Plasmapheresis Protocol

1-2 plasma volume/session
PV= (1-Hct)(b+cW)
Hct= Hematocrit
b=1530 for males, 864 for females
c=41 for males, 47.2 for females
W= lean body weight

Rough estimation: at Hct 45.
Plasma Volume=40ml/kg (BW)
Usually 5-7 sessions of plasmapheresis is required exchanges is usu done 24 hours apart
Replacement flluid- 5% human albumin
Monitor VS every 15 min
Measure PT,PTT and pre&post procedure RP, LFT, FBC

Anticoagulation: Heparin 50u/kg stat than 1000u/h
target ACT 1.5-2.0X normal
adjust dose accordingly
stop heparin 30min prior to end of procedure

To avoid hemolysis, PE must be done at
TMP 50-60mmHg
Qb 100-150mls/min

Complications of PE
Hypotension- bld loss, decrease oncotic pressure
Bleeding d/t reduction in coagulation factors
Edema- reduction of intravascular oncotic pressure
Loss of cellular elements
Ethylene Oxide hypersensitivity

Related to anticoagulation
Bleeding- heparin related
Hypocalcemia leading to arrhythmias/ hypotension/ numbness/ tingling sensation

Recipient Clerking

Recipient Clerking Date:

Name:

Age:

I/C:


Occupation:

Referred by:


ESRD


Primary Etiology:

Duration:

Mode of RRT

Stab PD:

IPD:

CAPD:

HD: Place of HD: Vascular access:
Previous Femoral catheterization:

Surgical History:

Previous Op:


Other Medical Problems:

1. 2.

3. 4.

5. 6.

7. 8.



Dry Wt:


Residual Urine Output:


Uro-Nephro conference:


Renal transplant date:


Allergies:

Op site:

Latest Medications:







Work-up

USG
1. Native kidneys
2. Doppler Femoral Vessels

IVU

GFR DTPA



GFR Cr EDTA



Cardiac Assessment
1. Chest X Ray
2. ECG
3. Echocardiography
4. Exercise Stress Test
5. Coronary angiography


Lung Function Test


HLA, Cross match results




Psychiatry assessment


Blood Ix

Infectious screen

HIV- Hep B- Hep C- VDRL- CMV-

HSV- EBV- VZV- Toxo-


Urine FEME


Urine Cysteine


24h urine protein


24h urine urate


24h urine calcium


24h urine phosphate


24h creatinine clearance


Renal Angiogram

Plan:-

Pre-transplant investigations:

Renal Profile

Ca PO4

LFT

RBS

FBC

PT/PTT/INR

Urine C&S

Swab C&S

Nasal

Throat

Ear

CXR

ECG

GXM 4 pint PC

Tacrolimus Level


Consent

Informed consent for Blood transfusion


Prophylactic Antibiotic
IV Cefuroxime 750mg TDS

Medications:

IV Hydrocortisone 200mg IV stat on call to OT
Then IV Hydrocotisone 200mg TDS

IV Methylprednisolone 500mg at anastomosis

Tacrolimus 0.2mg/kg/d in 2 divided doses (0.3mg/kg/d for cadaveric transplant)
ie

Tacrolimus level daily
Tacrolimus level
<6months: 10-15 ng/ml 6 months or more: 5-10 ng/ml Mycophenolate Mofetil 1g BD IV Basiliximab 20mg on call to OT (Day 1) and Day 4 Day 1: Day 4: IV Ranitidine 50mg TDS

Cyclosporin
Living related 8mg/kg/day x 5 days
Cadaveric transplant 10mg/kg/day

Post Operative Care

• Isolation nursing until tubes/drains removed
• Proper hand washing before and after examining patient
• Hourly Input/Output charting
• Daily Weight
• RP BD for 2 days then,
• Daily RP, Ca, PO4, FBC, LFT, Urine C&S
• Intravenous Fluids
o Replace with previous hours’ urine output
o Use Normal Saline alternate with D5%
• CXR post op
• Daily Tacrolimus Level
• USG Doppler Appointment
• DTPA Scan Appt
• Syr Nystatin 250,000uto gargle and swallow QID for 3 months
• T. Bactrim 480mg dly when renal function normalized

Donor Work-Up List

USG
IVU
GFR DTPA
GFR Cr EDTA
Cardiac Assessment
Lung Function Test
HLA, Cross match results
Psychiatry assessment
Blood Ix
Infectious screen
HIV, Hep B/C, VDRL, CMV, HSV, EBV, VZV, Toxo
Urine FEME
Urine Cysteine
24h urine protein
24h urine urate
24h urine calcium
24h urine phosphate
24h creat clearance
Renal Angiogram

Recipient Work-Up List

Blood Ix results
OGDS
MCU
Dental clearance
Ultrasound
Serology results
HIV, Hep B/C, VDRL
Toxoplasma
CMV
EBV
VZV
Cardiac clearance
ECG, Echo, CXR, EST

Follow-up schedule post renal transplant

1st 3 months ==> 3 times a week
3-6 months ==> 2 times a week
6-9 months ==> 1 time a week
9-12 months ==> 3 weekly
>12months monthly or longer depending on pt

Thymoglobulin

• Events surrounding the renal transplant procedure and initial hospitalization are important determinants of long-term allograft function.
  

• The initial immunosuppressive regimen may have a significant impact on these events although this is not predictable and is controversial. "Induction
  

• immunosuppressive therapy" generally refers to the use of anti-lymphocyte antibodies at the time of transplant which includes both monoclonal antibodies such as OKT3 or polyclonals such as ATGAM, ALG, or Thymoglobulin.
  
• The theoretical advantages with antibodies are to avoid the use of vasoconstrictive calcineurin inhibitors such as Neoral or Prograf in the immediate posttransplant period and to block immune interactions at the time of transplant.

• It is important to note that release of cytokines with antibodies may increase the risk of coagulation in some allografts. The combined immunological effects may improve early allograft function, delay or prevent rejection, and improve longterm allograft survival.
  

• Several studies have demonstrated that there are advantages of the use of antilymphocyte induction therapy in high-risk groups and perhaps in low-risk groups. Induction therapy, however, is associated with ncreased initial expense, increased risk for cytomegalovirus (CMV) disease, and posttransplant lymphoproliferative disease (PTLD). Also long term studies beyond 3 years suggest that long term survival is not predictably improved by induction therapy.
  

• Both monoclonal and polyclonal agents have been used for induction therapy. Polyclonal agents may have an advantage over monoclonal antilymphocyte therapy in the number of “target” that can be blocked.
  

• ATGAM (Pharmacia-UpJohn, Kalamazoo, MI) is available for induction immunosuppressive therapy and is obtained by immunization of horses with human thymocytes. It contains antibodies to a wide variety of human T-cell surface antigens including CD3, LFA-1, and CD45 as well as major histocompatibility complex (MHC) antigens. However some patients are sensitized to horse proteins prior to transplant, while others develop sensitization after exposure to Atgam.
  

• Thymoglobulin (SangStat Medical Corporation, Menlo Park, CA) is a polyclonal immunosuppressive agent similar to Atgam but is produced in the rabbit. Both Atgam and Thymoglobulin have been shown to reverse acute rejection as well as being useful in induction therapy. Unlike ATGAM, Thymoglobulin is pasteurized and is thought to have less batch-to-batch variability as well as being slightly less expensive at an equipotent dose. There is limited data that it may also have better effect in preventing rejection and for this reason we have adopted it for primary therapy in induction.
  

Indications:
• High risk immunological patients (previous severe rejections, high PRA
with historical T or B cell positivity)
• Delayed graft function in marginal or comprimised donors
• Steroid resistant rejection and unable to administer OKT3, ATGAM

Administration
Thymoglobulin is contraindicated in patients with a known allergy to rabbit
protein.
Thymoglobulin should be started in the operating room following vascular
anastamosis. This obviously requires communication with the anesthesist prior
to the patient going to the operating room. If it is not possible to give in the
operating room, administration should not be delayed beyond the recovery
room.
Infusion should occur into a central vein over 4-12 hrs. A 0.2-0.22 micron in-line
filter may be used, but is not absolutely required. Infusions prepared in saline
are stable for 20 hours from time of preparation.

Dose and Dose Adjustment
• The initial dose i s 1.5 mg/kg/day with a range of 1.25-2.5 mg/kg/day to
achieve a lymphocyte count of approximately 100/mm3. Thymoglobulin
should be diluted in 0.9% saline to a maximum concentration of 150 mg/500
ml (suggested dilution is 50 ml for each 25 mg vial). All infusions at University
Campus - LHSC should be ordered in 500 ml 0.9% saline.
•Pre-medication with diphenhydramine 25-50 mg and acetaminophen 30-60
minutes prior to infusion is advised. The usual daily dose of corticosteroid is
sufficient, and additional steroid is not required. The need for pre-medications
should be reviewed after the first 2 doses of Thymoglobulin.
• Dosage can be adjusted using absolute lymphocyte count from Hematology
or by CD2 counts using FACS. The latter is not necessary every day in most
patients.
• If the total WBC falls bel ow 2, 000 cells /mm3 or pl atelets fall below 50, 000
cells/mm3 , Thymoglobulin should be held
• If the total WBC is between 2,000 and 3,000, or the platelets are between
50,000 and 75,000, the next dose should be reduced by one-half
• CMV prophylaxis is absolutely required for CMV negative recipients of a
CMV positive kidney and highly suggested for if either the donor or recipient
are CMV positive recipients.
Thymoglobulin is available in vials containing 25 mg. Wherever possible the
total daily dose should be a multiple of 25 to help reduce cost due to drug
wastage as each 25 mg ampoule costs $173.00 CDN.
Duration of treatment for induction is until the creatinine is < style="font-weight: bold;">Side Effects
fever, chills, arthralgias, skin rashes, serum sickness (may be seen by end of 1st
week of treatment), leukopenia (more common with Thymoglobulin than
ATGAM), thrombocytopenia (rare), anaphylaxis (rare)

Basiliximab- adverse events

ADVERSE REACTIONS

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. The adverse reaction information from clinical trials does, however, provide a basis for identifying the adverse events that appear to be related to drug use and for approximating rates.

The incidence of adverse events for Simulect® was determined in four randomized, double-blind, placebo-controlled clinical trials for the prevention of renal allograft rejection. Two of the studies (Study 1 and Study 2), used a dual maintenance immunosuppressive regimen comprised of cyclosporine, USP (MODIFIED) and corticosteroids, whereas the other two studies (Study 3 and Study 4) used a triple immunosuppressive regimen comprised of cyclosporine, USP (MODIFIED), corticosteroids, and either azathioprine or mycophenolate mofetil.

Simulect® did not appear to add to the background of adverse events seen in organ transplantation patients as a consequence of their underlying disease and the concurrent administration of immunosuppressants and other medications. Adverse events were reported by 96% of the patients in the placebo-treated group and 96% of the patients in the Simulect® -treated group. In the four placebo-controlled studies, the pattern of adverse events in 590 patients treated with the recommended dose of Simulect® was similar to that in 594 patients treated with placebo. Simulect® did not increase the incidence of serious adverse events observed compared with placebo.

The most frequently reported adverse events were gastrointestinal disorders, reported in 69% of Simulect® -treated patients and 67% of placebo-treated patients.

The incidence and types of adverse events were similar in Simulect® -treated and placebo-treated patients. The following adverse events occurred in >10% of Simulect®-treated patients: Gastrointestinal System: constipation, nausea, abdominal pain, vomiting, diarrhea, dyspepsia; Body as a Whole-General: pain, peripheral edema, fever, viral infection; Metabolic and Nutritional: hyperkalemia, hypokalemia, hyperglycemia, hypercholesterolemia, hypophosphatemia, hyperuricemia; Urinary System: urinary tract infection; Respiratory System: dyspnea, upper respiratory tract infection; Skin and Appendages: surgical wound complications, acne; Cardiovascular Disorders-General: hypertension; Central and Peripheral Nervous System: headache, tremor; Psychiatric: insomnia; Red Blood Cell: anemia.

The following adverse events, not mentioned above, were reported with an incidence of >3% and <10%>Body as a Whole-General: accidental trauma, asthenia, chest pain, increased drug level, infection, face edema, fatigue, dependent edema, generalized edema, leg edema, malaise, rigors, sepsis; Cardiovascular: abnormal heart sounds, aggravated hypertension, angina pectoris, cardiac failure, chest pain, hypotension; Endocrine: increased glucocorticoids; Gastrointestinal: enlarged abdomen, esophagitis, flatulence, gastrointestinal disorder, gastroenteritis, GI hemorrhage, gum hyperplasia, melena, moniliasis, ulcerative stomatitis; Heart Rate and Rhythm: arrhythmia, atrial fibrillation, tachycardia; Metabolic and Nutritional: acidosis, dehydration, diabetes mellitus, fluid overload, hypercalcemia, hyperlipemia, hypertriglyceridemia, hypocalcemia, hypoglycemia, hypomagnesemia, hypoproteinemia, weight increase; Musculo-Skeletal: arthralgia, arthropathy, back pain, bone fracture, cramps, hernia, myalgia, leg pain; Nervous System: dizziness, neuropathy, paraesthesia, hypoesthesia; Platelet and Bleeding: hematoma, hemorrhage, purpura, thrombocytopenia, thrombosis; Psychiatric: agitation, anxiety, depression; Red Blood Cell: polycythemia; Reproductive Disorders, Male: genital edema, impotence; Respiratory: bronchitis, bronchospasm, abnormal chest sounds, coughing, pharyngitis, pneumonia, pulmonary disorder, pulmonary edema, rhinitis, sinusitis; Skin and Appendages: cyst, herpes simplex, herpes zoster, hypertrichosis, pruritus, rash, skin disorder, skin ulceration; Urinary: albuminuria, bladder disorder, dysuria, frequent micturition, hematuria, increased non-protein nitrogen, oliguria, abnormal renal function, renal tubular necrosis, surgery, ureteral disorder, urinary retention; Vascular Disorders: vascular disorder; Vision Disorders: cataract, conjunctivitis, abnormal vision; White Blood Cell: leucopenia. Among these events, leucopenia and hypertriglyceridemia occurred more frequently in the two triple-therapy studies using azathioprine and mycophenolate mofetil than in the dual-therapy studies.

Malignancies

The overall incidence of malignancies among all patients in the controlled studies was not significantly different between the Simulect®- and placebo-treatment groups. Overall, lymphoma/lymphoproliferative disease occurred in 1/590 patients in the Simulect® group compared with 3/594 patients in the placebo group. Other malignancies were reported among 8/590 patients in the Simulect® group compared with 9/594 patients in the placebo group.

Infections

The overall incidence of cytomegalovirus infection was similar in Simulect® and placebo-treated patients (15% vs. 17%) receiving a dual or triple immunosuppression regimen. However, in patients receiving a triple immunosupppression regimen, the incidence of serious cytomegalovirus infection was higher in Simulect® -treated patients compared to placebo-treated patients (11% vs. 5%). The rates of infections, serious infections, and infectious organisms were similar in the Simulect® and placebo treatment groups among dual-and triple therapy-treated patients.

Post-Marketing Experience

Severe acute hypersensitivity reactions including anaphylaxis characterized by hypotension, tachycardia, cardiac failure, dyspnea, wheezing, bronchospasm, pulmonary edema, respiratory failure, urticaria, rash, pruritus, and/or sneezing, as well as capillary leak syndrome and cytokine release syndrome, have been reported during post-marketing experience with Simulect®.

Basiliximab- Dosage and Administration

Simulect® is used as part of an immunosuppressive regimen that includes cyclosporine, USP (MODIFIED) and corticosteroids. Simulect® is for central or peripheral intravenous administration only. Reconstituted Simulect® should be given either as a bolus injection or diluted to a volume of 25 mL (10 mg vial) or 50 mL (20 mg vial) with normal saline or dextrose 5% and administered as an intravenous infusion over 20 to 30 minutes. Bolus administration may be associated with nausea, vomiting and local reactions, including pain.

Simulect® should only be administered once it has been determined that the patient will receive the graft and concomitant immunosuppression. Patients previously administered Simulect® should only be re-exposed to a subsequent course of therapy with extreme caution.

Parenteral drug products should be inspected visually for particulate matter and discoloration before administration. After reconstitution, Simulect® should be a clear to opalescent, colorless solution. If particulate matter is present or the solution is colored, do not use.

Care must be taken to assure sterility of the prepared solution because the drug product does not contain any antimicrobial preservatives or bacteriostatic agents.

It is recommended that after reconstitution, the solution should be used immediately. If not used immediately, it can be stored at 2ºC to 8ºC for 24 hours or at room temperature for 4 hours. Discard the reconstituted solution if not used within 24 hours.

No incompatibility between Simulect® and polyvinyl chloride bags or infusion sets has been observed. No data are available on the compatibility of Simulect® with other intravenous substances. Other drug substances should not be added or infused simultaneously through the same intravenous line.

Adults

In adult patients, the recommended regimen is two doses of 20 mg each. The first 20 mg dose should be given within 2 hours prior to transplantation surgery. The recommended second 20 mg dose should be given 4 days after transplantation. The second dose should be withheld if complications such as severe hypersensitivity reactions to Simulect® or graft loss occur.

Pediatric

In pediatric patients weighing less than 35 kg, the recommended regimen is two doses of 10 mg each. In pediatric patients weighing 35 kg or more, the recommended regimen is two doses of 20 mg each. The first dose should be given within 2 hours prior to transplantation surgery. The recommended second dose should be given 4 days after transplantation. The second dose should be withheld if complications such as severe hypersensitivity reactions to Simulect® or graft loss occur.

Reconstitution of 10 mg Simulect Vial

To prepare the reconstituted solution, add 2.5 mL of Sterile Water for Injection, USP, using aseptic technique, to the vial containing the Simulect® powder. Shake the vial gently to dissolve the powder.

The reconstituted solution is isotonic and may be given either as a bolus injection or diluted to a volume of 25 mL with normal saline or dextrose 5% for infusion. When mixing the solution, gently invert the bag in order to avoid foaming; DO NOT SHAKE.

Reconstitution of 20 mg Simulect Vial

To prepare the reconstituted solution, add 5 mL of Sterile Water for Injection, USP, using aseptic technique, to the vial containing the Simulect® powder. Shake the vial gently to dissolve the powder.

The reconstituted solution is isotonic and may be given either as a bolus injection or diluted to a volume of 50 mL with normal saline or dextrose 5% for infusion. When mixing the solution, gently invert the bag in order to avoid foaming; DO NOT SHAKE.

Immunosuppression

Tacolimus/Cyclosporin, Mycophenolate mofetil (MMF), Prednisolone is standard IS protocol

Highly sensitized recipients→ Can Use FK and/or induction agents
Multiparous
Multiple blood transfusion
Prev Transplant
PRA>20%

Steroids
• Hydrocort 200mg IV stat on OT call then 100mg TDS post op
• IV methylprednisolone 500mg at anastomosis
• Replace with Prednisolone 20mg when taking orally
• Taper Prednisolone at 3 months post transplant
o 2.5mg per month till 10mg

Cyclosporin
• LRRT: Neoral 8mg/kg/d 5 days before transplant
• Cad RT: Neoral 10mg/kg/d pre transplant
• C0: <6 mths→250-374ng/ml, 6 mths or more→100-250ng/ml
• C2:<1 month→ 1.7ug/ml, 1-2mth→ 1.5ug/ml, 2-3mth→ 1.3ug/ml, 4-6 mth→1.1ug/ml, 7-12mth→0.9ug/ml, 12mths or more→0.8ug/ml

Tacrolimus
• LRRT: 0.2mg/kg/d in 2 divided doses 5 days before transplant
• Cad RT: 0.3mg/kg/d given when called to OT
• FK level: <6mths→10-15ng/ml, 6 mths or more→5-10ng/ml

MMF
• 1g when OT calls
• Post transplant 1g BD (500mg BD if FK is used)
• Reduce dose if WBC <4

Azathioprine
• 1.5mg/kg/d
• omit in :-
o HepBsAg +ve patients
o Hep C +ve patients
o Post Transplant CAH
o Recipients with Chronic hepatitis and worsening transaminase

Basiliximab
• 20mg on call to OT and D4 post transplant

Donor Assessment

• Cardiology
o ECG
o CXR
o FSL
o Cardiology referral in:-
• Male > 45y/o
• Female > 50y/o or premature menopause
• Donor > 35 y/o with coronary risk factors


Respiratory
o Resp referral in:-
• Chr lung disease
• Chr smoker

Renal
o RP
o Sugars
o Ca, Po4
o Uric Acid
o Urine cysteine, uric acid, ca, po4 (3 times)
o 24h creat cl (3 times)
• Exclude < 80mls/min/1.73m2
o 24h urine protein (3 times)
o USG KUB
o IVP
o DTPA
o Cr EDTA if DTPA is different from cr cl
o Renal angiogram/ MRA/ CTA

• Infectious screen
o VDRL
o TB
o UTI
o HIV
o HepB/C
o Toxo
o CMV

Donor Work-Up

Short Term Complications
Mortality- 0.03-0.05%
Atelectasis- 15-30%
Nerve injury- 6%
UTI- 5%
Pneumothorax- 5%
Wound infection- 3%
Blood transfusion- 3%
Pneumonia- 1%
Splenectomy- 0.3%
Pulmonary embolism- 0.3%

Selection criteria
• Siblings/parents → best
• 18-65 y/o
• ABO compatibility
• HLA A, B, DR phenotype →priority in 1 or 2 haplotype match

Absolute Contraindication
• Proteinuria > 0.3g/24h Hematuria
• Impaired renal function
• BP>140/90
• DM, IGT in family with T2DM, Gestational DM
• Psychiatric illness
• Coagulopathy
• Systemic illness with potential to cause renal ds
• Drug abuse
• Severe cardiac/pulmonary disease
• Infectious disease
• Pregnancy
• ADPKD
<30y/o: 2 cyst in either kidney, 30-59 y/o: 2 cyst in each kidney
Over 60: 4 cyst in each kidney

Relative Contraindication
• BMI>30
• Related donor and recipient has T1DM
• Nephrolithiasis. Safe if
o Inactive for 10 yrs
o 1 stone passes only
o no radiological evidence of stone
• Malignancy
• HepB/C
o Hep B: OK if donor is eAg-ve and recipient has AB
o Hep C: OK if both have same genotype
• Alport. Safe if
o Male and no hematuria
o Female relatives may be carrier. Need to counsel that their son may have the disease
o Donor with no alport may cause anti GBM