Double filtration plasmapheresis for children with different types of critical kidney diseases: a single-center retrospective cohort study

Introduction

Double filtration plasmapheresis (DFPP) is a membrane-based treatment modality that selectively removes large molecules through double filtration of the plasma of the patients. As a pioneer, Agishi et al. first used this technology in 1980s to desensitize patients receiving blood group incompatible renal transplantation (1). Afterwards, DFPP is proposed as a treatment option for the excessive production of abnormal immunoglobulins, or for the hyperviscosity syndrome as an adjunctive therapy. The procedure of DFPP requires two types of filters with different pore sizes. The blood of patients is drawn extracorporeally into a plasma separator, and filtrated plasma is then introduced to a plasma fractionator, in which the condensed plasma fraction containing molecules larger than fractionator pore size is partially discarded. On the other hand, the albumin-rich smaller molecules are allowed to filtrate and return to patients in combination with supplementation fluid of sufficient volume. As the filtration fraction of plasma fractionators is generally set at 0.8 in DFPP, nearly five-fold condensed immunoglobulins are discarded and one-fifth of the volume of supplementation fluid is used compared to single filtration plasmapheresis. However, limitations exist regarding the applicability of DFPP in children, due to the excessive extracorporeal volume within plasma fractionators (up to 150 mL). Consequently, there is a gap in knowledge on the efficiency of removal of various plasma components by DFPP procedure and the safety and tolerability of high-volume extracorporeal circulation in pediatric patients.

To address this issue, the study analyzed the efficiency and safety of DFPP in the treatment of children with different critical renal diseases, including systemic lupus erythematosus (SLE), antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV), rapidly progressive glomerulonephritis (RPGN), and those receiving ABO incompatible renal transplantation. We present the following article in accordance with the STROBE reporting checklist (available at https://tp.amegroups.com/article/view/10.21037/tp-22-322/rc).

Methods

Patient identification

The study was conducted in accordance with the Declaration of Helsinki (as revised in 2013). This study was approved by the Ethical Committee of Tongji Hospital (TJ-IRB20221290). Written informed consent was obtained from the parents of the patients before DFPP treatment.

This was a single-center retrospective cohort study of DFPP treatment in pediatric patients between December 2017 and December 2020. Patients were excluded if conventional plasmapheresis was applied prior to or during DFPP treatment. Identified patients were classified into four sub-groups as per the types of renal disease: SLE (group I), AAV (group II), RPGN (group III), and those receiving ABO-incompatible renal transplantation (group IV). The immunosuppressive regimens were recorded from patients of each group. For group I patients, their baseline data including Systemic Lupus Erythematosus Disease Activity Index (SLEDAI) score, renal function [serum creatinine, estimated glomerular filtration rate (eGFR), proteinuria, and urinary sediment], antinuclear antibody (ANA), anti-double strand DNA antibody (Anti-dsDNA), complement C3 and extra-renal manifestations were recorded. For group II patients, the diagnosis of AAV was made according to the Chapel Hill 2012 definition (2). Their baseline data including renal function (serum creatinine, eGFR, proteinuria, and urinary sediment), renal biopsy category, ANCA, complement C3, neutrophils, hemoglobin, platelets, serum albumin and extra-renal manifestations were recorded. For groups III and IV patients, their clinical features and laboratory profiles were recorded. The pre- and post-DFPP serum levels of pathogenic autoantibodies, immunoglobulin G (IgG), IgA, IgM, C3, albumin, cholesterol, calcium, phosphate, potassium, magnesium, and fibrinogen were synchronously recorded. Post-DFPP sera were taken before intravenous immunoglobulin or fibrinogen/fresh frozen plasma (FFP) administration. Furthermore, the complications during DFPP treatment and the hospital stay were also monitored.

DFPP technique

In all patients, DFPP was performed using a plasma separator (Plasmaflow OP-08W Asahi Kasai) and a plasma fractionator (EC-20W Asahi Kasai). The plasma fractionator had a membrane with a cutoff value of around 200 KDa molecular weight. A double lumen catheter was inserted in the femoral vein and retained for 2 to 3 weeks. Each patient was treated with 3 to 6 sessions within two to three consecutive weeks. DFPP was performed by a continuous blood purification machine (Plasauto iQ21, Asahi Kasai). Blood and plasma flow were set at 100 to 120 mL/min and 20 to 24 mL/min, respectively. 600 to 800 mL of FFP were used as the replacement fluid. The arterial and venous pressure of two blood purification apparatuses were monitored during DFPP, and the duration of each session was 2 to 3 hours. Regional citrate anticoagulation or heparin anticoagulation was used for DFPP.

Statistical analysis

The data were described as median (if continuous variables) and frequency or percentage (if categorical variables). For continuous variables, statistical analyses were performed with GraphPad Prism 5.0 software using paired Wilcoxon rank tests for comparing parameters with baseline values. For categorical variables, paired Chi-squared test was used to evaluate the differences between before and after DFPP treatment. Significance test with two sides was applied, and a P value ≤0.05 was considered statistically significant.

Results

Clinical response to treatments

Ten patients were identified and enrolled in this study. In group I, five female children were included, with their data shown in Table 1. All of the patients in group 1 showed a deterioration of renal function. Renal pathologies showed that three had class IV lupus nephritis (LN) and two had mixed classes (V+VI). Patients in Group I were first put on methylprednisolone pulse therapy (0.5 g/day) for three days, and then treated with DFPP combined with prednisone (2.0 mg/kg/day). They continued to receive prednisone plus immunosuppressive agents as cyclophosphamide or calcineurin inhibitors (CNIs) for induction therapy for six months. All had a clinical response to induction therapy (Figure 1). Unfortunately, one passed away within two months of initiating DFPP due to intracerebral hemorrhage secondary to lupus encephalopathy. Three shifted to maintenance with oral prednisone plus oral cyclosporine A or mycophenolate mofetil (MMF). The other one received tacrolimus plus MMF in addition to prednisone. After more than two years of follow-up, there was no relapse, no renal function deterioration, and prednisone and immunosuppressive agents were gradually reduced.

Figure 1 Clinical efficacy of DFPP in patients with SLE. DFPP, double filtration plasmapheresis; SLE, systemic lupus erythematosus; SCr, serum creatinine; UAlb/Cr, urinary albumin creatinine ratio; Anti-dsDNA, anti-double-stranded DNA antibody.

As shown in Table 2, three children with AAV were included in group II, among whom one showed crescentic glomerulonephritis with glomerulosclerosis. All patients in group II initially received methylprednisolone pulse therapy (0.5 g/day) for three days, followed by DFPP and oral prednisone (2.0 mg/kg/day). They later received intravenous cyclophosphamide (IV-CTX) plus prednisone for further induction, and maintenance regimens with oral prednisone plus CNIs and/or MMF. Some of them had a clinical response to induction therapy (Figure 2). After induction therapy for six months, one dialysis-dependent child prior to enrollment remained on dialysis, while of the two dialysis-independent patients prior to enrollment, one showed improvement in renal function and proteinuria level, and another required maintenance dialysis. Improvements in extra-renal symptoms were noted in all group II patients.

Figure 2 Clinical efficacy of DFPP in patients with AAV. DFPP, double filtration plasmapheresis; AAV, antineutrophil cytoplasmic antibody-associated vasculitis; MPO, myeloperoxidase; PR3, proteinase 3; AI, antibody intensity; SCr, serum creatinine.

In group III, one 12-year-old boy with C3 glomerulopathy was included. His body weight was 45 kg initially, and he presented with acute renal failure (creatinine 202 µmol/L), malignant hypertension, severe proteinuria (1,250 mg/day), hematuria, hypocomplementemia (C3 0.47 mg/L), hypergammaglobulinemia (15.2 g/L), hypoalbuminemia (24.7 g/L) and anemia (Hb 78 g/L). Renal biopsy showed crescentic glomerulonephritis with predominant mesangial and glomerular basement membrane C3 deposits. The child received methylprednisolone (500 mg once daily for three days intravenously, followed by 2 mg/kg/day orally) plus IV-CTX monthly. He simultaneously received DFPP for 4 sessions as an adjuvant induction therapy within two weeks. After five months, the child achieved partial remission with a normal renal function (serum creatinine 84 µmol/L), with 960 mg of daily proteinuria and a serum C3 of 0.89 g/L (Figure 3).

Figure 3 Biochemical parameters of the patient with C3 glomerulopathy during induction and maintenance therapies. 24 h-Upro, 24-hour urinary protein quantity; Cr, creatinine.

In group IV, one 5-year-old boy (body weight: 20 kg) with CKD stage 5D due to PAX2 mutation-associated nephrotic syndrome was included. His blood group was O+, and received ABO-incompatible renal transplantation with his grandmother as the donor (blood group AB+). The degree of HLA mismatch was 4/8, and the initial anti-A/anti-B antibody titer was 1:4 (IgG), 1:256 (IgM) and 1:2 (IgG), 1:128 (IgM) respectively, without any anti-HLA antibodies detected. He received one dose of rituximab (375 mg/m²) and tacrolimus, MMF and prednisolone starting one week pre-operatively. He also received DFPP in order to achieve an anti-A and anti-B IgG titers lower than 1:16 pre- and post-operatively. The anti-A and anti-B antibody titers fell progressively with each DFPP session, reaching less than 1:16 on the day of operation. Pre-operative coagulation abnormalities were ameliorated with fibrinogen infusion. His surgery was uneventful without post-operative complications. Graft kidney functioned well post-operatively, and his serum creatinine stabilized at 30 to 50 µmol/L since post-operative day two. Post-operative anti-A IgM titers remained at 1:64 during the second week and rose to 1:128 one week later, necessitating another 3 DFPP sessions. His anti-A IgM and IgG titers stabilized at 1:8 since four weeks after operation, and he did not receive DFPP thereafter.

Immunokinetics response to DFPP

The study found that the proportion of serum IgG removed by DFPP was statistically significant (P=0.028) (Figure 4), with a cumulative proportional removal rate after the entire treatment period of 58.8%. The proportional removal rate of IgA removal was similar to that of IgG (54.6%). The removal rate of IgM, whose molecular weight was larger than IgA and IgG, was more than 74.6% at the end of last session. On the other hand, the cumulative removal rate of C3 was at 39.1% at the end of DFPP treatment.

Figure 4 Removal of immunoglobulins and complements. P values were calculated according to the model described in the Method section. *, P<0.05. IgA, immunoglobulin A; IgG, immunoglobulin G; IgM, immunoglobulin M; C3, complement C3.

Impact of DFPP on hemoglobin level, platelets, prothrombin time (PT), activated partial thromboplastin time (aPTT), international normalized ratio (INR) and fibrinogen over a series of sessions

Hemoglobin levels and platelet counts were not affected by DFPP (Figure 5), reflecting an absence of hemodilution. PT and INR increased after the last DFPP session. The cumulative proportional removal rate of fibrinogen was similar to that of IgM, at 67.69%. One of the weaknesses of DFPP is the massive removal of fibrinogen, which could lead to elevated PT and INR and even spontaneous bleeding episode. Therefore, if the fibrinogen level is too low, fibrinogen or FFP infusion is necessary.

Figure 5 The course of hemoglobin level, platelet count, PT, aPTT, INR, and fibrinogen. Hemogram and coagulation tests were assessed before the first DFPP session and after the last DFPP session. P values were calculated according to the model described in the Method section. *, P<0.05. Hb, hemoglobin; PLT, platelet; PT, prothrombin time; aPTT, activated partial thromboplastin time; INR, international normalized ratio; Fib, fibrinogen; ns, no significance.

Impact of DFPP on other plasma components

Through the use of FFP as the replacement fluids, the cumulative proportional removal rate of serum albumin was 14.05% (Figure 6), while that of serum cholesterol was 53.1%. No significant change in serum creatinine, potassium (P=0.263), magnesium (P=0.932), or phosphate (P=0.150) was observed, and none required magnesium or potassium supplementation throughout the hospital stay. Mild hypocalcemia after DFPP treatment occurred, possibly related to the use of regional citrate anticoagulation and sodium citrate contained in FFP. Even if 10% calcium gluconate injection (0.5 mL/kg, Max 20 mL) supplementation was used before each DFPP session for preventing hypocalcemia.

Figure 6 Removal of albumin, cholesterol and electrolytes. P values were calculated according to the model described in the Method section. *, P<0.05. Alb, albumin; TC, total cholesterol; K, potassium; Mg, magnesium; Ca, calcium; P, phosphorus; ns, no significance.

Adverse effects associated with DFPP

The study found few complications in the total of 44 DFPP sessions. Traditionally, the most dreadful adverse effect is bleeding tendency related to fibrinogen and factor VIII removal. Transient hypotension is also one of the most common adverse effects of plasmapheresis in children. However, the patients included in this study did not have any spontaneous bleeding, likely due to the use of FFP as the replacement fluid and using fibrinogen infusion. There were two hypotensive episodes during 44 DFPP sessions, equivalent to 4.55% incidence of having symptomatic hypotension. Finally, there were two episodes of mild allergic reactions presenting as pruritus. None of the patients had bloodstream infection, significant post-operative drop of hemoglobin or platelets, or access failure during their hospital stay.

Discussion

Although apheresis is a widely established therapeutic option in pediatric patients, reports involving the use of DFPP in this population are scarce regarding the indications, technical details, and procedural outcomes. This study described a group of children with different renal indications treated by DFPP from December 2017 to December 2020. With regard to the indications, as per the 2019 American Society for Apheresis (ASFA) guideline (3), 70% and 20% patients in this study received plasmapheresis for category I/II and category III diseases, respectively, while one (10%) received apheresis due to RPGN (C3 glomerulonephritis), which was not included in the ASFA guideline. According to the guideline, clinical outcomes of these specified diseases were associated with the degree of disease-specific antibodies removal. The present study found that after the last DFPP session, plasma autoantibodies decreased substantially by 93% and 89% in patients with SLE and AAV, respectively. The rate of achieving complete or partial responses to apheresis-based regimens was 80%, 33.3%, 100% and 100% in children with SLE, AAV, RPGN, and those receiving ABO-incompatible renal transplantation, respectively.

Few studies have evaluated the efficacy of DFPP to remove serum immunoglobulins to date. Hebibi et al. showed that the percentage removal of IgG, IgA and IgM was 37.8%, 52.8% and 61.5%, respectively, without using replacement solutions (4). Jagdish et al. found that the proportional removal rate of IgG, IgA, and IgM after 4 sessions were 72%, 89%, and 96%, respectively, with the use of either 5% albumin or effluent albumin concentration as replacement solution which is roughly 1.75 to 2 times the serum albumin (5). This study also found the cumulative removal rate of serum IgG, IgA, IgM and C3 at the end of DFPP sessions at 58.8%, 54.6%, 74.6% and 39.1%, respectively, using FFP as the replacement fluid. However, a significant decrease in immunoglobulin levels could increase patients’ susceptibility to infection. If patients’ serum IgG level is too low, supplemental post-DFPP IVIG will be necessary.

Fibrinogen is a high molecular weight protein and has a cumulative removal rate of 67.69% in this study, similar to that of IgM. Yeh et al. described that after one DFPP session, it took 3 to 4 days for fibrinogen to return to the pre-procedure level (6). Jouve et al. also showed that fibrinogen reconstitution was depending on the time between two apheresis sessions and reached 1 g/L in the best-case scenario with a 2-day interval using albumin as the replacement fluid (7,8). In this sense, sufficient interval between each DFPP session is required to allow patients’ fibrinogen levels to recover. In this study, each DFPP session was undertaken with an interval of 3 days, and FFP was routinely used as the replacement fluid. This may be the reason why there were no active bleeding episodes observed during DFPP, although patients’ PT and INR increased. However, if the fibrinogen level becomes too low, fibrinogen or FFP infusion would become necessary.

With regard to the apheretic complications, only mild adverse events including symptomatic hypotension and mild allergy were observed during 9.1% of all the DFPP sessions. This incidence is similar to those reported in previously published reports (9,10). During DFPP treatment, serum albumin decreases as well as globulin. The sieving coefficient of DFPP membranes for albumin is 0.2 to 0.6, as suggested by most manufacturers, which means that 80% to 40% of albumin will be removed during each DFPP session. This drop of colloidal oncotic pressure due to albumin removal can lead to intravascular dehydration-associated complications such as hypotension. Therefore, symptomatic hypotension is common during DFPP treatment, but this can be mitigated by restoring serum albumin concentrations. Agishi et al. (1) initially performed DFPP without using the replacement fluid, but others started to use albumin-containing replacement fluid to improve hypoalbuminemia later. In this study, 0.5 to 0.8 L FFP was used as the replacement fluid, leading to a serum albumin reduction of 14.05% and only 2 episodes of symptomatic hypotension observed during 44 DFPP sessions. Nishi et al. reported that if using 12.5% albumin as the replacement fluid, a significant decline in globulins with a higher post-DFPP serum albumin was observed, without any hypotensive episode (11). Undoubtedly, a lower incidence of hypotension can accompany a higher albumin concentration in the replacement fluid. However, albumin is rather expensive, and albumin-containing replacement fluid (1–2 times concentration compared to serum albumin) was usually use. During this practice, the incidence of symptomatic hypotension was much lower than practices without using any replacement fluid [the former vs. the latter, 4.55% vs. 100% (4)].

Two episodes of mild allergy occurred in group I and IV patients, presenting as pruritus quickly relievable by intravenous dexamethasone. Paglialonga et al. described that DFPP and plasma adsorption carried the advantage of reducing the risk of allergic reactions (such as pruritus, urticaria, dyspnea) in PE (9). In addition, any electrolyte imbalance was not observed during treatment. The calcium supplement was given only once at pre-procedure, even though regional citrate anticoagulation was used routinely for DFPP.

The limitations of this study included its retrospective design, the low number of patients included, and the absence of a control arm receiving conventional plasmapheresis. In addition, all children received immunosuppression simultaneously, and the exact therapeutic efficacy of DFPP could not be ascertained.

Conclusions

In conclusion, this report showed that DFPP could efficiently remove macromolecular pathogens from blood with reduced plasma or albumin supplements in pediatric patients with different critical kidney diseases including SLE, AAV, RPGN due to C3 glomerulopathy, and those receiving ABO-incompatible renal transplantation. Based on the findings of this study, DFPP in children is feasible and safe. Except for hypotension and mild allergy, other serious adverse effects such as abnormal bleeding were not observed in the patients included in the study. Nonetheless, serum fibrinogen and immunoglobulins levels should still be monitored.

Acknowledgments

Funding: This work was supported by the grant from the National Natural Science Foundation of China (No. 81770700) and the Key R&D project of Hubei province (No. 2022BCA047).

Footnote

Reporting Checklist: The authors have completed the STROBE reporting checklist. Available at https://tp.amegroups.com/article/view/10.21037/tp-22-322/rc

Data Sharing Statement: Available at https://tp.amegroups.com/article/view/10.21037/tp-22-322/dss

Peer Review File: Available at https://tp.amegroups.com/article/view/10.21037/tp-22-322/prf

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://tp.amegroups.com/article/view/10.21037/tp-22-322/coif). The authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. The study was conducted in accordance with the Declaration of Helsinki (as revised in 2013). The study was approved by the Ethics Committee of Tongji Hospital. Written informed consent was obtained from patients’ father or mother before DFPP treatment.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

References

1. Agishi T, Kaneko I, Hasuo Y, et al. DFPP utilizing new membrane technology. J Jpn Soc Dial Ther 1981;14:61-5. [Crossref]
2. Jennette JC, Falk RJ, Bacon PA, et al. 2012 revised International Chapel Hill Consensus Conference Nomenclature of Vasculitides. Arthritis Rheum 2013;65:1-11. [Crossref] [PubMed]
3. Padmanabhan A, Connelly-Smith L, Aqui N, et al. Guidelines on the Use of Therapeutic Apheresis in Clinical Practice - Evidence-Based Approach from the Writing Committee of the American Society for Apheresis: The Eighth Special Issue. J Clin Apher 2019;34:171-354. [Crossref] [PubMed]
4. Hebibi H, Weclawiak H, Rostaing L, et al. Non-tolerability of double-filtration plasmapheresis in antibody-incompatible kidney transplant candidates. Saudi J Kidney Dis Transpl 2015;26:297-301. [Crossref] [PubMed]
5. Jagdish K, Jacob S, Varughese S, et al. Effect of Double Filtration Plasmapheresis on Various Plasma Components and Patient Safety: A Prospective Observational Cohort Study. Indian J Nephrol 2017;27:377-83. [Crossref] [PubMed]
6. Yeh JH, Chen WH, Chiu HC. Complications of double-filtration plasmapheresis. Transfusion 2004;44:1621-5. [Crossref] [PubMed]
7. Jouve T, Marlu R, Malvezzi P, et al. Reducing Fibrinogen and Factor XIII Using Double-Filtration Plasmapheresis for Antibody-Mediated Rejection: Predictive Models. Blood Purif 2018;46:239-45. [Crossref] [PubMed]
8. Jouve T, Marlu R, Naciri Bennani H, et al. Fibrinogen reconstitution after therapeutic apheresis: Comparison of double-filtration plasmapheresis, plasma exchange, and immunoadsorption. J Clin Apher 2021;36:574-83. [Crossref] [PubMed]
9. Paglialonga F, Schmitt CP, Shroff R, et al. Indications, technique, and outcome of therapeutic apheresis in European pediatric nephrology units. Pediatr Nephrol 2015;30:103-11. [Crossref] [PubMed]
10. Maxted AP, Connell R, Hussain F. Double filtration plasmapheresis - 10-year pediatric experience as an alternative to plasma exchange. Transfus Apher Sci 2020;59:102928. [Crossref] [PubMed]
11. Nishi S, Hasegawa S, Gejyo F, et al. The safety measures for double filtration plasma apheresis (DFPP) before ABO-incompatible kidney transplantation. Int Congr Ser 2006;1292:91-5. [Crossref]