Early Use of Long-acting Tacrolimus in Lung Transplant Recipients

Lung transplantation is a life-saving therapy for patients with end-stage lung disease refractory to medical treatment, providing an improvement in both survival and quality of life.\[1,2\] Despite the benefits, patients are at risk for myriad side effects including infection, malignancy, neurologic complications (headache, tremor, seizures), gastrointestinal distress and renal failure, to name a few.\[3\] Many of these are related to the requisite need for life-long immunosuppression. Current standard immunosuppressive regimens for lung transplant recipients include calcineurin inhibitors (tacrolimus preferred over cyclosporine), antiproliferative agents (mycophenolate mofetil vs. azathioprine) and corticosteroids; calcineurin inhibitors serve as the backbone of immunosuppression.\[4\] Renal dysfunction is perhaps the most prevalent complication after lung transplantation, affecting up to 90% of post-transplant recipients.\[5\] By 5-year post-transplant, \~8% of patients may require renal replacement therapy and/or renal transplantation.\[6\] Renal dysfunction tends to occur early on in the post-transplant period. Monnier and colleagues showed in a single-center analysis that the incidence of acute kidney injury within the index hospitalization was \~75%; the median loss of glomerular function within the first year was \~45%.\[7\] Moreover, Canales and colleagues showed that \>55% of patients in a cohort of 219 lung transplant recipients had a doubling of their pre-transplant serum creatinine, the majority occurring within the first year post-transplant.\[8\] Early renal dysfunction in lung transplant recipients is associated with a poor overall prognosis. Broelkroleof and colleagues demonstrated that loss of renal function within he first month post-transplant is predictive of chronic kidney disease.\[9\] Moreover, chronic kidney disease is associated with a five times increased risk of mortality.\[5\] Perhaps the greatest contributor to the development of CKD in solid-organ transplant recipients are the calcineurin inhibitors (CNIs).\[10\] CNIs cause renal compromise (calcineurin inhibitor nephropathy, CIN) via acute and chronic mechanisms. Acute CIN is due to potent vasoconstriction of afferent arterioles in the kidney, resulting in ischemia.\[11,12\] Chronic CIN is thought to be largely mediated by interstitial fibrosis as the end-result of arteriolar sclerosis, oxygen free-radical injury, and upregulation of pro-fibrotic pathways including PDGF, renin-angiotensin-aldosterone signaling, TGFB and matrix metalloproteinase-9.\[11,13\] Attempts at utilizing CNI-free or CNI-reduced regimens in the lung transplantation population has been understudied and/or unsuccessful to date. Belatacept, a CTLA4-fusion molecule that prevents CD28-mediated co-stimulation to activate T-lymphocytes, has been well-studied in renal transplantation as an alternative to CNIs. The BENEFIT Trial, a phase III clinical study of Belatacept vs. Cyclosporine in renal transplant recipients, demonstrated improvement in patient and allograft survival, and mean eGFR (\~70 cc/min vs \~45cc/min) at seven years. However, rates of biopsy proven acute cellular rejection were twice as much with Belatacept.\[14\] Case reports of Belatacept as rescue therapy in lung transplant recipients intolerant of CNIs are mixed; there are reports of increased ACR and fulminant acute respiratory distress syndrome.\[15,16\] The mTOR inhibitor class of immunosuppression has also been incorporated into regimens in an effort to ameliorate CNI-toxicity. Villanueva and colleagues assessed outcomes of conversion to Sirolimus and reduced Tacrolimus in 49 patients with bronchiolitis obliterans syndrome (chronic rejection) or CNI-intolerance; there was no difference in renal function one year following sirolimus initiation.\[17\] Conversely, Shitrit and colleagues demonstrated that sirolimus plus low-dose tacrolimus led to an improvement in GFR of 10 mL/min, compared to control maintenance immunosuppression in a pilot study of sixteen lung allograft recipients.\[18\] More recently, Gottlieb and colleagues demonstrated that conversion to quadruple immunosuppression therapy with low-dose CNI (target tacrolimus trough 3-5) led to improvements in eGFR of 10cc/mL compared to standard immunosuppression (tacrolimus trough \>5). There was no considerable difference in biopsy-proven acute rejection, chronic rejection and death.\[20\] The conversion for those in the 4-drug experimental group occurred on average 11 months following transplant, which may account for the muted benefit; perhaps an earlier change in immunosuppression management would have led to more clinically significant results. Notably, discontinuation rates of sirolimus in case reports are variable, with most studies reporting a 20-80% discontinuation rate due to gastrointestinal distress, pneumonitis, thrombocytopenia, etc., making the mTOR inhibitor class less appealing.\[19\] It is apparent that changes to immunosuppression management earlier in the post-transplant period are ideal to see a maximum benefit in preserved renal function.9 However, this is complicated by the concerns for acute cellular rejection, which has a peak incidence at 6 months post-lung transplantation.\[21,22\] Acute cellular rejection is a leading risk factor for the development of chronic lung allograft dysfunction (CLAD, chronic rejection).\[23\] Hence any dose reduction in CNI or the use of an agent associated with ACR (Belatacept) is less desirable within the first few months post-transplant.