Division of Organ Transplantation

Resident Manual

Rhode Island Hospital A Lifespan Partner

Compiled by:

Paul Morrissey, MD Revised: December 2011

Available at: http://intra.lifespan.org/surgery.

Actuarial Survival

Tacrolimus + Mycophenolate regimen

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Table of Contents

ORDERS

Admissions to the Transplant Surgical and Medical Services

ORDERS after donor nephrectomy

ORDERS for renal transplant patients

Post-op

MEDICATIONS

Transplantation historical timeline

Immunosuppressive medications – Mechanism of Action

Transplant medications - routine dosing and prescriptions

Steroids

GRAFT DYSFUNCTION

Early considerations after renal transplant

Algorithm for work-up of rising creatinine

Infectious complications

Late complications after transplantation (Ciba)

Clinical rejection

Hyperacute

Acute rejection

Chronic rejection

GENERAL INFORMATION

Success of renal transplantation

Live donor versus Cadaver Renal Transplant (CRT)

Organ Donation

Dialysis Access Game Plan

ASTS WEBSITE (Resident Education in Transplantation) http://www.asts.org/FellowshipTraining/ResidentEducati

on/Resident1.aspx

Administrative issues

Transplant office and clinic

APC 921

444-5285 or 444-8345

Transplant surgeons

Kevin Charpentier 350-3848 (b)

Paul Morrissey 350-1385 (b)

Transplant physicians

Reg Gohh 350-5553 (b)

Terri Montague 350-7227 (b)

Staci Fischer 350-9022 (b)

Transplant Manager

Bette Hopkins-Senecal 350-5523 (b)

Transplant Clinical Coordinators

Nancy McNamara, RN 444-3186

Mary Ellen Espanola, RN 444-3284

Rounds

The team meets at 9:00 (8:30 on Thursday for Journal Club) to

discuss patients. Walk rounds begin at 4:00 PM on 4A or 5ISC.

Clinic (Surgery residents attend one clinic per week)

Tuesday - Dr. Morrissey (1:00 PM)

Friday - Dr. Charpentier (9:30 AM)

Surgery

Renal transplant with Senior Resident or AR-III (cadaveric)

Donors by AR-II; AV access with AR I or II

PD catheters and PermCaths with AR I or II

Resident Duties – Routine care of in-house transplant surgical

patients, discharge summaries, admissions, consultations and in-

house pre-ops.

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Kidney Donors Donor nephrectomy is unique among surgical procedures as the patient is

undergoing major surgery with all its risks (1% incidence of major

complication, 0.03% incidence of mortality) for no medical benefit.

Therefore, special attention to detail is required for the donor‟s safety.

Eligible donors are in good health, ABO compatible with the recipient

and have normal renal function. Spouses and close friends are potential

unrelated donors. Pre-op testing consists of physical exam, labs, 24-hr.

urine collection for creatinine clearance, renal ultrasound and CT

angiogram (for renal anatomy). The surgery is performed (1)

laparoscopically, (2) mini-open nephrectomy via an anterior-

retroperitoneal approach or (3) via a flank incision (over 11th rib).

POST-OP – Typical course through discharge

Prophylactic Rx: Spirometer, heparin 5000U sc bid x 48 hr

Sequential compression devices (Venodyne boots)

Pain management: PCA for 1-2 days

Clear liquid diet

POD #1

Heplock or KVO I.V. when tolerates adequate P.O.

D/c Foley catheter; d/c Venodyne boots when ambulating

Advance to regular diet as tolerated.

Check CBC, BUN/creatinine

POD #2

Check CBC, BUN/creatinine

POD #3

D/c PCA

Vicodin (or Percocet) for analgesia

Laxative prn (begin P.O., then use suppository if no effect)

D/c to home today or next day

F/U 10-14 days in Transplant Clinic

One week supply of analgesics (usually 20-30 tablets)

Donors

There are two sources of kidneys: either a living donor (relative,

spouse or friend, e.g.) or a deceased donor (brain dead or donor

after circulatory death (DCD)). Live donors are preferred for many

reasons, especially the reduced time on dialysis for the recipient.

Item Live donor Deceased donor

Allograft half-life 12-14 years 8-9 years

Waiting time 2 - 4 months 18 - 48 months

Donor Age 18 - 65 4 - 70

Quality of kidney Excellent Fair to excellent

Immediate function 97 % 50 %

DGF* 2 % 30 %

Hospital LOS 5 - 7 days 5 - 14 days

Surgery Planned Urgent

Immunosuppression Lower doses Standard

Risk of acute rejection 5 - 10 % 15 - 20%

*Delayed graft function – requires dialysis after transplant.

Requirements for live donor renal transplants

1. Compatible blood type – ABO, HLA matching not required

2. Excellent health – low operative risk

3. Normal renal function – 24 hour urine collection, U/S and CT

4. Proper motivation (voluntary donation)

Risks to the Donor

Hyperchloremic metabolic acidosis (Kellum JA. CCM 2002; 30: 259.)

Major complication < 1 % (e.g. - bleeding, injure adjacent structure,

AMI, DVT or PE, significant injury to donor kidney)

Lifetime risk of HTN, ESRD – same as general population.

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DECEASED ORGAN DONORS

Brain Dead Donor

Standard criteria donor (SCD) – other than ECD

Expanded criteria donor (ECD)

1. Donor age > 60 years or

2. Donor age > 50 with 2 of the following:

a. Pre-retrieval creatinine > 1.5 mg/dL

b. Death from CVA

c. History of hypertension

Donor after Circulatory Death (DCD)

Donor with irreversible brain injury, family decides on CMO

status, organs (usually kidneys ± liver) are recovered after

extubation and progression to circulatory arrest (5 minutes).

TRANSPLANT RECIPIENT MANAGEMENT - FLUIDS

0.9 % Saline

Volume - most patients get 2-3 L in the OR and cc/cc

replacement of UO thereafter. Hypovolemia is unusual post-

op. The CVP is a rough (though inaccurate) measure;

however aiming for a CVP > 10 is a reasonable guide.

Urine output – most live donors have an initial UO of 200-1000

cc/hr, while a deceased donor with ATN might be expected

to be oliguric.

BP - high normal or slightly elevated BP is best for renal

reperfusion. Even low normal BP can result in ATN and

requirements for dialysis post-op. Goal > 130 mm Hg.

BP MANAGEMENT POST-OP

The short-term effects of hypotension (ATN, DGF) complicate

patient care after renal transplantation. The short-term effects

of hypertension are minimal, especially in this population with

> 85% incidence of hypertension. SBP <100 should be treated

promptly with IV fluids or a vasopressor (Neosynephrine qtt).

Pre-operative β-blockers should be continued as tolerated. .

KIDNEY TRANSPLANT RECIPIENT ORDERS

Expected LOS – 5 days (longer with delayed graft function, DGF)

ORDERS FOR PATIENT CARE

ADMIT to PACU, then 5ISCU

DIAGNOSIS: S/P renal transplant

VITALS: Hourly BP; target SBP > 130. Use neosynephrine PRN

for BP support if SBP and urine output are low.

ACTIVITY: OOB to chair POD #1, then ambulate

NURSING:

Strict I & O

CXR in PACU – R/O pneumothorax if new line placed.

Foley to gravity, d/c Foley catheter on POD #5

MEDS:

Induction: Thymoglobulin (high immune risk or high risk

of DGF) or basiliximab (Simulect).

Immunosuppression: usually tacrolimus (Prograf),

mycophenolate mofetil (CellCept) or EC-MPA (Myfortic)

and steroid taper as below.

Day 1 Solumedrol 250 mg IV times one, then

Prednisone taper as follows:

STANDARD

Day 2-6 Prednisone 30 mg po BID

Day 7-14 Prednisone 20 mg po BID

Day 15-21 Prednisone 10 mg po BID

Day 22-28 Prednisone 10 mg po AM, 5 mg PM

Day 29 onward Prednisone 10 mg po QD.

or

RAPID TAPER

Day 1 Solumedrol 250 mg

Day 2 Prednisone 40 mg po BID

Day 3 Prednisone 20 mg po BID

Day 4 Prednisone 10 mg po BID

Day 5 onward. Prednisone 10 mg po QD

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POM contains order sets for the donor and recipient. Some

explanations and instructions are given below.

LABS:

Every 6 hours x 24 hours, then q 12 hr on POD#2, then QD.

Tacrolimus level or CsA level QD beginning day after

medication begins.

Ca, Mg, PO4 may become depleted with high volume diuresis.

CBC with differential (lymph count guides Thymoglobulin

dosing)

IV Fluids:

Replacement cc/cc of urine output due to tubular injury

Replacement IVF is ½ NS (similar [Na+] to urine)

D5 ½ NS is “maintenance” until adequate PO intake

Other management issues:

JP Drain – d/c when output < 50 cc/ day

Foley – d/c on POD #5

PCA – d/c on POD # 2

Dressing – change prn and always by POD # 2

Daily weights

CVL – d/c on AM of discharge

RN may draw labs from CVL

Rationale for ancillary medications after renal transplant

Antacids – Ulcer prophylaxis due to steroids and for dyspepsia

due to Cellcept (common side effect)

Bactrim Single Strength – PCP, Nocardia and UTI prophylaxis

Mycelex – Thrush prophylaxis

Ketoconazole - Fungal prophylaxis and CYT p450 3A

inhibition (used when CsA is 1* immunosuppressant).

Valganciclovir - CMV and EBV (Mononucleosis and

lymphoma) prophylaxis.

BP medications – 85% of recipients have HTN. Blood pressure

at the time of discharge is often high (due in part to immuno-

suppression and volume overload) and BP is gradually adjusted

as an outpatient.

Insulin – Type I DM or patients on oral agents at the time of

transplant invariably require insulin therapy on discharge.

Managing BS after transplant is optimally done with a QD

Lantus regimen and Humolog sliding scale transitioned to pre-

meal short-acting insulin. Minimally elevated FSBS (120 –

200s) can initially be controlled with sliding scale insulin and

adding an oral agent or longer-acting preparation as indicated.

Prudent use of peri-operative Lantus (for patients on insulin pre-

transplant) and sliding scale insulin should limit the need for an

insulin drip in most patients.

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Preferred peri-operative and long-term blood pressure management:

Class Example Note

Beta-blocker Atenolol, Toprol First line

CaCB (Dihydropyridine) Norvasc Second line

Alpha blocker Cardura QHS dosing

Diuretic Lasix Volume overload

Treatment of Hypertensive Urgency vs. Emergency

A hypertensive emergency is a condition in which elevated blood

pressure results in acute target organ damage. The systems primarily

involved are the CNS, the CV system, and the kidneys. In order to

diagnose malignant hypertension, papilledema must be present.

Accelerated Htn is defined as a recent significant increase over

baseline blood pressure that is associated with target organ damage.

Funduscopic exam may show vascular damage (flame-shaped

hemorrhages).

Hypertensive urgency must be distinguished from emergency.

Urgency is defined as severely elevated blood pressure (systolic

>220 mm Hg or diastolic >120 mm Hg) with no evidence of target

organ damage.

Hypertensive emergencies require immediate therapy to decrease

BP within minutes to hours. No evidence suggests a benefit from

rapidly reducing BP in patients with hypertensive urgency. Such

aggressive therapy may harm the patient, resulting in cardiac, renal,

or cerebral hypo-perfusion. Increasing the dose of an existing BP

med or adding another medication is the best approach.

The cardiac presentation of malignant Htn is angina, AMI or CHF.

Neurological presentations are occipital headaches, cerebral infarct,

cerebral hemorrhage, or hypertensive encephalopathy. Hypertensive

encephalopathy is a symptom complex of severe hypertension,

headache, vomiting, visual disturbance, mental status changes,

seizure, and retinopathy with papilledema. Focal signs and

symptoms are uncommon. Renal disease presents as proteinuria,

microscopic hematuria, red blood cell casts, and oliguric renal

failure.

Differential Diagnosis: complications of pregnancy; cocaine;

withdrawal of alcohol, beta-blockers, or alpha-stimulants; renal

artery stenosis, pheo, Ao coarctation, and hyperaldosteronism.

Treatment of Hypertensive Urgency/Emergency – borderline cases

requiring more than gradual increasing of Htn medication.

Labetalol (alpha and beta-blocker) is a safe and effective agent to

consider, provided that the patient does not have asthma, heart

failure, or heart block.

Add 2 vials of Labetalol (40ml) to 250 ml D5W and start at

3ml/min. The BP should start to drop within half an hour. Labetalol

can also be given as a 20mg bolus over 2 minutes; repeated with a

40 mg dose every 10 minutes until the desired BP is reached or 300

mg have been given. Response is usually within 5-10 minutes.

Hypertensive Emergency (Encephalopathy, AMI, CHF or unstable

angina) - Admission to ICU is warranted.

Nitroprusside (Nipride, 0.25 ug/kg/min). It dilates both arteries and

veins and is not associated with tachyphylaxis. It's onset of action is

rapid and minute by minute BP monitoring is required.

Hydralazine 5-25 mg IV, coupled with a beta blocker to prevent

reflex tachycardia is a safe alternative. Hydralazine may be repeated

q4h as necessary.

Esmolol is also a reliable drug in this situation and can be

administered by IV infusion.

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Timeline of Immunosuppressive Agents in Transplantation

1954 – None available (Identical twin transplant - PBBH)

1959 - Total body irradiation and cancer chemotherapeutics

Fraternal Twins in Boston and Paris are first successful

transplants with immunosuppression.

1960 - 6-mercaptopurine

1961 – Azathioprine (imidazole derivative of 6-MP)

First successful Cadaver Renal Transplant reported.

1962 - Prednisone

1965 – Polyclonal antibodies to T-cells: ALG / ATGAM with

serum obtained from horses, goats, and rabbits.

1975 - Donor specific transfusions given pre-transplant

1975 - OKT3 (mouse monoclonal Ab versus CD3)

CD3 = receptor expressed on all T cells

1978 - Cyclosporine (available clinically in 1983)

1994 - Tacrolimus (FK506)

1995 - Mycophenolate mofetil (Cellcept)

1998 - IL-2R monoclonal Ab (Simulect, Zenapax)

1999 – Thymoglobulin Rabbit – ATG)*

1999 - Sirolimus (Rapamune)

* FDA approved for treatment of rejection versus other agents

approved for the prevention of organ rejection following

renal transplantation.

Drug Protocols and Rationale

Triple Therapy: a three-drug combination for immunosuppression,

which allows for adequate immunosuppression with modest doses

of all three drugs. In theory, side effects of each drug are

minimized. Prograf® (tacrolimus)

Cellcept® (mycophenolate mofetil) of Myfortic (MPA)

Prednisone

Prograf® (tacrolimus)

Imuran® (azathioprine, if Cellcept not tolerated)

Prednisone

Neoral® (cyclosporine)

Azathioprine or Cellcept

Prednisone

Rapamune® may be substituted for Prograf, Neoral or Cellcept

Induction Therapy – Antibody (Simulect, Thymoglobulin (rabbit

antithymocyte globulin) or OKT3) used at the time of the initial

transplant as prophylaxis rather than therapy for acute rejection.

Currently, we offer Ab induction to patients with a PRA > 20%,

repeat transplant, high likelihood of delayed graft function or a plan

to limit other immunosuppression (steroid withdrawal, e.g.).

OKT3 – monoclonal Ab to CD3 (First mAb ever in clinical use.)

Used for the treatment of severe acute rejection. Associated with

cytokine release syndrome (fever, hypotension, CHF).

Basiliximab – chimeric mouse-human mAb to IL-2 receptor (CD25)

Benefit in reducing acute rejection (40% versus 20% at 6

months) and allowing safe steroid minimization.

rATG – polyclonal Ab against many T-cell antigens produced by

immunizing rabbits with human thymocytes. Pre-medicate with

steroids, diphenhydramine (25 mg) and acetaminophen (650 mg) to

prevent cytokine release syndrome.

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TYPICAL IMMUNOSUPPRESSION PLAN

INDUCTION

Basiliximab (Simulect) Dose: 20 mg on POD #0 and #4

Indications: Low immunologic risk, future Thymoglobulin

exposure planned (PAK), high medical risk for over-

immunosuppression

Utility: A meta-analysis of randomized trials. Transplantation

2004; 77: 166.

rATG (Thymoglobulin) Dose: 1.5 mg/kg/d (round to 25 mg increments; maximum dose

150 mg) via CVL

Higher immunologic risk (High PRA, DSA) or high likelihood

of DGF

Usual dose: 1.5 mg/kg on day of surgery and 2 more doses

(4.5 mg/kg)

DGF or high immunologic risk: 1.5 mg/kg for 4-5 doses

(6.0-7.5 mg/kg)

MAINTENANCE

Prograf (Tacrolimus) Dose: Target 7-10 ng/ml first 2 months, 6-8 ng/ml 2-6 months,

5-8 ng/ml after 6 months.

Mycophenolic acid (EC-MPA, Myfortic) Dose: 720 BID

Consider: 540 BID less than 50 kg or 360 BID for elderly

patients, prior GI symptoms, or current leukopenia.

Methylprednisolone / Prednisone Rapid taper (10 mg by day 5) = 500, 250, 40 bid x 1 day, 20

bid x 1 day, 10 bid x 1 day, 10 QD.

Standard taper (10 mg by day 29) = 500, 250, 30 bid x 5

days, 20 bid x 7 d, 10 bid x 7 d, 15 mg/d x 7, then 10 mg/d.

Pancreas: see taper (including methylprednisolone x 3 d) to

10 mg/d on POD #7.

NOTES:

1. Pancreas Transplantation: as above with routine

Thymoglobulin induction.

2. 0-MM allograft: consider no induction, rapid steroid taper or

two-drug regimen.

3. DSA present – consider IVIG at induction and

Plasmapheresis.

PROPHYLAXIS

Bactrim SS – begin post-op day #3 and continue for one year.

Clotrimazole troches – begin post-op day #3 and continue for

one month.

Valganciclovir – 900 mg QD* x 3 months for D+R+, D-R+. Rx

D+R- for six months. D-R- (Donor and Recipient negative

for CMV IgG): obtain serial CMV PCR every 2-4 weeks for

6 months, pre-emptive therapy if PCR > 500 copies.

(*450 mg/d for creatinine > 2.5, leukopenia, $$$ issues or low

body weight.)

Pancreas Transplant - Steroid Taper:

Methylprednisolone 70 mg IV 2XD for one day then

Methylprednisolone 35 mg IV 2XD for one day then

Methylprednisolone 17.5 mg 2XD for one day then

Prednisone 15 mg PO 2XD for one day then

Prednisone 25 mg PO daily for one day then

Prednisone 20 mg PO daily for one day then

Prednisone 10 mg PO daily until discontinued

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CORTICOSTEROIDS (Prednisone, Solumedrol)

Rapid taper to 10 mg daily

1. Bind intracellular receptors blocking DNA/RNA synthesis

2. Inhibit IL-1 secretion (costimulator); Inhibit MAC chemotaxis

3. Anti-inflammatory

4. Apoptosis at high doses (pulse therapy lympholysis)

5. Toxicity: Steroid side effects

Hypertension, Sodium / fluid retention

Psychosis / emotional instability

Peptic ulcer disease

Delayed growth, Amenorrhea, Osteopenia

Centripetal obesity (Cushingoid appearance)

Glucose intolerance, Hyperlipidemia

Glaucoma / cataracts

Neutrophil dysfunction / sepsis

AZATHIOPRINE (Imuran)

2-3 mg / kg / day

1. Blocks the synthesis of purine nucleotides

2. Toxicity: leukopenia (common), GI upset (rare)

MYCOPHENOLATE MOFETIL (Cellcept)

500 - 1000 mg BID

Enteric Coated - MYCOPHENOLIC ACID (Myfortic)

360 - 720 mg BID

1. Inhibitor of inosine monophosphate dehydrogenase (IMPDH)

2. Blocks de novo synthesis of purine nucleotides

3. Most cells, but not lymphocytes, can make purines via a salvage

pathway

4. Increased activity against Type II IMPDH which is abundant in

active lymphocytes

5. Efficacy: reduced AR to 20% compared to 40% with Imuran

6. Toxicity - leukopenia (common), gastritis, diarrhea.

CYCLOSPORINE (Sandimmune, Neoral)

Dose to achieve trough levels of 100-400 ng/ml

1. Peptide derived from fungus Tolypocladium inflatum

2. Blocks the mRNA (transcription) for IL-2 and INF-g

3. IL-2 formerly called “T cell growth factor” stimulates the

proliferation of T lymphocytes

4. Toxicity: Nephrotoxic in high dose

Hypertension

Neurotoxic (tremor, parethesias)

HyperK+

Renal tubular acidosis

Gout

Excess hair growth

Gum hyperplasia

TACROLIMUS (Prograf, "FK506")

Dose to achieve trough levels or 5-15 ng/ml

1. Macrolide ABx derived from Strep . tsukubaenis

2. Inhibits transcription of IL-2 similar to CsA (Also IL-3, 4, 5,

INF-g, TNF, GM-CSF, IL-2R)

3. Similar toxicity profile to CsA

4. Differences from CsA: More post-transplant diabetes

No cosmetic or lipid SE

Can reverse acute rejection

SIROLIMUS (Rapamune)

Dose to achieve trough levels 5-15 ng/ml

1. Derived from Streptomyces hygroscopicus (Easter Island)

2. Inhibits IL-2 signal; arresting T-cell in G1-S phase

3. Synergistic with CsA or tacrolimus (which fx in G0-G1 phase)

4. Not nephrotoxic (board question) !

5. Toxicity: hyperlipidemia, low cell counts, delayed healing,

lymphocele formation, Pneumonitis

6. Less mutagenic; actually in trials as CA chemotherapeutic

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Immunosuppression - DOSING

DRUG Low dose Moderate High Too much

CsA 80-150 150-250 250-400 Greater 400

Prograf 3-6 ng/ml 6 - 10 10 - 15 Greater than 15

Azathioprine (Imuran): 1-3 mg/kg once daily.

Mycophenolate mofetil (Cellcept, Myfortic): 500 – 1000 mg/ BID

depending on body size, GI side effects (heartburn, gastritis,

diarrhea) and WBC (reduce dose if < 3.0)

Steroids – slow taper to 10 mg/d at one month or rapid taper to 10

mg/d at POD #5 (see orders). If there is no history of acute

rejection continue taper to 5 mg/d after 3-6 months.

TRANSPLANT PRESCRIPTIONS:

Most patients use a mail-order pharmacy and Rx are filled by

our Transplant RNs, otherwise please discharge from the

hospital with a six-month supply of all meds (one month supply

with 5 refills). Pain med (narcotic) scripts must be written.

Immunosuppression

Prograf (tacrolimus) - supplied as 1 and 5 mg capsules

Neoral (cyclosporine) - supplied as 100 and 25 mg capsules

Cellcept - supplied as 250 or 500 mg capsules, 180 or 360 for MPA.

Prednisone - discharge with 10 mg capsules (#100)

Prophylaxis

Axid – QD or bid; Protonix (pantoprazole) if previous Hx of PUD

Bactrim SS (for PCP and UTI) - QD (6 months); then every MWF

Mycelex (for thrush) – QID with meals for 1 month.

Valganciclovir (for CMV) - 450 or 900 mg QD for 3-6 months.

Steroid equivalents

Duration Potency t1/2 Equivalent

Short

Hydrocortisone 1 8-12 hr 20 mg

Intermediate

Prednisone* 4 18-36 5 mg

Methylprednisolone 5** 12-36 4 mg

Long

Dexamethasone 25 36-54 0.75 mg

* Physiologic equivalent is 7.5 mg per day

** For simplicity we usually convert methylprednisolone

(Solumedrol) 1:1 with prednisone when patients can not take PO.

Stress steroids

Stress doses of steroids are not required for mild-moderate medical

illnesses (infections, MI, etc.) or for surgery after transplant (re-

operations, catheter removals, elective general surgery). Patients

require only their usual maintenance dose of prednisone. “Stress

steroids” may be beneficial in severely ill patients on long-term

steroids (sepsis in the ICU, severe asthma attacks, major multiple

trauma victim). Patients with evidence of adrenal insufficiency

(low BP, low sodium, unexplained MS changes, etc.) should

receive stress steroids.

References:

(1) Stress steroids are not required for patients receiving a renal

allograft and undergoing operation. JACS 1995, 180:532.

(2) Corticosteroid therapy in severe illness. NEJM 1997, 337:

1285.

11

Early Considerations after Renal Transplantation

The one and five year allograft survivals are:

1-year 5-year

Live donor renal transplant - 95 % 88 %

Cadaver renal transplant* - 88 % 70 %

*(immediate function)

Cadaver renal Tx (DGF*) - 70 % 50 %

DGF – delayed graft function defined as oliguria necessitating dialysis

after transplantation.

Surgical considerations

Bleeding - anastomotic, hematuria, peri-graft.

Thrombosis - renal artery or vein (1%)

Ureteral or urethral (Foley) obstruction - use of stent

Urine leak - immediate or delayed (weeks)

Ureteral stricture – weeks to years later

Obstruction by compression (lymphocele, urinoma)

Early renal transplant dysfunction

Immediate function with high output diuresis – due to fluid

overload, osmotic diuresis from inadequate hemodialysis,

intraoperative diuretics, proximal renal tubular injury

Delayed function – due to ischemia-reperfusion injury

Risks: donor age, donor hypotension and vasopressor use,

cold and warm ischemic times

SE: cardiac, pulmonary edema

Cytokine release syndrome with use of ATG

ATN

Hypovolemia (CVP), hypotension, MI, CHF, seizure,

sepsis

Cyclosporine or tacrolimus (CNI) toxicity

Rejection – unusual in the first week after transplantation.

Algorithm: renal transplant dysfunction

Hx and PEx Differential Dx

Weight gain / edema Dehydration

Oliguria Drug toxicity

Hypertension Infection

Allograft pain Hydronephrosis Stricture

Fever, chills, myalgias Rejection Lymphocele

Technical pblm Compression

EVALUATION

Labs: Chem 7, CBC, LFT‟s, CsA or Tacrolimus level, U/A + C &

S, Urine sediment (ATN, PMN).

Pre-biopsy labs: PT, PTT, CBC, T & C 2U, bleeding time.

Usual approach:

Hydrate overnight, thorough history (new meds such as ACEI,

NSAIDs, Abx; recent illness, change in BP, glucose control).

Check labs, urinalysis, and urine sediment.

Renal consult to assist with assessment and perform biopsy.

Ultrasound to R/O technical problem.

Renal biopsy (2 U/S-guided 18G core biopsies of renal cortex).

Common surgical complications after renal transplantation

Ureteral complications (10%) – leak or stricture (obstruction)

Lymphocele (5%) – may be incidental or cause compression

Wound infection (3%), Hernia (3%)

Colon perforation (diverticulitis - 3%)

Pathologic fractures

Tertiary hyperparathyroidism – most resolve in 6-12 months. Some

require cinacalcet or parathyroidectomy (one gland or 3 ½ glands).

Progressive vascular disease including amputation

Cancer – skin, renal and other solid tumors.

12

Infectious complications after transplantation

Early Middle Late

(0 - 6 weeks) (6 weeks - 6 months) (> 6 months)

Wound infection CMV disease PCP*

Line sepsis PCP* Cryptococcus

UTI / urosepsis Candidiasis Pneumonia

Herpes Nocardia UTI

Pneumonia Polyoma virus PML

Thrush EBV Viral infections**

Dialysis access Legionella Mycoplasma

* Incidence <0.1 % with Bactrim prophylaxis.

** CMV most likely in middle period. RSV, HSV, adenovirus, influenza

can occur in middle and late periods.

Routine work-up is based on Hx, PEx, post-op period, etc., but may

include bacterial, fungal, and viral cultures, mycoplasma and acid

fast (TB), Legionella cultures, silver stains for PCP, cryptococcal

Ag.

CMV is diagnosed by rapid spin-amplified viral culture, IgM

antibody, CMV PCR or by inclusion bodies in a tissue biopsy. The

diagnosis is suspected when the triad of leukopenia, unexplained

fevers and flu-like symptoms is noted.

Pneumonia is evaluated by appropriate sputum samples. If these

can not be obtained within 6-12 hours of admission, proceed to

bronchoscopy. PCP is extremely rare with Bactrim prophylaxis.

Polyoma (BK) virus affects the urinary tract and causes renal

transplant dysfunction. The inflammatory infiltrate mimics acute

rejection.

Pneumonia evaluation

Sputum or induced sputum

Bronchoscopy PRN

AFB

Fungal stains and cultures

PCP DFA

Legionella urinary Ag

Histoplasmosis serology (P. Rico and Ohio River Valley)

Coccidioidomycosis (Southwestern USA)

Cryptococcus serum Ag

Nocardia smear and stain

Respiratory viral cultures

CMV – biopsy

Chlamydia

Open lung biopsy - PRN

13

Success Rates for Renal Transplantation

Allograft survival based on donor source and HLA matching.

Graft survival

Category N 1-year 3-year

HLA-ID sibling 1984 97 95

Spouse donor 368 95 85

Other living unrelated 129 97 81

Parent donor 3368 95 82

Cadaver donor 43,341 85 70

CRT with DGF 11,060 70 60

Terasaki et al. High survival rates of kidney transplants from spousal and

unrelated donors. NEJM 1995; 333: 333-6.

Long-term Survival after AMI in Dialysis Patients

Overall mortality after AMI (%)

Category 1-yr 2-yr 3-yr 4-yr

Patients on hemodialysis 59 73 81 90

Dialysis + DM 62 77 86 93

Dialysis + Htn 61 73 81 90

Transplant recipients* 24 30 36 47

Renal Tx + DM 29 36 43 54

* Differences persisted after adjustment for age and other demographic

factors, cause of renal failure, duration of ESRD and coexisting illnesses.

Herzog et al. NEJM 1998; 339: 799-805.

Chronic Renal Failure – A Vasculopathic State (NEJM 1998;

339:841.)

2/3 of ESRD patients have DM or Htn

Reasons are multi-factorial

Renal dysfunction

Chronic inflammatory state

Hyperhomocysteinemia

Syndrome X

Anemia

Chronic volume overload

Elevated oxidized low-density lipoprotein

Secondary hyperparathyroidism

Endothelial cell dysfunction: excess ET-1 and diminished NO

LVH, impaired cardiac microcirculation, tendency to

arrhythmias.

14

Rejection – Banff Schema (Am J Tx: 2008 8(4):753-60.)

Borderline changes: „Suspicious‟ for acute cellular rejection. No

intimal arteritis is present, but there are foci of mild tubulitis (1–

4 cells/tubular cross-section) and mild inflammation.

Acute/active cellular rejection

T-cell-mediated rejection graded by histopathological findings:

IA Cases with significant interstitial infiltration (>25% of

parenchyma affected) and foci of moderate tubulitis (>4

mononuclear cells/tubular cross section or group of 10 tubular cells)

IB Cases with significant interstitial infiltration (>25% of

parenchyma affected) and foci of severe tubulitis (>10 mononuclear

cells/tubular cross-section or group of 10 tubular cells)

IIA Cases with mild-to-moderate intimal arteritis (v1)

IIB Cases with severe intimal arteritis comprising >25% of the

luminal area (v2)

III Cases with ‘transmural’ arteritis and/or arterial fibrinoid

change and necrosis of medial smooth muscle cells also with

lymphocytic inflammation (v3).

Chronic/sclerosing allograft nephropathy

Fibrosing changes in the allograft, with or without features of true

alloimmune injury to the graft. Histopathological findings

reveal “IFTA” interstitial fibrosis and tubular atrophy which is

graded mild, moderate and severe, usually with features of

glomerular injury or sclerosis.

Humoral rejection (B cell (Ab) mediated):

Allo-Ab may cause immune injury to the allograft kidney. The

diagnosis requires (1) renal transplant dysfunction, (2) presence

of circulating anti-donor Ab (donor specific Ab) and (3) C4d

detected by immunoperoxidase. Evidence of acute cellular with

occult humoral rejection is often identified with late AR

episodes.

Pancreas transplantation

Since the first performance of pancreatic transplantation (PTx) in

1966 the procedure has come of age. As of June 2003, the

International Pancreas Transplant Registry (www.iptr.umn.edu) had

recorded more than 19,600 PTx, out of which over 14,300 were

done in the USA. Most PTx are performed in patients with diabetic

nephropathy requiring kidney transplantation. These patients

already require chronic immunosuppression and a functioning

pancreas transplant provides the most efficacious method for

achieving a normal glucose and hemoglobin A1C. In this setting

there are two options:

SPK - simultaneous pancreas and kidney transplantation

where one deceased donor provides kidney and pancreas or

PAK - pancreas after a previously performed kidney

transplant (PAK), usually after a LDRT.

Less common is pancreas transplant alone (PTA), performed in a

patient without diabetic nephropathy, where the trades off of

achieving normoglycemia with the possible complications of

chronic immunosuppression have to be weighed closely. Each year

in the U.S., approximately 900 SPK and 500 solitary pancreas

transplants are performed (compared with 16,000 kidney Tx).

Currently the whole organ obtained from a cadaver donor is used.

The organ is placed in the pelvis opposite to the kidney transplant

and receives its blood supply through the iliac vessels with the

exocrine secretions drained into the small intestine or the bladder.

A newer surgical innovation has been portal venous drainage of the

pancreas allograft. The traditional systemic venous drainage

achieves euglycemia at the expense of hyperinsulinemia. Portal

venous drainage replicates the physiological state and due to the

first pass effect achieves euglycemia with normal insulin levels.

15

Patient survival at one year for 1999-2003 US cadaveric pancreas

transplants was at least 94% in all categories (SPK 95%; PAK 94%;

PTA 98%). After SPK, pancreas graft survival rate at one year for

1996-2000 was 84.7%; kidney graft survival was 92%. For solitary

pancreas transplants, pancreas graft survival at one year was 78.5%

for PAK and 78.2% for PTA.

Indications for pancreas transplantation

1. Presence of insulin-requiring diabetes mellitus*.

2. Ability to tolerate surgery and immunosuppression.

3. Adequate cardiopulmonary function.

4. Absence of organ system failure (other than kidney: creatinine

clearance < 30mL/min for SPK; for PAK > 40 mL/min.).

5. Emotional and psychosocial suitability.

6. Presence of 2 or more diabetic complications

Proliferative retinopathy

Nephropathy (hypertension, proteinuria, decreased GFR)

Peripheral or autonomic neuropathy

Microangiopathy

Accelerated atherosclerosis

Glucose hyperlability, hypoglycemia unawareness

* As a general rule, most candidates have absolute insulin deficiency as

determined by an undetectable c-peptide, rather than a component of

insulin resistance (Type II DM).

Absolute contraindications

1. Insufficient cardiovascular reserve (coronary angiography with

uncorrectable or untreatable CAD, or recent MI).

2. Active infection.

3. History of malignancy treated within the past 3 years (excluding

nonmelanoma skin cancer).

4. Positive HIV serology.

5. Positive hepatitis B surface antigen serology.

6. Active, untreated peptic ulcer disease.

7. Ongoing substance abuse (drug or alcohol).

8. Major ongoing untreated psychiatric illness.

9. Recent history of medical noncompliance.

10. Inability to provide informed consent.

11. Any systemic illness that would severely limit life expectancy or

compromise recovery.

12. Significant, irreversible hepatic or pulmonary dysfunction.

13. Positive lymphocytotoxic cross-match.

Relative contraindications

1. Age less that 18 or greater than 50 years.

2. Recent retinal hemorrhage.

3. Symptomatic cerebrovascular or peripheral vascular disease.

4. Absence of appropriate social support network.

5. Extreme obesity (greater that 150% ideal body weight).

6. Active smoking.

7. Severe, untreatable peripheral vascular (aorto-iliac) disease.

Risk factors

1. History of myocardial infarction, congestive heart failure, or

previous open heart surgery;

2. History of major amputation or peripheral bypass graft;

3. History of cerebrovascular event or carotid endarterectomy;

4. History of hypercoagulable syndrome.

16

Care for the Pancreas Transplant Recipient

POST-OP – Typical course through discharge

Immediate Postop Orders:

-Basic orders: NPO, IVF, SCD/TEDs, Foley, NGT, Clinical

Nutrition consult, OOB and ambulate > TID with help

starting POD 1, Physical therapy consult, case management,

may take meds with sips, clamp NGT for 1hr after meds

-Daily Labs: Chem 10, Amylase, Lipase, CBC w/Diff,

Tacrolimus level (if tacrolimus has been started)

-Radiology: First thing in the AM patient should have an

abdominal US and put in the comment that it should be the

pancreas transplant protocol. Must call ultrasound first

thing in the AM to make sure patient is scheduled first.

-Medications:

Fluconazole 100mg IV 1XD

Bactrim SS PO 1XD

Valcyte 900mg PO 1XD (Adjust based on GFR)

Tacrolimus PO 2XD (dose to be determined)

Myfortic or Cellcept IV 2XD (Ask re: dose)

Steroid taper as follows:

POD 1 – Methylprednisolone 70mg IV 2XD

POD 2 - Methylprednisolone 35mg IV 2XD

POD 3 - Methylprednisolone 17.5mg IV 2XD

POD 4 – Prednisone PO 15mg 2XD

POD 5 - Prednisone PO 25mg 1XD

POD 6 - Prednisone PO 20mg 1XD

POD 7 - Prednisone PO 10mg 1XD

Aspirin 81mg PO

Heparin 5000 units SQ 3XD

Zofran PRN

Scopolamine patch PRN

PCA for pain

Home beta blocker and statin meds

POD#2:

-Induction with Thymoglobulin (1-2mg/kg) dose.

Premedicate 30 -60 min before with solumedrol, Tylenol

650mg PR, and 50mg IV Benadryl. Run Thymo over 6 hrs.

-DC arterial line.

POD#3:

-Flag to 4A/4AE if clinically appropriate

POD#4:

-Induction with Thymoglobulin (see POD#2)

POD#5-7:

-DC home with services

**Refer to the pancreas transplant manual on the Lifespan intranet

for a more detailed description of the procedure and protocols.

17

GAME PLAN FOR HEMODIALYSIS ACCESS

Renal replacement therapy

Hemodialysis (HD): Catheter, fistula or graft (PTFE)

Peritoneal dialysis (CAPD)

Renal transplantation (Cadaver or Live Donor)

CAPD (developed in the 1970‟s) is available to individuals with the

direction and ability (physical and emotional) to perform dialysis at

home. Most patients prefer HD. Less than 10% opt for CAPD in RI

Evaluation for hemodialysis access includes:

Pulse – Bilateral brachial artery and radial artery pulses

Suitable vein

Superficial – cephalic or basilic

Deep – basilic vein in upper arm

Two questions must be answered before access surgery:

1. Is the patient medically stable for surgery?

No CHF, chest pain, K+ > 6.5, sepsis, etc.

2. What access operation should be done?

Wrist fistula, BCF, Basilic vein fistula (TPBVF), leg loop,

AV graft, PermCath or consider peritoneal dialysis.

Access considerations

Prefer non-dominant arm in case of paresthesia or steal.

Ask the RN to place a “red band” on the arm indicating “No IV

placement or blood draws”.

Transposed basilic vein fistula if no superficial vein noted on

exam.

Ultrasound or venogram multiple prior access procedures or

evidence of central stenosis (arm swelling, collateral veins,

etc.).

Graft (6-mm PTFE or Bovine carotid artery) considered if

dialysis required in fewer than 6 weeks, no reasonable vein, or

patient with limited life expectancy. (NEJM 2009; 360:2191).

OPTIONS:

Fistula: RCF, BCF below the antecubital fossa, BCF above

the elbow, TPBVF (transposed basilic vein fistula).

Graft: Forearm loop, upper arm, subclavian artery, femoral.

Catheter: highest likelihood of sepsis, clotting, inadequate

flow.

Uncommon (last resort) options:

Translumbar or transhepatic catheter

HERO: hybrid AVG-central catheter.

Work-up: CBC, Chem 7, EKG OR. Dialysis access is an

“urgent” surgery; only acute medical issues (CHF, hyperkalemia >

6.5, active angina, new arrhythmia, active bleeding, etc.) require

investigation or treatment prior to surgery.

Note:

Patients on routine dialysis should have a recent K+.

Patients with dialysis access problems (poor flow, incomplete

dialysis treatment prior to surgery); those with a history of high K+

or patients not yet on dialysis should have the K+ checked on the

day of surgery.

Cardiac pacers: when possible document the type, make and

model of the pacer. This information is useful for re-programming

after surgery. Consider placing access on the opposite side of the

pacer as SCV stenosis is fairly common 2* to pacing wires.