The principle aim of this study was to build a national cohort of children with Steroid Resistant Nephrotic Syndrome (SRNS). The secondary aims were to establish a national registry of rare renal disease in order to build the SRNS cohort. Furthermore, to phenotype and genotype the cohort and undertake development of assays that may be effective biomarkers of disease activity peritransplantation. The successful introduction of the National Registry of Rare Renal Disease, www.renalradar.org. has enabled the nephrology community in the UK to change how it approaches patients that were otherwise considered rare, isolated and difficult to manage. Patients and their families benefit directly, not only from the research but also from the on-going education of treating clinicians and by accessing patient support through the registry. This project has produced novel work in different forms: Firstly it has built a cohort of 226 paediatric patients from around the UK with SRNS, 10% of whom have congenital nephrotic syndrome. With the collection of clinical data from a mean follow-up period of 6 years, it can be shown that in this cohort, there is a 50% risk of end stage renal failure within 10years of diagnosis. In addition, 26% of transplants were complicated by recurrence of disease. Secondly, the use of massively parallel sequencing to analyse 24 genes associated with nephrotic syndrome in 108 patients identifies a definite or probable disease causing mutation in 18.5%, including in genes that would not normally be tested in this age group. It also clearly demonstrates the need to test a panel of genes, as phenotype does not accurately predict genotype. Lastly, the identification of potential biomarkers of disease in post-transplant recurrence: Both an increase in the phosphorylation of VASP (vasodilator stimulated phosphoprotein), and an increase in motility in human podocyte cell lines occur in response to human disease plasma compared to paired remission plasma from the same patients. Identifying those patients most likely to benefit from therapy and developing effective clinical agents remain the goal in SRNS, and this work will significantly aid progress towards that end.

Benign familial haematuria (BFH) is an inherited renal disorder characterised by the presence of haematuria and the absence of progressive renal dysfiinction. Analysis of renal biopsies from affected individuals has shown that typically the only abnormality is widespread thinning of the glomerular basement membrane (GEM) visible on electron microscopy (EM). Thinning of the GBM has also been observed as the sole abnormality in patients with nonfamilial (isolated) haematuria, resulting in the diagnostic term thin basement membrane disease (TBMD). It is possible that some patients with benign familial haematuria have normal basement membranes, while others have thin basement membranes. The predominance of TBMD in patients with BFH has led some authors to use the terms interchangeably, but there are also some patients with thin basement membrane who do not have a benign prognosis. Thus the precise relationship between an abnormally thin GBM, isolated haematuria and BFH remains unclear.

The identification of mechanisms by which congenital renal tract malformations arise is an important area of research given that these defects account for approximately half of all children who progress to end-stage renal failure. Understanding the genetic contribution to this pathogenesis is of particular value, facilitating the counselling of families with a history of disease, serving to highlight the critical window(s) during which the course of development is altered, and aiding in the identification of molecular pathways that might be amenable to therapy in the future. This thesis is focused on furthering our understanding of how non-syndromic renal tract malformations are genetically determined. It was hypothesised that human renal tract malformations may be caused by mutations of genes in the Uroplakin (UP) family and Sonic hedgehog (SHH), and that these genes are expressed at specific sites in tissues during normal human renal tract development. It was shown that UPIIIa, a gene expressed in early human development, is mutated in a subset of patients with severe bilateral renal adysplasia. However, no definitive evidence was found that UPII mutations cause renal tract malformations, although variants in this gene might be a rare predisposing factor. Furthermore, no support was found for SHH mutations in human persistent cloaca, although UPIIIa mutations are occasionally associated with this condition. The expression patterns of SHH signalling proteins in normal human renal tract development is consistent with a variety of signalling modes, namely epithelial-to-epithelium canonical signalling in the cloaca, epithelial-to- mesenchyme canonical signalling in the urogenital sinus and epithelial-to-epithelium non-canonical signalling in kidney medullary collecting ducts. The discovery of mutations in children with renal tract malformations will provide families with long-sought explanations regarding the pathogenesis of disease and may also have implications for genetic counselling. The proposed studies will also shed light on the cell biology of normal human renal tract development.

Advances in health care have led to an increasing emphasis on family involvement in the day-to-day care of children with chronic renal disease, but if families do not become competent in this it can negatively influence the child's management. Research into the psychosocial implications of childhood chronic disease has been prolific in recent years, although relatively few studies have investigated the way that families learn about chronic disease management. However, a body of work is emerging in the human sciences around the premise that social engagement in communities of practice is a fundamental process by which people learn. Building on these lines of research this study, therefore, aimed to explore the way that children with chronic renal disease and their families learned to manage the condition, and to determine the impact of relationships between families and professionals on the learning process. Using grounded theory within a symbolic interactionist approach, data were collected and analysed in two phases (retrospective and prospective). Phase one aimed to uncover the issues that eight children and/or their parents identified as important in learning about the condition since diagnosis in the preceding four years. In phase two, a longitudinal approach (building on phase one analysis) involving six families and key professionals, allowed detailed exploration, over eighteen months, of learning events that arose following referral to a Children's Kidney Unit. A focus on learning by families as social participation in care was identified in the study. A novel, substantive theory, the social theory of learning in childhood chronic renal disease is proposed comprising three categories: the processes of assessing; interacting and synthesising. Assessing is the process by which families and professionals learn through assessing the disease course as well as each others' ability and social positioning. Interacting is the process whereby families and professionals learn through sharing knowledge, earning and maintaining trust and engaging jointly in decision making. Synthesising is the process whereby families' and professionals' learn through a new, shared understanding based on knowledge of each others' communities of practice, cultures and patterns of learning. The theory conceptualises family learning as: a two way process of interaction in developing an ongoing practice between family members and professionals; the influence of interpersonal as well as intrapersonal learning; and not only acquisition of skills but also the formation of identities in the context where the skills are learned. Three patterns of learning also emerged from the data (parallel, integrated and synthesised). These help to explain some of the differences and similarities between families' learning as they move through the chronic disease journey. This study develops and modifies Wenger's (1998) social theory of learning and Gibson's concept of participatory competence (1995) and contributes an innovative perspective to the growing body of knowledge around childhood chronic disease. Testing and further development of the theory and its use in child health is indicated.