Anti-Tumor Necrosis Factor Treatment for Glomerulopathy: Case Report and Review of Literature
Background: Glomerulopathy involves damage to the glomerular filtration barrier for several reasons, resulting in idiopathic nephrotic syndrome (NS). Treatment options are limited and often include steroids with varying levels of response.
Case Presentation: A 7-year-old male with a history of NS at age 2 years that developed following a respiratory tract infection was found to have a heterozygous variant of uncertain significance in COL4A4 and TRPC6 genes. Biopsy findings included podocytopathy and changes in the basement membrane. Upon initial response to steroids, the patient was treated with a brief course of anakinra followed by adalimumab for > 2 years as steroid-sparing biological response modifiers. After a gradual taper, the patient remains in remission and has not received treatment in the last 12 months.
Conclusions: This case shows the complex nature of biologically predetermined cascading events in the emergence of glomerular disease with environmental triggers and genetic factors. Downregulation of somatic tissue-driven proinflammatory milieu originating from the constituents of the glomerular microenvironment can help in recovery from emerging podocytopathy. Blocking tumor necrosis factor-α early in the disease course, even temporarily, may allow time for the de novo regenerative process to prevail. Additional research is warranted to test this hypothesis and minimize steroid use.
Podocytes are terminally differentiated, highly specialized cells located in juxtaposition to the basement membrane over the abluminal surfaces of endothelial cells within the glomerular tuft. This triad structure is the site of the filtration barrier, which forms highly delicate and tightly regulated architecture to carry out the ultrafiltration function of the kidney.1 The filtration barrier is characterized by foot processes that are connected by specialized junctions called slit diaphragms.
Insults to components of the filtration barrier can initiate cascading events and perpetuate structural alterations that may eventually result in sclerotic changes.2 Common causes among children include minimal change disease (MCD) with the collapse of foot processes resulting in proteinuria, Alport syndrome due to mutation of collagen fibers within the basement membrane leading to hematuria and proteinuria, immune complex mediated nephropathy following common infections or autoimmune diseases, and focal segmental glomerulosclerosis (FSGS) that can show variable histopathology toward eventual glomerular scarring.3,4 These children often clinically have minimal, if any, signs of systemic inflammation.3-5 This has been a limiting factor for the commitment to immunomodulatory treatment, except for steroids for the treatment of MCD.6 Although prolonged steroid treatment may be efficacious, adverse effects are significant in a growing child. Alternative treatments, such as tacrolimus and rituximab have been suggested as second-line steroid-sparing agents.7,8 Not uncommonly, however, these cases are managed by supportive measures only during the progression of the natural course of the disease, which may eventually lead to renal failure, requiring transplant for survival.8,9
This case report highlights a child with a variant of uncertain significance (VUS) in genes involved in Alport syndrome and FSGS who developed an abrupt onset of proteinuria and hematuria after a respiratory illness. To our knowledge, he represents the youngest case demonstrating the benefit of targeted treatment against tumor necrosis factor-α (TNF-α) for glomerulopathy using biologic response modifiers.
Case Description
This is currently a 7-year-old male patient who was born at 39 weeks gestation to gravida 3 para 3 following induced labor due to elevated maternal blood pressure. During the first 2 years of life, his growth and development were normal and his immunizations were up to date. The patient's medical history included upper respiratory tract infections (URIs), respiratory syncytial virus, as well as 3 bouts of pneumonia and multiple otitis media that resulted in 18 rounds of antibiotics. The child was also allergic to nuts and milk protein. The patient’s parents are of Northern European and Native American descent. There is no known family history of eye, ear, or kidney diseases.
Renal concerns were first noted at the age of 2 years and 6 months when he presented to an emergency department in Fall 2019 (week 0) for several weeks of intermittent dark-colored urine. His mother reported that the discoloration recently progressed in intensity to cola-colored, along with the onset of persistent vomiting without any fever or diarrhea. On physical examination, the patient had normal vitals: weight 14.8 kg (68th percentile), height 91 cm (24th percentile), and body surface area 0.6 m2. There was no edema, rash, or lymphadenopathy, but he appeared pale.
