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