Rethinking Creatinine in Children With Down Syndrome

Abbreviations

CAKUT

congenital anomalies of the kidneys and urinary tract

eGFR

estimated glomerular filtration rate

GFR

glomerular filtration rate

In a study by Farrell et al. published in Acta Paediatrica, the authors have added important Irish data to a growing international literature suggesting that serum creatinine behaves differently in children with Down syndrome [1]. In their cohort, more than one‐quarter of children had creatinine values above standard paediatric reference intervals, yet clinically significant chronic kidney disease appeared uncommon. Their findings are consistent with reports from Japan, France, Belgium and Italy, which have all identified unexpected abnormalities in markers of kidney function in children with trisomy 21 [1].

The immediate temptation is to conclude that children with Down syndrome require their own creatinine reference intervals [2]. However, this may not be the most important question. A more fundamental issue is whether conventional approaches to estimating and indexing kidney function are valid in this population.

Several studies now suggest that the phenomenon extends beyond creatinine alone. Yamakawa and colleagues reported that both creatinine‐based and cystatin C‐based estimated glomerular filtration rates (eGFR) were approximately 80% of those observed in healthy Japanese children [3]. Similarly, recent imaging studies have demonstrated increased rates of congenital abnormalities of the kidney and urinary tract, smaller kidneys and renal hypoplasia [4]. These observations raise the possibility that at least some individuals with Down syndrome may have genuine reductions in nephron endowment or kidney size [5, 6]. The challenge is determining how much of the observed reduction in eGFR reflects true physiology and how much reflects limitations of the biomarkers and indexing methods that we use.

An alternative explanation is suggested by the distinctive anthropometry of trisomy 21. Children with Down syndrome exhibit altered body composition, with increased fat mass and reduced lean body mass compared with peers [7]. In addition, studies of body proportions have demonstrated that much of the reduction in stature is attributable to shortened lower limbs, whereas sitting height is relatively preserved [8]. These findings have potentially important implications for nephrology because both kidney function estimation and body surface area normalization assume relationships between height, body composition and organ size that may not apply in Down syndrome.

One way to conceptualize this problem is through a three‐compartment distortion model. The first component is geometric distortion. Shortened lower limbs reduce standing height and therefore reduce calculated body surface area. Because measured GFR is routinely indexed to 1.73 m², errors in body surface area estimation may influence interpretation of kidney function. The second component is distribution‐volume distortion. Increased adiposity and reduced lean mass alter total body water and extracellular volume, potentially affecting the volume of distribution of endogenous filtration markers. The third component is generation‐rate distortion. Creatinine production depends on muscle mass and body composition, which differ substantially in trisomy 21. Together, these factors may lead to systematic differences between measured kidney function and biomarker‐based estimates. This helps explain why Farrell et al. observed markedly elevated creatinine without corresponding clinical kidney disease.

A clinical example illustrates the challenge. A young child with Down syndrome undergoing a ⁵¹Cr‐EDTA clearance study had a measured GFR of 106 mL/min/1.73 m² despite creatinine‐ and cystatin C‐based estimates [9] that were substantially lower. Although anecdotal, this observation highlights the possibility that current estimating equations may not be adequately calibrated for the unique physiology of trisomy 21. Importantly, the discrepancy was greater for creatinine than for cystatin C, suggesting that differences in body composition and distribution volumes may contribute to the observed bias.

At present, the field lacks the data necessary to distinguish among these competing explanations. The ideal study would combine gold‐standard measurement of GFR using iohexol or an equivalent tracer, detailed body composition analysis, assessment of extracellular volume, anthropometric measurements including sitting height and leg length, and high‐resolution assessment of kidney volume. Such an integrated physiological approach would allow investigators to determine whether children with Down syndrome truly have reduced nephron endowment, altered biomarker behaviour, or both [10].

The study by Farrell et al. [1] therefore contributes more than another report of elevated creatinine concentrations. It highlights a fundamental uncertainty in our understanding of kidney physiology in Down syndrome. Before redefining reference intervals or introducing kidney‐protective therapies on the basis of estimated GFR alone, we must first establish whether existing biomarkers and indexing methods accurately reflect renal function in this unique population. Answering that question may ultimately teach us as much about the limitations of our current nephrological paradigms as it does about trisomy 21 itself.

Author Contributions

Guido Filler: conceptualization, writing – original draft, methodology, validation, visualization, writing – review and editing, software, resources.

Funding

The author has nothing to report.

Conflicts of Interest

The author declares no conflicts of interest.

Linked Articles

This article is linked to Farrell et al. papers. To view this article, visit https://doi.org/10.1111/apa.70640.

Data Availability Statement

Data sharing not applicable to this article as no datasets were generated or analysed during the current study.