Microsoft word - immunosuppression protocols.doc

There is no consensus as to the perfect immunosuppressive regimen. This is emphasized by the wide variation in immunosuppressive protocols used by different centers in Europe and US. Protocols are important because they create some uniformity in treatment for patients, they allow each center to become familiar with particular combinations of immunosuppressive drugs and they allow for better study of patient outcome. The ability to deviate from protocol (according to set guidelines and suggestions for management) is also important because this enables the physician to better tailor immunosuppressive drugs to minimize side effects in particular patient populations. Data from WTC 2006 shows that patients who received a kidney transplant in 2004 in the US were discharged on the following medications: In general, use of tacrolimus and MMF is increasing, use of cyclosporine is decreasing and azathioprine is no longer used in US. Sirolimus is used more in Europe but its use in US appears to be decreasing (less than 10%). New trial data on sirolimus (conversion from CNI to sirolimus in all patients at 3 months post transplantation) is awaited. Induction with antibody therapy continues to increase (>90% of all kidney transplants). Approximately 60% receive ATG (increasing) and 20% Il-2 receptor antagonists and 10% campath. Optimizing long term graft survival
Chronic allograft nephropathy (CAN) and death with a functioning graft are the main two causes of graft loss. Reduction in the latter requires close attention to cardiovascular risk factors. CAN results from immune (acute cellular rejection and antibody mediated rejection) and non- immune (CNI toxicity, ATN, HTN, hyperfiltration) mediated injury. Most studies show that rejection is the biggest risk factor for CAN (CNI toxicity plays second place as a promotor of CAN). Therefore achieving very low rates of rejection should remain the principle goal of
immunosuppressive protocols.
There is increasing awareness from protocol biopsies, that the rates of subclinical rejection can be high in certain immunosuppressive regimens. Subclinical rejection is minimal but still present in patients on TAC and MMF (1,3,6 month rates of 5%, 8% and 9%) Prevalence of subclinical rejection at 3 months (Nankivell et al) Subclinical rejection at 3 months also correlates strongly with prevalence of CAN at 12 months. Good immunosuppressive cover in the first 6 -12 months (when risk of rejection is highest) is therefore the most important factor to prevent rejection and minimize CAN. This is best achieved CNI nephrotoxicity is almost universal however. The best marker is de novo nodular hyaline arteriosclerosis. This can appear as early as 1-3 months post transplantation and is a predictive marker for the fibrosis score at a year and the percentage glomerulosclerosis at 5-10 years. Although good levels of immunosuppression (and hence good levels of CNI ) are important in the first 6 to 12 months to prevent ACR, CNI minimization or withdrawal is increasingly seen as an Chronic CNI toxicity is detected in 100% of grafts by 10 years (Nankivell et al) Data at the WTC 2006 shed some light on CNI minimization and withdrawal and will be discussed Induction agents
NICE guidelines recommend use of IL-2 receptor antagonists (IL-2 RA) for all patients. In combination with CsA and azathioprine, IL-2 RAs lower acute rejection rates. This beneficial effect is not observed when Il-2 RA is combined with CsA and MMF. In low risk transplant patients, IL-2 RAs are as effective as rATG in preventing ACR. However in high risk patients rATG is better. ATG is associated with twice the amount of PTLD compared to IL-2 RA (0.9% vs 0.5% incidence at 1 year). ATG is used less in highly sensitized patients because it is associated with increased rates of de novo anti-donor antibodies post transplantation. Maintenance agents
Many studies (prospective and retrospective) have compared TAC and CsA. Overall there is no difference in patient or graft survival between agents. There may be some reduction in death censored graft survival with TAC. The main differences are a reduction in ACR with tacrolimus and an increased rate of post transplant diabetes. In a metanalysis in the BMJ, Webster et al reported that for every 100 patients on TAC compared with CsA, 12 episodes of ACR will be avoided, and 2 grafts will be spared from loss, but there would be 5 more cases of PTDM. Tacrolimus is associated with less HTN, less hyperlipidaemia, less hirustism but more alopecia and more neurotoxicty. The combination of tacrolimus and MMF is particularly potent because the bioavailability of MMF is greater associated with tacrolimus compared to CsA. This combination is associated with more polyoma virus nephropathy. CsA may be preferred in patients with HCV due in part to a need for less potent immunosuppression but perhaps also a direct anti-viral effect of When both drugs are to be used in one centre then it is preferable to reserve TAC for younger patients, and those with higher immunological risk (younger, second Tx, black race, highly sensitized, risk of DGF). CsA may be preferred in older patients, those with lower immunological risk (old age, first transplant, LRD) and those with increased risk of diabetes (obesity). However there is logic to recommend the use of one agent for the majority of transplant patients in any single centre to enable increased familiarity with one drug. Sirolimus should not be used from day 0 post transplant. It is associated with increased DGF, decreased wound healing and increased lymphocoele formation. More importantly it is not as potent as CNI when used with an antimetabolite (even MMF) and is associated with much higher ACR when used as first line treatment post transplantation. This was highlighted in the Symphony trial reported at WTC 2006 which showed that when combined with IL-2RA and MMF and steroids the rejection rate was 30-40%. ACR rates are acceptable with Sirolimus if combined with ATG induction. There is interest in this combination because both drugs cause an expansion of T regulatory cells and may be more tolerogenic (in clear disctinction to effects of CNI and IL-2 RA). Sirolimus is associated with less CMV infection than CNI. The role of sirolimus in CNI withdrawal remains under study but is likely beneficial if the switch is performed after 1 year post transplantation and graft function is good. (GFR>40) It is generally agreed that sirolimus should not be used in combination with either CsA or TAC because of an exacerbation of CNI toxicity. An increasing indication for sirolimus is in patients at high risk of malignancy or patients with proven malignancy particularly renal cell cancer. It is very beneficial in patient with skin cancer. Patients who are many years post transplant and have multiple skin lesions show marked improvement in skin lesions when switched to sirolimus. Aim for sirolimus levels 3-6. Do not give loading dose. Elderly patients do not tolerate high levels of sirolimus A big dilemma with CNI use is that they are needed within the first 6 to 12 months because they are the most effective agents at preventing ACR (which is the biggest cause of CAN), yet they contribute to CAN due to CNI toxicity and this unfortunately from protocol biopsy data can manifest as early as 1-3 months. A summary of recent trials assessing CNI withdrawal is given below: 1) CNIs cannot be withdrawn within 1 year post transplant successfully if patient left on MMF and steroids alone (unacceptable rate of ACR – 38%) (CAESAR STUDY-WTC 2006) 2) CNI can be converted to sirolimus at 1 year if GFR > 40 and no history of ACR. Small increase in ACR / Renal function better / less malignancy. 3) CNI cannot be converted to sirolimus at 1 year if GFR<40. Less favourable safety profile and no beneficial effect on renal function 4) CNI can be converted to MMF alone if greater than 1 year out with creeping creatinine without increased ACR. Improved renal function 5) CNI conversion to sirolimus at 6 months if GFR>40: some data to suggest possible if on MMF .Expect some increase in ACR but improved function 6) CNI conversion to sirolimus at 3 months (DATA to presented at ATC 2007 avoid loading dose and have 50% reduction in CNI as an Because CNI toxicity can manifest early (nodular hyaline arteriosclerosis at 3 months predicts graft fibrosis score at 1 year, which predicts glomerulosclerosis scores at 5 years), CNI avoidance may seem preferable. CNI avoidance may be achieved with: Problem: sirolimus not advised immediately post transplant because of increased DGF, Steroid avoidance is preferable to steroid withdrawal because the majority of bone loss due to steroids is within the first 3 months. Also steroids contribute greatly to the higher PTDM rate seen with TAC and since the levels of TAC need to be higher within the first 3-6 months it is beneficial not to have steroid exposure during this early period. Steroid avoidance is very achievable with either ATG / TAC / MMF or IL-2 RA / TAC / MMF combination. In the Freedom study (reported WTC 2006) the combination of IL-2 RA, CsA and EC- MPS was associated with 20% ACR vs 7% ACR with standard steroids. Steroid avoidance is therefore more successful with TAC vs CsA and probably reflects better MMF bioavailability with TAC. Steroid avoidance can also be achieved with IL-2 RA / TAC / Sirolimus. However as explained previously the TAC / Sirolimus combination is thought not to be good for long term graft survival due to enhanced CNI toxicity. Steroid avoidance may be considered in those with low immunological risk and those with increased risk of PTDM, and / or steroid associated bone complications (known osteoporosis, or severe hyperparathyroidism and diabetics) Steroid withdrawal later post transplant is most successful when done slowly and associated with concomitant MMF therapy rather than azathioprine. Steroid withdrawal should be avoided in high risk patients such as high PRA, black race, previous ACR, poor renal function, and proteinuria. Close follow up is required. There is a feeling among the transplant community that steroid avoidance is easier than steroid withdrawal, suggesting that early exposure to steroids “imprints” a steroid dependence (even low doses) on the immune system to prevent rejection. Controlled non heart beating donor kidney
CNHBD kidneys may have more ischaemic injury. Therefore they may benefit from less CNI exposure to encourage recovery from ATN. However they are more immunogenic because of the inflammatory reaction set up by ischaemic injury. Therefore they need good immunosuppressive coverage. For this reason most centres use the TAC / MMF combination with IL-2 RA induction and steroids. Steroid avoidance / early withdrawal should be avoided. CNI minimization may be important later post transplant (>6 months) but should be avoided early because of the greater rejection risk. The starting dose of tacrolimus is reduced (0.1mg/Kg) compared to normal • Methylprednisolone 500mg iv at induction • Basiliximab 20mg iv x2 day 0 and day 4 • Tacrolimus 0.1mg/Kg in 2 divided doses o Aim for tac level 8 – 10 for 6 months o Aim for tac level 6 – 8 for 6 to 12 months o Aim for tac level 4 – 6 thereafter if remaining on MMF Cadaveric Renal Transplant in high immunological risk patient
High immunological risk patients include paediatric recipient, black race, previous transplant, sensitized (high PRA), DR mismatch, 3-6 HLA mismatch, any cross match concern. • Methylprednisolone 500mg iv at induction • Basiliximab 20mg iv x2 day 0 and day 4 • Tacrolimus 0.15mg/kg in 2 divided doses o Aim for tac level 8-10 for 6 to 12 months • Mycophenolate mofetil 1g bd • Prednisolone 20mg reducing Cadaveric Renal Transplant in low immunological risk patient
Low immunological risk is elderly, first transplant, white, Low PRA, no DR mismatchs • Methylprednisolone 500mg iv at induction • Basiliximab 20mg iv x2 day 0 and day 4 • Tacrolimus 0.15mg/kg in 2 divided doses o Aim for tac level 8-10 for 6 to 12 months Live donor transplant
The following regime is advised for recipients of living donor transplants who are at low immunological risk. Recipients who are sensitized or who have previous transplants should follow the cadaveric protocol for high immunologic risk • Methylprednisolone 500mg iv at induction • Basiliximab 20mg iv x2 day 0 and day 4 • Tacrolimus 0.15mg/kg in 2 divided doses o Aim for tac level 8-10 for 6 to 12 months Steroid taper recommended in all protocols listed above
Notes on MMF usage
Mycophenolate mofetil dose may need to be reduced due to GI side effects or neutropenia. • small reductions should be made and the dose split into tds or qds. • Exclude infective causes. • Check MMF trough • Try to reestablish MMF 1g total dose later. • Try • Make small reductions • Tolerate a stable but low WBC (2-4) Maintaining a good total MMF dose is important because the priority in all transplant patients should be CNI minimization which can be achieved more successfully with good MMF exposure. Notes on polymoma virus nephropathy
Polymoma virus nephropathy is more common in patients on TAC / MMF combination. (approx 5% prevalence). Up to 70% of patients with established polyoma virus nephropathy lose the transplant
from the infection. BK viuria is the first sign of active viral replication and progression to viraemia appears to be a prerequisite for the development of BK nephropathy. Gold standard for diagnosis is biopsy. Light microscopy alone is usually sufficient to make the diagnosis (large, “washed out” nuclei in tubular epithelial cells but special immunohistochemical stains (SV40) are available. An accompanying inflammatory infiltrate may or may not be present. Treatment involves reducing immunosuppression (some favour stopping antimetabolite) and consideration of either low dose cidofovir or leflunomide treatment. Brennan reported success with monitoring viraemia and preemptive reduction of immunosuppression (stopping antimetabolite first followed by reduction in CNI if persisting viraemia 4 weeks after stopping antimetabolite). This preemptive approach • Monitor BK virus DNA in blood (purple top tube : send out test to Bristol)
• BK virus DNA assessed fortnightly from 1 month to 4 then at month 5, 6, 9 and 12
• Stop MMF if BK virus DNA >10,000 copies per ml
• Reduce CNI dose if BK virus DNA > 10,000 copies per ml for >4 weeks after stopping MMF
Steroid avoidance protocol
Should be reserved for those with low immunological risk and patients who may benefit from • those at high risk of diabetes, • established osteoporosis, • those with previous steroid exposure • those with hyperparathyroid associated bone disease • Methylprednisolone 500mg iv at induction • Basiliximab 20mg iv x2 day 0 and day 4 • Tacrolimus 0.15mg/kg in 2 divided doses o Aim for tac level 8-10 for 6 to 12 months CNI withdrawal
CNI withdrawal should always be based on biopsy proven chronic CNI toxicity. The most specific pathologic manifestation is de novo nodular hyaline arteriosclerosis. This is best assessed with information from an implantation biopsy to exclude donor disease. Other features of chronic CNI toxicity are striped fibrosis, and tubular calcification. Isometric vacuolation is a feature of acute CNI toxicity and usually necessitates dose reduction but is not an indicator of chronic CNI toxicity or need to withdraw CNI. Tubular atrophy and interstitial fibrosis are non specific features and are just as likely to be a consequence of clinical or subclinical rejection. Therefore fibrosis alone is not an indicator for CNI withdrawal. Transplant glomerulopathy have now been removed from the BANF classification for CAN because it is now considered to be a specific marker of prior acute humoral rejection or chronic humroal rejection. This is not an indicator for CNI withdrawal. In the ideal world CNI withdrawal is best done early post transplant in patients with documented CNI toxicity. This is because nodular hyaline arteriosclerosis can be seen as early as 3 months and correlates with the development of graft fibrosis. However the risk of rejection is greatest during this period and CNI may be essential during this period. CNI withdrawal should be avoided in the high immunological risk patient and in patients off steroids. CNI withdrawal at 3-6 months
Data from trial assessing outcome in patients switched to sirolimus at 3 months is awaited (ATC 2007). Therefore hold on initial plan to switch patients with CNI toxicity based on protocol biopsy at 3 months. Close attention paid to those with previous ACR or high immunological risk. CNI withdrawal at 1 year
• Ensure GFR>40 and proteinuria <800mg/day
• Reduce CNI by 50% for 2 weeks
• Start Sirolimus 3mg (no loading dose)
• Aim for level 5-10
• Monitor creatinine closely (early biopsy if suspicious of ACR)
• Look out for
CNI withdrawal greater than 1 year in low immunological risk and or GFR<40
Patients with poor renal function and or proteinuria>1g/day do not do well with sirolimus. If patient • switch to MMF 1g bd • or maximize presxisting MMF dose and • slowly withdraw CNI over 2 months • Close monitoring and early biopsy if required Management of patients with suspected rejection
• Remember high rates of subclinical rejection in patients not on MMF / Tac combination • Send red top to tissue typing for assessment of anti-donor antibodies • Early biopsy: 2 cores • Avoid preemptive treatment if possible particularly diabetics who are at increased risk Management of acute cellular rejection
• Methylprednisolone 500mg iv x3 • Repeat biopsy day 4 if no response If patient rejected because of low CNI levels then restoring good level suffices If patient rejected on adequate CNI levels and on aza switch to MMF If patient rejected on adequate CsA level and is already on MMF then switch CsA to TAC • Methylprednislone 500mg iv x3 • Rabbit ATG 1.5mg/Kg iv x4 daily to run concomitantly with steroids • Usually renal function improves and 4 doses sufficient • Max 7 doses of rabbit ATG given according to T cell subsets • Repeat Remember to send red top for anti-donor antibodies prior to giving ATG During ATG treatment ensure good level of CNI and MMF Remember add PCP prophylaxis and CMV prophylaxis Start 3 month valganciclovir course if not CMV neg to neg after ATG Treatment of acute humoral rejection
Acute humroal rejection is more prevalent than previously thought. It is present in 5-10% of renal transplant patients It is present in 30% of biopsies performed in some centers in the US. 50% of the time it coincides with acute cellular rejection. AHR rejection is particulary common and coincides with type II ACR in patients who present with graft dysfunction due to a non compliance. AHR appears to be more prevalent because: • Development of the C4d stain has improved the ability to diagnose AHR • More highly sensitized patients are being transplanted • The development of more potent immunosuppressives has reduced the rate of ACR and the numbers of biopsies performed, hence AHR is seen in a greater proportion of biopsies Diagnosis requires finding the following • Histologic evidence for graft injury o Circulating anti-donor antibody (based on repeat crossmatch if donor tissue o Anti-HLA antibodies detected by ELISA or luminex technology • Methylprednisolone 500mg x3 • Plasmapheresis x5 consecutive days • IVIG 0.6mg/kg after final plasmapheresis • Ensure good TAC level (12-15) amd good MMF dose
Treatment of chronic humoral rejection.
Chronic humoral rejection is diagnosed by presence of transplant glomerulopathy, C4d positivity
and detection of anti-HLA antibody in serum greater than 1 year post transplantation. It carries a poor prognosis and confirms prospective data showing that appearance of anti-HLA antibody in serum years post transplantation is a poor prognostic marker and precedes graft loss by a period of months. There is no established treatment for chronic humoral rejection. MMF is a better anti-B cell drug than Azathioprine. Studies are assessing the role of rituximab in chronic humoral
Other medications

• Aspirin 75mg od commenced on post op day 2 and continued • Omeprazole 20mg od continued until prednisolone dose at baseline • Calcium channel blocker first line for hypertension unless contraindicated. Beneficial effect on graft function ? due to protection from CNI (best data with Lacidipine) • Hold ACEI for 3 months post transplantation • Simvastatin 40mg od initially progressing to Rosuvastatin 20mg od /then Rosuvastatin20 mg+ ezetimibe 10mg od to achieve cholesterol <4. Aggressive cholesterol lowering should not be attempted until CNI at stable level after 6 months • Isoniazid 200mg od and pyridoxine25mg od if prior TB exposure or from Africa / Asian o Valganciclovir 900mg od if GFR>50
o Valganciclovir 450mg od if GFR<50
o Duration 3 to 4 months
o In D+ / R- make sure immunosuppressive levels reduced prior to discontinuation of

• CMV treatment (when CMV DNA>log 3.7)

o Valganciclovir 900mg bd if GFR>50 o Valganciclovir 450mg bd if GFR<50 o Treat until CMV DNA negative (at least 3 weeks) o If neutropenic and on valganciclovir and MMF reduce latter not former
Desenzitization Protocol for Living Donor Kidney Transplant Recipients
1. Immunosuppression:

-Rituximab 375mg/Kg iv; x 1 starting 1 month pre transplant (IF TITRE>1/32)
-MMF 1g bid
-Tacrolimus 0.15mg/kg bid [target trough 10-15] ) started 3 weeks pre transplant -Prednisone
2. Other medications:
-Cotrimoxazole 480mg od
-CMV prophylaxis with valganciclovir
3. Plasmapheresis
-Use table to gain rough estimate of # of PP sessions required based on starting antibody titer
Dilution at which AHG-
CDC turns neg

-Convert patient to MWF dialysis schedule
-Perform PP on 3 consecutive days (Wed / Fri / Mon) pre HD
-Remove minimum 1 plasma volume (40ml/kg)
-Replace 50% volume with 5% albumin and remaining with Normal Saline. Give FFP instead of
Normal Saline if (i) transplant anticipated in next 24 hrs or (ii) pt is requiring multiple runs of PP and
coags are prolonged
-5-10 tabs of CaCO3 during each PP
-CBC, chem7, tacrolimus level before each PP

-Give IVIG (10g) over 2 hrs on HD
-Use an IVIG prep with low osmolarity
5. Repeat Crossmatching
-Check CXM on following monday
-Use AHG-CDC CXM for T cells and Amos-CDC for B cells
-If rituximab given will need pronase treatment to enable identification of positive B cell crossmatch
-When CXM neg – transplant in next 24hrs
-Ensure coags normal pretransplant


1. Induction immunosuppression

-basiliximab 20mg iv given day 0 and day 4 after PP
-Tacrolimus (trough 10-15),
-Increase MMF to 3g/day if tolerated,
-Standard steroid protocol
-PCP, and CMV prophylaxis as per usual.
2. Post-transplant PP and IVIG:
-Routine in all patients day 4 and 7 post transplant
-If very high PRA or high CXM titers against donor (>1:32) or required >6 PP pre-transplant routine
PP/IVIG should also be given on day 11 and 14
-Check post transplant CXM routinely 1x per week for 4 weeks
-IVIG prep should have low osmolarity and be given very slowly to avoid nephrotoxicty
-Note thymoglobulin, rituximab may interfere with CXM tests

3. Post transplant follow-up
-Post transplant check Cr every 48–72 hrs after discharge for first month.
-If Cr elevated (in absence of volume depletion or very high tacrolimus levels) need urgent biopsy
and urgent CXM
- Protocol biopsy at 2 weeks and 4 weeks
-If AHR 5 consecutive daily PP followed by IVIG 0.6mg/kg iv
-Ensure tacrolimus levels are >12
-If acute cellular rejection start with methylprednisolone 500mg x3


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