Het is echter wel schadelijk om overmatig te alcohol te drinken, zeker als u een infectie heeft. Dit komt de infectie eerder verergerd door het gebruik van alcohol https://antibiotica-kopen.com Doorgaans worden ze voorgeschreven bij bacteriële infecties die om de één of andere reden niet uit zichzelf over gaan; ze doden dan de bacteriën.
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 A. PRE-TRANSPLANT 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 4. IVIG -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 B. POST-TRANSPLANT
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
Journal of Forensic and Legal Medicine xxx (2010) 1e6Drug-facilitated sexual assault in Ontario, Canada: Toxicological and DNA findingsJanice Du Mont EdD Research Scientist, Associate Professor ,,Sheila Macdonald MN ProvincialCoordinator Nomi Rotbard MPH Research Associate, PhD Student , Deidre Bainbridge BSc NursePractitioner Eriola Asllani BSc Data Analyst , Norman Smith PhD Associate Pro
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