Case Study 1: Newly Diagnosed C3 Glomerulopathy
Complement-Mediated Kidney Disorders: A Case SeriesLearning Goals:
- Review the diagnostic criteria for C3 Glomerulopathy
- Identify the drivers of C3 Glomerulopathy
- Review the management of C3 Glomerulopathy
Case Presentation
Chief Complaint: Progressive lower extremity edema in a 53-year-old male.
Case Presentation: SH is a previously healthy factory worker who has noted a pattern of intermittent swelling of his legs over the last 4 weeks. He denies recent travel. Two of his high school-age children have had a viral illness within the last week – however, he denies having had symptoms. He reports two episodes over the last week where his urine seemed to be “very dark”. He denies pain complaints. There have been no new rashes, joint complaints, or gastrointestinal symptoms.
Past Medical History: The patient reports a history of essential hypertension since the age of 24 years and seasonal allergies. He has well-controlled blood pressure and good compliance with his antihypertensive medication. During allergy season he will take an antihistamine almost daily but during the off-season, he takes no medications. Occasionally he has noted periorbital edema – though it does not seem to correlate necessarily with allergy season.
Past Surgical History: No prior surgeries.
Medications: Amlodipine 10mg daily, Cetirizine PRN.
Family History: His father has type II diabetes and hypertension. He has a 50-year-old sister with thyroid disease though he is not sure what kind. The patient has two healthy brothers.
Social History: He works full-time in a car factory and lives with his spouse and two high school-age children who are well. He denies tobacco exposure. He generally does not use over-the-counter medications.
Physical Examination: Temperature: 37.1°C. Blood pressure: 172/88 mmHg. Heartrate: 98 bpm. Weight: 84 kg. Height:180 cm.
General: The patient appears to be in no distress. Repeated blood pressure measurements confirm that his blood pressure is 170/90 mmHg. There is no overt facial edema. Heart and lung exams are normal. No organomegaly is noted, though there appears to be 1+ abdominal wall edema. Joints and skin appear normal. He has 3+ lower extremity edema.
Laboratory Studies: Creatinine: 1.6 mg/dL. Sodium: 138 mmol/L. Potassium: 4.9 mmol/L. Blood urea nitrogen (BUN): 38 mg/dl. Albumin: 2.1 mg/dl. Complement C3: 14 mg/dl. A urinalysis reveals hematuria (3+ blood), proteinuria (3+ protein), and a urine protein to creatinine ratio (UPCR) of 10 mg/mg. The patient undergoes a kidney biopsy, and a C3 dominant glomerulonephritis is identified.
Preventative Health History: Age-appropriate immunizations are up to date. The patient reports yearly influenza vaccination, and he has had 3 COVID-19 immunizations. He has had one normal colonoscopy.
Learner Reflection Questions Click each to view answers
What are your initial considerations once a C3 dominant lesion has been identified on biopsy?
Correct Answer Rationale and Clinical Commentary
New onset worsening of baseline blood pressure control is common in acute glomerulonephritis. [1] The C3 dominant lesion may be seen in up to 30% of postinfectious glomerulonephritis lesions (PIGN). While PIGN classically occurs in the 5-15-year-old group – it must be included in the differential for a patient in any age group. Importantly, up to 30% of patients with clinically substantiated disease will not recall a recent infection. Alternatively, C3 dominant glomerulonephritis on biopsy (C3 2X greater than any other immunoreaction) is the hallmark and the sole diagnostic criteria for C3 Glomerulopathy (C3G) – a disease that results from underlying complement dysregulation. [2] The distinction between the two is critical since one is generally a transient, self-limited disease (PIGN) often not requiring aggressive management, and the other is more likely to be a chronic progressive glomerular disease that mandates more intensive treatment. Importantly, there are no distinctions in kidney biopsy that will allow you to tell the difference between the two diseases.
A consensus statement established the diagnostic criteria for C3 Glomerulopathy: a C3 dominant lesion identified in a patient with active glomerulonephritis after PIGN has been ruled out. [3] Classically, PIGN is considered ruled out when there is a persistence of active glomerulonephritis and a low C3 ≥12 weeks after presentation. At that point, it is reasonable to assign the diagnosis of C3 Glomerulopathy. It should be noted that complement biomarkers are not a requirement for the diagnosis of C3G.
What additional laboratory studies may be useful to help confirm the diagnosis of C3 Glomerulopathy?
Correct Answer Rationale and Clinical Commentary
It would be important to consider what this patient’s C3 level is approximately 12 weeks after presentation. If it remains low, then the C3 glomerulopathy diagnosis is more likely. The consensus statement referred to a number of complement labs that would help identify the degree of underlying complement dysregulation in a classic C3 glomerulopathy patient. [1] However, more recently it has become clear that one of the first studies to be done in the over 50-year-old group is a test for paraproteins. Up to 80% of patients who present for the first time with C3 glomerulopathy will have a paraprotein. [4] Importantly, limited data suggest that when the C3 glomerulopathy biopsy is found in conjunction with a paraprotein, patients may do better clinically if the paraprotein is treated. Hence, the evaluation for paraprotein-related disease is directed by expert guidance.
Despite their usefulness in defining the degree of underlying disease, the more detailed complement protein evaluations may be difficult to obtain, as these assays are often only available through specialty labs. With that in mind, a limited evaluation should at least consider an investigation for the driver of disease. The majority of patients (up to 80%) have disease driven by autoantibodies referred to as nephritic factors. [5] [Interestingly, these antibodies tend to cluster in families with another autoimmune disease such as Type II diabetes and thyroid disease, as seen in this case.] Approximately 20% of patients may have an underlying complement gene abnormality as their driver – most often in complement proteins C3, CFB, or CFH. [6] Therefore one of the first steps would be to do nephritic factor assays. Nephritic factors are immune globulins that cause dysregulation of the alternative pathway of complement, the underlying mechanism of disease for C3 glomerulopathy. While a number of other biomarkers will help to characterize the extent to which the complement system is dysregulated, they are not required to plan for initial treatment.
What are the initial steps in the management of C3 Glomerulopathy?
Correct Answer Rationale and Clinical Commentary
The management of C3 glomerulopathy is guideline-based.[3] Using the KDIGO Glomerular Disease Guidelines 2021, the initial treatment is considered supportive – i.e., the goal should be to control blood pressure in the normal range, preferably with ACE inhibitors or angiotensin blockers, which also provides antiproteinuric benefit.[3] In addition, the guideline encouraged the implementation of all measures designed to optimize healthy body weight, lipids, physical activity, and diet. Patients with a UPCR that remains greater than 1g despite the above measures should then be considered for immune suppression. There is also the possibility for the patient to enter a clinical trial, assuming they are eligible at the time of the discussion (search clinicaltrials.org for current clinical trials). These include studies that are evaluating agents that inhibit factor B (iptacopan), C3 (pegcetacoplan), and C5 (ravulizumab). [7-13] Initial immune suppression guidelines were not based on randomized controlled trials. Instead, they were derived from approximately seven separate cohorts where the recommended immune suppression (a combination of mycophenolate mofetil and prednisone) was trialed and appeared to have efficacy in ~30-70% of patients.
Working Together as a Team
The pathologist is critical to facilitating the diagnosis of C3 glomerulopathy. Once the diagnosis is made, most patients benefit from a nutrition consult to assist with good diet measures, particularly as it applies to the control of salt intake given its effect on blood pressure in the setting of glomerulonephritis.
Closing Commentary
C3 glomerulopathy is an ultra-rare glomerular disease caused by dysregulation of the alternative pathway of complement. [14] The natural history of the disease is one of frequent progression to end-stage kidney disease as well as frequent recurrence in transplant. Most cases are autoimmune – caused by nephritic factors. A less common cause of C3 glomerulopathy is a genetic abnormality in a protein that is part of the alternative pathway of complement. [15] Current therapy is a combination of supportive care with the addition of standard immune suppression if there are signs of progressive disease (>1g of urine protein, and/or a rising creatinine). While it is a complement-mediated kidney disease, treatment with terminal complement pathway agents has had only marginal success. The future of the treatment of this disease is poised to dramatically change with the alternative pathway complement inhibitors that have just recently completed their phase III clinical trials.
References
- Sethi S et al. Mayo Clinic/Renal Pathology Society consensus report on pathologic classification, diagnosis, and reporting of GN. J Am Soc Nephrol. 2016;27:1278-1287.
- Riedl M et al. C3 glomerulopathy. Pediatr Nephrol. 2017;32:43-57.
- Kidney Disease: Improving Global Outcomes (KDIGO) Glomerular Diseases Work Group. KDIGO 2021 Clinical Practice Guideline for the Management of Glomerular Diseases. Kidney Int. 2021 Oct;100(4S):S1-S276.
- Lloyd IE et al. C3 glomerulopathy in adults: a distinct patient subset showing frequent association with monoclonal gammopathy and poor renal outcome. Clin Kidney J. 2016;9:794-799.
- Hauer JJ et al. Defining Nephritic Factors as Diverse Drivers of Systemic Complement Dysregulation in C3 Glomerulopathy. Kidney Int Rep. 2023;9:464-477.
- Bu F et al. High-throughput genetic testing for thrombotic microangiopathies and C3 glomerulopathies. J Am Soc Nephrol. 2016;27:1245-53.
- Rabasco C et al. Effectiveness of mycophenolate mofetil in C3 glomerulonephritis. Kidney Int. 2015;88:1153–60.
- Avasare RS et al. Mycophenolate Mofetil in Combination with Steroids for Treatment of C3 Glomerulopathy: A Case Series. Clin J Am Soc Nephrol. 2018;13:406–13.
- Caravaca Fontan F et al. Mycophenolate Mofetil in C3 Glomerulopathy and Pathogenic Drivers of the Disease. Clin J Am Soc Nephrol. 2020;15: 287–1298.
- Bharati J et al. The usefulness of mycophenolate mofetil in Indian patients with C3 glomerulopathy. Clin Kidney J. 2019;12:483–487.
- Caliskan Y et al. Immunosuppressive Treatment in C3 Glomerulopathy: Is it Really Effective? Am J Nephrol 2017;46:96-107.
- Khandelwal P et al. Therapy and outcomes of C3 glomerulopathy and immune-complex membranoproliferative glomerulonephritis. Pediatr Nephrol. 2021;36:591–600.
- Ravindran A et al C3 Glomerulopathy: Ten Years’ Experience at Mayo Clinic. Mayo Clin Proc. 2018;93:991-1008.
- Noris M, et al. STEC-HUS, atypical HUS and TTP are all diseases of complement activation. Nat Rev Nephrol. 2012;8:622-33.
- Bu F et al. Genetic analysis of 400 patients refines understanding and implicates a new gene in atypical hemolytic uremic syndrome. J Am Soc Nephrol. 2018;29:2809-2819.
