Global glomerulosclerosis with nephrotic syndrome; the clinical importance of age adjustment
2017; Elsevier BV; Volume: 93; Issue: 5 Linguagem: Inglês
10.1016/j.kint.2017.09.028
ISSN1523-1755
AutoresMusab S. Hommos, Caihong Zeng, Zhihong Liu, Jonathan P. Troost, Avi Z. Rosenberg, Matthew Palmer, Walter K. Kremers, Lynn D. Cornell, Fernando C. Fervenza, Laura Barisoni, Andrew D. Rule,
Tópico(s)Ion Transport and Channel Regulation
ResumoGlobally sclerotic glomeruli (GSG) occur with both normal aging and kidney disease. However, it is unknown whether any GSG or only GSG exceeding that expected for age is clinically important. To evaluate this, we identified patients with a glomerulopathy that often presents with nephrotic syndrome (focal segmental glomerulosclerosis, membranous nephropathy, or minimal change disease) in the setting of the Nephrotic Syndrome Study Network (NEPTUNE), China-Digital Kidney Pathology (DiKiP), and the Southeast Minnesota cohorts. Age-based thresholds (95th percentile) for GSG based on normotensive living kidney donors were used to classify each patient into one of three groups; no GSG, GSG normal for age, or GSG abnormal for age. The risk of end-stage renal disease or a 40% decline in glomerular filtration rate during follow-up was then compared between groups. Among the 425 patients studied, 170 had no GSG, 107 had GSG normal for age, and 148 had GSG abnormal for age. Compared to those with no GSG, the risk of kidney disease progression with GSG normal for age was similar but was significantly higher with GSG abnormal for age. This increased risk with GSG abnormal for age remained significant after adjustment for interstitial fibrosis, arteriosclerosis, age, hypertension, diabetes, body mass index, glomerulopathy type, glomerular filtration rate, and proteinuria. Thus, in patients with glomerulopathy that often presents with nephrotic syndrome, global glomerulosclerosis is clinically important only if it exceeds that expected for age. Globally sclerotic glomeruli (GSG) occur with both normal aging and kidney disease. However, it is unknown whether any GSG or only GSG exceeding that expected for age is clinically important. To evaluate this, we identified patients with a glomerulopathy that often presents with nephrotic syndrome (focal segmental glomerulosclerosis, membranous nephropathy, or minimal change disease) in the setting of the Nephrotic Syndrome Study Network (NEPTUNE), China-Digital Kidney Pathology (DiKiP), and the Southeast Minnesota cohorts. Age-based thresholds (95th percentile) for GSG based on normotensive living kidney donors were used to classify each patient into one of three groups; no GSG, GSG normal for age, or GSG abnormal for age. The risk of end-stage renal disease or a 40% decline in glomerular filtration rate during follow-up was then compared between groups. Among the 425 patients studied, 170 had no GSG, 107 had GSG normal for age, and 148 had GSG abnormal for age. Compared to those with no GSG, the risk of kidney disease progression with GSG normal for age was similar but was significantly higher with GSG abnormal for age. This increased risk with GSG abnormal for age remained significant after adjustment for interstitial fibrosis, arteriosclerosis, age, hypertension, diabetes, body mass index, glomerulopathy type, glomerular filtration rate, and proteinuria. Thus, in patients with glomerulopathy that often presents with nephrotic syndrome, global glomerulosclerosis is clinically important only if it exceeds that expected for age. Nephrosclerosis is a term often used to describe chronic irreversible changes observed on a kidney biopsy specimen. These changes include global glomerulosclerosis, arteriosclerosis, arteriolosclerosis, and interstitial fibrosis and tubular atrophy (IFTA).1Tracy R.E. Ishii T. What is 'nephrosclerosis'? lessons from the US, Japan, and Mexico.Nephrol Dial Transplant. 2000; 15: 1357-1366Crossref PubMed Scopus (39) Google Scholar These histologic findings also predict a worse renal prognosis in patients with chronic kidney disease (CKD).2Howie A.J. Ferreira M.A. Adu D. Prognostic value of simple measurement of chronic damage in renal biopsy specimens.Nephrol Dial Transplant. 2001; 16: 1163-1169Crossref PubMed Scopus (78) Google Scholar, 3Takebayashi S. Kiyoshi Y. Hisano S. et al.Benign nephrosclerosis: incidence, morphology and prognosis.Clin Nephrol. 2001; 55: 349-356PubMed Google Scholar, 4Nath K.A. Tubulointerstitial changes as a major determinant in the progression of renal damage.Am J Kidney Dis. 1992; 20: 1-17Abstract Full Text PDF PubMed Scopus (860) Google Scholar, 5Kapitsinou P.P. Ioannidis J.P. Boletis J.N. et al.Clinicopathologic predictors of death and ESRD in patients with pauci-immune necrotizing glomerulonephritis.Am J Kidney Dis. 2003; 41: 29-37Abstract Full Text Full Text PDF PubMed Scopus (22) Google Scholar, 6Okada T. Nagao T. Matsumoto H. et al.Histological predictors for renal prognosis in diabetic nephropathy in diabetes mellitus type 2 patients with overt proteinuria.Nephrology (Carlton). 2012; 17: 68-75Crossref PubMed Scopus (73) Google Scholar, 7Kang S.H. Choi S.R. Park H.S. et al.The Oxford classification as a predictor of prognosis in patients with IgA nephropathy.Nephrol Dial Transplant. 2012; 27: 252-258Crossref PubMed Scopus (80) Google Scholar Accordingly, nephrologists often use these “chronic changes” to inform patients about their prognosis and to guide their management.8Sethi S. D'Agati V.D. Nast C.C. et al.A proposal for standardized grading of chronic changes in native kidney biopsy specimens.Kidney Int. 2017; 91: 787-789Abstract Full Text Full Text PDF PubMed Scopus (99) Google Scholar However, some degree of nephrosclerosis can also be observed with normal healthy aging in the absence of kidney disease.9Wiggins J.E. Aging in the glomerulus.J Gerontol A Biol Sci Med Sci. 2012; 67: 1358-1364Crossref PubMed Scopus (43) Google Scholar, 10Rule A.D. Amer H. Cornell L.D. et al.The association between age and nephrosclerosis on renal biopsy among healthy adults.Ann Intern Med. 2010; 152: 561-567Crossref PubMed Scopus (329) Google Scholar, 11Anderson S. Brenner B.M. Effects of aging on the renal glomerulus.Am J Med. 1986; 80: 435-442Abstract Full Text PDF PubMed Scopus (295) Google Scholar, 12Neugarten J. Gallo G. Silbiger S. Kasiske B. Glomerulosclerosis in aging humans is not influenced by gender.Am J Kidney Dis. 1999; 34: 884-888Abstract Full Text Full Text PDF PubMed Scopus (69) Google Scholar Recent grading systems for chronic changes are not age-calibrated, but acknowledge uncertainty as to whether age-related changes are of prognostic importance.8Sethi S. D'Agati V.D. Nast C.C. et al.A proposal for standardized grading of chronic changes in native kidney biopsy specimens.Kidney Int. 2017; 91: 787-789Abstract Full Text Full Text PDF PubMed Scopus (99) Google Scholar A recent study used carefully screened living kidney donors data to calculate the upper reference limit (95th percentile) for the number of globally sclerotic glomeruli (GSG) at a given age and number of glomeruli on a biopsy specimen (https://qxmd.com/calculate/glomerulosclerosis-on-biopsy-2015).13Kremers W.K. Denic A. Lieske J.C. et al.Distinguishing age-related from disease-related glomerulosclerosis on kidney biopsy: the Aging Kidney Anatomy study.Nephrol Dial Transplant. 2015; 30: 2034-2039Crossref PubMed Scopus (67) Google Scholar The clinical relevance of determining whether the amount of GSG on a patient’s biopsy specimen is abnormal is unclear. In particular, is any global glomerulosclerosis of prognostic significance or just glomerulosclerosis that is abnormal for age? For example, 3 of 20 glomeruli being globally sclerosed would be a biopsy finding commonly expected for a healthy 60-year-old individual (95th percentile would be 4 globally sclerosed glomeruli) but abnormal for a 20-year-old individual (the 95th percentile would be 1 globally sclerotic glomerulus) (Table 1). The older patient may only have a gradual process of age-related nephrosclerosis of limited clinical relevance, whereas the younger patient may have a more rapid glomerular loss from an underlying disease with an increased risk of kidney failure. However, validation of these age-based reference limits has not yet been performed in a diseased population. Whether glomerulosclerosis is prognostically important independent of other clinical characteristics and biopsy findings is also unclear.Table 1Upper reference limit (95th percentile) for the number of globally sclerotic glomeruli based on age and number of glomeruliAge (yr)No. of glomeruli123–45–89–1617–3233–4849–6418–290.50.50.50.5111130–340.50.50.50.51111.535–390.50.50.50.511.52240–440.50.50.51122.5345–490.50.5111.523450–541111.5234555–59111.51.523.54.5660–6411.51.522.545.5765–691222.534.56.5870–74122.5345.57.5975–77122.534689.5These 95th percentile thresholds were determined with quantile regression using 1847 healthy normotensive living kidney donors in the Aging Kidney Anatomy study.13Kremers W.K. Denic A. Lieske J.C. et al.Distinguishing age-related from disease-related glomerulosclerosis on kidney biopsy: the Aging Kidney Anatomy study.Nephrol Dial Transplant. 2015; 30: 2034-2039Crossref PubMed Scopus (67) Google Scholar The percentage globally sclerotic glomeruli for these thresholds decreases with more glomeruli undergoing biopsy. For example, a 70-year-old patient with 5 glomeruli would have a 95th percentile of 60% (3/5) but with 49 glomeruli would have a 95th percentile of 18% (9/49). This occurs because the precision for distinguishing abnormal from normal improves when more glomeruli undergo biopsy. Open table in a new tab These 95th percentile thresholds were determined with quantile regression using 1847 healthy normotensive living kidney donors in the Aging Kidney Anatomy study.13Kremers W.K. Denic A. Lieske J.C. et al.Distinguishing age-related from disease-related glomerulosclerosis on kidney biopsy: the Aging Kidney Anatomy study.Nephrol Dial Transplant. 2015; 30: 2034-2039Crossref PubMed Scopus (67) Google Scholar The percentage globally sclerotic glomeruli for these thresholds decreases with more glomeruli undergoing biopsy. For example, a 70-year-old patient with 5 glomeruli would have a 95th percentile of 60% (3/5) but with 49 glomeruli would have a 95th percentile of 18% (9/49). This occurs because the precision for distinguishing abnormal from normal improves when more glomeruli undergo biopsy. To validate the prognostic utility of age-based reference limits for glomerulosclerosis, we assessed the risk of kidney disease progression as predicted by glomerulosclerosis in 3 different cohorts of patients defined by glomerulopathy on biopsy that often presents with nephrotic syndrome. Our primary objective was to compare the risk of kidney disease progression between patients with no GSG, GSG normal for age, and GSG abnormal for age. Our secondary objective was to determine whether GSG abnormal for age is predictive of kidney disease progression independent of other clinical and biopsy characteristics and across different populations. There were a total of 425 patients studied; 183 patients from the Nephrotic Syndrome Study Network (NEPTUNE) cohort, 129 from the China-Digital Kidney Pathology (China DiKiP) cohort, and 113 patients from the Southeast (SE) Minnesota cohort (Figure 1). Baseline characteristics for each cohort and the overall cohort are summarized in Table 2. The prospective NEPTUNE cohort had up to 5 years of follow-up, with 28% leaving the study (2% died); the prospective China DiKiP cohort had up to 4.6 years of follow-up, with 18% leaving the study (0.5% died); and the historical SE Minnesota cohort had up to 22 years of follow-up, with 29% lost to follow-up in the medical record (12% died). Compared with the NEPTUNE and SE Minnesota cohorts, the China DiKiP cohort was younger; had a lower body mass index, less hypertension, and less diabetes; had higher estimated glomerular filtration rate (eGFR); had more minimal change disease (MCD) and less focal segmental glomerulosclerosis (FSGS); and had a lower incidence of CKD progression. The NEPTUNE and SE Minnesota cohorts were more similar.Table 2Characteristics of each cohort and the overall cohortCharacteristicsNEPTUNE (N = 183)aOther includes multiracial, Native American, Alaskan, and unknown.China DiKiP (N = 129)aOther includes multiracial, Native American, Alaskan, and unknown.SE Minnesota (N = 113)aOther includes multiracial, Native American, Alaskan, and unknown.Overall (N = 425)aOther includes multiracial, Native American, Alaskan, and unknown.Demographic Male113 (62)84 (65)65 (58)262 (62) Age, yr46 ± 16.132 ± 12.450 ± 18.643 ± 17.5 Race, no. (%)White112 (61)0 (0)96 (85)208 (49)Black30 (16)0 (0)3 (3)33 (8)Asian24 (13)129 (100)2 (2)155 (36)OtheraOther includes multiracial, Native American, Alaskan, and unknown.17 (10)0 (0)12 (10)29 (7)Comorbidities Body mass index, kg/m229.7 ± 724.3 ± 6.031.4 ± 7.228.5 ± 7.3 Hypertension, no. (%)118 (64)36 (28)70 (62)224 (53) Diabetes, no. (%)13 (7)0 (0)13 (12)26 (6) Systolic BP, mm Hg125 ± 18.1125 ± 12.7136 ± 19.5128 ± 17.6 Diastolic BP, mm Hg78 ± 11.878 ± 9.979 ± 12.678.2 ± 11.4Laboratory studies 24-hr urine protein, g/d2.0 [0.9, 3.8]5.1 [3.7, 7.8]6.1 [3.1, 10.9]3.9 [1.8, 7.5] Serum creatinine, mg/dl1.2 [0.9, 1.7]0.8 [0.6, 0.9]1.3 [0.9, 1.7]1.0 [0.8, 1.5] eGFR, ml/min per 1.73 m2beGFR using the CKD-EPI (Chronic Kidney Disease Epidemiology Collaboration) equation.65.4 [41.7, 96.0]117.0 [97.1, 127.3]63.0 [34.2, 90.9]81.2 [46.3, 112.7]Diagnoses Focal segmental glomerulosclerosis106 (58)46 (36)55 (49)207 (49) Membranous nephropathy51 (28)46 (36)45 (40)142 (33) Minimal change disease26 (14)37 (28)13 (11)76 (18)Follow-up duration, yr2.5 [1.0, 3.6]3.5 [2.5, 4]3.7 [1.4, 8.4]3.0 [1.4, 4.0]Outcome (CKD progression) ESRD or 40% decline in eGFR59 (32%)10 (8%)40 (35%)109 (26%)BP, blood pressure; China DiKiP, China Digital Kidney Pathology study; CKD, chronic kidney disease; eGFR, estimated glomerular filtration rate; ESRD, end-stage renal disease; NEPTUNE, the Nephrotic Syndrome Study Network; SE Minnesota, Southeast Minnesota.Values are N (%), mean ± SD, or median [25%, 75% percentiles].a Other includes multiracial, Native American, Alaskan, and unknown.b eGFR using the CKD-EPI (Chronic Kidney Disease Epidemiology Collaboration) equation. Open table in a new tab BP, blood pressure; China DiKiP, China Digital Kidney Pathology study; CKD, chronic kidney disease; eGFR, estimated glomerular filtration rate; ESRD, end-stage renal disease; NEPTUNE, the Nephrotic Syndrome Study Network; SE Minnesota, Southeast Minnesota. Values are N (%), mean ± SD, or median [25%, 75% percentiles]. The mean ± SD of the total number of glomeruli present on biopsy specimen was 24 ± 17 glomeruli (16% had 29 glomeruli). By global glomerulosclerosis category, 170 patients (40%) had no GSG, 107 patients (25%) had GSG normal for age, and 148 patients (35%) had GSG abnormal for age. Because GSG abnormal for age was defined using the 95th percentile threshold in healthy kidney donors, this exceeds what would be expected in a healthy population (35% vs. expected 5%, P < 0.0001). By primary diagnosis, FSGS (56% vs. expected 5.0%, P < 0.0001) and membranous nephropathy (MN) (19% vs. expected 5.0%, P < 0.0001) had more GSG than expected in a healthy population, but MCD (6.5% vs. expected 5.0%, P = 0.53) did not. The percentage of GSG showed substantial overlap between patients with GSG normal for age and patients with GSG abnormal for age for each of the 3 diagnoses (Figure 2). Table 3 compares the characteristics of those with no GSG, GSG normal for age, and GSG abnormal for age. The presence of GSG normal for age compared with no GSG was associated with older age, hypertension, diabetes, and a lower eGFR. On multivariable analysis adjusting for each other clinical characteristic, only older age (odds ratio = 1.07 per year, P < 0.001) was independently associated with GSG normal for age compared with no GSG. The presence of GSG abnormal for age compared with no GSG was associated with older age, higher body mass index, hypertension, diabetes, lower proteinuria, and lower eGFR. On multivariable analysis including each of these clinical characteristics (age, body mass index, hypertension, diabetes, proteinuria, and eGFR), only lower eGFR (P < 0.0001) and lower proteinuria (P = 0.01) were independently associated with GSG abnormal for age compared with no GSG. Other biopsy findings (IFTA, arteriolar hyalinosis, and arteriosclerosis) were higher in those with GSG (normal or abnormal for age) compared with no GSG. The amount of IFTA was markedly more severe with GSG abnormal for age compared with GSG normal for age, whereas arteriosclerosis and arteriolar hyalinosis were only slightly more severe with GSG abnormal for age compared with GSG normal for age.Table 3Characteristics for the overall cohorts by GSG categoryCharacteristicsNo GSG (N = 170)GSG normal for age (N = 107)P valueaP value (Fisher exact test or Wilcoxon rank sum test) comparing GSG normal for age versus no GSG.GSG abnormal for age (N = 148)P valuebP value comparing GSG abnormal for age versus no GSG.Clinical Male110 (65)66 (62)0.6186 (58)0.25 Age, yr35 ± 14.952 ± 17.5<0.000145 ± 16.0<0.0001 Body mass index, kg/m227.5 ± 7.228.8 ± 6.50.0729.5 ± 7.90.03 Hypertension, %54 (32)66 (62)<0.0001104 ± 70<0.0001 Diabetes, %2 (1)11 (10)0.000713 (9)0.002 Systolic BP, mm Hg125 ± 15.8128 ± 18.90.22130 ± 18.40.03 Diastolic BP, mm Hg78 ± 11.376 ± 11.90.2380 ± 11.00.07 24-hr urine protein, g/d4.7 [2.5, 8.3]4.3 [2.1, 8.1]0.432.4 [1.1, 4.8]<0.0001 Serum creatinine, mg/dl0.9 [0.7, 1.1]1.0 [0.8, 1.4]0.0091.4 [1.0, 2.2]<0.0001 eGFR, ml/min per 1.73 m2ceGFR calculated using the CKD-EPI (Chronic Kidney Disease Epidemiology Collaboration) equation.106.4 [74.0, 121.8]78.0 [52.2, 103.8]<0.000153.5 [32.2, 87.9]<0.0001Biopsy findings No. of glomeruli22 (11.9)24 (14.4)0.5225 (22.2)0.73 No. of GSG01.6 (1)<0.00018 (8.5)<0.0001 Percentage GSG09<0.000138<0.0001 Cortical IFTA 0–3dCortical IFTA was semiquantified as 0 ( 50%).0.001<0.00010127 (75)62 (58)49 (33)135 (20)29 (27)44 (30)2 or 38 (5)16 (15)55 (37) Arteriolar hyalinosis 0–3eArteriosclerosis was defined as thickening of arterial intima with fibrosis. Arteriolar hyalinosis was defined as thickening of arteriolar wall with hyaline material. Both were scored semiquantitatively according to the following score: 0 = absent; 1= mild thickening 50%.0.001<0.00010130 (77)63 (60)77 (53)138 (22)33 (31)52 (36)2 or 31 (1%)9 (9%)17 (11%) Arteriosclerosis 0–3eArteriosclerosis was defined as thickening of arterial intima with fibrosis. Arteriolar hyalinosis was defined as thickening of arteriolar wall with hyaline material. Both were scored semiquantitatively according to the following score: 0 = absent; 1= mild thickening 50%.<0.0001<0.00010113 (69)48 (46)41 (29)143 (26)29 (28)54 (39)2 or 38 (5)27 (26)45 (32)Primary diagnosis Focal segmental glomerulosclerosis55 (32)36 (34)0.90116 (78)<0.0001 Membranous nephropathy61 (36)54 (50)0.0227 (18)0.0004 Minimal change disease54 (32)17 (16)0.0035 (4)<0.0001Outcome (CKD progression) ESRD or 40% decline in eGFR26 (15)19 (18)0.6264 (43)<0.0001BP, blood pressure; CKD, chronic kidney disease; eGFR, estimated glomerular filtration rate; ESRD, end-stage renal disease; GSG, globally sclerotic glomeruli; IFTA, interstitial fibrosis and tubular atrophy. Values are N (%), mean ± SD, or median [25%, 75% percentile].a P value (Fisher exact test or Wilcoxon rank sum test) comparing GSG normal for age versus no GSG.b P value comparing GSG abnormal for age versus no GSG.c eGFR calculated using the CKD-EPI (Chronic Kidney Disease Epidemiology Collaboration) equation.d Cortical IFTA was semiquantified as 0 ( 50%).e Arteriosclerosis was defined as thickening of arterial intima with fibrosis. Arteriolar hyalinosis was defined as thickening of arteriolar wall with hyaline material. Both were scored semiquantitatively according to the following score: 0 = absent; 1= mild thickening 50%. Open table in a new tab BP, blood pressure; CKD, chronic kidney disease; eGFR, estimated glomerular filtration rate; ESRD, end-stage renal disease; GSG, globally sclerotic glomeruli; IFTA, interstitial fibrosis and tubular atrophy. Values are N (%), mean ± SD, or median [25%, 75% percentile]. The risk of CKD progression was not different in those with GSG normal for age compared with no GSG (hazard ratio = 1.0, P = 0.98) but was higher in those with GSG abnormal for age compared with no GSG (HR = 3.7, P < 0.0001) (Figure 3). In a sensitivity analysis limited to NEPTUNE, classifying GSG as abnormal for age using digitally scanned and annotated images versus using clinical biopsy reports showed good agreement (κ = 0.66, P < 0.0001). Although the annotated images (rigorous method) detected more glomeruli (mean, 27 vs. 18, P < 0.0001) and more GSG (mean, 5 vs. 3, P < 0.0001) than the biopsy report (convenient method), the percentage of glomeruli that were GSG between the 2 methods showed a minimal difference (21% by annotated images vs. 20% by biopsy report, P = 0.03) and was highly correlated (r = 0.90). Furthermore, the risk of CKD progression with GSG abnormal for age compared with no GSG or GSG normal for age was similar by annotated images (HR = 2.4, P = 0.0008) or by pathology report (HR = 2.5, P = 0.0006) (Supplementary Figure S1). Given the lack of a detectable difference in CKD progression between no GSG and GSG normal for age, these 2 categories were combined for subsequent analysis. The risk of CKD progression with GSG abnormal for age versus no GSG or GSG normal for age remained significant even after adjustment for biopsy findings, the primary diagnosis, or clinical characteristics (Table 4). Findings were similar when GSG abnormal for age was only compared with GSG normal for age (Supplementary Table S1). Subgroup analysis did not find evidence that the risk of CKD progression with GSG abnormal for age differed between women and men (P = 0.23 for statistical interaction), differed between ages younger than 40 years and 40 years and older (P = 0.35 for statistical interaction), differed between FSGS and MN (P = 0.12 for statistical interaction), differed between the 3 sites (P = 0.51 for statistical interaction), or differed between the total number of glomeruli on biopsy specimen (P = 0.98). Analysis restricted to those with only 1 or 2 GSG more than the upper reference limit for age versus no GSG or GSG normal for age revealed that the risk of CKD progression remained.Table 4Risk of CKD progression (ESRD or 40% decrease in eGFR) with globally sclerotic glomeruli abnormal for age versus having no globally sclerotic glomeruli or having globally sclerotic glomeruli normal for ageAnalysis for predicting CKD progression with GSG abnormal for ageHazard ratio (95% CI)P valueUnadjusted3.6 (2.4–5.3)<0.0001Adjusted for Biopsy findingsInterstitial fibrosis 0–3aCortical interstitial fibrosis and tubular atrophy were semiquantified as 0 ( 50%).2.6 (1.7–3.9)<0.0001Arteriosclerosis 0–3bArteriosclerosis was defined as thickening of arterial intima with fibrosis. Arteriolar hyalinosis was defined as thickening of arteriolar wall with hyaline material. Both were scored semiquantitatively according to the following scoring: 0 = absent; 1= mild thickening 50%.3.1 (2.1–4.8)<0.0001Arteriolar hyalinosis 0–3bArteriosclerosis was defined as thickening of arterial intima with fibrosis. Arteriolar hyalinosis was defined as thickening of arteriolar wall with hyaline material. Both were scored semiquantitatively according to the following scoring: 0 = absent; 1= mild thickening 50%.3.3 (2.2–4.9)<0.0001Interstitial fibrosis, arteriosclerosis, and arteriolar hyalinosis2.5 (1.6–3.9)<0.0001 Clinical characteristicsHypertension2.9 (2.0–4.3)<0.0001Diabetes3.4 (2.3–5.0)<0.0001Body mass index3.2 (2.1–4.8)<0.0001Age3.5 (2.4–5.2)<0.0001Primary diagnosis2.4 (1.6–3.7)<0.0001Hypertension, diabetes, body mass index, age, and primary diagnosis2.0 (1.3–3.2)0.0017 Kidney function measureseGFR, ml/min per 1.7322.2 (1.5–3.3)0.0001Proteinuria, g/d3.5 (2.3–5.3) 0.05 for statistical interaction between subgroups.Male2.9 (1.8–4.7)<0.0001Female5.6 (2.8–12) 0.05 for statistical interaction between subgroups.<404.8 (2.4–9.9)<0.0001≥403.1 (1.9–5.1) 0.05 for statistical interaction between subgroups.Focal segmental glomerulosclerosis3.2 (1.9–5.4) 0.05 for statistical interaction between subgroups.SE Minnesota3.8 (2.0–7.4) 0.05 for statistical interaction between subgroups.Total no. glomeruli on biopsy 3–92.6 (1.2–6.2)0.02Total no. glomeruli on biopsy 10–193.9 (2.1–7.8) 293.8 (1.6–9.3)0.002Restricted analysis GSG only slightly abnormal (1 or 2 GSG above the reference limit)2.3 (1.3–3.8)0.005BMI, body mass index; China DiKiP, China-Digital Kidney Pathology; CI, confidence interval; CKD, chronic kidney disease; DM, diabetes mellitus; eGFR, estimated glomerular filtration rate; ESRD, end-stage renal disease; GSG, globally sclerotic glomeruli; HTN, hypertension; NEPTUNE, the Nephrotic Syndrome Study Network; N/A, not available (only 2 events in minimal change disease patients); SE Minnesota, Southeast Minnesota.a Cortical interstitial fibrosis and tubular atrophy were semiquantified as 0 ( 50%).b Arteriosclerosis was defined as thickening of arterial intima with fibrosis. Arteriolar hyalinosis was defined as thickening of arteriolar wall with hyaline material. Both were scored semiquantitatively according to the following scoring: 0 = absent; 1= mild thickening 50%.c P > 0.05 for statistical interaction between subgroups. Open table in a new tab BMI, body mass index; China DiKiP, China-Digital Kidney Pathology; CI, confidence interval; CKD, chronic kidney disease; DM, diabetes mellitus; eGFR, estimated glomerular filtration rate; ESRD, end-stage renal disease; GSG, globally sclerotic glomeruli; HTN, hypertension; NEPTUNE, the Nephrotic Syndrome Study Network; N/A, not available (only 2 events in minimal change disease patients); SE Minnesota, Southeast Minnesota. In this study, we demonstrated that in patients with glomerulopathy commonly presenting as nephrotic syndrome (MCD, MN, and FSGS), global glomerulosclerosis on the baseline kidney biopsy was only predictive of CKD progression when it exceeded the age-specific 95th percentile for global glomerulosclerosis in healthy adults.13Kremers W.K. Denic A. Lieske J.C. et al.Distinguishing age-related from disease-related glomerulosclerosis on kidney biopsy: the Aging Kidney Anatomy study.Nephrol Dial Transplant. 2015; 30: 2034-2039Crossref PubMed Scopus (67) Google Scholar Glomerulosclerosis exceeding that expected for age informs prognosis independent of other clinical and biopsy specimen characteristics (including commonly reported IFTA scores). This finding was robust, showing consistency between different cohorts, different methods for counting glomeruli, and different numbers of glomeruli. This study validates age-based thresholds developed in normotensive living kidney donors applied to patients with MCD, MN, and FSGS. Clinicians can now more clearly delineate whether the amount of global glomerulosclerosis on a biopsy specimen is age related (of little clinical significance) or disease related (increased risk of CKD progression). An age-based approach to CKD has been considered controversial,14Glassock R. Delanaye P. El Nahas M. An Age-Calibrated Classification of Chronic Kidney Disease.JAMA. 2015; 314: 559-560Crossref PubMed Scopus (84) Google Scholar, 15Levey A.S. Inker L.A. Coresh J. Chronic Kidney Disease in Older People.JAMA. 2015; 314: 557-558Crossref PubMed Scopus (75) Google Scholar but is supported by both structural and epidemiologic studies.16Hommos M.S. Glassock R.J. Rule A.D. Structural and Functional Changes in Human Kidneys with Healthy Aging.J Am Soc Nephrol. 2017; 28: 2838-2844Crossref PubMed Scopus (177) Google Scholar Precedence already exists for age-based thresholds in CKD. By using age-based thresholds for the number of renal cysts, nephrologists avoid misdiagnosing age-related cysts in older patients as autosomal dominant polycystic kidney disease.17Ravine D. Gibson R.N. Walker R.G. et al.Evaluation of ultrasonographic diagnostic criteria for autosomal dominant polycystic kidney disease 1.Lancet. 1994; 343: 824-827Abstract PubMed Scopus (481) Google Scholar, 18Rule A.D. Sasiwimonphan K. Lieske J.C. et al.Characteristics of renal cystic and solid lesions based on contrast-enhanced computed tomography of potential kidney donors.Am J Kidney Dis. 2012; 59: 611-618Abstract Full Text Full Text PDF PubMed Scopus (66) Google Scholar Similarly, the use of age-based thresholds can help the nephrologist differentiate normal age-related global glomerulosclerosis of little clinical relevance from disease-related
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