Low-renin status in therapy-resistant hypertension: a clue to efficient treatment
Abstract
OBJECTIVE: Therapy resistance is an enduring problem in clinical hypertension. Our aims were to estimate: (1) the contribution of a low-renin status in therapy resistance; (2) whether such status could give a clue to more successful treatment; and (3) the contribution by adrenal cortical adenomas and by primary aldosteronism. SETTING: Patients were referred from general and internal medicine practices following written invitations and included consecutively. Participants were examined and followed-up on an outpatient basis. DESIGN AND INTERVENTIONS: Patients were divided according to renin status. Low-renin patients were treated with an aldosterone inhibitor in a prospective, randomized, placebo-controlled, double-blind, cross-over study. MAIN OUTCOME MEASURES: Prevalence of low-renin status in therapy resistance. Blood pressure and hormonal responses to specific treatment. Numbers of adrenocortical adenomas and primary aldosteronism. RESULTS: In 90 treatment-resistant hypertensive, 67% had plasma renin activity (PRA) below 0.5 nmol/l per hour. Of the 60 low-renin patients, 38 were studied on a fixed combination of amiloride and hydrochlorothiazide. Three weeks' treatment reduced blood pressure by 31/15 mmHg compared to placebo (P < or = 0.0001). Serum aldosterone and plasma renin activity increased substantially during active treatment. Through the subsequent 6-12 months of open treatment, seven patients (18%) showing an escape phenomenon had their high blood pressure effectively treated by extra amiloride. Of the 60 low-renin patients, eight had adrenal adenoma. CONCLUSION: A low-renin status characterized two-thirds of patients with treatment-resistant hypertension, who could be treated efficiently by aldosterone inhibition. Patients with an escape phenomenon (18%) could effectively be treated by increasing the aldosterone inhibitor. Low-renin hypertensives had high prevalence of adrenocortical adenomas and primary aldosteronism.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
The majority of studies indicate that primary aldosteronism is a particularly common cause of resistant hypertension.
“The majority of studies indicate that primary aldosteronism is a particularly common cause of RH.”
From Resistant Hypertension: Detection, Evaluation, and Management: A Scientific Statement From the American Heart Association (2018) · cites this paper as [57]
Observational studies from many different countries have demonstrated a prevalence rate of primary aldosteronism of ≈20% in patients with confirmed resistant hypertension.
“Observational studies from many different countries have demonstrated a prevalence rate of primary aldosteronism of ≈20% in patients with confirmed RH.57,160,294–296”
From Resistant Hypertension: Detection, Evaluation, and Management: A Scientific Statement From the American Heart Association (2018) · cites this paper as [57]
Cites
The Effect of Spironolactone on Morbidity and Mortality in Patients with Severe Heart Failure
Pitt, B., Zannad, F., Remme, W. J., Cody, R., Castaigne, A., Perez, A., Palensky, J., & Wittes, J. (1999) · New England Journal of Medicine · doi:10.1056/nejm199909023411001 · Cited by 9,214 · see citing works
(1997) · Archives of Internal Medicine · doi:10.1001/archinte.157.21.2413 · Cited by 6,345 · see citing works
Hansson, L., Zanchetti, A., Carruthers, S. G., Dahlöf, B., Elmfeldt, D., Julius, S., Ménard, J., Rahn, K. H., Wedel, H., & Westerling, S. (1998) · The Lancet · doi:10.1016/s0140-6736(98)04311-6 · Cited by 5,728 · see citing works
Stearne, M. R., Palmer, S. L., Hammersley, M. S., Franklin, S. L., Spivey, R. S., Lévy, J., Tidy, C. R., Bell, N. J., Steemson, J., Barrow, B. A., et al. (1998) · UCL Discovery (University College London) · Cited by 4,803 · see citing works
(1997) · Archives of Internal Medicine · doi:10.1001/archinte.1997.00440420033005 · Cited by 3,777 · see citing works
Simultaneous single isotope radioenzymatic assay of plasma norepinephrine, epinephrine and dopamine
Peuler, J. D., & Johnson, G. A. (1977) · Life Sciences · doi:10.1016/0024-3205(77)90070-4 · Cited by 1,899 · see citing works
Essential Hypertension: Renin and Aldosterone, Heart Attack and Stroke
Brunner, H. R., Laragh, J. H., Baer, L., Newton, M. A., Goodwin, F. T., Krakoff, L. R., Bard, R. H., & Bühler, F. R. (1972) · New England Journal of Medicine · doi:10.1056/nejm197203022860901 · Cited by 1,091 · see citing works
Hyperaldosteronism Among Black and White Subjects With Resistant Hypertension
Calhoun, D. A., Nishizaka, M. K., Zaman, M. A., Thakkar, R. B., & Weissmann, P. (2002) · Hypertension · doi:10.1161/01.hyp.0000040261.30455.b6 · Cited by 763 · see citing works
Propranolol Inhibition of Renin Secretion
Bühler, F. R., Laragh, J. H., Baer, L., Vaughan, E. D., & Brunner, H. R. (1972) · New England Journal of Medicine · doi:10.1056/nejm197212142872401 · Cited by 718 · see citing works
Laragh, J. H. (1973) · The American Journal of Medicine · doi:10.1016/0002-9343(73)90128-9 · Cited by 489 · see citing works
Primary Aldosteronism and Hypertensive Disease
Mosso, L. M., Carvajal, C. A., González, A. A., Barraza, A., Avila, F., Montero, J., Alvaro Huete, G., Alessandra Gederlini, G., & Fardella, C. (2003) · Hypertension · doi:10.1161/01.hyp.0000079505.25750.11 · Cited by 484 · see citing works
Brilla, C. G., Matsubara, L. S., & Weber, K. T. (1993) · Journal of Molecular and Cellular Cardiology · doi:10.1006/jmcc.1993.1066 · Cited by 427 · see citing works
Drug Effects on Aldosterone/Plasma Renin Activity Ratio in Primary Aldosteronism
Mulatero, P., Rabbia, F., Milan, A., Paglieri, C., Morello, F., Chiandussi, L., & Veglio, F. (2002) · Hypertension · doi:10.1161/01.hyp.0000038478.59760.41 · Cited by 389 · see citing works
Gallay, B. J., Ahmad, S., Xu, L., Toivola, B., & Davidson, R. C. (2001) · American Journal of Kidney Diseases · doi:10.1016/s0272-6386(01)80117-7 · Cited by 304 · see citing works
Prevalence of primary and secondary hypertension: studies in a random population sample.
Berglund, G., Andersson, O., & Wilhelmsen, L. (1976) · BMJ · doi:10.1136/bmj.2.6035.554 · Cited by 268 · see citing works
McDonald, F. J., Yang, B., Hrstka, R. F., Drummond, H. A., Tarr, D. E. K., McCray, P. B., Stokes, J. B., Welsh, M. J., & Williamson, R. A. (1999) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.96.4.1727 · Cited by 247 · see citing works
Secondary Hypertension in a Blood Pressure Clinic
Sinclair, A. (1987) · Archives of Internal Medicine · doi:10.1001/archinte.1987.00370070103015 · Cited by 243 · see citing works
Volume factor in low and normal renin essential hypertension
Vaughan, E. D., Laragh, J. H., Gavras, I., et al. (1973) · The American Journal of Cardiology · doi:10.1016/s0002-9149(73)80044-x · Cited by 195 · see citing works
The Diagnosis of Primary Aldosteronism and Separation of Two Major Subtypes
Weinberger, M. H. (1993) · Archives of Internal Medicine · doi:10.1001/archinte.1993.00410180075008 · Cited by 195 · see citing works
Gordon, R. D., Ziesak, M. D., Tunny, T. J., Stowasser, M., & Klemm, S. A. (1993) · Clinical and Experimental Pharmacology and Physiology · doi:10.1111/j.1440-1681.1993.tb01687.x · Cited by 190 · see citing works
White, M., Yusuf, S., McKelvie, R. S., Pericak, D., Young, J. B., Latini, R., Pogue, J., Burns, R. J., Probstfield, J. L., Tsuyuki, R. T., et al. (2000) · Circulation · Cited by 183 · see citing works
Proposed Mechanisms of Propranolol's Antihypertensive Effect in Essential Hypertension
Hollifield, J. W., Sherman, K., Zwagg, R. V., et al. (1976) · New England Journal of Medicine · doi:10.1056/nejm197607082950203 · Cited by 181 · see citing works
Effects of Metoprolol CR in Patients With Ischemic and Dilated Cardiomyopathy
(2000) · Circulation · doi:10.1161/01.cir.101.4.378 · Cited by 181 · see citing works
Carey, R. M. (1972) · Archives of Internal Medicine · doi:10.1001/archinte.130.6.849 · Cited by 174 · see citing works
Mineralocorticoid hypertension
Stewart, P. M. (1999) · The Lancet · doi:10.1016/s0140-6736(98)06102-9 · Cited by 162 · see citing works
The Syndrome of Essential Hypertension and Suppressed Plasma Renin Activity
Carey, R. M. (1972) · Archives of Internal Medicine · doi:10.1001/archinte.1972.03650060041007 · Cited by 124 · see citing works
Kjeldsen, S. E., Flaaten, B., Eide, I. A., Helgeland, A., & Leren, P. (1982) · Scandinavian Journal of Clinical and Laboratory Investigation · doi:10.1080/00365518209168076 · Cited by 100 · see citing works
Self-citationMineralocorticoid hypertension
Gordon, R. D. (1994) · The Lancet · doi:10.1016/s0140-6736(94)93003-1 · Cited by 99 · see citing works
Stimulated Renin: A Screening Test for Hypertension
WALLACH, L., NYARAI, I., & DAWSON, K. G. (1975) · Annals of Internal Medicine · doi:10.7326/0003-4819-82-1-27 · Cited by 89 · see citing works
Effects of bucindolol on neurohormonal activation in congestive heart failure
Eichhorn, E. J., McGhie, A. I., Bedotto, J. B., Corbett, J. R., Malloy, C. R., Hatfield, B. A., Deitchman, D., Willard, J. E., & Grayburn, P. A. (1991) · The American Journal of Cardiology · doi:10.1016/0002-9149(91)90102-q · Cited by 80 · see citing works
Kjeldsen, S. E., Flaaten, B., Eide, I. A., et al. (1982) · Scandinavian Journal of Clinical and Laboratory Investigation · doi:10.3109/00365518209168076 · Cited by 68 · see citing works
Self-citationDerkx, F. H. M., de Bruin, R. J., van Gool, J. M., et al. (1996) · Clinical Chemistry · doi:10.1093/clinchem/42.7.1051 · Cited by 67 · see citing works
Screening for Primary Aldosteronism: Implications of an Increased Plasma Aldosterone/Renin Ratio
Schwartz, G. L., Chapman, A. B., Boerwinkle, E., Kisabeth, R. M., & Turner, S. T. (2002) · Clinical Chemistry · doi:10.1093/clinchem/48.11.1919 · Cited by 66 · see citing works
Pathophysiologic and pharmacokinetic determinants of the antihypertensive response to propranolol
Esler, M., Zweifler, A. J., Randall, O. S., et al. (1977) · Clinical Pharmacology & Therapeutics · doi:10.1002/cpt1977223299 · Cited by 66 · see citing works
Kjeldsen, S., Dahlöf, B., Devereux, R. B., Julius, S., Fairé, U. D., Fyhrquist, F., Ibsen, H., Kristianson, K. J., Lederballe‐Pedersen, O., Lindholm, L. H., et al. (2000) · American Journal of Hypertension · doi:10.1016/s0895-7061(00)00280-6 · Cited by 60 · see citing works
Effect of microvibration on activity of ureteral and portal smooth muscles
Ohhashi, T., Azuma, T., & Sakaguchi, M. (1979) · American Journal of Physiology-Cell Physiology · doi:10.1152/ajpcell.1979.236.5.c192 · Cited by 56 · see citing works
Aldosterone Secretion and Various Forms of Hypertensive Vascular Disease
Laragh, J. H., CANNON, P. J., & AMES, R. P. (1963) · Annals of Internal Medicine · doi:10.7326/0003-4819-59-1-117 · Cited by 32 · see citing works
Pitt, B. (2002) · American Journal of Hypertension · doi:10.1016/s0895-7061(02)02332-4 · Cited by 28 · see citing works
Renin and prorenin: advances and declines in methodology
Sealey, J. E., & LARAGH, J. H. (1996) · Clinical Chemistry · doi:10.1093/clinchem/42.7.993 · Cited by 20 · see citing works
Azizi, M., Bissery, A., Bura-Rivière, A., & M??nard, J. (2003) · Journal of Hypertension · doi:10.1097/00004872-200310000-00016 · Cited by 17 · see citing works
Low-renin hypertension: more common than we think?
Pratt, J. H. (2001) · PubMed · Cited by 17 · see citing works
Pratt, H. J. (2000) · Cardiology in Review · doi:10.1097/00045415-200008040-00005 · Cited by 16 · see citing works
Functional tests for primary aldosteronism: Value of captopril suppression
Racine, M.-C., Douville, P., & Lebel, M. (2002) · Current Hypertension Reports · doi:10.1007/s11906-002-0014-5 · Cited by 14 · see citing works
Heparin Interference with Sodium and Albumin Assays
Karon, B. S., Kempe, K. C., & Scott, M. G. (1997) · Clinical Chemistry · doi:10.1093/clinchem/43.4.697 · Cited by 10 · see citing works
Derkx, F. H. M., & Schalekamp, M. A. D. H. (1997) · Clinical Chemistry · doi:10.1093/clinchem/43.4.694 · Cited by 10 · see citing works
Flagged first, then by citations
Cited by
Sorted by citations
Funder, J. W., Carey, R. M., Mantero, F., Murad, M. H., Reincke, M., Shibata, H., Stowasser, M., & Young, W. F. (2016) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jc.2015-4061 · Cited by 2,925 · see citing works
Funder, J. W., Carey, R. M., Fardella, C., Gomez-Sanchez, C. E., Mantero, F., Stowasser, M., Young, W. F., & Montori, V. M. (2008) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jc.2008-0104 · Cited by 1,554 · see citing works
Carey, R. M., Calhoun, D. A., Bakris, G. L., Brook, R. D., Daugherty, S. L., Dennison-Himmelfarb, C. R., Egan, B. M., Flack, J. M., Gidding, S. S., Judd, E., et al. (2018) · Hypertension · doi:10.1161/hyp.0000000000000084 · Cited by 1,153 · see citing works
Beuschlein, F., Boulkroun, S., Osswald, A., Wieland, T., Nielsen, H. N., Lichtenauer, U. D., Penton, D., Schack, V. R., Amar, L., Fischer, E., et al. (2013) · Nature Genetics · doi:10.1038/ng.2550 · Cited by 577 · see citing works
Sowers, J. R., Whaley-Connell, A., & Epstein, M. (2009) · Annals of Internal Medicine · doi:10.7326/0003-4819-150-11-200906020-00005 · Cited by 351 · see citing works
Pratt-Ubunama, M. N., Nishizaka, M. K., Boedefeld, R. L., Cofield, S. S., Harding, S. M., & Calhoun, D. A. (2007) · Chest · doi:10.1378/chest.06-1442 · Cited by 331 · see citing works
Gaddam, K. K. (2008) · Archives of Internal Medicine · doi:10.1001/archinte.168.11.1159 · Cited by 301 · see citing works
Gaddam, K., Pimenta, E., Thomas, S. J., Cofield, S. S., Oparil, S., Harding, S. M., & Calhoun, D. A. (2010) · Journal of Human Hypertension · doi:10.1038/jhh.2009.96 · Cited by 289 · see citing works
Gonzaga, C. C., Gaddam, K. K., Ahmed, M. I., Pimenta, E., Thomas, S. J., Harding, S. M., Oparil, S., Cofield, S. S., & Calhoun, D. A. (2010) · Journal of Clinical Sleep Medicine · doi:10.5664/jcsm.27878 · Cited by 188 · see citing works
Resistant Hypertension: Incidence, Prevalence, and Prognosis
Pimenta, E., & Calhoun, D. A. (2012) · Circulation · doi:10.1161/circulationaha.112.097345 · Cited by 188 · see citing works
Diuretics for Hypertension: A Review and Update
Roush, G. C., & Sica, D. A. (2016) · American Journal of Hypertension · doi:10.1093/ajh/hpw030 · Cited by 142 · see citing works
Hyperaldosteronism as a Common Cause of Resistant Hypertension
Calhoun, D. A. (2013) · Annual Review of Medicine · doi:10.1146/annurev-med-042711-135929 · Cited by 108 · see citing works
Effect of spironolactone on patients with resistant hypertension and obstructive sleep apnea
Yang, L., Zhang, H., Cai, M., Zou, Y., Jiang, X., Song, L., Liang, E., Bian, J., Wu, H., & Hui, R. (2016) · Clinical and Experimental Hypertension · doi:10.3109/10641963.2015.1131290 · Cited by 99 · see citing works
The Role of Aldosteronism in Causing Obesity-Related Cardiovascular Risk
Calhoun, D. A., & Sharma, K. (2010) · Cardiology Clinics · doi:10.1016/j.ccl.2010.04.001 · Cited by 74 · see citing works
Quinaglia, T., Martins, L. C., Figueiredo, V. N., Santos, R. C., Yugar-Toledo, J. C., Martin, J. F. V., Demacq, C., Pimenta, E., Calhoun, D. A., & Moreno, H. (2011) · Journal of Human Hypertension · doi:10.1038/jhh.2011.43 · Cited by 57 · see citing works
Use of Aldosterone Antagonists for Treatment of Uncontrolled Resistant Hypertension
Dudenbostel, T., & Calhoun, D. A. (2017) · American Journal of Hypertension · doi:10.1093/ajh/hpw105 · Cited by 51 · see citing works
Börgel, J., Springer, S., Ghafoor, J., Arndt, D., Duchna, H.-W., Barthel, A., Werner, S., Van Helden, J., Hanefeld, C., Neubauer, H., et al. (2010) · Clinical Research in Cardiology · doi:10.1007/s00392-010-0148-4 · Cited by 47 · see citing works
Screening for Adrenal-Endocrine Hypertension: Overview of Accuracy and Cost-effectiveness
Schwartz, G. L. (2011) · Endocrinology and Metabolism Clinics of North America · doi:10.1016/j.ecl.2011.02.001 · Cited by 36 · see citing works
Role of Aldosterone Blockade in Resistant Hypertension
Egan, B. M., & Li, J. (2014) · Seminars in Nephrology · doi:10.1016/j.semnephrol.2014.04.004 · Cited by 33 · see citing works
Management of hypertension in patients with chronic kidney disease
Hamrahian, S. M. (2017) · Current Hypertension Reports · doi:10.1007/s11906-017-0739-9 · Cited by 26 · see citing works
- Authors
- Eide, I. K., Torjesen, P. A., Drolsum, A., Babovic, A., & Lilledahl, N. P.
- Affiliations
- Oslo University Hospital (NO)
- Corresponding author
- Eide, Ivar K
- Venue
- Journal of Hypertension
- Published
- 2004-11
- Volume
- 22
- Issue
- 11
- Pages
- 2217-2226
- ISSN
- 0263-6352 (ISSN-L)
- OpenAlex
- W2073002995
- Cited by
- 265
- References
- 46
- Citations by year
- 2026: 5 · 2025: 6 · 2024: 1 · 2023: 5 · 2022: 4 · 2021: 9 · 2020: 8 · 2019: 3 · 2018: 9 · 2017: 16 · 2016: 17 · 2015: 13 · 2014: 17 · 2013: 21 · 2012: 13
- FWCI
- 9.30
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Journal of Hypertension (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Hormonal Regulation and Hypertension
- Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Renin-Angiotensin System Studies
- Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Blood Pressure and Hypertension Studies
- Keywords
- treatment-resistant hypertension, plasma renin activity, amiloride, hydrochlorothiazide, adrenal adenoma, primary aldosteronism, blood pressure reduction
- MeSH terms
- Adenoma, Adrenal Gland Neoplasms, Adult, Aged, Aged, 80 and over, Mineralocorticoid Receptor Antagonists, Amiloride, Antihypertensive Agents, Drug Combinations, Drug Resistance, Female, Humans, Hydrochlorothiazide, Hyperaldosteronism, Hypertension, Male, Middle Aged, Potassium, Prospective Studies, Renin, Retinal Diseases, Prevalence, Cross-Over Studies
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
