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Q.701. How to maintain immunosuppressive therapy in R. Tx. in adults?



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Suspected/confirmed COVID-19 may show an AKI as part of their overall illness. One meta-analysis of hospitalized 13,000 patients, AKI incidence = 17 %, despite the range of AKI incidence was broad (0.5-80 %). About 5 % of ptns required RRT. Incidence may vary by geographic location & % of critically ill ptns in each study.

Clinical characteristics & histopathology: Renal disease among ptns e COVID-19 can manifest as AKI, hematuria/proteinuria syndrome, with a higher risk of mortality (MR). It is unclear if AKI is mainly due to hemodynamic instability and cytokine release or if it is viral-induced direct cytotoxicity. In one observational study of 5449 COVID-19 ptns in New York, AKI was diagnosed in 37 %. Mild AKI (1.5- 2-fold rise in SCr) was observed in 47 %, moderate AKI in 22 %, & severe AKI (> tripled SCr) in 31 %. Hematuria/proteinuria syndrome was seen in 46 and 42 %. DX was required in 15 % of all ptns with AKI, and 97 % of ptns requiring DX were mechanically ventilated. AKI was noted on or within 24 hs of admission in one-third of ptns. AKI correlated with severity of illness; AKI was nearly universal among mechanically ventilated ptns (90 %) but was less common in ptns who’re not critically ill (22 %). Independent predictors of AKI include:

1)    DM,

2)    Older age,

3)    Black race,

4)    hypertension,

5)    CVS disease,

6)    Mechanical ventilation,

7)    Higher interleukin-6 level, and,

8)    Use of vasopressor medications. 


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Q.701. How to maintain immunosuppressive therapy in R. Tx. in adults?


A. As adequate im/m. is required to dampen the immune response, ch. im/m. is slowly decrease over time to 🠞risk of infection & malignancy. Mj. im/m.: [steroids (oral prednisone), Aza, MMF, M. sodiom (myFortic), Csp (standard or micro emulsion), tcrol., evrol & rapamycin (Siros)]. Many combinations: including: triple [CNI, antimetab-olite & steroids], double im/m. & single agent therapy (CNI). Other than recip. of HLA two-haplo-type allograft & HLA identical allog. from monozygotic twin, we sugg.: [maintenance on triple im/m.[CNI, anti-metabolite & prednisone] . Aiming regimen:

Prednisone t.: 1 mg/kg/d./1st3 d. post-Tx., then🠟to 20 mg/d./1st w. Daily dose then 🠟every w. by 5 mg. 🠞15 mg/d. for one w.; 10 mg/d. for one w. & then 5 mg/d.. If No Ac. Rj, we 🠟 steroids to 🠞5 mg/d., one m. following R.Tx..                                             

Antimetabolites: Aza rather thn MMF. Aza 2.5 mg/kg/d., adj. for leukopenia. Use MMF é é Rj. risk or dis. recurrence & in gout é need for allopurinol.

Alternative strategy: which’s most commonly used🠞MMF as anti-metabolite for most ptn.. With this strategy, Aza is used in men planning on becoming fathers & in women of child bearing age, as MMF is teratogenic & C.I. in pregnancy.

MMF:1000 mg twice/d/. during 1st hospital admission. Ptn discharged at doses fr. 500 mg twice/d. (esp. é tacro.) to 1000 mg twice/ d. (esp. é Csp or ptn. at high risk for Rj.). Ptn. é marked G.I. S.E. é MMF, first switch to myFortic fr. MMF at a molecularly equiv. dose. {MMF at 500 mg twice/d. 🠞 equiv. to = myFortic 360 mg twice/d.}. If tht is ineffective,🠟dose further or switch to Aza.   🗘

CNI: tcrol rather than Csp. Give tcrol at doses fr.1-4 mg twice/d., é doses adjust to 🠞target whole-bld trough= 8-10 ng/mL /1st 3 m. & 3-8 ng/mL after that. Microemulsion Csp is preferred: 3-5 mg/kg/d. If monitoring of pl. or whole blood Csp trough levels is used, adj. doses to maintain 12 h. trough=200-300 ng/mL/ 1st 3 m. post-Tx.; after this period, 🠟doses to a trough levels: 50-150 ng/ mL. When C2 monitoring is used, we use C2 target of 800-1000 ng/mL in m.s 1-3 after Tx. & C2 targets of 400-600 ng/mL for subsequent  months.

Recurrent Ac. Rj. episodes who’re on triple therapy, alternate combinations can be tried. We avoid combin. of Siros + CNI (either Csp or tacro.) because both CNI are synergistically nephrotoxic when used é Siros. Among recipients of HLA two-haplotype allograft🠞[Prednisone + antimetabolite OR:  prednisone + CNI ].

HLA identical allograft recp. fr. monozygotic twin🠞Aza 50 mg/d.+ prednisone 5 mg/d./3 m.s only. After 3rd m.: maintained without im/m. medication.      😃

Q.702.When to consider Csp. & Tacrolimus having a high trough level?

A. High trough level of Csp> 350 ng/ml & Tacro>15 ng/ml.    💣 💣

Q.703. What is the role of mammalian target of rapamycin (mTOR) inhibitors in renal transplantation?

A. Mech. of action: Foll. entry into cytoplasm, Siros & evrol bind to FK binding protein & modulate activity of mammalian target of rapamycin. (mTOR), which🠟IL2-mediated signal transduction cell cycle arrest in G1-S phase. Siros & evrol block the response of T- & B-cell activation by cytokines, which. prevents cell-cycle progression & proliferation; in contrast, tcrol & Csp🠟cytokines production.

Siros” also ê proliferation of s.m. cells, and since there’s activation of Siros target in tuberous sclerosis (T.S) les., may dampen the growth of angiomyolip-omas é T.S. Siros also have anti-malignancy potential. Evrol (Afinitor) received approval for ttt of advanced renal cell carcinoma in March 2009.

Q.704. Describe the metabolism and excretion of mTOR?       👉

A. MetabolismSiros & evrol are extensively metabolized in the liver, and are substrates for cytochrome P450 3A4 & P-glycoprotein. Extent of Siros metabolism in intestinal wall is unknown. Siros is countertrans-ported in gut lumen by P-glyco-protein. These processes account for low bio-availability & high pharmacokinetic variability. Metabolites contribute to <10 % of im/m. activity of the parent compound, Siros. Known metabolites incl.: hydroxyl Siros, desmethyl Siros & hydroxyl -methyl Siros. An investingational im/m., RAD, (evrol) is: 40-O-(2 hydroxyethyl) derivative of Siros. Evrol hs 6 metabolites, all é minimal im/m. activity.

Excretion:Total clearance of Siros = 127-240 mL/hr/kg . Large inter subject variability occur in oral clearance of Siros, which reported to be 45 % higher in blacks, comp. to non-black ptns. Siros & evrol are mainly excretion. in👉feces é small % in urine . Elimination ½ life of Siros is 57-63 h., which enables once/d. dosing. Evrol hs a shorter ½ life of about 30 h..

Q.705. What are the doses and availability for mTor?   👓

A. Dosage & availabilitySiros is available in 1 mg/mL oral solution (60 mL) & 0.5, 1 & 2 mg triangular shaped tab.. Although oral solution & tab. are not bioequivalent, clinical equivalence has been demonstrated . Evrol is available as: 0.25, 0.5, & 0.75 mg round, flat tab.. Adult kid.Tx.: Trials of initial im/m. reg. after kidney. Tx. including: Siros as a component of a reg. including: Csp & steroids: onetime loading dose of 6 mg or 15 mg (3 times maintenance dose) followed by maintenance of either 2 or 5 mg/d. was utilized. Initial evrol dose: 0.75 mg orally twice/d. is recommended for adult kidn. Tx. in combination é reduced dose Csp. In clinical practice, dosage adj. for both mTOR inhibitors are made based upon several f.s incl.[concomitant use of P450 enzyme inducers or inhibitors, hepatic insufficiency, toxicity, and/or infection]. Limited data on Siros are available in geriatrics & pediatrics.

Organ impairmentDosage adj. of Siros is not required é R.I., but dosage red-uctions to one 1/3rd N. maintenance dose should be used é hepatic impairment. Moderate hepatic impairment (Child-Pugh class B): daily dose of evrol needs to be decreased by one ½ recommended initial daily dose. There’s no information é severe hepatic impairment (Child-Pugh class C) on everolimus pharmacokinetics . Close monitoring of mTOR inhibitors é whole-blood concentrations is indicated.

Q.706. How to do therapeutic drug monitoring?        

A. Steady-state concentrations: of Siros occur 5-7 d. after start of thpy or dose change. Clinical trials: mean whole-bld trough levels (by immunoassay) = 9 ng/mL & 17 ng/mL in the 2 & 5 mg ttt groups, resp..  Routine drug monitoring:  An excellent correlation exists between trough whole-blood levels & area under the time-concent-ration curve for Siros. Routine drug monitoring of Siros is recommended for all ptns. Clinically, Siros whole blood are measured by both chromategraphic & immun- oassay. Recomm. time for collection=one h. prior to next oral dose. Whole-blood samples shd be collected in tubes é EDTA & protected fr. light; samples collected in this fashion are stable for 24 h. at room ◦C, up to one w. at 2-8 ◦C, & up to 3 m. at -20◦C.

When Siros is used with Csp & predn., trough whole-bld Siros of 5-15 ng/mL were ass. é protection fr. Ac. Rj. & adverse effects. Siros trough>15 ng/mL 🠞[hypertrG, thrombocytopenia & leucopenia]. Siros levels<5 ng /mL 🠞Ac. Rj.. When Siros is used é Aza & predn., higher trough levels may be necessary. In a clinical trial of R.Tx. recipient, Siros trough levels were maintained at 30 ng/mL for the 1st two m. posttransplant then 🠟to 15 ng/mL thereafter. Ac. Rj. episodes were rep. in 28-41 % of ptns. Monitoring{“phosphorylation status” of p70S6 kinase in peripheral blood mononuclear cells} has been proposed as an alternative strategy for Siros monitoring. Routine monitoring of evrol trough levels is recommended & concentration should fall é 3-8 ng/mL target range. Optimally, dose adj. should be based on trough level obtained 4-5 d. after a prev. dosing change .

Kidney histopathology was examined in an autopsy of 42 ptns died e COVID-19. Mean age was 72 ys; 88 % were > 60 ys. Co-morbidities, e.g. HT (73 %), DM (42 %), coronary artery or cerebrovascular dis (32%), obesity (31%), & CKD (29 %) were common. AKI (mostly stage 3) was noted in 31 of 33 ptns. Most ptns (62%) exhibited varying degrees of ATN, one hd collapsing focal segmental glomerulosclerosis (FSGS), & many show sequelae of their medical comorbidities (eg, HT nephron-sclerosis). ATN was the predominant kidney pathological finding in other studies. Some ptns show collapsing FSGS, called COVID-associated nephropathy (COVAN); such ptns may show nephrotic-range proteinuria. Presence of viral particles have been reported in the kidneys of COVID-19 ptns. However, these may instead be endosomal subcellular structures (eg, clathrin-coated vesicles and multivesicular bodies). Confirmatory ultrastructural in-situ hybridization used in other studies has failed to recognise the presence of virus in the kidney.


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