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 dem- IntroductionMutations in the genes encoding the complement regulators factor H, 1-6 factor I, 7,8 and membrane cofactor protein (MCP; CD46), 9,10 as well as in the activating component factor B, 11 have been detected in approximately 50% of patients with atypical hemolytic uremic syndrome (aHUS). 12 A proportion of the remaining patients have persistently low serum levels of C3. In this study we have examined the hypothesis that mutations in the gene encoding C3 could be associated with aHUS in these patients.C3 is the pivotal component of the complement system. 13 Activation of the classical, lectin, and alternative pathways results in cleavage of C3 to generate C3b and the anaphylatoxin C3a. When C3b is produced, the thioester is cleaved, and then this highly reactive species may bind covalently to targets. Interaction of the zymogen factor B with C3b and subsequent cleavage of factor B by factor D results in formation of the alternative pathway C3 convertase C3bBb. This set of reactions represents an amplification loop.A series of complement regulators including factor H and MCP prevent feedback via this loop by increasing the rate of dissociation of C3bBb and/or by serving as cofactors for the serine protease factor I to cleave C3b. Mutations in the gene encoding factor B were recently found to enhance formation of C3bBb or increase resistance to inactivation. 11 The importance of C3 as a susceptibility factor for human disease has been emphasized by recent studies documenting that a common nonsynonymous coding change in C3 (rs2230199, Arg80Gly, corresponding to C3S and C3F) is both a susceptibility factor for age-related macular degeneration 14 and associated with long-term renal allograft survival. 15 Methods SubjectsIn 2 independent cohorts of aHUS patients (Paris, France and Newcastle upon Tyne, United Kingdom), 26 patients (17 Paris, 9 Newcastle) with a serum C3 level persistently below the lower end of the normal range of 680 to 1380 mg/L were identified. In these patients functionally significant mutations in CFH, MCP, CFI, and CFB had not previously been detected. Mutation screening of C3 was undertaken in these patients.Approval for this study was obtained from the Departement de la Rechereche Clinique et du Developement, DRRC Ile de France, France and the Northern and Mutation screeningThe coding sequence of C3 was amplified with flanking primers (Table S1, available on the Blood website; see the Supplemental Materials link at the top of the online article). Direct sequencing was undertaken using a 96-capillary Sequencer 3700 (Applied Biosyst...

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 incidence and outcome of children with INS are similar to overseas studies. A large variety of steroid treatment regimens were noted. Current evidenced-based guidelines to treat INS were used infrequently.

Post-streptococcal glomerulonephritis (PSGN) is the commonest cause of severe acute glomerulonephritis in New Zealand children, with the majority (85%) of the patients being of either Pacific Island or Maori ethnicity. We have performed a retrospective study on 27 pediatric patients with acute PSGN. Of these patients, those with crescentic glomerulonephritis (n = 11) had a greater tendency (72.7%) for needing acute dialysis and were left with persistent urinary sediment abnormalities after a mean follow-up of 3.2 years (95% confidence interval 2.1-4.3). The efficacy of immunosuppression in the group with crescentic disease was uncertain. The severity of renal histopathological abnormalities as judged by the total biopsy score did not correlate with either presentation or eventual outcome. Severe childhood acute post-streptococcal glomerulonephritis, although uncommon, results in significant long-term renal morbidity, particularly among Maori and Pacific Island children.

Idiopathic nephrotic syndrome is the most frequent pediatric glomerular disease, affecting from 1.15 to 16.9 per 100,000 children per year globally. It is characterized by massive proteinuria, hypoalbuminemia, and/or concomitant edema. Approximately 85–90% of patients attain complete remission of proteinuria within 4–6 weeks of treatment with glucocorticoids, and therefore, have steroid-sensitive nephrotic syndrome (SSNS). Among those patients who are steroid sensitive, 70–80% will have at least one relapse during follow-up, and up to 50% of these patients will experience frequent relapses or become dependent on glucocorticoids to maintain remission. The dose and duration of steroid treatment to prolong time between relapses remains a subject of much debate, and patients continue to experience a high prevalence of steroid-related morbidity. Various steroid-sparing immunosuppressive drugs have been used in clinical practice; however, there is marked practice variation in the selection of these drugs and timing of their introduction during the course of the disease. Therefore, international evidence-based clinical practice recommendations (CPRs) are needed to guide clinical practice and reduce practice variation. The International Pediatric Nephrology Association (IPNA) convened a team of experts including pediatric nephrologists, an adult nephrologist, and a patient representative to develop comprehensive CPRs on the diagnosis and management of SSNS in children. After performing a systematic literature review on 12 clinically relevant PICO (Patient or Population covered, Intervention, Comparator, Outcome) questions, recommendations were formulated and formally graded at several virtual consensus meetings. New definitions for treatment outcomes to help guide change of therapy and recommendations for important research questions are given.