Introduction:
Membranous Nephropathy (MN) is one of the common causes of nephrotic syndrome in adults. It is distinguished by immune deposits on the glomerular capillary wall's epithelial side and thickening of the basement membrane with little to no cellular growth. 70-80% of cases of MN are associated with PLA2R-positive staining on immunohistochemistry (IHC)1. About 75% of cases with MN are primary, with the remainder of cases possibly having different secondary causes of infection, systemic autoimmune illness, malignancy, herbal medicines or a side effect of drugs. In last decade or two, lot of research has been done in MN with identification of new antigens with tissue proteomics like Thrombospondin (THSD7A), exostosin 1/2 (EXT1/2),7 neural epidermal growth factor-like 1 (NELL1),8 serine protease HTRA1 (HTRA1),9 Semaphorin 3B, and 10 protocadherin 7A (PCDH7A)2.
THSD7A is a 250-kD protein. It is a type I transmembrane protein with a large extracellular region and a short intracellular tail 3. This antigen’s association with MN was first defined in 2014 when they identified a new antigen in glomerular podocyte cells with mass spectrometry and antibody in serum by Western blot. 15 patients out of 154 in their cohort had antibodies against THSD7A 3. Subsequent reports found an association of thrombospondin-positive MN with malignancy and concluded that underlying malignancy should be ruled out in THSD7A-positive MN patients 4,5.
Methods:
A 21-year-old unmarried female presented with complaints of gradual onset and progressive swelling in both lower limbs for 2 months. She had frothy urine not associated with dysuria, hematuria, pyuria or change in urine output. She gave a history of joint pains in small joints of her hands and feet for 6 months. It was not associated with morning stiffness, swelling, or redness. Past medical history included hypothyroidism for 7 years. Apart from this, there was no major past medical or surgical history. Her medications included oral thyroxine. General physical examination revealed she was normotensive, and had bilateral lower limbs, abdominal wall and sacral edema. Systems examination was unremarkable. Her laboratory results are as in Table 1. Ultrasound of the abdomen showed normal-sized kidneys with maintained corticomedullary differentiation with moderate ascites and mild bilateral pleural effusions.
A diagnosis of adult Nephrotic syndrome was made and she underwent an ultrasound-guided kidney biopsy. On light microscopy, there were 34 glomeruli, appearing enlarged and revealing diffuse thickening of capillaries which show membrane texture alterations & intramembranous “mottling” discernible in silver methenamine stained sections (Figure 1). On immunofluorescence staining IgA was 1+, IgG 3+, C1q, C3, and IgM negative. On subclass analysis of IgG, IgG1 and IgG4 both were strongly positive (3+). On immunohistochemistry, diffuse granular staining for Thrombospondin (THSD7A) was noted along glomerular capillary walls(Figure 2). The rest of the antigens including PLA2R, NELL1, and EXT-1 were negative. Given thrombospondin positivity, her radiological imaging including high-resolution computer tomography (CT) of the chest and CT scan of the abdomen and pelvis did not reveal any abnormality. Given her strong positivity of anti-SSA (Table 1), her Schirmer test was done and was borderline positive (5mm-10mm). Minor salivary gland biopsy was done which was suggestive of diffuse and mild lymphocytic infiltration confirming Sjogren syndrome. She was started on a Modified Ponticelli regimen (cyclical steroid and cyclophosphamide) given a profound nephrotic state. She achieved partial remission at the end of 3 months while writing this paper.
We could not check serum titres of anti-thrombospondin antibody due to the unavailability of resources.
Results:
Discussion:
THSD7A is a soluble N-glycosylated membrane-bound protein. It is found in abundance in human embryo kidneys and promotes endothelial cell migration during angiogenesis and tube formation being a neuroangiogenic factor 6. It is overexpressed in placental vasculature and human umbilical vein endothelial cells7. In the kidney, it is expressed in podocytes and antibodies against thrombospondin lead to disruption of slit diaphragm structure and proteinuria. Pathogenic causative association of anti-thrombospondin antibody was shown in murine model where they injected sera from THSD7A+ MN patient with anti THSD7A antibody into mice expressing antigen in podocyte foot process who develop proteinuria indicating pathogenicity of anti-thrombospondin antibody 8.
A lot of cases have shown an association between malignancy and THSD7A+ MN. It is found in gall bladder cancer, rectal cancer, and endometrial cancers 4,5,9 . In patients with endometrial cancer, diagnosis of THSD7A-positive MN was preceded by cancer diagnosis. Thrombospondin was expressed in tumor cells leading to anti-THSD7A antibody formation and podocyte cytoskeleton disruption. Another cohort analysis showed a 20% prevalence of malignancy in THSD7A+ MN and 8 of the patients developed malignancy within 3 months of diagnosis of MN4.
On extensive evaluation of our patient, we did not find any underlying malignancy. Clinically also patient did not have any symptoms pointing towards malignancy. Our patient was a young female in her early 20s as compared to a study where most patients were males with a mean age of 62 years 10. There was a case report of thrombospondin MN associated with eosinophilia 11. Our patient had no prior history of allergic disease and her absolute eosinophilic counts were normal. On further workup, her anti-SSA antibody was positive and a minor salivary gland biopsy revealed lymphocytic infiltration further supporting the diagnosis of Sjogren syndrome. MN is the most common glomerulonephritis in Sjogren syndrome12. There is a case report of anti-PLA2R positivity in MN in primary Sjogren Syndrome13. In the literature review, we did not find an association of thrombospondin-positive MN with primary Sjogren syndrome. It is not SLE-related MN as anti-ds-DNA was negative and IF on biopsy did not have a full house pattern (negative for c1q, C3, IgM). Primary MN is generally associated with the IgG4 subclass of immunoglobulin deposit while secondary is with IgG1 though one study has shown that there might be class switching of antibodies and they found in their cohort that early-stage (stage1) had IgG1 dominant while late stages has IgG4 dominant 14. Interestingly in our patient, both IgG1 and IgG4 were dominant with 3+ staining, so whether it’s primary THSD7A+ MN with coexisting Sjogren syndrome or Immune dysregulation due to Sjogren syndrome causing antibody against THSD7A and secondary MN is unclear.
Conclusions:
Conclusion:
In summary, we report Thrombospondin positive MN in a young female with primary Sjogren syndrome without underlying malignancy. There are prior reports of PLA2R-positive MN with Sjogren syndrome, but to our best knowledge, this is the first case of THSD7A-positive MN in primary Sjogren syndrome. As with NELL-1, initially, it was thought to be commonly associated with underlying malignancy but later it was associated with many secondary causes of MN. We feel this might open the door to a new spectrum of diseases associated with thrombospondin-positive MN.
References:
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I have no potential conflict of interest to disclose.
I did not use generative AI and AI-assisted technologies in the writing process.