The Clinical Study On Selected Plasmapheresis For Treatment Of Non-renal Diseases

Background:The blood purification technology, which originates from the dialysis of kidney diseases but has gone beyond the traditional concept of the treatment of uremia and multiple organ failure, is widely used in non-renal diseases. In particular, the plasma exchange technology is often used in autoimmune disease, hyperlipidemia, hyperbilirubinemia and rhabdomyolysis syndrome.To achieve therapeutic effects, plasmapheresis including plasma exchange, double filtration plasmapheresis, cryofiltration, immunoadsorption plasmapheresis, cytapheresis, etc. was used to remove related pathogenic substances in the blood by the technology of centrifugal separation, membrane separation or adsorption separation. Through development of nearly 50 years, this therapy has been widely used in a variety of diseases, especially some immune related diseases, including rheumatoid arthritis, systemic lupus erythematosus, dermatomyositis and other immune related diseases such as multiple sclerosis, graft rejection, acute and chronic renal failure, Guillain Barre syndrome, etc. Recently, some new researches found that immunoadsorption was also effective for treatment of some severe diseases, such as hypertrophic cardiomyopathy, refractory hypertension, refractory heart failure, severe liver disease, severe acute pancreatitis, etc.Selective plasma separation mainly utilizes double filtration. Theoretically, any substances with particle sizes between apertures of first-level membrane and second-level membrane may be removed.In order to remove large particles which are cut off by the second-level membrane in the plasma, the choice of second-level membrane is critical. In fact, a part of small molecular protein may lose because of closure. The ability of going through the membrane is represented by sieve coefficient. For example, the sieve coefficients of CE-50W on the albumin (Alb) and cholesterol are 0.87 and 0.43 respectively. With EC-50W as second-level membrane, more albumin and high density lipoprotein and other useful components would through the second-level membrane and be loosed fewer, reducing the loss of beneficial ingredients of treatment.With the applications of Plasmapheresis in autoimmune rheumatic diseases, many pathological agents, such as anomaly antibody, circulating immune complexes, complement, inflammatory mediators in blood circulation, or the immune cells, such as lymphocytes and neutrophils can be effectively removed. So it was used for treatment of various immune related diseases, including traditional glomerulonephritis, vasculitis, rheumatics and other immune related diseases. Rheumatoid arthritis, lupus erythematosus (SLE), vasculitis, systemic or multiple sclerosis, Sjogren syndrome, dermatomyositis, scleroderma, etc., which are caused by autoimmune dysfunction, are common indications of immune purification therapy. In 2002, the American College of Rheumatology brings the immune adsorption into the guidelines for the treatment of rheumatoid arthritis. The applications of plasmapheresis in acute inflammatory diseases can remove the pathogenic components in a safe, fast and effective way, and play a role in rapid relief of the progress of the diseases and improve the efficacy of medications, especially in the treatment of severe liver disease, severe chronic humoral rejection, severe acute pancreatitis and severe acute hemolysis, etc. Our preliminary study shown that plasma purification was also effective on treatment of idiopathic interstitial fibrosis in pulmonary.Refractory hyperlipidemia, which is difficult to be controlled with drugs, is often an important cause of recurrent pancreatitis and atherosclerosis, both of which can cause serious or even fatal consequences. In vivo, triglyceride mainly exists in the larger particles, such as chylomicrons (MC), very low density lipoprotein (VLDL), intermediate density lipoprotein (IDL), while cholesterol mainly exists in the smaller particles, such as IDL, low density lipoprotein (LDL), high density lipoprotein (HDL). Therefore, triglyceride is easier to be removed than cholesterol through the selective plasma separation technique. Some of our observed results also verify this theory, which show that selective separation of plasma treatment is more suitable for hypertriglyceridemia patients.Objective:By optimizing combination of plasma separation technology, to establish a blood product saving treatment solution with high specificity, good effects and high safety coefficient. On one hand, the cost of treatment and the pressure of shortage of blood supply in society will be reduced through saving the application of blood products; on the other hand,, the success rate of treatment of refractory diseases will be enhanced since more diseases can be treated by plasma purification.1. Study the therapeutic mechanism of t double filtration technology to achieve the selective plasma separation, and the substances to be removed for different diseases with correct treatment modes.2. Further research the treatment parameters, such as the sieve coefficients of filter membranes, plasma separation, removed plasma ratio, treatment time, and the relationship between the use of blood products in the replacement fluid and the effect of the treatment of various non-renal diseases.3. Study how to reduce the need of blood products in replacement fluid and the risk of blood borne diseases.4. Study combination of the blood purification with drugs and other treatments, so as to improve the success rate of treatment in refractory diseases.Methods:Selective dual plasma exchange separates the specific sizes of molecular substances from plasma by using two plasma component separators with different membrane apertures. Substances in patients’plasma, with molecular sizes between apertures of the two separators, can beremoved, while the other components of plasma are transfused back into the body. Plasma component separators with different apertures can be used of to control plasma protein clearance ranges.(1) According to the goals of treatments, patients are divided into three groups for clearance of macromolecules (lipoprotein, IgM, etc.), middle molecular substances (IgG, etc.) and small molecules (such as albumin bound substances, inflammatory mediators, etc.).(2) For patients with macromolecules to be removed, OP-08 with aperture of 0.2μm is used as first-level membrane of plasma separator; EC-50W or EC-40W with apertures of 0.03-0.035μm is used as second-level membrane.. Besides, patients need supplement of small amounts of albumin or equivalent compound sodium chloride solution. For those who without pancreatitis or other diseases with normal diet, supplement of albumin is unnecessary.(3) For patients with middle molecular substances to be removed, the plasma separator EC-50W with aperture of 0.035μm is used as first-level membrane,, and EC-30W or EC-20W with apertures of 0.01-0.02μm is used as second-level membrane. The patients need supplement of the same amount of plasma or 4% albumin solution.(4) For patients with small molecules to be removed, EC-30W or EC-20W with apertures of 0.02-0.01 μm is used as first-level membrane of plasma separator. For patients of single plasma exchange treatment, supplement with 4% albumin solution is needed.(5) Efficacy and safety evaluation:before and after treatment, every patient needs to be checked for indexes of hemoglobin, liver functions, renal functions, coagulation functions, especially albumin, blood lipid and immunoglobulin.(6) Long term effect analysis:the duration of disease stable and the incidence of end-stage organ failure.5. Statistical AnalysisUsing statistical software SPSS13.0, measurement data is expressed with x ± s. One-Way ANOVA was used in comparison of multiple groups and independent samples t testing was used in comparison between two groups. SPSS 13.0 statistical software was used for statistical processing, P<0.05 represent statistical significance.Results:1. Selective plasma separation applied to blood purificationFive patients received a total of 9 sessions of selective plasma separation using EC-50W (aperture 0.035μm, sieve coefficient of TC and Alb are 0.43 and 0.87 respectively) as the second-level membrane, average disposable plasma is 750ml without supplement of plasma and albumin. After treatment, except for HDLC and albumin, all kind of lipid levels decrease significantly, P< 0.05, among which TG levels decrease the most significantly. The average decreases of TC, TG, HDL-C, LDL-C, ALB is 3.24+1.36,885+3.87,0.03 0.02,0.63+0.13,5.88+467 (把单位 写全) respectively and the average removal rate is 33%,35%,3%,20%,8.5% respectively.2. The treatment of selective plasma separation in hyperbilirubinemia.Seven patients were treated for 42 times, among which 16 cases of selective plasma separation useEC-30W or EC-20W (aperture 0.01-0.02μm) as the first-level membrane,11 cases of bilirubin adsorption use plasma separator OP-08 as the first-level membrane, then use domestic bilirubin adsorption column BS330 (Zhuhai Jianfan company) for plasma adsorption; 15 cases of selective plasma separation integrate with bilirubin adsorption.Compare of the level of total bilirubin (TB) pre and post treatment among the three treatment modes, TB removal rate of (SPE+PA) group was the highest (37.8+ 3.9)%, which is significantly higher than that of SPE groups, P<0.01. TB removal rate of SPE groups was the minimum (23.4+6.7)%, lower than that of PA group, P<0.01.Compared PA group with (SPE+PA) group, the differences of TB decline and removal rate were not significant, P>0.05.3. Treatment of selective plasma separation in sensitized recipients of kidney transplantationFour renal transplantation of recipients in highly sensitized transplant received 7 sessions of double membrane filtration plasmapheresis, using EC-30W (aperture 0.02μm, the sieve coefficient IgG and albumin was 0.33 and 0.51 respectively) as second-level membrane, mean waste plasma was 932.86+110.56ml, supplement albumin 40-60g. Before DFPP, the average titer of DSA was 8227.78+4256.568; after treatment, the mean titer was 4986.04+4614.223, P< 0.05. The average removal of immunoglobulin IgG, IgA, IgM are 69.2%,64.9%,70.9% respectively; the decline rate of albumin was 17.8%(the supplemented albumin was 45g in average). Through follow-up of 4-19 months, one-year survival rate of patients was 100%; one-year survival rate of kidney was 100%. After 4 months, the mean creatinine was 107+15.1 μmol/L.4. The treatment of selective plasma separation in chronic hepatitis C after kidney transplantation Eight patients with hepatitis C received 22 sessions double filtration plasmapheresis using EC-50W (diameter 0.035μm, the sieve coefficient of TC and Alb are 0.43 and 0.87 respectively) as second-level membrane. HCVRNA decreased significantly (P< 0.05). After a single DFPP, HCVRNA decreased by 1.13±1.10×106, with a decline rate 30.80% ± 25.2%; after the second-level membrane, HCVRNA decreased by 2.02 ±3.23×106, with a decline rate of 30.80% ± 25.2%. After 81.8%(18/22) second-level membrane HCV,RNA titer was 0. The decline rates of TBIL, DBIL, AST, ALT and ALB were 17% ± 16%,17% ± 11.5%,20.9% ± 13.9%,31.2% ± 16.3% and 8.8% ± 9.4%, respectively.Conclusions:1. For double filtration plasma separation, plasma separators with different apertures can be adopted based on sizes of the target substances to be removed. For the purpose of blood purification, EC-50 should be adopted as the second-level membrane. For the purpose of removal of antibodies, EC-30 should be adopted as the second-level membrane.2. To remove small molecules, such as bilirubin, and albumin bound substances, inflammatory mediators, using EC-20W or 30W should be adopted as the first-level membrane for single plasma exchange.3. For treatment of hyperbilirubinemia, combination treatment of SPE and PA should be much more effective than using SPE or PA only. Better effect can be achieved by using bilirubin adsorption first and then SPE. We recommend that treatment of SPA+PA should be adopted for severe hyperbilirubinemia for pursuit of better cost-effectiveness of treatment4. Double filtration plasmapheresis can remove HLA antibodies existed in the patients’blood, especially donor specific antibody. It can effectively prevent acute rejection after renal transplantation, and also can reduce the incidence of adverse outcomes if acute rejection has occurred.5. Double filtration plasmapheresis using EC-50 as the second-level membrane not only eliminate the HCV virus, but also reduce the loss of plasma albumin.