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BACKGROUND: Guidelines advise eculizumab prophylaxis for most kidney transplant recipients with atypical hemolytic uremic syndrome (aHUS). However, recurrence rates may be overestimated, and starting eculizumab at relapse ("rescue therapy") may prevent graft loss. Randomized controlled trials have not compared the efficacy, safety, and costs of different treatment strategies. We performed a comparative study, including a previously described Dutch cohort treated with rescue therapy and a UK cohort using eculizumab prophylaxis. METHODS: In the Netherlands, we selected all adult patients with aHUS who received a kidney transplant between 2010 and 2021 in the Radboud University Medical Center (nâ =â 30) and enriched this cohort with 8 patients who received rescue therapy in other centers. The UK cohort included all adult patients with aHUS at moderate or high risk of recurrence, transplanted between 2013 and 2017 with prophylactic eculizumab. RESULTS: We included 38 Dutch patients and 35 UK patients. Characteristics were comparable, although the UK cohort included more patients with a complement factor H SCR20 mutation or hybrid gene (31% versus 5%; P < 0.01), and more Dutch patients received living donor kidneys (66% versus 20%; P < 0.001). Follow-up was comparable (the Dutch patients 70.8 mo, range, 10-134; UK patients 55.4 mo, range, 2-95). Eighteen (47%) Dutch patients received rescue therapy. Death-censored graft survival was not significantly different (the Dutch patients 1 y, 3 y, and 6 y: 97.4%, 91.2%, and 87.1%, respectively; UK patients 1 y, 3 y, and 6 y: 97.1%, 88.2%, and 65.6%, respectively, log-rank P = 0.189). CONCLUSIONS: In a population characterized by low prevalence of "very high risk" genes, who were predominantly transplanted using an endothelial protective regime, death-censored graft survival with eculizumab rescue therapy was not inferior to prophylaxis.
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Introduction: In 2014, a complement assay, which evaluates C5b-9 deposition on endothelial cells, was proposed as a biomarker for atypical hemolytic uremic syndrome (aHUS). Early diagnosis and/or prediction of aHUS (relapse) is pivotal in aHUS kidney transplant recipients who do not receive eculizumab prophylaxis. Methods: In this pilot study, serum samples of transplanted patients with aHUS in remission without eculizumab and patients with other primary kidney diseases (controls) were blinded and evaluated in the complement assay. Results: We included 13 patients with aHUS (4 males, 9 females) of median age of 54 years (range: 35-69) and median of 5.9 years (range: 0.25-14.1) after transplantation; and 13 controls (7 males, 6 females) of median age of 42 years (range: 27-60) and median of 5.8 years (range: 1.6-11.7) after transplantation. There were no significant differences in C5b-9 deposits between patients with aHUS and controls on resting cells (median of 136% [range: 93%-382%] and 121% [range: 75%-200%], respectively) and activated cells (median of 196% [range: 99%-388%] and 170% [range: 113%-260%], respectively). Three patients with aHUS and 4 controls showed elevated C5b-9 deposits on resting cells, which should correspond to active aHUS. None of these patients had laboratory signs of thrombotic microangiopathy (TMA). During follow-up (15.8 months, range: 6-21), estimated glomerular filtration rate remained stable in all. In 5 patients with aHUS with a genetic variant, no increase in C5b-9 deposits was found on activated endothelial cells, which contrasts with the literature suggesting that the test should identify carriers of a genetic variant. Conclusion: Our data question the routine use of the ex vivo complement assay in kidney transplant patients. Future studies should evaluate the test characteristics of assay in kidney transplant patients.
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Monoclonal gammopathy with cryoactivity (ie, cryoglobulins) that causes glomerulonephritis is considered within the spectrum of monoclonal gammopathy of renal significance. Cryofibrinogenemia (cryoactivity of coagulation factors) is very rarely associated with glomerulonephritis. We present a 39-year-old woman with a relapsing nephrotic syndrome. Laboratory investigation detected cryofibrinogen; the precipitate consisted of fibrinogen and a monoclonal immunoglobulin (M-protein; IgG-λ), and the latter was also detected in serum (4g/L). Initial conventional immunosuppressive therapy resulted in temporary renal remission. In view of the M-protein, subsequent therapy consisted of bortezomib/dexamethasone and high-dose melphalan followed by autologous hematopoietic stem cell transplantation, and resulted in a very good partial hematological response and temporary renal remission. However, after hematological and renal relapse, we performed unique experiments to clarify the role of the M-protein. Mixing patient serum with donor plasma resulted in cryoactivity, composed of M-protein+fibrinogen. Patient plasma deprived of M-protein did not have cryoactivity. Therefore, cryoactivity was dependent on the M-protein. We started lenalidomide, which resulted in very good partial hematological and renal remission. Thus, cryofibrinogenemia can be the consequence of an M-protein, which we suggest should be defined as monoclonal gammopathy of renal significance.
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Crioglobulinemia , Glomerulonefritis , Paraproteinemias , Vasculitis , Femenino , Humanos , Adulto , Paraproteinemias/complicaciones , Paraproteinemias/terapia , FibrinógenoRESUMEN
Introduction: Atypical hemolytic uremic syndrome (aHUS) is a rare kidney disease caused by dysregulation of the complement alternative pathway. The complement dysregulation specifically leads to damage to the glomerular endothelium. To further understand aHUS pathophysiology, we validated an ex vivo model for measuring complement deposition on both control and patient human glomerular microvascular endothelial cells (GMVECs). Methods: Endothelial cells were incubated with human test sera and stained with an anti-C5b-9 antibody to visualize and quantify complement depositions on the cells with immunofluorescence microscopy. Results: First, we showed that zymosan-activated sera resulted in increased endothelial C5b-9 depositions compared to normal human serum (NHS). The levels of C5b-9 depositions were similar between conditionally immortalized (ci)GMVECs and primary control GMVECs. The protocol with ciGMVECs was further validated and we additionally generated ciGMVECs from an aHUS patient. The increased C5b-9 deposition on control ciGMVECs by zymosan-activated serum could be dose-dependently inhibited by adding the C5 inhibitor eculizumab. Next, sera from five aHUS patients were tested on control ciGMVECs. Sera from acute disease phases of all patients showed increased endothelial C5b-9 deposition levels compared to NHS. The remission samples showed normalized C5b-9 depositions, whether remission was reached with or without complement blockage by eculizumab. We also monitored the glomerular endothelial complement deposition of an aHUS patient with a hybrid complement factor H (CFH)/CFH-related 1 gene during follow-up. This patient had already chronic kidney failure and an ongoing deterioration of kidney function despite absence of markers indicating an aHUS flare. Increased C5b-9 depositions on ciGMVECs were observed in all samples obtained throughout different diseases phases, except for the samples with eculizumab levels above target. We then tested the samples on the patient's own ciGMVECs. The C5b-9 deposition pattern was comparable and these aHUS patient ciGMVECs also responded similar to NHS as control ciGMVECs. Discussion: In conclusion, we demonstrate a robust and reliable model to adequately measure C5b-9-based complement deposition on human control and patient ciGMVECs. This model can be used to study the pathophysiological mechanisms of aHUS or other diseases associated with endothelial complement activation ex vivo.
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Síndrome Hemolítico Urémico Atípico , Complejo de Ataque a Membrana del Sistema Complemento , Humanos , Complejo de Ataque a Membrana del Sistema Complemento/metabolismo , Células Endoteliales/metabolismo , Zimosan/metabolismo , Activación de Complemento/genética , Síndrome Hemolítico Urémico Atípico/genética , Proteínas del Sistema Complemento/metabolismoRESUMEN
Membranous nephropathy (MN) is a pattern of injury caused by autoantibodies binding to specific target antigens, with accumulation of immune complexes along the subepithelial region of glomerular basement membranes. The past 20 years have brought revolutionary advances in the understanding of MN, particularly via the discovery of novel target antigens and their respective autoantibodies. These discoveries have challenged the traditional classification of MN into primary and secondary forms. At least 14 target antigens have been identified, accounting for 80%-90% of cases of MN. Many of the forms of MN associated with these novel MN target antigens have distinctive clinical and pathologic phenotypes. The Mayo Clinic consensus report on MN proposes a 2-step classification of MN. The first step, when possible, is identification of the target antigen, based on a multistep algorithm and using a combination of serology, staining of the kidney biopsy tissue by immunofluorescence or immunohistochemistry, and/or mass spectrometry methodology. The second step is the search for a potential underlying disease or associated condition, which is particularly relevant when knowledge of the target antigen is available to direct it. The meeting acknowledges that the resources and equipment required to perform the proposed testing may not be generally available. However, the meeting consensus was that the time has come to adopt an antigen-based classification of MN because this approach will allow for accurate and specific MN diagnosis, with significant implications for patient management and targeted treatment.
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Glomerulonefritis Membranosa , Humanos , Glomerulonefritis Membranosa/diagnóstico , Glomerulonefritis Membranosa/terapia , Consenso , Autoanticuerpos , Nefrectomía , Membrana Basal Glomerular/patología , Receptores de Fosfolipasa A2RESUMEN
Membranous nephropathy (MN) is a pattern of injury caused by autoantibodies binding to specific target antigens, with accumulation of immune complexes along the subepithelial region of glomerular basement membranes. The past 20 years have brought revolutionary advances in the understanding of MN, particularly via the discovery of novel target antigens and their respective autoantibodies. These discoveries have challenged the traditional classification of MN into primary and secondary forms. At least 14 target antigens have been identified, accounting for 80%-90% of cases of MN. Many of the forms of MN associated with these novel MN target antigens have distinctive clinical and pathologic phenotypes. The Mayo Clinic consensus report on MN proposes a 2-step classification of MN. The first step, when possible, is identification of the target antigen, based on a multistep algorithm and using a combination of serology, staining of the kidney biopsy tissue by immunofluorescence or immunohistochemistry, and/or mass spectrometry methodology. The second step is the search for a potential underlying disease or associated condition, which is particularly relevant when knowledge of the target antigen is available to direct it. The meeting acknowledges that the resources and equipment required to perform the proposed testing may not be generally available. However, the meeting consensus was that the time has come to adopt an antigen-based classification of MN because this approach will allow for accurate and specific MN diagnosis, with significant implications for patient management and targeted treatment.
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Glomerulonefritis Membranosa , Humanos , Glomerulonefritis Membranosa/diagnóstico , Glomerulonefritis Membranosa/terapia , Consenso , Autoanticuerpos , Nefrectomía , FenotipoRESUMEN
Glomerular filtration rate (GFR) decline is causally associated with kidney failure and is a candidate surrogate endpoint for clinical trials of chronic kidney disease (CKD) progression. Analyses across a diverse spectrum of interventions and populations is required for acceptance of GFR decline as an endpoint. In an analysis of individual participant data, for each of 66 studies (total of 186,312 participants), we estimated treatment effects on the total GFR slope, computed from baseline to 3 years, and chronic slope, starting at 3 months after randomization, and on the clinical endpoint (doubling of serum creatinine, GFR < 15 ml min-1 per 1.73 m2 or kidney failure with replacement therapy). We used a Bayesian mixed-effects meta-regression model to relate treatment effects on GFR slope with those on the clinical endpoint across all studies and by disease groups (diabetes, glomerular diseases, CKD or cardiovascular diseases). Treatment effects on the clinical endpoint were strongly associated with treatment effects on total slope (median coefficient of determination (R2) = 0.97 (95% Bayesian credible interval (BCI) 0.82-1.00)) and moderately associated with those on chronic slope (R2 = 0.55 (95% BCI 0.25-0.77)). There was no evidence of heterogeneity across disease. Our results support the use of total slope as a primary endpoint for clinical trials of CKD progression.
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Fallo Renal Crónico , Insuficiencia Renal Crónica , Humanos , Tasa de Filtración Glomerular , Teorema de Bayes , Progresión de la Enfermedad , BiomarcadoresRESUMEN
Introduction: Since 2016, kidney transplantation in patients with atypical hemolytic uremic syndrome (aHUS) in the Netherlands is performed without eculizumab prophylaxis. Eculizumab is given in case of posttransplant aHUS recurrence. Eculizumab therapy is monitored in the CUREiHUS study. Methods: All participating kidney transplant patients who received eculizumab therapy for a suspected posttransplant aHUS recurrence were evaluated. Overall recurrence rate was monitored prospectively at Radboud University Medical Center. Results: In the period from January 2016 until October 2020, we included 15 (12 females, 3 males; median age 42 years, range 24-66 years) patients with suspected aHUS recurrence after kidney transplantation in this study. The time interval to recurrence showed a bimodal distribution. Seven patients presented early after transplantation (median 3 months, range 0.3-8.8 months), with typical aHUS features: rapid loss of estimated glomerular filtration rate (eGFR) and laboratory signs of thrombotic microangiopathy (TMA). Eight patients presented late (median 46 months, range 18-69 months) after transplantation. Of these, only 3 patients had systemic TMA, whereas 5 patients presented with slowly deteriorating eGFR without systemic TMA. Treatment with eculizumab resulted in improvement or stabilization of eGFR in 14 patients. Eculizumab discontinuation was tried in 7 patients; however, it was successful only in 3. At the end of the follow-up (median 29 months, range 3-54 months after start of eculizumab), 6 patients had eGFR <30 ml/min per 1.73 m2. Graft loss had occurred in 3 of them. Overall, aHUS recurrence rate without eculizumab prophylaxis was 23%. Conclusions: Rescue treatment of posttransplant aHUS recurrence is effective; however, some patients suffer from irreversible loss of kidney function, likely caused by delayed diagnosis and treatment and/or too aggressive discontinuation of eculizumab. Physicians should be aware that recurrence of aHUS can present without evidence of systemic TMA.
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BACKGROUND: Eculizumab is a monoclonal antibody for the treatment of atypical hemolytic uremic syndrome (aHUS). Kidney damage, a common condition in patients with aHUS, may result in proteinuria. Because proteinuria may affect the pharmacokinetics of therapeutic proteins such as eculizumab, the aim of our study was to investigate the effect of proteinuria on eculizumab pharmacokinetics. METHODS: This study was an ancillary study of a previously performed pharmacokinetic-pharmacodynamic study of eculizumab in aHUS. Proteinuria, measured as urinary protein-creatinine ratios (UPCR), was investigated as covariate for eculizumab clearance. Thereafter, we evaluated the effect of proteinuria on the exposure to eculizumab in a simulation study for the initial phase and for a 2-weekly and 3-weekly interval in the maintenance phase. RESULTS: The addition of UPCR as a linear covariate on clearance to our base model resulted in a statistically improved fit ( P < 0.001) and reduction of unexplained variability in clearance. From our data, we predicted that in the initial phase, 16% of the adult patients with severe proteinuria (UPCR >3.1 g/g) will have inadequate complement inhibition (classical pathway activity >10%) on day 7 of treatment, compared with 3% of the adult patients without proteinuria. None of the pediatric patients will have inadequate complement inhibition at day 7 of treatment. For the 2- and 3-weekly dosing intervals, we predicted that, respectively, 18% and 49% of the adult patients and, respectively, 19% and 57% of the pediatric patients with persistent severe proteinuria will have inadequate complement inhibition, compared with, respectively, 2% and 13% of the adult patients and, respectively, 4% and 22% of the pediatric patients without proteinuria. CONCLUSIONS: Severe proteinuria is associated with a higher risk of underexposure to eculizumab. CLINICAL TRIAL REGISTRY NAME AND REGISTRATION NUMBER: CUREiHUS, Dutch Trial Register, NTR5988/NL5833.
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Síndrome Hemolítico Urémico Atípico , Adulto , Humanos , Niño , Síndrome Hemolítico Urémico Atípico/tratamiento farmacológico , Anticuerpos Monoclonales Humanizados/efectos adversos , Pruebas de Función Renal , Proteinuria/tratamiento farmacológico , Proteinuria/etiologíaRESUMEN
Rationale & Objective: Mono-allelic variants in COL4A3 and COL4A4 (COL4A3/COL4A4) have been identified in a spectrum of glomerular basement membrane nephropathies, including thin basement membrane nephropathy and autosomal dominant Alport syndrome. With the increasing use of next generation sequencing, mono-allelic COL4A3/COL4A4 variants are detected more frequently, but phenotypic heterogeneity impedes counseling. We aimed to investigate the phenotypic spectrum, kidney biopsy results, and segregation patterns of patients with mono-allelic COL4A3/COL4A4 variants identified by whole exome sequencing. Study Design: Case series. Setting & Participants: We evaluated clinical and pathologic characteristics of 17 Dutch index patients with mono-allelic variants in COL4A3/COL4A4 detected by diagnostic whole exome sequencing and 25 affected family members with variants confirmed by Sanger sequencing. Results: Eight different mono-allelic COL4A3/COL4A4 variants were identified across members of 11 families, comprising 7 glycine substituted missense variants and 1 frameshift variant. All index patients had microscopic hematuria at clinical presentation (median age 43 years) and 14 had (micro)albuminuria/proteinuria. All family members showed co-segregation of the variant with at least hematuria. At end of follow-up of all 42 individuals (median age 54 years), 16/42 patients had kidney function impairment, of whom 6 had kidney failure. Reports of kidney biopsies of 14 patients described thin basement membrane nephropathy, focal segmental glomerulosclerosis, minimal change lesions, and Alport syndrome. Electron microscopy images of 7 patients showed a significantly thinner glomerular basement membrane compared with images of patients with idiopathic focal segmental glomerulosclerosis and other hereditary glomerular diseases. No genotype-phenotype correlations could be established. Limitations: Retrospective design, ascertainment bias toward severe kidney phenotypes, and familial hematuria. Conclusions: This study confirms the wide phenotypic spectrum associated with mono-allelic COL4A3/COL4A4 variants, extending from isolated microscopic hematuria to kidney failure with high intra- and interfamilial variability.
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Introduction: A 6-month course of cyclophosphamide (CP) and steroids is effective in primary membranous nephropathy (MN), but unappealing because of long-term side effects. We evaluated efficacy of an "antibody-guided" treatment schedule. Methods: Patients with phospholipase A2 receptor (PLA2R)-related MN and high risk of progression were treated with CP 1.5 mg/kg/d and steroids in cycles of 8 weeks. Anti-PLA2R antibodies were measured by indirect immunofluorescence (IIFT) at 8, 16, and 24 weeks, and a negative test resulted in withdrawal of CP, and rapid tapering of prednisone. In patients with persistent anti-PLA2R antibodies at 24 weeks, CP was switched to mycophenolate mofetil. Treatment was repeated in patients with a relapse. Results: Our analysis included 65 patients (48 males, 17 females), age 61 ± 12 years, estimated glomerular filtration rate (eGFR) 46 ml/min per 1.73 m2 (35-68), urine protein-to-creatinine ratio 7.7 grams/10 mmol creatinine (5.4-11.1) and serum albumin 20 g/l (16-26). Immunologic remission rate was 71% after 8 weeks, 86% after 16 weeks, 88% after 24 weeks, and 94% after 3 years. Twenty-seven patients (42%) had persistent clinical remission after only 8 weeks of therapy. Sixteen patients needed a second course of therapy because of immunologic or clinical relapse. Follow-up was 37 (26-58) months. Overall partial remission rate was 92%. One patient developed end-stage kidney disease. Antibody-guided therapy (ABG) was as effective as the standard 6-month course, whereas providing a lower cumulative dose of CP (11.1 [8.0-18.5] vs. 18.9 [14.2-23.6] grams). Conclusion: ABG is effective, and allows individualized therapy, with many patients responding to 8 weeks of CP-based therapy.
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Introduction: The introduction of eculizumab has improved the outcome in patients with atypical hemolytic uremic syndrome (aHUS). The optimal treatment strategy is debated. Here, we report the results of the CUREiHUS study, a 4-year prospective, observational study monitoring unbiased eculizumab discontinuation in Dutch patients with aHUS after 3 months of therapy. Methods: All pediatric and adult patients with aHUS in native kidneys and a first-time eculizumab treatment were evaluated. In addition, an extensive cost-consequence analysis was conducted. Results: A total of 21 patients were included in the study from January 2016 to October 2020. In 17 patients (81%), a complement genetic variant or antibodies against factor H were identified. All patients showed full recovery of hematological thrombotic microangiopathy (TMA) parameters after the start of eculizumab. A renal response was noted in 18 patients. After a median treatment duration of 13.6 weeks (range 2.1-43.9), eculizumab was withdrawn in all patients. During follow-up (80.7 weeks [0.0-236.9]), relapses occurred in 4 patients. Median time to first relapse was 19.5 (14.3-53.6) weeks. Eculizumab was reinitiated within 24 hours in all relapsing patients. At last follow-up, there were no chronic sequelae, i.e., no clinically relevant increase in serum creatinine (sCr), proteinuria, and/or hypertension in relapsing patients. The low sample size and event rate did not allow to determine predictors of relapse. However, relapses only occurred in patients with a likely pathogenic variant. The cost-effectiveness analysis revealed that the total medical expenses of our population were only 30% of the fictive expenses that would have been made when patients received eculizumab every fortnight. Conclusion: It is safe and cost-effective to discontinue eculizumab after 3 months of therapy in patients with aHUS in native kidneys. Larger data registries are needed to determine factors associated with suboptimal kidney function recovery during eculizumab treatment, factors to predict relapses, and long-term outcomes of eculizumab discontinuation.
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Monoclonal gammopathy of renal significance (MGRS) defines disorders characterized by direct or indirect kidney injury caused by a monoclonal immunoglobulin produced by a B-cell or plasma-cell clone that does not meet current hematologic criteria for therapy. MGRS-associated kidney diseases are diverse and can result in the development of end-stage kidney disease. The current paradigm states that the underlying hematologic condition should be treated and in deep remission before kidney transplantation can be performed because recurrence has been reported for all MGRS-associated kidney diseases. However, we suggest that decisions regarding kidney transplantation in MGRS patients should be individualized considering many factors such as the subtype of MGRS-associated kidney disease, patient age and comorbidity, presence and risk of extrarenal complications, estimated waiting time, the availability of a living kidney donor, and previous hematological treatment and response. Thus, kidney transplantation should be considered even in treatment-naive patients, with hematological treatment initiated after successful kidney transplantation.
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Enfermedades Renales , Fallo Renal Crónico , Trasplante de Riñón , Gammopatía Monoclonal de Relevancia Indeterminada , Paraproteinemias , Humanos , Trasplante de Riñón/efectos adversos , Riñón , Paraproteinemias/complicaciones , Enfermedades Renales/etiología , Fallo Renal Crónico/diagnóstico , Fallo Renal Crónico/cirugía , Fallo Renal Crónico/complicaciones , Gammopatía Monoclonal de Relevancia Indeterminada/complicacionesRESUMEN
BACKGROUND: Eculizumab is a lifesaving yet expensive drug for atypical haemolytic uraemic syndrome (aHUS). Current guidelines advise a fixed-dosing schedule, which can be suboptimal and inflexible in the individual patient. METHODS: We evaluated the pharmacokinetics (PK) and pharmacodynamics (PD) [classical pathway (CP) activity levels] of eculizumab in 48 patients, consisting of 849 time-concentration data and 569 CP activity levels. PK-PD modelling was performed with non-linear mixed-effects modelling. The final model was used to develop improved dosing strategies. RESULTS: A PK model with parallel linear and non-linear elimination rates best described the data with the parameter estimates clearance 0.163 L/day, volume of distribution 6.42 L, maximal rate 29.6 mg/day and concentration for 50% of maximum rate 37.9 mg/L. The PK-PD relation between eculizumab concentration and CP activity was described using an inhibitory Emax model with the parameter estimates baseline 101%, maximal inhibitory effect 95.9%, concentration for 50% inhibition 22.0 mg/L and Hill coefficient 5.42. A weight-based loading dose, followed by PK-guided dosing was found to improve treatment. On day 7, we predict 99.95% of the patients to reach the efficacy target (CP activity <10%), compared with 94.75% with standard dosing. Comparable efficacy was predicted during the maintenance phase, while the dosing interval could be prolonged in â¼33% of the population by means of individualized dosing. With a fixed-dose 4-week dosing interval to allow for holidays, treatment costs will increase by 7.1% and we predict 91% of the patients will reach the efficacy target. CONCLUSIONS: A patient-friendly individualized dosing strategy of eculizumab has the potential to improve treatment response at reduced costs.
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Síndrome Hemolítico Urémico Atípico , Humanos , Síndrome Hemolítico Urémico Atípico/tratamiento farmacológico , Análisis Costo-Beneficio , Anticuerpos Monoclonales Humanizados/uso terapéuticoRESUMEN
Introduction: COVID-19 vaccination has been associated with rare but severe complications characterized by thrombosis and thrombocytopenia. Methods and Results: Here we present three patients who developed de novo or relapse atypical hemolytic uremic syndrome (aHUS) in native kidneys, a median of 3 days (range 2-15) after mRNA-based (Pfizer/BioNTech's, BNT162b2) or adenoviral (AstraZeneca, ChAdOx1 nCoV-19) COVID-19 vaccination. All three patients presented with evident hematological signs of TMA and AKI, and other aHUS triggering or explanatory events were absent. After eculizumab treatment, kidney function fully recovered in 2/3 patients. In addition, we describe two patients with dubious aHUS relapse after COVID-19 vaccination. To assess the risks of vaccination, we retrospectively evaluated 29 aHUS patients (n=8 with native kidneys) without complement-inhibitory treatment, who received a total of 73 COVID-19 vaccinations. None developed aHUS relapse after vaccination. Conclusion: In conclusion, aHUS should be included in the differential diagnosis of patients with vaccine-induced thrombocytopenia, especially if co-occuring with mechanical hemolytic anemia (MAHA) and acute kidney injury (AKI). Still, the overall risk is limited and we clearly advise continuation of COVID-19 vaccination in patients with a previous episode of aHUS, yet conditional upon clear patient instruction on how to recognize symptoms of recurrence. At last, we suggest monitoring serum creatinine (sCr), proteinuria, MAHA parameters, and blood pressure days after vaccination.
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Lesión Renal Aguda , Anemia Hemolítica , Síndrome Hemolítico Urémico Atípico , Vacunas contra la COVID-19 , COVID-19 , Humanos , Lesión Renal Aguda/inducido químicamente , Síndrome Hemolítico Urémico Atípico/etiología , Síndrome Hemolítico Urémico Atípico/terapia , Vacuna BNT162 , ChAdOx1 nCoV-19 , COVID-19/prevención & control , COVID-19/complicaciones , Vacunas contra la COVID-19/efectos adversos , Recurrencia , Estudios Retrospectivos , Vacunación/efectos adversosRESUMEN
INTRODUCTION: C3 glomerulopathy (C3G) is a rare, progressive kidney disease resulting from dysregulation of the alternative pathway (AP) of complement. Biomarkers at baseline were investigated in patients with C3G who participated in two phase 2 studies with the factor D (FD) inhibitor, danicopan. METHODS: Patients with biopsy-confirmed C3G, proteinuria ≥500 mg/day, and estimated glomerular filtration rate (eGFR) ≥30 mL/min/1.73 m2 were enrolled into two studies (NCT03369236 and NCT03459443). Biomarker analysis was performed for patients with C3G confirmed by central pathology laboratory re-evaluation. Complement and clinical biomarkers, biopsy composite score, and activity and chronicity indices were assessed at baseline and analyzed by pairwise Spearman correlation analysis. RESULTS: Twenty-nine patients were included in the analysis (median [interquartile range] age: 24.0 [10.0] years). Systemic complement AP activation was evident by reduced median concentrations of C3 and C5, elevated sC5b-9, and normal C4, relative to reference ranges. C3 showed strong pairwise correlations with C5 and sC5b-9 (r = 0.80 and -0.73, respectively; p < 0.0001). Baseline Ba and FD concentrations were inversely correlated with eGFR (r = -0.83 and -0.87, respectively; p < 0.0001). Urinary concentrations of sC5b-9 were correlated with both plasma sC5b-9 and proteinuria (r = 0.69 and r = 0.83, respectively; p < 0.0001). Biopsy activity indices correlated strongly with biomarkers of systemic AP activation, including C3 (r = -0.76, p < 0.0001), whereas chronicity indices aligned more closely with eGFR (r = -0.57, p = 0.0021). CONCLUSION: Associations among complement biomarkers, kidney function, and kidney histology may add to the current understanding of C3G and assist with the characterization of patients with this heterogenous disease.