Abstract
BackgroundPodocyte depletion, which drives progressive glomerulosclerosis in glomerular diseases, is caused by a reduction in podocyte number, size or function in the context of increasing glomerular volume.MethodsKidneys obtained at autopsy from premature and mature infants who died in the first year of life (n = 24) were used to measure podometric parameters for comparison with previously reported data from older kidneys.ResultsGlomerular volume increased 4.6-fold from 0.13 ± 0.07 μm3 x106 in the pre-capillary loop stage, through 0.35 μm3 x106 at the capillary loop, to 0.60 μm3 x106 at the mature glomerular stage. Podocyte number per glomerulus increased from 326 ± 154 per glomerulus at the pre-capillary loop stage to 584 ± 131 per glomerulus at the capillary loop stage of glomerular development to reach a value of 589 ± 166 per glomerulus in mature glomeruli. Thus, the major podocyte number increase occurs in the early stages of glomerular development, in contradistinction to glomerular volume increase, which continues after birth in association with body growth.ConclusionsAs glomeruli continue to enlarge, podocyte density (number per volume) rapidly decreases, requiring a parallel rapid increase in podocyte size that allows podocyte foot processes to maintain complete coverage of the filtration surface area. Hypertrophic stresses on the glomerulus and podocyte during development and early rapid growth periods of life are therefore likely to play significant roles in determining how and when defects in podocyte structure and function due to genetic variants become clinically manifest. Therapeutic strategies aimed at minimizing mismatch between these factors may prove clinically useful.
Highlights
Podocytes are highly differentiated post-mitotic neuron-like cells with a limited capacity for replacement [1,2,3,4,5]
The realization that glomerular failure can be initiated and driven in a podocyte-dependent manner by glomerular enlargement per se, in the absence of immune, inflammatory or other insults to the glomerulus, provides insight into potential mechanisms of the progression of glomerular diseases [6, 7]. This concept is further amplified by recent studies on glomerular aging in which progressively decreasing podocyte density with age is associated with hypertrophic podocyte stress and mass podocyte detachment, glomerular tuft collapse, and focal global glomerulosclerosis [8]
All progressive glomerular diseases that have an impact on adults can be seen to be superimposed upon a steadily declining podocyte density with age, such that older people are more severely affected
Summary
Podocytes are highly differentiated post-mitotic neuron-like cells with a limited capacity for replacement [1,2,3,4,5]. The realization that glomerular failure can be initiated and driven in a podocyte-dependent manner by glomerular enlargement per se, in the absence of immune, inflammatory or other insults to the glomerulus, provides insight into potential mechanisms of the progression of glomerular diseases [6, 7] This concept is further amplified by recent studies on glomerular aging in which progressively decreasing podocyte density (number per glomerular tuft volume) with age is associated with hypertrophic podocyte stress and mass podocyte detachment, glomerular tuft collapse, and focal global glomerulosclerosis [8]. Pediatr Nephrol (2017) 32:823–834 than younger people, whatever the underlying glomerular insult [8] These concepts can help to explain the over-riding impact of older age as a dominant risk factor for both chronic kidney disease and end-stage kidney disease (ESKD) [10]. Podocyte depletion, which drives progressive glomerulosclerosis in glomerular diseases, is caused by a reduction in podocyte number, size or function in the context of increasing glomerular volume
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