Renal 2 - Kidney transplant Flashcards by Drew Yates

What are living donor criteria for transplant?

Willing, informed, over 18yo
Spouse or relative
Compatible blood type and tissue type, negative x-match
normal kidneys, negative family history, pHx
acceptable comorbidities and surgical risk

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What are deceased donor critieria for transplant?

Brain dead in ICU, relative consent, any age
absence of malignancy, uncontrolled infection
ATN is OK

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What is associated with deceased cardiovascular donors?

Higher risk of delayed graft function

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What is increased in donors post transplantation?

SBP and proteinuria
30% reduction in GFR
Overall mortality is = to the general population when compared to controls who would have been eligible for transplantation

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What are components of the immunology of transplantation?

ABO compatibility (less of an issue now)
Tissue typing - HLA
Panel reactive antibody test (PRA)

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What are features of hyperacute rejection?

Rare, early and untreatable
Pre-formed antibodies, on table, black kidney, anuria.
Predictable by cytotoxic crossmatch.
Pathology = vascular thrombosis, PMNs, infarction

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What are features of acute rejection?

Common (15-25%), early (1 week, peaks 3 months), treatable - prednisone
T-cell mediated (classical)
Diagnosed by Bx (DDx ATN, drugs, obstruction etc.)
Pathology:
cellular/interstitial - tubulitis, infiltrate
vascular/glomerular - endothelialitis
antibody mediated - PMNs, C4d+

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What are features of chronic rejection?

common (30%+), late, no specific treatment
unknown aetiology - immune plus non-immune
progressive renal dysfunction, proteinuria and HTN
Diagnosed clinically +/- Bx, DDX GN, drugs, hypertension.
Path - glomerulopathy, chronic interstitial nephritis, vessels.

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What are findings in chronic allograft nepropathy?

tubular atrophy
intesrtitial fibrosis
patchy infiltrate
arteriolar hyalinosis
glomerulopathy - glomerulosclerosis, rarely MCGN

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What is the number 1 cause of late transplant failure?

chronic allograft nephropathy (after death with a working allograft)

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What are principles of immunosuppression in renal transplantation? (8)

multiple agents to max efficacy, minimse toxicity
tailor immunosuppression to risk of acute rejection
- induction for hi risk patients
- taper over time
clinical and pharmacokinetic monitoring
- CSA AUC
prophylaxis for predictable SEs
- osteoporosis
- valaciclovir
avoidance of drug interactions
manage risk of cancer and infection
use newer agents
acknowledge uncertain effects on chronic rejection

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What are two examples of Ab induction agents?

Thymoglobulin

Basilixumab

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What are features of thymoglobulin?

rabbit immunoglobulin, polyclonal
targets T-cells, ICAM etc.
causes significant depletion of T-cells
duration of effect is days
excellent for induction and acute rejection and vascular rejection
Issues - cytokine release, LVF, meningitis, cytopenias, neutralising ab, cancer and infection (70% increased risk of all cancer, infections esp PJP)

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What are features of basilixumab?

human/mouse Ab, chimeric
Targets CD25+ T-cells, IL-2r activated
Causes inactivation
Duration of effect is months
Useful for induction but NOT so for acute rejection
Cost

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What are the predominant drugs in Signal 1 inhibition?

Cyclosporin - binds cyclophillin

Tacrolimus - binds FK-BP

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What is the main outcome of signal 1 inhibition?

inhibit IL-2 generation
cornerstone of anti-rejection prophylaxis
tacrolimus is more potent and preferred
synergistic with other agents

Target B and T-cells

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What are 5 key clinical issues with signal 1 inhibitors?

CYP450 interaction
Concentration dependent action and toxicities, need to monitor levels and concentrations.
CSA - measure peak, tacro, measure trough
Both nephrotoxic - key contributors to CAN
Aim for high exposure early, minimal exposure late

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What are two anti-metabolites used in renal transplantation?

mycophenolates

azathioprine

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What is the mechanism of action of mycophenolate?

more potent in 1st 12 months, and relatively leukocyte specific
Inhibits IMPDH(II) - preferential action against proliferating lymphocytes - binds tissue receptors
blocks de-novo purine synthesis, G1 arrest
mycophenolate sodium absorbed more distally - less GI toxicity
mycophenolate levels are lower with CSA
cause bone marrow suppression

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What is the mechnism of mTOR inhibitors?

bind to FKBP-12 (signal 3 inhibition) - binds FK-BP
Rapa-FKBP complex binds to mTOR
Inhibits IL-2/co-stim triggered cell signalling
- inhibits DNA synthesis - p27 - cdk2 interference - g1 arrest
- protein synthesis - IL-2 IFNg, IL-4, IL-10 (lesser)

Blocks T-cells, B-cells and VSM

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What is the advantage of everolimus vs CSA in renal transplant?

shown to cause better long term GFR

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What is the best agent for the management of acute rejection, apart from Ab induction agents?

Tacrolimus

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What is tacrolimus C/I with?

tacrolimus is contraindicated with cyclosporin

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What are significant toxicities associated with CSA?

Nephrotoxicity
Hypertension
Dyslipidaemia
Mild assoc DM
Avascular necrosis
Haemolytic uraemic syndrome
Hepatotoxicitiy
Mild issues with PO4/MG wasting

Significantly gum hyperplasia

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Which immunosuppressant is ok in pregnancy?

Cyclosporin

What are significant toxicities associated with Tacrolimus?

``` nephrotoxic (less so than CSA) Hypertension Lipids Diabetes +++ Neurotoxicity +++ HUS Liver toxicity PO4/Mg wasting alopecia C/I in pregnancy ```

What are significant toxicities associated with rapamycin/sirolimus?

``` NOT nephrotoxic significant lipid derangement (KEY!) thrombocytopenia +++ anaemia Lung disease (reversible, non-infective) slight GI toxicity slight neurotoxicity PO4/Mg derangement Stomatitis C/I in pregnancy ```

What are significant toxicities associated with MMF?

Significant reduction in WCC/neutropenia anaemia/thrombocytopenia/Bm suppression GI upset +++ C/I in pregnancy

What is the general management of acute rejection?

1) tissue Dx essential - following USS 2) IV methylprednisone - 90% effective 3) OKT3 or ATG lymphocyte depleting antibodies - if steroid resistant or evidence of vascular rejection - non-depleting antibodies not useful - adjust other immunosuppressants 4. plasma exchange, IVIg - if Ab mediated rejection 5. Rescue - refractory or recurrent rejection - high dose tacrolimus and mycophenolate 6. reversal provides good prognosis 7. number of episodes predicts mortality

What are some examples of early complications of kidney transplantation?

Infection - bacterial, viral - CMV, polioma/BK Rejection - Acute Drugs - tremor, ARF, GI, mood, bone (MMF) Tumours - 2-3x risk, PTLD (EBV related), KS (HHV8+ve) General - surgical complications

What are some examples of late complications of kidney transplantation?

Infection - viral - warts, zoster, PCP (impaired cellular immunity) Rejection - chronic, CAN Drugs - hair (CYC), kidney, bone, CVS (except MMF) Tumours - carcinoma, lymphoma General - CVS disease, recurrence

When is wound infection expected in transplant, and what are the clinical manifestations?

early | fever and cellulitis

When is pneumonia expected in KTRs, and what are the features?

any time | fever, cough, hypoxia

When is UTI expected in KTRs and what are the features?

early - sepsis | late - more benign, treat conventionally

When is CMV expected in KTRs?

M2-12, features include fever, colitis, LFT derangement and lung involvement

When is PCP expected in KTRs and it's clinical features?

M3-12, dyspnoea, fever

When is BK virus expected in KTRs and it's clinical features?

graft dysfunction only, months 4-24

when is HSV expected in renal transplantation?

Any time

When is varicella expected, and what are it's features?

any time, if primary, there is a 50% mortality rate

When are fungal infections expected in KTRs and what are their clinical features?

post ART - fever, abscess (t-cell depleting therapy)

When are decoy cells seen on urine?

in the presence of BK virus nephropathy

What are features of the BK virus?

``` DNA virus Primary infection in childhood - persistence Reactivated by: - immunosuppression - hormonal changes (preg, DM) - tissue injury - coinfection w HIV, CMV, HHV6 Asymptomatic ```

What are features of BK nephropathy?

``` interstitial nephritis intranuclear inclusions Tubular injury and necrosis Evidence - SV40 antigen positive and Electron micro Blood or urine PCR ``` Mx - reduce immunosuppression, unclear role of antivirals

What is the role of prophylaxis in CMV and KTRs?

D+ to R- or D+ and Antibody Rx - 50% risk of CMV valacyclovir has 65% reduction in CMV at 6 months and 50% reduction in acute rejection

Osteoporosis prophylaxis in KTRs?

palmidronate pre and pst Tx prevents BMD loss | calcitriol plus Ca++

What is the primary cause of death with a functioning graft?

Cardiovascular disease

What is the most common cancer in KTRs?

Skin cancer most common, 70% by 30 y post transplant. 80% will have a cancer of some description by 30 years. 40% have solid organ. Bulk of skin cancers are SCC or BCC

What are risks for disease recurrence and graft loss in KTRs?

Risk exists for subjects with - glomerulonephritis - metabolic Dz (DM, oxalosis) - malignancy Disease recurrence doubles the risk of graft loss at 5 years Risk of graft loss increases with time - diabetes, common after 10 years, glomerulonephritis

What proportion of patients have GN recurrence post transplant?

6-19.4%

What are predictors of GN recurrence post transplant?

rapid original course to renal failure FSGS/MCGN live/hla matched donor (Paed FSGS) recurrence in previous graft Rx - FSGS - screen ACR, Rx pheresis (removal of suPAR) Vasculitis - steroids and cyclophosphamide

What is the effect of steroids in recurrent IgA nephropathy post transplantation?

reduce the rate of IgA nephropathy recurrence related graft loss

What is appropriate treatment of ABMR?

increase steroids increase MMF find a new donor

What are the two organ transplants associated most strongly with CKD?

Intestine Lung Heart

What is the strongest risk factor for CRF in non-renal tx patients?

GFR

What proportion of transplant recipients develop NODAT?

25-40%

What immunosuppressant is not implicated in NODAT?

MMF

What causes insulin resistance in NODAT?

``` steroids CNIs, mTOR inflammation HCV, CMV Obesity Inactivity ```

What causes insulin deficiency in NODAT?

``` tacrolimus >> CSA mTOR age insulin degradation (tacro inhibits pancreatic insulin secretion) ```

What other medication is assocaited with NODAT?

sirolimus is associated with NODAT, regardless of CNI usage. Sirolimus and CSA has highest prob of developing NODAT

What is the key impact of NODAT on transplant patients?

increases rates of death with a functioning transplant

What glomerulonephritis is least likely to recur?

post streptococcal glomerulonephritis

What agents induce t-cell lysis?

thymoglobulin

Which agents primarily interrupt signal 1 of t-cell activation during acute rejection?

tacrolimus | cyclosporin

What agents are effective in treating acute allograft rejection?

thymoglobulin mycophenolate (high dose) tacrolimus rapamycin

Which medication is least likely to contribute to the development of diabetes after transplantation?

Myophenolate

What are risk factors for CAN?

excess or inadequate CNI exposure prior acute rejection presence of donor specific antibodies.