities. There was no history of nephrotic or nephritic illnesses and any episode of urinary tract infection during her childhood period. Physical examination showed severe anemia, pedal edema, blood pressure 150/90 mm Hg, pulse 92/min, weight 43 kg and body mass index of 18 kg/m2. Complete urine examination showed protein 2+, microscopic hematuria (6–8 red blood cell/high power field), and no casts. Urinary spot protein to creatinine ratio was 17.65. Laboratory evaluation showed Hb 8.1 g/dL, serum creatinine 11.89 mg/dL, blood urea nitrogen 65.99 mg/dL, sodium 135 mmol/L, potassium 4.1 mmol /L, serum albumin 1.5 g/dL, globulin 2.9 g/dL, alkaline phosphates of 86 IU/L, serum glutamic oxaloacetic transaminase 17 IU/L, and serum glutamic pyruvic transaminase 25 IU/L. Lupus serology was negative (antinuclear antibody 3.35 units, dsDNA 10.76 units). Serum complement C3 was low (44.5 mg/dL) and complement C4 was normal. Ultrasound of abdomen showed the right kidney of 9 cm × 3 cm and left kidney 8.6 cm × 3.8 cm with mild increase in echogenicity and normal corticomedullary differentiation. A percutaneous renal biopsy was done to evaluate the cause of the apparently rapidly progressive renal failure. Renal biopsy showed renal cortex with adjoining medulla with up to 14 glomeruli. Four glomeruli were obsolescent. The other glomeruli were enlarged with marked mesangial widening with brightly eosinophilic, periodic acid-Schiff (PAS) positive, silver negative deposits in the mesangium extending around the capillary loops with thickening of the basement membrane [Figure 1]. The deposits were red on trichrome stain [Figure 1]c. The tubules showed atrophic changes involving 30%–40% of the cortex sampled and these tubules showed marked PAS positive thickened basement membrane. The interstitium showed a mild lymphocytic infiltrate and prominent aggregates of foamy histiocytes. There was arteriolar hyalinosis, intimal, fibrosis with focal myxoid change, and medial hyperplasia. Immunofluorescence study showed 12 glomeruli with the absence of immunoglobulin and peripheral and mesangial irregular deposits of C3c [Figure 2]. Deposits of C3c were also seen along the tubular basement membrane. Immunohistochemistry was strongly positive for FN [Figure 2]. Sequencing of the entire coding region (Exons 1–46) of the FN1 gene did not reveal mutations in this patient. Hence, a diagnosis of FN glomerulopathy was made. There was no family history of renal disease in her family.
Figure 1: Panel a (periodic acid–Schiff stain ×100) showing globally sclerosed glomeruli with periodic acid-Schiff positive solidified tufts and the others are showing marked periodic acid-Schiff positive mesangial deposits. These deposits are sliver negative in panel b (PASM Jones ×100) and have a prominent fuschinophilia in the trichrome stain in panel c (Masson's trichrome ×100). Patchy tubular atrophy is also evident in all the stains.

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Figure 2: The direct IF study shows absent immunoglobulins in the left panel and minimal capillary and mesangial deposits of C3c in the middle panel (direct IF with fluorescein isothiocyanate-labeled antibodies ×200)The right panel shows strong positivity with fibronectin (Immunoperoxidase ×200).

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She was advised antihypertensive drugs and is on regular maintenance hemodialysis.

   Discussion Top

A case of rapidly progressive renal disease due to FN glomerulopathy in young girl that resulted in end-stage renal disease is described.

Patients with FN glomerulopathy present with subnephrotic proteinuria, rarely nephrotic proteinuria, microscopic hematuria, arterial hypertension, renal tubular acidosis type IV, and end-stage renal disease in the 2nd to 6th decade of life. Gemperle et al in their longterm follow-up of this disease described it as a slowly progressive disease over the period of 15–20 years.[4] The case is unique in that the patient was very young and presented with advanced renal failure and is probably the first such case presentation in literature. It is possible that this patient had developed this disease at very early stage of her life and she was asymptomatic during the early stage. All the other 50 case reports of this disease have presented with only a mild degree of renal failure.[5]

Although whole-genome linkage studies suggested a gene locus for glomerulopathy with FN deposits (GFND) on chromosome 1 (1q32), further studies failed to confirm any abnormality in this region.[6],[7] In 2008, Castelletti et al,[8] detected by linkage analysis a region on chromosome 2 (2q34). This region includes the FN1 gene that encodes FN. Genetic analysis of FN1 disclosed mutations in 40% of cases.[8] However, in our patient and in a few other familial cases of GFND, no mutations have been found in FN1 suggesting the involvement of unknown genes.

As renal biopsy findings showed chronicity of more than 30%–40% in the sampled cortex and as she was very symptomatic with uremic features, she was explained about renal replacement therapy and opted for hemodialysis. She is undergoing hemodialysis thrice weekly at the present.

Fibrillary pattern of deposition diseases in glomerular compartment have been described commonly in three different disease entities: amyloidosis, fibrillary glomerulopathy, and immunotactoid glomerulonephritis. Collagenofibrotic glomerulopathy also known as collagen Type III glomerulopathy, is a rare disorder that is characterized by the massive accumulation of atypical Type III collagen fibrils in the mesangium and subendothelial space. They are differentiated by their ultrastructural appearance on electron microscope and different staining properties [Table 1].[9]
Table 1. Different fibrillary proteins and their staining characteristics.

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FN is an adhesive, multifunctional, high-molecular-weight glycoprotein and is found in extracellular matrix. It takes part in cellular proliferation, wound healing, phagocytosis, and platelet aggregation.[10] It is present in the mesangial matrix of not only normal glomeruli but also shows increased expression in several types of glomerular diseases such as lupus nephritis and diabetic nephropathy, likely because of local production by mesangial and glomerular epithelial cells. It promotes the clearance of particulate material from the circulation.[11]

The functional FN molecule consists of two similar subunits of 220–250 kDa.[12] There are two varieties of FN. The first is a soluble plasma FN, which is a spherical form secreted by the hepatocytes. When soluble form of FN binds to receptors on the cell surface such as integrin, proteoglycan, and collagen, it transforms into a linear structure that can bind to the other FN molecules to make fibers[13],[14]

The second type is an insoluble cellular FN, which is secreted from fibroblasts. This type of FN can be assembled into an insoluble extracellular matrix. The presence of arginine in the FN molecule helps in FN polymerization.

They can be advised renal replacement therapy such as hemodialysis and renal transplantation similar to other kidney disease patients. This disease has been demonstrated to present as recurrent disease after renal transplantation. Otsuka et al from Japan reported a recurrent FN disease after 134 days of renal transplantation.[15]

This case tells us that FN disease can present at an early stage of life with end stage of renal disease and as a sporadic disease.

   Acknowledgment Top

The authors wish to thank Dr. Patrick D. Walker at NEPHROPATH, USA, for immunohistochemical analysis of kidney tissue.

Conflict of interest: None declared.

   References Top

Mazzucco G, Maran E, Rollino C, Monga G. Glomerulonephritis with organized deposits: A mesangiopathic, not immune complexmediated disease? A pathologic study of two cases in the same family. Hum Pathol 1992; 23:63-8.  Back to cited text no. 1
Yong JL, Killingsworth MC, Spicer ST, Wu XJ. Fibronectin non-amyloid glomerulopathy. Int J Clin Exp Pathol 2009;3:210-6.  Back to cited text no. 2
Sanders PW. Dysproteinemias and amyloidosis. In: Greenberg A, Cheung AK, Coffmann TM, et al., eds. Primer of Kidney Diseases. 2nd ed. San Diego: Academic Press; 1998. p. 220.  Back to cited text no. 3
Gemperle O, Neuweiler J, Reutter FW, Hildebrandt F, Krapf R. Familial glomerulopathy with giant fibrillar (fibronectin-positive) deposits: 15-year follow-up in a large kindred. Am J Kidney Dis 1996;28:668-75.  Back to cited text no. 4
Ishimoto I, Sohara E, Ito E, et al. Fibronectin glomerulopathy. Clin Kidney J 2013;6:513-5.  Back to cited text no. 5
Vollmer M, Jung M, Rüschendorf F, et al. The gene for human fibronectin glomerulopathy maps to 1q32, in the region of the regulation of complement activation gene cluster. Am J Hum Genet 1998;63:1724-31.  Back to cited text no. 6
Vollmer M, Kremer M, Ruf R, et al. Molecular cloning of the critical region for glomerulopathy with fibronectin deposits (GFND) and evaluation of candidate genes. Genomics 2000;68:127-35.  Back to cited text no. 7
Castelletti F, Donadelli R, Banterla F, et al. Mutations in FN1 cause glomerulopathy with fibronectin deposits. Proc Natl Acad Sci U S A 2008;105:2538-43.  Back to cited text no. 8
Olson JL, Laszik ZG. Diabetic Nephrppathy. In: Jennette JC, Olson JL, Schwartz MM, Silva FG, eds. Heptinstall’s Pathology of the kidney. Philadelphia: Lippincott Williams & Wilkins; 2007. p. 803-42.  Back to cited text no. 9
White ES, Muro AF. Fibronectin splice variants: Understanding their multiple roles in health and disease using engineered mouse models. IUBMB Life 2011;63:538-46.  Back to cited text no. 10
Büyükbabani N, Droz D. Distribution of the extracellular matrix components in human glomerular lesions. J Pathol 1994;172:199-207.  Back to cited text no. 11
Pankov R, Yamada KM. Fibronectin at a glance. J Cell Sci 2002;115:3861-3.  Back to cited text no. 12
Maqueda A, Moyano JV, Hernández Del Cerro M, Peters DM, Garcia-Pardo A. The heparin III-binding domain of fibronectin (III4-5 repeats) binds to fibronectin and inhibits fibronectin matrix assembly. Matrix Biol 2007;26: 642-51.  Back to cited text no. 13
Ohashi T, Erickson HP. Fibronectin aggregation and assembly: The unfolding of the second fibronectin type III domain. J Biol Chem 2011;286:39188-99.  Back to cited text no. 14
Otsuka Y, Takeda A, Horike K, et al. A recurrent fibronectin glomerulopathy in a renal transplant patient: A case report. Clin Transplant 2012;26 Suppl 24:58-63.  Back to cited text no. 15

Correspondence Address:
Surya Narayan Mandal
Department of Nephrology, NH Malla Reddy Narayana Multispeciality Hospital, Telangana, Hyderabad
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DOI: 10.4103/1319-2442.220860

PMID: 29265057

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  [Table 1]


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