Kidney Transplantation

Dr. Rawi Ramadan.

Director Kidney Transplantation Unit.
Rambam Medical Center

Treatment Options of ESRD

1. Hemodialysis
2. Peritonial Dialysis
3. Kidney Transplantation + Best choice (?)
- Decreased donor transplantation
- Living donor transplantation
- D./L. (?)

Transplantation is the Perception of

Choice for ESRD

ESRD patients on waiting list have

survival> dialysis patients not on list.
Transplanted patients in all categories live
longer than non- transplanted patients on list.

??
Allograft half-life is the time that 50% of the
patients who survive beyond the first year posttransplant are still alive with a functioning kidney.
T1/2 is determined by both the rate of death and
return to dialysis( or pre-transplantation).
T1/2 of cadaveric transplant in 1988=7.6 years.
T1/2 of cadaveric transplant in 1995=11.6 years.
T1/2 of two-haplotype- matched living-related
kidney recipients over the same period 22.8 years.

Transplantation
- Blood Group
- HLA- Typing
- Cross Match
- PRA- Panel

Mortality on Dialysis
Annual Death Rate

All dialysis patients

16.1 per 100 patient years

229K

Patients on list

6.3 per 100 patient years

46K

Cadaver transplant
patients

3.8 per 100 patient years

23K

Renal Transplantation: Present Status

Short-term graft survival: 90-95% at 1 year
Acute rejection rates: 10-15%
Well-controlled clinical trials to guide decision
making
Can individualize combination regimens
- Minimize rejection
- Minimize toxicity
- Minimize co-morbidities

Improved long-term graft survival by use of living donors

Prevention of chronic allograft nephropathy has remained
elusive.

Immunosuppression
Maintenance Agents
+
Induction Agents
- Additional immunosuppression
- Allows delay use of CNIs
- Long term benefits??

Maintenance Agents

Steroids
Azarthioprine
Mycophenolate mofetil
Cyclosporine
Tacrolimus
Sirolimus

Antimetabolite

Calcineurin Inhibitors
CNI
mTOR Inhibitor

Induction Patients

Basiliximab
Daclizumab

OKT3
Thymoglobylin
Alemtuzumab
(Campath-1H)

Anti-CD 25 Antibody

Depletional Antibodies

Standard Regimens

Prednisone/MMF/CSA
Prednisone/MMF/FK
Prednisone/CSA/RAPA
Prednisone/MMF/RAPA
Immuran still in use; cytoxan rarely

Anti-CD 25 induction
rATG or OKT3 induction

Glucocorticoids
Indication
- Maintenance therapy
- Treatment of acute rejection
- Pro-med for antibody therapy

Mechanisms
- Inhibits cytokine synthesis in lymphocytes, antigen cells,
macrophages

Adverse Events
- Glucose intolerance
- Osteoporosis
- Myopathy
- Growth delay (kids)

Dose
- 1 mg/kg/day with taper 10 mg qd
- IV bolus therapy of 250 mg- 500 mg.

Mycophenolate Mofetil (MMF) Cellcept

Indication
Maintenance therapy

Mechanisms
Inhibits leukocyte proliferation by blocking purine synthesis

Adverse Events
Leukopenia
Diarrhea
GI upset
Dose
500 1000 mg BID

Cyclosporine A (CsA) Sandimmune, Neoral

Indication
Maintenance therapy

Mechanism
Inhibits the phosphate calcineurin, inhibiting the migration of NF-AT
(Nuclear Factor of Activated T Cells) from the cytoplasm to the
nucleus, inhibiting transcription of IL-2, IL-4, IFN-g, TNF-a.

Adverse Events
-

Nephrotoxicity (!!)
Hypertension
Hisutism
Tremor

Dose
- Use through concentrations (some centers using C2).

Tacrolimus (FK506) Prograft

Indication
Maintenance therapy

Mechanism
Same as Cyclosporin

Adverse Events
Nephrotoxicity (!!)
Diabetes mellitus
Other metabolic effects less common
Tremor

Dose
- Use through concentrations (some centers using C2)
- Dosing based on level (5-20 ng/ml), typically 0.1mg/kg/day divided
BID.

Sirolimus (Rapa) Rapamycin

Indication
Maintenance therapy

Mechanism
Antiproliferative-binds FKBP (the same as FK506), but the complex
binds mTOR (Target of Rapamycin) which inactivates cyclindependent kinases and blocks cell cycle progression.

Adverse Events
-

Bone marrow depression

Hyperlipidemia (TGLs)
Edema, arthralgias
Proteinuria

Dose
- Dosing based on blood levels *8-20 ng/dl) using 0.5-12 mg qd.

Common Drug Interactions

CNIs and sirolimus metabolized by cytochrome P450 (3A4).

Increase Levels

Decrease Levels

Diltiazem, verapamil

Phenobarbital

Voriconazole,
clotriamzole,
itraconazole, diflucan

Rifampin

Erythromycin,
clarithromycin

St. Johns Wort

Grapefruit Juice

Limiting Immunosuppression
Complete Elimination
Selective Elimination
- Withdrawal
- Substitution
* Conversion
* Avoidance

Major Current Strategies

- Calcineurin inhibitor- free protocols
- Steroid-free protocols

Kidney Allograft Loss After the First Year:

- 50% chronic renal allograft dysfunction.
- 50% death with graft function

Cardiovascular
40%

Infection
25%

Malignancy
10%

Other
25%

Kidney Risk Factors for

Post-transplant C-V Disease

Pre-transpl.C-V disease
DM(including posttranspl.)
Cigarette smoking
HLP
HTN
Allograft dysfunction
Hypoalbuminemia
Hyperhomocysteinemia
Infections

4+.
4+.
3+.
3+.
2+.
2+.
2+.
1+.
1+.

Pre-transplant C-V Disease

- Pretransplant C-V disease will increase the risk for
post-transplant CVD complications.
- Aggressive management of modifiable CVD risk
factors.
- Atherosclerosis is diffuse so patients with a history of
cerebrovascular disease are at increased risk for IHD.
- Much of the risk for CVD in the late post-transplant
period is acquired after transplantation.

Diabetes Mellitus
-

The most common cause of ESRD leading to transplantation.

The most important risk factor for post-transplant CVD.
Both type 1+2 increases the risk for ASCVD.
Diabetic control is more difficult post-transplantation.
20% of non-diabetics develop hyperglycemia posttransplantation. (obese, blacks, older patients, strong family
history of DM).
- CN-I(Tacrolimus >Cyclosporine) and Steroids contribute to
varying degrees to glucose intolerance

Hyperlipidemia
- High LDL, Low HDL, High TG.
- The most important cause of HLP post-transplantation
is immunosuppressive medications (Sirolimus, Cys,
Tac).
- Other causes :corticosteroid dose, diet, genetic
predisposition, proteinuria and possibly decreased
renal function.

Arterial Hypertension
-

Contributes to CVD.
Corticosteroids.
CNI(CYS>TAC).
Graft dysfunction.

Pre-emptive transplantation

Impact on Transplantation
Prevent LV growth on dialysis
Regress LV growth that has accurred on dialysis
May be the preferred intervention for reversing LV
regression!
Transplant early, ideally preemptively
- Evidence: C (observational)

Anemia
Observational data suggest a very strong relationship
between anemia and:
- CHF
- LV growth
- Death

Seen in all CKD populations

Suggest Hgb normalization would be beneficial.

Risk of Infection after

Renal Transplantation
Determined by the interaction of four factors:
- Anatomic/ technical misadventure
- Net state of immunosuppresion
- Epidemiologic/ Environmental Ecposures
- Darwinian Issues.

Timetable of Infection Following Organ

Transplantation
1st Month:
Contaminated allograft
Preexisting infection
>95% are the same as non-immunosuppressed patients
undergoing similar surgery: wound infection, vascular
access, pneumonia, catheter related
No opportunistic infection (if present= environmental hazard)
Immunnosuppressive therapy is like buying on creditimmediate gratification of better graft function; the bill comes
due in 3 weeks.

Timetable of Infection Following Organ

Transplantation
1-6 months:
Viral Infection (CMV, EBV, HBV, HCV, HIV)
Opportunistic infections

>6 months:
80% good result; biggest risk is community respiratory
viruses
10% chronic HBV or HCV
10% bad result
Excessive immunosuppression, chronic viral infection,
highest risk of opportunistic infection (Listeria,
Pneumocystis, Cryptococcus, Aspergillus, etc)
chronic neer-do-wells

Utility of Timetable
Differential diagnosis for an infectious disease syndrome
Infection Control Device- opportunistic infection in 1st
month golden period= environmental hazard.
Basis of Preventative Strategies:
- 1st Moth: preoperative antibiotic prophylaxis
- 1-6 Months: anti-CMV; trimethoprim- sulfamethoxazole
(TMP/SMX)
- >6 Months: TMP/ SMX; ? Anti-fungal (e.g., fluconazole) for
chronic neer-do-wells.

Net State of Immunosuppression

Host defense deficits engendered by the underlying disease.
Dose, duration, and temporal sequence of
immunosuppressive drugs.
Neutropenia.
Metabolic derangements (e.g., protein-calorie malnutrition,
anemia, hyperglycemia).
Viral infection (CMV, EBV, hepatitis B and C, HIV).
Age
? Race (? Immune response genes).

Environmental Exposures
Community
- TB, geographically restricted systemic mycoses (Earth Day)
- Opportunistic infections- Aspergillus, Pneumocystis,
Nocardia, Crypotococcus (construction)
- Community acquired respiratory viruses (influenza, RSV, SRAS,
bird Flu)

Nosocomial: domicilliary vs. nondomicilliary

- Aspergillus (new and emerging angioinvasive fungi)
- Legionella
- Pseudomonas, other gram negative
Person-to-Person:
- Hands of medical personnel- MRSA, VRE, azole-resistant yeast.

Darwinian Issues in Transplantation

Selection of resistant
flora by previous
antibacterials and
antifungals
- Gram negative,
MRSA, VRE
New and emerging
fungi
- Fusarium
- Scedosporium
- Mucor

Effects of Immunosuppression on Viral

Reactivation in Latently Infected Mice

Drug

Effect

ATG, ALS

4+

Cyclophosphamide,
azathioprine, MMF

0-1+

Prednisone

Cyclosporine, Tacrolimus

Sirolimus

Approach to Antimicrobial Therapy in

Transplant Patients

Modes of Prescription:
- Therapeutic
- Prophylaxis
Failure of preventive strategy= prolonged
- Preemptive
incubation therapy
(from 1-4 months

100-600 days post- Tx)

Antibiotic Therapy
- Induction
- Consolidation
- Maintenance

How long to treat?

- No fixed regimen
- long enough (the therapeutic prescription)

Death after Graft Loss

Kaplan AJT 2002;2:970
Annual adjusted death rates per 100 patient years based on 10 year
follow up by cause of death

Death with Tx
Annual rate
percentage

Death after graft

Loss
Annual rate
percentage

Overall

2.81

9.41

Cardiovascular

0.69

4.31

Infectious

0.37

1.63

Malignancy

0.19

0.11

Hepatitis C
New cases decreasing in
some areas with practice
patterns (drug preparation)
influencing conversions.
Classic treatment not
possible in renal
transplants but good pretransplant.
Survival decreased in HCV+
recipients in most series.
Survival decreased in all
with HCV positive donor.

Espinosa AJKD 2004;43:685, Tokars Semin Dialy 2004;17:310, Goodkin AJKD 2004

Esophageal Candidiasis
Not much problem early
with prophylaxis
10-30% without prophylaxis
Risk: DM/ triple drug/
myelosuppression
Look now for late
problems, given new
myelosuppressive drugs

Gupta AM j Gstroent 1994;69:1062

Differential of Late Allograft

Dysfunction:
search for infection
1.
2.
3.
4.
5.
6.
7.
8.
9.

Drug toxicity- calcineurin inhibitor

Chronic rejection
Acute rejection
Obstruction- lymphocele, ureteric stenosis
Infection- adenovirus, BK, CMV, EBV, bacteria
Tumor- PTLD, renal cell cancer
Vascular lesions (RAS, nephrosclerosis, AVF)
Recurrent or De Novo disease
Other causes of ARF

Polyoma Virus Nephritis in Renal

Allografts

Human Polyoma Virus

Background

Double stranded DNA viruses (40-45 nm).

The sub-group of polyoma includes:
- JC
- BK
- SV40
Although JC is primarily associated with progressive
multifunctional leukoencephalopaty, both JC and BK have
been associated with pathological changes in the urinary
tract. Some believe that SV40 can also co-infect
transplants.

Human Polyoma Virus

Background

PV are ubiquitous
Positive serology is found in 65-100%of the population
depending on age group and geographical location.

Human Polyoma Virus

Background

Infection with BK occurs in childhood though the

respiratory route.
In the latent stage the virus localizes in the renal
epithelium.
Active infection and associated clinical disease have
been demonstrated only in immunosuppressed patients.

Human Polyoma Virus

Clinical Significance

Affects 2-8% of renal transplants

Selective tendency to affect the transplanted kidney
leading to allograft dysfunction and premature graft
loss.
Up to 45% of patients with biopsy proven PV have been
reported to lose their grafts prematurely.
No specific treatment available.
Unpredictable course. With decrease in
immunosuppression, improvement in some patients.

Human Polyoma Virus

Clinical Significance
1) LATENT INFECTION
After primary infection BK and
JC remain latent in the kidney and
urothelium of ureters and urinary
bladder.
Demonstration by tissue PCR.
No viruria (absence of decoy cell
in urine, negative PCR studies
in urine).
No viremia
No clinical significance (normal
renal function).

Human Polyoma Virus

Clinical Significance
2) LIMITED (low level) VIRAL
REPLICATION
Mostly limited to the urothelium is
common in immunosuppressed patients
and may occur rarely in healthy
individuals (i.e. pregnant women).
20-65% of renal transplant
Patients.
Transient or intermittent viruria
- Decoy cells on urine cytology
- Demonstration of viruria with
PCR methods
No viremia
No clinical significance, normal renal
function.

Human Polyoma Virus

Clinical Significance
3) HIGH LEVEL VIRAL REPLICATION WITH
TISSUE DESTRUCTION
POLYOMA VIRUS ALLOGRAFT
NEPHROPATHY
Occurs only in a minority of renal
transplant patients (5-10%)/
Persistent viruria:
- Decoy cells on urine cytology.
- Significant viruria by quant.
PCR.
Viremia
Abnormal renal function if parenchymal
disease is extensive.

Human Polyoma Virus

Histological Picture

Human Polyoma Virus

Clinical Menifastations

Asymptomatic viruria
Pyuria
Renal Dysfunction
Ureteral stenosis
Hemorrhagic Cystitis

Human Polyoma Virus

Treatment

Judicious decrease in immunosuppression

FK-506 levels (6-8 ng/ml)

CSA levels (75-100 mg/ml)
Rapamycin levels (6-8 ng/ml)
Halve the dose, or discontinue, MMF

Careful monitoring for evidence of rejection.

BK Nephropathy

BK Nephropathy

Median onset 9-10 months after transplant

No clinical symptoms, unexplained renal dysfunction
Graft loss 30-70%
Depends upon when discovered
Depends upon treatment

Risk factors: ?Male gender, age, FK/MMF, serostatus

The Impact of Early and Late

CMV Infections on
(Renal) Allograft Function

Cytomegalovirus: a major problem

following transplantation
Most common opportunisti infection afer
transplantation
Incidence of clinically apparent CMV disease between
20 and 60%.
High mortality if untreated (up to 90%).

Primary Effects of CMV

CMV syndrome
Gastroenteritis
Nephritis
Hepatitis
Pneumonitis
Retinitis

Secondary Effects of CMV

Acute rejection
Chronic rejection
Super- infections
Cardiac complications
Atherosclerosis
Biliary Complications
Diabetes
Lymphoma

CMV and Cardiovascular Mortality after

Renal Transplantation
Independent risk factors for cardiovascular death after
renal transplantation
- Increasing age (p<0.004)
- Presence of diabetes (p<0.04)
- CMV seropositivity (p<0.01)

Kalil RSN et Al. Am J Transplant 2003;3:79-81

CMV and Oncogenesis

CMV increases EBV lymphoma 10 fold
CMV detected in many malignant gliomas, prostatic
carcinomas and colonic adenocarcinomas

Basgoz N, Infect Dis Clin N Am 1995;9:901-23

Manez R, et al. J Infect Dis 1997;6:1462-7
Cobbs CS et al. Cancer Res 2002;62:3347-50
Samanta M et al. J Urol 2003;170:998-1002
Harkins L et al. Lancet 2002;360:1557-63

Common Screening Strategies for

Cytomegalovirus

Sell- vial culture

Early antigen detection from blood
PCR
DNA hybridization
Respiratory specimens
Other suspected fluids

Kubak BM, et al. Handbook of Kidney Transplantation, 3rd Edition. Philadelphia, PA

Drugs for CMV Prophylaxis

CMV immunoglobulin

Valacyclovir
Acyclovir
Ganciclovir (IV and PO)
Valganciclovir

Approved Indication

Cytomegalovirus

Cytomegalovirus

All organs
Prophylaxis, later post-transplant
Associated with rejection in renal
transplant
Cofactor for PTLD
Recurrent disease
Resistant disease

Kaposis Sarcoma

Management of
Malignancy After Renal
Transplantation

Introduction
With recent transplant success and increasing survival
rates, the complication of malignancy is encountered more
The principles guiding management decisions and issues
pertaining to specific tumors are divided into 3 areas:
1. De novo malignancies.
2. Impact of preexisting malignancy on transplant
candidacy.
3. Malignancy acquired from organ donor.
The risks of cancer associated with immunosuppressive
agents demand attention.
The community nephrologist must find the right balance
between the level of immunosuppression required to
prevent rejection and the level that will minimize
malignancy.

Overall Incidence of malignancy

after transplantation

Penn I. Transplant Sci.1994;4:23-32

Most Commonly Reported Post-

Transplant Malignancies *
Skin and lip cancer
Squamous cell carcinoma (SCC)
Basal cell carcinoma (BCC)
Merkel cell carcinoma
Melanoma

PTLD
Liver and kidney cancers.

* Confirmed by different registries, including the Israel Penn International

Transplant Tumor Registry (formerly Cincinnati Transplant Tumor
Registry), the Astralia- New Zealand Dialysis and Transplantation registry.

Most Common De Novo Cancers in Renal

Allograft Recipients (1968-1999)
Type of neoplasm *

n. of tumors

Skin and lip cancer

3897

PTLD

1108

Lung carcinomas

515

Kaposis sarcoma

422

Uterus carcinomas

406

Kidney carcinomas

393

Colon and return carcinomas

342

Breast carcinomas

330

Vulva/perineum/penis/scrotum/
carcinoma

272

* Data collected by the Israel Penn International Transplant Tumor Registry

from 9032 renal allograft recipients.

Skin Cancer in Transplant Recipients

Differs From the General Populaion
SCC is more common than BCC.
Merkel cell carcinoma, a neuroendocrine cancer of
the skin, is more frequent in the transplant
population.
Lesions develop at a younger age (30 vs. 60 years)
and occur in multiple sites.
Tumors are more aggressive and are more likely to
recur after resection.

Viruses Associated with Certain

Types of Cancer
EBV with nonHodgkins
lymphoma and
PTLD

- Ubiquitous virus in >90% of general population

- 90% overall incidence of EBV+tumors
- Higher incidence of PTLD in pediatric population is
potentially related to the higher incidence of EBV- nave
recipients.

HPV with cervical

cancer

- Etiologic factor for cervical cancer in the general population

- Higher incidence of HPV co-infection in transplant
recipients than non-transplant patients with cervical cancer.

HHV-* with
Kaposis sarcoma

- Sporadic or epidemic occurrence

- Presents as either cutaneous or visceral
- often seen in immunocompromised patients
-Correlated with Mediterranean heritage

HHV-8 and Kaposis Sarcoma

Three studies demonstrate the possible affiliation in
renal transplant recipients:
- Saudi Arabian Study:
* 10-fold higher incidence of Kaposis sarcoma
than western countries.
* Higher incidence of specific ant-HHV-8
antibodies in patients with Kaposis sarcoma
- Another report found evidence of transmission of
HHV-8 from donor to renal transplant recipient:
* 2 developed Kaposis sarcoma
* Both of whom seroconverted after
transplantation.
- Study of 400 consecutive patients:
* 32 with antibodies to HHV-8 at the time of
transplantation.
* 3 years after surgery, 28% developed Kaposis
sarcoma; no cases developed in antibodynegative patients.

Increased Risk of RCC in the Native

Kidneys
Related in part to prolonged period of advanced renal failure
Can lead to:
- Tubular Hyperplasia
- Cyst formation
- Malignant transformation
Frequency of RCC after renal transplantation necessitates
careful evaluation of native kidneys.
Annual ultrasonographic surveillance of renal grafts is
recommended.
- Pediatric population
- Long-time dialysis patients.

Very low Recurrence of Pretransplant

Malignancies in Renal Transplantation

Suggested Disease-Free Intervals for

Specific Malignancies

PTLD
The incidence in solid- organ .= 0.8- 15%/
The incidence in RTR= 1-2%
Incidence vary with :
- Age
- Type of th
- .
M..al features of PTLD:
1) Mortare (?) NHL, of B-cell and are CD 20+.
2) PTLD often presents as dysfunction of the graft and
may be cared histologically with sever rejection.
Disease is often localized near the allograft.
3) Kh rate of arra..tion with EBV + .
4) Extra modal is common (CMS, liver, lungs, kidney,
.), and multiple sites are involved.

PTLD
5)

6)
7)
8)

Mortality rate is greater in PTLD than for LY in general

population. The cause may be . .. death in months of
transplantation.
Lymph. Depleting antibody= a . Risk factor for PTLD.
PTLD may .. To with . Or . Standard radiation
and chemotherapy usually is not helpful.
R- anti CD 20.

PTLD
Pctions of poor from PTLD:
- increased age
- increasing LDH
- Severe organ dysfunction
- Multiple organ involvement
- Contrnal symptom (fever, high sweats, weight loss).

Thank you
for Listening!