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 Table of Contents  
ORIGINAL ARTICLE
Year : 2016  |  Volume : 3  |  Issue : 3  |  Page : 79-83

Risks Associated with Renin-angiotensin System Inhibitor Therapy in Elderly Patients with Nephrosclerosis


1 Department of Nephrology, Nakatsugawa City Hospital, Nakatsugawa, Gifu, Japan
2 Department of Emergency Medicine, Nagoya Ekisaikai Hospital, Nagoya, Aichi, Japan
3 Department of Hospital Pharmacy, Nagoya University Graduate School of Medicine, Nagoya, Aichi, Japan

Date of Web Publication4-Aug-2016

Correspondence Address:
Akihito Tanaka
Department of Nephrology, Nakatsugawa City Hospital, 1522-1 Komaba, Nakatsugawa, Gifu 508-8502
Japan
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/2394-2916.187788

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  Abstract 

Background and Objectives: Studies have investigated the effect of antihypertensive treatment in patients with hypertensive nephrosclerosis. To our knowledge, there is no cohort study on the effect of antihypertensive treatment in elderly patients with nephrosclerosis. Therefore, our aim was to evaluate the efficacy and risks associated with the use of antihypertensive agents, especially renin-angiotensin system (RAS) inhibitors, in this population. Patients and Methods: This was a retrospective cohort study. Patients aged ≥65 years and diagnosed with nephrosclerosis who were treated in our department between August 2013 and October 2014 were included in this study and were observed for 12 consecutive months. Results: Forty-three patients were included in this study. Thirty-three patients were men, and 10 were women. The mean age of the subjects was 79.3 ± 7.1 years. At the start of this study, mean values of serum creatinine (Cr) and estimated glomerular filtration rate (eGFR) were 2.48 ± 1.32 mg/dL and 25.0 ± 12.8 mL/min/1.73 m 2 , respectively. At the end of the observation period, hemodialysis was initiated for 5 patients. The mean value of eGFR decreased by 12.2 ± 21.5%, and 3 patients had a decrease of more than 30% in eGFR. Cr values at the start correlated positively with the percentage of decrease in eGFR. Cr values at the start and RAS inhibitor usage rate were significantly associated with adverse effects, such as hyperkalemia and transient Cr elevation. Conclusion: Our study suggests that antihypertensive treatment with RAS inhibitors may cause adverse effects in elderly patients with nephrosclerosis. Caution should be exercised when administering RAS inhibitors to these patients.

Keywords: Chronic kidney disease, hypertension, nephrosclerosis, renin-angiotensin system inhibitor


How to cite this article:
Tanaka A, Kobayashi Y, Ito Y, Tanaka N. Risks Associated with Renin-angiotensin System Inhibitor Therapy in Elderly Patients with Nephrosclerosis. J Integr Nephrol Androl 2016;3:79-83

How to cite this URL:
Tanaka A, Kobayashi Y, Ito Y, Tanaka N. Risks Associated with Renin-angiotensin System Inhibitor Therapy in Elderly Patients with Nephrosclerosis. J Integr Nephrol Androl [serial online] 2016 [cited 2021 Sep 19];3:79-83. Available from: http://www.journal-ina.com/text.asp?2016/3/3/79/187788


  Introduction Top


In our Department of Nephrology, we occasionally experience complications, such as transient serum creatinine (Cr) elevation or hyperkalemia, in elderly patients with nephrosclerosis taking renin-angiotensin system (RAS) inhibitors.

Nephrosclerosis is a clinical condition based on glomerulosclerosis and kidney tissue fibrosis resulting from chronic persistent hypertension. Studies have evaluated the effect of antihypertensive treatment in patients with hypertensive nephrosclerosis. Furthermore, it has been demonstrated that the choice of antihypertensive agent varies with the degree of proteinuria. Although nephrosclerosis is a common disorder among the elderly, the target level of blood pressure (BP) remains controversial, and the incidence of adverse effects of RAS inhibitors is higher in this population. To our knowledge, there is no cohort study on the effect of antihypertensive treatment in the elderly patients with nephrosclerosis. Therefore, we aimed to evaluate the efficacy and risk of antihypertensive agents, especially RAS inhibitors, in this population.


  Patients and methods Top


This study was performed in compliance with the Declaration of Helsinki and Japanese National Ethical Guidelines, and with the approval of the Institutional Review Board of Nakatsugawa City Hospital (approval number: 2014-03).

This was a retrospective cohort study. Patients aged ≥65 years and diagnosed with nephrosclerosis who were treated in our department between August 2013 and October 2014 were included in this study while those with diabetes mellitus were excluded from the study. Diagnosis of nephrosclerosis was based on the biopsy results or the presumed by clinical course. Following parameters were evaluated at the start of the study and at least every 3 months thereafter: Age, sex, incidence of cerebral stroke and cardiovascular disease (CVD), systolic BP (SBP), diastolic BP (DBP), laboratory data (Cr, estimated glomerular filtration rate [eGFR], low-density lipoprotein cholesterol [LDL-C], and electrolytic status), and incidence of adverse effects, such as hyperkalemia or transient serum Cr elevation. We calculated eGFR using Japanese Society of Nephrology formula. [1] We defined hyperkalemia as a serum potassium level ≥5.5 mEq/L or necessity of lowering the serum potassium level according to physician judgment and Cr elevation as a transient increase of ≥30% above baseline serum Cr values and need for discontinuation or transient reduction of RAS inhibitor dose. RAS inhibitor includes angiotensin-converting enzyme inhibitor (ACEi), angiotensin receptor blocker, direct renin inhibitor, and spironolactone. Primary endpoints were initiation into dialysis and decrease of more than 30% in eGFR after 12 months observation period. Secondary endpoints were above-mentioned adverse effects.

Data are expressed as mean ± standard deviation or percentage. Correlation between decrease in eGFR and various parameters was analyzed using the Spearman correlation coefficient. The Student's t-test and Chi-square test were used to evaluate differences between the following subgroups: Patients with or without primary endpoint events and patients with or without adverse effects. A logistic regression analysis was used to evaluate the effect of Cr, RAS inhibitor, and other parameters on the primary endpoint events and incidence of adverse effects.


  Results Top


Baseline characteristics

Forty-three patients were included in the study. [Table 1] summarizes the baseline patient characteristics. A diagnosis of nephrosclerosis was made based on the biopsy results in one patient and the clinical course in other patients. Thirty-three patients were men and 10 patients were women. The mean age of the subjects was 79.3 ± 7.1 years. At the start of this study, mean values of Cr, eGFR, SBP, and DBP were 2.48 ± 1.32 mg/dL, 25.0 ± 12.8 mL/min/1.73 m 2 , 128.0 ± 20.7 mmHg, and 69.5 ± 12.3 mmHg, respectively. The DBP data were missing for four patients. [Table 2] outlines the patient characteristics at the end of observation period. Hemodialysis was initiated for five patients. Mean value of eGFR decreased by 12.2 ± 21.5%, and three patients had a decrease of more than 30% in eGFR. Eight patients reached the primary endpoint. Adverse effects, such as hyperkalemia or Cr elevation, occurred in 19 patients. New stroke or CVD did not occur in any patient. [Table 3] presents the correlation between the percentage of eGFR decrease and various parameters at the start of the study. Cr at the start correlated positively and eGFR at the start negatively with the percentage of eGFR decrease. These results might indicate impaired renal function at the start of the study period associated with poor kidney prognosis.
Table 1: Baseline characteristics patients at the start of this study (n=43)


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Table 2: Results of the observation (n=43)


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Table 3: Correlation between decrease of estimated glomerular filtration rate (%) and various parameters (n=43)


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Comparison between patients with or without primary endpoint events

[Table 4] outlines differences between patients with or without primary endpoint events. Mean values of patient age, SBP, and DBP were 79.2 ± 7.3 years, 129.0 ± 21.3 mmHg, and 71.0 ± 13.1 (n = 31) mmHg, respectively, for patients with primary endpoint events; and 79.8 ± 6.3 years, 126.0 ± 18.5 mmHg, and 63.6 ± 6.3 (n = 8) mmHg, respectively, for patients without endpoint events. There was no significant difference in these values between two groups. The proportion of patients taking RAS inhibitor was 74.3% and 62.5%, respectively, without significant difference between groups. However, Cr and chloride (Cl) levels were significantly higher, and eGFR and LDL-C levels were significantly lower in the group with primary endpoint events. Furthermore, adverse effects, such as hyperkalemia and transient Cr elevation, occurred more frequently among patients with primary endpoint events. With regard to Cr and eGFR values at the start, these results seem to indicate that impaired renal function at the start of the study is associated with greater probability of primary endpoint events. [Table 5] presents the unadjusted odds ratio of Cr, Cl, and LDL-C levels for primary endpoint events while [Table 6] outlines the adjusted odds ratio of these parameters. When adjusted by age and sex, only Cr level showed a significant association with primary endpoint events.
Table 4: Parameters in patients with or without reaching primary endpoint events (n=43)


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Table 5: Unadjusted odds ratio 95% confidence intervals of parameters on reaching primary endpoint events (n=43)


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Table 6: Adjusted odds ratio 95% confidence intervals of parameters on reaching primary endpoint events (n=43)


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Comparison between patients with or without adverse effects

[Table 7] summarizes the differences between patients with or without adverse effects. There was no significant difference in age, sex, and BP between two groups. However, patients with adverse effects had a significantly higher ACEi usage rate and eGFR decrease rate. Furthermore, RAS inhibitor usage rate and Cr levels were higher in the group with adverse effects, without significant difference between two groups. [Table 8] presents the unadjusted odds ratio of Cr levels and RAS inhibitor usage rate for adverse effects. [Table 9] outlines the odds ratio adjusted by age, sex, and Cr levels or RAS inhibitor usage rate. When eliminating the effect of Cr levels, RAS inhibitor usage rate showed a significant association with adverse effects.
Table 7: Parameters in patients with or without adverse effects (n=43)


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Table 8: Unadjusted odds ratio 95% confidence intervals of parameters on adverse effects (n=43)


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Table 9: Adjusted odds ratio 95% confidence intervals of parameters on adverse effects (n=43)


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  Discussion Top


Nephrosclerosis is a clinical condition based on the glomerulosclerosis and kidney tissue fibrosis resulting from chronic persistent hypertension. The effect of antihypertensive treatment in patients with hypertensive nephrosclerosis has been investigated. [2],[3],[4] Furthermore, the choice of antihypertensive agent is associated with the degree of proteinuria. RAS inhibitors are recommended for antihypertensive treatment in patients with significant proteinuria. [5],[6],[7] On the other hand, RAS inhibitors may be less effective in patients with nephrosclerosis because they often have lower urine protein levels compared to patients with nephritic syndrome or diabetes mellitus.

Although nephrosclerosis is a common disorder of the elderly, the target level of BP remains controversial, and the incidence of adverse effects of RAS inhibitors is higher in this population. [8],[9] Some studies reported that moderate renal insufficiency and diabetic nephropathy in elderly patients should not be considered as contraindications for the use of RAS inhibitors. [10],[11] However, there is no consensus on RAS inhibitor therapy in elderly patients with renal insufficiency.

Recently, it has been revealed that multiple blockades in RAS cause severe adverse effects rather than benefits. [12],[13] On the other hand, some studies reported better prognosis for patients with the strong blockade in RAS at chronic kidney disease stage 5. Therefore, it is important to select appropriate patients for RAS blockade. [14],[15]

In this study, we investigated an elderly nephrosclerosis cohort in our hospital. RAS inhibitor therapy resulted in higher incidence of adverse effects in our cohort. There were no deaths, and the effect of RAS inhibitor therapy on renal function and long-term prognosis was not clear due to small sample size and a relatively short observation period of 12 months. Nevertheless, the effect of RAS inhibitor therapy on the incidence of side effects seemed to be significant. Elderly patients are likely to have an atherosclerotic disease and may easily become dehydrated. [16] Hence, atherosclerotic renal artery stenosis or dehydration may make apparent the adverse effects of RAS inhibitors. Furthermore, dehydration in summer may cause irreversible fall in eGFR. [17] In our study, LDL-C levels were significantly higher in patients without primary endpoint events than in patients with primary endpoint events. This finding, although difficult to explain, in our opinion is the result of variations in small sample size. Studies with a large sample size should be conducted to clarify whether high or low levels of LDL-C are involved in renal prognosis.

The advantage of RAS inhibitor therapy for elderly patients with nephrosclerosis may be small since these patients have relatively low urine protein levels. Furthermore, adverse effects may occur frequently. Hence, RAS inhibitors should be carefully administered in elderly patients with nephrosclerosis. This study has some limitations. This is a single-center study with a small sample size. The dose effects of the RAS inhibitor were not examined. A multicenter, long-term follow-up study with a larger sample size should be conducted to confirm the risks associated with RAS inhibitor therapy in elderly patients with nephrosclerosis.


  Conclusion Top


Our study suggests that RAS inhibitor therapy may cause adverse effects, such as hyperkalemia and transient serum Cr elevation, in elderly patients with nephrosclerosis. Therefore, caution should be exercised when administering RAS inhibitors to these patients.

Acknowledgment

We would like to thank Editage (www.editage.jp) for English language editing.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.

 
  References Top

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Matsuo S, Imai E, Horio M, Yasuda Y, Tomita K, Nitta K, et al. Revised equations for estimated GFR from serum creatinine in Japan. Am J Kidney Dis 2009;53:982-92.  Back to cited text no. 1
    
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Fogo A, Breyer JA, Smith MC, Cleveland WH, Agodoa L, Kirk KA, et al. Accuracy of the diagnosis of hypertensive nephrosclerosis in African Americans: A report from the African American Study of Kidney Disease (AASK) Trial. AASK Pilot Study Investigators. Kidney Int 1997;51:244-52.  Back to cited text no. 2
    
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Upadhyay A, Earley A, Haynes SM, Uhlig K. Systematic review: Blood pressure target in chronic kidney disease and proteinuria as an effect modifier. Ann Intern Med 2011;154:541-8.  Back to cited text no. 3
    
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Wright JT Jr., Bakris G, Greene T, Agodoa LY, Appel LJ, Charleston J, et al. Effect of blood pressure lowering and antihypertensive drug class on progression of hypertensive kidney disease: Results from the AASK trial. JAMA 2002;288:2421-31.  Back to cited text no. 4
    
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Agodoa LY, Appel L, Bakris GL, Beck G, Bourgoignie J, Briggs JP, et al. Effect of ramipril vs amlodipine on renal outcomes in hypertensive nephrosclerosis: A randomized controlled trial. JAMA 2001;285:2719-28.  Back to cited text no. 5
    
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Appel LJ, Wright JT Jr., Greene T, Kusek JW, Lewis JB, Wang X, et al. Long-term effects of renin-angiotensin system-blocking therapy and a low blood pressure goal on progression of hypertensive chronic kidney disease in African Americans. Arch Intern Med 2008;168:832-9.  Back to cited text no. 6
    
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Appel LJ, Wright JT Jr., Greene T, Agodoa LY, Astor BC, Bakris GL, et al. Intensive blood-pressure control in hypertensive chronic kidney disease. N Engl J Med 2010;363:918-29.  Back to cited text no. 7
    
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Rothwell PM, Howard SC, Spence JD; Carotid Endarterectomy Trialists' Collaboration. Relationship between blood pressure and stroke risk in patients with symptomatic carotid occlusive disease. Stroke 2003;34:2583-90.  Back to cited text no. 8
    
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Butt DA, Mamdani M, Austin PC, Tu K, Gomes T, Glazier RH. The risk of hip fracture after initiating antihypertensive drugs in the elderly. Arch Intern Med 2012;172:1739-44.  Back to cited text no. 9
    
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Frances CD, Noguchi H, Massie BM, Browner WS, McClellan M. Are we inhibited? Renal insufficiency should not preclude the use of ACE inhibitors for patients with myocardial infarction and depressed left ventricular function. Arch Intern Med 2000;160:2645-50.  Back to cited text no. 10
    
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Winkelmayer WC, Zhang Z, Shahinfar S, Cooper ME, Avorn J, Brenner BM. Efficacy and safety of angiotensin II receptor blockade in elderly patients with diabetes. Diabetes Care 2006;29:2210-7.  Back to cited text no. 11
    
12.
Teo K, Yusuf S, Sleight P, Anderson C, Mookadam F, Ramos B, et al. Rationale, design, and baseline characteristics of 2 large, simple, randomized trials evaluating telmisartan, ramipril, and their combination in high-risk patients: The Ongoing Telmisartan Alone and in Combination with Ramipril Global Endpoint Trial/Telmisartan Randomized Assessment Study in ACE Intolerant Subjects with Cardiovascular Disease (ONTARGET/TRANSCEND) trials. Am Heart J 2004;148:52-61.  Back to cited text no. 12
    
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Fried LF, Emanuele N, Zhang JH, Brophy M, Conner TA, Duckworth W, et al. Combined angiotensin inhibition for the treatment of diabetic nephropathy. N Engl J Med 2013;369:1892-903.  Back to cited text no. 13
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Kidney Disease: Improving Global Outcomes (KDIGO) CKD Work Group. KDIGO clinical practice guideline for the evaluation and management of chronic kidney disease. Kidney Int Suppl 2013;3:1-150.  Back to cited text no. 14
    
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Hsu TW, Liu JS, Hung SC, Kuo KL, Chang YK, Chen YC, et al. Renoprotective effect of renin-angiotensin-aldosterone system blockade in patients with predialysis advanced chronic kidney disease, hypertension, and anemia. JAMA Intern Med 2014;174:347-54.  Back to cited text no. 15
    
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Weinberg AD, Minaker KL. Dehydration. Evaluation and management in older adults. Council on Scientific Affairs, American Medical Association. JAMA 1995;274:1552-6.  Back to cited text no. 16
    
17.
Imai E, Abe K. Blood pressure drop in summer may cause acute kidney injury with irreversible reduction of glomerular filtration rate. Clin Exp Nephrol 2013;17:1-2.  Back to cited text no. 17
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  [Table 1], [Table 2], [Table 3], [Table 4], [Table 5], [Table 6], [Table 7], [Table 8], [Table 9]



 

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