Transfusion and Apheresis Science 51 (2014) 83–89
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Transfusion and Apheresis Science j o u r n a l h o m e p a g e : w w w. e l s e v i e r. c o m / l o c a t e / t r a n s c i
Patients treated with therapeutic plasma exchange: A single center experience Nilay Sengul Samanci a,*, Mesut Ayer b, Meltem Gursu c, Muhlis Cem Ar d, Kubra Yel a, Abdulkadir Ergen a, Elif Ece Dogan a, Serhat Karadag c, Egemen Cebeci c, Mehmet Toptas e, Rumeyza Kazancioglu f, Savas Ozturk c a
Department of Internal Medicine, Haseki Training and Research Hospital, Istanbul, Turkey Department of Hematology, Haseki Training and Research Hospital, Istanbul, Turkey Department of Nephrology, Haseki Training and Research Hospital, Istanbul, Turkey d Department of Hematology, Istanbul University Cerrahpasa Medical Faculty, Istanbul, Turkey e Department of Intensive Care Medicine, Haseki Training and Research Hospital, Istanbul, Turkey f Department of Nephrology, Bezmialem Vakif University Medical Faculty, Istanbul, Turkey b c
A R T I C L E
I N F O
Article history: Received 19 July 2014 Accepted 6 October 2014 Keywords: Plasma exchange Hemodialysis Fresh frozen plasma Hemodiafiltration Plasma volume
A B S T R A C T
Introduction: Therapeutic Plasma Exchange (TPE) is a therapeutic procedure that is used to remove high molecular weight substances from plasma. We analyzed data of patients who received TPE during the last 7 years, and focused on the efficiency of TPE in various disease groups. Material and Methods: We studied 110 patients treated with TPE by membrane plasma separation technique from 2007 to 2013. We examined the demographic data, underlying disease, biochemical parameters, volume and type of replacement fluid, complications, concomitant treatment, the need for hemodialysis and number of TPE sessions. Results: One hundred ten patients, 58 male, 52 female were included. The mean age was 47.3 ± 17.6 years. A total of 734 TPE sessions were performed and the mean number of TPE sessions per patient was 6.6 ± 4.3. The underlying disease was renal transplantation in 26 patients, ANCA-associated vasculitis in 18, rapidly progressive glomerulonephritis in 17, hemolytic uremic syndrome in 11, thrombotic thrombocytopenic purpura in 9, autoimmunic hemolytic anemia in 6, focal segmental glomerulosclerosis in 6 and other diseases. Partial and complete remission was obtained in 65 (59.1%) and 24 patients (21.8%) respectively, while 14 (12.7%) patients had no response and 7 (6.4%) patients died. Complications were muscle cramps (6.4%), allergic reactions (4.5%), severe hypotension (3.6%), fever (1.8%), unconsciousness (0.9%), leukopenia (0.9%) and catheter related hematoma (0.9%). Conclusion: According to our 7 years of experience in TPE, we can say that therapeutic plasma exchange by membrane separation technique is a useful, easy, available and effective lifesaving therapeutic treatment. © 2014 Elsevier Ltd. All rights reserved.
1. Introduction Therapeutic plasma exchange (TPE) is a therapeutic procedure in which the blood of the patient is passed through
* Corresponding author. Department of Internal Medicine, Haseki Training and Research Hospital, Istanbul, Turkey. Tel.: +90 2125294400/ 1709; fax: +90 2125294463. E-mail address: [email protected] (N. Sengul Samanci). http://dx.doi.org/10.1016/j.transci.2014.10.006 1473-0502/© 2014 Elsevier Ltd. All rights reserved.
a medical apparatus which extracts high molecular weight substances such as immune complexes, endotoxins, myeloma light chains, autoantibodies, lipoproteins, cryoglobulins from the plasma in exchange for a replacement solution such as albumin or fresh frozen plasma [1,2]. Plasma exchange has been used mainly for two purposes: removing high molecular weight substances like antibodies, immune complexes, etc. from the plasma and supplementing plasma with the missing essential factors [3]. It is indicated for various renal, hematological, rheumatologic, neurological, oncological,
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nephrological and multisystemic diseases usually in conjunction with classical medical therapy. TPE can be made by cytocentrifuge or membrane separation techniques. Especially membrane separation technique applied with hemodiafiltration equipment has gained increasing popularity because of being a relatively easy procedure. Furthermore it does not require a separate unit, device or hospitalization [4]. Herein, we retrospectively analyzed the performance and efficiency of TPE in various disease groups. 2. Material and Methods In this study we retrospectively analyzed 110 patients treated with TPE between January 2007 and December 2013 in our hospital by membrane separation technique. Patient files were reviewed and data on demographic data (age, sex), underlying disease, biochemical parameters, volume and the type of replacement fluid used for TPE (human albumin and/ or fresh frozen plasma), complications related with the procedure, concomitant immunosuppressive treatment, concurrent hemodialysis (HD) requirement, and the number of TPE sessions were collected. The laboratory results before and after each TPE session were also recorded. All patients had given written consent before the TPE procedure. 2.1. Procedure Plasmapheresis was performed using a Prismaflex machine (Gambro, Lund, Sweden) via double lumen HD catheter placed to all patients. Hemodynamic parameters were monitored throughout the procedure. The patient’s plasma volume was calculated using the following formula: plasma volume (L) = weight × 0.065 × (1 − hematocrit) [4]. Twenty percent human albumin (diluted to 5% albumin in isotonic saline) and/or fresh frozen plasma (FFP) were used as the replacement fluid. 2.2. Indication of TPE The indications of TPE were principally based on the relevant guideline of the American Society for Apheresis (ASFA). Requirement of additional treatment and/or HD was predicated by the underlying disease [1,2]. 2.3. Response to treatment The response to treatment was graded as partial, complete or none. Resolution of all the pathological clinical and laboratory findings following adequate number of TPE was defined as complete response. Patients with no improvement in clinical and laboratory findings after at least five TPE sessions or patients with an initial response in whom cessation of TPE led to a prompt recurrence of the disease were identified as non-responders. Partial response includes clinical and laboratory results not fitting into both of the aforementioned categories. 2.4. Statistical analysis Descriptive and comparative studies were done using SPSS for Windows, Version 20.0 (SPSS Inc., Chicago, IL, USA).
Wilcoxon Signed Rank Test was used to compare laboratory parameters before and after treatment. P-value was accepted as statistically significant if it was less than 0.05.
3. Results Over a period of 7 years, 110 patients [58 male (52.7%) and 52 female (47.3%)] received TPE. The mean age was 47.3 ± 17.6 years (range: 19–86 years). A total of 734 TPE sessions were performed and the mean number of TPE sessions per patient was 6.6 ± 4.3 (range: 1–25) sessions. Fifty percent of the patients required daily therapy while 50% received TPE every other day. The replacement fluid used was FFP in 83 patients (75.5%), albumin in 13 patients (11.8%) and the combination of both in 14 patients (12.7%) (Fig. 1). The indication for TPE was renal transplantation in 26 patients (23.6%), ANCA-associated vasculitis in 18 (16.4%), rapidly progressive glomerulonephritis in 17 (15.5%), hemolytic uremic syndrome (HUS) in 11 (10%), thrombotic thrombocytopenic purpura (TTP) in 9 (8.2%), autoimmune hemolytic anemia in 6 (5.5%), focal segmental glomerulosclerosis (FSGS) in 6 (5.5%), multiple myeloma in 4 (3.6%) chronic inflammatory demyalinating polyradiculoneuropathy in 3 (2.7%), systemic lupus erythematosus (SLE) in 2 (1.8%), paraneoplastic neurologic syndromes in 2 (1.8%), Devic’s syndrome in 2 (1.8%), Stiff-person syndrome in 1 (0.9%), hypertriglyceridemic pancreatitis in 1 (0.9%), acute liver failure in 1 (0.9%) and Guillain–Barré Syndrome in 1 patient (0.9%). Table 1 displays the biochemical test results of the patients recorded before and after TPE. All of the patients with paraneoplastic neurological syndromes (n = 2), 8 (72.7%) of patients with HUS, 11 (64.7%) of patients with RPGN, 2 (50%) of the patients with multiple myeloma, 1 (50%) of the patients with SLE, 7 (26.9%) of patients with renal transplantation, 9 (50%) of patients with ANCA-associated vasculitis concurrently required HD at the time of diagnosis. TPE and HD were usually done on alternate days. All the patients with paraneoplastic neurologic syndromes, 23.1% patients with renal transplantation, 35.3% patients with RPGN, 36.4% patients with HUS, 16.7% patients with ANCAassociated vasculitis, 50% patients with SLE, 16.7% patients with FSGS and 25% patients with multiple myeloma remained HD dependent. None of the patients with TTP required HD at the time of diagnosis. Additional treatment with steroids, cyclophosphamide etc. was noted in 62.7% of the patients. Sixty-five (59.1%) patients had partial and 24 (21.8%) had complete remission, while 14 (12.7%) had no remission and 7 (6.4%) patients died during the treatment period. Outcome of the patients according to the primary disease is presented in Table 2. The cause of death was acute respiratory failure in five, sepsis and multi organ failure in two of the patients. There were no deaths related to the TPE procedure itself. Complications of the procedure included hypocalcemia induced muscle cramps (n = 7, 6.4%), allergic reactions (n = 5, 4.5%), hypotension (n = 4, 3.6%), fever (n = 2, 1.8%), loss of consciousness (n = 1, 0.9%), leukopenia (n = 1, 0.9%) and catheter related hematoma (n = 1, 0.9%). No complications were observed in 80.9% of patients. No catheter related infection was observed. A significant decrease was found in the creatinine levels before
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Fig. 1. Replacement fluids used.
and after TPE in patients with renal transplantation (p < 0.001), RPGN (p = 0.006), HUS (p = 0.013), autoimmune hemolytic anemia (p = 0.043) and ANCA-associated vasculitis (p = 0.007). There was a statistically significant fall in lactate dehydrogenase levels in patients with HUS (p = 0.003) and autoimmune hemolytic anemia (p = 0.028) and platelet levels increased after TPE in patients with HUS (p = 0.004).
4. Discussion Therapeutic plasma exchange is a procedure in which a predetermined amount of plasma with its constituents, mainly high molecular weight substances, are removed, and replaced by a replacement solution [5]. TPE is used for some diseases in which conventional therapy is not sufficient to control the disease progression. In our hospital, TPE has been
Table 1 Biochemical analysis of the patients before and after TPE.
9/L)
WBC count (10 Neutrophil (109/L) Hemoglobin (g/dL) Hematocrit (%) Platelets (109/L) Creatinine (mg/dL) LDH (U/L) Albumin (g/dL) Ca (mg/dL) ALT (U/L) AST (U/L) ALP (U/L) GGT (U/L) Na (mEq/L) K (mEq/L) CL (mEq/L) CRP (mg/L) 24-hour urine protein (mg)
n
Before TPE (Mean ± SD)
After TPE (Mean ± SD)
p
106 108 108 108 108 110 108 110 108 110 110 66 53 108 108 107 24 34
10482 ± 7162 7073 ± 5399 9.57 ± 2.48 28.69 ± 7.72 237 ± 147 3.95 ± 2.87 381 ± 321 3.35 ± 0.68 8.76 ± 1.01 27.95 ± 38.66 37.39 ± 57.36 133.02 ± 341.33 53.63 ± 65.88 137.01 ± 4.83 4.37 ± 0.72 102.09 ± 4.34 72.33 ± 77.53 3871 ± 4162
8959 ± 4459 6044 ± 3786 9.84 ± 2.92 31.64 ± 26.75 240 ± 228 2.61 ± 2.05 274 ± 237 3.62 ± 0.43 10.00 ± 12.55 25.02 ± 18.51 24.70 ± 22.43 83.42 ± 67.31 67.33 ± 88.70 138.15 ± 3.46 4.40 ± 0.80 101.42 ± 9.68 5.09 ± 13.40 3632 ± 3804
0.015 0.018 0.320 0.259 0.901 0.000 0.000 0.001 0.309 0.405 0.024 0.298 0.640 0.023 0.762 0.493 0.000 0.006
LDH: lactate dehydrogenase, Ca: calcium, ALT: alanine transaminase, AST: aspartate transaminase, ALP: alkaline phosphatase, GGT: gama glutamyl transferase, Na: sodium, K: potassium, CL: chlorine, CRP: C-reactive protein, SD: standard deviation, WBC: white blood cell; n: number of patients.
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Table 2 Outcome of the patients according to the primary disease. n
Multiple myeloma
4
Renal transplantation
26
RPGN
17
HUS
11
TTP
9
Autoimmune hemolytic anemia
6
ANCA-associated vasculitis
18
SLE
2
Hypertriglyceridemic pancreatitis Acute liver failure Paraneoplastic neurologic syndromes Guillain–Barré Syndrome Devic’s syndrome
1 1 2 1 2
Chronic inflammatory demyalinating polyradiculoneuropathy Stiff-person syndrome FSGS
3 1 6
Additional treatment(n)
Outcome (n)
None (1) VAD (2) BD (1) None (16) Pred + MMF + CI (4) Pred + Cy (2) Rituximab (1) Pred + CI (1) Pred (1) IVIG (1) None (3) Pred + Cy (9) Pred (2) Vertebral RT (1) Pred + chloroquine + IVIG + Cy (1) Pred + IVIG (1) None (5) Pred (3) Pred + Cy (2) Pred + IVIG (1) None (6) Pred + Vincristine (1) Pred (2) Pred (3) Pred + Splenectomy (1) Pred + IVIG (1) IVIG (1) None (1) Pred + Cy (13) Pred + IVIG (2) Pred (1) Pred + IVIG + Cy (1) Pred + Cy (1) Pred + IVIG (1) None None None IVIG (1) Pred (1) Pred + Cy (1) Pred (2) Pred + IVIG (1) IVIG (1) None (5) Pred (1)
Complications (n)
HD (n)
1
None (3) Hypotension (1)
No (2) Chronic (1)
4
1
None (20) Allergic reaction (3) Muscle cramps (1) Leucopenia (1) Hypotension (1)
No (19) Chronic (6)
1
4
0
None (14) Muscle cramps (2) Allergic reaction (1)
No (6) Chronic (6) Temporary (5)
7
3
1
0
No (3) Chronic (4) is Temporary (4)
1
5
0
3
3
2
0
1
None (8) Allergic reaction (1) Catheter related (1) Fever (1) None (6) Hypotension (1) Fever (1) Loss of consciousness (1) None (4) Muscle cramps (1) Hypotension (1)
11
4
2
1
None (16) Muscle cramps (2)
No (9) Chronic (3) Temporary (5)
1
0
1
0
None (2)
0 0 0 1 2
1 1 1 0 0
0 0 1 0 0
0 0 0 0 0
None None None None None
No (1) Chronic (1) No No Chronic (2) No No
3
0
0
0
1 4
0 1
0 1
0 0
None (2) Muscle cramps (1) None None
PR
CR
NoR
Died
1
2
0
18
3
12
No (9)
No (5) Temporary (1)
No No No (4) Chronic (1) Temporary (1)
RPGN: rapidly progressive glomerulonephritis, HUS: hemolytic uremic syndrome, TTP: thrombotic thrombocytopenic purpura, SLE: systemic lupus erythematosus, FSGS: focal segmental glomerulosclerosis, VAD: vincristine, doxorubicin, dexamethasone, BD: bortezomib, dexamethasone, HD: hemodialysis, PR: partial remission, CR: complete remission, NoR: no response, n: number of patients, Pred: prednisolone, MMF: mycophenolate mofetil, CI: calcineurin inhibitors, Cy: cyclophosphamide, IVIG: intravenous immunoglobulin, RT: radiotherapy.
performed by a hemodiafiltration machine using membrane separation technique. For membrane separation technique, there is a need for a large bore catheter or arteriovenous fistula to obtain effective blood flow. We used double lumen HD catheters inserted into femoral or internal jugular vein if the patient had no arteriovenous fistula. Catheter related complication rate was low due to routine use of ultrasound guidance [6]. Five percent human serum albumin solution is preferred in most cases as the replacement fluid. However, long term use of albumin may lead to temporary deficiency of plasma proteins, mainly coagulation factors. FFP has the po-
tential of causing febrile or allergic reactions and viral contamination while this risk is negligible for albumin. FFP has the advantage of containing all the plasma proteins including coagulation factors and complement components which are critical in the treatment of TTP and in the presence of coagulopathy [7]. Hypocalcaemia is the major complication due to the presence of anticoagulant citrate in the replacement fluid [8]. Therefore, patients should receive 10% calcium gluconate intravenous infusions during the procedure as needed. Depending on the type of disease to be treated, FFP, albumin solutions or the combination of both can be used. With current available techniques, very
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few and mild side effects are seen during TPE. These are bradycardia, hypotension, pallor, nausea, vomiting, paresthesia, muscle cramps, fever, allergic reactions, unconsciousness, leukopenia and catheter related complications [6]. Some of these complications were observed in 21 of our patients. The evidence is of high quality regarding the TPE indication in Guillain–Barré syndrome, TTP-HUS, ANCAassociated vasculitis. Guillain–Barré syndrome (GBS) is a subacute immune-mediated polyneuropathy. It is characterized by progressive symmetric flaccid paralysis and loss of deep tendon reflexes. Six eligible trials including 649 patients showed that TPE is effective in the treatment of GBS [9]. In this study, improvement in muscle strength was better and the time required for separation from the ventilator was shorter in the group treated with TPE for 4 weeks. The treatment should begin after the diagnosis. In our study there was only one case with GBS, and we have given intravenous immune globulin as an additional treatment. Partial clinical improvement was observed. Anti-neutrophilic cytoplasmic antibody (ANCA) positivity is seen with some forms of vasculitis such as polyangiitis granulomatoses and microscopic polyangiitis (MPA) [10]. Plasmapheresis should be considered for the patients with renal failure, those who need HD, with severe alveolar hemorrhage and with increasing hemoptysis despite conventional immunosuppressive treatment [11]. In our study there were 18 cases with ANCA-associated vasculitis. One of the 18 patients died due to acute respiratory distress syndrome (ARDS). Nine patients required HD therapy, of whom three patients remained HD dependent despite immunosuppressive treatment combined with TPE. After TPE, pretreatment creatinine levels decreased from 4.25 ± 2.79 mg/dL to 2.66 ± 1.33 mg/dL (p = 0.007). Steroid and cyclophosphamide were used as additional treatment in 13 patients. Complete remission was seen in four patients only. Autoimmune hemolytic anemia (AIHA) is one of the most common causes of acquired hemolytic anemia. Classifications of AIHA include warm AIHA, cold agglutinin syndrome. According to the ASFA criteria, warm autoimmune hemolytic anemia is in category III, and cold agglutinin disease is in category II, indicating a weak evidence [2]. There are case reports on the success of TPE in cases with autoimmune hemolytic anemia [12]. In our study there were six patients with autoimmune hemolytic anemia. One patient required temporary HD. Five TPE sessions were performed to four patients, seven sessions were performed to one patient and one session was performed to one patient. After TPE treatment, pretreatment hemoglobin levels increased from 6.3 ± 1.4 mg/dL to 9.1 ± 1.3 mg/dL (p = 0.028). Pretreatment LDH levels decreased from 842 ± 616 mg/dL to 322 ± 143 mg/dL (p = 0.028). Partial remission was seen in three of patients, complete remission was seen in two patients and one patient died because of sepsis. FSGS is a histologically defined group of glomerular diseases. TPE for FSGS in the native kidneys is used if the nephrotic problems persist despite steroid and other immunosuppressive treatments [13]. In our study there were six patients with FSGS, two patients required HD therapy one of whom remained HD dependent. One patient had complete remission. After TPE treatment there was no
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significant change in creatinine levels. One study reported sustained remission with TPE in conjunction with corticosteroids and cyclophosphamide in 8 of the 11 patients with FSGS [14]. In renal transplant patients, we used TPE for antibody-mediated rejection (AMR), PRA (panel reactive antibody) positivity and recurrence of FSGS after transplantation. There were 26 patients in our study and there was significant difference between creatinine levels before and after the treatment (p = .000). Seven patients required HD therapy and five of them became HD dependent. TTP is characterized by the classic pentad of symptoms that includes microangiopathic hemolytic anemia, thrombocytopenia, fever, neurologic deficits, and renal impairment. For TTP, the main defect is deficiency of the von Willebrand factor cleaving protease, ADAMTS13 [13]. Plasma exchange supplies the deficient ADAMTS13 metalloprotease while removing the inhibitory antibodies. According to the ASFA criteria, it is in category I [2]. HUS is characterized by microangiopathic hemolytic anemia, thrombocytopenia, and acute renal failure [1,2]. In atypical HUS there are mutations in complement factor H (CFH), membrane cofactor protein (MCP), complement factor I (CFI) and thrombomodulin (THBD) in the alternative pathway of complement activation. TPE is used as the treatment of atypical HUS in order to replace the mutated CFH, CFI, CFB (complement factor B) [15]. In our study there were nine patients with TTP, 11 patients with HUS of whom two patients had atypical HUS. Eight of eleven patients with HUS had HD therapy, four of them remained HD dependent and three of them had complete remission. Five of the patients did not need additional treatment. There was significant difference between creatinine levels (p = 0.013), lactate dehydrogenase levels (p = 0.003) and thrombocyte counts (p = 0.004) before and after treatment. None of the nine patients with TTP needed HD therapy. Three (33.3%) of them died and five (55.6%) of them had complete remission. But there was no significant difference before and after treatment in creatinine, LDH and thrombocyte counts. Randomized clinical trials comparing TPE with plasma transfusion in TTP/HUS therapy have shown that TPE was superior even when equal volumes of plasma were used in both procedures [16]. RPGN is one form of presentation of immune complex glomerulonephritis [1,2]. Some of the cases are due to SLE, IgA nephropathy or Henoch–Schönlein nephritis, and some are idiopathic [13]. TPE has got a category III recommendation for immune-complex RPGN by ASFA [2]. In our study, 17 patients had immune complex RPGN and immunosuppressive therapy was also used. Eleven of them required HD and six of them remained dialysis dependent despite immunosuppressive treatment combined with TPE. One of them has complete remission and four of them had no remission. There was significant difference between creatinine before and after treatment (p = 0.006). There are many studies reporting successful results with TPE in immunecomplex mediated RPGN. TPE is more beneficial and better results are achieved in renal function when it is used in combination with immunosuppressive therapy [17]. SLE is a chronic disease that leads to tissue injury with immune complexes, circulating autoantibodies and complement deposition. Renal involvement in SLE (lupus
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nephritis) is associated with high mortality. Lupus nephritis is classified as Category IV by ASFA [2], and a large randomized prospective trial in 1992 showed no benefit from addition of TPE to cyclophosphamide and steroid treatment [18]. But there are multiple case reports that show beneficial effect of TPE in SLE associated TTP or pulmonary hemorrhage, hyperviscosity and cryoglobulinemia [19]. In our study there were two patients with lupus nephritis, one patient required HD and did not recover, the other patient did not need HD and showed partial remission. Multiple myeloma is a neoplastic plasma cell disorder consisting of anemia, a monoclonal protein in serum and/ or urine, abnormal bone radiographs, hypercalcemia and renal insufficiency. Renal failure occurs in 50% of patients with multiple myeloma [1,2]. Myeloma cast nephropathy occurs in patients with high circulating levels of free immunoglobulin light chain concentration in the distal tubular urine (kappa or lambda). According to the ASFA criteria myeloma cast nephropathy was classified as Category II [2]. There are many randomized controlled trials on myeloma cast nephropathy. The recent Mayo Clinic randomized controlled trials showed that TPE used in patients with biopsy proven cast nephropathy, provides 50% reduction of free immunoglobulin light chain and may reverse renal failure and prolong survival [20]. In our study, there were four patients with myeloma cast nephropathy, two of them required hemodialysis and obtained complete remission, one had partial remission and one died. Doxorubicin, vincristine and dexamethasone were used in addition to TPE. The hypertriglyceridemic pancreatitis occurs in the presence of severe hypertriglyceridemia (>1000–2000 mg/dL) [21]. Primary causes are deficiency of lipoprotein lipase (LPL), apoprotein C-II (apo C-II) or familial hypertriglyceridemia and secondary causes are alcohol abuse, diabetes, drugs, pregnancy, hypothyroidism [22]. TPE is used to remove triglyceride-rich lipoproteins from plasma and today this therapeutic approach in the Category III of the ASFA classification is being used in acute hypertriglyceridemic pancreatitis [2]. In 1978, the first use of plasmapheresis hypertriglyceridemia has been reported by Betteridge et al. [23]. In 2003 Yeh et al. reported that TPE was more eligible for the initial treatment of hypertriglyceridemic pancreatitis [24]. Also, there are many cases about pregnant women with hypertriglyceridemic pancreatitis [1,2,6]. In our study there was only one patient with hypertriglyceridemic pancreatitis and her initial triglyceride level was 7500 mg/dL which decreased to 908 mg/dL after three sessions of TPE. Stiff-Person Syndrome (SPS) is a disease characterized by progressive muscle stiffness, rigidity affecting axial and proximal limb muscles. Approximately 90% of patients have antibodies against 65-kD isoform of glutamic acid decarboxylase (GAD) in the serum and/or cerebrospinal fluid [2]. Brashear and Phillips reported that plasmapheresis reduces GAD autoantibodies and provides clinical improvement [25]. In our study there was one patient with Stiff-Person Syndrome who had partial remission with IVIG and six sessions of TPE. According to ASFA criteria, Stiff-Person Syndrome is classified as Category III [2]. Acute liver failure (ALF) is one of the most severe diseases with a mortality rate of 50–90% [2]. It can develop in
a normal liver or in chronic liver disease. Viral hepatitis is the most common reason of ALF in the United States [1,2]. TPE is in the category III according to the ASFA criteria [2]. In our study there was one patient with acute liver failure caused by TTV virus. She had complete remission after two sessions of TPE. In our study there were also patients with neuromyelitis optica (Devic’s syndrome), paraneoplastic neurologic syndromes and chronic inflammatory demyelinating polyradiculoneuropathy. According to ASFA criteria these diseases are classified as Category II [2]. There were only two patients with Devic’s syndrome who showed a partial remission after TPE. Paraneoplastic neurological syndromes are nervous system dysfunctions and seen in 1% of cancer patients [1,2]. An autoimmune etiology has been suspected in these patients. It is classified as category III in the ASFA criteria [2]. In our study group we had two patients, one of them has small cell lung cancer and the other has tumor of unknown origin. Two of them received hemodialysis and remained hemodialysis dependent. One of them had complete remission, the other had partial remission with TPE. Chronic inflammatory demyelinating polyradiculoneuropathy is a motor and sensory neuropathy characterized by proximal and distal symmetrical muscle weakness. Its pathogenesis is defined as both cellular and humoral immune responses to the myelin sheath [26]. TPE is used as the treatment of the disease and it is classified as category I in the ASFA criteria [2]. There were three cases in our study, two of them received steroid and one of them received steroid and IVIG additionally. After average 5.3 TPE sessions they obtained partial remission. 5. Conclusion In conclusion TPE by membrane separation technique is a useful and readily available treatment option with new emerging areas of therapeutic application. In this study we showed that when its indications and patients were selected correctly with a skilled and experienced team, TPE is an effective life-saving therapeutic intervention which can be used in heterogeneous groups of diseases. It is our hope that this study can contribute to improving the efficacy of TPE. New research will be useful for effective utilization of these therapies. References [1] Szczepiorkowski ZM, Winters JL, Bandarenko N, Kim HC, Linenberger ML, Marques MB, et al. Guidelines on the use of therapeutic apheresis in clinical practice-evidence-based approach from the Apheresis Applications Committee of the American Society for Apheresis. J Clin Apher 2010;25(3):83–177. [2] Schwartz J, Winters JL, Padmanabhan A, Balogun RA, Delaney M, Linenberger ML, 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 sixth special issue. J Clin Apher 2013;28(3):145–284. [3] Nakanishi T, Suzuki N, Kuragano T, Nagasawa Y, Hasuike Y. Current topics in therapeutic plasmapheresis. Clin Exp Nephrol 2014;18(1):41–9. [4] Aydin Z, Gursu M, Karadag S, Uzun S, Tatli E, Sumnu A, et al. Role of plasmapheresis performed in hemodialysis units for the treatment of anti-neutrophilic cytoplasmic antibody-associated systemic vasculitides. Ther Apher Dial 2011;15(5):493–8.
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[5] Rufino Hernández M, Escamilla Cabrera B, Alvarez Sosa D, García Rebollo S, Losada Cabrera M, Hernández Marrero D, et al. Patients treated with plasmapheresis: a case review from University Hospital of the Canary Islands. Nefrologia 2011;31(4):415–34. [6] Eren G, Çukurova Z, Kucur E, Kendir V, Gezmis C, Kozanhan B, et al. Yoğun bakım ünitemizde çeşitli endikasyonlarla uyguladığımız terapötik plazmaferez deneyimlerimiz. Turkiye Klinikleri J Med Sci 2010;30(5):1683–9. [7] McLeod BC. Plasma and plasma derivatives in therapeutic plasmapheresis. Transfusion 2012;52:38S–44S. [8] Haddad S, Leitman SF, Wesley RA, Cecco S, Yau YY, Starling J, et al. Placebo-controlled study of intravenous magnesium supplementation during large-volume leukapheresis in healthy allogeneic donors. Transfusion 2005;45(6):934–44. [9] Hughes RA. Systematic reviews of treatment for inflammatory demyelinating neuropathy. J Anat 2002;200(4):331–9. [10] Hoffman GS, Kerr GS, Leavitt RY, Hallahan CW, Lebovics RS, Travis WD, et al. Wegener granulomatosis: an analysis of 158 patients. Ann Intern Med 1992;116(6):488–98. [11] Jayne DR, Gaskin G, Rasmussen N, Abramowicz D, Ferrario F, Guillevin L, et al. Randomized trial of plasma exchange or high-dosage methylprednisolone as adjunctive therapy for severe renal vasculitis. J Am Soc Nephrol 2007;18(7):2180–8. [12] Takahashi T, Hara T, Shimomura Y, Yoshikawa T, Tomita E. Plasmapheresis for fulminant autoimmune hemolytic anemia with rapidly progressing disturbance of consciousness. Rinsho Ketsueki 2006;47(8):787–9. [13] Sanchez AP, Ward DM. Therapeutic apheresis for renal disorders. Semin Dial 2012;25(2):119–31. [14] Mitwalli AH. Adding plasmapheresis to corticosteroids and alkylating agents: does it benefit patients with focal segmental glomerulosclerosis? Nephrol Dial Transplant 1998;13(6):1524–8. [15] Clark, WF. Plasma exchange for renal disease: evidence and use 2011. Clin Apher 2012;27(3):112–6.
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[16] Von Baeyer H. Plasmapheresis in thrombotic microangiopathyassociated syndromes: review of outcome data derived from clinical trials and open studies. Ther Apher 2002;6(4):320–8. [17] Harada T, Ozono Y, Miyazaki M. Plasmapheresis in the treatment of rapidly progressive glomerulonephritis. Ther Apher 1997;1(4): 366–9. [18] Lewis EJ, Hunsicker LG, Lan SP, Rohde RD, Lachin JM. A controlled trial of plasmapheresis therapy in severe lupus nephritis. The Lupus Nephritis Collaborative Study Group. N Engl J Med 1992;326(21): 1373–9. [19] Pagnoux C. Plasma exchange for systemic lupus erythematosus. Transfus Apher Sci 2007;36(2):187–93. [20] Leung N, Gertz MA, Zeldenrust SR, Rajkumar SV, Dispenzieri A, Fervenza FC, et al. Improvement of cast nephropathy with plasma exchange depends on the diagnosis and on reduction of serum free light chains. Kidney Int 2008;73(11):1282–8. [21] Steinberg W, Tenner S. Acute pancreatitis. N Engl J Med 1994; 330(17):1198–210. [22] Yadav D, Pitchumoni CS. Issues in hyperlipidemic pancreatitis. J Clin Gastroenterol 2003;36(1):54–62. [23] Betteridge DJ, Bakowski M, Taylor KG, Reckless JP, de Silva SR, Galton DJ. Treatment of severe diabetic hypertriglyceridaemia by plasma exchange. Lancet 1978;1(8078):1368. [24] Yeh JH, Lee MF, Chiu HC. Plasmapheresis for severe lipemia: comparison of serum-lipid clearance rates for the plasmaexchange and double-filtration variants. J Clin Apher 2003;18(1): 32–6. [25] Brashear HR, Phillips LH. Autoantibodies to GABAergic neurons and response to plasmapheresis in stiff-man syndrome. Neurology 1991;41(10):1588–92. [26] Iijima M. Topics of chronic inflammatory demyelinating polyradiculoneuropathy – diagnosis and treatment situation in Japan. Rinsho Byori 2013;61(5):407–13.
Contents lists available at ScienceDirect
Transfusion and Apheresis Science j o u r n a l h o m e p a g e : w w w. e l s e v i e r. c o m / l o c a t e / t r a n s c i
Patients treated with therapeutic plasma exchange: A single center experience Nilay Sengul Samanci a,*, Mesut Ayer b, Meltem Gursu c, Muhlis Cem Ar d, Kubra Yel a, Abdulkadir Ergen a, Elif Ece Dogan a, Serhat Karadag c, Egemen Cebeci c, Mehmet Toptas e, Rumeyza Kazancioglu f, Savas Ozturk c a
Department of Internal Medicine, Haseki Training and Research Hospital, Istanbul, Turkey Department of Hematology, Haseki Training and Research Hospital, Istanbul, Turkey Department of Nephrology, Haseki Training and Research Hospital, Istanbul, Turkey d Department of Hematology, Istanbul University Cerrahpasa Medical Faculty, Istanbul, Turkey e Department of Intensive Care Medicine, Haseki Training and Research Hospital, Istanbul, Turkey f Department of Nephrology, Bezmialem Vakif University Medical Faculty, Istanbul, Turkey b c
A R T I C L E
I N F O
Article history: Received 19 July 2014 Accepted 6 October 2014 Keywords: Plasma exchange Hemodialysis Fresh frozen plasma Hemodiafiltration Plasma volume
A B S T R A C T
Introduction: Therapeutic Plasma Exchange (TPE) is a therapeutic procedure that is used to remove high molecular weight substances from plasma. We analyzed data of patients who received TPE during the last 7 years, and focused on the efficiency of TPE in various disease groups. Material and Methods: We studied 110 patients treated with TPE by membrane plasma separation technique from 2007 to 2013. We examined the demographic data, underlying disease, biochemical parameters, volume and type of replacement fluid, complications, concomitant treatment, the need for hemodialysis and number of TPE sessions. Results: One hundred ten patients, 58 male, 52 female were included. The mean age was 47.3 ± 17.6 years. A total of 734 TPE sessions were performed and the mean number of TPE sessions per patient was 6.6 ± 4.3. The underlying disease was renal transplantation in 26 patients, ANCA-associated vasculitis in 18, rapidly progressive glomerulonephritis in 17, hemolytic uremic syndrome in 11, thrombotic thrombocytopenic purpura in 9, autoimmunic hemolytic anemia in 6, focal segmental glomerulosclerosis in 6 and other diseases. Partial and complete remission was obtained in 65 (59.1%) and 24 patients (21.8%) respectively, while 14 (12.7%) patients had no response and 7 (6.4%) patients died. Complications were muscle cramps (6.4%), allergic reactions (4.5%), severe hypotension (3.6%), fever (1.8%), unconsciousness (0.9%), leukopenia (0.9%) and catheter related hematoma (0.9%). Conclusion: According to our 7 years of experience in TPE, we can say that therapeutic plasma exchange by membrane separation technique is a useful, easy, available and effective lifesaving therapeutic treatment. © 2014 Elsevier Ltd. All rights reserved.
1. Introduction Therapeutic plasma exchange (TPE) is a therapeutic procedure in which the blood of the patient is passed through
* Corresponding author. Department of Internal Medicine, Haseki Training and Research Hospital, Istanbul, Turkey. Tel.: +90 2125294400/ 1709; fax: +90 2125294463. E-mail address: [email protected] (N. Sengul Samanci). http://dx.doi.org/10.1016/j.transci.2014.10.006 1473-0502/© 2014 Elsevier Ltd. All rights reserved.
a medical apparatus which extracts high molecular weight substances such as immune complexes, endotoxins, myeloma light chains, autoantibodies, lipoproteins, cryoglobulins from the plasma in exchange for a replacement solution such as albumin or fresh frozen plasma [1,2]. Plasma exchange has been used mainly for two purposes: removing high molecular weight substances like antibodies, immune complexes, etc. from the plasma and supplementing plasma with the missing essential factors [3]. It is indicated for various renal, hematological, rheumatologic, neurological, oncological,
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nephrological and multisystemic diseases usually in conjunction with classical medical therapy. TPE can be made by cytocentrifuge or membrane separation techniques. Especially membrane separation technique applied with hemodiafiltration equipment has gained increasing popularity because of being a relatively easy procedure. Furthermore it does not require a separate unit, device or hospitalization [4]. Herein, we retrospectively analyzed the performance and efficiency of TPE in various disease groups. 2. Material and Methods In this study we retrospectively analyzed 110 patients treated with TPE between January 2007 and December 2013 in our hospital by membrane separation technique. Patient files were reviewed and data on demographic data (age, sex), underlying disease, biochemical parameters, volume and the type of replacement fluid used for TPE (human albumin and/ or fresh frozen plasma), complications related with the procedure, concomitant immunosuppressive treatment, concurrent hemodialysis (HD) requirement, and the number of TPE sessions were collected. The laboratory results before and after each TPE session were also recorded. All patients had given written consent before the TPE procedure. 2.1. Procedure Plasmapheresis was performed using a Prismaflex machine (Gambro, Lund, Sweden) via double lumen HD catheter placed to all patients. Hemodynamic parameters were monitored throughout the procedure. The patient’s plasma volume was calculated using the following formula: plasma volume (L) = weight × 0.065 × (1 − hematocrit) [4]. Twenty percent human albumin (diluted to 5% albumin in isotonic saline) and/or fresh frozen plasma (FFP) were used as the replacement fluid. 2.2. Indication of TPE The indications of TPE were principally based on the relevant guideline of the American Society for Apheresis (ASFA). Requirement of additional treatment and/or HD was predicated by the underlying disease [1,2]. 2.3. Response to treatment The response to treatment was graded as partial, complete or none. Resolution of all the pathological clinical and laboratory findings following adequate number of TPE was defined as complete response. Patients with no improvement in clinical and laboratory findings after at least five TPE sessions or patients with an initial response in whom cessation of TPE led to a prompt recurrence of the disease were identified as non-responders. Partial response includes clinical and laboratory results not fitting into both of the aforementioned categories. 2.4. Statistical analysis Descriptive and comparative studies were done using SPSS for Windows, Version 20.0 (SPSS Inc., Chicago, IL, USA).
Wilcoxon Signed Rank Test was used to compare laboratory parameters before and after treatment. P-value was accepted as statistically significant if it was less than 0.05.
3. Results Over a period of 7 years, 110 patients [58 male (52.7%) and 52 female (47.3%)] received TPE. The mean age was 47.3 ± 17.6 years (range: 19–86 years). A total of 734 TPE sessions were performed and the mean number of TPE sessions per patient was 6.6 ± 4.3 (range: 1–25) sessions. Fifty percent of the patients required daily therapy while 50% received TPE every other day. The replacement fluid used was FFP in 83 patients (75.5%), albumin in 13 patients (11.8%) and the combination of both in 14 patients (12.7%) (Fig. 1). The indication for TPE was renal transplantation in 26 patients (23.6%), ANCA-associated vasculitis in 18 (16.4%), rapidly progressive glomerulonephritis in 17 (15.5%), hemolytic uremic syndrome (HUS) in 11 (10%), thrombotic thrombocytopenic purpura (TTP) in 9 (8.2%), autoimmune hemolytic anemia in 6 (5.5%), focal segmental glomerulosclerosis (FSGS) in 6 (5.5%), multiple myeloma in 4 (3.6%) chronic inflammatory demyalinating polyradiculoneuropathy in 3 (2.7%), systemic lupus erythematosus (SLE) in 2 (1.8%), paraneoplastic neurologic syndromes in 2 (1.8%), Devic’s syndrome in 2 (1.8%), Stiff-person syndrome in 1 (0.9%), hypertriglyceridemic pancreatitis in 1 (0.9%), acute liver failure in 1 (0.9%) and Guillain–Barré Syndrome in 1 patient (0.9%). Table 1 displays the biochemical test results of the patients recorded before and after TPE. All of the patients with paraneoplastic neurological syndromes (n = 2), 8 (72.7%) of patients with HUS, 11 (64.7%) of patients with RPGN, 2 (50%) of the patients with multiple myeloma, 1 (50%) of the patients with SLE, 7 (26.9%) of patients with renal transplantation, 9 (50%) of patients with ANCA-associated vasculitis concurrently required HD at the time of diagnosis. TPE and HD were usually done on alternate days. All the patients with paraneoplastic neurologic syndromes, 23.1% patients with renal transplantation, 35.3% patients with RPGN, 36.4% patients with HUS, 16.7% patients with ANCAassociated vasculitis, 50% patients with SLE, 16.7% patients with FSGS and 25% patients with multiple myeloma remained HD dependent. None of the patients with TTP required HD at the time of diagnosis. Additional treatment with steroids, cyclophosphamide etc. was noted in 62.7% of the patients. Sixty-five (59.1%) patients had partial and 24 (21.8%) had complete remission, while 14 (12.7%) had no remission and 7 (6.4%) patients died during the treatment period. Outcome of the patients according to the primary disease is presented in Table 2. The cause of death was acute respiratory failure in five, sepsis and multi organ failure in two of the patients. There were no deaths related to the TPE procedure itself. Complications of the procedure included hypocalcemia induced muscle cramps (n = 7, 6.4%), allergic reactions (n = 5, 4.5%), hypotension (n = 4, 3.6%), fever (n = 2, 1.8%), loss of consciousness (n = 1, 0.9%), leukopenia (n = 1, 0.9%) and catheter related hematoma (n = 1, 0.9%). No complications were observed in 80.9% of patients. No catheter related infection was observed. A significant decrease was found in the creatinine levels before
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Fig. 1. Replacement fluids used.
and after TPE in patients with renal transplantation (p < 0.001), RPGN (p = 0.006), HUS (p = 0.013), autoimmune hemolytic anemia (p = 0.043) and ANCA-associated vasculitis (p = 0.007). There was a statistically significant fall in lactate dehydrogenase levels in patients with HUS (p = 0.003) and autoimmune hemolytic anemia (p = 0.028) and platelet levels increased after TPE in patients with HUS (p = 0.004).
4. Discussion Therapeutic plasma exchange is a procedure in which a predetermined amount of plasma with its constituents, mainly high molecular weight substances, are removed, and replaced by a replacement solution [5]. TPE is used for some diseases in which conventional therapy is not sufficient to control the disease progression. In our hospital, TPE has been
Table 1 Biochemical analysis of the patients before and after TPE.
9/L)
WBC count (10 Neutrophil (109/L) Hemoglobin (g/dL) Hematocrit (%) Platelets (109/L) Creatinine (mg/dL) LDH (U/L) Albumin (g/dL) Ca (mg/dL) ALT (U/L) AST (U/L) ALP (U/L) GGT (U/L) Na (mEq/L) K (mEq/L) CL (mEq/L) CRP (mg/L) 24-hour urine protein (mg)
n
Before TPE (Mean ± SD)
After TPE (Mean ± SD)
p
106 108 108 108 108 110 108 110 108 110 110 66 53 108 108 107 24 34
10482 ± 7162 7073 ± 5399 9.57 ± 2.48 28.69 ± 7.72 237 ± 147 3.95 ± 2.87 381 ± 321 3.35 ± 0.68 8.76 ± 1.01 27.95 ± 38.66 37.39 ± 57.36 133.02 ± 341.33 53.63 ± 65.88 137.01 ± 4.83 4.37 ± 0.72 102.09 ± 4.34 72.33 ± 77.53 3871 ± 4162
8959 ± 4459 6044 ± 3786 9.84 ± 2.92 31.64 ± 26.75 240 ± 228 2.61 ± 2.05 274 ± 237 3.62 ± 0.43 10.00 ± 12.55 25.02 ± 18.51 24.70 ± 22.43 83.42 ± 67.31 67.33 ± 88.70 138.15 ± 3.46 4.40 ± 0.80 101.42 ± 9.68 5.09 ± 13.40 3632 ± 3804
0.015 0.018 0.320 0.259 0.901 0.000 0.000 0.001 0.309 0.405 0.024 0.298 0.640 0.023 0.762 0.493 0.000 0.006
LDH: lactate dehydrogenase, Ca: calcium, ALT: alanine transaminase, AST: aspartate transaminase, ALP: alkaline phosphatase, GGT: gama glutamyl transferase, Na: sodium, K: potassium, CL: chlorine, CRP: C-reactive protein, SD: standard deviation, WBC: white blood cell; n: number of patients.
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Table 2 Outcome of the patients according to the primary disease. n
Multiple myeloma
4
Renal transplantation
26
RPGN
17
HUS
11
TTP
9
Autoimmune hemolytic anemia
6
ANCA-associated vasculitis
18
SLE
2
Hypertriglyceridemic pancreatitis Acute liver failure Paraneoplastic neurologic syndromes Guillain–Barré Syndrome Devic’s syndrome
1 1 2 1 2
Chronic inflammatory demyalinating polyradiculoneuropathy Stiff-person syndrome FSGS
3 1 6
Additional treatment(n)
Outcome (n)
None (1) VAD (2) BD (1) None (16) Pred + MMF + CI (4) Pred + Cy (2) Rituximab (1) Pred + CI (1) Pred (1) IVIG (1) None (3) Pred + Cy (9) Pred (2) Vertebral RT (1) Pred + chloroquine + IVIG + Cy (1) Pred + IVIG (1) None (5) Pred (3) Pred + Cy (2) Pred + IVIG (1) None (6) Pred + Vincristine (1) Pred (2) Pred (3) Pred + Splenectomy (1) Pred + IVIG (1) IVIG (1) None (1) Pred + Cy (13) Pred + IVIG (2) Pred (1) Pred + IVIG + Cy (1) Pred + Cy (1) Pred + IVIG (1) None None None IVIG (1) Pred (1) Pred + Cy (1) Pred (2) Pred + IVIG (1) IVIG (1) None (5) Pred (1)
Complications (n)
HD (n)
1
None (3) Hypotension (1)
No (2) Chronic (1)
4
1
None (20) Allergic reaction (3) Muscle cramps (1) Leucopenia (1) Hypotension (1)
No (19) Chronic (6)
1
4
0
None (14) Muscle cramps (2) Allergic reaction (1)
No (6) Chronic (6) Temporary (5)
7
3
1
0
No (3) Chronic (4) is Temporary (4)
1
5
0
3
3
2
0
1
None (8) Allergic reaction (1) Catheter related (1) Fever (1) None (6) Hypotension (1) Fever (1) Loss of consciousness (1) None (4) Muscle cramps (1) Hypotension (1)
11
4
2
1
None (16) Muscle cramps (2)
No (9) Chronic (3) Temporary (5)
1
0
1
0
None (2)
0 0 0 1 2
1 1 1 0 0
0 0 1 0 0
0 0 0 0 0
None None None None None
No (1) Chronic (1) No No Chronic (2) No No
3
0
0
0
1 4
0 1
0 1
0 0
None (2) Muscle cramps (1) None None
PR
CR
NoR
Died
1
2
0
18
3
12
No (9)
No (5) Temporary (1)
No No No (4) Chronic (1) Temporary (1)
RPGN: rapidly progressive glomerulonephritis, HUS: hemolytic uremic syndrome, TTP: thrombotic thrombocytopenic purpura, SLE: systemic lupus erythematosus, FSGS: focal segmental glomerulosclerosis, VAD: vincristine, doxorubicin, dexamethasone, BD: bortezomib, dexamethasone, HD: hemodialysis, PR: partial remission, CR: complete remission, NoR: no response, n: number of patients, Pred: prednisolone, MMF: mycophenolate mofetil, CI: calcineurin inhibitors, Cy: cyclophosphamide, IVIG: intravenous immunoglobulin, RT: radiotherapy.
performed by a hemodiafiltration machine using membrane separation technique. For membrane separation technique, there is a need for a large bore catheter or arteriovenous fistula to obtain effective blood flow. We used double lumen HD catheters inserted into femoral or internal jugular vein if the patient had no arteriovenous fistula. Catheter related complication rate was low due to routine use of ultrasound guidance [6]. Five percent human serum albumin solution is preferred in most cases as the replacement fluid. However, long term use of albumin may lead to temporary deficiency of plasma proteins, mainly coagulation factors. FFP has the po-
tential of causing febrile or allergic reactions and viral contamination while this risk is negligible for albumin. FFP has the advantage of containing all the plasma proteins including coagulation factors and complement components which are critical in the treatment of TTP and in the presence of coagulopathy [7]. Hypocalcaemia is the major complication due to the presence of anticoagulant citrate in the replacement fluid [8]. Therefore, patients should receive 10% calcium gluconate intravenous infusions during the procedure as needed. Depending on the type of disease to be treated, FFP, albumin solutions or the combination of both can be used. With current available techniques, very
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few and mild side effects are seen during TPE. These are bradycardia, hypotension, pallor, nausea, vomiting, paresthesia, muscle cramps, fever, allergic reactions, unconsciousness, leukopenia and catheter related complications [6]. Some of these complications were observed in 21 of our patients. The evidence is of high quality regarding the TPE indication in Guillain–Barré syndrome, TTP-HUS, ANCAassociated vasculitis. Guillain–Barré syndrome (GBS) is a subacute immune-mediated polyneuropathy. It is characterized by progressive symmetric flaccid paralysis and loss of deep tendon reflexes. Six eligible trials including 649 patients showed that TPE is effective in the treatment of GBS [9]. In this study, improvement in muscle strength was better and the time required for separation from the ventilator was shorter in the group treated with TPE for 4 weeks. The treatment should begin after the diagnosis. In our study there was only one case with GBS, and we have given intravenous immune globulin as an additional treatment. Partial clinical improvement was observed. Anti-neutrophilic cytoplasmic antibody (ANCA) positivity is seen with some forms of vasculitis such as polyangiitis granulomatoses and microscopic polyangiitis (MPA) [10]. Plasmapheresis should be considered for the patients with renal failure, those who need HD, with severe alveolar hemorrhage and with increasing hemoptysis despite conventional immunosuppressive treatment [11]. In our study there were 18 cases with ANCA-associated vasculitis. One of the 18 patients died due to acute respiratory distress syndrome (ARDS). Nine patients required HD therapy, of whom three patients remained HD dependent despite immunosuppressive treatment combined with TPE. After TPE, pretreatment creatinine levels decreased from 4.25 ± 2.79 mg/dL to 2.66 ± 1.33 mg/dL (p = 0.007). Steroid and cyclophosphamide were used as additional treatment in 13 patients. Complete remission was seen in four patients only. Autoimmune hemolytic anemia (AIHA) is one of the most common causes of acquired hemolytic anemia. Classifications of AIHA include warm AIHA, cold agglutinin syndrome. According to the ASFA criteria, warm autoimmune hemolytic anemia is in category III, and cold agglutinin disease is in category II, indicating a weak evidence [2]. There are case reports on the success of TPE in cases with autoimmune hemolytic anemia [12]. In our study there were six patients with autoimmune hemolytic anemia. One patient required temporary HD. Five TPE sessions were performed to four patients, seven sessions were performed to one patient and one session was performed to one patient. After TPE treatment, pretreatment hemoglobin levels increased from 6.3 ± 1.4 mg/dL to 9.1 ± 1.3 mg/dL (p = 0.028). Pretreatment LDH levels decreased from 842 ± 616 mg/dL to 322 ± 143 mg/dL (p = 0.028). Partial remission was seen in three of patients, complete remission was seen in two patients and one patient died because of sepsis. FSGS is a histologically defined group of glomerular diseases. TPE for FSGS in the native kidneys is used if the nephrotic problems persist despite steroid and other immunosuppressive treatments [13]. In our study there were six patients with FSGS, two patients required HD therapy one of whom remained HD dependent. One patient had complete remission. After TPE treatment there was no
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significant change in creatinine levels. One study reported sustained remission with TPE in conjunction with corticosteroids and cyclophosphamide in 8 of the 11 patients with FSGS [14]. In renal transplant patients, we used TPE for antibody-mediated rejection (AMR), PRA (panel reactive antibody) positivity and recurrence of FSGS after transplantation. There were 26 patients in our study and there was significant difference between creatinine levels before and after the treatment (p = .000). Seven patients required HD therapy and five of them became HD dependent. TTP is characterized by the classic pentad of symptoms that includes microangiopathic hemolytic anemia, thrombocytopenia, fever, neurologic deficits, and renal impairment. For TTP, the main defect is deficiency of the von Willebrand factor cleaving protease, ADAMTS13 [13]. Plasma exchange supplies the deficient ADAMTS13 metalloprotease while removing the inhibitory antibodies. According to the ASFA criteria, it is in category I [2]. HUS is characterized by microangiopathic hemolytic anemia, thrombocytopenia, and acute renal failure [1,2]. In atypical HUS there are mutations in complement factor H (CFH), membrane cofactor protein (MCP), complement factor I (CFI) and thrombomodulin (THBD) in the alternative pathway of complement activation. TPE is used as the treatment of atypical HUS in order to replace the mutated CFH, CFI, CFB (complement factor B) [15]. In our study there were nine patients with TTP, 11 patients with HUS of whom two patients had atypical HUS. Eight of eleven patients with HUS had HD therapy, four of them remained HD dependent and three of them had complete remission. Five of the patients did not need additional treatment. There was significant difference between creatinine levels (p = 0.013), lactate dehydrogenase levels (p = 0.003) and thrombocyte counts (p = 0.004) before and after treatment. None of the nine patients with TTP needed HD therapy. Three (33.3%) of them died and five (55.6%) of them had complete remission. But there was no significant difference before and after treatment in creatinine, LDH and thrombocyte counts. Randomized clinical trials comparing TPE with plasma transfusion in TTP/HUS therapy have shown that TPE was superior even when equal volumes of plasma were used in both procedures [16]. RPGN is one form of presentation of immune complex glomerulonephritis [1,2]. Some of the cases are due to SLE, IgA nephropathy or Henoch–Schönlein nephritis, and some are idiopathic [13]. TPE has got a category III recommendation for immune-complex RPGN by ASFA [2]. In our study, 17 patients had immune complex RPGN and immunosuppressive therapy was also used. Eleven of them required HD and six of them remained dialysis dependent despite immunosuppressive treatment combined with TPE. One of them has complete remission and four of them had no remission. There was significant difference between creatinine before and after treatment (p = 0.006). There are many studies reporting successful results with TPE in immunecomplex mediated RPGN. TPE is more beneficial and better results are achieved in renal function when it is used in combination with immunosuppressive therapy [17]. SLE is a chronic disease that leads to tissue injury with immune complexes, circulating autoantibodies and complement deposition. Renal involvement in SLE (lupus
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nephritis) is associated with high mortality. Lupus nephritis is classified as Category IV by ASFA [2], and a large randomized prospective trial in 1992 showed no benefit from addition of TPE to cyclophosphamide and steroid treatment [18]. But there are multiple case reports that show beneficial effect of TPE in SLE associated TTP or pulmonary hemorrhage, hyperviscosity and cryoglobulinemia [19]. In our study there were two patients with lupus nephritis, one patient required HD and did not recover, the other patient did not need HD and showed partial remission. Multiple myeloma is a neoplastic plasma cell disorder consisting of anemia, a monoclonal protein in serum and/ or urine, abnormal bone radiographs, hypercalcemia and renal insufficiency. Renal failure occurs in 50% of patients with multiple myeloma [1,2]. Myeloma cast nephropathy occurs in patients with high circulating levels of free immunoglobulin light chain concentration in the distal tubular urine (kappa or lambda). According to the ASFA criteria myeloma cast nephropathy was classified as Category II [2]. There are many randomized controlled trials on myeloma cast nephropathy. The recent Mayo Clinic randomized controlled trials showed that TPE used in patients with biopsy proven cast nephropathy, provides 50% reduction of free immunoglobulin light chain and may reverse renal failure and prolong survival [20]. In our study, there were four patients with myeloma cast nephropathy, two of them required hemodialysis and obtained complete remission, one had partial remission and one died. Doxorubicin, vincristine and dexamethasone were used in addition to TPE. The hypertriglyceridemic pancreatitis occurs in the presence of severe hypertriglyceridemia (>1000–2000 mg/dL) [21]. Primary causes are deficiency of lipoprotein lipase (LPL), apoprotein C-II (apo C-II) or familial hypertriglyceridemia and secondary causes are alcohol abuse, diabetes, drugs, pregnancy, hypothyroidism [22]. TPE is used to remove triglyceride-rich lipoproteins from plasma and today this therapeutic approach in the Category III of the ASFA classification is being used in acute hypertriglyceridemic pancreatitis [2]. In 1978, the first use of plasmapheresis hypertriglyceridemia has been reported by Betteridge et al. [23]. In 2003 Yeh et al. reported that TPE was more eligible for the initial treatment of hypertriglyceridemic pancreatitis [24]. Also, there are many cases about pregnant women with hypertriglyceridemic pancreatitis [1,2,6]. In our study there was only one patient with hypertriglyceridemic pancreatitis and her initial triglyceride level was 7500 mg/dL which decreased to 908 mg/dL after three sessions of TPE. Stiff-Person Syndrome (SPS) is a disease characterized by progressive muscle stiffness, rigidity affecting axial and proximal limb muscles. Approximately 90% of patients have antibodies against 65-kD isoform of glutamic acid decarboxylase (GAD) in the serum and/or cerebrospinal fluid [2]. Brashear and Phillips reported that plasmapheresis reduces GAD autoantibodies and provides clinical improvement [25]. In our study there was one patient with Stiff-Person Syndrome who had partial remission with IVIG and six sessions of TPE. According to ASFA criteria, Stiff-Person Syndrome is classified as Category III [2]. Acute liver failure (ALF) is one of the most severe diseases with a mortality rate of 50–90% [2]. It can develop in
a normal liver or in chronic liver disease. Viral hepatitis is the most common reason of ALF in the United States [1,2]. TPE is in the category III according to the ASFA criteria [2]. In our study there was one patient with acute liver failure caused by TTV virus. She had complete remission after two sessions of TPE. In our study there were also patients with neuromyelitis optica (Devic’s syndrome), paraneoplastic neurologic syndromes and chronic inflammatory demyelinating polyradiculoneuropathy. According to ASFA criteria these diseases are classified as Category II [2]. There were only two patients with Devic’s syndrome who showed a partial remission after TPE. Paraneoplastic neurological syndromes are nervous system dysfunctions and seen in 1% of cancer patients [1,2]. An autoimmune etiology has been suspected in these patients. It is classified as category III in the ASFA criteria [2]. In our study group we had two patients, one of them has small cell lung cancer and the other has tumor of unknown origin. Two of them received hemodialysis and remained hemodialysis dependent. One of them had complete remission, the other had partial remission with TPE. Chronic inflammatory demyelinating polyradiculoneuropathy is a motor and sensory neuropathy characterized by proximal and distal symmetrical muscle weakness. Its pathogenesis is defined as both cellular and humoral immune responses to the myelin sheath [26]. TPE is used as the treatment of the disease and it is classified as category I in the ASFA criteria [2]. There were three cases in our study, two of them received steroid and one of them received steroid and IVIG additionally. After average 5.3 TPE sessions they obtained partial remission. 5. Conclusion In conclusion TPE by membrane separation technique is a useful and readily available treatment option with new emerging areas of therapeutic application. In this study we showed that when its indications and patients were selected correctly with a skilled and experienced team, TPE is an effective life-saving therapeutic intervention which can be used in heterogeneous groups of diseases. It is our hope that this study can contribute to improving the efficacy of TPE. New research will be useful for effective utilization of these therapies. References [1] Szczepiorkowski ZM, Winters JL, Bandarenko N, Kim HC, Linenberger ML, Marques MB, et al. Guidelines on the use of therapeutic apheresis in clinical practice-evidence-based approach from the Apheresis Applications Committee of the American Society for Apheresis. J Clin Apher 2010;25(3):83–177. [2] Schwartz J, Winters JL, Padmanabhan A, Balogun RA, Delaney M, Linenberger ML, 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 sixth special issue. J Clin Apher 2013;28(3):145–284. [3] Nakanishi T, Suzuki N, Kuragano T, Nagasawa Y, Hasuike Y. Current topics in therapeutic plasmapheresis. Clin Exp Nephrol 2014;18(1):41–9. [4] Aydin Z, Gursu M, Karadag S, Uzun S, Tatli E, Sumnu A, et al. Role of plasmapheresis performed in hemodialysis units for the treatment of anti-neutrophilic cytoplasmic antibody-associated systemic vasculitides. Ther Apher Dial 2011;15(5):493–8.
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