2026 年 72 巻 2 号 p. 171-176
C3 glomerulopathy (C3G) is a type of complement-associated glomerulopathy caused by a defect in the alternative complement pathway and is regarded as a rare disease. We report a 14-year-old boy with C3G and Sjögren’s syndrome (SS) whose school urinary screening revealed abnormalities, but the diagnosis was delayed because he refused to consult a medical institution. Histopathological examination revealed histologic features of membranoproliferative glomerulonephritis. He was diagnosed with C3G and Sjögren’s syndrome based on proteinuria, the histopathological findings, high levels of antibodies against SS-A, and lymphocytic infiltration around the salivary glands. He was treated with combination therapy, consisting of methylprednisolone pulse, prednisolone, and mycophenolate mofetil. At 3 months after treatment, urinary protein excretion was decreased and hematuria had disappeared, and improvement in hypocomplementemia and the levels of antibodies against SS-A were observed. The course of our case suggests that the management of patients with C3G should take into consideration the possibility of the coexistence of SS, and that those with positive findings on school urine screening should be encouraged to visit a medical institution.
C3 glomerulopathy (C3G) is a disease caused by autoantibodies or genetic abnormalities in regulators of the alternative pathway, and is characterized by the predominant deposition of C3 in the glomeruli1-9). In 2007, Servais et al. coined the term C3G to describe the group of Membranoproliferative Glomerulonephritis (MPGN) types I and III in which only C3 is deposited due to impaired control of the alternative complement pathway1). This includes Dense Deposit Disease (DDD), which exhibits an MPGN II morphology, as well as C3 glomerulonephritis (C3GN), which mainly exhibits MPGN I and MPGN III morphologies3,4). The cause of the disease in more than half of cases is the formation of autoantibodies against C3 nephritic factor (C3NeF), Factor H, and Factor B, which continuously activate C3. Further, it has also been revealed that other causes include various genetic mutations that lead to dysfunction of the alternative complement pathway4-6).
On the other hand, Sjogren’s syndrome (SS) is a systemic autoimmune disease that causes inflammation around the ducts and acini of the salivary and lacrimal glands10-13). SS is known to be accompanied by a variety of organ lesions apart from those affecting the salivary and lacrimal glands, one of which is renal damage12,13). Although the incidence of renal dysfunction in SS overall is low, there have been occasional reports of interstitial nephritis, glomerular nephritis including MPGN, and mesangial proliferative nephritis14,15). Here, we report a rare case of a 14-year-old boy with C3G diagnosed by school urine screening and complicated by SS, and discuss our patient together with a literature review.
At 12 and again at 13 years old, urinary protein was detected by school urine screening and further examination was recommended, but he did not visit a medical institution and left it untreated. Subsequently, at the age of 14, school urine screening again revealed a urinary protein level of 4+, and the patient visited a local doctor. The patient was referred to our department for further examination and treatment.
He weighed 53 kg and was 161 cm in height. His systolic and diastolic blood pressures were 126 and 66 mmHg, respectively. Physical examination found no swelling of the salivary glands, normal respiratory and cardiac sounds, a flat and soft abdomen, no palpable hepatosplenomegaly, and there was no pretibial or eyelid edema. Chest X-ray findings showed no abnormalities. Laboratory investigations on admission revealed a leukocyte count of 4,700/mm3, erythrocyte count of 554×104/mm3, platelet count of 18.9×104/mm3, serum total protein of 7.1 g/dl, serum albumin of 3.5 g/dl, serum creatinine of 0.60 mg/dl, uric acid of 4.7 mg/dl, and serum total cholesterol of 223 mg/dl. Urinalysis revealed a protein concentration of 624 mg/ml, with sediment containing 10-19 erythrocytes and 5-9 leukocytes per high-power field. Urinalysis revealed urine protein/creatinine of 3.83. The estimated glomerular filtration rate (e-GFR) was 116.1 ml/min per 1.73 m2. Immunological studies revealed C3 at 16 mg/dl (normal range 65-135), C4 at 32 mg/dl (13-35), and CH50 <12 CH50/ml (30-45). The antinuclear antibody titer was <160 X, the anti-DNA antibody level was 10 IU/ml, the serum titer for antibody against SS-A was 52.0 U/ml, and the serum titer for antibody against SS-B was < 0.5 U/ml, while the serum titers for myeloperoxidase (MPO)-ANCA and serine proteinase 3 (PR3)-ANCA were negative. The anti-Smith (anti-Sm) antibody level was <0.5 U/ml, and the anti-U1-ribonucleoprotein (RNP) antibody level was 0.5 U/ml. Prothrombin time and activated partial thromboplastin time were both normal.
On day 2 of hospitalization, a renal biopsy was performed (Figure 1, Figure 2). Light microscopy (LM) revealed 23 glomeruli, with three that were sclerotic and collapsed circumferentially, and one that had formed a fibrous crescent in one-third of the circumference. Diffuse and global moderate proliferation of mesangial cells and widespread expansion of the mesangial matrix were found in the other glomeruli (Figure 1-a). However, there was no degeneration or atrophy of the renal tubules. An immunofluorescence study revealed granular C3 deposition alone from the glomerular capillary wall to the mesangial region (Figure 1-b). Further, electron microscopy revealed that the electron-dense deposits were less well-defined and randomly distributed within the subepithelial, subendothelial, and intraglomerular membranous regions, resulting in the glomerular basement membrane showing an irregular thickness (Figure 2-a, b). The patient was diagnosed with C3G based on the decreased serum C3 and CH50 levels, predominant C3 deposition, and pathological findings of MPGN. Furthermore, a salivary gland biopsy was performed on day 6 of hospitalization, and severe lymphocytic infiltration was found around the salivary gland. Although there were no symptoms of dryness, the diagnosis of SS was made according to the Japanese diagnostic criteria16). The patient was treated with combination therapy, consisting of methylprednisolone (500 mg/day) for three consecutive days followed by daily prednisolone (40 mg/day), and mycophenolate mofetil (MMF, 500 mg/day). Methylprednisolone pulse therapy was also performed on day 14. Before treatment, urine protein/creatinine was 3.89, but one month after treatment, it decreased to about 1.1-1.3. Furthermore, the hypocomplementemia present at the time of admission improved, and the patient’s condition was monitored as an outpatient. The dose of prednisolone was gradually tapered, but there was no worsening of proteinuria or hematuria. Two years after the start of treatment, prednisolone could be tapered to 7.5 mg/day, the urinary protein/creatinine ratio remained at 0.1-0.2 and hematuria had disappeared.
Pathological findings of our patients.
a:Mild proliferation of mesangial cells and widespread expansion of the mesangial matrix are observed. Light Microscopy:PAS stain ×100
b:Immunofluorescence shows granular C3 deposition only from the glomerular capillary wall to the mesangial region. ×400
Electron microscopy findings of our patient.
a:Electron microscopy shows electron-dense deposits in the subendothelial lesions (single arrow). ×3,000
b:Electron microscopy shows electron-dense deposits in the subepithelial cell (single arrows) and irregular thickness of the glomerular basement membrane (double arrows). ×3,000
C3G is an extremely rare disease, with an incidence of approximately 0.2 to 2 cases per million people per year2-4). In the Japanese Society of Nephrology Registry, 0.2% of renal biopsy cases registered were C3G17,18). At our institution, 20 of 1,832 pediatric patients (1.1%) who underwent renal biopsy over 36 years from 1975 to 2011 had C3G8,9). In Japan, about 80% of cases of C3G in children are discovered through SUS8,9). According to our clinical epidemiological review of 18 patients with C3GN, 14 patients (77.8%) were discovered by school urinary screening9). Of the 18 patients, all 6 patients (100%) in the good prognosis group were discovered by school urinary screening, while 3 of the 4 patients in the ESRD group were discovered after presenting with nephrotic syndrome or acute nephritic syndrome, and one patient (25%) was discovered by school urinary screening. Although the number of patients is small, these results demonstrate that patients with C3GN detected early by school urinary screening have a better prognosis than those diagnosed after the onset of symptoms such as nephrotic syndrome and acute nephritic syndrome. In our case, proteinuria was detected in school urine screening at the age of 12 and again at 13, but the patient did not visit a medical institution. At the age of 14, proteinuria of 4+ was detected by school urine screening, and the patient was referred to our department. Renal biopsy findings showed widespread expansion of the mesangial matrix in the glomeruli, with fibrous crescents in 4.3% and sclerotic glomeruli in 13%, indicating severe chronic lesions and progression of sclerotic lesions. Our case fails to demonstrate the effectiveness of school urine screening aimed at early detection and treatment, but shows the need for early examination of findings detected by school urine screening and the importance of confirming the examination results.
Complications of C3G include acquired partial lipodystrophy, multiple subretinal white spots, and drusen; however, in our case, the patient also developed SS19,20). Regarding the association of C3G with autoimmune diseases, Alexander et al. mentioned the association between C3G and autoimmune diseases, and showed that of 80 patients with C3G, 10 patients had abnormal ANA titers, 6 had positive ds-DNA titers, 5 had mutations or diversity in C3G-related genes, and one had C3 nephritic factor. These results also suggest that an autoimmune agent may act as a trigger for the development of C3GN in genetically susceptible patients21). Furthermore, although the number of cases is not large, there have been occasional reports of the coexistence of SLE, RA, type 1 diabetes, and ANCA-associated vasculitis. However, there have been no reports of its coexistence with SS, and our case is the first to be reported22-25). In general, there have been a few reports of renal dysfunction in SS patients, but there have been occasional reports of interstitial nephritis, MPGN, mesangial proliferative nephritis, and other glomerular nephritis in 0.3% to 3.1% of patients10-13). To date, there have been no reports of the combination of C3G and SS; however, considering that C3G has been diagnosed as MPGN14,15), it is possible that C3G may have been involved in cases diagnosed as MPGN with SS.
Recently, a randomized controlled trial (RCT) was conducted to examine the efficacy of anticomplement drugs in the treatment of C3G. Iptacopan is an anticomplement agent that specifically inhibits the enzymatic activity of C3 convertase by binding to factors B and Bb. A placebo-controlled RCT of iptacopan showed a proteinuria-reducing effect in a small number of patients with C3G26). In Japan, the use of iptacopan for C3G was approved in 2025. Additionally, pegcetacoplan is currently undergoing clinical trials. Pegcetacoplan is a synthetic cyclic peptide that inhibits C3 activation by binding to C3. In a phase 2 open-label trial (DISCOVERY, NCT03453619), it was administered to seven patients with C3G and resulted in a reduction in proteinuria, an increase in serum albumin levels, an increase in serum C3 levels, and a decrease in membrane-attack complex (MAC) levels27). In the future, clinical trials are expected to be conducted to examine the long-term effectiveness of these anti-complement drugs in a larger number of pediatric patients. Other than complement inhibitors, there have been occasional reports on the effectiveness of Renin-angiotensin system (RAS) inhibitors, steroids, combination therapy with immunosuppressants, plasma exchange, eculizumab, kidney transplantation, and anticomplement drugs28-33).
Regarding combination therapy of steroids and immunosuppressants for C3G, Kawasaki et al. provided combination therapy including steroid pulse therapy, post-treatment prednisolone, and cyclophosphamide (CPA) for 18 children with C3G and retrospectively examined the therapeutic effects8,9). In terms of prognosis, 33% of patients were in the good prognosis group, with normal urinary findings or mild proteinuria, but 44% of patients had persistent active nephritis or decreased renal function, and 4 patients (22%) experienced renal death. In addition, Rabasco et al. compared the prognosis of 60 patients with C3G between those treated with only steroids, those treated with steroids and MMF, and those treated with steroids and CPA28). They found that renal death occurred in 35% of patients in the group treated with only steroids, but no renal death was observed in the group treated with steroids and MMF. In our case, we selected MMF as the immunosuppressant, which has been reported to have a high remission rate for C3G, and has maintained remission. In more than half of C3G patients, autoantibodies such as C3NeF have been implicated in the pathogenesis, and it has been reported that combination therapy with steroids and immunosuppressants is highly effective in treating these patients. On the other hand, patients with genetic causes have been shown to have lower remission rates34). In our case, the patient had an autoimmune disease (SS) and responded relatively well to treatment; therefore, although we were unable to measure C3NeF, we speculate that autoantibodies are likely involved in the onset mechanism.
Our patient refused workup for the abnormal urinalysis, which delayed initiation of treatment. The course of our case suggests that the management of C3G patients should take into consideration the possibility of SS, and that those with positive findings on school urine screening should be encouraged to visit a medical institution.
