Renal Transplantation

Question 1

What is the recurrence rate of FSGS after renal transplantation?

Answer 1

30% (1 in 3) on first transplant. Up to 70% with the second

Question 2

What is the most common de novo nephritis to occur in the transplanted kidney?

Answer 2

Membranous occurs in 1 - 2%

Question 3

What is the most common nephritis (in Australia) that leads to transplant?

Answer 3

IgA disease

Question 4

What is the recurrence rate of mesangiocapillary disease?

Answer 4

15 - 35% with type 1 90% with type 2, but usually clinically benign

Question 5

What are the most important HLA for renal transplantation? (in order) and what chromosome are they on?

Answer 5

They are on chromosome 6 DR > B > A

Question 6

What are the long term risks for a live donor? (kidney)

Answer 6

There is apparently no increase in mortality, no increase in prevalence of hypertension and no increase in glomerular sclerosis

Question 7

The next slide is important to understand a concept about immunosuppression for transplants. Just stimulating a T cell receptor will not lead to lymphocyte proliferation and cytokine response. There is also a costimulatory signal which is essential for response.

This is important because newer immunosuppressant agents target this costimulatory response. Next picture demonstrates this.

Answer 7

Question 8

This next slide is an example of the targets for some MAb used in stopping rejection of renal transplantation.

Answer 8

Question 9

What are some of the causes of early renal transplant failure?

Answer 9

Ischaemia - ATN

immunosuppressant toxicty - cyclosporin and tacro

pre-renal - hypovolaemia

“dead kidneys” (non functioning on transplant)

vascular occlusion

post-renal - obstruction

Hyperacute rejection - very early and uncommon - requires antibodies against donor to be present prior to transplantation

Question 10

What are the histological signs that one might see in acute renal transplant rejection?

Answer 10

Firstly, there is non-specific cellular infiltrate

Secondly, we see tubulitis (evidence of cellular rejection) and vasculitis (vascular rejection)

this is clinically important, because cellular rejection is less severe. Vascular requires heavy suppression.

Question 11

What is the treatment of acute rejection?

Answer 11

Initially,

heavy steroid burst (methyl pred)

—- if steroid resistant or vasc rejection, use T cell depletion—

Anti-thymocyte globulin (for polyclonic T cell depletion)

OKT-3 (monoclonal T cell depletion)

Tacrolimus

Question 12

What is chronic allograft nephropathy?

now also called “interstitial fibrosis and tubular atrophy not otherwise specified”!

Answer 12

it is a chronic fibrosing condition leading to eventual failure. iut is immune or non-immune injury leading to stereotyped T cell and cytokine response in the kidney leading to more inflammation!

it must be differentiated from the following:

Late acute rejection

drug toxicity (e.g. cyclosporine)

urological causes (obstruction)

vasc obstruction

recurrent GN

Question 13

Where do steroids, MMF, Aza, sirolimus work?

What about cyclosporin and tacrolimus?

Answer 13

Question 14

what is the standard renal transplant drugs?

Answer 14

The most common is the triple therapy. Each from a slightly different class.

1. calcineurin inhibitor - tacrolimus or cyclosporin
2. mycophenolatae
3. prednisolone

Question 15

what are the side effects of mycophenolate?

Answer 15

increased GI symptoms compared to azathioprine. This is probably related to the metabolites, not the local drug effect. (happens with IV therapy too)

possible increase in PTLD and CMV

Question 16

How does cyclosporine work?

what SE?

Answer 16

it is a calcineurin inhibitor. It binds to cyclophilin in the lymphocyte and inhibits calcineurin.

it is nephrotoxic

SE: hair growth (hirsutism), gum hyperplasia, HTN, tremor

occasionally diabetes

Question 17

How does tacrolimus work?

Answer 17

It is a calcineurin inhibitor too.

it binds to the FK-binding protein and inhibits calcineurin.

it is also a nephrotoxic agent.

It has less of the cyclosporine side effects (less of the hypercholesterolaemia, HTN), but does suffer more diabetes, neurotoxicity. It also causes low magnesium!

possibly 10 - 20% will get DM!

Question 18

Are there any potential interactions with calcineurin inhibitors? Anything related to metabolism?

Answer 18

They are metabolised by Cyto P450 (3A4)

this means there is an interaction with diltiazem, verapamil, voriconazole, erythro/clarithromycin and grapefruit juice.

Question 19

What are the M-TOR inhibitors?

Answer 19

They are now being called “proliferation signal inhibitors”

M-TOR = mammalian target of rapamycin

Sirolimus and everolimus are examples.

Question 20

How does rapamycin (sirolimus) work?

Answer 20

this medication is super weird. It was scaped off a rock on Easter Island. It works similar to tacro (binds to a FK-binding protein) but instead of interfering with IL-2 synthesis, it BLOCKS IL-2 signalling pathway.

BIG SE: hyperlipidaemia and low platelets

Question 21

What are the anti-T cell medications that we use in transplants?

what are their side effects?

Answer 21

Polyclonal anti-T-cell:

1. anti-thymocyte globulin

monoclonal:

OKT-3

SE:

Early side effects include cytokine release (as the cells are just lysed, releasing all their goodness)

Late SE: opportunistic infections and PTLD

Question 22

Are there any other MAb that one might use around the time of transplantation to minimise acute rejection?

Answer 22

We believe that IL-2 is the most important cytokine for T-LL proliferation.

We have created an antibody for the receptor of this cytokine (CD25)

The available agent is BASILIXIMAB (the basilix!!!) and it is used pre-theatre and day 4 as routine. Good for 3 - 4 months.

Question 23

What does acute humoral rejection mean to you?

Answer 23

This means acute antibody mediated rejection.

Because of this, it would be reliant on B cells.

Because of this, THEORETICALLY, rituximab (an anti-B-cell) may be useful in treatment of rejection

Question 24

How does CMV infection cause problems in renal transplantation?

Answer 24

It can cause fever, hepatitis, gastritis and pneumonitis.

Primary infection is most severe. Reactivation is typically less so. It is important to know about donor/recipient status of CMV exposure.

Usually we use prophylaxis now.

Question 25

EBV infection can cause problems in renal transplant. What sorts of things does it cause?

Answer 25

Interesting question!

Primary infection is more severe (and so, EBV-naive paediatric transplants can become tricky)

Can cause PTLD, which is much more common with primary infection. 2% if donor+/recipient-

Question 26

What is BK virus?

Answer 26

This is another of those polyoma viruses

It is very common (?5 - 10%?), and survives on in the urothelium. Reactivates more on suppression.

It can cause an inflammatory interstitial nephritis and even graft loss.

Question 27

What sorts of malignancy screening is important before transplantation?

Answer 27

Derm

pap smear (as it is virally mediated, so becomes a mega issue with suppression)

mammogram

TCC screening (analgesic nephropaths and previously cyclophosphamide)

Question 28

What secretes IL-2?

What causes secretion?

Answer 28

It is produced by T-LL (CD8 AND CD4 LLs) to promote the proliferation of T cells

Production is decreased by cyclosporin A and FK506 (tacro) therapy. (Its action is blocked by sirolimus)

It is produced optimally in the presence of CD28 costimulation

Question 29

How does cyclosporin A cause renal toxicity?

Answer 29

It is by damaging the afferent arteriole, which then leads to fibrosis in a striped pattern.

Question 30

If you have a patient at day 50 post renal transplant, who presents with creatinine going from 100 last week, to 180 today.

What is the next investigation?

What is the definitive investigation?

The patient is making 800mL urine per day.

Answer 30

Despite the urine output, renal tract USS is important.

Not only do we need to exclude an obstruction, it would also be useful to mark up for biopsy.

HOWEVER, the definitive investigation is actually the renal biopsy.

Question 31

Would you have any worries about giving someone allopurinol and azathioprine?

Answer 31

There is a severely potent interaction between these medications, leading to very high levels of azathioprine, leading to severe bone marrow suppression.

Question 32

Hypomagnesaemia is a common phenomenon in the immediate post-transplant setting. This is due to which of the drugs we use?

Answer 32

Tacrolimus is the most potent.

Cyclosporin (similar drug, similar action) also causes this

Question 33

What is the worth pronostic in a renal transplant?

Answer 33

Diabetes in the recipient.

Question 34

Does azathioprine do anything to the FBC over a long period of time? (hint: it does something to the MCV)

Answer 34

It causes an elevation in the MCV when taken on several years

Question 36

Median graft survival for renal transplant (deceased vs live donor):

Answer 36

Graft survival in renal transplant:

Deceased donor: 13yrs

Live donor: 17-18 years

Question 38

What is very important to remember in a patient on azathioprine who develops gout?

Answer 38

Very serious drug interaction between azathioprine and ALLOPURINOL causing BM suppression.

Allopurinol and azathioprine should not be co-prescribed unless the combination cannot be avoided. Allopurinol interferes with the metabolism of azathioprine, increasing plasma levels of 6-mercaptopurine which may result in potentially fatal blood dyscrasias. Concomitant use requires special precautions: the dose of azathioprine should be reduced to 25% of the recommended dose and the patient’s blood count should be monitored assiduously.

Question 39

What are decoy cells associated with in urine?

Answer 39

Associated with BK virus (which causes a nephropathy several months after renal transplantation.

Question 40

Hypomagnesemia is a common biochemical abnormality after renal transplantation and may cause serious cardiac arrhythmias. In this setting, it is most commonly due to:

A. persistent hyperparathyroidism.

B. vitamin D deficiency.

C. mycophenolate.

D. cyclosporin.

E. prednisolone.

Answer 40

cyclosporin is the important one to be aware of