Kidney aging is associated with an increasing proportion of globally scarred glomeruli, decreasing renal function, and exponentially increasing ESRD prevalence. In model systems, podocyte depletion causes glomerulosclerosis, suggesting age-associated glomerulosclerosis could be caused by a similar mechanism. We measured podocyte number, size, density, and glomerular volume in 89 normal kidney samples from living and deceased kidney donors and normal poles of nephrectomies. Podocyte nuclear density decreased with age due to a combination of decreased podocyte number per glomerulus and increased glomerular volume. Compensatory podocyte cell hypertrophy prevented a change in the proportion of tuft volume occupied by podocytes. Young kidneys had high podocyte reserve (podocyte density .300 per 10 6 mm 3 ), but by 70-80 years of age, average podocyte nuclear density decreased to, ,100 per 10 6 mm 3 , with corresponding podocyte hypertrophy. In older age podocyte detachment rate (urine podocin mRNA-to-creatinine ratio) was higher than at younger ages and podocytes were stressed (increased urine podocin-to-nephrin mRNA ratio). Moreover, in older kidneys, proteinaceous material accumulated in the Bowman space of glomeruli with low podocyte density. In a subset of these glomeruli, mass podocyte detachment events occurred in association with podocytes becoming binucleate (mitotic podocyte catastrophe) and subsequent wrinkling of glomerular capillaries, tuft collapse, and periglomerular fibrosis. In kidneys of young patients with underlying glomerular diseases similar pathologic events were identified in association with focal global glomerulosclerosis. Podocyte density reduction with age may therefore directly lead to focal global glomerulosclerosis, and all progressive glomerular diseases can be considered superimposed accelerators of this underlying process.

We examine factors affecting the success and failure of collective action toward the management of local commons. Using cross-section survey data on the activities of irrigators' associations in the Philippines, regression analysis is conducted to identify factors underlying the success and failure in farmers' organizing collective action for the maintenance and operation of irrigation systems. We find that collective action is difficult to organize where (a) water supply is uniformly abundant; (b) water supply is greatly different between upper and lower streams in lateral; (c) the size of the association is large; (d) population density is low; (e) the share of nonfarm households is high; and (f) the history of irrigated farming is short. Our findings suggest that these difficulties can be overcome with adequate supports of state agencies to promote community-level cooperation. Copyright 2005 International Association of Agricultural Economics.

The attrition rate of functioning allografts beyond the first year has not improved despite improved immunosuppression, suggesting that nonimmune mechanisms could be involved. Notably, glomerulopathies may account for about 40% of failed kidney allografts beyond the first year of engraftment, and glomerulosclerosis and progression to ESRD are caused by podocyte depletion. Model systems demonstrate that nephrectomy can precipitate hypertrophic podocyte stress that triggers progressive podocyte depletion leading to ESRD, and that this process is accompanied by accelerated podocyte detachment that can be measured in urine. Here, we show that kidney transplantation "reverse nephrectomy" is also associated with podocyte hypertrophy and increased podocyte detachment. Patients with stable normal allograft function and no proteinuria had levels of podocyte detachment similar to levels in two-kidney controls as measured by urine podocyte assay. By contrast, patients who developed transplant glomerulopathy had 10-to 20-fold increased levels of podocyte detachment. Morphometric studies showed that a subset of these patients developed reduced glomerular podocyte density within 2 years of transplantation due to reduced podocyte number per glomerulus. A second subset developed glomerulopathy by an average of 10 years after transplantation due to reduced glomerular podocyte number and glomerular tuft enlargement. Reduced podocyte density was associated with reduced eGFR, glomerulosclerosis, and proteinuria. These data are compatible with the hypothesis that podocyte depletion contributes to allograft failure and reduced allograft half-life. Mechanisms may include immune-driven processes affecting the podocyte or other cells and/or hypertrophy-induced podocyte stress causing accelerated podocyte detachment, which would be amenable to nonimmune therapeutic targeting. Podocytes are complex neuron-like postmitotic cells adherent to the underlying glomerular basement membrane via foot processes that must contiguously cover the filtration surface area to maintain the normal filtration barrier. Podocytes cannot divide in situ and have limited capacity for replacement. 1 This means that when podocytes are lost, or the glomerular surface area increases due to glomerular growth, the major adaptive response is by hypertrophy. At the same time, the podocyte's structural complexity means that its capacity to hypertrophy is limited. Inability to maintain contiguous coverage of the filtration surface by foot processes results in protein leak into the filtrate. If podocyte detachment exceeds hypertrophic capacity, other glomerular cells adapt by proliferating and laying down matrix resulting in glomerulosclerosis. [2][3][4][5][6]

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Glomerular sclerotic lesions develop when the glomerular filtration surface area exceeds the availability of podocyte foot process coverage, but the mechanisms involved are incompletely characterized. We evaluated potential mechanisms using a transgenic (podocin promoter-AA-4E-BP1) rat in which podocyte capacity for hypertrophy in response to growth factor/nutrient signaling is impaired. FSGS lesions resembling human FSGS developed spontaneously by 7 months of age, and could be induced earlier by accelerating kidney hypertrophy by nephrectomy. Early segmental glomerular lesions occurred in the absence of a detectable reduction in average podocyte number per glomerulus and resulted from the loss of podocytes in individual glomerular capillary loops. Parietal epithelial cell division, accumulation on Bowman's capsule, and tuft invasion occurred at these sites. Three different interventions that prevented kidney growth and glomerular enlargement (calorie intake reduction, inhibition of mammalian target of rapamycin complex, and inhibition of angiotensin-converting enzyme) protected against FSGS lesion development, even when initiated late in the process. Ki67 nuclear staining and unbiased transcriptomic analysis identified increased glomerular (but not podocyte) cell cycling as necessary for FSGS lesion development. The rat FSGS-associated transcriptomic signature correlated with human glomerular transcriptomes associated with disease progression, compatible with similar processes occurring in man. We conclude that FSGS lesion development resulted from glomerular growth that exceeded the capacity of podocytes to adapt and adequately cover some parts of the filtration surface. Modest modulation of the growth side of this equation significantly ameliorated FSGS progression, suggesting that glomerular growth is an underappreciated therapeutic target for preservation of renal function.