Transplant Flashcards
Diseases that can recur post-transplant?
Highest recurrence rates:
- Primary FSGS
- C3GN, DDD
- Atypical HUS
- IgA
- Membranous
- Others:
- Diabetic nephropathy
- Primary Oxalosis if liver not transplanted
Transplant recipient contraindications?
- Recent or metastatic cancer
- Untreated current infection
- Severe irreversible extrarenal disease
- Recalcitrant treatment nonadherence
- Psychiatric illness impairing consent and adherence
- Current recreational drug abuse
- Aggressive recurrent native kidney disease - ???
- Limited, irreversible rehabilitative potential
- Primary oxalosis
- Uncorrectable chronic hypotension
Contraindications to deceased donation?
- Most cancers
- Apart from non-melanoma skin cancer or small RCC that can be resected at time of transplant, most are contraindicated
- Certain infections
- Severe, multifocal, difficult to treat
- Active HIV
- Severe fungal
- Viral - Measles, adenovirus
- Prion disease
Banff criteria for acute antibody-mediated rejection?
Need all of:
- No AMR chronicity criteria met
- AMR activity criteria (any of):
- g >0
- ptc >0
- v >0
- Acute TMA in the absence of other cause
- ATN in the absence of other cause
-
Antibody interaction with tissue (any of):
- +C4d
- g+ptc >=2
- increased expression of validated gene transcripts/classifiers in biopsy tissue strongly correlated with AMR
- +DSA
What is exceptional distribution?
= “increased risk distribution”. NOT about kidney quality and more about social history/med history of donor.
- Unknown travel history, ?TB ?Zika
- Remote history of low risk cancer
- Infection that can be treated
- High risk sexual or substance use behavior
- MSM
- IVDU
- Sex worker
- Jail
- Lived somewhere with high risk of infections
- Neurodegenerative disease
What is expanded criteria (ECD)?
- Age >= 60 or
- Age >= 50 and 2 out of 3 of:
- HTN
- Death from stroke
- Cr >132
Transplant list exceptions/prioritization criteria?
- Pediatric (growth retardation)
- Medical emergency
- Uremic cardiomyopathy
- Lack of vascular access
- 2 organs needed
- HLA 6/6 match (too good of a match)
- PRA>95%
- If a living donor gets ESRD
Treatment of ABMR?
- IVIG
- PLEX if +DSA
- Rituximab
- Steroids
- +/- eculizumab
What features make BKVN more likely (vs. ABMR)?
- BK viremia >10,000 copies
- +SV40
- Intranuclear viral inclusions in renal tubular nuclei
- Decoy cells in urine
- More likely medullary inflammation as opposed to cortex
- Ureteral stenosis
How does BKVN usually present?
Asymptomatic rise in creatinine during the 1st year post-transplant
Biopsy findings for diagnosis of BKVN?
- Allograft biopsy shows BK viral inclusions in renal tubular nuclei and glomerular parietal epithelium. Intersititial mononuclear inflammation (plasma cell-rich), focal tubulitis. SV40 positive.
Treatment algorithm/options for BKVN?
- Reduce CNI
- Reduce anti-metabolite
- Reduce both CNI and anti-metabolite
- Change tac to cyclosporine or sirolimus
- Switch MMF to AZA or leflunomide
- Other alternatives: cidofovir, quinolone, IVIG
Renal allocation system considerations
- Prioritization – multiple organ, children, medical urgency
- Age matching
- Waiting time
- Sharing within national registry
- Seek to avoid wasting organs
- Not be based on patients’ residence
- Testing to prevent the spread of infectious diseases
- Reduce inequalities from SES
CMV prophylaxis - when and how long?
- Donor - / Recipient – No treatment
- Donor + / Recipient – Valganciclovir x 6mos (CMV mismatch)
- Donor - / Recipient + Valganciclovir x 3 months (If induction with thymoglobulin x 6mos)
- Donor + / Recipient + Valganciclovir x 3 months (If induction with thymoglobulin x 6mos)
Immediate and long-term complications of living kidney donation
- Immediate complications
- Surgical complications – Pain, bleeding, infection, risk of laceration to another organ, PE/DVT, hospital-acquired illnesses
- Time away from work, financial loss
- Psychosocial – fear, anxiety, depression
- Longterm complications
- Increased risk of proteinuria
- Increased risk of HTN
- No effect on fertility or outcome of future pregnancies (preterm delivery or low birth weight), but greater incidence of pre-eclampsia (11% in donors compared to 5% in matched no-donors). Therefore, advisable to delay pregnancy for up to at least 6 months to allow for maximal compensatory hypertrophy of the single kidney.
Causes of anemia post-transplant (pharmacological and non-pharmacological)
- Pharmacological
- Immunosuppression: MMF, AZA, sirolimus, everolimus
- Septra
- Dapsone (hemolytic anemia)
- Discontinuation of EPO therapy
- Non-pharmacological
- Post-op bleeding
- Iron deficiency
- Infection eg. parvovirus
- Tertiary hyperparathyroidism
- Occult GIB
Causes of graft loss after 1 year?
- Chronic antibody rejection
- CNI toxicity
- Native disease recurrence
- BK nephropathy
3 antigen-presenting cells
- Macrophages
- Dendritic
- B lymphocytes
Pathologic features of chronic CNI toxicity
- arteriolar hyalinosis, then progresses to obliterative arteriolopathy (suggesting primary endothelial damage) – both afferent and efferent arterioles are affected as compared with diabetes having usually only afferent hyalinosis
- ischemic collapse or scarring of the glomeruli,
- vacuolization of the tubules,
- global and focal segmental glomerulosclerosis,
- focal areas of IFTA (producing a picture of “striped” fibrosis).
How do CNI’s cause nephrotoxicity
- Renal vasoconstriction / afferent arteriole
- Interstitial fibrosis
- TMA
Risk factors for developing diabetes post-transplant
- Obesity (RR 1.7)
- Older age >60 (RR 2.6)
- Black/Hispanic (RR 1.7)
- Hep C (RR 1.3)
- Immunosuppression with steroids, CNI (Tac RR 1.3), sirolimus
MMF in pregnancy?
- Black box warning: number of reports of 1st trimester pregnancy loss and congenital fetal abnormalities (face and ear).
- Stop months before attempting conception. Must be off minimum 6 weeks (washout period), but usually 3 months to ensure new immunosuppressive regimen stable.
What immunosuppression meds are safe and not safe in pregnancy?
Safe: prednisone (note: high dose a/w cleft lip), CNI, azathioprine
Not safe: MMR, sirolmius, belatacept
What criteria to consider to decrease risk of pregnancy in transplant recipents?
- >1 year post-transplant
- Serum Cr <133
- No recent episodes of acute rejection
- Normotensive or minimal antihypertensive regimen
- Minimal or no proteinuria (<500 mg/day)
- Normal allograft ultrasound
- Pregnancy-safe drug regimen
Active CMV infection vs. CMV disease?
- Active CMV infection – CMV viremia (with or without symptoms) (~5000)
- CMV disease – CMV viremia + clinical manifestations of CMV disease (CMV syndrome OR tissue-invasive CMV disease)
- CMV syndrome – CMV viremia + attributable symptoms/signs (fever, arthralgia, leukopenia, thrombocytopenia, etc.)
- Tissue-invasive CMV disease – End-organ disease (eg. enteritis, colitis, hepatitis, nephritis, pneumonitis, meningitis, encephalitis, retinitis)
When to treat CMV in transplant, how, and how long?
- Management:
- Active CMV infection – Stop antimetabolite, monitor PCR. If continued replication, start antiviral.
- CMV disease
- Stop antimetabolite
- Start antivirals
- IV ganciclovir 5mg/kg q12h for severe disease, or
- Oral valganciclovir 900 mg bid (adjust for kidney fxn)
- CMV PCR weekly x 4 weeks
- Duration of treatment: Usually 3 weeks. Treat until no CMV viremia in 2 PCRs, 1 wk apart. May be longer for more severe disease.
- Secondary prophylaxis for 1-3 months (valgan 900 mg daily)
HLA desensitization protocol?
- IVIG (immunomodulation of recipient)
- Rituximab (deplete B cells responsiblefor anti-HLA antibody production)
- PLEX (removal of anti-HLA antibodies)
Window period for HIV, Hep C, HepB in the setting of exceptional distribution?
For NAT testing:
HIV - 5-6 days
Hep C - 3-5 days
Hep B - 20-22 days
Transplant tourism cons?
- Compared to local donation, increased risk of infections
- Increased risk of graft loss
- Increased risk of mortality
- Increased risk of adverse outcomes for living donor and unethical
Pros/cons of basiliximab vs. ATG
- Basilximab (IL-2 antibody)
- Lower risk of opportunistic infection and malignancy
- Use if rabbit allergy
- ATG
- Decreased risk of DGF
- Use for highly sensitized
Cytotoxic vs. Flow cytometry cross-match?
- Cytotoxic: Recipent serum + Donor lymphocytes + Complement
- Cell lysis if positive
- Specific but not sensitive
- Flow: Recipient serum + Donor lymphocytes + Fluroscent antibodies that binds al human IgG
- Run through machine to see signal strength
- Sensitive
T and B cell cross-match interpretation:
T cell neg, B cell neg
T cell pos, B cell neg
T cell neg, B cell pos
T cell pos, B cell pos
T cell neg, B cell neg - NEGATIVE XMatch
T cell pos, B cell neg - POSITIVE Class I
T cell neg, B cell pos - POSITIVE Class II antibodies
T cell pos, B cell pos - POSITIVE Class I and II
(T cells express Class I, B cells express both Class I and II)
KDPI
KDPI (Kidney Donor Profile Index) - <85% okay, >85% higher risk
The KDPI is derived from the kidney donor risk index (KDRI) score and is the percentage of donors in a reference population that have a KDRI score less than or equal to the donor’s KDRI score.
The KDRI estimates the relative risk of posttransplant graft failure and is calculated from the donor age, ethnicity, creatinine, history of hypertension or diabetes, cause of death, height, weight, hepatitis C virus (HCV) status, and whether the kidney was donated after circulatory death.
Risk factors for PTLD
EBV mismatch
Younger age at transplant (EBV-naive)
ATG (prolonged or repeated doses)
Degree of immunosuppression
First year of transplant (highest immunosuppression)
History of pre-transplant malignancy
Fewer HLA matches
Risk factors for acute antibody-mediated rejection
- Preexisting sensitization due to blood transfusion, prior transplant, pregnancy
- PRA >80%
- High degree of HLA-mismatch
- Positive B-cell crossmatch
- Patients with donor specific antibodies
- ABO incompatibility
- Steroid minimization
- Non-compliant with immunosuppression
- African American recipient
- Previous rejection episodes
Risk factors for NODAT
- Pre-transplant impaired fasting glucose, perioperative hyperglycemia
- FHx T2DM
- Hx of gestational DM
- Obesity
- Older age >60
- African American/Hispanic
- Hep C
- Immunosuppression with steroids, CNI (Cyclosporine and Tac), sirolimus
2 reasons you would switch to sirolimus?
CNI-nephrotoxicity
CNI-neurotoxicity or TMA
BK nephropathy
Skin cancer
Pathologic findings of chronic allograft nephropathy
- interstitial fibrosis and tubular atrophy (IFTA)
- double contouring of GBM
- subintimal vessel wall thickening
Risk factors for chronic allograft nephropathy
- Acute rejection
- Hypertension
- Glomerular hyperfiltration and hypertrophy
- Superimposed recurrent or de novo kidney parenchymal disease
- Delayed graft function
- Hyperlipidemia
How does chronic allograft nephropathy usually present?
Slow, progressive decrease in kidney function, usually associated with hypertension and worsening proteinuria
Treatment of acute T-cell mediated rejection
Pulse steroids
Increase immunosuppression
ATG (if v lesion)
Post-transplant patient with thigh pain and difficulty weight-bearing, normal xray. Diagnosis and 2 tests?
Avascular necrosis
MRI gold standard, bone scan (but not very sensitive)
How long should a patient wait before being transplanted after the following malignancies: basal cell carcinoma, colon cancer, breast cancer
- Basal cell – 0
- Colon CA – 5
- Breast CA – 5
- Per guidelines, the following do NOT need waiting period:
- Non-metastatic basal cell or squamous cell of skin
- Melanoma in situ
- Small RCC <3cm
- Prostate cancer Gleason <=6
- Carcinoma in situ (ductal, cervical)
- Thyroid (papillary, follicular) <2cm, of low grade histology
- Superficial bladder cancer
- Others require waiting period depending on cancer
Mechanism of action of MMF
Inhibits purine synthesis required for lymphocyte proliferation
Mechanism of action for tacrolimus
Binds to FK-binding protein, which inhibits calcineurin. Calcineurin normally stimulates IL-2 transcription, so this inhibits IL-2 -> inhibits T-cell proliferation.
Mechanism of ATG
Polyclonal IgG from horses or rabbits immunized with human thymocytes
They block T-cell membrane proteins and are cytotoxic, leading to depletion of peripheral lymphocytes
Side effects/risks of ATG
Anaphylaxis from rabbit allergy
Cytokine-release syndrome (fever, hypotension, cytopenias, rare-capillary leak syndrome)
Serum sickness
Leukopenia, thrombocytopenia
PTLD, EBV activation
Infections - viral eg. CMV (hence why CMV proph)
Mechanism of sirolimus, everolimus
Binds FKBP12 (which normally engages TOR protein) -> inhibition of TOR -> decrease cytokine-dependent cellular proliferation at the G1 to S phase of cell-division cycle
Side effects of sirolimus
- Dyslipidemia
- HTN
- Delayed wound healing
- Proteinuria, progressive glomerulopathy (FSGS), AKI
- TMA
- Teratogenic
- Progressive interstitial pneumonitis
- Cytopenias (any)
- Peripheral edema
Mechanism of action of azathioprine
Purine analogue incoporated into cellular DNA -> inhibits purine nucleotide synthesis
What is the EPTS
- Estimated Post Transplant Score (0-100%, lower score are better)
- Score dependent on:
- Prior transplant
- DM
- Time on dialysis
- Age
- EPTS =<20% recipients should receive kidneys with KDPI <=20%
Meds that will decrease CNI levels
- Anti-TB meds (rifampin, rifabutin, isoniazid)
- Anti-consulvants (phenytoin, carbamazepine, barbiturates)
- Cephalosporins
- Imipenem
- St. Johns wort
Meds that will increase CNI levels
- ABx - macrolides
- CCB, non-dihydropyridine (eg. diltiazem)
- Amiodarone
- Antifugnals -azoles (eg. ketoconazole)
- Anti-retrovirals - HIV protease inhibitors
- mTOR inhibitors
What is C4d?
C4d is a breakdown product of the classical complement pathway.
Binds to endothelial and collagent basement membrane (evidence antibody activity is or was present)
4 steps of T cell activation
- 1. Signal 1: Antigen-presenting cell presents antigen as a MHC-peptide complex to the T-cell receptor, transduced through the CD3 complex.
- 2. Signal 2: Co-stimulation occurs when co-receptor proteins recognized by T-cells (CD80/86 on antigen-presenting cell engages CD28 on T-cells)
- Signal 1+2 stimulate 3 pathways:
* Calcium/calcineurin pathway
* RAS-MAP-kinase pathway
* Nuclear factor-KB pathway
* –> these lead to IL-2 and other cytokine expression
- Signal 1+2 stimulate 3 pathways:
- 4. Signal 3: IL-2 binds to its receptor, activating mTOR pathway, which triggers T-cell generation and amplification.
What causes a high PRA?
Blood transfusions
Pregnancy
Prior transplants
Definition of delayed graft function and its effect on longterm allograft function
Requirement of dialysis or oliguria within the first 7 days post-transplant
Associated with short and longterm allograft failure
5 types of viral-associated malignancy that can occur post-transplant and associated virus?
- PTLD - EBV
- Adult T-cell lymphoma - HTLV
- Squamous cell (skin, cervix, etc) - HPV
- Kaposi sarcoma - HHV-8
- Merkel cell carcinoma - Merkel cell polyomavirus
- Liver cancer - HBV, HCV
3 tests to detect CMV
CMV IgM and IgG antibody
CMV PCR
Histopathology/biopsy showing basophilic intranuclear inclusions
Shell vial culture
Fresh post-transplant, initial good graft function then AKI with thrombocytopenia PLT 80 -> 30s
Diagnosis and management?
- Diagnosis:
- De-novo drug-induced TMA from CNI
- Management:
- Confirm TMA process with labs
- Kidney biopsy
- Check CNI levels first - if they are supra therapeutic, hold. If the levels are NOT high, you do NOT hold CNI. You try switching from cyclosporine to tac or vice versa.
- Stop sirolmus if also on that.
- Exclude other causes of TMA - complement panel, ADAMTS13, stool C&S
- Assess for other causes of AKI - HLA, US, tac levels
- Ensure viral work-up done for eculizumab (CMV, HIV, Parvo, BK)
- If treating with eculizumab, ensure protection against meningococcal infections
- PLEX if any concern for TTP or eculizumab not available
Advantages and disadvantages of laparoscopic living kidney donation
- Advantages of laporoscopic living kidney donation
- Shorter post-op hospital stay
- Quicker return to work
- Less post-operative pain
- Minimal surgical score
- Magnified view of renal vessels
- Disadvantages of laporoscopic living kidney donation
- Pneumoperitoneum may compromise renal blood flow
- Longer OR time
- Tendancy to have shorter renal vessels and multiple arteries
- Impaired early graft function, but no difference at 6 months
- Increased risk of ureteral injury with multiple renal arteries
Effect/benefits of MMF in glomerular disease
Benefit over cyclophosphamide?
- Decrease lymphocyte proliferation
- Decrease antibody production
- Impairs binding of lymphocytes to vascular endothelial cells by downregulating expression of adhesion molecules
Benefit over cyclophosphamide - is lymphocyte-specific, less infertility, malignancy
Reasons why switch from cyclosporine to tacrolimus?
Tac superior for preservation of graft function (Symphony study)
Cyclosporine has some worse side effects: hirsutism, gingival hypertrophy
HTN worse with cyclosporine
Any rejection on cyclosporine
What side effects are worse with tacrolimus than cyclosporine
Tremor, headache
NODAT
GI symptoms
Alopecia
cyclosporine plus statin - how to prevent/manage potential rhabdo
- As a result of cyclosporine-induced impairment in metabolism of the statin (cyclosporine is cytchromc P450 inhibitor)
- Start at low dose, avoid lovastatin and simvastatin
- Prava and fluvastatin better
- Avoid coadministration of gemfibrozil/fibrates
- Follow CK monthly
- Inform patients of potential interaction and symptoms (myopathy)
Define moderate tubulitis
Moderate tubulitis = 5-10 cells per tubular cross section in cortex (t2 per Banff Classification of renal allograft rejection)
MSK problems after transplant?
Osteoporosis
AVN
Steroid myopathy
CNI myopathy
Statin myopathy
Persistent hyperparathyroidism
When picking recipient for cadaveric kidney, 5 recipient-related factors that you consider?
- Increased time on waiting list (time on dialysis)
- 0 HLA mismatch
- Highly sensitized
- Limited vascular access options
- Previous living donor
- Pediatric
- Age match <15 years
- Multi-organ transplant
Brother of pt with ADPKD living donor evaluation?
If age <40 and >=1 cyst on US/CT -> genetic testing
If age >=40 and >1 cyst on US/CT -> genetic testing
If age >=40 and only 1 cyst, rules out ADPKD
(UpToDate and KDIGO Living Donor guidelines)
Antimicrobial prophylaxis for post-transplant
- Surgical prophylaxis: Cefazolin IV at time of OR
- PCP PPx: tmp-smx 1 DS MWF for 1 year
- CMV PPx:
- Donor - / Recipient – No treatment
- Donor + / Recipient – Valganciclovir x 6mos (CMV mismatch)
- Donor - / Recipient + Valganciclovir x 3 months (If induction with thymoglobulin x 6mos)
- Donor + / Recipient + Valganciclovir x 3 months (If induction with thymoglobulin x 6mos)
- Nystatin x 1 mo
- Vaccines:
- Wait 3-6 months before any vaccines
- Annual influenza, Pneumococcus q 5 years
- Routine vaccine schedule, but no live vaccines
- Hepatitis B vaccine pre-transplant
Most common skin cancer post-transplant
Management?
- Squamous cell carcinoma
- (Other skin cancers: basal cell, melanoma, Kaposi sarcoma, Merkel cell carcinoma)
- Management:
- Reduction of immunosuppression
- Switch CNI to mTOR inhibitor (sirolimus)
- MMF better than AZA
Pt who is 36h post-Tx w/ Cr 170 to 195 and U/S shows hydro. What to arrange?
- Early hydronephrosis post-transplant
- UVJ stenosis is most common site of obstruction
- DDx:
- 1) Blood clot in the ureter, bladder, or catheter
- 2) Kinked ureter
- 3) Incorrect suture placement
- Management:
- Gentle bladder irrigation with 3-way foley
- Consult urology to work-up stent thrombosis/obstruction/stenosis
- In olden days, pre-stents: Nephrostomy → antegrade pyelogram
Management of CNI-induced TMA post-transplant
- Confirm TMA process with labs
- Kidney biopsy
- Check CNI levels first - if they are supra therapeutic, hold. If the levels are NOT high, you do NOT hold CNI. You try switching from cyclosporine to tac or vice versa.
- Stop sirolmus if also on that.
- Exclude other causes of TMA - complement panel, ADAMTS13, stool C&S
- Ensure viral work-up done for eculizumab (CMV, HIV, Parvo, BK)
- If treating with eculizumab, ensure protection against meningococcal infections
Minimum GFR to donate kidney?
Per KDIGO 2020 Living donor guidelines:
eGFR:
>90 OK
60-90 individualized
<60 should not donate
Albuminuria:
ACR <3
ACR 3-10 individualized
ACR >10 should not donate
Hematuria:
If reversible cause, OK
If due to IgA, should not donate
(Amsterdam guidelines: eGFR >80)
6mos post-Tx on MMF, tacrolimus, Septra, prednisone, ranitidine, diltiazem. Stable Cr at 220. K=6.1. 3 reasons for hyperK?
- Hyperkalemia post transplant
- Tacrolimus (impairs potassium secretion in the cortical collecting duct)
- Septra (ENaC blocker)
- Trimethoprim (an organic cation) acts like amiloride and blocks apical membrane sodium channels in the mammalian distal nephron. As a consequence, the transepithelial voltage is reduced and potassium secretion is inhibited. Decreased renal potassium excretion secondary to these direct effects on kidney tubules leads to hyperkalemia in a substantial number of patients being treated with trimethoprim-containing drugs
- Diltiazem increases CNI levels, which may contribute to the CNI nephrotoxicity
- Decreased GFR and poor dietary compliance
Anti-GBM disease after transplantation in Alport’s disease - how often does this occur and why?
Incidence of graft loss in these patients?
<5%
Alport’s have a defect in their type IV collagen, leading to an altered Goodpasture antigen. The donor kidney has a normal antigen that was previously “unseen” by the recipient, potentially causing an immune response -> anti-GBM antibodies.
Of those who get anti-GBM, ~75% lose graft
Risk factors for DGF?
- Prolonged cold ischemia time
- Donor >50 years of age
- Peak PRA >50%, HLA mismatch
- Donor brain death
- Donor acute renal dysfunction
- Recipient factors: obesity, dm
Causes of hypophosphatemia early post-transplant?
- Persistent hyperparathyroidism
- High FGF-23
- Massive initial diuresis
- Osmotic diuresis from glucosuria
- Impaired phosphate reabsorption from ischemic injury
- Steroids (inhibit proximal reabsorption)
- Continued phosphate binders
- Malnutrition
Side effects with MMF
GI, cytopenias, pregnancy (1st trimester loss and malformations like cleft palate, heart/kidney/limb/esophagus anomalies), infection, malignancy
Side effects with rituximab
Infusion reaction (can be anaphylactic, occur during first infusion), decrease response to vaccines, hypogammaglobulinemia, infection, HepB reactivation, PML
Indications for combined kidney liver transplant
Candidate for liver transplant plus:
- CKD
- on regular dialysis
- GFR <=35
- Sustained AKI
- Dialysis x6 weeks at least
- GFR <=25 x 6 weeks at least
- Metabolic disease
- Primary hyperoxalosis
- Familial nonneuropathic systemic amyloid
- Inborn errors of metabolism - methylmalonic aciduria
