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Transplantation and Medications

Q.692. Many drugs can ppt. ARF in R.Tx., discuss?


﴾﴾III. Transplantation and Medications  ﴿﴿


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Allograft of the 
Renal transplantation

Q.692. Many drugs can ppt. ARF in R.Tx., discuss?

A. The following drugs  👉 are accused:

1. NSAID 🠞Functional pre-renal, esp. é hopovolemia, RASAvoid.                                                    2. ACE/ARB🠞Functional pre-renal, esp. é hopovolemia, RASAvoid early use.                                3. SMX/TMP: High dose TMP🠞🠟tub. Cr. secretion (no effect é GFR), well tolerated.                                                                                                                                                     4. Acyclovir/foscarnet🠞Tubular crystal deposition🠞Obstruction🠞ttt: good hydration.                      5. INFa 🠞Immune stimulatory effect 🠞Ac. Rj. 🠞use cautiously.                                                          6. Verapamil, Diltiazem, erythromycin, ketokenazol🠞🠟CNI metb.🠞🠝s. level.                                                                                                                                                              7. CNI: 🠞🠝Statin level 🠞Rhbdo. risk🠞use CNI é lower dose.  Monitor C.K., .. Pravastatin & Fluvastatin are less affected.

Q.693. Give general idea about the current immunosuppression?

A. I. Anti-T-cell receptor A.B.

    II. Glucocorticoids.

    III. Calcineurin inhibitors (C.N.I.s) : Csp. (Neural ) & Tacrolimus (Prograf ).

    IV. Target of Rapamycin, m(TOR) inhibitors, Sirolimus (Rapamycin).

    IV. Antiproliferative Ag.: MMF(Sp. Purine inhibitors)& Aza.(Non-sp. purine inhibitors).

Q.694. Specify anti-“T” cell receptor A.B.?

A. Twomain groups:                                                                                                                             I. Anti-lymphocytes A.B. targeting All T-cells 🠞 Non sp., targeting All T-cell, not just those reacting é allograft, it incl. two  ✌  main preparations:                       

   i. OKT3 (Orthoclone) 🠞 Mouse monoclonal A.B. agnst CD3 receptor Cx. on T-cells.

  ii. Polyclonal A.B.🠞 Rabbit (thymoglobin, rATG) or Horse (ATGAMأنغام الحصان), immunized é human lymphoid cells 🠞 multiple. A.B. agnst multiple leukocyte Ag.

Both i. & ii. are equally effective, but Polyclonal esp. (Rabbit thymoglobin) are  most effective/tolerated due🠞 more sustained depletion of reciptor lymphocytes.           

 * Indications:   

v Induction: additional initial im/m. thpy (1st 5-14 d.) e.g. DGF & high risk ptn.       

v  Reversal of Ac. Rejection.

II. Humanized/Chimeric Anti-IL2 receptors [monoclonal A.B.]: more specific im/m., because full IL2 receptors only expressed on👉 activated T. cells. Humanization or Chimerization of A.B.🠞 minimize recipient generation of anti-mouse A.B. (a problem in O.K.T3)🠞 prolongation of ½ life & drug efficacy.    

* Indications: Only as initial im/m. (induction thpy), Not for Ac. Rj..

* Members: Anti-CD 25 (anti IL2) recep. A.B.🠞

*      Basileximab. (Simulect).

*      Daclizumab. (Zanapax).

…. Well 😊 tolerated é minimal S.E. é induction thpy.

Q.695. How can Corticosteroids exert their action? What is the impact of glucocorticoid-free immunosuppression?

A. They’re the cornerstone in im/m. therapy. Tapering of the initial dose is continued until reaching a maintenance of 5-10 mg/d.

* Mechanism of action: Anticytokine” (incl. IL.2) + Antinflammatory effects.

* S.E. : [Glucose intolerance- H.T.- Hyperlipidemia- Osteoporosis & necrosis -Myopathy- Growth retardation in children- cosmetic & neuropsychiatric effects].

A.The 10-y. outcomes of a glucocorticoid avoidance strategy foll. R.Tx. have been reported. Among 1241 low-risk adult Tx. recipients receiving allografts betw. 1999 & 2010, in whom prednisone ws discontinued within one w. after Tx., both ptn. & graft survival were comparable to national data rep. by the Scientific Registry of Tx. Recipients in 2009. 

Q696. Describe the role & S.E. of calcineurin inhibitors (CNIs.)?

A. Calcineurin inhibitors (CNIs.):

I.    Csp 🠞🠋 CALCINEURIN (Key enzyme for T-cell activation) 🠞🠋of IL2. & other molecules necessary for “T cell” activation.

S.E.: [Nephrotoxicity, Ac. & ch. Rj., G.H.H. (Glucose intolerance- H.T.- Hyperlipi-demia)- Cosmetic effects (Hirsutism). ].

II.    Tacrolimus: Same mechanism & S.E. as Csp, but More diabetogenic & Less [ H.T.- Hyper-lipidemic & cosmetic effects].

Disadv.: More (Nephrotoxic & neurotoxic)- more D.M. , more G.I. esp.  é MMF.

Q.697. What about antiproliferative group?

A. Antiproliferative agents:

i.    Aza: a purine analogue 🠞🠟DNA & RNA synthesis🠞🠟“T”-cell & “B” lymphocytic replication. S.E.: 🠞[B.M. suppression- rarely hepatitis & pancreatitis.].     N.B.: Concurrent “Allopurinol” use 🠞 Fatal B.M. suppression.,💀  as Xanthi-ne Oxidase, responsible for Aza metab., will be suppressed by Allopurinol 🠞🠝🠝s. level of Aza🠞 Sev. B.M. suppressionSo, Reduce Aza dose by 75 %.

ii.    MMF: Inhibit De Novo pathway of purine biosynthesis (more selective)      🠞          

🠋🠋 Lymphocytic replication. It hs the foll. effects:   

1)   Block T & B cell proliferation. 

2)   Inhibit A.B. formation.

3)   Dcr. expression of “adhesion molecules”. 

4)   Reversible inhibition of “Inosine monophosphate dehydrogenase”.                                                                                                                                                                                                                                                                S.E.:Ö[n. & v.- G.I. upset.- B.M. suppression- more CMV. tissue invasion].

Q.698. What are m. T.O.R.s.?

A. Sirolimus (Rapamycin):[Siriolimus-F.K.B.P.(f. k.- binding protein) Cx.], binds & inhibits a kinase called (T.O.R.)=target of rapamycin🠞🠋lymphocytic proliferation.

Both CNIs & Siros 🠞 are mtb.by “Cytochrome P 450 🠞 many drug interactions. “Rapamycin” most appropriately used as:       

1) CNIs-sparing drug: (stopping CNIs improves GFR) &   in

2) Ptn é  Neoplasia.

Q.699.What are the possible side effects?

S.E.🠞[B.M. suppression-Hyperlipidemia-Interstitial pneumonitis-🠝Csp. toxicity.].

Q.700. How to start induction immunosuppressive therapy in R.Tx. in adults?

A. Im/m. for R. allog. recipientis recommended but optimal reg. is unclear. Induction:is recomm. for R. allograft, it consists of: [A.B.+standard im/m.] rather thn standard im/m. thpy alone. Caucasian recip. of two haplotypeidentical L.R.A. don’t require induction thpy é A.B. thpy given the dcr. immunologic risk of Ac. Rj.. A.B.s incl. [rATG- thymoglobulin, ATGAM, alemtuzumab, OKT3 & two IL-2 receptor A.B.: basiliximab & daclizumab].  Ptns at incr. risk of Rj., start of rATG-thymoglobulin rather thn IL-2 receptor antagonist is recommended. Ptns not at increased risk of Rj., giving of rATG-thymoglobulin rather thn IL-2 receptor antagonist is suggested. If rATG-thymoglobulin cannot be administered, IL-2 receptor A.B. is recommended.