Fibronectin Glomerulopathy: A First African Case Report Open Access

Fibronectin is a large glycoprotein that commonly exists as a disulfide-bonded dimer. It is found in the extracellular matrix as well as in plasma and plays important roles in the body. Its functions include roles in epithelial branching during embryogenesis, wound healing, and hemostasis, and it may also regulate oral cavity bacterial colonization [1‒4]. Abnormal deposition of this protein in the kidney leads to a disease condition labeled fibronectin glomerulopathy (FG) or glomerulopathy with fibronectin deposits. FG is a rare autosomal dominant disorder initially described in 1980 that is associated with several variant mutations in the FN1 gene [5‒8]. It is a disorder predominantly characterized by proteinuria that can reach the nephrotic range, and it has been primarily described in Asian and White populations. Here, we report the case of a 17-year-old female with FG from Ethiopia, which, to our knowledge, is the first ever reported in Africa.

We report a 17-year-old Ethiopian female patient who presented with a 1-year history of generalized body swelling and nephrotic range proteinuria of 4.2 grams/24 h. She is the fifth child of six children for her mother, and the oldest five children have the same father except for her younger brother, who has a different father. There is no known Asian or European ancestry within the family. Her father died from liver disease and was not known to have any kidney disease. Her mother and siblings had no known kidney disease and possible secondary causes of nephrotic syndrome were also excluded. She was initially put on diuretics and enalapril followed by prednisolone for 4 weeks. Subsequently, she experienced a puffy face and worsening body swelling requiring admission, after which enalapril and prednisolone were discontinued, and the patient was referred to our center.

At presentation to us, she had a slightly cushingoid appearance, her blood pressure was 129/90 mm Hg, and her height and weight were 155 cm and 40 kg, respectively. Prednisolone had been discontinued for 2 weeks, and she had proteinuria of 4.2 g/24 h. She had a normal creatinine of 0.6 mg/dL (eGFR_CKD-EPI = 134 mL/min/1.73 m²), her urinalysis showed dipstick proteinuria of +2, and she also exhibited other features of nephrotic syndrome with a serum albumin of 1.8 g/dL and an elevated total cholesterol of 394 mg/dL. Hepatitis B surface antigen, hepatitis C antibody, human immunodeficiency virus antibody, and antinuclear antibody tests were all negative. Her laboratory findings are summarized in Table 1. After evaluation, her diuretic and renin-angiotensin system inhibitor were optimized and a statin was added. At the same time, a kidney biopsy was offered but was not performed because of financial constraints at the time. After 4 months of conservative therapy, a decision was made to start her on prednisolone combined with calcium, a proton pump inhibitor, and cotrimoxazole prophylaxis. Still, after an initial transient reduction in proteinuria, the patient continued to have nephrotic range proteinuria while on high-dose prednisolone and she also had an increment in weight from 40 kg to 45 kg within the period of prednisolone use. Prednisolone was then tapered, and after rigorous discussions, the challenging decision to empirically initiate tacrolimus was made. Subsequently, the patient developed a progressive worsening of hypertension with in-clinic blood pressure measurements of 138/120 mm Hg and 160/100 mm Hg, and she also developed hyperkalemia, for which tacrolimus also had to be withdrawn. Afterward, the patient was once more put back on prednisolone based on the presumed initial partial response, while a kidney biopsy was being pursued. Twenty-four-hour urine protein and treatment correlations are shown in Figure 1. Subsequently, a kidney biopsy was performed, and the tissue sample was sent to a pathology lab in India for examination.

The kidney biopsy sample was processed for light microscopy (LM), direct immunofluorescence microscopy, immunohistochemistry (IHC), and electron microscopy (EM) using standard techniques. For LM, sections were systematically stained with hematoxylin and eosin, periodic acid-Schiff (PAS), Jones’ methenamine silver, Masson’s trichrome, and Congo red (CR) stains. Tissue stained with CR was also examined under polarized light. Direct immunofluorescence microscopy was performed on fresh frozen tissue as well as on pronase-treated paraffin-embedded tissue to assess the presence of immune deposits based on immunostaining for IgG, IgM, IgA, C3, C1q, kappa, and lambda light chains. IHC was performed on formalin-fixed paraffin-embedded tissue for fibronectin 1 with a monoclonal mouse-origin antibody (Abnova, clone 568). Glutaraldehyde-fixed tissue was processed for transmission EM, and ultrathin sections were stained with uranyl acetate and lead citrate. Figure 2 depicts the kidney biopsy findings.

Multiple sections stained with hematoxylin and eosin, PAS, Jones’ methenamine silver, Masson’s trichrome, and CR revealed renal cortical parenchymal areas with up to 17 glomeruli, 1 globally sclerosed. The viable glomeruli were enlarged and exhibited diffuse increases in the mesangial matrix with thickened capillary walls. The mesangial areas and capillary walls were expanded by a material that was positive for PAS staining, non-argyrophilic, and negative for CR staining (shown in Fig. 2a–c). Segmental tuft sclerosis was noted in 3 glomeruli. There was no evidence of endocapillary hypercellularity, tuft necrosis, or crescent formation. Tubular atrophy and interstitial fibrosis involved less than 10% of the sampled cortex. Few small collections of interstitial foam cells were observed. The arteries sampled were unremarkable, while the arterioles showed focal hyalinosis lesions.

This revealed negative staining for IgG, IgM, IgA, C3, C1q, lambda, and kappa.

IHC staining for fibronectin 1 revealed strong positivity along the mesangial and capillary wall deposits in the glomeruli (shown in Fig. 2e). EM findings were also consistent with these findings, as massive mesangial and subendothelial granular deposits were observed (shown in Fig. 2f). Diffuse foot process effacement was also noted.

The age of presentation, the clinical features of our patient, and the kidney biopsy findings were all consistent with FG. We were unable to perform genetic testing to identify FN1 gene mutations, but the family history was negative for kidney disease. Screening of family members was attempted, and all three of her sisters had normal kidney function and 24-h urine protein. We were not able to screen her mother or her brothers with laboratory testing, but they report no symptoms consistent with kidney disease.

FG is a rare autosomal dominant kidney disease that has been described in the literature. It is associated with FN1 mutations, but mutation has been found in only 40% of patients with FG [6]. In our patient, we were unable to perform genetic testing to sequence the FN1 gene, but the lack of a family history of known kidney disease and the lack of proteinuria and renal dysfunction in her screened siblings may point toward this being a potentially sporadic case. The hallmark of presentation in affected individuals is proteinuria, which can commonly reach the nephrotic range. Nephrotic syndrome is also a common presentation, but microscopic hematuria, hypertension, a reduced glomerular filtration rate, and type IV renal tubular acidosis can also occur [9‒12]. Our patient also presented with features of nephrotic syndrome consistent with the reports by Zhang et al. [10]. The usual age at the time of diagnosis can vary given the significant delay between the onset of symptoms and the diagnosis of FG [10]. Diagnoses at ages as early as 3 years and as late as 88 years have been reported by Ohtsubo et al. [7] and Cheng et al. [13] respectively.

FG exhibits nonspecific LM findings that could also be variable. The commonly reported pattern is a lobular glomerular pattern with mesangial expansion and deposits that are PAS positive and CR stain negative [9, 10]. However, membranoproliferative glomerulonephritis has also been described [14]. Immunofluorescence typically shows negative staining or nonspecific positivity for the various immunoglobulins and complement components [10, 14]. The most specific diagnostic feature is positive immunostaining for fibronectin, whereas fibrillary structures can also be found via EM [9, 10]. Our patient’s biopsy specimen had LM, showing deposits that were PAS positive and immunofluorescence for immunoglobulins and complement components was negative. EM showed extensive granular deposits, and IHC for fibronectin showed strong positivity, confirming the diagnosis.

Treatment for FG is generally supportive, focused on the management of proteinuria with a renin-angiotensin system inhibitor, the management of complications of chronic kidney disease, followed by renal replacement therapy (RRT) when end-stage kidney disease (ESKD) develops. Immunosuppressive treatment is generally not recommended because FG is not considered an autoimmune or inflammatory disease. However, there is a report of sustained remission following steroid therapy in a patient with FG [15]. Two additional patients also had partial responses to immunosuppressive treatments, but in both instances, the patients had concomitant diseases in the form of lupus nephritis and monoclonal gammopathy, which partly could confound the response to immunosuppressives [16, 17]. Another report demonstrated a response to steroids and mizoribine, with a later recurrence of nephrotic range proteinuria and a decline in kidney function [18]. In contrast, a report by Hata et al. [14] revealed no response to steroid therapy. Our patient experienced a reduction in proteinuria to the subnephrotic range at various points in her follow-up, but no clear sustained response to steroids was observed. Definitive conclusions about the effects of tacrolimus cannot be drawn because of the initial low tacrolimus drug level and subsequent discontinuation after only 6 weeks of therapy with a higher dose. However, both 24-h urine protein values determined at the beginning and at the time of discontinuation of tacrolimus were comparable, suggesting a possible lack of response.

A progressive decline in glomerular filtration rate can occur and may lead to the development of ESKD requiring treatment with RRT [6, 9, 10]. In a relatively large case series by Zhang et al. [10] that included 19 patients, seven progressed to ESKD and required RRT, indicating that a decline in kidney function and the development of ESKD are significant complications of FG. FG can recur after a kidney transplant, but the true risk of recurrence is not known, and FG is not considered a contraindication for a kidney transplant [8, 19]. Our patient has been on follow-up for 2.4 years since her initial presentation to our hospital. Her last 24-h urine protein was 2.3 g, and she remains to have normal kidney function.

Overall, our case report describes the first ever reported case of FG in Africa. The diagnosis of FG could be challenging in many developing nations due to a lack of easy access to kidney biopsy and a lack of proper pathological and genetic testing infrastructure. For example, in our center where we see up to 100 nephrotic syndrome patients and more than 500 patients with glomerulonephritis yearly, only 10% or less may undergo kidney biopsies. Moreover, our patient would likely have been misdiagnosed if only locally available LM and IHC studies were performed without specific fibronectin IHC studies and EM. The case report also has limitations because of the lack of genetic testing to identify FN genetic mutations and to assess for remote Asian and European ancestry.

This case highlights the need to improve local health infrastructures, particularly by increasing the accessibility to kidney biopsy and enhancing the quality of pathology facilities, for better diagnosis and patient care in developing nations. A timely kidney biopsy and appropriate diagnosis could have helped our patient avoid the administration of unnecessary medications that have the potential for serious adverse events. International collaborations for better diagnosis can also be utilized to temporarily fill gaps in infrastructure. The CARE Checklist has been completed by the authors for this case report, attached as online supplementary material (for all online suppl. material, see https://doi.org/10.1159/000546060).

The authors would like to acknowledge everyone who was involved in the care of the patient and also acknowledge the contributions made toward the pathological examination of specimens by Dr. Alok Sharma, the director of the Department of Renal Pathology and TEM at Dr. Lal Path Labs Ltd.

Ethical approval was waived by the Addis Ababa University Institutional Review Board because no personal identifiers would be used in the publication material. Written informed consent was obtained both from the legal guardian of the patient and from the patient for the publication of the details of their medical case and any accompanying images.

None of the authors report any conflict of interest.

No funding was obtained for the study.

A.T. compiled the document, wrote the draft of the manuscript, and edited the manuscript. H.G. compiled the case details, prepared the graphs, and edited the manuscript. A.T. and H.G. were involved in patient care. S.S. performed pathological testing and contributed to the pathological description and images. All authors reviewed and approved the final manuscript.

The data supporting this case report's findings are not publicly available because they contain information that could compromise the patient's privacy, but are available from the corresponding author [A.T.] upon reasonable request.