As technologic improvements in the field of transplantation have yielded improved graft survival for life saving organs, a secondary set of complications has emerged. CKD after non-renal solid organ transplantation (NRSOT) is one of the more prominent and costly of these complications.
Since the advent of cyclosporine for solid organ transplantation in the early 1980’s and the subsequent development of tacrolimus, there has been a steady decline in the risk of acute rejection and subsequent organ loss in NRSOT recipients. Prior to the development of these calcineurin inhibitors (CNIs), the risk of rejection prevented almost all recipients from reaping long-term benefits from transplantation.
However, this is no longer the case: Current one-year graft survival rates for heart, liver, and lung transplants are 87.5%, 83.2% and 83.6% , respectively.1 Lower rejection rates in all categories of NRSOT have improved long-term survival, leading to more long-term recipients with each passing decade.
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Although CNIs have dramatically improved graft survival, they have also been shown to contribute to renal tubular atrophy and fibrosis through their powerful vasoconstrictive affects on renal blood flow.2 The dose and the overall duration of CNI exposure are associated with the development of tubular atrophy and interstitial fibrosis causing CKD.3,4
Numerous studies have shown the risk of CKD following heart transplantation ranges from approximately 20% to 50%, depending on the definition of CKD and the time of follow up.3,5,6 Similar rates of CKD are noted in liver and lung transplant recipients as well.4,7,8
In one of the largest studies of the SRTR database and Centers for Medicare and Medicaid (CMS), Ojo and colleagues demonstrated a significant rate of CKD (defined as eGFR less than 29 mL/min) in recipients five years after transplant.9 Of the more than 69,000 recipients studied, CKD was discovered in 10.9%, 15.8%, and 18.1% of heart, lung, and liver recipients after five years, respectively. Of those diagnosed with CKD, 28.9% progressed to end-stage renal disease (ESRD).9
Economic consequences
Consequently, the dramatic improvement in survival of NRSOT recipients over the past several decades has revealed the double edged sword of chronic CNI exposure. According to the 2008 SRTR annual report, more than 9,000 NRSOTs were performed in the United States, a number that continues to increase slowly each year. This increase in transplantation combined with improved survival translates into more than 60,000 prevalent recipients of NRSOT in the United States in 2006 possibly at risk for developing CKD and/or ESRD, particularly because more than 90% of all recipients are receiving CNI as part of their long term immunosuppressive regimen.1
If even 20% of these recipients were to progress to ESRD over the next decade, this would come at a significant cost because the average ESRD patient on maintenance hemodialysis costs CMS in excess of $60,000 per year, according to the 2008 U.S. Renal Data System annual report).
In addition to the costs associated with a NRSOT recipient reaching ESRD, there is an increased risk of mortality.7,10 Patients who have NRSOTs and have reached ESRD have an even higher mortality rate than patients on dialysis who have never been transplanted. Interestingly, this added risk returns to normal after renal transplantation.11 Therefore, these patients become a priority for renal transplantation. However, this adds yet another population seeking benefit from this limited resource and further increases numbers on the renal transplant wait list.
It is even more difficult to gauge the costs of CKD in NRSOT recipients. CKD is associated with a greater risk of hospitalization and increased utilization of resources12 in nontransplant recipients and likely this same risk would be realized in NRSOT recipients as well. Aside from the costs to our health care system of increased utilization, frequent hospitalizations may also contribute to an increased risk of job loss due to absenteeism. If recipients lose employment, they will have to rely primarily on Medicare for insurance and they no longer will contribute to federal employment taxes.
Therapies
Current therapies for CKD in NRSOT recipient focus primarily on modification of immunosuppression regimens. A reduction in CNI dosing13 or substitution of a CNI with an antiproliferative agent typically leads to an improvement in glomerular filtration rate (GFR)14-16; however, this benefit must be balanced against the risk of inducing rejection.17 Sirolimus (SRL), which targets the mammalian target for rapamycin (mTOR inhibitor) is typically substituted for CNIs because it does not have the renal vasoconstriction associated with CNIs.
Although there is usually an early improvement in GFR seen with SRL, it is unclear whether this improvement is sustained long-term (Dr. Hofmann: Can you provide a reference?). SRL is often poorly tolerated due to the many adverse side effects associated with this medication. Common side effects include oral ulcers, edema, leukopenia, pneumonitis arthralgias, edema, and increased risk of infections compared to CNIs.18 In addition, SRL has been demonstrated to worsen proteinuria in some patients with CKD and may in fact be deleterious to renal function.19 It appears that careful selection of recipients as well as timing may be beneficial in targeting those patients who will receive the greatest benefit from SRL.20,21 It still remains unclear at what stage of CKD should modification of immunosuppression be considered to optimize the likelihood of success without putting the recipient at excess risk.
Additional long-term trials are needed to better answer this question. Perhaps newer medications such as everolimus may be better suited in this regard. Everolimus is another currently available mTOR inhibitor with a more benign side effect profile than sirolimus; however, it remains largely unproven as treatment for advanced CKD in NRSOT recipients.14
