LONG TERM DISEASE REMISSION IN A CASE OF RAPIDLY PROGRESSIVE RENAL FAILURE DUE TO C3 GLOMERULONEPHRITIS

Introduction:

C3 glomerulopathy (C3G) is a rare kidney disease with two histological patterns: C3 glomerulonephritis and dense deposit disease. Pathogenesis of both entities is due to dysregulation in the alternative complement pathway.

C3 glomerulopathy results from complement dysregulation in the fluid phase and glomerular microenvironment. C3 glomerulopathy (C3G) diagnosis relies on renal biopsy immunofluorescence and complement biomarker profiles. Acquired causes of C3G are mainly due to autoantibodies associated with complement dysregulation. Genetic variants of C3G occur due to mutations in the C3, CFB, CFH, CFI , and CFHR1–CFHR5 genes. Convertase dysregulation is central to the pathogenesis of C3 glomerulopathy (C3G).

Methods:

Case History:  

13 years’ male child came with generalized edema, anorexia, and reduced urine output with no fever or apparent nephrotoxic drug exposure.  2-month history of fatigue, poor oral intake, and swelling of the face, hands, and feet. He was previously in good health with no significant illnesses in past. 

 Patient presented to a tertiary care teaching hospital from western Maharashtra, India on 09/07/21 with renal dysfunction (creatinine 2.1 mg/dL), hypertension with 24-hour urine protein of 2907 mg/liter, serum albumin 2. 4. gm/liter, urine RBC 18-20/HPF, pus cells 25-30 /HPF and urine protein 3 +. Due to generalized edema, he received diuretics, anti-hypertensive and supportive care. Subsequently, he underwent renal biopsy on 17/07/21. The renal biopsy showed C3GN 07 glomeruli characterized with segmental endocapillary and diffuse mesangial hypercellularity with few infiltrating polymorphs. Diffuse thickening of glomerular basement membrane, lobular accentuation and segmental tram tracking was also noted in each glomerulus. Immunofluorescence study showed 06 glomeruli with positive (+++) C3 and negative for IgG, IgM, IgA, C1q. The family received counselling for the nature of the disease and all available treatment options. We advised the family about the need to do genetic exome sequencing to identify any significant mutation. The family declined to do the genetic testing due to financial constraints. Patient received prednisolone 1 m/kg/day, mycophenolate mofetil 500 mg twice daily, Ramipril 2.5 mg once a day. We decided to avoid methyl prednisolone pulses to contain cumulative steroid dose to its minimum. Patient showed improvement with serum creatinine coming down to 1.5 mg/dL and discharged home on 20/07/21 in stable condition.  We advised regular monthly follow up for the patient. We prescribed prednisolone for 6 months in gradually tapering dose and mycophenolate mofetil for 6 months duration (July 2021 to January 2022).  We examined the patient in October 2023.  He showed no signs of fluid overload with no proteinuria (uPCR 0.09 mcg/gm) and normal renal functions (urea 26 mg/dL and creatinine 0.9 mg/dL)). Patient continues to be in complete renal remission receiving no medications on a regular basis. He has normal vital parameters and growth pattern for a 16-year-old boy.

Results:

Discussion:

Conditions such as post-infectious glomerulonephritis are difficult to differentiate from C3 glomerulopathy by renal biopsy alone, which can confound early diagnosis and treatment. No disease-specific treatments are available, although immunosuppressive agents and complement pathway blocking agents (e.g. eculizumab) are helpful in certain patients. Unfortunately, no treatment is universally effective or curative except allogenic liver transplantation in a few select cases. [1] Moreover, recent advances in research have clarified the role of complement in other glomerular diseases in which its role was less established, namely in immune-complex membranoproliferative glomerulonephritis (IC-MPGN), ANCA-vasculitis, IgA nephropathy, and idiopathic membranous nephropathy. As a standard of care, we would advise complement pathway analysis (C3, C4, CH-50, CFH antibody) and autoimmune work up (ANA profile) for all patients with C3G as a histological picture. As the patient reached complete renal remission (normalising creatinine and proteinuria less than 300 mg/day), we decided to continue with dual immunosuppression. The management required meticulous in-person and telephonic follow up.

Due to the rarity of the disease, optimal management options established through randomized clinical trials are not sufficient to guide therapeutic decision-making. [2,3] In this particular case, renal remission was the only parameter that guides the management without the need to perform genetic tests or complement factor analysis.

Conclusions:

Conclusion:

The C3 glomerulonephritis is a recently coined disease entity with variable natural history. It is a rare disease with minimum therapeutic options like eculizumab, plasma exchange or in few cases cyclophosphamide and ACE inhibitors. In this case report, we highlight a case scenario with complete and sustained disease remission with short course (6 months) of glucocorticoids and mycophenolate mofetil. We did not do genetic testing or plasma exchange. This indicated that morphological and IF diagnosis of C3GN need not be a genetic entity always but likely to respond to multi-targeted immunosuppression. Close monitoring of these patients is also equally important to identify and treat relapses.

References:

1. Smith RJH, Appel GB, Blom AM, Cook HT, D'Agati VD, Fakhouri F, Fremeaux-Bacchi V, Józsi M, Kavanagh D, Lambris JD, Noris M, Pickering MC, Remuzzi G, de Córdoba SR, Sethi S, Van der Vlag J, Zipfel PF, Nester CM. C3 glomerulopathy - understanding a rare complement-driven renal disease. Nat Rev Nephrol. 2019 Mar;15(3):129-143. doi: 10.1038/s41581-018-0107-2. PMID: 30692664; PMCID: PMC6876298.

2. Vivarelli M, van de Kar N, Labbadia R, Diomedi-Camassei F, Thurman JM. A clinical approach to children with C3 glomerulopathy. Pediatr Nephrol. 2022 Mar;37(3):521-535. doi: 10.1007/s00467-021-05088-7. Epub 2021 May 18. PMID: 34002292.

3. Bomback AS, Santoriello D, Avasare RS, Regunathan-Shenk R, Canetta PA, Ahn W, Radhakrishnan J, Marasa M, Rosenstiel PE, Herlitz LC, Markowitz GS, D'Agati VD, Appel GB. C3 glomerulonephritis and dense deposit disease share a similar disease course in a large United States cohort of patients with C3 glomerulopathy. Kidney Int. 2018 Apr;93(4):977-985. doi: 10.1016/j.kint.2017.10.022. Epub 2018 Jan 6. PMID: 29310824

I have no potential conflict of interest to disclose.

I did not use generative AI and AI-assisted technologies in the writing process.