Glomerular Effects of Age and APOL1.

Two articles in this issue of JASN seek to identify structural weaknesses that render glomeruli liable to failure. Hodgin et al.1 examine glomerular loss with aging and propose that a gradual reduction in the number of podocytes per unit glomerular volume reaches a point where it triggers glomerular failure. As glomeruli are lost, compensatory hypertrophy of those that remain leads to additional reduction in podocyte density, because podocytes are terminally differentiated and cannot divide. The resultant self–perpetuating process of glomerular destruction causes age-related loss of renal function. In advancing their podometric view, Hodgin et al.1 reexamine the problem of age-related loss of renal function at increased structural resolution. However, as noted in the introduction to the work by Hodgin et al.1 and recently reviewed byGlassock and Rule,2 it has been remarkably hard to characterize even the more basic structural features of renal aging. This difficulty is exemplified by the two JASN papers that we are considering. Hodgin et al.1 report that glomerular volume increases markedly with age. Hoy et al.3 see little change in glomerular volume with age, except perhaps in African Americans with APOL1 risk alleles. Differences in tissue processing and clinical parameters, including body size, may account for some of the variation in these descriptions and others of renal aging. We suspect that differing morphometric methods are also a major source of variation. Hodgin et al.1 calculate average glomerular volume on the basis of the area of open glomerular profiles. Sclerosed glomeruli are not included in the calculation. Hoy et al.3 calculate average glomerular volume as the aggregate volume of glomeruli divided by the number of glomeruli. Inclusion of sclerosed glomeruli will tend to keep the average volume stable if some glomeruli enlarge while others are sclerosed. The magnitude of the difference will be increased by underrepresentation of shrunken glomeruli in small biopsy specimens as opposed to larger autopsy specimens unless mathematical corrections are made. Measurements may also be affected by inclusion of more superficial glomeruli in biopsy specimens. Recognizing that average glomerular volume is assessed by different methods, we can accept that some glomeruli enlarge while others are lost over the course of a lifetime. We presume that this occurs to varying extents in different people depending on factors, including birth weight, sex, dietary habits, body size, BP, and genetic inheritance, including race. Wedonot undertake to say that the process is normal, but only that it occurs in our society. Additionally, the extension of a fixed number of podocytes over an enlarged glomerular surface may cause injury because of podocyte insufficiency, whichwas originally proposed by Fries et al.4 The concept that podocyte insufficiency is central to progressive loss of glomerular function has since received support from studies in both human and animal disease.5 In the work by Hodgin et al.,1 they extend this concept to account for age-related loss of renal function in people without clinical renal disease. The findings in the work by Hodgin et al.1 are intriguing and will undoubtedly stimulate additional study. One question is whyHodgin et al.1 find glomerular enlargement that is out of proportion to the extent of glomerular loss with age as reflected by the prevalence of sclerosed glomeruli. A possible answer is that sclerosed glomeruli are not only underrepresented in tissue sections because of their small size but also, that, over time, they are resorbed.6 More difficult to explain, if we accept the primacy of podocyte insufficiency in agerelated injury, is why aging humans do not exhibit proteinuria and segmental glomerular sclerosis. Proteinuria and segmental sclerosis appear when podocyte loss is induced in animals and have also been considered hallmarks of secondary injury to hypertrophied remnant glomeruli after nephron loss in humans.5 Hodgin et al.1 suggest that glomeruli slowly enlarge to a point where they rapidly fail, and therefore, only small numbers of glomeruli are in the process of failing at any time. Inferences on the basis of protein excretion and GFR decline rates in secondary glomerular sclerosis, however, lead us to expect that age-related loss of renal function should still be accompanied by proteinuria and segmental sclerosis if it were similarly ascribable to podocyte insufficiency.7 Although they do not find segmental sclerosis in aging glomeruli, Hodgin et al.1 do see evidence of mass podocyte detachment events and proteinaceous material in Bowman’s space. These findings may provide new clues to the mechanisms of age–related glomerular loss, and we can hope to see them examined further at still higher resolution. Recent studies have emphasized the role of autophagy, which removes dysfunctional mitochondria and other cytoplasmic Published online ahead of print. Publication date available at www.jasn.org.