Catherine Quinlan

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 patients 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.

Eosinophilic peritonitis in children on chronic peritoneal dialysis

Eosinophilic peritonitis is a response of the peritoneum to foreign substances. It presents as cloudy dialysate and may be missed because not all laboratories report the eosinophil count, giving only the total number of polymorphonuclear cells. Over a 2-year period, eight children developed 13 episodes of eosinophilic peritonitis. Three episodes were asymptomatic other than cloudy fluid, five followed surgery and two were associated with gastroenteritis. Despite recurrent episodes, there were no adverse outcomes, although a raised peritoneal eosinophil count persisted in most cases. Eosinophilic peritonitis is under-diagnosed and may lead to unnecessary antibiotic therapy.

Cyanide poisoning in the post-transplantation patient—a cautionary tale

There have been few reported cases of cyanide toxicity following treatment with sodium nitroprusside. We report on the case of a paediatric patient who had received sodium nitroprusside for intractable hypertension in the post-operative period, resulting in cyanide toxicity. Treatment with sodium thiosulphate, sodium nitrate and haemodialysis resulted in the elimination of cyanide from the circulation. The patient made a full recovery with no neurological sequelae.

Tinzaparin is safe and effective in the management of hemodialysis catheter thrombosis.

Children on hemodialysis are at increased risk of thrombosis, especially when dialyzed via a central venous catheter (CVC); there are limited published data regarding the safety and efficacy of tinzaparin in this group. We conducted a retrospective chart review of all children in the National Pediatric Hemodialysis Centre for Ireland diagnosed with a CVC thrombus and treated with subcutaneous tinzaparin over a 10 year period. Seven children were treated with subcutaneous tinzaparin for 10 CVC thrombi. Tinzaparin was commenced at 175 IU/kg/day and the dose was titrated by measuring anti-factor Xa levels, aiming for levels of 0.3–1.0 IU/ml. Treatment was continued until resolution of the CVC thrombus. Restoration of normal flows during dialysis occurred within 3 days in all patients. There were no episodes of bleeding and all children tolerated the treatment well.

Pediatric Renal Transplantation in a Highly Sensitised Child—8 Years On

Highly sensitised children have markedly reduced chances of receiving a successful deceased donor renal transplant, increased risk of rejection, and decreased graft survival. There is limited experience with the long-term followup of children who have undergone desensitization. Following 2 failed transplants, our patient was highly sensitised. She had some immunological response to intravenous immunoglobulin (IVIg) but this was not sustained. We developed a protocol involving sequential therapies with rituximab, IVIg, and plasma exchange. Immunosuppressant therapy at transplantation consisted of basiliximab, tacrolimus, mycophenolate mofetil, and steroids. At the time of transplantation, historical crossmatch was ignored. Current CDC crossmatch was negative, but T and B cell flow crossmatch was positive, due to donor-specific HLA Class I antibodies. Further plasma exchange and immunoglobulin therapy were given pre- and postoperatively. Our patient received a deceased donor-kidney-bearing HLA antigens to which she originally had antibodies, which would have precluded transplant. The graft kidney continues to function well 8 years posttransplant.

Why are kids with lupus at an increased risk of cardiovascular disease

Juvenile-onset systemic lupus erythematosus (SLE) is an aggressive multisystem autoimmune disease. Despite improvements in outcomes for adult patients, children with SLE continue to have a lower life expectancy than adults with SLE, with more aggressive disease, a higher incidence of lupus nephritis and there is an emerging awareness of their increased risk of cardiovascular disease (CVD). In this review, we discuss the evidence for an increased risk of CVD in SLE, its pathogenesis, and the clinical approach to its management.

Meeting report of the 2017 KidGen Renal Genetics Symposium

The 2017 KidGen Renal Genetics Symposium was held at the Royal Children’s Hospital and Murdoch Children’s Research Institute, Melbourne, from 6 to 8 December 2017. This meeting addressed clinical, diagnostic, and research aspects of inherited kidney disease. More than 100 clinicians, researchers, and patient representatives attended the conference. The overall goal was to improve the understanding and direction of genomics in renal medicine in Australia and discuss barriers to the use of genomic testing within this area. It also aimed to strengthen collaborations between local, state, and global research and diagnostic and clinical groups.

Use of neutrophil gelatinase-associated lipocalin (NGAL) in CF

a Infection and Immunity Theme, Murdoch Childrens Research Institute, 50 Flemington Road, Parkville, Victoria 3052, Australia b Department of Respiratory Medicine, The Royal Childrens Hospital Melbourne, 50 Flemington Road, Parkville, Victoria 3052, Australia c Department of Paediatrics, University of Melbourne, Parkville, Victoria 3052, Australia d School of Pharmacy and Medical Sciences, University of South Australia, City East Campus, North Terrace, Adelaide, South Australia 5001, Australia e Department of Nephrology, The Royal Childrens Hospital Melbourne, 50 Flemington Road, Parkville, Victoria 3052, Australia

Rhabdomyolysis in a Tertiary PICU: A 10-Year Study.

Objectives: Rhabdomyolysis is a disorder of muscle breakdown. The aim of this study was to describe the epidemiology of rhabdomyolysis in children admitted to a PICU and to assess the relationship between peak creatinine kinase and mortality. Design: Retrospective cohort study in children admitted to the PICU with rhabdomyolysis between January 1, 2005, and December 31, 2014. Demographic, clinical, and outcome data were recorded. Outcomes were analyzed by level of peak creatinine kinase value (0–10,000, 10,001–50,000, > 50,000IU/L). Long-term renal outcomes were reported for PICU survivors. Setting: A single-centre academic tertiary PICU. Patients: Children admitted to the PICU with serum creatinine kinase level greater than 1,000 IU/L. Interventions: None. Measurements and Main Results: There were 182 children with rhabdomyolysis. The median peak creatinine kinase value was 3,583 IU/L (1,554–9,608). The primary diagnostic categories included sepsis, trauma, and cardiac arrest. Mortality for peak creatinine kinase values 0–10,000, 10,001–50,000, and > 50,000 IU/L were 24/138 (17%), 6/28 (21%), and 3/16 (19%), respectively (p = 0.87). Children with a peak creatinine kinase greater than 10,000 IU/L had a longer duration of mechanical ventilation and ICU length of stay than children with peak creatinine kinase less than 10,000. Renal replacement therapy was administered in 29/182 (16%). There was longer duration of mechanical ventilation (273 [141–548] vs. 73 [17–206] hr [p < 0.001]) and ICU length of stay (334 [147–618] vs. 100 [37–232] hr (p < 0.001)] in children receiving renal replacement therapy. Continuous veno-venous hemofiltration was the most common modality 23/29 (79%). Only one child required renal replacement therapy postintensive care stay, and adverse long-term renal outcomes were uncommon. Conclusions: In children with rhabdomyolysis requiring intensive care, peak creatinine kinase was not associated with mortality but is associated with greater use of intensive care resources. Chronic kidney disease is an uncommon sequelae of rhabdomyolysis in children requiring intensive care.

Renal genetics in Australia: Kidney medicine in the genomic age: Kidney medicine in the genomic age

There have been few new therapies for patients with chronic kidney disease in the last decade. However, the management of patients affected by genetic kidney disease is rapidly evolving. Inherited or genetic kidney disease affects around 10% of adults with end‐stage kidney disease and up to 70% of children with early onset kidney disease. Advances in next‐generation sequencing have enabled rapid and cost‐effective sequencing of large amounts of DNA. Next‐generation sequencing‐based diagnostic tests now enable identification of a monogenic cause in around 20% of patients with early‐onset chronic kidney disease. A definitive diagnosis through genomic testing may negate the need for prolonged diagnostic investigations and surveillance, facilitate reproductive planning and provide accurate counselling for at‐risk relatives. Genomics has allowed the better understanding of disease pathogenesis, providing prognostic information and facilitating development of targeted treatments for patients with inherited or genetic kidney disease. Although genomic testing is becoming more readily available, there are many challenges to implementation in clinical practice. Multidisciplinary renal genetics clinics serve as a model of how some of these challenges may be overcome. Such clinics are already well established in most parts of Australia, with more to follow in future. With the rapid pace of new technology and gene discovery, collaboration between expert clinicians, laboratory and research scientists is of increasing importance to maximize benefits to patients and health‐care systems.