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Year : 2018  |  Volume : 1  |  Issue : 2  |  Page : 78-83

Eculizumab as treatment in dense deposit disease in children

1 Department of Paediatric Nephrology, King Fahad Medical City, Riyadh, Saudi Arabia
2 Department of Laboratory and Pathology, King Fahad Medical City, Riyadh, Saudi Arabia
3 Basic Sciences Department, Faculty of Medicine, King Fahad Medical City, Riyadh, Saudi Arabia

Date of Web Publication27-Dec-2018

Correspondence Address:
Dr Saeed M Alzabli
Pediatric Nephrology Section, Children Specialized Hospital, King Fahad Medical City, P. O. Box 59046, Riyadh 11525
Saudi Arabia
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/AJPN.AJPN_30_18

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Background: Dense deposit disease (DDD), a subtype of C3 glomerulopathy, is a rare disease that occurs secondary to hyperactivity of the alternative complement pathway. Renal biopsy typically reveals electron-dense deposits in the glomerular basement membrane. However, treatment options are limited. Till date, to the best of our knowledge, no evidence exists for specific treatment influencing the disease course. Eculizumab, a monoclonal antibody, has been reported to prevent membrane attack complex formation by binding to C5 and leads to improvement in clinical findings. However, the number of reported cases in which eculizumab was administered, particularly in children, is limited. Subjects and Methods: In this report, we present our experience with three pediatric cases of DDD receiving eculizumab treatment. All three patients were diagnosed with DDD on kidney biopsy. All patients showed acute kidney injury, high blood pressure, proteinuria >1 g/day, and decreased C3 levels. Immunosuppressive therapy, which included high-dose methylprednisolone, prednisolone, mycophenolate mofetil, or plasma exchange (in the third patient), as well as antihypertensive drugs, was administered to all the patients. Eculizumab treatment was initiated early in two patients but was initiated later in the third patient, who underwent dialysis initially. Results: The two patients with early initiation of eculizumab treatment showed significant improvement of proteinuria and renal function within weeks of treatment. C3 levels were normalized in one patient but remained decreased in the other. The third patient showed no response. She ultimately progressed to end-stage renal disease and eventually needed maintenance dialysis. Conclusions: Early initiation of eculizumab was associated with decreased proteinuria and improved renal function in two patients. These findings were in agreement with previous reports on the beneficial effects of eculizumab in DDD patients.

Keywords: C3 glomerulopathy, membranoproliferative glomerulonephritis, end-stage renal disease

How to cite this article:
Alzabli SM, Al Anazi A, Faqeehi HY, Ur Rahman MA, Suliman ME, Rahim KA. Eculizumab as treatment in dense deposit disease in children. Asian J Pediatr Nephrol 2018;1:78-83

How to cite this URL:
Alzabli SM, Al Anazi A, Faqeehi HY, Ur Rahman MA, Suliman ME, Rahim KA. Eculizumab as treatment in dense deposit disease in children. Asian J Pediatr Nephrol [serial online] 2018 [cited 2021 Sep 19];1:78-83. Available from: https://www.ajpn-online.org/text.asp?2018/1/2/78/248643

  Introduction Top

C3 glomerulopathy (C3G) is an extremely rare disease characterized by uncontrolled activation of the complement system, resulting in the glomerular deposition of C3 fragments. It is further subclassified by electron microscopy into dense deposit disease (DDD) and C3 glomerulonephritis (C3GN).[1],[2] C3G follows a chronic indolent course in most patients but can also present as rapidly progressive GN (RPGN).[3],[4],[5] The light microscopy findings of C3G are often diverse. Immunofluorescence (IF) shows dominant C3 staining and electron microscopy reveals dense osmiophilic intramembranous deposits (DDD) or less dense, amorphous mesangial, paramesangial, subendothelial, and subepithelial deposits (C3GN).[2],[6] End-stage renal disease typically occurs within 10 years of the diagnosis in 50% of patients, with younger patients being more prone; in addition, DDD may recur after kidney transplantation.[7]

Treatment strategies for DDD have included various immunosuppressive medications such as corticosteroids, calcineurin inhibitors, mycophenolate mofetil (MMF), and rituximab, but none of these herapie are shown to have major influence on disease course.[3],[7],[8] Eculizumab is a humanized monoclonal antibody that binds to C5 and prevents generation of the membrane attack complex (MAC), C5b–9. It is approved for the treatment of paroxysmal nocturnal hemoglobinuria (PNH) and atypical hemolytic uremic syndrome (aHUS).[9] Recent reports describe its utility through amelioration of the impact of alternate pathway of complement activation in patients with C3G in a few patients.[8],[10] This report presents our experience with use of eculizumab in patients who were diagnosed with DDD after presenting with severe nephritic or nephrotic syndrome and had failed to respond to immunosuppressive therapy.[10]

  Patients Top

Three patients (one boy and two girls), with age between 7 and 13 years, presented with decreased urine output, facial puffiness, and macroscopic hematuria, preceded by upper respiratory tract infection, abdominal pain, and vomiting. On admission, all three patients had renal impairment, hypertension, gross hematuria, and nephrotic range proteinuria. Patient 1 also developed cardiac tamponade two months after presentation, which resolved completely on pericardiocentesis. Patients 1 and 3 had positive antistreptolysin O titers. All three patients demonstrated low C3 and normal C4 levels [Table 1]. Patients 1 and 2 had high serum soluble C5b–C9 levels, whereas patient 3 presented with high C3 nephritic factor (C3NeF) levels and normal C5b–C9 levels [Table 1]. In patient 3, we infused rituximab at a dose of 375 mg/m2 of body surface area, with the aim of depleting the B-cell clones producing C3NeF. However, her condition deteriorated over time, necessitating plasma exchange for eight sessions. Later, she was started on dialysis and eventually became dialysis dependent.
Table 1: Laboratory findings of patients

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All patients underwent renal biopsy [Figure 1], with the severity of the findings varying considerably. Patient 1's biopsy findings were limited by few (4) glomeruli sampled, of which two glomeruli were crescentic. Biopsy in patient 2 showed global sclerosis in 8 of 21 glomeruli. Tubular atrophy and interstitial fibrosis were found in 15%–20% glomeruli in patients 2 and 3. Immunofluorescence showed marked C3 deposition in patient 3. Electron microscopic findings were typical for DDD, with varying amounts of deposition on the glomerular basement membrane. All patients received five doses of intravenous methylprednisolone pulse therapy (30 mg/kg) and mycophenolate mofetil (MMF, 600–1200 mg/m2). Patient 3 also received intravenous rituximab (375 mg/m2 of body surface area). For clinical deterioration, she also underwent plasma exchange for eight sessions. However, she eventually became dialysis dependent.
Figure 1: Examination of renal biopsy findings by electron microscopy shows dense deposit disease in patients 1, 2, and 3. There were diffuse linear dense deposits along the glomerular basement membrane (within the lamina densa) (panels 1–3) along with occasional irregular variable sized discrete nodular subendothelial deposits (panel 2)

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Following informed parental consent and meningococcal vaccination, therapy with eculizumab was initiated 3, 7, and 24 weeks after the presentation in patients 1, 2, and 3, respectively. Prednisolone, MMF, and antihypertensive medications were maintained at eculizumab therapy initiation. The response to therapy is summarized in [Table 2].
Table 2: Response to eculizumab

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Over follow-up periods of 68 and 51 weeks in patients 1 and 2, respectively, the levels of serum albumin normalized, creatinine decreased to 50 μmol/L, proteinuria decreased to below the nephrotic range (0.05 g/mmol) [Figure 2], and the blood pressure was controlled. C3 levels remained low in patient 1 despite improvement in renal function. Eculizumab treatment was continued in these two patients, albeit less frequently (once a month) and stopped in the third because of a lack of response [Figure 2]. Overall, eculizumab therapy was well tolerated, and no adverse events or infections were observed.
Figure 2: Effect of eculizumab therapy on serum and urine biochemistry in the three patients. Rena l function recovered and proteinuria declined in patients 1 and 3, despite persistently low complement C3 levels in patient 1. However, patient 3 showed progressive worsening of renal function leading to dialysis dependence

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  Discussion Top

This case series summarizes our experience of using eculizumab in patients with DDD. Two of the three patients showed marked improvement in serum creatinine and proteinuria, while the third patient demonstrated a decline in renal function during treatment and became dialysis dependent. All patients tolerated eculizumab therapy well.

DDD is caused by dysregulation of the alternate pathway (AP) of complement C3 convertase with subsequent glomerular deposition of C3 degradation products such as C3d) and/or C5 convertase (with subsequent production of the MAC).[11],[12],[13],[14] The complement dysregulation in DDD occurs in the fluid phase rather than on the endothelial surface, leading to release of C3 into the bloodstream and. eventually, deposition in the kidney.[3],[12] This dysregulation is usually induced by C3NeF, an autoantibody that stabilizes the AP C3 convertase.[15] Increased levels of circulating soluble C5b–9 and the presence of endocapillary or extracapillary proliferation, observed in the kidney biopsy, were correlated with the beneficial effects of eculizumab on DDD.[10],[16],[17]

Conservative management of DDD involves aggressive blood pressure control and proteinuria reduction.[18] Previous case reports and series have reported that immunosuppressive therapies such as glucocorticoids, cyclophosphamide, and calcineurin inhibitors have shown limited success in altering renal outcomes and do not specifically target the AP of complement.[19],[20] A combination of MMF and glucocorticoids was found to be effective in a retrospective cohort study of 60 patients with C3GN.[21] On the other hand, rituximab was found to be useful in patients who were positive for C3NeF and showed evidence of C3 consumption.[18]

While no drug has been shown to specifically inhibit the AP C3 convertase, blockade of the final common pathway using the clinically available anti-C5 antibody, eculizumab, has been suggested as a therapy for DDD. Although eculizumab has been approved to treat PNH or aHUS[9] there is limited evidence on its use in patients with DDD, particularly in children.[22],[23] Several case reports and case series have suggested that eculizumab may be beneficial in some patients with DDD, with either native or allograft refractory disease, although contradictory results have also been reported [Table 3]. Some of the patients demonstrated clinical improvements, while rebiopsy showed reduction of glomerular inflammation in others. The lack of controlled clinical trials examining the use of eculizumab in DDD patients[23] led Bomback et al.[10] to publish the first case series report of six patients treated with eculizumab, three of which were diagnosed with DDD. They reported that the responses varied from no effects to a partial or a transient effect. The first pediatric case series was published in 2015 by Oosterveld et al.,[8] who examined five patients and reported marked improvements in their proteinuria and renal function within 12 weeks of treatment. On the other hand, Berthe-Aucejo et al.[24] reported unsuccessful treatment of DDD using eculizumab, characterized by no apparent improvement in proteinuria and blood pressure after 3 months of treatment. Partial response to eculizumab was reported by Gurkan et al.[25] Recovery of renal function can occur after eculizumab therapy even in the presence of C3NeF-related disease, as described by Ozkaya et al.[26] Daina et al.[16] reported that eculizumab was effective in improving the condition of patients with elevated levels of C3NeF and soluble C5b–9.
Table 3: Reports of eculizumab use in dense deposit disease

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Beneficial responses to eculizumab have been reported even after dialysis initiation, as described by Rousset-Rouvière et al.,[27] who reported a rapid response in a patient with refractory DDD with positive C3NeF.[27] Rodriguez-Osorio and Ortiz reported renal function recovery in dialysis-dependent patients with C3G or aHUS when eculizumab was initiated after just 4 months of dialysis, which resulted in a recovery of renal function 2.0–3.5 months after initiation of eculizumab.[23] Hence, prolonged therapeutic trial of 3–6 months on eculizumab is required to evaluate treatment response. However, in our patients, the administration of eculizumab at an early stage was associated with a good result as observed in patients 1 and 2, in contrast to patient 3, who was administered eculizumab at a later stage. Moreover, eculizumab has also been used to treat DDD recurrence after renal transplantation.[28],[29] Vivarelli et al.[7] reported relapse of DDD following discontinuation of eculizumab and found that resuming therapy 6 months after discontinuation resulted in improvement of proteinuria.

Normalization of elevated soluble MAC levels can help predict the response to eculizumab and therefore can be used as a good marker for responsive to use.[10] According to this, we hypothesized that high soluble C5b–9 levels, as seen in patients 1 and 2, can help predict the response of patients with DDD to eculizumab. In contrast, patient 3 exhibited high C3NeF and normal soluble MAC. The presence of elevated soluble C5b–9 led us to use eculizumab, with the goal of preventing terminal complement pathway activity in patients 1 and 2. The renal biopsies were not correlated with the responses in patients 2 and 3 despite the presence of 38% and 10% global sclerosis, respectively.

The findings of this study suggest that eculizumab may be an appropriate treatment option for patients with DDD. To the best of our knowledge, this the among the few case series of eculizumab use for DDD among children. Additional research questions that need to be answered include the following: When is it too late to initiate treatment for a patient already on dialysis and showing no extrarenal symptoms? How long should therapy be continued in dialysis-dependent patients? It is also unclear what level of improvement of kidney function can be anticipated with eculizumab in patients who have been dialysis dependent for several weeks.

  Conclusions Top

There is increasing evidence to suggest that eculizumab may be beneficial for the treatment of some patients with DDD. The rarity of this disease makes it difficult for clinicians to establish evidence-based clinical practice for its management. Controlled studies are necessary to confirm our findings and to establish whether complement biomarker profiling and functional analysis of complement activity may guide the use of this complement blocking therapy.

Financial support and sponsorship


Conflicts of interest

There are no conflicts of interest.


WE are grateful for the support towards academic and training activities made available at the King Fahad Medical City.

  References Top

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  [Figure 1], [Figure 2]

  [Table 1], [Table 2], [Table 3]


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