This cross-sectional analysis of baseline lipid data from the CKiD cohort demonstrates that among children with moderate CKD, dyslipidemia is common and independently associated with lower GFR and nephrotic range proteinuria. In particular, we report a high prevalence of hypertriglyceridemia, increased non-HDL-C, reduced HDL-C, and combined dyslipidemias, particularly with lower GFR. Nephrotic range proteinuria is associated with increased TG and non-HDL-C without significant effect on HDL-C. While these findings are compatible with data from adult populations with CKD,(19
) this report is a significant contribution beyond the adult literature because the majority of participants have primary renal disease and few co-existing conditions; hence, the dyslipidemic effects of CKD are more clearly delineated. The clinical significance of the high prevalence of “atherogenic dyslipidemia”(20
) in this pediatric population lies in the potential risks of premature morbidity and mortality due to accelerated ASCVD as well as the potential to accelerate CKD progression.
The primary mechanisms of dyslipidemia in CKD are thought to involve impaired TG lipolysis, associated with increased Apolipoprotein C-III (an inhibitor of lipoprotein lipase) and reduced insulin sensitivity in the vascular endothelium of skeletal muscle and other major sites of TG (fatty acid) energy utilization.(3
) As a result, chylomicron and VLDL remnants (in our study, these are best represented by non-HDL-C) are increased and there is secondary TG enrichment of all of the lipoprotein fractions. Triglyceride enrichment of HDL mediated by cholesterol ester transfer protein (CETP) is of particular relevance as it simultaneously depletes cholesterol from HDL. Furthermore, TG enrichment of HDL leads to its accelerated degradation, noting that impaired maturation of HDL may also contribute to lower HDL-C. Conversely, impaired hepatic clearance of non-HDL lipoproteins results in prolonged circulation, and therefore higher serum concentrations. Our findings are consistent with these proposed mechanisms both in terms of individual lipid abnormalities and combined dyslipidemia.
It is note-worthy that while combined dyslipidemias were present in only 20% in our overall study population, among those children with dyslipidemia, almost half had combined dyslipidemia. Even after adjusting for age, sex, proteinuria level and BMI, lower kidney function was strongly associated with combined dyslipidemia. The excess burden of combined dyslipidemia was present among children with GFR in the 30–40 ml/min/1.73m2 range but more evident among children with GFR<30 ml/min/1.73m2: they were 3 times more likely to have some profile of dyslipidemia (65% prevalence) and nearly 9 times more likely (39% prevalence) to have combined dyslipidemia. This suggests that declining GFR progressively elicits and intensifies abnormal lipoprotein metabolism, both in terms of the proportion expressing dyslipidemia and the degree to which it is expressed. It is important to highlight that the presented odds of dyslipidemia and combined dyslipidemia are not in relation to healthy children but rather to other children in the cohort with CKD and GFR > 50 ml/min/1.73m2. Therefore, as striking as the relative odds of dyslipidemia are, these findings likely under represent the odds of dyslipidemia in relation to the general population.
Little information exists about the dyslipidemic effects of proteinuria in the sub-nephrotic range and our results are somewhat unexpected. Compared to no proteinuria, mild proteinuria (0.2 ≤ Up/c < 1.0) was associated with higher TG but the next higher level of proteinuria (1.0 ≤ Up/c < 2.0) was not. Lower HDL-C was associated with mild proteinuria despite the fact HDL-C was not affected by nephrotic range proteinuria. We interpret these findings with caution, considering these are sub-group analyses and there is potential for unknown confounders despite multivariate adjustment. At the same time, analysis of proteinuria as a categorical variable is useful as this approach provides results which are both clinically applicable and which quantitatively acknowledge significant elements of nonlinearity that exist between lipid levels and continuous Up/c values (not shown).
It is worthwhile to consider potential mechanisms to explain the dyslipidemic effects of the various levels of proteinuria. The lipid profile of nephrotic syndrome reflects a composite and extreme expression of multiple concomitant disturbances of lipoprotein metabolism(23
) and we can hypothesize that intermediate levels of proteinuria elicit graded and differential expression of those pathophysiological mechanisms. For example, lipolysis may be inhibited with only mild proteinuria, leading to increased TG and resulting in decreased HDL-C via (cholesterol ester transfer protein (CETP)-mediated) exchange of cholesteryl esters (CE) into ApoB lipoproteins in exchange for TG. Decreased lecithin-cholesterol acyltransferase (LCAT) activity could also reduce HDL-C. Hepatic expression of the scavenger receptor class B member 1 (SCARB1, also known as SR-B1, a receptor for HDL that mediates the selective uptake of HDL-C) might be diminished by increasing degrees of proteinuria, reducing reverse cholesterol transport and restoring HDL-C levels. The latter might sustain CE-TG exchange, facilitating TG catabolism via the action of hepatic lipase on TG-enriched HDL, offering a potential explanation of the null effect of moderate proteinuria on TG. With nephrotic range proteinuria, perhaps the hepatic lipase pathway is down-regulated or becomes fully saturated, allowing unmitigated elevation of TG despite preserved HDL-C.
A general limitation of defining dyslipidemia in children is a lack of a comprehensive normative set of data that includes TG levels in young (< 12 years) children and significant variability in lipid values with respect to gender, age, and ethnicity. Furthermore, because ASCVD does not occur in the general population of children, levels associated with “risk” must be inferred from adult populations. We adopted conservative cut-points to define “dyslipidemia” with respect to these considerations; as such, our results may further underestimate the prevalence of dyslipidemia, particularly in younger children and among African American children in the cohort, in whom TG levels are generally lower. Our analysis however, did not rely only on these cut points; the variation of lipids with GFR and proteinuria was independent of such considerations. Another limitation of this report is the lack of comprehensive lipoprotein analysis. Alterations in lipoprotein particle number, differences in apolipoprotein content and biophysical abnormalities of lipoproteins such as small dense LDL (low density lipoproteins) or altered oxidation status are relevant examples of expected abnormalities in CKD. As discussed below, the performance of the direct HDL-C assay could hypothetically be affected by those unique abnormalities, noting that the other techniques suitable for automation and small sample volumes are also subject to this problem. For example, a mean difference of 3.5 mg/dl HDL-C between an unrelated homogenous assay and a precipitation technique was reported in nephrotic subjects.(24
) Stored biorepository samples, samples obtained at future visits, and analysis of important ancillary measures like insulin will provide opportunity for further investigation of these important physiological and technical issues. Finally, the cross-sectional design of the analysis does not permit us to draw conclusions about the temporal relationship between dyslipidemia and CKD progression. The longitudinal design of CKiD is ideal for addressing this limitation, and ongoing study goals include describing the evolution of dyslipidemic profiles over time and in relation to CKD progression.
The CKiD study has many other strengths, including a large sample size, precise measurement of GFR by iohexol clearance, and standardized demographic, clinical and laboratory measures. These aspects of the study, in addition to the previously mentioned advantage of studying lipoprotein physiology in children with primary CKD and little co-morbidity greatly enhance the significance of the findings.
Discussion of the risk of atherosclerosis in the CKiD cohort requires a long-term perspective about the lifetime of children with CKD. Unfortunately, CKD remains an irreversible and progressive condition. Historically, the majority of children with significant CKD develop ESRD--half within five years, 70% within ten years.(25
) Functional abnormalities of the vascular endothelium have implicated ASCVD in children with moderate (stage 3–4) CKD and ESRD.(27
) Subclinical ASCVD during childhood has been demonstrated by vascular imaging, in small autopsy series, and by sampling vasculature at the time of kidney transplant during the course of childhood CKD/ESRD.(35
) The expected remaining lifetime after ESRD in the 0–14 year age group is 30 years(43
) and the principal cause of death during young adulthood is premature cardiovascular disease, including ASCVD.(13
) Dyslipidemia and other CVD risk factors are a research focus because they are deep-rooted barriers to improving long-term survival in this population.
This study does not address treatment of dyslipidemia among children with CKD. Surprisingly, while the dyslipidemic profile itself is amenable to pharmaceutical treatment in CKD and ESRD, this has not been convincingly demonstrated to reduce mortality. Recently, two large clinical trials (“SHARP” and “AURORA”) were initiated to answer the question of whether LDL lowering therapy benefits patients with CKD or ESRD.(44
) Recently, the results of AURORA indicated that rosuvastatin has no effect on ASCVD-related mortality in hemodialysis patients. SHARP is still ongoing. Two other studies addressing the issue of whether statin therapy slows progression of CKD issue are underway.(46
) These studies should help fill the gap in evidence-based treatment recommendations for adult CKD patients and even greater uncertainty about potential use of pharmaceutical agents to treat dyslipidemia among children.
Current guidelines for management of dyslipidemias in patients with severe CKD from the 2003 National Kidney Foundation/Kidney Disease Outcomes Quality Initiative (KDOQI)(2
) do encompass children from the onset of puberty. Given the high prevalence of dyslipidemia in the CKiD cohort, our findings support the recommendation to screen children with CKD for dyslipidemia.