Calcineurin Inhibitor-Associated Early Renal Insufficiency in Cardiac Transplant Recipients

Abstract

Cardiac transplantation is the definitive treatment for eligible patients with end-stage cardiac failure. Techniques have evolved to reduce surgical mortality to under 5%. Immediate and subsequent long-term survival is more dependent on acute and chronic rejection and the complications of immunosuppressive therapy. Ten-year survival is greater than 50%.The success of transplantation over the last 20 years has been largely due to the advances in immunosuppression. The most notable and dramatic milestone was the introduction of cyclosporine in the early 1980s, which resulted in a significant improvement in allograft and patient survival. Cyclosporine is a peptide that inhibits the immune system by suppressing T-helper cell activation via inhibition of calcineurin, a critical intracellular enzyme. Tacrolimus has a similar (but not identical) mechanism of action, and was introduced in the 1990s. Drugs such as cyclosporine and tacrolimus, generically referred to as calcineurin inhibitors, have become the cornerstones of immunosuppressive protocols. As a group, calcineurin inhibitors have adverse effects, including neurotoxicity, hypertension, and nephrotoxicity, which complicate their use. Early renal insufficiency manifests as postoperative oliguria (<50 mL/h urine output) or rising serum creatinine levels. There are a variety of postulated causes for calcineurin inhibitor-associated early renal insufficiency including direct calcineurin inhibitor-mediated renal arteriolar vasoconstriction, increased levels of endothelin-1 (a potent vasoconstrictor), as well as decreased nitric oxide production and alterations in the kidney's ability to adjust to changes in serum tonicity. Once early renal insufficiency occurs, no single treatment has been shown to be effective. Approaches discussed in this paper include reduction in calcineurin inhibitor dosages, as well as various drugs to promote increased renal perfusion such as misoprostol and dopamine. In addition, the paper emphasizes the importance of ruling out other causes of renal insufficiency in the early postoperative period, including volume depletion, depressed cardiac output, and mechanical obstruction to urine flow. Given that there is no highly efficacious treatment for this syndrome, ways to avoid its occurrence are desirable. One paper is referenced that suggests that avoidance of rapid changes in tacrolimus level during the first three days of therapy is associated with a low occurrence of early renal insufficiency.

Acute inhibition of calcineurin restores associative learning and memory in Tg2576 APP transgenic mice

“…However, while we observed that a single injection with FK506 improved fear conditioned memory function in Tg2576 mice, prolonged treatment of humans with FK506 has been reported to be associated with significant side effects, most notably nephrotoxicity (Olyaei et al, 2001;Baran et al, 2004;Staatz and Tett, 2004). Therefore, before considering clinically attractive the idea of CaN inhibitors for treating AD, future studies will have to determine whether lower, less nephrotoxic doses of FK506 administered for longer periods of time still provide behavioral benefits or whether novel behaviorally-active drugs that selectively target only CaN in the CNS could eventually be designed.…”

Successful Conversion to Everolimus After Cytomegalovirus Infection in a Heart Transplant Recipient

“…13) Recent studies have suggested that switching CNI to EVL can spare renal function in HTx and renal transplantation recipients. 10,14,15) We consistently found that reducing the dose of CNIs along with administration of EVL improved renal function in the present case.…”

End-Stage Kidney Disease After Pediatric Nonrenal Solid Organ Transplantation

“…[7][8][9][10][11][12][13][14][15][16] The risk of ESKD in adult SOT recipients varies by organ transplanted. 4 This variability may be explained by differences in the burden of baseline comorbidities, variations in intensity of immunosuppressive regimens, and distinct rates of peritransplant AKI.…”