Dyslipidemia in Children with Chronic Kidney Disease: A Report of the Chronic Kidney Disease in Children (CKiD) Study

Purpose—To describe the prevalence and pattern of dyslipidemia in children with chronic kidney disease (CKD). Methods—391 children aged 1–16 yrs underwent measurement of serum triglyceride (TG), total cholesterol (TC), and high-density lipoprotein cholesterol (HDL-C). GFR by plasma disappearance of iohexol and urine protein/creatinine ratio (Up/c) were concomitantly measured. Multivariate analysis adjusted for age, gender, body mass index (BMI), GFR, and Up/c. Results—The median GFR and age were 43 ml/min/1.73m2 and 12 years. Proteinuria was nephrotic range (Up/c > 2) in 12% and BMI exceeded the 95th percentile in 15%. 32% of the cohort had TG > 130 mg/dL. 21% had HDL-C < 40 mg/dl, and 16% had non-HDL-C > 160 mg/dL. Lower GFR was associated with higher TG, lower HDL-C and higher non-HDL-C. Overall, 45% of the cohort had dyslipidemia, defined as one or more abnormal lipid measure; 45% of those had combined dyslipidemia. Nephrotic range proteinuria was associated with dyslipidemia and combined dyslipidemia to an equal and large degree: odds ratio (OR) of 4.16 (95% CI: 1.96, 8.79). Compared to children with GFR > 50 ml/min/1.73m2, children with GFR < 30 ml/min/1.73m2 had an OR of 2.9 (95% CI: 1.47, 5.70) for any dyslipidemia and an OR of 8.58 (95% CI: 3.70, 19.88) for combined dyslipidemia. Conclusions—Among children with moderate CKD, dyslipidemia is common and is associated with lower GFR, nephrotic proteinuria, and non-renal factors including age and obesity. Corresponding Author: Jeffrey M. Saland, M.D., Department of Pediatrics, Box 1664, The Mount Sinai Medical Center, One Gustave L. Levy Place, New York, NY 10029, Tel: 212-241-6187, Fax: 212-426-1972, Jeff.Saland@MSSM.EDU. Disclosure: None of the authors’ have relationships with companies that may have a financial interest in the information contained in the manuscript. Preliminary results of this study were presented as a poster at the 2008 annual meeting of the American Society of Nephrology/World Congress of Nephrology in Philadelphia PA. NIH Public Access Author Manuscript Kidney Int. Author manuscript; available in PMC 2011 November 22. Published in final edited form as: Kidney Int. 2010 December ; 78(11): 1154–1163. doi:10.1038/ki.2010.311. N IH PA Athor M anscript N IH PA Athor M anscript N IH PA Athor M anscript Introduction Individuals with chronic kidney disease (CKD) suffer an exceptionally high burden of atherosclerotic cardiovascular disease (ASCVD).(1) Dyslipidemia, a known risk factor for atherosclerosis, is frequent among both adults and children with CKD.(2, 3) In addition, there is evidence to suggest that dyslipidemia contributes to the initiation and progression of CKD itself.(4–9) While CKD patients are commonly burdened with multiple cardiovascular risk factors, dyslipidemia is an important focus of clinical CKD research since it is both highly prevalent and a potentially modifiable exposure. Accelerated atherosclerosis in children with CKD is likely. Within the general population, atherosclerosis begins during childhood and dyslipidemia is a risk factor for its development.(10–12) Young adult survivors of childhood end-stage renal disease (ESRD) experience an extremely high rate of premature mortality due to ASCVD, their principal cause of death.(13–16) However, compared to the adult population, data about dyslipidemia in children with CKD remain scarce. The primary aim of this cross-sectional investigation was to describe the prevalence and pattern of dyslipidemia in children with moderate CKD using data collected on participants in the Chronic Kidney Disease in Children (CKiD) Study. We also aimed to identify clinical and laboratory factors associated with dyslipidemia in children with CKD. Results As of May 2009, 574 children had completed a baseline study visit in CKiD. A subset of 427 children with known age, sex, race and CKD diagnosis had complete lipid and GFR. After excluding 11 children currently taking lipid lowering medication and 25 children known not to be fasting, 391 children remained for analysis. In 29% (n=112) of this group, fasting status was not recorded while the remainder (71%, n=279) of the children were confirmed to be fasting. Of all GFR measures, 94% (n=368) were direct (iGFR) by plasma iohexol disappearance. Characteristics of the study population are shown in Table 1, including overall lipid measures. In general, the population had a slight male predominance, was mostly Caucasian, and was skewed toward overweight. A significant minority (31%) had moderate or nephrotic range proteinuria. Triglycerides Figure 1a shows the relationship between TG levels and GFR. Univariately, log(TG) and GFR displayed a linear relationship with TG levels increasing on average 8% (95% CI: 5%, 11%) for every 10 ml/min/1.73m2 decrease in GFR (Table 2a).While a relationship was suggested between elevated TG and subnephrotic proteinuria, this was clearer in subjects with nephrotic range proteinuria, who displayed TG levels on average 55% higher (95% CI: 32, 84) than those with normal Up/c. The prevalence of hypertriglyceridemia in children with nephrotic range proteinuria was 61%, as compared to 21%, 30% and 24% in children with normal, mild, and moderate proteinuria, respectively. After multivariate adjustment, higher TG levels continued to be associated with increased age, decreased GFR, proteinuria, and being either overweight or obese (Table 2a). Children who were overweight or obese, or had nephrotic proteinuria had TG levels on average 30% higher than those of children with normal weight and normal Up/c, a magnitude of association greater than that for a 30 ml/min/1.73m2 decrease in GFR (23%, not shown in table). Higher TG levels were associated with mild proteinuria (18% increase in TG) and Saland et al. Page 2 Kidney Int. Author manuscript; available in PMC 2011 November 22. N IH PA Athor M anscript N IH PA Athor M anscript N IH PA Athor M anscript nephrotic proteinuria (34% increase in TG), but not with moderate proteinuria (3% increase in TG). Restricting analysis to the n=279 children who self-reported overnight fasting did not qualitatively change the reported associations. Cholesterol The cohort demonstrated modest hypercholesterolemia: 21% of the cohort had total cholesterol (TC) greater than 200 mg/dL; 21% had HDL-C less than 40 mg/dL, and 16% had non-HDL-C greater than 160 mg/dL. HDL-C Analysis—As shown in Figure 1b, a linear relationship was observed between log(HDL-C) and GFR. After multivariate adjustment, lower HDL-C levels were associated with increased age, decreased GFR, mild proteinuria, and obesity (Table 2b). In general, the magnitudes of association were smaller between HDL-C and the set of modeled risk factors than those observed with TG. Each 10 ml/min/1.73 m2 decrease of GFR was associated with a 3% decrease in HDL-C (95% CI: −4%, −1%). Compared to those children without proteinuria, HDL-C levels were 7% lower (95% CI −13%, −2%) in children with mild proteinuria, while children with moderate or nephrotic range proteinuria showed no decrease in HDL-C levels. Obese children had average HDL-C levels 14% (95% CI: −20%, −8%) lower than those neither overweight nor obese. Non-HDL-C and TC Analysis—There was a borderline statistically significant and quantitatively smallassociation between higher non-HDL-C and lower GFR (Figure 1c). After multivariate adjustment, for each 10 ml/min/1.73 m2 lower GFR, non-HDL-C was approximately 2% greater (95% CI: 0%, 3%) as shown in (Table 2c). No relationship was observed between TC and GFR (not shown). In contrast, compared to normal Up/c, nephrotic range proteinuria was associated with a 31% (95% CI: 18%, 44%) increase in nonHDL-C and a 23% (95% CI: 14%, 32%) increase in TC (not shown). Dyslipidemic Profiles One third (32%) of children had elevated TG, while 21% had low HDL-C and 16% had high non-HDL-C. Of the 45% with dyslipidemia, 45% displayed combined (multiple-marker) dyslipidemia, defined as the presence of 2 or more lipid abnormalities, as shown in Table 3. (17, 18) While both low HDL-C and high non-HDL-C were univariately associated with hypertriglyceremia (Chi-square p-value<0.01 for both), the joint bivariate distribution of the two abnormal cholesterol markers did not differ by hypertriglyeremia status (p=0.16 by Breslow-Day Test for homogeneity of odds ratios) suggesting that neither abnormal cholesterol marker was more likely to be associated with hypertriglyeremia than the other. Analysis of the prevalence of dyslipidemia profiles is presented in Figures 2a, 2b and Table 4. As shown in Figure 2a, lower levels of GFR were associated not only with an increased prevalence of dyslipidemia as defined by the presence of at least one abnormal lipid measure, but also with an increased prevalence of combined dyslipidemia (multiple abnormal lipid measures) (p<0.01 for differences in the distribution of number of dyslipidemia markers by GFR category based on Chi-Square Test of Association for an R x C contingency table). Similarly, increased prevalence of dyslipidemia and combined dyslipidemia was also seen with increasing levels of proteinuria (Figure 2b; p<0.01 for differences in the distribution of number of dyslipidemia markers by level of proteinuria based on Chi-Square Test of Association for an R x C contingency table). The results of the multivariate PPOM estimating associations between the prevalence of dyslipidemic measure and GFR, proteinuria, age, sex and BMI are displayed in Table 4. The adjusted relative odds of having combined dyslipidemia (≥2 vs. <2 lipid abnormalities) for Saland et al. Page 3 Kidney Int. Author manuscript; available in PMC 2011 November 22. N IH PA Athor M anscript N IH PA Athor M anscript N IH PA Athor M anscript different levels of proteinuria, increasing age and female sex, respectively, were similar to those for having any level of dyslipidemia (≥1 vs. 0 lipid abnormalities) and were therefore modeled using a single estimate (i