Objectives: Therapeutic plasma exchange has become an increasingly important extracorporeal therapy in pediatric intensive care and transplant settings. However, evaluations in large real-world pediatric cohorts of its effectiveness and safety across multiple indications remain limited. In this 5-year single-center study, we provided our experience with therapeutic plasma exchange in critically ill children and assessed clinical outcomes, indications, and procedure-related complications.
Materials and Methods: This retrospective observational study included 88 pediatric patients who underwent 702 therapeutic plasma exchange sessions in the pediatric transplant and nephrology intensive care unit of Başkent University Hospital (Ankara, Turkey) between December 2018 and December 2023. Indications were classified according to new American Society for Apheresis categories. We analyzed demographic data, indications, replacement fluids, treatment response, and adverse events.
Results: Median age of the 88 pediatric patients who underwent 702 therapeutic plasma exchange sessions was 7.5 years (range, 0-18 y), and 52.3% of patients were male. Fresh frozen plasma was used in 89.8% of sessions and albumin in 23.9%. The most frequent indications for therapeutic plasma exchange were posttransplant hepatic dysfunction (36.4%) and acute or chronic liver failure (28.4%), followed by antibody-mediated renal disease (13.6%) and multiorgan failure or sepsis (8%). Overall, 73 of 88 patients achieved complete or partial improvement, corresponding to a favorable response rate of 82.9%. Renal transplant-related indications demonstrated higher response rates compared with liver-related conditions (91% vs 78.9%). No life-threatening or procedure-terminating complications occurred; minor adverse events included hypotension, fever, allergic reactions, and thrombosis.
Conclusions: Therapeutic plasma exchange is a safe and effective supportive therapy for critically ill pediatric patients across a wide range of indications. When performed in experienced centers with close monitoring, complication rates are low. Multicenter prospective studies are needed to establish standardized protocols and further clarify disease-specific outcomes. Key words: Acute/chronic liver failure, Antibody-mediated rejection, Kidney transplantation, Liver transplantation, Pediatric intensive care

Introduction
Therapeutic plasma exchange (TPE) is an extracorporeal treatment modality used to remove circulating pathogenic substances or to replace deficient plasma components. By elimination of autoantibodies, immune complexes, cytokines, and toxic metabolites, this method may provide clinical benefit, particularly in immune-mediated and inflammatory diseases.¹ In recent years, with technological advances and increasing clinical experience, TPE has gained a progressively broader role in pediatric intensive care practice. Although data on pediatric TPE applications remain limited compared with applications in adults, existing studies have shown that the procedure is safe and effective when used for appropriate indications. Smaller vascular diameter, lower circulating blood volume, and the risk of hemodynamic instability make TPE technically more challenging in children; however, when performed in experienced centers, complication rates remain acceptable.^2,3 Therefore, TPE has become an important supportive therapy in selected pediatric intensive care unit cases. According to the latest guideline published by the American Society for Apheresis (ASFA), TPE indications are classified by level of evidence, and recommendations for category I and II are indicated for many pediatric diseases. Thrombotic microangiopathies, acute liver failure, antibody-mediated rejection, focal segmental glomerulosclerosis (FSGS) recurrence, BK virus nephropathy, and several neuro-immunologic disorders are among the strongest indications.¹ In pediatric nephrology practice, one of the most common indications for TPE is thrombotic microangiopathy. Atypical hemolytic uremic syndrome (HUS) is a rapidly progressive disease associated with high mortality as a result of dysregulation of the complement system. Therapeutic plasma exchange plays an important role in limiting acute kidney injury by removing pathogenic complement factors and replacing deficient plasma components.⁴ Similarly, TPE is considered a life-saving treatment option for thrombotic thrombocytopenic purpura and secondary thrombotic microangiopathies. Antibody-mediated rejection after kidney transplantation is one of the leading causes of graft loss in pediatric transplant recipients. Therapeutic plasma exchange, used to remove circulating donor-specific antibodies, is frequently combined with intravenous immunoglobulin and immunosuppressive therapies. Studies have shown that graft function can be preserved and rejection can be controlled in pediatric transplant patients treated with TPE.^1,3 Another important indication for TPE in pediatric patients is acute and acute-on-chronic liver failure. Acute liver failure in pediatric patients is a rare but highly lethal condition that often requires liver transplant. Stabilization of patients during the waiting period for transplant is critical. In this setting, TPE temporarily supports liver function by removing bilirubin, ammonia, and inflammatory mediators.⁵ Recent studies have demonstrated significant improvements in biochemical parameters and clinical stabilization before transplant in pediatric patients with acute liver failure treated with TPE.⁶ In recent years, the use of TPE in pediatric acute and acute-on-chronic liver failure has increased. Studies in this population have evaluated the effects of TPE on biochemical parameters, particularly in severe clinical presentations. A recent systematic review and meta-analysis reported improved survival and clinical stabilization until transplant, with significant reductions in international normalized ratio, serum bilirubin, and ammonia levels following TPE, and low rates of serious adverse events.⁷ These findings have highlighted the growing interest in TPE as a supportive therapy in the management of pediatric liver failure. In pediatric intensive care practice, TPE is increasingly used in the management of high-mortality conditions such as sepsis and multiorgan failure. Removal of cytokines and inflammatory mediators may help suppress the inflammatory response. Studies have reported improved survival, particularly in patients with thrombocytopenia and multiorgan failure.^8,9 The type of replacement fluid used during TPE may also influence clinical outcomes. Albumin and fresh frozen plasma are the most commonly used replacement fluids. Fresh frozen plasma is preferred in the presence of coagulopathy, whereas albumin is often favored because of its lower risk of allergic reactions. Studies have shown that allergic reactions are more frequent with fresh frozen plasma, whereas coagulation parameters improve more rapidly.^3,8 Therapeutic plasma exchange plays a vital role in pediatric intensive care, offering lifesaving support for renal and hepatic disorders. Despite benefits, it carries risks depending on diagnosis and context. The aim of our study was to evaluate the 5-year single-center experience with TPE in pediatric nephrology and pediatric transplant intensive care units, to assess the safety and effectiveness of TPE across a broad spectrum of diseases, and to provide a comprehensive contribution to the literature. Although the present literature has shown the effectiveness of TPE in pediatric patients, studies on long-term outcomes in large patient populations across multiple indications have remained limited. In particular, studies simultaneously assessing efficacy, complication profiles, and the effects of replacement fluids across different disease groups are scarce. In this study, TPE sessions performed for diverse clinical conditions, including atypical HUS, anti-glomerular basement membrane disease, acute and chronic liver failure, posttransplant rejection, antibody-mediated kidney injury, FSGS, BK virus nephropathy, recurrent HUS, and multiorgan failure, were analyzed. We also compared sessions using fresh frozen plasma and albumin to evaluate complication profiles and clinical outcomes. We conducted this study with the aim to contribute to the pediatric TPE literature through real-world data, a substantial patient cohort, and broad range of clinical indications.

Materials and Methods
This retrospective observational study included 88 pediatric patients who underwent 702 TPE sessions in the pediatric nephrology and pediatric transplant intensive care unit of Başkent University Hospital (Ankara, Turkey), between December 2018 and December 2023. All patients were aged <18 years and had received at least 1 TPE session during their stay in the intensive care unit. Indications were classified according to the 2023 ASFA guidelines. For category I and II indications, TPE was recommended as a first- or second-line therapy, whereas for category III and IV indications, treatment decisions were individualized based on multidisciplinary assessment and patient-specific clinical considerations.¹ The effectiveness of TPE was evaluated based on clinical response and laboratory improvement in accordance with the therapeutic goals outlined in the ASFA guidelines. Primary outcome was favorable clinical response (complete + partial improvement). We retrieved retrospective data on demographics, primary diagnoses, TPE indications, number of sessions, laboratory findings before and after TPE, replacement fluids used, and procedure-related complications from electronic medical records and apheresis unit databases. Complications were recorded per session. We used IBM SPSS Statistics version 25.0 (IBM Corp) for statistical analyses.

Results

Patient characteristics
Among the 88 pediatric patients who underwent 702 TPE sessions in our pediatric intensive care unit during the study period, median age was 7.5 years (range, 0-18 y), and 52.3% were male patients. Median number of TPE sessions per patient was 7.98 (range, 1-32). Fresh frozen plasma was used as the replacement fluid in 89.8% of sessions, and albumin was used in 23.9% (Table 1).

Clinical indications
The primary underlying disease group was liver-related disease in 63.6% of patients (n = 56), renal diseases in 27.3% (n = 24), and combined liver and renal involvement in 9.1% (n = 8) (Table 1).

Indications for therapeutic plasma exchange
The most common indication for TPE was posttransplant hepatic dysfunction, accounting for 36.4% of cases. Acute and chronic liver failure represented the second most frequent indication (28.4%), followed by antibody-mediated renal disease in 13.6% of patients and multiorgan failure and sepsis in 8%. Less common indications included HUS (4.5%), FSGS (4.5%), recurrent HUS (2.3%), and BK virus infection (2.3%).

American Society for Apheresis classification
According to the ASFA classification, 43.2% of patients (n = 38 of 88) were categorized as category I, 10.2% (n = 9 of 88) as category II, and 46.6% (n = 41 of 88) as category III (Figure 1).

Clinical outcomes
Overall treatment response was favorable in most patients. Complete or partial improvement was observed in 73 of 88 patients, corresponding to an overall response rate of 82.9%. When analyzed by indication, response was observed in 71.9% (23 of 32) of patients with posttransplant hepatic dysfunction, 88.0% (22 of 25) with acute or chronic liver failure, 83.3% (10 of 12) with antibody-mediated renal disease, and 71.4% (5 of 7) with multiorgan failure. All patients with FSGS (4/4), recurrent HUS (2/2), and BK virus infection (2/2) responded to therapy, and 75.0% (3/4) of patients with HUS showed a response. In terms of overall clinical outcome, among the 88 patients, partial improvement was observed in 61.4% (n = 54), complete recovery in 21.6% (n = 19), and intermittent improvement in 15.9% (n = 14). Only 1 patient (1.1%) showed no response to therapy (Table 2). Univariate analysis demonstrated that renal-related indications were associated with higher favorable response rates compared with liver-related indications (91% vs 78.9%). Indications in ASFA category I and II showed numerically higher response compared with category III.

Adverse events
Therapeutic plasma exchange was generally well tolerated. No major procedure-related adverse events or mortalities were observed. Minor complications were observed in a small proportion of patients, including hypotension (13.6%), fever (6.8%), allergic reactions (4.5%), and thrombosis (3.4%) (Figure 2).

Discussion
Therapeutic plasma exchange has become an increasingly important extracorporeal therapy in pediatric intensive care, particularly for immune-mediated, renal, hepatic, and transplant-related disorders. However, the pediatric evidence base remains largely limited to retrospective single-center series, and real-world data from multidisciplinary pediatric intensive care cohorts are still relatively scarce. The present study contributes to this growing field by providing real-world experience from a large series of critically ill children undergoing TPE. This study represents one of the largest single-center TPE cohorts focusing on transplant-related indications and organ failure scenarios.

Expansion of therapeutic plasma exchange in pediatric critical care
The ASFA guidelines remain the cornerstone for clinical decision-making in therapeutic apheresis. Current recommendations support TPE as a first- or second-line therapy for several immune-mediated and transplant-related conditions and emphasize individualized decision-making for other indications. The distribution of ASFA categories in the present cohort reflects real-world practice, where treatment decisions frequently extend beyond classical indications and require multidisciplinary assessment.¹

Comparison with previous pediatric cohorts
Previous pediatric studies consistently demonstrated that TPE can be safely performed in critically ill children. Reported outcomes across different cohorts have shown favorable clinical responses and low complication rates, although results have varied depending on disease severity and underlying diagnosis.^2,4,8 Therapeutic plasma exchange is frequently used in transplant medicine; however, pediatric transplant-focused outcome data remain scarce. In this single-center cohort of 88 children undergoing 702 TPE sessions, we demonstrated an 82% overall favorable response rate, showing particularly strong outcomes in renal transplant-related immune-mediated conditions. The high overall response rate observed in the present study is consistent with the growing body of evidence and likely reflects improvements in clinical experience, patient selection, and supportive care.

Safety profile of therapeutic plasma exchange
Safety remains a central concern when applying extra-corporeal therapies in children. Pediatric patients present unique challenges, including limited vascular access, reduced circulating blood volume, and an increased risk of hemodynamic instability. Nevertheless, multiple studies have confirmed that most complications are mild and manageable, with hypotension and allergic reactions being the most frequently reported events.^3,8 The low complication rate observed in our cohort further supports the safety of TPE when performed in experienced centers. The type of replacement fluid has also been identified as an important determinant of complication profiles. Previous studies have suggested that allergic reactions occur more frequently with fresh frozen plasma, whereas albumin is associated with fewer hypersensitivity reactions.^3,8 These findings highlight the importance of individualized replacement fluid selection based on clinical context.

Role in renal and thrombotic microangiopathy
Renal disorders, particularly thrombotic microangiopathies, remain among the most established indications for pediatric TPE. Complement-mediated diseases such as atypical HUS are characterized by rapid progression and high mortality, and extracorporeal removal of pathogenic complement factors could help limit kidney injury and improve outcomes.⁴ Therapeutic plasma exchange has also been associated with improved renal outcomes in critically ill patients with thrombocytopenia receiving kidney replacementtherapy.⁹

Role in liver failure
The role of TPE in acute liver failure in pediatric patients has gained increasing attention in recent years. Previous studies have shown significant improvements in biochemical parameters and clinical stabilization, supporting its use as a bridge to transplant or recovery.^5,6 Evidence from meta-analysis has suggested improvements in survival and key laboratory parameters, including international normalized ratio, bilirubin, and ammonia levels.⁷ The high proportion of liver-related indications in the present study reflects this evolving clinical trend.

Therapeutic plasma exchange in sepsis and multiorgan failure
Beyond classical indications, TPE is increasingly applied in severe inflammatory states such as sepsis and multiorgan failure. Removal of circulating cytokines and inflammatory mediators may contribute to immune modulation and improved outcomes, supporting the concept of TPE as a multiorgan supportive therapy.^8,9

Limitations
This study had several limitations. First, the retrospective and single-center design may have introduced selection bias. In addition, the heterogeneity of the patient population limited disease-specific subgroup analyses and prevented definitive conclusions regarding disease-specific effectiveness.

Conclusions
Therapeutic plasma exchange is a safe and effective supportive therapy for critically ill pediatric patients across a broad spectrum of indications. Although minor adverse events may occur, the procedure is generally well-tolerated when performed in experienced centers with appropriate monitoring. Our findings highlighted the expanding role of TPE as a multidisciplinary treatment modality in pediatric intensive care and transplant settings. Individualized, disease-specific treatment strategies appear essential to optimize clinical outcomes. Future multicenter prospective studies are needed to further define standardized protocols and clarify disease-specific effectiveness.