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Saudi Journal of Kidney Diseases and Transplantation
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Year : 2021  |  Volume : 32  |  Issue : 6  |  Page : 1782-1789
Recurrent C3 Glomerulonephritis with an ADAMTS 13 Gene Variant: A Case Report and Literature Review

1 Department of Pathology, Faculty of Medicine, King Abdulaziz University, Jeddah, Saudi Arabia
2 Department of Kidney and Pancreas Transplantation and Department of Pathology and Laboratory Medicine (MBC-10), Riyadh, Saudi Arabia
3 Department of Pathology and Laboratory Medicine (MBC-10), King Faisal Specialist Hospital and Research Center; College of Medicine, Alfaisal University, Riyadh, Saudi Arabia

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Date of Web Publication27-Jul-2022


C3 glomerulonephritis (C3GN) is a recently described form of GN that mainly occurs in children and young adults. It results from dysregulation of the alternative complement pathway. Studies have shown that dense deposit disease has a high recurrence rate; however, since C3GN is a recently described disorder, its recurrence rate is still variable. A 28-year-old male with end-stage renal disease caused by C3GN underwent renal transplantation. After 19 months, the patient experienced recurrent C3GN (rC3GN) that involved a variant of unknown significance in the ADAMTS13 gene. Over a short span of time, the patient suffered from rapid deterioration of the graft function that required renal replacement therapy. This is the first case of rC3GN that possibly involved genetic alteration, a variant within the ADAMTS 13 gene.

How to cite this article:
Zahrani RA, Nazmi AY, Hussain TA. Recurrent C3 Glomerulonephritis with an ADAMTS 13 Gene Variant: A Case Report and Literature Review. Saudi J Kidney Dis Transpl 2021;32:1782-9

How to cite this URL:
Zahrani RA, Nazmi AY, Hussain TA. Recurrent C3 Glomerulonephritis with an ADAMTS 13 Gene Variant: A Case Report and Literature Review. Saudi J Kidney Dis Transpl [serial online] 2021 [cited 2023 Feb 4];32:1782-9. Available from: https://www.sjkdt.org/text.asp?2021/32/6/1782/352441

   Introduction Top

C3 glomerulopathy is a glomerular disease caused by dysregulation of the complement system and includes C3 glomerulonephritis (C3GN) and dense deposit disease (DDD).[1] Abnormal control of the alternative pathway (AP) has emerged as a risk factor for different adverse conditions, including age-related macular degeneration, atypical hemolytic uremic syndrome (aHUs), and C3GN.[2] The disease seems to have a chronic progressive course that leads to the development of endstage renal disease (ESRD) in approximately 50% of patients.[3] The current case has highlighted some factors behind this difference and discussed the rationale behind using eculizumab as a potential novel therapy with variable outcomes.

   Case Report Top

A 28-year-old male who was suffering from C3GN; the disease was proven via biopsy in another institution at the age of 16. Over seven years, the disease progressed into ESRD. Then he underwent living-related (paternal uncle) renal transplantation after five months of regular hemodialysis (HD). The induction immunosuppressive regimen was intravenous (IV) rituximab 500 mg and a total of 100 g IV immunoglobulin were administered four weeks before transplantation in addition to 1.5 mg/kg of thymoglobulin (total of 225 mg) which was injected on the day of transplantation.

His tissue type was HLA-A*02, A*29, HLA-B*51, B*27, HLA-DRB1*03:01, *13:01, HLA-DQB1 *02:01, *06:03. He received the standard post transplantation immunosuppressant regimen, including prednisone, tacrolimus, and mycophenolic acid. His creatinine level was stabilized at 60 umol/L. Two months after transplantation, the creatinine level increased to 87 umol/L with unremarkable urinalysis. Kidney biopsy revealed only mildly acute tubular injury. With proper hydration, his creatinine level became stabilized at 70 umol/L over a period of 16 months.

Afterward, his creatinine level increased to 135 umol/L over the next two months with mild proteinuria (0.86 g/24 h) and hematuria [11-20 cells/high power field (hpf)]. His serum albumin was 38.5 g/L, and blood pressure (BP) was maintained at 122/80 mm Hg.

His serum C3 level was low: 0.24 g/L (normal level: 0.90-1.8), while (C4 level was normal:0. 21 g/L (normal level: 0.1-0.4). His serum was consistently negative for C3NeF and for monoclonal paraproteins. His blood cell count, including platelets level, was normal and there were no red blood cells schistocytes on the blood film at any time. Furthermore, serum lactate dehydrogenase and haptoglobin levels were within the normal range. The second renal biopsy was carried out after nineteen months following transplantation. The light microscopic (LM) examination revealed mild-to-moderate mesangial proliferation with normal thickness of the glomerular basement membrane (GBM) [Figure 1a]. The background showed mild interstitial fibrosis and tubular atrophy (20% of the cortical tissue). The characteristic morphological changes of rejection were absent. Direct immunofluorescence stains (DIF) revealed strong diffuse granular mesangial and segmental capillary wall staining with antiserum specific for C3 (3+) [Figure 1b]. There was no staining seen with antisera specific for IgA, IgG, IgM, C1q, and Kappa and Lambda light chains. The EM examination demonstrated mesangial, paramesangial, and few small sub-endothelial electron-dense deposits [Figure 1c-e]. The diagnosis of recurrent C3GN (rC3GN) was rendered with a comment recommending the exclusion of resolving post-infectious GN. The patient denied any history of recent upper respiratory tract infection, and his serum was negative for anti-streptolysin O antibodies. He received high dose of steroids (three doses of 5 mg/kg of methylprednisolone) followed by the standard immunosuppressive regimen. The creatinine level remained stable at 140-147 umol/L. The blood sample was sent for complement genetic testing. The blood sample test for complement genetic testing was carried out in the Molecular Otolaryngology and Renal Research Laboratories, University of Iowa Health Care, by using custom-based renal panel sequenced by capture-based next-generation sequencing method. The Genetic Renal Panel v5 platform was carried out. The final result identified a variant of unknown significance in the ADAMTS13 gene. The variant c.1978C>T, p.Arg660Trp(chr9:136307529:C>T) is located in exon 17 of the ADAMTS13 gene. This variant has been predicted pathogenic by four of five available pathogenicity prediction algorithms: GERP++RS (conserved, score: 3.17), PhyloP (conserved, score 1, 180000), Polyphen2- HDIV (probably damaging, score: 1.0) and SIFT (damaging, score: 0.010000). The functional significance of this variant is unknown. The highest minor allele frequency is 0.012% detected in the East Asian population, as reported in Exome Aggregation Consortium (ExAC) Server. ADAMTS-13 activity was measured and found to be 100% with no evidence of deficiency.
Figure 1. Pathological findings of the second post-transplant biopsy (a) Light microscopy finding. Glomerulus reveals mild mesangial matrix expansion and mild mesangial hypercellularity with delicate capillary walls (×400). (b) Direct immunofluorescence findings. Glomerulus shows global mesangial and segmental capillary wall granular staining of C3c. There was no immunoglobulin (Ig; IgG, IgM), C1q, Kappa and Lambda light chains deposition, (not shown), (×400). (c and d) Electron microscopy findings: Mesangial expansion, prominent mesangial cells and electron dense deposits mainly in the mesangial and para-mesangial area with few small subendothelial ones. (e) The podocytes are focally effaced (×1000).

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Nine months later, another episode of sudden rising in creatinine level occurred, which increased to 280 umol/L; this was accompanied by generalized body edema, hypertension (BP of 144/95 mm Hg), nephrotic range proteinuria (3.85 g/24 h), and hematuria (6-16 cells/hpf). Serum albumin level was 18 g/L. Serum C3 level remained persistently low since the first biopsy and was never more than 0.2 g/L. The 3rd renal biopsy was carried out after 28 months following transplantation. The glomeruli showed membranoproliferative pattern of injury on LM examination accompanied by interstitial inflammation and moderate tubulitis with a background of mild interstitial fibrosis and tubular atrophy [Figure 2a-c]. DIF revealed strong diffuse granular mesangial and capillary wall staining with antiserum specific for C3 (3+) [Figure 2d] only. EM examination demonstrated numerous mesangial electrondense deposits and GBM double contour with mesangial inter-position and sub-endothelial deposits [Figure 2e and f]. The case was diagnosed as acute T-cell-mediated rejection, Banff grade IA with rC3GN.
Figure 2. Pathological findings of the third post-transplant biopsy (a) Light microscopy finding; Glomerulus reveals accentuated lobular architecture with marked mesangial proliferation, endocapillary hypercellularity and early crescent formation, (×200). (b) Capillary walls double contours are highlighted with Jones’s silver stain (×400). (c) Interstitial edema, interstitial inflammation, and noticeable tubulitis, (×200). (d) Direct immunofluorescence finding: glomerulus shows global mesangial and capillary wall course granular staining with C3c, (×400). (e and f) Electron microscopy findings: mesangial expansion, endocapillary hypercellularity and electron dense deposits mainly in the mesangial, para-mesangial area, and subendothelium with double contour of the glomerular basement membrane due to mesangial interposition and subendothelial deposits (×1000).

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The patient received three boluses of 5 mg/Kg methylprednisolone. The graft function improved, and the serum creatinine level sloped downward to 179 umol/L. The patient was discharged with a prescription of daily 5 mg of oral prednisone, the standard dose of tacrolimus and mycophenolate, in addition to 50 mg of losartan. Two months later, he developed anasarca, high creatinine (213 umol/L), significant proteinuria (6 g/24 h), and low serum albumin (16 g/L). Three sessions of therapeutic plasma exchange were conducted to address the possibility of concurrent antibody-mediated rejection; however, the donor-specific antibody test turned out to be negative. Although eculizumab was considered as a useful treatment option for this patient, it was not administered on account of limited access and unavailability. There was no remarkable response obtained by the plasma exchange, and subsequently, HD was initiated.

   Discussion Top

C3GN is an inflammatory glomerular disease that occurs in people of all ages without clear gender predilection. The morphological changes vary from mesangial proliferation to membranoproliferative GN patterns with or without crescent formation. The DIF staining pattern is a characteristic with strong C3 staining associated with little or no immunoglobulin staining. The EM examination shows mesangial and subendothelial amorphous electron-dense deposits and mesangial interposition in addition to a few subepithelial deposits, but the ribbonlike dense replacement of the GBM should not be encountered since it is the defining feature of DDD [4]

Clinically, C3GN is characterized with hematuria, proteinuria of variable severity and progressive rising level of serum creatinine. It shows a chronic progressive course and tends to progress slowly to ESRD. In a large cohort of 87 patients suffering from C3GN, who were followed up for over an average of 72 months, remission occurred in 38% of patients and progression to ESRD occurred in approximately 39% of patients.[5] Zand et al[6] described 21 patients with ESRD caused by C3GN and 14 (~67%) of them developed rC3GN. The disease course in the transplanted kidneys was shorter and more progressive in comparison with its course in the native kidney and 50% of rC3GN cases were complicated by graft failure.[6]

The median time from the occurrence of the disease recurrence to graft failure was 18 months which is approximately three times shorter than the primary disease course in the native kidney (62.4 months).[6] In the current case study, the primary disease took 84 months of time before it developed into ESRD, while in the graft it progressed in the course of 11 months into ESRD. Early disease recurrence is also a noticeable trend in the case of rC3GN. The two patients with rC3GN described by Sethi et al suffered from the primary disease for more than 10 years and developed rC3GN within 18 months following the transplant.[7] Furthermore, rC3GN recurred as early as 9 days, as shown in [Table 1].[3],[6],[7],[8],[9],[10],[11],[12] This phenomenon of early recurrence and rapid loss of allograft function as compared to the slow progression of the disease in the native kidney is not specific for rC3GN and applicable to many renal diseases including focal segmental glomerulosclerosis, membranous nephropathy and MPGN.[13]
Table 1. Reports of post-transplant recurrent complement factor 3 glomerulopathy.

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C3GN disease is classified under the umbrella of the disorders caused by AP alteration. The peri transplant factors that affect the AP need to be explored in order to understand the mechanism behind the accelerated course of rC3GN. Abnormal control of the AP may be acquired or genetic in nature [Figure 3]. Examples of genetic causes include gain of function mutations in genes that encode activators proteins of the AP and loss of function mutations in genes that encode regulators of the AP.[14] The prototype activating proteins of the AP are C3 and complement factor B. Two plasma proteins known as complement factor H (CFH) and complement factor I (CFI), together with the membrane-bound regulator CD46 (also termed as membrane cofactor protein, MCP) are the key inhibitory proteins of the AP.[2] Acquired causes of altered AP include antibodies that either block the action of natural regulatory proteins of the AP, such as; anti-complement factor H antibodies or directly stimulate activation of the alternative pathway such as C3 nephritic factor (C3NeF). C3NeF is an IgG autoantibody serum protein that directly stabilizes the C3 activating complex of the AP, thereby it prevents the normal inhibitory effect of CFH. C3NeF causes activation of plasma C3, despite normal levels of CFH. Considerable proportion of the reported cases of rC3GN expressed persistently positive serum for C3NeF.[4]
Figure 3. Pathogenesis of complement factor 3 glomerulopathy.

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Any inflammatory event that requires complement activation could provoke or aggravate a complement-mediated disease such as C3GN. The kidney is one of the organs which has been proved to be capable of production of local C3 and/or C4. Ischemia-reperfusion injury due to transplantation with the oxidative burst fate activates the complement cascade. Subsequently, C3 production is upregulated in the mesangial cells, endothelium, tubular epithelial cells, and glomerular parietal cells in the grafted kidney.[15] From this viewpoint, the transplant surgery itself could trigger C3GN. This could explain the risk of early recurrence of C3GN observed in the allograft which is amplified in the cadaveric graft because of longer cold ischemia time. The current case report shows a well-established MPGN morphology in association with acute cellular rejection. This might represent the eventual disease evolution and/or exacerbation of the complement activation triggered by the concurrent inflammatory process of rejection. Sethi et al raised the possibility of intra-renal hypertension and hyperfiltration in the solitary kidney as a triggering factor for complement deposition in the allograft and further activation of AP.[7]

Understanding the genetic background of AP alteration and the mechanism of acquired disorders with their subsequent influence on AP in each patient is required to develop the proper treatment of rC3GN or hopefully avoiding the disease recurrence. In the current literature, the mutational analysis is not available for all the reported rC3GN cases. Of those with available genetic data, some showed no identifiable genetic mutation, such as the case described by Servais et al,[3] while some showed mutation that explains the C3GN development. For instance, one of the two patients with rC3GN, described by Sethi et al was positive for serum C3NeFs and his genetic analysis revealed C3 risk allele (c. 463A>C, p.Lys155Gln) and CFHR3-1 gene deletion.[7] Heterozygous internal duplication in CFHR5 was identified in a British male patient of Cypriot ancestry with rC3GN described by Vernon et al.[11] Garg et al described a patient with rC3GN having familial AP abnormality. The patient’s genetic analysis revealed a pathogenic variant in the CFH gene (c.790^1G>A) inherited from the father. The product of this variant was a CFH protein with reduced AP controlling capability; additionally, a missense variant in exon 5 of CFI (c.719C>G, p.Ala240Gly) was inherited from the mother.[12]

Our patient had a heterogeneous variant of the ADAMTS13 gene, which is located on Chromosome 9q. It encodes a member of a family of proteins containing several distinct regions, including a metalloproteinase domain, a disintegrin-like domain, and a thrombospondin type 1 (TS) motif. The enzyme encoded by this gene specifically cleaves von Willebrand factor. Defects in this gene are associated with thrombotic thrombocytopenic purpura.[16] It has been known that variants detected in this patient were not reported in association with AP dysregulation. Moreover, the family members of this patient were not investigated for AP genetic abnormality.

Eculizumab is a recently proposed modality of treatment for rC3GN. It showed a successful outcome with aHUS and now started to be considered a novel therapy in rC3GN. It is a long-acting humanized monoclonal antibody targeted against complement factor 5 (C5). It inhibits the cleavage of C5 into C5a and C5b; thereby it prevents the development of the terminal complement system including the formation of serum membrane attack complex.[17] Treatment of rC3GN with eculizumab was carried out as a trial in a few of the reported cases with variable outcomes. Kaartinen reported about a patient who had a heterozygous aHUS risk haplotype in the MCP gene in addition to CFB and C3 genetic mutation; the patient showed early partial response followed by graft failure after being treated with eculizumab for six months.[9] On the other hand, in Garg et al study, the patient had a familial AP disorder and experienced a successful response when treated with eculizumab.[12] The regimen recommended for treatment of aHUS has been followed in both studies.[9],[12] The two patients described by Bomback showed clinical improvement when treated with eculizumab and also no adverse events. Pathologic variant MCP (c.475+1G.A) was also discovered in one of the patients.[8]

   Conclusion Top

This is a case report of a young patient suffering from C3GN; the patient received a living related kidney and showed an early recurrence of C3GN with a progressive course that resulted in the loss of his graft. This course was compatible with that of the majority of the reported rC3GN cases. The genetic background of the patient suffering from rC3GN plays a vital role in predicting disease recurrence. The long ischemia time, reperfusion injury, and concurrent rejection are considered potential cofactors that accelerate the C3GN recurrence and progression in the allograft. The rule of the described ADAMTS13 gene variant in rC3GN has not been discovered yet and will be explored after the accumulation of more data. Treatment of rC3GN with eculizumab showed variable outcomes, and the use of this therapy as a standard modality of treatment in rC3GN requires further evidence and regimen specification.

Conflict of interest: None declared.

   References Top

Pickering MC, D'Agati VD, Nester CM, et al. C3 glomerulopathy: Consensus report. Kidney Int 2013;84:1079-89.  Back to cited text no. 1
Lachmann PJ. The amplification loop of the complement pathways. Adv Immunol 2009; 104:115-49.  Back to cited text no. 2
Servais A, Frémeaux-Bacchi V, Lequintrec M, et al. Primary glomerulonephritis with isolated C3 deposits: A new entity which shares common genetic risk factors with haemolyticurae-mic syndrome. J Med Genet 2007;44:193-9.  Back to cited text no. 3
Fakhouri F, Frémeaux-Bacchi V, Noël LH, Cook HT, Pickering MC. C3 glomerulopathy: A new classification. Nat Rev Nephrol 2010; 6:494-9.  Back to cited text no. 4
Bomback AS, Santoriello D, Avasare RS, et al. 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;93:977-85.  Back to cited text no. 5
Zand L, Lorenz EC, Cosio FG, et al. Clinical findings, pathology, and outcomes of C3GN after kidney transplantation. J Am Soc Nephrol 2014;25:1110-7.  Back to cited text no. 6
Sethi S, Fervenza FC, Zhang Y, et al. C3 glomerulonephritis: Clinicopathological findings, complement abnormalities, glomerular proteomic profile, treatment, and follow-up. Kidney Int 2012;82:465-73.  Back to cited text no. 7
Bomback AS, Smith RJ, Barile GR, et al. Eculizumab for dense deposit disease and C3 glomerulonephritis. Clin J Am Soc Nephrol 2012;7:748-56.  Back to cited text no. 8
Kaartinen K, Martola L, Räisänen-Sokolowski A, Meri S. Recurrent allograft C3 glomerulonephritis and unsuccessful eculizumab treatment. Clin Immunol 2018;187:104-6.  Back to cited text no. 9
Kakita H, Miyake T, Komiya T, Tsukamoto T, Muso E. A case report of recurrent C3 glomerulonephritis 18 months after renal transplantation. Ren Replace Ther 2016;2:38.  Back to cited text no. 10
Vernon KA, Gale DP, de Jorge EG, et al. Recurrence of complement factor H-related protein 5 nephropathy in a renal transplant. Am J Transplant 2011;11:152-5.  Back to cited text no. 11
Garg N, Zhang Y, Nicholson-Weller A, et al. C3 glomerulonephritis secondary to mutations in factors H and I: Rapid recurrence in deceased donor kidney transplant effectively treated with eculizumab. Nephrol Dial Transplant 2018;33:2260-5.  Back to cited text no. 12
Karakayali FY, Ozdemir H, Kivrakdal S, Co-lak T, Emiroglu R, Haberal M. Recurrent glomerular diseases after renal transplantation. Transplant Proc 2006;38:470-2.  Back to cited text no. 13
Montes T, Tortajada A, Morgan BP, Rodríguez de Córdoba S, Harris CL. Functional basis of protection against age-related macular degeneration conferred by a common polymorphism in complement factor B. Proc Natl Acad Sci U S A 2009;106:4366-71.  Back to cited text no. 14
Pratt JR, Basheer SA, Sacks SH. Local synthesis of complement component C3 regulates acute renal transplant rejection. Nat Med 2002; 8:582-7.  Back to cited text no. 15
Rogers HJ, Allen C, Lichtin AE. Thrombotic thrombocytopenic purpura: The role of ADAMTS13. Cleve Clin J Med 2016;83:597- 603.  Back to cited text no. 16
Dubois EA, Rissmann R, Cohen AF. Deno-sumab. Br J ClinPharmacol2011;71:804-6.  Back to cited text no. 17

Correspondence Address:
Reem A. Al Zahrani
Department of Pathology, Faculty of Medicine, King Abdulaziz University, P. O. Box 80205, Jeddah 21589, Saudi Arabia.
Saudi Arabia
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/1319-2442.352441

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  [Figure 1], [Figure 2], [Figure 3]

  [Table 1]


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