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• W2739027167 abstract "Podocyte depletion is a common mechanism driving progression in glomerular diseases. Alport Syndrome glomerulopathy, caused by defective α3α4α5 (IV) collagen heterotrimer production by podocytes, is associated with an increased rate of podocyte detachment detectable in urine and reduced glomerular podocyte number suggesting that defective podocyte adherence to the glomerular basement membrane might play a role in driving progression. Here a genetically phenotyped Alport Syndrome cohort of 95 individuals [urine study] and 41 archived biopsies [biopsy study] were used to test this hypothesis. Podocyte detachment rate (measured by podocin mRNA in urine pellets expressed either per creatinine or 24-hour excretion) was significantly increased 11-fold above control, and prior to a detectably increased proteinuria or microalbuminuria. In parallel, Alport Syndrome glomeruli lose an average 26 podocytes per year versus control glomeruli that lose 2.3 podocytes per year, an 11-fold difference corresponding to the increased urine podocyte detachment rate. Podocyte number per glomerulus in Alport Syndrome biopsies is projected to be normal at birth (558/glomerulus) but accelerated podocyte loss was projected to cause end-stage kidney disease by about 22 years. Biopsy data from two independent cohorts showed a similar estimated glomerular podocyte loss rate comparable to the measured 11-fold increase in podocyte detachment rate. Reduction in podocyte number and density in biopsies correlated with proteinuria, glomerulosclerosis, and reduced renal function. Thus, the podocyte detachment rate appears to be increased from birth in Alport Syndrome, drives the progression process, and could potentially help predict time to end-stage kidney disease and response to treatment. Podocyte depletion is a common mechanism driving progression in glomerular diseases. Alport Syndrome glomerulopathy, caused by defective α3α4α5 (IV) collagen heterotrimer production by podocytes, is associated with an increased rate of podocyte detachment detectable in urine and reduced glomerular podocyte number suggesting that defective podocyte adherence to the glomerular basement membrane might play a role in driving progression. Here a genetically phenotyped Alport Syndrome cohort of 95 individuals [urine study] and 41 archived biopsies [biopsy study] were used to test this hypothesis. Podocyte detachment rate (measured by podocin mRNA in urine pellets expressed either per creatinine or 24-hour excretion) was significantly increased 11-fold above control, and prior to a detectably increased proteinuria or microalbuminuria. In parallel, Alport Syndrome glomeruli lose an average 26 podocytes per year versus control glomeruli that lose 2.3 podocytes per year, an 11-fold difference corresponding to the increased urine podocyte detachment rate. Podocyte number per glomerulus in Alport Syndrome biopsies is projected to be normal at birth (558/glomerulus) but accelerated podocyte loss was projected to cause end-stage kidney disease by about 22 years. Biopsy data from two independent cohorts showed a similar estimated glomerular podocyte loss rate comparable to the measured 11-fold increase in podocyte detachment rate. Reduction in podocyte number and density in biopsies correlated with proteinuria, glomerulosclerosis, and reduced renal function. Thus, the podocyte detachment rate appears to be increased from birth in Alport Syndrome, drives the progression process, and could potentially help predict time to end-stage kidney disease and response to treatment. Based on a combination of animal modeling, genetic studies in man, and observational data from human kidney biopsies, there is now substantial data supporting the podocyte depletion hypothesis as a major driver of progressive glomerulosclerosis and kidney failure in glomerular diseases.1Kriz W. LeHir M. Pathways to nephron loss starting from glomerular diseases: Insights from animal models.Kidney Int. 2005; 67: 404-419Abstract Full Text Full Text PDF PubMed Scopus (378) Google Scholar, 2Kim Y.H. Goyal M. Kurnit D. et al.Podocyte depletion and glomerulosclerosis have a direct relationship in the PAN-treated rat.Kidney Int. 2001; 60: 957-968Abstract Full Text Full Text PDF PubMed Scopus (317) Google Scholar, 3Wharram B.L. Goyal M. Wiggins J.E. et al.Podocyte depletion causes glomerulosclerosis: diphtheria toxin-induced podocyte depletion in rats expressing human diphtheria toxin receptor transgene.J Am Soc Nephrol. 2005; 16: 2941-2952Crossref PubMed Scopus (584) Google Scholar, 4Matsusaka T. Xin J. Niwa S. et al.Genetic engineering of glomerular sclerosis in the mouse via control of onset and severity of podocyte-specific injury.J Am Soc Nephrol. 2005; 16: 1013-1023Crossref PubMed Scopus (213) Google Scholar, 5Wiggins R.C. The spectrum of podocytopathies: a unifying view of glomerular diseases.Kidney Int. 2007; 71: 1205-1214Abstract Full Text Full Text PDF PubMed Scopus (581) Google Scholar, 6Sadowski C.E. Lovric S. Ashraf S. et al.A single-gene cause in 29.5% of cases of steroid-resistant nephrotic syndrome.J Am Soc Nephrol. 2015; 26: 1279-1289Crossref PubMed Scopus (395) Google Scholar, 7Pagtalunan M.E. Miller P.L. Jumping-Eagle S. et al.Podocyte loss and progressive glomerular injury in type II diabetes.J Clin Invest. 1997; 99: 342-348Crossref PubMed Scopus (901) Google Scholar, 8Steffes M.W. Schmidt D. McCrery R. et al.Glomerular cell number in normal subjects and in type 1 diabetic patients.Kidney Int. 2001; 59: 2104-2113Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar, 9White K.E. Bilous R.W. Marshall S.M. et al.Podocyte number in normotensive type 1 diabetic patients with albuminuria.Diabetes. 2002; 51: 3083-3089Crossref PubMed Scopus (269) Google Scholar, 10Meyer T.W. Bennett P.H. Nelson R.G. Podocyte number predicts long-term urinary albumin excretion in Pima Indians with type II diabetes and microalbuminuria.Daibetologia. 1999; 42: 1341-1344Crossref PubMed Scopus (383) Google Scholar, 11Lemley K.V. Lafayette R.A. Safai M. et al.Podocytopenia and disease severity in IgA nephropathy.Kidney Int. 2002; 61: 1475-1485Abstract Full Text Full Text PDF PubMed Scopus (256) Google Scholar, 12Della Vestra M. Masiero A. Roiter A.M. et al.Is podocyte injury relevant in diabetic nephropathy? Studies in patients with type 2 diabetes.Diabetes. 2003; 52: 1031-1035Crossref PubMed Scopus (265) Google Scholar, 13Wang G. Lai F.M. Kwan B.C. et al.Podocyte loss in human hypertensive nephrosclerosis.Am J Hypertens. 2009; 22: 300-306Crossref PubMed Scopus (73) Google Scholar, 14Fukuda A. Sato Y. Iwakiri T. et al.Urine podocyte mRNAs mark disease activity in IgA nephropathy.Nephrol Dial Transplant. 2015; 30: 1140-1150Crossref PubMed Scopus (18) Google Scholar, 15Fukuda A, Minakawa A, Sato Y, et al. Urinary podocyte and TGFb1 mRNA as markers for disease activity and progression in anti-GBM nephritis [e-pub ahead of print]. Nephrol Dial Transplant. htp://dx.doi.org/10.1093/ndt/gfx047.Google Scholar “Podometric” methodologies for measuring podocyte parameters in archival biopsy tissue and the rate of podocyte detachment noninvasively in the urine pellet have been developed to understand the progression mechanism and test potential utility for clinical decision making.16Kikuchi M. Wickman L. Hodgin J. et al.Podometrics as a potential clinical tool for glomerular disease management. Seminars in nephrology.Semin Nephrol. 2015; 35: 245-255Abstract Full Text Full Text PDF PubMed Scopus (33) Google Scholar Cohorts with Alport syndrome (AS) were noted to have both an increased rate of podocyte detachment measured in the urine pellet,17Wickman L. Afshinnia F. Wang S.Q. et al.Urine podocyte mRNAs, proteinuria, and progression in human glomerular diseases.J Am Soc Nephrol. 2013; 24: 2081-2095Crossref PubMed Scopus (89) Google Scholar and reduced podocyte number per glomerulus in renal biopsies in relation to clinical parameters.18Wickman L. Hodgin J.B. Wang S.Q. et al.Podocyte depletion in thin GBM and Alport Syndrome.PLoS One. 2016; 11: e0155255Crossref Scopus (36) Google Scholar This suggested that accelerated podocyte detachment and depletion could be an unrecognized mechanism driving kidney failure in AS, and if so, might be a mechanism by which AS risk for progression could be identified, monitored, and perhaps treated. During early life the glomerulus enlarges in parallel with body growth although podocyte number per glomerulus does not change, thereby requiring that podocytes undergo extensive hypertrophy to maintain foot process coverage of the filtration surface.19Kikuchi M. Wickman L. Rabah R. et al.Podocyte number and density changes during early human life.Pediatr Nephrol. 2017; 32: 823-834Crossref PubMed Scopus (18) Google Scholar During late development the major glomerular basement membrane (GBM) collagen IV α1α1α2 heterotrimer is replaced by collagen IV α3α4α5 heterotrimers produced by podocytes.20Abrahamson D.R. Role of the podocyte (and glomerular endothelium) in building the GBM.Semin Nephrol. 2012; 32: 342-349Abstract Full Text Full Text PDF PubMed Scopus (61) Google Scholar Variants in COL4A3, COL4A4, or COL4A5 genes cause incorrect assembly and insertion of the α3α4α5 (IV) collagen heterotrimer into the GBM.21Hudson B.G. The molecular basis of Goodpasture and Alport syndromes: beacons for the discovery of the collagen IV family.J Am Soc Nephrol. 2004; 15: 2514-2527Crossref PubMed Scopus (143) Google Scholar By time of clinical presentation genetic variants cause characteristic thinning, thickening and splitting of the tri-laminate GBM.22Barker D.F. Hostikka S.L. Zhou J. et al.Identification of mutations in the COL4A5 collagen gene in Alport syndrome.Science. 1990; 248: 1224-1227Crossref PubMed Scopus (658) Google Scholar, 23Mochizuki T. Lemmink H.H. Mariyama M. et al.Identification of mutations in the alpha 3(IV) and alpha 4(IV) collagen genes in autosomal recessive Alport syndrome.Nat Genet. 1994; 8: 77-81Crossref PubMed Scopus (437) Google Scholar, 24Nagel M. Nagorka S. Gross O. Novel COL4A5, COL4A4, and COL4A3 mutations in Alport syndrome.Hum Mutat. 2005; 26: 60Crossref PubMed Scopus (47) Google Scholar Alport syndrome, the clinical phenotype associated with these variants, is recognized to transition through a sequence of events beginning with persistent microscopic hematuria and progressing through increasing proteinuria, progressive glomerulosclerosis, and decreasing renal function. Classic AS reaches end-stage kidney disease (ESKD) by 20 to 30 years of age,25Savige J. Storey H. Cheong H. et al.X-linked and autosomal recessive Alport Syndrome: Pathogenic variant features and further genotype-phenotype correlations.PLOS One. 2016; 11: e0161802Crossref Scopus (51) Google Scholar although milder forms are increasingly recognized as contributing to loss of kidney function and premature end-stage kidney disease in all phases of adult life. In addition to the characteristic ultrastructural changes in the GBM, AS glomeruli commonly exhibit a focal and segmental pattern off glomerulosclerosis well-recognized to be associated with podocyte dysfunction, injury, and depletion.26Pierides A. Voskarides K. Athanasiou Y. et al.Clinico-pathological correlations in 127 patients in 11 large pedigrees, segregating one of three heterozygous mutations in the COL4A3/ COL4A4 genes associated with familial haematuria and significant late progression to proteinuria and chronic kidney disease from focal segmental glomerulosclerosis.Nephrol Dial Transplant. 2009; 24: 2721-2729Crossref PubMed Scopus (100) Google Scholar, 27Voskarides K. Damianou L. Neocleous V. et al.COL4A3/COL4A4 mutations producing focal segmental glomerulosclerosis and renal failure in thin basement membrane nephropathy.J Am Soc Nephrol. 2007; 18: 3004-3016Crossref PubMed Scopus (160) Google Scholar, 28Malone A. Phelan P. Hall G. et al.Rare hereditary COL4A3/ COL4A4 variants may be mistaken for familial focal segmental glomerulosclerosis.Kidney Int. 2014; 86: 1253-1259Abstract Full Text Full Text PDF PubMed Scopus (155) Google Scholar, 29Gast C. Pengelly R. Lyon M. et al.Collagen (COL4A) mutations are the most frequent mutations underlying adult focal segmental glomerulosclerosis.Nephrol Dial Transplant. 2016; 31: 961-970Crossref PubMed Scopus (149) Google Scholar, 30Deltas C. Savva I. Voskarides K. et al.Carriers of autosomal recessive Alport Syndrome with thin GBM nephropathy presenting as focal segmental glomerulosclerosis in later life.Nephron. 2015; 130: 271-280Crossref PubMed Scopus (45) Google Scholar, 31Hodgin J. Bitzer M. Wickman L. et al.Kidney aging and focal global glomerulosclerosis. A podometric perspective.J Am Soc Nephrol. 2015; 26: 3162-3178Crossref PubMed Scopus (140) Google Scholar An AS podocyte depletion hypothesis posits that absent or dysfunctional α3α4α5 (IV) collagen heterotrimer insertion into the GBM by podocytes is associated with their defective adherence and accelerated detachment that in turn causes progressive podocyte depletion leading to proteinuria, an FSGS phenotype, and loss of kidney function. If this hypothesis is correct it would be expected that accelerated podocyte loss would begin at birth and lead to progressive reduction in podocyte number per glomerulus with time (age). In this report we evaluate genetically defined AS cohorts to determine whether or not this hypothesis can be disproven. Table 1 shows demographics and clinical characteristics of AS patients and controls. The diagnosis of AS was confirmed by genetic analysis in 88 of 95 patients (92.6%) and in the remaining 7 by skin and kidney biopsy. Of the AS patients, 71.6% were receiving treatment with angiotensin II blockade. Controls (n = 38) were from the same region of China and were comparable.Table 1Characteristics of the control and AS groups and subgroups included in the urine podocin mRNA assayCharacteristicsControlsAll AS patientsIsolated hematuriaAS group 1Micro-albuminuriaAS group 224-hour UP0.2–3 gAS group 324 hour UP>0.3 gAS group 4Number of patients/controls389512214517Median age (range) (years)9 (2–16)9 (2–17)7.5 (2–11)5.0 (2–11)10 (3–17)10 (8–16)Male (%)21 (55.3%)75 (78.9%)5 (41.7%)13 (61.9%)40 (88.9%)17 (100%)Mean height ± SD (cm)113.3 ± 18.6131.7 ± 21.4121.1 ± 17.5113.4 ± 18.6136.1 ± 17.1148.5 ± 18.7Mean weight ± SD (kg)20.5 ± 6.431.7 ± 14.926.2 ± 9.620.5 ± 6.434.4 ± 14.542.5 ± 16.7Mean BMI ± SD (kg/m2)15.6 ± 1.417.4 ± 3.517.4 ± 2.415.7 ± 1.417.7 ± 4.018.6 ± 3.9X-chromosome inheritanceNA68919319Autosomal-recessive inheritanceNA2012116ACEI/ARB treatment (%)NA68 (71.6%)1 (8.3%)11 (52.4%)41 (91.1%)15 (88.2%)Mean microalbuminuria ± SD (mg/l)NA791 ± 14369.3 ± 5.949 ± 23670 ± 13832799 ± 1345Mean MA-to-creatinine ratio ± SD (mg/g)NA1,323 ± 224846 ± 4898 ± 45974 ± 13434623 ± 3179Mean 24 hour UP (g/24) ± SDNA1.61 ± 2.300.09 ± 0.050.11 ± 0.031.04 ± 0.765.68 ± 2.39Mean urine protein-to-creatinine ratio ± SD (g/g)0.02 ± 0.023.04 ± 4.450.08 ± 0.070.29 ± 0.222.53 ± 2.119.74 ± 6.21Mean eGFR ± SD (ml/min per 1.73cm2)NA120.5 ± 54.9163.7 ± 53.1130.1 ± 52.5120.6 ± 53.192.8 ± 52.1ACEI, angiotensin converting enzyme inhibitors; ARB, angiotensin II type I receptor blockers; AS, Alport syndrome; BMI, body mass index; eGFR, estimated glomerular filtration rate; MA, microalbumin; NA, not available; UP, urine proteinEighty-eight of 95 AS patients were genotyped, and the remainder were assigned on the basis of skin biopsy and kidney biopsy. Open table in a new tab ACEI, angiotensin converting enzyme inhibitors; ARB, angiotensin II type I receptor blockers; AS, Alport syndrome; BMI, body mass index; eGFR, estimated glomerular filtration rate; MA, microalbumin; NA, not available; UP, urine protein Eighty-eight of 95 AS patients were genotyped, and the remainder were assigned on the basis of skin biopsy and kidney biopsy. Podocyte detachment rate was estimated using podocyte-specific podocin mRNA measured in the urine cell pellet. No signal was detected for 1 patient who was not included in further analysis. Data were expressed as the urine podocin mRNA-to-creatinine ratio (analogous to the urine protein-to-creatinine ratio) to compensate for variation in urine volume. However, because AS occurs during phases of rapid growth and therefore with changing muscle mass that would change urine creatinine excretion rates, we also express data as the 24-hour urine podocin mRNA excretion (see Methods). As shown in Figure 1, no differences were observed between the 2 methods of expressing podocyte detachment rate. Figure 1a and b shows that the urine podocyte detachment rate was, on average, about 11-fold increased in AS patients compared with controls (P < .001). The AS cohort was divided into 4 subgroups according to level of proteinuria as shown in Table 1. Figure 2a and b shows that even in group 1 AS patients with normal proteinuria as measured by both 24-hour urine protein and microalbuminuria the rate of podocyte detachment was significantly increased above control (P =.02 and.04, respectively). Podocyte detachment rate was increased in all 4 groups with no statistical difference between any of the AS groups. We conclude that increased podocyte detachment occurs prior to a measurable increase in either proteinuria or microalbuminuria. The podocyte detachment rate was measured by urine pellet podocin mRNA per 24-hour for X-linked AS (XLAS) (1.09 ± 0.70, n = 68) and autosomal recessive AS (1.02 ± 0.72, n = 19) (ARAS) were not statistically different. In addition, since males with X-linked AS (XLAS-M) and ARAS have a more severe clinical phenotype than females with X-linked AS (XLAS-F),25Savige J. Storey H. Cheong H. et al.X-linked and autosomal recessive Alport Syndrome: Pathogenic variant features and further genotype-phenotype correlations.PLOS One. 2016; 11: e0161802Crossref Scopus (51) Google Scholar the AS cohort was divided into XLAS-M (n = 52), XLAS-F (n = 16), and ARAS (n = 19). The podocin mRNA per 24-hour for XLAS-M was statistically higher than for XLAS-F (1.26 ± 0.11 vs. 0.77 ± 0.16, respectively, P = .03). Podocin mRNA per 24-hour between XLAS-M (1.26 ± 0.11) and ARAS (0.88 ± 0.19) (P = .07) and between XLAS-F and ARAS (0.77 ± 0.16 vs. 0.88 ± 0.19, P = .69) did not reach statistical significance. In addition, there was no statistical difference comparing all groups with severe mutations (nonsense, splicing, deletion, insertion) (n = 38) versus those with missense (n = 29) mutations (1.18 ± 0.13 vs. 1.06 ± 0.14, P = .54). Forty-one biopsies were evaluated. One biopsy had glomerulomegaly with glomerular volumes >2 SDs above both the AS and normal range and was therefore excluded from further analysis. Nine of the remaining original 40 biopsies had <8 tuft profiles present, leaving 31 biopsy samples with adequate glomerular profiles for analysis shown in Table 2.Table 2Characteristics of control and AS patients included in biopsy analysisCharacteristicsMean ± 1SDControlsNumber20Age years at biopsy (range)12.6 ± 4.9 (4–18)Male female7 and 13AS patientsAll AS biopsiesAS biopsies >7 tuftsNumber4131Age years at biopsy (range)9.2 ± 4.6 (2–21)8.2 ± 4.5 (2–21)Male/female31/1022/9Height (cm)132.2 ± 21.0127.9 ± 20.1Weight (kg)31.1 ± 12.728.1 ± 11.5X-chromosome inheritance1914Autosomal-recessive inheritance131124 hour urine protein (g/24 h)1.7 ± 1.8 (0.01–6.3)1.1 ± 1.4 (0.01–4.7)eGFR (ml/min/1.73 cm2)112.0 ± 51.7120.1 ± 50.1AS, Alport syndrome.Only biopsies with >7 tufts available was used for podocyte number per tuft data analysis shown in Figure 4. All AS biopsies were used for data shown in Figure 5. X-chromosome inheritance and autosomal recessive inheritance indicates genetic analysis showing variants on the α5 and α3/α4 collagen IV genes, respectively. Open table in a new tab AS, Alport syndrome. Only biopsies with >7 tufts available was used for podocyte number per tuft data analysis shown in Figure 4. All AS biopsies were used for data shown in Figure 5. X-chromosome inheritance and autosomal recessive inheritance indicates genetic analysis showing variants on the α5 and α3/α4 collagen IV genes, respectively. Figure 3 and Table 3 show biopsy podometric data for the Peking University First Hospital (PUFH) AS cohort compared with a previously reported Ann Arbor AS and control cohorts.18Wickman L. Hodgin J.B. Wang S.Q. et al.Podocyte depletion in thin GBM and Alport Syndrome.PLoS One. 2016; 11: e0155255Crossref Scopus (36) Google Scholar No differences were observed between the Beijing and Ann Arbor AS cohorts except that the PUFH cohort biopsies contained significantly fewer glomerular tuft profiles (P = .01). There were no differences in glomerular volume between control and either group. However, in both the PUFH and Ann Arbor AS groups the podocyte nuclear density, the podocyte nuclear number per glomerulus, and the Glepp1 area density were all significantly decreased compared with control.Table 3Comparison of AS groups with >7 tufts per glomerular profile and used for analysis shown in Figure 4Study groupsTuftsn/sectionGVx 106 μm3Pod densityper 106 μm3Pod numbern per GlomGLP1 area% tuft areaMPVum3Control (n = 20)21.5 ± 8.92.03 ± 1.14318 ± 127544 ± 16444.0 ± 5.01598 ± 596PUFH AS patients (n = 31)17.3 ± 6.32.15 ± 0.91182 ± 87346 ± 12630.8 ± 10.82016 ± 1172 Beijing AS versus controlP value.83>.99<.001<.001<.001>.99Ann Arbor AS patients (n = 26)23.4 ± 8.72.08 ± 1.11180 ± 129291 ± 14029.4 ± 12.62176 ± 1150 Ann Arbor AS versus controlP value>.99>.99<.001<.001<.001>.99 Beijing AS versus Ann Arbor ASP value.05>.99>.99>.99>.99>.99PUFH AS subgroup analysisAS group A (n = 11)Urine protein <0.2g/24 hours17.5 ± 6.52.12 ± 0.62191 ± 33393 ± 9538.2 ± 7.52112 ± 776 Group A versus controlP value>.99>.99.03.05>.99>.99AS group B (n = 15)Urine protein 0.21-3g/24 hours17.8 ± 6.91.94 ± 0.93203 ± 110343 ± 13529.5 ± 9.41848 ± 1123 Group B versus controlP value>.99>.99.03.001<.001>.99AS group C (n = 5)Urine protein >3g/24 hours15.0 ± 4.02.82 ± 1.2395 ± 44253 ± 12618.0 ± 7.82310 ± 2037 Group C versus controlP value>.99>.99.001.001<.001>.99Statistical comparisons between groups are by analysis of variance using the Bonferroni correction.AS, Alport Syndrome; GV, glomerular volume; GLP1, Glepp1 immunoperoxidase; MPV, mean podocyte volume; Peking University First Hospital. Open table in a new tab Statistical comparisons between groups are by analysis of variance using the Bonferroni correction. AS, Alport Syndrome; GV, glomerular volume; GLP1, Glepp1 immunoperoxidase; MPV, mean podocyte volume; Peking University First Hospital. PUFH AS biopsies were grouped according to 24-hour urine protein at time of biopsy as shown in Table 3 (lower). In AS group A with proteinuria levels close to the normal range, the podocyte density and podocyte number per glomerulus were decreased compared with control (P = .04 and .05, respectively). In AS group B (24-hour urine protein 0.2–3 g) podocyte density, podocyte number per glomerulus, and podocyte area density (Glepp1 area percentage of tuft) were all highly significantly decreased compared with control (P < .002). In AS group C (24-hour urine protein >3 g) had the lowest podocyte density, number per tuft, and area density compared with the other AS groups (P < .001). These data show that increasing level of proteinuria was associated with decreasing podocyte number per glomerulus and density measured by 2 different methods. If podocyte detachment rate is increased in AS from birth then one would expect that with increasing age the average podocyte number per glomerulus would decrease. Table 4 shows demographic characteristics of the biopsy AS groups A, B, and C showing that higher level proteinuria was associated with higher age, weight, and more glomerulosclerosis. Figure 4a shows that there is a linear relationship between age and podocyte number per tuft for AS groups A, B, and C defined by proteinuria level. Also shown in Figure 4a is the normal range for podocyte number per glomerulus in relation to age derived from prior studies.19Kikuchi M. Wickman L. Rabah R. et al.Podocyte number and density changes during early human life.Pediatr Nephrol. 2017; 32: 823-834Crossref PubMed Scopus (18) Google Scholar, 31Hodgin J. Bitzer M. Wickman L. et al.Kidney aging and focal global glomerulosclerosis. A podometric perspective.J Am Soc Nephrol. 2015; 26: 3162-3178Crossref PubMed Scopus (140) Google Scholar The normal slope is –2.3 (i.e., average 2.3 podocytes lost per glomerulus per year) while the projected average normal number of podocytes at birth is 580. In contrast the AS biopsy slope is –26 (i.e., 26 podocytes lost per glomerulus per year). Projecting the data (dashed line) indicates that AS glomeruli at birth would have a normal number of podocytes (average: 558). Projecting the dashed line to intersect with the X axis shows that a critically low podocyte number per glomerulus (i.e., ESKD) will be reached by average about 22 years of age. Comparison of the normal glomerular podocyte loss rate (–2.3 podocytes per year) to the AS podocyte loss rate (–26 podocytes per year) represents an 11.3-fold higher than the normal rate in AS glomeruli corresponding to the 11-fold increased podocyte detachment rate found in AS urine (Figure 1).Table 4Demographics of AS with >7 tufts grouped by 24-hour urine protein as shown in Figure 4Study groupAge(yr)Height(cm)Weight(kg)Urineprotein(g/24 h)CrCl(ml/min/1.73 m2)GSscore(% glom)AS group A. 24-hour urine protein ≤ 0.2g/24 h (n = 11)Mean6.5 ± 3.1120.2 ± 17.723.3 ± 8.20.13 ± 0.07135 ± 530.0 0.0P value versus group Bnsnsns<.01nsAS group B. 24-hour urine protein 0.21-3g/24 h (n = 15)Mean8.0 ± 5.0128.1 ± 19.928.1 ± 11.80.92 vs. 0.78124 vs. 414.8 ± 10.1P value versus group Cnsnsns<.001nsAS group C. 24-hour urine protein >3g (n = 5)Mean12.6 ± 2.8147.2 ± 18.939.1 ± 9.64.3 ± 1.083 ± 4834.3 ± 29.3P value versus group A0.04ns0.03<.001ns0.003Group C has significantly higher age, weight, and glomerulosclerosis score than group A. Group B is intermediate between groups A and C. Groups were compared using the Bonferroni adjustment except for the GS score, where the distribution was skewed so a nonparametric test (Kruskal-Wallis) was used and the mean ranks compared (P = .003).GS, glomerulosclerosis. Open table in a new tab Group C has significantly higher age, weight, and glomerulosclerosis score than group A. Group B is intermediate between groups A and C. Groups were compared using the Bonferroni adjustment except for the GS score, where the distribution was skewed so a nonparametric test (Kruskal-Wallis) was used and the mean ranks compared (P = .003). GS, glomerulosclerosis. Figure 4b shows normal values for podocyte number per glomerulus with age with the average glomerulus starting life with 580 podocytes and losing podocytes at a rate of 2.3 per glomerulus per year. Using the measured 11-fold increase in podocyte detachment rate measured in the urine pellet the expected number of podocytes left in a glomerulus can be estimated for any age (podocytes left = 580 – (2.3×11×age). The projected dashed line based on this calculation is shown in Figure 4b. Individual data points from the AS biopsy cohort are shown by open circles that reasonably correspond to the predicted data. From the open circles in Figure 4b it can be seen that AS biopsies are quite heterogeneous with respect to rate of podocyte loss in relation to age. Table 5 shows that the estimated rate of podocyte detachment per year in 2 independent AS cohorts are similar. The fold-increased podocyte loss rate from glomeruli in AS in the 2 cohorts is not statistically different from the fold-increased podocyte detachment rate as measured in the urine pellet (Figure 1).Table 5Estimation of podocytes loss per glomerulus per year in 2 AS cohortsCohortnAge at biopsyAverage podocyte loss per glomerulusPodocyte loss per glomerulus per yearFold-increase in pod loss ratePUFH cohort318.2 ± 4.5234 ± 12636.2 ± 30.715.7 ± 13.4Ann Arbor cohort269.2 ± 4.9289 ± 14031.4 ± 28.413.6 ± 12.4AS, Alport syndrome.Reduction in podocyte number per glomerulus below a designated normal value (580 podocyte per glomerulus; see Figure 3) divided by age at time of biopsy gives the average rate of podocyte loss per glomerulus per year. From Figure 3 the average normal rate of podocyte loss from glomeruli is 2.3 podocyte per glomerulus per year. The fold-increase in podocyte loss per glomerulus is therefore given by the podocyte loss per glomerulus per year divided by 2.3. The fold-increase in podocyte loss values obtained in 2 independent cohorts are not different from the measured fold increase in podocyte detachment rate measured in the urine pellet (see Figure 1).PUFH, Peking University First Hospital. Open table in a new tab AS, Alport syndrome. Reduction in podocyte number per glomerulus below a designated normal value (580 podocyte per glomerulus; see Figure 3) divided by age at time of biopsy gives the average rate of podocyte loss per glomerulus per year. From Figure 3 the average normal rate of podocyte loss from glomeruli is 2.3 podocyte per glomerulus per year. The fold-increase in podocyte loss per glomerulus is therefore given by the podocyte loss per glomerulus per year divided by 2.3. The fold-increase in podocyte loss values obtained in 2 independent cohorts are not different from the measured fold increase in podocyte detachment rate measured in the urine pellet (see Figure 1). PUFH, Peking University First Hospital. Figure 5 shows combined data from the 2 biopsy AS cohorts illustrating the relationship of podocyte depletion to renal structure or function as previously reported.18Wickman L. Hodgin J.B. Wang S.Q. e" @default.
• W2739027167 created "2017-07-31" @default.
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• W2739027167 date "2017-12-01" @default.
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• W2739027167 title "Accelerated podocyte detachment and progressive podocyte loss from glomeruli with age in Alport Syndrome" @default.
• W2739027167 cites W1107469811 @default.
• W2739027167 cites W1539201801 @default.
• W2739027167 cites W1550732922 @default.
• W2739027167 cites W1677887083 @default.
• W2739027167 cites W1822665054 @default.
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• W2739027167 cites W1964821165 @default.
• W2739027167 cites W1977314871 @default.
• W2739027167 cites W1984703530 @default.
• W2739027167 cites W1995605291 @default.
• W2739027167 cites W1998740840 @default.
• W2739027167 cites W2029774820 @default.
• W2739027167 cites W2029863361 @default.
• W2739027167 cites W2032950904 @default.
• W2739027167 cites W2033071425 @default.
• W2739027167 cites W2045028092 @default.
• W2739027167 cites W2049384286 @default.
• W2739027167 cites W2058691614 @default.
• W2739027167 cites W2065013649 @default.
• W2739027167 cites W2087367592 @default.
• W2739027167 cites W2091754751 @default.
• W2739027167 cites W2093448087 @default.
• W2739027167 cites W2100781772 @default.
• W2739027167 cites W2103956578 @default.
• W2739027167 cites W2108560266 @default.
• W2739027167 cites W2111190612 @default.
• W2739027167 cites W2115073390 @default.
• W2739027167 cites W2124364796 @default.
• W2739027167 cites W2127530565 @default.
• W2739027167 cites W2128352469 @default.
• W2739027167 cites W2131738077 @default.
• W2739027167 cites W2133198522 @default.
• W2739027167 cites W2136303791 @default.
• W2739027167 cites W2152238541 @default.
• W2739027167 cites W2155587088 @default.
• W2739027167 cites W2157230648 @default.
• W2739027167 cites W2163406006 @default.
• W2739027167 cites W2163605874 @default.
• W2739027167 cites W2167175000 @default.
• W2739027167 cites W2169570354 @default.
• W2739027167 cites W2181477489 @default.
• W2739027167 cites W2335847319 @default.
• W2739027167 cites W2346347415 @default.
• W2739027167 cites W2398250395 @default.
• W2739027167 cites W2402101528 @default.
• W2739027167 cites W2519419350 @default.
• W2739027167 cites W2563131801 @default.
• W2739027167 cites W2606874539 @default.
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