Hypertrophy of human renal glomeruli: links with disease risk factors and podocyte depletion
Creators: name: Puelles, Victor
Publisher: name: Monash University
Year: 2017
Subjects: Uncategorized

description: Chronic kidney disease (CKD) is a global pandemic associated with increasingly high health care costs and great burden of disease. Once CKD is established, it usually progresses to end stage kidney disease (ESKD), which requires dialysis or renal transplantation as life-saving interventions. In order to develop preventive strategies for CKD, a better understanding of the structural changes that occur in kidneys in pre-disease stages is needed. The studies described in this thesis constitute a rigorous analysis of human glomerular volume (and thereby glomerular hypertrophy) in subjects without renal disease, and its association with: (1) multiple CKD risk factors; and (2) cellular components of these hypertrophic glomeruli, with a focus on podocytes. The general hypothesis of this thesis, as reviewed in Chapter 1, is that “glomerular hypertrophy is multifactorial, compensatory and associated with relative podocyte depletion in subjects without renal disease”. Glomerular hypertrophy is classically viewed as a result of a nephron deficit. However, Chapters 2 and 3 challenge this perception by introducing the concept of multifactorial glomerular hypertrophy. Chapter 2 shows that multiple risk factors for CKD (including older age, obesity and hypertension) are associated with higher degrees of glomerular hypertrophy than is observed in subjects with one or no CKD risk factors. Chapter 3 provides evidence of greater glomerular hypertrophy in African Americans in the context of older age, lower nephron number and higher body mass index, which further highlights the contribution of combined CKD risk factors to glomerular hypertrophy. The findings presented in Chapter 4 suggest that glomerular hypertrophy is a compensatory response to an imbalance between nephron number and body size. However, the main issue with these extrapolations is the lack of longitudinal studies to confirm this hypothesis. Chapter 5 provides the first report of glomerular number and size in ex vivo human kidneys obtained with magnetic resonance imaging. This represents the first step towards the development of a non-invasive method for quantifying human glomerular number and size in vivo. Glomerular hypertrophy is often associated with the development of glomerulosclerosis. Recent studies suggest that podocyte depletion is a key step in the development of glomerulosclerosis. Chapter 6 describes the recommended disector/fractionator method for quantifying podocyte number in individual glomeruli when sufficient tissue is available. Chapter 7 shows the application of the disector/fractionator method to estimate podocyte number in glomeruli from children and adults. The results show that glomeruli in children are significantly smaller than in adults, and contain fewer podocytes (452 podocytes per glomerulus compared with 558 in adults). However, while large adult glomeruli contained more podocytes than small adult glomeruli and glomeruli in children, they also presented a significantly lower podocyte density, which may render them more susceptible to glomerulosclerosis. Chapter 8 summarizes the major findings of the thesis and suggests avenues for future research. These include studies of podocyte endowment in children, development of more efficient semi-automated methods for counting podocytes, and studies of podocyte numbers in renal biopsies.