Publications by authors named "Lambertus P W J van den Heuvel"

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.

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Podocytes play a central role in glomerular diseases such as (idiopathic) nephrotic syndrome (iNS). Glucocorticoids are the gold standard therapy for iNS. Nevertheless, frequent relapses are common.

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Article Synopsis
  • - The study focuses on how proteinuria (high levels of protein in urine) affects the pharmacokinetics of eculizumab, a treatment for atypical hemolytic uremic syndrome (aHUS), as kidney damage can lead to proteinuria.
  • - Researchers analyzed urine protein-creatinine ratios to see how they influenced the clearance of eculizumab, finding that higher proteinuria levels resulted in a statistically significant reduction in eculizumab effectiveness for some patients.
  • - Results indicated that adults with severe proteinuria were more likely to have inadequate response to eculizumab treatment compared to those without proteinuria, highlighting the need for careful monitoring and potential dose adjustments in these patients.
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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.

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Introduction: The recurrence of proteinuria after kidney transplantation in patients with focal segmental glomerulosclerosis (FSGS) is considered proof of the presence of circulating permeability factors (CPFs). The aim of this study is to demonstrate the presence of plasma CPFs using series of assays.

Methods: Podocytes and endothelial cells (glomerular microvascular endothelial cells [GMVECs]) were incubated with plasma from FSGS patients with presumed CPFs in relapse and remission and from steroid-resistant nephrotic syndrome (SRNS), steroid-sensitive nephrotic syndrome (SSNS), membranous nephropathy (MN), and healthy controls (hCtrls).

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Nephritic factors (NeFs) are autoantibodies promoting the activity of the central enzymes of the complement cascade, an important first line of defense of our innate immune system. NeFs stabilize the complement convertase complexes and prevent their natural and regulator-mediated decay. They are mostly associated with rare complement-mediated kidney disorders, in particular with C3 glomerulopathy and related diseases.

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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.

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The complement system is an important part of innate immunity. Complement activation leads to formation of convertase enzymes, switch of their specificity from C3 to C5 cleavage, and generation of lytic membrane attack complexes (C5b-9) on surfaces of pathogens. Most C5 cleavage occurs via the complement alternative pathway (AP).

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Background: C3 glomerulopathy (C3G) is a rare kidney disorder characterized by predominant glomerular depositions of complement C3. C3G can be subdivided into dense deposit disease (DDD) and C3 glomerulonephritis (C3GN). This study describes the long-term follow-up with extensive complement analysis of 29 Dutch children with C3G.

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The rare and heterogeneous kidney disorder C3 glomerulopathy (C3G) is characterized by dysregulation of the alternative pathway (AP) of the complement system. C3G is often associated with autoantibodies stabilizing the AP C3 convertase named C3 nephritic factors (C3NeF). The role of classical pathway (CP) convertase stabilization in C3G and related diseases such as immune complex-mediated membranoproliferative glomerulonephritis (IC-MPGN) remains largely unknown.

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Parietal epithelial cells (PECs) are epithelial cells in the kidney, surrounding Bowman's space. When activated, PECs increase in cell volume, proliferate, migrate to the glomerular tuft and excrete extracellular matrix. Activated PECs are crucially involved in the formation of sclerotic lesions, seen in focal segmental glomerulosclerosis (FSGS).

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Background: With the introduction of eculizumab, a C5-inhibitor, morbidity and mortality improved significantly for patients with atypical hemolytic uremic syndrome (aHUS). In view of the high costs, actual needs of the drug, and increasing evidence in literature, aHUS patients can be treated according to a restrictive eculizumab regimen. We retrospectively analyzed the pharmacokinetic and dynamic parameters of eculizumab in one patient in time, emphasizing various factors which could be taken into account during tapering of treatment.

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Hemolytic uremic syndrome (HUS) is a severe renal disease that is often preceded by infection with Shiga toxin (Stx)-producing (STEC). The exact mechanism of Stx-mediated inflammation on human glomerular microvascular endothelial cells (HGMVECs) during HUS is still not well understood. In this study, we investigated the effect of Stx1 on the gene expression of proteins involved in leucocyte-mediated and complement-mediated inflammation.

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C3 glomerulopathy (C3G) is an umbrella classification for severe renal diseases characterized by predominant staining for complement component C3 in the glomeruli. The disease is caused by a dysregulation of the alternative pathway (AP) of the complement system. In more than half of C3G patients C3 nephritic factors (C3NeFs) are found.

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Background: Providing proof of presence of Shiga toxin-producing E. coli (STEC) infection forms the basis for differentiating STEC-hemolytic uremic syndrome (HUS) and atypical HUS. As the gold standard to diagnose STEC-HUS has limitations, using ELISA to detect serum antibodies against STEC lipopolysaccharides (LPS) has proven additional value.

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Properdin is known as the only positive regulator of the complement system. Properdin promotes the activity of this defense system by stabilizing its key enzymatic complexes: the complement alternative pathway (AP) convertases. Besides, some studies have indicated a role for properdin as an initiator of complement activity.

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Overactivation of the alternative pathway of the complement system is associated with the renal diseases atypical hemolytic uremic syndrome (aHUS) and C3 glomerulopathy (C3G). C3 nephritic factors (C3NeF) play an important role in C3G pathogenesis by stabilizing the key enzymatic complex of complement, the C3 convertase. However, the reliability of assays detecting these autoantibodies is limited.

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Age-related macular degeneration (AMD) is the leading cause of irreversible blindness in elderly people worldwide. Cuticular drusen (CD) is a clinical subtype of AMD, which typically displays an earlier age at onset, and has a strong genetic component. Genetic studies support a role for rare sequence variants in CD susceptibility, and rare sequence variants in the CFH gene have been identified in 8.

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Age-related macular degeneration (AMD) is a progressive retinal disorder affecting over 33 million people worldwide. Genome-wide association studies (GWASs) for AMD identified common variants at 19 loci accounting for 15-65% of the heritability and it has been hypothesized that the missing heritability may be attributed to rare variants with large effect sizes. Common variants in the complement component 3 (C3) gene have been associated with AMD and recently a rare C3 variant (Lys155Gln) was identified which exerts a large effect on AMD susceptibility independent of the common variants.

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Congenital disorders of glycosylation (CDG) form a group of metabolic disorders caused by deficient glycosylation of proteins and/or lipids. Isoelectric focusing (IEF) of serum transferrin is the most common screening method to detect abnormalities of protein N-glycosylation. On the basis of the IEF profile, patients can be grouped into CDG type I or CDG type II.

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The cytotoxic effect of Shiga-like toxin (Stx; produced by certain Escherichia coli strains) plays a central role in typical hemolytic uremic syndrome (HUS). It damages the renal endothelium by inhibiting the cellular protein synthesis. Also, the monocyte has a specific receptor for Stx but is not sensitive for the cytotoxic effect.

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Background: After gastrointestinal infection with Shiga-like toxin (Stx) producing Escherichia coli, the toxin is transported from the intestine to the renal microvascular endothelium. This is the main target for Stx in humans. Previous studies indicated that polymorphonuclear leucocytes (PMN) could serve as carriers for Stx in the systemic circulation.

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Background: Epithelial cells lining the distal convoluted tubule express the thiazide-sensitive Na-Cl cotransporter (NCC) that is responsible for the reabsorption of 5-10% of the filtered load of Na(+) and Cl(-). Mutations in NCC cause the autosomal recessive renal disorder Gitelman's syndrome (GS). GS mutations give rise to mutant transporters that are either fully (class I) or partially (class II) retarded.

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