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Saudi Journal of Kidney Diseases and Transplantation
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Year : 2017  |  Volume : 28  |  Issue : 4  |  Page : 898-905
Collagenofibrotic (Collagen Type III) glomerulopathy in association with diabetic nephropathy

1 Department of Pathology and Laboratory Medicine, King Abdulaziz Medical City and College of Medicine, King Saud bin Abdulaziz University for Health Sciences, Riyadh, Saudi Arabia
2 Section of Nephrology, Department of Pediatric, King Fahad Medical City, Riyadh, Saudi Arabia
3 Section of Nephrology, Department of Pediatric, Tabuk Military Hospital, Tabuk, Saudi Arabia

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Date of Web Publication21-Jul-2017


Collagenofìbrotic (collagen type III) glomerulopathy (CG) is a rare nonimmune-mediated glomerular disease. It is characterized by massive deposition of organized collagen type III fibers, which is localized in the mesangial and subendothelial glomerular areas and associated with increased serum levels of procollagen type III peptide. Association with systemic diseases and malignancies is extremely rare. Herein, we present a case of a nine-year-old girl, known case of type I diabetes mellitus, who presented with fever, nephrotic range proteinuria, generalized edema, and hypertension. Clinical examination did not show nail abnormalities or bone abnormalities. Renal biopsy revealed mesangial expansion and remarkable narrowing and obliteration of the glomerular capillaries by pale, amorphous material. Immunohistochemical study demonstrated diffuse linear glomerular capillary and tubular basement membrane staining for immunoglobulin G (IgG) and albumin. Ultrastructural examination identified massive mesangial and sub-endothelial deposition of dense frayed, curvilinear banded fibers with characteristic features of type III collagen. The patient was diagnosed to have combined CG and diabetic nephropathy (DN). This is the first report of CG in association with diabetic changes in renal biopsy. In this report, we describe the clinicopathological characteristics of this disease, review CG in pediatric population, and explore its association with DN.

How to cite this article:
Alsaad KO, Edrees B, Rahim KA, Alanazi A, Ahmad M, Aloudah N. Collagenofibrotic (Collagen Type III) glomerulopathy in association with diabetic nephropathy. Saudi J Kidney Dis Transpl 2017;28:898-905

How to cite this URL:
Alsaad KO, Edrees B, Rahim KA, Alanazi A, Ahmad M, Aloudah N. Collagenofibrotic (Collagen Type III) glomerulopathy in association with diabetic nephropathy. Saudi J Kidney Dis Transpl [serial online] 2017 [cited 2021 Jul 25];28:898-905. Available from: https://www.sjkdt.org/text.asp?2017/28/4/898/211324

   Introduction Top

Type III collagen is an extraglomerular structural form of collagen, which in kidney, normally presents in the interstitium and blood vessels.[1] Pathological glomerular accumulation of type III collagen occurs in various immune-mediated glomerulonephritis and nonimmune glomerular diseases.[2] Collagenofìbrotic glomerulopathy (CG) (collagen type III glomerulopathy) is a rare nonimmune-mediated glomerular disease, characterized by progressive, abundant, and organized, mesangial and sub-endothelial accumulation of type III collagen fibers. The disease has no sex predilection and involves pediatric and adult age-group patients.[3] Although most reported cases, particularly in adults, are sporadic, few cases have occurred in families and siblings, and hence, a genetic mode of transmission, mostly by an autosomal recessive trait, has been assumed.[4],[5] Clinically, CG is characterized by proteinuria, nephrotic syndrome (NS), hypertension (HTN), and slowly progressive decline of renal function that results in end-stage renal disease (ESRD). Although serum levels of precursor collagen type III peptide (PIIIP) tend to be elevated in patients with CG (10–100 folds more than normal participants) and is considered a marker for disease activity, the diagnosis of CG is usually made by pathological examination of renal biopsy. Contrary to some other amyloidotic and nonamyloidotic glomerular diseases with organized deposits such as fibrillary glomerulopathy (FG) and immunotactoid glomerulopathy (ITG), association of CG with systemic or neoplastic diseases has been rarely described.[6],[7] Herein, we report a case of CG in association with type I diabetes mellitus (DM) and diabetic nephropathy (DN) in a child, discuss the pathogenesis of CG, and review the reported cases in the pediatric population.

   Case Report Top

A 9-year-old female, known patient of poorly controlled type I DM for five years, presented to the emergency room with fever and generalized edema for approximately 14 days. Her past medical history revealed DN-related steroid-resistant NS, which was managed by losartan (25 mg once per day), enalapril (7.5 mg twice/day), and insulin 0.9 IU/kg/day for the past five months. At the time of admission, she was within the 10th centile for her age and sex. She was conscious, and her temperature and blood pressure (BP) were 38.4°C and 136/92 mm Hg, respectively, and the other vital signs were normal. Physical examination showed periorbital and bilateral lower limb edema. There was no evidence of otitis media or jaundice. No facial dysmorphic features, abnormal nails, or skeletal abnormalities were identified on clinical and radiological examinations. Fundus examination was unremarkable with no evidence of retinopathy. There was no clinical evidence of peripheral neuropathy. Family history revealed positive parental consanguinity and history of DM in her father and sister. Urine analysis was positive for protein, glucose, bilirubin, and ketones and showed no microscopic hematuria. Liver function test was within normal limits. Renal profile showed blood urea nitrogen of 5.6 mmol/L, serum creatinine of 45 μmol/L, and serum albumin of 7 g/L. The protein/creatinine ratio was 1800 mg/mmol. The serum sodium and potassium levels were 134 and 3.8 mmol/L, respectively. Complete blood count revealed white blood cell count of 16.9×109/L, hemoglobin of 12.4 g/L, and platelet count of 349×109/L. Serum C3 and C4 levels were normal (1.7 g/L and 0.2 g/L, respectively). Screening for antinuclear antibodies and anti-neutrophil cytoplasmic antibody was negative. Serum glycosylated hemoglobin level was 18%. Twenty-four hours collection of urine showed protein content of 3.76 g/day. Abdominal ultrasound showed echogenic, minimally enlarged kidneys (the right and left kidneys measured 11 cm and 10.5 cm, respectively), with poor corticomedullary differentiation.

She was admitted to the pediatric Intensive Care Unit (PICU) and started on labetalol infusion (0.4–1 mg/kg/h) to control the elevated BP. In addition, 20% albumin (2 g/kg) and furosemide (20 mg) were administrated intravenously on a daily basis to mobilize the edema. The patient was previously started on oral prednisolone (50 mg) every other day by the referring treating team, but with no response; accordingly, this was tapered gradually over few weeks. Her HTN was controlled over a three-day period; however, the edema required 12 days to achieve her near dry weight. The BP was maintained by amlodipine (5 mg/oral every 12 h) and enalapril (5 mg/oral every 12 h).

Ultrasound-guided renal biopsy was performed. Two micrometers thick sections from the formalin-fixed, paraffin-embedded tissue were stained with hematoxylin and eosin, periodic acid-Schiff (PAS), Masson’s trichrome, methenamine silver, and Congo Red special stains. For direct immunofluorescence (IF) study, 3 μm thick cryostat sections were stained with fluorescein isothiocyanate-conjugated rabbit antihuman immunoglobulin G (IgG), IgM, IgA, C3, C4, C1q, Kappa, and Lambda light chains (LC), albumin, and fibrinogen (Dako, Carpinteria, CA, USA). Grading of the intensity of IF positivity was made on a scale ranging from 0, traces and 1-3+. Immunoperoxidase and IF staining for type III collagen was not performed. Ultrastructural analysis was performed on glutaraldehyde-fixed tissue after usual processing and staining with JOEL1230 transmission electron microscope (Akishima, Japan).

Histopathological examination showed 13 glomeruli, of which none was globally sclerosed. The glomeruli appeared large and showed mild-to-moderate mesangial expansion, mild focal and segmental increase in mesangial cellularity, and mild accentuation of the glomerular tufts. Segmental glomerular scarring in the form of obliteration of the glomerular capillaries and adhesion of the glomerular tufts to the Bowman’s capsule was seen in two glomeruli. Most of the glomerular capillary lumina were narrowed due to diffuse marked subendothelial expansion by homogenous, faintly PAS-positive material [Figure 1]A and [Figure 1]B. There was no spike reaction or double contouring of the glomerular basement membranes (GBM). The tubular basement membranes (TBM) showed mild increase in thickness. There was no evidence of glomerular proliferative features or microthrombi. Glomerular hyalinosis in the form of fibrous cap and capsular drop lesions was seen in occasional glomeruli. There were mild interstitial edema and chronic lymphocytic interstitial inflammation. Focal mild interstitial fibrosis and tubular atrophy (IFTA) were seen. There was no arteriolar hyalinosis and no arterial sclerosis. Congo Red special stain was negative and showed no apple-green birefringence under polarization. Direct IF microscopy demonstrated diffuse linear staining along the GBM and TBM for IgG (2+) [Figure 2]A, Kappa (3+) and Lambda (3+) LC, and albumin (3+). This was associated with diffuse subendothelial staining for IgM (3+) [Figure 2]B, IgA (2+), and C4 (1+), corresponding to the subendothelial expansion by the amorphous material, which was identified by light microscopy. There was no staining for C3 and C1q.
Figure 1: (A) Light micrograph of the renal biopsy showing mesangial expansion, segmental mild increase in mesangial cellularity, and global subendothelial and mesangial accumulation of homogenous, weakly periodic acid-Schiff-positive material (PAS ×200), (B) Higher magnification micrograph highlighting the abundance amount of deposited homogenous material (PAS ×400).

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Figure 2: (A) Immunofluorescence staining for IgG showing linear staining along the glomerular basement membranes, a finding commonly seen in the setting of diabetes-related changes in kidney (×400). (B) Immunofluorescence staining for IgM demonstrating global glomerular basement membranes and infra-membranous staining (×400).

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Ultrastructurally [Figure 3]A and [Figure 3]B, the mesangium appeared expanded by increased mesangial matrix. The GBM exhibited increase in thickness but showed normal texture and no evidence of abnormalities in the lamina densa. Global marked subendothelial expansion by randomly distributed, numerous, curved, frayed-looking thin dense organized fibrils were identified. These fibrils were also abundantly seen in the mesangial matrix but not in the subepithelial area or within the lamina densa of the GBM. The fibrils measured between 40 and 150 nm in diameter. Cross-striations with periodicity of 20–50 nm, characteristic of collagen fibers were seen in these fibrils. No immune-type dense deposits were found. Microtubular structures and typical amyloid fibrils were not observed. The foot processes of the glomerular visceral epithelial cells were effaced over the entire GBM. Accordingly, the serum PIIIP level was measured and was > 6.0 U/mL (normal range 0.6–1.7 U/mL); this, in conjunction with the pathological findings, was compatible with the diagnosis of CG.
Figure 3: Electron micrographs showing subendothelial expansion by marked accumulation of fibrillary structures (A ×10,000), which exhibit spiral-shaped arrangement and ultrastructural characteristics of type III collagen (B ×25,000).

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The patient was discharged after controlling the BP. During the outpatient clinical follow-up, her BP was maintained, and she did not have edema but continued to have proteinuria with normal renal function. After few months, the patient did not show up for further clinical follow-up. Thirty-four months after the initial clinical presentation, she presented to the emergency room and was readmitted because of uncontrolled HTN and rapidly increasing serum creatinine (from 101 to 400 μmol/L over a three-week period). A second renal biopsy to assess the disease progression and exclude concurrent renal diseases was performed. The light microscopic and ultrastructural pathological findings were similar to those seen in the first biopsy with noticeable progression of the disease in the form of increased extent of mesangial expansion, nodular accentuation of the glomerular tufts, obliteration of the glomerular capillaries, and IFTA. Repeated measurement of serum PIIIP was not performed. Her renal function deteriorated rapidly and was associated with oliguria and fluid overload that required PICU admission and starting of hemodialysis, which she continued to be maintained on.

   Discussion Top

CG was first described in late 1979 by Arakawa and Yamanaka,[8] who described deposition of collagen fibers, mainly in the mesangium, in two patients who showed no evidence of nail or skeletal abnormalities. In 1982, Dombros and Katz[9] described a case of microscopic hematuria and glomerular pathological alterations similar to those seen in the nail-patella syndrome (NPS) but lacking the skeletal abnormalities associated with NPS. In 1990, Ikeda et al[6] characterized the fibrillary deposits as type III collagen, and in 1991, Arakawa and Yamanaka[10] and Imbasciati et al[11] proposed the term “CG” and “collagen type III glomerulopathy,” respectively. In 1995, CG was included in the classification of glomerular diseases published in collaboration with the World Health Organization.[12]

Because most of the previously reported cases of CG occurred in Asians and clustered in adult patients of Japanese descent,[3],[4],[13],[14] ethnic, geographic, and environmental risk factors and preponderance were assumed.[5] However, few cases from North and South Americas,[9],[15],[16] Europe,[11],[17],[18] and India[7],[8],[19] were also reported. This case represents the first patient with CG of Middle Eastern descent. CG was reported in both males and females with no sex predilection, and most of the patients were adults. To the date of this report, only 14 cases of CG in the pediatric age group (including the current case) have been previously reported. [15],[16],[17],[20] [Table 1] summarizes the clinical presentation and the laboratory findings at the time of diagnosis of CG in children. In a small number of adult patients, concurrent benign and malignant clinical conditions that include psoriasis,[3] gout,[6] and mixed cellularity type of classic Hodgkin’s lymphoma[7] were reported. In pediatric patients, CG was associated with persistent anemia of the hemolytic type and ichthyosis vulgaris.[17] Current report describes the first concurrence of CG in the setting of DM and DN.
Table 1: Clinical presentation, laboratory findings, and outcome of collagenofibrotic glomerulopathy in pediatric cases.

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Type III collagen is a triple helix fibrillary connective tissue protein, formed of three identical α-1 chains, which are encoded by a single gene COL3A1, located on chromosome 2. It is synthesized as a precursor molecule “type III procollagen,” which is converted into type III collagen after enzymatic cleavage into its N-terminal peptide. It is found in various tissues and organs such as blood vessels, skin, tendon, and lung. In normal kidney, type III collagen is present in the interstitium and renal vasculature but not in the glomeruli.[1] Glomerular deposition of type III collagen occurs at different stages in various proliferative and non-proliferative, immune-mediated, and non-immune-mediated glomerular diseases.[1],[2],[21] In DM, hyperglycemia induces endogenous synthesis of type III collagen by mesangial and glomerular epithelial cells, which contributes to glomerulosclerosis in DN.[22] The pathogenesis of CG is not fully understood; whether glomerular deposition of type III collagen is endogenously induced by synthesis from the the mesangial or endothelial cells, or results from systemic disease with abnormal metabolism of type III collagen, or both mechanisms are involved, is not certain.[3],[5]

Histologically, CG is characterized by diffuse and global deposition of weakly positive PAS amorphous material in the subendothelial and mesangial areas. As the disease progresses, glomerular scarring evolves. By IF and IHC studies, CG demonstrates intense diffuse and global mesangial and subendothelial staining for anticollagen type III antibody. In general, staining for immunoglobulins and complement components is negative. In our case, diffuse strong staining for IgG, LC, and albumin was detected and was consistent with DN. Interestingly, strong and diffuse global staining for IgM and to a lesser extent IgA was also seen, corresponding to the subendothelial expansion and accumulation of type III collagen detected by ultrastructural analysis. A recent case of CG associated with “full-house” expression of immunoglobulins with complement components and LC was reported, expanding the immune profile properties of CG.[14]

CG should be differentiated from various glomerular diseases. The NPS is a pleiotropic autosomal dominant disorder characterized by absent or hypoplastic finger and toe nails and patella, other musculoskeletal abnormalities, and renal involvement with glomerular accumulation of type III collagen.[23] In contrast to CG, collagen fibers in NPS are seen within the lamina densa of the GBM, whereas in CG, the collagen fibers are seen in the subendothelial area and sometimes rara interna of the GBM. Light microscopic, IF, and ultrastructural examinations help in distinguishing CG from other amyloidotic and nonamyloidotic FG, ITG and cryoglobulinemic glomerulopathies.

The natural history and biological behavior of CG are variable, but in general, the disease is progressive. Unremitting clinical course, impaired renal function, and ESRD were reported in both adult and pediatric patients. In our patient, the disease evolved in a relatively short period of time, causing marked scarring to the kidney and ESRD. Histopathological, biochemical, and clinical factors that are associated with progressive disease and affect the biological behavior of CG are not well defined, largely because of the small number of reported cases. No specific treatment is available for CG. Clinical management in patients with preserved kidney function generally focuses on controlling BP, maintaining renal function, and decreasing the proteinuria. Renal transplant may be an option in patients with ESRD. Renal transplant with no evidence of clinical recurrence after three-year follow-up was reported in one patient.[20]

In summary, we describe an unusual case of a patient of Middle Eastern descent, who expressed characteristic and diagnostic pathological features of CG, associated with DN secondary to type I DM. This case explores the possibility of concurrence of CG with systemic and metabolic diseases such as DM. Reporting and pooling of similar cases will certainly contribute to better understanding of the pathogenesis and biological behavior of this disease.

Conflict of interest: None declared.

   References Top

Yoshioka K, Takemura T, Tohda M, et al. Glomerular localization of type III collagen in human kidney disease. Kidney Int 1989;35: 1203-11.  Back to cited text no. 1
Oomura A, Nakamura T, Arakawa M, Ooshima A, Isemura M. Alterations in the extracellular matrix components in human glomerular diseases. Virchows Arch A Pathol Anat Histopathol 1989;415:151-9.  Back to cited text no. 2
Duggal R, Nada R, Rayat CS, Rane SU, Sakhuja V, Joshi K. Collagenofibrotic glomerulopathy -a review. Clin Kidney J 2012;5:7-12.  Back to cited text no. 3
Chen N, Pan X, Xu Y, et al. Two brothers in one Chinese family with collagen type III glomerulopathy. Am J Kidney Dis 2007;50: 1037-42.  Back to cited text no. 4
Alchi B, Nishi S, Narita I, Gejyo F. Collagenofibrotic glomerulopathy: Clinicopathologic overview of a rare glomerular disease. Am J Kidney Dis 2007;49:499-506.  Back to cited text no. 5
Ikeda K, Yokoyama H, Tomosugi N, Kida H, Ooshima A, Kobayashi K. Primary glomerular fibrosis: A new nephropathy caused by diffuse intra-glomerular increase in atypical type III collagen fibers. Clin Nephrol 1990;33:155-9.  Back to cited text no. 6
Soni SS, Gowrishankar S, Nagarik AP, Barnela SR, De Padua M, Adikey GK, et al. Collagenofibrotic glomerulopathy in association with Hodgkin’s lymphoma. Saudi J Kidney Dis Transpl 2011;22:126-9.  Back to cited text no. 7
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Arakawa M, Fueki H, Hirano H, et al. Idiopathic mesangio-degenerative glomerulopathy. Jpn J Nephrol 1979;21:914-5.  Back to cited text no. 8
Dombros N, Katz A. Nail patella-like renal lesions in the absence of skeletal abnormalities. Am J Kidney Dis 1982;1:237-40.  Back to cited text no. 9
Arakawa M, Yamanaka N. Collagenofibrotic glomerulopathy: A new type of primary glomerulopathy revealing massive collagen deposition in the renal glomerulus. In: Arakawa M, Yamanaka H, editors. Collagenofibrotic Glomerulopathy. 1st ed. London, UK: Smith Gordon; 1991. p. 3-8.  Back to cited text no. 10
Imbasciati E, Gherardi G, Morozumi K, Gudat F, Epper R, Basler V, et al. Collagen type III glomerulopathy: A new idiopathic glomerular disease. Am J Nephrol 1991;11:422-9.  Back to cited text no. 11
Churg J, Bernstein J, Glassok RJ. Collagenofibrotic glomerulopathy. In: Churg J, editor. Renal Disease: Classification and Atlas of Glomerular Diseases. 2nd ed., Ch. 17. New York, NY: Igaku Shoin; 1995. p. 406-43.  Back to cited text no. 12
Li L, Zou WZ, Wang SX, et al. Collagen type III glomerulo-pathy: A morphologic study. Zhonghua Bing Li Xue Za Zhi 2005;34:385-8.  Back to cited text no. 13
Fukami K, Yamagishi S, Minezaki T, Nishi S, Hisano S, Okuda S. First reported case of collagenofibrotic glomerulopathy with a full-house pattern of immune deposits. Clin Nephrol 2014;81:290-5.  Back to cited text no. 14
Vogt BA, Wyatt RJ, Burke BA, Simonton SC, Kashtan CE. Inherited factor H deficiency and collagen type III glomerulopathy. Pediatr Nephrol 1995;9:11-5.  Back to cited text no. 15
Ferreira RD, Custódio FB, Guimarães CS, Corrêa RR, Reis MA. Collagenofibrotic glomerulopathy: Three case reports in Brazil. Diagn Pathol 2009;4:33.  Back to cited text no. 16
Gubler MC, Dommergues JP, Foulard M, et al. Collagen type III glomerulopathy: A new type of hereditary nephropathy. Pediatr Nephrol 1993;7:354-60.  Back to cited text no. 17
Khubchandani SR, Chitale AR, Gowrishankar S. Banded collagen in the kidney with special reference to collagenofibrotic glomerulopathy. Ultrastruct Pathol 2010;34:68-72.  Back to cited text no. 18
Patro KC, Jha R, Sahay M, Swarnalatha G. Collagenofibrotic glomerulopathy – Case report with review of literature. Indian J Nephrol 2011;21:52-5.  Back to cited text no. 19
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Suzuki T, Okubo S, Ikezumi Y, al. Favorable course of collagenofibrotic glomerulopathy after kidney transplantation and questionnaire survey about the prognosis of collagenofibrotic glomerulopathy. Nihon Jinzo Gakkai Shi 2004;46:360-4.  Back to cited text no. 20
Funabiki K, Horikoshi S, Tomino Y, Nagai Y, Koide H. Immunohistochemical analysis of extracellular components in the glomerular sclerosis of patients with glomerulonephritis. Clin Nephrol 1990;34:239-46.  Back to cited text no. 21
Razzaque MS, Koji T, Taguchi T, Harada T, Nakane PK. In situ localization of type III and type IV collagen-expressing cells in human diabetic nephropathy. J Pathol 1994;174:131-8.  Back to cited text no. 22
Lemley KV. Kidney disease in nail-patella syndrome. Pediatr Nephrol 2009;24:2345-54.  Back to cited text no. 23

Correspondence Address:
Khaled O Alsaad
Department of Pathology and Laboratory Medicine, King Abdulaziz Medical City, P. O. Box 22490, Riyadh 11426
Saudi Arabia
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