Podocyte density as a predictor of long-term kidney outcome in obesity-related glomerulopathy

Abstract

Glomerulomegaly and focal segmental glomerulosclerosis are histopathological hallmarks of obesity-related glomerulopathy (ORG). Podocyte injury and subsequent depletion are regarded as key processes in the development of these glomerular lesions in patients with ORG, but their impact on long-term kidney outcome is undetermined. Here, we correlated clinicopathological findings and podocyte depletion retrospectively in patients with ORG. Relative (podocyte density) and absolute (podocyte number per glomerulus) measures of podocyte depletion were estimated using model-based stereology in 46 patients with ORG. The combined endpoint of kidney outcomes was defined as a 30% decline in estimated glomerular filtration rate (eGFR) or kidney failure. Patients with lower podocyte density were predominantly male and had larger body surface area, greater proteinuria, fewer non-sclerotic glomeruli, larger glomeruli and higher single-nephron eGFR. During a median follow-up of 4.1 years, 18 (39%) patients reached endpoint. Kidney survival in patients with lower podocyte density was significantly worse than in patients with higher podocyte density. However, there was no difference in kidney survival between patient groups based on podocyte number per glomerulus. Cox hazard analysis showed that podocyte density, but not podocyte number per glomerulus, was associated with the kidney outcomes after adjustment for clinicopathological confounders. Thus, our study demonstrates that a relative depletion of podocytes better predicts long-term kidney outcomes than does absolute depletion of podocytes. Hence, the findings implicate mismatch between glomerular enlargement and podocyte number as a crucial determinant of disease progression in ORG. Glomerulomegaly and focal segmental glomerulosclerosis are histopathological hallmarks of obesity-related glomerulopathy (ORG). Podocyte injury and subsequent depletion are regarded as key processes in the development of these glomerular lesions in patients with ORG, but their impact on long-term kidney outcome is undetermined. Here, we correlated clinicopathological findings and podocyte depletion retrospectively in patients with ORG. Relative (podocyte density) and absolute (podocyte number per glomerulus) measures of podocyte depletion were estimated using model-based stereology in 46 patients with ORG. The combined endpoint of kidney outcomes was defined as a 30% decline in estimated glomerular filtration rate (eGFR) or kidney failure. Patients with lower podocyte density were predominantly male and had larger body surface area, greater proteinuria, fewer non-sclerotic glomeruli, larger glomeruli and higher single-nephron eGFR. During a median follow-up of 4.1 years, 18 (39%) patients reached endpoint. Kidney survival in patients with lower podocyte density was significantly worse than in patients with higher podocyte density. However, there was no difference in kidney survival between patient groups based on podocyte number per glomerulus. Cox hazard analysis showed that podocyte density, but not podocyte number per glomerulus, was associated with the kidney outcomes after adjustment for clinicopathological confounders. Thus, our study demonstrates that a relative depletion of podocytes better predicts long-term kidney outcomes than does absolute depletion of podocytes. Hence, the findings implicate mismatch between glomerular enlargement and podocyte number as a crucial determinant of disease progression in ORG. Lay SummaryPodocyte injury is recognized as the key event in the development and progression of obesity-related glomerulopathy (ORG). Because podocytes have a limited ability to proliferate or regenerate, podocyte density decreases as glomeruli enlarge by hyperfiltration (relative podocyte depletion), whereas persistent podocyte injury may accelerate podocyte loss (absolute podocyte depletion). However, it is not clear which form of podocyte insufficiency more closely associates with ORG pathophysiology. This study suggests that alterations in podometrics, including reduced podocyte density, are early morphologic features and possible predisposing factors for ORG. Furthermore, this is the first study to show that relative podocyte depletion better predicts worse long-term kidney outcomes of ORG than absolute podocyte depletion, suggesting a utility of podocyte density in the clinical setting. Podocyte injury is recognized as the key event in the development and progression of obesity-related glomerulopathy (ORG). Because podocytes have a limited ability to proliferate or regenerate, podocyte density decreases as glomeruli enlarge by hyperfiltration (relative podocyte depletion), whereas persistent podocyte injury may accelerate podocyte loss (absolute podocyte depletion). However, it is not clear which form of podocyte insufficiency more closely associates with ORG pathophysiology. This study suggests that alterations in podometrics, including reduced podocyte density, are early morphologic features and possible predisposing factors for ORG. Furthermore, this is the first study to show that relative podocyte depletion better predicts worse long-term kidney outcomes of ORG than absolute podocyte depletion, suggesting a utility of podocyte density in the clinical setting. Obesity is associated with many comorbidities and is 1 of the major public health issues worldwide.1Ortega F.B. Lavie C.J. Blair S.N. Obesity and cardiovascular disease.Circ Res. 2016; 118: 1752-1770Crossref PubMed Scopus (785) Google Scholar It has been established that obesity is not only a factor involved in the progression of chronic kidney disease, but is also an independent risk factor for the development of chronic kidney disease.2Fox C.S. Larson M.G. Leip E.P. et al.Predictors of new-onset kidney disease in a community-based population.JAMA. 2004; 291: 844-850Crossref PubMed Scopus (1048) Google Scholar,3Garofalo C. Borrelli S. Minutolo R. et al.A systematic review and meta-analysis suggests obesity predicts onset of chronic kidney disease in the general population.Kidney Int. 2017; 91: 1224-1235Abstract Full Text Full Text PDF PubMed Scopus (220) Google Scholar Despite the fact that a substantial proportion of the global population is obese, only a minority of obese individuals exhibit obvious kidney disease, as evidenced by urinary abnormalities or impaired kidney function.4Lin W.Y. Pi-Sunyer F.X. Liu C.S. et al.Central obesity and albuminuria: both cross-sectional and longitudinal studies in Chinese.PLoS One. 2012; 7e47960Crossref Scopus (26) Google Scholar,5Hashimoto Y. Tanaka M. Okada H. et al.Metabolically healthy obesity and risk of incident CKD.Clin J Am Soc Nephrol. 2015; 10: 578-583Crossref PubMed Scopus (130) Google Scholar This suggests that the kidney injury associated with obesity is not simply attributable to obesity. Obesity-related glomerulopathy (ORG) is a clinical-pathologic condition occurring in obese subjects that requires kidney biopsy for diagnosis.6Kambham N. Markowitz G.S. Valeri A.M. et al.Obesity-related glomerulopathy: an emerging epidemic.Kidney Int. 2001; 59: 1498-1509Abstract Full Text Full Text PDF PubMed Scopus (1083) Google Scholar,7D'Agati V.D. Chagnac A. de Vries A.P. et al.Obesity-related glomerulopathy: clinical and pathologic characteristics and pathogenesis.Nat Rev Nephrol. 2016; 12: 453-471Crossref PubMed Scopus (475) Google Scholar The clinical manifestations of ORG include mild to massive proteinuria, low incidence of nephrotic syndrome, and slowly progressive kidney functional decline.6Kambham N. Markowitz G.S. Valeri A.M. et al.Obesity-related glomerulopathy: an emerging epidemic.Kidney Int. 2001; 59: 1498-1509Abstract Full Text Full Text PDF PubMed Scopus (1083) Google Scholar,7D'Agati V.D. Chagnac A. de Vries A.P. et al.Obesity-related glomerulopathy: clinical and pathologic characteristics and pathogenesis.Nat Rev Nephrol. 2016; 12: 453-471Crossref PubMed Scopus (475) Google Scholar Previous studies reported that heavy proteinuria and reduced kidney function are associated with worse long-term kidney outcomes in patients with ORG.6Kambham N. Markowitz G.S. Valeri A.M. et al.Obesity-related glomerulopathy: an emerging epidemic.Kidney Int. 2001; 59: 1498-1509Abstract Full Text Full Text PDF PubMed Scopus (1083) Google Scholar,8Praga M. Hernández E. Morales E. et al.Clinical features and long-term outcome of obesity-associated focal segmental glomerulosclerosis.Nephrol Dial Transplant. 2001; 16: 1790-1798Crossref PubMed Scopus (265) Google Scholar,9Tsuboi N. Koike K. Hirano K. et al.Clinical features and long-term renal outcomes of Japanese patients with obesity-related glomerulopathy.Clin Exp Nephrol. 2013; 17: 379-385Crossref PubMed Scopus (43) Google Scholar ORG is histologically characterized by glomerulomegaly, low glomerular density (decreased number of glomerular profiles on a histologic focal segmental glomerular of the and mild to podocyte V.D. Chagnac A. de Vries A.P. et al.Obesity-related glomerulopathy: clinical and pathologic characteristics and pathogenesis.Nat Rev Nephrol. 2016; 12: 453-471Crossref PubMed Scopus (475) Google N. Y. A. et renal of 2017; Full Text Full Text PDF PubMed Scopus Google N. Y. et glomerular density with in obesity-related glomerulopathy.Clin J Am Soc Nephrol. 2012; PubMed Scopus Google et in obesity-related glomerulopathy in of J PubMed Scopus Google Scholar loss studies in obese individuals have that obesity may including kidney and glomerular filtration A. M. et of loss on renal function in patients with Am Soc Nephrol. PubMed Scopus Google Scholar a a combined using and stereology showed that glomerular filtration rate in patients with ORG was the Y. N. et in patients with obesity-related Full Text Full Text PDF PubMed Scopus Google Scholar on patients with ORG the have the of kidney injury associated with in of Nephrol. Full Text Full Text PDF PubMed Scopus Google Scholar However, there is limited on factors that long-term kidney disease outcomes in ORG, that more the of ORG. Podocyte injury and subsequent podocyte depletion are recognized as key in the development and progression of V.D. Chagnac A. de Vries A.P. et al.Obesity-related glomerulopathy: clinical and pathologic characteristics and pathogenesis.Nat Rev Nephrol. 2016; 12: 453-471Crossref PubMed Scopus (475) Google Scholar podocyte obese subjects proteinuria or M. et in obesity are of podocyte 2015; PubMed Scopus Google C. et the for early renal in Nephrol. 2016; PubMed Scopus Google Scholar study in patients with ORG reported a significantly lower podocyte density with kidney Liu et lesions in patients with obesity-related J Kidney Full Text Full Text PDF PubMed Scopus Google Scholar However, the impact of podocyte depletion on long-term kidney outcomes in patients with ORG to Because podocytes have a limited ability to proliferate or regenerate, the density of podocytes decreases as glomeruli enlarge by hyperfiltration (relative podocyte depletion), whereas persistent injury to podocytes may accelerate podocyte loss (absolute podocyte depletion). 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surface area, and number of estimated glomerular filtration hazard podocyte density, but not higher podocyte number per glomerulus, was significantly associated with lower incidence of a 30% decline in with or adjustment for confounders. 1 was for urinary was for single-nephron eGFR. was for number of was for body surface area, and urinary was for body surface area, and single-nephron eGFR. was for body surface area, and number of estimated glomerular filtration hazard glomerular was not significantly associated with lower incidence of a 30% decline in with or adjustment for confounders. 1 was for urinary was for single-nephron eGFR. was for number of was for body surface area, and urinary was for body surface area, and single-nephron eGFR. was for body surface area, and number of The podocyte depletion which that podocyte loss is involved in the to glomerular and kidney disease, is The of a of glomerular Int. Full Text Full Text PDF PubMed Scopus Google Scholar Despite the of podocyte in progressive glomerular their with long-term kidney outcomes has been Y. et injury predicts in patients with using a of renal biopsy Res. 2001; PubMed Scopus Google et density is reduced in kidney with Transplant. Scopus Google Scholar it a relative podocyte depletion or absolute podocyte depletion is a higher risk for the progression of glomerular this we stereology to patients with ORG and the with including long-term kidney The findings of the study are as patients with ORG with kidney function showed relative and absolute podocyte depletion with and obese kidney patients with ORG with lower podocyte density had larger glomeruli the absolute number of podocytes per and showed as lower number and higher and in patients with ORG, a lower podocyte density, but not lower podocyte number per or larger glomerular was significantly associated with worse long-term kidney outcomes after adjustment for confounders. our healthy obesity was associated with larger glomeruli in number and that the of obesity per is not associated with the number of or and that ORG is not a disease that of obesity. patients with ORG with kidney function showed glomerular enlargement and in in that glomerular enlargement attributable to obesity and alterations in podometrics, or may 1 of the predisposing factors in ORG Patients with ORG in this study are with persistent proteinuria for an their kidney function was the of biopsy we the that the alterations in a of progressive glomerular injury attributable to ORG. of in patients with ORG on the of the number of podocytes per showed no difference in podocyte that the of podocytes a their and However, podocyte density and podocyte are closely it is to a between these a of a cross-sectional the of the of our this is the first study to the between in the kidney biopsy and subsequent kidney Previous studies showed that glomerular K. de N. et in Japanese with and Am Soc Nephrol. PubMed Scopus Google K. et between number and in Int. Full Text Full Text PDF PubMed Scopus Google et number in and with glomerular and of glomerular Am Soc Nephrol. 2015; PubMed Scopus Google Scholar Thus, we on the impact of in patients with ORG, a characterized by V.D. Chagnac A. de Vries A.P. et al.Obesity-related glomerulopathy: clinical and pathologic characteristics and pathogenesis.Nat Rev Nephrol. 2016; 12: 453-471Crossref PubMed Scopus (475) Google N. Y. A. et renal of 2017; Full Text Full Text PDF PubMed Scopus Google N. Y. et glomerular density with in obesity-related glomerulopathy.Clin J Am Soc Nephrol. 2012; PubMed Scopus Google Scholar the we that lower podocyte density, but not lower podocyte number per or larger glomerular was significantly associated with worse kidney outcome after adjustment for as proteinuria, and the number of this patients with lower podocyte density had larger glomerular a in podocyte number per glomerulus. studies in and glomerular showed that podocyte number per correlated with glomerular K. de N. et in Japanese with and Am Soc Nephrol. PubMed Scopus Google K. et between number and in Int. Full Text Full Text PDF PubMed Scopus Google Scholar a study that the glomerular and podocyte number in in patients kidney et number in and with glomerular and of glomerular Am Soc Nephrol. 2015; PubMed Scopus Google Scholar findings the that the for glomerular enlargement may by podocyte number per glomerulus. lower of podocyte density may a of function of podocytes to glomeruli and may have for the development of massive proteinuria, glomerular the outcome of glomerular including ORG. the clinical more as body by or for patients with ORG with lower podocyte density, their kidney disease is relative depletion of but not absolute depletion of was associated with worse kidney the between podocyte density and subsequent kidney function decline were after adjustment for to with kidney outcomes in patients with ORG. major of our is the of number and in the which to the and that podocyte density, but not podocyte number per glomerulus, was correlated with the number of glomeruli per kidney and correlated with et reported that the single-nephron using not significantly to or in kidney their a higher single-nephron was associated with of kidney disease, and larger including glomerular A. et glomerular filtration rate in healthy J 2017; PubMed Scopus Google Scholar Thus, attributable to larger body and number may to an in patients with ORG, which may and relative in podocyte density, to depletion of podocytes. that the factors involved in ORG progression is in that podocyte depletion glomerular and our that glomerular hyperfiltration is a factor the between low podocyte density and subsequent development of glomerular to kidney function decline in patients with A. Obesity-related glomerulopathy and single-nephron Full Text Full Text PDF PubMed Scopus Google Scholar The study has the number of patients in our the study the of ORG onset relative to kidney biopsy which our ability to relative or absolute podocyte depletion in patients with ORG kidney the urinary However, our patients to have had their urinary in a early of the Japanese health The study showed that alterations in were in patients with ORG with a number of glomeruli and kidney suggesting that are an early morphologic of ORG. it is not possible to in podocyte number were or as the study not podocyte Y. et and are risk factors for and focal segmental J Nephrol. 2013; PubMed Scopus Google K. et and the impact of body on kidney J PubMed Scopus Google Scholar of the patients with ORG had major and may have kidney it is this have and long-term kidney this study only Japanese patients with ORG and may not to and findings the study that alterations in podometrics, including reduced podocyte density and podocyte number per and podocyte are early morphologic features and possible predisposing factors for ORG. Furthermore, the study is the first to show that relative depletion of podocytes better predicts worse long-term kidney outcomes of patients with ORG than absolute depletion of suggesting a utility of podocyte density that biopsy in the clinical setting. studies are to our findings in with ORG and to their to glomerular characterized by progressive loss of podocytes and a the no The that we not and in the The this findings are the on However, of or are not of this study were the of Kidney This was by for the of and

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