Anti CFH-associated HUS: do we still need Plasma Exchange?

doi:10.21203/rs.3.rs-3730218/v1

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Anti CFH-associated HUS: do we still need Plasma Exchange?

https://doi.org/10.21203/rs.3.rs-3730218/v1

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Background

Five to 50% of atypical hemolytic and uremic syndrome (aHUS) in children are caused by autoantibodies against complement Factor H (CFH). Given the acquired autoimmune nature of the disease, plasma exchange and various immunosuppressive treatments have been used. More recently, eculizumab has been proposed.

Methods

In this multicenter, retrospective study, we report the outcome of 12 children with anti-CFH antibody-associated HUS treated with eculizumab associated with various immunosuppressive regimens.

Results

Patients were treated with eculizumab for 15.5 [9.5;23.0] months and 3 received plasma exchange (PE) or IgG adsorption. Three patients received MMF alone, 1 patient received an association of MMF and steroids, 1 patient received an association of MMF and rituximab, 3 patients received MMF/steroids and rituximab and 4 patients did not receive any immunosuppression. Anti-CFH ab levels significantly decreased but no difference was observed based on the immunosuppressive regimen. ECZ was discontinued in 7/10 patients after 11 [7.5–15.5] months and MMF in 6/8 patients after 36 [35;40] months. Anti-CFH titers at MMF discontinuation ranged from 257 to 3425 UI/L. None of these patients relapsed and eGFR at last follow-up was above 70mL/min/1.73m² in all patients.

Conclusion

Eculizumab is effective and safe in inducing and maintaining remission in aHUS secondary to anti-CFH antibodies and renders anti-CFH titers reduction less urgent. Anti-CFH antibody titers decreased in most patients irrespective of the immunosuppressive treatment chosen, so that a strategy consisting of associating eculizumab with MMF monotherapy seems sufficient at least in non-Indian or less severe forms of anti-CFH antibody-associated HUS.

Atypical Hemolytic Uremic Syndrome (aHUS) is defined by the association of hemolytic anemia, thrombocytopenia and renal impairment and is usually related to a dysregulation of the alternative complement pathway. Unlike typical HUS triggered by a shigatoxin-releasing germ or other types of infection, aHUS is rare and accounts for only 5–10% of childhood HUS (1, 2). While the majority of aHUS are caused by genetic mutations in genes coding for alternative complement pathway, endothelial protection or coagulation proteins, around 6 to 10% of aHUS in patients of Caucasian ancestry and up to 50% of pediatric patients of Indian ancestry are caused by the development of auto-antibodies against Factor H (3). Factor H is a soluble protein able to accelerate the decay of the alternative pathway C3 convertase (C3bBb) and is a cofactor for factor I-mediated cleavage and inactivation of C3b. Anti-factor H antibodies can be found either isolated often associated with homozygous mutations in genes encoding for FH-related proteins 1–3 or in a context of other auto-immunity (e.g: systemic lupus erythematosus) and are responsible for an acquired deficiency in factor H (4, 5).

Based on the auto-immune pathophysiology of anti-CFH antibody-associated HUS, several studies reported that plasma exchange (PE) and immunosuppression (cyclophosphamide (CYP), mycophenolate mofetil (MMF) or rituximab (RTX)) represent the main treatment strategies (6, 7). In a French national cohort, patients with anti-CFH antibody-associated HUS treated with PE, immunosuppressants and corticosteroids presented more favorable outcomes than most genetic aHUS (8). Another report of 138 Indian children confirmed that combined PE and immunosuppression (oral prednisolone with cyclophosphamide or rituximab) was associated with hematological remission and a significant reduction of the risk of chronic kidney disease or death (9).

Since 2009, the availability of anti-complement therapeutic agent, eculizumab, has dramatically changed the management of aHUS (10) and improved patient outcomes and is nowadays the treatment of reference in patients with genetic atypical HUS. Several studies reported the successful use of eculizumab in the treatment of anti-CFH antibody-associated HUS (11).

However, eculizumab can block the microthrombotic process but has no effect on the upstream mechanism of disease, while decreasing anti-CFH antibody is an important target of the treatment of patients with anti-CFH antibody-associated HUS since lower anti-CFH ab titers are associated with an increased probability of relapse-free survival (9). Immunosuppressive treatments (CYP, RTX or MMF) are associated with a significant decrease of anti-CFH antibody titers, while a spontaneous disappearance of anti-CFH antibodies is thought to be rare (3). Eculizumab is not expected to inhibit anti-CFH antibody production. Therefore, the association of eculizumab with immunosuppressive treatments seems a promising treatment option to decrease anti-CFH antibody production but few data are available to determine the optimal treatment protocol in these patients.

In this multicenter, retrospective study we report the outcome of 12 pediatric patients with anti-CFH antibody-associated HUS treated with eculizumab associated with various immunosuppressive regimens.

In this multicenter, retrospective study, we included 12 pediatric (< 18 years old) patients with anti-CFH antibody-associated HUS treated with eculizumab in 4 centers from Italy and France between 2011 and 2021. Two of these patients were previously reported (12). Inclusion criteria included 1/the diagnosis of HUS defined by the following criteria: acute hemolytic anemia, fragmented erythrocytes in a peripheral blood smear, thrombocytopenia (platelet count < 150 G/L) and renal involvement (defined by the presence of renal failure and/or the combination of proteinuria and hematuria) and 2/ an increased titer of anti-CFH antibodies measured by ELISA according to each center’s reference lab.

Clinical data were collected from the patients’ medical reports and included demographic and clinical data at the time of disease onset, hematological parameters, kidney function parameters, immunological parameters (complement C3 and C4, factor H, I and B serum levels and anti-CFH titers) and genetic testing. Detailed treatment history was recorded and follow-up data were collected at 1 month then every 3 months during the first year, every 6 months during the second year then at 3 years and at last follow-up. Hematological remission was defined by normalization of red blood cell and platelet counts and kidney complete remission was defined as a GFR > 90mL/min/1.73m² estimated by the Schwartz bedside formula based on height and serum creatinine. The study was approved by the ethics committee of Robert Debré hospital, APHP, France.

Patients description and initial presentation

We included 12 patients aged 5 months to 17 years, 8 girls and 5 boys. All patients presented hematological features of TMA with regenerative anemia (median 6.3 [5.9–8.8] g/dL), thrombocytopenia (median 45 [30.8–62.3] G/L) and fragmented erythrocytes in blood smear. At presentation all had renal impairment with proteinuria (median UPCR 0.24 [0.11;1.17] g/mmol) and acute kidney injury (median eGFR 20.3 [15.8–44.4]ml/min/1,73 m²). Two patients required dialysis. Five patients had decreased serum C3 levels at presentation with normal C4 levels. At disease onset, 7 (58%) and 3 (25%) patients had digestive signs and upper respiratory tract infection, respectively. Extrarenal manifestations were rare and included neurological and cardiac involvement in one patient, cytolysis in 3 patients and diabetes in one patient (Table 1).

Table 1

Patients characteristics at initial presentation
Clinical features	Patients’charateristics
Age (years, median [IQR])	5 [4;10]
Male sex (N, %)	8 (67%)
Infection at time of onset (N, %)	7 (58%)
Digestive prodrome (N, %)	7 (58%)
Spontaneous bleeding(N, %)	1 (8%)
Clinical presentation
Hypertension (N, %)	7 (58%)
Dialysis (N, %)	2 (16%)
Extrarenal manifestations
Seizures (N, %)	1 (8%)
Pancreatitis (N, %)	0 (0%)
Diabetes (N, %)	1 (8%)
Hepatitis (N, %)	3 (25%)
Cardiac involvement (N, %)	1 (8%)
Biological features
Urine Protein/creatinine ratio (g/mmol, median [IQR])	0.24 [0.11;1.17]
eGFR (mL/min/1.73m², median [IQR])	20.3 [15.8;44.4]
Serum albumin (g/L, median [IQR])	30.5 [25.0; 39.9]
Hemoglobin (g/dL, median [IQR])	6.3 [5.9–8.8]
Platelets (G/L, median [IQR])	45 000 [30 800;62 300]
LDH (UI/L, median [IQR])	2496 [1801;4423]
C3 (g/L, median [IQR])	0.6 [0.5;0.8]
C4(g/L, median [IQR])	0.2 [0.2;0.3]

In France, the median anti-factor H antibody level at diagnosis was 25217 UA/mL [2007–50,000] (positivity threshold: >100 UA/mL) and in Italy 1015 UA/mL [386–2000] (positivity threshold: >127 UA/mL). All but one patient had a genetic testing and a homozygous deletion for CFHR1-CFHR3 was found in 10 patients. One of these patients also had a variant of unknown significance on the CFH gene. One patient had a homozygous deletion for CFHR1 and a heterozygous deletion for CFHR3-CFHR4.

Treatments and outcomes

Induction treatment consisted in Eculizumab according to weight-based dosing in 10/12 patients (83%). Three patients received plasma exchange or IgG adsorption, two combined with eculizumab. Median time from disease onset to eculizumab initiation was 6 [3;12] days. Median duration of eculizumab treatment was 15.5 [9.5;23.0] months, three patients were still treated with eculizumab at the last follow-up. One patient did not receive eculizumab or PE.

Immunosuppressive treatment consisted in steroids in 4 patients, MMF in 8 patients and RTX in 4. Overall, 3 patients received MMF alone, 1 patient received an association of MMF and steroids, 1 patient received an association of MMF and rituximab, 3 patients received MMF/steroids and rituximab and 4 patients did not receive any immunosuppression (Table 2, Supplemental Fig. 1).

Table 2

Patients treatments and outcomes
	Treatment	Time to hematologic remission (days)	Time to complete Renal remission (days)
Patient 1	IgGIA + ECZ + RTX + MMF	231	Not achieved
Patient 2	ECZ + MMF	57	68
Patient 3	PE + ECZ + RTX + MMF	172	17
Patient 4	ECZ	30	10
Patient 5	ECZ + RTX + MMF	112	1114
Patient 6	ECZ + MMF	38	5
Patient 7	ECZ + MMF	54	26
Patient 8	ECZ + RTX + MMF	55	15
Patient 9	ECZ + MMF	26	26
Patient 10	ECZ	24	14
Patient 11	None	92	92
Patient 12	PE	62	62

Figure 1 presents the hematological and renal evolution of the cohort. Median time from disease onset to hematological remission and eGFR normalization were 56 [34;102] days and 26 [14;80] days, respectively. Among patients treated with eculizumab, time from eculizumab initiation to hematological remission and eGFR normalization were 42 [28; 73] days and 14 [9;23] days, respectively. eGFR at last follow-up was above 90mL/min/1.73m² except for one patient with a eGFR of 77mL/min/1.73m² at last follow-up. Anti-CFH antibody serum levels decreased in all patients but one with a decrease of -54%, -58% and − 74% at 3, 9 and 12 months, respectively. No difference was observed in anti-CFH antibody titers decrease based on the immunosuppressive regimen and four patients without immunosuppressive treatment showed a spontaneous decrease in anti-CFH antibody titers (Fig. 2).

Treatment discontinuation

Median follow-up of the cohort was 49 [37;64] months. Eculizumab was discontinued in 7/10 patients after a median time of 11 [7.5–15.5] months and MMF in 6/8 patients after a median time of 36 [35;40] months. Anti-CFH titers at MMF discontinuation ranged from 257 to 3425 UI/L. None of these patients relapsed with a median follow-up since MMF discontinuation of 21 [17.5;38.5] months. No severe infectious complication requiring hospitalization was observed.

Our results suggest that eculizumab is effective and safe in inducing remission in aHUS secondary to anti-CFH antibodies. We also found that, unlike what was previously reported, anti-CFH antibody titers decreased in most patients irrespective of the immunosuppressive treatment chosen. Taken together, our results suggest that a strategy associating eculizumab with MMF monotherapy could be sufficient in some anti-CFH antibody-associated HUS and that PE may be avoided in most patients.

The experience of treating anti-CFH antibody-associated HUS with eculizumab remains scarce. Some patients with anti-CFH antibody-associated HUS were included in the trials demonstrating the efficacy of eculizumab in aHUS but were not independently analyzed (13). In 2014, Noone et al. reported the use of eculizumab in 2 PE-dependent anti-CFH antibody-associated HUS (11). More recently, Matrat et al. reported 3 pediatric patients successfully treated with eculizumab (12). Conversely, large cohorts of patients with anti-CFH antibody-associated HUS treated with plasma exchange have been published. Sinha et al. reported the outcome of 138 Indian children with anti-complement factor H antibody associated HUS including 105 treated with plasma exchange(9). PE was associated with a rapid decrease in anti-CFH antibodies titers and hematological remission was achieved at a mean time of 31.0 ± 22.0 days from onset, compared with median remission time of 42 [28; 73] days after eculizumab initiation in our cohort. Thirty-six patients (30%) were still on dialysis at 3 months in the Indian cohort compared to 119 (86%) at disease presentation. Our patients, of Caucasian or North African ancestry, presented with milder cases compared to those described in this Indian cohort, with only 2 patients requiring transient dialysis at presentation, withdrawn in both cases.

Previous reports in patients treated with PE found an association between high anti-CFH antibody titers at baseline and delay between diagnosis and PE initiation with poorer outcomes. In our patients, eculizumab was started early and, although the small size of the cohort precludes formal statistical analysis, high anti-CFH antibody titers were not associated with more severe presentation or worse outcomes. This observation suggests that terminal complement inhibition with eculizumab allows a complete resolution of the TMA process and renders anti-CFH titers reduction less urgent. Plasma exchange may therefore not be mandatory in all patients with anti-CFH antibody-associated HUS.

However, high anti-CFH antibody titers and increase in antibody titers is associated with a higher risk of relapse so that reduction of antibody titers remains a crucial aspect in the treatment of these patients. Various immunosuppressive protocols were reported including the association of steroids and cyclophosphamide(6), rituximab (14, 15) or MMF(7, 12). In the largest cohort published to date, Sinha et al. demonstrated that maintenance immunosuppression (including in this study steroids, cyclophosphamide, rituximab or MMF) was associated with a major reduction of the risk of relapse, however they did not report any difference between treatment groups(9). Moreover, in an important prospective study on relapse of aHUS following eculizumab withdrawal, Fakhouri et al. showed that patients with low anti-CFH titers had the lowest relapse risk (16). In our study, we did not observe differences in clinical outcomes or anti-CFH antibody titers decrease between treatment groups. Specifically, the addition of pulse steroids or rituximab to MMF did not result in a faster decline of antibody titers. In some patients, antibody titers decline spontaneously without any immunosuppressive treatment. Overall, treatment with MMF alone seems effective in decreasing anti-CFH antibody titers.

Another matter of debate is when to withdraw immunosuppression. Previous studies suggested that anti-CFH antibody titer greater than 2000 UA/mL was associated with increased risk of relapse and could therefore be used to decide when to withdraw immunosuppression. The main limitation to establishing a threshold is the variability of normal range of anti-CFH levels in different reference laboratories, which currently makes establishing a safe value impossible. In our study, 6 out of 8 patients treated with immunosuppressive drugs stopped immunosuppression and the median antibody titer at treatment discontinuation was 1550 [min 257;max 3425] UA/mL. Therefore, although treatment withdrawal should be attempted under careful clinical and biological monitoring, establishing a prudent threshold is challenging.

Our study has some limitations. First, our patients had less severe presentations and fewer extra-renal complications at disease onset than reported in the literature, reflecting the non-Indian population included in this study. Indeed only 16% required dialysis in the acute phase, only 8% patient presented with neurological and cardiac involvement, 8% patient with diabetes and 25% patients with liver involvement. In the literature, dialysis in the acute phase is reported in 33 to 86% of cases of atypical HUS, 16 to 25% of patients would present neurologic involvement, 7 to 25% pancreatitis and 6 to 62.5% hepatitis depending on the study. Therefore, our results may not be generalizable in patients with severe presentation and plasma exchange could be offered in these patients especially when a catheter for hemodialysis is in place. Finally, the small number of patients in our cohort precluded formal statistical comparisons.

Conflict of interest:

ALL received travel grants from Alexion and honararia from Alexion, JH received travel grants from Alexion.

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FiguresAntiCFH.png
Supplemental Figure 1: Description of individual patients’ treatments over 24 months

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You are reading this latest preprint version

Anti CFH-associated HUS: do we still need Plasma Exchange?

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Version 1

Abstract

Background

Methods

Results

Conclusion

Figures

INTRODUCTION

METHODS

RESULTS

Patients description and initial presentation

Treatments and outcomes

Treatment discontinuation

DISCUSSION

CONCLUSION

Declarations

Conflict of interest:

References

Supplementary Files

Status:

Version 1