WELCOME

RENAL TRANSPLANTATION: AN OVERVIEW

Ayman Refaie,MD

Chief, Nephrology & transplantation Unit

Urology and Nephrology Center

University of Mansoura

Agenda

• Benefits of transplantation

• Patient and donor selection

• The transplant anatomy

• Immunosuppressive medications

• Common post-transplant complications

• Mansoura Experience

Renal Transplantation

• Kidney transplantation is the most effective therapy for end-

stage renal disease.

• The transplanted organ can come from either a live donor or

deceased donor.

• Most deceased donor organs come from brain dead donors.

• Non-standard criteria donors:

– Expanded criteria donors (ECD).

– Donation after cardiac death (DCD).

Benefits of Transplantation

• Life expectancy

• Cardiovascular benefits

• Quality of life

• Socioeconomic benefits

Life Expectancy

Ojo, J Am Soc Neph, 2001;12:589

Life Expectancy

Cardiovascular Benefits

Foley, Am J Kidney Dis, 1998;32(S1):8Slide courtesy of Dr. Robert Gaston

Quality of Life

• Numerous studies have detailed improved quality of life.

• Life satisfaction, physical and emotional well-being and

ability to return to work higher in transplant recipients.

• Uremic complications more fully reversed.

• Fertility returns.

A healthy child born to a female transplant recipient, 3 years after a successful engraftment.

Socioeconomic Benefits

• Increased rates of return to work.

• Mean cumulative costs of dialysis and transplantation

are equal for first year, then lower for transplantation.

Patient survival after kidney transplantation VS

hemodialysis

• Annual mortality rates for patients under dialysis range

from 21%-25%, but <8% with cadaveric and <4% with

living-related transplant recepients.

• The benefit of transplantation is most notable in young

people and in those with diabetes mellitus.

Projected years of life for patients 20-39 years old:

Dialysis Transplant

Non diabetic 20 31 years

Diabetic 8 25years

Patients selection for kidney transplantation

All patients with ESRD are candidates for KT unless

contraindicated

Contraindications to renal transplantation

- ABO incompatibility.

- Cystoxic antibodies against HLA antigens of donor.

- Recent or metastatic malignancy.

- Active infection.

- Severe extrarenal disease (cardiac, pulmonary, hepatic).

- Active vasculitis or glomeulonephritis.

- Noncompliance.

- Psychiatric illness including alcoholism and drug addiction.

- Primary oxalosis.

Recipient Selection

• General medical condition.

• Cardiovascular screening.

• Age-appropriate routine cancer screening (pap smear,

mammography, colonoscopy, PSA).

• Infection (HIV, Hepatitis, TB).

• Presence of preformed antibody (PRA).

– Pregnancy, prior transplant, blood transfusion

• Psychosocial evaluation, including compliance.

The kidney donor

Living

- Living related.

- Living unrelated (emotionally motivated).

Cadaveric

- Heart Beating

- Non-beating heart.

Criteria for living donor selection

- Highly motivated.

- Excellent medical condition with normal renal function.

- ABO blood group-compatible.

- HLA-identical or haploidentical with negative cross-

match.

Matching between Recipient and Donor

A- Compatible ABO blood group

B- Cross matching

C- Tissue typing

• Determined by 6 antigens located on cell surface encoded for by the HLA gen located on the short arm of chromosome 6.

• Class I antigens (HLA-A and HLA-B) are expressed on the surface of most nucleated cells.

• Class II antigen (HLA-DR) are expressed on surface of APC and activated lymphocytes.

Effect of HLA Matching on The Graft Outcome

Whether there is a medical condition that will put donor

at increased risk for complications for general anesthesia

or surgery.

Whether the removal of one kidney will increase the

donor’s risk for developing renal insufficiency.

Principles involved in evaluating a prospective

living kidney donor

The living kidney donor:

giving life, avoiding harm

Medical conditions that exclude living kidney donation

Renal parenchymal disease.

Conditions that may predispose to renal disease

History of stone disease

History of frequent UTI

Hypertension

D.M.

Conditions that increase the risks of anesthesia and surgery.

Recent malignancy.

• Is it an easy task?

Potential living donors should undergo a rigorous screening

procedure to ensure the best functional outcome for recipients with

no or minimal morbidity for donors.

Between 1992 and 2001, 1,661 ABO compatible potential living donors were evaluated

clinically as well as by laboratory and imaging studies.

814 potential donors (49%) were excluded.

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Does donation of a kidney pose a long-term risk

for the donor?

Following nephrectomy, compensatory hypertrophy and

increase in GFR occur in the remaining kidney.

Slight risk of poteinuria and hypertension.

Meta-analysis of data from donors followed for >20y

confirmed safety of kidney donation.

• Over the last decade.

• Mansoura Post donation Clinic.

• Recipient (hand in hand) with his/her related donor

• Evaluation:

Clinical: BP, BMI

Lab: urinalysis, S. Cr, Cr Clearance, etc…..

U/s for the remaining kidney

• Medications: provided when needed.

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Anatomy of Renal Transplantation

An adult donor kidney transplanted to a pediatric recipient

Principles of immunosuppressive treatment

1- Immunosuppressive therapy is required indefinitely.

2- The benefits of a successful transplant outweigh the risks of

chronic immunosuppression.

3- Large doses of immunosuppressant drugs are used in the

early transplant period.

4- Multidrug regimens are generally employed.

Induction immunosuppressive therapy

• Induction therapy

• Maintenance therapy

• Treatment of rejection

Induction Therapy: Why?

• To decrease rejection rate.

• To decrease graft loss.

• To lower DGF.

• To avoid or withdraw steroids.

• To avoid or delay CNIs.

• To transplant high risk patients.

• To induce tolerance……

Induction Therapy: Agents

Depleting Non-Depleting

Class Examples

Glucocoriticoids

Immunophilin-binding agents Calcineurin inhibitors

CyclosporineTacrolimus (FK506)

Calcinurin-independent agentsSirolimus (rapamycin)

Antimetabolites Purine inhibitors: nonselectiveAzathioprine (Imuran)

Purine inhibitors:lymphocyte selectiveMycophenolate mofetil (Cellcept)

Classes of Maintenance Immunosuppressive Drugs

• Treatment of Rejection:– Corticosteroids

– Anti-thymocyte globulin

– Intravenous Immunoglobulin (IVIG)

– Rituximab

– Plasmapheresis

Immunosuppressive Medications

Immunosuppressive Medications

Immunosuppressive Medications

Slide courtesy of Dr. Meier-Kriesche

Calcineurin Inhibitors (CNIs)

• Used for maintenance immunosuppression.

• Two agents in clinical practice:

– Cyclosporine (Sandimmune®, Neoral®)

– Tacrolimus (Prograf®).

• At present are key to maintenance immunosuppression

and a component of the majority of transplant protocols.

mTOR Inhibitors

• Target site is the mammalian target of rapamycin

(mTOR), a key regulatory kinase in cell division.

• Sirolimus (Rapamune®)

Administered once daily, 24-hour trough levels

monitored.

• Everolimus (Certcan®)

Administered twice daily, 12-hour trough levels

monitored.

Sirolimus: Adverse Effects

• Nephrotoxicity:

– Delays recovery from ATN.

– Potentiates cyclosporine nephrotoxicity.

– Induces proteinuria.

– Tubulotoxic.

• Impairment of wound healing.

• Dyslipidemia (increased LDL and TGs).

• Pneumonitis.

• Cytopenias and anemia.

Antimetabolites

• Azathioprine (Imuran®) is a purine analogue that is

incorporated into RNA and inhibits cell replication.

• A mainstay of transplantation for 30 years, it has largely

been replaced by the below drugs.

• Mycophenolate mofetil (Cellcept®) and enteric-coated

mycophenolate sodium (Myfortic®) are prodrugs of

mycophenolic acid (MPA), an inhibitor of inosine

monophosphate dehydrogenase (IMPDH).

Antimetabolites: Adverse Effects

• Azathioprine:– Bone marrow suppression.

– Hepatitis.

– Azathioprine is inactivated by xanthine oxidase, therefore should not be used in combination with allopurinol.

• MPA prodrugs:– GI toxicity: diarrhea, nausea, esophagitis.

– Leukopenia and anemia.

– Not different between formulations.

Immunosuppression: Adverse Effects

Common Complications of Transplantation

Early complications Surgical complications

Delayed or slow graft function

Lymphocele

Acute rejection Acute cellular rejection

Antibody-mediated rejection

Infectious complications Cytomegalovirus

BK virus

Others

Malignancy

Chronic allograft dysfunction

Surgical Complications

Graft thrombosis: Caused by thrombosis of donor renal artery or vein. Usually happens in first week. Diagnosed by ultrasound with doppler studies. Almost always requires explant of kidney.

Urine leak: Elevated creatinine. May or may not have abdominal pain. Diagnose with nuclear medicine scans (DTPA or

MAG3). Surgical repair and/or relief of obstruction.

Delayed Graft Function

• Need for dialysis in the first week after transplantation.

• Causes:

– ATN from prolonged cold ischemia.

– Acute rejection.

– Recurrent disease.

• Usually requires biopsy for diagnosis and management.

Lymphocele

• Collection of lymph caused by leakage from iliac lymphatics.

• Presents several weeks post-operatively.

• Symptoms:

– Compression of kidney, ureter, bladder: obstructive uropathy and ARF.

– Compression of iliac vessels: unilateral lower extremity edema and DVT.

– Abdominal mass.

• Treatment is surgical.

Renal Allograft Rejection

1- Hyper acute.

2- Acute.

3- Chronic.

Hyperacute Rejection

Mediated by preformed antibodies that recognize HLA antigens in

donor organ.

Usually these are formed as a consequence of blood transfusion,

pregnancy, prior organ transplantation, autoimmune diseases.

Modern CM tests detect these antibodies.

Fibrinoid necrosis lead to immediate graft loss.

Delayed form may occur several days following transplantation.

Plasmapheresis and pulse steroid may be used.

Hyperacute rejection.

Acute Renal Allograft Rejection

Mediated by activated T-lymphocytes.

Activations of T-cells occur after recognition of graft

antigen either directly or after being processed and

presented by APC.

This usually occur during the first 6 months.

It manifest as increase in s. creatinine with or without

oliguria.

Histology of acute cellular rejection

Vasculitis

Treatment Of Acute Rejection

1. Pulse steroids

2. ATG.

Chronic rejection with tubulointerstitial lesions.

Fibrointimal proliferation in renal arterioles in chronic rejection.

Chronic allograft Rejection

• A- Immunologic

C4d deposits in peritubular capillaries as marker of

ongoing immune injury

• B- Non-lummunologic

• hypertension

• Hyperlipidemia

• Drug toxicity (CsA, FK)

• Ischemic injury

• Viral infection (CMV)

• Manifest clinically by a slow and gradual decline in renal

function, usually more than 6 mon after transplant and typically

accompanied by moderate to heavy proteinuria.

• Histologically, characterized by glomerulo-sclerosis, interstitial

fibrosis, and obliteration of arteriolar lumina.

• Treatment is unsatisfactory.

Chronic allograft Rejection

What Are The Major Causes Of Long-Term Allograft Failure ?

• Chronic rejection.

• Death with functioning graft.

Cardiovascular disease.

Infection.

What Are The Most Common causes Of Death After

Kidney Transplantation?

Malignancy

Recipient of organ transplants are at higher risk of developing malignancy.

May be related to impaired immune surveillance as a result of immunosuppression.

Skin cancer most common: sun protection mandatory.

Routine cancer screening.

Specific malignancies:

Kaposi sarcoma

Post-transplant lymphoproliferative disorder (PTLD)

Kidney Transplantation: Mansoura Experience

Sir Roy CalnePioneers in Transplantation

ATC, Philadelphia 2015

1967 consecutive living donor renal transplants

Between March 1976 and March 2008

Various variables that may have an impact on patients and/or graft survival

were studied in two steps.

Initially, a univariate analysis was carried out. Thereafter, significant

variables were embedded in a stepwise regression analysis.

Five variables were identified as factors with an independent impact

on graft survival:

Donor’s age

Five variables were identified as factors with an independent impact

on graft survival:

Donor’s age

Genetic considerations

Five variables were identified as factors with an independent impact

on graft survival:

Donor’s age

Genetic considerations

Type of primary immunosuppression

Five variables were identified as factors with an independent impact

on graft survival:

Donor’s age

Genetic considerations

Type of primary immunosuppression

Number of acute rejection episodes

Five variables were identified as factors with an independent impact

on graft survival:

Donor’s age

Genetic considerations

Type of primary immunosuppression

Number of acute rejection episodes

Total steroid dose during the first 3 months after transplantation.

Five variables were identified as factors with an independent impact

on graft survival:

Donor’s age

Genetic considerations

Type of primary immunosuppression

Number of acute rejection episodes

Total steroid dose during the first 3 months after transplantation.

Patient survival: 89 % at 5 years and 77 % at 10 years

Graft survival: 86 % at 5 years and 65 % at 10 years

Conclusions

• Renal transplantation should be recommended as the preferred

mode of RRT for most patients with ESRD in whom surgery and

subsequent I.S. is safe and feasible

• Cr CI 50-100 ml/min.

• Anemia.

• Conception and childbearing.

• Growth in children.

• Bone metabolism.

• Work rehabilitation.

Conclusions

Factors Influencing The Longevity Of Renal Allograft

• Donor age

• HLA matching

• Delayed graft function

• Ischemia time.

• Number of acute rejection episodes.

• Native kidney disease.

• Ethnicity.

Risks associated with chronic Immunosuppression

• 1- Malignancy

• 2- Infection

• 3- Side effects of different drugs (steroids, CsA,

tacrolimus, MMF, …..)

Conclusions

A healthy child born to a female transplant recipient, 3 years after a successful engraftment.

CONGRATULATIONS

Accepted abstracts (17)

CONGRATULATIONS

Accepted abstracts (5)

Thank You