1. A 32-year-old female patient received a kidney transplant from her brother 2 months ago, 100 mismatch, and excellent kidney function. She is on dual immunosuppression (tacrolimus and 15 mg of prednisolone). She is suffering from intractable acne not responding to topical treatment.
What is your management?
Suppose this kidney failed, what is your immunosuppression plan for the next transplant?
I will go for tapering steroid as it is mostly the cause of acne .
In case of failed graft and pt is going for 2nd transplant ,We will do FCXM ,PRA and HLA typing and if positive cross match or DSA we will do desensitization and induction will be ATG ,methylene pred with early withdrawal of steroids
Maintenance will be tac ,MMF and prednisone
Ahmed Omran
3 years ago
Tapering steroid therapy looks reasonable with suitable acne treatment and starting MMF .In case of graft failure, with need for second Tx ,we will do XM (CDC &FC) and DSA assay considering sensitization. Desensitization will be indicated in case of positive XM. Additionally, induction must be aggressive with ATG, and early tapering of steroid in maintenance therapy before development of acne as a side effect.
Reference :
Mujtaba, MA et al Early steroid withdrawal in repeat kidney transplantation, Clin J Am Soc Nephrol:2011,6:404-411
Mujtaba Zuhair
3 years ago
Acne is one of the recognized side effects of steroids. neglecting this problem can affect compliance of immunosuppression drugs. if the topical treatment is not effective we need to gradually reduce the steroid dose ( to 5 mg every other day) and we can replace it with MMF . We may obligate to stop the steroid completely .
Immunosuppression of the second transplantation depend on the cPRA , DSA , and HLA compatibility with the second donor .
Hinda Hassan
3 years ago
· What is your management?
I will give oral doxycycline 100 mg daily. If no improvement, systemic and topical isotretinoin for 6 months . Again if no response steroid dose may need to be reduced but with addition of MMF. Withdrawal of steroid is preferred within 6 month post transplant(to guarantee no episodes of acute rejection, long-term patient and graft survivals compared with withdrawal after 6 months but with the risk of a rise in urine protein excretion during 10 yr of follow-up). The incidence of rejection in steroid-free regimen is 48% compared with a 30%in steroid-treated control. The criteria for steroid withdrawal were that the patient have stable renal function for at least 2 months and that the patient understand the potential risks and benefits of steroid discontinuation Suppose this kidney failed, what is your immunosuppression plan for the next transplant?
I will give induction ( for fear of withdrawal of steroid) and then tacrolimus, mycophenolate mofetil (MMF). if she develops again side effect of steroid, I may consider steroid withdrawal according to her situation and time after transplant.
– Late Steroid Withdrawal with Tacrolimus-Based Immunosuppression after 3 months is better when the MMF is used but steroid should be withdrawn only if she is free of acute rejection for the first 3 mo and her serum creatinine <1.4 mg/dl
– Early steroid withdrawal on day 3 post operatively is possible with Induction ( either alemtuzumab or basiliximab) ,5 year follow up proved comparable results of decline in GFR between withdrawal and maintence . Ciancio reported a small series of 44 kidney transplant recipients who were treated with alemtuzumab, MMF, and low-dosages of tacrolimus. Prednisone was discontinued after 1 wk. With a median follow-up of 9 mo, patient and graft survival each were 100%, and biopsy-proven acute rejection occurred in four patients.
– Early Steroid Withdrawal or Steroid Avoidance with Tacrolimus-Based Immunosuppression is assessed with 2 short term studies. CARMEN study proved that the rejection incidence is equal in steroid free versus steroid base but ATLAS study proved that acute rejection was significantly higher with steroid free regimen . A recent RCT , not finished yet, compared tacrolimus/MMF/steroids versus tacrolimus/MMF and 7 d of steroids . All patients received induction antibody therapy . After 12 mo of follow-up, the incidence of biopsy-proven acute rejection was 6% in steroid-treated patients and 12% in the steroid withdrawal group (p= 0.04). There were no significant differences in graft or patient survival.
Joshua J. Augustine, Donald E. Hricik,Steroid Sparing in Kidney Transplantation: Changing Paradigms, Improving Outcomes, and Remaining Questions ,CJASN Sep 2006, 1 (5) 1080-1089; DOI: 10.2215/CJN.01800506
Nasrin Esfandiar
3 years ago
Acne is a known side effect of prednisolone. Her Tx is considered low risk due to one-mismatch HLA. So, tapering prednisolone dose to 5 mg and to follow-up her is an option. If the acne is not cured despite of steroid minimization and dermatological treatment, MMF can start and steroid halt. For second transplant, immunosuppression depends on existence of DSA. If XM is negative with no DSA there is standard risk. If cPRA is high and no donor without DSA could be found, then desensitization and potent immunosuppression and protocol biopsy based on level of MFI would be an option.
Tahani Hadi
3 years ago
Corticosteroids are used in kidney transplant to decrease the risk of acute rejection although corticosteroids have many side effects but it stills the cornerstone of immunosuppression regimens.
Due to their side effects and discovery of new immunosuppressive agents in the transplant protocols many centres adapted to reduce the dose or even discontinue the usage of steroid by different protocols for tapering steroids in transplanted patients either early or late withdrawal of steroid starting after the first 3 to 6 months after transplantation.
Regarding this patient with dermatological side effects of prednisolone we can seek for dermatologist consultation and start to decrease the dose of steroid with close monitoring of renal function and if not responding we can withdraw prednisolone but after adding a new immunosuppressive agent like MMF .
For the second transplant usage of ATG in the induction treatment and she may need to be put on triple immunosuppressants and for desensitization it’s depend on presence of DSA and CDC crossmatch.
Radwa Ellisy
3 years ago
Management
1- Dermatological consultation about a trial of systemic medication as isotrtinoin
2- Steroid withdrawal
· After informing the patient with the risk of early minimization of steroid may be associated with as increasing risk of CAN and mild rejection
· Original kidney disease as will as the induction protocol using ATG or basiliximab should be taken in consideration when early steroid withdrawal is considered.
· Also level level of DSA should be checked before steroid withdrawal.
· Introduction of antimetabolite (MMF / Aza ) before withdrawal of steroids with insuring that Tac level in its target level
2nd transplantation
Immunosuppression protocol would be decided according
· According to the result of crossmatch
· DSA presence or absence and their specificity and intensity
· cPRA
· Timing of acute rejection
· The original kidney disease
Steroid free protocol
Steroid free maintenance or lower maintenance dose (0.05-.1/kg) the first year
Desensitization protocols
Not an easy job at all
Costly when compared with tx with matched tx but still cost-effective when compared with being on dialysis and associated with a better life expectancy
References
1. Banerjee A, Julie BM, Sharma A, Halawa A (2018) Steroid withdrawal protocols in RenalTransplantation. Archives of nephrology of clinical nephrology
2. Nelson J. Corticosteroid-Sparing in Adult Renal Transplantation: Gambling with Allografts, or Strong Data?
3. Orandi BG, Luo X, Massie AB et al., “Survival benefit with kidney transplants from HLA-incompatible live donors,” The New England Journal of Medicine, vol. 374, no. 10, pp. 940–950, 2016.
Wael Hassan
3 years ago
managment of this case Acne not responding to topical corticosteroid by using cortisol free rejemin (tappring of corticosteroid gradully to minimal dose 5mg then try to stop it if normal creatinine and no signs of rejection & add cellecept twice daily.
cortisol free protocol
use it in the first week only &using of tacrolimus & mmf)
Heba Wagdy
3 years ago
Steroid induced cutaneous manifestations are common and dose dependent
The acne lesions are mostly monomorphous with papules and papulopustules affecting face, upper limbs and trunk
topicl treatment as topical retinoids and benzoyl peroxide can be used with topical antibiotics as erythromycin 2% and clindamycin 1%
adding a steroid sparing drug as MMF or azathioprine with gradual withdrawal of steroids till reach minimal dose with strict monitoring of kidney function Suppose this kidney failed, what is your immunosuppression plan for the next transplant?
patient is considered sensitized due to previous transplant, if DSA positive and CDC crossmatch positive, desensitization protocol before transplant
if DSA is negative with negative CDC crossmatch, retransplant with induction therapy rATG as considered at high immunological risk and maintenance therapy with tacrolimus, mycophenolic acid and minimal dose steroids.
Mahé, E., 2014. Acne in Transplantation Patients. In Pathogenesis and Treatment of Acne and Rosacea (pp. 591-602). Springer, Berlin, Heidelberg.
Salvadori, M. and Bertoni, E., 2012. Renal transplant allocation criteria, desensitization strategies and immunosuppressive therapy in retransplant renal patients. Journal of nephrology, 25(6), p.890.
Pratschke, J., Dragun, D., Hauser, I.A., Horn, S., Mueller, T.F., Schemmer, P. and Thaiss, F., 2016. Immunological risk assessment: The key to individualized immunosuppression after kidney transplantation. Transplantation Reviews, 30(2), pp.77-84.
Wessam Moustafa
3 years ago
The patient is resistant to all topical treatment of acne , I would taper her steroid dose and use steroid sparing agent, either azathioprine or MMF .
If her graft fails , next transplantation I would suggest a steroid free regimen, with induction therapy ( thymoglobulin) with tacrolimus +MMF as maintainence ttt
Although steroid free rejimens are at increased risk of acute rejection , yet these regimens markedly reduces steroid induced complications
Veenstra DL, Best JH, Hornberger J, Sullivan SD, Hricik DE: The incidence and long-term cost of steroid-related side effects after renal transplantation. Am J Kidney Dis33 :829– 839,1999
Dalia Eltahir
3 years ago
Steroid acne is characterized by the abrupt onset of monomorphous pink papules on the face and trunk. Even at low doses, prednisone can cause skin problems. These include skin thinning, acne, hirsutism , hair thinning, face redness, stripe-like marks on the skin (stria) , impaired wound healing and perioral dermatitis There are a few reports of the successful use of the systemic retinoid isotretinoin in young adults who have undergone organ transplantation. But there are many side effect including pancreatitis and hyperlipidemia, and early experimental evidence that vitamin A derivatives may increase the likelihood of allograft rejection . Topical retinoids such as tretinoin cream or gel may be beneficial . If the graft fail , she need induction with ATG early steroid withdrawal in 1st week and maintenance with Tacrolimus and MMF .
Ramy Elshahat
3 years ago
What is your management?
Acne is one of the common complication of steroids specially with doses more than 20mg
Plus topical treatment decreasing steroids to 5mg at least first 6m to 1year post transplant
Adding AZA OR MMF may support repaid decreasing of steroids
My center experience is never to stop steroids but we decrease it to the lowest possible dose.
Also young females with low immunological risk we give non depleting basilixmab induction to be able to afford rapid steroids reduction.
Suppose this kidney failed, what is your immunosuppression plan for the next transplant
According to matching, CDC DTT cross match, flow cytometry crossmatch,single antigen bead but generally she will need depleting induction ATG or alemutzumab to be able to afford rapid steroids reduction plus plasma exchange just if CDC DTT cross match was positive or DSA with RIS more than 17.
Professor Ahmed Halawa
Admin
3 years ago
Dear All Is the presence of DSA is an indication of desensitisation? Is it easy to desensitise?
We have to ask first?
1- is flow cytometry cross match positive or negative? And if positive is it t cell or b cell or both?
2-what is the level of dsa ,some centres have variable levels of mfi they can go ahead witout desentization 2000 or 5000 mfi
3-what is class of dsa present is it class 1 or class 2?
4-is this for living transplantion or deceased one?
5- is paired exchange programm is avilable some where near the pt?
All these questins can answer wether can i go ahead for desentization or not
In the rising era of paired ecxhange programm ,most centres recommend any pt with bad mismatch or having dsa for paired exchange for better outcome.
Actually not all dsa is gioing to be senstized.as an example for dsa levels below 5000 mfi or HLA C,DP,DQ
Desentization protocols are very expensive and hectic for both centres and patients as we are using guns like rituximab plasampharesis and iv igg to clear theses dsa ,and this puts the pt at very high risk of infections and risks of bleeding .
So desentization protocls should be only done for carefully selected pt who only have this donor with this dsa aiming for negative flow cytometry cross match with accepted level of dsa .
and dsa should be monitored carfully and some centres may offer protcol biobises for this kind of patients
Desensitization will be required if crossmatch is positive. DSA alone with a negative crossmatch does not require desensitization.
It is not easy to remove antibodies by desensitization. I do not have much experience in desensitization, but i have not seen may successful desensitizations.
the presence of DSA alone is not enough to decide about the desensitazation , many other factors to be be considered like Living donor KT in crossmatch (XM)-positive/DSA+ve ,or ABOI kidney transplantaion , history of sensitazation like female genderwith preganacy , transfusion history previous transplantion all are consider high-risk and requires an optimal desensitization protocol .
Desenitization protocal not easy , expensive , not standardazied worldwide and not free from side effects, and the transplant outcome with desensitazation still Questionable inmany studies (1,2).
Desensitization is only done if positive crossmatch
It’s not easy to desensitize patient
My own center experience we do 5 sessions of plasma exchange 1.5 plasma volume on every other day base then give 0.5gm/kg IVIG with the last session plus one or two doses of rutiximab
Positive crossmatch with the presence of DSA is an indication for desensitization
Desensitization is not an easy process, it is coasty and associated with many complications related to plasmapheresis such as:
Desensitization protocol depends on multiple factors like DSA , CDC crossmatch also whether living or deceased donor .
DSA level and if it is associated with CDC B and /or T cells and their level all contribute in the desensitization decision for example DSA positive with MFI less than 5000 and Tcell negative and B cell positive crossmatch with deceased donor no need desensitization just induction by ATG and IVIG.
Once crossmatch test is positive , desensitisation is indicted. This is a tedious process and involved a lot of experience cost, labour and time to get negative crossmatch. so is not easy and that is why some centre are not considering this specially in low resource setting.
Ofonime Udoh
3 years ago
A known and common side effect of the use of steroids is acne. Corticosteroids are used in maintaining immununsoppression following renal transplant. A study by woodle et al has shown that 15 years post transplant there was no signficant difference in patient survival rates and graft surivial rates in those who wer on long term steroid use and in those who stopped stroid use early. I would reduce the dose of prednisolone in a steep wise manner in this 32 year old female with a 100 mismatch in HLA typing and intractable acne not responding to topical management.
If this kidney fails i would use steroid sparing medications like Mycophenolate Mofetil as part of the immunosuppression protocol for this patient
References
Woodle, E.S., et al. (2021) Early Corticosteroid Cessation vs Long-term Corticosteroid Therapy in Kidney Transplant Recipients Long-term Outcomes of a Randomized Clinical Trial. JAMA Surgery.doi.org/10.1001/jamasurg.2020.6929.
Thank you Ofonime
But you need also aggressive induction such as ATG or alemtuzumab
Jamila Elamouri
3 years ago
A 32-year-old female patient received a kidney transplant from her brother 2 months ago, 100 mismatches, and excellent kidney function. She is on dual immunosuppression (tacrolimus and 15 mg of prednisolone). She is suffering from intractable acne not responding to topical treatment.
The patient has a good match living donor, and her renal function is good. Has intractable acne,
1. Patient reassurance, dermatologist consultation, and psychiatrist may also.
2. Steroid dose can be tapered and even withdrawal over the 6 months of transplantation after the introduction of cellcept.
s. creatinine and tacrolimus levels should be checked days after each change and before the next change is made.
If the kidney failed, the next transplantation will be risky more as she is sensitized, FCXM, DSA screen, CDC-XM, the induction will be with ATG, and if DSA positive desensitization protocol is needed.
Thanks, Jamila
Looks you understand the principle.
Steroid tapering till it is steroid-free, introduction on MMF. The next transplant should be steroid-free with aggressive induction.
Please write references
Ahmed mehlis
3 years ago
Acne is a common skin disease in transplant recipients. It is directly related to pharmacological properties of immunosuppressive drugs
١. Topicall treatment
topical retinoids and benzoyl peroxide—can be used in transplant recipients. Xerosis is a frequent side effect of immunosuppressive drugs and may be exacerbated by topical treatments of acne. Topical retinoids are indicated in mild or moderate cyclosporine-induced acne, with predominant comedonal aspects, and are generally considered as efficient in steroid acne and sirolimus acne.
2:there is debate about effectiveness of antibiotics but some prefers to add doxacycline .
3.Isotretinoin ..
Use with caution with monitor liver and renal function .
4 .tapering steroids. To 5mg /day .
●Suppose this kidney failed, what is your immunosuppression plan for the next transplant?
This patient is sensetized and we should go for DSA detection . and cross matching
Induction by ATG and maintenance by triple therapy
Tacromilus mmf steroids
Would you like steroid sparing regimen for the retransplant rather than triple IS
Shereen Yousef
3 years ago
Cutaneous complications of systemic steroids include steroid acne, skin fragility, purpura, striae, altered wound healing, and exogenous Cushing syndrome .
Skin changes were observed in nearly half of the patients treated with prednisone doses of >20 mg/day for 3 months .
Steroid acne is characterized by abrupt onset of monomorphic erythematous papules and pustules on the upper trunk. Compared with acne vulgaris, steroid acne rarely presents with comedones, cysts, nodules, and scarring. Treatment includes topical retinoids such as adapalene 0.1% or tazarotene 0.1%. Additionally, benzoyl peroxide 2.5% with topical antibiotics including erythromycin 2% or clindamycin 1% or oral doxycycline 100 mg daily may resolve lesions. When these methods are not efficacious, then the steroid dose may need to be reduced and i would recommendto start lowering the dose gradually to 5 mg together with topical ttt as long as she has excellent kidney function with introductionof MMF to avoidt the risk of rejection in the first year.
If the graft failed first we have to look for the cause and for her second transplantation CDC-XM ; FCXM ,detection of DSA as she will be sensitized by the previous transplantation
Induction with ATG
With triple Is steroid, tacrolimus ,MMF with early teparing of steroid
M. Ilyas,O. R. Colegio,B. Kaplan,A. Sharma.Cutaneous Toxicities From Transplantation-Related Medications
First published: 27 April 2017
Well done I will quote this from your answer “Compared with acne vulgaris, steroid acne rarely presents with comedones, cysts, nodules, and scarring”
Abdulrahman Ishag
3 years ago
Steroid acne can appear on the face , chest ,or back and is commonly associated with two forms; acne vulgaris and malassezia folliculitis . Acne vulgaris is the main type of acne and the one most often occurs with high dose prednisolone therapy .usually occurs within two weeks of starting treatment . it often appears as uniform lesions and prevalent in people with tendece towards acne in the first place . Malassezia folliculitis is caused by a fungus in and around hair follicles . its estimated from 755% to 98% of people have this type of fungus on their skin .while its presence is normal , overgrowth is not . this itchy acne is most common on the the chest and trunk . Steroid acne will begin to recede once prednisone is discontinued . The type of treatment depends on the type of acne ,severity and medication that are taken . In moderate to severe steroid acne ,common prescription treatments include oral antibiotic such as ;doxycycline ,minocycline or tetracycline . for fungal acne is best treated with ;topical antifungal , oral antifungal like itraconazole or shampoos containing ketoconazole
In this patient it is better to reduce the prednisone dose gradually to 5 mg with addition of anti metabolite(according to her immunological risk ) . Others type of treatment could consider ,if there is no clinical improvement.
Reference;
By Amber j.Tresca Updated on January 2021 Medically reviewed by Casey Gallaghher ,MD.
Suppose this kidney failed ,what is your immunosuppression plan for the next transplant?
The second transplant protocol depend on immunological risk ,as she is sensitized patient . if she has DSA with negative FCXM ,she needs desensitization , induction with ATG and maintenance triple TAC protocol. If no DSA with negative FCXM with high HLA mismatch , induction with ATG and maintenance triple TAG protocol .
Steroid withdrawal in kidney re-transplantation
Few studies focused on the outcome of ESW in the setting of kidney re transplantation . The available studies showed an acceptable short and intermediate-term patient and graft outcome provided that the recipient received
Aref A et al. Steroid free immune suppression WJT https://www.wjgnet.com102 April 18, 2021 Volume 11 Issue 4 induction therapy with a T-cell depleting agent[18,19]. Mujtaba MA, Taber TE, Goggins WC, Yaqub MS, Mishler DP, Milgrom ML, Fridell JA,
Lobashevsky A, Powelson JA, Sharfuddin AA. Early steroid withdrawal in repeat kidney
transplantation. Clin J Am Soc Nephrol 2011; 6: 404-411 [PMID: 21051751 DOI: 10.2215/CJN.05110610]
Alloway RR, Hanaway MJ, Trofe J, Boardman R, Rogers CC, Buell JF, Munda R, Alexander JW
Thomas MJ, Roy-Chaudhury P, Cardi M, Woodle ES. A prospective, pilot study of early
corticosteroid cessation in high-immunologic-risk patients: the Cincinnati experience. Transplant Proc 2005; 37: 802-803 [PMID: 15848537 DOI: 10.1016/j.transproceed.2004.12.129]
Thanks, Abdelrahman I admire you for writing in your own words. Regarding desensitization, it should be limited for those who have positive crossmatch. The presence of DSA alone is not an indication of desensitisation.
thank ,professor
yes ; no need to desensitized negative cross matched patient
AMAL Anan
3 years ago
Acne is complication due to steroid occurs in transplanted patient.
Plan :
1- Tapering steroid up to 5 mg once daily. As withdrawal of steroid within first 18 month of transplantation increases rate of graft loss
2- Dermatology consultation.
3- Add MMF .
For second transplantation, patient consider sensitised due to previous transplantation.
Plan here :
1- Desensitisation protocol.
2- HLA typing .
3- FCXM.
4-DSA.
With induction by ATG and maintenance by triple therapy steroid free.
References:
Haller M, Gutjahr G, Kramar R, Harnoncourt F, Oberbauer R. Cost-effectiveness analysis of renal replacement therapy in Austria. Nephrol Dial Transplant. 2011;26(9):2988–2995. doi: 10.1093/ndt/gfq780. [PubMed]
2. Woodroffe R, Yao GL, Meads C, Bayliss S, Ready A, Raftery J, et al. Clinical and cost-effectiveness of newer immunosuppressive regimens in renal transplantation: a systematic review and modelling study. Health Technol Assess. 2005;9(21):1–179. doi: 10.3310/hta9210.
Amal, your answer needs tweeking. For second transplant, would you institute Desensitisation protocol at first or would send DSA/ crossmatching instead. I am not sure what do you mean by triple therapy steroid free. Please explain.
Acne in transplant patients is mostly due to one of three medications (steroid, cyclosporin, and sirolimus). the one related to steroids responds to lowering the dose
In our patient, high dose steroid may be tapered to 5 mg and the regimen can be strengthened by the addition of MMF for example. detailed information is available in the reference below (Acne in Transplantation Patients)
In case of graft failure of the ongoing transplant, this patient should be considered as high-risk patient and should be depleted with multiple doses of rATG plus 3 drug regimen mainly (steroid tapered quickly because of acne but with keeping MMF at high dose 2×2, plus tacrolimus with close monitoring trying to keep C0 level at the high normal for the period of management, namely 10-15 in fist couple of months then 7-10 for one year, etc.
Tailor the answer in your own words according to the question. What do you think in this scenario is the cause of acne. Also comment on graft failure is not warranted, when the scenario mentions excellent renal function.
hi dr, these are my own words, in this patient, it is most probably due to steroids as I indirectly mentioned. (3 drugs mostly are: steroid used here, cyclosporin and sirolimus) .. in case of the patient has been on tacrolimus steroid and sirolimus or steroid plus cyclosporin and any other drugs we may need a clinical physical exam and help of dermatology experience as this could be more right because of little differences highlighted in the book chapter referenced above.. I liked the article as we need there’s information even in normal practice as we most commonly use CsA and steroids for nephritic/nephrotic syndromes
Asmaa Khudhur
3 years ago
First we should start to decrease the dose of steroid and seek for dermatologist advice to treat the achne.
Other option is to proceed to steroid free rigmen by adding MMF and stop steroid
If the graft failed for 2nd transplantation the patient will regarded as highly sensitized one so seeking for DSA by doing very well CDC,FXM,Luminex and cPRA
Doing desensitization if need ,
Use ATG for induction and triple IS for maintenance
Good short reply but work up for next transplant needs to be explained in a better and systematic manner. Would you not get risk of acne with steroids in event of triple IS?
Regarding to me I will try to protect the graft from rejection as it the 2nd one and neglect achne , but if this achne make a deal to the patient I will exclude steroid from the regimen and consider dual therapy with good doses.
re-assuring the patient that this is related to steroid side effects and the dose will be gradually decreased. psychological support may be needed by an expert psychologist.
dermatologist openion regarding possible other treatment or procedures as camfoulage or others.
as long as the kidney has an excellent function, steroids can be tapered and tried for complete withdrawal.
Suppose this kidney failed, what is your immunosuppression plan for the next transplant?
he will be sensitised from the 1st transplant, so adequate DSA screaning should be sought.
if cross match is highly +ve, desensitization protocols should be applied.
ATG, rather than Basiliximab, should be used in induction.
early steroid withdrawal or even avoidance protocols should be considered.
Nice point to point reply. If you taper steroids, would you keep the patient on mono therapy IS? Do you any published evidence of mono therapy efficacy?
regarding monotherapy, I didn’t have any experience with it but I think steroid sparing agent as AZA can be added to Tacrolimus. Belatacept can be tried as monotherapy.
Sure Aza/Tacro will be dual therapy. Belatecept has been studied and can be an alternative but the BENEFIT trial data showed that belatacept was associated with higher rates of early low-grade steroid responsive acute rejection
Fatima AlTaher
3 years ago
This patient is of low immunological risk as has 100 mismatch with good kidney function during second month posttranplantation. This steroid dose (15 mg ) is high dose so1-start by decreasing steroid dose to 5 gradually .
2- Add MMF 1 gm /day to minimize risk of rejection
3- Dermatological treatment ;
Topical treatment :
a- tretinoin
b- Adalpene
c- Tazarotene
Oral antibiotic treatment : tretracyclin as doxycycline for 3-6 m
For second transplant :
The pt is a high risk and possibly sensitized due to previous transplantation , thus her sensitization status must be assess carefully based on (HLA mismatch , FCXM, c PRA , presence of DSA)
For negative FCXM and presence of DSA:
– Desensitization protocol
– Induction with ATG followed by triple IS (Streoid , MMF and TAc ).
Would you be worried about acne if you retransplant and use triple IS (Steroid , MMF and Tac ). What precautions would you take?
Doaa Elwasly
3 years ago
-This intractable acne is Steroid induced currently she is on 15 mg prednisolone
so oral doxycycline 100 mg daily can be tried(1)
If not effective , then the steroid dose need to be reduced gradualy since her kidney function is excellent on the other side she is in the first 2 months period posttransplanation
Some studies demonstrated an increased rate of acute rejections after steroid withdrawal compared with steroid maintenance, while more recent meta-analyses trails using newer immunosuppressants found no difference in graft loss
Steroid withdrawal 3–6 months following kidney transplantation was suggested.
Haller MC et al mentioned that the optimal time point for steroid withdrawal in kidney transplant recipients is beyond the first 18 months after transplantation.
Meanwhile there is no consensus on the optimal timing for steroid withdrawal after kidney transplantation. (2)
Another study published that in patients with a low immunological risk, with an immunosuppression regimen based on Tacrolimus and MMF, Early steroid withdrawal does not change graft survival, renal function or the rate of Acute Rejection .(3)
So MMF can be given while steroid withdrawn gradualy
-In the second trasnplanation reassessment need to be done if the donor is cadaveric or live as well as the sensitisation of the patient, cross matching ,HLA typing ,DSA ,PRA and CPRA
induction agent can be anti-thymocyte globulin
maintenance agents tacrolimus and MMF
with close monitoring of graft survival
Reference
1-Ilyas M etal. Cutaneous Toxicities From Transplantation-Related Medications,American journal of transplanation2017; 17,11, 2782-2789
2-Haller MC etal .Steroid withdrawal after renal transplantation: a retrospective cohort study.BMC Medicine 2017 ;15 ( 8 ) 3- Andrade-Sierra J .Early steroid withdrawal in a renal transplant cohort treated with tacrolimus, mycophenolate mofetil and basiliximab. Nefrologia 2014,34,2;0-272
May be stopped due to side effects as GIT problems are some time not tolerated with MMF even in low doses or even enteric coated preparations. or bone marrow suppression with AZA. Usually sntimetsbolites are hold if there is any active infection with worsening renal functions.Also MMF may be stopped and shifted to AZA in planned pregnancy after the first year and it is that time it is replaced by AZA being safe during pregnancy
The low immunological risk ( live related donor, low mismatch, no DSA).
Ahmed Fouad Omar
3 years ago
Corticosteroids have been the main stay immunosuppression for kidney transplant recipients for decades. However the rationale for minimizing, avoiding or withdrawal of steroids (steroid free protocols)is compelling due to the well-established risks and complications.
Acne is one of the cosmetic complications of corticosteroid therapy and in our patient it is intractable to topical treatment. However, tapering prednisolone to 5 mg more rapidly and dermatology review for oral preparations are required before deciding to withdraw steroids (patient has a good cross match and excellent graft function).
Moreover, it is not mentioned in the scenario why patient is on this dose of steroids and why not taking an antimetabolite (MMF) as standard practice for maintenance immunosuppression.
An acceptable solution in our case if not tolerating low dose steroids is to withdraw it, introduce MMF in full dose(dual immunosuppression Tacrolimus and MMF).
If this graft fails, we should verify the cause of that in view of current good cross match status and whether there is recurrence of the recipient original kidney disease.
The next transplant risk needs to be checked based on the patient sensitization status from current transplant and the result of the cross match and the type of graft whether live or cadaveric.
In high risk transplant protocols ATG is used as induction but in standard risk anti IL2 mABAlemtuzumab (anti CD 52 is preferable) together with dual immunosuppression (Tacrolimus and MMF)
References:
Brent W Miller and Daniel C Brennan. Kidney transplantation in adults: Withdrawal or avoidance of glucocorticoids after kidney transplantation Uptodate 2021.
Kidney transplantation in adults: withdrawal or avoidance of glucocorticoids after kidney transplantation. Uptodate 2021.
maybe because of low risk or may have been stopped due to side effects like diarhhrea etc. but I could force low dose MMF plus lowering steroid to 5 towards the third month keeping tacrolimus effective . first 3 months are important. I don’t know why they kept 15 (3rd drug with lowering steroid is a good option)
Primarily due to drug-related SEs Even in low Imm risk, you’ll need Antimetabolite (MMF or AZA) to allow for CNI minimization and steroid cessation f. The Imm risk allows
Dalia Ali
3 years ago
taper glucocorticoids to approximately 0.05 to 0.1 mg/kg per day of prednisone by one year or sooner.
In the absence of acute rejection, we generally reduce glucocorticoids to a dose of 5 mg per day by one month following kidney transplantation.with Maintenance therapy consisted of tacrolimus, mycophenolate mofetil
Such doses are associated with decreased rejection and avoidance of chronic kidney allograft nephropathy compared with early glucocorticoid withdrawal/avoidance.
In case of 2nd transplantation the decision for immune suppressive drugs depends on the state of HLA typing,crosshatching between donor and recipients and .titer of DSA
Reference
1. Woodle ES, First MR, Pirsch J, et al. A prospective, randomized, double-blind, placebo-controlled multicenter trial comparing early (7 day) corticosteroid cessation versus long-term, low-dose corticosteroid therapy. Ann Surg 2008; 248:564.
What do you think is causing the acne? CNI or Steroid. The answer to the cause is vague and needs to be answered in a directed way. For the retransplant, if the patient is sensitised , how would you approach induction and maintenance IS?
here mostly steroid as its dose is still high and not maintenance dose. FKA (tacrolimus has more prominent acne side effect). A physical examination will give a clue of course
Acne is complications of corticosteroid therapy in renal transplantation
In 2nd transplant
If screening for DSAs is negative and crossmatch is negative so no need for desensitization
induction therapy will be done by ATG
Maintenance therapy consisted of tacrolimus, mycophenolate and reduce glucocorticoids to a dose of 5 mg per day by one month following kidney transplantation
fakhriya Alalawi
3 years ago
This lady has an excellent allograft function, and her transplant is just 2 months old and she is on dual therapy. For her severe acne, I will try to tapper steroids dosage fast to a minimum while monitoring graft function to avoid rejection. However, if I think to minimize steroids till stop completely within the next coming months, then I should add another agent such as MMf with tacrolimus.
In case this kidney failed, probably I will try a steroid-free regimen for a second transplant.
This question testing our knowledge about early steroid withdrawal to reduce the complications of steroid induced cosmetic changes
Since the results of ELITE- SYMPHONY, many centres in US have experimented with steroid free maintainance IS protocols.
Freedom trial – landmark trial showed that in a standard risk renal transplantation population receiving CsA-ME,EC-MPS and basiliximab, withdrawal of steroids by the end if the first week post transplantation may offer a favourable risk -benefit balance, with comparable 1 year renal function to a standard steroid regimes. However longer follow up is required.
Aref et al 2021, showed that induction with lymphocyte depleting agents induction agents is recommended whenever steroid free maintainance protocol is planned. Steroid free regimes has been evaluated in multiple studies and showed it is important in reducing drug-induced complications while keeping patient and graft survival comparable to steroids based protocols.steroid free regimes can be evaluated for those who are elderly, African Americans and borderline diabetics while the approaches should be individualised based on risk vs benefit.
Having know about the protocols:early steroid withdrawal, late steroid withdrawal and steroid avoidance, to reduce steroids induced cosmetic changes, metabolic disturbances, skeletal complications, growth affection in paediatrics patients and increased risk of cardiovascular morbidity and mortality, without compromising patient and graft survival provide and excellent solution for the aforementioned patient.
The patient developed cosmetic changes and not responding to topical treatment.it’s obvious that the culprit drug is the steroid. Having said that the patient had low immunological risk with only 100 ismatc, the steroid should be withdrawn early. Most of trial suggest to maximize the usage of MMF and tacrolimus at therapeutic range while reduce the steroid early. So I would recommend to start MMF on top of tacrolimus and reduce the steroid over few days to weeks.
Suppose this kidney failed, what is your immunosuppression plan for the next transplant?
The IS protocol for retransplantation depends on future type of transplant – cadaveric vs living , HLA and blood group compatibility, PRA, and DSA. If there is high immunological risk rATG or alemtuzumab should be the induction agent.
Recently published by Guthoff et al 2020 showed that low dose alentuzumab dose of 20mg intraoperatively with initial suspension of MPA umntil total lymphocyte count >5% was reached and triple maintenance IS provides and great patient and allograft outcome in sensitised renal allograft recipients.
Is basiliximab a good choice?
I would choose this drug is its low immunological risk. The evidence is by HARMONY study.
HARMONY study showed similar outcome between induction between basiliximab and rATG and it can be considered with low immunological risk.
References
Vincenti, F., Schena, F., Paraskevas, S., Hauser, I., Walker, R. and Grinyo, J., 2021. A Randomized, Multicenter Study of Steroid Avoidance, Early Steroid Withdrawal or Standard Steroid Therapy in Kidney Transplant Recipients.
Aref, A., Sharma, A. and Halawa, A., 2021. Does steroid-free immunosuppression improve the outcome in kidney transplant recipients compared to conventional protocols?. World Journal of Transplantation, 11(4), pp.99-113.
Guthoff, M., Berger, K., Althaus, K., Mühlbacher, T., Bakchoul, T., Steurer, W., Nadalin, S., Königsrainer, A. and Heyne, N., 2020. Low-dose alemtuzumab induction in a tailored immunosuppression protocol for sensitized kidney transplant recipients. BMC Nephrology, 21(1).
Thomusch, O., Wiesener, M., Opgenoorth, M., Pascher, A., Woitas, R., Witzke, O., Jaenigen, B., Rentsch, M., Wolters, H., Rath, T., Cingöz, T., Benck, U., Banas, B. and Hugo, C., 2016. Rabbit-ATG or basiliximab induction for rapid steroid withdrawal after renal transplantation (Harmony): an open-label, multicentre, randomised controlled trial. The Lancet, 388(10063), pp.3006-3016.
Thank you Theepa Good to mention the ELITE-SYMPHONY Study The response needs to be summarized more to be up to the point Good Luck
Reem Younis
3 years ago
-This lady has a renal transplant 2 months ago and is still on a high dose of steroid 15mg/day.acne can be a side-effect of steroids, so we need to taper the dose of steroid until reach 5mg/day and add MMF in stander dose.
-Doxycycline tablet can be prescribed for her acne and dermatological consultation may be needed.
-If this kidney failed, the patient became a sensitized and high-risk patient.
-After screening for DSAs and desensitization of the patient if her crossmatch is positive then induction therapy will be done by ATG which provides 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
but her steroid must be taper early until she reaches minim dose with close follow-up for steroid side-effects.
good reply. I would recommend steroid sparing or minimisation for retransplant
Ranjanee Muthu
3 years ago
Acne common in 20-25 % of renal transplant recipients and most probably due to steroid (15 mg at 2 nd month ) in this case. Tacrolimus has lesser propensity than Cyclosporine to cause acne ( increases sebum production and high drug lipid solubility leads to cutaneous depositin leading to dysplastic cutaneous proliferation)——responds to topical treatment . In current scenatrio, intractable acne may respond to oral doxycycline or erythromycin or oral isotretinoin 40 mg per day x 2 months then 20 mg per day x 6 months to avoid recurrence ).
Also prednisolone needs dose reduction to 5 mg over 4 weeks to reach 5 mg per day at 3 month with addition of MMF 1 gm per day , inspite of excellent graft fn with only one mismatch at A locus as early post transplant period to avoid acute cellularrejection . Suppose this kidney failed, what is your immunosuppression plan for the next transplant?
If this kidney fails ,this patient would be sensitised and in view of high risk second live renal transplant , would be a candidate for induction therapy with rATG or monthly alemtuzumab with early steroid withdrawl ( 1 week ) or low dose steroid by 3 rd month aong with Tacrolimus and MMF as maintenance regimen . i would not recommend late steroid withdrawl or no steroid regimen here. Pre transplant immunological work up warrants DSA , flow cross match in addition to conventional CDC cross match.
.
Do you think that oral doxycycline or erythromycin or oral isotretinoin are safe options? What do you need to consider prior to prescribing such medications?
isotretinoin is planned half the dose in renal transplants and once a week for liver transplant followed by increasing dose with close monitoring. hyperlipidemia and hepatotoxicity are the main concerns
Before prescribing any medication for a patient using CNIs, you should consider Metabolism and Drug Interactions. This is the message
Vijayarajakumari D
3 years ago
I agree with above discussion of steroid reduction from 15mg to 5 mg over a period of three weeks monitoring the kidney function test’s
At the same time will introduce mmf 360 mgtwo tabs twice a day
Also advise local retinoids
And oral doxycyclin for A longer period
If she needs a second transplant .. based on her evaluation pre transplant will use inductiontherapyand triple immunosuppression with early steroidwitdrawal if uecs are stable
It is not a matter of agreeing or not, you should have your opinion with evidence. Why 360 mg MMF? Is it the only available option at your unit?
Last edited 3 years ago by Ala Ali
Akram Abdullah
3 years ago
This patient is considered low risk, stable graft function post operative , her management of intractable acne as the following :
1-Tapering the dose of the steroid ,mycophenolate is added .if still , withdrawal of steroid is an opinion with careful monitoring of renal function test.
2-Dermatology consult.
if the renal allograft failed , the second transplant immnomosupressive protocol depends on her immunological risk(as she is sensitized patient , HLA typing ,FCXM &DSA)
If patient has DSA with negative FCXM , she might need desensitization( according to SAB & MFI) , induction with ATG , & maintenance triple TAC protocol .
If negative FCXM &no DSA , with high HLA mismatch , induction with ATG , & maintenance triple TAC protocol .
reduction of steroids to 5 mg is the first option for the patient as it is one of the side effects of steroids. if no response shifts to MMFand TACROLIMUS(steroid-free) as she is considered as a low immunological risk.
If she underwent 2nd transplant for induction ATG unless she had a contraindication to ATG.maitenance on (tacrolimus, MMF and steroid with rapid withdrawal to 5mg prednisolone on the 6th-week post-transplantation).
good. What does evidence suggests about use of Campath?
Ben Lomatayo
3 years ago
This is difficult scenario to deal with because she is still less than 6 month post-transplant and on dual rather than triple immunosuppression. Now with steroid-induced intractable ache, the matter is getting worse because any attempt to reduce steroids at this early post-transplant in patient already on dual immunosuppression will be at the expense of increase risk of rejection. I will counsel carefully her about this and tell her frankly ache will not kill her at the moment(temporary) and she should wait for sometime then we come down to maintenance steroid of 5 mg and the acne is likely to get better. I will also get some opinion from dermatologist. I will introduce MMF and she goes on triple therapy for sometime , then gradually reduced steroids so that by 6 month she will be on 5 mg.
Next transplant ; Issues here are mainly immunological and therefore we need to consider
Counselling about second transplant being high immunological risk patient
Sensitised patient due to previous transplant
De-sensitization protocol may be needed depending on her crossmatch result
Augmented immunosuppression e.g. rATG
Serial protocol biopsies to detect any SCR or CAN
Aggressive monitoring as there is increase risk of infections, cardiovascular diseases & malignancies
Patient counseling is an integral part of our job to have a shared decision. The scenario mentioned Intractable Acne that affects the patient’s QOL. Would you wait and keep her to suffer. An active management needed.
My opinion is ;Interactable ache Versus Increased risk of rejection, yes ache can affect quality of life but is not life threating condition, and it is drug -induce . steroid can be reduced but at least patient should have MPA on board before doing that. I want to believe that steroid reduction is gradually process and it is likely to weeks to months and I do not expect resolution of ache immediately. In any case I will put this on table ; dual therapy high rejection rate, early steroid reduction in the same setting not favourable, interactable ache not life threating and take some times to go away, then she make her own decision.
Nazik Mahmoud
3 years ago
Cosmetics side effects is one of immunosuppressive medication so we can reduce the steroids dose although it is challenging in the 100 mismatch kidney,also we can introduce anti metabolites like MMF or MPA.
If this kidney failed ,it will be considered as moderate immunological risk and if he had positive PRA ;ATG will be the choice for induction and Tac,MMF and steroid will be the maintenance therapy
would you still give 15 mg pred for retransplant or do minimisation/steroid sparing
Esmat MD
3 years ago
Acne is one of the cosmetic complications of corticosteroid therapy.
This patient gets a high dose of prednisolone at the end of the second month of kidney transplantation. In this patient, tapering of prednisolone could be done with a faster rate, and after 2 months of kidney transplantation, should be continued at a dose of 5 mg/day.
Another option for this patient is withdrawal of prednisolone and getting tacrolimus in combination with MMF.
For the next transplant, I suggest using rATG for the induction therapy and combination of tacrolimus and MMF with or without a low dose of prednisolone as maintenance therapy.
Important tips about minimizing or withdrawal of glucocorticoids in kidney transplantation:
· To minimize toxicity, tapering and ultimate withdrawal of glucocorticoids has been a goal in transplantation.
· Although glucocorticoids are used in the majority of kidney allograft recipients, some strategies avoid using this agent (in one study in 30% of recipients).
· There are different strategies for minimizing glucocorticoid use, such as a) Lower doses administered earlier after transplantation, b) Complete withdrawal, which can either be performed early after transplantation (approximately three to six months post surgery) or at a later time (after one year) c) Complete avoidance, which most frequently has been utilized with a calcineurin inhibitor-based immunosuppressive regimen and polyclonal antibody induction therapy
· There are controversies between studies regarding outcomes are associated with minimizing glucocorticoid use. Although it is reported in general, the risk of acute rejection is markedly increased with the withdrawal of glucocorticoids weeks to months after transplantation, 2009 KDIGO clinical practice guidelines suggest that glucocorticoids may be discontinued during the first week after transplantation in patients who are at low immunologic risk and who also receive induction therapy. A systematic review reported no significant differences in patient and graft survival in comparing avoidance or withdrawal of glucocorticoids to with glucocorticoid strategies. However, the risk of acute rejection was higher by withdrawal before 14 days.
· Glucocorticoid-free maintenance immunosuppression may be associated with reduced risk of infectious complications and DM.
· Early glucocorticoid withdrawal is particularly harmful in patients with DGF.
· Reducing prednisolone dose to a dose of 5mg/day by one month following transplantation can be appropriate.
· It is reported that withdrawal of prednisolone following 7 days of transplantation was associated with a significant increase in the incidence of chronic allograft nephropathy.
· The success with glucocorticoid withdrawal is relatively dependent on remaining immunosuppressive agents that are used as induction and maintenance therapy as well as rejection risk of recipients. Utilizing antilymphocyte agents for induction therapy in patients with low to standard risk correlates with good outcomes.
· Many glucocorticoid avoidance protocols have chosen low risk recipients and utilized aggressive induction therapy such as rATG, and also maintenance therapy with CNIs (particularly tacrolimus) in combination with MMF.
· Tacrolimus/MMF compared with tacrolimus/sirolimus has been associated with better allograft survival, and Tacrolimus/MMF is also better tolerated compared with sirolimus/MMF.
· Steroid avoidance is associated with increased risks of recurrent glomerulonephritis, thus the etiology of ESKD should be taken into consideration for selecting steroid avoidance protocols.
Haller MC, Royuela A, Nagler EV, et al. Steroid avoidance or withdrawal for kidney transplant recipients. Cochrane Database Syst Rev 2016; :CD005632
Dharnidharka VR, Schnitzler MA, Chen J, et al. Differential risks for adverse outcomes 3 years after kidney transplantation based on initial immunosuppression regimen: a national study. Transpl Int 2016; 29:1226.
Wong G, Lim WH, Craig JC. When Less Becomes More: Life and Losses without the ‘Roids’? J Am Soc Nephrol 2020; 31:6.
Bae S, Garonzik Wang JM, Massie AB, et al. Early Steroid Withdrawal in Deceased-Donor Kidney Transplant Recipients with Delayed Graft Function. J Am Soc Nephrol 2020; 31:175.
Excellent Essmat Yes, reducing steroids and introducing MMF if no response to steroid reduction. I disagree with the liberal use of rATG without a clear indication. You have noticed that the match is excellent (100 mismatch). Also, there is no mention of the presence of DSA.
even on low dose 1.5 mg/kg ??????
(here I do not expect 100 to be easily lost) there should be an important reason. supposing it is something other than incompliance, infection etc. etc ..
I think the cause and timing of failure of the graft is the leading point
Last edited 3 years ago by Mahmud Islam
Mahmoud Rabie
3 years ago
STEROID DEPENADANT ACNE MAY OCCUR IN PATIENTS RECEIVING STEROIDS FOR LONG DURATION. IN THIS PATIENT AS SHE DID NOT RESPOND TO TOPICAL TREATMENT , WE MAY NEED TO REDUCE THE DOSE OF STEROID GRADULLAY UP TO COMPLETE WITHDROWAL AND ADDING MMF AND INCREASING DOSE OF TACOLIMUS. STEROID FREE REGIMEN MAY INCREASE THE RISK OF REJECTION AND REDUCE THE SURVIVAL OF THE GRAFT. IF REJECTION OCCURED , THE PATIENT IS CONSIDERED SENSITIZED AND MAY NEED DESENSITIZATION ACCORDING TO DSA LEVEL , ATG AS INDUCTION AND CNI,MMF, LOW DOSE STEROID POST TRANSPLANT WITH EARLY WITHDROWAL.
Thanks, Mahmoud
Please do not use capital letters in writing. I agree with the first part of your answer but completely disagree with the second part. What is the likelihood of rejection in 100 mismatch without DSA?
saja Mohammed
3 years ago
What’s your management?
She is female kidney Tx from her brother assume this is LD Tx with one mismatch white ? Or black race ?
What’s her induction IS type ?
Excellent graft function two on dual IS with predisolone 15 mg ? I would ask why such combination ?
Still she need to be on triple IS. Including CNI preferred tacrolimus with target trough level after 1 month of 7-10 GN as she is still less than 3 months with full dose MMF and tapper dose of prednisolone after the first month to 5 mg / day
This is the standards of care. Protocol as Maintenance IS in her case and off course any early modification of IS during this period. Need to be individuals case by case as she had complicated acne valgaris will tapper her predisolone. To 5 mg and add MMF along with tacrolimus
Will be referred to dermatologist for specific local and systemic therapy
Steriod withdraw or minimization in less than 3 months post TX. Better to be avoided with the available evidence and depending on the type of induction IS
Using steriod free protocol all depend on the induction IS like induction with ATG many centers used steriod free or rapid tapering based on careful assessment
Some they not recommend steriod withdraws in first 6 months post TX. Due to clear risk of Acute rejection
Some centers recommend steriod withdraws with almetuzmab induction but again with close fu and protocol biopsies {1}.
If she failed her transplant. What’s my plan for IS ?
If she failed her transplantation she is high risk group and need to be assessed for DSA and need of desensitized protocol prior to second transplantation also definitely she need ATG induction followed by triple Maintenance IS based on tacrolimus MMF , predisolone with DSA monitoring
Reference
1- up to date medicine 2021
2-KIDGO guilde line for kidney transplantation
Dear prof Ahmed
for the first part of the question i assume that her first transplant induction IS will be with monoclonal AB basiliximab as she is 1 mismatch ,LD ktx her brother ( maled donor ) and to be followed by maintenance IS with triple IS preferred tacrolimus based with MMF and tapper dose of prednisolone
some centres including ours we still use ATG modified dose in low immunologicl risk based on the resources , we dont have access to basiliximab or alemtuzumb for induction in first transplant so ATG can be used in lower than recommeded dose of 1-1.5mg /kg and not more than 4-4.5mg / kg total accumlative dose avrrage doses for induction 2-3 doses and first dose usually to be given intraoperative , followed by triple maintenace IS with tacrolimus and MMF, tapperdose of predisolone not more than 20mg in the first month then fruther tappering by second month usually patinet on 5mg od
in case induction with almetuzumab (Campath1H) Its Huminazed monoclononal AB against CD52,potent depleting agent for both T-B cells its use for induction IS and for treatmnet of rejection , relative lower cost compaired to ATG , some centres preferred steriod with draws but with close monitoring and protocal biopsies recommended as there is arisk of acute rejection based on available evidnece , i have no experience with almetuzumab , not available in oman , but ihave some patient have their transplany done in US under my FU they are donig well off steriod .
for second kidney transplant she is high immunological risk ( second transplantion ) and type of induction IS will be decided according to repeat crossmatch , the presence DSA or not , Minor MHC antigen ( male donor to femaile recipient ) and desenzitation protocal or not
i would still consider ATG for second induction , i dont know if still monoclonal AB would be an option for second induction based on evdince ATG induction associated with lower incidnce of rejection and found more effective than basiliximab in preventing acute rejection (6-9,15,25,28) also the efficacy of basiliximab vs ATG in high risk was assessed in multicenter randomized prosepctive study of 278 first DD KTX they compare the safety and efficacy between the two gruops as primary outcome all continued on triple IS with cyclosporine based and MMF , prediolone the risk of rejection again lower in ATG gruop , im looking for your expert oponion hope no wrong answer
thanks
reference
up to date , induction immunsuppression in kideny transplantion 2021
Good but to clarify. the acne in transplant patients is different clinically from acne Vulgaris. here acre Vulgaris as far as I remember if used here could be a misnomer or misleading. It is s special form of acne different even according to cause. I am not a dermatologist to keep in mind but I will try to do so as this is really a problem we are facing in clinical practice as a side effect of our immune suppressant even other than transplant patients. I think we may manage better than many dermatologists as many colleagues even do not search for reasons of pruritus in patients with eGFR of 60 urea of 60 for example and just attributing it uremia for example (: though clinical scenario and duration with previous as the latest lab. should be evaluated thoroughly. uremic pruritus is some thing else. pruritis in ESRD is something else. either uremic or due xerosis or phosphorus etc. etc.
sorry for long comment but just to serve the aim of our discussions which are helping ourselves increase our standards..
I have the chance these days of being the only nephrologist in my city so I see nearly every patient even unnecessary cases (namely, who do not realy need a nephrologist) some times just coming for loin pain (: without being evaluated even with a simple urine test
The intractable acne not responding to topical treatment seems to be due to steroid use in the patient.
A dermatology opinion is a must in such patients. But if no respite with topical/ oral medications, then the immunosuppression need to be modified.
The question is why the patient is on dual immunosuppression in current era where it has been shown that patients on triple immunosuppression (CNI, antimetabolites and steroids) have better graft function.
If antimetabolites were not used as a protocol, I would like to introduce MMF at a dose of 500 MG twice a day and taper steroids to 5 mg per day. If the acne persist even at 5 mg per day of steroids, I would withdraw steroids altogether.
But if the patient was initially on antimetabolites and they were stopped due to some side effects (like leukopenia), then reintroduction of low dose antimetabolite (MMF 250 mg twice a day) may be tried and if no side effects, then steroids can be tapered off.
Suppose this kidney failed, what is your immunosuppression plan for the next transplant?
If her transplant kidney fails, it is most probably due to underimmunosuppression and has a high probability of DSA formation.
Prior to second transplant, the basic workup should include flow cytometry cross match and DSA titers.
In presence of DSA, she will require ATG induction.
Post transplant maintenance immunosuppression should be Tacrolimus, MMF and steroids with early steroid withdrawal.
Post transplant monitoring of DSA and protocol biopsy would be needed to pick graft rejection at an early stage.
References:
1) Luan FL, et al. Steroid-free maintenance immunosuppression in kidney transplantation: is it time to consider it as a standard therapy? Kidney Int 2009;76:825-830.
2) Aref A, Sharma A, Halawa A. Does steroid-free immunosuppression improve the outcome in kidney transplant recipients compared to conventional protocols? World J Transplant 2021;11:99-113.
Well done Amit I rather give a full dose of MMF rather than a small dose. ATG induction is reasonable in steroid withdrawal protocol (second transplant), but alemtuzumab would better
I think Alemtuzumab is less used in Turkey because of insurance policies giving the opportunity to other drugs. Alemtuzumab is reserved for T cell lymphoma, KLL etc.
I saw the drug for one time in my life. We used it for my patient in year 2001 . the box was around 1m2 (:, included tens of ice packs to have a small carton containing 10 ml sized (flacon; vial?) . It was named MabCAMPATH. we used it for T cell lymphoma patient
Mohamed Fouad
3 years ago
Acne is a known side effect of systemic steroids and several retrospective reviews have shown that long-term glucocorticoid use, even in low doses, is a significant independent predictor of numerous adverse effects and that the risk is both dose- and duration-dependent.
The mentioned patient has intractable acne not responding to topical treatments , so I think it will be better to do steroid withdrawal with introduction of one of the antimetabolites Azathioprine or MMF to maintain optimum immunosuppression. *Steroid withdrawal
There are several different strategies for steroid minimization or withdrawal:
1-Lower doses administered earlier after transplantation
2-Complete withdrawal, which can be done early after transplantation (approximately three to six months post transplant) or later (after one year)
3-Complete avoidance, which most frequently has been utilized with a calcineurin inhibitor-based immunosuppressive regimen and polyclonal antibody induction therapy *Regarding the second transplant:
Immunosuppression protocol will depends on many factors: HLA sensitization, HLA matching,DSA and cross match.
The Second transplant considered a high immunological risk so ATG induction will be warranted.
Steroids and Acne; Its management in this patient:
Steroids can cause exacerbation of pre existing acne vulgaris or develop acneiform eruptions in the skin. Acneiform eruptions after steroids are sudden onset of follicular papules and pustules shortly after starting either oral or topical steroids. They incidence of steroid induced acneiform eruptions is around 14.6% reported from a study in India1. Skin changes after steroid use has been reported after 3 months of use with more than 20mg per day2. It has been found that steroids have a direct effect on the follicular epithelium causing follicular and peri follicular neutrophilic inflammation which lead to follicular pustules. This is in contrast to acne vulgaris were in abnormal keratinization of the follicular epithelium and comedones are the primary lesions. Corticosteroid may induce abnormal keratinization in the long term after the initial pustular stages and may predispose to comedone formation later. Topical corticosteroids have also been described to induce acne through variable levels of absorption from the skin especially from the face and neck. Topical steroid absorption is higher in skin conditions like atopic dermatitis. Treatment of acneform eruptions include topical retiniods such as adapalene 0.1% or tazarotene 0.1%, benzoyl peroxide 2.5% with topical antibiotics including erythromycin or clindamycin or oral doxycycline. These treatments may resolve the lesions.
In this patient topical treatment did not work. If we look into oral retinoid therapy which remain the gold standard treatment for acne vulgaris, a brief review is needed before considering it for our patient. Oral Isotretinoin in a dose of 40mg/day given for 1 to 4 months is known to induce remission in acne vulgaris. But their treatment in stroid induced acne remain questionable. There are hardly any studies which quote their use in steroid induced acne. With rare reported side effects of nephrotic syndrome, mesangio proliferative glomerulonephritis, proteinuria and hematuria I would not recommend to use in this patient.
The dose of the steroids maybe reduced, but considering the 100 mismatch, we need to balance the immunosuppressive drugs, increase the dose of tacrolimus and introduce an antimetabolite like MMF in standard dose of 500mg twice daily, before reducing steroids. I would gradually taper steroids and stop over period of one month as rapid steroid tapering has been reported to cause acute cellular rejection which can lead to early graft loss.
Immunosuppression for the next transplant:
as the patient is highly sensitized after the 1st kidney transplant, i would evaluate her DSA status by luminex with the available donor or PRA if waitlisted on a cadaver program. I would prefer to do Desensitization if MFI values to class I and II are more than 3000 with Plasmaphresis 2 litre plasma removal for 3 to 4 exchanges, Inj Rituximab 500mg 2 doses 2 weeks before and triple immunosuppression commenced minus 2 weeks before planned transplant and proceed if repeat DSA titre are < 1000. I would use Inj Anti thymocyte globulin as induction agent at the time of transplant. Regarding her steroid dose after transplant, I would consider tapering doses after 1 month of 1mg/kg/day and maintain her on 10mg/day of prednisolone after 1 month with Tacrolimus and MMF in the standard dose
References;
Sharma R, Dogra D, Dogra N. A Study of cutaneous adverse drug reactions at a tertiary center in Jammu, India. Indian Dermatol Online J. 2015;6(3):168-71.
Fardet L, Flahault A, Kettaneh A, et al. Corticosteroid-induced clinical adverse events: Frequency, risk factors and patient’s opinion. Br J Dermatol 2007; 157: 142– 148.
Balaji
Thank you for your excellent contribution as ever
I disagree with desensitization without positive crossmatch. The Desensitisation principle is to make crossmatch negative. We need to consider the crossmatch results (positive or negative) before discussing desensitisation.
Last edited 3 years ago by Professor Ahmed Halawa
Sherif Yusuf
3 years ago
Systemic corticosteroids can either precipitate or exacerbate acne thus they are considered acnegenic so it is recommended to avoid corticosteroids as much as we can in acne prone patients (1)
Corticosteroids is important member of triple maintenance immunosuppressive therapy recommended for most of renal transplant patients.
The ideal regimen for corticosteroid use is not identified (2) but the usual regimen is to give methylprednisolone at a dose of 7 mg/ kg (maximum 500 mg) intraoperatively before reperfusion, then from day-1 oral prednisolone in a dose of 1 mg/kg (maximum 80 mg )is started for 3 days followed by rapid tapering to 20 mg at the end of the first week then taped 5 mg/week till reaching 5 mg which is continued for life.
Because of the side effects of corticosteroids, there are many trial on corticosteroid minimization which include one of the following protocols :
1. Complete withdrawal which can be done either early within 3- 6 months after transplantation or late after 1 year.
2. Complete avoidance from the start
Draw backs of corticosteroid minimization :
1. Corticosteroid withdrawal may increase the risk of acute rejection and lower graft survival especially if withdrawn early within 3-6 months after transplantation with highest risk if withdrawn before first 14 days (3), withdrawal after 1 year is also associated with small but significant risk of acute rejection and lower graft survival (4)
2. Magnify myelosuppressive effects of MMF, azathioprine when compared to continuing on prednisolone 5 mg
3. Rapid corticosteroid withdrawal and corticosteroid avoidance are found to increase the risk of recurrent glomerulonephritis such as FSGS, membranous nephropathy, IgA nephropathy, MPGN, ANCA related GN without improvement in patient or graft survival(5)
4. Increase risk of chronic allograft nephropathy (6)
5. In patients with DGF, early glucocorticoid withdrawal was found to increase the risk of graft loss when compared to maintaining low dose of corticosteroids (7)
Precautions in the use of CS minimization protocol- recommendations:
⦁ Patients that are candidate for corticosteroid avoidance and early glucocorticoid withdrawal < 6 m post transplantation should receive CNI, MMF and a polyclonal antibody induction
⦁ Corticosteroid withdrawal can be started in low risk patients if there are side effects of corticosteroids, stable renal function with no episode of acute rejection in the past 6-12 months
⦁ Glucocorticoid minimization should not be initiated in the following patients :
1. Patients with DGF
2. Patients with graft dysfunction
3. High immunological risk patients
4. Patients with possible recurrence of glomerulonephritis
⦁ Alternate day corticosteroid use is not recommended as it will not significantly reduce the side effects of corticosteroids and may increase the risk of rejection compared to daily corticosteroid use.
So back to our patient
this patient should be on triple therapy including tacrolimus, MMF and low dose corticosteroids, thus I will recommend tapering of corticosteroids to 5 mg and introducing MMF
If kidney flailed this patient will not be considered as low risk (re- transplantation) so corticosteroids minimization will offer a risk for acute rejection and lower graft survival.
So.. the next immunosuppression regimen will include induction with ATG and maintenance immunosuppressive regimen with tacrolimus, MMF and corticosteroid that is rapidly reduced to 5 mg at 1 month and can be withdrawn completely after 6 m if no graft dysfunction
REFERANCES
1- Fung M, Berger T. A prospective study of acute-onset steroid acne associated with administration of intravenous corticosteroids. Dermatology. 2000;200:43-44
2- 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.
3- Haller MC, Royuela A, Nagler EV, et al. Steroid avoidance or withdrawal for kidney transplant recipients. Cochrane Database Syst Rev 2016; :CD005632.
4- Kasiske BL, Chakkera HA, Louis TA, Ma JZ. A meta-analysis of immunosuppression withdrawal trials in renal transplantation. J Am Soc Nephrol 2000; 11:1910.
5- Kukla A, Chen E, Spong R, et al. Recurrent glomerulonephritis under rapid discontinuation of steroids. Transplantation 2011; 91:1386.
6- Woodle ES, First MR, Pirsch J, et al. A prospective, randomized, double-blind, placebo-controlled multicenter trial comparing early (7 day) corticosteroid cessation versus long-term, low-dose corticosteroid therapy. Ann Surg 2008; 248:564.
7- Bae S, Garonzik Wang JM, Massie AB, et al. Early Steroid Withdrawal in Deceased-Donor Kidney Transplant Recipients with Delayed Graft Function. J Am Soc Nephrol 2020; 31:175.
Thanks, Dr Sherif for your excellent response How popular is this steroid induction regime “then from day-1 oral prednisolone in a dose of 1 mg/kg (maximum 80 mg )is started for 3 days followed by rapid tapering to 20 mg at the end of the first week then taped 5 mg/week till reaching 5 mg which is continued for life”?
In the whole UK, we use 20 mg of prednisolone just on day 1. We do the same regarding 500 mg of methylprednisolone before declamping
in Alexandria we were using more prolonged regimen for corticosteroids than that prescribed, i am not sure of the popularity of this regimen but i did not imagine that we can use just methylprednisolone intraoperatively and then 20 mg on day 1
This mean that the usual protocol used in UK is using corticosteroid minimization
but after 20 mg used in day 1 do you recommend to continue on 5 mg or on dual iimmunosupressive therapy ?
Differing from centre to centre , I Turkey prednisiolone is lowered to 20 mg towards the second week. makismum 10 mg before the third month. Here periopeatively 500-1000, postoperatively 120-150 mg then halfing the doses I think as you do aim is 20 towards the end of second week
Assafi Mohammed
3 years ago
Management of intractable Acne post-transplant:
In this case her acne is mostly related to Steroids. In managing this patient I will consider reducing her dose of Prednisolone.
Supposing graft failure and second transplant being considered ; this patient becoming highly sensitized because of her previous transplant. I will consider densitization beside induction using monoclonal antibody. For maintenance immunosuppression I will consider tacrolimus, MMF and low dose Prednisolone.
Systemic steroids
Systemic corticosteroids are used in many immunosuppressive regimens, often prescribed at higher doses early in the post-transplantation period before being tapered to low doses or discontinued.
Steroids:
can reduce the collagen synthesis.
decrease fibroblast proliferation.
down-regulate elastin synthesis, the cumulative effect is manifested by easy tearing and bruising of the skin.
by inhibiting fibroblast function and collagen production along with inhibiting angiogenesis and the production of ground substance, systemic steroids may also limit re-epithelialization of wounds
mild atrophy is reversible by reducing or stopping the steroids; once significant atrophy has developed, the changes may be permanent.
Cutaneous complications of systemic steroids include steroid acne, skin fragility, purpura, striae, altered wound healing, and exogenous Cushing syndrome .
Skin changes were observed in nearly half of the patients treated with prednisone doses of >20 mg/day for 3 months. Skin fragility and purpura occur with weeks to months of commencing systemic steroids. {Fardet L, Flahault A, Kettaneh A, et al. Corticosteroid-induced clinical adverse events: Frequency, risk factors and patient’s opinion. Br J Dermatol 2007; 157: 142–148.}
Steroid acne is characterized by abrupt onset of monomorphic erythematous papules and pustules on the upper trunk. Compared with acne vulgaris, steroid acne rarely presents with comedones, cysts, nodules, and scarring.
Treatment of steroid Cutaneous complications :
topical retinoids such as adapalene 0.1% or tazarotene 0.1%.
Additionally, benzoyl peroxide 2.5% with topical antibiotics including erythromycin 2% or clindamycin 1% or oral doxycycline 100 mg daily may resolve lesions.
When these methods are not efficacious, then the steroid dose may need to be reduced.
Striae distensae secondary to systemic steroids appear on the abdomen, thighs, and buttocks.A primarily cosmetic concern, striae are difficult to treat. The use of topical agents and laser treatments may improve the appearance of striae, but no current therapeutic option is effective while having minimal adverse effects .
The development of cushingoid features, defined as redistribution of body fat with truncal obesity, buffalo hump, and moon face is dependent on both steroid dose and duration. These features were found in 25% of patients who had received >7.5 mg of prednisone daily for 1 year compared with only 4% of those taking <5 mg daily {Huscher D, Thiele K, Gromnica-Ihle E, et al. Dose-related patterns of glucocorticoid-induced side effects. Ann Rheum Dis 2009; 68: 1119–1124} Reduction in or elimination of the steroid may resolve the cushingoid features.
Thanks, Safi for your answer
You said” I will consider desensitization beside induction using monoclonal antibody”
You need to know the DSA level and the results of crossmatch (positive or negative before you proceed to desensitization).
MOHAMMED GAFAR medi913911@gmail.com
3 years ago
maintinace immunosuppresion is one of the key sucess for increasing graft survival.
most centres and guidlines recommends triple immunsuppreesion after kidney transplant in form of (CNIS WITH ANTIMEATBOLITES WITH STEROIDS).
in this scenario , the recipent on dual immusoppresion without apprent cause,
and she is on 15 mg of steroids which is unclearly to be understand? How far is the pt from transplantion?
regardless this questions , this side effect may be realted to steroids which can be tappered to lowest minimal dose as recommened by most of the centres and guidlines to 5 mg od as the pt with this mismatch has a low immunological risk.
the qustion here if she didnt improve, what is the next step?
i think we can reffer her to dermatologist for furhter more potential oral tratment.
and if no improvent occurs , we have to counsil her that she may be offerd stroid free rigmen immusouppresion and expalinning to her that the risk of rejection is alittle bit higher in most of the studies compared to the pt on low ldose maintinace steroids and better to put her back to antietabolite if she prefered to the steroid free rigemen streoid like mmf .
steroid-free immunosuppression should be considered as a standard of care only for a carefully selected group of patients.
IF HER KIDNIES FAILED, WHAT IS MY IMMUNOSPPURESSION?
first thing we have to ask many questions ? 1-what is her cPRA? 2-what is her cross match(flow cytometry, luminx)? 3-how many mismatches between her and the donor? 4-is she offered a cadaveric kidney? 5-dose she have a dsa afanist the donor ? 6-is the donor the same blood group? 7-what is the cause of her failed graft(recurrence of primary disease)?
once answerd all these questions , i can decide what is my immunsuppresion plan , desciding wether she is low immunological risk or high immunological risk pt.
reffernce Kidney Int. 2009 October ; 76(8): . doi:10.1038/ki.2009.248
Excellent Mohamed This is a model answer (I will quote it from you and pass it to all colleagues
Yes, IF HER KIDNEY FAILED, WHAT IS MY IMMUNOSPPURESSION? firstly: thing we have to ask many questions? 1-what is her cPRA? 2-what is her cross match(flow cytometry, luminx)? 3-how many mismatches between her and the donor? 4-is she offered a cadaveric kidney? 5-dose she has a DSA afanist the donor ? 6-is the donor the same blood group? 7-what is the cause of her failed graft(recurrence of primary disease)?
It may be a steroid adverse effect.
although 15 mg is a not high dose of steroid, still, I will try to taper the dose gradually.to 10 mg then 5 mg ; other wise, this patient if still has same problem, she would be steroid free.
If the kidney failed, she should be on steroid free immunosupressive protocol consisting of Tacrolimus/MMF.
Mohamad Habli
3 years ago
What is your management?
Steroids are well known cause of acne. Acne steroid is observed as monomorphous papulopustules predominantly located on the trunk and extremities, although can be observed on the face but less frequently. Acne is not life threatening adverse effect ,however is displeasing and annoying to patients.
Several reviews have shown that side effects of steroids is both dose- and duration-dependent. In this patient with intractable acne, we initially can try decreasing the dose of steroids. However we should take in consideration that reducing the dose of steroids may increase the risk of rejection, although the risk in not high with 1 mismatch at A locus, which was shown to be mostly associtaed with rejection after 1 year of transplantation.
Alternatively, to minimize toxicity and side effects, we may shift the patient to steroid free regimen including Tacrolimus and MMF. Steroid free regimens have been attempted widely in the USA. In the United States, in 2004, glucocorticoid avoidance regimens were administered to 23 percent of all first kidney transplant recipients . Approximately 10 % recipients discharged on steroids had glucocorticoids completely withdrawn 1 year after transplantation.
Suppose this kidney failed, what is your immunosuppression plan for the next transplant?
For the next transplantation,the risk of rejection is higher but will be based on DSAs and crossmatch results. In this setting to dreduce or to avoid the side effects of steroids, lower doses administered earlier after transplantation could be attempted.Another option is to completely avoid steroids , with the use of a calcineurin inhibitor-based immunosuppressive regimen and polyclonal antibody induction therapy.
References:
-Uptodate
1. Hricik DE, Almawi WY, Strom TB. Trends in the use of glucocorticoids in renal transplantation. Transplantation 1994; 57:979.
2. Bodziak KA, Hricik DE. Minimizing the side effects of immunosuppression in kidney transplant recipients. Curr Opin Organ Transplant 2003; 8:160.
3. Vincenti F. Immunosuppression minimization: current and future trends in transplant immunosuppression. J Am Soc Nephrol 2003; 14:1940.
4. Meier-Kriesche HU, Li S, Gruessner RW, et al. Immunosuppression: evolution in practice and trends, 1994-2004. Am J Transplant 2006; 6:1111.
Excellent Mohamed, yes risk stratification is based on the DSA and results of crossmatch.
Ban Mezher
3 years ago
Steroids used since the beginning of organ transplantation, but it has several serious side effects including cosmetic, metabolic, skeletal, growth retardation in pediatrics. So to decrease these complication, the steroid early withdrawal or avoidance of it in immunosuppression protocol suggested. Early steroid withdrawal mean stopping the steroids after first few days post-transplantation, while late steroid withdrawal mean stopping it after weeks to months of transplantation.
Random controlled studies showed that steroid free protocol was associated with significant improvement in CV risk but increased risk of AR without significant effect on patient & graft survival in first & 5 years after transplantation. Short & intermediate patient & graft survival with early steroid withdrawal in second transplant found to be acceptable if T cell depleting agents used in induction.
In our patient can change to Tac + MMF with steroid withdrawal without increased risk of graft loss & if her graft lost & she planned to had 2nd transplant she should have ATG for induction with early steroid withdrawal protocol.
References:
Are A., Sharma A. and Halawa A. Does steroids-free immunosuppression improve the out come in kidney transplant recipients compared to conventional protocol?. World J Transplant. 2021, 11(4):99-113.
We need to know the HLA typing of both recipient & donor to determine the degree of mismatch, with DSA & PRA & DDT or LDT to classify the risk, in high risk & sensitized recipient we do desensitization with T cell depleting agent for induction & maintenance with CNI, MMF & steroid.
I would choose this drug is its low immunological risk. The evidence is by HARMONY study.
HARMONY study showed similar outcome between induction between basiliximab and rATG and it can be considered with low immunological risk.
Huda Al-Taee
3 years ago
What is your management?
I may try to reduce the dose of steroid gradually to 5 mg/day if the risk of rejection is low and if there is no risk of recurrent glomerular disease and may consider adding MMF if there is evidence of allograft dysfunction after steroid minimization.
Suppose this kidney failed, what is your immunosuppression plan for the next transplant?
Second transplant is considered as a high immunological risk transplant so the patient will need induction with ATG and maintenance immunosuppression with Tac, MMF and low dose steroid (5mg/day).
Reference: Kidney transplantation in adults: withdrawal or avoidance of glucocorticoids after kidney transplantation. Uptodate 2021. cited at 4-12-2021.
I need to raise an issue here, i had seen one of my pt 6 month post transplant with zero mismatch.donor is his son and his cPRA is negative with uncontrolled htn , and also with brittle diabtes despite maximaizing his insulin and his A1c is trending up and also his lipid profile is sky high regardless maximaizing statins . Is it wise to dc his steroid at this stage ?just to control his cbs and his blood pressure and also minimize the risk of dyslipdemia that he is facing?
Last edited 3 years ago by MOHAMMED GAFAR medi913911@gmail.com
I know the risk should be stratified based on the cross matching and the presence of DSA and the degree of mismatching with the potential donor but what am concerning about is the presence of memory cells as the patient had exposed to a previous sensitizing event( 1st transplant).
Riham Marzouk
3 years ago
management is introduction of MMF , with rapid tapering of steroid and then stop it…will be on tacrolimus-MMF (steroid free protocol) which avoids disfigurement of the body and face and other steroid side effects.
if kidney failed, my immunosuppressive plan will be tacrolimus-MMF(steroid free regimen from the start), after doing desensitization protocol if there is DSA. induction will be ATG.
S A Birkeland. Steroid-free immunosuppression in renal transplantation: a long-term follow-up of 100 consecutive patients.
Transplantation.2001 Apr 27;71(8):1089-90.
I will go for tapering steroid as it is mostly the cause of acne .
In case of failed graft and pt is going for 2nd transplant ,We will do FCXM ,PRA and HLA typing and if positive cross match or DSA we will do desensitization and induction will be ATG ,methylene pred with early withdrawal of steroids
Maintenance will be tac ,MMF and prednisone
Tapering steroid therapy looks reasonable with suitable acne treatment and starting MMF .In case of graft failure, with need for second Tx ,we will do XM (CDC &FC) and DSA assay considering sensitization. Desensitization will be indicated in case of positive XM. Additionally, induction must be aggressive with ATG, and early tapering of steroid in maintenance therapy before development of acne as a side effect.
Reference :
Mujtaba, MA et al Early steroid withdrawal in repeat kidney transplantation, Clin J Am Soc Nephrol:2011,6:404-411
Acne is one of the recognized side effects of steroids. neglecting this problem can affect compliance of immunosuppression drugs. if the topical treatment is not effective we need to gradually reduce the steroid dose ( to 5 mg every other day) and we can replace it with MMF . We may obligate to stop the steroid completely .
Immunosuppression of the second transplantation depend on the cPRA , DSA , and HLA compatibility with the second donor .
· What is your management?
I will give oral doxycycline 100 mg daily. If no improvement, systemic and topical isotretinoin for 6 months . Again if no response steroid dose may need to be reduced but with addition of MMF. Withdrawal of steroid is preferred within 6 month post transplant(to guarantee no episodes of acute rejection, long-term patient and graft survivals compared with withdrawal after 6 months but with the risk of a rise in urine protein excretion during 10 yr of follow-up). The incidence of rejection in steroid-free regimen is 48% compared with a 30%in steroid-treated control. The criteria for steroid withdrawal were that the patient have stable renal function for at least 2 months and that the patient understand the potential risks and benefits of steroid discontinuation
Suppose this kidney failed, what is your immunosuppression plan for the next transplant?
I will give induction ( for fear of withdrawal of steroid) and then tacrolimus, mycophenolate mofetil (MMF). if she develops again side effect of steroid, I may consider steroid withdrawal according to her situation and time after transplant.
– Late Steroid Withdrawal with Tacrolimus-Based Immunosuppression after 3 months is better when the MMF is used but steroid should be withdrawn only if she is free of acute rejection for the first 3 mo and her serum creatinine <1.4 mg/dl
– Early steroid withdrawal on day 3 post operatively is possible with Induction ( either alemtuzumab or basiliximab) ,5 year follow up proved comparable results of decline in GFR between withdrawal and maintence . Ciancio reported a small series of 44 kidney transplant recipients who were treated with alemtuzumab, MMF, and low-dosages of tacrolimus. Prednisone was discontinued after 1 wk. With a median follow-up of 9 mo, patient and graft survival each were 100%, and biopsy-proven acute rejection occurred in four patients.
– Early Steroid Withdrawal or Steroid Avoidance with Tacrolimus-Based Immunosuppression is assessed with 2 short term studies. CARMEN study proved that the rejection incidence is equal in steroid free versus steroid base but ATLAS study proved that acute rejection was significantly higher with steroid free regimen . A recent RCT , not finished yet, compared tacrolimus/MMF/steroids versus tacrolimus/MMF and 7 d of steroids . All patients received induction antibody therapy . After 12 mo of follow-up, the incidence of biopsy-proven acute rejection was 6% in steroid-treated patients and 12% in the steroid withdrawal group (p= 0.04). There were no significant differences in graft or patient survival.
Joshua J. Augustine, Donald E. Hricik,Steroid Sparing in Kidney Transplantation: Changing Paradigms, Improving Outcomes, and Remaining Questions ,CJASN Sep 2006, 1 (5) 1080-1089; DOI: 10.2215/CJN.01800506
Acne is a known side effect of prednisolone. Her Tx is considered low risk due to one-mismatch HLA. So, tapering prednisolone dose to 5 mg and to follow-up her is an option. If the acne is not cured despite of steroid minimization and dermatological treatment, MMF can start and steroid halt.
For second transplant, immunosuppression depends on existence of DSA. If XM is negative with no DSA there is standard risk. If cPRA is high and no donor without DSA could be found, then desensitization and potent immunosuppression and protocol biopsy based on level of MFI would be an option.
Corticosteroids are used in kidney transplant to decrease the risk of acute rejection although corticosteroids have many side effects but it stills the cornerstone of immunosuppression regimens.
Due to their side effects and discovery of new immunosuppressive agents in the transplant protocols many centres adapted to reduce the dose or even discontinue the usage of steroid by different protocols for tapering steroids in transplanted patients either early or late withdrawal of steroid starting after the first 3 to 6 months after transplantation.
Regarding this patient with dermatological side effects of prednisolone we can seek for dermatologist consultation and start to decrease the dose of steroid with close monitoring of renal function and if not responding we can withdraw prednisolone but after adding a new immunosuppressive agent like MMF .
For the second transplant usage of ATG in the induction treatment and she may need to be put on triple immunosuppressants and for desensitization it’s depend on presence of DSA and CDC crossmatch.
Management
1- Dermatological consultation about a trial of systemic medication as isotrtinoin
2- Steroid withdrawal
· After informing the patient with the risk of early minimization of steroid may be associated with as increasing risk of CAN and mild rejection
· Original kidney disease as will as the induction protocol using ATG or basiliximab should be taken in consideration when early steroid withdrawal is considered.
· Also level level of DSA should be checked before steroid withdrawal.
· Introduction of antimetabolite (MMF / Aza ) before withdrawal of steroids with insuring that Tac level in its target level
2nd transplantation
Immunosuppression protocol would be decided according
· According to the result of crossmatch
· DSA presence or absence and their specificity and intensity
· cPRA
· Timing of acute rejection
· The original kidney disease
Steroid free protocol
Steroid free maintenance or lower maintenance dose (0.05-.1/kg) the first year
Desensitization protocols
Not an easy job at all
Costly when compared with tx with matched tx but still cost-effective when compared with being on dialysis and associated with a better life expectancy
References
1. Banerjee A, Julie BM, Sharma A, Halawa A (2018) Steroid withdrawal protocols in RenalTransplantation. Archives of nephrology of clinical nephrology
2. Nelson J. Corticosteroid-Sparing in Adult Renal Transplantation: Gambling with Allografts, or Strong Data?
3. Orandi BG, Luo X, Massie AB et al., “Survival benefit with kidney transplants from HLA-incompatible live donors,” The New England Journal of Medicine, vol. 374, no. 10, pp. 940–950, 2016.
Steroid induced cutaneous manifestations are common and dose dependent
The acne lesions are mostly monomorphous with papules and papulopustules affecting face, upper limbs and trunk
topicl treatment as topical retinoids and benzoyl peroxide can be used with topical antibiotics as erythromycin 2% and clindamycin 1%
adding a steroid sparing drug as MMF or azathioprine with gradual withdrawal of steroids till reach minimal dose with strict monitoring of kidney function
Suppose this kidney failed, what is your immunosuppression plan for the next transplant?
patient is considered sensitized due to previous transplant,
if DSA positive and CDC crossmatch positive, desensitization protocol before transplant
if DSA is negative with negative CDC crossmatch, retransplant with induction therapy rATG as considered at high immunological risk and maintenance therapy with tacrolimus, mycophenolic acid and minimal dose steroids.
Mahé, E., 2014. Acne in Transplantation Patients. In Pathogenesis and Treatment of Acne and Rosacea (pp. 591-602). Springer, Berlin, Heidelberg.
Salvadori, M. and Bertoni, E., 2012. Renal transplant allocation criteria, desensitization strategies and immunosuppressive therapy in retransplant renal patients. Journal of nephrology, 25(6), p.890.
Pratschke, J., Dragun, D., Hauser, I.A., Horn, S., Mueller, T.F., Schemmer, P. and Thaiss, F., 2016. Immunological risk assessment: The key to individualized immunosuppression after kidney transplantation. Transplantation Reviews, 30(2), pp.77-84.
The patient is resistant to all topical treatment of acne , I would taper her steroid dose and use steroid sparing agent, either azathioprine or MMF .
If her graft fails , next transplantation I would suggest a steroid free regimen, with induction therapy ( thymoglobulin) with tacrolimus +MMF as maintainence ttt
Although steroid free rejimens are at increased risk of acute rejection , yet these regimens markedly reduces steroid induced complications
Veenstra DL, Best JH, Hornberger J, Sullivan SD, Hricik DE: The incidence and long-term cost of steroid-related side effects after renal transplantation. Am J Kidney Dis33 :829– 839,1999
Steroid acne is characterized by the abrupt onset of monomorphous pink papules on the face and trunk. Even at low doses, prednisone can cause skin problems. These include skin thinning, acne, hirsutism , hair thinning, face redness, stripe-like marks on the skin (stria) , impaired wound healing and perioral dermatitis There are a few reports of the successful use of the systemic retinoid isotretinoin in young adults who have undergone organ transplantation. But there are many side effect including pancreatitis and hyperlipidemia, and early experimental evidence that vitamin A derivatives may increase the likelihood of allograft rejection . Topical retinoids such as tretinoin cream or gel may be beneficial .
If the graft fail , she need induction with ATG early steroid withdrawal in 1st week and maintenance with Tacrolimus and MMF .
What is your management?
Acne is one of the common complication of steroids specially with doses more than 20mg
Plus topical treatment decreasing steroids to 5mg at least first 6m to 1year post transplant
Adding AZA OR MMF may support repaid decreasing of steroids
My center experience is never to stop steroids but we decrease it to the lowest possible dose.
Also young females with low immunological risk we give non depleting basilixmab induction to be able to afford rapid steroids reduction.
Suppose this kidney failed, what is your immunosuppression plan for the next transplant
According to matching, CDC DTT cross match, flow cytometry crossmatch,single antigen bead but generally she will need depleting induction ATG or alemutzumab to be able to afford rapid steroids reduction plus plasma exchange just if CDC DTT cross match was positive or DSA with RIS more than 17.
Dear All
Is the presence of DSA is an indication of desensitisation?
Is it easy to desensitise?
We have to ask first?
1- is flow cytometry cross match positive or negative? And if positive is it t cell or b cell or both?
2-what is the level of dsa ,some centres have variable levels of mfi they can go ahead witout desentization 2000 or 5000 mfi
3-what is class of dsa present is it class 1 or class 2?
4-is this for living transplantion or deceased one?
5- is paired exchange programm is avilable some where near the pt?
All these questins can answer wether can i go ahead for desentization or not
In the rising era of paired ecxhange programm ,most centres recommend any pt with bad mismatch or having dsa for paired exchange for better outcome.
Actually not all dsa is gioing to be senstized.as an example for dsa levels below 5000 mfi or HLA C,DP,DQ
Desentization protocols are very expensive and hectic for both centres and patients as we are using guns like rituximab plasampharesis and iv igg to clear theses dsa ,and this puts the pt at very high risk of infections and risks of bleeding .
So desentization protocls should be only done for carefully selected pt who only have this donor with this dsa aiming for negative flow cytometry cross match with accepted level of dsa .
and dsa should be monitored carfully and some centres may offer protcol biobises for this kind of patients
Desensitization will be required if crossmatch is positive. DSA alone with a negative crossmatch does not require desensitization.
It is not easy to remove antibodies by desensitization. I do not have much experience in desensitization, but i have not seen may successful desensitizations.
the presence of DSA alone is not enough to decide about the desensitazation , many other factors to be be considered like Living donor KT in crossmatch (XM)-positive/DSA+ve ,or ABOI kidney transplantaion , history of sensitazation like female genderwith preganacy , transfusion history previous transplantion all are consider high-risk and requires an optimal desensitization protocol .
Desenitization protocal not easy , expensive , not standardazied worldwide and not free from side effects, and the transplant outcome with desensitazation still Questionable inmany studies (1,2).
1-Outcome of Desensitization Therapy in Immunologically High-Risk Kidney Transplantation: Single-Center ExperienceAyse Sinangil 1, Zuhal Atan Ucar 1, Yener Koc 2, Soykan Barlas 3, Sana Abouzahir 4, Suleyman Tevfik Ecder 1, Emin Baris Akin 3
2-Outcome of the risk-stratified desensitization
protocol in donor-specific antibody-positive living
kidney transplant recipients: a retrospective study
Daigo Okada
Masayoshi Okumi1, Yoichi Kakuta Kohei Unagami2, Junpei Iizuka,Toshio Takagi Hideki Ishida1& Kazunari Tanabe
Transplant International 2018; 31: 1008–1017.
Excellent. Thank you, Dr. Saja
Desensitization is an area of no consensus n the transplantation world.
The main task at first is Risk Stratification.
Desensitization is only done if positive crossmatch
It’s not easy to desensitize patient
My own center experience we do 5 sessions of plasma exchange 1.5 plasma volume on every other day base then give 0.5gm/kg IVIG with the last session plus one or two doses of rutiximab
Positive crossmatch with the presence of DSA is an indication for desensitization
Desensitization is not an easy process, it is coasty and associated with many complications related to plasmapheresis such as:
Desensitization protocol depends on multiple factors like DSA , CDC crossmatch also whether living or deceased donor .
DSA level and if it is associated with CDC B and /or T cells and their level all contribute in the desensitization decision for example DSA positive with MFI less than 5000 and Tcell negative and B cell positive crossmatch with deceased donor no need desensitization just induction by ATG and IVIG.
Once crossmatch test is positive , desensitisation is indicted. This is a tedious process and involved a lot of experience cost, labour and time to get negative crossmatch. so is not easy and that is why some centre are not considering this specially in low resource setting.
A known and common side effect of the use of steroids is acne. Corticosteroids are used in maintaining immununsoppression following renal transplant. A study by woodle et al has shown that 15 years post transplant there was no signficant difference in patient survival rates and graft surivial rates in those who wer on long term steroid use and in those who stopped stroid use early. I would reduce the dose of prednisolone in a steep wise manner in this 32 year old female with a 100 mismatch in HLA typing and intractable acne not responding to topical management.
References
Woodle, E.S., et al. (2021) Early Corticosteroid Cessation vs Long-term Corticosteroid Therapy in Kidney Transplant Recipients Long-term Outcomes of a Randomized Clinical Trial. JAMA Surgery. doi.org/10.1001/jamasurg.2020.6929.
Thank you Ofonime
But you need also aggressive induction such as ATG or alemtuzumab
A 32-year-old female patient received a kidney transplant from her brother 2 months ago, 100 mismatches, and excellent kidney function. She is on dual immunosuppression (tacrolimus and 15 mg of prednisolone). She is suffering from intractable acne not responding to topical treatment.
The patient has a good match living donor, and her renal function is good. Has intractable acne,
1. Patient reassurance, dermatologist consultation, and psychiatrist may also.
2. Steroid dose can be tapered and even withdrawal over the 6 months of transplantation after the introduction of cellcept.
s. creatinine and tacrolimus levels should be checked days after each change and before the next change is made.
If the kidney failed, the next transplantation will be risky more as she is sensitized, FCXM, DSA screen, CDC-XM, the induction will be with ATG, and if DSA positive desensitization protocol is needed.
Thanks, Jamila
Looks you understand the principle.
Steroid tapering till it is steroid-free, introduction on MMF. The next transplant should be steroid-free with aggressive induction.
Please write references
Acne is a common skin disease in transplant recipients. It is directly related to pharmacological properties of immunosuppressive drugs
١. Topicall treatment
topical retinoids and benzoyl peroxide—can be used in transplant recipients. Xerosis is a frequent side effect of immunosuppressive drugs and may be exacerbated by topical treatments of acne. Topical retinoids are indicated in mild or moderate cyclosporine-induced acne, with predominant comedonal aspects, and are generally considered as efficient in steroid acne and sirolimus acne.
2:there is debate about effectiveness of antibiotics but some prefers to add doxacycline .
3.Isotretinoin ..
Use with caution with monitor liver and renal function .
4 .tapering steroids. To 5mg /day .
●Suppose this kidney failed, what is your immunosuppression plan for the next transplant?
This patient is sensetized and we should go for DSA detection . and cross matching
Induction by ATG and maintenance by triple therapy
Tacromilus mmf steroids
https://link.springer.com/chapter/10.1007/978-3-540-69375-8_79
Would you like steroid sparing regimen for the retransplant rather than triple IS
Cutaneous complications of systemic steroids include steroid acne, skin fragility, purpura, striae, altered wound healing, and exogenous Cushing syndrome .
Skin changes were observed in nearly half of the patients treated with prednisone doses of >20 mg/day for 3 months .
Steroid acne is characterized by abrupt onset of monomorphic erythematous papules and pustules on the upper trunk. Compared with acne vulgaris, steroid acne rarely presents with comedones, cysts, nodules, and scarring. Treatment includes topical retinoids such as adapalene 0.1% or tazarotene 0.1%. Additionally, benzoyl peroxide 2.5% with topical antibiotics including erythromycin 2% or clindamycin 1% or oral doxycycline 100 mg daily may resolve lesions. When these methods are not efficacious, then the steroid dose may need to be reduced and i would recommendto start lowering the dose gradually to 5 mg together with topical ttt as long as she has excellent kidney function with introductionof MMF to avoidt the risk of rejection in the first year.
If the graft failed first we have to look for the cause and for her second transplantation CDC-XM ; FCXM ,detection of DSA as she will be sensitized by the previous transplantation
Induction with ATG
With triple Is steroid, tacrolimus ,MMF with early teparing of steroid
M. Ilyas,O. R. Colegio,B. Kaplan,A. Sharma.Cutaneous Toxicities From Transplantation-Related Medications
First published: 27 April 2017
https://doi.org/10.1111/ajt.14337
Well done
I will quote this from your answer “Compared with acne vulgaris, steroid acne rarely presents with comedones, cysts, nodules, and scarring”
Steroid acne can appear on the face , chest ,or back and is commonly associated with two forms; acne vulgaris and malassezia folliculitis . Acne vulgaris is the main type of acne and the one most often occurs with high dose prednisolone therapy .usually occurs within two weeks of starting treatment . it often appears as uniform lesions and prevalent in people with tendece towards acne in the first place . Malassezia folliculitis is caused by a fungus in and around hair follicles . its estimated from 755% to 98% of people have this type of fungus on their skin .while its presence is normal , overgrowth is not . this itchy acne is most common on the the chest and trunk . Steroid acne will begin to recede once prednisone is discontinued . The type of treatment depends on the type of acne ,severity and medication that are taken . In moderate to severe steroid acne ,common prescription treatments include oral antibiotic such as ;doxycycline ,minocycline or tetracycline . for fungal acne is best treated with ;topical antifungal , oral antifungal like itraconazole or shampoos containing ketoconazole
In this patient it is better to reduce the prednisone dose gradually to 5 mg with addition of anti metabolite(according to her immunological risk ) . Others type of treatment could consider ,if there is no clinical improvement.
Reference;
By Amber j.Tresca Updated on January 2021 Medically reviewed by Casey Gallaghher ,MD.
Suppose this kidney failed ,what is your immunosuppression plan for the next transplant?
The second transplant protocol depend on immunological risk ,as she is sensitized patient . if she has DSA with negative FCXM ,she needs desensitization , induction with ATG and maintenance triple TAC protocol. If no DSA with negative FCXM with high HLA mismatch , induction with ATG and maintenance triple TAG protocol .
Steroid withdrawal in kidney re-transplantation
Few studies focused on the outcome of ESW in the setting of kidney re transplantation . The available studies showed an acceptable short and intermediate-term patient and graft outcome provided that the recipient received
Aref A et al. Steroid free immune suppression WJT https://www.wjgnet.com 102 April 18, 2021 Volume 11 Issue 4 induction therapy with a T-cell depleting agent[18,19].
Mujtaba MA, Taber TE, Goggins WC, Yaqub MS, Mishler DP, Milgrom ML, Fridell JA,
Lobashevsky A, Powelson JA, Sharfuddin AA. Early steroid withdrawal in repeat kidney
transplantation. Clin J Am Soc Nephrol 2011; 6: 404-411 [PMID: 21051751 DOI:
10.2215/CJN.05110610]
Alloway RR, Hanaway MJ, Trofe J, Boardman R, Rogers CC, Buell JF, Munda R, Alexander JW
Thomas MJ, Roy-Chaudhury P, Cardi M, Woodle ES. A prospective, pilot study of early
corticosteroid cessation in high-immunologic-risk patients: the Cincinnati experience. Transplant
Proc 2005; 37: 802-803 [PMID: 15848537 DOI: 10.1016/j.transproceed.2004.12.129]
Thanks, Abdelrahman
I admire you for writing in your own words.
Regarding desensitization, it should be limited for those who have positive crossmatch. The presence of DSA alone is not an indication of desensitisation.
thank ,professor
yes ; no need to desensitized negative cross matched patient
Acne is complication due to steroid occurs in transplanted patient.
Plan :
1- Tapering steroid up to 5 mg once daily. As withdrawal of steroid within first 18 month of transplantation increases rate of graft loss
2- Dermatology consultation.
3- Add MMF .
For second transplantation, patient consider sensitised due to previous transplantation.
Plan here :
1- Desensitisation protocol.
2- HLA typing .
3- FCXM.
4-DSA.
With induction by ATG and maintenance by triple therapy steroid free.
References:
Haller M, Gutjahr G, Kramar R, Harnoncourt F, Oberbauer R. Cost-effectiveness analysis of renal replacement therapy in Austria. Nephrol Dial Transplant. 2011;26(9):2988–2995. doi: 10.1093/ndt/gfq780. [PubMed]
2. Woodroffe R, Yao GL, Meads C, Bayliss S, Ready A, Raftery J, et al. Clinical and cost-effectiveness of newer immunosuppressive regimens in renal transplantation: a systematic review and modelling study. Health Technol Assess. 2005;9(21):1–179. doi: 10.3310/hta9210.
Amal, your answer needs tweeking. For second transplant, would you institute Desensitisation protocol at first or would send DSA/ crossmatching instead. I am not sure what do you mean by triple therapy steroid free. Please explain.
Agree with Dr Sharma
Acne in transplant patients is mostly due to one of three medications (steroid, cyclosporin, and sirolimus). the one related to steroids responds to lowering the dose
In our patient, high dose steroid may be tapered to 5 mg and the regimen can be strengthened by the addition of MMF for example. detailed information is available in the reference below (Acne in Transplantation Patients)
In case of graft failure of the ongoing transplant, this patient should be considered as high-risk patient and should be depleted with multiple doses of rATG plus 3 drug regimen mainly (steroid tapered quickly because of acne but with keeping MMF at high dose 2×2, plus tacrolimus with close monitoring trying to keep C0 level at the high normal for the period of management, namely 10-15 in fist couple of months then 7-10 for one year, etc.
https://link.springer.com/chapter/10.1007/978-3-540-69375-8_79
https://click.endnote.com/viewer?doi=10.1007%2F978-3-540-69375-8_79&token=WzM0MTQzMzUsIjEwLjEwMDcvOTc4LTMtNTQwLTY5Mzc1LThfNzkiXQ.YzuBbErnQ3PUFX_SjKt2LLGg3QY
Tailor the answer in your own words according to the question. What do you think in this scenario is the cause of acne. Also comment on graft failure is not warranted, when the scenario mentions excellent renal function.
Agreed about your comment on graft failure , I overlooked the question
hi dr, these are my own words, in this patient, it is most probably due to steroids as I indirectly mentioned. (3 drugs mostly are: steroid used here, cyclosporin and sirolimus) .. in case of the patient has been on tacrolimus steroid and sirolimus or steroid plus cyclosporin and any other drugs we may need a clinical physical exam and help of dermatology experience as this could be more right because of little differences highlighted in the book chapter referenced above.. I liked the article as we need there’s information even in normal practice as we most commonly use CsA and steroids for nephritic/nephrotic syndromes
First we should start to decrease the dose of steroid and seek for dermatologist advice to treat the achne.
Other option is to proceed to steroid free rigmen by adding MMF and stop steroid
If the graft failed for 2nd transplantation the patient will regarded as highly sensitized one so seeking for DSA by doing very well CDC,FXM,Luminex and cPRA
Doing desensitization if need ,
Use ATG for induction and triple IS for maintenance
Good short reply but work up for next transplant needs to be explained in a better and systematic manner. Would you not get risk of acne with steroids in event of triple IS?
Regarding to me I will try to protect the graft from rejection as it the 2nd one and neglect achne , but if this achne make a deal to the patient I will exclude steroid from the regimen and consider dual therapy with good doses.
Or may be triple therapy with low dose steroid
What is your management?
Suppose this kidney failed, what is your immunosuppression plan for the next transplant?
Nice point to point reply. If you taper steroids, would you keep the patient on mono therapy IS? Do you any published evidence of mono therapy efficacy?
regarding monotherapy, I didn’t have any experience with it but I think steroid sparing agent as AZA can be added to Tacrolimus. Belatacept can be tried as monotherapy.
Sure Aza/Tacro will be dual therapy. Belatecept has been studied and can be an alternative but the BENEFIT trial data showed that belatacept was associated with higher rates of early low-grade steroid responsive acute rejection
This patient is of low immunological risk as has 100 mismatch with good kidney function during second month posttranplantation. This steroid dose (15 mg ) is high dose so1-start by decreasing steroid dose to 5 gradually .
2- Add MMF 1 gm /day to minimize risk of rejection
3- Dermatological treatment ;
Topical treatment :
a- tretinoin
b- Adalpene
c- Tazarotene
Oral antibiotic treatment : tretracyclin as doxycycline for 3-6 m
For second transplant :
The pt is a high risk and possibly sensitized due to previous transplantation , thus her sensitization status must be assess carefully based on (HLA mismatch , FCXM, c PRA , presence of DSA)
For negative FCXM and presence of DSA:
– Desensitization protocol
– Induction with ATG followed by triple IS (Streoid , MMF and TAc ).
Would you be worried about acne if you retransplant and use triple IS (Steroid , MMF and Tac ). What precautions would you take?
-This intractable acne is Steroid induced currently she is on 15 mg prednisolone
so oral doxycycline 100 mg daily can be tried(1)
If not effective , then the steroid dose need to be reduced gradualy since her kidney function is excellent on the other side she is in the first 2 months period posttransplanation
Some studies demonstrated an increased rate of acute rejections after steroid withdrawal compared with steroid maintenance, while more recent meta-analyses trails using newer immunosuppressants found no difference in graft loss
Steroid withdrawal 3–6 months following kidney transplantation was suggested.
Haller MC et al mentioned that the optimal time point for steroid withdrawal in kidney transplant recipients is beyond the first 18 months after transplantation.
Meanwhile there is no consensus on the optimal timing for steroid withdrawal after kidney transplantation. (2)
Another study published that in patients with a low immunological risk, with an immunosuppression regimen based on Tacrolimus and MMF, Early steroid withdrawal does not change graft survival, renal function or the rate of Acute Rejection .(3)
So MMF can be given while steroid withdrawn gradualy
-In the second trasnplanation reassessment need to be done if the donor is cadaveric or live as well as the sensitisation of the patient, cross matching ,HLA typing ,DSA ,PRA and CPRA
induction agent can be anti-thymocyte globulin
maintenance agents tacrolimus and MMF
with close monitoring of graft survival
Reference
1-Ilyas M etal. Cutaneous Toxicities From Transplantation-Related Medications,American journal of transplanation2017; 17,11, 2782-2789
2-Haller MC etal .Steroid withdrawal after renal transplantation: a retrospective cohort study.BMC Medicine 2017 ;15 ( 8 )
3- Andrade-Sierra J . Early steroid withdrawal in a renal transplant cohort treated with tacrolimus, mycophenolate mofetil and basiliximab. Nefrologia 2014,34,2;0-272
Thank you, Doaa.
What factors make you feel safe with steroid withdrawal for this particular patient two months post-transplant?
May be stopped due to side effects as GIT problems are some time not tolerated with MMF even in low doses or even enteric coated preparations. or bone marrow suppression with AZA. Usually sntimetsbolites are hold if there is any active infection with worsening renal functions.Also MMF may be stopped and shifted to AZA in planned pregnancy after the first year and it is that time it is replaced by AZA being safe during pregnancy
The low immunological risk ( live related donor, low mismatch, no DSA).
Corticosteroids have been the main stay immunosuppression for kidney transplant recipients for decades. However the rationale for minimizing, avoiding or withdrawal of steroids (steroid free protocols)is compelling due to the well-established risks and complications.
Acne is one of the cosmetic complications of corticosteroid therapy and in our patient it is intractable to topical treatment. However, tapering prednisolone to 5 mg more rapidly and dermatology review for oral preparations are required before deciding to withdraw steroids (patient has a good cross match and excellent graft function).
Moreover, it is not mentioned in the scenario why patient is on this dose of steroids and why not taking an antimetabolite (MMF) as standard practice for maintenance immunosuppression.
An acceptable solution in our case if not tolerating low dose steroids is to withdraw it, introduce MMF in full dose(dual immunosuppression Tacrolimus and MMF).
If this graft fails, we should verify the cause of that in view of current good cross match status and whether there is recurrence of the recipient original kidney disease.
The next transplant risk needs to be checked based on the patient sensitization status from current transplant and the result of the cross match and the type of graft whether live or cadaveric.
In high risk transplant protocols ATG is used as induction but in standard risk anti IL2 mAB Alemtuzumab (anti CD 52 is preferable) together with dual immunosuppression (Tacrolimus and MMF)
References:
Brent W Miller and Daniel C Brennan. Kidney transplantation in adults: Withdrawal or avoidance of glucocorticoids after kidney transplantation Uptodate 2021.
Kidney transplantation in adults: withdrawal or avoidance of glucocorticoids after kidney transplantation. Uptodate 2021.
In your opinion, why is she not using MMF or other antiproliferative therapy? What are the possible reasons?
maybe because of low risk or may have been stopped due to side effects like diarhhrea etc. but I could force low dose MMF plus lowering steroid to 5 towards the third month keeping tacrolimus effective . first 3 months are important. I don’t know why they kept 15 (3rd drug with lowering steroid is a good option)
Primarily due to drug-related SEs
Even in low Imm risk, you’ll need Antimetabolite (MMF or AZA) to allow for CNI minimization and steroid cessation f. The Imm risk allows
taper glucocorticoids to approximately 0.05 to 0.1 mg/kg per day of prednisone by one year or sooner.
In the absence of acute rejection, we generally reduce glucocorticoids to a dose of 5 mg per day by one month following kidney transplantation.with Maintenance therapy consisted of tacrolimus, mycophenolate mofetil
Such doses are associated with decreased rejection and avoidance of chronic kidney allograft nephropathy compared with early glucocorticoid withdrawal/avoidance.
In case of 2nd transplantation the decision for immune suppressive drugs depends on the state of HLA typing,crosshatching between donor and recipients and .titer of DSA
Reference
1. Woodle ES, First MR, Pirsch J, et al. A prospective, randomized, double-blind, placebo-controlled multicenter trial comparing early (7 day) corticosteroid cessation versus long-term, low-dose corticosteroid therapy. Ann Surg 2008; 248:564.
What do you think is causing the acne? CNI or Steroid. The answer to the cause is vague and needs to be answered in a directed way. For the retransplant, if the patient is sensitised , how would you approach induction and maintenance IS?
here mostly steroid as its dose is still high and not maintenance dose. FKA (tacrolimus has more prominent acne side effect). A physical examination will give a clue of course
Acne is complications of corticosteroid therapy in renal transplantation
In 2nd transplant
If screening for DSAs is negative and crossmatch is negative so no need for desensitization
induction therapy will be done by ATG
Maintenance therapy consisted of tacrolimus, mycophenolate and reduce glucocorticoids to a dose of 5 mg per day by one month following kidney transplantation
This lady has an excellent allograft function, and her transplant is just 2 months old and she is on dual therapy. For her severe acne, I will try to tapper steroids dosage fast to a minimum while monitoring graft function to avoid rejection. However, if I think to minimize steroids till stop completely within the next coming months, then I should add another agent such as MMf with tacrolimus.
In case this kidney failed, probably I will try a steroid-free regimen for a second transplant.
Very crisp reply for part 1 of the scenario but the part 2 of the scenario ( if kidney fails) needs further explanation
completely agree
What is your management?
This question testing our knowledge about early steroid withdrawal to reduce the complications of steroid induced cosmetic changes
Since the results of ELITE- SYMPHONY, many centres in US have experimented with steroid free maintainance IS protocols.
Freedom trial – landmark trial showed that in a standard risk renal transplantation population receiving CsA-ME,EC-MPS and basiliximab, withdrawal of steroids by the end if the first week post transplantation may offer a favourable risk -benefit balance, with comparable 1 year renal function to a standard steroid regimes. However longer follow up is required.
Aref et al 2021, showed that induction with lymphocyte depleting agents induction agents is recommended whenever steroid free maintainance protocol is planned. Steroid free regimes has been evaluated in multiple studies and showed it is important in reducing drug-induced complications while keeping patient and graft survival comparable to steroids based protocols.steroid free regimes can be evaluated for those who are elderly, African Americans and borderline diabetics while the approaches should be individualised based on risk vs benefit.
Having know about the protocols:early steroid withdrawal, late steroid withdrawal and steroid avoidance, to reduce steroids induced cosmetic changes, metabolic disturbances, skeletal complications, growth affection in paediatrics patients and increased risk of cardiovascular morbidity and mortality, without compromising patient and graft survival provide and excellent solution for the aforementioned patient.
The patient developed cosmetic changes and not responding to topical treatment.it’s obvious that the culprit drug is the steroid. Having said that the patient had low immunological risk with only 100 ismatc, the steroid should be withdrawn early. Most of trial suggest to maximize the usage of MMF and tacrolimus at therapeutic range while reduce the steroid early. So I would recommend to start MMF on top of tacrolimus and reduce the steroid over few days to weeks.
Suppose this kidney failed, what is your immunosuppression plan for the next transplant?
The IS protocol for retransplantation depends on future type of transplant – cadaveric vs living , HLA and blood group compatibility, PRA, and DSA. If there is high immunological risk rATG or alemtuzumab should be the induction agent.
Recently published by Guthoff et al 2020 showed that low dose alentuzumab dose of 20mg intraoperatively with initial suspension of MPA umntil total lymphocyte count >5% was reached and triple maintenance IS provides and great patient and allograft outcome in sensitised renal allograft recipients.
Is basiliximab a good choice?
I would choose this drug is its low immunological risk. The evidence is by HARMONY study.
HARMONY study showed similar outcome between induction between basiliximab and rATG and it can be considered with low immunological risk.
References
Vincenti, F., Schena, F., Paraskevas, S., Hauser, I., Walker, R. and Grinyo, J., 2021. A Randomized, Multicenter Study of Steroid Avoidance, Early Steroid Withdrawal or Standard Steroid Therapy in Kidney Transplant Recipients.
Aref, A., Sharma, A. and Halawa, A., 2021. Does steroid-free immunosuppression improve the outcome in kidney transplant recipients compared to conventional protocols?. World Journal of Transplantation, 11(4), pp.99-113.
Guthoff, M., Berger, K., Althaus, K., Mühlbacher, T., Bakchoul, T., Steurer, W., Nadalin, S., Königsrainer, A. and Heyne, N., 2020. Low-dose alemtuzumab induction in a tailored immunosuppression protocol for sensitized kidney transplant recipients. BMC Nephrology, 21(1).
Thomusch, O., Wiesener, M., Opgenoorth, M., Pascher, A., Woitas, R., Witzke, O., Jaenigen, B., Rentsch, M., Wolters, H., Rath, T., Cingöz, T., Benck, U., Banas, B. and Hugo, C., 2016. Rabbit-ATG or basiliximab induction for rapid steroid withdrawal after renal transplantation (Harmony): an open-label, multicentre, randomised controlled trial. The Lancet, 388(10063), pp.3006-3016.
Thank you Theepa
Good to mention the ELITE-SYMPHONY Study
The response needs to be summarized more to be up to the point
Good Luck
-This lady has a renal transplant 2 months ago and is still on a high dose of steroid 15mg/day.acne can be a side-effect of steroids, so we need to taper the dose of steroid until reach 5mg/day and add MMF in stander dose.
-Doxycycline tablet can be prescribed for her acne and dermatological consultation may be needed.
-If this kidney failed, the patient became a sensitized and high-risk patient.
-After screening for DSAs and desensitization of the patient if her crossmatch is positive then induction therapy will be done by ATG which provides 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
but her steroid must be taper early until she reaches minim dose with close follow-up for steroid side-effects.
good reply. I would recommend steroid sparing or minimisation for retransplant
Acne common in 20-25 % of renal transplant recipients and most probably due to steroid (15 mg at 2 nd month ) in this case. Tacrolimus has lesser propensity than Cyclosporine to cause acne ( increases sebum production and high drug lipid solubility leads to cutaneous depositin leading to dysplastic cutaneous proliferation)——responds to topical treatment . In current scenatrio, intractable acne may respond to oral doxycycline or erythromycin or oral isotretinoin 40 mg per day x 2 months then 20 mg per day x 6 months to avoid recurrence ).
Also prednisolone needs dose reduction to 5 mg over 4 weeks to reach 5 mg per day at 3 month with addition of MMF 1 gm per day , inspite of excellent graft fn with only one mismatch at A locus as early post transplant period to avoid acute cellularrejection .
Suppose this kidney failed, what is your immunosuppression plan for the next transplant?
If this kidney fails ,this patient would be sensitised and in view of high risk second live renal transplant , would be a candidate for induction therapy with rATG or monthly alemtuzumab with early steroid withdrawl ( 1 week ) or low dose steroid by 3 rd month aong with Tacrolimus and MMF as maintenance regimen . i would not recommend late steroid withdrawl or no steroid regimen here. Pre transplant immunological work up warrants DSA , flow cross match in addition to conventional CDC cross match.
.
Do you think that oral doxycycline or erythromycin or oral isotretinoin are safe options? What do you need to consider prior to prescribing such medications?
isotretinoin is planned half the dose in renal transplants and once a week for liver transplant followed by increasing dose with close monitoring. hyperlipidemia and hepatotoxicity are the main concerns
I referred to the chapter in my first comment: https://link.springer.com/chapter/10.1007/978-3-540-69375-8_79
Before prescribing any medication for a patient using CNIs, you should consider Metabolism and Drug Interactions. This is the message
I agree with above discussion of steroid reduction from 15mg to 5 mg over a period of three weeks monitoring the kidney function test’s
At the same time will introduce mmf 360 mgtwo tabs twice a day
Also advise local retinoids
And oral doxycyclin for A longer period
If she needs a second transplant .. based on her evaluation pre transplant will use inductiontherapyand triple immunosuppression with early steroidwitdrawal if uecs are stable
It is not a matter of agreeing or not, you should have your opinion with evidence.
Why 360 mg MMF? Is it the only available option at your unit?
This patient is considered low risk, stable graft function post operative , her management of intractable acne as the following :
1-Tapering the dose of the steroid ,mycophenolate is added .if still , withdrawal of steroid is an opinion with careful monitoring of renal function test.
2-Dermatology consult.
if the renal allograft failed , the second transplant immnomosupressive protocol depends on her immunological risk(as she is sensitized patient , HLA typing ,FCXM &DSA)
If patient has DSA with negative FCXM , she might need desensitization( according to SAB & MFI) , induction with ATG , & maintenance triple TAC protocol .
If negative FCXM &no DSA , with high HLA mismatch , induction with ATG , & maintenance triple TAC protocol .
Well done
reduction of steroids to 5 mg is the first option for the patient as it is one of the side effects of steroids. if no response shifts to MMFand TACROLIMUS(steroid-free) as she is considered as a low immunological risk.
If she underwent 2nd transplant for induction ATG unless she had a contraindication to ATG.maitenance on (tacrolimus, MMF and steroid with rapid withdrawal to 5mg prednisolone on the 6th-week post-transplantation).
good. What does evidence suggests about use of Campath?
Patient counseling is an integral part of our job to have a shared decision.
The scenario mentioned Intractable Acne that affects the patient’s QOL.
Would you wait and keep her to suffer.
An active management needed.
My opinion is ;Interactable ache Versus Increased risk of rejection, yes ache can affect quality of life but is not life threating condition, and it is drug -induce . steroid can be reduced but at least patient should have MPA on board before doing that. I want to believe that steroid reduction is gradually process and it is likely to weeks to months and I do not expect resolution of ache immediately. In any case I will put this on table ; dual therapy high rejection rate, early steroid reduction in the same setting not favourable, interactable ache not life threating and take some times to go away, then she make her own decision.
Cosmetics side effects is one of immunosuppressive medication so we can reduce the steroids dose although it is challenging in the 100 mismatch kidney,also we can introduce anti metabolites like MMF or MPA.
If this kidney failed ,it will be considered as moderate immunological risk and if he had positive PRA ;ATG will be the choice for induction and Tac,MMF and steroid will be the maintenance therapy
would you still give 15 mg pred for retransplant or do minimisation/steroid sparing
Acne is one of the cosmetic complications of corticosteroid therapy.
This patient gets a high dose of prednisolone at the end of the second month of kidney transplantation. In this patient, tapering of prednisolone could be done with a faster rate, and after 2 months of kidney transplantation, should be continued at a dose of 5 mg/day.
Another option for this patient is withdrawal of prednisolone and getting tacrolimus in combination with MMF.
For the next transplant, I suggest using rATG for the induction therapy and combination of tacrolimus and MMF with or without a low dose of prednisolone as maintenance therapy.
Important tips about minimizing or withdrawal of glucocorticoids in kidney transplantation:
· To minimize toxicity, tapering and ultimate withdrawal of glucocorticoids has been a goal in transplantation.
· Although glucocorticoids are used in the majority of kidney allograft recipients, some strategies avoid using this agent (in one study in 30% of recipients).
· There are different strategies for minimizing glucocorticoid use, such as a) Lower doses administered earlier after transplantation, b) Complete withdrawal, which can either be performed early after transplantation (approximately three to six months post surgery) or at a later time (after one year) c) Complete avoidance, which most frequently has been utilized with a calcineurin inhibitor-based immunosuppressive regimen and polyclonal antibody induction therapy
· There are controversies between studies regarding outcomes are associated with minimizing glucocorticoid use. Although it is reported in general, the risk of acute rejection is markedly increased with the withdrawal of glucocorticoids weeks to months after transplantation, 2009 KDIGO clinical practice guidelines suggest that glucocorticoids may be discontinued during the first week after transplantation in patients who are at low immunologic risk and who also receive induction therapy. A systematic review reported no significant differences in patient and graft survival in comparing avoidance or withdrawal of glucocorticoids to with glucocorticoid strategies. However, the risk of acute rejection was higher by withdrawal before 14 days.
· Glucocorticoid-free maintenance immunosuppression may be associated with reduced risk of infectious complications and DM.
· Early glucocorticoid withdrawal is particularly harmful in patients with DGF.
· Reducing prednisolone dose to a dose of 5mg/day by one month following transplantation can be appropriate.
· It is reported that withdrawal of prednisolone following 7 days of transplantation was associated with a significant increase in the incidence of chronic allograft nephropathy.
· The success with glucocorticoid withdrawal is relatively dependent on remaining immunosuppressive agents that are used as induction and maintenance therapy as well as rejection risk of recipients. Utilizing antilymphocyte agents for induction therapy in patients with low to standard risk correlates with good outcomes.
· Many glucocorticoid avoidance protocols have chosen low risk recipients and utilized aggressive induction therapy such as rATG, and also maintenance therapy with CNIs (particularly tacrolimus) in combination with MMF.
· Tacrolimus/MMF compared with tacrolimus/sirolimus has been associated with better allograft survival, and Tacrolimus/MMF is also better tolerated compared with sirolimus/MMF.
· Steroid avoidance is associated with increased risks of recurrent glomerulonephritis, thus the etiology of ESKD should be taken into consideration for selecting steroid avoidance protocols.
Haller MC, Royuela A, Nagler EV, et al. Steroid avoidance or withdrawal for kidney transplant recipients. Cochrane Database Syst Rev 2016; :CD005632
Dharnidharka VR, Schnitzler MA, Chen J, et al. Differential risks for adverse outcomes 3 years after kidney transplantation based on initial immunosuppression regimen: a national study. Transpl Int 2016; 29:1226.
Wong G, Lim WH, Craig JC. When Less Becomes More: Life and Losses without the ‘Roids’? J Am Soc Nephrol 2020; 31:6.
Bae S, Garonzik Wang JM, Massie AB, et al. Early Steroid Withdrawal in Deceased-Donor Kidney Transplant Recipients with Delayed Graft Function. J Am Soc Nephrol 2020; 31:175.
Excellent Essmat
Yes, reducing steroids and introducing MMF if no response to steroid reduction. I disagree with the liberal use of rATG without a clear indication. You have noticed that the match is excellent (100 mismatch). Also, there is no mention of the presence of DSA.
What would you do for the second transplant?
even on low dose 1.5 mg/kg ??????
(here I do not expect 100 to be easily lost) there should be an important reason. supposing it is something other than incompliance, infection etc. etc ..
I think the cause and timing of failure of the graft is the leading point
STEROID DEPENADANT ACNE MAY OCCUR IN PATIENTS RECEIVING STEROIDS FOR LONG DURATION. IN THIS PATIENT AS SHE DID NOT RESPOND TO TOPICAL TREATMENT , WE MAY NEED TO REDUCE THE DOSE OF STEROID GRADULLAY UP TO COMPLETE WITHDROWAL AND ADDING MMF AND INCREASING DOSE OF TACOLIMUS. STEROID FREE REGIMEN MAY INCREASE THE RISK OF REJECTION AND REDUCE THE SURVIVAL OF THE GRAFT. IF REJECTION OCCURED , THE PATIENT IS CONSIDERED SENSITIZED AND MAY NEED DESENSITIZATION ACCORDING TO DSA LEVEL , ATG AS INDUCTION AND CNI,MMF, LOW DOSE STEROID POST TRANSPLANT WITH EARLY WITHDROWAL.
Thanks, Mahmoud
Please do not use capital letters in writing. I agree with the first part of your answer but completely disagree with the second part.
What is the likelihood of rejection in 100 mismatch without DSA?
What’s your management?
She is female kidney Tx from her brother assume this is LD Tx with one mismatch white ? Or black race ?
What’s her induction IS type ?
Excellent graft function two on dual IS with predisolone 15 mg ? I would ask why such combination ?
Still she need to be on triple IS. Including CNI preferred tacrolimus with target trough level after 1 month of 7-10 GN as she is still less than 3 months with full dose MMF and tapper dose of prednisolone after the first month to 5 mg / day
This is the standards of care. Protocol as Maintenance IS in her case and off course any early modification of IS during this period. Need to be individuals case by case as she had complicated acne valgaris will tapper her predisolone. To 5 mg and add MMF along with tacrolimus
Will be referred to dermatologist for specific local and systemic therapy
Steriod withdraw or minimization in less than 3 months post TX. Better to be avoided with the available evidence and depending on the type of induction IS
Using steriod free protocol all depend on the induction IS like induction with ATG many centers used steriod free or rapid tapering based on careful assessment
Some they not recommend steriod withdraws in first 6 months post TX. Due to clear risk of Acute rejection
Some centers recommend steriod withdraws with almetuzmab induction but again with close fu and protocol biopsies {1}.
If she failed her transplant. What’s my plan for IS ?
If she failed her transplantation she is high risk group and need to be assessed for DSA and need of desensitized protocol prior to second transplantation also definitely she need ATG induction followed by triple Maintenance IS based on tacrolimus MMF , predisolone with DSA monitoring
Reference
1- up to date medicine 2021
2-KIDGO guilde line for kidney transplantation
Excellent reflection Saja
I will answer your questions by asking you a few questions as you are excellent:
Dear prof Ahmed
for the first part of the question i assume that her first transplant induction IS will be with monoclonal AB basiliximab as she is 1 mismatch ,LD ktx her brother ( maled donor ) and to be followed by maintenance IS with triple IS preferred tacrolimus based with MMF and tapper dose of prednisolone
Thank you, Dr. Saja
What is the evidence that triple therapy is the standard of care?
Good but to clarify. the acne in transplant patients is different clinically from acne Vulgaris. here acre Vulgaris as far as I remember if used here could be a misnomer or misleading. It is s special form of acne different even according to cause. I am not a dermatologist to keep in mind but I will try to do so as this is really a problem we are facing in clinical practice as a side effect of our immune suppressant even other than transplant patients. I think we may manage better than many dermatologists as many colleagues even do not search for reasons of pruritus in patients with eGFR of 60 urea of 60 for example and just attributing it uremia for example (: though clinical scenario and duration with previous as the latest lab. should be evaluated thoroughly. uremic pruritus is some thing else. pruritis in ESRD is something else. either uremic or due xerosis or phosphorus etc. etc.
sorry for long comment but just to serve the aim of our discussions which are helping ourselves increase our standards..
I have the chance these days of being the only nephrologist in my city so I see nearly every patient even unnecessary cases (namely, who do not realy need a nephrologist) some times just coming for loin pain (: without being evaluated even with a simple urine test
back to the point: I refer you to Acne in Transplantation Patients
The side effects associated with corticosteroids have led to efforts to minimize their use
in renal transplant patients.
Variable approaches were adopted by different transplant centers to decrease the
burden of steroid side effects either by steroids withdrawal or total steroid avoidance.
early steroid withdrawal (ESW):
Discontinuation of steroids after few days of transplantation .
late steroid withdrawal (LSW) :
implies holding steroids after weeks or months after the transplantation.
steroid avoidance :
On the other hand, if steroids were not administered at all.
Many of the existing co-morbidities include our patient are likely to benefit from ESW,
with addition of antimetabolite i.e. MMF after gradual CS withdrawal .
IF patient be retranslated ?
re-transplantation candidates are likely to have antibodies to HLA that are expressed on
the donor’s kidney, and they will be progressively sensitized with each failed allograft
experience.
Therefore, they are more prone to poor graft outcome secondary to immunological
causes unless potent immune suppression was implemented i.e. Ant t lymphocyte plus
early steroid withdrawal and double immunosuppression.
Reference:
Ahmed Aref, Ajay Sharma, and Ahmed Halawa. Does steroid-free immunosuppression
improve the outcome in kidney transplant recipients compared to conventional
protocols? World J Transplant. 2021 Apr 18; 11(4): 99–113.
Excellent Mohamed
What is your management?
The intractable acne not responding to topical treatment seems to be due to steroid use in the patient.
A dermatology opinion is a must in such patients. But if no respite with topical/ oral medications, then the immunosuppression need to be modified.
The question is why the patient is on dual immunosuppression in current era where it has been shown that patients on triple immunosuppression (CNI, antimetabolites and steroids) have better graft function.
If antimetabolites were not used as a protocol, I would like to introduce MMF at a dose of 500 MG twice a day and taper steroids to 5 mg per day. If the acne persist even at 5 mg per day of steroids, I would withdraw steroids altogether.
But if the patient was initially on antimetabolites and they were stopped due to some side effects (like leukopenia), then reintroduction of low dose antimetabolite (MMF 250 mg twice a day) may be tried and if no side effects, then steroids can be tapered off.
Suppose this kidney failed, what is your immunosuppression plan for the next transplant?
If her transplant kidney fails, it is most probably due to underimmunosuppression and has a high probability of DSA formation.
Prior to second transplant, the basic workup should include flow cytometry cross match and DSA titers.
In presence of DSA, she will require ATG induction.
Post transplant maintenance immunosuppression should be Tacrolimus, MMF and steroids with early steroid withdrawal.
Post transplant monitoring of DSA and protocol biopsy would be needed to pick graft rejection at an early stage.
References:
1) Luan FL, et al. Steroid-free maintenance immunosuppression in kidney transplantation: is it time to consider it as a standard therapy? Kidney Int 2009;76:825-830.
2) Aref A, Sharma A, Halawa A. Does steroid-free immunosuppression improve the outcome in kidney transplant recipients compared to conventional protocols? World J Transplant 2021;11:99-113.
Well done Amit
I rather give a full dose of MMF rather than a small dose. ATG induction is reasonable in steroid withdrawal protocol (second transplant), but alemtuzumab would better
I think Alemtuzumab is less used in Turkey because of insurance policies giving the opportunity to other drugs. Alemtuzumab is reserved for T cell lymphoma, KLL etc.
I saw the drug for one time in my life. We used it for my patient in year 2001 . the box was around 1m2 (:, included tens of ice packs to have a small carton containing 10 ml sized (flacon; vial?) . It was named MabCAMPATH. we used it for T cell lymphoma patient
Acne is a known side effect of systemic steroids and several retrospective reviews have shown that long-term glucocorticoid use, even in low doses, is a significant independent predictor of numerous adverse effects and that the risk is both dose- and duration-dependent.
The mentioned patient has intractable acne not responding to topical treatments , so I think it will be better to do steroid withdrawal with introduction of one of the antimetabolites Azathioprine or MMF to maintain optimum immunosuppression.
*Steroid withdrawal
There are several different strategies for steroid minimization or withdrawal:
1-Lower doses administered earlier after transplantation
2-Complete withdrawal, which can be done early after transplantation (approximately three to six months post transplant) or later (after one year)
3-Complete avoidance, which most frequently has been utilized with a calcineurin inhibitor-based immunosuppressive regimen and polyclonal antibody induction therapy
*Regarding the second transplant:
Immunosuppression protocol will depends on many factors: HLA sensitization, HLA matching,DSA and cross match.
The Second transplant considered a high immunological risk so ATG induction will be warranted.
And maintenance immunosuppression: She has to be on triple immunosuppression including small dose steroids administered earlier after transplantation
Reference:
Pascual J, Quereda C, Zamora J, et al. Steroid withdrawal in renal transplant patients on triple therapy with a calcineurin inhibitor and mycophenolate mofetil: a meta-analysis of randomized, controlled trials. Transplantation 2004; 78:1548.
Well done
Steroids and Acne; Its management in this patient:
Steroids can cause exacerbation of pre existing acne vulgaris or develop acneiform eruptions in the skin. Acneiform eruptions after steroids are sudden onset of follicular papules and pustules shortly after starting either oral or topical steroids. They incidence of steroid induced acneiform eruptions is around 14.6% reported from a study in India1. Skin changes after steroid use has been reported after 3 months of use with more than 20mg per day2. It has been found that steroids have a direct effect on the follicular epithelium causing follicular and peri follicular neutrophilic inflammation which lead to follicular pustules. This is in contrast to acne vulgaris were in abnormal keratinization of the follicular epithelium and comedones are the primary lesions. Corticosteroid may induce abnormal keratinization in the long term after the initial pustular stages and may predispose to comedone formation later. Topical corticosteroids have also been described to induce acne through variable levels of absorption from the skin especially from the face and neck. Topical steroid absorption is higher in skin conditions like atopic dermatitis. Treatment of acneform eruptions include topical retiniods such as adapalene 0.1% or tazarotene 0.1%, benzoyl peroxide 2.5% with topical antibiotics including erythromycin or clindamycin or oral doxycycline. These treatments may resolve the lesions.
In this patient topical treatment did not work. If we look into oral retinoid therapy which remain the gold standard treatment for acne vulgaris, a brief review is needed before considering it for our patient. Oral Isotretinoin in a dose of 40mg/day given for 1 to 4 months is known to induce remission in acne vulgaris. But their treatment in stroid induced acne remain questionable. There are hardly any studies which quote their use in steroid induced acne. With rare reported side effects of nephrotic syndrome, mesangio proliferative glomerulonephritis, proteinuria and hematuria I would not recommend to use in this patient.
The dose of the steroids maybe reduced, but considering the 100 mismatch, we need to balance the immunosuppressive drugs, increase the dose of tacrolimus and introduce an antimetabolite like MMF in standard dose of 500mg twice daily, before reducing steroids. I would gradually taper steroids and stop over period of one month as rapid steroid tapering has been reported to cause acute cellular rejection which can lead to early graft loss.
Immunosuppression for the next transplant:
as the patient is highly sensitized after the 1st kidney transplant, i would evaluate her DSA status by luminex with the available donor or PRA if waitlisted on a cadaver program. I would prefer to do Desensitization if MFI values to class I and II are more than 3000 with Plasmaphresis 2 litre plasma removal for 3 to 4 exchanges, Inj Rituximab 500mg 2 doses 2 weeks before and triple immunosuppression commenced minus 2 weeks before planned transplant and proceed if repeat DSA titre are < 1000. I would use Inj Anti thymocyte globulin as induction agent at the time of transplant. Regarding her steroid dose after transplant, I would consider tapering doses after 1 month of 1mg/kg/day and maintain her on 10mg/day of prednisolone after 1 month with Tacrolimus and MMF in the standard dose
References;
Balaji
Thank you for your excellent contribution as ever
I disagree with desensitization without positive crossmatch. The Desensitisation principle is to make crossmatch negative. We need to consider the crossmatch results (positive or negative) before discussing desensitisation.
Systemic corticosteroids can either precipitate or exacerbate acne thus they are considered acnegenic so it is recommended to avoid corticosteroids as much as we can in acne prone patients (1)
Corticosteroids is important member of triple maintenance immunosuppressive therapy recommended for most of renal transplant patients.
The ideal regimen for corticosteroid use is not identified (2) but the usual regimen is to give methylprednisolone at a dose of 7 mg/ kg (maximum 500 mg) intraoperatively before reperfusion, then from day-1 oral prednisolone in a dose of 1 mg/kg (maximum 80 mg )is started for 3 days followed by rapid tapering to 20 mg at the end of the first week then taped 5 mg/week till reaching 5 mg which is continued for life.
Because of the side effects of corticosteroids, there are many trial on corticosteroid minimization which include one of the following protocols :
1. Complete withdrawal which can be done either early within 3- 6 months after transplantation or late after 1 year.
2. Complete avoidance from the start
Draw backs of corticosteroid minimization :
1. Corticosteroid withdrawal may increase the risk of acute rejection and lower graft survival especially if withdrawn early within 3-6 months after transplantation with highest risk if withdrawn before first 14 days (3), withdrawal after 1 year is also associated with small but significant risk of acute rejection and lower graft survival (4)
2. Magnify myelosuppressive effects of MMF, azathioprine when compared to continuing on prednisolone 5 mg
3. Rapid corticosteroid withdrawal and corticosteroid avoidance are found to increase the risk of recurrent glomerulonephritis such as FSGS, membranous nephropathy, IgA nephropathy, MPGN, ANCA related GN without improvement in patient or graft survival(5)
4. Increase risk of chronic allograft nephropathy (6)
5. In patients with DGF, early glucocorticoid withdrawal was found to increase the risk of graft loss when compared to maintaining low dose of corticosteroids (7)
Precautions in the use of CS minimization protocol- recommendations:
⦁ Patients that are candidate for corticosteroid avoidance and early glucocorticoid withdrawal < 6 m post transplantation should receive CNI, MMF and a polyclonal antibody induction
⦁ Corticosteroid withdrawal can be started in low risk patients if there are side effects of corticosteroids, stable renal function with no episode of acute rejection in the past 6-12 months
⦁ Glucocorticoid minimization should not be initiated in the following patients :
1. Patients with DGF
2. Patients with graft dysfunction
3. High immunological risk patients
4. Patients with possible recurrence of glomerulonephritis
⦁ Alternate day corticosteroid use is not recommended as it will not significantly reduce the side effects of corticosteroids and may increase the risk of rejection compared to daily corticosteroid use.
So back to our patient
REFERANCES
1- Fung M, Berger T. A prospective study of acute-onset steroid acne associated with administration of intravenous corticosteroids. Dermatology. 2000;200:43-44
2- 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.
3- Haller MC, Royuela A, Nagler EV, et al. Steroid avoidance or withdrawal for kidney transplant recipients. Cochrane Database Syst Rev 2016; :CD005632.
4- Kasiske BL, Chakkera HA, Louis TA, Ma JZ. A meta-analysis of immunosuppression withdrawal trials in renal transplantation. J Am Soc Nephrol 2000; 11:1910.
5- Kukla A, Chen E, Spong R, et al. Recurrent glomerulonephritis under rapid discontinuation of steroids. Transplantation 2011; 91:1386.
6- Woodle ES, First MR, Pirsch J, et al. A prospective, randomized, double-blind, placebo-controlled multicenter trial comparing early (7 day) corticosteroid cessation versus long-term, low-dose corticosteroid therapy. Ann Surg 2008; 248:564.
7- Bae S, Garonzik Wang JM, Massie AB, et al. Early Steroid Withdrawal in Deceased-Donor Kidney Transplant Recipients with Delayed Graft Function. J Am Soc Nephrol 2020; 31:175.
Thanks, Dr Sherif for your excellent response
How popular is this steroid induction regime “then from day-1 oral prednisolone in a dose of 1 mg/kg (maximum 80 mg )is started for 3 days followed by rapid tapering to 20 mg at the end of the first week then taped 5 mg/week till reaching 5 mg which is continued for life”?
In the whole UK, we use 20 mg of prednisolone just on day 1. We do the same regarding 500 mg of methylprednisolone before declamping
Thanks a lot Dr Ahmed …
in Alexandria we were using more prolonged regimen for corticosteroids than that prescribed, i am not sure of the popularity of this regimen but i did not imagine that we can use just methylprednisolone intraoperatively and then 20 mg on day 1
This mean that the usual protocol used in UK is using corticosteroid minimization
but after 20 mg used in day 1 do you recommend to continue on 5 mg or on dual iimmunosupressive therapy ?
Differing from centre to centre , I Turkey prednisiolone is lowered to 20 mg towards the second week. makismum 10 mg before the third month. Here periopeatively 500-1000, postoperatively 120-150 mg then halfing the doses I think as you do aim is 20 towards the end of second week
Management of intractable Acne post-transplant:
Systemic steroids
Systemic corticosteroids are used in many immunosuppressive regimens, often prescribed at higher doses early in the post-transplantation period before being tapered to low doses or discontinued.
Steroids:
Cutaneous complications of systemic steroids include steroid acne, skin fragility, purpura, striae, altered wound healing, and exogenous Cushing syndrome .
Treatment of steroid Cutaneous complications :
Thanks, Safi for your answer
You said” I will consider desensitization beside induction using monoclonal antibody”
You need to know the DSA level and the results of crossmatch (positive or negative before you proceed to desensitization).
maintinace immunosuppresion is one of the key sucess for increasing graft survival.
most centres and guidlines recommends triple immunsuppreesion after kidney transplant in form of (CNIS WITH ANTIMEATBOLITES WITH STEROIDS).
in this scenario , the recipent on dual immusoppresion without apprent cause,
and she is on 15 mg of steroids which is unclearly to be understand? How far is the pt from transplantion?
regardless this questions , this side effect may be realted to steroids which can be tappered to lowest minimal dose as recommened by most of the centres and guidlines to 5 mg od as the pt with this mismatch has a low immunological risk.
the qustion here if she didnt improve, what is the next step?
i think we can reffer her to dermatologist for furhter more potential oral tratment.
and if no improvent occurs , we have to counsil her that she may be offerd stroid free rigmen immusouppresion and expalinning to her that the risk of rejection is alittle bit higher in most of the studies compared to the pt on low ldose maintinace steroids and better to put her back to antietabolite if she prefered to the steroid free rigemen streoid like mmf .
steroid-free immunosuppression should be considered as a standard of care only for a carefully selected group of patients.
IF HER KIDNIES FAILED, WHAT IS MY IMMUNOSPPURESSION?
first thing we have to ask many questions ?
1-what is her cPRA?
2-what is her cross match(flow cytometry, luminx)?
3-how many mismatches between her and the donor?
4-is she offered a cadaveric kidney?
5-dose she have a dsa afanist the donor ?
6-is the donor the same blood group?
7-what is the cause of her failed graft(recurrence of primary disease)?
once answerd all these questions , i can decide what is my immunsuppresion plan , desciding wether she is low immunological risk or high immunological risk pt.
reffernce
Kidney Int. 2009 October ; 76(8): . doi:10.1038/ki.2009.248
Exellent.
THANKS ALOT
Excellent Mohamed
This is a model answer (I will quote it from you and pass it to all colleagues
Yes, IF HER KIDNEY FAILED, WHAT IS MY IMMUNOSPPURESSION?
firstly: thing we have to ask many questions?
1-what is her cPRA?
2-what is her cross match(flow cytometry, luminx)?
3-how many mismatches between her and the donor?
4-is she offered a cadaveric kidney?
5-dose she has a DSA afanist the donor ?
6-is the donor the same blood group?
7-what is the cause of her failed graft(recurrence of primary disease)?
Thanks prof
It may be a steroid adverse effect.
although 15 mg is a not high dose of steroid, still, I will try to taper the dose gradually.to 10 mg then 5 mg ; other wise, this patient if still has same problem, she would be steroid free.
If the kidney failed, she should be on steroid free immunosupressive protocol consisting of Tacrolimus/MMF.
What is your management?
Steroids are well known cause of acne. Acne steroid is observed as monomorphous papulopustules predominantly located on the trunk and extremities, although can be observed on the face but less frequently. Acne is not life threatening adverse effect ,however is displeasing and annoying to patients.
Several reviews have shown that side effects of steroids is both dose- and duration-dependent. In this patient with intractable acne, we initially can try decreasing the dose of steroids. However we should take in consideration that reducing the dose of steroids may increase the risk of rejection, although the risk in not high with 1 mismatch at A locus, which was shown to be mostly associtaed with rejection after 1 year of transplantation.
Alternatively, to minimize toxicity and side effects, we may shift the patient to steroid free regimen including Tacrolimus and MMF. Steroid free regimens have been attempted widely in the USA. In the United States, in 2004, glucocorticoid avoidance regimens were administered to 23 percent of all first kidney transplant recipients . Approximately 10 % recipients discharged on steroids had glucocorticoids completely withdrawn 1 year after transplantation.
Suppose this kidney failed, what is your immunosuppression plan for the next transplant?
For the next transplantation,the risk of rejection is higher but will be based on DSAs and crossmatch results. In this setting to dreduce or to avoid the side effects of steroids, lower doses administered earlier after transplantation could be attempted.Another option is to completely avoid steroids , with the use of a calcineurin inhibitor-based immunosuppressive regimen and polyclonal antibody induction therapy.
References:
-Uptodate
1. Hricik DE, Almawi WY, Strom TB. Trends in the use of glucocorticoids in renal transplantation. Transplantation 1994; 57:979.
2. Bodziak KA, Hricik DE. Minimizing the side effects of immunosuppression in kidney transplant recipients. Curr Opin Organ Transplant 2003; 8:160.
3. Vincenti F. Immunosuppression minimization: current and future trends in transplant immunosuppression. J Am Soc Nephrol 2003; 14:1940.
4. Meier-Kriesche HU, Li S, Gruessner RW, et al. Immunosuppression: evolution in practice and trends, 1994-2004. Am J Transplant 2006; 6:1111.
Excellent Mohamed, yes risk stratification is based on the DSA and results of crossmatch.
Steroids used since the beginning of organ transplantation, but it has several serious side effects including cosmetic, metabolic, skeletal, growth retardation in pediatrics. So to decrease these complication, the steroid early withdrawal or avoidance of it in immunosuppression protocol suggested. Early steroid withdrawal mean stopping the steroids after first few days post-transplantation, while late steroid withdrawal mean stopping it after weeks to months of transplantation.
Random controlled studies showed that steroid free protocol was associated with significant improvement in CV risk but increased risk of AR without significant effect on patient & graft survival in first & 5 years after transplantation. Short & intermediate patient & graft survival with early steroid withdrawal in second transplant found to be acceptable if T cell depleting agents used in induction.
In our patient can change to Tac + MMF with steroid withdrawal without increased risk of graft loss & if her graft lost & she planned to had 2nd transplant she should have ATG for induction with early steroid withdrawal protocol.
References:
Are A., Sharma A. and Halawa A. Does steroids-free immunosuppression improve the out come in kidney transplant recipients compared to conventional protocol?. World J Transplant. 2021, 11(4):99-113.
Thanks, Ban for your excellent reply
What do we need to make a conclusion regarding IS for the second transplant?
I transplanted second transplants successfully with basiliximab induction. Why did I do this?
We need to know the HLA typing of both recipient & donor to determine the degree of mismatch, with DSA & PRA & DDT or LDT to classify the risk, in high risk & sensitized recipient we do desensitization with T cell depleting agent for induction & maintenance with CNI, MMF & steroid.
desensitization protocol ( plasmapharesis, IVIG, retuximab), induction therapy with T cell depleting agent ( ATG, or alemtuzumab)
Is basiliximab a good choice?
I would choose this drug is its low immunological risk. The evidence is by HARMONY study.
HARMONY study showed similar outcome between induction between basiliximab and rATG and it can be considered with low immunological risk.
What is your management?
I may try to reduce the dose of steroid gradually to 5 mg/day if the risk of rejection is low and if there is no risk of recurrent glomerular disease and may consider adding MMF if there is evidence of allograft dysfunction after steroid minimization.
Suppose this kidney failed, what is your immunosuppression plan for the next transplant?
Second transplant is considered as a high immunological risk transplant so the patient will need induction with ATG and maintenance immunosuppression with Tac, MMF and low dose steroid (5mg/day).
Reference:
Kidney transplantation in adults: withdrawal or avoidance of glucocorticoids after kidney transplantation. Uptodate 2021. cited at 4-12-2021.
The second transplant is not necessary a high immunological risk. Please See Dr Mohamed Gafar
I need to raise an issue here, i had seen one of my pt 6 month post transplant with zero mismatch.donor is his son and his cPRA is negative with uncontrolled htn , and also with brittle diabtes despite maximaizing his insulin and his A1c is trending up and also his lipid profile is sky high regardless maximaizing statins . Is it wise to dc his steroid at this stage ?just to control his cbs and his blood pressure and also minimize the risk of dyslipdemia that he is facing?
It may not be high, but higher. SO as previous colleagues highlihtened many questions need to be answered
Thank you all for this good discussion, especially our mentors (ALL)
I know the risk should be stratified based on the cross matching and the presence of DSA and the degree of mismatching with the potential donor but what am concerning about is the presence of memory cells as the patient had exposed to a previous sensitizing event( 1st transplant).
management is introduction of MMF , with rapid tapering of steroid and then stop it…will be on tacrolimus-MMF (steroid free protocol) which avoids disfigurement of the body and face and other steroid side effects.
if kidney failed, my immunosuppressive plan will be tacrolimus-MMF(steroid free regimen from the start), after doing desensitization protocol if there is DSA. induction will be ATG.
S A Birkeland. Steroid-free immunosuppression in renal transplantation: a long-term follow-up of 100 consecutive patients.
Transplantation. 2001 Apr 27;71(8):1089-90.