Our patient’s renal biopsy exhibited C3c-dominant deposition on immunofluorescence and though had weak staining for IgA. Complement alternative pathway was over-activated with normal plasma C4 levels and decreased plasma C3 levels. Thus, a definitive diagnosis of C3G was made. The electron microscopy further excluded the subtype of DDD, giving this patient a diagnosis of C3GN with an MPGN pattern.
The diagnosis of C3G depends on pathology, the evidence of abnormal activation of complement pathway, and the clinical characteristics of prolonged course and recurrent attack. The clinical manifestations of C3G are mainly characterized by proteinuria and / or hematuria of varying degrees, which are nonspecific. In most patients, serum complement C3 is decreased while complement C4 is normal, and the renal tissue immunofluorescence is mainly C3 deposition. These characteristics can help to exclude some diseases with similar clinical manifestations, such as IgA nephropathy, lupus nephritis, cryoglobulinemia and renal damage. The overall prognosis of C3G is poor. Due to the lack of large-scale observation on the long-term prognosis of C3GN patients, it has been reported that C3 glomerulonephritis progresses rapidly with poor prognosis. 36% − 50% of patients progress to end-stage renal disease within 10 years [3], The fluorescence intensity of C3 in pathology is inversely proportional to the prognosis of C3G [4]. Generally speaking, the prognosis of C3GN is better than that of DDD. The current clinical observation mainly comes from non MPGN type C3GN, whose short-term prognosis is good, but the long-term prognosis may be poor; the differences reported may be related to the region, race and different diagnostic criteria [5]. C3GN has multiple clinical and pathologic phenotypes. The varied therapeutic strategies and prognoses are attributed to the different pathogeneses. Thus, it is important to identify the precise causes after the diagnosis of C3GN in order to guide individualized treatment. we conducted gene screening tests for this patient. As a result, she was found to harbor multiple genetic changes, including common variants of C3 and CD46.
Variants in the C3 and CD46 genes were most frequently detected among the C3G patient. C3 plays a central role in the activation of classical and alternative complement activation pathways. It has been reported that C3 mutation can produce immune effect on inhibitory regulatory factors, and enhance disease activity in disguise[6, 7]. The protein encoded by CD46 is a type I membrane protein and is a regulatory part of the complement system. The encoded protein has cofactor activity for inactivation of complement components C3b and C4b by serum factor I, which protects the host cell from damage by complement. Mutant C3 showed a reduced binding to CD46 led to a decrease in proteolytic inactivation of C3b which may be a part of molecular mechanism of pathogenesis atypical hemolytic uremic syndrome (aHUS)[8, 9]. It has also been reported that CD46 enhances the internalization of Escherichia coli in urinary tract infection, making chronic urinary tract infection difficult to recover [10].
The therapy for the C3G is variable due to no randomized clinical trials for treatments, though some recommendations were made to follow but none has been proven effective and beneficial, mainly including glucocorticoid combined immunosuppressive agents (such as mycophenolate mofetil, tacrolimus, etc.)[11, 12]、biological agents (such as rituximab, ekuzumab) [13]、plasma infusion [14], and the development of new drugs (such as C3 invertase inhibitor cp40, recombinant human factor H, factor B inhibitor)[15–17]. It has been reported that factor B (FB) inhibitors shows a significant benefit for C3G in phase 2 clinical trials, phase 3 clinical trials are under way.
The clinical manifestations of this patient were persistent hematuria and moderate proteinuria which lasted for more than eight years, besides there was a long history of chronic urinary tract infection. Before hospitalization, she had a history of upper respiratory tract infection. Her renal function was in normal range and C3 was significantly decreased. Combined with clinical symptoms and laboratory indicators, we can not exclude Infection-related glomerulonephritis (IRGN). After hospitalization, urine culture showed gram-negative bacteria infection. At present, most IRGN was caused by gram-positive bacteria, and a few were caused by gram-negative bacteria [18]. One case reported a patient who is a 13-year-old female with Henoch-Schönlein purpura and similar symptoms -- a history of recurrent urinary tract infection – diagnosed glomerulonephritis after Campylobacter jejuni infection[19]。Unlike the 13-year-old female patient, our patient had no obvious gastrointestinal symptoms. Another case reported a 65-year-old patient with stable allograft function and Escherichia coli urosepsis. Renal biopsy finding revealed IgA-dominant postinfectious glomerulonephritis caused by Escherichia coli infection[20]. Our patient’s urine culture showed Escherichia coli infection too, but renal biopsy showed C3GN not IRGN.
In the process of clinical diagnosis and treatment, C3GN should be distinguished from IRGN, including streptococcal infection associated glomerulonephritis and staphylococcal infection associated glomerulonephritis, because it is very similar to C3GN in clinical manifestations, pathological morphology and complement activation form.
Streptococcal infection associated glomerulonephritis is more common in children with acute nephritis syndrome and decreased complement C3. The typical renal pathological manifestations can be seen as proliferative glomerulonephritis in capillaries under light microscope. Immunofluorescence often has bright C3 deposition with or without IgG deposition. Under electron microscopy, more "Hump" like substances can be seen in subepithelial deposition. The clinical course of glomerulonephritis after streptococcal infection is often self limiting. The level of complement C3 usually recovers naturally in 8–12 weeks, and the prognosis is good. A small number of patients can not recover, or even progress to the end stage. For those who got streptococcal infection, C3 glomerulopathy should be noted with persistent renal injury and continuous decrease of complement. It has been reported that glomerulonephritis can be transformed into C3 nephropathy after Streptococcus infection [21]
Staphylococcal infection associated glomerulonephritis is more common in middle-aged and elderly patients. Unlike post infection nephritis, Staphylococcus (common Staphylococcus aureus) infection associated glomerulonephritis and infection occur at the same time. Clinical manifestations include hematuria, varying degrees of proteinuria and renal dysfunction. Most of the patients were accompanied by hypocomplementation. The pathological manifestations of kidney were mainly C3 or co deposition with IgA or IgG in the kidney. Most of the patients showed capillary hyperplasia or exudative lesions under light microscope. With the removal of infection foci in most patients, renal disease was alleviated, but the prognosis of kidney disease was worse than that of Staphylococcal infection associated glomerulonephritis. The key to differentiate from C3G is that complement C3 in C3G often decreases continuously, while the decrease of C3 level in patients with staphylococcal infection associated glomerulonephritis is often temporary. With the control of infection and the improvement of disease condition, C3 level can return to normal [18, 22].
In this case, there is no direct evidence that C3GN is caused by infection, despite an interesting phenomenon that with the remission of urinary tract infection symptoms, complement C3 increased, but whether there is a direct relationship between chronic infection of Gram-negative bacteria and C3GN with a CD46 variation is still uncertain. The patient refused to use glucocorticoid and immunosuppressant, and was treated with ARB. The patient is under follow-up.