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. 2025 May 6;47(1):2500662. doi: 10.1080/0886022X.2025.2500662

Pathophysiological changes in patients during hemodialysis and blood reinfusion predict potential development of hemodialysis reactions

Ákos Géza Pethő a,✉, Csaba Révész b, Tamás Mészáros b, Orsolya Sáfár c, László Rosivall b, József Domán d, Gábor Szénási b, Tünde Gigacz d, László Dézsi b
PMCID: PMC12057777  PMID: 40328739

Abstract

Hemodialysis reactions (HDRs) are a type of hypersensitivity reactions (HSRs), such as complement activation-related pseudoallergy (CARPA) observed during nanoparticle infusions. Our study aimed to elucidate the mechanisms of human HDRs by focusing on hemodynamic and clinical chemistry changes of HSR-related or biocompatibility issues during human hemodialysis (HD) and the reinfusion of blood. Based on our recent animal experiments, we hypothesize that increased pulmonary arterial pressure (PAP), and increases in thromboxane B2 (TXB2) and complement 3a (C3a) plasma concentrations will likely manifest in, or at least predict, human HDRs during HD and blood reinfusion. To verify our hypothesis, we measured these parameters during high-flux HD in patients. Since direct PAP measurement was not possible, the plasma concentration of the N-terminal fragment of the brain natriuretic peptide (NT-proBNP) was determined for the noninvasive estimation of PAP. Our results show an increase in NT-proBNP and TXB2 during the reinfusion of extracorporeal blood. The plasma concentration of C3a increased in early HD already and remained elevated up to blood reinfusion. In conclusion, the observed changes in HSR-related parameters or biocompatibility issues in otherwise asymptomatic patients may suggest that a greater activation of these mechanisms could explain the development of human hemodialysis reactions.

Keywords: Hemodialysis, hypersensitivity reactions, blood reinfusion, CARPA, pulmonary hypertension, anaphylatoxins

Introduction

Renal replacement therapy, and (HD) in particular, is a crucial treatment for an increasing number of individuals with stage-5 chronic kidney disease worldwide. HD is the most widely used form of kidney replacement therapy globally, accounting for approximately 69% of all kidney replacement therapy and 89% of all dialysis cases. While there have been significant advancements in dialysis technology and patient access to HD, particularly in high-income countries, the availability, accessibility, cost, and outcomes of HD differ worldwide. As a result, rates of impaired quality of life, morbidity, and mortality remain high overall [1].

Despite advancements in technology and biocompatible materials, hemodialysis procedures still carry a low but significant risk of acute allergy-like reactions, referred to as HD reactions (HDRs), which can quickly escalate to life-threatening conditions. In recent years, a growing number of reported hypersensitivity reactions (HSRs) with hemodialyzers has presented a new concern within the field of nephrology [2–4].

These acute adverse events can present with a range of clinical manifestations, including itching, a burning sensation at the access site, urticaria, flushing, coughing, sneezing, wheezing, abdominal cramps, diarrhea, headache, back and chest pain, nausea, vomiting, fever, and chills. The most common symptoms are chest and back pain, shortness of breath, nausea, vomiting, and low blood pressure, typically occurring within 15-30 min after the start of dialysis. Depending on their severity, the discontinuation of hemodialysis treatment may become necessary. If HD treatment is not discontinued despite the onset of clinical symptoms, there may be a risk of anaphylactic shock with symptoms such as shortness of breath, low blood pressure, and sudden cardiac death [5].

Currently, hypersensitivity reactions during hemodialysis are frequently attributed to dialysis membranes. These reactions may occur via IgE-dependent and IgE-independent pathways, referred to as ‘immune’ or ‘true’ allergy and non-immune or ‘pseudoallergy’, respectively. Consequently, ongoing improvements in dialyzer technology, including modifications to the membrane surface, can aid in reducing the immune system activation [6–8].

This study aimed to investigate potential acute reactions and/or biocompatibility issues related to human hemodialysis. It was conducted based on our recent animal experiments, which revealed elevated pulmonary arterial pressure (PAP) and thromboxane B2 (TXB2) levels during the reinfusion of blood at the end of hemodialysis treatments [9]. As per our hypothesis, the outcomes observed in animal experiments are likely to manifest in, or at least show some predicting signs, in human hemodialysis. To substantiate our proposed hypothesis, we assessed human high-flux hemodialysis patients, and formerly identified markers of HSRs were followed.

Materials and methods

Ethical issues

This cross-sectional study was approved by the Ethics Committee of the Hungarian Health Ministry (equivalent to an Independent Review Board) (TUKEB BM/24034-1/2023). The study complied with the Helsinki Declaration developed by the World Medical Association. The study did not alter the routine hemodialysis prescription, and did not include any interventions. The involved patients provided written consents upon receiving detailed information about the procedures. All patients were hemodialyzed at Semmelweis University, Budapest, Hungary. The size of the hemodialysis center and the number of patients treated there determined the number of patients who could be included in our study.

Hemodialysis prescription

The patients received a four-hour high-flux bicarbonate hemodialysis with a bodyweight-dependent polyethersulfone membrane surface (Nipro ELISIOTM 17 or 21, Nipro Corporation, Mechelen, Belgium). They either had an arteriovenous fistula or a central venous catheter. The type of vascular access is not relevant to the study. The HD settings were individually adjusted for each patient. The common setting was Na+: 138 mmol/L; K+: 3 mmol/L; Ca2+: 1.5 mmol/L; bicarbonate: 30 mmol/L. The dialysis fluid concentration settings are irrelevant to the study as well; therefore, we do not provide the individual settings of the patients included in the study. The patients’ blood pressure was continuously monitored using the noninvasive oscillometric principle integrated into the hemodialysis unit, so there was no need for a separate blood pressure measuring device.

Laboratory assays

Blood samples (3 mL each) were collected and stored in EDTA tubes (containing indomethacin) before (0 min) and at every 60 min of the 240-min dialysis as well as 5 and 10 min after the start of reinfusion. Samples were analyzed for blood cell count by an Abacus hematology analyzer (Diatron MI PLC, Budapest, Hungary) and for the TXB2 and complement 3a (C3a) levels in plasma. A fraction of the samples was centrifuged at 2500 × g for 15 min at 4 °C, and then the supernatant was aspired and aliquots of 1 mL were stored at −70 °C until further analysis. TXB2 was measured with an ELISA kit (Cayman Chemicals, Ann Arbor, MI, USA), while C3a was determined by a human C3a ELISA kit (TECOmedical AG, Sissach, Switzerland) using a FLUOstar Omega microplate reader (BMG Labtech). We also measured the human N-terminal fragment of the brain natriuretic peptide (NT-proBNP) with an ELISA kit (Biomedica GmbH, Vienna, Austria).

Data analysis

A statistical analysis was performed by a one-way repeated-measures ANOVA, and changes to baseline or between two time points were calculated using Dunnett’s multiple comparison test with the aid of the GraphPad Prism software (GraphPad Software, La Jolla, CA, USA). A p-value of less than 0.05 was considered statistically significant. We made two kinds of graphic representations (Figures 2–5): the time course of changes showed by individual time points (left) and treatment stages represented via data pooling (right).

Figure 2.

Figure 2.

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Hematological changes during hemodialysis (HD) and reinfusion. The restitution of extracorporeal blood started at 240 min. There are no significant changes in blood cell count, but individual variations (increase or decrease) can be observed. WBC: white blood cells, PLT: platelets. Plasma hemoglobin (hgb) concentration significantly increases during HD but not in reinfusion.

Figure 3.

Figure 3.

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TXB2 Changes during hemodialysis (HD) and reinfusion. The restitution of extracorporeal blood started at 240 min. No significant changes occurred during HD, but TXB2 levels increased significantly after reinfusion.

Figure 4.

Figure 4.

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Changes in NT-proBNP during hemodialysis and reinfusion. The restitution of extracorporeal blood started at 240 min. A significant decrease (p < 0.001) during HD treatment and a significant increase (p < 0.05) after reinfusion was detected in patients.

Figure 5.

Figure 5.

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Changes in complement 3a (C3a) during hemodialysis and reinfusion. The restitution of extracorporeal blood started at 240 min. C3a increased significantly from the beginning of HD treatment. No further significant changes were detected during reinfusion, however, individual data reveal large increases during HD as well as after reinfusion in many patients.

Results

Patient characteristics

We enrolled 29 chronic hemodialysis patients in our study. There were more men (n = 16; 55.0%) than women. The average age was 56.7 years (SD 29.3). The primary causes of end-stage kidney disease (ESKD) were diabetic nephropathy (n = 11; 37.9%) and hypertensive nephropathy (n = 7; 24.1%). The patients’ characteristics are detailed in Table 1. We conducted multiple measurements with each hemodialysis session taking place at different times. In certain cases, we assessed the reproducibility of our findings through repeated measurements.

Table 1.

Patient characteristics.

  Variable Mean/median/n  
  n 29 SD/IQR/%
Demographics Age (years) 56.7 29.3
  Male/Female 16/13 55%/45%
Primary renal diseases ADPKD 2 6.8%
  FSGS 1 3.4%
  SLE 3 10.3%
  ANCA 1 3.4%
  Chronic pyelonephritis 2 6.8%
  Analgesic nephropathy 1 3.4%
  Diabetic nephropathy 11 37.9%
  Hypertonic nephropathy 7 24.1%
  Unknown 1 3.4%
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ADPKD: autosomal polycystic kidney disease; FSGS: focal segmental glomerulosclerosis; SLE: systemic lupus erythematosus; ANCA: anti-neutrophil cytoplasmic antibody.

Hemodynamic changes during hemodialysis and the restitution of extracorporeal blood

Monitoring patients’ blood pressure is a routine procedure during HD treatment. According to the protocol, blood pressure should be checked at least once every hour, but possibly more often if the patient’s cardiac stability makes it necessary. No significant changes in systolic and diastolic blood pressure (BP) or heart rate were observed at any point of time (Figure 1).

Figure 1.

Figure 1.

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Systolic and diastolic blood pressure (BP, left) and heart rate (right) changes during hemodialysis and reinfusion. The restitution of extracorporeal blood started at 240 min. No significant changes in these parameters have been found.

Hematological changes during hemodialysis and the restitution of extracorporeal blood

We observed no significant changes in white blood cell count and platelets during HD and reinfusion. However, there was a decreasing tendency in both parameters. Figure 2 shows individual changes in white blood cell (WBC) count (leucopenia or leukocytosis), and platelet (PLT) count (thrombocytopenia) during HD and the restitution of extracorporeal blood. On the other hand, plasma hemoglobin concentration (Hgb) increased significantly during HD (p < 0.05) but not throughout the course of reinfusion. Individual data show some variation as well.

Plasma TXB2 changes during hemodialysis and the restitution of extracorporeal blood

Another known biomarker of HSRs (e.g., CARPA) caused by i.v. nanoparticle administration is the release of TXA2 into the bloodstream, which induces pulmonary hypertension. To examine the possible role of this mechanism in acute reactions during hemodialysis (HD) and reinfusion, we conducted serial TXB2 (the stable metabolite of TXA2) assays throughout the observation period.

The measured TXB2 levels displayed a heterogeneous distribution, with varying data obtained from different patients. The mean TXB2 did not change during HD, but increased significantly following reinfusion (p < 0.05). In some patients, large individual elevations could be observed (Figure 3).

Plasma NT-proBNP changes during hemodialysis and the restitution of extracorporeal blood

In order to get a noninvasive estimate of potential PAP changes, we measured the NT-proBNP levels of patients. As anticipated, we observed a higher value at the beginning of HD due to moderate hypervolemia caused by disturbed kidney function. This elevated NT-proBNP showed a gradual decrease during HD treatment (Figure 4), which was highly significant (p < 0.001). However, to our surprise, the NT-proBNP levels started to climb again after reinfusion, and this increase was also significant (p < 0.05).

Plasma complement 3a (C3a) changes during HD and the restitution of extracorporeal blood

Complement activation often plays a role in both HSRs (e.g., in CARPA) and acute reactions during HD. Therefore, we measured the changes in plasma C3a levels during hemodialysis (HD) and reinfusion. C3a exhibited a significant increase (p < 0.01) from the beginning of HD treatment. Although we did not see any further significant increase after reinfusion, individual patients’ data revealed large elevations both during HD and after the restitution of extracorporeal blood (Figure 5).

Correlation of plasma complement 3a (C3a) levels and platelet counts during HD and the restitution of extracorporeal blood

The activation of the complement system is closely linked to platelet presence and function. Analyzing our data, we confirmed a correlation between serum C3a and platelet count, as documented in the literature [10–12]. These findings also support our hypothesis that the activation of the complement system can be detected during and after HD treatment, albeit at a lower level (Figure 6).

Figure 6.

Figure 6.

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The correlation between C3a and platelet counts. Our results confirm that the activation of the complement system can be detected during and after HD treatment, albeit at a low level.

Discussion

In certain patients, hypersensitivity reactions can pose a risk during hemodialysis, although they are relatively uncommon. These reactions can range from mild skin rashes to severe anaphylactic reactions [13]. The cause of these reactions is not yet clear. Depending on the severity of the reaction, the hemodialysis treatment may be discontinued. Hypersensitivity reactions are classified as Type A and Type B [14]. Type A reactions occur shortly after starting dialysis [14]. Studies suggest that these reactions may be caused by typical IgE-mediated allergies, with ethylene oxide and polyvinyl-pyrrolidone (PVP) being potential culprits [15,16]. Type B reactions are more common and occur later in the dialysis session with milder symptoms, such as back pain, chest pain, itching, and chills. Evidence suggests that these reactions may involve a non-IgE-mediated mechanism, called complement activation specifically [17,18]. Type B reactions may occur due to the activation of the complement, especially the alternative pathway, leading to the generation of anaphylatoxins C3a and C5a, which cause mast cell degranulation and the recruitment of neutrophils and monocytes [18]. Due to the role of complement activation, these reactions have been termed as complement activation-related pseudoallergy (CARPA) [19].

In our recent experiments, we have demonstrated the safety of HD treatment in an animal model. However, pathological changes can occur not only during hemodialysis treatment, but during blood reinfusion after the treatment as well. Following the reinfusion, we observed an unexpected elevation in TXB2 levels and an increase in PAP. In our experimental model, we demonstrated for the first time the release of inflammatory mediators upon blood reinfusion that subsequently induced pulmonary hypertension [9].

In this study, our goal was to confirm our previous experimental findings on hemodynamic and inflammatory changes under human hemodialysis conditions. We did not alter the routine HD treatment; we collected blood samples and measured the patients’ vital parameters. Systemic arterial pressure did not change significantly throughout the study, neither during hemodialysis nor during the restitution of extracorporeal blood.

Changes in hematological parameters, e.g., white blood cell and platelet counts represent important markers of hypersensitivity reactions, e.g., CARPA development. In the present study, no significant changes were observed; however, a decreasing trend could be seen in the case of both cell types. This was paralleled by a significant increase in Hgb concentration, suggesting the extravasation of plasma and the above-mentioned cells in the background, a common feature of HSRs. The decrease in white blood cell and platelet counts detected during HD treatment may refer to slow immunological changes in the background.

Interestingly, despite no significant changes in PLT count, there was a good correlation between plasma C3a concentration, and PLT count during and after HD treatment. Such an observation can also indicate a hidden HSR, as our previous studies have repeatedly shown that CARPA is associated with an increase in plasma C3a concentration and a decrease in PLT count in animal species. The role of C3a receptors in platelet function has already been demonstrated [20].

We utilized an indirect and noninvasive method, from which we could draw conclusions about PAP changes. For an accurate determination of PAP, the invasive measurement of pulmonary capillary wedge pressure should have been used [21]. However, numerous publications reveal that the noninvasive measurement of the N-terminal fragment of the brain natriuretic peptide (NT-proBNP) provides relevant information on PAP [22–24]. Invasive measurement of PAP is not possible during routine ambulatory hemodialysis. At the beginning of hemodialysis, NT-proBNP was high due to volume overload, which gradually decreased as extracorporeal ultrafiltration removed excess fluid. Further intravascular expansion was eliminated by stopping the hemodialysis treatment and rinsing back the patient’s blood. Blood samples were then taken after 5 and 10 min for NT-proBNP. During this time, no other cause of left atrial excitation could have distorted the obtained results.

The activation of the complement system during hemodialysis (HD) treatment had been previously explored. The reaction to cuprophan membranes is also well-documented [25,26]. Later, it became evident that despite the utilization of modern polysulfone or polyethersulfone dialyzers, the activation of the complement system and infrequent, yet severe reactions were associated with hemodialysis treatment. Several papers in the literature addressed the pathobiology of these hemodialysis-related reactions [4,27–29]. In the context of HDR, which was mentioned earlier, the surface charge of the dialyzer was considered a significant factor. Manufacturers have been exploring and adding various materials to the polysulfone membrane to maintain its effectiveness despite potential changes in surface charge [6,8,30]. In the current study, we also observed the activation of the complement system in the early stages of HD treatment (Figure 5), suggesting the contribution of dialysis material to the reaction. In addition, individual changes show the presence of complement activation during reinfusion as well.

Our current study demonstrates that inflammatory mediators (TXB2, Figure 3) are released after reinfusion following human HD treatment. Moreover, following an initial decline, NT-proBNP levels also increased during reinfusion that predicts the presence of pulmonary hypertension (Figure 4). Pulmonary hypertension affects 21–41% of individuals with chronic kidney disease (CKD) and is found in up to 60% of patients undergoing hemodialysis due to kidney failure. The coexistence of pre- and post-capillary pulmonary hypertension is prevalent in this population and indicative of the lowest survival rate among CKD patients [31,32].

As for pulmonary hypertension, clinical studies suggest an increase in pulmonary vascular resistance during HDRs, but the pathogenesis is unknown. In pigs, pulmonary hypertension induced by liposomes and liposome-encapsulated hemoglobin was abolished by indomethacin, a cyclooxygenase inhibitor; thus, the role of TXB2 in increasing pulmonary vascular tone is evident [33]. In the present study, parallel increases in plasma TXB2 and NT-proBNP concentrations after blood reinfusion may suggest a similar mechanism in patients, but this possibility requires direct confirmation. This increase, along with significantly elevated levels of Fibroblast Growth Factor 23 (FGF23) observed in CKD, also contributes to the presence of inflammatory markers [31,34]. FGF23 plays a central role in CKD progression, cardiovascular events, and mortality [35]. Additionally, FGF23 might be involved in the development of idiopathic pulmonary fibrosis [34].

The uremic environment also contributes to the development of pulmonary hypertension in end-stage renal disease (ESRD) [36]. An increase in acute phase protein alpha-1-acid glycoprotein levels can be observed in patients treated with HD [37]. In addition to inflammatory acute phase proteins, an increase in the levels of cytokines, such as IL-1-beta, TNF-alpha, and IL-6 was also observed in the serum of HD patients with pulmonary hypertension [38]. Apelin, an endogenous peptide, improves cardiac function in patients with pulmonary hypertension. Apelin can particularly enhance myocardial contractility and decrease blood pressure [39]. The apelin receptor (APJ) and its associated apelin ligand are crucial in maintaining pulmonary vascular homeostasis. Given its influence on pulmonary hypertension, the apelin-APJ pathway could potentially be a target for future therapeutic interventions [40,41].

Summary and outlook

In our study, we demonstrated that the restitution of extracorporeal blood after HD significantly influences the body’s hemodynamic regulation and immune response. Pathophysiological changes, which involve the release of inflammatory mediators, complement activation and consequently the development of pulmonary hypertension, when become more severe can predict the development of HDRs even in asymptomatic patients. It should be noted that these human hemodialysis data are not so robust compared with the output from our experimental model. However, this can be explained by the several limitations of our study.

First, it is based on a small sample and the experience of a single HD center. Nevertheless, we conducted multiple measurements with separate hemodialysis sessions, and in some patients, data from repeated settings demonstrated the reproducibility of our hypothesis. Second, for ethical reasons, we employed a noninvasive method to estimate pulmonary hypertension as opposed to the invasive measurement of exact pulmonary hypertension. Third, contrary to the experimental data, the large variability of human data may have masked significant changes in certain parameters, but tendencies and individual values showed direction of changes, e.g., NT-proBNP, C3a, PLT and TXB2.

Despite its limitations, we believe that we have successfully replicated our results of animal experiments in a human study. To the best of our knowledge, this is the first observational human study of its kind. A more robust data set could be obtained by a selective acquisition of data from patients who develop clinical symptoms during HD and reinfusion, which would require further investigations. Building on our findings to date, it is crucial to delve into the development of advanced biocompatible materials that can better integrate with biological systems. Additionally, it is important to examine the specific pharmacological treatments that may influence various immunological mechanisms. Understanding how these drug interventions affect the immune response could yield significant insights into their potential to enhance patient survival rates.

Acknowledgement

The authors are thankful for the expert technical assistance of Erika Tanyi throughout the hemodialysis treatments and blood collection as well as Maria Harvich-Velkei for sample handling, measurements and data processing. Á.P. was involved in study design and wrote the original draft. T.G. and J.D. collected the blood samples from the patients. T.M. and Cs.R. made the laboratory analyses. O.S. collected the patients’ data. L.R. was involved in study design. G.Sz. performed statistics and produced the figures. L.D. was involved in study design, sample processing, and manuscript edition. All authors revised the manuscript, approved the final version to be published, and agreed to be accountable for all aspects of the work.

Declaration of generative AI in scientific writing

The authors declare that all of the results are human writing, and no AI was used for scientific writing.

Disclosure statement

No potential conflict of interest was reported by the author(s).

Institutional Review Board statement

All study-related procedures were performed in line with the 1964 Declaration of Helsinki’s ethical standards and later amendments. This cross-sectional study was approved by the Ethics Committee of the Hungarian Health Ministry (equivalent to an Independent Review Board) (TUKEB BM/24034-1/2023).

Patient consent to participate and to publish

Informed written permission was obtained from the patients regarding participation and publishing the data.

Availability of data and materials

The datasets generated and analyzed during the current study are not publicly available due to intellectual property but can be accessed through the corresponding author upon reasonable request.

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Associated Data

This section collects any data citations, data availability statements, or supplementary materials included in this article.

Data Availability Statement

The datasets generated and analyzed during the current study are not publicly available due to intellectual property but can be accessed through the corresponding author upon reasonable request.

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