Uttam G. Reddy, MD
Medical Director, Kidney Transplant Program
August 11th, 2015
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Background & Importance of Transplantation
Basics of Kidney Transplant Management
Immunosuppressive Medications
Common Post Transplantation Issues
Vaccinations
Key drug-drug interactions
Summary
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The first kidney transplant surgery was in
December 1954 (over 60 years ago) at what is
now Brigham and Women’s Hospital in Boston.
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The recipient, who received the kidney from his
identical twin, lived for 8 more years.
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The lead surgeon, Dr. John Murray was awarded
the Nobel Prize for his work in organ
transplantation.
Wolfe et al. NEJM 1999
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Currently 123, 193 people waiting for
lifesaving organ transplants in the US
 101,662 are on the KIDNEY transplant waitlist
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In 2014, 17,105 kidney transplants took place
in the United States.
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The Greater Los Angeles area is
represented by the One Legacy
Organ Procurement Organization.
• O Blood Group: 10 Years
• A Blood Group: 7- 8 years
• B Blood Group: 8 -10 years
• AB Blood Group: 5 - 6 years
OPTN/SRTR 2013 Annual Data Report: Kidney AJT Jan 2015.
“The Chain”
Trailer from Documentary entitled “The Chain” in 2014
OPTN/SRTR Annual Report 2012
OPTN/SRTR Annual Report 2012
More priority for Younger ESRD patients.
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Active infection
Recent Malignancy
Uncontrolled psychiatric disorders
Lack of social support
Substance abuse
Severe or Irreversible heart-lungliver disease
 Can be considered for dual organ
transplant
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AGE?????
 Some centers have age <70.
 UCI will evaluate them on a case by
case basis.
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Immunosuppressive drug coverage for 3
years post transplant for Medicare patients
 Continuation for payment requires either
disability OR > 65 years of age
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Medical coverage
 20% co payment beyond year 3
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Compared to remaining on dialysis patient’s
undergoing kidney transplantation
 Live longer
 Have a better quality of life
 Save on overall medical costs
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Kidney Transplantation is the optimal therapy
for ESRD patients who can undergo
transplantation
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Living
 Related
 Unrelated
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Deceased
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Directed
KDPI < 85%
KDPI > 85%
Pediatric
Dual Kidney
Public Health Service (PHS) High Risk
Death after Cardiac Death (DCD)
Hepatitis C
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Complexity of Immunosuppressive medications
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Susceptibility
 Infection
 Malignancy
 CVD
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Multiple co-morbidities
 DM
 Peripheral Vascular Disease
 Frailty
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Followed closely by a Transplant
specialist (nephrologist or
surgeon) for the first 3-6 months..
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Thereafter, they are often comanaged by the general
nephrologist or primary care
provider.
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Communication between
transplant team and outside
provider is KEY to post transplant
management.
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Transplant Surgeons
Transplant Nephrologists
Social Worker
Transplant pharmacist
Dietician
Nursing Coordinators
 Pre Transplant, Wait-List, Post-Transplant
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Internal Medicine (PCP, inpatient hospitalizations)
General Nephrologists
Cardiology (pre and post transplant)
Endocrinology (post transplant diabetes)
Infectious disease (pre and post transplant)
Hematology/Oncology (pre and post)
Interventional Radiology
Pathology
Administrative support
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Assuming no major post transplant issues,
patients are followed up:
 Twice a week for the first month
 Once a week for the second month
 Every 2 weeks for the third month
 Every 1-3 months for the first year.
 After 1 year, some centers follow annually.
 At UCI, we follow every 3 months for the first 3 years.
 Primary nephrologist/PCP usually get involved in patients
care after 3-6 months post transplantation.
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Dosing of immunosuppressive medications
 Tacrolimus/CsA, steroid tapering
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Assessing allograft function
 Creatinine
 Urine Protein
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Screening/Monitoring for infections
 CMV, BK virus
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Bone Mineral Disease
 PTH, Vitamin D, Ca, P
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Risk for malignancy
 Skin cancer
 PTLD
 Age appropriate cancer screening
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Every Visit:
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Basic chemistry panel (includes Mg,Phos,Ca)
CBC (with diff is recommended)
Urinalysis
Immunosuppression drug level
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▪
▪
▪
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Tacrolimus (Prograf)
Cyclosporine (Neoral)
Sirolimus (Rapamune)
Everolimus (Zortress)
Occasional:
 CMV DNA PCR, BK PCR
 HgA1c, Vitamin D, PTH, Lipid Panel
 Urine protein/creatinine ratio (if proteinuria)
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Induction Agents
 Thymoglobulin
▪ Rabbit antithymocyte globulin
 Basilixumab (Simulect)
▪ Chimeric mouse-human Ab (CD-25) of IL-2 Receptor
 High dose steroids (tapered)
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Maintenance Agents
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Calcineurin Inhibitors: Tacrolimus or Cyclosporine
Anti-metabolite: Mycophenolate or Azathioprine
Steroids: Prednisone
mTOR inhibitors: Sirolimus, Everolimus
Belatacept (newer medication) – CD80/86 antagonist
▪ Used in place of Tacrolimus or Cyclosportine
Outcomes of Renal Allografts
100
80
96
• Radiation
• Prednisone
• 6-MP
85
90
80
65
Percent
90
65
60
60
60
40
40
20
• AZA
•ATGAM
• Cyclosporine Emulsion
• Tacrolimus
• MMF
• Dicluzimab
• Basiliximab
• CY-A
• OKT3
45
45
• Thymoglobulin
• Sirolimus
35
25
Rejection <12 mo
1 Year Survival
15
0
‘60
‘65
‘70
‘75
‘80
‘85
Year
‘90
‘95
‘00
Adapted from Stewart F, Organ Transplantation, 1999
OPTN/SRTR 2013 Annual Data Report: Kidney AJT Jan 2015.
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General Guidelines to Tacrolimus Dosing
Months After Transplant
Tacrolimus Goal
0-3 months
8-12 ng/ml
3-6 months
7-9 ng/ml
6-12 months
5-8 ng/ml
> 12 months
4-7 ng/ml
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Dosing is based on checking TROUGH levels of
Tacrolimus.
 IMPORTANT to check Trough levels at 7-8am on all
inpatients with kidney transplant.
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Half life (t ½) is on the order of 12 hours in a
steady state for most patients.
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Strong correlation between AUC and whole
blood trough levels.
 Good estimate of systemic exposure
CNI TOXICITY
INFECTION
REJECTION
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Allograft dysfunction
 Elevated Creatinine or Proteinuria
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Side effects of immunosuppression
Co-morbidities
 DM, HTN, Recurrent disease
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Infectious disease
Anemia
Cardi0vascular Disease
Malignancy
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Following transplantation, baseline creatinine tends
to be higher than 1.1, which is equivalent to a GFR of
less than 60 ml/min per 1.73m2
 Single Kidney
 Ischemic injury (deceased donor)
 Quality of the Kidney (Elevated KDPI)
 Use of Calcineurin inhibitors – Vasoconstriction,
ATN
 Size mismatch
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Pre Renal
 Over-diuresis or under hydration
 Diarrhea/GI issues
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Post Renal Obstruction
CNI Toxicity
Allograft rejection
Recurrent Glomerulonephritis
De Novo Renal Diseases (ATN, toxins)
Drug induced AIN
Renal Artery Stenosis
Infection
 Pyelonephritis
 BK nephropathy
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Two Categories of Acute Rejection
 Cellular (ACR) and Antibody mediated (AMR)
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Acute Cellular Rejection
 Interstitial infiltration with mononuclear cells and occasionally
eosinophils, and disruption of the tubular basement membranes by
the infiltrating cells (lymphocytes, plasma cells, etc)
 Tubulitis and intimal arteritis are the primary lesions.
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Antibody Mediated Rejection
 Capillary endothelial swelling, peritubular capillaritis, arteriolar
fibrinoid necrosis, fibrin thrombi in glomerular capillaries, and frank
cortical necrosis in severe cases.
 Donor Specific Ab
 C4d staining on biopsy – highly suggestive of AMR
ACUTE CELLULAR REJECTION
AB-MEDIATED REJECTION
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Acute Cellular Rejection
 For simple ACR, treatment is pulse dose steroids x 3 days,
followed by oral steroid taper
 If rejection is more severe (significant tubulitis, vascular
involvement), treat with Thymoglobulin x 5-7 days.
 Goal Tacrolimus increases to 8-10 ng/ml during rejection.
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Antibody Mediated Rejection
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Plasmapheresis and IVIG
If severe, can consider Rituximab
More recent studies looking into Eculizumab
Monitor Donor Specific Antibodies
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Recurrent Disease
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FSGS – 30%
IgA Nephropathy – 10-30%
Membranous 10-30%
Diabetes
De Novo Disease
 Transplant Glomerulopathy
 Secondary FSGS
 Diabetes
Gallon L, et al. NEJM, 2012; 366,: 1648
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Childhood onset of initial FSGS disease.
Rapid progression of initial disease.
White race.
Hx of recurrence in a prior allograft.
FSGS
Less frequent in African American populations.
White recipients of African American kidneys at a higher
risk.
Histological subtype does not predict recurrence.
Family history of FSGS - low risk of recurrence
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Concern for rejection
Unexplained rise in creatinine
Concern for BK nephropathy
Evaluate for recurrent disease
Proteinuria exceeding 1 gram/day
Protocol Biopsy
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Risk of biopsy
 Bleeding, Damage to other organs, infection, loss of
allograft.
 Complication rate on the order of 0.4-1%
 Graft loss occurs in 1/2500 biopsies.
Furness PN, et al. Transplantation, 2002
Magnesium wasting
associated with CNI use.
 Down-regulation of
renal expression of
TRPM6
 Thought to play a role in
NODAT, and CNI toxicity
 Risk of cardiac
arrhythmias.
 Treat with Mg
supplements.
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New Onset Diabetes after Transplant
(NODAT)
Insulin metabolism and excretion
 Hidden Diabetes
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Transplanted kidney – gluconeogenic
Immunosuppression increase blood sugars
 Tacrolimus
 Steroids
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Pre-existing risk factors predispose to DM
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Develops within the first few months
Continued risk for life of patient & allograft
Monitor fasting blood sugars and check
HgBA1C accordingly
Some Centers check HgBA1c at 3, 6, and 12
months, and annually thereafter.
Treat with diet modifications, exercise,
weight loss, pharmacological options
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Major cause of graft loss and death
 Common Infections
 Opportunistic Infections
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Higher risk in months 1-3 given
that’s when immunosuppression
is at its maximum.
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Can occur anytime, as long as
immunosuppressed.
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Upper respiratory tract infections
 Common Cold, Pharyngitis, Influenza
 Similar to general population
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Urinary tract infections
 Most common bacterial infection post transplant
 Avoid prolonged catheterization
 Could be related to reflux in transplanted kidney
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High incidence of complicated UTIs
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Recurrent UTI s
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Imaging of Transplanted and Native kidneys
Cystoscopy
Preventive behavioral changes
Vitamin C, Hiprex
ESBL E.Coli Infection
 Treatment with IV Carbapenem, Cefepmine
 Oral treatment with Fosfomycin
 Please do NOT treat with Macrobid (despite what sensitivites
show)
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Important to keep in mind that many transplant
patients have a ureteral stent placed at time of
transplant that is typically removed by Urology
4-6 weeks after transplant.
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Any UA from these patients will show up as
positive, so keep this in mind before jumping to
start IV Abx in the ER if patient comes in for
other complaints in the early post transplant
period.
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Cytomegalovirus (CMV)
 Hepatitis, Retinitis, PNA, encephalitis, GI
Ulcerations
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Polyomavirus (BK and JC virus)
 Viruria, Viremia
 BK Nephropathy
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Pneumocystis jirovecci pneumonia (PCP)
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All transplant patients receive prophylaxis for
CMV and PCP.
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CVD remains the major cause of death and graft loss
in diabetic renal transplant patients.
USRDS 2007 Annual Report
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Risk Factors:
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ESRD
Anemia
DM
HTN
Obesity
Immunosuppressive medications can worsen some of
these
USRDS Annual Report – Transplantation, 2014
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Most patients with ESRD are anemic at time of
transplant
Transplant factors can perpetuate anemia
 Surgical blood loss
 Inflammation
 Delayed graft function
 Induction/Immunosuppression agents
 Antiviral agents
 Discontinuing of erythropoietin stimulating agents.
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Typically resolve 6-12 months post transplant
 Sooner if good allograft function
 If the patient is not iron deficient
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Can re-develop later in transplant life with progressive
allograft dysfunction, infections, use of ACE/ARB.
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Persistently elevated HgB/Hct
following transplantation
Hct >51% (HgB > 17)
Occurs in 8-15% of renal transplant patients
Typically occurs 8-24 months after
transplantation.
Treatment: ACE/ARB, and in severe cases
phlebotomy.
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50% of transplant patients may be
categorized as obese or morbidly obese.
Gore JL, Danovitch GM. AJT 2006.
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Weight gain may be related to:
 Appetite improves after transplant.
 Effect of steroids may play a part in weight gain.
 Feeling better in general by being off dialysis
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Lifestyle modifications, dietary control, and
weight loss are frequently emphasized.
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Cancer after transplantation is 3x more likely than general
population.
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These cancers have 5 fold or > increase in transplant
patients
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Kaposi Sarcoma
Skin Cancer
Non-Hodgkin Lymphoma
Liver
Anus/Lip/Vulva
Malignancy represents the 3rd most common cause of
death in renal transplant recipients.
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Highest risk is for skin cancer
 Recommended to screen yearly in most patients and
in some high risk patients, every 3-6 months by
dermatology.
 Minimize sun exposure and use UV blocking agents.
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Consider switching immunosuppression or
decreasing immunosuppression
 Reduction in Trough goal, and MMF dosing
 Switching CNI to Rapamune (Sirolimus)
July 2012
Conclusion: Switching from CNI to Sirolimus had
an anti-tumoral effect in kidney transplant
patients with previous squamous cell carcinoma.
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Overall level of immunosuppression appears to
be related to post transplant malignancy.
Induction Agents
Buell JF. Transplantation, 2005
 Increased Cancer Risk with T-Cell Depleting Antibody
therapy such as Thymoglobulin
Reddy U. Nature Reviews Nephrology, 2014
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Coexisting Viral Infection associated with
Malignancy:
 EPV, HHV-8, HPV, Merkel Cell Polyomavirus
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Post Transplant Lymphoproliferative disease
 Lymphoid and/or plasmacytic proliferations related to
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immunosuppression that can occur in transplant
patients.
Most common malignancy after skin cancer in solid
organ transplants
Usually EBV+ [most common in EBV-(R)/EBV+(D)]
Related to B-cell proliferation induced by EBV
infection.
Host derived (multisystem) or donor derived
(allograft)
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62 year old male ESRD due to HTN s/p DDRT
in July 2013. Induction: Simulect.
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7 months after transplantation, presented
with nausea, malaise, and found to have AKI
with creatinine of 1.8.
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Ultrasound of his allograft was done which
revealed a soft tissue mass at the hilum of his
kidney.
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Reduction in Immunosuppression
 Stop Mycophenolate
 Decrease trough Prograf levels
 Consider switching Prograf to Sirolimus
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Referral to Hematology-Oncology
If lesion is Cd20+  Rituximab
Chemotherapy (EPOCH)
In certain cases: Surgery, XRT
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SIMPLE RULE OF THUMB:
“Do NOT give patients LIVE or
LIVE ATTENUATED VACCINES
after transplantation”
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Do Not Give these:
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Varicella Zoster
Intranasal Influenza
Bacillus Calmette-Guerin (BCG)
Live oral typhoid
Measles
Mumps
Rubella
Oral polio
Live Japanese B encephalitis vaccine
Yellow fever
Smallpox
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Okay to give INACTIVATED vaccines.
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Influenza (type A and B) – yearly
Pneumovax (Prevnar-13)– every 3-5 years
Haemophilus influenza B
Hepatitis B
Typhoid Vi
Inactivated polio
Meningococcus
Hepatitis A
A transplant patient on the same tacrolimus dose for 5 years started on a health
food diet and over-the-counter herbal products. The transplant center noted that his
tacrolimus levels have abruptly decreased to unacceptably low levels, putting him at
risk for rejection. The nurse coordinator accused him of being noncompliant, but the
patient insisted he was taking his medication as prescribed.
What is your assessment?
A. This patient is becoming noncompliant after 5 years and is in denial; he needs an
immediate psychiatry consult
B. This patient is taking grapefruit extracts, which are preventing the absorption of
his tacrolimus.
C. This patient is taking St. John’s Wort.
D. This patient is taking creatine supplements, which increase the activity of Pglycoprotein, leading to enhanced tacrolimus excretion
E. This patient is taking echinacea, which activates renal tubular excretion of
tacrolimus.
CYP1A2
CYP2C9
CYP2C19
CYP2D6
CYP2E1
CYP3A4
Tylenol
Caffeine
Theophylline
Diclofenac
Fluvastatin
Phenytoin
Tolbutaminde
Warfarin
Diazepam
Ibuprofen
Mephenytoin
Omeprazole
Phenytoin
Proguanyl
Amitriptyline
Codeine
Flecainide
Imipramine
Metoprolol
Nortriptyline
Propafenone
Propanolol
Thioridazine
Tylenol
Ethanol
Halothane
Amiodarone
Atorvastatin
Timolol
CYTOCHROME P450 ISOENZYMES
Metabolize many clinically relevant drugs
Clarithromycin
Cyclosporine
Diltiazem
Erythromycin
Everolimus
Itraconazole
Ketoconazole
Lovastatin
Midazolam
Nefazodone
Nifedipine
Protease
Inhib.
Quinidine
Sildanefil
Simvastatin
Sirolimus
Tacrolimus
Terbinafine
Verapamil
Warfarin
Class
Inhibiting Drugs
Antibacterial (macrolide)
Clarithroymycin, Erythromycin
Antidepressants
Fluvoxamine, Nefazodone
Azole Antifungals
Fluconazole, Voriconazole, Itraconazole
etc
Calcium Channel Blockers
Diltiazem, Verapamil
Foods
Grapefruit, pomegranate
Protease Inhibitors (Hep C)
Boceprevir, Telaprevir
Protease Inhibitors (HIV)
Atazanavir, darunavir
Fosamprenavir, indinavir
Nelfinavir, ritonavir, saquinavir
Others
Amiodarone, Dalfopristin
Statins
Tacrolimus/Cyclosporine
Class
Inducing Drug
Antiseizure Medications
Carbamazepine
Fosphenytoin
Oxcarbazepine
Phenobarbital
Phenytoin
Anittuberculosis
Rifabutin
Rifampin
Antiviral
Efavirenz
Others
Bosentin
Modafanil
St. John Wort
A transplant patient on the same tacrolimus dose for 5 years started on a health
food diet and over-the-counter herbal products. The transplant center noted that his
tacrolimus levels have abruptly decreased to unacceptably low levels, putting him at
risk for rejection. The nurse coordinator accused him of being noncompliant, but the
patient insisted he was taking his medication as prescribed.
What is your assessment?
A. This patient is becoming noncompliant after 5 years and is in denial; he needs an
immediate psychiatry consult
B. This patient is taking grapefruit extracts, which are preventing the absorption of
his tacrolimus.
C. This patient is taking St. John’s Wort.
D. This patient is taking creatine supplements, which increase the activity of Pglycoprotein, leading to enhanced tacrolimus excretion
E. This patient is taking echinacea, which activates renal tubular excretion of
tacrolimus.
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Transplant Nephrology service is here to serve you for ALL Kidney
Transplant patients
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Consists of Renal Fellow on Service, and myself.
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All day, everyday.
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We have clinics - 4 days a week – soon to be 5 days a week.
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Please check Prograf/CsA/Everolimus/Sirolimus levels EVERYDAY
at 7-8am (TROUGH levels) for any inpatient transplant patient
who remains on immunosuppression.
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Please page Transplant Nephrology IMMEDIATELY for all admitted
patients or any patient in the ER who there is a question on.
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Consult Transplant Nephrology on ALL Kidney,
and Kidney-Pancreas transplant patients
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All patients within the first year of K/KP transplant
will be admitted to Transplant Surgery team (unless
otherwise indicated)
Think twice before considering PICC line in a
transplant patient.
 Discuss PICC lines with Transplant Nephrology
BEFORE ordering them.
 Placing a PICC jeopardizes future AV access by
the dilation of vein by PICC line placement.
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Hoggard J, et al. Semin Dial, 2008
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Home health can alternate IVs to avoid PICC
Slightly longer hospital stay
Oral Antibiotic alternatives
Close follow up
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Kidney transplant is the treatment of choice in terms
of renal replacement therapy for a majority of ESRD
patients.
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Multi-disciplinary approach
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Only Inactivated Vaccines are okay after transplant.
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Increased comfort level in dealing with kidney
transplant patients, their immunosuppression, and
common post transplant management issues.
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Transplant Nephrology Service is here to
happily SERVE you for all your Kidney
Transplant patients.
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Uttam G. Reddy, MD
 Pager = 714-506-0846
 Email = ureddy@uci.edu