High intrapatient variability (IPV) of tacrolimus concentrations is increasingly recognized as a predictor of poor outcome in solid organ recipients. How it relates to evolution of histology has not been explored. We analyzed tacrolimus IPV using the coefficient of variability (CV) from months 6-12 after transplantation in a cohort of 220 renal recipients for whom paired protocol biopsies at 3 mo and 2 years were available. Recipients in the highest CV tertile had an increased risk of moderate to severe fibrosis and tubular atrophy by 2 years compared with the low-IPV tertile (odds ratio [OR] 2.47, 95% confidence interval [CI] 1.09-5.60, p = 0.031; and OR 2.40, 95% CI 1.03-5.60, p = 0.043, respectively). Other predictors were donor age, severity of chronic lesions at 3 mo, and presence of borderline or subclinical rejection at 3 mo. Chronicity score increased significantly more in the high CV tertile group than in the middle and low tertiles (mean increase 1.97 ± 2.03 vs. 1.18 ± 2.44 and 1.12 ± 1.80, respectively; p < 0.05). CV did not predict evolution of renal function, which did not deteriorate within the 2-year follow-up period. These results indicate that high IPV is related to accelerated progression of chronic histologic lesions before any evidence of renal dysfunction.

The calcineurin inhibitors (CNIs) tacrolimus and cyclosporine are widely used immunosuppressive drugs characterized by high pharmacokinetic and pharmacodynamic variability, both between and within patients. CNIs are highly lipophilic, poorly soluble, undergo extensive first-pass metabolism and are cleared by the liver. In both gut and liver, CNIs are substrates for the cytochrome P450 (CYP) enzymes 3A4 and 3A5 as well as the P-glycoprotein (P-gp) transporter, whose functions are determined by a complex interplay between genetic polymorphisms, the inductive or inhibitory effects of many drugs, herbs, food constituents and endogenous substances such as uremic toxins in case of end-stage renal disease. The current literature is reviewed for all common clinical determinants of variability in CNI disposition such as food intake, diarrhea and other intestinal pathology, anemia, hypoalbuminemia, hyperlipidemia, liver and kidney disease, aging, ethnicity, formulation and time post-transplant, focusing on the underlying mechanisms. Drugs and herb- and food constituents mainly interact with CNIs at the gut level by affecting bioavailability, with interactions generally being much more pronounced in case of oral compared with intravenous co-administration. Cyclosporine disposition is less susceptible to these interactions compared with tacrolimus, possibly because cyclosporine is itself a moderately strong CYP3A4- and strong P-gp inhibitor, blunting the effect of additional inhibitors. P-gp also has a major role in limiting distribution of CNI to tissues such as the brain, placenta, lymphocytes and kidney. Inactivating polymorphisms and inhibition of P-gp have the potential to significantly increase CNI exposure in these tissues with possible implications for toxicity and efficacy.

Administration of azole antifungals to tacrolimus-treated solid organ recipients results in a major drug-drug interaction characterized by increased exposure to tacrolimus. The magnitude of this interaction is highly variable but cannot currently be predicted. We performed a retrospective analysis of 126 solid organ recipients (95 lung, 31 kidney) co-treated with tacrolimus and voriconazole (n = 100) or posaconazole (n = 26). Predictors of the change in tacrolimus dose-corrected trough concentrations (C/D) between baseline and tacrolimus-azole co-therapy were assessed using linear mixed modeling. Patients were genotyped for relevant polymorphisms in CYP3A4, CYP3A5, MDR1, CYP2C19, POR, and UGT1A4. Tacrolimus C/D increased by a factor 5.0 ± 2.7 (range 1.0-20.2) for voriconazole and 4.4 ± 2.6 (range 0.9-18.0) for posaconazole, suggesting that a 66% dose reduction is insufficient for the majority of patients. Change in C/D was blunted in CYP3A5 expressors (estimated effect: -43%, p = 0.017) and affected by hematocrit (+8% per %, p = 0.004), baseline C/D (-14% per 100% increase, p < 0.001), and age (+1%, p = 0.008). However, the final model explained only 22% of interindividual variability in C/D change. In conclusion, CYP3A5 genotype and several clinical variables were identified as modulators of the tacrolimus-azole interaction, but these did not permit accurate predictions in individual patients.

All causes of renal allograft injury, when severe and/or sustained, can result in chronic histological damage of which interstitial fibrosis and tubular atrophy are dominant features. Unless a specific disease process can be identified, what drives interstitial fibrosis and tubular atrophy progression in individual patients is often unclear. In general, clinicopathological factors known to predict and drive allograft fibrosis include graft quality, inflammation (whether "nonspecific" or related to a specific diagnosis), infections, such as polyomavirus-associated nephropathy, calcineurin inhibitors (CNI), and genetic factors. The incidence and severity of chronic histological damage have decreased substantially over the last 3 decades, but it is difficult to disentangle what effects individual innovations (eg, better matching and preservation techniques, lower CNI dosing, BK viremia screening) may have had. There is little evidence that CNI-sparing/minimization strategies, steroid minimization or renin-angiotensin-aldosterone system blockade result in better preservation of intermediate-term histology. Treatment of subclinical rejections has only proven beneficial to histological and functional outcome in studies in which the rate of subclinical rejection in the first 3 months was greater than 10% to 15%. Potential novel antifibrotic strategies include antagonists of transforming growth factor-β, connective tissue growth factor, several tyrosine kinase ligands (epidermal growth factor, platelet-derived growth factor, vascular endothelial growth factor), endothelin and inhibitors of chemotaxis. Although many of these drugs are mainly being developed and marketed for oncological indications and diseases, such as idiopathic pulmonary fibrosis, a number may hold promise in the treatment of diabetic nephropathy, which could eventually lead to applications in renal transplantation.