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Higher plasma renin activity is associated with increased kidney damage risk in patients with hypertension and glucose metabolic disorders

Abstract The impact of renin on kidney remain unclear among hypertensives with glucose metabolic disorders (GMD). We aimed to evaluate the association between plasma renin activity (PRA) and kidney damage in hypertensive patients with GMD. Overall, 2033 inpatients with hypertension and GMD free of chronic kidney disease (CKD) at baseline were included. CKD was defined using estimated glomerular filtration rate (eGFR) and urine protein. PRA was treated as continuous variable, and also dichotomized as high (≥0.65) or low (< 0.65) groups. The association of PRA with incident CKD was evaluated using multivariable Cox model controlling for antihypertensive medications and baseline aldosterone, and traditional parameters. Subgroup and interaction analyses were performed to evaluate heterogeneity. During a median follow‐up of 31 months, 291 participants developed CKD. The incidence was higher in high‐renin group than that in low‐renin group (54.6 vs 36.6/1000 person‐years). Significant association was observed between PRA and incident CKD, and the association was mainly driven by an increased risk for proteinuria. Each standard deviation increment in log‐transformed PRA was associated with 16.7% increased risk of proteinuria (hazard ratio = 1.167, P = .03); compared with low‐renin group, there was 78.4% increased risk for high‐renin group (hazard ratio = 1.784, P = .001). Nonlinear associations were observed between PRA and kidney damage. Higher PRA is associated with greater risk of incident kidney damage, especially for positive proteinuria, in patients with coexistence of hypertension and diabetes, independent of aldosterone. In this patient population with high risk for kidney damage, PRA may serve as an important predictor.


INTRODUCTION
Chronic kidney disease (CKD) has been recognized as a major public health issue due to high prevalence and its strong association with cardiovascular events and premature death. 1 Incidence and prevalence of CKD have been increasing largely due to an ongoing epidemic of hypertension and glucose metabolic disorders (GMD). 2 Our previous study showed that prevalence of kidney dysfunction in hypertensive diabetic patients is higher than in those with either hypertension or diabetes mellitus (DM) alone, 3 suggesting higher risk for CKD in patients with coexistent hypertension and DM.
Hypertension and GMD often coexist due to common risk factors and overlapping pathophysiological processes, such as over activation of renin-angiotensin-aldosterone system (RAAS). 4,5 Evidences suggest that renin is an important mediator for vascular and organ damage. 6 By binding to its receptor, renin mediates an increase in angiotensin II (Ang II) and aldosterone, and induces a series of intracellular signaling pathways in cardiomyocytes, vascular, and renal cells, resulting in tissue and organ damage. 7 In addition, renin has also been demonstrated as an Ang II-independent profibrotic factor. 8 Plasma renin has been associated with cardiovascular mortality in clinical studies. [9][10][11] However, conflicting evidence remains between plasma renin activity (PRA) and the development of CKD. John and colleagues reported in a cross-sectional study that higher PRA is associated with greater rates of CKD in population of primarily hypertensive patients. 12 Another case-control study with relatively small sample of high-risk population suggested a positive but marginal significant association between PRA and renal impairment. 13 On the contrary, longitudinal results from the Ohasama study showed a negative association that lower PRA is associated with the development of CKD in general Japanese population. 14 The most probable explanation for the variation in results is the different populations under observation.
Previous studies mainly focused on patients with coronary heart disease or heart failure, and evaluated the association of PRA with cardiac events and all-cause mortality. 15,16 Few studies have focused specifically on patients with both hypertension and GMD, who have been proven to have excessive activation of RAAS and higher risk of kidney damage. 17 In addition, results may be biased by insufficient adjustment for confounding factors, such as aldosterone, which has recently been shown to be independently associated with incident CKD in hypertensive patients with GMD. 18 Therefore, the independently predictive value of PRA for kidney damage needs further validation.
To this aim, we evaluated whether PRA is independently associated with incident CKD in hypertensive patients with GMD, even after eliminating the confounding effects of aldosterone.

Study population
Participants in this retrospective study were inpatients from Hyper-

Measurements of PRA and plasma aldosterone concentration (PAC)
Blood samples were collected under standardized conditions. That is, interfering drugs, including angiotensin converting enzyme inhibitor (ACEI), angiotensin receptor blockers (ARB), dihydropyridine calcium channel antagonist (CCB), β-blocker, diuretic, and aldosterone antagonist, were withdrawn for 4-6 weeks or replaced with slow-release verapamil and/or α1-adrenergic antagonists to minimize interference with measurements, as described in previous studies from the Center. 20 Fasting blood samples were collected in sitting posture between 08:00 am and 11:00 am after patients had been ambulant for at least 2 hours and seated for 15 minutes. PRA was measured using a radioimmunoassay kit from Northern Biotechnology Institutes, and the intra-and interassay coefficients of variation were 9.2% and 12.5%, respectively. PAC was measured by radioimmunoassay using a commercially available kit (Beckman Coulter), and the intra-and interassay coefficients of variation were 4.3% and 9.2%, respectively.

Follow-up and outcome
The outcome for the current study was a new-onset CKD and its components (DRF and positive proteinuria) during follow up. Follow-up data were obtained using annual health check-ups or hospital readmission. Examination time of 3 months or longer after baseline was considered to be a valid data. If a participant experienced the outcomes more than once during follow-up, only the first outcome was used for analysis. For those without CKD events during follow-up, the data of the last follow-up was included in the analysis.
CKD was defined as estimated glomerular filtration rate (eGFR) < 60 mL/min/1.73 m 2 and/or the presence of proteinuria. eGFR was calculated by the simplified modification of diet in renal disease (MDRD) equation on the basis of data from Chinese adults. 21 Decreased renal function (DRF) was defined as eGFR < 60 mL/min/ 1.73 m 2 . Urine protein was determined using urine dipstick results, and a positive of proteinuria was defined as urine protein ≥1+.

Statistical analysis
Continuous variables were presented as mean ± standard deviation (SD) or median (interquartile range) according to results of normality test, and compared between groups using Student t test or Mann- suggesting potential differences of pathophysiological mechanism.
Therefore, we first used 0.65 as the cut-off value of PRA. In addition, to describe the shape of the association between PRA and incident renal damage, we used restricted cubic splines incorporated into the Cox models. Furthermore, interaction terms were introduced into multivariable model to evaluate whether the association between PRA and renal outcomes differed according to age (group by mean of 55 years),

Baseline characteristics
A total of 2,033 participants with complete baseline and follow-up data were analyzed. Baseline characteristics and comparison between high-and low-renin groups were shown in Table 1

Association of PRA with CKD
Kaplan-Meier curve showed that the cumulative incidence of CKD was significantly higher in high-renin group (Figure 2-A). In univariate Cox regression analysis, age, SBP, duration of hypertension, FPG,  (Table 2). Accordingly, these factors except for FPG (due to the strong relation with HbA1c) were first included for adjustment and resulted in a significant association between PRA and incident CKD (

Association of PRA with proteinuria and DRF
Incidence of proteinuria events was 47.9/1000 person-years in high renin group and 28.6/1000 person-years in low-renin group. Consistent trend in cumulative incidence of proteinuria was also observed ( Figure 2-B). Univariable analysis for incident proteinuria was shown in Table S1. In multivariate Cox regression analysis (Table 4) (Table S2) and multivariable (

Additional analyses
Restricted cubic splines showed a nonlinear association between PRA and incident CKD (Figure 3-A). There was a positive dose-response relationship between PRA and incident CKD when PRA is less than 2.5, with a highest HR for the points of PRA ≈2.5. Although a downward trend was observed for CKD risk when PRA exceeds 2.5, the HR remains greater than 1. Similar results were found for outcomes of positive proteinuria (Figure 3-B). Given the nonlinear shape of the association between PRA and renal damage, we further analyzed the entire cohort according to tertiles and quartiles of PRA. Although a decrease in the HR was observed in the third and fourth groups compared with the second group, it remained significantly higher compared to the lowest PRA group (Table S3).
Above results indicated that the association of PRA with CKD was mainly driven by an increased risk for positive proteinuria. Therefore, we conducted subgroup and interactional analyses to further evaluate whether the association was homogeneous across the cohort.
As shown in Figure 4, the association of PRA with incident proteinuria remained consistent in subgroup analyses by age, sex, and PAC.
A strong association between PRA and higher risk of proteinuria was found in those with DM compared with those with pre-DM. The association of PRA and proteinuria was affected by taking ACEI/ARB or β-blockers. No interaction was found excepted for treatment with βblockers (P for interaction = .041).

DISCUSSION
These results extend and reinforce previous evidence to hypertensive diabetic patients that PRA is significantly and independently associated with incident kidney damage. The association between PRA and CKD is mainly driven by an increase in the risk for positive proteinuria but not decreased renal function. The increased risk of incident proteinuria associated with higher PRA is not changed by the adjustment for all factors including antihypertensive therapies and PAC, indicating the independently predictive value of PRA.
Renin is the initial and rate-limiting step of the RAAS and many experimental and clinical studies provide evidence that the RAAS is capable of stimulating atherosclerosis by triggering basic reactions, ultimately leading to growth, instability, and rupture of atherosclerotic plaques and facilitation of thrombosis. 26 Similar to previous studies that reported interaction between plasma renin concentration and use of β-blockers on cardiovascular death, 10 there is significant interaction term between PRA-related kidney damage and beta-blockers in the present study. Sever and colleagues also reported a greater effect of PRA on renal outcome when persons with β-blockers therapy were excluded. 13 It seems that use of β-blockers could attenuate the association of PRA with renal impairment. However, small sample size in the subgroup analysis restricted an accurate conclusion.
Although longitudinal design with large sample of high-risk population for CKD and reliable method for PRA measurement, several limitations warrant discussion. First, we failed to evaluate other therapy at baseline, such as lipid-lowering drugs; we also lacked 24-hour urinary sodium to evaluate the influence of dietary sodium intake on PRA. In addition, confounding of Ang II and other parameters, such as inflammatory factors, need to be considered in future studies. Second, serum creatinine and urinary protein were measured only one time, and proteinuria was examined through qualitative, but not quantitative methods. Third, the study was conducted in a single center, although conducted in a regional center for hypertension with patients of large age range and ethnic groups. Moreover, potential bias from undetected secondary hypertension limits the generalizability of the results. Fourth, the portion of lost to follow-up may potentially bias the results, although we combined rehospitalization and annual health check-up data for reducing the loss of follow-up rate. Finally, the obser-vational design of the present study precludes the conclusion of direct cause-and-effect association between PRA and renal damage. Heizhati, and Lin Gan analyzed the data together and drafted the manuscript. All authors reviewed and approved the final manuscript.