1. Plasmapheresis Principles, Indications and Evidence
Dr. Vaibhav Keskar MD, DM
Consultant Nephrologist
Bombay Hospital & Medical Research Centre, Mumbai.

2. Apheresis Apheresis (Greek)= to remove/ take away Plasmapheresis:
Plasma is removed
Therapeutic Plasma Exchange (TPE):
The plasma is removed and replaced with a replacement solution such as colloid solution (e.g., albumin and/or plasma) or combination of crystalloid/colloid solution.
Therapeutic Plasma exchange (TPE)
A therapeutic procedure in which blood of the patient is passed through a medical device which separates out plasma from other components of blood, the plasma is removed and replaced with a replacement solution such as colloid solution (e.g., albumin and/or plasma) or combination of crystalloid/colloid solution.
Plasmapheresis
A procedure in which blood of the patient or the donor is passed through a medical device which separates out plasma from other components of blood and the plasma is removed (i.e., less than 15% of total plasma volume) without the use of replacement solution.

3. Effects of Plasmapheresis
Depletion of specific pathogenic molecules
- Autoantibodies, immune complexes
Depletion of inflammatory mediators
- Coagulation factors, complement proteins
Provision of deficient factors
- HUS/TTP, complement regulators
Reduction in plasma viscocity
- E.g. in myeloma, cryoglobulinemia

4. Centrifugal Cell Separation
Centrifugal flow devices most commonly deliver continuous flow from the patient to the centrifuge (Figure 2A). An anticoagulant, usually citrate, is added before centrifugation, which is then followed by return of the rest of the blood components with the appropriate replacement fluid (typically albumin or plasma) so that a continuous flow extracorporeal circuit is formed (7). The functional unit is the centrifuge itself, which spins at typical speeds of 2000–2500 rpm to separate the contents of the anticoagulated blood based on the density or specific gravity of various components of blood. Nonselective plasma removal is achieved through layering of plasma near
the axis of rotation, adjacent to which is a buffy coat consisting of platelets, lymphocytes, monocytes, and granulocytes in that order extending from the axis of rotation with the red blood cells forming the outermost layer (8). The efficiency of separation of the various blood components depends on the dimensions of the centrifuge and the variable speed (revolutions per minute) of the centrifuge, which creates gravitational forces, as well as the dwell time, which is the amount of time that the blood spends in the centrifuge.
Levy, Pusey. Plasmapheresis. Comprehensive Clinical Nephrology 2010

5. Membrane Plasma Separation
Non-selective: removes both pathologic and beneficial plasma proteins
Fresenius multiFiltrate
Levy, Pusey. Plasmapheresis. Comprehensive Clinical Nephrology 2010

6. Clearance of Plasma Proteins by Plasma Exchange
Molecule Molecular weight % intravascular half life normal serum conc (mg/dL)
Albumin k %
IgG k %
IgA 150k %
IgM 900k %
LDL-Chol (beta-lipoprot) 1300k %
Derksen J Lab Clin Med 1984

7. Kinetics of Protein Removal
The Percentage of Pathologic Substance Removed With a Single Treatment Of Plasma Exchange
Plasma levels of IgG before and after plasmapheresis
A single exchange of 1 (approximately 3 l for a 70-kg patient), 1.5, and 2 plasma volume removes 63%, 78%, and 86% of all solutes in plasma, respectively
Carter Ped Nephrol 2014

8. Ideal Target Molecule Identified etiologic agent or toxic substance
High molecular weight (≥15000 D)
Slow rate of formation
Low turnover
Low volume of distribution

9. Is It Going to Work? McLeod’s Criteria
MacLeod’s Criteria
Evidence
Explanation
Plausible Pathogenesis
Mechanism of the disease
The current understanding of the disease process supports a clear rationale for the use of therapeutic apheresis modality.
Better Blood
Correction
The abnormality, which makes therapeutic apheresis plausible,
can be meaningfully corrected by its use.
Perkier Patient
Clinical effect
There is a strong evidence that therapeutic apheresis confers benefit that is clinically worthwhile, and not just statistically significant.

10. Guidelines on the Use of Therapeutic Apheresis in Clinical Practice: American Society for Apheresis
Category I: Disorders for which apheresis is accepted as first-line therapy (dialysis-dependent AAV, pulmonary hemorrhage, dialysis-independent anti-GBM, )
Category II: Disorders for which apheresis is accepted as second-line therapy (Cat APLA)
Category III: Optimum role of apheresis therapy is not established. Decision making should be individualized. (dialysis-dependent anti-GBM)
Category IV: Apheresis to be ineffective or harmful (amyloid, MCP4 mutation)
Therapeutic Apheresis–Guidelines 2013, Journal of Clinical Apheresis

11. ASFA Category I Renal Indications for Therapeutic Plasma Exchange
Kidney Disease
Indication
Reported RCTs
ANCA- associated RPGN
Dialysis dependence or diffuse alveolar hemorrhage 8
Anti-GBM disease
Diffuse alveolar hemorrhage or dialysis
independence 1
Cryoglobulinemia
Symptomatic, severe
Atypical HUS
Factor H antibodies
Kidney transplant
ABMR 3
Desensitization for (cross-match positive; ABO incompatible)
TTP 7
Drug-associated TMA
Ticlopidine
Therapeutic Apheresis–Guidelines 2013, Journal of Clinical Apheresis

12. General issues to be Considered
Rationale
Technical issues
anticoagulant, replacement solution, vascular access, and volume of whole blood processed
Therapeutic plan
Total number and/or frequency
Clinical/ laboratory end points
Impact on drugs

13. Plasmapheresis in Children
Age group
Blood volume
Infants
85 ml/kg
Toddlers
80 ml/kg
Early school children
ml/kg
Older prepubertal children
ml/kg
Adolescents
70 ml/kg
Kaplan (1992) uses a simplified method for predicting the estimated plasma volume:
EPV = [0.065 × weight (kg)] × (1 – Hct)
Circuit Volume-
If > 15% of blood volume, use packed cells to prime the circuit.
plasmaFlux Psu 1S= 36 ml; Psu 2S= 70 ml

14. Drugs and Plasmapheresis
Determinants of Drug Removal by Plasmapheresis
Drug Dependent:
Time between dose administration and plasmapheresis
Protein binding
Volume of distribution
Plasmapheresis Dependent
Volume of plasma removed
Frequency of plasmapheresis
Time-
1) 75% of the immunosuppressant mycophenolate mofetil dose was recovered in waste plasma when it was concurrently infused in a patient undergoing TPE.
2) In addition, studies assessing vancomycin (23), gentamycin (24,25), cefepime (13), thyroxine (26), and aspirin (27) removal by TPE found a strong correlation between the concentration of these compounds before TPE initiation and the amount removed by the procedure.
3) A notable exception is digoxin: owing to its large Vd, the amount removed with early TPE comprised a small fraction of total body stores.
4) A recent study with the cephalosporin cefepime suggested that most drugs (including ones with low Vd)may not be significantly eliminated by TPE if they are allowed to distribute fully leaving much lower concentrations of drug in the plasma (13).
Rebound-
post-TPE concentration rebound was documented with gentamycin (25,47), tobramycin (48,49), vancomycin (23), phenytoin (50,51), and carbamazepine (52), cisplatin, disopyramide.

15. Drugs and Plasmapheresis
Basiliximab, Rituximab, IVIg, ATG
Removed; administer after plasmapheresis
MMF
Removed if given <4 hr prior
Prednisolone
No significant removal
Cyclosporine and Tacrolimus
While it is well established that plasma exchange (PE) is ineffective in removing amiodarone (36,37), it successfully treated amiodarone-induced thyrotoxicosis (38). This was
explained by its ability to remove, albeit transiently, total T4 ⁄T3 and free T4 ⁄T3 (37,39).
Severe infusion-related reactions to rituximab were successfully treated with four TPE sessions started within 24 hours of the antibody infusion (40). The authors postulated that the successful outcome was largely due to the removal of unbound rituximab (theorized to be 30–38%) and the clearing of circulating inflammatory cytokines.
TPE was effective in removing digoxin bound to digoxin-specific antibody fragments (Fab) in patients with renal failure, potentially preventing rebound digoxin toxicity despite the fact that it was not effective in improving total digoxin clearance (41).
Clinical benefits conferred by TPE have also been described in the management of cisplatin toxicity, known to be mainly due to the protein-bound, not free, platinum (42).
Other Drugs Likely to be Removed:
Amlodipine, Diltiazem, Propranolol, Dalteparin,
Ampicillin, Gentamycin, Teicoplanin, Thyroxine

16. Anti-GBM Disease
Circulating antibodies against the NC1 domain of the alpha-3 chain of type IV collagen
Monophasic illness; recurrence exceptional
Poor prognosis without prompt treatment
Prednisolone + cyclophosphamide + plasmapheresis
Recovery is much more likely if treatment started before oliguria sets in.

17. Anti-GBM Disease: Timing Matters
Pts on HD- weigh risks and benefits
Levy Annals of Internal Medicine 2001

18. Plasma Exchange in AntiGBM Disease
Johnson et al 1985
Prednisone + oral cyclophosphamide with or without plasma exchange 4L every 3rd day till antibody <5%/ dialysis for 1 month
N= 17 (9/8)
Two of eight patients who received plasmapheresis, compared with six of nine in the immunosuppression alone group, became dialysis dependent.
Less severe disease in PE group
underpowered
Johnson Medicine 1985

19. Plasma Exchange in Anti-GBM Disease
Category I: Dialysis-independent disease, pulmonary hemorrhage
Category III: Dialysis requirement
Daily or alternate-day
50 ml/kg or 4 liter exchanges
Two to three weeks
Replacement: albumin
Recent renal biopsy or has pulmonary hemorrhage, then one to two liters of fresh frozen plasma should be substituted for albumin at the end of the procedure
Therapeutic Apheresis Guidelines- American Society for apheresis 2013

20. ANCA-associated Vasculitis
Pathogenesis of anti-neutrophil cytoplasm antibody (ANCA)-associated vasculitides (AAV). In a (genetically) susceptible individual who is exposed to an environmental trigger, such as Staphylococcus aureus, antigen-presenting cells (APCs) result in the proliferation of helper T (TH; TH-17) cells via interleukin (IL)-23. These activated TH-17 cells release IL-17 that activates macrophages and attracts neutrophils. Macrophages release the pro-inflammatory cytokines IL-1β and tumor necrosis factor
alpha (TNFα), both of which prime neutrophils to display myeloperoxidase (MPO) and proteinase 3 (PR3). APCs process and present these antigens to TH cells, and chronically activated TH cells form effector memory T cells (TEM), which then form granulomata. TH cells activate B cells (B) that release ANCAs of the immunoglobulin G type into the bloodstream. In addition, the number of regulatory T cells (TREG) is likely reduced and their function impaired, allowing for persistent or enhanced B-cell activation. Circulating primed neutrophils become activated by ANCAs following binding to both Fcγ and Fab2. Degranulation of bound neutrophils leads to further neutrophil recruitment to the site and releases reactive oxygen species (ROS) and neutrophil extracellular traps (NETs) leading to endothelial cell damage and inflammation
Noone Ped Nephrol 2016

21. ANCA-associated Vasculitis: Treatment
Steroid + cyclophosphamide or rituximab
Plasmapheresis if:
Rapidly increasing creatinine or need of dialysis
Diffuse pulmonary hemorrhage
Coexisting anti-GBM antibody
KDIGO GN Guidelines 2012

22. Plasma Exchange in RPGN (ANCA Vasculitis)
MEPEX trial (EUVAS group )
137 patients with RPGN due to ANCA vasculitis, Cr> 5.8
Prednisolone and cyclophosphamide +
IV methylprednisolone OR
7 plasma exchange
Systemic vasculitis associated with autoantibodies to neutrophil cytoplasmic antigens (ANCA) is the most frequent cause of rapidly progressive glomerulonephritis. Renal failure at presentation carries an increased risk for ESRD and death despite immunosuppressive therapy. This study investigated whether the addition of plasma exchange was more effective than intravenous methylprednisolone in the achievement of renal recovery in those who presented with a serum creatinine>500 micromol/L (5.8 mg/dl). A total of 137 patients with a new diagnosis of ANCA-associated systemic vasculitis confirmed by renal biopsy and serum creatinine>500 micromol/L (5.8 mg/dl) were randomly assigned to receive seven plasma exchanges (n = 70) or 3000 mg of intravenous methylprednisolone (n = 67). Both groups received oral cyclophosphamide and oral prednisolone. The primary end point was dialysis independence at 3 mo. Secondary end points included renal and patient survival at 1 yr and severe adverse event rates. At 3 mo, 33 (49%) of 67 after intravenous methylprednisolone compared with 48 (69%) or 70 after plasma exchange were alive and independent of dialysis (95% confidence interval for the difference 18 to 35%; P = 0.02). As comparedwith intravenous methylprednisolone, plasma exchange was associated with a reduction in risk for progression to ESRD of 24% (95% confidence interval 6.1 to 41%), from 43 to 19%, at 12 mo. Patient survival and severe adverse event rates at 1 yr were 51 (76%) of 67 and 32 of 67 (48%) in the intravenous methylprednisolone group and 51 (73%) of 70 and 35 of (50%) 70 in the plasma exchange group, respectively. Plasma exchange increased the rate of renal recovery in ANCA-associated systemic vasculitis that presented with renal failure when compared with intravenous methylprednisolone. Patient survival and severe adverse event rates were similar in both groups.
Jayne, JASN 2007

23. Plasma Exchange in AAV/ RPGN
Background: Plasma exchange may be effective adjunctive treatment for renal vasculitis. We performed a
systematic review and meta-analysis of randomized controlled trials of plasma exchange for renal vasculitis.
Study Design: Systematic review and meta-analysis of articles identified from electronic databases,
bibliographies, and studies identified by experts. Data were abstracted in parallel by 2 reviewers.
Setting & Population: Adults with idiopathic renal vasculitis or rapidly progressive glomerulonephritis.
Selection Criteria for Studies: Randomized controlled trials that compared standard care with standard
care plus adjuvant plasma exchange in adult patients with either renal vasculitis or idiopathic rapidly
progressive glomerulonephritis.
Intervention: Adjuvant plasma exchange.
Outcome: Composite of end-stage renal disease or death.
Results: We identified 9 trials including 387 patients. In a fixed-effects model, the pooled RR for end-stage
renal disease or death was 0.80 for patients treated with adjunctive plasma exchange compared with standard
care alone (95% CI, ; P 0.04). No significant heterogeneity was detected (P 0.5; I2 0%). The
effect of plasma exchange did not differ significantly across the range of baseline serum creatinine values (P
0.7) or number of plasma exchange treatments (P 0.8). The RR for end-stage renal disease was 0.64 (95%
CI, ; P ), whereas the RR for death alone was 1.01 (95% CI, ; P 0.9).
Limitations: Although the primary result was statistically significant, there is insufficient statistical information
to reliably determine whether plasma exchange decreases the composite of end-stage renal disease or
death.
Conclusions: Plasma exchange may decrease the composite end point of end-stage renal disease or death
in patients with renal vasculitis. Additional trials are required given the limited data available.
Am J Kidney Dis. 57(4): © 2011 by the National Kidney Foundation, Inc.
Walsh, AJKD 2011

24. PEXIVAS Trial Walsh, Trials 2013 - eGFR < 50
- Diffuse alveolar hemorrhage
Walsh, Trials 2013

25. Plasma Exchange in AAV
Category I: Dialysis-dependent disease, pulmonary hemorrhage
Category III: Dialysis independent
Daily or alternate-day
50 ml/kg or 4 liter exchanges
Seven treatments over 14 days
If diffuse pulmonary hemorrhage, daily until the bleeding stops, then every other day, total 7–10 treatments.
Replacement: albumin
Recent renal biopsy or has pulmonary hemorrhage, then one to two liters of fresh frozen plasma should be substituted for albumin at the end of the procedure

26. Rituximab Puisset, BJCP 2012 AIMS
Both rituximab and plasmapheresis can be associated in the treatment of immune-mediated kidney diseases. The real impact of plasmapheresis on rituximab pharmacokinetics is unknown. The aim of this study was to compare rituximab pharmacokinetics between patients requiring plasmapheresis and others without
plasmapheresis.
METHODS
The study included 20 patients receiving one or several infusions of rituximab. In 10 patients, plasmapheresis sessions were also performed (between two and six sessions
per patient). Rituximab concentrations were measured in blood samples in all patients and in discarded plasma obtained by plasmapheresis using an enzyme-linked immunosorbent assay method. Data were analysed according to a population pharmacokinetic approach.
RESULTS
The mean percentage of rituximab removed during the first plasmapheresis session ranged between 47 and 54% when plasmapheresis was performed between 24 and
72 h after rituximab infusion. Rituximab pharmacokinetics was adequately described by a two-compartment model with first-order elimination. Plasmapheresis had a
significant impact on rituximab pharmacokinetics, with an increase of rituximab clearance by a factor of 261 (95% confidence interval 146–376), i.e. from 6.64 to 1733 ml h-1. Plasmapheresis performed 24 h after rituximab infusion decreased the rituximab area under the curve by 26%.
CONCLUSIONS
Plasmapheresis removed an important amount of rituximab when performed less than 3 days after infusion. The removal of rituximab led to a significant decrease of
the area under the curve. This pharmacokinetic observation should be taken into account for rituximab dosing, e.g. an additional third rituximab infusion may be
recommended when three plasmapheresis sessions are performed after the first rituximab infusion.
Puisset, BJCP 2012

27. Rituximab and Daily Plasma Exchange
Darabi, Am J Clin Pathol 2006

28. Atypical HUS
Lorait, Ped Nephrol 2016

29. Atypical HUS Factor H autoantibodies: Category I
Complement factor gene mutations: Category II
MCP mutations: Category IV
Therapeutic Apheresis–Guidelines 2013, Journal of Clinical Apheresis
Sinha, Kideny International 2013

30. aHUS: Plasmapheresis Schedule
Exceptions.
There are some occasions when clinicians may elect not to use this empirical guideline.
where the effect of an alternative treatment can be anticipated. For example,HUS in a sibling of a patient with congenital ADAMTS13 deficiency is likely to have the same diagnosis and might be expected to respond to plasma infusion 10 ml/kg per day.
(b) where the clinical presentation strongly suggests early onset cobalamin-C disorder (feeding difficulty, failure to thrive, hypotonia, lethargy, leukopenia and megaloblastic anemia).
(c) where there are technical difficulties in achieving vascular access in small children.
(d) where the clinician considers that the risks of plasmapheresis outweigh the benefits in a child with apparently mild renal involvement and conserved urine output, in which case the decision might be deferred. However, clinicians should be aware that thrombotic microangiopathy is a destructive process, and that, in the few reported
patients with factor H mutations in whom plasma therapy appeared successful, treatment had been started before there was renal impairment
Step 4: defining patient outcome
The end-point for determining early outcome has been set arbitrarily at 1 month (to be precise day 33). The guideline does not address ongoing active treatment in patients who appear to have remission from their disease, nor does it advise on what action to take in patients who have failed to respond at the end of the first month. The authors recognize that, for some patients, the etiological sub-group diagnosis may not be available at that time. We propose that a clinical record of each patient’s outcome be made, using the following terminology:
Hematological remission is defined as a platelet count >150×109/l for 2 weeks and no signs of hemolysis [fragmented red cells, elevated lactic dehydrogenase (LDH)
level]. This definition is independent of renal function.
Hematological relapse of HUS is defined as a return of microangiopathic hemolytic anemia and thrombocytopenia after these parameters have normalized for a period of a
least 2 weeks.
Renal function is graded under three levels for simplicity:
1) renal failure requiring dialysis,
2) renal impairment, in which there is independent kidney function but plasma creatinine level is elevated for age or glomerular filtration
rate (GFR) <80 ml/min per 1.73 m2 body surface area (BSA) by the Schwartz formula or a formal clearance assay, and
3) normal in which plasma creatinine level is appropriate for age or GFR ≥80 ml/min per 1.73 m2 BSA.
Proteinuria should be assessed as a numerical variable, protein/creatinine ratio on first-voided urine sample in the morning.
Blood pressure should be assessed as a numerical variable and expressed as a centile factored for age and gender [23, 24]. In addition, if antihypertensive therapy is
used, the number of different antihypertensive drugs should be stated.
The European Paediatric Study Group for HUS, Ped Nephrol 2009

31. Recurrent FSGS

32. Recurrent FSGS
3 daily TPEs followed by at least six more TPEs in the subsequent 2 weeks, for a minimum of nine procedures.
1-1.5 plasma volumes
Replacement with albumin; FFP if recent biopsy.

33. Myeloma Cast Nephropathy
Renal disease develops in up to 50% of patients with multiple myeloma and shortens their survival. Myeloma kidney (cast nephropathy)
accounts for approximately 30–80% of such cases, depending on the class of M-protein. Autopsy studies show distal renal tubules
obstructed by laminated casts composed of light chains (Bence-Jones protein), albumin, Tamm-Horsfall protein and others. As tubular
obstruction progresses the decline in renal function becomes irreversible. Hypotheses regarding the mechanism of pathological distal tubule
cast formation focus on an increase in light chain concentration in the distal tubular urine. This may result from the overwhelming of proximal
tubule processing of light chains when light chain production is rising due to tumor progression. Other contributing factors may include
hypercalcemia, hyperuricemia, dehydration, intravenous contrast media, toxic effects of light chains on distal tubular epithelium, etc.

34. Myeloma Cast Nephropathy
Anti-myeloma therapy, fluid management, and, in patients with severe AKI, dialysis.
Role of plasma exchange is disputed.
Serum protein electrophoresis before (left panel) and after (right panel) four consecutive daily plasma exchanges in a patient with multiple myeloma and acute renal failure. The monoclonal peak representing the circulating light chains (arrow) has essentially disappeared.

35. Plasma Exchange when Myeloma Presents as Acute Renal Failure
Ann Intern Med. 2005 Dec 6;143(11):
Plasma exchange when myeloma presents as acute renal failure: a randomized, controlled trial.
Clark WF1, Stewart AK, Rock GA, Sternbach M, Sutton DM, Barrett BJ, Heidenheim AP, Garg AX, Churchill DN; Canadian Apheresis Group.
Author information
Erratum in
Correction: Plasma exchange when myeloma presents as acute renal failure. [Ann Intern Med. 2007]
Abstract
BACKGROUND:
Two small, randomized trials provide conflicting evidence about the benefits of plasma exchange for patients with acute renal failure at the onset of multiple myeloma.
OBJECTIVE:
To assess the effect of 5 to 7 plasma exchanges on a composite outcome in patients with acute renal failure at the onset of multiple myeloma.
DESIGN:
Randomized, open, controlled trial, stratified by chemotherapy and dialysis dependence, conducted from 1998 to 2004.
SETTING:
Hospital plasma exchange units in 14 Canadian medical centers.
PARTICIPANTS:
104 patients between 18 and 81 years of age with acute renal failure at the onset of myeloma.
INTERVENTION:
Study participants were randomly assigned to conventional therapy plus 5 to 7 plasma exchanges of 50 mL per kg of body weight of 5% human serum albumin for 10 days or conventional therapy alone. Ninety-seven participants completed the 6-month follow-up.
MEASUREMENTS:
The primary outcome was a composite measure of death, dialysis dependence, or glomerular filtration rate less than 0.29 mL x s(-2) x m(-2) (<30 mL/min per 1.73 m2).
RESULTS:
At enrollment, the plasma exchange and control groups were similar for dialysis dependence, chemotherapy, sex, age, hypercalcemia, serum albumin level, 24-hour urine protein level, serum creatinine level, and Durie-Salmon staging. The primary composite end point occurred in 33 of 57 (57.9%) patients in the plasma exchange group and in 27 of 39 (69.2%) patients in the control group (difference between groups, 11.3% [95% CI, -8.3% to 29.1%]; P = 0.36). One third of patients in each group died.
LIMITATIONS:
The study was small, used a composite outcome, and did not use renal biopsy as an inclusion criterion. Recruiting physicians were blinded to treatment allocation but not to treatment thereafter.
CONCLUSIONS:
In patients with acute renal failure at the onset of multiple myeloma, there is no conclusive evidence that 5 to 7 plasma exchanges substantially reduce a composite outcome of death, dialysis dependence, or glomerular filtration rate less than 0.29 mL.s(-2).m(-2) (<30 mL/min per 1.73 m2) at 6 months.
Less compelling results were reported from a multicenter trial of 97 patients with newly diagnosed multiple myeloma and AKI who were randomly assigned to plasmapheresis and chemotherapy or to chemotherapy alone [18]. Patients were included if they met the following criteria: progressive worsening of kidney function (serum creatinine of >2.3 mg/dL [200 micromol/L], with an increase of >0.6 mg/dL [50 micromol/L] over the preceding two weeks) despite correction of hypercalcemia and hypovolemia; monoclonal light chains in urine, plasma, or renal tissue; and no other identifiable, precipitating cause of AKI.
In the control and plasmapheresis groups, 14 and 15 patients (36 and 26 percent), respectively, were on dialysis at baseline, and five and nine patients (13 and 16 percent), respectively, began dialysis during treatment. At six months, mortality was 33 percent in each group. The following additional results were noted:
•The composite outcome (death, dialysis dependence, or glomerular filtration rate [GFR] of <30 mL/min/1.73 m2) was not significantly different (58 versus 69 percent in the plasmapheresis and control patients, respectively [95% CI -8.3 to 29.1 percent]).
•Among six-month survivors, fewer patients in the plasmapheresis group remained dialysis dependent, but the difference was not significant (13 versus 27 percent, respectively [95% CI -5.1 to 34.6 percent]).
However, it is uncertain that all patients in this trial had light chain cast nephropathy as the cause of AKI and, therefore, not all patients would have benefited from plasmapheresis [20]. Only 78 percent of the patients had increased free light chains in the plasma, and only 61 percent had light chains in the urine; relatively few patients had a tissue diagnosis of cast nephropathy by biopsy. The potential benefits of plasmapheresis may also have been obscured since more patients in the control group received a dexamethasone-containing regimen, which leads to faster reduction in light chain production than melphalan and prednisone. (See "Management of multiple myeloma in resource-poor settings".)
This study does not disprove a benefit from plasmapheresis; the procedure was associated with a 52 percent reduction in dialysis dependency among survivors at six months (13 versus 27 percent). The ability to show a statistically significant benefit in renal recovery was probably limited by the large number of deaths in both arms, an outcome unlikely to have been affected by plasmapheresis.
Clark, Annals of Internal Medicine 2005

36. Cast Nephropathy Improves after Reduction in FLC
Cast nephropathy is the most common cause of renal disease in multiple myeloma, however, treatment with plasma exchange remains controversial even after 3 randomized controlled studies. We sought to determine the importance of diagnostic confirmation and goal directed therapy in the treatment of cast nephropathy in forty patients with confirmed multiple myeloma and renal failure who underwent plasma exchange. A positive renal response was defined as a decrease by half in the presenting serum creatinine and dialysis independence. No baseline differences were noted between eventual renal responders and non-responders. Three quarters of the patients with biopsy proven cast nephropathy resolved their renal disease when the free light chains present in the serum were reduced by half or more but there was no significant response when the reduction was less. The median time to a response was about 2 months. In patients without cast nephropathy, renal recovery occurred despite reductions in free light chain levels of the serum. No association was found between free light chains in the serum, urinary monoclonal proteins, overall proteinuria and cast nephropathy. We found that the relationship between renal recovery and free light chain reduction was present only in patients with biopsy proven cast nephropathy showing the importance of extracorporeal light chain removal in this disease.
Leung, KI 2008

37. Myeloma Cast Nephropathy
Category II
Five to seven exchanges within 7 to 10 days
However, the duration of plasmapheresis should be guided by SFLC levels (daily)
The goal of plasmapheresis is a 50 to 60 percent or greater reduction in the pathogenic SFLC level; this degree of light chain reduction is associated with recovery of renal function
Concomitant bortezomib-based chemotherapy is essential
Therapeutic Apheresis–Guidelines 2013, Journal of Clinical Apheresis

38. Desensitization: ABO Incompatible Tx
Antigen-specific immunoadsorption
The GlycoSorb ABO column is a low-molecular carbohydrate column with A or B blood-group antigen linked to a Sepharose matrix. A detailed description of the apheresis procedure has recently been published (4). The protocol calls for four preoperative apheresis sessions and we aim for a preoperative antibody titer of IgG 1:8. If this is not achieved after four sessions, the transplantation is postponed for a week and four more sessions are performed. Before transplantation 0.5 g/kg of intravenous immunoglobulin (IVIG) was administered. Postoperatively three more apheresis sessions were given every third day over a total period of 9 days in Stockholm and Uppsala, while in Freiburg postoperative adsorptions were only performed if there were signs of rebound of antibodies (a twofold increase in antibody titer).

39. Acute Antibody-mediated Rejection

40. Acute Antibody-mediated Rejection
Daily or alternate-day
One/ one-half volume exchange
Replacement: albumin, with fresh frozen plasma as indicated.
IVIg
- 100 mg/kg of IVIG after each exchange and often 500 mg/kg per day for one to two days after the final planned exchange, with a total cumulative target dose of at least 1000 mg/kg of IVIG.
Plasma exchange is generally continued for 5-6 sessions or until the serum creatinine concentration is within 20 to 30 percent of the previous baseline for a minimum of four treatment sessions.
Tacrolimus and MMF regimen, we switch to this combination. If they are already on tacrolimus and MMF, we augment the dose if it appears that this is necessary. 
Methylprednisolone 300 to 500 mg daily for three to five days, followed by a rapid taper to maintenance prednisone dosing

41. Complications Related to Vascular Access Related to the Procedure
- Hematoma, pneumothorax, retroperitoneal bleeding, local/ systemic infection
Related to the Procedure
- Hypotension, bleeding, hypoalbuminemia, thrombocytopenia, hypersensitivity reactions (e.g. EtO)
Related to Anticoagulation
- heparin/ citrate
Related to Replacement Fluid
- Anaphylaxis (FFP), dilutional hypokalemia
Canadian Apheresis Registry 2003
Plasma exchange by centrifugation had a lower risk for adverse events than by filtration.
Incidence 12% (severe 0.4%; require interruption)

42. To Sum Up..
Plasmapheresis is integral part of many life/ organ-threatening disorders.
Adequately powered RCTs are needed to elucidate the role of plasmapheresis in various disorders.
Drug removal by plasmapheresis needs to considered in every case.

43. Thank You! Acknowledgement Dr. N.K. Hase, Mumbai
Dr. Tukaram Jamale, Mumbai
Dr. Viswanath Billa, Mumbai
Dr. Todd Fairhead, Ottawa
Dr. Elizabeth Harvey, Toronto