Comparison of bias and accuracy using cystatin C and creatinine in CKD-EPI equations for GFR estimation.

BACKGROUND: The directly measured glomerular filtrate rate (mGFR) is the gold standard for kidney function, but it is invasive and costly. The Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equations have been widely used to estimate GFR, however, the comparative accuracy of estimated GFR (eGFR) using creatinine and cystatin C in CKD-EPI equations remains unclear. We performed this meta-analysis to assess the bias and accuracy of eGFR using equations of CKD-EPIcrea, CKD-EPIcys, and CKD-EPIcrea/cys in adult populations relevant to primary health care. METHODS: Pubmed, Web of Science, EMBASE, and the Cochrane Library were searched from inception until December 2019 for related studies. RESULTS: A total of 35 studies with 23,667 participants, which reported the data on the bias, and/or P30, and/or R were included. The difference in the bias of eGFR using CKD-EPIcys was 4.84 mL/min/1.73 m2 (95% CI, 1.88~7.80) lower than using CKD-EPIcrea, and 1.50 mL/min/1.73 m2 (95% CI, 0.05~2.95) lower than using CKD-EPIcrea/cys. These gaps increased in subgroups of low mGFR (<60 mL/min/1.73 m2). CKD-EPIcrea/cys eGFR achieved the highest accuracy, 7.50% higher than CKD-EPIcrea (95% CI, 4.81~10.18), and 3.21% higher than CKD-EPIcys (95% CI, -0.43~6.85); and the best correlation with mGFR, with Fisher's z transformed R of 1.20 (95% CI, 0.89-1.50). CONCLUSIONS: CKD-EPIcrea/cys and CKD-EPIcys gave less bias and more accurate estimates of mGFR than CKD-EPIcrea. More variables and coefficients could be added in CKD-EPI equations to achieve less bias and more accuracy in future research.

Role of A20/TNFAIP3 deficiency in lupus nephritis in MRL/lpr mice.

BACKGROUND: The activation of the nuclear factor-κB (NF-κB) signaling pathway gives rise to inflammation in the pathogenesis of lupus nephritis (LN), with A20 serving as a negative feedback regulator and ubiquitin C­terminal hydrolase L1 (UCH-L1) acting as a downstream target protein. However, their roles in the mechanism of LN remain undetermined. METHODS: In the present study, the expression of A20 and UCH-L1, the activity of NF-κB and ubiquitin-proteasome system (UPS) were measured in MRL/lpr mice and A20 gene silenced podocytes. The severity of podocyte injury and immune complex deposits were detected by transmission electron microscopy. RESULTS: The in vivo experiments revealed that A20 failed to terminate the activation of NF-κB, which was accompanied by UCH-L1 overexpression, ubiquitin accumulation, and glomerular injury in LN mice. Immunosuppression therapy did improve LN progression by attenuating A20 deficiency. In vitro experiments confirmed that tumor necrosis factor-α induced NF-κB activation, which led to UCH-L1 overexpression, UPS impairment, the upregulation of desmin and the downregulation of synaptopodin in A20 gene silenced podocytes. CONCLUSION: Thus, the results of the present study suggest that A20 regulates UCH-L1 expression via the NF-κB signaling pathway and A20 deficiency might play an important role in LN pathogenesis. Therefore, the A20 protein may serve as a promising therapeutic target for LN.

Mucin 4 Gene Silencing Reduces Oxidative Stress and Calcium Oxalate Crystal Formation in Renal Tubular Epithelial Cells Through the Extracellular Signal-Regulated Kinase Signaling Pathway in Nephrolithiasis Rat Model.

BACKGROUND/AIMS: Nephrolithiasis plagues a great number of patients all over the world. Increasing evidence shows that the extracellular signal-regulated kinase (ERK) signaling pathway and renal tubular epithelial cell (RTEC) dysfunction and attrition are central to the pathogenesis of kidney diseases. Mucin 4 (MUC4) is reported as an activator of ERK signaling pathway in epithelial cells. In this study, using rat models of calcium oxalate (CaOx) nephrolithiasis, the present study aims to define the roles of MUC4 and ERK signaling pathway as contributors to oxidative stress and CaOx crystal formation in RTEC. METHODS: Data sets of nephrolithiasis were searched using GEO database and a heat flow map was drawn. Then MUC4 function was predicted. Wistar rats were prepared for the purpose of model establishment of ethylene glycol and ammonium chloride induced CaOx nephrolithiasis. In order to assess the detailed regulatory mechanism of MUC4 silencing on the ERK signaling pathway and RTEC, we used recombinant plasmid to downregulate MUC4 expression in Wistar rat-based models. Samples from rat urine, serum and kidney tissues were reviewed to identify oxalic acid and calcium contents, BUN, Cr, Ca2+ and P3+ levels, calcium crystal formation in renal tubules and MUC4 positive expression rate. Finally, RT-qPCR, Western blot analysis, and ELISA were employed to access oxidative stress state and CaOx crystal formation in RTEC. RESULTS: Initially, MUC4 was found to have an influence on the process of nephrolithiasis. MUC4 was upregulated in the CaOx nephrolithiasis model rats. We proved that the silencing of MUC4 triggered the inactivation of ERK signaling pathway. Following the silencing of MUC4 or the inhibition of ERK signaling pathway, the oxalic acid and calcium contents in rat urine, BUN, Cr, Ca2+ and P3+ levels in rat serum, p-ERK1/2, MCP-1 and OPN expressions in RTEC and H2O2 and MDA levels in the cultured supernatant were downregulated, but the GSH-Px, CAT and SOD levels in the cultured supernatant were increased. Moreover, MUC4 silencing or ERK signaling pathway inactivation may decrease the formation of CaOx crystals. CONCLUSION: Taken together, silencing of MUC4 can inactivate the ERK signaling pathway and further restrain oxidative stress and CaOx crystal formation in RTEC. Thus, MUC4 represents a potential investigative focus target in nephrolithiasis.