RENAL TRANSPLANTATION AN OVERVIEW
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RENAL TRANSPLANTATION AN OVERVIEW. Patients Selection For Kidney Transplanatation. All patients with ESRD are condidates for KT unless Systemic malignancy. Chronic infection. Severe cardiovascular disease. Neuropsychiatric disorder. Extremes of age (relative).

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Patients selection for kidney transplanatation l.jpg
Patients Selection For Kidney Transplanatation

All patients with ESRD are condidates for KT unless

  • Systemic malignancy.

  • Chronic infection.

  • Severe cardiovascular disease.

  • Neuropsychiatric disorder.

  • Extremes of age (relative).


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Patient Survival After Kidney Transplantation VS haemodialysis

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

  • Healthier patients generally are selected for transplantation.

  • 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



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Kidney Donor of an adult recipient.

  • Living related.

  • Living unrelated (emotionally motivated).

  • Cadaveric (Brain-dead)

    Beating and non-beating heart.


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CRITERIA FOR LIVING DONOR SELECTION of an adult recipient.

  • Blood relative.

  • Highly motivated.

  • ABO blood group-compatible.

  • HLA-identical or haploidentical with negative cross-match.

  • Excellent medical condition with normal renal function.


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CRITERIA FOR CADAVER DONOR SELECTION of an adult recipient.

  • Irreversible brain damage.

  • Normal renal function appropriate for age.

  • No evidence of preexisting renal disease.

  • No evidence of transmissible diseases.

  • ABO blood group-compatible.

  • Negative cross-match.

  • Best HLA match possible, particularly at the DR and B loci.


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Principles Involved In evaluating A Prospective Living Kidney Donor

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

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


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Evaluation Of Kidney Function In Potential Kidney Donor Kidney Donor

  • Serum creatinine.

  • Creatinine clearance.

  • Radionuclide glomerular filtration rate.

  • Urine analysis.

  • Urine Culture.

  • GFR > 70 ml/min.


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Medical Conditions That Exclude Living Kidney Donation Kidney Donor

  • 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 anaesthesia and surgery.

  • Recent malignancy.


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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.


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CONTRAINDICATIONS TO RENAL TRANSPLANTATION Donor?

  • ABO incompatibility.

  • Cystoxic antibodies against HLA antigens of donor.

  • Recent or metastatic malignancy.

  • Active infection.

  • AIDS.

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

  • Active vasculitis or glomeulonephritis.

  • Uncorrectable lower urinary tract disease.

  • Noncompliance.

  • Psychiatric illness including alcoholism and drug addiction.

  • Morbid obesity.

  • Age > 70 years.

  • Primary oxalosis.

  • Persistent coagulation disorder.


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Matching between Recepient And Donor Donor?

A- Tissue typing

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

These 6 antigens are refered to as major transplant antigens.

The match between donor and recepient can range from 0 to six.


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Matching between Recepient And Donor Donor?

B- Cross matching

  • A laboratory test that determines weather a potential transplant recepient has preformed antibodies against the HLA antigens of the potential donor. (Donor Lymphocytest +Recepient Serum)

  • A Final CM is mandatory

    C- Compatible ABO blood group.




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Effect Of HLA Matching On The Graft Outcome Donor?

  • Data from large registries indicate that, the better the HLA-match, the better the long-term survival of the allograft.

  • The benefits of matching are particularly notworthy in recipients of kidneys from donors with zero missmatch.

  • The benefits of lesser degrees of matching have become less obvious with the use of newer and more potent immunosuppressive drugs.

  • Matching for DR antigens are more favorable than others.


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


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Factors Influencing The Longivity Of Renal Allograft with and without the benefit of cyclosporine.

  • Age

  • HLA matching

  • Delayed graft function

  • Ischemia time.

  • Number of acute rejection episodes.

  • Native kidney disease.

  • Ethnicity.

  • Others



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What Are The Major Causes Of Long-Term Allograft Failure ? the year following transplantation.

Chronic rejection.

Death with functioning graft.


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

  • Cardiovascular disease.

  • Infection.



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Contraindications To Renal Transplantation Transplantation?

Absolute :

  • Severe vascular disease.

    Relative :

  • Recent malignancy.

  • Coronary artery disease.

  • Active bacterial, fungal, or viral disease.

  • HIV positivity.

  • Social conditions.

  • Others.


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Renal Allograft Rejection Transplantation?

1- Hyperacute.

2- Acute.

3- Chronic.


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Hyperacute Rejection Transplantation?

Is 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.

Fibrinoid necrosis lead to immediate graft loss.

Delayed form may occur several days following transplantation.

Plasmapheresis and pulse steroid may be used.


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Hyperacute rejection. Transplantation?


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Acute Renal Allograft Rejection Transplantation?

  • IS mediated by activated T-lymphocytes.

  • Activations of T-cells occure after recognition of graft antigen either directly or after being processed and presented by APC.

  • This usually occur during the first 6 mon.

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



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Vasculitis Transplantation?


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How Common Is acute Rejection ? Transplantation?

  • At least one episode of acute rejection occurs in 62% in patients treated by CsA, Aza and steroids.

  • With Newer immunosuppressants drugs rates are less.

    CSA, Aza, Steroid+Simulect is 36%

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


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Treatment Of Acute Rejection Transplantation?

  • Pulse steroids

  • ATG, OKT3.

  • MMF, Tacrolimus.

  • IVIG.

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


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Chronic allograft Rejection Transplantation?

  • 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.




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Chronic allograft Rejection VS rejection.Transplant glomerulopathy

  • A- Immunologic

  • B- Non-lummunologic

    • hypertension

    • Hyperlipidemia

    • Drug toxicity (CsA, FK)

    • Ischaemic injury

    • Viral infection (CMV)

    • Others

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


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Management of Transplant glomerulopathy rejection.

  • Switch from calcineurin inhibitor.

  • ACEIs or ARBs.

  • Statins.

  • Increasing immunosuppression?

  • Others


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Banff criteria for diagnosis of allograft rejection 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.


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Principles underlying current immunosuppressive treatment rejection.

1- The benefits of a successful transplant outweight the risks of chronic immunosuppression.

2- Immunosuppressive therapy is required indefinitely.

3- Multidrug regimens are generally employed.

4- Large doses of immunosuppressant drugs are used in the early transplant period.


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Classes of Maintenance Immunosuppressive Drugs rejection.

Class Examples

Immunophilin-binding

agents Calcineurin inhibitors

Cyclosporine

Tacrolimus (FK506)

Calcinurin-independent agents

Sirolimus (rapamycin)

Glucocoriticoids

Antimetabolites Purine inhibitors: nonselective

Azathioprine

Purine inhibitors:lymphocyte selective

Mycophenolate mofetil (RS-61443)

Mizoribine*

Pyrimidine inhibitors

Brequinar*

Poorly understood mechanisms

Deoxyspergualin*

Leflunomide*

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



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Risks associated with chronic Immunosuppression rejection.

  • 1- Malignancy

  • 2- Infection

  • 3- Side effects of different drugs (steroids, CsA, tacrolimus, MMF, …..)


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Side Effects of Glucocoriticoids rejection.

  • ____________________________________________________

  • Weight gain with cushingoid ▪ Dermatologic effects

  • features (acne, striae, easy bruisability,

  • Hypertension impaired wound healing)

  • Hyperlipidemia ▪Impaired growth

  • Osteopenia ▪Glucose intolerance

  • Cataracts

  • ______________________________________________________________________


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Side Effects of Immunophiline-binding Agents rejection.

Side Effect Cyclosporine Tacrolimus Sirolimus

Nephrotoxicity ++ ++

Neurotoxicity + ++ -

(tremor, seizures)

Hirsutism ++ - -

Gingival hyperplasia + - -

Hypertension ++ +

Hyperlipidemia ++ +/- +++

Glucose intolerance + +++

Bone marrow suppression - - ++


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Side Effects of Antimetabolites rejection.

_____________________________________________________

Side effect Azathioprine Mycophenolate

Mofetil

______________________________________________________________________

Bone marrow suppression +++ ++

Gastrointestinal + ++

_____________________________________________________________________


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Induction Immunosuppressive therapy rejection.

  • During the first 1-3 weeks post transplant.

  • Usually refer to use of anti-T-cell antibodies

    - polyclonal (ATGAM, thymoglobin).

    - Monoclonal (Simulect, Zinapax, OKT3).

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

  • Expensive, risk of infection and malignancy

  • Better used in selected patients.


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Side Effects of Induction Antibodies rejection.

Side effect OKT3 Polyclonals Anti-CD25

Agets

Fever +++ + _

Headache ++ + _

Myalgias ++ + _

Gastrointestinal ++ _ _

(diarrhea, nausea)

Respiratory distress + +/- _


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Some commonly used combinations of maintenance Immunosuppressive drugs

1- Prednisolon + Azathiaprine

2- Prednisolon + cyclosporine (or tacrolimus)

3- Prednisolon + cyclosporine + Azathioprine

4- MMF (cell cept) may replace Azathioprine.

5- Sirolimus (Rapaimmune) may replace Azathioprine or cyclosprine


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Common drug interactions Immunosuppressive drugs

- Drugs acting on cytochrome P450 affect the metabolism of CsA, tacrolimus, and sirolimus.

1- ↑ Metabolism ↓ level

• Anticonvulsants • Antituberculous

2- ↓ Metabolism ↑ level

• anti-fungus (ketoconazole..)

• erythromycin and clarithromycin

• calcium channel blockers

• metoclopramide

- Azathioprine and allopurinol.




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Sonogram consistent with ureteral obstruction extravasation

showing hydronephrosis.


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


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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).


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Kaposi’s sarcoma infection in an 18 year old man with a rapidly deteriorating febrile condition 5 weeks posttransplant, after a course of antilymphocyte globulin (for rejection).


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Bone scan of the hip in later stage aseptic necrosis, showing increased perfusion of the femoral heads (arrows).


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In geneal, renal transplantation should be recommended as the preferred mode of RRT for most patients with ESRD in whome surgery and subsequent I.S. is safe and feasible.

  • Cr CI 50-100 ml/min.

  • Anaemia.

  • Conception and childbearing.

  • Growth in children.

  • Bone metabolism.

  • Work rehabilitation.


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


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