Visual Abstract

Introduction: Prorenin, a precursor of renin, and renin play an important role in regulation of the renin-angiotensin system. More recently, receptor-bound prorenin has been shown to activate intracellular signaling pathways that mediate fibrosis, independent of angiotensin II. Prorenin and renin may thus be of physiologic significance in CKD, but their plasma concentrations have not been well characterized in CKD. Methods: We evaluated distribution and longitudinal changes of prorenin and renin concentrations in the plasma samples collected at follow-up years 1, 2, 3, and 5 of the Chronic Renal Insufficiency Cohort (CRIC) study, an ongoing longitudinal observational study of 3,939 adults with CKD. Descriptive statistics and multivariable regression of log-transformed values were used to describe cross-sectional and longitudinal variation and associations with participant characteristics. Results: A total of 3,361 CRIC participants had plasma available for analysis at year 1. The mean age (±standard deviation, SD) was 59 ± 11 years, and the mean estimated glomerular filtration rate (eGFR, ± SD) was 43 ± 17 mL/min per 1.73 m2. Median (interquartile range) values of plasma prorenin and renin at study entry were 4.4 (2.1, 8.8) ng/mL and 2.0 (0.8, 5.9) ng/dL, respectively. Prorenin and renin were positively correlated (Spearman correlation 0.51, p < 0.001) with each other. Women and non-Hispanic blacks had lower prorenin and renin values at year 1. Diabetes, lower eGFR, and use of angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, statins, and diuretics were associated with higher levels. Prorenin and renin decreased by a mean of 2 and 5% per year, respectively. Non-Hispanic black race and eGFR <30 mL/min/1.73 m2 at year 1 predicted a steeper decrease in prorenin and renin over time. In addition, each increase in urinary sodium excretion by 2 SDs at year 1 increased prorenin and renin levels by 4 and 5% per year, respectively. Discussion/Conclusions: The cross-sectional clinical factors associated with prorenin and renin values were similar. Overall, both plasma prorenin and renin concentrations decreased over the years, particularly in those with severe CKD at study entry.

Activation of the renin-angiotensin-aldosterone system (RAAS), including angiotensin (Ang) II, is thought to mediate the progression of CKD and cardiovascular disease. Although higher plasma aldosterone levels were associated with development of heart failure in CKD, no independent association was observed between plasma aldosterone levels and atherosclerotic events, progression to end-stage kidney disease, or death [1]. More recently, additional components of RAAS have been identified [2], including a novel receptor of prorenin and renin, termed the (pro)renin receptor (PRR) [3]. Both prorenin and renin bind to the PRR, and binding to the PRR makes prorenin active by inducing a conformational change that exposes its angiotensinogen-binding site without proteolysis [3]. Prorenin thus may contribute to the generation of Ang II without being converted to renin. Furthermore, prorenin or renin binding to the PRR activates intracellular signal transduction pathways involved in tissue damage, independent of Ang II [3]. Prorenin, which was previously considered to be an inactive precursor of renin, therefore, may play an important role in regulation of RAAS activity.

While renin is exclusively synthesized in the renal juxtaglomerular cells, prorenin is synthesized both in the kidney and a number of other tissues including the adrenal gland, ovary, testis, placenta, and retina [4]. Plasma prorenin levels are approximately 10-fold higher than renin [5] and can increase up to 100-fold higher in conditions where renin is suppressed [6]. Although plasma renin levels are inversely associated with salt intake [7], no such association has thus far been described with plasma prorenin levels. Further, it is unknown what factors stimulate conversion of prorenin to renin, particularly in pathological conditions.

Elevated plasma prorenin levels have been reported in patients with diabetes [8-10], and several small clinical observational studies have demonstrated correlations between plasma prorenin levels and microvascular disease (albuminuria and retinopathy) in diabetes [11-13]. Recent studies suggest that PRR mediates development of cardiac dysfunction [14], diabetic [15] and nondiabetic nephropathy [16], and vascular injury [17]. Several reviews have recently detailed the physiologic and pathophysiologic roles of PRR in hypertension, sodium homeostasis, and metabolic disorders [18-21].

Given the potential pathophysiologic role for prorenin and renin in CKD, particularly in diabetic patients, there is a need to characterize the distribution of plasma prorenin and renin levels and their longitudinal variation in CKD. While renin activity has been reported to be elevated in CKD [22], there is paucity of data on plasma prorenin concentrations in CKD. There has been no systematic profiling of plasma prorenin and renin in patients with diverse etiologies of CKD. Furthermore, there are no data available to describe the longitudinal variation of prorenin and renin in a large CKD cohort.

The Chronic Renal Insufficiency Cohort (CRIC) study enrolled adults of diverse race and ethnic backgrounds with CKD of various etiologies in a longitudinal observational study. Clinical and laboratory data as well as biospecimens were collected at timed intervals during the ongoing follow-up period. The goals of the present study were to (1) characterize the year 1 distribution of plasma prorenin and renin concentrations in the CRIC as well as in participants with and without diabetes, (2) delineate the longitudinal variations of plasma prorenin and renin concentrations in the CRIC study participants, and (3) examine the participant characteristics that are associated with plasma prorenin or renin concentrations and their changes over time.

Study Design

The CRIC study protocol has been described in detail elsewhere [23, 24]. In brief, the CRIC study is an ongoing observational cohort study that enrolled 3,939 individuals aged 21–74 years at 7 US clinical centers between 2003 and 2008. Eligible participants were individuals whose estimated glomerular filtration rates (eGFRs) fell within age-dependent limits representing mild to moderate CKD severity [24]. Participants who previously received dialysis for ≥1 month or a kidney transplant and those requiring immunosuppression, with advanced heart failure, cirrhosis, or polycystic kidney disease were excluded.

At the baseline visit, sociodemographic characteristics, medical history, lifestyle behaviors, and current medications were recorded. An overnight fasting blood sample was collected to measure serum Cr, lipids, and plasma glucose using standard methods. Hypertension was defined as a mean blood pressure (BP) ≥140/90 mm Hg or self-reported use of antihypertensive medication. Diabetes was defined as a fasting plasma glucose ≥126 mg/dL, a nonfasting plasma glucose ≥200 mg/days or self-reported use of anti-diabetes medication. Kidney function was assessed annually during the follow-up period using the CKD Epidemiology Collaboration (CKD-EPI) eGFR equation. The CRIC study participants were requested to collect 24-h urine specimens at baseline and follow-up years 1 and 2. At annual visits, the participants underwent review of clinical and medication history and physical examination and provided blood and urine samples. Plasma samples from each annual blood draw were aliquoted, frozen on-site at −20 or −80°C, and shipped on dry ice to the CRIC Central Laboratory at the University of Pennsylvania, where they were stored at −80°C.

The CRIC study follow-up visit at 1 year after enrollment served as the time of study entry for this ancillary study. Plasma samples collected from each participant at year 1 follow-up of the CRIC study and at 3 subsequent annual study visits (years 2, 3, and 5) were accessed for measurement of prorenin and renin. All assays were performed in the CRIC Central Laboratory. For prorenin, a sandwich ELISA (Innovative Research, Novi, MI, USA) employed a monoclonal antibody directed against the amino terminal portion of the human prorenin molecule [25] in order to avoid cross-reactivity with renin. The prorenin assay quantitation range was 0.1–10 ng/mL, with the limit of detection threshold of <0.013 ng/mL. Renin was assayed using a sandwich ELISA (DRG International). The quantitation range for renin was 0–12.8 ng/dL, with the limit of detection threshold of <0.081 ng/dL. Samples above the laboratory quantification threshold were diluted 1:10 and then reassayed. In order to evaluate the reliability of assays, samples were assayed in duplicate for 150 randomly selected participants, including a total of 509 samples from all available time points for these participants.

Statistical Analyses

Assay Reliability

We estimated the variance of log-transformed prorenin and renin levels resulting from assay measurement error based on plasma samples obtained at 1 or more visits from 150 participants from a total of 509 samples analyzed in duplicate, 1,018 assays. Reliability of results for prorenin and renin concentrations from duplicate samples was estimated using Pearson correlation coefficients of the log-transformed paired values and intra-assay cross-sectional coefficient of variation, after accounting for the inter-assay variation.

Cross-Sectional Analysis

The distribution of plasma prorenin and renin concentrations at study entry was summarized using histograms and kernel density curves for the entire cohort and for subgroups defined by diabetes status and eGFR level. We used contour plots to display joint distributions of plasma prorenin and renin levels. Due to the skewed distribution of both prorenin and renin concentrations, histograms, kernel density curves, and contour plots were plotted on the log base 2 (log2) scale. Log2-transformed values were used for statistical testing and regression analysis. The log2 transformation was chosen because of its ease of interpretation; 1 unit change on the log2 scale translates to a doubling on the original scale. We summarized prorenin and renin values by clinical or laboratory variables using median and interquartile range (IQR). Univariable differences in prorenin or renin between groups defined by clinical characteristics were assessed using Kruskal-Wallis tests of the concentrations.

In order to evaluate independence of associations between multiple participant characteristics, clinical or laboratory variables, and prorenin and renin concentrations, we used multivariable linear regression analysis modeling the log2 distribution of prorenin and renin. The explanatory variables, based on review of the literature [26], included age, race, diabetes status, eGFR, blood pressure, urinary sodium and potassium concentrations, heart failure history, as well as angiotensin-converting enzyme inhibitor/angiotensin receptor blocker (ACEI/ARB), and diuretic use. History of renal artery stenosis was not readily available in the CRIC and thus not included in our analyses. This set of explanatory variables was found to be free of strong multicollinearity in preliminary analyses (with a maximum variance inflation factor of 2.30).

Sources of Variation in Prorenin and Renin

Biological variation in longitudinal prorenin and renin measurements was characterized based on the residual variances from the following series of mixed-effects models applied to the log-transformed prorenin and renin measurements from the full cohort: (1) intercept as fixed effect only, (2) intercept as both fixed and random effects, (3) intercept and follow-up time as fixed effects and intercept as a random effect, and (4) intercept and follow-up time as both fixed and random effects. We estimated specific sources of biological variation from differences in the residual variances between these models as follows: residual variation about linear participant trajectories as (3)–(1), varying slopes between participants as (3)–(4), linear changes in population mean levels as (2)–(3), and varying mean levels between participants as (1)–(2).

Association between Year 1 Factors and Longitudinal Changes

Prorenin and renin were assayed in plasma samples obtained during annual follow-up visits at years 1, 2, 3, and 5. A multivariable longitudinal model assessed the association of year 1 eGFR with subsequent changes in plasma prorenin or renin over time, adjusting for clinical and laboratory covariates at year 1, including age, sex, race, smoking status, BMI, diabetes status, systolic BP, urinary sodium and potassium, and time-dependent ACEI/ARB use and time-dependent diuretic use at each visit. In this last analysis, time was treated as a categorical fixed effect, with covariate by time interaction terms included to allow separate assessments of the association of baseline eGFR and each covariate with prorenin and renin at each follow-up visit. From these models, we estimated the adjusted geometric mean of plasma prorenin or renin at each visit by year 1 eGFR status.

Next, we implemented a separate set of longitudinal linear mixed-effects models with random intercepts and slopes to characterize the longitudinal variation of log-transformed plasma prorenin and renin and subsequently to assess the association of year 1 characteristics with the subsequent changes in plasma prorenin and renin. We first used bivariate models to relate individual year 1 covariates to subsequent change in plasma prorenin and renin. These models included the year 1 covariate being examined, time as a continuous variable, and the covariate-by-time interaction as fixed effects, as well as intercepts and slopes as random effects. The main effect for each covariate represented the year 1 association with the mean level of log-transformed plasma prorenin or renin, while the time-by-covariate interaction represented the association with the mean change over time. We then fitted multivariable models that included each year 1 covariate and their interactions with time, again as a continuous variable. All modeling analyses were performed in SAS version 9.4 and figures completed in R using ggplot2.

Baseline (Year 1) Demographic and Clinical Characteristics of Participants

Of the participants with at least 1 measure of prorenin or renin at any time during the study (N = 3,585), 3,361 had a measure of plasma prorenin or renin at year 1 and are included in Table 1. Our CRIC has a mean ± standard deviation (SD) age of 59 ± 11 years with excellent representation of women (45%) and participants with diabetes (50%). The cohort is racially and ethnically diverse, with 1,456 (43%) non-Hispanic white participants, 1,383 (42%) non-Hispanic black/African American participants, 390 (12%) Hispanic participants, and 132 (4%) Asian/Pacific Islander/Native American participants. The mean eGFR for our cohort was 43 ± 17 mL/min per 1.73 m2, and median (IQR) proteinuria was 0.16 g per 24 h (0.07–0.87 g per 24 h). Nearly 70% of the cohort was taking an ACEI or ARB.

Table 1.

Plasma prorenin and renin concentrations at year 1 by participant demographics, CKD severity, medical history, and medication use in the CRIC

Plasma prorenin and renin concentrations at year 1 by participant demographics, CKD severity, medical history, and medication use in the CRIC
Plasma prorenin and renin concentrations at year 1 by participant demographics, CKD severity, medical history, and medication use in the CRIC

Assay Reliability

The Pearson correlation coefficients between paired results from 509 pairs of samples for log-transformed prorenin and renin were 0.993 and 0.997, respectively. For prorenin and renin, the coefficient of variations attributable to assay variation (duplicates) were 0.0043 and 0.019, respectively. Due to these high levels of reliability, samples for the remaining participants were analyzed without replicates.

Approximately half of the cohort had 4 measurements of plasma prorenin (N = 1,713) and renin (N = 1,679). Roughly 10% of the cohort had only 1 measurement of plasma prorenin (N = 381) and renin (N = 385). The range of plasma prorenin was 0.008–168 ng/mL, and it was 0.004–107.5 ng/dL for plasma renin. Very few participants had plasma prorenin (N = 1) or renin (N = 2) levels below the level of detection.

Cross-Sectional Variation at Study Entry

The median (IQR) plasma prorenin and renin concentrations at study entry were 4.4 (2.1, 8.8) ng/mL and 2.0 (0.8, 5.9) ng/dL, respectively (online suppl. Fig. 1a, b; see www.karger.com/doi/10.1159/000514302 for all online suppl. material). Both prorenin and renin concentrations were significantly higher in men, non-Hispanic whites, and nonsmokers (Table 1). Diabetes was associated with a median prorenin concentration (5.8 ng/mL) almost twice as high as that for nondiabetes (3.0 ng/mL); accordingly, there were notable areas of nonoverlap in the kernel density curves for diabetes and nondiabetes (online suppl. Fig. 2a). Participants with diabetes also had higher renin concentrations, but the contrast between those with and without diabetes for renin was less marked than that for prorenin, with the kernel density curves largely overlapping (online suppl. Fig. 2b). Prorenin and renin levels increased with CKD severity (Table 1; online suppl. Fig. 2c, d). Participants with prevalent hypertension also had higher prorenin and renin concentrations. The use of diuretics, statins, aldosterone antagonists, and RAAS blockers was associated with higher prorenin and renin plasma levels in the univariate analysis. β-blocker use was associated with higher prorenin and lower renin levels. Year 1 proteinuria was positively associated with plasma prorenin concentrations but inversely associated with renin concentrations.

The within-participant correlation between plasma prorenin and renin concentrations was positive but of only moderate strength (Spearman correlation values 0.51, p < 0.001). The contour plot of the joint densities of the 2 analytes (online suppl. Fig. 1c) shows that the cross-sectional relation between the 2 is complex, with a wide range of values on both scales needed to encompass 50% of participants.

In the multivariable model including demographics and key clinical variables as predictors of prorenin and renin concentrations at year 1 (Table 2), age was no longer significantly associated with prorenin concentrations when other demographic and clinical variables were considered. Female sex and race remained significantly associated with lower prorenin values. For renin, age, female sex, and race all remained significantly associated with lower concentrations. Diabetes and more severe CKD as measured by eGFR were associated with higher prorenin and renin concentrations. Urine sodium excretion was inversely associated with plasma prorenin and renin levels. There was no significant association between urinary potassium excretion and prorenin or renin. The use of ACEI/ARB and diuretics was associated with higher prorenin and renin concentrations compared to nonuse after adjusting for other predictors in the multivariable model.

Table 2.

Cross-sectional associations of demographics and CKD clinical factors with plasma prorenin and renin concentrations at year 1 in the CRIC, multivariable model*

Cross-sectional associations of demographics and CKD clinical factors with plasma prorenin and renin concentrations at year 1 in the CRIC, multivariable model*
Cross-sectional associations of demographics and CKD clinical factors with plasma prorenin and renin concentrations at year 1 in the CRIC, multivariable model*

Longitudinal Variation

We developed histograms characterizing the fold change in prorenin and renin from CRIC year 1 to year 3 to understand the distribution of change in these analytes (online suppl. Fig. 3a, b). While the median change over the 2-year period was minimal for both prorenin and renin, there was much variability in the cohort with changes in both directions. About half of the participants exhibited a decrease in concentration of plasma prorenin over the years, while it increased in the other half of the participants. Plasma renin concentration increased in about 65% of the participants over the years, with the remaining 35% showing a decrease in renin concentration. When the joint distributions of within-participant change in prorenin and renin values were examined (online suppl. Fig. 3c), the change values were positively correlated.

Sources of Longitudinal Variation

Online suppl. Table 1 decomposes the total variance in log-transformed prorenin and renin levels into different sources of biological and assay variability. Approximately 67 and 63% of the total variance in the prorenin and renin measurements, respectively, resulted from variation in their overall mean levels between participants. An additional 4% was explained by participant variation in the slopes of the trajectories of the prorenin and renin measurements over time, and most of the remaining variation (about 29 and 32%, respectively) was due to nonsystematic biological fluctuations in the prorenin and renin measurements around the underlying linear trajectories. Assay measurement error contributed <0.3% of the total variance.

Association between Year 1 Factors and Longitudinal Changes

Over the 4-year period, prorenin levels decreased by a mean of 2% per year and renin levels by a mean of 5% per year in the CRIC. Those with an eGFR <30 mL/min/1.73 m2 had more significant reduction in prorenin and renin levels (Tables 3, 4). The age at study entry and sex were not predictors of longitudinal change in prorenin and renin (Table 5). Hispanic ethnicity and non-Hispanic black race predicted 7 and 4% decreases in prorenin concentrations per year compared to non-Hispanic white race, respectively. Only non-Hispanic black race was associated with 4% annual reduction in plasma renin levels. Prevalent diabetes at study entry was not associated with longitudinal change in either analytes, while a baseline eGFR < 30 was associated with 6 and 11% annual reductions in prorenin and renin levels, respectively. ACEI or ARB therapy was associated with 9% reduction in the plasma renin level per year, and each increase in systolic BP by 2 SDs was associated with a 14% increase in the plasma renin level per year, and diuretic use was associated with 3% reduction in prorenin per year. In addition, each increase in urinary sodium excretion by 2 SDs increased prorenin and renin levels by 4 and 5% per year, respectively.

Table 3.

Longitudinal changes in plasma prorenin concentration (ng/mL), mixed regression model

Longitudinal changes in plasma prorenin concentration (ng/mL), mixed regression model
Longitudinal changes in plasma prorenin concentration (ng/mL), mixed regression model
Table 4.

Longitudinal changes in plasma renin concentration (ng/mL), mixed regression model

Longitudinal changes in plasma renin concentration (ng/mL), mixed regression model
Longitudinal changes in plasma renin concentration (ng/mL), mixed regression model
Table 5.

Longitudinal associations of year 1 demographics and CKD clinical factors with plasma prorenin and renin concentrations over time in the CRIC

Longitudinal associations of year 1 demographics and CKD clinical factors with plasma prorenin and renin concentrations over time in the CRIC
Longitudinal associations of year 1 demographics and CKD clinical factors with plasma prorenin and renin concentrations over time in the CRIC

This is the first study to characterize plasma prorenin and renin concentrations in a large CKD cohort and to assess their longitudinal changes over 4 years. The cross-sectional clinical factors associated with prorenin and renin concentrations were similar, including sex, race, smoking, eGFR, diabetes, hypertension, as well as RAAS inhibitor and diuretic use. As previously described in smaller cohorts [27], plasma prorenin levels were particularly increased in men with diabetes. Animal data suggest that the renal collecting duct may be the major source of the excess prorenin in diabetes [28], and the higher plasma levels of prorenin in men have been attributed to androgen-induced release of prorenin from the kidney [29]. Statin use was also associated with higher baseline levels of prorenin and renin levels. The higher prevalence of coronary artery disease and diabetes in those treated with statin may be a factor to explain the association between statin use and higher prorenin and renin levels.

In our present univariable cross-sectional analysis, year 1 proteinuria was associated with plasma prorenin concentrations but inversely associated with renin concentrations. It is unclear if the opposite trend is in part related to the fact that plasma prorenin derives from multiple sources other than the kidney, whereas circulating renin is mostly of renal origin. Previous small studies in diabetic populations have found a close correlation between increased plasma prorenin levels and microvascular complications, including retinopathy and albuminuria [11-13, 27].

Overall, both plasma prorenin and renin concentrations decreased over the years, particularly in those with an eGFR <30 mL/min/1.73 m2 at year 1. Given that the kidney is an important source of circulating prorenin and renin [5, 30, 31], it is unclear why lower eGFR (<30 mL/min/1.73 m2) range is associated with higher prorenin and renin concentrations at year 1. The reason for this conflicting result between the cross-sectional and the longitudinal analyses is unknown and cannot be explained by a decrease in kidney mass. Of note, diabetes status had no influence on the longitudinal trends of either prorenin or renin concentrations over time. ACEI or ARB therapy was associated with increased prorenin and renin levels at year 1, but it was associated with a significant annual decrease (9%) in plasma renin concentrations. The only year-1 factors significantly associated with the longitudinal changes of both prorenin and renin were non-Hispanic black race, eGFR <30 mL/min/1.73 m2, and urinary sodium excretion.

Higher year 1 urinary sodium, which might reflect higher dietary salt intake, was positively associated with plasma prorenin and renin concentrations in the univariate, cross-sectional analysis, but the association became inverse in the multivariable model taking into account diuretic use, systolic BP, and other variables. Baseline urinary sodium was, however, associated with an increase in prorenin and renin longitudinally. For every increase in urinary sodium excretion by 2 SDs, prorenin and renin levels increased by 4 and 5% per year, respectively, after adjusting for important demographic and clinical covariates. It is possible that those with higher urinary sodium excretion had higher systolic BP, which also independently predicts increases of prorenin and renin levels. As a descriptive study, however, we are unable to investigate underlying mechanisms of our findings. Urinary potassium excretion was not associated with longitudinal changes of prorenin or renin in our study.

To date, this is the first study to describe the joint distribution of plasma prorenin and renin concentrations and their changes over time in a large CKD cohort. While the overall plasma prorenin and renin concentrations decreased over the 4-year observation period, changes among individuals varied greatly between years 1 and 3. In about half of individuals, plasma prorenin concentrations increased, rather than decreased, over 2 years. Plasma renin concentration increased in about 65% of the participants over the years. Further analyses are needed to evaluate if increases in prorenin and/or renin concentrations are associated with subsequent adverse clinical outcomes. It is plausible that longitudinal increases in plasma prorenin and renin levels are associated with greater risks for CKD progression, given that the PRR appears to be involved in the pathogenesis of kidney fibrosis [32].

There are several limitations in our study. Because of the observational study design, we are unable to adjust for all of the biases and confounders. Although our multivariate analyses treated the medications as time-dependent variables in order to mitigate the effect of changes in medication (such as ACEI/ARB) use on the plasma prorenin and renin levels, we cannot completely adjust for the variability of the drug use. Furthermore, the descriptive nature of our study does not allow us to make inference to the underlying physiologic mechanisms for our findings. Nonetheless, our study represents an important first step to characterize the distributions of plasma prorenin and renin concentrations and their changes over time in a large CKD cohort. Further analyses will evaluate potential roles of these molecules in microvascular, cardiovascular, and renal complications in both diabetic and nondiabetic CKD patients.

The CRIC study protocol was approved by institutional review boards at the participating institutions and was in accordance with the ethical principles of the Declaration of Helsinki.

There was no conflict of interest by any of the authors of the article.

Funding for this ancillary study to the CRIC was obtained by Dr. Alfred K. Cheung from the National Institute of Diabetes and Digestive and Kidney Diseases (1R01DK099098). The CRIC study was funded under a cooperative agreement from the National Institute of Diabetes and Digestive and Kidney Diseases (U01DK060990, U01DK060984, U01DK061022, U01DK061021, U01DK061028, U01DK060980, U01DK060963, U01DK060902, and U24DK060990). In addition, this work was supported in part by the Perelman School of Medicine at the University of Pennsylvania Clinical and Translational Science Award NIH/NCATS UL1TR000003, Johns Hopkins University UL1 TR-000424, University of Maryland GCRC M01 RR-16500, Clinical and Translational Science Collaborative of Cleveland UL1TR000439 from the National Center for Advancing Translational Sciences (NCATS) component of the National Institutes of Health and NIH Roadmap for Medical Research, Michigan Institute for Clinical and Health Research (MICHR) UL1TR000433, University of Illinois at Chicago CTSA UL1RR029879, Tulane COBRE for Clinical and Translational Research in Cardiometabolic Diseases P20 GM109036, Kaiser Permanente NIH/NCRR UCSF-CTSI UL1 RR-024131, Department of Internal Medicine, and University of New Mexico School of Medicine Albuquerque, NM R01DK119199.

Monique Cho coordinated analyses, interpretation, and organization of the manuscript; wrote the initial draft; and incorporated suggestions by all authors. Carol Sweeney, Nora Fino, and Tom Greene analyzed and helped to interpret and organize data. Alfred Cheung conceived and designed research and edited the manuscript. Niru Ramkumar provided her scientific expertise to guide interpretation of data and drafting of the manuscript. Yufeng Huang provided her basic scientific expertise with development of the research grant and reviewed the manuscript. Ana Ricardo, Tariq Shafi, Rajat Deo, Amand Anderson, and Katherine Mills critically reviewed the data and manuscript and edited the manuscript.

1.
Deo
R
,
Yang
W
,
Khan
AM
,
Bansal
N
,
Zhang
X
,
Leonard
MB
, et al
Serum aldosterone and death, end-stage renal disease, and cardiovascular events in blacks and whites: findings from the Chronic Renal Insufficiency Cohort (CRIC) Study
.
Hypertension
.
2014 Jul
;
64
(
1
):
103
10
. .
2.
Crowley
SD
,
Coffman
TM
.
Recent advances involving the renin-angiotensin system
.
Exp Cell Res
.
2012 May 15
;
318
(
9
):
1049
56
. .
3.
Nguyen
G
,
Delarue
F
,
Burcklé
C
,
Bouzhir
L
,
Giller
T
,
Sraer
JD
.
Pivotal role of the renin/prorenin receptor in angiotensin II production and cellular responses to renin
.
J Clin Invest
.
2002 Jun
;
109
(
11
):
1417
27
. .
4.
Danser
AH
,
van den Dorpel
MA
,
Deinum
J
,
Derkx
FH
,
Franken
AA
,
Peperkamp
E
, et al
Renin, prorenin, and immunoreactive renin in vitreous fluid from eyes with and without diabetic retinopathy
.
J Clin Endocrinol Metab
.
1989 Jan
;
68
(
1
):
160
7
. .
5.
Campbell
DJ
,
Kladis
A
,
Skinner
SL
,
Whitworth
JA
.
Characterization of angiotensin peptides in plasma of anephric man
.
J Hypertens
.
1991 Mar
;
9
(
3
):
265
74
. .
6.
Sealey
JE
,
Blumenfeld
J
,
Laragh
JH
.
Prorenin cryoactivation as a possible cause of normal renin levels in patients with primary aldosteronism
.
J Hypertens
.
2005 Feb
;
23
(
2
):
459
60
. .
7.
Graudal
NA
,
Hubeck-Graudal
T
,
Jurgens
G
.
Effects of low sodium diet versus high sodium diet on blood pressure, renin, aldosterone, catecholamines, cholesterol, and triglyceride
.
Cochrane Database Syst Rev
.
2017 Apr 9
;
4
(
11
):
CD004022
. .
8.
Luetscher
JA
,
Kraemer
FB
.
Microalbuminuria and increased plasma prorenin. Prevalence in diabetics followed up for four years
.
Arch Intern Med
.
1988 Apr
;
148
(
4
):
937
41
. .
9.
Hsueh
WA
,
Baxter
JD
.
Human prorenin
.
Hypertension
.
1991 Apr
;
17
(
4
):
469
77
. .
10.
Stankovic
AR
,
Fisher
ND
,
Hollenberg
NK
.
Prorenin and angiotensin-dependent renal vasoconstriction in type 1 and type 2 diabetes
.
J Am Soc Nephrol
.
2006 Dec
;
17
(
12
):
3293
9
. .
11.
Franken
AA
,
Derkx
FH
,
Man in’t Veld
AJ
,
Hop
WC
,
van Rens
GH
,
Peperkamp
E
, et al
High plasma prorenin in diabetes mellitus and its correlation with some complications
.
J Clin Endocrinol Metab
.
1990 Oct
;
71
(
4
):
1008
15
. .
12.
Davies
L
,
Fulcher
GR
,
Atkins
A
,
Frumar
K
,
Monaghan
J
,
Stokes
G
, et al
The relationship of prorenin values to microvascular complications in patients with insulin-dependent diabetes mellitus
.
J Diabetes Complicat
.
1999 Jan–Feb
;
13
(
1
):
45
51
. .
13.
Yokota
H
,
Mori
F
,
Kai
K
,
Nagaoka
T
,
Izumi
N
,
Takahashi
A
, et al
Serum prorenin levels and diabetic retinopathy in type 2 diabetes: new method to measure serum level of prorenin using antibody activating direct kinetic assay
.
Br J Ophthalmol
.
2005 Jul
;
89
(
7
):
871
3
. .
14.
Susic
D
,
Zhou
X
,
Frohlich
ED
,
Lippton
H
,
Knight
M
.
Cardiovascular effects of prorenin blockade in genetically spontaneously hypertensive rats on normal and high-salt diet
.
Am J Physiol Heart Circ Physiol
.
2008 Sep
;
295
(
3
):
H1117
H21
. .
15.
Ichihara
A
,
Hayashi
M
,
Kaneshiro
Y
,
Suzuki
F
,
Nakagawa
T
,
Tada
Y
, et al
Inhibition of diabetic nephropathy by a decoy peptide corresponding to the “handle” region for nonproteolytic activation of prorenin
.
J Clin Invest
.
2004 Oct
;
114
(
8
):
1128
35
. .
16.
Kaneshiro
Y
,
Ichihara
A
,
Sakoda
M
,
Takemitsu
T
,
Nabi
AH
,
Uddin
MN
, et al
Slowly progressive, angiotensin II-independent glomerulosclerosis in human (pro)renin receptor-transgenic rats
.
J Am Soc Nephrol
.
2007 Jun
;
18
(
6
):
1789
95
. .
17.
Veniant
M
,
Menard
J
,
Bruneval
P
,
Morley
S
,
Gonzales
MF
,
Mullins
J
.
Vascular damage without hypertension in transgenic rats expressing prorenin exclusively in the liver
.
J Clin Invest
.
1996 Nov 1
;
98
(
9
):
1966
70
.
18.
Ramkumar
N
,
Kohan
DE
.
The nephron (pro)renin receptor: function and significance
.
Am J Physiol Renal Physiol
.
2016 Dec 1
;
311
(
6
):
F1145
8
. .
19.
Ramkumar
N
,
Kohan
DE
.
Role of the collecting duct renin angiotensin system in regulation of blood pressure and renal function
.
Curr Hypertens Rep
.
2016 Apr
;
18
(
4
):
29
. .
20.
Yang
T
.
Unraveling the physiology of (Pro)renin receptor in the distal nephron
.
Hypertension
.
2017 Apr
;
69
(
4
):
564
74
. .
21.
Ramkumar
N
,
Kohan
DE
.
The (pro)renin receptor: an emerging player in hypertension and metabolic syndrome
.
Kidney Int
.
2019 May
;
95
(
5
):
1041
52
. .
22.
Sim
JJ
,
Shi
J
,
Calara
F
,
Rasgon
S
,
Jacobsen
S
,
Kalantar-Zadeh
K
.
Association of plasma renin activity and aldosterone-renin ratio with prevalence of chronic kidney disease: the Kaiser Permanente Southern California cohort
.
J Hypertens
.
2011 Nov
;
29
(
11
):
2226
35
. .
23.
Feldman
HI
,
Appel
LJ
,
Chertow
GM
,
Cifelli
D
,
Cizman
B
,
Daugirdas
J
, et al
The chronic renal insufficiency cohort (CRIC) study: design and methods
.
J Am Soc Nephrol
.
2003 Jul
;
14
(
7 Suppl 2
):
S148
53
. .
24.
Lash
JP
,
Go
AS
,
Appel
LJ
,
He
J
,
Ojo
A
,
Rahman
M
, et al
Chronic renal insufficiency cohort (CRIC) study: baseline characteristics and associations with kidney function
.
Clin J Am Soc Nephrol
.
2009 Aug
;
4
(
8
):
1302
11
. .
25.
Mercure
C
,
Thibault
G
,
Lussier-Cacan
S
,
Davignon
J
,
Schiffrin
EL
,
Reudelhuber
TL
.
Molecular analysis of human prorenin prosegment variants in vitro and in vivo
.
J Biol Chem
.
1995 Jul 7
;
270
(
27
):
16355
9
. .
26.
Kurtz
A
.
Control of renin synthesis and secretion
.
Am J Hypertens
.
2012 Aug
;
25
(
8
):
839
47
. .
27.
Yokota
H
,
Nagaoka
T
,
Tani
T
,
Takahashi
A
,
Sato
E
,
Kato
Y
, et al
Higher levels of prorenin predict development of diabetic retinopathy in patients with type 2 diabetes
.
J Renin Angiotensin Aldosterone Syst
.
2011 Sep
;
12
(
3
):
290
4
. .
28.
Kang
JJ
,
Toma
I
,
Sipos
A
,
Meer
EJ
,
Vargas
SL
,
Peti-Peterdi
J
.
The collecting duct is the major source of prorenin in diabetes
.
Hypertension
.
2008 Jun
;
51
(
6
):
1597
604
. .
29.
Chen
YF
,
Naftilan
AJ
,
Oparil
S
.
Androgen-dependent angiotensinogen and renin messenger RNA expression in hypertensive rats
.
Hypertension
.
1992 May
;
19
(
5
):
456
63
. .
30.
Krop
M
,
Danser
AH
.
Circulating versus tissue renin-angiotensin system: on the origin of (pro)renin
.
Curr Hypertens Rep
.
2008 Apr
;
10
(
2
):
112
8
. .
31.
Krop
M
,
de Bruyn
JH
,
Derkx
FH
,
Danser
AH
.
Renin and prorenin disappearance in humans post-nephrectomy: evidence for binding?
Front Biosci
.
2008 May 1
;
13
:
3931
9
. .
32.
Li
Z
,
Zhou
L
,
Wang
Y
,
Miao
J
,
Hong
X
,
Hou
FF
, et al
(Pro)renin receptor is an amplifier of Wnt/beta-catenin signaling in kidney injury and fibrosis
.
J Am Soc Nephrol
.
2017 Aug
;
28
(
8
):
2393
408
.

CRIC Study Investigators: Lawrence J. Appel, MD, MPH, Harold I. Feldman, MD, MSCEAlan S. Go, MD, Jiang He, MD, PhD, James P. Lash, MD, Robert G. Nelson, MD, PhD, MS, Mahboob Rahman, MD, Panduranga S. Rao, MD, Vallabh O. Shah, PhD, MS, Raymond R. Townsend, MD, Mark L. Unruh, MD, MS.

Copyright / Drug Dosage / Disclaimer
Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher.
Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in government regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug.
Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.