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Diabetic kidney disease (DKD) is the most common cause of CKD. A spot urine albumin-creatinine ratio (UACR) and serum creatinine are used as an indicator of DKD progression. These indicators may not reflect the renal damage of early DKD. The N-acetyl-β-D-glucosaminidase (NAG) is found in the lysosomes of renal proximal tubular cells and the urinary NAG can reflect even subclinical tubular damage. Expression of sodium-glucose cotransporter 2 (SGLT2) is prominently increased in diabetes. This can increase urinary excretion of NAG, involved in carbohydrate metabolism. SGLT2 inhibitor has been widely used in DKD patients. There has been no study yet that clearly explains the theoretical effect of SGLT2i on urinary NAG. We tried to investigate the clinical relevance of clinical parameters including urinary NAG after SGLT2i-use in DKD.
We investigated the change of clinical parameters including urinary NAG in DKD patients. Total 60 patients were prospectively investigated during 1 year. We measured UPCR, UACR, urine NAG-creatinine ratio (UNAGCR, U/g), serum Cr and eGFR with 6-month interval. In addition, the patients were divided into 2 groups according to levels of baseline UNAGCR (high UNAGCR group ≥ 13.9 U/g and low UNAGCR group <13.9 U/g) We performed an analysis to determine whether there were significant changes of mean values of above parameters after use of SGLTi (Forxiga® 10mg once a day).
Baseline parameters except UPCR, UACR and UNAGCR of 2 groups according to baseline UNAGCR did not show significant difference before using SGLT2i. High UNAGCR group showed significantly high levels of UPCR and UACR before using of SGLT2i. (UPCR, p=0.001; UACR, p=0.005, respectively) (Table 1.) The significant difference of UPCR and UACR between two groups maintained until 6 months after using SGLT2i. Based on recent large RCTs on SGLT2i, this study expected dramatic changes in various urinary biomarkers, such as UPCR, UACR and UNAGCR after using SGLT2i. Unfortunately, the significant decrease of various urinary biomarkers, such as UPCR, UACR and UNAGCR after using SGLT2i did not show significantly. (UPCR, -0.44 ± 1.82, p=0.094; UACR, -0.30 ± 1.39, p=0.054; UNAGCR, -0.99 ± 14.76, p=0.755, respectively) (Table 2.) The values of eGFR in patients with DKD showing high level of UNAGCR on baseline decreased significantly during 12 months (p<0.001), and there was significant difference of change in values of eGFR between 2 groups (p=0.039). However, values of parameters such as UPCR and UACR decreased during 12 months in only high UNAGCR group compared to low UNAGCR group (UPCR, p=0.025 and UACR, p=0.039, respectively), and there was significant difference of change in values of UPCR and UACR between 2 groups. (UPCR, p=0.028 and UACR, p=0.034, respectively). (Fig.1) (Table 3, 4.)
Conclusions
DKD patients with only high UNAGCR levels showed marked reduction in UPCR and UACR after using SGLT2i. This trend raises expectation that the renal protective effect through reduction of proteinuria of SGLT2i will be more pronounced in DKD patients with high UNAG levels. Additionally, urinary NAG showed rarely false positives and has been used to determine disease activity and prognosis of various kidney diseases in previous literatures. Conclusively, UNAGCR level before SGLT2i-use in DKD may be a valuable indicator for the active use of SGLT2i when considering our results.