management of the unwell transplant patient
TRANSCRIPT
Management of the unwell transplant patient
Neil Hoye
Nephrology StR
SJUH
The Transplant Patient
• Immunosuppressive Medications
• Drug Interactions
• Example Cases (5)
The Transplant Patient
• Takes immunosuppression
• Has some degree of CKD
Technically Speaking
Transplant Immunosuppression
• Induction therapy
• Alemtuzumab (CD52) / basiliximab (CD25)
• Calcineurin inhibitors
• Tacrolimus/ciclosporin
• Anti-proliferative agents
• Mycophenolate/azathioprine/sirolimus
• Corticosteroids
The Calcineurin Inhibitors (CNIs)
• Tacrolimus and Ciclosporin
• Both metabolized by cytochrome P450 enzymes
• Monitored using trough blood levels
• Cause intrarenal vasoconstriction
• Acute toxicity results in AKI and hyperkalaemia
• Chronic toxicity causes renal fibrosis
Tacrolimus (FK506)
• Comes as Prograf, Adoport, Advagraf (amongst others)
• Advagraf is once daily
• It is important to stick to the same brand of tacrolimus
• Side-effects include tremor, diabetes, skeletal pains
Mycophenolate Mofetil (MMF)
• Inhibits IMPDH – purine synthesis
• Dosed 2-4 times per day typically
• Monitoring of drug levels is not usually done (although maybe it should be)
• Most significant side effect is diarrhoea or dyspepsia, which may be severe.
Azathioprine
• Also inhibits purine metabolism
• Usually taken once a day
• After many years, results in characteristic skin changes, and contributes to skin cancers
• Not usually first-choice these days, but may be used if mycophenolate is intolerable
Sirolimus
• Not commonly used, but may have certain “niche” indications
• Some in vivo evidence of anti-cancer effects, particularly against skin cancers
• Reduced efficacy for initial immunosuppression after transplant
• Plagued by multiple side-effects:
• Oedema, mouth ulcers, proteinuria, acne, hyperlipidaemia
Levels • Tacrolimus
• Months 0-3 9-14 ng/mL
• >3 months 5-9 ng/ml
• Cyclosporin
• Months 0-3 200-300 µg/L
• Months 3-6 150-250 µg/L
• Months 6-12 100-200 µg/L
• >12 months 50-150 µg/L
• Sirolimus
• Months 0-6 4-8 ng/ml
• >6 months 3-6 ng/ml
Troublesome
Interactions • Any inhibitor of CP450 enzymes
will potentiate tacrolimus or ciclosporin
• This may cause AKI
• Clarithromycin is the usual culprit
• Also see: Diltiazem/Verapamil, Antifungals, Ciprofloxacin
Troublesome Interactions
• Allopurinol inhibits xanthine oxidase, an important enzyme in the breakdown of azathioprine
• Can result in pancytopaenia
Reasons For Presentation
• The same reasons as everyone else
• Infections – common pathogens
• Infections – unusual pathogens
Standard Considerations
• Prescribe the usual immunosuppression
• There is no “one size fits all” adjustment to be made in the case of infection (for example)
• It is better to prescribe usual doses initially, and then adjust once more information is available
• Nephrology advice should be available at all times if necessary
When To Call?
• Acute graft dysfunction
• When you feel immunosuppression should be reviewed
• When someone needs organ support
Infections in Transplant Patients
• Immunosuppressed transplant recipients are more susceptible to common infections
• Unusual organisms may cause infection
• Obtaining samples for microbiological testing is vital to identify unusual pathogens
Some Cases…
Case 1 – EW
• 34 year-old male
• ESRF due to membranous nephropathy
• Deceased donor transplant December 2012
• Acute rejection episodes January 2013, May 2014
• Urinary sepsis with E.coli bacteraemia May 2014
• Admitted with diarrhoea, vomiting, fever
Case 1 – EW
• Urinalysis: Blood, Protein, Nitrite, Leucocyte
• Urea 39, Creatinine 770 (Baseline 180)
• Hb 121, WCC 15.7, Plats 304
• MSU: E. Coli
• Blood Cultures: E. Coli
Case 1 – EW
• Management: iv Tazocin, then PO co-amoxiclav
• iv fluids
• Creatinine returned to 280 (New baseline)
Urinary Tract Infection
• Antibiotic choice is more restricted
• Trimethoprim usually results in elevated serum creatinine +/- hyperkalaemia
• Nitrofurantoin contra-indicated in CKD
• Empirical amoxicillin lacks broad coverage
• Consider co-amoxiclav / cephradine / ciprofloxacin
Case 2 – JS
• 46 year old male
• ESRF ? cause
• DBD 8/4/15 0:1:0 D+/R-
• Alemtuzumab + FK506 monotherapy
• NODAT, creat 110
• Post operative deranged LFTs – ALT 171, Alk Phos 1228
• Stopped co-trimoxazole/valganciclovir 13/05/15
• Improvement in LFTs
Case 2 – JS
• 08/06/15 -> 22/06/15 10 day h/o vomiting, fever with 48h history of anuria
• Creat 112 -> 707
• Sterile pyuria, USS NAD, stool culture –ve
• CMV PCR 1 x 107 copies/ml
• Commenced iv ganciclovir and ultimately foscarnet
• HD 12/07/15
• Graft loss 02/01/16
Cytomegalovirus Infection
• CMV is a herpes virus with high seroprevalence
• May reactivate after transplantation
• Clinical features include:
Fever, leucopaenia, hepatitis, diarrhoea, ulcers, elevated creatinine
• The crucial test is a blood PCR for viral replication
• Serology is unhelpful
Case 3 – AG
• 47 year old male
• ESRF due to IgA nephropathy
• DCD 03/01/12 0:1:0 D+/R-
• Basiliximab + FK506 + MMF + prednisolone
• Ureteric stricture -> reconstructed 13/03/12
• Recurrent IgA at biopsy July ‘15 -> pulsed methylpred and prednisolone
Case 3 – AG • October ‘15 -> SOB, non-settling LRTI
• Jan ‘16 -> admitted:
• CT thorax – patchy ground glass changes in mid/lower zones; Echo – normal LV
• S/B respiratory – atypical screen (-ve), OPD f/u
• April ‘16 -> readmitted (unwell, lethargy, anorexia, SOBOE, wt loss, cough)
• Pyrexia > 39 0C, BCs –ve, urinalysis –ve, atypicals –ve, sputum staph aureus ?colonisation
• CT TAP -> progressive ground glass changes in lungs
• AAFB –ve, throat swab: rhinovirus PCR +ve, TOE –ve, MRI spine –ve
• BAL Parainfluenzae type 3 PCR +ve, PCP PCR +ve
• Commenced co-trimoxazole 960mg BD
• Failed graft 20/09/16 (recurrent IgAN)
Pneumocystis Pneumonia
• Caused by Pneumocystis jirovecii
• Abbreviated to PCP
• Affects patients early post-transplant, or after augmented immunosuppression
• Can be hard to diagnose – usually requires BAL
• Suggested by dry cough, fever, exertional desaturation
Case 4 – JR
• 48 year old female
• ESRF due to reflux nephropathy
• LRD 22/11/11 (ABO incompatible)
• MMF & PEX pre-conditioning -> Basiliximab + FK506 + MMF + prednisolone
• Early AB-mediated rejection -> PEX and iv methylpred
• d/c 19/12/11 creat 188 eGFR 25
Case 4 – JR
• Readmitted from OPD 22/2/12: Creat 398 eGFR 10
• MSU –ve, FK506 12, USS NAD
• BK PCR 6.9 x 106 copies/ml
• Biopsy -> diffuse polyoma viral infiltrate
• Stopped MMF, reduced FK506, commenced leflunomide, ciprofloxacin, IVIG
• Cidofovir commenced 20/03/12
• Progressive renal functional decline
• Recommenced HD 16/04/12
BK Nephropathy
• Caused by polyoma virus
• The consequence of modern potent immunosuppression
• BK and JC were the first patients known to suffer the respective infections
• Typically presents with asymptomatic creatinine rise
• BK PCR key test
Case 5 – JA
• 51 year old female
• ESRF due to polycystic kidney disease
• Deceased donor transplant 2007
• CMV disease 2012
• PTLD 2012 (Hodgkin’s disease)
• Immunosuppression with Sirolimus and Prednisolone
• Presents with fever, cough, dyspnoea in late 2014
Chest X-ray
Case 5 – JA
• Initially prescribed co-amoxiclav and clarithromycin
• Clarithromycin discontinued after one dose
• Prednisolone dose doubled during inpatient stay
• Blood cultures negative
• Clinical improvement after 5 days
• 10 days total antibiotics (co-amoxiclav)
“Straightforward” Community-Acquired Pneumonia
Treat the transplant patient as anyone else except:
• Adjust maintenance dose of corticosteroids
• Avoid macrolides
• Make extra effort to culture blood and sputum
In Summary…
• Always prescribe the regular immunosuppression
• Beware drug interactions
• Avoid clarithromycin / azole antifungals / trimethoprim
• If in doubt, ask a nephrologist
Acknowledgements
• Dr Matthew Edey
• Dr Matthew Welberry-Smith