William Wong

Mutations in complement C3 predispose to development of atypical hemolytic uremic syndrome

Atypical hemolytic uremic syndrome (aHUS) is a disease of complement dysregulation. In approximately 50% of patients, mutations have been described in the genes encoding the complement regulators factor H, MCP, and factor I or the activator factor B. We report here mutations in the central component of the complement cascade, C3, in association with aHUS. We describe 9 novel C3 mutations in 14 aHUS patients with a persistently low serum C3 level. We have demonstrated that 5 of these mutations are gain-of-function and 2 are inactivating. This establishes C3 as a susceptibility factor for aHUS.

Uromodulin mutations causing Familial Juvenile Hyperuricaemic Nephropathy lead to protein maturation defects and retention in the endoplasmic reticulum

Familial juvenile hyperuricaemic nephropathy (FJHN), an autosomal dominant disorder, is caused by mutations in the UMOD gene, which encodes Uromodulin, a glycosylphosphatidylinositol-anchored protein that is expressed in the thick ascending limb of the loop of Henle and excreted in the urine. Uromodulin contains three epidermal growth factor (EGF)-like domains, a cysteine-rich region which includes a domain of eight cysteines and a zona pellucida (ZP) domain. Over 90% of UMOD mutations are missense, and 62% alter a cysteine residue, implicating a role for protein misfolding in the disease. We investigated 20 northern European FJHN probands for UMOD mutations. Wild-type and mutant Uromodulins were functionally studied by expression in HeLa cells and by the use of western blot analysis and confocal microscopy. Six different UMOD missense mutations (Cys32Trp, Arg185Gly, Asp196Asn, Cys217Trp, Cys223Arg and Gly488Arg) were identified. Patients with UMOD mutations were phenotypically similar to those without UMOD mutations. The mutant Uromodulins had significantly delayed maturation, retention in the endoplasmic reticulum (ER) and reduced expression at the plasma membrane. However, Gly488Arg, which is the only mutation we identified in the ZP domain, was found to be associated with milder in vitro abnormalities and to be the only mutant Uromodulin detected in conditioned medium from transfected cells, indicating that the severity of the mutant phenotypes may depend on their location within the protein. Thus, FJHN-causing Uromodulin mutants are retained in the ER, with impaired intracellular maturation and trafficking, thereby indicating mechanisms whereby Uromodulin mutants may cause the phenotype of FJHN.

The burden of kidney disease in Indigenous children of Australia and New Zealand, epidemiology, antecedent factors and progression to chronic kidney disease

Aims:  To review and present the most important issues related to kidney disease in Aboriginal, Torres Strait Islander, Maori and Pacific Islander children from Australia and New Zealand.

Idiopathic nephrotic syndrome in New Zealand children, demographic, clinical features, initial management and outcome after twelve-month follow-up: results of a three-year national surveillance study.

Aim:  To describe the demographic, clinical features, steroid response, histopathology and complications of all children diagnosed with idiopathic nephrotic syndrome (INS) in New Zealand over a 3‐year period.

A position statement on kidney disease from powdered infant formula-based melamine exposure in Chinese infants.

Melamine, a man-made non-nutritive substance containing nitrogen, can falsely elevate measures of protein content in foodstuffs. Several manufacturers of powdered infant formula in China apparently added melamine to raise the measured protein content and thereby exposed thousands of infants and young children to very high levels of melamine. Such exposure resulted in cases of acute kidney failure and nephrolithiasis. This Editorial from members of the world-wide Pediatric Nephrology community provides a common-sense approach to the care of infants who may have been exposed to powdered infant formula in 2007–2008.

Ten years of pneumococcal-associated haemolytic uraemic syndrome in New Zealand children

Aim:  To describe the epidemiology, clinical features, management and outcome of pneumococcal‐associated haemolytic‐uraemic syndrome (P‐HUS) in New Zealand over the past decade.

Prospective population-based study on the burden of disease from post-streptococcal glomerulonephritis of hospitalised children in New Zealand: Epidemiology, clinical features and complications

A nationwide 24‐month study was conducted (2007–2009), via the New Zealand Paediatric Surveillance Unit to define epidemiology and clinical features of acute poststreptococcal glomerulonephritis (APSGN) in children hospitalised with the illness.

Cerebral thrombosis in childhood nephrosis

Abstract:  Sinovenous thrombosis is an uncommon but serious complication associated with nephrotic syndrome in children. We describe a 9‐year‐old Caucasian boy who presented with dehydration, vague neurological symptoms and seizures. A diagnosis of nephrotic syndrome was made during the course of hospitalization. The serum antithrombin III level was decreased and brain imaging showed cerebral sinovenous thrombosis. Anticoagulant therapy with heparin was commenced and the patient made a slow but gradual clinical, as well as radiological recovery. We describe this case and review available literature to highlight the importance of suspecting and recognizing this potentially life threatening complication and initiating early treatment.

Cerebral vasculitis in a child following post-streptococcal glomerulonephritis

Abstract: Cerebral vasculitis following acute post‐streptococcal glomerulonephritis (APSGN) is a rare neurological complication. An 11‐year‐old girl with biopsy proven APSGN developed an acute seizure disorder. Clinical and computed tomography findings were consistent with vasculitis.

A case of neonatal Bartter’s syndrome

Abstract. We describe a child with a neonatal presentation of Bartter’s syndrome. Unlike infants previously described with a similar clinical presentation, the urinary excretion rate of prostaglandin E2 in this child was similar to normal children and Tamm-Horsfall protein was distributed normally in the thick ascending limb of the loop of Henle. The child failed to respond to indomethacin alone, but thrived after the addition of the angiotensin converting enzyme inhibitor, captopril.