Iptacopan treatment for recurrent dense deposit disease after kidney transplant: A case report

Abstract

C3 glomerulopathies, including dense deposit disease, are rare kidney disorders caused by dysregulation of the alternative complement pathway. Recurrence after kidney transplantation is common and can threaten graft survival. Iptacopan, an oral factor B inhibitor, was recently Food and Drug Administration-approved as the first targeted therapy for C3 glomerulopathies. We describe a 19-year-old woman with childhood-onset dense deposit disease who progressed to kidney failure and underwent deceased donor transplantation. Post-transplant, she experienced delayed graft function and persistently low serum C3. A biopsy on day 7 revealed C3-only deposits, indicating early recurrent disease. Iptacopan was initiated at 200 mg twice daily. Her serum C3 normalized within 1 week and remained stable over 6 months. Proteinuria decreased significantly, and renal function improved and stabilized. This case highlights the potential of iptacopan as a disease-specific therapy for post-transplant C3 glomerulopathies recurrence, reinforcing its clinical utility and mirroring outcomes from the APPEAR-C3G trial.

Introduction

C3 glomerulopathies (C3G), including dense deposit disease (DDD) and C3 glomerulonephritis (C3GN), are rare kidney diseases marked by complement dysregulation in both the fluid phase and the glomerular microenvironment. This dysregulation results in the significant deposition of complement C3 in the kidneys. The pathophysiology of both DDD and C3GN is attributed to dysregulated activation of the alternative complement pathway. The clinical presentation of these diseases can vary and may include proteinuria, hematuria, hypertension, or renal failure.^1,2

The lack of a clear understanding of the natural progression of C3G contributes to the current treatment gap. Consequently, no specific treatment has been established for the different forms of C3G. Current therapies focus on inhibiting complement pathway activation using medications such as corticosteroids, antiproliferative drugs (cyclophosphamide, mycophenolate mofetil (MMF)), monoclonal antibodies (rituximab), or complement inhibitors (eculizumab). ³

More than half of kidney transplant recipients experience a recurrence of the disease, which significantly impacts graft survival. Risk factors such as delayed graft function, infection, and monoclonal gammopathy increase the likelihood of recurrence. Standard treatments like corticosteroids and MMF are already used chronically in transplant recipients, emphasizing the need for additional therapies. ⁴ Several studies are currently underway to explore the use of anti-complement drugs for C3G in kidney transplant patients, with encouraging results. ⁴ Iptacopan, a proximal complement inhibitor that targets factor B to inhibit the alternative complement pathway, has shown a clinically significant reduction in proteinuria after 6 months of treatment in the APPEAR-C3G Phase 3 trial, with effects lasting up to 12 months.^5,6

Case presentation

We present the case of a 19-year-old female with a past medical history of DDD diagnosed at the age of 6. The patient’s treatment history included high-dose steroids, tacrolimus, and MMF for the management of her kidney disease. Despite these interventions, the patient eventually experienced kidney failure and was initiated on peritoneal dialysis (PD) at the age of 13.

The patient underwent deceased donor kidney transplantation on January 31, 2024, 5 years following the initiation of PD. Her post-transplantation course was complicated by delayed graft function, prompting the need for two sessions of hemodialysis. Her induction therapy consisted of anti-thymocyte globulin at a dose of 6 mg/kg, tacrolimus, MMF, and corticosteroids. On postoperative day 7, her serum creatinine was 6.4 mg/dL with an estimated glomerular filtration rate (eGFR) of 9 mL/min/1.73 m² and no significant improvement since transplantation; she remained oligoanuric. The urine protein-to-creatinine ratio (UPCR) had improved from 8 g/g immediately post-transplant to 2.1 g/g at the time of evaluation, and blood pressure averaged 120–130/70–80 mmHg. Her serum C3 (sC3) levels remained persistently low (5–7 mg/dL). In this clinical context, the decision to perform a kidney biopsy was based not solely on the low complement levels but on a combination of factors: delayed graft function, persistent hypocomplementemia, and the need to exclude acute rejection or early disease recurrence.

The biopsy, performed on February 7, 2024, revealed diffuse acute tubular injury (ATN) with C3-only deposits (+2), without C4d or C1q deposits, and was negative for acute rejection (Figures 1–3). There were no cultural or financial barriers that limited access to diagnostic evaluation or management throughout the patient’s care.

Figure 1.

Light microscopy showing a glomerulus without hypercellularity or mesangial expansion. Capillary loops are open and of normal thickness, without double-contour formation or basement membrane duplication. No endocapillary proliferation, segmental sclerosis, or crescents are identified. Arrows indicate patent, open capillary lumina. H&E, original magnification ×100.

H&E: hematoxylin and eosin.

Figure 2.

Immunofluorescence for C3 demonstrating bright, granular staining (2+) along the glomerular capillary loops and within the mesangium. This C3-dominant deposition pattern, in the absence of significant immunoglobulin staining, is characteristic of C3 glomerulopathy and supports the diagnosis of early recurrent dense deposit disease. Original magnification ×200.

Figure 3.

Transmission electron microscopy showing segmental, ribbon-like, osmiophilic intramembranous deposits (arrows) within the lamina densa of the glomerular basement membrane. These deposits are pathognomonic for dense deposit disease.

In light of these findings, which were consistent with recurrent DDD, the patient was initiated on treatment with iptacopan, 200 mg twice daily. One week later, her sC3 normalized to 92 mg/dL and remained stable throughout a 6-month follow-up period. Two months later, her UPCR decreased to <0.2 mg/mg and remained stable over the same period. By 3 months, her kidney function had improved, with creatinine levels ranging between 0.9 and 1.1 mg/dL and an eGFR between 74.4 and 90 mL/min/1.73 m², both of which remained stable over the subsequent 6 months. Table 1 demonstrates the trend in serum creatinine, C3 level, and UPCR following treatment with iptacopan.

Table 1.

Serum creatinine, C3, and urine protein-to-creatinine ratio trends pre- and post-treatment with iptacopan.

Time point	Serum C3 (mg/dL)	Serum creatinine (mg/dL)	Urine protein–creatinine ratio (mg/mg)
1 week prior to iptacopan	9	2.6	1.57
1 week after starting	92	2.4	0.91
1 month after starting	96	1.5	0.31
2 months after starting	92	1.3	0.15
3 months after starting	94	1.0	0.1
6 months after starting	106	1.0	0.11
Reference range	90–180	0.4–1.0	< 0.2 mg/mg

The patient demonstrated good adherence to iptacopan therapy and tolerated the medication well, with no major side effects reported. Adherence and tolerability were assessed through clinical follow-up and laboratory monitoring, including kidney function, complement levels, and UPCR, measured at 2-month intervals. No adverse or unanticipated events occurred following initiation of iptacopan.

Discussion

C3G is a relatively new pathological classification, initially defined by the presence of C3 accumulation in the glomeruli, accompanied by minimal or no immunoglobulin deposition. C3G primarily includes two main subtypes: DDD and C3GN.^2,7

C3G is driven by abnormal activation of the alternative complement pathway, which may result from either acquired or genetic alterations. In acquired cases, this dysfunction is frequently associated with C3 nephritic factors, which are autoantibodies that stabilize the C3 convertase enzyme, leading to prolonged complement activation. Genetic mutations in complement-related genes are less commonly implicated. While dysregulation of the alternative pathway is central to disease development, abnormalities in the terminal complement pathway are also frequently observed. Both DDD and C3GN can occur across all age groups. However, DDD is more often diagnosed in children, while C3GN typically presents in older individuals.^1,2 Commonly, patients present with proteinuria, microscopic hematuria, and mild kidney dysfunction. ⁸

More than 50% of kidney transplant recipients experience disease recurrence, which adversely affects graft survival. In C3G, the risk of recurrence after transplantation is heightened by factors such as delayed graft function, infections, and the presence of monoclonal gammopathy. ⁴

Several challenges contribute to the lack of a clearly defined, optimal therapy for C3G. The disease is rare and often affects children, which limits the feasibility of conducting large-scale randomized controlled trials. In addition, diagnostic tests for identifying genetic variants, complement activity, and complement-targeting autoantibodies are expensive and primarily confined to research settings. Lastly, the heterogeneity of C3G across clinical, pathological, and molecular levels further complicates the interpretation and comparison of findings, making the development of standardized treatment strategies complicated. ⁹

The current treatment approach for C3G consists of supportive care for patients with mild disease and immunosuppressive therapy, typically MMF combined with glucocorticoids, for those with moderate to severe manifestations (characterized by proteinuria >0.5–1 g/day and declining renal function). However, these nonspecific approaches have shown limited efficacy. Complement inhibition is emerging as a more promising therapeutic strategy. ⁹

In this case, iptacopan (LNP023), an oral proximal complement inhibitor targeting factor B, was selected over other available complement inhibitors, such as eculizumab, because of its direct action on the primary pathogenic mechanism of C3G – including DDD – which is driven by dysregulation of the alternative complement pathway and persistent activation of C3 convertase. By inhibiting factor B, iptacopan prevents the formation and stabilization of the alternative pathway C3 convertase (C3bBb), thereby reducing C3 cleavage, stabilizing sC3 levels, and limiting glomerular C3 deposition. ¹⁰ In contrast, eculizumab, a terminal complement inhibitor that blocks C5 activation, does not directly inhibit upstream C3 convertase activity, allowing continued C3 consumption and deposition – central features of C3G pathogenesis. ¹¹ Clinical responses to eculizumab in C3G have been variable and inconsistent. ¹²

Patient-specific factors also supported the choice of iptacopan. The patient had attempted to enroll in an iptacopan clinical trial at another academic center but was ineligible due to logistical constraints related to geographic distance and her minor status at the time. Given the early post-transplant recurrence of DDD with biopsy-proven C3-only deposition and persistently low sC3, there was a critical need for timely, targeted therapy. Access and affordability were addressed through the REMS program in collaboration with Novartis (FABHALTA), allowing the medication to be provided at a cost of $4/month. Although evidence in transplant recipients remains limited, the APPEAR-C3G Phase 3 trial demonstrated efficacy and safety in native kidney C3G, and published case reports suggest potential benefit in transplant settings. Our team further weighed iptacopan’s favorable safety profile, oral administration, and mechanistic appropriateness in targeting alternative pathway dysregulation, which collectively supported its selection in this clinical context.

The APPEAR-C3G trial (NCT04817618), a multicenter, randomized, double-blind, placebo-controlled Phase 3 study, assessed the efficacy, safety, and tolerability of iptacopan in adults with biopsy-confirmed native C3G. At 12 months, iptacopan demonstrated a significant and sustained reduction in proteinuria in addition to supportive care, with clinically meaningful benefits observed as early as 6 months. The treatment was well tolerated, with a favorable safety profile and no new safety concerns identified, underscoring its potential as a promising therapeutic option for patients with C3G. ⁶ Consequently, iptacopan is currently the first and only treatment approved by the Food and Drug Administration (FDA) for C3G (Supplemental Material).

This case highlights the clinical challenges and therapeutic opportunities in managing C3G, particularly DDD, a subtype frequently seen in the pediatric population. Our patient, a 19-year-old female with a long-standing history of DDD leading to kidney failure and subsequent transplantation, exemplifies the high risk of disease recurrence post-transplant, especially in the setting of delayed graft function. The pretreatment biopsy revealed C3-only deposits without evidence of rejection, consistent with early recurrent disease, as well as diffuse ATN. We believe that partial recovery of kidney function may have been attributable to the natural resolution of ATN, while the persistence of low sC3 and proteinuria indicated concurrent complement-mediated injury. The initiation of iptacopan during this dynamic period of graft recovery may have contributed to the rapid normalization of sC3 levels, substantial reduction in proteinuria, and stabilization of kidney function observed within weeks – earlier than typically reported in clinical studies, where benefits are often seen over 3–6 months. This accelerated improvement plausibly reflects the combined effects of ATN recovery and targeted complement inhibition. Over a 6-month follow-up, the patient’s clinical trajectory remained favorable, aligning with outcomes observed in the pivotal APPEAR-C3G Phase 3 trial. With iptacopan now approved by the U.S. FDA as the first treatment for C3G, this case supports its clinical utility in managing recurrent disease following kidney transplantation, offering new hope for improving graft outcomes in this challenging patient population.

A key strength of this case is its demonstration of the real-world application of iptacopan in a kidney transplant recipient with early recurrent DDD, showing biochemical and clinical stabilization consistent with outcomes reported in recent clinical trials. This observation adds to the limited clinical evidence on iptacopan use in transplant settings and underscores its potential therapeutic role. However, as a single-patient report, the findings are inherently limited in generalizability and cannot establish causality. The favorable response observed in this young adult without significant comorbidities may not be applicable to older recipients or those with complex medical histories. Furthermore, there remains a paucity of published data on iptacopan use in kidney transplant recipients, particularly among younger adults, limiting extrapolation across diverse patient populations. Finally, the follow-up period was restricted to 6 months. Although the patient demonstrated biochemical and clinical improvement during this time, the long-term durability of remission and implications for graft survival remain uncertain, highlighting the need for extended follow-up in future studies.

Conclusion

In summary, C3G represent a rare and challenging group of kidney diseases with limited treatment options, particularly in the post-transplant setting where recurrence is common and detrimental to graft survival. This case demonstrates the successful use of iptacopan in achieving disease control in a transplant recipient with recurrent DDD. The patient’s rapid biochemical and clinical improvement underscores the therapeutic potential of complement pathway modulation and highlights iptacopan’s role as a promising, disease-specific treatment for patients with C3G.

Patient perspective

I was diagnosed with DDD during childhood and underwent multiple treatments over the years, including immunosuppressive medications and dialysis. After receiving a kidney transplant, I experienced a recurrence of the disease, which was identified early through a biopsy and lab work.

My physicians recommended starting iptacopan, a newly available medication that targets the complement system. At first, I was nervous because I had never heard of it and was not sure what to expect. However, they explained how it works, and I felt more confident knowing that it specifically targets the part of the immune system involved in my disease. Starting a new medication after transplant was a big change, but I was committed to making it work. I also had regular check-ins with my transplant team, which helped me stay on track and feel supported.

One thing that helped me was that the medication was oral and easy to take. I did not experience any major side effects, which was a relief. I did worry at first about whether it would be affordable, but my doctors helped me enroll in a program that made it very accessible.