ABSTRACT
Background
Kidney disease is fairly unique due to the lack of symptoms associated with disease activity, and it is therefore dependent on biological monitoring. Dried biofluids, particularly ...dried capillary blood spots, are an accessible, easy‐to‐use technology that have seen increased utility in basic science research over the past decade. However, their use is yet to reach the kidney patient population clinically or in large‐scale discovery science initiatives. The aim of this study was to systematically evaluate the existing literature surrounding the use of dried biofluids in kidney research.
Methods
A systematic literature review was conducted using three search engines and a predefined search term strategy. Results were summarised according to the collection method, type of biofluid, application to kidney disease, cost, sample stability and patient acceptability.
Results
In total, 404 studies were identified and 67 were eligible. In total, 34,739 patients were recruited to these studies with a skew towards male participants (> 73%). The majority of samples were blood, which was used either for monitoring anti‐rejection immunosuppressive drug concentrations or for kidney function. Dried biofluids offered significant cost savings to the patient and healthcare service. The majority of patients preferred home microsampling when compared to conventional monitoring.
Conclusion
There is an unmet need in bringing dried microsampling technology to advance kidney disease despite its advantages. This technology provides an opportunity to upscale patient recruitment and longitudinal sampling, enhance vein preservation and overcome participation bias in research.
We carried out a systematic review of the use of dried biofluids in kidney disease. The majority of studies focused on drug quantification following transplant. However, dried biofluids were comparable with venous samples opening up the possibility to expand to biomarker discovery.
Immunoglobulin A nephropathy (IgAN) is the most common primary glomerulonephritis reported across the world and is characterized by immunoglobulin A (IgA) dominant mesangial deposits, which are ...poorly O -glycosylated. This deposition leads to a cascade of glomerular and tubulointerstitial inflammation and fibrosis, which can progress to chronic kidney disease. The variability in rate of progression reflects the many genetic and environmental factors that drive IgAN. Here, we summarize the contemporary understanding of the disease mechanisms that drive IgAN and provide an overview of new and emerging therapies, which target these mechanisms.
Immunoglobulin A (IgA) vasculitis (IgAV, also known as Henoch-Schoenlein purpura, HSP) is the most common vasculitis of childhood. It usually presents with a simple, self-limiting disease course; ...however, a small subset of patients may develop kidney involvement (IgAV-N) which occurs 4–12 weeks after disease onset and is the biggest contributor to long-term morbidity. Treatment currently targets patients with established kidney involvement; however; there is a desire to work towards early prevention of inflammation during the window of opportunity between disease presentation and onset of significant nephritis. There are no clinical trials evaluating drugs which may prevent or halt the progression of nephritis in children with IgAV apart from the early use of corticosteroids which have no benefit. This article summarises the latest scientific evidence and clinical trials that support potential therapeutic targets for IgAV-N that are currently being developed based on the evolving understanding of the pathophysiology of IgAV-N. These span the mucosal immunity, B-cell and T-cell modulation, RAAS inhibition, and regulation of complement pathways, amongst others. Novel drugs that may be considered for use in early nephritis include TRF-budesonide; B-cell inhibiting agents including belimumab, telitacicept, blisibimod, VIS649, and BION-1301; B-cell depleting agents such as rituximab, ofatumumab, and bortezomib; sparsentan; angiotensin converting enzyme inhibitors (ACE-Is); and complement pathway inhibitors including avacopan, iptacopan, and narsoplimab. Further clinical trials, as well as pre-clinical scientific studies, are needed to identify mechanistic pathways as there may be an opportunity to prevent nephritis in this condition.
Key Points
•
Kidney involvement is the main cause of long-term morbidity and mortality in IgA vasculitis despite the current treatment recommendations.
•
The evolving understanding of the pathophysiology of IgA vasculitis is allowing exploration of novel treatment options which target underlying immune pathways.
•
Novel treatments currently being trialled in IgA nephropathy may have benefit in IgA vasculitis due to the similarities in the underlying pathophysiology, such as TRF-budesonide, B-cell modulators, and complement inhibitors.
•
Further studies, including clinical trials of novel drugs, are urgently needed to improve the long-term outcomes for children with IgA vasculitis nephritis.
ABSTRACT
Background
IgA vasculitis (IgAV) is the most common form of childhood vasculitis. Nephritis (IgAVN) occurs in 50% of patients and 1–2% progress to chronic kidney disease stage 5. The ...pathophysiology of nephritis remains largely unknown, but recent evidence suggests that the complement system may be involved. The aim of this cross-sectional study was to explore whether there is evidence of alternative and/or lectin complement pathway activation in children with IgAVN.
Methods
Children with IgAV were recruited and grouped according to proteinuria: IgAVN or IgAV without nephritis (IgAVwoN). Age and sex-matched healthy controls (HCs) were also recruited. Cross-sectional urine and plasma concentrations of complement factor D (CFD), factor B (CFB), and MBL-associated protease 1 (MASP-1) were performed using commercially available enzyme-linked immunoassays.
Results
A total of 50 children were included (IgAVN, n = 15; IgAVwoN, n = 20, HCs, n = 15). The mean age was 8.5 ± 3.7 years old, male:female ratio was 1:1. Urinary CFD and CFB concentrations were statistically significantly increased in children with IgAVN (3.5 ± 5.4 μg/mmol; 25.9 ± 26.5 μg/mmol, respectively) compared to both IgAVwoN (0.4 ± 0.4 μg/mmol, P = 0.002; 9.2 ± 11.5 μg/mmol, P = 0.004) and HCs (0.3 ± 0.2 μg/mmol, P < 0.001; 5.1 ± 6.0 μg/mmol, P < 0.001). No statistically significant difference was reported for the plasma concentrations of CFD and CFB. Urinary MASP-1 concentrations were statistically significantly increased in IgAVN (116.9 ± 116.7 ng/mmol) compared to HCs (41.4 ± 56.1 ng/mmol, P = 0.006) and plasma MASP-1 concentrations were increased in IgAVwoN (254.2 ± 23.3 ng/mL) compared to HCs (233.4 ± 6.6 ng/mL, P = 0.046).
Conclusion
There is evidence of complement pathway products in the urine of children with IgAVN that warrants further investigation.
Graphical Abstract
Graphical Abstract
IgA vasculitis (IgAV) in adults has been relatively under-investigated. Since outcomes are worse in other forms of vasculitis with increasing age, we investigated the outcomes of IgAV comparing ...younger adults (18-34), middle aged adults (35-64) and elderly patients (≥64 years) focusing on kidney outcomes.
We identified patients with renal biopsy confirmed IgAV nephritis and collected data regarding clinical features and progression to end stage kidney disease (ESKD). The relationship between patient factors and ESKD was analysed by regression.
We identified 202 cases, 34% aged 18-34, 43% aged 35-64 and 23% were elderly (>64 years). Median follow up was 44 months. Elderly patients were more likely to present with ESKD (23.9%) compared with middle aged (13.7%) and younger adults (2.9%)(χ2 11.6, p= 0.002). In patients with independent kidney function at biopsy, there was no difference in outcomes between age groups. Male gender, Black ethnicity, diabetes, histological evidence of chronic renal damage and eGFR < 30mls/min were risk factors for development of ESKD. In this observational study 68.3% of patients received glucocorticoids and 56.9% additional immunosuppression.
Elderly patients with IgAV are more likely to have ESKD at presentation, but there is no difference in renal survival between age groups, among those presenting with independent renal function. Renal impairment at biopsy is an independent risk factor for subsequent development of ESKD. There is significant variability in the timing of kidney biopsy and management of these patients among specialist centres. Young adults have outcomes more in keeping with childhood IgAV.
Application of 'treat-to-target' (T2T) in childhood-onset systemic lupus erythematosus (cSLE) may improve care and health outcomes. This initiative aimed to harmonise existing evidence and expert ...opinion regarding T2T for cSLE.
An international T2T Task Force was formed of specialists in paediatric rheumatology, paediatric nephrology, adult rheumatology, patient and parent representatives. A steering committee formulated a set of draft overarching principles and points-to-consider, based on evidence from systematic literature review. Two on-line preconsensus meeting Delphi surveys explored healthcare professionals' views on these provisional overarching principles and points-to-consider. A virtual consensus meeting employed a modified nominal group technique to discuss, modify and vote on each overarching principle/point-to-consider. Agreement of >80% of Task Force members was considered consensus.
The Task Force agreed on four overarching principles and fourteen points-to-consider. It was agreed that both treatment targets and therapeutic strategies should be subject to shared decision making with the patient/caregivers, with full remission the preferred target, and low disease activity acceptable where remission cannot be achieved. Important elements of the points-to-consider included: aiming for prevention of flare and organ damage; glucocorticoid sparing; proactively addressing factors that impact health-related quality of life (fatigue, pain, mental health, educational challenges, medication side effects); and aiming for maintenance of the target over the long-term. An extensive research agenda was also formulated.
These international, consensus agreed overarching principles and points-to-consider for T2T in cSLE lay the foundation for future T2T approaches in cSLE, endorsed by the Paediatric Rheumatology European Society.
Consensus guidelines are not available for the use of immunoglobulin replacement therapy (IGRT) in patients developing iatrogenic secondary antibody deficiency following B-cell targeted therapy ...(BCTT) in autoimmune rheumatic disease.
To evaluate the role of IGRT to manage hypogammaglobulinemia following BCTT in autoimmune rheumatic disease (AIRD).
Using an agreed search string we performed a systematic literature search on Medline with Pubmed as vendor. We limited the search to English language papers with abstracts published over the last 10 years. Abstracts were screened for original data regarding hypogammaglobulinemia following BCTT and the use of IGRT for hypogammaglobulinemia following BCTT. We also searched current recommendations from national/international organisations including British Society for Rheumatology, UK Department of Health, American College of Rheumatology, and American Academy of Asthma, Allergy and Immunology.
222 abstracts were identified. Eight papers had original relevant data that met our search criteria. These studies were largely retrospective cohort studies with small patient numbers receiving IGRT. The literature highlights the induction of a sustained antibody deficiency, risk factors for hypogammaglobulinemia after BCTT including low baseline serum IgG levels, how to monitor patients for the development of hypogammaglobulinemia and the limited evidence available on intervention thresholds for commencing IGRT.
The benefit of BCTT needs to be balanced against the risk of inducing a sustained secondary antibody deficiency. Consensus guidelines would be useful to enable appropriate assessment prior to and following BCTT in preventing and diagnosing hypogammaglobulinemia. Definitions for symptomatic hypogammaglobulinemia, intervention thresholds and treatment targets for IGRT, and its cost-effectiveness are required.
•Immunoglobulin replacement therapy for secondary hypogammaglobulinemia is increasing in autoimmune rheumatic disease.•We review the currently available literature surrounding hypogammaglobulinemia after B-cell targeted therapy in AIRD.•Consensus guidelines are needed for appropriate assessment to prevent, diagnose and to treat hypogammaglobulinemia in AIRD.
IgA vasculitis with nephritis (IgAVN) is the most common vasculitis in children. Treatment recommendations are, due to a lack of evidence, based on expert opinion resulting in variation. The aim of ...this study was to describe clinical presentation, treatment and outcome of an extremely large cohort of children with biopsy proven IgAVN to identify prognostic risk factors and signals of treatment efficacy.
Retrospective data were collected on 1148 children with biopsy proven IgAVN between 2005 and 2019 from 41 international paediatric nephrology centres across 25 countries and analyzed using multivariate analysis. The primary outcome was estimated glomerular filtration rate (eGFR) and persistent proteinuria at last follow up.
The median follow up was 3.7 years (IQR 2-6.2). At last follow up, 29% of patients had an eGFR < 90 ml/min/1.73m2, 36% had proteinuria and 3% had chronic kidney disease stage 4-5. Older age, lower eGFR at onset, hypertension and histological features of tubular atrophy and segmental sclerosis were predictors of poor outcome. There was no evidence to support any specific second line immunosuppressive regimen to be superior to others, even when further analysing subgroups of children with reduced kidney function, nephrotic syndrome or hypoalbuminemia at onset. Delayed start of immunosuppressive treatment was associated with a lower eGFR at last follow up.
In this large retrospective cohort, key features associated with disease outcome are highlighted. Importantly there was no evidence to support that any specific immunosuppressive treatments were superior to others. Further discovery science and well-conducted clinical trials are needed to define accurate treatment and improve outcomes of IgAVN.
PDF
