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.