Baseline Urinary Angiotensinogen Excretion Predicts Deterioration Of The Kidney Function in Patients With Chronic Kidney Disease Ⅱ
Jan 11, 2024
Results Patient characteristics
Sixty-two patients with CKD who were admitted to our hospital during the study duration were included in this study. Their baseline characteristics are presented in Table 1. Due to most patients having been admitted to undergo a renal biopsy for chronic glomerulonephritis, most patients were middle-aged (48.5±17.7 years old), and their renal function was preserved (serum creatinine: 1.05±0.45 mg/dL; eGFR: 59.8±22.6 mL/min/1.73 m2 ), with logarithmic urinary albumin excretion of 2.42±0.60 mg/day. The number of patients administered RAS blockers was 17 [Ang II receptor blockers (ARBs), n=16; angiotensin-converting enzyme inhibitors (ACE-Is), n=1] at the start of this study and 35 (ARBs, n=33; ACE-Is, n=2) throughout this study.
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Annual change in the eGFR in all patients
The average follow-up period was 3.4±1.5 years, and the average annual change in the eGFR was -0.93±6.16 mL/ min/1.73 m2 during this period.
Relationship between the annual change in the eGFR and several clinical parameters, including the baseline urinary AGT excretion
We first evaluated the relationship between the annual change in the eGFR and several clinical parameters, including baseline urinary AGT excretion. Significant negative relationships were found between the annual change in the eGFR and the age (r=-0.35, p<0.01), systolic BP (r=-0.36, p <0.01), and daily urinary albumin excretion (r=-0.32, p= 0.011) (Table 2). In addition, the annual change in the eGFR was significantly and negatively correlated with the baseline urinary AGT excretion (r=-0.31, p=0.015) (Fig. 2). However, no significant relationships were found between the annual change in the eGFR and plasma Ang II (r=0.22, p=0.10) (Table 2). We also performed multiple linear regression analyses between the annual change in the eGFR and baseline urinary AGT excretion after adjusting for the age, sex, BMI, and baseline eGFR. A significant negative relationship was found between them after adjusting in this manner (β=- 0.27, p=0.032) (Table 3).
The comparison of the annual change in the eGFR among quartiles according to the baseline urinary AGT excretion
We then divided the patients into quartiles according to the baseline urinary AGT excretion and compared the levels of clinical parameters among the quartiles. The systolic and diastolic BPs in the highest quartile of baseline urinary AGT excretion (Group 4) (systolic BP: 124.9±12.7 mmHg and diastolic BP: 77.5±10.4 mmHg) were significantly higher than those in Group 1 (systolic BP: 109.2±9.9 mmHg; p< 0.05 and diastolic BP: 66.3±4.6 mmHg; p<0.01). In addition, the logarithmic daily urinary albumin excretion (2.99± 0.31 mg/day) in the highest quartile (Group 4) was higher than that in the other groups (Group 1: 1.98±0.43 mg/day; p<0.05, Group 2: 2.43±0.55 mg/day; p<0.05, and Group 3: 2.34±0.63 mg/day; p<0.05) (Supplementary material 1). The annual change in the eGFR in the highest quartile of baseline urinary AGT excretion (Group 4; -5.48±7.14 mL/min/ 1.73 m2 /year) was significantly lower than that in Group 2 (1.41±3.39 mL/min/1.73 m2 /year; p<0.01) and Group 3 (0.46±5.50 mL/min/1.73 m2 /year; p=0.023). In addition, a similar tendency was found between the lowest quartile of baseline urinary AGT excretion (Group 1: -0.31±6.11 mL/ min/1.73 m2 /year) and Group 4 (p=0.073) (Fig. 2).
Covariance analyses between the quartiles of baseline urinary AGT excretion and annual change in the eGFR after adjustment
Covariance analyses were also performed to examine the association between the quartiles of the baseline urinary AGT excretion and the annual change in the eGFR adjusted for age, sex, BMI, and baseline eGFR. Covariance analyses showed that the quartiles of baseline urinary AGT excretion differed significantly about the annual change in the eGFR after adjustment (Model 1: Group 1 vs. Group 4, p=0.11; Group 2 vs. Group 4, p<0.01; and Group 3 vs. Group 4, p=0.011; and Model 2: Group 1 vs. Group 4, p= 0.09; Group 2 vs. Group 4, p<0.01; and Group 3 vs. Group 4, p=0.031) (Fig. 3 and Table 4).
Hypertension is associated with an increased risk of development of CKD. Kanno et al. examined 2,150 individuals without preexisting CKD from the general population during a mean follow-up of 6.5 years, and 461 incidences of CKD were recorded. They indicated that the adjusted hazard ratios of CKD were significantly higher for pre-hypertension (1.49, p<0.003), Stage 1 (1.83, p<0.001), and Stage 2 (2.55, p<0.001) hypertension in the study than normotension (21).
In contrast, Kiriyama et al. examined 2,739 individuals who underwent repeated health checkups, and they found that an eGFR decline was more commonly observed in individuals with proteinuria at baseline than in those without proteinuria at baseline (individuals with proteinuria: 3.3% vs. individuals without proteinuria: 0.8%, p<0.001) (22). These previous reports coincide with our data indicating that systolic BP and urinary albumin excretion were predictors of renal dysfunction in the present study. Furthermore, it has also been demonstrated that urinary AGT is a surrogate marker of intrarenal RAS activity (2, 5, 6, 9-13) and that urinary AGT is associated with the levels of renal damage and BPs (2-6). Therefore, we suspect that the baseline urinary AGT levels predicted renal dysfunction in the present study.
It may not be meaningful to measure urinary AGT levels, as urinary AGT levels may serve as a replacement for renal damage or hypertension. However, we reported that systolic BP progressively increased in double transgenic mice expressing human renin systemically in addition to human AGT in the kidney (23). Saito et al. indicated that an increase in urinary AGT levels preceded an increase in urinary albumin levels in patients with type 1 diabetes (11). We previously indicated that the intrarenal RAS is activated in kidney transplant donors immediately after kidney donation, before an increase in urinary albumin levels (24). These findings indicate that intrarenal RAS activation induces renal damage, such as microalbuminuria and hypertension. Therefore, urinary AGT levels are not merely reflective of renal damage and hypertension; it is meaningful to measure urinary AGT levels.
Recently, Lee et al. reported that changes in urinary AGT correlated with a decline in kidney function in patients with type 2 diabetes (14), and Sawaguchi et al. reported that elevated levels of urinary AGT in type 2 diabetic patients with albuminuria were a risk factor for worsening renal and cardiovascular complications (15). In addition, we previously indicated that intrarenal RAS activation was significantly and positively correlated with renal damage and hypertension in patients with CKD, including diabetic nephropathy patients (2). This suggests that baseline urinary AGT levels predicted deterioration of kidney function in all patients with CKD in the present study. However, the AGT expression in glomerular mesangial cells is reportedly increased by high glucose levels (25, 26). Furthermore, the AGT expression in the proximal tubular cells is stimulated by high glucose levels. Immediately after a sodium-glucose co-transporter 2 (SGLT2) inhibitor is administered, urinary AGT levels are increased by increases in the glucose levels in the proximal tubular lumen. However, when glucose levels are decreased by an SGLT2 inhibitor, the glucose levels in the proximal tubular lumen decrease, as does the AGT expression in the proximal tubular cells (27). As mentioned previously, the degree of intrarenal RAS activation differs among certain conditions, such as based on glucose levels and prescription drug use. Therefore, the results of all patients with CKD in the present study might be different from those of only patients with diabetes in the previous studies. However, we obtained results that were similar to those in the previous studies, suggesting that urinary AGT levels predict renal dysfunction in the present study.
Several limitations associated with the present study warrant mention. First, its sample size was small, and patients were recruited from a single center. Second, the follow-up period was 3.4±1.5 years, and the duration was relatively short. Finally, although some interventions with diets, such as a low-sodium diet, were made during the follow-up period in our outpatient department, the interventions were not equal for all patients with CKD. In addition, the salt intake was not evaluated by the collection of daily urine for all patients. Therefore, it was difficult for us to evaluate the influence of food intake on the findings. Nevertheless, we were able to demonstrate that patients with CKD with elevated baseline urinary AGT levels, similar to those with elevated urinary albumin levels and BP values, showed rapid renal dysfunction compared with other patients.
In conclusion, the annual change in the eGFR was significantly and negatively associated with the baseline urinary AGT levels. Furthermore, patients in the highest quartile of baseline urinary AGT levels revealed a progressive decline in the eGFR. These results suggest that elevated baseline urinary AGT levels predict rapid renal dysfunction in patients with CKD. In the future, larger and longer-term studies will be required to further our findings.
References
1. Kobori H, Nangaku M, Navar LG, Nishiyama A. The intrarenal renin-angiotensin system: from physiology to the pathobiology of hypertension and kidney disease. Pharmacol Rev 59: 251-287, 2007.
2. Isobe S, Ohashi N, Fujikura T, et al. Disturbed circadian rhythm of the intrarenal renin-angiotensin system: relevant to nocturnal hypertension and renal damage. Clin Exp Nephrol 19: 231-239, 2015.
3. Ohashi N, Katsurada A, Miyata K, et al. Activation of reactive oxygen species and the renin-angiotensin system in IgA nephropathythy model mice. Clin Exp Pharmacol Physiol 36: 509-515, 2009.
4. Isobe S, Ohashi N, Ishigaki S, et al. Augmented circadian rhythm of the intrarenal renin-angiotensin systems in anti-thymocyte serum nephritis rats. Hypertens Res 39: 312-320, 2016.
5. Kobori H, Alper AB Jr, Shenava R, et al. Urinary angiotensinogen as a novel biomarker of the intrarenal renin-angiotensin system status in hypertensive patients. Hypertension 53: 344-350, 2009.
6. Kobori H, Ohashi N, Katsurada A, et al. Urinary angiotensinogen as a potential biomarker of severity of chronic kidney diseases. J Am Soc Hypertens 2: 349-354, 2008.
7. Gould AB, Green D. Kinetics of the human renin and human substrate reaction. Cardiovasc Res 5: 86-89, 1971
8. Brasier AR, Li J. Mechanisms for inducible control of angiotensinnogen gene transcription. Hypertension 27: 465-475, 1996.
9. Yamamoto T, Nakagawa T, Suzuki H, et al. Urinary angiotensingen as a marker of intrarenal angiotensin II activity associated with deterioration of renal function in patients with chronic kidney disease. J Am Soc Nephrol 18: 1558-1565, 2007.
10. Nishiyama A, Konishi Y, Ohashi N, et al. Urinary angiotensinogen reflects the activity of the intrarenal renin-angiotensin system in patients with IgA nephropathy. Nephrol Dial Transplant 26: 170-177, 2011.
11. Saito T, Urushihara M, Kotani Y, Kagami S, Kobori H. Increased urinary angiotensinogen is precedent to increased urinary albumin in patients with type 1 diabetes. Am J Med Sci 338: 478-480, 2009.
12. Kobori H, Harrison-Bernard LM, Navar LG. Urinary excretion of angiotensinogen reflects intrarenal angiotensinogen production. Kidney Int 61: 579-585, 2002.
13. Kobori H, Navar LG. Urinary angiotensinogen as a novel biomarker of intrarenal renin-angiotensin system in chronic kidney disease. Int Rev Thromb 6: 108-116, 2011.
14. Lee MJ, Kim SS, Kim IJ, et al. Changes in urinary angiotensingen associated with deterioration of kidney function in patients with type 2 diabetes mellitus. J Korean Med Sci 32: 782-788, 2017.
