Collagen type III glomerulopathy (ORPHA:84087)
A rare non-immune-mediated glomerular disease characterized by abnormal accumulation of type III collagen within the mesangium and subendothelial space of the glomerulus. Clinically it usually manifests with proteinuria (often in the nephrotic range), microscopic hematuria, peripheral edema and/or hypertension. Progression to end-stage kidney failure is possible.
Epidemiology
Approximately 100 cases have been reported worldwide. Most have been from Japan, where it was first described, though subsequently cases from China, the Indian subcontinent, Europe, North and South America. No definitive variation in penetrance by sex has been described.
Clinical description
The disorder typically presents as an adult onset nephrotic syndrome with hypertension, anemia and microangiopathic hemolytic anemia that may appear to be a hemolytic uremic syndrome (HUS). Presentations in pediatric patients is rare and typically associated with familial occurrence. There is some evidence that it may present as a systemic disease including with partial villous atrophy of the intestine, hepatic perisinusoidal fibrosis and on autopsy accumulation of collagen III in spleen, liver, myocardium, and thyroid gland has been reported.
Etiology
The etiology has not been established.
Diagnostic methods
Renal biopsy shows glomerular basement membrane double contours without hypercellularity, expansion of subendothelial space and mesangium that is birefringent on picrosirius red staining and negative on silver and congo red stains, and ultrastructural evidence of type III collagen fibers (40-65 nm). Immunostaining with antibodies for anti-Collagen III shows strong staining. Serum analysis will demonstrate increased procollagen III peptide (PIIIP) levels. There are reports of elevated serum hyaluronan levels (1000x normal). A rare case of full house staining and coincident diabetes in a pediatric patient has been reported. In one case where serial biopsies were available, the collagenofibrotic pattern evolved from more typical focal segmental glomerulosclerosis (FSGS). One patient with Hodkin lymphoma was reported to have co-incident collagenofibrotic glomerulopathy.
Differential diagnosis
Differential diagnosis includes nail-patella syndrome (an LMX1B-associated nephropathy where the lamina densa is not spared on ultrastructural examination), fibrillar collagen in glomerulosclerosis or in diabetic glomerulopathy (diabetic fibrillosis which is segmental with sparing of subendothelial space), fibronectin glomerulopathy (less fibrilar and not banded), Amyloidosis (straight, small, non-banded fibrils that are Congo red positive).
Genetic counseling
Genetic testing of LMX1B to exclude nail-patella syndrome is necessary, though a cases of renal limited LMX1B nephropathy has been identified. Familial occurrence in young patients, including in siblings, suggests autosomal recessive inheritance with adult onset cases more likely to be sporadic. Co-occurrence of an inherited Factor H deficiency has been reported.
Management and treatment
Definitive treatments, including renal transplantation, have not been established. A report of angiotensin II blocker (telmisartan) with improvement in clinical signs and symptoms, albeit with no significant change in laboratory findings, has been reported.
Prognosis
The disorder can be insidious with variable progression to end stage renal disease within 10 years. While no reports of recurrence following transplantation are reported, there is one case where PIIIP levels were elevated in a patient post-transplantation suggesting a risk for recurrence, and one de novo case occurring following a renal transplant.

                            Last update: 
                            March 2021


                            - Expert reviewer(s): 
                            Dr Avi ROSENBERG