Saturday, June 3, 2017

My Immunosuppression Protocol

I've written about the medications I take, their side effects, and some of the steps I take to counter those effects.  I don't think I've mentioned why I take these meds.

Each transplant center utilizes its own immunosuppressent protocol. I've searched all over tor data that lists the protocol used by each center along with the SRTR/OPTN annual reports on the centers. You can compare time on the wait list, mortality on the wait list, mortality rates post transplant and lots of other data. I just haven't found a way to compare protocols along with all of this data. That would be some interesting information.

The Journal of Thoracic Disease published "Immunosuppression in Lung Transplantation" which explains the different medications and protocols used to help keep us alive.

The following is what my Team uses in my protocol. All quotes are from the above journal article. I really appreciate that this is not hidden behind a paywall.

Lung transplantation can be a life-saving procedure for those with end-stage lung diseases. Unfortunately, long term graft and patient survival are limited by both acute and chronic allograft rejection, with a median survival of just over 6 years (1). Immunosuppressive regimens are employed to reduce the rate of rejection, and while protocols vary from center to center, conventional maintenance therapy consists of triple drug therapy with a calcineurin inhibitor (cyclosporine or tacrolimus), antiproliferative agent [azathioprine (AZA), mycophenolate, sirolimus (srl), everolimus (evl)], and corticosteroids (CS). Roughly 50% of lung transplant centers also utilize induction therapy, with polyclonal antibody preparations [equine or rabbit anti-thymocyte globulin (ATG)], interleukin 2 receptor antagonists (IL2RAs) (daclizumab or basiliximab), or alemtuzumab (2). While these agents are used to prevent acute and chronic rejection, they are not without adverse effects, including drug-specific toxicities, as well as opportunistic infections and malignancy. This review will summarize these agents and the data surrounding their use in lung transplantation, as well as additional common and novel therapies in lung transplantation.
I am going to focus on maintenance immunosuppression and novel therapies that I am taking.

Maintenance Immunosuppression:
Maintenance immunosuppression is lifelong immunosuppressive therapy that is given to prevent both acute and chronic rejection. The goal is to not only to prevent and minimize immune-mediated injury to the allograft but also to minimize adverse effects associated with the medications used. Conventional maintenance immunosuppressive regimens consist of triple drug therapy with a calcineurin inhibitor, antiproliferative agent, and CS.  Note: CS = Corticosteroids
Calcineurin Inhibitors 

The Calicneurin Inhibitor that I take is Prograf.  My highest dose was 4 mg twice/day.  Current dose is 1.5 mg twice/day.
A second calcineurin inhibitor, tacrolimus(previously known as FK506) (Prograf©) became available for use in 1997. It is 10-100 times more potent than cyclosporine. Tacrolimus binds to intracellular FKBP12, forming a complex that prevents transcription of cytokines, including interleukin 2, and ultimately prevents T lymphocyte activation and proliferation... 
...most centers utilize trough concentrations for therapeutic drug monitoring (31,32). Target ranges vary according to center-specific protocols and practices, and take into account patient characteristics, such as time post-transplant and rejection and infection history. Generally, target trough concentrations range from 5-15 ng/mL.
My current Tacrolimus goal is 10 - 12 ng/mL.

Anti-Proliferative Agents

For this leg of my therapy, I take CellCept (Mycophenolate). Current dose = 1750 mg twice/day. This is the highest dose I've been prescribed.
Mycophenolate is the most frequently used antiproliferative agent used according to the most recent ISHLT Registry report (2). Mycophenolate mofetil and mycophenolate sodium are converted to the active metabolite, mycophenolic acid (MPA), which inhibits inosine monophosphate dehydrogenase (IMPDH), the enzyme responsible for T and B lymphocyte production. Inhibiting this enzyme results in decreased T and B lymphocyte proliferation. Because lymphocytes lack the ability to utilize salvage pathways for nucleotide synthesis and thus rely on the IMPDH pathway, mycophenolate is selective for T and B lymphocyte proliferation inhibition (47). Mycophenolate undergoes rapid absorption and conversion to MPA. MPA is metabolized hepatically into mycophenolic acid glucuronide (MPAG). MPAG is excreted via bile into the intestines, where it is converted back to the active metabolite, MPA, resulting in a second peak concentration in the plasma. Doses range from 1-1.5 g IV or oral twice daily. Therapeutic drug monitoring is available for mycophenolate, with AUC being the optimal parameter for measuring treatment response...

This is pretty much common in all transplant centers.  I take prednisone, 10 mg/day with the occasional pulse of high dose IV Methylprednisolone. 
CS have been used in solid organ transplant since the very beginning and have not only remained a corner stone of both induction and maintenance immunosuppression but they are also used to treat acute cellular rejection (ACR) as well. The most commonly used CS in solid organ transplant are methylprednisolone and prednisone. CS are known to have antiinflammatory properties and exert their effects in a variety of ways, including inhibiting the NFkB pathway, preventing T cell proliferation, decreasing macrophage activation, inhibitingcytokine production and altering lymphocyte migration (67). According to the most recent ISHLT registry report, CS continue to be used by almost all transplant centers, at one and five years post-transplant. Initial doses range from 500-1,000 mg given intraoperatively, and are gradually tapered over weeks to months to 5-10 mg per day for maintenance...
Novel Approaches


Azithromycin is one of three routine antibiotics that I take.  My dose is 250 mg 3 times/week.
Azithromycin is a macrolide antibiotic with anti-inflammatory and immunomodulatory effects (89). These effects, in conjunction with the beneficial effects of maintenance azithromycin seen in cystic fibrosis patients led to pilot studies of azithromycin in lung transplant recipients with BOS (90-93). In 5 of 6 patients, thrice-weekly azithromycin for 13 weeks demonstrated an average 17% improvement in FEV1 (92) and an average 18% improvement in FEV1 after 12 weeks of therapy in 8 others (93). A retrospective analysis of 20 lung transplant recipients also demonstrated an improvement in FEV1 after 12 weeks of azithromycin therapy (average 110 mL from baseline) (94). However, not all patients respond to azithromycin therapy (95-97). Evidence suggests airway neutrophilia and elevated interleukin-8 bronchoalveolar (BAL) concentration may be predictors of response (95,97,98). Furthermore, studies have indicated that early initiation of azithromycin, e.g., BOS 0-p, may have more of an impact on preventing disease progression and may improve survival (97,99,100). In a randomized, placebo-controlled trial of 83 lung transplant recipients, there was a significant reduction in the incidence of BOS at 2-year in those who received azithromycin prophylactically compared to those who did not (12.5% vs. 44.2%, P=0.0017) (101). There was also a significant difference in BOS-free survival (HR 0.27, P=0.020), although overall survival was similar between groups. Collectively these data suggest early initiation of azithromycin in lung transplant recipients may prevent the incidence of BOS and prolong BOS-free survival, and may improve or stabilize pulmonary function after the onset of BOS, particularly in those with neutrophil- and IL-8-predominant BAL.

Being prescribed statins threw me for a loop. I really did not want to take statins and resisted when my Team first prescribed them. Then I learned how beneficial they could be for the lung tx recipient. I take 20 mg of Pravastatin daily.
Statins, 3-hydroxy-3-methylglutaryl coenzyme Areductase inhibitors, have been shown to have properties which may have a potential beneficial impact on lung allograft function post-transplant. They have been shown to reduce the gamma interferon induced expression of major histocompatibility molecules on cells, increase the number of CD4+CD25+ T regs, inhibit growth factor expression in lung fibroblasts and inhibit the development of obliterative airway disease in animal models (105-108).  
 These abovementioned immunomodulatory and anti-fibroproliferative properties have potential benefit for lung transplant recipients. However, clinical evidence in lung transplant recipients is limited to retrospective single center studies only. Johnson and colleagues showed improved 6-year survival in statin group compared to controls, 91% vs. 54%...
These are the immunosuppresents that I take. The list of meds/supplements that I take to counter the side effects of these medications is longer yet.  I've talked about many of them in the past.

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