Kidney transplantations

YYYYYYYYYYYEH BITCHES

Kidney functions

• removal of waste

• regulation of pH

• housekeeper for minerals

• regulation of body fluids

• activation of vitamin D - strong bones production

• production of EPO

EPO

Glycoprotein cytokine

Erythropoietin

Causes the body to make red blood cells

Noticing kidney failure thresholds

Transplantation = 45%

• bone breaking

• red blood cells

• pH balance

Dialysis = 15%

Dialysis

procedure to remove waste products and excess fluid from the blood when the kidneys stop working properly

Global burden of kidney failure

• Demographic predictions:

2010 - 2.6 million cases

2030 - 5.4 million cases

• 15-20% of patients die in a month of dialysis

• Many ppl live in LICs and LMICs, lack therapy to cure

Global prevalence - chronic kidney disease

• 64-74 years old = 1/5 men, ¼ women

• 75+ years = ½ adults

Total patients with kidney replacement therapy - NL

18,000 total

12,000 kidney transplant

6,000 dialysis

Why is a kidney transplant performed?

• feel more fit

• live longer

• gain more freedom

• improve chances to work

• live normal life + family

Why kidney transplant?

• better survival

• Better quality of life

• More integrated into society

• Cheaper

Relative risk of death after transplant

Risk equal: 106 days later

Survival equal: 244 days later

First living related transplant

Marius Renard (1952)

Utheral valves on the kidney

obstructive membranes that develop in the urethra (tube that drains urine from the bladder), close to the bladder

valve can obstruct or block the outflow of urine through the urethra.

What do you need a potential donor to be?

• healthy kidneys

• Match!!

HLA matching

• on A, B or DR loci

• ppl get an alele from each parent

Best/Worst fit - HLA matching

Best fit: mismatch 0-0-0

Worst fit: mismatch 2-2-2

• hope to match each allele to the recipient (6 alleles in total: 2 loci, 2 alleles from parents)

Chromosome responsible for HLA system

HLA I

• A, B, C loci

HLA II

• DP, DQ, DR loci

(HLA III)

• C4A, C4B

Major Histocompatibility Complex (MHC)

• highly polymorphic

• presents peptides from pathogens or “altered self” to the immune system

• Differences in HLA elicit immune responses (humoral + cellular)

• Big barrier in transplantation medicine

Refinement of MHC system over time

DP

• B1

• A1

DQ

• B1

• A1

DR

• B1

• B3, B4, B5

• A1

Worst response to transplantation

Immunization: antibodies against foreign tissue (vaccination style)

Maternal immunization

Antibodies pass naturally from mother to baby through the placenta

Reactivity to foreign HLA

????? COMPLETE THIS CARD

Interraction of APC / T cell regulated by uppers and downers

(APC == T cell)

• STIMULANTS

CD80/CD86 == CD28

• DEPRESSIVES

CD80/CD86 == CTLA-4

• Keeps T cells from killing tumor cells in the body

PD-L1 == PD-1

Best type of donor

Homozygous identical twin

Case: patient immunized against father? what happens?

Hyper acute rejection: complement binding by preformed antibodies

antigens are completely unmatched

Hyperacute rejection - characetristics

Type II rejection

• kidney colour not pink

• flabby tissue

• no urine production

Hyperacute rejection - cause

Performed HLA (or anti-blood types) antibodies:

preexisting antibodies in the recipient that are directed against donor antigens

Assay def

biochemical test that measures the presence or concentration of a macromolecule or a small molecule in a solution through the use of an antibody (usually) or an antigen (sometimes)

Crossmatch assay - prevent hyperacute rejection

• CDC-based assays

Patient serum

> (lympthocytes, T cells usually)

Rabbit complement

> cannot differenciate IgG from IgM)

Red = dead

Green = alive

Why use rabbit complement?

it is difficult to obtain normal human serum that lacks intrinsic bactericidal antibodies.

One approach to obtain human complement would be to absorb bactericidal antibodies from normal serum.

Different techniques - detect HLA antibodies

• Cell-based assays

CDC cross-match

Flow cytometry cross-match

• Solid-Phase assays

ELISA

Luminex (microbead with HLA antigen)

Prior sentization def

Someone whose immune system is highly sensitive to non‑self human leukocyte antigens (HLAs). Without the right treatment before surgery, their bodies will reject a new kidney

This feed-forward mechanism increases the response to a stimulus

how to detect prior sensitization?

• complement dependant cytotoxicity detects preformed antibodies

• Flow cytometry tests antibodies attached to lymphocytes

• Solid-phase assays

CDC

Complement dependent cytotoxicity

Solid-phase assays - prior sensitization

• antigen-bound microtiter plates

• single antigen beads (luminex)

DSA

Donor Sensitive Antibody

Techniques in detection of HLA antibodies have different sensitivity

LESS SENSITIVE

Luminex < Flow cytometry < ELISA < CDC-AHG < CDC

MOST SENSITIVE

Differences between CELL BASED ASSAYS / solid-phase assays

• positive assay = highly clinical relevance (80% rejection of graft)

• Often increased by IgG

• Dithiothreitol (DTT) to remove IgM

• Flowcytometer

Flowcytometer - cell based assays

both complement + non-compliment bindings depend on second antibody

Differences between cell-based assays / SOLID-PHASE ASSAYS

• sensitive

• both complement and non-complement bind antibodies, no IgGM autoantibodies or nonHLA antibodies

• Pathogenic threshold = unknown

Acute antibody mediated/humoral rejection - what is it

• within days/weeks after transplantation

• rapid graft dysfunction

• main target MHC antigens on the peritubular endothelium and glomerular capillaries

• sometimes non-HLA antibodies

Acute antibody mediated/humoral rejection - cause

anamnestic response by previous exposure generating complement-fixing antibodies

anamnestic response

renewed rapid production of an antibody on the second (or subsequent) encounter with the same antigen

Being sensitised increases the risk of:

• hyperacute rejection

• Memory B cell response => early ABMR

• chronic active ABMR

ABMR

Antibody-mediated rejection

=> most common cause of immune-mediated allograft failure after kidney transplantation

=> the earlier the less harm

Living VS post-mortem kidney transplant

Living donor kidneys = better chance of being accepted by the recipient's immune system

• kidney lasts longer

Blood type: ABO system, blood types // antibodies // antigens

• Group A

Anti-B

A antigen

• Group B

Anti-A

B antigen

• Group AB

NO antibody

A and B antigens

• Group O

Anti-A and Anti-B

NO antigens

Blood type donors // recipients

O => O AB A B

A => A AB

B => B AB

AB => AB

Blood transfusion - pretreatment

pretreatment (washing) of blood = no effect

Postmortal kidney dorors, where?

• Spain

• USA

• France

Living kidney donors, where ?

• Turkey

• Netherlands

Timing of transplantation after diagnosis = important

years later, impacts survival

Kidney donation in media before VS now

• Before

for compensation

commercial benefit? not good, poorer countries

• Now

Donor can choose a recipient

Conditions for kidney donation

• Organ donation act (1998): competent, >18, clearly informed consent, benefit someone else

• voluntary, not paid, always revokable

• socially feasible

• good chance of success of donation + transplantation

Who are the donors that volunteer?

• Related

family

• Unrelated

Collegues + friends = targeted donation (emotional bond)

Altruist not targeted = samaritan, charitable donor

Altruist targeted = supply/demand

CONCLUSION - vaguely

• HLA matching super important

• Immunosuppressants must be taken sadly

• Donor shortage possibly caused by: Xenotransplantation, Donation after euthanasia

Cross-match test (for ex: CDC)

test the compatibility of (a donor's and a recipient's blood or tissue).

anamnestic

enhanced reaction of the body's immune system to an antigen which is related to one previously encountered

3 different types of transpalnt rejections

• Hyperacute rejection occurs a few minutes after the transplant when the antigens are completely unmatched.

• Acute rejection may occur any time from the first week after the transplant to 3 months afterward.

• Chronic rejection can take place over many years.

Hyperacute rejection

the recipient is presensitized to alloantigens on the surface of the graft endothelium.

Acute rejection

when your body's immune system treats the new organ like a foreign object and attacks it.

treat this by reducing your immune system's response with medication.

chronic rejection

can take a year or more

progressive form of graft injury that usually results in graft failure