Dear Editor,
We read with great interest the insightful response [
1] to our Letter [
2] regarding the recent article by Yoon et al. [
3] and sincerely appreciate the authors’ thoughtful and rigorous analyses. In particular, their robust supplementary analyses provide strong support for inclusive, multi-organ modeling approaches in metabolic dysfunction–associated steatotic liver disease (MASLD).
We also thank the authors for underscoring the clinical relevance of chronic kidney disease (CKD) as an important comorbidity in MASLD [
1]. By framing the reported incremental cost-effectiveness ratio (ICER) as an upper-bound estimate and acknowledging the role of renal outcomes, their work offers valuable methodological clarity and further strengthens the rationale for integrated economic modeling.
More broadly, this work highlights a key opportunity for the field: the development of fully integrated, multi-organ disease models that explicitly reflect the systemic nature of MASLD. Increasingly recognized as a systemic disorder [
4,
5], MASLD is strongly associated with renal and cardiovascular morbidity and mortality, extending well beyond hepatic involvement alone [
5-
7].
Pediatric data further emphasize this systemic perspective [
8]. A heterogeneous spectrum of kidney damage (KD)-including hypo- or hyperfiltration, hypertension, and albuminuria—has been reported in a substantial proportion of children with MASLD [
9,
10] and is independently associated with fibrosis severity [
9]. Importantly, KD arising in childhood carries prognostic implications across the lifespan [
11]. Canonical evidence from pediatric and developmental nephrology studies demonstrates that early reductions in nephron endowment, along with sustained hyperfiltration, often persist into adulthood, predisposing individuals to progressive CKD, hypertension, and heightened cardiovascular risk [
12,
13]. Collectively, these observations indicate that pediatric MASLD represents a critical window in which early KD contributes to cumulative, lifelong disease burden [
9,
11].
The supplementary simulation presented by the authors [
2] – illustrating how fibrosis stage–specific CKD incidence can be incorporated into modeling-represents a constructive step toward more comprehensive approaches. Importantly, it supports the premise that inclusion of renal outcomes is likely to increase health utility gains and lower ICER estimates. Moreover, it provides a valuable foundation for future research aimed at elucidating multi-organ interactions and the long-term benefits of MASLD therapies.
From a lifespan and health technology assessment perspective, renal injury arising in childhood could have a disproportionate prognostic impact, as prolonged exposure to reduced renal reserve and cardiometabolic stressors may contribute to cumulative cardiometabolic risk and long-term losses in quality-adjusted life years (QALYs). Economic models with limited time horizons may therefore underestimate the full benefits of interventions that favorably modify early renal trajectories, highlighting the relevance of integrated cardio–reno–hepatic frameworks.
Taken together, these considerations strongly support the adoption of integrated liver–kidney–cardiovascular frameworks in future cost-effectiveness analyses [
14,
15]. MASLD represents a paradigmatic case in which siloed modeling approaches may fail to capture the full spectrum of disease biology and patient-centered outcomes. Previous economic analyses have highlighted the substantial clinical and economic burden associated with progressive MASLD, emphasizing that models incorporating extrahepatic benefits are essential to fully appreciate the value of effective therapies.
Recent integrative data further reinforce the concept of a cardio–reno–hepatic disease continuum [
16]. Even modest differences in renal disease progression may meaningfully affect cardiovascular events, survival, and healthcare utilization. Incorporating these mediated effects into economic models is therefore critical to accurately capture the full potential of disease-modifying therapies.
In conclusion, the analyses presented and the discussions offered support continued progress toward the development of integrated liver–kidney–cardiovascular economic models in MASLD. Such models will be particularly valuable for assessing long-term, cumulative effects on renal and cardiovascular outcomes across the lifespan. Both pediatric and adult perspectives underscore the importance of capturing early organ crosstalk to better inform clinical practice and health policy.
We are grateful for the opportunity to contribute to this collaborative scientific dialogue. The robust analyses presented by the authors exemplify the methodological rigor and innovation that will drive the field forward. MASLD represents a clinical challenge beginning in childhood, and effective management will require sustained, coordinated efforts of the entire scientific community.
Future research building on these integrated frameworks will be essential to refine our understanding of MASLD biology, improve prognostic assessment across the lifespan, and fully characterize the broader health and economic impact of emerging therapies.
FOOTNOTES
-
Authors’ contributions
Anna Di Sessa contributed to the writing, editing, and reviewing of the letter. Gianmario Forcina contributed to the writing of the letter Emanuele Miraglia del Giudice contributed to the editing and reviewing of the letter. All authors contributed to the approval of the final manuscript before submission.
-
Conflicts of Interest
The authors have no conflicts to disclose.
Abbreviations
incremental cost-effectiveness ratio
metabolic dysfunction–associated steatotic liver disease
quality-adjusted life years
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