CysC as a more sensitive biomarker of renal function
Scr does not significantly increase until at least 50% renal function is impaired leading to overestimation of GFR (20). As a second biomarker for GFR, CysC outperforms Scr in capturing earlier and more precise changes in renal function. In 2012, KDIGO proposed that CysC can improved accuracy of GFR estimation and CKD classification. CysC was strongly recommended when eGFRScr not be reliable to confirm CKD in absence of other diagnostic evidence (21).
Abundant pharmacokinetic evidence shows that CysC has a better correlation with drug CL and trough levels compared with Scr, which is crucial for dose of renally excreted drugs (22,23). In this study, PPK model showed that CysC was superior to Scr in predicting CL of MPA (ΔOFV= -100.11 vs -96.24, P<0.05). It similar with the conclusions that CysC was superior to Schwartzbed in estimating CL and optimizing dosage for children with vancomycin (24,25). Tan et al. also demonstrated that eGFRCysCimproved prediction of ceftriaxone CL in elder with moderate or severe renal impairment compared with eGFRScr (ΔOFV= -18.66 vs -15.83) (26). In addition, 60% of CKD 1-3 stages derived from eGFRScr were reclassified to a lower region by eGFRCysC, which was supported by 2012 KIDGO guideline that the prognostic advantage of CysC is most apparent among individuals with GFR >45 mL/min/1.73m2 (21). A large multicenter European pediatric cohort study strongly suggested that CysC should replace Scr as the primary biomarker when estimating GFR in children with moderate to severe renal function decline (27).
MPO play an integral role in AAN
MPO, a marker of oxidative stress and inflammation, was associated with a 10% increased risk of CKD progression (28). More importantly, we found that MPO levels were associated with increased drug CL, suggesting that MPO may not only be a biomarker of AAN, but also an independent predictor of kidney function. MPO plays important role in mediating glomerular injury in AAV (29,30). An inflammatory trigger such as infection and drug, activate the neutrophil-mediated immune system, leading to release of MPO. Subsequently, MPO localized in glomeruli activated adaptive immune response, leading to release of inflammatory mediators and oxidants, thereby damaging glomerular capillaries. It has been reported that inflammation has significant effects on drug metabolism by changing the expression levels of drug metabolizing enzymes, which is of great significance to personalized medicine (31). We speculated that MPO, as an inflammatory factor for AAN, increased drug elimination through a similar mechanism.
Although the liver is quantitatively the most important site of glucuronidation, extrahepatic tissues, particularly kidney, may play a significant role in MPA metabolism (32). MPA is primarily conjugated by UDP-glucuronosyltransferase enzymes (UGTs). MPA-glucuronide (MPAG) is the most abundant metabolite primarily produced by UGT1A8 and UGT1A9, with minor part produced by UGT1A1, 1A7 and 1A10; another metabolite AcMPAG is produced mainly by isoform 2B7. UGT1A9 plays a predominant role in hepatic MPA metabolism. UGT1A8 and UGT1A10 are responsible for MPA metabolism in the gastrointestinal tract. MPA and its metabolites are mainly excreted through urine probably mediated by Mrp2 (33,34). In addition to its traditional role of excretion, human kidney possesses an extraordinary capacity for drug metabolism that in some instances surpasses that of liver. It has been reported the expression of UGTs in human kidneys, among which the most abundant UGT enzyme is UGT1A9, followed by UGT2B7 (35).
Inflammation-induced dysregulation patterns of UGTs are probably pathology-dependent, tissue-specific and isoform-heterogeneous. The direction and extent of change depend on the type of inflammation, cytokine spectrum and time course (36,37). In rat colitis model, the expression and activity of hepatic UGTs were significantly down-regulated except for the up-regulation of UGT1A7, but those in small intestine were unaffected (36). Similarly, hepatic mRNA expression of UGT1A1, 1A9, and 2B5 were significantly down-regulated while renal UGT 1A9 and 2B5 were increased after LPS treatment (38). In arthritis rats, hepatic P-gp and Mrp2 significantly decreased, and those were up-regulated in kidney, but those were unchanged in small intestine (39). Interestingly, LPS-induced proinflammatory cytokines caused Mrp2 down-regulated in liver at 24 h post-treatment, but the Mrp2 rebounded at 48 h (40).
It has been reported that GFR failed to accurately predict 48% renal CL of the analyzed compounds, which may be confused by inflammation-mediated change of metabolic enzymes and transporters (41). Systemic inflammatory response to endotoxemia was associated with increased eGFR (42). In addition, augmented renal clearance is common in critically ill patients, which is also relevant to systemic inflammation (43). Consequently, we supposed that MPO was not only an important pathological marker of AAN, but also an inflammatory factor that can increase drug CL by regulating MPA-related metabolic enzymes and transporters.