Untangling the Web of Dietary Micronutrient Intake and the Metabolome in Children with CKD

Inadequate nutrition is a well-recognized sequela of CKD that is particularly impactful in the pediatric population due to its adverse effects on growth, development, and overall morbidity.^1,2 In addition to being a critical contributor to the high prevalence of short stature in pediatric CKD, inadequate nutrition has also been associated with neurocognitive deficits, infections, and disease progression in children with CKD.^1–3 The etiology of inadequate nutrition in pediatric CKD is multifactorial. Nutritional challenges in this population commonly include protein and electrolyte wasting, decreased appetite related to altered neuropeptide signaling, provider-recommended dietary restrictions, and gastrointestinal symptoms (nausea, vomiting, altered taste) due to the uremic milieu of CKD that causes disruptions in normal feeding.¹

As a consequence of inadequate nutrition, children with CKD may be at increased risk for vitamin, mineral, and other micronutrient deficiencies.¹ This is noteworthy because micronutrients are integral cofactors to several processes that maintain metabolic equilibrium. However, currently there is limited understanding of micronutrient status and its metabolic implications in children with CKD. Hasson et al., aimed to address this knowledge gap by investigating micronutrient intake and their influence on plasma metabolites and metabolic pathways using robust data from the largest North American cohort study of children with CKD—the CKD in Children (CKiD) study.⁴ The CKiD study includes over 50 sites across the United States and Canada and enrolls children aged 6 months through 16 years who have mild to moderate CKD (eGFR 30–90 ml/min per 1.73 m²) at study entry. In their study, Hasson and colleagues used self-reported food frequency questionnaires to quantify micronutrient intake, focusing on three trace minerals, eight water-soluble vitamins, and four fat-soluble vitamins. The micronutrient intake data used were restricted to time points that also had available plasma metabolomics data (CKiD study visits that occurred at 6 months, 2, and 4 years after enrollment). Linear regression models with mixed effects were used to describe associations between micronutrient intake and untargeted plasma metabolite levels.

The investigators assert that their principal findings were that (1) children with CKD reported intake below the recommended amount of at least one micronutrient despite appropriate caloric intake and weights for age; (2) associations between micronutrient intake and 99 plasma metabolites were observed (90% were positively associated); and (3) significant associations were detected between vitamins D and B12 intake and several plasma metabolites of the lipid pathways.

It is well known that nutritional requirements change as children grow and develop. However, definitive micronutrient requirements for children with CKD remain largely unknown as chronically impaired kidney function could predispose them to having either deficiency or excess of certain vitamins and minerals. With regard to vitamins, current pediatric CKD nutritional guidelines recommend routine monitoring and supplementation of vitamin D and the restriction of vitamin A.⁵ The Pediatric Renal Nutrition Taskforce Guidelines for assessment and management of trace elements acknowledge that it is not presently known whether the mineral needs of children with CKD are similar to those of healthy children. They do not currently recommend routine monitoring of trace elements and advise supplementing only when there is documented evidence of deficiency.⁶ There is no significant vitamin and mineral nutritional guidance beyond those recommendations, likely because there is a paucity of research describing micronutrient need and associated outcomes in pediatric CKD. In Table 1, we describe the limited research and study findings to date. This study is novel in that it both vastly expanded the evaluation of micronutrient intake in pediatric CKD and is the first to identify metabolic pathways that may be influenced by micronutrient deficiencies in this population. As such, their results provide more specific vitamin, mineral, and metabolome pathways of focus for future studies that quantify micronutrient status and its metabolic effect to refine our understanding of nutritional needs in children with CKD.

Table 1.

Summary of key studies related to micronutrient intake, levels, and/or metabolomics in children with CKD

Reference	Population	Methods	Key Findings
Foreman et al.,11 1996	120 children with CKD, single-center study	Prospective study of dietary intake assessed by 4-d food records and compared to DRI	Low dietary intake of calcium, zinc, vitamin B6, and folate
Joyce et al.,12 2020	112 children with CKD 3–5, single-center study	Retrospective cross-sectional review of micronutrient blood levels over 2 yr period	Vitamin A and vitamin B12 levels were elevated in 81% and 77%, respectively Majority of participants had adequate or high levels of vitamins D and E, folate, zinc, and copper
Lindeback et al.,10 2023	118 children (36 CKD, 82 controls)	Cross-sectional assessment of dietary intake by FFQ Intakes of CKD compared to controls	Children with CKD less likely to meet DRI for vitamin A, thiamine, folate, vitamin C, calcium, magnesium, and iron versus controls
Ren et al.,13 2024	484 children enrolled in CKiD multicenter study	Dietary intake assessed by FFQ Metabolic profiling of plasma samples Association between metabolites and CKD progression evaluated	Vitamin A metabolite (carotene diol) associated with increased risk of CKD progression
Hasson et al.,4 2025	575 children enrolled in CKiD multicenter study	Micronutrient intake assessed by FFQ Metabolic profiling of plasma samples Association between micronutrient intake and metabolites evaluated	Intake of at least one micronutrient below DRI in majority of children despite normal BMI Associations between vitamins D and B12 intake and several plasma metabolites of the lipid pathways were identified

BMI, body mass index; CKiD, CKD in children; DRI, dietary reference intake; FFQ, food frequency questionnaire.

An additional strength of this study is the investigators' use of such a large and well-defined pediatric CKD cohort (CKiD study participants) that encompasses patients from a wide network of pediatric institutions across North America. The use of this population provides strong evidence for the generalizability of study findings.

The primary limitation of this study was the lack of plasma or serum micronutrient concentration levels. The investigators used nutritional intake data from patient/parent-completed food frequency questionnaires as a surrogate of intake. However, such self-report measures are subject to recall bias and may not accurately reflect patient intake. Plasma or serum levels of micronutrients are needed to definitively represent nutritional status and to more precisely characterize associations with the metabolome. Although it must be stated that the investigators were limited in their ability to evaluate this, as expansive plasma or serum micronutrient data are not currently available in the CKiD study.

Another limitation that must be considered is the confounding influence of CKD severity. The investigators concede that they observed a decline in intake of several micronutrients at eGFRs near 40–50 ml/min per 1.73 m². Previous studies link eGFR or CKD severity to both excess and deficiencies in micronutrients.^5,6 Furthermore, there are also data to support a present but complex association between eGFR and the metabolome.⁷ Together, this could suggest that metabolic pathways described in this study are primarily influenced by kidney disease impairment and not necessarily nutritional intake/status. To address this, the investigators adjusted for both eGFR and proteinuria as of CKD severity and still observed associations between nutrient intake, particularly vitamins D and B12, and plasma metabolites—especially those involved in lipid metabolism. In addition, most samples analyzed were from the 6-month CKiD study visit, which may have skewed the results toward participants earlier in the course of their disease, and therefore not fully reflect changes in micronutrient intake and the metabolome as CKD progressed.

Finally, the study analyses were not stratified by CKD etiology groups, but doing so may have provided additional insight regarding micronutrient intake and metabolic associations. Previous studies have described that CKD comorbidities and associations may not be the same between the glomerular and nonglomerular disease groups.^8,9 Patients with nonglomerular diseases have a higher prevalence of tubular dysfunction which can lead to more significant wasting of electrolytes and amino acids compared with patients with glomerular etiologies of their CKD. However, patients with glomerular diseases have increased losses of vitamin D binding protein as well as protein-bound trace elements (copper, zinc, and selenium).¹⁰ As such, it is possible that micronutrient needs, status, and their association with metabolic pathways may differ between these two disease groups.

In conclusion, the information gleaned from this study fills a gap in knowledge regarding the micronutrient intake of children with CKD, representing an important step toward future development of stronger evidenced-based dietary guidelines for this nutritionally vulnerable population. Despite the limitations mentioned, Hasson et al. present extensive and clinically relevant findings regarding the micronutrient intake of children with CKD and describe novel links to metabolic pathways that may be influenced by certain nutritional deficiencies. This provides a valuable foundation of knowledge on which future investigations can build. Future studies should include prospectively collected serum or plasma micronutrient concentration levels to better inform our understanding of nutritional status in children with CKD and identify any metabolic implications from alterations in these micronutrients.

Disclosures

Disclosure forms, as provided by each author, are available with the online version of the article at http://links.lww.com/CJN/C454.

Author Contributions

Conceptualization: Marva M. Moxey-Mims.

Writing – original draft: Denver D. Brown, Marva M. Moxey-Mims, Kristen Sgambat.

Writing – review & editing: Denver D. Brown, Marva M. Moxey-Mims, Kristen Sgambat.

Funding

None.