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Saudi Journal of Kidney Diseases and Transplantation
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ORIGINAL ARTICLE  
Year : 2011  |  Volume : 22  |  Issue : 1  |  Page : 75-78
Efficacy of low dose spironolactone in chronic kidney disease with resistant hypertension


Nephrology Department, Shahid Beheshti University of Medical Science, Imam Hosein Hospital, Tehran, Iran

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Date of Web Publication30-Dec-2010
 

   Abstract 

To determine the antihypertensive benefit of adding low dose sprinolactone to multi≠drug regimens that included a diuretic, a calcium channel blocker and angiotensin-converting enzyme inhibitor or angiotensin receptor blocker in patients with moderately severe chronic kidney disease (CKD) [glomerular filtration rate (GFR) 25-50 mL/min] and resistant hyper≠tension, we studied 41 patients randomly divided into two groups: group 1: patients who received placebo as spironolactone and group 2: patients who received spironolactone 25-50 mg/day. The patients were evaluated during follow-up at the 6th and 12th weeks. The mean decrease in systolic and diastolic blood pressure after 6 weeks of spironolactone was 33 ± 8 and 13 ± 2 mmHg, respectively, and it was maintained after 12 weeks of spironolactone wherein the values were 36 ± 10 and 12 ± 2 mmHg, respectively, while there was no change in the blood pressure in the control group. Hyperkalemia (serum potassium >5.5 meq/L) occurred in one subject in the spironolactone group. We conclude that low-dose spironolactone may provide a significant additive blood pressure reduction in CKD patients (stage 2 and 3) with resistant hypertension.

How to cite this article:
Abolghasmi R, Taziki O. Efficacy of low dose spironolactone in chronic kidney disease with resistant hypertension. Saudi J Kidney Dis Transpl 2011;22:75-8

How to cite this URL:
Abolghasmi R, Taziki O. Efficacy of low dose spironolactone in chronic kidney disease with resistant hypertension. Saudi J Kidney Dis Transpl [serial online] 2011 [cited 2019 Aug 20];22:75-8. Available from: http://www.sjkdt.org/text.asp?2011/22/1/75/74355

   Introduction Top


Resistant hypertension defined as a failure of use of three or more different classes of anti≠hypertensive agents to control blood pressure (BP) to <140/90 mmHg remains a common clinical problem, especially in chronic kidney disease (CKD). Recent clinical trials suggest that 30% of hypertensive patients may be resistant to triple therapy combination. [1]

Angiotensin-converting enzyme (ACE) inhi≠bitors are potent members of the armamen≠tarium to treat hypertension in CKD patients. This class of drugs also reduces proteinuria and slows progression of CKD by reducing BP and decreasing intraglomerular pressure. [2],[3] Al≠dosterone, the end product of the rennin-an≠giotensin-aldosterone system (RAAS), has at≠tracted renewed attention as an important me≠diator of both cardiovascular and renal disease. [4],[5] Moreover, aldosterone blockade has been shown to greatly im-prove survival in patients with chronic heart failure. [6],[7]

The current study was designed to determine the anti-hypertensive benefit of low dose spi≠ronolactone (25 mg/day) as an add-on therapy in patients with resistant hypertension.


   Patients and Methods Top


We studied 41 patients with moderately severe CKD [glomerular filtration rate (GFR) 25-50 mL/min] and resistant hypertension, randomly divided into two groups in a double-blind fa≠shion, as follows: group 1: 22 patients who re≠ceived placebo as spironolactone and group 2: 19 patients who received spironolactone 25-50 mg/day. The patients in both the groups were matched for age and sex and antihypertensive drug. All the patients signed written informed consents be-fore enrollment. Resistant hyper≠tension was defined as uncontrolled hyperten≠sion, as determined at two or more clinic vi≠sits, in spite of the use of three or more anti≠hypertensive medications at pharmacologically effective doses, including a diuretic, an ACE inhibitor, and calcium channel blocker. The patients were required to be on the same anti≠hypertensive regimen for at least 4 weeks be≠fore evaluation.

Spironolactone, amiloride or triamterene were discontinued in all the patients for at least 6 weeks before the start of the study. None of the study patients was on treatment with erythro≠poietin. Other secondary causes of hyperten≠sion such as reno-vascular, primary aldostero≠nism, pheochromocytoma or Cushing syndrome had been excluded by laboratory analysis or radiological imaging as clinically indicated. All the study patients were encouraged to limit salt intake to less than 6 g/day.

Fasting plasma blood urea nitrogen (BUN), creatinine, sodium, and potassium levels were estimated. A 24-hour urinary collection for so≠dium (UNA) and creatinine was obtained three times during the study period.

Blood tests were repeated at 6 and 12 weeks. Serum potassium, BUN, creatinine were checked at each follow-up visit and 2 weeks after ini≠tiation of spironolactone therapy.

Blood pressure was measured by a physician according to the American Heart Association guidelines. If the systolic BP was not con≠trolled, the spironolactone dose was increased from the initial 25 mg/day up to 50 mg/day.


   Statistical Analysis Top


Values were expressed as the mean ± stan≠dard deviation (SD). Values between groups or time periods were compared by Student's "t" test or by one-way analysis of variance (ANO≠VA). A P-value <0.05 was considered signi≠ficant.


   Results Top


Baseline characteristics of the study patients are shown in [Table 1]. There were no diffe≠rences in the characteristics between the study groups.

The comparison of the response to therapy and side effects are shown in [Table 2]. The mean decrease in systolic and diastolic BP after 6 weeks of spironolactone was 33 ± 8 and 13 ± 2 mmHg, respectively, and it was maintained after 12 weeks of spironolactone, i.e., the mean decrease was 36 ± 10 and 12 ± 2 mmHg, res≠pectively, while there was no change in the BP in the control group. BP did not change in the control group after six and 12 weeks of therapy. Hyperkalemia (serum potassium > 5.5 mmol/L) occurred in one patient in the spironolactone group.
Table 1: Baseline characteristics of evaluated subjects.

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Table 2: BP and serum K, 6 and 12 weeks after treatment.

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   Discussion Top


The results of this study demonstrate that low-dose spironolactone can induce substantial BP reduction when added to multi-drug regi≠mens in CKD patients. Other studies showed that spironolactone could reduce BP in the non-CKD patients with resistant hypertension without hyperaldeosteronism . [8]

Extra-adrenal tissue may synthesize aldoste≠rone. The vasculature, kidney and heart have been reported as sites of synthesis. [9],[10] Besides the well-documented effect of aldosterone to expand extra-cellular volume with the net re≠sult of hypertension, direct vascular actions of aldosterone have been proposed. Systemic vas≠cular resistance has been reported to change modestly in response to acute aldosterone in≠fusion in normal humans. [11]

In the remnant kidney model of CKD, ACE inhibitors and angiotensin receptor blockers (ARB) attenuate renal injury. [12],[13] However, this protection, which is associated with sup≠pression of aldosterone secretion, is abrogated by exogenous aldosterone infusion with return of hypertension, proteinuria and nephroscle≠ rosis. [14]

Adding spironolactone 25 mg/day to an ARB in 22 patients with chronic glomerulonephritis resulted in further BP reduction and a 13% decrease in proteinuria. [15]

One study showed a strong correlation bet≠ween aldosterone levels and degree of proteinuria, [16] and others supported this association. [15],[17]

Even though data thus far are encouraging to use aldosterone antagonists in reducing protei≠nuria and BP, larger studies with long-term follow-up are still required.

In our study, hyperkalemia was observed in one patient. Another study showed a signifi≠cant increase in serum potassium with eple≠renone use regardless of renal function. [18]

We conclude that a low-dose spironolactone may provide a significant additive BP reduc≠tion in CKD patients (stage 2 and 3) with re≠sistant hypertension. Larger clinical studies are warranted to address more definitively the safety and efficacy of aldosterone antagonists in CKD patients.

 
   References Top

1.Calhoun DA, Zaman MA, Nishizaka MK. Resistant hypertension. Curr Hypertens Rep 2002;4(3):221-8.  Back to cited text no. 1
    
2.Maschio G, Alberti D, Janin G, et al. Effect of the angiotensin- converting- Enzyme inhibitor benazeprial on the progression of chronic renal insufficiency. N Engl J Med 1996;334(15): 939-45.  Back to cited text no. 2
    
3.The GISEN Group. Randomised placebo≠controlled trial of effect of ramipril on decline in glumerular filtration rate and risk of ter≠minal renal failure in proteinuric non diabetic nephropathy. Lancet 1997;349:1857-63.  Back to cited text no. 3
    
4.Eptien M. Aldosterone as a determinant of cardiovascular and renal dysfunction. J R Soc Med 2001;94:378-83.  Back to cited text no. 4
    
5.Epstein M. Aldosterone as a mediator of pro≠gressive renal disease: pathogenetic and cli≠nical implications. Am J Kidney Dis 2001;37: 677-88.  Back to cited text no. 5
[PUBMED]    
6.Pitt B, Remme W, Zannad F, et al. Eplerenone, a selective aldosterone blocker, in patients with left ventricular dysfunction after myocardial infarction. N Engl J Med 2003;348:1309-21.  Back to cited text no. 6
[PUBMED]  [FULLTEXT]  
7.Pitt B, Zannal F, Remme WJ, et al. the effect of spironolacton on morbidity and mortality in patients with severe heart failure. N Engl J Med 1999;341:709-17.  Back to cited text no. 7
    
8.Nishi Zaka MK, Zaman MA, Calhovn DA. Efficacy of low dose spironolactone in subjects with resistant hypertension. Am J Hypertension 2003;16:925-30.  Back to cited text no. 8
    
9.Takeday. Vascular synthesis of aldosterone: Role in lypertension. Mol Cell Endocrinol 2004;217:75-9.  Back to cited text no. 9
    
10.Xue C, Siragy HM. Local renal adosterone system and its regulation by salt, diabetes and angiotensin II type 1 receptor. Hypertension 2005;46:584-90.  Back to cited text no. 10
[PUBMED]  [FULLTEXT]  
11.Wehling M, spes CH, Win N, et al. Rapid cardiovascular action of aldosterone in man. J Clin Endocrinol Metab 1998;83:3517-22.  Back to cited text no. 11
[PUBMED]  [FULLTEXT]  
12.Hollenbery NK. Aldosterone in the develop≠ment and progression of renal injury. Kidney Int 2004;66:1-9.  Back to cited text no. 12
    
13.Greene EL, Kren S, Hostterter TH. Role of aldosterone in the remnant kidney model in the rat. J Clin Invest 1996;98:1063-8.  Back to cited text no. 13
    
14.Rocha R, Chander PN, Khanna K, et al. Mine≠ralocorticold blockade reduces vascular injury in stroke-prone hypertensive rate. Hypertension 1998;31:451-8.  Back to cited text no. 14
[PUBMED]  [FULLTEXT]  
15.Nitta K, Uchida K, Nihei H. Spironolactone and angiotensin receptor blocker in non diabetic renal disease. Am J Med 2004;117: 444-5  Back to cited text no. 15
    
16.Bianchi S, Bigassi R, Compere VM. Antagonists of aldosterone and proteinuriain patients with CKD: An uncontrolled pilot study. Am J Kidney Dis 2005;46:45-51.  Back to cited text no. 16
    
17.Sato A, Hayashi K, Naruse M, Saruta T. Effec≠tiveness of aldosterene blockade in patients with diabetic nephropathy. Hypertension 2003; 41:64-8 .  Back to cited text no. 17
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18.Sica DA. Eplerenone and serum potassium change relationship to renal function. Am J Hypertension 2003;16:A100.  Back to cited text no. 18
    

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Correspondence Address:
Rozita Abolghasmi
Imam Hosein Hospital, Shaheed Madani Street, Tehran
Iran
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PMID: 21196617

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    Tables

  [Table 1], [Table 2]

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    Abstract
    Introduction
    Patients and Methods
    Statistical Analysis
    Results
    Discussion
    References
    Article Tables
 

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