The effect of intrapatient variability in serum tacrolimus levels with the incidence and severity of nephrotoxicity in kidney transplant patients

Abstract

The vast majority of kidney transplant recipients receive the immunosuppressive drug tacrolimus to prevent graft rejection. One of the key challenges with tacrolimus is its narrow therapeutic window, meaning that the therapeutic dose is very close to the toxic dose. As a result, continuous serum titration is necessary, as increased serum levels can lead to toxicity and nephrotoxicity, while decreased levels can cause graft rejection. Therefore, determining an appropriate serum level is crucial to maximize benefits while minimizing adverse effects. Given the importance of serum tacrolimus levels in the outcomes of kidney transplant patients, we aimed to investigate the impact of intrapatient variability in tacrolimus levels (i.e., fluctuations in serum tacrolimus levels that occur within an individual during treatment) on nephrotoxicity in kidney transplant recipients. This study was designed to determine the effect of intrapatient tacrolimus level variability on the incidence and severity of nephrotoxicity in kidney transplant patients. Materials and Methods: This cross-sectional analytical study included all kidney transplant patients admitted to Imam Reza Hospital in Tabriz who were treated with the immunosuppressive drug tacrolimus. Data collected for this study included patient gender, age, medical history (such as a history of glomerulonephritis, hypertensive nephropathy, diabetes, new-onset diabetes, diabetic nephropathy, polycystic kidney disease, graft rejection, death during one-year follow-up, duration of dialysis, and graft duration), GFR of the transplanted kidney, serum concentrations of tacrolimus, creatinine, and urea, all of which were extracted from patient records. Results: Out of the 94 patients analyzed, 60 (63.8%) were male and 34 (36.2%) were female, with a mean age of 47.0 years (SD 12.9). A statistically significant direct correlation was found between intrapatient variability in tacrolimus levels and serum creatinine (P = 0.001, r = 0.351) as well as urea (P < 0.001, r = 0.490). A statistically significant inverse correlation was observed between intrapatient variability in tacrolimus levels and the GFR of the transplanted kidney (P < 0.001, r = -0.353). The intrapatient variability in tacrolimus levels was significantly higher in patients with graft rejection compared to those without rejection (P = 0.003) and was also significantly higher in patients who died compared to those who survived (P = 0.048).