Case Study 3: A Patient with C3 Glomerulopathy Entering Adulthood
Complement-Mediated Kidney Disorders: A Case Series
Learning Goal:
- Understand how to manage the transition in care in adolescent patients with C3 glomerulopathy
Case Presentation
Chief Complaint: Seeking advice on family planning
Case Presentation: The patient is a 21-year-old woman who has been under your care for 8 years for the management of her C3 glomerulopathy. She is graduating college in the spring and will be moving to another city to take on a new job opportunity. She has a serious partner and is considering marriage. She comes to you seeking advice about her prognosis, the advisability of having children, and the potential impact of pregnancies on her future health.
Past Medical History: The patient presented at age of 13 years for evaluation of persistent hematuria and proteinuria of 9 months duration. She had no episodes of gross hematuria, and her blood pressure was normal. Her urinary protein creatinine ratio in the first morning urine was consistently in the range of 1.5-2.0 mg/mg creatinine and her estimated glomerular filtration rate (eGFR) was 95-105 ml/min/1.73 m2. Her C3 level was depressed at 53 mg/dl. Her antinuclear antibodies (ANA) and double-stranded DNA titers were normal. She underwent a percutaneous kidney biopsy which revealed C3 glomerulopathy. Further workup indicated the presence of a C5 nephritic factor, but no genetic mutations in Factor B, H, or I, MCP, or decay accelerating factor.
She has been maintained on stable doses of renoprotective agents and immunosuppressive therapy. Her most recent level of proteinuria was 0.54 mg/mg creatinine and her eGFR is 89 ml/min/1.73 m2.
Past Surgical History: Other than the repair of a fractured radius she has not had any surgery.
Medications: Lisinopril 20 mg per day, empagliflozin 10 mg per day, mycophenolate mofetil (MMF) 1 g twice a day, and prednisone 20 mg every other day.
Family History: There are no family members with hypertension, proteinuria, or chronic kidney disease.
Social History: She is finishing college and plans to work in a government agency in international relations. She is hoping to live on her own in an apartment near her job. She does not smoke or use recreational drugs and drinks socially. She is sexually active and uses a low-dose oral contraceptive.
Physical Examination: She is fully grown and her menstrual periods are regular. Her blood pressure is 108/76 mm Hg. She has clear lungs and no cardiac murmur. She has no peripheral edema.
General: She is a healthy and active young woman.
Laboratory Studies: BUN: 14 mg/dL. Creatinine 0.76 mg/dl. eGFR: 86 ml/min/1.73 m2. UPCR: 0.5. C3 68mg/dl. Hemoglobin 12.4 g/dL. Hemocrit: 38%. White blood cells: 8.1 x 109/L, platelet count: 231,000.
Preventative Health History: She exercises regularly and uses a vitamin supplement daily.
Additional Important Information: She has been a model patient who keeps her appointments regularly and takes her medications without fail.
Learner Reflection Questions Click each to view answers
Based on this woman’s history, what would you advise her risk of progressing to kidney failure?
Correct Answer Rationale and Clinical Commentary
C3 glomerulopathy can arise due to mutations in complement regulatory proteins or autoantibodies that stabilize, C3 and C5 nephritic factors like the woman in this case, or inhibit the activity of complement cascade proteins, factor H. [1,2] The disease has a modest risk of progression with nearly 50% of patients progressing to ESRD over a 10-year follow-up. [1] The nature of the underlying immunological defect has not been consistently associated with the rate of disease progression.
Recent data from the RaDaR database in the United Kingdom suggest that patients who achieve a substantial reduction in proteinuria in response to treatment or who have persistent low-grade proteinuria during the follow-up, like this patient, have a favorable prognosis and are likely to maintain normal kidney function. [personal communication] While mycophenolate mofetil, corticosteroids, and eculizumab have been used to treat C3 glomerulopathy, none have been proven effective. [3]
If this woman were to progress to kidney failure and require a kidney transplant, what impact does this have on living related donation and what is the risk of recurrence in the allograft?
Correct Answer Rationale and Clinical Commentary
Because C3 glomerulopathy is a systemic disorder of complement regulation that is not corrected with a kidney transplant, there is always a risk of recurrence in a kidney transplant. [4] In addition, because it can reflect genetic abnormalities in complement regulatory proteins, caution needs to be exercised before proceeding with living related donation. In this case, the family history is negative and the woman has a C5 nephritic factor that is not a genetic abnormality. Therefore, family members, after appropriate testing, are likely to be suitable candidate donors. Nonetheless, because there is an immune abnormality leading to the production of the nephritic factor, she is at risk of recurrent disease. Previous studies suggest that this complication occurs in 40-60% of patients. [5] A recent study suggests that nearly all patients have recurrent disease in the transplant if surveillance biopsies are performed. [6] However, the disease is frequently mild at diagnosis with minimal impact on kidney function. Follow-up is essential to determine the long-term outcome.
Based on her current status and medications, what are the risks involved if she were to become pregnant?
Correct Answer Rationale and Clinical Commentary
Because of the presence of a C5 nephritic factor, this woman is likely to need treatment indefinitely to maintain control of her disease and preservation of kidney function. Renoprotective therapies are contributing to the antiproteinuric effect of therapy. However, the lisinopril will need to be discontinued if she becomes pregnant because of the association between ACE inhibitor use in the first trimester and renal dysgenesis. [7] The impact of SGLT2 inhibitors on the fetus is unclear. Mycophenolate mofetil and corticosteroids are teratogenic and both medications would need to be discontinued, or the dosage reduced to the lowest effective level. [8] The woman has CKD stage 2 with normal blood pressure and she is likely to deliver a full-term healthy baby without any decline in kidney function during the pregnancy or delivery. With that said, women with low eGFR and concomitant proteinuria are at higher risk for adverse pregnancy outcomes. [9]
Working Together as a Team
It is increasingly common for pediatric patients with primary glomerular disease like C3 glomerulopathy to be followed by pediatric nephrologists well into the beginning of the third decade of their lives. However, at that age, new life issues and health concerns emerge highlighting the importance of developing comprehensive strategies to smoothly and efficiently transfer care to adult colleagues. Like the woman in this case, these include adapting to new living circumstances, complete independence from parents, and major personal decisions like marriage and childbearing. Advance planning is essential to carry out the transfer without jeopardizing the health status and disrupting the continuity of care. Cooperation between pediatric and adult nephrologists is key to the process. Incorporation of other team members including ob-gyn, immunology, genetics, and nutrition can ensure successful outcomes during the transition.
The woman in this case is an ideal patient. But if the proper components are in place and open communication between services is routine, transitioning can be accomplished even for more challenging patients who may be experiencing a range of social or economic disadvantages.
Closing Commentary
This case represents a young woman with C3 glomerulopathy who has done remarkably well for 8 years. However, she has reached a stage in her life when she will need to transfer her care to internal medicine specialists. They will be better positioned to manage the challenges that she will encounter in adulthood. The case summarizes some of the key questions that will need to be addressed by the transition team to ensure the continuation of her medical care and the preservation of her kidney function.
References
- Smith RJH et al. C3 glomerulopathy – understanding a rare complement-driven renal disease. Nat Rev Nephrol. 2019;15:129-143.
- Heiderscheit AK et al. C3 glomerulopathy – understanding a rare complement-driven renal disease. Am J Med Genet C Semin Med Genet. 2022;190:344-357.
- Nester C et al. Developing therapies for C3 glomerulopathy: report of the kidney health initiative C3 glomerulopathy trial endpoints work group. Clin J Am Soc Nephrol. 2024;19:1201-1208.
- Patry C et al. Kidney transplantation in children and adolescents with C3 glomerulopathy or immune complex membranoproliferative glomerulonephritis: a real-world study within the CERTAIN research network. Pediatr Nephrol. 2024; [online ahead of print].
- Ahmed SB, Bomback AS. C3 glomerulopathy: pathogenesis and treatment. Adv Chronic Kidney Dis. 2020;27:104-110.
- Tarragon B et al. C3 glomerulopathy recurs early after kidney transplantation in serial biopsies performed within the first 2 years after transplantation. Clin J Am Soc Nephrol. 2024;19:1005-1015.
- Tabacova S. Mode of action: angiotensin-converting enzyme inhibition – development effects associated with exposure to ACE inhibitors. Crit Rev Toxicol. 2005;35:747-755.
- Parikh SV et al. Update on lupus nephritis: core curriculum 2020. Am J Kidney Dis. 2020;76:265-281.
- Tangren J et al. Pre-pregnancy eGFR and risk of adverse maternal and fetal outcomes: a population-based study. J Am Soc Nephrol. 2023;34:656-667.
