Summary
Background and objectives
Angiotensin-converting enzyme inhibitors and angiotensin receptor blockers are the cornerstones of pharmacologic therapy in diabetic nephropathy. Mineralocorticoid receptor blockers reduce proteinuria as single agents or add-on therapy to other renin-angiotensin-aldosterone system-inhibiting drugs in these patients. The long-term benefits and ultimate role of mineralocorticoid receptor blockers in diabetic nephropathy remain unknown. A clinical trial previously showed that the kalemic effect of spironolactone is higher than losartan when added to lisinopril in patients with diabetic nephropathy. The purpose of this study was to investigate if renal potassium handling was primarily responsible for that observation.
Design, setting, participants, & measurements
In a blinded, randomized, three-arm placebo-controlled clinical trial, 80 participants with diabetic nephropathy taking lisinopril (80 mg) were randomized to spironolactone (25 mg daily), losartan (100 mg daily), or placebo (trial dates from July of 2003 to December of 2006). Serum potassium, aldosterone, and 24-hour urine sodium, potassium, and creatinine were measured over 48 weeks. Differences were analyzed with repeated measures mixed models.
Results
Mean follow-up serum potassium was 5.0 mEq/L for spironolactone, 4.7 mEq/L for losartan (P=0.05 versus spironolactone), and 4.5 mEq/L for placebo (P<0.001 versus spironolactone; P=0.03 versus losartan). The difference in serum potassium was 0.23 mEq/L for losartan versus placebo (P=0.02), 0.43 mEq/L for spironolactone versus placebo (P<0.001), and 0.2 mEq/L for spironolactone versus losartan (P=0.05). Serum and urine potassium excretion and secretion rates were similar between groups throughout the study.
Conclusion
Spironolactone raised serum potassium more than losartan in patients with diabetic nephropathy receiving lisinopril, despite similar renal sodium and potassium excretion. This finding suggests that extrarenal potassium homeostasis contributes to hyperkalemia in these patients. A better understanding of extrarenal potassium homeostasis will provide an opportunity to use this drug more safely in patients with diabetic nephropathy as well as other patient populations.
Introduction
Diabetic nephropathy is the leading cause of ESRD in the United States. Inhibiting the renin-angiotensin-aldosterone system (RAAS) slows this progression (1–4). The incidence of ESRD remains unacceptably high, however, even among patients receiving RAAS inhibition. Various regimens combining RAAS-inhibiting drugs have been investigated to further slow the progression of diabetic nephropathy.
Combinations include an angiotensin-converting enzyme (ACE) inhibitor and an angiotensin receptor blocker (ARB), a direct renin inhibitor (DRI) and an ACE inhibitor or ARB, and ACE inhibitors and mineralocorticoid receptor blockers (MRBs). All strategies reduce proteinuria compared with single-agent therapy (5–11), but hyperkalemia is a risk (12,13). Regimens including an ACE inhibitor and ARB or either drug and DRI are not recommended not only because of the risk of hyperkalemia but also because of renal failure and hypotension, which were seen in large clinical trials (14,15).
MRBs reduce proteinuria in diabetic nephropathy but have yet to be evaluated in a long-term outcome trial in this population. Although potential benefits from MRBs exist, additional understanding of the exact mechanism responsible for their kalemic effect may provide insight for preventing and managing this complication.
In this secondary analysis of a randomized trial, we explored effects of different RAAS-inhibiting combinations on serum potassium in patients with diabetic nephropathy. The purpose was to determine how factors known to modify serum potassium levels were influenced by combination therapy with lisinopril and spironolactone compared with therapy with lisinopril and losartan or lisinopril and placebo. We hypothesized that between-group differences in serum potassium might be accounted for by differences in renal potassium handling.
Materials and Methods
Study Design
This study was a secondary analysis of a prospective, randomized, double-blind, placebo-controlled clinical trial (ClinicalTrials.gov NCT00381134) with previously published results (9).
Study Population
Participants were all enrolled in a randomized trial testing the hypothesis that, compared with placebo, addition of ARB or MRB to lisinopril (80 mg daily) would reduce albuminuria by 30%. Inclusion criteria were age>18 years, diabetes mellitus, seated systolic BP≥130 mmHg or treated systolic BP<130 mmHg and a history of hypertension, and a urinary albumin-to-creatinine ratio (UACR)>300 mg/g, despite ACE inhibition>3 months. Exclusion criteria were serum creatinine>3.0 mg/dl in women and >4.0 mg/dl in men; secondary hypertension; baseline serum potassium>5.5 mEq/L; hemoglobin A1c>11%; recent stroke, myocardial infarction, or coronary revascularization; congestive heart failure; and anticipated need for renal replacement therapy within 1 year. The protocol was approved by the Institutional Review Board of the University of Texas Southwestern Medical Center–Dallas, and procedures fully adhered to the Declaration of Helsinki. All participants provided written informed consent.
Study Procedures
Screening and Run-In Visits.
Screening visits, including BP measurement, serum chemistry, and spot urine collection for albumin and creatinine, were conducted on 235 participants, with 128 patients eligible for run-in. At the first run-in visit, participants started lisinopril at 20–40 mg daily. All other RAAS-inhibiting drugs were discontinued. A dietician prescribed a 2 g sodium, 0.8 mEq/kg potassium, and 0.8 g/kg protein diet. During the 4- to 8-week run-in period, lisinopril was increased to 80 mg daily. Each visit included BP measurement, serum potassium and creatinine, and spot UACR. Additional antihypertensives, excluding other RAAS-inhibiting drugs or calcium channel blockers, were prescribed to achieve systolic BP<130 mmHg. Participants were ineligible to proceed if serum potassium was persistently >5.5 mEq/L despite dietary and diuretic adjustment, albuminuria regressed, or systolic BP was persistently <100 mmHg after antihypertensive dose reduction and/or repeat measurement. After the final run-in, participants were admitted to our Clinical and Translational Research Center (CTRC) for measurements of 24-hour ambulatory BP and urine albumin, urea, creatinine, sodium, and potassium.
Randomization and Follow-Up.
After CTRC measurements, participants were randomly assigned in a double-blind manner to losartan (50 mg), spironolactone (12.5 mg), or placebo. After 1 week, titrations were made to losartan (100 mg) and spironolactone (25 mg). Every 4 weeks, office BP and serum chemistries were obtained. Every 12 weeks, 24-hour ambulatory BP and urine sodium, potassium, creatinine, and albumin were measured. At weeks 24 and 48, a 4-hour water-loaded clearance study was performed in the CTRC with measurement of an overnight supine aldosterone level. We calculated the 24-hour creatinine clearance, fractional excretion of potassium, and potassium excretion rate. After 48 weeks, study drugs were discontinued.
Study Measurements
BP.
Clinic BP was measured by certified staff according to the American Heart Association. Ambulatory measurements were obtained with a Spacelabs 90207 monitor every 30 minutes during the daytime and every 1 hour at night.
Laboratory Measurements.
Serum and urine chemistries were assayed in the CTRC Laboratory on a Beckman Model CX-9 Analyzer. Urine albumin was quantified by immunoprecipitation (DiaSorin, Stillwater, MN), with a within-assay coefficient of variation range of 1.7%–2.8% and a between-assay coefficient of variation range of 2.4%–4.2%.
Calculations.
Fractional excretion of potassium was calculated from the 24-hour urine sample as the ratio of the product of the urine potassium concentration multiplied by serum creatinine concentration to the product of the serum potassium concentration multiplied by urine creatinine concentration (expressed as a percent). Urine potassium secretion was calculated from the clearance study as the difference between the urine potassium excretion and the filtered load of potassium as follows: (urine potassium concentration×urine flow rate)/(creatinine clearance×serum potassium concentration); it was expressed in microequivalents per minute.
Statistical Analyses
Normally distributed data are expressed as means and SDs, and skewed data are expressed as geometric means and 95% confidence intervals. The primary outcome variable in this analysis was serum potassium. A mixed model repeated measures analysis compared serum potassium between treatment groups with the covariance pattern specification guided using Akaike information criterion. This model included the treatment effect, time, and randomization values as covariates, whereas participants were random effects. Similar models were individually used to compare between-group differences in plasma aldosterone and systolic BP as well as 24-hour measurements of urinary creatinine clearance, potassium excretion, and sodium excretion and UACR. These variables were then included as independent variables in an adjusted model using change in serum potassium as the primary outcome variable. Mixed models were used to compare between-group changes in fractional excretion rate of potassium and potassium secretion rate. We conducted a logistic regression analysis on occurrence of hyperkalemia (serum potassium≥6.0 mEq/L) using demographics and urine/serum chemistries as predictor variables. Statistical analyses were performed with SAS version 9.2 (SAS Institute, Cary, NC).
Results
Patient Characteristics
Baseline characteristics of 80 randomized participants are in Table 1. Most participants were African American or Hispanic. There were no differences in antihypertensive or diuretic use.
Table 1.
Baseline characteristics of participants at randomization
| Characteristics | Placebo (n=27) | Losartan (n=26) | Spironolactone (n=27) |
|---|---|---|---|
| Men (%) | 44 | 50 | 48 |
| African American (%) | 37 | 31 | 26 |
| Hispanic (%) | 44 | 46 | 63 |
| Age (yr) | 49.3 (±8.8) | 52.3 (±9.1) | 51.7 (±9.3) |
| Duration of diabetes (yr) | 14.4 (±9.6) | 17.0 (±7.7) | 17.0 (±9.1) |
| 24-h ambulatory systolic BP (mmHg) | 138 (±15) | 143 (±15) | 135 (±11) |
| 24-h ambulatory diastolic BP (mmHg) | 75 (±9) | 75 (±9) | 71 (±9) |
| Serum creatinine (mg/dl) | 1.4 (±0.7) | 1.7 (±0.7) | 1.8 (±0.9) |
| Urine albumin to creatinine ratio (mg/g) | 917 (633 to 1329) | 897 (611 to 1316) | 1094 (758 to 1579) |
| Hemoglobin A1c (%) | 8.1 (±1.3) | 7.6 (±1.3) | 7.4 (±1.6) |
| Antihypertensive regimens at randomization | |||
| Diuretic (% taking) | 85.5 | 88.5 | 96.3 |
| β-Blocker | 70.4 | 63.4 | 77.8 |
| α-Blocker | 29.6 | 30.8 | 25.9 |
| Central adrenergic antagonist | 7.4 | 11.5 | 11.1 |
| Vasodilator | 3.7 | 0 | 0 |
| Three or more drugs (%) | 59 | 65 | 48 |
Data are listed as mean (SD) or geometric mean (95% confidence interval). There were no statistically significant between-group differences.
Serum Potassium
Mean randomization serum potassium levels were 4.5 (±0.7), 4.5 (±0.4), and 4.5 (±0.7) mEq/L for placebo, losartan, and spironolactone groups, respectively. There were 838 measurements obtained during the study. The mean during the trial was 4.5 mEq/L (±0.38) for placebo, 4.7 mEq/L (±0.33) for losartan (P=0.03 versus placebo), and 5.0 mEq/L (±0.51) for the spironolactone group (P<0.001 versus placebo; P=0.05 versus losartan). The course of these potassium levels over time was previously published (9).
Twenty-Four-Hour Urine Chemistry
No significant between-group differences existed in repeated measures analyses of urine sodium, potassium, or creatinine clearance (complete data shown in Table 2). No between-group difference existed in the change in fractional excretion of potassium (complete data shown in Table 3). Within the spironolactone group, the potassium secretion rate was different between weeks 24 (244 µEq/min; 192 to 309) and 48 (203 µEq/min; 154 to 266; P=0.01). However, no between-group differences existed for the three treatment groups throughout the duration of the entire study (complete data shown in Table 3).
Table 2.
Measurements of urinary sodium excretion, potassium excretion, and 24-hour creatinine clearance at randomization and throughout the trial
| Measurements | Placebo | Losartan | Spironolactone |
|---|---|---|---|
| Week 0 | |||
| n | 27 | 26 | 27 |
| Urine Na (mEq/d) | 193 (82) | 220 (77) | 219 (127) |
| Urine K (mEq/d) | 56 (18) | 63 (15) | 58 (19) |
| Urinary creatinine clearance (ml/min) | 73 (59.6 to 89.4) | 64.8 (53 to 79.2) | 51.4 (40.1 to 65.8) |
| Week 24 | |||
| n | 22 | 23 | 20 |
| Urine Na (mEq/d) | 223 (120) | 206 (86) | 220 (97) |
| Urine K (mEq/d) | 59 (23) | 58 (16) | 54 (17) |
| Urinary creatinine clearance (ml/min) | 67.5 (54.4 to 83.8) | 60.5 (49.6 to 73.7) | 48.1 (36.2 to 64.0) |
| Week 48 | |||
| n | 21 | 21 | 17 |
| Urine Na (mEq/d) | 196 (107) | 213 (104) | 221 (101) |
| Urine K (mEq/d) | 53 (22) | 52 (16) | 55 (22) |
| Urinary creatinine clearance (ml/min) | 64.3 (49.6 to 83.4) | 54.1 (40.5 to 72.2) | 51.6 (39.6 to 67.4) |
Data are listed as mean (SD) or geometric mean (95% confidence interval). All treatment comparisons are not significant for repeated measures analysis (urine Na, P=0.28; urine K, P=0.11; creatinine clearance, P=0.80).
Table 3.
Fractional excretion of potassium and potassium secretion rates during the trial
| Measurements | Placebo | Losartan | Spironolactone |
|---|---|---|---|
| Week 0 | |||
| n | 26 | 26 | 27 |
| FEK (%) | 15.8 (12.4 to 20.2) | 17.2 (13.9 to 21.4) | 17.1 (13.7 to 21.4) |
| K secretion rate (µEq/min) | 265 (199 to 352) | 263 (206 to 335) | 213 (169 to 269) |
| Week 24 | |||
| n | 20 | 21 | 18 |
| FEK (%) | 14.9 (11.4 to 19.5) | 16.5 (12.5 to 21.9) | 14.8 (11.7 to 18.6) |
| K secretion rate (µEq/min) | 258 (191 to 348) | 258 (192 to 346) | 244 (192 to 309) |
| Week 48 | |||
| n | 20 | 20 | 15 |
| FEK (%) | 14.3 (11 to 18.6) | 15.1 (11.9 to 19.1) | 15.8 (12.4 to 20) |
| K secretion rate (µEq/min) | 247 (181 to 337) | 248 (192 to 32) | 203 (154 to 266)a |
Data are listed as geometric mean and 95% confidence interval. Repeated measures analysis: fractional excretion of potassium, P=0.64 for treatment, P=0.80 for week, P=0.50 for treatment week interaction; potassium secretion rate, P=0.80 for treatment, P=0.20 for treatment week interaction. FEK, fractional excretion of potassium.
Spironolactone K secretion rate, P=0.01 for week 24 versus week 48.
Plasma Aldosterone
Plasma aldosterone values (geometric mean and 95% confidence interval) at randomization, week 24, and week 48 were 4.0 (3.1 to 5.2), 4.1 (2.9 to 5.6), and 4.0 (2.7 to 6.1) ng/dl for placebo; 3.4 (2.4 to 4.9), 4.0 (2.9 to 5.5), and 2.8 (2.1 to 3.7) ng/dl for losartan; and 5.0 (3.7 to 6.7), 6.2 (4.5 to 8.5), and 4.9 (3.4 to 7.1) ng/dl for spironolactone, respectively. The between-group differences were not significant (P=0.78).
Changes in Serum Potassium throughout the Study
Between-group differences in serum potassium throughout the study are shown in Table 4. In unadjusted analyses, there were significant increases in potassium for spironolactone compared with both losartan and placebo. There was also a significant increase in serum potassium in the losartan group compared with placebo. In models adjusting for pre- or postrandomization measurements of systolic BP and plasma aldosterone as well as 24-hour urine sodium excretion, potassium excretion, UACR, and creatinine clearance, serum potassium was significantly higher in the spironolactone group and losartan group compared with placebo. The results were unchanged when accounting for available data on baseline urine pH and serum bicarbonate (data not shown).
Table 4.
Differences in serum potassium between treatment groups throughout the study
| Statistical Model | Losartan Versus Placebo | Spironolactone Versus Placebo | Spironolactone Versus Losartan |
|---|---|---|---|
| Unadjusted | 0.23 (0.04 to 0.42), P=0.02 | 0.43 (0.23 to 0.62), P<0.001 | 0.2 (0.0 to 0.39), P=0.05 |
| Adjusted for randomization variablesa | 0.22 (0.02 to 0.42), P=0.03 | 0.37 (0.15 to 0.59), P=0.001 | 0.15 (−0.05 to 0.36), P=0.14 |
| Adjusted for postrandomization variablesa | 0.25 (0.03 to 0.46), P=0.03 | 0.42 (0.21 to 0.64), P<0.001 | 0.17 (−0.03 to 0.46), P=0.16 |
Variables include systolic BP plasma aldosterone, 24-hour urinary creatinine clearance, 24-hour urinary excretion of sodium and potassium, and 24-hour urine albumin to creatinine ratio. Differences are linear model least squares means estimates and 95% confidence intervals.
Hyperkalemia
Hyperkalemia (serum potassium≥6.0 mEq/L) occurred in 7.4%, 38.5%, and 51.9% of participants in the placebo, losartan, and spironolactone groups, respectively. All episodes were managed with kayexalate, although two participants in the spironolactone group discontinued the drug because of recurrent hyperkalemia. Significant predictors of hyperkalemia while controlling for treatment included (1) baseline serum potassium (odds ratio [OR], 1.3; 95% confidence interval [95% CI], 1.1 to 1.5 per 0.1 mEq/L increase), (2) baseline creatinine clearance (OR, 0.7; 95% CI, 0.5 to 0.95 per 10 ml/min increase), and (3) urinary potassium (OR, 0.5; 95% CI, 0.2 to 0.9 per 10 mEq increase). Serum potassium>4.5 mEq/L was a significant risk for developing hyperkalemia in the spironolactone group (OR, 13.8; 95% CI, 2.1 to 92), and there was a nonsignificant risk for estimated GFR<45 ml/min per 1.73 m2 (OR, 4.3; 95% CI, 0.8 to 22.9). Among participants in all groups, baseline serum bicarbonate and urine pH levels were 24.6 (±2.9) and 5.6 (±0.5) among those participants who developed hyperkalemia and 26.2 (±2.6, P=0.02) and 5.7 (±0.4, P=0.08) for those participants who did not develop hyperkalemia, respectively.
Discussion
In patients with diabetic nephropathy receiving maximum doses of lisinopril, the addition of spironolactone increases serum potassium to a greater extent than losartan. Consequently, there are more episodes of hyperkalemia with spironolactone compared with the other dual RAAS-inhibiting regimens. Our data indicate that the differences in serum potassium cannot be explained by modification of renal potassium excretion alone. These findings came from a randomized trial accounting for potentially confounding variables.
Pharmacologic RAAS inhibition slows the diabetic nephropathy progression (1–4,16), but hyperkalemia remains a limitation (12,13). The Ongoing Telmisartan Alone and in Combination with Ramipril Global Endpoint Trial was not powered to conclusively show increased hyperkalemia and renal failure among patients with diabetes or microalbuminuria receiving combination therapy (15,17). The Diabetes in Nephropathy study, specifically designed to test the ACE inhibitor and ARB strategy in patients with diabetic nephropathy (18), was recently stopped for safety concerns. The Aliskiren Trial in Type 2 Diabetes Using Cardiorenal Endpoints was recently terminated, because individuals with diabetic nephropathy experienced more hyperkalemia and hypotension on a DRI-based combination compared with ACE inhibitor or ARB alone (14). However, the long-term effects of MRB in diabetic nephropathy as combination- or single-agent RAAS inhibition remain unexplored. As a potential option for managing diabetic nephropathy, understanding the mechanisms of hyperkalemia from their use is critical.
Similar to other combinations, short-term administration of combination RAAS inhibition including MRBs reduces proteinuria in patients with kidney disease (7,8,19,20), although potassium increases and medically manageable hyperkalemia remain risks associated with this intervention. No prior study has directly compared the effects of add-on therapy with an MRB versus ARB in patients with diabetic nephropathy already receiving maximal ACE inhibition. In this analysis of a randomized placebo-controlled trial, serum potassium and the incidence of hyperkalemia were highest in participants taking spironolactone compared with losartan or placebo. Prior studies show that reduced baseline GFR predicts the development of hyperkalemia in individuals with varying comorbidities receiving single- or dual-agent RAAS inhibition (21,22). There was a trend for lower creatinine clearance at randomization in the spironolactone group in our study, but follow-up measurements were not significantly different between groups during the trial. There were no between-group differences in serum potassium at the time of randomization in our study.
Our study had a unique design, which provided new insights into potassium homeostasis during dual blockade. These insights include repeated measurements of 24-hour urine electrolytes and plasma aldosterone and carefully controlled water-loaded clearance studies. Our findings suggest that reduced renal potassium excretion is not the primary mechanism responsible for increased serum potassium in participants taking spironolactone and lisinopril compared with the other regimens. Specifically, as illustrated in Tables 2 and 3, there were no between-group differences in 24-hour urine sodium or potassium excretion and no between-group differences in fractional excretion of potassium or potassium excretion rate. Other investigators found that the effects of lisinopril and spironolactone therapy on renal potassium excretion do not fully account for the observed increase in serum potassium that this regimen induces in patients with CKD (23), but no studies have compared different regimens. Even while adjusting for urinary sodium, potassium, and creatinine clearance in our study, the significant differences in serum potassium change between losartan and placebo and between spironolactone and placebo persisted.
Aldosterone levels were suppressed in all groups throughout the study. The low baseline levels likely reflect (1) hyporeninemic hypoaldosteronism related to diabetic nephropathy and (2) RAAS inhibition from lisinopril during run-in. Compared with placebo, the addition of losartan or spironolactone did not modify plasma aldosterone or urinary potassium secretion and excretion. This finding was unexpected given the potential aldosterone breakthrough in patients receiving ACE inhibitors, but we cannot exclude that extracellular volume overload was suppressing aldosterone. Overall, these findings suggest that extrarenal potassium homeostasis was responsible for the different levels of extracellular potassium between the groups. Some animal and human studies support the role of aldosterone in extrarenal potassium handling through gastrointestinal secretion or transcellular shifts (24–27), but a trial in anephric patients failed to identify a significant effect of exogenous mineralocorticoid on extracellular potassium (28). Angiotensin II may have varying effects on distal renal potassium channels, but effects of ARB on these channels in other tissues and extrarenal potassium homeostasis are unknown (29). We did not have stool electrolytes to make conclusions about gastrointestinal potassium handling. However, our study provides evidence that, among patients with renal impairment, there are currently unidentified factors, independent of renal function, that predispose individuals to hyperkalemia with dual RAAS inhibition. This finding has important implications for studying variation in extrarenal mineralocorticoid receptors and ultimately, modifying pharmacologic therapies to limit hyperkalemia with RAAS inhibition in not only diabetic nephropathy patients but also other populations. In patients with systolic heart failure, MRB added to other RAAS inhibitors can increase serum potassium; however, it is still implemented, because it offers the benefit of mortality reduction (30,31).
Identifying risk factors for hyperkalemia may allow for better selection of patients to use dual RAAS inhibition. Baseline serum potassium, urine potassium, and creatinine clearance predicted hyperkalemia independent of treatment group. A prior study specifically identified baseline serum potassium>4.5 mEq/L and estimated GFR<45 ml/min per 1.73 m2 as hyperkalemia predictors (>5.5 mEq/L) in CKD stages 2 and 3 patients receiving spironolactone and another RAAS-inhibiting drug (32). This serum potassium was predictive of hyperkalemia (>6.0 mEq/L), and this GFR was a nonsignificant predictor in our study. Although hyperkalemia was medically managed in our study, in rare cases, dual RAAS inhibition carries the potential risk of hyperkalemia that may require hemodialysis or cause cardiac arrest. Consequently, it is critical to monitor potassium on these regimens. Importantly, the ARB and DRI combination did not cause any hyperkalemia in one study done in diabetic patients with stages 1 and 2 CKD (33), supporting that this strategy is better tolerated in diabetic patients with only mildly reduced kidney function.
One limitation was exclusion of patients with severe renal disease and persistent hyperkalemia during run-in. Progression of CKD increases the hyperkalemia risk (34), and therefore, the hyperkalemia incidence and potassium levels may have been higher with these individuals included. In our results, higher serum potassium with spironolactone versus losartan was of borderline statistical significance. The original trial was powered for proteinuria changes. Finally, our population demographic makes it difficult to generalize in populations with more Caucasians.
The addition of spironolactone increases serum potassium more than losartan when added to the maximum dose of lisinopril in patients with diabetic nephropathy. There is evidence that extrarenal potassium homeostasis is involved in this effect. Combination therapies using ACE inhibitors and ARB or DRI plus either ACE inhibitors or ARBs are not recommended in diabetic nephropathy. MRBs effectively reduce proteinuria in patients with diabetic nephropathy, but long-term outcomes with this strategy have not been adequately assessed in clinical trials. Identifying specific mechanisms responsible for hyperkalemia may provide an opportunity to find more effective and safer uses of MRB to improve outcomes in diabetic nephropathy.
Disclosures
None.
Acknowledgments
The authors acknowledge the assistance of Ms. Martha Cruz and Mr. Robert Butsch in the preparation of the manuscript. We acknowledge the assistance of the following individuals who contributed to this project: Dr. Uzma Mehdi, Dr. Sandeep Singh, Ms. Tammy Lightfoot, and Ms. Zhengnan Wang.
This work was supported by funding from the American Heart Association Fellow to Faculty Transition Award (to P.N.V.B.), National Institute of Diabetes and Digestive and Kidney Diseases Grants 1K23DK096007-01A1 (to P.N.V.B.) and 2-RO1 DK6301001 (to R.D.T.), and the University of Texas Southwestern O’Brien Center through National Institutes of Health Grant P30DK079328. Additional institutional support is provided to P.N.V.B. as the Dedman Family Scholar in Clinical Care at the University of Texas Southwestern. This work was also conducted with support from University of Texas Southwestern Clinical and Translational Alliance For Research (UT-STAR) National Institutes of Health/National Center for Advancing Translational Sciences Grant Number KL2RR024983.
Some of these results were presented as an abstract at the American Society of Nephrology Annual Meeting in Philadelphia, PA, on November 4–9, 2008.
The conduct is solely the responsibility of the authors and does not necessarily represent the official views of the UT-STAR, the University of Texas Southwestern Medical Center at Dallas and its affiliated academic and health care centers, the National Center for Advancing Translational Sciences, or the National Institutes of Health.
Footnotes
Published online ahead of print. Publication date available at www.cjasn.org.
See related editorial, “Serum Potassium in Dual Renin-Angiotensin-Aldosterone System Blockade,” on pages 219–221.
References
- 1.Lewis EJ, Hunsicker LG, Clarke WR, Berl T, Pohl MA, Lewis JB, Ritz E, Atkins RC, Rohde R, Raz I, Collaborative Study Group : Renoprotective effect of the angiotensin-receptor antagonist irbesartan in patients with nephropathy due to type 2 diabetes. N Engl J Med 345: 851–860, 2001 [DOI] [PubMed] [Google Scholar]
- 2.Brenner BM, Cooper ME, de Zeeuw D, Keane WF, Mitch WE, Parving HH, Remuzzi G, Snapinn SM, Zhang Z, Shahinfar S, RENAAL Study Investigators : Effects of losartan on renal and cardiovascular outcomes in patients with type 2 diabetes and nephropathy. N Engl J Med 345: 861–869, 2001 [DOI] [PubMed] [Google Scholar]
- 3.Lewis EJ, Hunsicker LG, Bain RP, Rohde RD, The Collaborative Study Group : The effect of angiotensin-converting-enzyme inhibition on diabetic nephropathy. N Engl J Med 329: 1456–1462, 1993 [DOI] [PubMed] [Google Scholar]
- 4.Parving HH, Lehnert H, Bröchner-Mortensen J, Gomis R, Andersen S, Arner P, Irbesartan in Patients with Type 2 Diabetes and Microalbuminuria Study Group : The effect of irbesartan on the development of diabetic nephropathy in patients with type 2 diabetes. N Engl J Med 345: 870–878, 2001 [DOI] [PubMed] [Google Scholar]
- 5.Jacobsen P, Andersen S, Jensen BR, Parving HH: Additive effect of ACE inhibition and angiotensin II receptor blockade in type I diabetic patients with diabetic nephropathy. J Am Soc Nephrol 14: 992–999, 2003 [DOI] [PubMed] [Google Scholar]
- 6.Rossing K, Jacobsen P, Pietraszek L, Parving HH: Renoprotective effects of adding angiotensin II receptor blocker to maximal recommended doses of ACE inhibitor in diabetic nephropathy: A randomized double-blind crossover trial. Diabetes Care 26: 2268–2274, 2003 [DOI] [PubMed] [Google Scholar]
- 7.Schjoedt KJ, Rossing K, Juhl TR, Boomsma F, Rossing P, Tarnow L, Parving HH: Beneficial impact of spironolactone in diabetic nephropathy. Kidney Int 68: 2829–2836, 2005 [DOI] [PubMed] [Google Scholar]
- 8.Schjoedt KJ, Rossing K, Juhl TR, Boomsma F, Tarnow L, Rossing P, Parving HH: Beneficial impact of spironolactone on nephrotic range albuminuria in diabetic nephropathy. Kidney Int 70: 536–542, 2006 [DOI] [PubMed] [Google Scholar]
- 9.Mehdi UF, Adams-Huet B, Raskin P, Vega GL, Toto RD: Addition of angiotensin receptor blockade or mineralocorticoid antagonism to maximal angiotensin-converting enzyme inhibition in diabetic nephropathy. J Am Soc Nephrol 20: 2641–2650, 2009 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 10.Parving HH, Persson F, Lewis JB, Lewis EJ, Hollenberg NK, AVOID Study Investigators : Aliskiren combined with losartan in type 2 diabetes and nephropathy. N Engl J Med 358: 2433–2446, 2008 [DOI] [PubMed] [Google Scholar]
- 11.Persson F, Rossing P, Reinhard H, Juhl T, Stehouwer CD, Schalkwijk C, Danser AH, Boomsma F, Frandsen E, Parving HH: Renal effects of aliskiren compared with and in combination with irbesartan in patients with type 2 diabetes, hypertension, and albuminuria. Diabetes Care 32: 1873–1879, 2009 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 12.Bomback AS, Kshirsagar AV, Amamoo MA, Klemmer PJ: Change in proteinuria after adding aldosterone blockers to ACE inhibitors or angiotensin receptor blockers in CKD: A systematic review. Am J Kidney Dis 51: 199–211, 2008 [DOI] [PubMed] [Google Scholar]
- 13.Jennings DL, Kalus JS, Coleman CI, Manierski C, Yee J: Combination therapy with an ACE inhibitor and an angiotensin receptor blocker for diabetic nephropathy: A meta-analysis. Diabet Med 24: 486–493, 2007 [DOI] [PubMed] [Google Scholar]
- 14.Parving HH, Brenner BM, McMurray JJ, de Zeeuw D, Haffner SM, Solomon SD, Chaturvedi N, Persson F, Desai AS, Nicolaides M, Richard A, Xiang Z, Brunel P, Pfeffer MA, ALTITUDE Investigators : Cardiorenal end points in a trial of aliskiren for type 2 diabetes. N Engl J Med 367: 2204–2213, 2012 [DOI] [PubMed] [Google Scholar]
- 15.Yusuf S, Teo KK, Pogue J, Dyal L, Copland I, Schumacher H, Dagenais G, Sleight P, Anderson C, ONTARGET Investigators : Telmisartan, ramipril, or both in patients at high risk for vascular events. N Engl J Med 358: 1547–1559, 2008 [DOI] [PubMed] [Google Scholar]
- 16.Parving HH, Hommel E, Jensen BR, Hansen HP: Long-term beneficial effect of ACE inhibition on diabetic nephropathy in normotensive type 1 diabetic patients. Kidney Int 60: 228–234, 2001 [DOI] [PubMed] [Google Scholar]
- 17.Mann JF, Schmieder RE, McQueen M, Dyal L, Schumacher H, Pogue J, Wang X, Maggioni A, Budaj A, Chaithiraphan S, Dickstein K, Keltai M, Metsärinne K, Oto A, Parkhomenko A, Piegas LS, Svendsen TL, Teo KK, Yusuf S, ONTARGET investigators : Renal outcomes with telmisartan, ramipril, or both, in people at high vascular risk (the ONTARGET study): A multicentre, randomised, double-blind, controlled trial. Lancet 372: 547–553, 2008 [DOI] [PubMed] [Google Scholar]
- 18.Department of Veteran Affairs: Combination Angiotensin Receptor Blocker and Angiotensin Converting Enzyme Inhibitor for Treatment of Diabetic Nephropathy: VA NEPHRON-D Study: Nephropathy in Diabetes Study, 2000. Available at: http://www.clinicaltrials.gov/ct2/show/NCT00555217 Accessed March 26, 2012
- 19.Bianchi S, Bigazzi R, Campese VM: Long-term effects of spironolactone on proteinuria and kidney function in patients with chronic kidney disease. Kidney Int 70: 2116–2123, 2006 [DOI] [PubMed] [Google Scholar]
- 20.Rossing K, Schjoedt KJ, Smidt UM, Boomsma F, Parving HH: Beneficial effects of adding spironolactone to recommended antihypertensive treatment in diabetic nephropathy: A randomized, double-masked, cross-over study. Diabetes Care 28: 2106–2112, 2005 [DOI] [PubMed] [Google Scholar]
- 21.Maddirala SKA, Khan A, Vincent A, Lau K: Effect of angiotensin converting enzyme inhibitors and angiotensin receptor blockers on serum potassium levels and renal function in ambulatory outpatients: Risk factors analysis. Am J Med Sci 336: 330–335, 2008 [DOI] [PubMed] [Google Scholar]
- 22.Pitt B, Remme W, Zannad F, Neaton J, Martinez F, Roniker B, Bittman R, Hurley S, Kleiman J, Gatlin M, Eplerenone Post-Acute Myocardial Infarction Heart Failure Efficacy and Survival Study Investigators : Eplerenone, a selective aldosterone blocker, in patients with left ventricular dysfunction after myocardial infarction. N Engl J Med 348: 1309–1321, 2003 [DOI] [PubMed] [Google Scholar]
- 23.Preston RA, Afshartous D, Garg D, Medrano S, Alonso AB, Rodriguez R: Mechanisms of impaired potassium handling with dual renin-angiotensin-aldosterone blockade in chronic kidney disease. Hypertension 53: 754–760, 2009 [DOI] [PubMed] [Google Scholar]
- 24.Alexander EA, Levinsky NG: An extrarenal mechanism of potassium adaptation. J Clin Invest 47: 740–748, 1968 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 25.Blachley JD, Crider BP, Johnson JH: Extrarenal potassium adaptation: Role of skeletal muscle. Am J Physiol 251: F313–F318, 1986 [DOI] [PubMed] [Google Scholar]
- 26.Phakdeekitcharoen B, Kittikanokrat W, Kijkunasathian C, Chatsudthipong V: Aldosterone increases Na-K-ATPase activity in skeletal muscle of patients with Conn's syndrome. Clin Endocrinol 74: 152–159, 2011 [DOI] [PubMed] [Google Scholar]
- 27.Sweiry JH, Binder HJ: Characterization of aldosterone-induced potassium secretion in rat distal colon. J Clin Invest 83: 844–851, 1989 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 28.Kaisar MO, Wiggins KJ, Sturtevant JM, Hawley CM, Campbell SB, Isbel NM, Mudge DW, Bofinger A, Petrie JJ, Johnson DW: A randomized controlled trial of fludrocortisone for the treatment of hyperkalemia in hemodialysis patients. Am J Kidney Dis 47: 809–814, 2006 [DOI] [PubMed] [Google Scholar]
- 29.van der Lubbe N, Zietse R, Hoorn EJ: Effects of angiotensin II on kinase-mediated sodium and potassium transport in the distal nephron. Curr Opin Nephrol Hypertens 22: 120–126, 2013 [DOI] [PubMed] [Google Scholar]
- 30.Pitt B, Zannad F, Remme WJ, Cody R, Castaigne A, Perez A, Palensky J, Wittes J, Randomized Aldactone Evaluation Study Investigators : The effect of spironolactone on morbidity and mortality in patients with severe heart failure. N Engl J Med 341: 709–717, 1999 [DOI] [PubMed] [Google Scholar]
- 31.Zannad F, McMurray JJ, Krum H, van Veldhuisen DJ, Swedberg K, Shi H, Vincent J, Pocock SJ, Pitt B, EMPHASIS-HF Study Group : Eplerenone in patients with systolic heart failure and mild symptoms. N Engl J Med 364: 11–21, 2011. 21073363 [Google Scholar]
- 32.Khosla N, Kalaitzidis R, Bakris GL: Predictors of hyperkalemia risk following hypertension control with aldosterone blockade. Am J Nephrol 30: 418–424, 2009 [DOI] [PubMed] [Google Scholar]
- 33.Bakris GL, Oparil S, Purkayastha D, Yadao A, Alessi T, Sowers JR: Randomized study of antihypertensive efficacy and safety of combination aliskiren/valsartan vs valsartan monotherapy in hypertensive patients wtih type 2 diabetes mellitus. J Clin Hypertens (Greenwich) 15: 92–100, 2013 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 34.Bakris GL, Siomos M, Richardson D, Janssen I, Bolton WK, Hebert L, Agarwal R, Catanzaro D, VAL-K Study Group : ACE inhibition or angiotensin receptor blockade: Impact on potassium in renal failure. Kidney Int 58: 2084–2092, 2000 [DOI] [PubMed] [Google Scholar]