RSS 1.0Renal and Transplant
Browse by
Recent Submissions
-
Primary IgA nephropathy: new insights and emerging therapiesPrimary IgA nephropathy (IgAN) is a common glomerular disorder defined by predominant mesangial IgA deposition. Once thought to follow a progressive course in 10-20% of those diagnosed, emerging evidence now suggests most will progress to kidney failure over their lifetimes. Although the lack of safe and effective treatments to impede disease progression continues to present a challenge, the landscape of IgAN has dramatically evolved over the last 2 years. Driven by fundamental changes to accepted end points for IgAN clinical trials as well as fascinating new insights into the pathophysiology of IgAN, a swathe of novel and repurposed therapies are currently being evaluated. Already, two novel drugs, targeted-release formulation budesonide and sparsentan, have received conditional approvals for the treatment of IgAN, with sodium glucose co-transporter 2 inhibitors establishing themselves as further options. Soon to join this ensemble are likely to be treatments that modulate the complement system and B-cell activity; several are currently undergoing clinical trials in IgAN with promising interim results. In this review, we provide an overview of evolving epidemiological insights, disease mechanisms, emerging therapies, and contemporary challenges surrounding the management of IgAN.
-
Best practice for the selection, design and implementation of UK Kidney Association guidelines: a modified Delphi consensus approachBackground: Despite research into how to effectively implement evidence-based recommendations into clinical practice, a lack of standardisation in the commissioning and development of clinical practice guidelines can lead to inconsistencies and gaps in implementation. This research aimed to ascertain how topics in kidney care worthy of guideline development within the UK should be chosen, prioritised, designed and implemented. Methods: Following a modified Delphi methodology, a multi-disciplinary panel of experts in kidney healthcare from across the UK developed 35 statements on the issues surrounding the selection, development and implementation of nephrology guidelines. Consensus with these statements was determined by agreement using an online survey; the consensus threshold was defined as 75% agreement. Results: 419 responses were received. Of the 364 healthcare practitioners (HCPs), the majority had over 20 years of experience in their role (n=123) and most respondents were nephrologists (n=95). Of the 55 non-clinical respondents, the majority were people with kidney disease (n=41) and the rest were their carers or family. Participants were from across England, Northern Ireland, Scotland and Wales. Consensus between HCPs was achieved in 32/35 statements, with 28 statements reaching ≥90% agreement. Consensus between patients and patient representatives was achieved across all 20 statements, with 13/20 reaching ≥90% agreement. Conclusions: The current results have provided the basis for six recommendations to improve the selection, design and implementation of guidelines. Actioning these recommendations will help improve the accessibility of, and engagement with, clinical guidelines, contributing to the continuing development of best practice in UK kidney care.
-
Platelet membrane biomimetic nanoparticle-targeted delivery of TGF-β1 siRNA attenuates renal inflammation and fibrosisThe progression of renal fibrosis to end-stage renal disease (ESRD) is significantly influenced by transforming growth factor-beta (TGF-beta) signal pathway. This study aimed to develop nanoparticles (PMVs@PLGA complexes) with platelet membrane camouflage, which can transport interfering RNA to target and regulate the TGF-β1 pathway in damaged renal tissues. The aim is to reduce the severity of acute kidney injury and to reduce fibrosis in chronic kidney disease. Hence, we formulated PMVs@TGF-β1-siRNA NP complexes and employed them for both in vitro and in vivo therapy. From the experimental findings we know that the PMVs@siRNA NPs could effectively target the kidneys in unilateral ureteral obstruction (UUO) mice and ischemia/reperfusion injury (I/R) mice. In animal models of treatment, PMVs@siRNA NP complexes effectively decreased the expression of TGF-β1 and mitigated inflammation and fibrosis in the kidneys by blocking the TGF-β1/Smad3 pathway. Therefore, these PMVs@siRNA NP complexes can serve as a promising biological delivery system for treating kidney diseases.
-
Doppler ultrasound surveillance of recently formed haemodialysis arteriovenous fistula: the SONAR observational cohort studyBackground: Arteriovenous fistulas are considered the best option for haemodialysis provision, but as many as 30% fail to mature or suffer early failure. Objective: To assess the feasibility of performing a randomised controlled trial that examines whether, by informing early and effective salvage intervention of fistulas that would otherwise fail, Doppler ultrasound surveillance of developing arteriovenous fistulas improves longer-term arteriovenous fistula patency. Design: A prospective multicentre observational cohort study (the 'SONAR' study). Setting: Seventeen haemodialysis centres in the UK. Participants: Consenting adults with end-stage renal disease who were scheduled to have an arteriovenous fistula created. Intervention: Participants underwent Doppler ultrasound surveillance of their arteriovenous fistulas at 2, 4, 6 and 10 weeks after creation, with clinical teams blinded to the ultrasound surveillance findings. Main outcome measures: Fistula maturation at week 10 defined according to ultrasound surveillance parameters of representative venous diameter and blood flow (wrist arteriovenous fistulas: ≥ 4 mm and > 400 ml/minute; elbow arteriovenous fistulas: ≥ 5 mm and > 500 ml/minute). Mixed multivariable logistic regression modelling of the early ultrasound scan data was used to predict arteriovenous fistula non-maturation by 10 weeks and fistula failure at 6 months. Results: A total of 333 arteriovenous fistulas were created during the study window (47.7% wrist, 52.3% elbow). By 2 weeks, 37 (11.1%) arteriovenous fistulas had failed (thrombosed), but by 10 weeks, 219 of 333 (65.8%) of created arteriovenous fistulas had reached maturity (60.4% wrist, 67.2% elbow). Persistently lower flow rates and venous diameters were observed in those fistulas that did not mature. Models for arteriovenous fistulas' non-maturation could be optimally constructed using the week 4 scan data, with fistula venous diameter and flow rate the most significant variables in explaining wrist fistula maturity failure (positive predictive value 60.6%, 95% confidence interval 43.9% to 77.3%), whereas resistance index and flow rate were most significant for elbow arteriovenous fistulas (positive predictive value 66.7%, 95% confidence interval 48.9% to 84.4%). In contrast to non-maturation, both models predicted fistula maturation much more reliably [negative predictive values of 95.4% (95% confidence interval 91.0% to 99.8%) and 95.6% (95% confidence interval 91.8% to 99.4%) for wrist and elbow, respectively]. Additional follow-up and modelling on a subset (n = 192) of the original SONAR cohort (the SONAR-12M study) revealed the rates of primary, assisted primary and secondary patency arteriovenous fistulas at 6 months were 76.5, 80.7 and 83.3, respectively. Fistula vein size, flow rate and resistance index could identify primary patency failure at 6 months, with similar predictive power as for 10-week arteriovenous fistula maturity failure, but with wide confidence intervals for wrist (positive predictive value 72.7%, 95% confidence interval 46.4% to 99.0%) and elbow (positive predictive value 57.1%, 95% confidence interval 20.5% to 93.8%). These models, moreover, performed poorly at identifying assisted primary and secondary patency failure, likely because a subset of those arteriovenous fistulas identified on ultrasound surveillance as at risk underwent subsequent successful salvage intervention without recourse to early ultrasound data. Conclusions: Although early ultrasound can predict fistula maturation and longer-term patency very effectively, it was only moderately good at identifying those fistulas likely to remain immature or to fail within 6 months. Allied to the better- than-expected fistula patency rates achieved (that are further improved by successful salvage), we estimate that a randomised controlled trial comparing early ultrasound-guided intervention against standard care would require at least 1300 fistulas and would achieve only minimal patient benefit. Trial registration: This trial is registered as ISRCTN36033877 and ISRCTN17399438. Funding: This award was funded by the National Institute for Health and Care Research (NIHR) Health Technology Assessment programme (NIHR award ref: NIHR135572) and is published in full in Health Technology Assessment; Vol. 28, No. 24. See the NIHR Funding and Awards website for further award information.
-
Early ultrasound surveillance of newly-created hemodialysis arteriovenous fistulaIntroduction: We assess if ultrasound surveillance of newly-created arteriovenous fistulas (AVFs) can predict nonmaturation sufficiently reliably to justify randomized controlled trial (RCT) evaluation of ultrasound-directed salvage intervention. Methods: Consenting adults underwent blinded fortnightly ultrasound scanning of their AVF after creation, with scan characteristics that predicted AVF nonmaturation identified by logistic regression modeling. Results: Of 333 AVFs created, 65.8% matured by 10 weeks. Serial scanning revealed that maturation occurred rapidly, whereas consistently lower fistula flow rates and venous diameters were observed in those that did not mature. Wrist and elbow AVF nonmaturation could be optimally modeled from week 4 ultrasound parameters alone, but with only moderate positive predictive values (PPVs) (wrist, 60.6% [95% confidence interval, CI: 43.9-77.3]; elbow, 66.7% [48.9-84.4]). Moreover, 40 (70.2%) of the 57 AVFs that thrombosed by week 10 had already failed by the week 4 scan, thus limiting the potential of salvage procedures initiated by that scan's findings to alter overall maturation rates. Modeling of the early ultrasound characteristics could also predict primary patency failure at 6 months; however, that model performed poorly at predicting assisted primary failure (those AVFs that failed despite a salvage attempt), partly because patency of at-risk AVFs was maintained by successful salvage performed without recourse to the early scan data. Conclusion: Early ultrasound surveillance may predict fistula maturation, but is likely, at best, to result in only very modest improvements in fistula patency. Power calculations suggest that an impractically large number of participants (>1700) would be required for formal RCT evaluation.
-
Focal segmental glomerulosclerosis patient baseline characteristics in the sparsentan phase 3 DUPLEX studyIntroduction: The phase 3 DUPLEX trial is evaluating sparsentan, a novel, nonimmunosuppressive, single-molecule dual endothelin angiotensin receptor antagonist, in patients with focal segmental glomerulosclerosis (FSGS). Methods: DUPLEX (NCT03493685) is a global, multicenter, randomized, double-blind, parallel-group, active-controlled study evaluating the efficacy and safety of sparsentan 800 mg once daily versus irbesartan 300 mg once daily in patients aged 8 to 75 years (USA/UK) and 18 to 75 years (ex-USA/UK) weighing ≥20 kg with biopsy-proven FSGS or documented genetic mutation in a podocyte protein associated with FSGS, and urine protein-to-creatinine ratio (UP/C) ≥1.5 g/g. Baseline characteristics blinded to treatment allocation are reported descriptively. Results: The primary analysis population includes 371 patients (336 adult, 35 pediatric [<18 years]) who were randomized and received study drug (median age, 42 years). Patients were White (73.0%), Asian (13.2%), Black/African American (6.7%), or Other race (7.0%); and from North America (38.8%), Europe (36.1%), South America (12.7%), or Asia Pacific (12.4%). Baseline median UP/C was 3.0 g/g; 42.6% in nephrotic-range (UP/C >3.5 g/g [adults]; >2.0 g/g [pediatrics]). Patients were evenly distributed across estimated glomerular filtration rate (eGFR) categories corresponding to chronic kidney disease (CKD) stages 1 to 3b. Thirty-three patients (9.4% of 352 evaluable samples) had pathogenic or likely pathogenic (P/LP) variants of genes essential to podocyte structural integrity and function, 27 (7.7%) had P/LP collagen gene (COL4A3/4/5) variants, and 14 (4.0%) had high-risk APOL1 genotypes. Conclusions: Patient enrollment in DUPLEX, the largest interventional study in FSGS to date, will enable important characterization of the treatment effect of sparsentan in a geographically broad and clinically diverse FSGS population.
-
A National audit of the care of patients with acute kidney injury in England and Wales in 2019 and the association with patient outcomesBackground: Acute kidney injury (AKI) is a common complication of hospitalisations. This national audit assessed the care received by patients with AKI in hospital Trusts in England and Wales. Methods: Twenty four hospital Trusts across England and Wales took part. Patients with AKI stage2/3 were identified using the UK Renal Registry AKI master patient index. Data was returned through a secure portal with linkage to hospital episode statistic mortality and hospitalisation data. Completion rates of AKI care standards and regional variations in care were established. Results: 989 AKI episodes were included in the analyses. In-hospital 30-day mortality was 31-33.1% (AKI 2/3). Standard AKI interventions were completed in >80% of episodes. Significant inter-hospital variation remained in attainment of AKI care standards after adjustment for age and sex. Recording of urinalysis (41.9%) and timely imaging (37.2%) were low. Information on discharge summaries relating to medication changes/re-commencement and follow-up blood tests associated with reduced mortality. No quality indicators relating to clinical management associated with mortality. Better communication on discharge summaries associated with reduced mortality. Conclusions: Outcomes for patients with AKI in hospital remain poor. Regional variation in care exists. Work is needed to assess whether improving and standardising care improves patient outcomes.
-
What to do with foundation therapies for heart failure for patients with end-stage kidney disease on haemodialysisThere is a significant burden of cardiovascular disease morbidity and mortality in the end-stage kidney disease population, driven by traditional and non-traditional risk factors. Despite its prevalence, heart failure is difficult to diagnose in the dialysis population due to overlapping clinical presentations, limitations of investigations, and the impact on the cardiorenal axis. 'Foundation therapies' are the key medications which improve patient outcomes in heart failure with reduced ejection fraction and include beta-blockers, renin-angiotensin-aldosterone system inhibitors and sodium-glucose cotransporter-2 inhibitors. They are underutilised in the dialysis population due to the exclusion of chronic kidney disease patients from major trials and legitimate clinical concerns e.g. hyperkalaemia, intradialytic hypotension and residual kidney function preservation. A coordinated cardiorenal multidisciplinary approach can guide appropriate diagnostic considerations (biomarkers interpretation, imaging, addressing unique complications of kidney disease), optimise dialysis management (prescription length, frequency and ultrafiltration targets) and when at euvolaemia facilitate the stepwise introduction of appropriate foundation therapies.
-
Exploring the immunological relevance of pre-transplant donor-specific antibody in intestinal transplantation, with special consideration to the liverDespite recent advances that have improved outcomes following intestinal transplantation (ITx), achieving long-term patient survival and rejection-free survival is still challenging. Understanding the relevance of pre-transplant human leukocyte antigen (HLA) donor-specific antibody (DSA) in ITx and the immunomodulatory potential of the liver within the allograft is crucial to providing an accurate assessment of pre-transplant immunological risk, which could influence and improve post-transplant outcomes further. This was the primary objective of this retrospective study of 95 adult ITx transplants which took place at Cambridge University Hospitals (United Kingdom) between 2007 and 2019. Two novel programs were developed and validated to identify DSA (tested by Luminex single antigen beads) in this dataset. Data analysis utilised Kaplan-Meier survival methods, and statistical analysis was performed using log-rank tests and adjusted Cox models. Fifty-four (57%) ITx cases contained a liver, and 36 (38%) were sensitised to HLA. Pre-transplant DSA > 500 mean fluorescent intensity appeared to negatively affect post-ITx patient survival and rejection outcomes. Additionally, liver-inclusive allografts seemed to show particular resistance to HLA class I DSA. Our data hints towards consistency with other ITx studies where deleterious effects of DSA have been demonstrated, and where liver inclusion is protective from HLA class I DSA. This is in line with current national guidelines for immunological risk. Our publicly available research programs could support future large or multicentre studies where statistically relevant data might be gained.
-
The paradox of haemodialysis: the lived experience of the clocked treatment of chronic illnessStudies exploring the relationship between time and chronic illness have generally focused on measurable aspects of time, also known as linear time. Linear time follows a predictable, sequential order of past, present and future; measured using a clock and predicated on normative assumptions. Sociological concepts addressing lifecourse disruption following diagnosis of chronic illness have served to enhance the understanding of lived experience. To understand the nuanced relationship between time and chronic illness, however, requires further exploration. Here, we show how the implicit assumptions of linear time meet in tension with the lived experience of chronic illness. We draw on interviews and photovoice work with people with end-stage kidney disease in receipt of in-centre-daytime haemodialysis to show how the clocked treatment of chronic illness disrupts experiences of time. Drawing on concepts of 'crip' and 'chronic' time we argue that clocked treatment and the lived experience of chronic illness converge at a paradox whereby clocked treatment allows for the continuation of linear time yet limits freedom. We use the concept of 'crip time' to challenge the normative assumptions implicit within linear concepts of time and argue that the understanding of chronic illness and its treatment would benefit from a 'cripped' starting point.
-
Charting new frontiers in IgA nephropathy: a paradigm shift toward precision medicine and early intervention?Advancements in glomerular transcriptomics offer a promising avenue toward precision medicine in IgA nephropathy. Traditional prognostic biomarkers, including proteinuria, blood pressure, and histomorphometry, fall short at capturing the complexity of IgA nephropathy and can only crudely guide therapeutic decisions. This issue needs to be addressed urgently as pathway-specific treatments become available. Glomerular transcriptomics, although technically challenging, offers an opportunity to refine prognostic precision and identify therapeutic targets, even when apparent risk of disease progression is low.
-
Technological innovations to improve patient engagement in nephrologyTechnological innovation has accelerated exponentially over the last 2 decades. From the rise of smartphones and social media in the early 2000s to the mainstream accessibility of artificial intelligence (AI) in 2023, digital advancements have transformed the way we live and work. These innovations have permeated health care, covering a spectrum of applications from virtual reality training platforms to AI-powered clinical decision support tools. In this review, we explore fascinating recent innovations that have and can facilitate patient engagement in nephrology. These include integrated care mobile applications, wearable health monitoring tools, virtual/augmented reality consultation and education platforms, AI-powered appointment booking systems, and patient information tools. We also discuss potential pitfalls in implementation and paradigms to adopt that may protect patients from unintended consequences of being cared for in a digitalized health care system.
-
Lifestyle interventions delivered by eHealth in chronic kidney disease: A scoping reviewA method of overcoming barriers associated with implementing lifestyle interventions in CKD may be through the use of eHealth technologies. The aim of this review was to provide an up-to-date overview of the literature on this topic. Four bibliographical databases, two trial registers, and one database for conference proceedings were searched from inception to August 2023. Studies were eligible if they reported a lifestyle intervention using eHealth technologies. A narrative synthesis of the findings from the included studies structured around the type of eHealth intervention was presented. Where a sufficient number of studies overlapped in terms of the type of intervention and outcome measure these were brought together in a direction of effect plot. There were 54 included articles, of which 23 were randomised controlled trials (RCTs). The main component of the intervention for the included studies was mobile applications (n = 23), with the majority being in the dialysis population (n = 22). The majority of eHealth interventions were reported to be feasible and acceptable to participants. However, there was limited evidence that they were efficacious in improving clinical outcomes with the exception of blood pressure, intradialytic weight gain, potassium, and sodium. Although eHealth interventions appear acceptable and feasible to participants, there is insufficient evidence to make recommendations for specific interventions to be implemented into clinical care. Properly powered RCTs which not only demonstrate efficacy, but also address barriers to implementation are needed to enhance widespread adoption.
-
Novel treatment paradigms: primary IgA nephropathyIgA nephropathy (IgAN) is the most common primary glomerulonephritis worldwide. Approximately 30% to 45% of patients progress to kidney failure (KF) within 20 to 25 years of diagnosis, and there has long been a lack of effective treatments. The therapeutic landscape in IgAN is rapidly evolving, driven in large part by the acceptance of the surrogate clinical trial end point of proteinuria reduction by regulatory authorities for the accelerated approval of new therapies. Two drugs, targeted release formulation (TRF)-budesonide (nefecon) and sparsentan, have recently been approved under this scheme. Advancing insights into the pathophysiology of IgAN, including the roles of the mucosal immune system, B-cells, the complement system, and the endothelin system have driven development of therapies that target these factors. This review outlines current, recently approved, and emerging therapies for IgAN.
-
Resistant anemia in a kidney transplant recipient: pure red cell aplasia due to parvovirus B19 infectionAnemia in kidney transplant recipients can stem from a diverse array of etiologies, including dietary deficiencies, inflammatory processes, allograft dysfunction, as well as viral and bacterial infections. We present a case of refractory anemia in a 49-year-old male patient occurring within the initial month following a kidney transplant, which persisted despite numerous transfusions, posing a formidable challenge. The patient was maintained on the standard immunosuppressant regimen-Tacrolimus, Mycophenolate, and Prednisolone. Diagnostic evaluations eliminated well-established causes such as dietary deficiencies, gastrointestinal losses, and prevalent infections. Subsequently, after viral PCR testing, a diagnosis of Pure Red Cell Aplasia (PRCA) due to infection with parvovirus B19 was made. Although the patient had a reduction in the immunosuppression drugs and received a course of Intravenous Immunoglobulins (IVIG) on two separate occasions spanning two months, the anemia relapsed. Subsequently, after an additional dose of IVIG with further modification and reduction of the immunosuppressant regimen, including stopping the mycophenolate and switching tacrolimus with cyclosporine, the patient ultimately achieved successful resolution of his symptoms and a significant decrease in viral load. Our case highlights the significance of unconventional etiologies when confronted with anemia in the setting of kidney transplantation. Furthermore, it also provides further insights into therapeutic avenues for addressing PRCA in kidney transplant recipients.
-
The role of BAFF and APRIL in IgA nephropathy: pathogenic mechanisms and targeted therapiesImmunoglobulin A nephropathy (IgAN), characterized by mesangial deposition of galactose-deficient-IgA1 (Gd-IgA1), is the most common biopsy-proven primary glomerulonephritis worldwide. Recently, an improved understanding of its underlying pathogenesis and the substantial risk of progression to kidney failure has emerged. The "four-hit hypothesis" of IgAN pathogenesis outlines a process that begins with elevated circulating levels of Gd-IgA1 that trigger autoantibody production. This results in the formation and deposition of immune complexes in the mesangium, leading to inflammation and kidney injury. Key mediators of the production of Gd-IgA1 and its corresponding autoantibodies are B-cell activating factor (BAFF), and A proliferation-inducing ligand (APRIL), each playing essential roles in the survival and maintenance of B cells and humoral immunity. Elevated serum levels of both BAFF and APRIL are observed in patients with IgAN and correlate with disease severity. This review explores the complex pathogenesis of IgAN, highlighting the pivotal roles of BAFF and APRIL in the interplay between mucosal hyper-responsiveness, B-cell activation, and the consequent overproduction of Gd-IgA1 and its autoantibodies that are key features in this disease. Finally, the potential therapeutic benefits of inhibiting BAFF and APRIL in IgAN, and a summary of recent clinical trial data, will be discussed.