Extracorporeal kidney support in neonates and infants: therapeutic perspectives and outcomes in multiple organ dysfunction syndrome—a structured narrative review

Introduction

Multiple organ dysfunction syndrome (MODS) remains a major cause of morbidity and mortality among critically ill neonates and infants, particularly those with congenital heart defects, severe infections, postoperative complications, and acute kidney injury (AKI) (1–4). The development of MODS in neonatal and pediatric intensive care settings is associated with systemic inflammatory activation, metabolic dysregulation, impaired tissue perfusion, and progressive organ dysfunction, frequently resulting in prolonged intensive care support and unfavorable clinical outcomes (5–8).

Extracorporeal blood purification techniques have become an important supportive strategy in critically ill neonates and infants with severe metabolic disturbances, fluid overload, sepsis-associated complications, and renal dysfunction (9–12). Conventional extracorporeal modalities used in neonatal and pediatric intensive care include hemofiltration (HF), hemodialysis (HD), and continuous kidney replacement therapy (CKRT) (13–16).

Hemodiafiltration (HDF) combines convective and diffusive clearance mechanisms, allowing the removal of both small- and middle-molecular-weight solutes, including inflammatory mediators and metabolic byproducts (17–20). Because of these characteristics, HDF has been increasingly explored as a potential extracorporeal support modality in neonates and infants with systemic inflammatory response and MODS (21–24).

The application of HDF in neonates and infants remains technically challenging because of their small body size and age-specific physiological and anatomical characteristics, including low circulating blood volume, vascular access difficulties, and the limited availability of miniaturized extracorporeal systems (25–27). However, recent advances in technologies suitable for neonates and low-weight infants, including CARPEDIEM™, NIDUS, and modified Prismaflex HF20 systems, together with improvements in anticoagulation strategies, have increased the feasibility of extracorporeal therapies in these populations (28–33).

Published clinical studies suggest that HDF may be associated with metabolic stabilization, correction of acid–base imbalance, reduction in lactate levels, and improvement in hemodynamic parameters in selected neonates and infants (13, 22, 34–37). Nevertheless, the currently available evidence remains limited and heterogeneous. Most reports are based on observational studies, registry data, and small case series with variable indications, patient populations, and treatment protocols, limiting direct comparison of findings and the development of standardized recommendations (38–42).

Therefore, this structured narrative review aims to provide a descriptive overview and critical appraisal of the available literature on hemodiafiltration in neonates and infants, with particular attention to low-weight patients weighing ≤8 kg. Particular emphasis is placed on clinical applications, technical considerations, safety aspects, reported outcomes, and areas requiring further investigation. The review seeks to summarize current knowledge while acknowledging the limitations and heterogeneity of the existing evidence base (38).

Methods

Review design

This study was conducted as a structured narrative review incorporating systematic literature search elements. The review was designed to provide a descriptive overview of the current literature on hemodiafiltration (HDF) and related continuous kidney replacement therapy (CKRT) modalities in neonatal intensive care settings.

A narrative review approach was selected because the available evidence consists predominantly of observational studies, registry analyses, retrospective cohorts, and case series with substantial clinical and methodological heterogeneity. Therefore, quantitative synthesis and meta-analysis were not considered appropriate.

This review does not represent a formal systematic review and was not intended to generate pooled effect estimates.

PICOS framework

The review question was structured according to the PICOS framework to define the scope of the literature search and evidence synthesis.

Population (P)

Critically ill neonates (<28 days of life) requiring extracorporeal blood purification support in the setting of multiple organ dysfunction syndrome (MODS), sepsis, acute kidney injury (AKI), hyperammonemia, fluid overload, or other severe metabolic disturbances. The key terminology and abbreviations used throughout the review are summarized in Table 1.

Table 1. Key terminology and abbreviations used in this review.

Intervention (I)

Hemodiafiltration (HDF) and related continuous kidney replacement therapy (CKRT) modalities, including continuous venovenous hemodiafiltration (CVVHDF), continuous venovenous hemofiltration (CVVH), and other neonatal extracorporeal blood purification techniques.

Comparator (C)

No formal comparator was required because this review was designed as a structured narrative review intended to provide a descriptive synthesis of published clinical experiences and observational evidence. When comparative data were available within individual studies, these findings were described narratively without formal comparative analysis.

Primary outcome (O)

The primary outcome of interest was metabolic stabilization, including correction of acid-base disturbances and stabilization of electrolyte abnormalities following initiation of extracorporeal blood purification therapy.

Secondary outcomes (O)

Secondary outcomes included:

• - lactate reduction;
• - hemodynamic stabilization;
• - vasopressor requirements;
• - fluid balance control;
• - inflammatory biomarker trends;
• - anticoagulation-related observations;
• - safety outcomes and procedure-related complications;
• - technical feasibility of extracorporeal support.

Study design (S)

Observational studies, retrospective cohorts, registry reports, and case series evaluating HDF or related CKRT modalities in neonatal populations. Review articles and consensus publications were used exclusively for background information, contextual interpretation, and discussion of evolving technologies and clinical practice concepts and were not included in the descriptive synthesis of clinical outcomes.

Scope of the review

The review focused on critically ill neonates (<28 days of life) requiring extracorporeal blood purification support in the setting of multiple organ dysfunction syndrome (MODS), sepsis, acute kidney injury (AKI), hyperammonemia, fluid overload, or other severe metabolic disturbances.

Particular attention was given to reports describing metabolic, hemodynamic, safety-related, and technical outcomes associated with neonatal extracorporeal blood purification therapies, as specified in the PICOS framework.

When comparative data were available within individual studies, these findings were described narratively. No formal comparative analysis was performed.

Literature identification

Relevant literature was identified through searches of PubMed/MEDLINE, Scopus, Web of Science Core Collection, and the Cochrane Library.

The search focused on publications addressing neonatal hemodiafiltration, continuous kidney replacement therapy, acute kidney injury, sepsis, hyperammonemia, and extracorporeal blood purification techniques.

The search period covered January 2018 through October 2025. Additional relevant publications were identified through manual examination of reference lists from selected articles.

Search strategy

A structured literature search was conducted in PubMed/MEDLINE, Scopus, Web of Science Core Collection, and the Cochrane Library to identify publications relevant to neonatal hemodiafiltration and related extracorporeal blood purification therapies.

The search strategy combined controlled vocabulary (where applicable) and free-text keywords using Boolean operators (AND, OR). Representative search terms included: AND AND The search was limited to publications published between January 2018 and October 2025. Only English-language articles involving neonatal populations were considered. Additional relevant publications were identified by manually screening the reference lists of eligible studies.

• - “neonate” OR “newborn” OR “neonatal”;
• - AND “hemodiafiltration” OR “continuous venovenous hemodiafiltration” OR “CVVHDF”;
• - OR “continuous kidney replacement therapy” OR “CKRT” OR “continuous renal replacement therapy” OR “CRRT”;
• - AND “acute kidney injury” OR “AKI”;
• - OR “multiple organ dysfunction syndrome” OR “MODS”;
• - OR “sepsis”;
• - OR “hyperammonemia”;
• - OR “extracorporeal blood purification”.
• - representative PubMed search string was:
• - (“neonate” OR “newborn” OR neonatal)

• - (“hemodiafiltration” OR CVVHDF OR “continuous kidney replacement therapy” OR CKRT OR CRRT)

• - (“acute kidney injury” OR AKI OR sepsis OR MODS OR hyperammonemia)

Study selection, data extraction, and quality assessment

All retrieved records were exported to Microsoft Excel, where duplicates were identified electronically and verified manually. Two reviewers independently screened titles, abstracts, and full texts according to the PICOS criteria, recorded reasons for exclusion, and extracted data using a standardized form; disagreements were resolved by consensus. Methodological quality was evaluated based on study design, sample size, completeness of outcome reporting, and potential sources of bias and was considered when interpreting the evidence.

The literature identification and study selection process is summarized in Figure 1.

Data collection and narrative synthesis

• Information from relevant publications was summarized descriptively, including:
• - publication characteristics;
• - patient populations;
• - clinical indications;
• - extracorporeal techniques;
• - anticoagulation approaches;
• - treatment characteristics;
• - reported outcomes;
• - complications and safety observations.
• The evidence was synthesized narratively and organized according to major thematic domains:
• - clinical indications;
• - technical aspects of therapy;
• - metabolic effects;
• - hemodynamic effects;
• - anticoagulation strategies;
• - safety considerations;
• - emerging neonatal technologies.

Interpretation of evidence

Because of the substantial heterogeneity of the available literature, findings were interpreted descriptively.

Reported outcome ranges represent observations reported in individual studies and should not be interpreted as pooled quantitative estimates, epidemiological prevalence measures, or meta-analytic calculations.

The interpretation of findings considered important limitations of the existing evidence base, including small sample sizes, observational study designs, heterogeneous patient populations, variability in treatment protocols, and inconsistent outcome reporting.

In addition, evidence was interpreted according to the type and methodological strength of the included publications. Narrative reviews, systematic reviews, and consensus statements were used primarily to provide background context and describe current concepts in neonatal extracorporeal kidney support. Clinical conclusions regarding efficacy, safety, and patient outcomes were based predominantly on original clinical studies, including observational cohorts, registry analyses, retrospective studies, and case series. Given the predominance of non-randomized evidence, findings were interpreted cautiously with consideration of study design, sample size, potential sources of bias, and methodological limitations.

Methodological transparency

The methodological approach was designed to maximize transparency and reproducibility while maintaining the flexibility inherent to a structured narrative review. Literature identification, study selection, and evidence synthesis were performed according to predefined methodological principles. Owing to the substantial clinical and methodological heterogeneity across the available studies, findings were synthesized descriptively rather than quantitatively.

Results

Characteristics of the reviewed literature

The identified publications primarily comprised retrospective cohort studies, registry-based analyses, clinical series, and observational investigations examining the application of hemodiafiltration (HDF) and other continuous kidney replacement therapy (CKRT) modalities in critically ill neonates.

The most commonly reported indications for extracorporeal kidney support were acute kidney injury (AKI), sepsis, multiple organ dysfunction syndrome (MODS), hyperammonemia, severe metabolic derangements, and fluid overload.

Among the extracorporeal platforms, CARPEDIEM™, NIDUS, Prismaflex HF20, and Aquarius systems were most frequently utilized. Therapeutic approaches included continuous venovenous hemodiafiltration (CVVHDF), continuous venovenous hemofiltration (CVVH), and other CKRT-based techniques. Anticoagulation was predominantly achieved using unfractionated heparin or regional citrate anticoagulation.

Metabolic and hemodynamic findings

Across the reviewed studies, extracorporeal kidney support was consistently associated with improved metabolic control, including correction of acid-base imbalance, reduction of lactate levels, and stabilization of electrolyte disturbances.

Evidence regarding the hemodynamic and inflammatory effects of extracorporeal therapy remains limited. In a single neonatal case report, initiation of CVVH was followed by hemodynamic stabilization, reduced vasopressor doses, and decreases in C-reactive protein from 297 to 19 mg/L and procalcitonin from 24.7 to 1.1 ng/mL (42). However, because these findings were derived from a single patient receiving concurrent intensive care, they should be interpreted as descriptive and hypothesis-generating rather than as evidence of a causal treatment effect.

Overall, methodological quality was limited by small sample sizes, predominantly retrospective single-center designs, absent comparator groups, and heterogeneous outcome reporting. These limitations were considered in the narrative synthesis.

Safety profile

Reported adverse events included transient hypotension, circuit thrombosis, electrolyte abnormalities, vascular access complications, and occasional bleeding episodes.

The occurrence and severity of complications differed substantially among studies and appeared to depend on patient characteristics, device type, anticoagulation strategy, and center-specific expertise.

Clinical applications in specific neonatal populations

Sepsis

Available clinical reports indicate that extracorporeal blood purification may facilitate metabolic stabilization and cardiovascular support in neonates with severe sepsis. Improvements in circulatory performance and reductions in vasopressor requirements were frequently noted during treatment.

Multiple organ dysfunction syndrome

In neonates with MODS, HDF and related CKRT modalities were primarily applied as supportive interventions to maintain metabolic balance, optimize fluid status, and provide temporary organ support while definitive treatment of the underlying condition was undertaken.

Preterm and low-birth-weight neonates

The reviewed studies demonstrated the technical feasibility of individualized low-flow extracorporeal support in preterm and extremely low-birth-weight infants. However, experience remains restricted to relatively small cohorts, and robust outcome data are still scarce.

Combined ECMO and CKRT support

Several publications evaluated the integration of CKRT or HDF with extracorporeal membrane oxygenation (ECMO) in critically ill neonates. These reports suggested improved fluid management and enhanced metabolic control during extracorporeal support; however, the available data remain insufficient to establish definitive therapeutic advantages.

Summary of the available evidence

Collectively, the reviewed studies suggest that HDF and related CKRT modalities may serve as valuable supportive therapies for metabolic stabilization, fluid management, and hemodynamic optimization in selected critically ill neonatal populations.

At the same time, interpretation of the available literature is constrained by the predominance of non-randomized study designs, relatively small cohorts, clinical heterogeneity, and substantial variation in treatment protocols and outcome definitions. Therefore, the current body of evidence should be regarded as exploratory and hypothesis-generating rather than conclusive proof of therapeutic superiority or effectiveness.

Discussion

The application of hemodiafiltration (HDF) and related continuous kidney replacement therapy (CKRT) modalities in critically ill neonates has received growing attention over the past decade, particularly in the management of multiple organ dysfunction syndrome (MODS), severe sepsis, acute kidney injury (AKI), and hyperammonemia. Despite increasing clinical utilization, the current literature is characterized by relatively small cohorts, registry-based analyses, retrospective investigations, and single-center experiences.

From a physiological perspective, HDF integrates diffusive and convective clearance mechanisms, allowing the removal of both low-molecular-weight solutes and selected middle-molecular-weight substances. This combined approach has generated interest in the potential role of HDF as a supportive extracorporeal strategy in neonatal intensive care. Nevertheless, the extent to which these physiological advantages translate into measurable clinical benefit remains uncertain.

Across the reviewed studies, extracorporeal kidney support was associated with improvements in metabolic homeostasis, including correction of acid-base imbalance, normalization of electrolyte disturbances, and reduction of lactate concentrations. Several investigators also documented improved cardiovascular stability and decreased vasopressor requirements during treatment. Interpretation of these findings, however, remains challenging because of differences in patient characteristics, treatment indications, device configurations, and outcome definitions.

Fluid overload represents an additional therapeutic target in neonatal critical care. Excessive fluid accumulation has been linked to adverse outcomes, particularly in neonates with cardiac dysfunction, renal impairment, or severe systemic inflammation. Available data suggest that HDF and related CKRT techniques can facilitate individualized fluid management; however, adequately powered comparative studies are still lacking.

Comparative interpretation of current evidence

An important question arising from the current literature is whether HDF provides clinically relevant advantages over alternative CKRT modalities, particularly continuous venovenous hemofiltration (CVVH). Theoretically, the combination of convective and diffusive clearance may enhance solute removal while maintaining efficient clearance of middle molecules. However, neonatal studies directly comparing HDF and CVVH remain scarce, preventing reliable assessment of relative efficacy.

Current data indicate that extracorporeal kidney support may be particularly valuable in neonates with severe fluid overload, sepsis-associated MODS, AKI, hyperammonemia, and profound metabolic instability. In these clinical scenarios, HDF and related techniques appear capable of supporting metabolic regulation, fluid balance, and renal function while definitive treatment of the underlying disease is pursued. Nevertheless, considerable variation in patient selection practices persists among institutions.

A consistent finding across the reviewed literature is improvement in surrogate physiological markers, including lactate clearance, electrolyte normalization, correction of acid-base disturbances, and stabilization of hemodynamic parameters. In contrast, evidence supporting a direct survival advantage remains considerably less convincing. Outcomes in critically ill neonates are strongly influenced by congenital anomalies, severity of organ dysfunction, infectious burden, and coexisting comorbidities, making attribution of survival benefit to extracorporeal therapies alone difficult.

Several unresolved questions remain. These include the lack of randomized controlled trials, scarcity of prospective multicenter investigations, absence of standardized anticoagulation approaches, variability in outcome reporting, and limited information regarding long-term neurodevelopmental outcomes. Addressing these issues should represent a priority for future collaborative research initiatives.

Technical considerations

The implementation of extracorporeal therapies in neonates remains technically demanding. Small circulating blood volume, challenges in vascular access, anticoagulation management, and susceptibility to hemodynamic instability continue to represent major obstacles.

The introduction of neonatal-specific platforms such as CARPEDIEM™, NIDUS, and other low-volume CKRT systems has substantially improved technical feasibility in low-weight infants. Nevertheless, much of the published experience originates from highly specialized centers with extensive expertise, which may limit broader applicability.

Table 2 demonstrates that contemporary review articles consistently identify CKRT, including HDF, as a feasible supportive therapy for critically ill neonates. Across the available reviews, metabolic stabilization, fluid balance optimization, and correction of electrolyte disturbances represent the most consistently reported clinical benefits. At the same time, the evidence uniformly highlights the lack of prospective multicenter studies and standardized treatment protocols, emphasizing the need for further high-quality clinical research.

Table 2. Review articles and conceptual publications on continuous kidney replacement therapy in neonates and infants.

Table 2 summarizes review articles and conceptual publications that provide the current theoretical framework for neonatal CKRT, including indications, technical considerations, anticoagulation strategies, and emerging technologies.

Controversies in clinical indications

The optimal timing and indications for HDF initiation remain incompletely defined. Although AKI, severe fluid overload, and hyperammonemia are generally accepted indications for extracorporeal kidney support, the role of HDF in neonatal sepsis and MODS remains less clearly established.

Clinical practice varies considerably among institutions. Some centers favor earlier initiation in selected high-risk patients, whereas others reserve extracorporeal therapy for refractory clinical deterioration. Such differences likely reflect variations in institutional resources, experience, and local treatment protocols.

HDF in combination with ECMO

Integration of CKRT or HDF with extracorporeal membrane oxygenation (ECMO) represents an area of increasing clinical interest. Available reports suggest that combined extracorporeal support may improve fluid balance management and metabolic control in neonates requiring ECMO.

At present, however, available information is largely derived from small clinical cohorts and center-specific experiences. Consequently, the optimal timing, technical configuration, and anticoagulation strategies for combined ECMO-CKRT support remain to be established.

Future perspectives

Future investigations should prioritize prospective multicenter studies, standardized reporting of clinical outcomes, and harmonization of treatment protocols. Greater consistency in patient selection criteria, anticoagulation strategies, and outcome definitions would improve comparability across studies and facilitate more reliable assessment of therapeutic effectiveness

Conclusion of discussion

Collectively, the reviewed literature indicates that HDF may represent a feasible supportive extracorporeal intervention for selected critically ill neonates. Although encouraging effects on metabolic control, fluid management, and physiological stabilization have been reported, the current knowledge base remains insufficient to establish definitive therapeutic superiority. Reported improvements in vasopressor requirements and inflammatory biomarkers are based largely on isolated observational reports and should therefore be considered preliminary and hypothesis-generating. Therefore, available findings should be regarded as preliminary clinical evidence that supports further investigation rather than conclusive proof of efficacy.

Table 3 summarizes the currently available primary clinical evidence evaluating CKRT and HDF in neonatal populations. Most published studies are retrospective cohorts or case series originating from highly specialized centers with limited sample sizes. Despite this limitation, the findings consistently demonstrate technical feasibility, effective metabolic and fluid control, and acceptable safety profiles when therapy is performed by experienced multidisciplinary teams. Nevertheless, robust evidence regarding survival benefit and long-term outcomes remains insufficient.

Table 3. Primary clinical studies evaluating continuous kidney replacement therapy in neonates and young infants.

Table 3 summarizes primary clinical studies evaluating CKRT in neonates and young infants. These studies provide evidence regarding the feasibility, safety, anticoagulation strategies, technical performance, and clinical outcomes of extracorporeal kidney support across diverse neonatal conditions, including acute kidney injury, sepsis, hyperammonemia, and multiple organ dysfunction syndrome.

Limitations

This structured narrative review has several limitations that should be considered when interpreting the findings.

First, the available literature consists largely of retrospective investigations, registry-based analyses, and clinical case series. The absence of randomized controlled trials and the relatively small cohorts included in many studies reduce the overall strength of the evidence and limit the generalizability of reported findings.

Second, substantial variability exists among studies regarding patient characteristics, underlying diagnoses, indications for therapy, extracorporeal platforms, anticoagulation approaches, treatment protocols, and outcome measures. Such differences complicate direct comparisons and hinder consistent interpretation of reported results.

Third, publication bias cannot be excluded, as studies reporting favorable clinical experiences may be more likely to reach publication than those describing neutral or negative outcomes.

Additionally, reporting of clinical, laboratory, and long-term outcomes was frequently inconsistent, limiting assessment of both efficacy and safety across studies.

Finally, this work was conducted as a structured narrative review incorporating systematic search elements. Consequently, no formal meta-analysis, pooled effect estimates, or comparative effectiveness analyses were performed.

Clinical implications and future perspectives

The available literature indicates that HDF and related CKRT modalities may represent feasible extracorporeal support strategies in selected critically ill neonates requiring metabolic, fluid, or renal support.

Published studies have described improvements in metabolic homeostasis, acid-base balance, fluid management, and physiological stabilization following initiation of extracorporeal kidney support. However, current data do not permit definitive conclusions regarding superiority over alternative CKRT modalities.

Recent technological advances, including neonatal-adapted platforms such as CARPEDIEM™, NIDUS, and modified low-volume CKRT systems, have expanded the feasibility of extracorporeal therapies in very-low-birth-weight infants and other vulnerable neonatal populations.

Despite these developments, important knowledge gaps remain, highlighting the need for prospective multicenter studies, standardized treatment protocols, and long-term outcome evaluation.

Based on the currently available evidence, HDF appears to be most beneficial for critically ill neonates with acute kidney injury (AKI), severe fluid overload, hyperammonemia, sepsis-associated multiple organ dysfunction syndrome (MODS), and profound metabolic instability that cannot be adequately corrected by conventional intensive care alone. In these clinical scenarios, HDF may facilitate metabolic stabilization, optimize fluid balance, and provide temporary organ support while definitive treatment of the underlying disease is implemented.

However, the current evidence remains limited regarding the optimal timing of HDF initiation, patient selection criteria, standardized anticoagulation protocols, comparative effectiveness versus other CKRT modalities, and long-term neurodevelopmental outcomes. Therefore, treatment decisions should remain individualized and guided by multidisciplinary clinical expertise until stronger prospective evidence becomes available.

The decision to initiate HDF or other extracorporeal kidney support modalities in critically ill neonates should always be made by a multidisciplinary team. Careful assessment by neonatologists, pediatric intensivists, nephrologists, anesthesiologists, cardiac surgeons (when applicable), and specialized nursing staff is essential to evaluate the potential benefits, procedural risks, technical feasibility, and overall therapeutic goals for each individual patient.

Importantly, extracorporeal kidney support should not be considered a standalone treatment for neonatal sepsis or multiple organ dysfunction syndrome. Rather, it should be viewed as an adjunctive supportive therapy within a comprehensive intensive care strategy that includes source control of infection, appropriate antimicrobial therapy, hemodynamic optimization, respiratory support, and correction of metabolic disturbances. When applied to carefully selected patients, HDF may provide an important therapeutic opportunity to support organ recovery while definitive treatment of the underlying disease takes effect.

What this review adds

• Provides a structured narrative synthesis of contemporary literature addressing HDF and related CKRT modalities in neonatal intensive care.
• Summarizes current indications, technical considerations, and safety challenges associated with extracorporeal kidney support in neonates.
• Highlights the expanding role of neonatal-specific extracorporeal platforms, including CARPEDIEM™ and NIDUS, in facilitating treatment of low-weight infants.
• Identifies key knowledge gaps, including the lack of prospective multicenter investigations, standardized treatment protocols, and long-term outcome data.
• Emphasizes the need for cautious interpretation of currently available findings and the importance of future collaborative research initiatives.

Generative AI statement

The author(s) declared that generative AI was not used in the creation of this manuscript.

Any alternative text (alt text) provided alongside figures in this article has been generated by Frontiers with the support of artificial intelligence and reasonable efforts have been made to ensure accuracy, including review by the authors wherever possible. If you identify any issues, please contact us.

Publisher's note

All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.

Footnotes

Edited by: Pedja Kovacevic, University Clinical Center of Republika Srpska, Bosnia and Herzegovina

Reviewed by: Ranganatha A. Devaranavadagi, Manipal Hospital Old Airport Road, India

Fatih Varol, Sancaktepe Martyr Dr. İlhan Varank Training and Research Hospital, Türkiye