Therapeutic Plasma Exchange Using Membrane Plasma Separation Across a Broad Spectrum of Indications: An Eight-Year Single-Center Retrospective Cohort Study.

Introduction

Therapeutic plasma exchange (TPE) is an extracorporeal procedure in which a defined volume of patient plasma is removed and substituted with an appropriate replacement fluid, most commonly human albumin, fresh frozen plasma (FFP), or a combination of the two. 1 Its therapeutic rationale is the removal of high-molecular-weight pathogenic substances that participate in disease pathogenesis, including autoantibodies, alloantibodies, immune complexes, monoclonal proteins, cryoglobulins, lipoproteins, and protein-bound toxins, thereby attenuating disease activity and, in some settings, allowing time for immunosuppressive therapy to take effect. 1

TPE is applied as first-line or adjunctive therapy across a broad spectrum of renal, hematological, rheumatological, neurological, oncological, and systemic disorders, particularly in conditions refractory to conventional pharmacological treatment. 2 , 3 The American Society for Apheresis (ASFA) periodically publishes evidence-based guidelines that classify therapeutic apheresis indications into four categories: category I, disorders for which apheresis is accepted as first-line therapy, either alone or in conjunction with other treatment; category II, disorders for which apheresis is accepted as second-line therapy; category III, disorders for which the optimum role of apheresis is not established and decision-making should be individualized; and category IV, disorders in which published evidence suggests that apheresis is ineffective or harmful, so that treatment should be undertaken only under an approved research protocol. 2 The number of accepted indications and the assigned categories have both changed across successive editions of these guidelines, reflecting the accumulation of trial evidence over time. 3 , 4

Plasma can be separated by either of two technical approaches. In centrifugal TPE, plasma is separated from cellular blood components according to density gradient using a dedicated apheresis device. In membrane plasma separation (MPS), plasma is separated by convective transport across a highly permeable plasma filter using conventional continuous renal replacement therapy or dialysis platforms. Head-to-head comparisons have consistently shown longer procedure times with membrane systems: in a randomized crossover study, the centrifugal device completed a procedure in a mean of 101.5 minutes compared with 157 minutes for the membrane device. 5 Findings for plasma removal efficiency are less consistent and appear to depend on the membrane platform used, with earlier comparisons reporting substantially lower efficiency for membrane separation, 6 whereas a more recent comparison using a current-generation membrane system found efficiency equivalent to that of centrifugal separation, with only procedure time remaining significantly longer. 7 The practical advantages of MPS are that it can be delivered at the bedside on equipment already available in most intensive care and dialysis units, without a dedicated apheresis service or separately trained apheresis personnel, and that it can be combined with renal replacement therapy in the same circuit; its principal requirement is high-flow central venous access. 8

Despite the widespread use of MPS in routine practice, the published evidence base for TPE derives largely from studies employing centrifugal separation, and disease-specific recommendations, including those of ASFA, do not distinguish between the two techniques. 2 Reports describing MPS have generally been limited to single disease groups, to patients treated within intensive care units, or to single-center registries covering restricted numbers of patients. 8 , 9 Comprehensive real-world data covering the full spectrum of indications, the complication profile, laboratory response, and clinician-assessed treatment response of MPS-based TPE in a general hospital population therefore remain scarce. This is particularly relevant for rare indications, for which prospective controlled data are unlikely to become available, and for which practical considerations such as anticoagulation strategy and choice of replacement fluid must be individualized. 10

We therefore performed a retrospective, single-center cohort study of all patients who underwent TPE by the MPS technique at our institution over an eight-year period. Our objectives were to describe the demographic and clinical characteristics of this population and the distribution of TPE indications; to document the type and frequency of procedure-related complications; to compare routine laboratory parameters before and after treatment; and to report clinician-assessed treatment response overall and by indication. Given the observational design and the absence of a comparator group, this study is intended to describe institutional experience with MPS-based TPE rather than to establish its comparative effectiveness against centrifugal TPE or standard therapy.

Materials and Methods

This was a retrospective, single-center observational cohort study conducted at University of Health Sciences Haseki Training and Research Hospital, a tertiary referral center in Istanbul, Türkiye. The study was designed to describe institutional experience with therapeutic plasma exchange (TPE) performed by the membrane plasma separation (MPS) technique. No comparator group was available, and the design does not permit conclusions regarding the comparative effectiveness of MPS. All patients who underwent TPE by the MPS technique at our institution between January 2009 and March 2017 were eligible for inclusion. Eligibility required treatment with at least one TPE session performed by MPS during the study period, together with availability of the hospital record documenting the indication for TPE. Patients treated by centrifugal plasma separation were not eligible, and no further exclusion criteria were applied. A total of 131 consecutive patients were included, referred from the departments of hematology, anesthesiology and critical care, nephrology, neurology, and ophthalmology. The study was approved by the Clinical Research Ethics Committee of Haseki Training and Research Hospital (Decision No. 493, dated 8 June 2017) and was conducted in accordance with the Declaration of Helsinki. Owing to the retrospective design, the requirement for individual informed consent was waived. All patient data were anonymized and kept confidential.

All procedures were performed at the bedside using a Prismaflex system (Gambro, Lund, Sweden) equipped with a Prismaflex TPE 2000 plasma filter containing a polypropylene hollow-fiber membrane. Patients with a functioning arteriovenous fistula were treated through the fistula, whereas a double-lumen non-tunneled hemodialysis catheter was used in all other patients. The plasma volume to be exchanged was calculated as PV (L) = 0.065 × body weight (kg) × (1 − hematocrit), and 1.5 plasma volumes were exchanged per session. Sessions were performed daily or on alternate days according to the indication, with a mean duration of 120 minutes, a blood flow rate of 100 mL/min, and a plasma filtration rate of 30–40 mL/min. Hemodynamic parameters were monitored continuously throughout each procedure. Anticoagulation of the extracorporeal circuit was achieved with an initial bolus of 2500 IU unfractionated heparin; citrate anticoagulation was not used. Because fresh frozen plasma is anticoagulated with citrate during collection and storage, patients receiving it as replacement fluid are exposed to a citrate load, and 10 mL of 10% calcium gluconate was therefore administered intravenously at the beginning of the procedure in these patients to reduce the risk of hypocalcemia.

Either 20% human albumin, fresh frozen plasma (FFP), or a combination of the two was used as replacement fluid. FFP was preferred in patients with thrombotic microangiopathy, whereas albumin was combined with FFP in patients with a documented bleeding diathesis or a clinically or biochemically increased bleeding risk. The choice of replacement fluid was made by the treating physician according to the patient’s clinical condition and the nature of the underlying disease and was therefore not randomly assigned.

A series was defined as a set of consecutive TPE sessions prescribed for a single clinical episode. A repeat series was defined as a new set of sessions initiated after completion of a previous series following documented remission and subsequent relapse. Patients who received more than one series were analyzed once for demographic and response variables, and the first series was used for the assessment of treatment response. TPE was administered in addition to disease-specific standard treatment, including immunosuppressive therapy where indicated. Immunosuppressive regimens were not standardized and were determined by the referring department.

Data were retrospectively extracted from hospital electronic records and paper archives by two investigators using a standardized data collection form.

Recorded variables comprised age, sex, indication for TPE, number of series and total number of sessions, comorbid conditions (diabetes mellitus, hypertension, coronary artery disease, chronic kidney disease, bronchial asthma, and others), vascular access route, replacement fluid, dialysis status before and during TPE, receipt of immunosuppressive therapy, procedure-related complications, and clinician-assessed treatment response. Laboratory parameters, comprising glucose, urea, creatinine, aspartate aminotransferase, alanine aminotransferase, lactate dehydrogenase (LDH), total protein, albumin, leukocyte count, hemoglobin, hematocrit, and platelet count, were recorded at two defined time points: the pre-TPE value was the last measurement obtained within 24 hours before the first session of the series, and the post-TPE value was the first measurement obtained within 24 hours after the last session. Antineutrophil cytoplasmic antibodies (c-ANCA and p-ANCA) and anti-glomerular basement membrane (anti-GBM) antibodies were measured before the first session and only when clinically indicated.

The indication for TPE was taken from the request form completed by the referring department at the time of treatment. Because the study period spanned three successive editions of the American Society for Apheresis (ASFA) guidelines, indications were retrospectively assigned to ASFA categories and recommendation grades according to the Ninth Edition. 2 Where the diagnostic group recorded at the time of treatment comprised more than one ASFA entity, the constituent subtypes were identified from the clinical records and are reported separately. Treatment response was assessed by the treating physician of the referring department at the end of the TPE series, on the basis of the disease-specific clinical and laboratory parameters relevant to that condition, and was recorded in the clinical notes in one of three categories. Complete response was defined as resolution of the presenting disease manifestations together with normalization of the disease-specific laboratory abnormalities that had prompted TPE, for example normalization of platelet count and LDH with resolution of neurological findings in thrombotic thrombocytopenic purpura, recovery of kidney function with cessation of the requirement for dialysis or resolution of pulmonary hemorrhage in ANCA-associated vasculitis, and recovery of visual acuity in optic neuritis. Partial response was defined as measurable improvement in the presenting manifestations and in the corresponding laboratory abnormalities without complete normalization, and no response as the absence of meaningful improvement in clinical findings or laboratory parameters, or clinical deterioration. Standardized, validated disease-specific response criteria were not applied uniformly across indications, and the assessment was neither blinded nor independently adjudicated.

Because clinical records were maintained over an eight-year period without a dedicated apheresis registry, several variables were incompletely documented. All analyses were therefore performed on available data and no imputation was applied, with the denominator used for each analysis stated in the text and in the corresponding table legend. Indication, number of sessions, replacement fluid, and laboratory parameters were available for all 131 patients; treatment response was available for 113 patients (86.3%), vascular access route for 72 patients (55.0%), dialysis status during TPE for 51 patients (38.9%), immunosuppressive therapy status for 50 patients (38.2%), and comorbid conditions for 43 patients (32.8%). Vasculitic markers were tested only when clinically indicated, and the number tested is reported separately for each marker.

Statistical analysis of the collected data was performed using SPSS 26.0 for Windows (IBM Corp., Armonk, NY, USA) software. Descriptive statistics were generated, presenting categorical variables as numbers and percentages, while numerical variables were summarized using mean, standard deviation, minimum, and maximum values. For comparisons between two dependent groups of numerical variables, the Paired t -Test was utilized if the data met the assumption of normal distribution. If the normal distribution condition was not satisfied, the Wilcoxon Test was applied. The ratios between groups of categorical variables were tested using Chi-Square Analysis. In instances where the conditions for Chi-Square analysis were not met, Monte Carlo simulation was employed. A statistical significance level of p < 0.05 was accepted for all analyses. This rigorous statistical approach ensured the reliability and validity of the study’s findings. No a priori sample size or power calculation was performed, as the study included all consecutive patients treated during the study period, and multivariable analysis was not undertaken because the number of patients within individual indication groups was small and the cohort was clinically heterogeneous; subgroup comparisons are therefore exploratory and should be regarded as hypothesis-generating. Complications and treatment response were not compared between replacement fluid groups, because the replacement fluid was selected on clinical grounds rather than assigned, resulting in groups that differ systematically in disease severity and bleeding risk.

Results

The cohort comprised 131 patients with a nearly equal sex distribution, 64 women (48.9%) and 67 men (51.1%), and a mean age of 44.0 ± 17.0 years (range 13–82). Patients received a mean of 1.15 ± 0.47 TPE series (range 1–5) and a mean of 7.38 ± 4.33 sessions in total (range 1–28), amounting to 967 sessions over the study period. The wide range in session number indicates that treatment was individualized according to disease severity and clinical course rather than delivered as a fixed protocol, and the mean series number implies that approximately 15% of patients required a further course of TPE after completion of the initial one. Comorbidity data were documented for 43 patients, among whom hypertension was the most frequent condition, recorded in 21 patients (48.8%), followed by diabetes mellitus in 7 (16.3%), chronic kidney disease in 6 (14.0%), coronary artery disease in 4 (9.3%), bronchial asthma in 3 (7.0%), and a history of tuberculosis and depression in 1 patient each (2.3%). Demographic and treatment characteristics are summarized in Table 1 . Table 1 Patient Demographics, Treatment Characteristics, and Comorbid Conditions Variable Value Age, years (mean ± SD; range) 44.0 ± 17.0 (13–82) Female 64 (48.9) Male 67 (51.1) TPE series per patient (mean ± SD; range) 1.15 ± 0.47 (1–5) TPE sessions per patient (mean ± SD; range) 7.38 ± 4.33 (1–28) Total sessions performed 967 Comorbid conditions (n = 43 with available data) – Hypertension 21 (48.8) – Diabetes mellitus 7 (16.3) – Chronic kidney disease 6 (14.0) – Coronary artery disease 4 (9.3) – Bronchial asthma 3 (7.0) – History of tuberculosis 1 (2.3) – Depression 1 (2.3) Notes : Values are n (%) unless otherwise stated. Comorbidity data were documented for 43 of the 131 patients (32.8%); percentages for individual comorbidities are calculated using this denominator, and each patient is represented once. Abbreviations : SD, standard deviation; TPE, therapeutic plasma exchange.

The most frequent indication for TPE was ANCA-associated vasculitis presenting as granulomatosis with polyangiitis or microscopic polyangiitis, which accounted for 24 patients (18.3%), followed by thrombotic thrombocytopenic purpura or hemolytic uremic syndrome in 19 patients (14.5%) and crescentic glomerulonephritis in 18 patients (13.7%). Within the crescentic glomerulonephritis group, one patient had anti-GBM disease and the remaining 17 had immune complex–mediated disease, with no patient in this cohort having IgA nephropathy as the underlying cause. The nine patients treated for neurological demyelinating disease comprised three with acute inflammatory demyelinating polyradiculoneuropathy, two with chronic inflammatory demyelinating polyradiculoneuropathy, and four with an acute attack of multiple sclerosis, while of the nine patients treated for optic neuritis, four had neuromyelitis optica spectrum disorder and five had multiple sclerosis–associated disease. The seven patients with autoimmune hemolytic anemia comprised four with severe warm autoimmune hemolytic anemia and three with severe cold agglutinin disease. The full distribution of indications, together with the corresponding ASFA category and grade, is presented in Table 2 and Figure 1 . Figure 1 Distribution of indications for therapeutic plasma exchange in the study cohort (n = 131). Values are presented as percentages. A horizontal bar graph showing distribution of indications for therapeutic plasma exchange. Abbreviations : SLE, systemic lupus erythematosus; FSGS, focal segmental glomerulosclerosis; PRA, panel-reactive antibody; GN, glomerulonephritis; RPGN, rapidly progressive glomerulonephritis; TTP, thrombotic thrombocytopenic purpura; HUS, hemolytic uremic syndrome. Table 2 Indications for Therapeutic Plasma Exchange with Corresponding ASFA Category and Grade of Recommendation Indication n (%) ASFA Category Grade Granulomatosis with polyangiitis/microscopic polyangiitis 24 (18.3) III 1B Thrombotic thrombocytopenic purpura/hemolytic uremic syndrome a 19 (14.5) I–III 1A–2C Crescentic glomerulonephritis 18 (13.7) – Anti-GBM disease with diffuse alveolar hemorrhage b 1 (0.8) I 1C – Immune complex–mediated, other 17 (13.0) NC c — Post-transplant glomerulonephritis relapse d 14 (10.7) I 1B Neurological demyelinating diseases 9 (6.9) – Acute inflammatory demyelinating polyradiculoneuropathy 3 (2.3) I 1A – Chronic inflammatory demyelinating polyradiculoneuropathy 2 (1.5) I 1B – Multiple sclerosis, acute attack 4 (3.1) II 1A Optic neuritis 9 (6.9) – Neuromyelitis optica spectrum disorder 4 (3.1) II 1B – Multiple sclerosis–associated 5 (3.8) II 1A Systemic vasculitis e 8 (6.1) II–III 2A–2C Pre-transplant panel reactive antibody positivity 7 (5.3) I 1B Autoimmune hemolytic anemia 7 (5.3) – Severe warm autoimmune hemolytic anemia 4 (3.1) III 2C – Severe cold agglutinin disease 3 (2.3) II 2C Multiple myeloma f 5 (3.8) II 2B Systemic lupus erythematosus, severe 4 (3.1) II 2C Pre-transplant focal segmental glomerulosclerosis 3 (2.3) NC g — Treatment-resistant focal segmental glomerulosclerosis 2 (1.5) III 2C Fulminant hepatitis/disseminated intravascular coagulation h 2 (1.5) III 2B Total 131 (100.0) Notes : ASFA categories and recommendation grades were assigned retrospectively according to the Ninth Edition of the American Society for Apheresis guidelines. 1 Category I denotes disorders for which apheresis is accepted as first-line therapy; category II, accepted second-line therapy; category III, indications for which the optimum role of apheresis is not established and decision-making should be individualized; category IV, indications in which apheresis is considered ineffective or harmful. Grades follow the GRADE system, in which 1 denotes a strong and 2 a weak recommendation, and A, B, and C denote high, moderate, and low quality of supporting evidence, respectively. a Recorded as a single diagnostic group at the time of treatment and not separable retrospectively; thrombotic thrombocytopenic purpura is category I (1A), whereas complement-mediated and infection-associated hemolytic uremic syndrome are category I or III depending on subtype. b This patient was dialysis-dependent; diffuse alveolar hemorrhage is a category I indication irrespective of dialysis status. c Immune complex–mediated crescentic glomerulonephritis without an identified anti-GBM or IgA etiology is not assigned a separate category. d Assigned as recurrent focal segmental glomerulosclerosis in the kidney transplant. e Specific vasculitis subtypes were not recorded individually at the time of treatment; entities within this group range from category II (cryoglobulinemic vasculitis, hepatitis B–associated polyarteritis nodosa) to category III (IgA vasculitis, eosinophilic granulomatosis with polyangiitis). f Assigned as myeloma cast nephropathy. g Prophylactic pre-transplant plasma exchange for focal segmental glomerulosclerosis is not separately categorized. h Standard-volume therapeutic plasma exchange in acute liver failure is category III; high-volume plasma exchange is category I (1A). Abbreviations : anti-GBM, anti-glomerular basement membrane; ASFA, American Society for Apheresis; NC, not categorized.

When indications were classified according to the Ninth Edition of the ASFA guidelines, 27 patients (20.6%) were treated for a category I indication, 25 (19.1%) for a category II indication, and 32 (24.4%) for a category III indication, while no patient was treated for a category IV indication. A further 20 patients (15.3%) had indications that are not separately categorized in the current guidelines, comprising immune complex–mediated crescentic glomerulonephritis without an identified specific etiology and prophylactic pre-transplant plasma exchange for focal segmental glomerulosclerosis, and the remaining 27 patients (20.6%) belonged to diagnostic groups recorded collectively at the time of treatment that could not be resolved into single ASFA entities retrospectively. Almost 40% of the cohort was therefore treated either for a category III indication or for an indication that the guidelines do not categorize at all, a distribution that reflects the referral pattern of a tertiary center in which plasma exchange is frequently requested for severe or refractory presentations falling outside strongly evidence-supported indications.

Vasculitic markers were assessed only when clinically indicated. c-ANCA was tested in 58 patients and was positive in 11 (19.0%), p-ANCA was tested in 56 patients and was positive in 5 (8.9%), and anti-GBM antibody was tested in 31 patients and was positive in 1 (3.2%). The low positivity rates reflect the fact that markers were requested to exclude as well as to confirm a vasculitic etiology in patients presenting with rapidly progressive kidney disease.

Vascular access route could be determined for 72 patients, of whom 67 (93.1%) were treated through a double-lumen dialysis catheter and 5 (6.9%) through a native arteriovenous fistula, a distribution that reflects the acuity of the population and the frequent need for high-flow access established at short notice. Replacement fluid was documented for all 131 patients: 96 (73.3%) received predominantly FFP, 25 (19.1%) received a combination of albumin and FFP, and 10 (7.6%) received 20% human albumin exclusively throughout all sessions. The combined regimen was reserved for patients with a documented bleeding diathesis or an increased bleeding risk, so the choice of fluid was determined by the clinical condition of the patient rather than assigned. Dialysis status during TPE was documented for 51 patients, of whom 19 (37.3%) were not receiving dialysis, 12 (23.5%) had been receiving dialysis before TPE was started, and 16 (31.4%) received dialysis concurrently with TPE; one patient (2.0%) had established end-stage kidney disease and three patients (5.9%) progressed to end-stage kidney disease during the treatment period. These data are presented in Table 3 . Table 3 Vascular Access Route, Replacement Fluid, and Dialysis Status During Therapeutic Plasma Exchange Characteristic n (%) Vascular access route (n = 72) – Double-lumen dialysis catheter 67 (93.1) – Arteriovenous fistula 5 (6.9) Replacement fluid (n = 131) – Fresh frozen plasma, predominantly 96 (73.3) – Albumin combined with fresh frozen plasma 25 (19.1) – 20% human albumin exclusively 10 (7.6) Dialysis status (n = 51) – Not receiving dialysis 19 (37.3) – Receiving dialysis before TPE 12 (23.5) – Receiving dialysis during TPE 16 (31.4) – End-stage kidney disease 1 (2.0) – Receiving dialysis during TPE and progressed to end-stage kidney disease 3 (5.9) Notes : Percentages are calculated using the number of patients with available data for each variable, shown in parentheses in the row headings. Albumin was combined with fresh frozen plasma in patients with a documented bleeding diathesis or an increased bleeding risk. Dialysis status did not influence the assessment of treatment response, which was based on disease-specific clinical and laboratory criteria; however, the requirement for renal replacement therapy was itself a component of the response assessment in patients treated for rapidly progressive glomerular disease. Abbreviation : TPE, therapeutic plasma exchange.

A total of 69 adverse events were documented across 967 TPE sessions, corresponding to a per-session complication rate of 7.1%. Hypocalcemia was the most frequent event, recorded in 34 patients (26.0%), followed by allergic reactions in 13 (9.9%) and hypotension in 9 (6.9%), with less frequent events comprising nausea in 6 patients (4.6%), coagulopathy and headache in 2 patients each (1.5%), and muscle cramps, hyperthermia, and thrombocytopenia in 1 patient each (0.8%). No complication resulted in death and no procedure was abandoned because of an adverse event. The predominance of hypocalcemia is consistent with calcium chelation by the citrate contained in fresh frozen plasma, which was used as the replacement fluid in 73.3% of patients, and supports the use of routine calcium supplementation in this group. Complications were not compared between replacement fluid groups for the reasons stated in the Methods. Complications are presented in Table 4 . Table 4 Complications Recorded During Therapeutic Plasma Exchange Complication Patients, n (%) Hypocalcemia 34 (26.0) Allergic reaction 13 (9.9) Hypotension 9 (6.9) Nausea 6 (4.6) Coagulopathy 2 (1.5) Headache 2 (1.5) Muscle cramps 1 (0.8) Hyperthermia 1 (0.8) Thrombocytopenia 1 (0.8) Notes : Values are the number of patients in whom each complication was recorded, expressed as a proportion of the 131 patients in the cohort; individual patients may have experienced more than one type of complication. A total of 69 adverse events were documented across 967 sessions, corresponding to a per-session complication rate of 7.1%. No fatal complications occurred. Complications were recorded only when documented in the clinical notes, and mild or self-limiting events may therefore be under-reported.

Clinician-assessed treatment response could be retrieved for 113 of the 131 patients (86.3%), among whom 28 (24.8%) achieved a complete response and 44 (38.9%) a partial response, giving an overall response rate of 63.7%, while 41 patients (36.3%) showed no response. Information on concomitant immunosuppressive therapy was available for 50 patients, of whom 26 (52.0%) were receiving such treatment alongside TPE. Missing response data were not evenly distributed across indications: they affected 6 of 14 patients treated for post-transplant glomerulonephritis relapse and 5 of 7 treated for pre-transplant panel reactive antibody positivity, whereas response was documented for every patient in eight of the fourteen indication groups. Both of the most affected groups comprise transplant candidates or recipients whose subsequent follow-up took place at the transplantation center rather than at our institution, and response rates for these two indications are therefore based on fewer than half of the treated patients and are reported for completeness rather than as reliable estimates. Thrombotic thrombocytopenic purpura or hemolytic uremic syndrome was the second most frequent indication with 19 patients, of whom response was documented for 17, with 7 (41.2%) achieving a complete and 6 (35.3%) a partial response. In the 24 patients treated for granulomatosis with polyangiitis or microscopic polyangiitis, response was documented for all, with 2 (8.3%) complete and 12 (50.0%) partial responses, and among the 17 patients with immune complex–mediated crescentic glomerulonephritis, 5 (29.4%) achieved a complete and 6 (35.3%) a partial response. The lowest response rates were recorded in fulminant hepatitis with disseminated intravascular coagulation, in which neither of the two patients responded, and in post-transplant glomerulonephritis relapse, in which none of the eight patients with available data achieved a complete response. Differences in response rates between indications did not reach statistical significance. Response by indication is presented in Table 5 . Table 5 Clinician-Assessed Treatment Response by Indication Indication Response Data Available/Treated Complete, n (%) Partial, n (%) None, n (%) Thrombotic thrombocytopenic purpura/hemolytic uremic syndrome 17/19 7 (41.2) 6 (35.3) 4 (23.5) Multiple myeloma 5/5 1 (20.0) 2 (40.0) 2 (40.0) Post-transplant glomerulonephritis relapse 8/14 0 (0.0) 2 (25.0) 6 (75.0) Pre-transplant panel reactive antibody positivity 2/7 1 (50.0) 0 (0.0) 1 (50.0) Granulomatosis with polyangiitis/microscopic polyangiitis 24/24 2 (8.3) 12 (50.0) 10 (41.7) Neurological demyelinating diseases 7/9 3 (42.9) 2 (28.6) 2 (28.6) Systemic lupus erythematosus 4/4 2 (50.0) 1 (25.0) 1 (25.0) Crescentic glomerulonephritis 17/18 5 (29.4) 6 (35.3) 6 (35.3) Treatment-resistant focal segmental glomerulosclerosis 2/2 0 (0.0) 1 (50.0) 1 (50.0) Pre-transplant focal segmental glomerulosclerosis 3/3 1 (33.3) 1 (33.3) 1 (33.3) Autoimmune hemolytic anemia 5/7 0 (0.0) 4 (80.0) 1 (20.0) Optic neuritis 9/9 5 (55.6) 1 (11.1) 3 (33.3) Fulminant hepatitis/disseminated intravascular coagulation 2/2 0 (0.0) 0 (0.0) 2 (100.0) Systemic vasculitis 8/8 1 (12.5) 6 (75.0) 1 (12.5) Overall 113/131 28 (24.8) 44 (38.9) 41 (36.3) Notes : Values are n (%) of patients for whom treatment response was documented. Because of the retrospective design, response could not be retrieved for 18 of the 131 patients (13.7%); percentages are calculated using the number of patients with available response data as the denominator and may therefore differ from the number of patients per indication shown in Table 2 . Missing data were concentrated in the post-transplant glomerulonephritis relapse and pre-transplant panel reactive antibody groups, and response rates for these two indications should be interpreted with particular caution. Response categories are defined in the Materials and Methods section.

Response according to pre-treatment vasculitic marker status is shown in Table 6 . Response data were available for 56 of the 58 patients tested for c-ANCA, 53 of the 56 tested for p-ANCA, and 29 of the 31 tested for anti-GBM antibody. Among c-ANCA-negative patients (n = 46), 28.3% achieved a complete response, 34.8% a partial response, and 37.0% no response, while the corresponding proportions among the 10 c-ANCA-positive patients were 30.0%, 40.0%, and 30.0% (p = 1.000). Among p-ANCA-negative patients (n = 48), complete, partial, and absent responses were recorded in 27.1%, 37.5%, and 35.4%, respectively, compared with 40.0%, 40.0%, and 20.0% among the five p-ANCA-positive patients (p = 0.848). The single anti-GBM-positive patient did not respond. No comparison reached statistical significance, and all are underpowered given the small number of marker-positive patients. Table 6 Treatment Response According to Pre-Treatment Vasculitic Marker Status Marker Status n Complete, n (%) Partial, n (%) None, n (%) p c-ANCA Negative 46 13 (28.3) 16 (34.8) 17 (37.0) 1.000 Positive 10 3 (30.0) 4 (40.0) 3 (30.0) p-ANCA Negative 48 13 (27.1) 18 (37.5) 17 (35.4) 0.848 Positive 5 2 (40.0) 2 (40.0) 1 (20.0) Anti-GBM Negative 28 7 (25.0) 14 (50.0) 7 (25.0) 0.513 Positive 1 0 (0.0) 0 (0.0) 1 (100.0) Notes : Values are n (%). Markers were tested only when clinically indicated: c-ANCA in 58 patients (11 positive, 19.0%), p-ANCA in 56 patients (5 positive, 8.9%), and anti-GBM antibody in 31 patients (1 positive, 3.2%). Patients for whom treatment response was not documented were excluded from the corresponding comparison. Comparisons were performed using the chi-square test with Monte Carlo simulation where expected cell counts were insufficient. Given the small number of marker-positive patients, these comparisons are exploratory and underpowered; the anti-GBM comparison, based on a single positive patient, does not permit meaningful inference. Abbreviations : ANCA, antineutrophil cytoplasmic antibody; anti-GBM, anti-glomerular basement membrane.

Comparison of laboratory values obtained within 24 hours before the first session and within 24 hours after the last session of the series showed statistically significant reductions in urea (p = 0.024), creatinine (p < 0.001), LDH (p = 0.001), and total protein (p = 0.035), together with a significant increase in albumin (p < 0.001), while no significant change was observed in glucose, aspartate aminotransferase, alanine aminotransferase, leukocyte count, hemoglobin, hematocrit, or platelet count. The reduction in total protein and the rise in albumin are the expected consequences of albumin-containing replacement fluid rather than independent evidence of a therapeutic effect, whereas the stability of hemoglobin and platelet counts indicates that repeated procedures were not associated with clinically meaningful cytopenia. In the subgroups with kidney involvement, mean creatinine fell from 4.8 ± 3.2 mg/dL to 3.2 ± 2.0 mg/dL in patients with small-vessel vasculitis and from 5.4 ± 3.5 mg/dL to 2.3 ± 1.4 mg/dL in patients with immune complex–mediated rapidly progressive glomerulonephritis. Because TPE was administered together with immunosuppressive therapy and supportive care, these changes cannot be attributed to plasma exchange alone. Results are presented in Table 7 . Table 7 Laboratory Parameters Before and After Therapeutic Plasma Exchange Parameter Pre-TPE (Mean ± SD) Post-TPE (Mean ± SD) p Glucose (mg/dL) 115.4 ± 45.0 109.5 ± 42.8 0.061 Urea (mg/dL) 103.6 ± 71.5 86.5 ± 58.3 0.024 Creatinine (mg/dL) 3.72 ± 3.01 2.62 ± 2.08 <0.001 Aspartate aminotransferase (U/L) 57.7 ± 141.8 41.5 ± 116.1 0.075 Alanine aminotransferase (U/L) 45.4 ± 107.9 31.3 ± 38.7 0.473 Lactate dehydrogenase (U/L) 553.2 ± 810.9 378.0 ± 551.1 0.001 Total protein (g/dL) 6.12 ± 1.43 5.84 ± 1.04 0.035 Albumin (g/dL) 3.15 ± 0.76 3.46 ± 0.74 <0.001 Leukocytes (×10 3 /µL) 10.3 ± 6.1 10.5 ± 7.0 0.981 Hemoglobin (g/dL) 10.3 ± 8.2 9.5 ± 1.9 0.624 Hematocrit (%) 28.7 ± 8.0 28.8 ± 6.1 0.905 Platelets (×10 3 /µL) 216.2 ± 137.4 201.6 ± 115.9 0.150 Notes : Pre-TPE values are the last measurement obtained within 24 hours before the first session of the series; post-TPE values are the first measurement obtained within 24 hours after the last session. Comparisons were performed using the paired t -test or the Wilcoxon signed-rank test according to distribution. Abbreviations : SD, standard deviation; TPE, therapeutic plasma exchange.

Discussion

In this single-center retrospective cohort of 131 patients treated over eight years, TPE performed by MPS was delivered across fourteen distinct indications spanning the full range of ASFA categories. The procedure was associated with a per-session complication rate of 7.1%, no fatal adverse events, significant short-term improvement in kidney function markers and lactate dehydrogenase (LDH), and a clinician-assessed overall response rate of 63.7% among patients for whom response could be documented. Because no comparator group was available and TPE was administered alongside disease-specific standard therapy, these findings describe what was observed in this cohort and cannot be attributed to plasma exchange in isolation.

The principal interest of these data lies in the delivery technique rather than in the outcomes themselves. MPS allowed plasma exchange to be performed at the bedside for critically ill patients who could not safely be transferred, a pattern reflected in the predominance of central venous catheter access in this cohort. Most published outcome data for TPE derive from centrifugal separation, and disease-specific recommendations do not distinguish between the techniques; 2 series describing MPS have generally been confined to single disease groups, to intensive care populations, or to single-center registries. 8 , 9 The present cohort therefore adds real-world data on the indication profile, safety, and short-term outcomes of MPS-based TPE across an unselected general hospital population.

The indication profile itself merits comment, since almost 40% of our patients were treated for a category III indication or for one that the current guidelines do not categorize at all. This is consistent with the referral pattern of a tertiary center, in which plasma exchange is most often requested for severe, rapidly progressive, or treatment-refractory presentations, and it is comparable with distributions reported in other retrospective series from referral hospitals. 11–13 An important consideration when interpreting this profile is that the ASFA categories in force during the treatment period differ from those applied here. ANCA-associated vasculitis, the most frequent indication in our cohort, illustrates this directly: in the editions current when these patients were treated, plasma exchange for rapidly progressive glomerulonephritis in ANCA-associated vasculitis carried a category I or II recommendation, 3 whereas in the Ninth Edition both microscopic polyangiitis and granulomatosis with polyangiitis are assigned category III irrespective of creatinine level or the presence of diffuse alveolar hemorrhage. 2 Treatment decisions in this cohort were therefore taken under a different evidence framework from the one that applies today, and the indication profile reported here should be read as reflecting practice between 2009 and 2017 rather than current recommendations. The same caveat applies more broadly, since guideline revisions during a long retrospective study period introduce a temporal component to case selection that cannot be removed by analysis.

Turning to the safety of the procedure, the per-session complication rate of 7.1% is consistent with the range reported in comparable series, in which rates generally remain below 10%. 12 , 14 A Turkish national survey of TPE activity across 28 apheresis units reported an adverse event frequency of 12.6%, with hypocalcemia-related symptoms, hypotension, and urticaria the most common events and no severe adverse events leading to major morbidity or mortality; 15 the profile of events in our cohort was closely similar, with hypocalcemia recorded in 26.0% of patients, allergic reactions in 9.9%, and hypotension in 6.9%. The predominance of hypocalcemia is the expected consequence of calcium chelation by the citrate contained in fresh frozen plasma rather than of the anticoagulant used, since the circuit was anticoagulated with unfractionated heparin; it supports routine calcium supplementation during procedures using plasma as replacement fluid. 14 No event resulted in death and no procedure was abandoned because of an adverse event, and given the clinical acuity of this population the observed event profile suggests that MPS-based TPE can be delivered with an acceptable margin of safety when performed by an experienced team. Two qualifications apply: complications were captured only when documented in the clinical notes, so mild or self-limiting events are likely to be under-reported and the true rate is probably higher than that recorded; and in the absence of a comparator group these figures cannot be used to compare the safety of MPS with that of centrifugal TPE.

The laboratory changes observed require similarly careful reading. The reduction in total protein and the rise in albumin are the direct and expected consequence of albumin-containing replacement fluid and should not be read as evidence of therapeutic benefit. 1 The reduction in creatinine and LDH is more informative, since both reflect the pathophysiology of the conditions most frequently treated in this cohort, but it likewise cannot be attributed to plasma exchange alone, because patients received concurrent immunosuppression, supportive care, and in many cases renal replacement therapy, and because measurements were taken after the last session of a series rather than at a fixed interval from disease onset. The stability of hemoglobin, hematocrit, leukocyte, and platelet counts across a mean of seven sessions indicates that repeated procedures were not associated with clinically meaningful cytopenia, which is a relevant practical observation for a technique that processes plasma across a filter membrane. 1 , 10

Response rates varied considerably between indications, and the pattern broadly followed the strength of the underlying evidence base. The highest response among the larger groups was in thrombotic thrombocytopenic purpura or hemolytic uremic syndrome, in which 76.5% of patients achieved a complete or partial response, consistent with the strong evidence for plasma exchange in thrombotic thrombocytopenic purpura, where the procedure both replaces deficient ADAMTS13 and removes anti-ADAMTS13 antibodies and where TPE holds a category I, grade 1A recommendation. 2 A limitation specific to this group is that thrombotic thrombocytopenic purpura and hemolytic uremic syndrome were recorded as a single diagnostic entity at the time of treatment and could not be separated retrospectively, although the two conditions differ substantially in pathophysiology, in ASFA category, and in expected response.

Among patients with granulomatosis with polyangiitis or microscopic polyangiitis, 58.3% achieved a complete or partial response as assessed by the treating physician, although only 8.3% were classified as complete responders, and these figures require careful framing. The MEPEX trial reported better kidney recovery at three months with plasma exchange in severe renal vasculitis, 16 whereas PEXIVAS found no significant reduction in the composite of death or end-stage kidney disease with plasma exchange and showed that a reduced-dose glucocorticoid regimen was non-inferior to the standard regimen. 17 Our findings do not contradict PEXIVAS and should not be presented as doing so, because the two assessments address different questions over different time horizons: PEXIVAS was designed around long-term, hard endpoints, while the response categories used here capture the clinical and biochemical status of the patient at the end of the treatment series. Short-term clinician-assessed improvement of the kind recorded in our cohort is compatible with an absence of long-term benefit, and the reclassification of these indications to category III in the current guidelines reflects the weight now given to the PEXIVAS endpoints. 2 , 17 Our data therefore describe what was observed at the end of treatment and provide no evidence bearing on survival or on progression to end-stage kidney disease.

Response was documented for 17 of 18 patients with crescentic glomerulonephritis, with an overall response rate of 64.7% in the immune complex–mediated group, closely similar to that observed in small-vessel vasculitis, and mean creatinine in this group fell from 5.4 ± 3.5 to 2.3 ± 1.4 mg/dL. This group is not separately categorized in the ASFA guidelines, and evidence for plasma exchange in immune complex–mediated rapidly progressive glomerulonephritis without an identified anti-glomerular basement membrane (anti-GBM) or IgA etiology remains limited, 2 so the observations reported here are descriptive and hypothesis-generating. The single patient with anti-GBM disease presented with diffuse alveolar hemorrhage while dialysis-dependent, a constellation carrying a category I, grade 1C recommendation for plasma exchange, 2 yet was recorded as showing no response; dialysis dependence at presentation is a recognized predictor of poor kidney outcome in this condition, and the category I recommendation in the presence of alveolar hemorrhage relates principally to control of pulmonary rather than kidney disease. A single case permits no inference, but it illustrates that a strong guideline recommendation does not translate into response in every patient.

Among the neurological indications, complete or partial response was recorded in 71.5% of the demyelinating group and 66.7% of the optic neuritis group. Plasma exchange is established therapy in acute and chronic inflammatory demyelinating polyradiculoneuropathy, holding category I recommendations, and is category II for acute attacks of multiple sclerosis and of neuromyelitis optica spectrum disorder. 2 , 18 Comparable response rates have been reported from other Turkish tertiary centers treating neurological indications with plasma exchange. 19 The subgroups here are too small for any comparison between neurological entities, and response was assessed clinically at the end of the series rather than by a validated disability scale. In the seven patients treated for autoimmune hemolytic anemia, response data were available for five, of whom four achieved a partial response. Plasma exchange has a stronger mechanistic rationale in cold agglutinin disease, in which the pathogenic IgM is largely confined to the intravascular compartment, than in warm autoimmune hemolytic anemia, in which the responsible IgG is predominantly extravascular, and this is reflected in the respective ASFA categories of II and III, 2 although our numbers are too small to compare the subtypes.

Five patients with multiple myeloma were treated, with one complete and two partial responses. Plasma exchange in myeloma cast nephropathy is category II, grade 2B, 2 and the literature remains divided, with removal of free light chains associated with improved kidney function in some series 20 , 21 while a controlled trial found no benefit; 22 current practice reserves the procedure for patients with biopsy-proven cast nephropathy or high serum or urinary free light chain concentrations rather than for all patients with myeloma and kidney impairment. 20 Neither of the two patients with fulminant hepatitis and disseminated intravascular coagulation responded. Standard-volume TPE in acute liver failure is category III, whereas high-volume TPE holds a category I, grade 1A recommendation; 2 a randomized trial of standard-volume plasma exchange in acute liver failure reported improved outcomes compared with standard medical therapy alone, 23 and liver transplantation remains the definitive treatment where available. 24 Our patients received standard-volume exchange, and the number treated permits no conclusion.

One further observation concerns the replacement fluid. Response rates appeared numerically lower in the group receiving albumin combined with FFP than in the other two groups, but this observation was not tested statistically and should not be interpreted as an effect of the replacement fluid. The combined regimen was reserved for patients with a bleeding diathesis or an increased bleeding risk, so these patients differ systematically from the remainder of the cohort in disease severity and comorbidity, and the groups were small and unevenly distributed across a heterogeneous set of indications. It is therefore not possible to determine whether the difference reflects the fluid itself or the clinical condition that prompted its selection. Depletion of coagulation factors, particularly fibrinogen, with repeated exchange remains a recognized consideration when selecting replacement fluid, and has been examined directly in comparisons of membrane and centrifugal techniques. 1 , 7

Taken together, our complication profile, laboratory findings, and overall response rate are broadly in line with those of comparable retrospective series of TPE performed in tertiary centers. 11–13 This concordance is itself informative, since most of those series used centrifugal separation or did not specify the technique, and it suggests that the choice of separation method does not produce markedly different institutional-level outcomes; that inference, however, is drawn across studies rather than within one, and a direct comparison would require a study designed for that purpose.

Several limitations constrain the strength of any conclusion drawn from these data. The study is a retrospective, single-center analysis without a control or comparator group, and therefore cannot establish the effectiveness of MPS-based TPE or compare it with centrifugal TPE or with standard therapy alone; all patients received disease-specific treatment alongside plasma exchange, so observed changes cannot be attributed to the procedure. The cohort is clinically heterogeneous, comprising fourteen indications with different pathophysiology, treatment protocols, and expected outcomes, and several groups contain fewer than five patients, so pooled response rates across such a population have limited interpretability. Treatment response was assessed by the treating physician using disease-specific clinical and laboratory parameters rather than standardized, validated, disease-specific response criteria, and the assessment was neither blinded nor independently adjudicated, while thrombotic thrombocytopenic purpura and hemolytic uremic syndrome were recorded as a single group and could not be separated retrospectively. No a priori sample size or power calculation was performed, and no multivariable analysis was undertaken to adjust for confounding or to identify independent predictors of response or complications, so subgroup comparisons, particularly those by vasculitic marker status, are underpowered and exploratory. Data were incomplete for several variables because records were maintained over eight years without a dedicated apheresis registry: treatment response was unavailable for 13.7% of patients and was disproportionately missing in the post-transplant glomerulonephritis relapse and pre-transplant panel reactive antibody groups, while comorbidity, dialysis status, vascular access, and immunosuppressive therapy data were documented for approximately one third to one half of the cohort, and no imputation was performed. Session frequency, exchange volume, and the duration of each treatment series were determined by the treating physician according to the indication rather than by a standardized institutional protocol, and concomitant immunosuppressive regimens were likewise not standardized, so treatment intensity varied between patients in ways that were not captured as analyzable variables. Complications were captured only when documented, so mild events are likely under-reported, and mortality and long-term outcome data were not available, so no statement can be made about survival or progression to end-stage kidney disease. Finally, ASFA recommendations changed materially during and after the study period, most notably for ANCA-associated vasculitis, so the indication profile reflects the evidence framework of the treatment era rather than current guidance. 2 , 3

Conclusions

In this retrospective single-center cohort, therapeutic plasma exchange performed by membrane plasma separation was delivered at the bedside across fourteen indications spanning the full range of ASFA categories, with a per-session complication rate of 7.1%, no fatal adverse events, and short-term improvement in kidney function markers and lactate dehydrogenase. Clinician-assessed complete or partial response was recorded in 63.7% of the patients for whom response could be documented.

Because no comparator group was included and plasma exchange was administered alongside disease-specific standard therapy, these findings describe institutional experience and do not establish the comparative effectiveness of membrane plasma separation against centrifugal therapeutic plasma exchange or against standard treatment alone. They should be interpreted in the light of the retrospective design, the heterogeneity of the population, the absence of standardized disease-specific response criteria, the incompleteness of some records, and the absence of long-term outcome data. Almost 40% of the cohort was treated for indications that are currently classified as category III or are not categorized at all, and the ASFA categories in force during the treatment period differ from those applying today.

The value of these data lies in describing how a widely used but comparatively under-reported delivery technique performs in routine practice across an unselected patient population. Prospective studies using standardized, disease-specific response criteria and, where feasible, direct comparison between separation techniques would be required to determine whether the choice of technique affects clinical outcome, and to define the optimal timing, session frequency, exchange volume, and replacement fluid for individual indications.

Disclosure

The authors report no conflicts of interest in this work.

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