Chapter Two Renal function measures in the adolescent NHANES population

0 Chapter Two Renal function measures in the adolescent NHANES population In youth acquire that which may restore the damage of old age; and if you are mindful that old age has wisdom for its food, you will so exert yourself in youth, that your old age will not lack sustenance. LeoNARDo da Vinci Vol 1 ckd Ch pg 49

ContENts Characteristics of U.S. adolescents 4 Associations of abnormal GFR 6 Trends in renal function 8 Summary In adults, population-based studies over the last decade have shown that chronic kidney disease (CKD) is much more prevalent than previously believed. Although kidney function typically declines with age, rising burdens of obesity and hypertension have been implicated as modifiable contributors to the substantial burden of CKD in adults. As successive surveys from the National Health and Nutrition Examination Survey (NHANES) show that these risk factors are rapidly becoming more prevalent in U.S. children and adolescents, there is a clear need for studying kidney function in community-dwelling adolescents. Unfortunately, very little communitybased research has been performed in this area. It is unknown, for example, whether adults, children, and adolescents share the same risk factors for CKD, and whether the burden of CKD has changed over the years. In this regard, NHANES, a representative sample of the non-institutionalized U.S. population, is a valuable resource, as serum creatinine and urinary albumin-creatinine (ACR) levels have been measured in each cycle, and cystatin C levels have been measured in some cycles. In Figure.1 we define the NHANES samples for the adult and adolescent populations, including the cohorts and the laboratory equipment used for the serum creatinine measurements and the cystatin C assay. The adolescent population was included in the random sample of individuals age 1 9, as were all males with a creatinine level greater than 1. mg/dl and females with a level greater than 1.0 mg/dl. To address the definition of normal kidney function in the adolescent population, we define a group with blood pressure less than 10/80 mmhg, without hypertension or self-reported diabetes, and not currently pregnant or menstruating. Comparisons between the adolescent participants meeting these reference criteria and those not included are shown in Table.a. There are significant differences in estimated glomerular filtration rate (egfr, calculated by the Schwartz formula) and in serum creatinine and cystatin C levels. Other differences include a slight difference in mean age, and, in the non-reference population, greater height, greater weight, and higher systolic and diastolic blood pressures. In addition, racial differences reflect the burden of hypertension and diabetes in the African American adolescent population, consistent with data reported on the degree of obesity and Type diabetes in this population. Based on these restrictions, it appears that the normal average creatinine value in healthy adolescents is 0.71 mg/dl, and the estimated GFR is 144.6 ml/min/1.73 m. The urine albumin/creatinine ratio is 8 mg/g, a level higher than that in the adult population. The distribution of serum creatinine levels varies with age in the reference population, in a manner suggesting a role for differences in muscle mass. The distribution of cystatin C levels, however, is similar across age groups. For the Schwartz egfr, the 9 th percent confidence interval ranges from 16 to 18, with levels slightly lower in females than in males. Generally, albumin/creatinine ratios in the adolescents are less than mg/g, the 7 th percentile of the reference group; percent, however, have levels greater than 0 mg/g, and. percent have levels higher than 10 mg/g. Since there were no repeat samples to address the Ch pg 0

consistency of albumin/creatinine ratios over time it is difficult to assess the meaning of these higher values. This being said, sampling theory would suggest that for every subject exhibiting an atypically high value on the day of sampling, another study subject exhibited atypically low values. Multivariate associations of declining egfr (as indicated by a lower creatinine-based Schwartz-formula egfr or a rising cystatin C level) include older age, female gender, African American race, Hispanic/Mexican ethnicity, and higher body mass index. Associations of higher log-transformed urinary albumin/creatinine levels include female gender, white race, lower body mass index, and higher systolic blood pressure. We next examine associations between kidney function and abnormal biochemical tests. Kidney function tests are relatively poor predictors of laboratory tests, being outside the 9 th percentile of the reported range in the NHANES adolescent cohort. There are some univariate continuous associations worth noting, in that a rising serum creatinine is associated with a lower bicarbonate level, higher serum phosphorus, and a hemoglobin level less than 1. g/dl. Under multivariate models, however, most biochemical abnormalities are not significant. The chapter concludes with data on trends in renal function measures. There has been a significant rise in serum creatinine levels, but no change in cystatin C levels. Body mass index has risen 4. percent, and there has been a significant increase in systolic blood pressure. It is certainly of concern that creatinine levels appear to have risen in U.S. adolescents. levels, however, have remained unchanged over a decade, and it is hard not to speculate about the role played by differences in measurement and validation strategies. Figure.1; see page 143 for analytical methods. 1i Laboratory analyses for serum creatinine & cystatin C levels in the NHANES population NHANES 1988 1994 Routine creatinine: Roche/Hitachi 737 validation N = 00 per cycle. Participants age 60+. Roche coupled enzymatic assay. NHANES 1999 000 Routine creatinine: Roche/Hitachi 917 NHANES 001 00 Routine creatinine: Roche/Hitachi 917 (001); Beckman Coulter Synchron LX0 (00) All participants age 60+. All males with creatinine > 1. mg/dl; all females with creatinine > 1.0 mg/dl. % random sample of all participants age <60. NHANES 1988 1994 NHANES 1999 000 NHANES 001 00 009 USRDS Annual Data Report 4 RENAL FUNCTIon MEASURES IN ADoLESCENTS Vol 1 ckd Ch pg 1

Among NHANES 1999 006 participants age 1 17, mean values were as follows: age, 14. years; height, 164.8 cm; weight, 6.6 kg; serum creatinine, 0.7 mg/dl; serum cystatin C, 0.84 mg/l; ACR, 7. mg/g; and estimated glomerular filtration rate, 143.8 ml/min/1.73 m. For purposes of assembling an overtly healthy reference population, adolescents with the following characteristics were excluded: obesity, systolic blood pressure greater than 10 mmhg, diastolic blood pressure greater than 80 mmhg, self-reported hypertension, self-reported diabetes, and pregnancy or menstruation at the time of testing. Discriminating characteristics of excluded adolescents included lower GFR, higher serum creatinine, higher serum cystatin C, older age, and a lower proportion of white subjects. Table.A; see page 143 for analytical methods. NHANES 1999 006 (cystatin C, 1999 00) participants age 1 17. ai Characteristics of U.S adolescents age 1 17, NHANES 1999 006 (column percent; cystatin C, 1999 00 only) In reference population a All SE Yes SE No SE p-value Schwartz egfr ml/min/1.73 m 143.8 0.73 144.6 0.91 14.11 0.81 0.0198 Serum creatinine (mg/dl) 0.7 <0.01 0.71 <0.01 0.74 0.01 <0.0001 Serum cystatin C (mg/l) b 0.84 <0.01 0.83 <0.01 0.86 0.01 0.008 Urinary ACR, mg/g 7.19.06 8.04.34.3 4.00 Age (years) 14.49 0.04 14.40 0.04 14.69 0.06 <0.0001 Height (cm) 164.76 0.4 163.87 0.7 166.69 0.3 Weight (kg) 6.64 0.34 6.1 0.8 76.74 0.70 Body mass index (kg/m ).86 0.11 0.74 0.08 7.47 0. Systolic blood pressure (mmhg) 108.86 0. 10.3 0.19 116.08 0.4 Diastolic blood pressure, (mmhg) 60.8 0.31 9.90 0.30 61.1 0.4 Female (%) 49.33 0.87 49.1 0.96 48.93 1.6 0.7486 Race/ethnicity (%) 0.000 White 63.00 1.77 6.04 1.86 8. 0.00 African American 14.78 1.0 13.4 1.14 17.79 1.61 Hispanic 17. 1.48 16.9 1.49 18.88 1.78 Other 4.66 0.61 4.61 0.67 4.78 0.81 Obesity c (%) 17.40 0.80 0.0. 1.64 Systolic BP 10 mmhg (%) 13.69 0.71 0.0 43.41 1.74 Diastolic BP 80 mmhg (%).63 0.33 0.0 8.3 0.99 Hypertension (%) 0.84 0.14 0.0.69 0.46 Diabetes (%) 0.4 0.10 0.0 1.33 0.3 Pregnant (%) 0.37 0.04 0.0 1.17 0.14 Menstruating (%) 4.0 0.49 0.0 14.3 1.9 Abbreviations: egfr, estimated glomerular filtration rate; ACR, albumin/creatinine ratio; BP, blood pressure; SE, standard error. Missing data: urinary ACR, 61; weight, 0; systolic and diastolic blood pressure, 13. a Reference population: blood pressure <10/80 mmhg, without a diagnosis of hypertension, without self-reported diabetes, and not currently pregnant or menstruating. b was measured in the 1999 00 NHANES survey. c Obesity defined as a z-score for weight-to-height 1.64 on the CDC growth reference tables in 000. Cells with 0.0 values represent excluded criteria definitions. Ch pg

F i Serum creatinine percentiles in the reference population, by age & gender, NHANES 1999 006 1-13 years 14-1 T 3i 16-17 0 egfr (ml/min/1.73 m) Male Female 1.0 0.8 0.6 0.4 0. 0.0. 0 7 9 97.. 0 7 9 97. egfr (Schwartz formula) percentiles in the reference population, by age & gender, NHANES 1999 006 4i 1-13 years 14-1 i 16-17. 0 7 9 97. 00 ACR (mg/g) (mg/l) 0.6 0.0 ACR percentiles in the reference population, by age & gender, NHANES 1999 006 1-13 years Male Female. 0 7 9 97. 16-17. 0 7 9 97.. 0 7 9 97. 300 00 100. 0 7 9 97.. 0 7 9 97. 0. 0 7 9 97. Percentiles Percentiles ere we illustrate distributions of serum cystatin C levels. For ages 1 13, the 9th percentiles for males and females are 1.06 and 0.98 mg/l; for ages 14 1, 1.06 and 1.01 mg/l, and for ages 16 17, 1.07 and 0.9 mg/l. Regarding the 9th percentile for serum cystatin C in the healthy reference population, it is apparent that values remain stable with age, as does the discrepancy between males and females. Figure.4; see page 143 for analytical methods. NHANES 1999 00 participants age 1 17. H 14-1 Male Female 400 0.8 0.. 0 7 9 97. Male Female 0 1.0 0.4. 0 7 9 97. 100 Percentiles percentiles in the reference population, by age & gender, NHANES 1999 00 1. 16-17 10 Percentiles 14-1 00 0. 0 7 9 97. 1-13 years his figure presents distributions of urinary ACR levels. For ages 1 13, the 9th percentiles for males and females are.6 and 16.1 mg/g; for ages 14 1, 86. and 100.4 mg/g; and for ages 16 17, 79.1 and 69.4 mg/g. In terms of the 9th percentile for ACR in the healthy reference population, it is apparent that at, ages 1 13, values in males are lowest, values in females are highest, and the discrepancy between males and females is highest. Figure.; see page 143 for analytical methods. NHANES 1999 006 participants age 1 17. T 009 USRDS Annual Data Report Serum creatinine (mg/dl) 1. his figure illustrates distributions of Schwartzformula, creatinine-based GFR levels. For ages 1 13, the fifth percentiles for males and females are 118 and 11 ml/min/1.73 m; for ages 14 1, 11 and 106, and for ages 16 17, 111 and 97. Regarding the fifth percentile for egfr in the healthy reference population, it is apparent that values fall after age 1, and that the discrepancy between males and females is widest at age 14 1. Figure.3; see page 143 for analytical methods. NHANES 1999 006 participants age 1 17. Characteristics of U.S. adolescents 4 Renal function measures in adolescents igure. shows distributions of serum creatinine levels in the adolescent NHANES population. For ages 1 13, the 9th percentiles for males and females are 0.79 and 0.78 mg/dl; for ages 14 1, 0.98 and 0.86 mg/dl; and for age 16 17, 1.08 and 0.89 mg/dl. Regarding the 9th percentile for serum creatinine in the healthy reference population, it is apparent that values increase with age, as does the discrepancy between males and females. Figure.; see page 143 for analytical methods. NHANES 1999 006 participants age 1 17. Vol 1 ckd Ch pg 3

These tables look at associations of renal function measures in U.S. adolescents. With unadjusted linear regression analysis, there are inverse relationships between the Schwartz-formula, creatinine-based estimated glomerular filtration rate (egfr) and age, female gender, African American race, Hispanic ethnicity, body mass index (BMI), and diastolic blood pressure levels. With the exception of diastolic blood pressure, these findings persist in adjusted models. Also using unadjusted linear regression analysis, there are inverse relationships between cystatin C levels and female gender, African American race, Hispanic ethnicity, and systolic blood pressure levels. With covariate adjustment, there are inverse relationships with female gender, African American race, and Hispanic ethnicity, and a direct relationship with BMI. Looking at log-transformed urinary albumin/creatinine (ACR) levels, with unadjusted linear regression analysis there are inverse relationships with age, African American race, and BMI, and direct relationships with female gender and diastolic blood pressure. With covariate adjustment, there are inverse relationships with African American race and BMI, and direct relationships with female gender and systolic blood pressure. TablES.b d; see page 143 for analytical methods. NHANES 1999 006 (.b &.d) & NHANES 1999 00 (.c) participants age 1 17; reference: male, white. bi Unadjusted Adjusted Coeff. SE p-value Coeff. SE p-value Age, per 1. years -6.41 0.4 < 0.0001-6.31 0.37 < 0.0001 Female -17.3 0.86 < 0.0001-16.8 0.9 < 0.0001 African American -.0 1.04 < 0.0001 -.7 0.99 < 0.0001 Hispanic/Mexican 6.78 1.18 < 0.0001 6.9 1.1 < 0.0001 Other race -0.38.07 0.841 1.3 1.90 0.480 BMI, per.0 kg/m -0.88 0.0 < 0.0001-0.39 0.16 0.0183 Systolic BP, per.8 mmhg 0.1 0.8 0.4607 0.40 0.3 0.0887 Diastolic BP, per 6.9 mmhg -1.73 0.31 < 0.0001-0.43 0.9 0.1480 ci Unadjusted Adjusted Coeff. SE p-value Coeff. SE p-value Age, per 1. years -0.01 0.01 0.176-0.0 0.01 0.0 Female -0.10 0.01 < 0.0001-0.10 0.01 < 0.0001 African American -0.08 0.01 < 0.0001-0.09 0.01 < 0.0001 Hispanic/Mexican -0.07 0.01 < 0.0001-0.07 0.01 < 0.0001 Other race -0.0 0.0 0.306-0.0 0.0 0.467 BMI, per.0 kg/m 0.01 <0.01 0.008 0.01 <0.01 0.0363 Systolic BP, per.8 mmhg 0.01 <0.01 0.0409 < 0.01 <0.01 0.989 Diastolic BP, per 6.9 mmhg > -0.01 <0.01 0.1744 < 0.01 <0.01 0.9196 di Associations of renal function measures in U.S. adolescents in the general population: egfr (Schwartz formula), NHANES 1999 006 Associations of renal function measures in U.S adolescents in the general population: cystatin C, NHANES 1999 00 Associations of renal function measures in U.S adolescents in the general population:, NHANES 1999 006 Unadjusted Adjusted Coeff. SE p-value Coeff. SE p-value Age, per 1. years -0.04 0.0 0.0099-0.0 0.0 0.338 Female 0.46 0.04 < 0.0001 0.3 0.04 < 0.0001 African American -0.18 0.0 0.0003-0.1 0.0 0.001 Hispanic/Mexican -0.0 0.0 0.6436 0.01 0.0 0.83 Other race -0.0 0.09 0.084-0.7 0.09 0.0044 BMI, per.0 kg/m -0.07 0.01 < 0.0001-0.09 0.01 < 0.001 Systolic BP, per.8 mmhg -0.0 0.01 0.0799 0.06 0.01 0.0001 Diastolic BP, per 6.9 mmhg 0.03 0.01 0.0188 < 0.01 0.01 0.8748 Ch pg 4

ei Renal function measures as continuous variables to detect blood pressure & laboratory abnormalities in U.S. adolescents, NHANES 1999 006 (cystatin C, 1999 00) Unadjusted OR CI p-value C-statistic Adjusted OR CI T p-value C-statistic Potassium 4.6 mmol/l 0.90 0.81-1.01 0.0747 0.6 0.90 0.78-1.04 0.138 0.61 0.96 0.88-1.0 0.4137 0.0 1.04 0.93-1.17 0.4939 0.61 0.80 0.6-0.98 0.0347 0.6 0.87 0.68-1.1 0.77 0.6 1.13 1.01-1.7 0.036 0.7 1.09 0.97-1. 0.146 0.61 1. 1.00-1.48 0.0449 0.9 1.00 0.73-1.3 0.977 0.63 1.0 0.98-1.48 0.081 0. 1.1 0.87-1. 0.3178 0.6 1.09 0.79-1.0 0.6008 0.6 1.08 0.8-1.43 0.790 0.66 0.97 0.84-1.13 0.73 0.49 1.0 0.88-1.6 0.907 0.6 HCO3 19.89 mmol/l 1.40 1.3-1.60 < 0.0001 0.61 1.10 0.9-1.36 0.30 0.64 0.7 0.68-0.8 < 0.0001 0.6 0.90 0.81-1.00 0.0 0.8 0.74 0.38-1.4 0.3607 0.68 0.86 0.36 -.0 0.746 0.86 1.09 0.96-1.3 0.1786 0. 1.00 0.87-1.14 0.9438 0.8 Uric acid 7.14 mg/dl 0.6 0. - 0.60 < 0.0001 0.74 0.68 0.61-0.76 < 0.0001 0.81 1.0 0.94-1.11 0.6688 0.1 1.1 1.09-1.34 0.000 0.80 0.6 0. - 0.78 < 0.0001 0.73 0.7 0.4-0.96 0.034 0.80 1.13 1.00-1.7 0.04 0.61 1.00 0.91-1.10 0.981 0.79 0.70 0.6-0.76 < 0.0001 0.6 0.94 0.84-1.04 0.67 0.7 0.96 0.89-1.0 0.3800 0. 0.9 0.87-1.04 0.830 0.71 0.7 0.7-1.01 0.06 0.64 0.68 0.0-0.9 0.0130 0.78 1.0 0.97-1.14 0.080 0.6 0.97 0.91-1.04 0.31 0.7 0.7 0.68-0.83 < 0.0001 0.63 0.81 0.70-0.9 0.0070 0.64 1.18 1.0-1.33 0.0068 0.6 1.09 0.9-1. 0.38 0.63 1.03 0.73-1.47 0.87 0.48 1.01 0.73-1.39 0.9661 0.49 0.9 0.87-1.0 0.370 0.4 0.94 0.86-1.03 0.198 0.64 1.31 1.16-1.48 < 0.0001 0.61 1. 1.04-1.0 0.01 0.8 1.10 0.98-1.3 0.096 0.4 0.88 0.78-1.00 0.0463 0.81 1.7 1.37 -.4 < 0.0001 0.68 1.6 0.96-1.66 0.0979 0.80 0.98 0.88-1.08 0.6 1.03 0.9-1.14 0.6181 0.80 Systolic BP 1.81 mmhg Diastolic BP 76.0 mmhg Hemoglobin 1.0 g/dl 009 USRDS Annual Data Report Phosphorus.3 mg/dl Associations of abnormal GFR 4 Renal function measures in adolescents 0.633 his table shows associations between measures of renal function, as continuous variables, and potassium, bicarbonate, phosphorus, uric acid, blood pressure, and hemoglobin levels above or below the 9th percentiles of the overall population of adolescents. In general, as reflected by unadjusted C-statistics uniformly less than 0.80, renal function tests are poor discriminators of the presence or absence of these abnormalities. Regarding the different measures of renal function, rising serum creatinine levels are associated with a higher likelihood of abnormal bicarbonate, phosphorus, and hemoglobin, and a lower likelihood of abnormal uric acid, systolic blood pressure, and diastolic blood pressure. Schwartzformula, creatinine-based egfr levels are associated with a lower likelihood of abnormal phosphorus and a higher likelihood of abnormal diastolic blood pressure; cystatin C levels are associated with a lower likelihood of abnormal potassium and uric acid and a higher likelihood of abnormal hemoglobin; and log-transformed ACR levels are associated with a higher likelihood of abnormal potassium and uric acid levels. With multivariate analysis, serum creatinine is associated with a lower likelihood of abnormal uric acid and diastolic blood pressure, and a higher likelihood of abnormal hemoglobin; egfr levels are associated with a higher likelihood of abnormal uric acid and a lower likelihood of abnormal hemoglobin; cystatin C levels are associated with a lower likelihood of abnormal uric acid and systolic blood pressure; and log-transformed ACR levels are associated with none of these abnormalities. Table.e; see page 143 for analytical methods. NHANES 1999 006 (cystatin C, 1999 00) participants age 1 17. Vol 1 ckd Ch pg

fi Trends in renal function measures over time in U.S. adolescents in the general population, NHANES 1988 006 (cystatin C, 1988-00) NHANES 1988 1994 NHANES 1999 00 NHANES 003 006 Mean SE Mean SE Mean SE p-value (mg/dl) 0.70 0.01 0.7 0.01 0.73 <0.01 0.000 (mg/l) 0.8 0.01 0.84 0.01 Not measured 0.30 Log (ACR (mg/g).08 0.0.19 0.03.4 0.04 0.087 Age (years) 14.1 0.06 14.1 0.06 14.3 0.0 0.946 Height (cm) 164.9 0.3 164.8 0.9 16.07 0.36 0.4913 Weight (kg) 60.38 0.7 6. 0.41 63.9 0.3 0.010 Body mass index (kg/m ).0 0.3.74 0.13 3.0 0.19 0.00 Systolic BP (mmhg) 107.1 0.39 108.1 0.9 109.8 0.41 0.0004 Diastolic BP (mmhg) 60.3 0.47 61.8 0.40 8.76 0.4 < 0.0001 Female (%) 48..00 49.3 1.0 48.43 1.18 0.848 Race/ethnicity (%) < 0.0001 White 66.69. 61.48.01 63.94.89 African American 14.8 1.41 14.91 1.78 1.01 1.6 Hispanic 8.7 1.03 18.71.34 16.71 1.8 Other 9.88 1.7 4.90 0.8 4.34 0.80 This table compares the characteristics of U.S. adolescents in three NHANES cohorts. While mean age and height are similar in all three timeframes, body weight, body mass index, and systolic blood pressure have each increased. Regarding measures of renal function, serum creatinine levels rose from 0.70 mg/dl in 1988 1994 to 0.73 mg/dl in the 003. measurements were not performed in the 003 006 period, and no difference is observed in the 1988 1994 and 1999 00 populations. Urinary albumin/creatinine ratios, in contrast, increased from.08 mg/g in 1988 1994 to.4 mg/g in 003 006. Table.f & figures.6 8; see page 143 for analytical methods. NHANES 1988 006 (.f,.6,.8) & NHANES 1988 00 (.7) participants age 1 17. Ch pg 6

Trends in serum creatinine in U.S. adolescents in the general population, NHANES 1988 006 1.0 0.8 0.6 0.4 0. 0.0 7i 1999-00 003-006 Trends in serum cystatin C in U.S. adolescents in the general population, NHANES 1988 00 Mean serum cystatin C (mg/l) 1.0 0.8 0.6 0.4 cystatin C not available in 003-006 0. 0.0 8i 1988-1994 1999-00 003-006 Trends in log-transformed urinary ACR in U.S. adolescents in the general population, NHANES 1988 006 Mean log (ACR (mg/g))..0 1. 1.0 0. 0.0 1988-1994 1999-00 003-006 009 USRDS Annual Data Report 1988-1994 Trends in renal function 4 Renal function measures in adolescents Mean serum creatinine (mg/dl) 6i Vol 1 ckd Ch pg 7

chapter summary Mean values for age, height, & weight in 1999 006 U.S. adolescents age kg, respectively..a 1 17 were 14. years, 164.8 cm, & 6. Among U.S. adolescents age 1 17 in 1999 00, means for serum creatinine & serum cystatin C were 0.7 mg/dl & 0.84 mg/l, respectively..a Rising serum creatinine levels are associated with a higher likelihood of abnormal bicarbonate, phosphorus, & hemoglobin..e Rising serum creatinine levels are associated with a lower likelihood of abnormal uric acid, systolic blood pressure, & diastolic blood pressure..e When comparing the characteristics of U.S. adolescents in three NHANES cohorts, mean age & height are similar in all three timeframes..f Among U.S. adolescents in three NHANES cohorts, body weight, body mass index, & systolic blood pressure have each increased..f summary Ch pg 8