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بسم الله الرحمن الرحيم

بسم الله الرحمن الرحيم

RENAL TRANSPLANTATION RENAL TRANSPLANTATION AN OVERVIEWAN OVERVIEW

ByBy

Mohamed A. Sobh MD, FACPMohamed A. Sobh MD, FACPProfessor and Head of NephrologyProfessor and Head of Nephrology

Urology and Nephrology CenterUrology and Nephrology CenterUniversity of MansouraUniversity of Mansoura

EgyptEgypt

Patients Selection For Kidney Patients Selection For Kidney TransplanatationTransplanatation

All patients with ESRD are condidates All patients with ESRD are condidates for KT unless for KT unless

Systemic malignancy.Systemic malignancy.

Chronic infection.Chronic infection. Severe cardiovascular disease.Severe cardiovascular disease. Neuropsychiatric disorder.Neuropsychiatric disorder. Extremes of age (relative).Extremes of age (relative).

Patient Survival After Kidney Patient Survival After Kidney Transplantation VS haemodialysisTransplantation VS haemodialysis

Annual mortality rates for patients under dialysis range Annual mortality rates for patients under dialysis range from 21%-25%, but <8% with cadaveric and <4% with from 21%-25%, but <8% with cadaveric and <4% with living-related transplant recepients.living-related transplant recepients.

Healthier patients generally are selected for Healthier patients generally are selected for transplantation.transplantation.

The benefit of transplantation is most notable in young The benefit of transplantation is most notable in young people and in those with diabetes mellitus.people and in those with diabetes mellitus.

Projected years of life for patients 20-39 years old:Projected years of life for patients 20-39 years old: Dialysis TransplantDialysis Transplant

Non diabeticNon diabetic 20 20 31 years31 yearsDiabeticDiabetic 8 8 25years25years

An adult donor kidney transplanted to the left iliac fossa of an adult recipient.

An adult donor kidney transplanted intraperitoneally to a pediatric recipient.

Kidney DonorKidney Donor

Living related.Living related.

Living unrelated (emotionally motivated).Living unrelated (emotionally motivated).

Cadaveric Cadaveric (Brain-dead)(Brain-dead)

Beating and non-beating heart.Beating and non-beating heart.

CRITERIA FOR LIVING DONOR CRITERIA FOR LIVING DONOR SELECTIONSELECTION

- Blood relative.Blood relative.- Highly motivated.Highly motivated.- ABO blood group-compatible.ABO blood group-compatible.- HLA-identical or haploidentical with HLA-identical or haploidentical with

negative cross-match.negative cross-match.- Excellent medical condition with normal Excellent medical condition with normal

renal function.renal function.

CRITERIA FOR CADAVER CRITERIA FOR CADAVER DONOR SELECTIONDONOR SELECTION

- Irreversible brain damage.Irreversible brain damage.- Normal renal function appropriate for age.Normal renal function appropriate for age.- No evidence of preexisting renal disease.No evidence of preexisting renal disease.- No evidence of transmissible diseases.No evidence of transmissible diseases.- ABO blood group-compatible.ABO blood group-compatible.- Negative cross-match.Negative cross-match.- Best HLA match possible, particularly at the Best HLA match possible, particularly at the

DR and B loci.DR and B loci.

Principles Involved In evaluating A Principles Involved In evaluating A Prospective Living Kidney DonorProspective Living Kidney Donor

Whether there is a medical condition that Whether there is a medical condition that will put donor at increased risk for will put donor at increased risk for complications for general anaesthesia or complications for general anaesthesia or surgery.surgery.

Wether the removal of one kidney will Wether the removal of one kidney will increase the donor’s risk for developing increase the donor’s risk for developing renal insufficiency.renal insufficiency.

Evaluation Of Kidney Function In Evaluation Of Kidney Function In Potential Kidney DonorPotential Kidney Donor

Serum creatinine.Serum creatinine. Creatinine clearance.Creatinine clearance. Radionuclide glomerular filtration rate.Radionuclide glomerular filtration rate. Urine analysis.Urine analysis. Urine Culture.Urine Culture. GFR > 70 ml/min.GFR > 70 ml/min.

Medical Conditions That Exclude Living Medical Conditions That Exclude Living Kidney DonationKidney Donation

Renal parenchymal disease.Renal parenchymal disease. Conditions that may predispose to renal diseaseConditions that may predispose to renal disease

History of stone diseaseHistory of stone disease

History of frequent UTIHistory of frequent UTI

HypertensionHypertension

D.M.D.M. Conditions that increase the risks of anaesthesia and Conditions that increase the risks of anaesthesia and

surgery.surgery. Recent malignancy.Recent malignancy.

Does Donation Of A kidney Pose A long-Does Donation Of A kidney Pose A long-term Risk For The Donorterm Risk For The Donor??

Following nephrectomy, compensatory hypertrophy Following nephrectomy, compensatory hypertrophy

and increase in GFR occur in the remaining kidney.and increase in GFR occur in the remaining kidney.

Slight risk of poteinuria and hypertension.Slight risk of poteinuria and hypertension.

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

confirmed safety of kidney donation.confirmed safety of kidney donation.

CONTRAINDICATIONS TO RENAL CONTRAINDICATIONS TO RENAL TRANSPLANTATIONTRANSPLANTATION

- ABO incompatibility.ABO incompatibility.- Cystoxic antibodies against HLA antigens of donor.Cystoxic antibodies against HLA antigens of donor.- Recent or metastatic malignancy.Recent or metastatic malignancy.- Active infection.Active infection.- AIDS.AIDS.- Severe extrarenal disease (cardiac, pulmonary, hepatic).Severe extrarenal disease (cardiac, pulmonary, hepatic).- Active vasculitis or glomeulonephritis.Active vasculitis or glomeulonephritis.- Uncorrectable lower urinary tract disease.Uncorrectable lower urinary tract disease.- Noncompliance.Noncompliance.- Psychiatric illness including alcoholism and drug addiction.Psychiatric illness including alcoholism and drug addiction.- Morbid obesity.Morbid obesity.- Age > 70 years.Age > 70 years.- Primary oxalosis.Primary oxalosis.- Persistent coagulation disorder.Persistent coagulation disorder.

Matching between Recepient And DonorMatching between Recepient And Donor

A- Tissue typingA- Tissue typing Determined by 6 antigens located on cell surface encoded for Determined by 6 antigens located on cell surface encoded for

by the HLA gen located on the short arm of chromosom 6.by the HLA gen located on the short arm of chromosom 6. Class I antigens (HLA-A and HLA-B) are expressed on the Class I antigens (HLA-A and HLA-B) are expressed on the

surface of most nucleated cells.surface of most nucleated cells. Class II antigen (HLA-DR) are expressed on surface of APC Class II antigen (HLA-DR) are expressed on surface of APC

and activated lymphocytes.and activated lymphocytes. These 6 antigens are refered to as major transplant antigens.These 6 antigens are refered to as major transplant antigens. The match between donor and recepient can range from 0 to The match between donor and recepient can range from 0 to

six.six.

Matching between Recepient And DonorMatching between Recepient And Donor

B- Cross matchingB- Cross matching

A laboratory test that determines weather a potential transplant A laboratory test that determines weather a potential transplant

recepient has preformed antibodies against the HLA antigens of the recepient has preformed antibodies against the HLA antigens of the

potential donor. (Donor Lymphocytest +Recepient Serum)potential donor. (Donor Lymphocytest +Recepient Serum)

A Final CM is mandatoryA Final CM is mandatory

C- Compatible ABO blood group.C- Compatible ABO blood group.

Structure of the HLA class I and class II antigens.

Oraganization of the human HLA genes on chromosome 6.

Effect Of HLA Matching On The Graft OutcomeEffect Of HLA Matching On The Graft Outcome

Data from large registries indicate that, the better the Data from large registries indicate that, the better the

HLA-match, the better the long-term survival of the HLA-match, the better the long-term survival of the

allograft.allograft.

The benefits of matching are particularly notworthy in The benefits of matching are particularly notworthy in

recipients of kidneys from donors with zero missmatch.recipients of kidneys from donors with zero missmatch.

The benefits of lesser degrees of matching have become less The benefits of lesser degrees of matching have become less

obvious with the use of newer and more potent obvious with the use of newer and more potent

immunosuppressive drugs.immunosuppressive drugs.

Matching for DR antigens are more favorable than others.Matching for DR antigens are more favorable than others.

The beneficial effect of HLA B and DR matching in patients with and without the benefit of cyclosporine.

Factors Influencing The Longivity Of Factors Influencing The Longivity Of Renal AllograftRenal Allograft

AgeAge HLA matchingHLA matching Delayed graft functionDelayed graft function Ischemia time.Ischemia time. Number of acute rejection episodes.Number of acute rejection episodes. Native kidney disease.Native kidney disease. Ethnicity.Ethnicity. OthersOthers

Relative incidence of causes of allograft dysfunction during the year following transplantation.

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

Chronic rejection.Chronic rejection.

Death with functioning graft.Death with functioning graft.

What Are The Most Common causes Of What Are The Most Common causes Of Death After Kidney TransplantationDeath After Kidney Transplantation??

Cardiovascular disease.Cardiovascular disease.

Infection.Infection.

Immune responses to renal allograft

Contraindications To Renal Contraindications To Renal TransplantationTransplantation

Absolute :Absolute : Severe vascular disease.Severe vascular disease.

Relative :Relative : Recent malignancy.Recent malignancy. Coronary artery disease.Coronary artery disease. Active bacterial, fungal, or viral disease.Active bacterial, fungal, or viral disease. HIV positivity.HIV positivity. Social conditions.Social conditions. Others.Others.

Renal Allograft RejectionRenal Allograft Rejection

1- Hyperacute.1- Hyperacute.

2- Acute.2- Acute.

3- Chronic.3- Chronic.

Hyperacute RejectionHyperacute Rejection Is mediated by preformed antibodies that recognize HLA Is mediated by preformed antibodies that recognize HLA

antigens in donor organ.antigens in donor organ. Usually these are formed as a consequence of blood Usually these are formed as a consequence of blood

transfusion, pregnancy, prior organ transplantation, transfusion, pregnancy, prior organ transplantation, autoimmune diseases.autoimmune diseases.

Modern CM tests detect these antibodies.Modern CM tests detect these antibodies. Fibrinoid necrosis lead to immediate graft loss.Fibrinoid necrosis lead to immediate graft loss. Delayed form may occur several days following Delayed form may occur several days following

transplantation.transplantation. Plasmapheresis and pulse steroid may be used.Plasmapheresis and pulse steroid may be used.

Hyperacute rejection.

Acute Renal Allograft RejectionAcute Renal Allograft Rejection

IS mediated by activated T-lymphocytes.IS mediated by activated T-lymphocytes.

Activations of T-cells occure after recognition of graft Activations of T-cells occure after recognition of graft

antigen either directly or after being processed and presented antigen either directly or after being processed and presented

by APC.by APC.

This usually occur during the first 6 mon.This usually occur during the first 6 mon.

It manifest as increase in s. creatinine with or without It manifest as increase in s. creatinine with or without

oliguria.oliguria.

Histology of acute cellular rejection

Vasculitis

How Common Is acute RejectionHow Common Is acute Rejection? ?

At least one episode of acute rejection occurs in At least one episode of acute rejection occurs in

62% in patients treated by CsA, Aza and steroids.62% in patients treated by CsA, Aza and steroids.

With Newer immunosuppressants drugs rates are With Newer immunosuppressants drugs rates are

less.less.

CSA, Aza, Steroid+Simulect is 36% CSA, Aza, Steroid+Simulect is 36%

ST, Rapa+ (MM For FK) + Simulect is~ 18%ST, Rapa+ (MM For FK) + Simulect is~ 18%

Treatment Of Acute RejectionTreatment Of Acute Rejection

1.Pulse steroids

2.ATG, OKT3.

3.MMF, Tacrolimus.

4. IVIG.

More than 90% of acute rejection episodes occuring in the first 6 mon can be reversed.

Chronic allograft RejectionChronic allograft Rejection Manifest clinically by a slow and gradual Manifest clinically by a slow and gradual

decline in renal function, usually more decline in renal function, usually more than 6 mon after transplant and typically than 6 mon after transplant and typically accompanied by moderate to heavy accompanied by moderate to heavy proteinuria.proteinuria.

Histologically, characterized by Histologically, characterized by glomerulo-sclerosis, interstitial fibrosis, glomerulo-sclerosis, interstitial fibrosis, and obliteration of arteriolar lumina.and obliteration of arteriolar lumina.

Treatment is unsatisfactory.Treatment is unsatisfactory.

Chronic rejection with tubulointerstitial lesions.

Fibrointimal proliferation in renal

arterioles in chronic rejection.

Chronic allograft Rejection VS Chronic allograft Rejection VS Transplant glomerulopathyTransplant glomerulopathy

A- ImmunologicA- Immunologic B- Non-lummunologicB- Non-lummunologic

• • hypertensionhypertension• • HyperlipidemiaHyperlipidemia• • Drug toxicity (CsA, FK)Drug toxicity (CsA, FK) • • Ischaemic injuryIschaemic injury• • Viral infection (CMV)Viral infection (CMV)• • OthersOthers

- C4d deposits in peritubular capillaries as - C4d deposits in peritubular capillaries as marker of ongoing immune injurymarker of ongoing immune injury

Management of Transplant Management of Transplant glomerulopathyglomerulopathy

Switch from calcineurin inhibitor.Switch from calcineurin inhibitor.

ACEIs or ARBs.ACEIs or ARBs.

Statins.Statins.

Increasing immunosuppression?Increasing immunosuppression?

OthersOthers

Banff criteria for diagnosis of allograft rejection

BANFF GRADE HISTOLOGY

I Interstitial edema and tubulitis (i.e.,

lymphocytic invasion of tubular basement

membranes.

II More severe tubulitis with or without mild

vasculitis characterized by intimal

lymphocytic infiltrates

III Severe vasculitis with fibrinoid necrosis.

Principles underlying current Principles underlying current immunosuppressive treatmentimmunosuppressive treatment

1- The benefits of a successful transplant outweight the 1- The benefits of a successful transplant outweight the

risks of chronic immunosuppression. risks of chronic immunosuppression.

2- Immunosuppressive therapy is required indefinitely.2- Immunosuppressive therapy is required indefinitely.

3- Multidrug regimens are generally employed.3- Multidrug regimens are generally employed.

4- Large doses of immunosuppressant drugs are used in 4- Large doses of immunosuppressant drugs are used in

the early transplant period.the early transplant period.

Classes of Maintenance Immunosuppressive Drugs

Class Examples

Immunophilin-binding agents Calcineurin inhibitors

CyclosporineTacrolimus (FK506)Calcinurin-independent agentsSirolimus (rapamycin)

Glucocoriticoids

Antimetabolites Purine inhibitors: nonselectiveAzathioprinePurine inhibitors:lymphocyte selectiveMycophenolate mofetil (RS-61443)Mizoribine*Pyrimidine inhibitorsBrequinar*

Poorly understood mechanismsDeoxyspergualin*Leflunomide*

*Experimental or not yet approved by Food and Drug Administration (FDA).

Sites of action of immunosuppressive drugs.

Risks associated with chronic Risks associated with chronic ImmunosuppressionImmunosuppression

1- Malignancy1- Malignancy

2- Infection2- Infection

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

CsA, tacrolimus, MMF, …..)CsA, tacrolimus, MMF, …..)

Side Effects of Glucocoriticoids

____________________________________________________

•Weight gain with cushingoid ▪ Dermatologic effects

features (acne, striae, easy bruisability,

• Hypertension impaired wound healing)

•Hyperlipidemia ▪ Impaired growth

• Osteopenia ▪ Glucose intolerance

• Cataracts

______________________________________________________________________

Side Effect Cyclosporine Tacrolimus Sirolimus

Nephrotoxicity ++ ++

Neurotoxicity + ++ -

(tremor, seizures)

Hirsutism ++ - -

Gingival hyperplasia + - -

Hypertension ++ +

Hyperlipidemia ++ +/- +++

Glucose intolerance + +++

Bone marrow suppression - - ++

Side Effects of Immunophiline-binding Agents

Side Effects of Antimetabolites

_____________________________________________________

Side effect Azathioprine Mycophenolate

Mofetil______________________________________________________________________

Bone marrow suppression +++ ++

Gastrointestinal + ++_____________________________________________________________________

Induction Immunosuppressive therapyInduction Immunosuppressive therapy

During the first 1-3 weeks post transplant.During the first 1-3 weeks post transplant. Usually refer to use of anti-T-cell antibodiesUsually refer to use of anti-T-cell antibodies

- polyclonal (ATGAM, thymoglobin).- polyclonal (ATGAM, thymoglobin).- Monoclonal (Simulect, Zinapax, OKT3).- Monoclonal (Simulect, Zinapax, OKT3).

Helpful to delay use of calcineurin drugs, may Helpful to delay use of calcineurin drugs, may decrease acute rejection and improve graft decrease acute rejection and improve graft outcome (debatable).outcome (debatable).

Expensive, risk of infection and malignancyExpensive, risk of infection and malignancy Better used in selected patients. Better used in selected patients.

Side Effects of Induction Side Effects of Induction AntibodiesAntibodies

Side effect OKT3 Polyclonals Anti-CD25 Agets

Fever +++ + _Headache ++ + _Myalgias ++ + _Gastrointestinal ++ _ _(diarrhea, nausea)

Respiratory distress + +/- _

Some commonly used combinations of Some commonly used combinations of maintenance Immunosuppressive drugsmaintenance Immunosuppressive drugs

1- Prednisolon + Azathiaprine1- Prednisolon + Azathiaprine

2- Prednisolon + cyclosporine (or tacrolimus)2- Prednisolon + cyclosporine (or tacrolimus)

3- Prednisolon + cyclosporine + Azathioprine3- Prednisolon + cyclosporine + Azathioprine

4- MMF (cell cept) may replace Azathioprine.4- MMF (cell cept) may replace Azathioprine.

5- Sirolimus (Rapaimmune) may replace Azathioprine 5- Sirolimus (Rapaimmune) may replace Azathioprine

or cyclosprineor cyclosprine

Common drug interactionsCommon drug interactions- Drugs acting on cytochrome P- Drugs acting on cytochrome P450450 affect the affect the

metabolism of CsA, tacrolimus, and sirolimus.metabolism of CsA, tacrolimus, and sirolimus.

1- ↑ Metabolism ↓ level1- ↑ Metabolism ↓ level

• • AnticonvulsantsAnticonvulsants • Antituberculous • Antituberculous

2- ↓ Metabolism ↑ level 2- ↓ Metabolism ↑ level

• • anti-fungus (ketoconazole..)anti-fungus (ketoconazole..)

• • erythromycin and clarithromycinerythromycin and clarithromycin

• • calcium channel blockerscalcium channel blockers

• • metoclopramidemetoclopramide

- Azathioprine and allopurinol.- Azathioprine and allopurinol.

Sonogram showing a lympgocele adjacent to a kidney.

Lodohippurate sodium 1131 renal scan, showing urine extravasation

Sonogram consistent with ureteral obstruction

showing hydronephrosis.

Acute pyelonephritis in a renal which ultimately required nephrectomy, secondary to associated obstruction.

Diffuse perihilar inflitrate secondary to cytomegalovirus infection in an 18 year old man with a rapidly deteriorating febrile condition 5 weeks posttransplant, after a course of

antilymphocyte globulin (for rejection).

Kaposi’s sarcoma

Bone scan of the hip in later stage aseptic necrosis, showing increased perfusion of the

femoral heads (arrows).

In geneal, renal transplantation should be In geneal, renal transplantation should be

recommended as the preferred mode of RRT for recommended as the preferred mode of RRT for

most patients with ESRD in whome surgery and most patients with ESRD in whome surgery and

subsequent I.S. is safe and feasible.subsequent I.S. is safe and feasible.

Cr CI 50-100 ml/min.Cr CI 50-100 ml/min. Anaemia.Anaemia. Conception and childbearing.Conception and childbearing. Growth in children.Growth in children. Bone metabolism.Bone metabolism. Work rehabilitation.Work rehabilitation.

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

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