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Abstract

Hypothesis:

The aim of this study was to determine the effects of renin–angiotensin system (RAS) blockade maintenance on renal protection in chronic kidney disease (CKD) patients with hyperkalemia occurring during treatment with RAS blockade.

Materials and methods:

CKD III or IV patients, who were prescribed with RAS blockers and also had hyperkalemia, were included. The study population was divided into two groups based on maintenance or withdrawal of RAS blocker. Renal outcomes (doubling of creatinine or end-stage renal disease) and incidence of hyperkalemia were compared between the two groups.

Results:

Out of 258 subjects who developed hyperkalemia during treatment with RAS blockers, 150 (58.1%) patients continued on RAS blockades, while RAS blockades were discontinued for more than 3 months in the remaining 108 patients. Renal event-free survival was significantly higher in the maintenance group compared with the withdrawal group. Cox proportional hazard ratio for renal outcomes was 1.35 (95% CI: 1.08–1.92, p=0.04) in the withdrawal group compared with the maintenance group. However, the incidence of hyperkalemia and hyperkalemia-related hospitalization or mortality did not differ between the two groups.

Conclusions:

This study demonstrated that the maintenance of RAS blockade is beneficial for the preservation of renal function and relatively tolerable in patients with CKD and hyperkalemia occurring during treatment with RAS blockade.

Keywords

Renin-angiotensin blockade hyperkalemia renal outcomes

Introduction

The renin–angiotensin system (RAS) plays an important role in the pathogenesis and progression of chronic kidney disease (CKD). Numerous studies have reported that activation of the intra-renal RAS contributes to glomerular hypertrophy, mesangial expansion and glomerulosclerosis in various renal diseases.¹ Previous clinical and experimental studies have demonstrated that inhibition of the RAS using angiotensin-converting enzyme inhibitor (ACEI) or angiotensin II receptor blocker (ARB) results in the reduction of proteinuria and retards progression of renal disease in addition to lowering blood pressure. Even in normotensive or well-controlled hypertensive patients with CKD, use of RAS blockade resulted in reduction of proteinuria and may be beneficial in the preservation of renal function.^2–8 However, RAS blockade is frequently associated with several adverse events, including angioedema, dry cough, hyperkalemia, and aggravation of underlying renal insufficiency.⁹ In particular, the incidence of hyperkalemia is increased in patients with reduced glomerular filtration rate (GFR) and limits the use of RAS blockade in patients with advanced CKD.¹⁰ If the serum potassium level increases above 5.5 mmol/l during use of RAS blockade, discontinuation of RAS blockade should be considered,^11,12 with hyperkalemia managed by, for example, prescription of a low-potassium diet, thiazide or loop diuretics, and correction of metabolic acidosis. However, there are different approaches to cope with RAS blockers according to physician preference and decision. A practical strategy for maintaining the RAS blockade is needed not only for control of blood pressure, but also to delay the progression of CKD. In order to maintain the blocking effect of RAS, ACEI or ARB are frequently maintained in CKD patients with elevated potassium levels. Still, it is not clear whether or not maintenance of RAS blockade is beneficial in CKD patients with elevated potassium levels.

We examined renal outcomes (doubling of creatinine or progression to end-stage renal disease (ESRD)) in order to determine the effect of RAS blockade maintenance in patients with CKD stage III and IV, who had developed hyperkalemia during use of RAS blockade. In addition, we evaluated the impact on hyperkalemia of maintenance with RAS blockade in this population.

Materials and methods

This study was approved by the Institutional Review Board (IRB) of Yonsei University Health System Clinical Trial Center. This study was a retrospective medical record-based study and the IRB waived the requirement for written consent from the patients.

Study subjects

Patients with stage III or IV CKD, prescribed ACEI or ARB and with concurrent hyperkalemia during the use of RAS blockade were included in this study. We initially recruited 2124 patients who were followed-up for CKD at Yonsei University Health System from July 2008 to December 2011. ACEIs or ARBs except dual blockers including aldosterone antagonists were prescribed to 1239 patients, and 351 patients developed hyperkalemia during treatment with RAS blocker. Of these patients, 83 patients were excluded for the following reasons: age younger than 18 years or older than 75 years, terminal malignancy, previous history of kidney transplantation, and follow-up duration of less than 12 months. Patients whose serum creatinine and potassium levels at baseline or during the follow-up period were not available, or who were transiently discontinued RAS blockers for less than 3 months were also excluded. Therefore, a total of 258 patients were included for the final analysis (Figure 1).

Figure 1.

Flow diagram of the study. A total of 351 patients developed hyperkalemia during treatment with RAS blockers. Excluding 83 patients, a total of 258 patients were enrolled for final analysis. CKD: chronic kidney disease; ACEi: angiotensin converting enzyme inhibitor; ARB: angiotensin II receptor blocker; KT: kidney transplantation.

Data collection

Using medical records, demographic and clinical data were reviewed retrospectively for age, sex, medical history, medications, time to doubling of baseline serum creatinine levels and ESRD, and history of admission after study enrollment. Laboratory data included urinary protein-to-creatinine ratio (UPCR), and serum creatinine and potassium levels. The four-variable Modification of Diet in Renal Disease study equation was used for calculation of the estimated glomerular filtration (eGFR).

Definitions

CKD was defined as an eGFR of less than 60 ml/min/1.73m² and hyperkalemia was defined as potassium ≥5.5 mmol/l in a non-hemolyzed serum sample. Patients with hyperkalemia that occurred after initiation of renal replacement treatment were not included. When hyperkalemia developed during treatment with RAS blockade, three kinds of clinical practice patterns were recognized contingent on the maintenance of RAS blockade: 1) discontinuation of RAS blockade; and 2) reduction or 3) maintenance of doses of RAS blockade with supportive management for potassium reduction. Patients were categorized as the maintenance group if they were maintained on RAS blockade without discontinuation of drugs, and as the withdrawal group if RAS blockade had been discontinued for >3 months after development of hyperkalemia. The criteria for maintenance of RAS blockers were not specified. Maintenance or withdrawal of RAS blockades were decided according to individual physicians.

Outcome endpoints

The main outcomes were a doubling of the baseline serum creatinine concentration and ESRD. ESRD was defined as initiation of renal replacement therapy including permanent hemodialysis, peritoneal dialysis or renal transplantation. In addition, incidence of hyperkalemia and hyperkalemia-related hospitalization were also evaluated during the follow-up period.

Statistical analysis

SPSS, version 17.0 (SPSS Inc., Chicago, Illinois, USA) was used to perform statistical analysis. Continuous variables were expressed as mean ± standard deviation and categorical variables were expressed as percentages. T-test and chi-square test were used for comparison of the two groups. The Kolmogorov–Smirnov test was used for analysis of the normality of the distribution of parameters. Cumulative renal survival curves were derived using the Kaplan–Meier method, and differences between survival curves were compared using the log-rank test. Multivariate Cox proportional hazards models were used for determination of risk factors for renal outcomes. Hazard ratios (HRs) and 95% confidence intervals (CIs) were calculated using the estimated regression coefficients and standard errors in the Cox regression analysis; a p-value <0.05 was considered statistically significant.

Results

Baseline characteristics

The baseline demographic, clinical and biochemical data of study subjects are shown in Table 1. The mean age of patients was 61.8±14.5 years, and 145 patients (56%) were male. The mean eGFR and UPCR were 29.0±13.1 ml/min/1.73m² and 2.3±3.0 mg/mg, respectively. Based on maintenance of RAS blocker, 150 (58.1%) of 258 patients were maintained on RAS blockades; however, 108 patients were discontinued for more than 3 months. Most of the patients in the maintenance group were maintained on the previous dose of RAS blockers, and the dose of RAS blockers was reduced in 41/150 patients (27.3%). There were no significant differences in underlying renal diseases, serum potassium levels, eGFR, or UPCR ratio at baseline between the two groups.

Table 1.

Baseline demographic, clinical, and biochemical characteristics of the subjects.

	Maintenance group	Withdrawal group	p-value
	(n = 150)	(n = 108)	p-value
Age (years)	61.8 ± 14.8	60.3 ± 13.2	0.82
Sex (Male : Female)	82 : 68	63 : 45	0.38
Diabetes mellitus, n (%)	72 (48.0%)	49 (45.4%)	0.46
Systolic blood pressure (mmHg)	133.5 ± 21.8	132.9 ± 18.9	0.96
Diastolic blood pressure (mmHg)	74.9 ± 14.2	78.9 ± 8.4	0.16
Total cholesterol (mg/dl)	187.0 ± 44.4	173.9 ± 55.2	0.39
Serum potassium (mmol/l)	5.79 ± 0.38	5.77 ± 0.48	0.44
tCO2 (mg/dl)	20.8 ± 4.7	20.2 ± 5.2	0.15
albumin (g/dl)	3.8 ± 1.1	3.7 ± 0.7	0.81
BUN (mg/l)	39.6 ± 17.6	34.5 ± 15.7	0.12
Creatinine (mg/dl)	2.4 ± 1.2	2.3 ± 1.2	0.83
eGFR (ml/min/1.73m²)	28.3 ± 13.2	30.1 ± 12.9	0.23
UPCR (mg/mg)	2.5 ± 3.0	2.0 ± 2.4	0.66
Primary renal disease	65 (43.3%)	46 (42.6%)	0.61
Diabetic nephropathy	24 (16.0%)	18 (13.0%)
Hypertension	36 (24.0%)	24 (22.2%)
Chronic glomerulonephritis	25 (16.7%)	20 (18.5%)
Others

Data are expressed as n (%) or mean ± SD. eGFR: estimated glomerular filtration rate; UPCR: urine protein-to-creatinine ratio.

Renal outcomes

During a mean follow-up period of 45.7±18.3 months, 129 (50%) patients reached the primary outcome. ESRD or doubling of serum creatinine occurred in 68 (63%) patients in the withdrawal group compared with 61 (41%) patients in the maintenance group. Renal survival rate was significantly higher in the maintenance group compared with the withdrawal group (p=0.04, HR in the withdrawal group: 1.35, 95% CI: 1.08–1.92). In subgroup analysis based on the levels of baseline proteinuria, prognostic significance between two groups was much greater in subgroup of patients with UPCR above 1.0 (p=0.02, Figure 2). At baseline, serum creatinine levels were similar; however, after 18 months, serum creatinine levels were significantly lower in the maintenance group compared with the withdrawal group (p=0.03, Figure 3).

Figure 2.

Kaplan–Meier plots for renal event-free survival based on the maintenance of RAS blockers including (A) all study subjects, (B) patients with baseline UPCR ratio of less than 1, (C) patients with baseline UPCR ratio of more than 1. The cumulative renal event-free survival was significantly higher in patients maintained with RAS blockers.

Figure 3.

Changes in serum creatinine over time in maintenance or withdrawal group. Data are presented as means and SD values. At baseline, serum creatinine levels were similar; however, after 18 months, serum creatinine levels were significantly lower in the maintenance group compared with the withdrawal group (p<0.05).

In multivariate Cox proportional hazard models, use of RAS blockers still remained a significant prognostic factor for renal survival. However, after adjusting for baseline proteinuria (HR; 1.028, p<0.01) and baseline GFR (HR; 1.248, p<0.01), the significance of RAS blocker maintenance as a predictor of renal progression disappeared (HR=1.135, CI; 0.937–1.546, p=0.17) (Table 2).

Table 2.

Hazard ratios and 95% confidence intervals for renal survival based on treatment with RAS blockade (Cox proportional hazards analysis).

	HR (vs. RAS blockade use)	95% CI	p
¹Model 1	1.35	1.08–1.92	0.04
²Model 2	1.48	1.05–2.10	0.03
³Model 3	1.135	0.937–1.546	0.17

Model 1: unadjusted relative risk; ²Model 2: adjusted for age, sex; and original renal disease; ³Model 3: adjusted for Model 2 plus MDRD-GFR and urine protein/creatinine ratio.

Incidence of hyperkalemia and follow-up clinical outcomes

Baseline potassium levels were 5.79±0.38 mmol/l versus 5.77±0.48 mmol/l in the maintenance and withdrawal groups. During the follow-up period, 0.58 episodes per patient-year of hyperkalemia occurred in the maintenance group, and 0.47 episodes per patient-year developed in the withdrawal group (p=0.19). In addition, neither hyperkalemia-related hospitalizations nor mortality differed between the two groups (0.18 episodes per patient-year vs. 0.14 episodes per patient-year, p=0.42). At the end of the study, potassium levels were 5.39±0.52 mmol/l versus 5.23±0.61 mmol/l in maintenance and withdrawal groups (p=0.14). Blood pressures at various time points during the follow-up period are listed in Table 3. The blood pressures in the two groups were comparable during the follow-up period. During the follow-up period, 17 patients (11 patients in the maintenance group and six patients in the withdrawal group) died, and mortality rate was not different between two groups. One patient in each group died due to hyperkalemia-related events.

Table 3.

Changes in blood pressure over time in the maintenance and withdrawal group.

		Maintenance group	Withdrawal group	p-value
		(n=150)	(n=108)	p-value
baseline	SBP	128.4±17.6	124.6±20.7	0.12
baseline	DBP	81.4±10.2	79.5±4.5	0.31
6 months	SBP	129.6±15.7	129.5±19.4	0.94
6 months	DBP	82.5±7.8	80.4±5.8	0.83
12 months	SBP	131.6±17.2	132.5±23.2	0.78
12 months	DBP	82.8±11.2	81.6±10.8	0.84
18 months	SBP	135.3±16.4	133.6±15.9	0.59
18 months	DBP	83.4±13.2	84.3±11.4	0.51

Values are expressed as mean ± SD. SBP: systolic blood pressure; DBP: diastolic blood pressure.

Discussion

This study demonstrated that maintenance of RAS blockade is beneficial for the preservation of renal function, even in hyperkalemic CKD patients treated with RAS blocker. In addition, cautious use of RAS blockade does not lead to a significant increase in the episodes of hyperkalemia in CKD patients who develop hyperkalemia during treatment with ACEI or ARB.

Based on previous reports, long-term blockade of the renin–angiotensin–aldosterone system by ACEIs or ARBs resulted in increased levels of plasma renin or angiotensin II.¹³ In addition, occurrence of aldosterone breakthrough has been also reported during long-term ARB therapy, mainly by angiotensin II-dependent mechanisms.¹⁴ Since renin or angiotensin II levels are already elevated in conditions of chronic blocking of the RAS, it is possible that renal failure and hypertension might be aggravated due to the abrupt disappearance of the RAS-blocking effect. Blocking of RAS might be maintained in order to prevent rebound hypertension and progression of renal failure. Our data support that maintenance of RAS blockade rather than withdrawal is beneficial for the preservation of renal function in CKD patients who have accompanying hyperkalemia during RAS blockade treatment.

The renoprotective effect of the RAS blocker was much more prominent in the subgroup with a baseline UPCR ratio of more than 1 mg/mg. This finding is consistent with previous studies, indicating an association of a higher urinary protein excretion rate with a rapid decline rate in renal function,⁸ and ACEI has a distinguishable renoprotective effect in patients with baseline proteinuria of 3 g/day or more.³ The present study suggests that maintenance of RAS blockade should be considered in highly proteinuric CKD patients.

In patients with CKD, development of hyperkalemia frequently occurs due to various causes such as reduced renal excretion of potassium or metabolic acidosis.^15–17 Besides discontinuation of RAS blockade, various approaches should be considered. Potassium imbalance might be treatable by restricting potassium intake and correction of underlying causes, while maintaining treatment with RAS blockade. A previous study showed that most of the patients with hyperkalemia were resolved with either a low-potassium diet alone or with dietary advice and decrease in dose of the ACEI.¹⁸ Although the incidences of hyperkalemia after treatment with ACEI or ARB in patients with CKD were highly variable, clinical trials showed that prolonged use of RAS blockade did not lead to an increase in additional episodes of hyperkalemia in these patients. In addition, another study conducted in the CKD population reported no significant difference in the overall mortality rate among patients on ACEI/ARB therapy, compared with patients on placebo or conventional anti-hypertensive drugs.^3,4,7,19 The present study also demonstrated that the incidence of hyperkalemia, as well as hyperkalemia-related hospitalization in study subjects, was similar in both groups whether or not RAS blockade had been maintained. Therefore, maintenance of the RAS blocker with careful monitoring, rather than only discontinuing RAS blockade, could be applied.

This study has several limitations. Because its design is retrospective, this study may include sampling errors. There may be potential selection errors because maintenance of RAS blockade was decided by individual physicians. However, there are no specific guidelines and outcomes regarding whether use of RAS blocker is beneficial, due to a lack of appropriate guidelines. In addition, due to safety and ethical issues, it would be difficult to conduct a prospective study using RAS blockade in CKD patients who have hyperkalemia. Thus, in spite of the retrospective nature of the current study, we think that the study results are still valuable. Second, even though other drugs and conditions may have had an influence on serum potassium levels, these and dietary potassium intake were not evaluated. Therefore, further large-scale analysis is needed in order to confirm the risk and benefit of RAS blockade in this special population.

In conclusion, the renoprotective effects of RAS blockade in CKD patients with hyperkalemia disappeared after withdrawing RAS blockade. The results of the current study suggest that maintenance of RAS blockade retards the progression of renal failure, and these beneficial effects are more prominent in proteinuric CKD patients. In addition, ACEI/ARB is well tolerated in stage III or IV CKD patients with hyperkalemia occurring during treatment with RAS blockade.

Footnotes

Conflict of interest

None declared.

Funding

This study was supported by a new faculty research grant of Yonsei University for 2008.

References

Johnston

Fabris

Jandeleit

Intrarenal renin-angiotensin system in renal physiology and pathophysiology. Kidney Int Suppl 1993; 42: S59–S63.

Lewis

Hunsicker

Bain

. The effect of angiotensin-converting-enzyme inhibition on diabetic nephropathy. The Collaborative Study Group. N Engl J Med 1993; 329: 1456–1462.

The GISEN Group (Gruppo Italiano di Studi Epidemiologici in Nefrologia). Randomised placebo-controlled trial of effect of ramipril on decline in glomerular filtration rate and risk of terminal renal failure in proteinuric, non-diabetic nephropathy. Lancet 1997; 349: 1857–1863.

Brenner

Cooper

de Zeeuw

. Effects of losartan on renal and cardiovascular outcomes in patients with type 2 diabetes and nephropathy. N Engl J Med 2001; 345: 861–869.

de Zeeuw

Remuzzi

Parving

. Proteinuria, a target for renoprotection in patients with type 2 diabetic nephropathy: Lessons from RENAAL. Kidney Int 2004; 65: 2309–2320.

Hou

Zhang

. Efficacy and safety of benazepril for advanced chronic renal insufficiency. N Engl J Med 2006; 354: 131–140.

Lewis

Hunsicker

Clarke

. Renoprotective effect of the angiotensin-receptor antagonist irbesartan in patients with nephropathy due to type 2 diabetes. N Engl J Med 2001; 345: 851–860.

Maschio

Alberti

Janin

. Effect of the angiotensin-converting-enzyme inhibitor benazepril on the progression of chronic renal insufficiency. The Angiotensin-Converting-Enzyme Inhibition in Progressive Renal Insufficiency Study Group. N Engl J Med 1996; 334: 939–945.

Antonios

MacGregor

GA.

Angiotensin converting enzyme inhibitors in hypertension: Potential problems. J Hypertens Suppl 1995; 13: S11–S16.

10.

Einhorn

Zhan

Hsu

. The frequency of hyperkalemia and its significance in chronic kidney disease. Arch Intern Med 2009; 169: 1156–1162.

11.

Palmer

BF.

Managing hyperkalemia caused by inhibitors of the renin-angiotensin-aldosterone system. N Engl J Med 2004; 351: 585–592.

12.

Palmer

BF.

Angiotensin-converting enzyme inhibitors and angiotensin receptor blockers: What to do if the serum creatinine and/or serum potassium concentration rises. Nephrol Dial Transplant 2003; 18: 1973–1975.

13.

Schjoedt

Andersen

Rossing

. Aldosterone escape during blockade of the renin-angiotensin-aldosterone system in diabetic nephropathy is associated with enhanced decline in glomerular filtration rate. Diabetologia 2004; 47: 1936–1939.

14.

Naruse

Tanabe

Sato

. Aldosterone breakthrough during angiotensin II receptor antagonist therapy in stroke-prone spontaneously hypertensive rats. Hypertension 2002; 40: 28–33.

15.

Gennari

Segal

AS.

Hyperkalemia: An adaptive response in chronic renal insufficiency. Kidney Int 2002; 62: 1–9.

16.

Salem

Rosa

Batlle

DC.

Extrarenal potassium tolerance in chronic renal failure: Implications for the treatment of acute hyperkalemia. Am J Kidney Dis 1991; 18: 421–440.

17.

Allon

Hyperkalemia in end-stage renal disease: Mechanisms and management. J Am Soc Nephrol 1995; 6: 1134–1142.

18.

Khanna

White

WB.

The management of hyperkalemia in patients with cardiovascular disease. Am J Med 2009; 122: 215–221.

19.

Wright

Jr. Bakris

Greene

. Effect of blood pressure lowering and antihypertensive drug class on progression of hypertensive kidney disease: Results from the AASK trial. JAMA 2002; 288: 2421–2431.

The effect of renin–angiotensin system blockade on renal protection in chronic kidney disease patients with hyperkalemia