3. A 32-year-old female patient received a kidney transplant from her brother 13 months ago, 100 mismatch, and excellent kidney function. She is on dual immunosuppression (cyclosporine and steroids). Her cyclosporine level is 322 ng/ml. She is suffering from facial hirsutism.
- What is your management plan?
- Suppose this kidney failed, what is your immunosuppression plan for the next transplant?
Dear All
Do you always use ATG induction for the second transplant?
Remember
Over immunosuppression is associated with high risk of malignancy and infection
Second transplant
CDC negative, FCXM negative, DSA negative –
Basiliximab
CDC negative, FCXM positive, DSA negative-
ATG
CDC negative, FCXM positive, DSA positive with MFI<1000
ATG
CDC negative, FCXM positive, DSA positive with MFI 1000-10000
Plasmapheresis + IVIG + ATG
CDC negative, FCXM positive, DSA positive with MFI >10000
Avoid transplant
Utility of Induction Agents in Living Donor Kidney Transplantation
Radhika Chemmangattu Radhakrishnan et al
HLA Desensitization Based on Results of the Luminex Technique in Kidney Transplant – A Single-center Experience Original Article
S.B. Bansal et al
Great answer but what do you think is the role of cPRA. Also consider that degree MFI as an approximation of antibody strength or titre has its own limitations. I agree that MF>10000 has high risk of ABMR but I believe that spectrum of MFI is dynamic and a arbitrary cutoff is not in purview of realm.
Thanks, Prakash. I like your clear answer
Is it your unit protocol?
An episode of acute rejection is aperiod of uncertainty and is like to cause anxiety in ktrs and thier carers.
second transplantion of course is not like the first transplantion, especially in immunosuuprresion protocol like induction .
using rATG puts the pt at high risk of malignancy and infections but rejection may affect the pt graft survival and put him on arisk to return back to be dependent on dilaysis .
so counselling the pt s very important about the side effects of rTAG and pros and cons sould be explained carfully to him.
for me i will go for atg for 2nd transplant .
i had apt in our centre , it was the 4th transplant to him cPRA was 90 %, his sister offerd him akidney with 000 mismatch negtive flow cytometry cross match.
we went for atg , regardless his zero mismatch. better to be in safe side rtaher than to face rejection episode.
Agree but do you look at EBV status of the recipient
Ebv positive recipent, Ebv positibe donors ; we dont actually do routine follow after transplantion for recipent .but if ebv poisitive donors with ebv negative recipentwe will routinely follow them by pcr monthtly for one year trying to minimize long term immunosuprrseion as much as we can .
Induction with ATG is needed specially in those with
– high immunologic risk transplant candidates (i.e. cPRA ≥80%), or those who have previously rejected one or more transplants within 1 year posttransplant)
it is ideally given intra-operatively .
– high donor risk those with high risk for delayed graft function also ideally given intraoperatively
– at high risk of delayed graft function due to donation after cardiac death, or expanded criteria donor
Reference:
Genzyme Corporation. Thymoglobulin® (anti-thymocyte globulin [rabbit]) prescribing information. Cambridge, MA; July 2018.
Do you always use ATG? What factors would restrict you using ATG
it is preferred , but if the recipient old age with no DSA , can be replaced by basiliximab (simulect)
OK, clinically valid answer but what do think that old age does to immune response that ATG is not preferable
ATG is associated with high risk of infection and PTLD which will be aggressive in old age
old age recipient have less immune response than young recipient, so, ATG is better to be replaced by basiliximab
Based on the definition of high risk patients for acute rejection by KDIGO 2009, second transplant is not listed as high risk of acute rejection. However we clearly know that presence of DSA and one or more HLA mismatches carries a high risk of rejection.
So our decision to give or not to give r-ATG will be based on DSA screening results and Crossmatch.
Brief response , I would like to see in what circumstances will you use ATG. What are your DSA cutoffs and Crossmatch parameters
Second transplantation is associated with sensitization formation and DSA should be checked. Induction depends on risk stratification to be intermediate or standard risk. If patient has standard risk, induction with basiliximab will be enough. But if patient has intermediate risk, induction with ATG will be mandatory. For second transplant triple maintenance therapy is better.
Callus R, Buttigieg J, Anastasi AA, Halawa A. Basic concepts in kidney transplant immunology. Br J Hosp Med (Lond). 2017 Jan 2;78(1):32-37.
Great answer Nasrin but I would refrain from using the word “mandatory”. Would you consider any monoclonal antibody too?
Thanks. Yes, we can use Alemtuzumab(monoclonal antibody against CD52) as induction in these patients.
Usually the second or third transplant patients are sensitized and at high immunological risk for rejection ,so it will be more convenient to commence a strong induction therapy like ATG not only for preformed antibodies but also for de nofo DSAs.
Patients listed for second transplant are considered as sensitized patients even if their cross matching is negative, they have a memory cells that can lead to rejection, so induction with ATG is required.
Yes, I will use ATG induction for this patient for her second transplant, as she has high immunological risk, but I will council her about all risks including infections and malignancy
ATG can be use for second transplant. The idea is balancing the risk of immunosuppression on one hand and the risk of rejection on the other hand. Second transplant is complicated but can still happen despite all challenges including immunosuppression.
Hirsutism induced by cyclosporine high level
Management : we can give a trial of lowering the level and dermatology and decrease level to ATG if low risk>Basiliximab
Hirsutism is one of the side effects of cyclosporin , it is dose dependent and reversible .In this case as this patient transplantation before 13 month , the serum cyclosporin level is higher than accepted level for this time . therefore i will reduced the dose of cyclosporin to the target of 100-125 ng/ml . if there is no response to this measure second option is to change to TACROLIMUS .changing doesn’t need dose overlap or steroid coverage . TAC trough level target will be 5-8 ng/ml with close monitoring .
· Suppose this kidney failed, what is your immunosuppression plan for the next transplant?
retransplantation is an option for this young patient .
second transplantation is considered as one of high risk criteria for acute rejection . Because these patient are usually sensitized and has memory T lymphocyte . Therefore adequate risk stratification is needed . The immune suppression plan depend on the degree of the risk .This patient should be assessed carefully by
DSA, CDC cmx ,FCcmx .
According to one study
1- If CDC cmx positive avoid transplantation .
2- If CDC negative, FCXM negative, DSA negative – use Basiliximab
3- If CDC negative, FCXM positive, DSA negative- use ATG
4- CDC negative, FCXM positive, DSA positive with
a. MFI<1000- use ATG
b. with MFI 1000-10000- use Plasmapheresis + IVIG + ATG
c. with MFI >10000- Avoid transplant
maintenances immune suppression will be triple medication (steroid ,MMF,Tacrolimus ). With close monitoring for DSA .
Utility of Induction Agents in Living Donor Kidney Transplantation Radhika Chemmangattu Radhakrishnan et al
HLA Desensitization Based on Results of the Luminex Technique in Kidney Transplant – A Single-center Experience Original ArticleS.B. Bansal et al
Cyclosporin A is an immunosuppressive agent known to cause hirsutism. The mechanisms of action that cause hirsutism have not been fully elucidated, however. We have previously reported that several selective protein kinase C inhibitors promote the growth of murine hair epithelial cells and stimulate anagen induction. In this paper, we report on an investigation of the mechanisms of action of hair-growing activity possessed by cyclosporin A from the viewpoint of whether it promotes hair epithelial cell growth or whether it modulates the expression or translocation of protein kinase C isozymes in hair epithelial cells. Our results indicate that cyclosporin A (over a wide dosage range of 1-1000 ng per ml) stimulates cultured murine hair epithelial cell growth to about 150%-160% relative to controls. We also observed growth-promoting effects on murine epidermal keratinocytes (about 140%) at the dose range of 1-100 ng per ml. At high dose ranges above 3 microg per ml, the growth of both cells was inhibited. On the other hand, we found that cyclosporin A reduces the overall expression of protein kinase C alpha, betaI, and betaII in cultured murine hair epithelial cells, and reduces the levels of protein kinase C alpha, betaI, betaII, and eta in the particulate fraction from cultured murine hair epithelial cells. From these results, we speculate that the hair-growing activity of cyclosporin A is at least partially attributable to its growth-promoting influence on hair epithelial cells sequential to its downregulation of some protein kinase C isozymes in hair epithelial cells or inhibition of translocation of some protein kinase C isozymes to the membrane or cytoskeleton of hair epithelial cells.
Csa known to cause hirsutism among other side effect of CNI.
Management. Plan:
Switch to TAC medication, better side effect profile ,similar mode of action.
Dermatology consultation for chemical and lazer hair epilation.
-According to patient tolerance ,a trial of cyclosporine dose reduction could be adopted .otherwise shifting to Tac in dose of 0.1 mg/kg in divided doses. Following dose reduction ,we monitor creatinine and cyclosporine level targeting the suitable level (75-160 ng/ml .If for 4 months reaching the targeted level without improvement of hirsutism, shifting to Tac is done with periodic monitoring .
If the graft failed, we will proceed for ATG induction with triple IS; Tac, MMF and steroid.
This patient received a live related kidney with a 100 mismatch and excellent kidney function on dual immunosuppression at more than 1 year post transplant and now having facial hirsutism. Her cyclosporin levels are high at 322 ng/ml.
So, the first step would be to reduce cyclosporine dose so that the level can be reduced to 100-125 ng/ml. This hirsutism can be improved as it is dose-dependent.
If there is no response with dose reduction, the cyclosporine can be changed to Tacrolimus with target trough levels of 4-7 ng/ml. Tacrolimus does not cause hypertrichosis.
If this kidney failed, first and foremost the reason should be evaluated as this is a good match kidney with excellent graft function at 13 months. Probably the reason is non-adherence due to cosmetic side-effects.
Anyone being planned for second transplant should be evaluated for DSA presence.
The donor characteristics including HLA mismatch, age, type (living versus cadaveric) , EBV status, CMV status etc are important.
A second transplant is a high-risk transplant due to previous sensitization event of a prior transplant. Hence an induction therapy should be given.
Induction therapy:
If FCXM negative and no DSA: Induction with basiliximab
If FCXM negative with DSA: Induction with ATG
If FCXM positive: Desensitization with Plasmapheresis and IVIG
Maintenance therapy:
Triple drug – Tacrolimus, MMF and steroids
Post-transplant DSA monitoring at least once in first 3 months.
Protocol biopsy if patient in high risk group.
This 32 female patient with high cyc level and hirsutism should have her dose reduced with regular monitoring for improvement, otherwise, she may shifted to tacrolimus immunosuppression as less hirsutism.
We shall reduce of her Cyclosporin dose targeting a trough level around 100 while observing the response regarding her hirsutism, if no response we might shift her to tacrolimus which is more potent and associated with better graft survival than Cyclosporin and is associated with hair loss rather than hirsutism.
2nd transplantation carries more risk for sensitization, according to presence of DSAs and their strength she might need desensitization, induction whether by basiliximab or rATG, and maintenance IS protocol based on tacrolimus, MMf, and steroids from the start .
This patient had 100 mismatch with excellent kidney functions. after 13 months noted the CyA level is high and she had hirsutism. I would prefer tacrolimus in ladies as it has lesser cosmetic side effect though it is diabetogenic. medications such as diltiazem SR can be given to reduce the dose of CNI yet achieve therapeutic level. If reduction of CyA does not improve the creat level, i would do renal allograft biopsy to evaluate the HPE: rejection vs CNI toxivity.
If the kidney failed, i would check the FCXM and DSa level, if its abnormal, i would opt for thymoglobulin therapy as induction.
First cyclosporin dose should be adjusted and for it’s cosmetic side effect it can be switched to tacrolimus.
Regarding the 2nd transplantation the patient may need desensitization protocol according to crossmatch result and DSA test and ATG treatment must be use for induction and continue on triple immunosuppressants (steroid,MMF and tacrolimus) with prophylaxis medications to prevent infection.
Tacrolimus is an alternative calcineurin antagonist and is suitable for patients with unacceptable cyclosporine induced cosmetic side effect (1)
A study showed that hirsutism mostly resolved in 72% of patients following switch from cyclosporine to tacrolimus (2)
Non compliance with immunosuppression is a major cause of graft loss (3)
previous transplant is a risk for sensitization, risk factors of acute rejection include
one or more HLA mismatch, younger recipient and older donor age, PRA >0%, presence of DSA, delayed onset of graft function, blood group incompatibility and cold ischemia time >24hours (4)
Induction with rATG better prevent acute rejection in high immunological risk patients but with higher risk of infection than anti-IL-2 receptor antibody (5)
maintenance immune suppression with triple therapy MMF, tacrolimus and prednisolone
(1) Walker, Rowan G., Stephen Cottrell, Kathleen Sharp, Rosamaria Tripodi, Kathy M. Nicholls, Ian Fraser, George A. Varigos, and Belinda E. Butcher. “Conversion of cyclosporine to tacrolimus in stable renal allograft recipients: Quantification of effects on the severity of gingival enlargement and hirsutism and patient‐reported outcomes.” Nephrology 12, no. 6 (2007): 607-614
(2) Margreiter R, Pohanka E, Sparacino V et al. Open prospective multicenter study of conversion to tacrolimus therapy in renal transplant patients experiencing ciclosporin-related side-effects. Transpl. Int. 2005; 18: 816–23
(3)Chisholm MA, Lance CE, Mulloy LL. Patient factors associated with adherence to immunosuppressant therapy in renal transplant recipients. Am. J. Health Syst. Pharm. 2005; 62: 1775–81
(4) Kidney Disease: Improving Global Outcomes (KDIGO) Transplant Work Group. KDIGO clinical practice guideline for the care of kidney transplant recipients. Am J Transplant 2009; 9 Suppl 3:S1.
(5) Brennan DC, Daller JA, Lake KD, et al. Rabbit antithymocyte globulin versus basiliximab in renal transplantation. N Engl J Med 2006.
Cyclosporine level is high for this patient, the dose should be adjusted to maintain a level of 100- 125. Medications also should be revised if any is increasing cyclosporine levels, such as antibiotics, antifungals, antidepressants, or others.
If the patient is bothered by hirsutism, she can be switched to tacrolimus with an aim to maintain the level between 4-7.
If the kidney had failed, then to be managed as general management of CKD. Once she approached ESRD then immunosuppressants should be tapered slowly till discontinued. If she plans a second transplant, and her cPRA is high she will need to have a desensitization protocol before attempting a second transplant.
My management plan will be reducing the dose of cyclosporine due to its side effect (hirsutism) . But I should add another IS drug in order not to push the patient toward rejection like MMF ,or simply I can just change cyclosporine to Tac.
If the graft failed and we prepare for second transplantation, we consider this patient as highly sensitized and according to his crossmatch and CPRA results and the DSA result we chose our protocol and her we prefer ATG in induction and triple IS in maintenance (PRD,Tac , MMF)
The common side effect of cyclosporin is hirsutism occuring in 6% of pt .This is most concern in women .drug induced hirstism is reversable after stoping the drug . Iwill change CYS to Tacrolimus . Tacrolimus is better than CYS in graft survival .IF graft fail ,this pt consider as high risk transplant ,induction by ATG and mentanance therapy prednislone .tacrolimus and MMF . The risk of malignancy and infections are there but also there is high risk of ABMR .
1- This patient has higher cyclosporine trough level than therapeutic level , so start with decreasing cyclosporine dose if no improvement in haisutism , she can be shifted to tacrolimus instead.
2- For second transplant : it is commonly associated with sensitization and the choise of immunesuppresion will be based on risk stratification of the patient based on ( degree of HLA mismatch , CDC, Flowmerty, c PRA and presense of DSA), if
a- Low to intermediate risk : induction with basiliximab
b- High risk without DSA:
Induction with ATG
c- presence of DSA : desensitization with PE , Rituximab and induction with ATG.
Management plan:
In this scenario, we have 2 issues
Clinically: hirsutism
Laboratory: high level of cyclosporin
So the management plan should be directed to investigate and role out cyclosporin nephrotoxicity as this is more important concern, so we need the following concomitantly:
– Renal function test and if we detect deterioration in kidney function, we need to r/o other causes than ciclosporin toxicity (Work up urine analysis, infection screening, cbc, abd u/s)
– Urine output monitoring with good hydration
– Revise medications to identify if any offending drug interact with ciclosporin and resulted in increase of ciclosporin level or any other medications can cause nephrotoxicity
– Reduce the dose of cyclosporine and monitor RFT
If the cyclosporin toxicity is reversible, well and good but if not and there is suspicion of another cause of deteriorating rft so may need graft biopsy.
Regarding hirsutism secondary to cyclosporin toxicity, mostly is reversible; otherwise refer to a dermatologist for specific management
Immunosuppression weaning protocol following kidney transplant failure and return to dialysis
– Stop cyclosporine/tacrolimus or sirolimus immediately.
– Wean azathioprine or mycophenolate mofetil/mycophenolic acid off over 3 months; stop immediately with acute infection requiring hospitalization or IV antibiotics and do not resume.
– -Maintain prednisone 5 mg daily if plans to retransplant within 1 year of transplant failure or if residual renal function on 24-h urine provides for ≥0.5 mL/min urea clearance.
– Wean prednisone 1 mg/day per month to off if no plans to retransplant, no residual renal function or still on dialysis 6 months after kidney failure.
– – Surgical consult for nephrectomy if signs/symptoms of acute rejection after immunosuppression stopped (pain, redness, swelling over graft) or if signs/symptoms of rejection fail to respond to oral steroids.
– Stop all immunosuppression after nephrectomy.
Check PRA immediately upon return to dialysis and monthly if plans to retransplant.
(Nephrology Dialysis Transplantation, Volume 31, Issue 8, August 2016, Pages 1261–1269, https://doi.org/10.1093/ndt/gfv256)
Regarding plan of immunosuppression in second transplant:
We need to recognize that, this patient became sensitized and developed more antibodies with more likely graft rejection of the second transplant unless proper risk stratification and preparation done
Desensitization with IV Ig and rituximab in broadly HLA-sensitized living donor transplant
recipient has good long-term results with graft outcome similar to non-HLA-sensitized patients
despite higher immunologic risk
Induction Immunosuppressive Regimen
In our high-risk patients, a triple therapy-based regimen with IL-2 receptor antagonist induction was safe and produced good outcomes and excellent graft function
Maintenance Immunosuppression
A triple-drug regimen consisting of tacrolimus, mycophenolate, and prednisolone appears
to be most appropriate in sensitized, highimmunologic-risk transplant patients
Dear All
We are going to use these terms
000 mismatch means 100% match, 100 mismatch means 1 mismatch at the A locus, 111 mismatch means 3 antigen mismatch, 222 mismatch means 6 antigen mismatch and so on. Next week we are going to discuss reading cross-match reports. These are standard terminology in transplantation
What is the management plan?
The most common cutaneous side effect of cyclosporine was hypertrichosis which is a major cosmetic problem especially in females and children that may result in noncompliance with the drug.
It occurs in about 6% patients of the patients on long term treatment.
It is reversible when stopping the drug depending on the hair cycle (3 months in the face and 1 year in the arms).
· In this scenario, this young lady has 001 mismatch with normal graft function on dual immunosuppression, Accordingly:
1. Confirm the cyclosporine level (target 50-150 ng after the first year)
2. Exclude drug interactions such as drugs that inhibit CYP3A inhibitors which result in high level (example: Macrolides, ketoconazole, verapamil and grape fruit juice)
3. After exclusion of the above, reduce cyclosporine dose to keep within target and cosmetic measures like depilatory creams and electrolysis could be used
4. Shifting to Tacrolimus with a dose from 0.05-0.1 mcg/kg to keep a trough level (4-7 ng/ml) is a suitable alternative (Tacrolimus on the contrary is associated with alopecia)
Suppose this kidney failed, what is your immunosuppression protocol for the next transplant?
· The second transplantation immunosuppression protocol will depend on a number of factors like whether the second graft is living or deceased (will increase risk for DGF and more risk of ischemia reperfusion), the immunization status (sensitized from the current transplantation and being a female from any pregnancies) and the cross match result of the next transplantation with the proposed graft at that time.
· Additionally, if transplantation will happen within 1 year, I will keep the patient on steroids and CNI till transplant will happen
· Immunosuppression:
o If high immunological risk with positive FXCM-/+ DSA I will do to the polyclonal ATG with triple immunosuppression (TAC, MMF and Prednisolone) -/+ desensitization protocols if DSA is high
o However, in standard risk patient (with negative DSA, negative cross match result), I prefer to go for IL2 mABS+ triple therapy to reduce side effects caused by ATG(increased risk of infection, PTLD)
Cosmetically Disfiguring Side Effects of Cyclosporine. Vinitha Varghese Panicker , Anil Mathew, Ad Dhamramaratnam. Int J Trichology, 2012 Jan; 4(1):50.
Hair growth-stimulating effects of cyclosporin A and FK506, potent immunosuppressants.Satoshi Yamamoto, Ryuichi Kato. Journal of Dermatological Science. Volume 7, Supplement 1, July 1994, Pages S47-S54Handbook of kidney transplantation, 6th edition
Trough level of cyclosporine after 6 month post-transplantation should be around 100 ng /ml we must reduce the dose
and we can switch to tacrolimus due to cosmetic complication ( hirsutism)
second transplant the patient become sensitized and need high risk protocol (triple therapy) :steroid, Tacrolimus and MMF .
Some adverse effects, for example the cosmetic side effects of cyclosporine often have considerable distress, and should be treated promptly either
by dose reduction or IS treatment switch to tacrolimus in order to prevent patients discontinuing treatment and non compliance
If the kidney failed and planned for 2nd transplant so we will consider this patient at high risk group
Induction done by ATG
Maintenance with steroid,MMF,TAC
Nicholas Torpey, Nadeem E Moghal, Evelyn Watson, and David Talbot. OSH Renal Transplantation. Published online: Oct 2011
Reduction of her ciclosporin dose targeting a trough level around 100 then observing the response regarding her hirsutism , if no response we might shift her to tacrolimus which is more potent and is associated with hair loss rather than hirsutism .
In future transplantation, according to immunological risk, her immunosuppressive protocol will be tailored .
2nd transplantation carries more risk for sensitization , according to presence of DSAs and their strength she might need desensitization , induction agent, and maintenance IS protocol based on tacrolimus from the start .
What is your management plan?
Hirsutism is one of the most cosmetic complications relate to cyclosporine and not to tacrolimus and it affect patient compliance on immunosuppressant medications and should be respected and treated seriously.
It’s dose dependent and reversible
After 13m of transplantation in such low immunological risk patient..target trough level of cyclosporine will be around 100ng/ml so i will start decreasing the dose and fup in next 3 months.
If no response we used to give metronidazole/azithromycin and monitor improvement.
If still no improvement you should consider shifting from cyclosporine to tacrolimus
Before shifting you should make sure that your patient has no kind of rejection ongoing as tacrolimus will take time to build up a level so some centers prefer to do biopsy before shifting but according to current history and stable kidney function and no proteinuria in 24h urinary protein plus no DSA i will stop cyclosporine and start tacrolimus 0.15mg/kg and fup trough level every 3-5 days until its stabilization around 5ng/ml
If any abnormalities appeared in laboratories…i will proceed for biopsy before shifting to decide the best drug according to biopsy findings.
Suppose this kidney failed, what is your immunosuppression plan for the next transplant?
2nd transplantation in such patient i will go for quadriple depleting induction ATG (3mg/kg) plus tac/MMF/steroids
Sorry i mixed up hirsutism to gingival hyperplasia
Reference
{Trial of metronidazole vs. azithromycin for treatment of cyclosporine-induced gingival overgrowth},
volume = {8},
journal = {Pediatric transplantation},
doi = {10.1046/j.1397-3142.2003.00067.x}
The cosmetics side effects is a reason for switch the immunosuppressive medication ,but in this case the cyclosporine level is alittle bit high so will start by reducing the dose and then if no response so will switch to tac. If the graft fail usually the patient had some antibodies so his PRA will be positive; the protocol used is induction with ATG and continue with Tac,MMF and predinsilone
Cosmetics side effect is a reason for switch the immunosuppressive, but in this case I think the cyclosporine level it is little bit high, so starting by reduce the dose then switch to tac if no response. In a case of graft failure usually there is some antibodies and PRA almost positive so the induction will be by ATG and maintenance therapy will be tac,MMF and predinsilone
In the first week, I asked but did not get the answer because of comment trafficking I think
I am not familiar and could not find in resources:
what do we mean by 222/111/ here 100 mismatch
I guessed as 2222 means 6 mismatch
111 means 3 mismatch
100 here 1 mismatch
a colleague hereunder supposed 100 as 100% and answered according to that
may you clarify this??
Mahmud your conclusion about number of mismatches is correct
100 is not a percentage it is 1 mismatch.
Ithink you can go back to the first scenarios for more clarification but keep catching up.
Thank you ver much ..
cyclosporin level is high for the after 1-year post-transplantation, switching o tacrolimus with lower levels targeted as 5-7 plus 5 mg prednisolone or just lower the dose of CsA to a target level (C0) of 50-100.
as this is a low risk I may go on with two agents. I case of risk of failure I will add antiproliferative low doses such as MPA or MPa twice daily
In case of kidney failure after checking for donor specific antigens I think accepting patient as sensitized it may be acceptable to to give induction with thyroglobulin followed by three immune suppressive regimen (tacrolimus, MMF and steroid)
-Hirsutism is a common adverse effect associated with cyclosporine and is commonly observed in dark hair girls and women. It appears within a few months after the start of therapy with cyclosporin.
-Cyclosporin at various doses stimulated hair and epidermal keratinocyte growth and simultaneously down-regulating protein kinase C isoenzyme. Protein C has negative hair–growing effect so this maybe pathway lead to cyclosporine hypertrichosis.1
– I managed this young lady by conversion from cyclosporine to tacrolimus once daily that administered at a conversion ratio of 50 :1 .2
-If this kidney failed, the patient became a sensitized and high-risk patient.
-After screening for DSAs and desensitization of patient, induction therapy will be done by ATG which provide a better outcome for high immunological risk patients but is associated with higher rates of CMV infection.
-I will put her in maintenance triple therapy Tacrolimus, MMF, prednisolone.
References :
1.Takahashi T., Kamimura A. Cyclosporin a promotes hair epithelial cell proliferation and modulates protein kinase C expression and translocation in hair epithelial cells. J Invest Dermatol. 2001 Sep;117(3):605–611. [PubMed] [Google Scholar]
2 – Hisao Shimada, Junji Uchida, Akihiro Kosoku, Tomoaki Iwai, Kazuya Kabei, Shunji Nishide, Toshihide Naganuma, Norihiko Kumada, Yoshiaki Takemoto, Tatsuya Nakatani .Conversion From Cyclosporine to Once-Daily Tacrolimus on 50:1 mg Basis: A Short-Term Pilot Study. 2020 Feb;18(1):1-7.
correction again this is 1 mismatch
for this particular patient with exellant graft function as mentioned switch to Tacrolimus which has no hypertrichosis side effect would be enough and keep her on dual IS no need to add an antimetabolite.
thank you for your comments
Clinical use of Cyclosporin in organ transplant started in the late 1970s. Gingival hyperplasia and hirsutism are the known side effects of Cyclosporin therapy but not with tacrolimus. The exact mechanism of hypertrichosis is not known. It probably suggests androgenizing activities as studies have shown that there is increase in level of testosterone metabolites after treatment with cyclosporine. it caused major concern and the drug had to be stopped .
This effect is reversible and reverts on stoppage of drug. Sift her to tacrolimus may lead to an improvement in these effect with minimal risk of rejection or allograft dysfunction.
Cutolo M, Giusti M, Villaggio B, Barone A, Accardo S, Sulli A, et al. Testosterone metabolism and cyclosporin A treatment in rheumatoid arthritis. Br J Rheumatol. 1997;36:433–9.
Mihatsch MJ, Kyo M, Morozumi K, et al. The side-effects of ciclosporine-A and tacrolimus. Clin Nephrol 1998; 49 (6):356
Cyclosporine is a calcineurin inhibitor which blocks interleukin-2 production. Hirsutism is a well-known complication for cyclosporine which is dose dependent especially in children. CsA induces hair follicles by induction of anagenic phase and inhibition of catagenic phase or by increasing alfa-reductase activity.
Stopping cyclosporine and conversion to tacrolimus is a good and practical option in this case. Tacrolimus is more potent than cyclosporine which in this case with dual immunosuppression is better.
Second transplantation is associated with sensitization formation and DSA should be checked. Induction depends on risk stratification to be intermediate or standard risk. If patient has standard risk, induction with basiliximab will be enough. But if patient has intermediate risk, induction with ATG will be mandatory. For second transplant triple maintenance therapy is better.
1. Takahashi T, Kamimura A. Cyclosporin a promotes hair epithelial cell proliferation and modulates protein kinase C expression and translocation in hair epithelial cells. J Invest Dermatol. 2001 Sep;117(3):605-11.
2.Callus R, Buttigieg J, Anastasi AA, Halawa A. Basic concepts in kidney transplant immunology. Br J Hosp Med (Lond). 2017 Jan 2;78(1):32-37.
Agreed, do you think that this Hirsutism is reversible
No
Management plan for cyclosporine side effect ( hirsutism);
Hirsutism occurs in over 20 % of cyclosporine-treated patients, which can be aggravated by concomitant use of corticosteroids, or minoxidil for hypertension.. the pathogenesis of cyclosporine induced hirsutism is not well established , it may be may be dose dependent . On the other hand , Ponticelli et al. attribute this adverse reaction to a possible induction in the alpha-reductase enzyme activity increase, responsible for the conversion of androgens to dihydrotestosterone in tissues .
In this patient it is better to reduce the cyclosporine dose to the therapeutic range ( 50 -150)ng/ml with addition of anti metabolite(according to her immunological risk ) . If no improvement after 3 months ,she should be shifted to tacrolimus .
Referance;
Xu W, Fan W, Yao K. Cyclosporine A stimulated hair growth from
mouse vibrissae follicles in an organ culture model. J Biomed Res.
2012;26:372—80.
Ponticelli C, Bencini PL. Nonneoplastic mucocutaneous lesions in
organ transplant recipients. Transpl Int. 2011;24:1041—50.
If graft is failed what is the immune suppressive plan?
Transplant failure often comes with complex management decisions, such as when and how to wean immunosuppression and start the transition to a second transplant or to dialysis. These decisions are made in the context of important concerns about competing risks, including sensitization and infection .
Patient s are categorized according to their risk for infection , residual urine and re transplantation plan .
In those with high risk for infection CNI and anti metabolite showed be stopped in addition to reduction of 1 mg prednisolone monthly .
Patients (with low risk for infection) are categorized according to their urine preservation . Those with preserved urine, anti metabolite should be stopped immediately with monthly 1 mg reduction in prednisolone dose , after 3-6 months CNI dose showed be reduced by 50% and stopped with in 6months to one year . Those with no residual urine CNI showed be stopped immediately , anti metabolite reduced by 50%every 1-2 months while prednisolone is reduced by 1 mg every 1-2 months.
If anticipated re transplantation will be with in one year ,patient should continue in CNI ,steroid with 50% reduction of anti metabolite.
Reference;
British Transplant Society: Management of the failing kidney
transplant. Available at: https://bts.org.uk/wp-content/uploads/
2016/09/13_BTS_Failing_Graft-1.pdf. Accessed August 24, 2020
Du¨rr M, Lachmann N, Zukunft B, Schmidt D, Budde K,
Brakemeier S: Late conversion to belatacept after kidney transplantation: Outcome and prognostic factors. Transplant Proc 49:
1747–1756. e1, 2017
King KL, Husain SA, Jin Z, Brennan C, Mohan S: Trends in
disparities in preemptive kidney transplantation in the United
States. Clin J Am Soc Nephrol 14: 1500–1511, 2019
Nice answer.
●What is your management plan?
The most common cutaneous side effect of cyclosporine was hypertrichosis, occurring in about 6% patients.[1]
The exact mechanism of hypertrichosis is not known. It probably suggest androgenizing activities as studies have shown that there is increase in level of testosterone metabolites after treatment with cyclosporine.[2]
This effect is reversible usually within months on stoppage of drug.
It is mainly dose dependent rather than duration dependent as for this patient if she have no other side effect of cyclosporine like gingival hyperplasia some studies recommended either do dose reduction and wait for improvement in 3 months (especially that this patient has a high level ) or we can switch to tacrolimus since both are calceneurin inhibitors with a similar action. Tacrolimus causes fewer cutaneous abnormalities and does not trigger gingival
hyperplasia thereby making it more acceptable for patients [3].
Reference
1. Rosmarin DM, Lebwohl M, Elewski BE, Gottlieb AB. Cyclosporine and Psoriasis: 2008 National Psoriasis Foundation Consensus Conference. J Am Acad Dermatol. 2010;62:838–53.
2Cutolo M, Giusti M, Villaggio B, Barone A, Accardo S, Sulli A, et al. Testosterone metabolism and cyclosporin A treatment in rheumatoid arthritis. Br J Rheumatol. 1997;36:433–9.
3 Cutolo M, Giusti M, Villaggio B, et al. Long-term evaluation of
cyclosporine and tacrolimus based immunosuppression in pediatric liver
transplantation. Pediatr Transplant. 2006;10:938–942.
●Suppose this kidney failed, what is your immunosuppression plan for the next transplant?
First we need to know the cause of graft loss since the the patient was doing good and she had agood match
But in next transplantation patient is considered ahigh risk patient as one of the major causes of sensitization is previous transplant.
First we must know her PRA% as she had one HLA mismatch and she received kidney from a male doner so she had non HLA -antibodies and mostly she had positive DSA
I will think of induction with ATG and triple immunosuppression protocol with steroids ,tacrolimus and MMF .
Nice answer and you touched the valid points.
Level of cyclosporine is very high and presence of hirsutism supporting toxicity(dose dependant and reversible ), it’s better to exclude any nephropathy , in this case it’s seems stable …We can decrease dose and target trough level around 100 ng/ml
Also shifting to tacrolimus is an option with dose 0.05 to 0.1 mg/kg with trough level around 5ng/ ml
In case of failure , it’s considered high risk and needs induction ATG (3mg/kg) plus tac/MMF/steroids
Candidates for retransplantation are at increased immunological risk and usually have higher panel reactive antibodies compared to recipients of a first kidney transplant, frequently prompting the use of more intensive induction regimens.
I will give ATG induction and maintenance on (tacrolimus,myofortic , prednisolone)
Would you do DSA’s and why?
yes, I will do DSA. it is done routinely for all the recipients.
If DSA is positive and Flowcytometry cross-match positive, she will need a desensitisation protocol.
If DSA is positive and FCXM is negative, I will induce her with ATG +_ immunoglobulins.
I will shift the patient from cyclosporin to Tacrolimus. as she developed one of the side effects of cyclosporine, especially she is a young age female(cosmetic effect). and she is on a dual immunosuppressive medication only. tacrolimus strong immunosuppressive medication than cyclosporin.
Agree but would you first try dose reduction. Switching immunosuppression too has its own perils.
1-Her cyclosporine level being 322 ng/ml ,13 months after transplantation with excellent kidney function is acceptable and since cyclosporine side effects are dose dependent the dose can be descalated till reach ideal therapeutic dose (75 to 160 ng/ml one year after transplantation) with close monitoring of renal functions but if she is not tolerating the facial hirsutism ,cyclosporine can be substituted with Tacrolimus as both are calcineurin inhibitors but Tacrolimus has less dermatological side effects .
2-Since it is her second transplantation so it is possible for her to be sensitised so DSA need to be assessed as she can need desensitization protocol followed by Induction therapy by polyclonal antibodies (anti-thymocyte globulins) as a high risk patient ,followed by maintenance regimens include tacrolimus, antiproliferative agents (mycophenolic acid), and corticosteroids .
Nice and succinct answer. What do you think are the contra indications for ATG?
Dear Dr Hemant Sharma,
What do you think are the contra indications for ATG?
The contraindications include:
– Hypersensitivity to the drug or its components.
– Active infection.
Another important consideration with the current COVID-19 pandemic is that patients who received ATG may have a sluggish immune response to vaccination and they are recommended to receive a third dose of mRNA vaccines (live attenuated vaccines should be avoided during or shortly after treatment with ATG) (1).
References:
1) Antithymocyte globulin (rabbit derived, Thymoglobulin): Drug information. Copyright 1978-2021 Lexicomp. (Accessed on 1 December 2021).
first i will check the accuracy of the result of cyclosporine level. then i will take history to look for any food or drug interaction that might induced this high level. the next step will be reduction of her dose .
OK I agree but would you reconsider your answer for kidney failure and further management .
Does any one of you consider giving medications interfering with Cyclosporine metabolism to reduce the side effect? Also, do you think it would be helpful to mitigate the cosmetic side effects of CNI?
Does any one of you consider giving medications interfering with Cyclosporine metabolism to reduce the side effect?
antitubercular drug like rifampicin, antifungal like caspofungin, anticonvulsants like phenobarbitone, phenytoin, carbamazepine induce CYP3A4 and decrease levels of cyclosporine/tacrolimus but would not use these to decrease cyclosporine levels and side effects.
Also, do you think it would be helpful to mitigate the cosmetic side effects of CNI?
in a female patient if the cosmetic side effects are causing distress to her, then yes.
Does any one of you consider giving medications interfering with Cyclosporine metabolism to reduce the side effect?
Medicatins which interfers with cyclosporine metabolism as rifampicin and carbamazepine are not used in practice to decrease its side effect mainly due their own side eff3cts and reduction of the dose or switching to tacrolimus would is recommended in many studies.
Cosmetic side effects may result in noncompliance to medications leading to graft failure so it must be taken seriously
Thank you for mentioning the issue of medication noncompliance
No, I won’t give drugs like rifampin or phenytoin to decrease its blood level and to reduce its side effects because its effect will be unpredictable and it is better simply to decrease dosage or change to tacrolimus.
Cosmetic side effects would decrease compliance especially in young women and should be considered.
Dear Prof Alla
the evidence of such parctice came from few case reports of using of phenytoin or phenobarbital (as enzyme inducers agents), no report of rifampin or carbamazepine use. in addition the effect is not immediate need at least 48–72 hours after initiation of the medication which riase concerns for timing and the potential efficacy of this practice ,also patients with polymorphisms coding for functional CYP3A and P-glycoprotein and patients taking CYP3A or P-glycoprotein inducers, both of which increase overall CNI dose requirements, may be at an increased risk for chronic CNIs,further clinical studies are required before this approach can be recommended for routine treatment of acute CNI toxicity.on the otherhand the nondihydropyridines CCBs like diltiazem and verapamil, can be used to lower the total CNI dose with lower cost. Diltiazem also reduce the CNI induced vasoconstriction due to its vasodilation effect but there is no definitive evidence that CCB prevents chronic CNI nephrotoxicity.
References:
1-The Many Faces of Calcineurin Inhibitor Toxicity – What the FK?
Samira Farouk, MD, MS1,2, Joshua L. Rein, DO1
1Division of Nephrology, Department of Medicine, Icahn School of Medicine at Mount Sinai, New
York, NY, Recanati-Miller Transplant Institute, Mount Sinai Hospital, New York, NY
Excellent response, well explained.
Thank you for mentioning the Non-Dihydropyridines CCBs like diltiazem which could be a valuable option in daily practice for BP control and preventing overdoses of CNI but at low cost. It has dual actions of reducing the risk of toxicity and mitigating the afferent vasoconstriction induced by the CNI.
Good referencing
diltiazem is ver commonly used to lower the dose of tacrolimus especially in the first 3 months and helps as an anti-HT drug.. some centers stop it in case nf normotension when targeting tough level in maintainance period especially after 3rd month
macrolide like azithromycin could be used. it also has an additive effect on gingival hyperplasia
You could try enzyme inducers eg Rifampicin but the problem here is you reduce the CSA and increase risk of rejection. Cosmetic side effects is troublesome specially in young ladies and by it self is a risk factor for rejection because they could easily stop the drugs . The good thing is now days most centres moved away from the use of CSA and the standard of care is now tacrolimus.
No. Drugs reducing CNI levels like rifampicin, phenytoin (CYP3A4 inducers) should not be used, rather the dose of CNI can be reduced. This is because the drugs will have their own effects and adverse effects. Drugs inhibiting CYP3A4 like ketoconazole, diltiazem are commonly used to increase the level of CNO, but in my opinion even this practice has its own perils and should be avoided.
Yes, it would be helpful to mitigate the cosmetic side effects of CNI because these side effects are especially bothersome for young girls and may lead to non-adherence.
CNIS has a lot of complaictions, both (cyclosporine and tacrolimus ).
one of the most common complications of cyclosporine is hirshutiusm.
counselling the pt should be done , and explainning to her that this is a side of effect of the drug , and another drug is avilable to play the same role but has another side effect which may be agonizng to her which is her loss, which is not guaranted to occur or not .if she accepts we can switch her to tacrolimus with level adjusted acoording how far is form the transplantion.
IF HER GRAFT FAILED, WHAT IS MY IMMUNSUPPRESSION PALN?
regardin this question we have to ask many question.
a-what is her cPRA?
b-is she having a living donor or will recive a cadaveric kidney?
c-how many mismatches with her donor?
d-what is the cause of her graft failure , especially she has a good match?
once answered these questions we can decide what kind of her immunosuppriion she will take .
A-first induction immusouspresion,
ATG will be reasonaple regardless her matching and cPRA, as she is considered as high immunological risk pt as it is her second transplant.
B- maintinace immunosupprison ,
i will go for triple protocol with (pred , mmf and tacrolimus) as the tacrolimus has superior to cylo in reducing graft loss and caute rejection rate and hypercholsiterima but low in delveloping daibetes .
WHAT IS THE CAUSE THAT MAKE HER GRAFT LOST?
IS IT RECURRENCE OF PRIMARY DISAESE?
ACUTE REJECTION EPISODE,TCMR OR AMR OR CHRONIC REJECTION?
NONCOMPLANCE OF MEDICATIONS?
NON IMMUOLOGICAL CAUSES LIKE BK NEPHROPATHY ?
ALL THESE DATA WLL ALSO BE HELPFUL ON IMMUNSPURISSION MAINTINACE INTESIFICATION AND PRE TRANSPLANT PREAPRATION LIKE DESENTIZATION IF SHE HAS A DSA .
Tacrolimus versus cyclosporin as primary immunosuppression for kidney transplant recipients. Cochrane Database of Systematic Reviews 2005, Issue 4. Art. No.: CD003961. DOI: 10.1002/14651858.CD003961.pub2.
Th commonest cause for switching between CNI is cosmetic ( Tac to cycle A in case of hirsutism , cyclA to Tac in gingival hypertrophy). This patient has stable graft function on cycl A but complaining from hirsutism so she can switched to Tac is reasonable choice . The dose usually defer from one patient to another so the dose should be individualized. Also there is no need for overlap of the drug or coverage with steroid, but the patients should be closely monitored after switching.
If the patient lost her graft & planned for second transplantation she considered as high risk & if pre transplant DSA is positive she will need desensitization, if DSA is negative she will need close monitoring of DSA post transplantation.
Handbook of Transplantation. Danovitch G. 6th edition
Fascial hirsutism is a well known side effect of CSA and corticosteroids but not tacrolimus (1)
The pathogenesis of fascial hirsutism related to CSA is not well established.
CSA induced hirsutism is dose dependent and reversible within months to years depending on the area affected (fascial hirsutism may reverse in 3 m, while arm hirsutism can resolve in years). (2)
So… since our patient cyclosporine level is high, I will recommend decreasing the dose of CSA first to maintain trough of 50-150 ng/mL, Initiate MMF or azathioprine (since the patient is not 2 haplotype identical so it is recommended to be on triple therapy)
If no effect observed after 3 months i will switch from CSA to tacrolimus in a dose of 0.05 mg/kg daily with monitoring of trough level keeping level between 3-7 ng/mL.
If the kidney fail, i will choose tacrolimus based triple maintanance therapy
REFERANCES
1- Dongari A, McDonnell HT, Langlais RP. Drug-induced gingival overgrowth. Oral Surg Oral Med Oral Pathol 1993; 76:543.
2- Vashi R.A., Mancini A.J., Paller A.S. Primary generalizad and localized hypertrichosis in children. Arch Dermatol. 2001;137:877–884
This patient had one mismatch from LRD with stable graft function more than 1 year, the cyclosprine level if its trough level its high for the transplant duration , she is in daul IS with steriod no MMF.
cyclosprine in combination with steriod can fruther worsening the hirsutism and other cosmotic complications like coarseningof facial features, the cosmotic side effect of cyclosprine should be treated espcialy in women as can affect her compliance with IS therapy.
i will shift her to tacrolimus based IS its more potent IS and usually effective and the hirsutism will faint with time .
for second part of the question
Will you use Tacrolimus Saja?
Dear prof , Yes i would prefer to modify her IS as she is female recipient from male donor( male H-Y antigen)alloresponse to this type of antigens ( minor HLA -antigen ) might put her at risk of rejection,i m not comfortable with such combination such combination can put her at risk of rejection in addition she had cosmotic side effect with cyclosprine
but i got your piont may be best option will be the combination of minimize dose of CNI,prefered tacrolimus and M-Tor inhibitor like everolimus provide her renal function stable and no significant protienuria as first option.second option will be tacrolimus with MMF, predisolone combination.
The cosmetic side effects of CNI is an important issue , and it’s neglect can lead to noncompliance to the drugs and subsequent graft loss.
Cyclosporine and steroids can lead to hirsutism and in this case supratherapeutic level of cyclosporine can exacerbate the problem , so dose reduction of cyclosporine is advised and if no benefit we can use Tacrolimus instead of cyclosporine.
in this patient , no history is given about MMF , since MMF use is associated with lower risk of early rejection and also reduce the risk of late acute rejection.
If this graft is failed , and we prepare for 2nd transplantation , I will be regard her as high risk and induction with ATG , triple maintenance immunosuppression ( steroids, tacrolimus ,MMF).
Reference:
Gabriel M. Danovitch, MD Handbook of Kidney Transplantation SIXTH EDITION
ATG if cPRA is high or crossmatch is abnormal.
If the crossmatch is positive , and no other compatible donor is available , kidney paired transplantation is an option. and if this was not available we can do desensitization , and if the crossmatch became negative then we can proceed with transplantation with induction with ATG.
If the cPRA was high , this patient will have high risk of acute rejection and induction with ATG is needed.
Plan of management:
What is your management plan?
In patients treated with cyclosporine, we need to monitor cyclosporine trough (C0) concentrations. With this approach, our target levels is 50 to 150 ng/mL after 3 months of transplantation.
Patients on CNI may develop toxicity even in the narrow therapeutic level, so side effects and toxicity should be monitored. In this particular patient with HLA-A 100 mismatch, initially we have to decrease the dose of cyclosporine, as the higher the dose the more side effects and adverse events. If after adjusting the dose of cyclosporine, patient continued to have hypertrichosis, then shifting to tacrolimus is reasonable.
Tacrolimus is not associated with hypertrichosis and not inferior to cyclosporine in terms of immunosuppression.
Suppose this kidney failed, what is your immunosuppression plan for the next transplant?
In the initial workup for the second transplantation and donor allocation, screening for DSA is mandatory as this patient is sensitized. If DSAs are present and flow cytometry crossmatch is positive then desensitization protocol should be performed.
Following desensitization, induction therapy for this high risk patient should include rATG and steroids with triple therapy based maintenance immunosuppression composed of steroids, CNI mainly tacrolimus ,and antimetabolite in particular MMF.
Reference:
Handbook of kidney transplantation
Uptodate
Cosmetic complications of cyclosporin should be considered and must be treated seriously, particularly in women and adolescents that may lead to noncompliant behavior. Hypertrichosis in varying degrees occurs in nearly all patients receiving cyclosporin but not seen with tacrolimus. Instead, hair loss is seen with tacrolimus. Therefore, switching from cyclosporine to tacrolimus (with 40/1 ratio) can be suggested in this patient.
If the kidney failed, after evaluation for DSA and finding the appropriate donor, since a patient with a previously failed transplant is considered at high risk for rejection, induction therapy with ATG and intravenous methylprednisolone combined with maintenance immunosuppressive therapy, which begins preoperatively, would be appropriate. Suggested maintenance therapy is tacrolimus, MMF and steroids.
shift from cyclosporin to tacrolimus, this will not add any risk of rejection.
shift dose from cyclosporin to tacrolimus is 50:1. every 50 mg cyclosporin shifted to 1 mg tacrolimus as once daily dose.
Hisao Shimada , Junji Uchida, Akihiro Kosoku, Tomoaki Iwai, Kazuya Kabei, Shunji Nishide, Toshihide Naganuma, Norihiko Kumada, Yoshiaki Takemoto, Tatsuya Nakatani.Conversion From Cyclosporine to Once-Daily Tacrolimus on 50:1 mg Basis: A Short-Term Pilot Study. Exp Clin Transplant. 2020 Feb;18(1):1-7.
if kidney failed , my plan for next transplant: 1- detection of DSA to decide desensitization protocol or not.2-induction by ATG
3- maintenance ISD (immunosuppression drugs) tacrolimus , MMF and steroid with slow tapering protocol.
For this patient, cyclosporine dose reduction may be tried( if DSA testing is negative and there is no evidence of subclinical rejection in protocol biopsy) ,and if this is not effective or can not be done, then conversion from Cyclosporine to Tacrolimus can help without increasing the risk of rejection or allograft dysfunction. usually the ratio of conversion is 40:1, so for the patient who uses 250 mg/day of cyclosporine, he will need 6 mg/day tacrolimus.
If the graft is failed, immunosuppressive protocol for the second transplantation will be induction with ATG, pulse steroid and maintenance therapy consist of Tac, MMF, gradually tapered doses of steroids.
Reference:
Uptodate 2021 cited at 27th, Nov. 2021
I will give option to the patient to continue cyclosporine at reduced dose or if the facial hirsutism is distressing to her and cannot wait for the cyclosporine dose reduction trial and see if it works, the immediately shift to 0.1mg/kg in divided doses. Patient is 13 months post transplant, target cyclosporine CO level should be between 75 – 160ng/ml after 1 year of transplant. So first i will reduce cyclosporine the morning and night dose by 50mg each and repeat creat and cyclosporine levels weekly and keep decreasing the cyclosporine dose till levels are in the recommended range. i will keep a keen watch on sr creatinine and watch for rejection.
After 4 months of CO levels within therapeutic range if the there is no subsidence seen in the hirsutism, shift her onto tacrolimus 0.1mg/kg in BD divided doses and check tacrolimus levels and sr creatinine every 3 days initially in the first week then weekly until 3 consecutive weekly levels were stable( within 4-8 ng/ml) and titrate tacrolimus levels as per levels and creatinine.
Thymoglobulin induction ,and triple immunosuppression consisting of tacrolimus, mycophenolate, prednisolone.