A Phase 2 Trial of Sibeprenlimab in Patients with IgA Nephropathy.

BACKGROUND: A proliferation-inducing ligand (APRIL) is implicated in the pathogenesis of IgA nephropathy. Sibeprenlimab is a humanized IgG2 monoclonal antibody that binds to and neutralizes APRIL. METHODS: In this phase 2, multicenter, double-blind, randomized, placebo-controlled, parallel-group trial, we randomly assigned adults with biopsy-confirmed IgA nephropathy who were at high risk for disease progression, despite having received standard-care treatment, in a 1:1:1:1 ratio to receive intravenous sibeprenlimab at a dose of 2, 4, or 8 mg per kilogram of body weight or placebo once monthly for 12 months. The primary end point was the change from baseline in the log-transformed 24-hour urinary protein-to-creatinine ratio at month 12. Secondary end points included the change from baseline in the estimated glomerular filtration rate (eGFR) at month 12. Safety was also assessed. RESULTS: Among 155 patients who underwent randomization, 38 received sibeprenlimab at a dose of 2 mg per kilogram, 41 received sibeprenlimab at a dose of 4 mg per kilogram, 38 received sibeprenlimab at a dose of 8 mg per kilogram, and 38 received placebo. At 12 months, the geometric mean ratio reduction (±SE) from baseline in the 24-hour urinary protein-to-creatinine ratio was 47.2±8.2%, 58.8±6.1%, 62.0±5.7%, and 20.0±12.6% in the sibeprenlimab 2-mg, 4-mg, and 8-mg groups and the placebo group, respectively. At 12 months, the least-squares mean (±SE) change from baseline in eGFR was -2.7±1.8, 0.2±1.7, -1.5±1.8, and -7.4±1.8 ml per minute per 1.73 m2 in the sibeprenlimab 2-mg, 4-mg, and 8-mg groups and the placebo group, respectively. The incidence of adverse events that occurred after the start of administration of sibeprenlimab or placebo was 78.6% in the pooled sibeprenlimab groups and 71.1% in the placebo group. CONCLUSIONS: In patients with IgA nephropathy, 12 months of treatment with sibeprenlimab resulted in a significantly greater decrease in proteinuria than placebo. (Funded by Visterra; ENVISION ClinicalTrials.gov number, NCT04287985; EudraCT number, 2019-002531-29.).

The C3 conundrum.

A 62-year-old man with nephritic syndrome underwent a kidney biopsy which revealed a C3 dominant pattern on immunofluorescence. A diagnosis of C3 glomerulopathy (C3G) was suspected. However, a recent skin infection and high levels of anti-streptococcal antibodies were indicative of post-infectious glomerulonephritis (PIGN). This paper compares PIGN and C3G and describes an atypical form of PIGN with alternative complement pathway dysregulation.

'A disease of disparity': chronic kidney disease of unknown aetiology in endemic immigrant communities.

Chronic kidney disease (CKD) of unknown aetiology is a form of tubulointerstitial CKD in the absence of traditional and known predisposing risk factors. Since the early 2000s, there is an emerging trend in marginalised agricultural communities among workers exposed to occupational and environmental hazards. CKD of unknown aetiology has received significant attention in recent years and is becoming increasingly relevant to the Australian medical community with the growing migrant population, which this case-based communication illustrates.

Guillain-Barré syndrome post renal transplant: A systematic review.

BACKGROUND: Guillain-Barré syndrome (GBS) is a common ascending polyneuropathy in adults. It is often associated with preceding viral or diarrhoeal illness with cytomegalovirus (CMV), Epstein-Barr virus (EBV), or Campylobacter jejuni. Solid organ transplant recipients are more susceptible to opportunistic infections with CMV than the general population as a result of immunosuppressive therapies to prevent graft rejection. However, reports of GBS are rare in this population. OBJECTIVE: To systematically review cases of GBS in renal transplant patients to evaluate causative pathogens or triggers, management and associated morbidity and mortality. METHODS AND RESULTS: We conducted a systematic search of the MEDLINE database uncovering 17 cases of GBS in renal transplant patients in the literature. The majority of cases were in males (81%) and patients who received deceased donor renal transplants (87%). The mean age was 44.7 years (SD 13). The time between transplant and onset of symptoms ranged from 2 days to 10 years (Mean = 720 days). GBS was commonly associated with antecedent viral (CMV 12; EBV 1) or diarrhoeal (2) illness while two cases were attributed to calcineurin inhibitor use. All patients recovered fully or partially after treatment with anti-viral or anti-bacterial agents, immunoglobulins, and/or plasma exchange. CONCLUSION: Cytomegalovirus is the most common trigger for GBS in the post-renal transplant setting. Other triggers include campylobacter jejuni and calcineurin inhibitors. GBS should be considered in transplant patients presenting with weakness or paralysis in order to institute timely management.

What is the best fluid type for management of patients with an identified acute kidney injury?
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Acute kidney injury and fluid management are linked in a close and complex relationship. The exact nature of this relationship and the role of differing fluid composition in the development of acute kidney injury has been studied within several populations. Several recent large studies have highlighted that we should be judicious in our approach and aware of the risks and benefits different fluid management regimens pose to those at risk of developing an acute kidney injury. Despite this, no studies have yet adequately explored if there is a difference in outcomes for patients with an identified AKI who are subsequently managed with different fluid regimens. This brief review rationalizes the need for further investigation into what fluid type is best for the management of patients with an identified acute kidney injury. In the absence of any true evidence to provide guidance, we suggest that, in general, crystalloids should be given with specific attention to patients' tonicity, fluid balance, and acid-base status. The choice of IV fluids in AKI will be dependent on the clinical context and clinicians' best-judgement, until such time when definitive evidence exists to guide practice.
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Contrast-associated nephropathy: Does the route of administration matter?
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Contrast-associated nephropathy (CAN) is an extensively studied but equally controversial sequela of intravascular contrast use. Despite this, there is still significant debate about its definition and thus incidence, the impact of route of contrast administration, and ultimately, what constitutes appropriate clinical practice in light of risks. While guidelines cannot replace clinical judgment, without consensus either enthusiastic withholding of contrast from necessary procedures or its administration despite increased risk may be deleterious to patient outcomes. This article reviews current literature on route-dependent risk and other interplaying factors impacting incidence of CAN.
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Management considerations in the failing renal allograft.

Patients with a failed or failing renal transplant are increasing in number. Graft failure resulting in dialysis re-initiation is not uncommon, yet there are limited data to guide management of these patients. Physician practices vary regarding timing of dialysis initiation and the timing and extent of immunosuppression withdrawal. The risks of immunosuppression withdrawal need to be carefully balanced against the benefits of continuing low-dose therapy. The latter helps minimize the risk of sensitisation and has been proposed to possibly slow the loss of residual renal function; however, the use of common immunosuppressive agents may contribute to cardiovascular disease, malignancy, and infection, the major causes of death following the loss of a renal transplant. The evolving area of personalised transplant immunosuppression may offer future tools for monitoring and managing patients during and after transplant failure. This article aims to discuss some of the important issues that arise when managing these patients.

Acute kidney injury as the presenting manifestation of sarcoidosis: A case series and review of literature.

Acute kidney injury is rarely the presenting feature of sarcoidosis. We present a case series of patients whose diagnosis of sarcoidosis was only brought to light by the development of renal impairment. Concurrent hypercalcaemia was noted, prompting further investigation. The patients discussed experienced a significant and rapid improvement in both renal function and hypercalcaemia in response to therapy with prednisolone. This is out of keeping with previous reports of sarcoidosis-induced renal impairment. Our case series highlights the importance of testing for hypercalcaemia in the context of acute kidney injury. Sarcoidosis is primarily a disease of the lungs and reticuloendothelial system; however, the prevalence of renal involvement with sarcoidosis may be under-recognized. The renal manifestations of sarcoidosis are discussed in the context of the current literature. Furthermore, from our experience, we postulate that in the context of sarcoidosis-induced renal injury, concurrent hypercalcaemia may present prior to the development of chronic renal injury and therefore these patients may be more likely to recover renal function.

An isolated elevation in blood urea level is not 'uraemia' and not an indication for renal replacement therapy in the ICU.

The decision to initiate renal replacement therapy (RRT) and the optimal timing for commencement is a difficult decision faced by clinicians when treating acute kidney injury (AKI) in the intensive care setting. Without clinically significant ureamic symptoms or emergent indications (electrolyte abnormalities, volume overload) the timing of RRT initiation remains contentious and inconsistent across health providers. Current trends of initiating RRT in the ICU are often based on isolated blood urea levels without clear guidelines demonstrating an upper limit for treatment. Although the appropriate upper limit remains unclear, it is reasonable to conclude that a blood urea level less than 40 mmol/L is not in itself an indication for RRT, especially in the absence of supporting evidence of kidney impairment (anuria, elevated serum creatinine), presenting a welcome reminder to treat the patient and not a number.

Anncaliia algerae microsporidial myositis.

The insect microsporidian Anncaliia algerae was first described in 2004 as a cause of fatal myositis in an immunosuppressed person from Pennsylvania, USA. Two cases were subsequently reported, and we detail 2 additional cases, including the only nonfatal case. We reviewed all 5 case histories with respect to clinical characteristics, diagnosis, and management and summarized organism life cycle and epidemiology. Before infection, all case-patients were using immunosuppressive medications for rheumatoid arthritis or solid-organ transplantation. Four of the 5 case-patients were from Australia. All diagnoses were confirmed by skeletal muscle biopsy; however, peripheral nerves and other tissues may be infected. The surviving patient received albendazole and had a reduction of immunosuppressive medications and measures to prevent complications. Although insects are the natural hosts for A. algerae, human contact with water contaminated by spores may be a mode of transmission. A. algerae has emerged as a cause of myositis, particularly in coastal Australia.

Protocol for a hybrid effectiveness-implementation clinical trial evaluating video-assisted electronic consent vs standard consent for patients initiating and continuing haemodialysis in Australia (eConsent HD).

INTRODUCTION: Communicating complex information about haemodialysis (HD) and ensuring it is well understood remains a challenge for clinicians. Informed consent is a high-impact checkpoint in augmenting patients' decision awareness and engagement prior to HD. The aims of this study are to (1) develop a digital information interface to better equip patients in the decision-making process to undergo HD; (2) evaluate the effectiveness of the co-designed digital information interface to improve patient outcomes; and (3) evaluate an implementation strategy. METHODS AND ANALYSIS: First, a co-design process involving consumers and clinicians to develop audio-visual content for an innovative digital platform. Next a two-armed, open-label, multicentre, randomised controlled trial will compare the digital interface to the current informed consent practice among adult HD patients (n=244). Participants will be randomly assigned to either the intervention or control group. Intervention group: Participants will be coached to an online platform that delivers a simple-to-understand animation and knowledge test questions prior to signing an electronic consent form. CONTROL GROUP: Participants will be consented conventionally by a clinician and sign a paper consent form. Primary outcome is decision regret, with secondary outcomes including patient-reported experience, comprehension, anxiety, satisfaction, adherence to renal care, dialysis withdrawal, consent time and qualitative feedback. Implementation of eConsent for HD will be evaluated concurrently using the Consolidation Framework for Implementation Research (CFIR) methodology. ANALYSIS: For the randomised controlled trial, data will be analysed using intention-to-treat statistical methods. Descriptive statistics and CFIR-based analyses will inform implementation evaluation. ETHICS AND DISSEMINATION: Human Research Ethics approval has been secured (Metro North Health Human Research Ethics Committee B, HREC/2022/MNHB/86890), and Dissemination will occur through partnerships with stakeholder and consumer groups, scientific meetings, publications and social media releases. TRIAL REGISTRATION NUMBER: Australian and New Zealand Clinical Trials Registry (ACTRN12622001354774).

Complex, Crusty Calculi: A Case Study Report of Renal Transplant Lithiasis and Encrustation.

Ureteric encrustation and lithiasis after renal transplantation are rare but not without risk of obstruction and graft loss. Patients are usually asymptomatic, and a majority present with graft dysfunction with imaging demonstrating hydronephrosis and rarely with acute graft pyelonephritis. We compare a case of transplant lithiasis with encrusted pyelitis and highlight key differences in their presentation and workup. A key focus for transplant physicians is to recognize when dealing with transplant hydronephrosis that the presence of a high urine pH and pyuria should be a key indicator to suspect ureteric encrustation to look for a urease-producing organism, recognizing that such organisms require prolonged incubation with urine culturing for up to 72 h.

Exploring the factors affecting home dialysis patients' participation in telehealth-assisted home visits: A mixed-methods study.

BACKGROUND: Technology, such as telehealth, is increasingly used to support home dialysis patients. The challenges patients and carers face when home dialysis nursing visits are provided via telehealth have yet to be explored. OBJECTIVES: To explore patients' and carers' perspectives as they transition to telehealth-assisted home visits and identify the factors influencing their engagement in this modality. DESIGN: A mixed-methods approach, guideed by the behaviour change wheel using the capability, opportunity, motivation-behaviour model to explore individual's perceptions of telehealth. PARTCIPANTS: Home dialysis patients and their carers. MEASURUEMENTS: Suveys and qualitative interviews. METHODS: A mixed-methods approach was undertaken, combining surveys and qualitative interviews. It was guided by the Behaviour Change Wheel using the Capability, Opportunity, Motivation- Behaviour model to explore individuals' perceptions of telehealth. RESULTS: Thirty-four surveys and 21 interviews were completed. Of 34 survey participants, 24 (70%) preferred face-to-face home visits and 23 (68%) had previously engaged in telehealth. The main perceived barrier identified in the surveys was knowledge of telehealth, but participants believed there were opportunities for them to use telehealth. Interview results revealed that the convenience and flexibility of telehealth were perceived as the main advantages of telehealth. However, challenges such as the ability to conduct virtual assessments and to communicate effectively between clinicians and patients were identified. Patients from non-English speaking backgrounds and those with disabilities were particularly vulnerable because of the many barriers they faced. These challenges may further entrench the negative view regarding technology, as discussed by interview participants. CONCLUSION: This study suggested that a blended model combining telehealth and face-to-face services would allow patient choice and is important to facilitate equity of care, particularly for those patients who were unwilling or had difficulty adopting technology.

A PRoliferation-Inducing Ligand (APRIL) in the Pathogenesis of Immunoglobulin A Nephropathy: A Review of the Evidence.

A PRoliferation-Inducing Ligand (APRIL), the thirteenth member of the tumor necrosis factor superfamily, plays a key role in the regulation of activated B cells, the survival of long-lived plasma cells, and immunoglobulin (Ig) isotype class switching. Several lines of evidence have implicated APRIL in the pathogenesis of IgA nephropathy (IgAN). Globally, IgAN is the most common primary glomerulonephritis, and it can progress to end-stage kidney disease; yet, disease-modifying treatments for this condition have historically been lacking. The preliminary data in ongoing clinical trials indicate that APRIL inhibition can reduce proteinuria and slow the rate of kidney disease progression by acting at an upstream level in IgAN pathogenesis. In this review, we examine what is known about the physiologic roles of APRIL and evaluate the experimental and epidemiological evidence describing how these normal biologic processes are thought to be subverted in IgAN. The weight of the preclinical, clinical, and genetic data supporting a key role for APRIL in IgAN has galvanized pharmacologic research, and several anti-APRIL drug candidates have now entered clinical development for IgAN. Herein, we present an overview of the clinical results to date. Finally, we explore where more research and evidence are needed to transform potential therapies into clinical benefits for patients with IgAN.