Original Article
Plasma Prorenin Activity and Complications in Children with Insulin-Dependent Diabetes Mellitus
N Engl J Med 1990; 323:1101-1106October 18, 1990
- Abstract
- Abstract
Background.
Renin, secreted into the blood by the juxtaglomerular cells of the kidneys, is derived from a larger precursor, prorenin. Plasma prorenin activity is increased in patients with insulin-dependent (Type I) diabetes mellitus who have microvascular complications of their disease. We undertook this study to determine prospectively whether rising prorenin activity can predict the development of complications in young patients with Type I diabetes.
Methods and Results.
Plasma prorenin was measured in 135 children and adolescents with Type I diabetes. The mean (±SE) plasma prorenin activity among the 32 patients over the age of 10 years who had had uncomplicated diabetes for 0.1 to 5 years was 8.43±0.58 ng of angiotensin I per liter · second, as compared with 7.06±0.32 in 37 control subjects of the same age (P<0.05). In the 9 patients older than 10 who had retinopathy or overt albuminuria, the mean plasma prorenin activity was 13.09±1.43 ng of angiotensin I per liter · second (P<0.0001).
In 34 patients 10 years old or older with uncomplicated diabetes, 3 to 13 measurements of plasma prorenin activity were taken during a follow-up period of 6 to 39 months. Urinary albumin was determined at each visit, and the patients had regular retinal examinations. Only 1 of the 20 patients who had consistently normal plasma prorenin values had overt albuminuria (ratio of urinary albumin to creatinine, >0.017) or retinopathy, whereas one or both of these complications appeared in 8 of the 14 who had at least one high prorenin value. The plasma prorenin value was significantly higher in these eight patients at least 18 months before a complication was found.
Conclusions.
Increased plasma prorenin activity identifies a group of young patients with diabetes who are at high risk for retinopathy or nephropathy. (N Engl J Med 1990; 323:1101–6.)
Media in This Article
Figure 1
Initial Plasma Prorenin Activity in 86 Patients with Early Uncomplicated Diabetes (Squares) and in 54 Nondiabetic Controls (Triangles).Figure 2
Consecutive Measurements of Plasma Prorenin Activity in 14 Patients 10 Years of Age or Older with Initially Uncomplicated Diabetes and Three or More Prorenin Determinations, at Least One of Which Was above the Normal Range.Article Activity
- Article
MICROVASCULAR complications begin to appear approximately five years after the onset of insulin-dependent (Type I) diabetes mellitus. The majority of patients have background retinopathy, and in nearly half these patients, proliferative retinopathy ultimately poses a serious threat to vision.1 At least 25 percent of patients with Type I diabetes have overt albuminuria, which is a sign of nephropathy and which progresses to end-stage renal failure. The pathogenesis of these complications remains unclear. Although retrospective studies suggest that meticulous regulation of blood glucose concentrations can delay the development of diabetic complications,2 , 3 it is quite difficult to maintain such regulation in many children and adolescents. Except for a possible connection with a family history of hypertension,4 , 5 there is currently no method to determine prospectively which patients with diabetes are at higher risk of complications. A means of identifying such patients would allow clinicians to concentrate their efforts on this important subgroup. Moreover, research protocols designed to prevent these diabetic complications could focus on patients at high risk.
Renin, secreted into the blood by the juxtaglomerular cells of the kidneys, is derived from a larger precursor, prorenin. Increased plasma prorenin activity is associated with the microvascular complications of diabetes in normotensive adults6 7 8 and children9 , 10 with diabetes. The purpose of our study was to determine whether increased plasma prorenin activity predicts the development of diabetic complications in children and adolescents.
Methods
Patients
The study group included 135 patients with Type I diabetes followed in the Stanford Pediatric Diabetes Clinic. Patients with non-insulin-dependent (Type II) diabetes, diabetes following 95 percent pancreatectomy for intractable hypoglycemia, or diabetes following the hemolytic uremic syndrome were excluded. When first seen in this clinic, the patients ranged in age from 1 to 20 years (mean [±SD], 10.3±4.8) and the duration of their diabetes ranged from 0 to 15.4 years (mean, 3.6±4.0). Fifty-three percent were male, and 47 percent were female.
We studied these patients during 468 outpatient visits, with the permission of the patients or their parents, as approved by the Stanford Committee for the Protection of Human Subjects in Research. At their first visit, all the patients were normotensive while eating a diabetic, unrestricted-sodium diet. All were taking insulin, and none were taking any medications, such as diuretic agents, that alter plasma renin activity. Fifty-three patients were seen only once. The remaining 82 patients were seen on 2 to 13 occasions (average, 5.1) at intervals averaging 5.4 months for a mean (±SD) of 2.0±1.4 years. During this period, they continued to receive insulin (a combination of human isophane insulin suspension and regular insulin twice daily) and a diabetic, unrestricted-sodium diet. The patients or their parents were instructed to measure capillary-blood glucose concentrations before each meal and at bedtime, and the insulin therapy was adjusted to maintain glucose concentrations between 5.5 and 8.5 mmol per liter.
The presence of retinopathy was recorded when an abnormality was observed by the clinic physician or during the annual examination by the patient's ophthalmologist. At each visit, blood for determinations of prorenin and renin activity was drawn when venipuncture was performed for the measurement of glycosylated hemoglobin, and at 85 percent of all clinic visits a urine sample was obtained to measure albumin. These blood and urine samples were obtained between 10 a.m. and noon after the patients had taken their usual doses of insulin, eaten breakfast, and been normally active.
We also measured plasma prorenin activity in 54 control children and adolescents ranging in age from 4 to 21 years, some of whom have been reported on elsewhere.11 Although most of these children were normal, some were being followed for short stature or corrected thyroid disorders. In addition, we determined the ratio of urinary albumin to creatinine in 23 normal subjects 5 to 18 years old.
Albuminuria
Urinary albumin was measured by radioimmunoassay, and creatinine was measured with the picric acid (trinitrophenol) method.7 To avoid problems of inaccurate timing, albumin excretion was expressed as the ratio of albumin (in grams) to creatinine (in millimoles) in urine. In 39 24-hour urine specimens from 14 adult patients with diabetes, the rate of albumin excretion (in micrograms per minute) was closely correlated (r = 0.96) with the ratio of albumin to creatinine.7 A close correlation between the log of the ratio of albumin to creatinine in urine and the 24-hour urinary excretion of albumin has also been reported in children with diabetes.12 , 13
In the 23 normal subjects, the ratio of grams of albumin to millimoles of creatinine ranged from 0.00011 to 0.0021 (median, 0.00034). These results are similar to those of Mathiesen et al.14 and Chavers et al.,15 who defined a rate of albumin excretion under 20 μg per minute (the equivalent, for an adult, of an albumin—creatinine ratio of 0.0023) as normal for children, and a rate between 20 and 150 μg per minute (the equivalent of an albumin—creatinine ratio of 0.0023 to 0.017) as microalbuminuria. A small, transient increase in albumin excretion in patients with newly diagnosed Type I diabetes was disregarded.16 Occasional small increases in albumin excretion were classified as intermittent albuminuria,7 whereas continuous microalbuminuria was considered to exist if at least two of any three consecutive measurements of the ratio were above 0.0023 but less than 0.017. Patients with diabetes who had an albumin—creatinine ratio higher than 0.017 at any visit were classified as having overt albuminuria.
Assay of Plasma Renin and Prorenin Activity
Blood was collected in a tube containing EDTA and promptly centrifuged. Plasma was separated, frozen, and stored at −20°C. Active renin activity in plasma was measured by determining the rate of formation of angiotensin I in plasma incubated at 37°C (pH 7.4) with sheep angiotensinogen.6 The angiotensin I was measured by radioimmunoassay. The results were expressed as nanograms of angiotensin I generated per liter of plasma each second (nanograms of angiotensin I per liter · second). To determine total renin activity, an aliquot of plasma underwent dialysis, first to pH 3.3 and then to pH 7.4, to activate prorenin before incubation with sheep angiotensinogen. Plasma prorenin activity was calculated by subtracting active renin activity from total renin activity. The interassay coefficient of variation was 7 percent.
These measurements were performed in batches at various times after the samples had been coded and delivered to the laboratory. Clinical information was not available to laboratory personnel, and laboratory results were not transmitted to the clinical staff. We met once or twice a year to exchange information, which was entered in the coded computer file. Examinations continued according to the protocol and were not altered during the study.
Glycosylated hemoglobin was measured by the affinity-column method (BioRad, Oakland, Calif.). The normal range was 3.2 to 6.4 percent.
Statistical Analysis
The results were analyzed with use of the Statistical Analysis System (SAS Institute, Cary, N.C.). To establish an expected range for plasma prorenin according to age, we analyzed the first prorenin measurement from each patient who had uncomplicated diabetes of more than 0.1 and less than 5 years' duration (Fig. 1Figure 1
Initial Plasma Prorenin Activity in 86 Patients with Early Uncomplicated Diabetes (Squares) and in 54 Nondiabetic Controls (Triangles).). Patients with newly diagnosed diabetes were excluded, because they can have transient elevations in plasma prorenin activity, and patients with diabetes of more than five years' duration were excluded to eliminate those with possible inapparent diabetic complications. The relation of plasma prorenin activity to age in children with diabetes was analyzed by cubic regression, and the regression line and confidence limits for an individual observation were plotted. The regression line for prorenin against age in control subjects 4 to 21 years old11 did not differ significantly from that in patients with early, uncomplicated diabetes. We calculated the upper limit of the expected prorenin value for age as the 95 percent one-sided tolerance limit for an individual observation17 using the patients with uncomplicated diabetes as defined above. Two-tailed statistical tests were used to compare groups. P values of less than 0.05 were considered significant.Results
Plasma Prorenin Activity in Young Children
In both the children with uncomplicated diabetes and the controls under the age of seven, plasma prorenin activity was sometimes higher than in older children (Fig. 1). The plasma prorenin activity in children with diabetes and in the controls decreased with age. When prorenin was measured on successive visits, the levels in the children with high values declined into the normal range with increasing age. The nadir of mean initial prorenin activity occurred between the ages of 9 and 12, and thereafter the values rose slowly with increasing age (Fig. 1). Among the patients with diabetes, the plasma active renin activity was also higher in younger than in older children and adolescents (Table 1Table 1
Plasma Prorenin and Active Renin Activity in 135 Children and Adolescents with Type I Diabetes, According to Age and the Findings on Retinoscopy and Urinalysis.*). None of the children with diabetes under the age of 10 years had retinopathy or overt albuminuria (Table 1), but in some children in the two younger groups microalbuminuria developed during follow-up (Table 2Table 2
Prevalence of Retinopathy and Various Levels of Urinary Albumin Excretion (Ratio of Albumin to Creatinine) in Patients with Normal Plasma Prorenin Activity, as Compared with Patients with Increased Plasma Prorenin Activity on at Least One Occasion.*).Upper Limit of Normal Plasma Prorenin Activity in Older Children and Adolescents
The control subjects had values for plasma prorenin activity that were similar to those of the patients who had had uncomplicated diabetes for five years or less (Fig. 1). The mean (±SE) plasma prorenin activity was 8.43±0.58 ng of angiotensin I per liter · second at the time of the first clinic visit in the 32 patients older than 10 (mean age, 13.6 years) who had had uncomplicated diabetes for between 0.1 and 5 years, a value slightly larger than that in the 37 control subjects of the same age (7.06±0.32 ng of angiotensin I per liter · second; P<0.05). Since regression analysis demonstrated a small increase in plasma prorenin activity with age (0.15 ng of angiotensin I per liter · second per year; r = 0.26), we adjusted plasma prorenin activity for age (mean [±SD] adjusted value, 7.54±1.92). Calculation of the one-sided tolerance limit indicated that at least 95 percent of the prorenin measurements (as adjusted for age) among the patients with uncomplicated diabetes were below 11.51 ng of angiotensin I per liter · second. A value of less than 11.51 was therefore considered the upper limit of normal in patients with diabetes who were 8 to 20 years old.
Clinical Findings in Older Children and Adolescents with Diabetes and Normal Plasma Prorenin Activity
There was much variation in plasma prorenin activity among patients and in individual patients on successive visits, but as long as the highest value remained below 11.51 ng of angiotensin I per liter · second, diabetic complications were rare. Among the 77 patients 6 to 20 years old who had normal prorenin activity, retinopathy was seen in only 1, and overt albuminuria was found in only 2 of the 67 patients whose urine was tested (Table 2). Although intermittent or continuous microalbuminuria was detected in 29 percent of these patients, the frequency of intermittent and continuous microalbuminuria and overt albuminuria was significantly lower among them than among the patients with high plasma prorenin activity (60 percent; P<0.01).
Clinical Findings in Older Children and Adolescents with Diabetes and High Plasma Prorenin Activity
At least one plasma prorenin value above 11.51 ng of angiotensin I per liter · second was found in 26 patients over 10 years old (Table 2). Six of these patients had retinopathy and 12 had overt albuminuria, for a total of 16 patients (62 percent) with complications. The frequency of retinopathy or albuminuria was clearly greater (P<0.01) in the patients who had a high prorenin value at some time than in those whose prorenin values were consistently normal.
Prospective Course of Patients with Uncomplicated Diabetes and High Plasma Prorenin Activity
Figure 2Figure 2
Consecutive Measurements of Plasma Prorenin Activity in 14 Patients 10 Years of Age or Older with Initially Uncomplicated Diabetes and Three or More Prorenin Determinations, at Least One of Which Was above the Normal Range. shows the variations in plasma prorenin activity in 14 patients with three or more measurements, at least one of which was higher than 11.51 ng of angiotensin I per liter · second. Of the 34 patients 10 or older with initially uncomplicated diabetes who had at least three prorenin determinations, retinopathy or overt albuminuria developed in 9. Eight of these nine patients had at least one prorenin value higher than 11.51 ng of angiotensin I per liter · second. Only one patient in whom diabetic complications developed had consistently normal prorenin values. Of the 25 patients in whom complications did not develop during the study, 6 had at least one elevated prorenin value (sensitivity, 89 percent; specificity, 79 percent) (Fig. 3Figure 3
Incidence of Retinopathy or Overt Albuminuria in 34 Patients with Previously Uncomplicated Diabetes during 12 to 54 Months of Follow-up.). Among the patients who had had diabetes for more than four years, the mean plasma prorenin activity in those in whom retinopathy or overt albuminuria developed was significantly higher 18 months before the complication appeared than in those in whom no complication appeared during a similar period of observation (Table 3Table 3
Mean (±SE) Plasma Prorenin Activity before the Appearance of Retinopathy or Overt Albuminuria in Patients 10 or Older Who Had Had Type I Diabetes for More Than Four Years.*). The data presented here indicate a much greater risk of a microvascular complication in a patient with a high plasma prorenin level, and the test achieves useful sensitivity and specificity. Plasma active renin activity did not change with the development of complications.Other Factors
Increasing duration of diabetes was weakly correlated with plasma prorenin activity (r = 0.22 and P = 0.01 for the first visit). With the presence or absence of a complication (retinopathy or overt albuminuria) as the dependent variable, stepwise discriminant analysis demonstrated that the maximal plasma prorenin activity was significantly associated (partial r2 = 0.33, P<0.0001) with complications, even after the associations with age (partial r2 = 0.03, P = 0.04) and duration of diabetes (partial r2 = 0.17, P<0.0001) were removed. Multiple linear-regression analysis with the log of the maximal ratio of albumin to creatinine in urine (our only continuous measure of a diabetic complication) as the dependent variable and mean age, mean duration of diabetes, and maximal prorenin activity as the independent variables also demonstrated that prorenin activity was significantly associated with the ratio of albumin to creatinine (P<0.0001).
The mean ratio of albumin to creatinine in urine was associated with the mean plasma prorenin activity (r = 0.39, P<0.0001), but the association was not significant in an analysis of variance. In 70 patients with consistently normal urinary albumin excretion (<0.0023 g of albumin per millimole of creatinine), the mean maximal plasma prorenin activity was 9.09±0.43 ng of angiotensin I per liter · second. In 22 patients with intermittent microalbuminuria and 6 with continuous microalbuminuria, the mean maximal plasma prorenin activity was 10.67±1.12 and 12.00±3.06, respectively. Overt albuminuria was significantly related to plasma prorenin activity. In 14 patients with overt albuminuria, the mean maximal plasma prorenin activity was 17.63±1.79 (P<0.001 for the comparison with 70 patients with a normal ratio of albumin to creatinine).
The glycosylated hemoglobin value was higher in patients in whom overt albuminuria developed (mean, 11.6 percent; range, 8 to 19) than in those whose albumin excretion was normal (mean, 9.6 percent; range, 6 to 22). Although the difference between the two mean values was significant (P<0.001), the large number of overlapping values in the two groups made measurements of glycosylated hemoglobin of little use in anticipating the appearance of overt albuminuria.
The blood pressure was higher in the patients with continuous microalbuminuria or overt albuminuria (Table 4Table 4
Mean (±SE) Blood Pressure in 34 Age-Matched Patients with Diabetes, with or without Albuminuria.). Each of 17 patients with these forms of albuminuria was matched for age with a patient without albuminuria, resulting in identical mean ages for the two groups, in order to minimize the effect of age on blood pressure. The duration of diabetes was longer in the patients with albuminuria. The mean systolic and diastolic pressures were significantly higher in the group with albuminuria than in the group without albuminuria, but the range of blood pressures was similar in the two groups. In the 17 patients with albuminuria, who were followed for several years, a rise in blood pressure to 135/85 mm Hg or above occurred in 2 before albuminuria appeared and in 5 after it had appeared, whereas in the other 10 the blood pressure did not change, averaging 112/67 mm Hg. Thus, a rise in blood pressure neither reliably predicted nor consistently accompanied albuminuria.Discussion
Normotensive adults with microvascular complications of diabetes have higher plasma prorenin activity than patients without such complications,6 7 8 , 18 19 20 and patients with diabetes whose rate of albumin excretion is higher than 40 mg per day have increased plasma prorenin activity.21 Increased plasma prorenin activity has also been described in children who had diabetes with complications.6 , 9 Among 14 adolescents who had diabetes without overt albuminuria and 16 normal subjects matched for age, the mean plasma prorenin activity was reported to be 50 percent higher among those with diabetes.10
We found that adolescents with diabetic complications had significantly higher plasma prorenin activity than patients with uncomplicated diabetes matched for age. Furthermore, an increase in plasma prorenin activity preceded the development of complications in adolescents with diabetes, the value being above the upper limit of the expected range as much as 36 months before a complication was detected. The mean plasma prorenin activity in patients in whom retinopathy or overt albuminuria subsequently developed was significantly higher 18 months before the complication appeared than in those in whom these complications did not develop.
The mechanisms responsible for the association between elevated plasma prorenin activity and diabetic complications are not known. Both Misbin et al.8 and Chimori et al.22 have suggested that the rise in prorenin activity is related to the presence of autonomic neuropathy. Diabetic neuropathy is rare in children and adolescents,23 and none of our patients had any symptoms or signs of neuropathy. These findings suggest that factors other than neuropathy are important in the pathogenesis of elevated plasma prorenin activity among young patients who have diabetes with complications.
The juxtaglomerular cells of the kidney are the source of active renin and most of the prorenin in plasma. Plasma prorenin activity increases along with plasma active renin activity in response to sodium deprivation or the administration of furosemide. In adults with diabetes, large increases in plasma prorenin activity follow the intravenous administration of furosemide,24 especially in those with albuminuria and in those in whom the increase in plasma renin is below normal. These findings support the hypothesis that the processing of prorenin to renin is less efficient in diabetes and may be seriously impaired in patients with diabetes who have hyporeninemic hypoaldosteronism.
Microalbuminuria may be a sign of incipient nephropathy in Type I diabetes.25 In our study, the patients with either intermittent or continuous microalbuminuria had higher levels of plasma prorenin activity than the patients without microalbuminuria, but the difference was not statistically significant.
Diabetic complications are uncommon in young children with diabetes.26 As these children enter adolescence and as the duration of diabetes lengthens, microvascular complications become increasingly common.1 2 3 Complications developed in two thirds of our patients with increased plasma prorenin activity, whereas complications developed infrequently in those with normal plasma prorenin activity. High plasma prorenin values thus indicate a high risk of complications of diabetes.
Supported by a research grant (HL-17364) from the National Heart, Lung, and Blood Institute.
Presented in part at the Third Joint Meeting of the European Society for Pediatric Endocrinology and the Lawson Wilkins Pediatric Endocrinology Society, November 1989, Jerusalem, Israel.
We are indebted to Ms. J. Bialek and Ms. G. Grislis for expert technical assistance; to L. Rountree, R.N., for the collection of blood samples; and to Professor L.E. Moses for statistical advice.
Source Information
From the Departments of Pediatrics (D.M.W.) and Medicine (J.A.L.), Stanford University School of Medicine, Stanford, Calif. Address reprint requests to Dr. Wilson at the Department of Pediatrics, Endocrine Division, Rm. S-322, Stanford Medical Center, Stanford, CA 94305.
- References
References
1
Krolewski
Full Text | Web of Science | Medline2
Leslie
CrossRef | Web of Science | Medline3
Chase
CrossRef | Web of Science | Medline4
Mangili
Full Text | Web of Science | Medline5
Krolewski
Full Text | Web of Science | Medline6
Luetscher
Full Text | Web of Science | Medline7
Luetscher
CrossRef | Web of Science | Medline8
Misbin
CrossRef | Web of Science | Medline9
Luetscher
Web of Science | Medline10
Takaori
CrossRef | Medline11
Wilson
Web of Science | Medline12
Sochett
CrossRef | Web of Science | Medline13
Houser
CrossRef | Web of Science | Medline14
Mathiesen
CrossRef | Web of Science | Medline15
Chavers
Full Text | Web of Science | Medline16
Parving
CrossRef | Web of Science | Medline17
Bowker AH, Lieberman GJ. Engineering statistics. Englewood Cliffs, N.J.: Prentice-Hall, 1959:224–5.
18
Day
CrossRef | Web of Science | Medline19
Fujii
CrossRef | Medline20
Derkx
Medline21
Mossetti
Medline22
Chimori
CrossRef | Medline23
The DCCT Research Group
CrossRef | Web of Science | Medline24
Bryer-Ash
CrossRef | Web of Science | Medline25
Viberti
CrossRef | Web of Science | Medline26
Ellis
CrossRef | Web of Science | Medline
- Citing Articles (32)
Citing Articles
1
Gang Liu, Hirofumi Hitomi, Naohisa Hosomi, Yuki Shibayama, Daisuke Nakano, Hideyasu Kiyomoto, Hong Ma, Yasuyoshi Yamaji, Masakazu Kohno, Atsuhiro Ichihara, Hiroshi Itoh, Akira Nishiyama. (2011) Prorenin induces vascular smooth muscle cell proliferation and hypertrophy via epidermal growth factor receptor-mediated extracellular signal-regulated kinase and Akt activation pathway. Journal of Hypertension 29:4, 696-705
CrossRef2
Genevieve Nguyen. (2011) Renin, (pro)renin and receptor: an update. Clinical Science 120:5, 169-178
CrossRef3
John Fray. 2011. Endocrine Control of Sodium Balance. .
CrossRef4
Pitchai Balakumar, Gowraganahalli Jagadeesh. (2010) Cardiovascular and Renal Pathologic Implications of Prorenin, Renin, and the (Pro)renin Receptor: Promising Young Players From the Old Renin-Angiotensin-Aldosterone System. Journal of Cardiovascular Pharmacology 56:5, 570-579
CrossRef5
Erica L. Fletcher, Joanna A. Phipps, Michelle M. Ward, Kirstan A. Vessey, Jennifer L. Wilkinson-Berka. (2010) The renin–angiotensin system in retinal health and disease: Its influence on neurons, glia and the vasculature. Progress in Retinal and Eye Research 29:4, 284-311
CrossRef6
David Benavente, Colin D. Chue, Charles J. Ferro. (2010) THE IMPORTANCE OF RENIN-ANGIOTENSIN BLOCKADE IN PATIENTS WITH CARDIO-RENAL DISEASE. Journal of Renal Care 36, 97-105
CrossRef7
Genevieve Nguyen. (2010) The (pro)renin receptor in health and disease. Annals of Medicine 42:1, 13-18
CrossRef8
Heiko Funke-Kaiser, Frank S Zollmann, Jan H Schefe, Thomas Unger. (2010) Signal transduction of the (pro)renin receptor as a novel therapeutic target for preventing end-organ damage. Hypertension Research 33:2, 98-104
CrossRef9
Norman K. Hollenberg. (2010) Direct renin inhibition and the kidney. Nature Reviews Nephrology 6:1, 49-55
CrossRef10
Maki Uraoka, Koji Ikeda, Yusuke Nakagawa, Masahiro Koide, Yoshiki Akakabe, Ritsuko Nakano-Kurimoto, Tomosaburo Takahashi, Satoaki Matoba, Hiroyuki Yamada, Mitsuhiko Okigaki, Hiroaki Matsubara. (2009) Prorenin induces ERK activation in endothelial cells to enhance neovascularization independently of the renin–angiotensin system. Biochemical and Biophysical Research Communications 390:4, 1202-1207
CrossRef11
Richard N. Re. (2009) New Insights into Target Organ Involvement in Hypertension. Medical Clinics of North America 93:3, 559-567
CrossRef12
D. Muller, D. N. Muller. (2008) Battle against the renin-angiotensin system: help from an unexpected party. Nephrology Dialysis Transplantation 24:4, 1110-1112
CrossRef13
Atsuhiro Ichihara, Mariyo Sakoda, Asako Mito-Kurauchi, Hiroshi Itoh. (2008) Activated prorenin as a therapeutic target for diabetic nephropathy. Diabetes Research and Clinical Practice 82, S63-S66
CrossRef14
Atsuhiro Ichihara, Mariyo Sakoda, Asako Kurauchi-Mito, Akira Nishiyama, Hiroshi Itoh. (2008) Involvement of receptor-bound prorenin in development of nephropathy in diabetic db/db mice. Journal of the American Society of Hypertension 2:5, 332-340
CrossRef15
Jan H Schefe, Christian Neumann, Matthias Goebel, Jan Danser, Sebastian Kirsch, Ronald Gust, Ulrich Kintscher, Thomas Unger, Heiko Funke-Kaiser. (2008) Prorenin engages the (pro)renin receptor like renin and both ligand activities are unopposed by aliskiren. Journal of Hypertension 26:9, 1787-1794
CrossRef16
Suma Dronavalli, Irena Duka, George L Bakris. (2008) The pathogenesis of diabetic nephropathy. Nature Clinical Practice Endocrinology & Metabolism 4:8, 444-452
CrossRef17
F C Luft, M H Weinberger. (2008) Antihypertensive therapy with aliskiren. Kidney International 73:6, 679-683
CrossRef18
Geneviève Nguyen. (2008) Twenty years of the (pro)renin receptor. Journal of the American Society of Hypertension 2:2, 59-63
CrossRef19
Atsuhiro Ichihara, Hiroshi Itoh, Tadashi Inagami. (2008) Critical roles of (pro)renin receptor-bound prorenin in diabetes and hypertension: sallies into therapeutic approach. Journal of the American Society of Hypertension 2:1, 15-19
CrossRef20
Roland E Schmieder. (2007) The potential role of prorenin in diabetic nephropathy. Journal of Hypertension 25:7, 1323-1326
CrossRef21
Linda Davies, Greg R Fulcher, Andrew Atkins, Kim Frumar, Judith Monaghan, Gordon Stokes, Philip Clifton-Bligh, Aidan McElduff, Bruce Robinson, John Stiel, Stephen Twigg, Errol Wilmshurst. (1999) The Relationship of Prorenin Values to Microvascular Complications in Patients with Insulin-Dependent Diabetes Mellitus. Journal of Diabetes and its Complications 13:1, 45-51
CrossRef22
Terri J Allen, Mark E Cooper, Richard E Gilbert, Judy Winikoff, Sandford L Skinner, George Jerums. (1996) Serum total renin is increased before microalbuminuria in diabetes. Kidney International 50:3, 902-907
CrossRef23
Alessandro Doria, James H. Warram, Andrzej S. Krolewski. (1995) Genetic susceptibility to nephropathy in insulin-dependent diabetes: From epidemiology to molecular genetics. Diabetes / Metabolism Reviews 11:4, 287-314
CrossRef24
C.C. Cronin, B. Crowley, J.B. Ferriss, D. Barry. (1995) Reduced Plasma Aldosterone Concentrations in Randomly Selected Patients with Insulin-dependent Diabetes Mellitus. Diabetic Medicine 12:9, 809-815
CrossRef25
Denis Daneman, Charles H Crompton, J Williamson Balfe, Etienne B Sochett, Alice Chatzilias, Bruce R Cotter, Daniel H Osmond. (1994) Plasma prorenin as an early marker of nephropathy in diabetic (IDDM) adolescents. Kidney International 46:4, 1154-1159
CrossRef26
P.H. Winocour, C. Catalano, T.H. Thomas, R. Wilkinson, K.G.M.M. Alberti. (1993) Increased Red Cell Sodium Lithium Countertransport Activity, Total Exchangeable Sodium, and Hormonal Control of Sodium Balance in Normoalbuminuric Type 1 Diabetes. Diabetic Medicine 10:9, 825-832
CrossRef27
David J Lush, Jean A King, John C S Fray. (1993) Pathophysiology of low renin syndromes: Sites of renal renin secretory impairment and prorenin overexpression. Kidney International 43:5, 983-999
CrossRef28
Cristino Cruz, Maria Elena Ibarra-Rubio, José Pedraza-Chaverrí. (1993) CIRCULATING LEVELS OF ACTIVE, TOTAL AND INACTIVE RENIN (PRORENIN), ANGIOTENSIN I AND ANGIOTENSINOGEN IN CARBON TETRACHLORIDE-TREATED RATS. Clinical and Experimental Pharmacology and Physiology 20:2, 83-88
CrossRef29
Chrysanthus Chukwuma. (1993) Type I diabetic nephropathy: Clinical characteristics and economic impact. Journal of Diabetes and its Complications 7:1, 15-27
CrossRef30
Jean-Michel Halimi, Jean E. Sealey. (1992) Prorenin in diabetes mellitus. Trends in Endocrinology & Metabolism 3:7, 270-275
CrossRef31
L. Duntas, F.S. Keck, C. Haug, W. Hetzel, C.F. Wolf, J. Rosenthal, E.F. Pfeiffer. (1992) Serum angiotensin-converting enzyme activity and active renin plasma concentrations in insulin-dependent diabetes mellitus. Diabetes Research and Clinical Practice 16:3, 203-208
CrossRef32
Kem, David C., Brown, Ronald D., . (1990) Renin — From Beginning to End. New England Journal of Medicine 323:16, 1136-1137
Full Text
