MMF Rocks!!

Am J Transplant. 2007 Feb;7(2):366-76.

Mycophenolate mofetil is associated with altered expression of chronic renal transplant histology.

* Nankivell BJ,
* Wavamunno MD,
* Borrows RJ,
* Vitalone M,
* Fung CL,
* Allen RD,
* Chapman JR,
* O'Connell PJ.

Department of Renal Medicine, University of Sydney, Westmead Hospital, Westmead 2145, Sydney, NSW, Australia. Brian_Nankivell@wsahs.nsw.gov.au

Mycophenolate mofetil (MMF) reduces acute rejection in controlled trials of kidney transplantation and is associated with better registry graft survival. Recent experimental studies have demonstrated additional antifibrotic properties of MMF, however, human histological data are lacking.

We evaluated sequential prospective protocol kidney biopsies from two historical cohorts treated with cyclosporine (CSA)-based triple therapy including prednisolone and either MMF (n = 25) or azathioprine (AZA, n = 25). Biopsies (n = 360) were taken from euglycemic kidney-pancreas transplant recipients. Histology was independently assessed by the Banff schema and electron microscopic morphometry.

MMF reduced
acute rejection and OKT3 use (p < 0.05) compared with AZA.
MMF therapy was associated with
limited chronic interstitial fibrosis,
striped fibrosis and periglomerular fibrosis (p < 0.05-0.001),
mesangial matrix accumulation (p < 0.01),
chronic glomerulopathy scores (p < 0.05)
glomerulosclerosis (p < 0.05).
MMF was associated with
delayed expression of CSA nephrotoxicity,
reduced arteriolar hyalinosis,
striped fibrosis and
tubular microcalcification (p < 0.05-0.001).
The beneficial effects of MMF remained in recipients without acute rejection.

MMF therapy was associated with
substantially reduced fibrosis in the glomerular,
microvascular and interstitial compartments,
delayed expression of CSA nephrotoxicity.

These outcomes may be due to a limitation of immune-mediated injury and suggest a direct effect of reduced fibrogenesis.

Steroid free induction and maintainence protocols in kidney transplant

Excellent Kidney-Transplant Outcomes Seen After Early Steroid Withdrawal

Marlene Busko

January 18, 2007 — Primary kidney-transplant recipients maintained on sirolimus (Rapamune, Wyeth) and cyclosporine (Neoral, Novartis) immunosuppression after a 5-day induction with antithymocyte globulin (Thymoglobulin, Genzyme Transplant) and prednisone (Solu-Medrol, Pfizer) had excellent 1-year graft and patient survival, similar to that of a comparator group receiving steroids. In this single-center study, the steroid-free group also had a lower incidence of biopsy-proven acute rejection than the comparator group (4.9% vs 9.4%; P < .01).

"We conclude that excellent graft survival with a significantly lower incidence of acute rejection can be achieved using a steroid-free maintenance immunosuppressive protocol consisting of Neoral and sirolimus," the group, led by Amer Rajab, MD, from Ohio State University in Columbus, write.

The article is published in the December 2006 issue of Clinical Transplantation.
The immunosuppressive regimens of the 2 groups were:

• Steroid-free-maintenance group (n=301) — Induction therapy with Thymoglobulin and prednisone over 5 and 4 days, respectively, followed by maintenance therapy with sirolimus and Neoral.
• Steroid-based-maintenance group (n = 502) — Induction therapy with basiliximab (Simulect, Novartis), followed by maintenance therapy with prednisone, mycophenolate mofetil (MMF, Cellcept, Roche), and Neoral.

The low rate of acute rejection is a "remarkable" contrast with studies from the early 1990s that suggested that early steroid withdrawal was associated with high rates of acute rejection, said Dr. Hricik. He added that the only logical explanation is that the combination of sirolimus and Neoral is more potent than earlier immunosuppressants, which is discussed in a recent review article about steroid sparing that he coauthored (Clin J Am Soc Nephrol. 2006;1:1080-1089). In the current study, therapy with sirolimus and Neoral produced no significant adverse effects.

He noted that 1 weakness of this study is that there were more cadaveric donors and fewer living donors in the comparator group than in the steroid-free group, possibly accounting for the different rejection rates. Also, it is also not clear whether the results can be extrapolated to high-risk patients such as non-primary-kidney-transplant recipients or African Americans.

Clin Transplant. 2006;20:537-546.

Calcineurin Inhibitors and Transplant immunosuppression

From American Journal of Health-System Pharmacy

Effects of Genetic Polymorphisms on the Pharmacokinetics of Calcineurin Inhibitors

Posted 01/12/2007

Kyle N. Utecht; Jon J. Hiles; Jill Kolesar

Abstract

Purpose. The effects of genetic polymorphisms on the pharmacokinetics of calcineurin inhibitors were examined.
Summary. The bioavailability and metabolism of cyclosporine and tacrolimus are primarily controlled by efflux pumps and members of the cytochrome P-450 (CYP) isoenzyme system found in the liver and gastrointestinal tract. The number and severity of adverse effects from these drugs are related to the overall exposure, measured by length of therapy and blood drug concentration. One contributing factor to the inconsistent pharmacokinetics of calcineurin inhibitors may be variable expression of functional CYP3A4, CYP3A5, and P-glycoprotein (PGP) efflux pumps, which may be the result of single-nucleotide polymorphisms found on the genes encoding for CYP3A4, CYP3A5, and PGP. CYP3A5*3 and CYP3A5*6 are the most common polymorphisms of CYP3A5. Using genetic markers to adjust initial doses of cyclosporine or tacrolimus may prove difficult, considering the variety of polymorphism known to affect CYP3A4, CYP3A5, and the multidrug resistance-1 (MDR1) gene (the gene that codes for PGP). Studies have found that carriers of CYP3A5*1 consistently have higher clearance rates of tacrolimus than do CYP3A5*3 homozygotes. The influences of CYP3A5 alleles on cyclosporine metabolism and the MDR1 C3435T polymorphism on tacrolimus metabolism remain controversial.
Conclusion. For renal transplant recipients receiving tacrolimus as an immunosuppressant, practitioners can expect CYP3A5*1 carriers to have a tacrolimus clearance 25–45% greater than that of CYP3A5*3 homozygotes, with proportional dosing needs to maintain adequate immunosuppression. Since inadequate immunosuppression is linked to graft rejection, evaluation of CYP3A5 polymorphisms may be helpful in determining an appropriate starting dosage, rapidly achieving adequate immunosuppression, and ultimately improving the outcome of renal transplantation.

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Is anyone actually involved in the study of pharmacogenomics amongst us??
How soon can we actually tailor not just our immunosuppression doses but mundane things as anti hypertensive drugs, on the basis of the genetic picture of the patient. Is it really looking too far in the future or it may happen soon?? Only time will tell.
Any comments??
EK