Late Recurrence of C3 Glomerulopathy After SARS-CoV-2 Infection in a Long-Term Kidney Transplant Recipient: A Case Report

Introduction

Kidney transplantation is the optimal treatment for end stage kidney disease, improving patient quality of life and reducing mortality risk [1,2]. Over the last few decades, the long-term survival of kidney allografts has significantly increased [3,4]. Nevertheless, the recurrence of renal disease is the second main cause of graft loss after rejection [5]. C3 glomerulopathy (C3GN) is a rare disease, characterized by an abnormal activation of the alternative pathway of complement that leads to the accumulation of C3 complement component in the glomeruli. Before the Consensus Statement of 2012, C3 glomerulopathy was usually diagnosed as membranoproliferative glomerulonephritis type II [6], which included dense deposit disease and C3GN. C3GN can be caused by genetic mutations (complement factors or proteins associated with complement factors mutations) or autoantibodies (anti-FH, anti-FB, C3Nef, anti-C3 antibodies) [7]. C3Nef can be identified in 40% to 60% of patients with C3GN, but it is a non-specific serologic marker. Clinical manifestations of C3GN are various, and frequently patients present proteinuria, microhematuria, impaired kidney function, and elevated blood pressure. C3GN treatment in native kidney is based on mycophenolate mofetil and corticosteroids. However, there are no guidelines on the treatment of C3GN recurrence on the graft, and currently, new anti-complement drugs are being tested, including eculizumab, iptacopan, and avacopan [8–12].

C3GN recurs in 70% of kidney allograft during the first years after transplantation, leading to graft loss [13]. Since C3GN can be preceded by an infection, a differential diagnosis with post-infectious glomerulonephritis, showing a different prognosis and allograft recurrence, is deemed necessary [14]. Generally, an incomplete recovery of kidney function associated with persistence of low serum C3 can be considered a sign of C3GN [15,16]. During the Covid-19 pandemic, the outcome of kidney transplant patients worsened because of long-lasting immunosuppressive therapy. Although SARS-CoV-2 infection causes severe acute respiratory syndrome, based on ACE 2 receptor expression [17], it can affect other organs, including the kidneys, causing direct and indirect damage [18], and also lead to complement activation [19].

Several studies have compared the outcomes of kidney transplant recipients with SARS-CoV-2 infection with outcomes of kidney transplant recipients without SARS-CoV-2 infection and SARS-CoV-2-positive patients who were non-kidney transplant recipients. The data in the literature show that hospitalized SARS-CoV-2-positive kidney transplant recipients have an increased risk of mortality and hospital complications, including ventilation and acute kidney injury [20].

Case Report

A 50-year-old woman presented with worsening of renal function 28 years after transplantation. In 1994, she received a living-donor kidney (mother) for end-stage kidney disease due to acute post-infectious glomerulonephritis. She received double maintenance therapy, which initially included oral cyclosporine and steroids. In May 2000, cyclosporine was replaced with tacrolimus, and mycophenolate mofetil was introduced. Renal function remained stable over the years. She had an history of breast lumps and post-transplant recurrent urinary tract infections. In 2018, a basal cell carcinoma was removed from her left leg.

During the previous 2 years, she had received a diagnosis of SARS-CoV-2 infection 2 times (in October 2020 and March 2022), with diagnosis via a molecular COVID test. At the time of the second infection, the patient was vaccinated for SARSCoV-2. In both cases, she was not hospitalized, and she discontinued immunosuppressive agents and received monoclonal antibodies in March 2022.

After the first infection, renal function progressively declined (serum creatinine levels 2.2 mg/dL), and proteinuria progressively increased (1.4 g/24 h in June 2021) (Figure 1). The graft dysfunction prompted us to perform a kidney transplant biopsy. It revealed chronic active antibody-mediated rejection and C3 glomerolupathy with significant C3 glomerular deposition (+++) with no IgG or IgA deposits (Figure 2). Additional examinations showed the presence of circulating donor-specific antibodies (DSA; A2 MFI 8196), a negative PCR for Epstein-Barr virus, BK virus, and cytomegalovirus in the circulation, and slightly reduced serum C3 levels of 80.9 ng/mL (reference range, 90–180 ng/mL). Immunosuppressive therapy was optimized by increasing the mycophenolate mofetil dosage and by adding prednisone. In April 2022, routine blood test results showed an improvement of kidney function (serum creatinine 1.8 mg/dL) but a further reduction of serum C3 values (73.5 ng/mL) and a worsening of proteinuria (1.99 g/24 h).

Based on the recent description of C3GN and the effect of SARS-CoV-2 on the kidneys, we revised the patients’ medical history in order to determine whether C3GN was a de novo diagnosis or a late recurrence in the graft.

The patients’ medical history began in 1982, at the age of 10 years, with bronchopneumonia, which was treated with antibiotic therapy. Two months later, she presented eyelid edema and had proteinuria. The first diagnosis on native kidney biopsy was a diffuse, extracapillary, subacute proliferative glomerulonephritis with a positive immunofluorescence for mesangial, parietal, subendothelial deposits of C3 and IgG. Electron microscopy was not available.

In 1988, because of moderate bilateral sensorineural deafness, Alport syndrome was suspected, and a second renal biopsy was performed. The diagnosis was chronic glomerulonephritis with nephroangiosclerosis. Immunofluorescence was positive for C3 (+++) and electron microscopy showed subepithelial deposits. Therefore, both biopsies were suggestive of C3GN. In both cases, the treatment was based on high doses of corticosteroids.

In May 2022, genetic tests were negative for complement abnormalities (C3, CFH, DGKE, CD46, CFI, CFB, ADAMTS13, THBD), and in June 2022, we observed a stable renal function, with slightly altered serum C3 levels (85.6 ng/mL), normal C4, absence of autoantibodies (ANA, ANCA, ENA) and normal immunoglobulins levels.

Given the stable graft function, we increased the dosage of immunosuppressive drugs but did not administer eculizumab or therapeutic plasma exchange.

After 6 months, in December 2022, a breast cancer was diagnosed (invasive carcinoma NST G2-B5b; ER <1%, PgR <1%, Ki67 30%, HER2 3+), surgically removed with a right lower quadrantectomy followed by radiotherapy and chemotherapy (paclitaxel, trastuzumab).

We then replaced mycophenolate with everolimus, which was eventually discontinued after 2 months. At the time of this report, the patient was having chemotherapy and her renal function was stable (serum creatinine 2.37 mg/dL, eGFR CKD EPI 2021 24 mL/min, proteinuria 728–1100 mg/24 h, C3c 93.2 mg/dL) after 3 years from the diagnosis of recurrent C3GN.

Discussion

We present the clinical case of a kidney transplant recipient whose renal function worsened after 28 years from transplantation concurrently with two SARS-CoV-2 infections. Allograft biopsy and blood sampling showed chronic rejection (immunofluorescence C4d+ and DSA+) and C3GN, with decreased C3 levels and glomerular C3 deposits in the absence of immunoglobulin deposition. Based on the recent diagnosis of C3GN and the similarities between acute post-infectious glomerulonephritis and C3 glomerulopathy [16], we reanalyzed native renal biopsies that showed the presence of prevalent C3 deposition. Genetic testing was negative and slowly C3 levels returned near normal levels, with stable renal function.

C3GN recurs in more than 50% of cases, generally with a slow progression [21] and during the first year after kidney transplantation. Several studies show that C3GN and SARS-CoV-2 infection can lead to a worsening of renal function, and that SARS-CoV-2 can lead to the reactivation of pre-existing glomerular diseases [6,19,22]. The association between C3GN recurrence and viral infections has been described, such as in cytomegalovirus infection [23]. To date, there are few studies that describe the association between SARS-CoV-2 infection and C3GN, either in native kidneys or in kidney grafts. Gambella et al described a clinical case of C3GN after SARSCoV-2 infection in a 15-year-old pediatric patient without risk factors [24]. Sometimes, SARS-CoV-2 infection can aggravate the patient’s disease. Dabeshgar et al analyzed a case of a young kidney transplant patient who developed, first, an early recurrence of C3GN at 7 months after transplantation, and then, acute cellular rejection. For C3GN, the patient received anti-complement treatment with iptacopan, and steroids for rejection treatment. Then, he developed an asymptomatic SARS-CoV-2 infection, and the subsequent graft biopsy revealed worsening complement dysregulation and development of cryoglobulinemia, with histological diagnosis of “full-house” immune-complex mediated glomerulonephritis and a borderline acute T cells [25].

Indeed, SARS-CoV-2 infection can prime complement system activation through the alternative pathway, resulting in complement deposition, in particular C3, in different organs, including the lung and kidney [19]. In the present clinical case, the patient developed two SARS-CoV-2 infections, the second in March 2022 after vaccination. In March 2022, the most widespread SARS-CoV-2 variant was Omicron (99.86%). The Omicron variant was characterized by less virulence and less replication than the past variants. Furthermore, it has a different cell entry pathway, and this affects the tissue sites preferred for viral replication. These differences can affect the clinical manifestations and infection severity [26].

During both SARS-CoV-2 infections, immunosuppressive therapy was interrupted and only steroids were administered. Obviously, the immunosuppression reduction may have been a risk factor for the development of rejection. COVID-19 Treatment Guidelines do not give specific indications on how to treat solid organ transplant recipients and suggest to treat them as non-transplant patients. Antiviral drugs are recommended, with attention needed to drugs interaction (ritonavir-boosted nirmatrelvir and tacrolimus). Guidelines do not give indications about the immunosuppressive drugs, leaving this decision to clinicians based on the individual clinical case (NIH, Transplants-COVID-19 Treatment Guidelines).

Furthermore, C3GN can reduce graft survival in patients with transplant glomerolupathy, an important complication of kidney transplantation [27]. In 2019, Panzer et al demonstrated that patients with transplant glomerolupathy and glomerular C3 deposition show a higher risk of allograft failure than do patients with transplant glomerolupathy and no C3 deposition, suggesting that complement activation and C3 deposition are independent risk factors [28]. Despite the high recurrence of C3GN and the impact on graft survival, there is no evidence on how to treat the disease in kidney transplant recipients. Currently, the most commonly used therapy for the treatment of C3GN recurrence is mycophenolate mofetil and corticosteroids. Several studies investigated the potential use of eculizumab and other drugs, such as rituximab, or therapeutic plasma exchange [8,29,30].

Conclusions

In conclusion, based on current evidence and on our data, including negative genetic testing and the association of the SARS-CoV-2 infection with the worsening of renal function, it is possible that the C3GN in our case could have been a recurrence disease caused by the activation of the complement alternative pathway induced by SARS-CoV-2 infection. Furthermore, the worsening of renal function may have been related both to C3GN and to the development of humoral rejection, due to the cessation of immunosuppression during SARS-CoV-2 infection.