Complement detection in kidney biopsies – utility and challenges

Tomaszewski, Kristen; Herlitz, Leal

doi:10.1097/mnh.0000000000000872

Cited by 5 publications

(4 citation statements)

References 38 publications

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“…In the general dogma, proteinuria is always damaging. It is typically linked to unfavorable renal outcomes, and kidney biopsy is the only means to establish a definitive histological diagnosis for many of the conditions for which nephrologists care, as well as the gold standard for kidney tissue analysis [ 5 , 6 ]. However, there is controversy among nephrologists worldwide, especially in pediatrics, over whether to perform renal biopsy and the appropriate timing of biopsy and ACEI application.…”

Section: Discussionmentioning

confidence: 99%

Controversy between biopsy and risk in children with proteinuria: is there a paradigm war?

Yang,

Liu

2024

BMC Nephrol

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Background Proteinuria is a prevalent symptom of pediatric nephrology, while kidney biopsy remains the gold standard for kidney tissue analysis, and it is currently controversial. We report the rare case that the mutation in the AMN gene was considered to cause chronically isolated proteinuria and also suggest that renal biopsy should be chosen with caution in children with chronic isolated non-nephrotic levels of proteinuria and that genetic testing may be feasible for the early precise diagnosis. Case presentation A 35-month-old boy presented with excessive urine foaming for more than half a month; his proteinuria was considered non-nephrotic range and urine protein electrophoresis was suggestive of mixed proteinuria; other than that, the investigations are non-specific. Given the child’s chronic isolated proteinuria and good renal function, we chose to refine the genetic test rather than a renal biopsy; a compound heterozygous variant was found in the AMN gene of this child which was caused by a point mutation in the father, and a partial chromosomal deletion in the mother. Conclusions Cubilin(encoded by CUBN), amnionless(encoded by AMN), and megalin form a multiligand receptor complex; CUBN or AMN gene variants have been implicated as a hereditary cause of megaloblastic anemia, proteinuria, and neurological impairment. In the past few decades, chronic isolated proteinuria caused by CUBN gene variants is benign, non-progressive, and has normal renal function. However, the child is the first reported case of isolated proteinuria of AMN gene mutation, indicating that the earlier diagnostic genetic sequencing in an otherwise well, not nephrotic proteinuria child may be a convenient, cost-effective, and harmless option, challenging the traditional paradigm.

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Section: Discussionmentioning

confidence: 99%

Controversy between biopsy and risk in children with proteinuria: is there a paradigm war?

Yang,

Liu

2024

BMC Nephrol

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“…Complement deposition in kidney tissue has been found in various glomerulonephritides, including lupus nephritis, membranous nephropathy, IgA nephropathy, C3 glomerulopathies, ANCA-associated vasculitis, and thrombotic microangiopathies (3,(9)(10)(11). Beyond immune complex deposition, emerging data shows that complement is being synthesized inside the kidney and can cause direct injury through various mechanisms such as 1) cytokine production contributing to interstitial inflammation (12), 2) direct stimulation of extracellular matrix production (12)(13)(14)(15) and 3) activation of the renal renin angiotensin system leading to progressive kidney injury and damage (16).…”

Section: Introductionmentioning

confidence: 99%

Urinary complement biomarkers in immune-mediated kidney diseases

Kesarwani,

Bukhari,

Kahlenberg

et al. 2024

Front. Immunol.

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The complement system, an important part of the innate system, is known to play a central role in many immune mediated kidney diseases. All parts of the complement system including the classical, alternative, and mannose-binding lectin pathways have been implicated in complement-mediated kidney injury. Although complement components are thought to be mainly synthesized in the liver and activated in the circulation, emerging data suggest that complement is synthesized and activated inside the kidney leading to direct injury. Urinary complement biomarkers are likely a better reflection of inflammation within the kidneys as compared to traditional serum complement biomarkers which may be influenced by systemic inflammation. In addition, urinary complement biomarkers have the advantage of being non-invasive and easily accessible. With the rise of therapies targeting the complement pathways, there is a critical need to better understand the role of complement in kidney diseases and to develop reliable and non-invasive biomarkers to assess disease activity, predict treatment response and guide therapeutic interventions. In this review, we summarized the current knowledge on urinary complement biomarkers of kidney diseases due to immune complex deposition (lupus nephritis, primary membranous nephropathy, IgA nephropathy) and due to activation of the alternative pathway (C3 glomerulopathy, thrombotic microangiography, ANCA-associated vasculitis). We also address the limitations of current research and propose future directions for the discovery of urinary complement biomarkers.

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“…In summary, the significance of C4d can be described as a degradation product of complement cascade and in different kidney pathologies, it serves as an evidence of complement activation (2). C4d has been regarded also as a footprint of tissue damage in antibody-mediated rejection in transplantology, and the introduction of C4d staining in daily clinical practice aroused an ever-increasing interest in the role of antibody-mediated mechanisms in kidney allograft rejection (3,4). Antibody-mediated rejection is highly detrimental to the prolonged survival of transplanted kidneys.…”

Section: Introductionmentioning

confidence: 99%

The diagnostic significance of C4d deposits, as an immunohistochemical proof of complement activation, in kidney glomerular pathologies and kidney transplantation

HRESKO,

MADAROVA,

DOBOSOVA

et al. 2024

BLL

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C4d, a split product of C4 activation in classical and lectin pathways of the complement system activation, has been regarded as a footprint of tissue damage in antibody-mediated rejection in transplantology. The introduction of C4d staining into daily clinical practice aroused an ever-increasing interest in the role of antibody-mediated mechanisms in kidney allograft rejection. However, this marker of complement activation is also important in other various kidney glomerular pathologies such as immunoglobulin A nephropathy, membranoproliferative glomerulonephritis, lupus nephritis, and others. In routine histopathological practice, C4d staining can be done by two histological methods, specifically by immunofluorescence on frozen tissue using monoclonal antibody to C4d (with the downside of unsteady availability of frozen tissue) or by immunohistochemistry using C4d antibodies on formalin-fixed and paraffin-embedded renal tissue. The aim of this narrative review is to summarize recent knowledge about the complement fragment C4d and its significance in different kidney pathologies, focusing on its immunohistochemical detection in renal tissue biopsies. We have supplemented this review with our experience with our proprietary methodology of preparation and practical use of antibodies such as anti-C4d, on a small national level. Immunohistochemical staining for C4d has revolutionized the field of renal histopathology. Despite being a simple diagnostic test, its utility can be of utmost importance, especially in a resource-poor setting where immunofluorescence and frozen tissue may not be available (Fig. 2, Ref. 53).

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Complement detection in kidney biopsies – utility and challenges

Cited by 5 publications

References 38 publications

Controversy between biopsy and risk in children with proteinuria: is there a paradigm war?

Controversy between biopsy and risk in children with proteinuria: is there a paradigm war?

Urinary complement biomarkers in immune-mediated kidney diseases

The diagnostic significance of C4d deposits, as an immunohistochemical proof of complement activation, in kidney glomerular pathologies and kidney transplantation

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