Urinary Angiotensinogen Excretion Predicts Deterioration Of The Kidney Function in Patients With Chronic Kidney Disease

Contact: Audrey Hu (Whatsapp:008613880143964) Email: audrey.hu@wecistanche.com

Sayaka Ishigaki, Naro Ohashi, Taro Aoki, Takashi Matsuyama, Shinsuke Isobe & et al.

Abstract

Objective: The intrarenal renin-angiotensin system (RAS) is activated in patients with chronic kidney disease(CKD), and urinary angiotensinogen(AGT)levels, a surrogate marker of the intrarenal RAS activation, are associated with blood pressure (BP)and urinary albumin excretion. In addition, it has been shown that changes in urinary AGT(urinary angiotensinogen) levels correlate with annual changes in the estimated glomerular filtration rate (eGFR) in patients with type 2 diabetes and that elevated levels of urinary AGT(urinary angiotensinogen) in type 2 diabetic patients with albuminuria are a high-risk factor for worsening renal and cardiovascular complications. However, whether or not baseline urinary AGT levels predict deterioration of the kidney function in all patients with CKD(chronic kidney disease) is unclear. Methods: We recruited 62 patients with CKD(chronic kidney disease) whose eGFR was >15 mL/min/1.73 m². We performed 24 hour ambulatory BP monitoring at 30 min intervals and daily urinary collection to examine the urinary AGT(urinary angiotensinogen) levels and albumin excretion and measured the levels of plasma angiotensin I(Ang I), a surrogate marker of circulating RAS. In addition, annual changes in the eGFR were followed up for 3.4±1.5 years. Results: Annual changes in the eGFR were significantly and negatively associated with urinary AGT(urinary angiotensinogen) levels (r=0.31,p=0.015)as well as the age, systolic BP, and urinary albumin levels.In contrast, annual changes in the eGFR were not correlated with plasma Ang I levels. Furthermore, when dividing patients into quartiles according to urinary AGT(urinary angiotensinogen) levels, patients with the highest urinary AGT(urinary angiotensinogen) levels showed a progressive decline in the eGFR. Conclusion: These results suggest that elevated baseline urinary AGT(urinary angiotensinogen) levels can predict renal dysfunction in patients with CKD(chronic kidney disease).

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Discussion

This study showed that the annual change in the eGFR was significantly and negatively associated with the baseline urinary AGT(urinary angiotensinogen) levels, even after adjusting for several factors. In addition, when the baseline urinary AGT(urinary angiotensinogen) levels were divided into quartiles, the patients with CKD(chronic kidney disease) with the highest baseline urinary AGT(urinary angiotensinogen) levels showed a progressive decline in the eGFR compared with the patients with lower baseline urinary AGT(urinary angiotensinogen) levels, and covariance analyses showed that the quartiles of the baseline urinary AGT(urinary angiotensinogen) excretion differed significantly with respect to the annual change in the eGFR after adjustment. These results suggest that elevated urinary AGT(urinary angiotensinogen) levels predict renal dysfunction in patients with CKD(chronic kidney disease).

Hypertension is associated with an increased risk of development of CKD(chronic kidney disease). Kanno et al.examined 2,150 individuals without preexisting CKD(chronic kidney disease) from the general population during a mean follow up of 6.5 years, and 461 incidences of CKD(chronic kidney disease) were recorded. They indicated that the adjusted hazard ratios of CKD(chronic kidney disease) were significantly higher for prehypertension (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).

urinary angiotensinogen levels

Figure 3. The comparison of the annual change in the estimated glomerular filtration rate (eGFR) among quartiles according to the baseline urinary angiotensinogen (AGT)excretion. The patients were divided into the quartiles according to the baseline urinary AGT(urinary angiotensinogen) excretion, and the levels of annual change in the eGFR were compared among the quartiles. Box plots represent the 25th percentile, median, and 75th percentile of each group. Error bars denote the 10th and 90th percentiles. Groups were numbered from the lowest quartile of baseline urinary AGT(urinary angiotensinogen) excretion. Data are means±standard deviation. **p<0.01 Group 2 vs.Group 4.*p<0.05 Group 3 vs.Group 4.

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(urinary angiotensinogen) is a surrogate marker of intrarenal RAS activity (2, 5,6, 9 13)and that urinary AGT(urinary angiotensinogen) is associated with the levels of renal damage and BPs(2-6). Therefore, we suspect that the baseline urinary AGT(urinary angiotensinogen) levels predicted renal dysfunction in the present study.

It may not be meaningful to measure urinary AGT(urinary angiotensinogen) levels, as urinary AGT(urinary angiotensinogen) 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(urinary angiotensinogen) in the kidney(23).Saito et al. indicated that an increase in urinary AGT(urinary angiotensinogen) 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, prior to an increase in urinary albumin levels (24). These findings indicate that intrarenal RASactivation induces renal damage, such as microalbuminuria and hypertension. Therefore, urinary AGT(urinary angiotensinogen) levels are not merely reflective of renal damage and hypertension; it is meaningful to measure urinary AGT(urinary angiotensinogen) levels.

Recently, Lee et al. reported that changes in urinary AGT(urinary angiotensinogen) correlated with a decline in the kidney function in patients with type 2 diabetes(14),and Sawaguchi et al. reported that elevated levels of urinary AGT(urinary angiotensinogen) 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(chronic kidney disease), including diabetic nephropathy patients(2). This suggests that baseline urinary AGT(urinary angiotensinogen) levels predicted deterioration of the kidney function in all patients with CKD(chronic kidney disease) in the present study. However, the AGT(urinary angiotensinogen) expression in glomerular mesangial cells is reportedly increased by high glucose levels(25,26). Furthermore, the AGT(urinary angiotensinogen) expression in the proximal tubular cells is stimulated by high glucose levels. Immediately after a sodium glucose cotransporter 2 (SGLT2)inhibitor is administered, urinary AGT(urinary angiotensinogen) 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(urinary angiotensinogen) expression in the proximal tubular cells(27). As mentioned previously, the degree of intrarenal RAS activation differs among certain conditions, such as based on the glucose levels and prescription drug use. Therefore, it was possible that the results of all patients with CKD(chronic kidney disease) in the present study are 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(urinary angiotensinogen) levels predict renal dysfunction in the present study.

Table 4. Covariance Analyses to Determine the Association between the Quartiles of Baseline Urinary Angiotensinogen (AGT) Excretion Levels and Annual Change in Estimated Glomerular Filtration Rate (eGFR) after Adjustment for Age, Sex, Body Mass Index (BMI) and Baseline eGFR.

urinary angiotensinogen

The patients with RAS blockers showed elevated values of systolic BP(with RAS blockers: 124.7±15.0 mmHg vs. without RAS blockers:110.4±9.0 mmHg;p<0.01), urinary Alb excretion(with RAS blockers: 2.63±0.55 mg/day vs. without RAS blockers: 2.22±0.58;p=0.014),and baseline urinary AGT(urinary angiotensinogen) excretion(with RAS blockers: 2.02±0.57 ug/gCr vs.without RAS blockers:1.67±0.60 ug/gCr; p=0.024). Furthermore, the annual decline in the eGFR with RAS blockers was greater than that without RAS blockers(with RAS blockers∶3.08±6.85 mL/min/1.73 m²vs.without RAS blockers∶1.68±3.94 mL/min/1.73 m²; p<0.01）（data not shown). These results suggest that RAS blockers were administered to patients with relatively severe CKD(chronic kidney disease) in our elevated levels of urinary AGT(urinary angiotensinogen) 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(chronic kidney disease), including diabetic nephropathy patients(2). This suggests that baseline urinary AGT(urinary angiotensinogen) levels predicted deterioration of the kidney function in all patients with CKD(chronic kidney disease) in the present study. However, the AGT(urinary angiotensinogen) expression in glomerular mesangial cells is reportedly increased by high glucose levels(25,26). Furthermore, the AGT(urinary angiotensinogen) expression in the proximal tubular cells is stimulated by high glucose levels. Immediately after a sodium glucose cotransporter 2 (SGLT2)inhibitor is administered, urinary AGT(urinary angiotensinogen) 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(urinary angiotensinogen) expression in the proximal tubular cells(27). As mentioned previously, the degree of intrarenal RAS activation differs among certain conditions, such as based on the glucose levels and prescription drug use. Therefore, it was possible that the results of all patients with CKD(chronic kidney disease) in the present study are 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(urinary angiotensinogen) 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(chronic kidney disease). 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(chronic kidney disease) with elevated baseline urinary AGT(urinary angiotensinogen) 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(urinary angiotensinogen) levels. Furthermore, patients in the highest quartile of baseline urinary AGT(urinary angiotensinogen) levels revealed a progressive decline in the eGFR. These results suggest that elevated baseline urinary AGT(urinary angiotensinogen) levels predict rapid renal dysfunction in patients with CKD(chronic kidney disease). In the future, larger and longerterm studies will be required to further our findings.

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How Important Is The Role Of Renin-angiotensin System in Chronic Kidney Disease Management

PART Ⅱ：Dietary Modification Alters The Intrarenal Immunologic Micromilieu And Susceptibility To Lschemic Acute Kidney Injury