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

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, is associated with blood pressure (BP) and urinary albumin excretion. In addition, it has been shown that changes in urinary AGT 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 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 kidney function in all patients with CKD is unclear. 

Methods We recruited 62 patients with CKD whose eGFR was >15 mL/min/1.73 m2 . We performed 24-hour ambulatory BP monitoring at 30-minute intervals and daily urinary collection to examine the urinary AGT levels and albumin excretion and measured the levels of plasma angiotensin II (Ang II), 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 levels (r=-0.31, p=0.015) as well as age, systolic BP, and urinary albumin levels. In contrast, annual changes in the eGFR were not correlated with plasma Ang II levels. Furthermore, when dividing patients into quartiles according to urinary AGT levels, patients with the highest urinary AGT levels showed a progressive decline in the eGFR. 

Conclusion These results suggest that elevated baseline urinary AGT levels can predict renal dysfunction in patients with CKD.

Keywords: chronic kidney disease, intrarenal renin-angiotensin system, renal prognosis, urinary

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Introduction 

The circulating renin-angiotensin system (RAS) plays a critical role in the regulation of arterial pressure and sodium homeostasis (1). A tissue-specific RAS, independent of the circulating RAS, has been characterized in several organs. Researchers have reported that the intrarenal RAS is activated in some animal models and patients with chronic kidney disease (CKD) or hypertension and that activation of the intrarenal RAS is intimately involved in the pathophysiology of renal damage (2-6).

Angiotensinogen (AGT) is the only known substrate for renin, the rate-limiting enzyme in the RAS. AGT levels influence RAS activation, since they are close to the Michaelis-Menten constant for renin (7, 8), and urinary AGT, is reported to be a useful biomarker that reflects the intrarenal RAS activity and CKD severity (2, 5, 6, 9-13).

Recently, Lee et al. recruited 91 patients with type 2 diabetes who were followed up for 52 months and found that changes in urinary AGT correlated with a decline in kidney function (14). In addition, 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). However, whether or not the baseline urinary AGT levels predict deterioration of kidney function in all CKD patients, irrespective of the cause of CKD, is unclear.

Therefore, in the present study, we examined the relationships between baseline urinary AGT levels and annual changes in the estimated glomerular filtration rate (eGFR) in quartiles according to baseline urinary AGT levels.

Materials and Methods 

Patients

This study was approved by the ethics committee of Hamamatsu University School of Medicine and adhered to the principles of the Declaration of Helsinki. We consecutively recruited 111 patients with CKD 20-80 years old who were admitted to our hospital for close investigation by a renal biopsy and whose baseline urinary AGT excretion had been measured to evaluate the RAS function in the kidney between January 2012 and December 2016. We excluded 25 patients with CKD whose eGFR was <15 mL/min/1.73 m2 (CKD stage 5) because those patients were introduced to dialysis or underwent a kidney transplant within less than 1 year and annual follow-up was not expected. In addition, we excluded 24 patients with CKD whose 1-year follow-up data were not obtained for reasons such as switching hospitals. We ultimately evaluated 62 patients with CKD in this study (Fig. 1). The patients were followed up annually in our outpatient department until December 2018. Written informed consent was obtained from all patients. 

Study protocols 

On admission, ambulatory blood pressure monitoring (ABPM) using an automatic device (TM-2431; A and D, Tokyo, Japan) was carried out for 24 hours with 30-min intervals, and blood samples were collected at 6:00 AM at the end of the ABPM after the patients with CKD had rested in the supine position for at least 15 minutes. Urine samples were also obtained all day long on the day the ABPM was performed. The blood samples were centrifuged at 3,000 rpm at 4℃ for 10 minutes, while the urine samples were centrifuged at 1,500 rpm at 4℃ for 5 minutes. Both samples were stored at -80℃ until assays were performed. These experiments were performed as described previously (2, 16-18). Thereafter, the patients were followed up annually at our outpatient department.

Clinical data 

The patient's clinical data, including their age, sex, and body mass index (BMI), were recorded at the time of admission. During 24-hour ABPM, the BP was measured non-invasively every 30 minutes, as described above. Serum and urinary creatinine concentrations were measured in the clinical laboratory of the Hamamatsu University School of Medicine, University Hospital. The levels of urinary AGT, which is known to be a surrogate marker of the intrarenal RAS activity (2, 5, 6, 9-13), were measured using an enzyme-linked immunosorbent assay as described previously (19). Urinary albumin concentrations and plasma angiotensin II (Ang II) levels were determined using a radioimmunoassay (SRL, Tokyo, Japan). Serum creatinine concentrations were measured in blood drawn at 6:00 AM, and the eGFR was calculated using the serum creatinine concentrations in the Japanese eGFR equation (20). The excretion ratios of urinary AGT/ creatinine (AGT/Cr) were calculated. The annual rate of change in the eGFR (mL/min/1.73 m2 /year) was determined from the slope calculated by a linear regression analysis of the eGFR measured for each individual annually during follow-up, as described previously (14, 15).

Statistical analyses 

The results are expressed as standard deviation. The Shapiro-Wilk test was performed to examine whether or not the variables were normally distributed. Because the levels of daily urinary albumin excretion and urinary AGT/Cr were not normally distributed, logarithmic transformation was applied. The correlations between the annual change in the eGFR and the age, sex, BMI, systolic and diastolic BPs, heart rate, and baseline levels of the eGFR, daily urinary albumin excretion, plasma Ang II, and urinary AGT/Cr on admission were evaluated using Pearson's product-moment correlation test. Multiple linear regression analyses were conducted to evaluate the relationships between the annual change in the eGFR and the baseline urinary AGT/Cr levels. The age, sex, BMI, and baseline eGFR were selected as independent variables, as these parameters were commonly included in multiple linear regression analyses.

We then divided all patients into quartiles according to the baseline urinary AGT/Cr excretion. Thereafter, a comparison among these four groups was performed by an analysis of variance (ANOVA) with the Tukey-Kramer HSD test or the Games Howell test. Covariance analyses were performed to examine the association between the quartiles of the baseline urinary AGT/Cr excretion and annual change in the eGFR adjusted for age, sex, BMI, and baseline eGFR. We considered values of p<0.05 to indicate statistical significance. Statistical analyses were performed using the IBMⓇSPSSⓇ software program, version 25 (IBM, Armonk, USA).

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