A multicenter retrospective study of calcineurin inhibitors in nephrotic syndrome secondary to podocyte gene variants.

While 44-83% of children with steroid-resistant nephrotic syndrome (SRNS) without a proven genetic cause respond to treatment with a calcineurin inhibitor (CNI), current guidelines recommend against the use of immunosuppression in monogenic SRNS. This is despite existing evidence suggesting that remission with CNI treatment is possible and can improve prognosis in some cases of monogenic SRNS. Herein, our retrospective study assessed response frequency, predictors of response and kidney function outcomes among children with monogenic SRNS treated with a CNI for at least three months. Data from 203 cases (age 0-18 years) were collected from 37 pediatric nephrology centers. Variant pathogenicity was reviewed by a geneticist, and 122 patients with a pathogenic and 19 with a possible pathogenic genotype were included in the analysis. After six months of treatment and at last visit, 27.6% and 22.5% of all patients respectively, demonstrated partial or full response. Achievement of at least partial response at six months of treatment conferred a significant reduction in kidney failure risk at last follow-up compared to no response (hazard ratio [95% confidence interval] 0.25, [0.10-0.62]). Moreover, risk of kidney failure was significantly lower when only those with a follow-up longer than two years were considered (hazard ratio 0.35, [0.14-0.91]). Higher serum albumin level at CNI initiation was the only factor related to increased likelihood of significant remission at six months (odds ratio [95% confidence interval] 1.16, [1.08-1.24]). Thus, our findings justify a treatment trial with a CNI also in children with monogenic SRNS.

Understanding the ongoing learning needs of Australian paediatricians: Evaluation of a pilot paediatric video teaching programme.

AIM: The purpose of this study was to evaluate whether pre-recorded video-based lectures (VBLs) covering a range of paediatric topics are an acceptable means of providing ongoing education for consultant and trainee paediatricians in Australia. METHODS: Previous participants (paediatric consultants and junior medical officers) of a neurology outreach teleconference programme offered by a paediatric neurologist between 2017 and 2020 were invited to participate in a multi-specialty pre-recorded video-based education programme. Acceptability was explored by assessing relevance, likelihood of utilising VBL's in the future, uptake and learning activity preferences. The impact of VBLs on confidence, currency and practice was also explored. Additional data including topics of interest, preferred video format, duration, viewing method and frequency of delivery were captured, to better understand participant preferences to inform future efforts. RESULTS: A total of 135 consented; 116 returned baseline; 94 returned follow-up surveys. Preferred learning activities included a live/interactive component. Videos were considered relevant. Preferences for pre-recorded videos improved from ninth to sixth most preferred learning activity post-intervention. VBL convenience and accessibility were valued. Practice was altered in: approach to management, use of treatments, confidence in decision-making, and discussion with families and patients. The average view duration was 16 min. Longer videos yielded slightly lower audience retention rates. For future offerings, the majority endorsed a preference for a 'mixed' video format and duration of 20-40 min, offered monthly. CONCLUSION: Video-based medical education is an appealing and sustainable alternative, given the convenience of unrestricted accessibility, in meeting ongoing learning needs of Australian paediatricians and trainees.

Variant Location Is a Novel Risk Factor for Individuals With Arrhythmogenic Cardiomyopathy Due to a Desmoplakin (DSP) Truncating Variant.

BACKGROUND: Truncating variants in desmoplakin (DSPtv) are an important cause of arrhythmogenic cardiomyopathy; however the genetic architecture and genotype-specific risk factors are incompletely understood. We evaluated phenotype, risk factors for ventricular arrhythmias, and underlying genetics of DSPtv cardiomyopathy. METHODS: Individuals with DSPtv and any cardiac phenotype, and their gene-positive family members were included from multiple international centers. Clinical data and family history information were collected. Event-free survival from ventricular arrhythmia was assessed. Variant location was compared between cases and controls, and literature review of reported DSPtv performed. RESULTS: There were 98 probands and 72 family members (mean age at diagnosis 43±8 years, 59% women) with a DSPtv, of which 146 were considered clinically affected. Ventricular arrhythmia (sudden cardiac arrest, sustained ventricular tachycardia, appropriate implantable cardioverter defibrillator therapy) occurred in 56 (33%) individuals. DSPtv location and proband status were independent risk factors for ventricular arrhythmia. Further, gene region was important with variants in cases (cohort n=98; Clinvar n=167) more likely to occur in the regions resulting in nonsense mediated decay of both major DSP isoforms, compared with n=124 genome aggregation database control variants (148 [83.6%] versus 29 [16.4%]; P<0.0001). CONCLUSIONS: In the largest series of individuals with DSPtv, we demonstrate that variant location is a novel risk factor for ventricular arrhythmia, can inform variant interpretation, and provide critical insights to allow for precision-based clinical management.

Baseline characteristics of participants in the NAVKIDS2 trial: a patient navigator program in children with chronic kidney disease.

BACKGROUND: Children with chronic kidney disease (CKD) require multidisciplinary care to meet their complex healthcare needs. Patient navigators are trained non-medical personnel who assist patients and caregivers to overcome barriers to accessing health services through care coordination. This trial aims to determine the effectiveness of a patient navigator program in children with CKD. METHODS: The NAVKIDS2 trial is a multi-center, waitlisted, randomized controlled trial of patient navigators in children with CKD conducted at five sites across Australia. Children (0-16 years) with CKD from low socioeconomic status rural or remote areas were randomized to an intervention group or a waitlisted control group (to receive intervention after 6 months). The study primary and secondary endpoints include the self-rated health (SRH) (primary), and utility-based quality of life, progression of kidney dysfunction of the child, SRH, and satisfaction with healthcare of the caregiver at 6 months post-randomization. RESULTS: The trial completed recruitment in October 2021 with expected completion of follow-up by October 2022. There were 162 patients enrolled with 80 and 82 patients randomized to the immediate intervention and waitlisted groups, respectively. Fifty-eight (36%) participants were from regional/remote areas, with a median (IQR) age of 9.5 (5.0, 13.0) years, 46% were of European Australian ethnicity, and 65% were male. A total of 109 children (67%) had CKD stages 1-5, 42 (26%) were transplant recipients, and 11 (7%) were receiving dialysis. CONCLUSION: The NAVKIDS2 trial is designed to evaluate the effectiveness of patient navigation in children with CKD from families experiencing socioeconomic disadvantage. A higher resolution version of the Graphical abstract is available as Supplementary information.

Immunologic response to SARS-CoV-2 mRNA vaccination in pediatric kidney transplant recipients.

BACKGROUND: COVID-19 disease in kidney transplant (KT) recipients is associated with increased morbidity, mortality, and hospitalization rates. Unfortunately, KT recipients also have a reduced response to SARS-CoV-2 immunization. The primary aim of this study was to assess immunologic response to SARS-CoV-2 mRNA vaccines in pediatric kidney transplant recipients 12-18 years of age. Secondary aims were to assess response rates following a third immunization and determine factors that influence immunization response. METHODS: Pediatric KT recipients in a single tertiary center received SARS-CoV-2 mRNA vaccination as per local protocol. SARS-CoV-2 immunoglobulin (IgG) was measured following second and/or third vaccination. Demographics including patient factors (age, gender, and underlying disease), transplant factors (time and type of transplant), and immunosuppression (induction, maintenance, and immunomodulatory therapies such as IVIG) were collected from the medical records. RESULTS: Of 20 participants, 10 (50%) responded following a two-dose vaccine schedule, which increased to 15 (75%) after three doses. Maintenance immunosuppression affected immunologic response, with azathioprine demonstrating a higher rate of response to vaccine compared to mycophenolate (100% vs. 38%, p = 0.04). Increasing prednisolone dose had a negative impact on immunologic response (0.01 mg/kg/day increase: OR 1.60 95% CI 1.01 to 2.57). Tacrolimus dose and trough levels, age, time post-transplant, underlying disease, and other immunosuppression did not impact immunologic response. CONCLUSIONS: Pediatric KT recipients had similar response rates following SARS-CoV-2 immunization as adult KT recipients. Immunologic response improved following a third immunization. Choice of antimetabolite and prednisolone dosing influenced the rate of response. A higher resolution version of the Graphical abstract is available as Supplementary Information.

Participant Choice towards Receiving Potential Additional Findings in an Australian Nephrology Research Genomics Study.

The choices of participants in nephrology research genomics studies about receiving additional findings (AFs) are unclear as are participant factors that might influence those choices. Methods: Participant choices and factors potentially impacting decisions about AFs were examined in an Australian study applying research genomic testing following uninformative diagnostic genetic testing for suspected monogenic kidney disease. Results: 93% of participants (195/210) chose to receive potential AFs. There were no statistically significant differences between those consenting to receive AFs or not in terms of gender (p = 0.97), median age (p = 0.56), being personally affected by the inherited kidney disease of interest (p = 0.38), or by the inheritance pattern (p = 0.12-0.19). Participants were more likely to choose not to receive AFs if the family proband presented in adulthood (p = 0.01), if there was family history of another genetic disorder (p = 0.01), and where the consent process was undertaken by an adult nephrologist (p = 0.01). Conclusion: The majority of participants in this nephrology research genomics study chose to receive potential AFs. Younger age of the family proband, family history of an alternate genetic disorder, and consenting by some multidisciplinary team members might impact upon participant choices.

NAVKIDS2 trial: a multi-centre, waitlisted randomised controlled trial of a patient navigator intervention in children with chronic kidney disease - statistical analysis plan and update to the protocol.

BACKGROUND: This update summarises key changes made to the protocol since the publication of the original protocol for the NAVKIDS2 trial of patient navigators for children with chronic kidney disease (CKD) experiencing social disadvantage and provides the statistical analysis plan (SAP) which has not previously been published. METHODS/DESIGN: The original protocol was published in BMC Nephrology ( https://doi.org/10.1186/s12882-019-1325-y ) prior to the commencement of trial recruitment. During the course of the trial, some key methodological changes needed to be made including changes to eligibility criteria (addition of patients with CKD stages 1-2, broadening of financial status eligibility criterion, addition of patients living in rural/remote areas, modification of age eligibility to 0-16 years, addition of limits related to the language spoken by family, guidance regarding families with multiple eligible children), changes to sites, reduction of sample size, addition of virtual options for consent and study procedures in response to the COVID-19 pandemic, removal of staggered recruitment across sites, addition of outcomes, and changes to the timing and number of assessments. This update summarises the changes made and their rationale and provides the detailed plan for statistical analysis of the trial. These changes have been finalised prior to the completion of study follow-up and the commencement of data analysis. TRIAL REGISTRATION: Australian New Zealand Clinical Trials Registry (ANZCTR) ACTRN12618001152213 . Prospectively registered on 12 July 2018.

Genetic Testing in the Pediatric Nephrology Clinic: Understanding Families' Experiences.

Genomics is rapidly being integrated into the routine care of children and families living with renal disease, principally as a diagnostic tool but also to direct therapy, identify at-risk relatives, and facilitate family planning. However, despite significant progress in understanding the genetic heterogeneity of inherited renal disease, the impact of genetic testing on parents and families of affected children is not well understood. This study aimed to investigate the experiences of families undergoing genetic testing, the psychosocial impact of receiving a genetic test result, and parent information and support needs. In-depth semistructured interviews were conducted with 26 parents of pediatric patients (<18 years of age) who had undergone genomic investigation for a suspected genetic renal disease at two tertiary pediatric nephrology services. Interviews were transcribed verbatim, coded, using NVivo software, and thematic analysis was undertaken. Key themes included emotional adjustment to a genetic diagnosis, the importance of parent-provider relationships, empowerment through social connection, and the value of family-centered care. Results highlighted the wide-ranging psychosocial impact of genetic testing on parents, as well as the importance of patient-support networks in enabling parents/families to cope and adapt. Targeted approaches to enhance communication of genetic information and the development of tailored resources to address parents' genetics and health service needs may lead to more satisfactory experiences of genetic testing.

Interleukin-33 Exacerbates IgA Glomerulonephritis in Transgenic Mice Overexpressing B Cell Activating Factor.

BACKGROUND: The cytokine IL-33 is an activator of innate lymphoid cells 2 (ILC2s) in innate immunity and allergic inflammation. B cell activating factor (BAFF) plays a central role in B cell proliferation and differentiation, and high levels of this protein cause excess antibody production, including IgA. BAFF-transgenic mice overexpress BAFF and spontaneously develop glomerulonephritis that resembles human IgA nephropathy. METHODS: We administered IL-33 or PBS to wild-type and BAFF-transgenic mice. After treating Rag1-deficient mice with IL-33, with or without anti-CD90.2 to preferentially deplete ILC2s, we isolated splenocytes, which were adoptively transferred into BAFF-transgenic mice. RESULTS: BAFF-transgenic mice treated with IL-33 developed more severe kidney dysfunction and proteinuria, glomerular sclerosis, tubulointerstitial damage, and glomerular deposition of IgA and C3. Compared with wild-type mice, BAFF-transgenic mice exhibited increases of CD19+ B cells in spleen and kidney and ILC2s in kidney and intestine, which were further increased by administration of IL-33. Administering IL-33 to wild-type mice had no effect on kidney function or histology, nor did it alter the number of ILC2s in spleen, kidney, or intestine. To understand the role of ILC2s, splenocytes were transferred from IL-33-treated Rag1-deficient mice into BAFF-transgenic mice. Glomerulonephritis and IgA deposition were exacerbated by transfer of IL-33-stimulated Rag1-deficient splenocytes, but not by ILC2 (anti-CD90.2)-depleted splenocytes. Wild-type mice infused with IL-33-treated Rag1-deficient splenocytes showed no change in kidney function or ILC2 numbers or distribution. CONCLUSIONS: IL-33-expanded ILC2s exacerbated IgA glomerulonephritis in a mouse model. These findings indicate that IL-33 and ILC2s warrant evaluation as possible mediators of human IgA nephropathy.

Exploring the relevance of NUP93 variants in steroid-resistant nephrotic syndrome using next generation sequencing and a fly kidney model.

BACKGROUND: Variants in genes encoding nuclear pore complex (NPC) proteins are a newly identified cause of paediatric steroid-resistant nephrotic syndrome (SRNS). Recent reports describing NUP93 variants suggest these could be a significant cause of paediatric onset SRNS. We report NUP93 cases in the UK and demonstrate in vivo functional effects of Nup93 depletion in a fly (Drosophila melanogaster) nephrocyte model. METHODS: Three hundred thirty-seven paediatric SRNS patients from the National cohort of patients with Nephrotic Syndrome (NephroS) were whole exome and/or whole genome sequenced. Patients were screened for over 70 genes known to be associated with Nephrotic Syndrome (NS). D. melanogaster Nup93 knockdown was achieved by RNA interference using nephrocyte-restricted drivers. RESULTS: Six novel homozygous and compound heterozygous NUP93 variants were detected in 3 sporadic and 2 familial paediatric onset SRNS characterised histologically by focal segmental glomerulosclerosis (FSGS) and progressing to kidney failure by 12 months from clinical diagnosis. Silencing of the two orthologs of human NUP93 expressed in D. melanogaster, Nup93-1, and Nup93-2 resulted in significant signal reduction of up to 82% in adult pericardial nephrocytes with concomitant disruption of NPC protein expression. Additionally, nephrocyte morphology was highly abnormal in Nup93-1 and Nup93-2 silenced flies surviving to adulthood. CONCLUSION: We expand the spectrum of NUP93 variants detected in paediatric onset SRNS and demonstrate its incidence within a national cohort. Silencing of either D. melanogaster Nup93 ortholog caused a severe nephrocyte phenotype, signaling an important role for the nucleoporin complex in podocyte biology. A higher resolution version of the Graphical abstract is available as Supplementary information.

A working partnership: A review of shared decision-making in nephrology.

Patients with chronic kidney disease are required to make difficult decisions, negotiating between the risks, burdens and benefits for any proposed course. This process can be extremely challenging, since these decisions involve inherent risks, which can impact on survival and quality of life. Shared decision-making offers a patient-centred approach in partnering with patients to make decisions about their treatment, which reflect their values and preferences. Shared decision-making can improve patient preparedness, motivation, satisfaction, and adherence to the treatment or decision agreed upon. In this review article, we outline the key principles of shared decision-making, and provide a framework with communication strategies to facilitate shared decision-making. We highlight the broad range and context of decisions faced by patients in several areas of nephrology care and discuss patient-important outcomes, priorities and motivations that underpin their decision-making. Preserving patient autonomy through shared decision-making ensures close consideration of patient preferences to enhance satisfaction with the decision reached and optimize outcomes important to patients.

Australia and New Zealand renal gene panel testing in routine clinical practice of 542 families.

Genetic testing in nephrology clinical practice has moved rapidly from a rare specialized test to routine practice both in pediatric and adult nephrology. However, clear information pertaining to the likely outcome of testing is still missing. Here we describe the experience of the accredited Australia and New Zealand Renal Gene Panels clinical service, reporting on sequencing for 552 individuals from 542 families with suspected kidney disease in Australia and New Zealand. An increasing number of referrals have been processed since service inception with an overall diagnostic rate of 35%. The likelihood of identifying a causative variant varies according to both age at referral and gene panel. Although results from high throughput genetic testing have been primarily for diagnostic purposes, they will increasingly play an important role in directing treatment, genetic counseling, and family planning.

The impact of caring for children with posterior urethral valves.

AIM: To investigate and describe factors contributing to the impact of caring for a child with posterior urethral valves and to determine the extent to which families view their care as family-centred, and whether this can affect the impact of care. METHODS: A cross-sectional, survey-based study involving primary caregivers of children with posterior urethral valves. Caregivers completed the Impact on Family Scale (IOFS) and the Measure of Processes of Care (MPOC). Regression analyses were used to assess the relationship between child-related variables, demographic variables, MPOC and IOFS scores. RESULTS: Thirty-one primary caregivers completed both questionnaires. Caregivers of children with moderate/severe chronic kidney disease (CKD) scored higher on the IOFS compared to those caring for children with mild CKD. Caregivers rated care received highly but reported lower scores in subscales related to information provision. Receiving less respectful and supportive care was significantly associated with lower IOFS scores. CONCLUSION: The impact of caring for a child with posterior urethral valves is variable and is strongly determined by the severity of the associated CKD. Further research is required to show whether improving family centredness of care can reduce the impact of caring for children with posterior urethral valves.

Massively parallel sequencing and targeted exomes in familial kidney disease can diagnose underlying genetic disorders.

Inherited kidney disease encompasses a broad range of disorders, with both multiple genes contributing to specific phenotypes and single gene defects having multiple clinical presentations. Advances in sequencing capacity may allow a genetic diagnosis for familial renal disease, by testing the increasing number of known causative genes. However, there has been limited translation of research findings of causative genes into clinical settings. Here, we report the results of a national accredited diagnostic genetic service for familial renal disease. An expert multidisciplinary team developed a targeted exomic sequencing approach with ten curated multigene panels (207 genes) and variant assessment individualized to the patient's phenotype. A genetic diagnosis (pathogenic genetic variant[s]) was identified in 58 of 135 families referred in two years. The genetic diagnosis rate was similar between families with a pediatric versus adult proband (46% vs 40%), although significant differences were found in certain panels such as atypical hemolytic uremic syndrome (88% vs 17%). High diagnostic rates were found for Alport syndrome (22 of 27) and tubular disorders (8 of 10), whereas the monogenic diagnostic rate for congenital anomalies of the kidney and urinary tract was one of 13. Quality reporting was aided by a strong clinical renal and genetic multidisciplinary committee review. Importantly, for a diagnostic service, few variants of uncertain significance were found with this targeted, phenotype-based approach. Thus, use of targeted massively parallel sequencing approaches in inherited kidney disease has a significant capacity to diagnose the underlying genetic disorder across most renal phenotypes.

Genomic and clinical profiling of a national nephrotic syndrome cohort advocates a precision medicine approach to disease management.

Steroid Resistant Nephrotic Syndrome (SRNS) in children and young adults has differing etiologies with monogenic disease accounting for 2.9-30% in selected series. Using whole exome sequencing we sought to stratify a national population of children with SRNS into monogenic and non-monogenic forms, and further define those groups by detailed phenotypic analysis. Pediatric patients with SRNS were identified via a national United Kingdom Renal Registry. Whole exome sequencing was performed on 187 patients, of which 12% have a positive family history with a focus on the 53 genes currently known to be associated with nephrotic syndrome. Genetic findings were correlated with individual case disease characteristics. Disease causing variants were detected in 26.2% of patients. Most often this occurred in the three most common SRNS-associated genes: NPHS1, NPHS2, and WT1 but also in 14 other genes. The genotype did not always correlate with expected phenotype since mutations in OCRL, COL4A3, and DGKE associated with specific syndromes were detected in patients with isolated renal disease. Analysis by primary/presumed compared with secondary steroid resistance found 30.8% monogenic disease in primary compared with none in secondary SRNS permitting further mechanistic stratification. Genetic SRNS progressed faster to end stage renal failure, with no documented disease recurrence post-transplantation within this cohort. Primary steroid resistance in which no gene mutation was identified had a 47.8% risk of recurrence. In this unbiased pediatric population, whole exome sequencing allowed screening of all current candidate genes. Thus, deep phenotyping combined with whole exome sequencing is an effective tool for early identification of SRNS etiology, yielding an evidence-based algorithm for clinical management.