Presentation
A 24-year-old man with no significant past medical history presents to urgent care with a 1-week history of sudden-onset dark urine, leg swelling, and unusually high blood pressure readings, with recent values around 160/100 mm Hg. Physical examination reveals pitting edema up to the mid-shins and mild periorbital edema, with an elevated blood pressure of 158/98 mm Hg. Past medical history was significant for frequent upper respiratory tract infections over the past year. Laboratory findings include hematuria, proteinuria, and a raised serum creatinine level at 1.8 mg/dL, indicating a reduced estimated glomerular filtration rate (eGFR) of 45 mL/min/1.73 m2. Other tests such as a complete blood count and comprehensive metabolic panel (except for creatinine and albumin) are within normal limits. Given these findings, the patient is referred to nephrology for further evaluation to determine the underlying cause of his renal symptoms.
Differential Diagnosis
A glomerular disease can be assumed to be present if the patient manifests glomerular hematuria, glomerular proteinuria, or both, such as in this patient.
Glomerulonephritis occurs due to inflammation in the glomeruli, which leads to blood in urine, variable degrees of protein in urine (sometimes in the nephrotic range), and white blood cells in urine without any urinary tract infection. Patients may also experience hypertension and kidney function impairment. Diagnoses to consider include:
- Postinfectious glomerulonephritis
- Crescentic glomerulonephritis
- Diffuse proliferative glomerulonephritis
- Glomerulonephritis associated with nonstreptococcal infection
- Membranoproliferative glomerulonephritis
- Membranous glomerulonephritis
- Poststreptococcal glomerulonephritis
- Rapidly Progressive glomerulonephritis
All patients presenting with proteinuria and hematuria should undergo a thorough evaluation for glomerular disease, which generally involves laboratory testing and, in most patients, a kidney biopsy to obtain a definitive diagnosis.
Diagnosis
This patient underwent a renal biopsy, which showed C3-dominant deposition by immunofluorescence; electron microscopy (EM) showed discontinuous, ill-defined intramembranous deposits; and mass spectrometry showed terminal complement components in C3 deposits. The patient was diagnosed with C3 glomerulonephritis (C3G).
The diagnosis of C3G is established by kidney biopsy demonstrating the characteristic findings on immunofluorescence microscopy or EM in a patient with suspected glomerulonephritis. In patients with biopsy-confirmed C3G, additional testing should be performed to help identify the underlying etiology of the glomerulopathy to help determine therapy.
For all patients diagnosed with C3G, especially those who are older than 50 years, it is important to rule out monoclonal gammopathy which can be done through various tests such as serum protein electrophoresis and immunofixation, serum free light chains, and urine protein electrophoresis and immunofixation. The presence of a paraprotein, including a monoclonal light chain, can activate the alternative complement cascade and may be responsible for the condition.
Expert opinion recommends a comprehensive complement evaluation for all C3 glomerulopathy patients, including overall complement activity assessment, serum levels measurement of complement proteins and their split products, and autoantibodies screening.
Complement evaluation may include:
- Serum C3 and C4
- Soluble C5b-9 (soluble membrane attack complex)
- Serum factor H
- Serum factor B, factor I, and membrane cofactor protein (MCP; CD46)