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.).

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.

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.

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.

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.

'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.

A Systematic Review of Prophylactic Anticoagulation in Nephrotic Syndrome.

INTRODUCTION: Nephrotic syndrome is associated with an increased risk of venous and arterial thromboembolism, which can be as high as 40% depending on the severity and underlying cause of nephrotic syndrome. The 2012 Kidney Disease: Improving Global Outcomes (KDIGO) guidelines recommend prophylactic anticoagulation only in idiopathic membranous nephropathy but acknowledge that existing data are limited and of low quality. There is a need for better identification of vulnerable patients in order to balance the risks of anticoagulation. METHODS: We undertook a systematic search of the topic in MEDLINE, EMBASE and COCHRANE databases, for relevant articles between 1990 and 2019. RESULTS: A total of 2381 articles were screened, with 51 full-text articles reviewed. In all, 28 articles were included in the final review. CONCLUSION: We discuss the key questions of whom to anticoagulate, when to anticoagulate, and how to prophylactically anticoagulate adults with nephrotic syndrome. Using available evidence, we expand upon current KDIGO guidelines and construct a clinical algorithm to aid decision making for prophylactic anticoagulation in nephrotic syndrome.

Placebo-controlled, randomized clinical trial of high-dose cholecalciferol in renal dialysis patients: effect on muscle strength and quality of life.

BACKGROUND: The importance of vitamin D sufficiency in deficient dialysis patients is uncertain. This study aimed to determine if high-dose cholecalciferol for 1-year affected symptoms, muscle strength, blood pressure (BP), cardiac ischaemia, parathyroid hormone, calcium or phosphate. METHODS: This was a randomized, double-blind, placebo-controlled trial with 1-year follow-up that enrolled dialysis patients with 25-hydroxy-vitamin D [25(OH)D] concentration <50 nmol/L. Consenting patients were randomized to 50 000 U/week oral cholecalciferol or matching placebo. Dosage was adjusted at 3- and 6-month study visits, targeting a 25(OH)D concentration >80 nmol/L. The primary objectives were to assess the effect of supplementation on renal-specific symptoms and on hand-grip strength. Symptoms were assessed using the Kidney Disease Quality of Life Short Form and muscle strength with a hand grip-strength dynamometer. Hypothesis testing was by two-group t-test and Wilcoxon rank-sum on an intention-to-treat basis. RESULTS: In all, 68 participants were randomized and received study medication. Median 12-month plasma 25(OH)D concentration was 119 nmol/L and 37 nmol/L in the cholecalciferol and placebo groups, respectively. There was no statistical difference in primary outcomes at 12 months. Mean symptom scores at 12 months were two lower in the cholecalciferol group (95% confidence interval -10 to 6) and geometric mean grip-strength was 27 kg in both groups. Symptoms, strength, BP, plasma mineral bone parameters and adverse events were not different between the groups at follow-up. CONCLUSIONS: High-dose cholecalciferol in a deficient dialysis population had no effect on muscle strength or symptoms but appears safe.

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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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.

Effect of Increased Blood Flow Rate on Hemodialysis Tolerability and Achieved Urea Reduction Ratio.

Long-term hemodialysis (HD) imposes a significant burden on the quality of life of end-stage kidney disease patients. Optimizing dialysis dose is an important consideration in this population; however, evidence exists that suggests that attainment of population dialysis targets is associated with increased intradialytic complications. In this prospective, before-after study, the blood flow rate (BFR) of 63 maintenance HD patients was increased by 100 mL/min to a maximum BFR of 400 mL/min to determine the impact on patient tolerability and urea reduction ratio (URR) of an increased BFR. Tolerability was assessed by time to recovery (TTR) after dialysis, a validated measure of patient tolerability, and intradialytic complications. Median pre-increase BFR was 252 mL/min compared to 349 mL/min post-increase. Mean TTR decreased from 4.67 h to 4.03 h (P = 0.688). No association was observed between percentage change in BFR (R2 = 0.0) or post-increase BFR (R2 = 0.0) and absolute change in TTR. A significant, positive association was observed between both the absolute and relative changes to BFR and the achieved URR. We found no evidence that increasing BFR by 100 mL/min diminishes patient tolerability.

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.