Point: A Call for Advanced Pharmacokinetic and Pharmacodynamic Monitoring to Guide Calcineurin Inhibitor Dosing in Renal Transplant Recipients

The calcineurin inhibitors (CNIs)1 cyclosporin A and, later, tacrolimus, have revolutionized the results of organ transplantation, leading to current acute-rejection rates of 10%–20%(1). Despite substantial reductions in acute-rejection rates, however, late graft loss remains a critical issue after renal transplantation, with a progressive decline in long-term graft survival(2). The 2 major causes of graft loss are death with a functioning graft and chronic allograft nephropathy. The latter has long been considered a late-onset condition, but recent studies have shown a high prevalence of interstitial fibrosis and tubular atrophy at a median of 3 months after transplantation(3). Protocol biopsies obtained 2 years after transplantation from grafts with stable renal function have identified previous acute-rejection episodes and acute CNI-related nephrotoxicity as the most important predictors of chronic allograft nephropathy(4). Donor and recipient characteristics, as well as subclinical rejection (SCR), also play a role in disease progression. SCR is found on protocol biopsy and is defined as tubulointerstitial infiltrates of the renal allograft without functional deterioration. In daily practice, renal function is evaluated by measuring the serum creatinine concentration, but for several reasons this variable is not an adequate marker of the glomerular filtration rate (GFR)(5). The relationship between the serum creatinine concentration and the GFR is not linear, and at a certain part of the curve only a small increment in the creatinine concentration is associated with a marked decrease in the GFR. Moreover, SCR is a patchy process in which uninvolved nephrons can hyperfiltrate and thereby maintain a typical serum creatinine concentration. Although the causal relationship and clinical consequences of SCR are still under debate, prevention of late acute rejection after empirical reduction in the CNI dose appears to be critical(6). Recently, CNI minimization has been advocated as the preferred approach early after renal …