Proteinuria and Exposure to Eculizumab in Atypical Hemolytic Uremic Syndrome

Avest, Mendy Ter; Steenbreker, Hilbert; Bouwmeester, Romy N.; Duineveld, Caroline; Wijnsma, Kioa L.; Heuvel, L.P.W.J. van den; Langemeijer, Saskia; Wetzels, Jack F.M.; Kar, Nicole C. A. J. van de; Heine, Rob ter

doi:10.2215/cjn.0000000000000145

Cited by 4 publications

(4 citation statements)

References 31 publications

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“…Antibody‐based therapies have been attracting increasing attention as novel treatments, but there have been few reports of urinary leakage of high molecular weight protein after kidney transplantation or in the setting of renal disease, even in the field of allo transplantation . To the best of our knowledge, there has been one report of loss of eculizumab when proteinuria was present 19 . In that report, ter Avest et al 19 .…”

Section: Resultsmentioning

confidence: 96%

“…To the best of our knowledge, there has been one report of loss of eculizumab when proteinuria was present 19 . In that report, ter Avest et al 19 . drew attention to the fact that, when kidney function is good, mAbs are not filtered by the kidneys and not eliminated in the urine because of their large molecular size (approximately 150 kD for all IgG mAbs 20 ).…”

Section: Resultsmentioning

confidence: 99%

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Novel factors potentially initiating acute antibody‐mediated rejection in pig kidney xenografts despite an efficient immunosuppressive regimen

Kinoshita,

Maenaka,

Rosales

et al. 2024

Xenotransplantation

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Antibody‐mediated rejection (AMR) is a common cause of graft failure after pig‐to‐nonhuman primate organ transplantation, even when the graft is from a pig with multiple genetic modifications. The specific factors that initiate AMR are often uncertain. We report two cases of pig kidney transplantation into immunosuppressed baboons in which we identify novel factors associated with the initiation of AMR. In the first, membranous nephropathy was the initiating factor that was then associated with the apparent loss of the therapeutic anti‐CD154 monoclonal antibody in the urine when severe proteinuria was present. This observation suggests that proteinuria may be associated with the loss of any therapeutic monoclonal antibody, for example, anti‐CD154 or eculizumab, in the urine, resulting in xenograft rejection. In the second case, the sequence of events and histopathology tentatively suggested that pyelonephritis may have initiated acute‐onset AMR. The association of a urinary infection with graft rejection has been well‐documented in ABO‐incompatible kidney allotransplantation based on the expression of an antigen on the invading microorganism shared with the kidney graft, generating an immune response to the graft. To our knowledge, these potential initiating factors of AMR in pig xenografts have not been highlighted previously.

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Section: Resultsmentioning

confidence: 96%

Section: Resultsmentioning

confidence: 99%

Novel factors potentially initiating acute antibody‐mediated rejection in pig kidney xenografts despite an efficient immunosuppressive regimen

Kinoshita,

Maenaka,

Rosales

et al. 2024

Xenotransplantation

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show abstract

“…In addition, our ‘simple’ Michaelis–Menten model would be easy to reproduce and would require less computation time than complex TMDD models. While we assumed nonlinearity to result from target‐mediated elimination, it should be noted that a relapsing disease (explained by low eculizumab concentrations) may result in proteinuria and therefore kidney elimination of eculizumab 29–31 . We did not investigate the presence of eculizumab in the urine of our patients.…”

Section: Discussionmentioning

confidence: 97%

“…While we assumed nonlinearity to result from targetmediated elimination, it should be noted that a relapsing disease (explained by low eculizumab concentrations) may result in proteinuria and therefore kidney elimination of eculizumab. [29][30][31] We did not investigate the presence of eculizumab in the urine of our patients. A high intra-individual variability in eculizumab clearance has been described in another study 15 but adding inter-occasion variability for patients with longer follow-up did not improve our results and we only took into consideration changes in BW through time.…”

Section: Limitationsmentioning

confidence: 98%

Eculizumab dose tapering should take into account the nonlinearity of its pharmacokinetics

Le Tilly,

Gatault,

Semlali

et al. 2024

Brit J Clinical Pharma

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AimsEculizumab is a monoclonal antibody targeting complement protein C5 used in renal diseases. As recommended dosing regimen leads to unnecessarily high concentrations in some patients, tailored dosing therapeutic drug monitoring was proposed to reduce treatment cost. The objectives of the present work were (i) to investigate the target‐mediated elimination of eculizumab and (ii) whether a pharmacokinetic model integrating a nonlinear elimination allows a better prediction of eculizumab concentrations than a linear model.MethodsWe analysed 377 eculizumab serum concentrations from 44 patients treated for atypical haemolytic uraemic syndrome and C3 glomerulopathy with a population pharmacokinetic approach. Critical concentrations (below which a non‐log‐linear decline of concentration over time is evidenced) were computed to estimate the relevance of the target‐mediated elimination. Simulations of dosing regimens were then performed to predict probabilities of target attainment (i.e. trough >100 mg/L).ResultsPharmacokinetics of eculizumab was nonlinear and followed a mixture of first‐order (CL = 1.318 mL/day/kg) and Michaelis–Menten elimination (Vmax = 26.07 mg/day, Km = 24.06 mg/L). Volume of distribution (72.39 mL/kg) and clearance were weight‐dependent. Critical concentrations (Vmax/CL) ranged from 144.7 to 759.7 mg/L and were inversely related to body weight (P = .013). Nonlinearity was thus noticeable at therapeutic concentrations. Simulations predicted that 1200 mg of eculizumab every 21 days would allow 85% and 76% of patients to maintain a therapeutic exposure, for 50 or 90 kg body weight, respectively.ConclusionsOur study investigates the nonlinear elimination of eculizumab and discusses the importance of accounting for eculizumab target‐mediated elimination in therapeutic drug monitoring.

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Severe proteinuria (but not being on dialysis) may be associated with initial inadequate complement inhibition and delayed hematological response to eculizumab therapy

Allinovi,

Mazzierli,

Caroti

et al. 2023

J Nephrol

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Proteinuria and Exposure to Eculizumab in Atypical Hemolytic Uremic Syndrome

Abstract: Visual Abstract

Cited by 4 publications

References 31 publications

Novel factors potentially initiating acute antibody‐mediated rejection in pig kidney xenografts despite an efficient immunosuppressive regimen

Novel factors potentially initiating acute antibody‐mediated rejection in pig kidney xenografts despite an efficient immunosuppressive regimen

Eculizumab dose tapering should take into account the nonlinearity of its pharmacokinetics

Severe proteinuria (but not being on dialysis) may be associated with initial inadequate complement inhibition and delayed hematological response to eculizumab therapy

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