| Abstract|| |
Collagen type III is a normal component of interstitium and blood vessels. Collagenofibrotic glomerulopathy (CG) and nail patella syndrome (NPS) are the diseases of abnormal type III collagen deposition. In spite of these curved frayed structures with a periodicity of 45-60 nm are deposited in subendothelium and mesangium in CG, they are found only in the basement membrane in NPS. The clinical features of CG are confined to the kidney, NPS has associated extra-renal manifestations. Electron microscopy is essential to make the renal diagnosis in both these rare diseases. Both the entities considered to be systemic diseases evidence to suggest similar deposition in other organs, understanding etiopathogenesis and disease progression await research.
Keywords: Collagen type III, collagenofibrotic glomerulopathy, electron microscopy, nail patella syndrome, renal replacement therapy
|How to cite this article:|
Anitha A, Vankalakunti M, Siddini V, Babu K, Bonu R, Ballal S. Type III collagen disorders: A case report and review of literature
. Indian J Pathol Microbiol 2016;59:75-7
|How to cite this URL:|
Anitha A, Vankalakunti M, Siddini V, Babu K, Bonu R, Ballal S. Type III collagen disorders: A case report and review of literature
. Indian J Pathol Microbiol [serial online] 2016 [cited 2020 Feb 29];59:75-7. Available from: http://www.ijpmonline.org/text.asp?2016/59/1/75/174822
| Introduction|| |
Type III collagen is normally seen in the interstitium and blood vessel; type IV, V, and VI are seen in glomerular mesangium and capillary basement membranes (BM). Dysregulated formation of type III collagen results in a deposition, culminating in two different rare diseases, collagenofibrotic glomerulopathy (CG) and nail patella syndrome (NPS) with heterogeneous presentation and prognosis.  Though there is some knowledge about the pathogenesis, specific treatment awaits further research. There are only a few cases reported in the literature, especially from the Indian sub-continent and transplant options need exploration. ,,,
| Case Reports|| |
A 53-year-old female visited her doctor with pedal edema in March 2007. She was found to have blood pressure (BP) of 140/90 mmHg, 3.6 g/24 h proteinuria, serum creatinine of 1.2 mg/dL, and normal sized kidney on ultrasound. The serum/urine protein electrophoreses and bone marrow examinations were normal. Renal biopsy revealed 22 glomeruli, all enlarged with amorphous eosinophilic deposits. She was presumed to have amyloidosis though Congo-red was negative and treated with oral prednisolone 1 mg/kg for a few weeks, gradually tapered and stopped.
In June 2007, she visited us since pedal edema persisted. On examination she was hypertensive, edematous, the jugular venous pressure was elevated; the rest of the systemic examination was unremarkable. Investigations showed 3+ proteinuria and inactive sediment, urine protein creatinine ratio (PCR) was 3.4, creatinine 1.4 mg/dL, and serum albumin 3.1 g/dL. Echocardiogram and ultrasonography were normal. She achieved a partial remission with enalapril 2.5 mg/day and losartan 50 mg/day.
In 2010, her 24 h protein was 7 g; serum creatinine 2.3 mg/dL (estimated glomerular filtration rate - 23 mL/min modification of diet in renal disease). Repeat renal biopsy revealed 24 glomeruli of which 6 were obsolete. Viable glomeruli showed eosinophilic nodular deposits in the mesangium and capillary loops; weakly PAS-positive; silver and Congo-red stains were negative [Figure 1]. There was 30% interstitial fibrosis and tubular atrophy. The immunofluorescence (IF) study was negative for immunoglobulins complements and kappa and lambda light chains. Electron microscopy (EM) showed typical curved and frayed collagen fibrils, which demonstrated periodicity of 50-60 nm [Figure 2]b] in the subendothelial and mesangial regions, with effacement of podocyte foot processes, findings consistent with the diagnosis of CG. Her renal function gradually worsened and was electively started on hemodialysis in May 2012.
|Figure 1: Glomerulus in collagenofibrotic glomerulopathy. (a) Lobular accentuation with deposition of the matrix, that is, variably stained with silver stain (×40, PASM). (b) Deposition is found to be negative (arrow) with Congo-red stain (×40 Congo-red)|
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|Figure 2: Electron microscopy showing deposition of the curved frayed tubular structures (a) In the basement membrane of the nail patella syndrome, (b) in the mesangium and subendothelium in case of collagenofibrotic glomerulopathy. Periodicity is shown in the inset|
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A 21-year-old female incidentally found to have proteinuria in June 2008, was referred for evaluation. On examination, her BP was 100/70 mmHg; she was not edematous. She had hypoplastic nails and deformed knee joints; the systemic examination was essentially normal. None of her family members had any renal disease or nail/skeletal deformities.
Her investigation revealed 2+ proteinuria and inactive sediment, urine PCR 4.5, total cholesterol 187 mg/dL, C3 1.22 g/L, serum potassium 4.1 mEq/L, and serum thyroid stimulating hormone 2.15 μIU/mL. The x-ray showed bilateral iliac spur, elbows, and hands was normal. Kidneys appeared normal on ultrasound.
Renal biopsy showed normal glomerular morphology, without any intra- or extra-capillary proliferation, or BM abnormality. The tubulointerstitium and blood vessels were unremarkable; IF was negative. EM showed irregular thickening of the glomerular membrane with deposition of abnormal collagen possessing periodicity of 50 nm in the lamina densa and interna of BMs [Figure 2]a]. She was managed with enalapril 2.5 mg/day. At 6 years follow-up, her 24 h urine protein was 1.26 g/day; normal serum creatinine (0.55 mg/dL) and serum albumin were 3.78 g/dL.
| Discussion|| |
Normal glomerular BM contains collagen type IV, V, and VI; type III collagen is normally seen in the interstitium and blood vessels throughout the body but is undetectable in glomeruli.  When there is dysregulated formation of type III collagen it gets deposited in the BM, subendothelium or mesangium and propagates fibrosis. Pathogenesis leading to dysregulation remains unclear, with some evidence implicating interleukin-4, which selectively stimulates type III collagen synthesis and the suppression of collagen type I and V in CG. Antibodies to interleukin-4 have prevented fibrosis in mouse models. Though it appears to be renal specific, CG may be a systemic disease, as it is identified in association with factor H deficiency diseases like hemolytic uremic syndrome, where collagen fiber deposition has been seen in various organs.  Genetic abnormality alters encoding of collagen in NPS, permitting abnormalities in structures originating from ectoderm and mesoderm along with the deposition of collagen in the kidneys. Though deposition of collagen type III prompts us to connect the two diseases, the etiological link remains to be discovered. 
CG, a rare glomerular deposition disease, often encountered in the Asian population, is also reported from other parts of the globe. It was reported in 3 out of the 3067 native kidney biopsies with nephrotic syndrome.  It is inherited as autosomal recessive though sporadic cases are reported. It occurs across wide age range without any gender predilection. ,, The manifestations can vary from sub nephrotic proteinuria, inactive urine sediment, normal renal functions and normal BP to nephrotic syndrome, active urine sediment, renal failure, and hypertension. Renal failure progresses over time, eventually requiring renal replacement therapy. The clinical presentations are similar to any other glomerular disease; there are no typical features, only biopsy with EM is diagnostic.
Histologically, CG is diagnosed by the eosinophilic mesangial deposits, which are weakly PAS positive; silver/Congo-red stain, and IF negative. EM findings of collagen fibers seen as curved frayed structures with a periodicity of 45-60 nm in the mesangial and subendothelial regions are diagnostic.  The ultrastructural location of abnormal collagen deposits in the mesangial and subendothelial region is characteristic of CG. Eosinophilic nodular deposits are seen in many other diseases such as nodular diabetic nephropathy, membranoproliferative glomerulonephritis, amyloidosis, monoclonal immunoglobulin deposition disease, and rarely fibronectin glomerulopathy. A clinical history of longstanding diabetes, distribution of nodular lesions (uniform or variable), Congo-red staining characteristics, IF findings of immunglobulins/complements/kappa-lambda light chain; and ultrastructure study helps in differentiating almost all the differential diagnoses. 
CG is a progressive disease, and no specific therapy is available till date. Steroids, cyclosporine, cyclophosphamide, low-density lipoprotein apheresis, anticoagulants, and antiplatelet have been tried, but the progression could not be halted.  The progression of the disease probably depends on the extent of deposition and the amount of tubulointerstitial atrophy. Elevated levels (serum/urine) of procollagen type III, a precursor molecule for collagen type III is associated with a higher degree of fibrosis indicating increased conversion and deposition.  Renal transplantation can be offered to these patients with possible recurrence of the disease, however graft loss is rare. There is only one case report of renal transplantation being done for patients with CG reported from Japan.  The progressively increasing serum levels of procollagen type III might suggest new collagen deposition in the graft.  At the end of 10 years, the procollagen levels and graft functions were reported normal. 
Nail patella Syndrome (NPS) is a tetrad of hypoplastic or absent patella, hypoplastic or absent thumb nails, elbow abnormalities including hypoplastic or subluxed radial heads and iliac horns, first reported by Chatelian in 1820, who described a patient with congenital anomaly of the nail, elbow, and knees. This is an autosomal dominant disorder of the ectoderm and mesoderm seen 1: 50,000 live births. The loss of function mutation of the LIM homeobox transcription factor 1 beta (LMX1B) gene (chromosome 9q) produces an abnormal LMX1B protein, which alters the regulation of the podocyte genes encoding nephrin, podocin, CD2AP, and alpha 3 and 4 type IV collagen chains. Phenotypic presentation depends on the variable penetrance.  The renal involvement occurs in 30-50% manifesting as the variable degree of proteinuria with or without hematuria. Typical histological finding is the moth-eaten appearance of the thickened glomerular BM. These lucent areas are occupied by clusters of cross-banded type III collagen fibers. The renal involvement generally does not influence morbidity, and renal prognosis is good; <5% developing and renal prognosis is good; <5% developing end-stage renal disease. Though there is no specific treatment, renin-angiotensin system blockade helps maintain BP and reducing proteinuria. End-stage kidney disease patients can be transplanted, as this does not recur in the transplanted kidney.
Few questions remain unanswered: (1) Collagen III deposition is the common factor between the two diseases, however interstitial fibrosis, a common end point of chronic kidney diseases of various origin is also associated with deposition of collagen type III in the interstitium and is rightly considered a biomarker for chronic kidney disease progression. Collagen III deposition is detected during the fibrogenic phase and increases through the destruction phase.  If we consider fibrogenic signals promote synthesis and deposition of collagen in interstitial fibrosis, what then triggers the synthesis of collagen III in CG and NPS. (2) Alpha smooth muscle actin positive, mesangial cells are found to be activated in CG, and they are capable of producing type III collagen fibers. However, the serum procollagen III levels increase are considered to predict renal deposition. This questions the origin of collagen in CG.  (3) In NPS, a systemic disease collagen is deposited in the BM, mesangium and interstitium are spared, we need to know if any structural differences explain trapping.
| Conclusion|| |
Type III collagen disorders are rare; occur due to dysregulated production and deposition in abnormal locations and fibrosis. There are no typical features for clinical suspicion in CG though the skeletal abnormalities are often a clue in NPS. An high index of suspicion and ultrastructure is needed to diagnose. NPS has a relatively better renal prognosis than CG. A transplant can be offered in both these conditions. The pathogenic link between the two awaits further research.
We sincerely thank Mrs. Tulasi Kumari, Mrs. Hema Nagaraj and Mr. Bindu for their stupendous technical support in histopathology section.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
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[Figure 1], [Figure 2]