THE USEFULNESS OF URINARY N-ACETYL- Β-D-GLUCOSAMINIDASE-CREATININE RATIO AS THE BIOMARKER TO DECIDE LONG-TERM USE OF SODIUM-GLUCOSE COTRANSPORTER-2 INHIBITOR IN DIABETIC KIDNEY DISEASE

Introduction:

Diabetic kidney disease (DKD) is rapidly increasing worldwide. Albuminuria and serum creatinine are clinically used as biomarkers indicating the progression of DKD. Unfortunately, these biomarkers cannot reflect early renal damage in chronic kidney disease including 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. Recently, the use of sodium-glucose cotransporter 2 inhibitor (SGLT2i) is prominently increased in diabetic kidney disease. In DKD patients, urinary excretion of NAG, which is involved in carbohydrate metabolism, is prominently increased compared to other patients. probably because SGLT2 expression in proximal tubules of DKD patients is increased. However, there has been no study yet that clearly explains the theoretical effect of SGLT2i on urinary NAG in DKD patients. We have already reported the clinical relevance of clinical parameters including urinary NAG after SGLT2i-use during 12 months in DKD patients at 2023 WCN meeting. Here, we report clinical data for the usefulness of urinary NAG-creatinine ratio (UANGCR) in DKD patients using SGLT2i during 24 months

Methods:

Total 43 patients were prospectively investigated during two year. Initially, total 60 patients were enrolled but, 17 patients were dropped out of this study after one year. We measured UPCR, UACR, urine NAG-creatinine ratio (UNAGCR, U/g), serum Cr and eGFR with 12-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 SGLT2i (Forxiga® 10mg once a day). According to finally enrolled data, baseline parameters except UNAGCR of two groups did not show significant difference before using SGLT2i. (Table 1)

Results:

In baseline, high UNAGCR group did not showed significantly high levels of UPCR and UACR before using of SGLT2i. (UPCR: 2.38 ± 2.07 vs 1.20 ± 1.61, p=0.061; UACR: 1.54 ± 1.24 vs 0.92 ± 1.23, p=0.161, respectively) (Table 1.)  Serum creatinine levels of total 43 patients increased significant during two years. (p=0.001) However, other parameters including eGFR, UACR, UPCR and UNAGCR of total 43 patients did not show significant change during two years. There was a significant change of UNAGCR values according to several factors, such as CKD stage, CKD cause, and SGLT2i dose in one-year data (2023 WCN meeting reported) (CKD stage, p=0.012; CKD cause, p=0.004; SGLT2i dose, p=0.001, respectively), but change of UNAGCR values according to above factors did not show statistically significant in two-year data. (CKD stage, p=0.390 and CKD cause, p=0.779, respectively) However, in two-year data, high UNAGCR group showed significant decrease of values of UNAGCR after long-term use of SGLT2i and there was significant difference between two groups. (p=0.001) (Figure 1.) Unfortunately, high UNAGCR group did not show significant decrease of values of several parameters, such as UPCR, UACR, serum Cr, and eGFR, after long-term use of SGLT2i, and there was no also significant difference between two groups. (UPCR, p=0.123; UACR, p=0.265; Serum Cr, p=0.823; eGFR, p=0.828, respectively) (Figure 1.) This study was small-sized single center study and total 17 patients after one-year were dropped. Due to point, we think that there were no significant changes of several parameters in two-year data. Theoretically, the long-term use of SGLT2i in DKD patients may have long-term renal protective effects by reducing proximal tubular energy expenditure, which may be manifested as a significant decrease in urine NAG excretion. 

Conclusions:

The results of this study showed that in DKD patients with high baseline urine NAG levels, long-term use of SGLT2i resulted in significantly lower urine NAG levels throughout the study period compared to patients with low urine NAG levels. Conclusively, high UNAGCR level before long-term use of SGLT2i may be a valuable indicator for the active use of SGLT2i.

I have no potential conflict of interest to disclose.

I did not use generative AI and AI-assisted technologies in the writing process.