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Increased serum potassium affects renal outcomes: a post hoc analysis of the Reduction of Endpoints in NIDDM with the Angiotensin II Antagonist Losartan (RENAAL) trial

Increased serum potassium affects renal outcomes: a post hoc analysis of the Reduction of... Diabetologia (2011) 54:44–50 DOI 10.1007/s00125-010-1922-6 ARTICLE Increased serum potassium affects renal outcomes: a post hoc analysis of the Reduction of Endpoints in NIDDM with the Angiotensin II Antagonist Losartan (RENAAL) trial Y. Miao & D. Dobre & H. J. Lambers Heerspink & B. M. Brenner & M. E. Cooper & H-H. Parving & S. Shahinfar & D. Grobbee & D. de Zeeuw Received: 24 June 2010 /Accepted: 1 September 2010 /Published online: 30 September 2010 # The Author(s) 2010. This article is published with open access at Springerlink.com Abstract NIDDM with the Angiotensin II Antagonist Losartan Aims/hypothesis To assess the effect of an angiotensin (RENAAL) study. Renal outcomes were defined as a compos- receptor blocker (ARB) on serum potassium and the effect ite of doubling of serum creatinine or end-stage renal disease. of a serum potassium change on renal outcomes in patients Results At month 6, 259 (38.4%) and 73 (10.8%) patients with type 2 diabetes and nephropathy. in the losartan group and 151 (22.8%) and 34 (5.1%) patients Methods We performed a post hoc analysis in patients with in the placebo group had serum potassium ≥5.0 mmol/l and type 2 diabetes participating in the Reduction of Endpoints in ≥5.5 mmol/l, (p<0.001), respectively. Losartan was an independent predictor for serum potassium ≥5.0 mmol/l at month 6 (OR 2.8; 95% CI 2.0–3.9). Serum potassium at : : : Y. Miao D. Dobre H. J. Lambers Heerspink (*) D. de Zeeuw month 6 ≥ 5.0 mmol/l was in turn associated with increased Department of Clinical Pharmacology, risk for renal events (HR 1.22; 95% CI 1.00–1.50), University Medical Centre Groningen, independent of other risk factors. Adjustment of the overall Antonius Deusinglaan 1, 9713 AV Groningen, the Netherlands treatment effects for serum potassium augmented losartan’s e-mail: [email protected] renoprotective effect from 21% (6–34%) to 35% (20–48%), suggesting that the renoprotective effects of losartan are B. M. Brenner offset by its effect on serum potassium. Brigham and Women’s Hospital and Harvard School of Medicine, Boston, MA, USA Conclusions/interpretation In this study, we found that treatment with the ARB losartan is associated with a high M. E. Cooper risk of increased serum potassium levels, which is in turn Baker IDI Heart and Diabetes Research Institute, associated with an increased risk of renal outcomes in Melbourne, VIC, Australia patients with diabetes and nephropathy. Whether additional H.-H. Parving management of high serum potassium would further Department of Medical Endocrinology, increase the renal protective properties of losartan is an University Hospital of Copenhagen, important clinical question. Copenhagen, Denmark H.-H. Parving . . Keywords Angiotensin receptor blocker Losartan The Faculty of Health Science, Aarhus University, . . Nephropathy Potassium Type 2 diabetes Aarhus, Denmark S. Shahinfar Abbreviations Shahinfar Consulting, The Children’s Hospital of Philadelphia, Philadelphia, PA, USA ACR Albumin:creatinine ratio ARB Angiotensin receptor blocker D. Grobbee CV Cardiovascular Julius Center for Health Science and Primary Care, DSCR Doubling of serum creatinine University Medical Center Utrecht, Utrecht, the Netherlands ESRD End-stage renal disease Diabetologia (2011) 54:44–50 45 eGFR Estimated glomerular filtration rate 250 centres in 28 countries and involved 1,513 patients. NIDDM Non-insulin-dependent diabetes mellitus The study design, the inclusion/exclusion criteria, and the RAAS Renin–angiotensin–aldosterone system treatment protocol have been reported previously [3, 10]. In RENAAL Reduction of Endpoints in NIDDM with the short, after a 6-week screening phase, patients were Angiotensin II Antagonist Losartan randomised to either losartan 50 mg (titrated to 100 mg after 4 weeks) or placebo. Additional antihypertensive medications (calcium channel blockers, β-blockers, centrally Introduction acting agents, and diuretics, excluding angiotensin- converting enzyme inhibitors or other angiotensin receptor Diabetic nephropathy is the leading cause of end-stage renal antagonists) were permitted to reach the blood pressure goal disease (ESRD) in western societies. As the prevalence of of <140/90 mmHg (systolic/diastolic). All patients signed diabetes is increasing, ESRD accounts for substantial informed consent before enrolment, and the local Institutional morbidity and mortality [1, 2]. Review Board of each participating centre approved the Angiotensin receptor blockers (ARBs) have several study. The mean duration of follow-up was 3.4 years. Blood important beneficial effects in patients with diabetes and pressure, serum potassium level, serum creatinine and nephropathy, such as decreasing systemic blood pressure albumin:creatinine ratio were measured at first month, third and reducing albuminuria. These effects are related to long- month, and then every 3 months until the end of the study. term renal protection [3, 4]. However, these beneficial effects are accompanied by a so-called side effect of ARBs, Change in serum potassium and outcomes In this study, we induction of a rise in serum potassium levels even leading performed a post hoc analysis of all individuals with to hyperkalaemia. This situation may in turn lead to potassium measurements included in the RENAAL trial. detrimental long-term effects [5]. The risk of hyperkalaemia We assessed the relationship between serum potassium is particularly high in patients with diabetes as these level and renal outcomes in two ways. First, we assessed patients already have reduced aldosterone production the relationship between serum potassium and renal out- secondary to renin deficiency, the so-called hyporeninemic comes at month 6. The month 6 values were chosen as the hypoaldosteronism syndrome [6, 7]. Diabetes, low renal treatment effects were considered to be fully present and function and use of renin–angiotensin–aldosterone system relatively few renal events occurred before month 6. The (RAAS) inhibitors are independent factors that increase month 6 serum potassium level was classified into two serum potassium level. In combination, these factors pose categories: <5.0 mmol/l (reference, and ≥5.0 mmol/l [11]. patients at even higher risk of hyperkalaemia [8]. We selected this threshold (instead of the clinical accepted Increased serum potassium levels are associated with value of 5.5 mmol/l) because the risk of adverse renal increased risk for cardiovascular (CV) morbidity and outcomes started to increase from 5.0 mmol/l, and a small mortality. Hyperkalaemia as a result of ARB therapy has number of patients reached serum potassium levels been related to worse CV outcomes [9]. However, the ≥5.5 mmol/l in our population. As a single elevated relationship between change in serum potassium levels in potassium measurement may be an erroneous finding, we response to RAAS therapy and renal outcomes is not well also assessed the relationship between persistent drug- established. Therefore, we assessed the relationship be- induced serum potassium at months 6 and 9 and its tween ARB treatment, serum potassium levels and renal association with renal outcome. These individuals were outcomes in patients with type 2 diabetes and nephropathy either compared with those with a single elevated serum participating in the Reduction of Endpoints in NIDDM with potassium measurement at month 6 or 9, or compared with the Angiotensin II Antagonist Losartan (RENAAL) trial those without increases in serum potassium above (Clinical trials.gov identifier: NCT 00308347). 5.0 mmol/l during the first 9 months of follow-up. In the second approach, we calculated the average serum potassium concentration during follow-up and explored the Methods relationship between the average serum potassium level during follow-up with renal outcomes. The average serum Study design The RENAAL trial was a multinational, potassium concentration, as well as average levels of other randomised, double-blind trial that compared the effects of relevant covariates was calculated as the mean of the first losartan vs placebo in addition to conventional anti- month and each consecutive third month potassium value hypertensive medication in patients with type 2 diabetes until the occurrence of the renal event. This approach was and nephropathy. Patients had serum creatinine levels chosen as it more accurately reflects the risk of a participant between 115 and 265 μmol/l (133 to 265 μmol/l for men to exposure to a high serum potassium load for a definite weighing more than 60 kg). The study was performed in period of time than a single elevated measure. Renal out- 46 Diabetologia (2011) 54:44–50 Table 1 Baseline and month 6 characteristics of the whole population comes were defined as a composite of doubling of serum creatinine (DSCR) or ESRD, and as DSCR and ESRD Serum potassium at month 6 (mmol/l) individually. All endpoints were adjudicated by a blinded Baseline characteristic <5.0 (n=928) ≥5.0 mmol/l (n=410) endpoint committee using rigorous guideline definitions. Age ( years) 60.0 (7.6) 60.4 (7.1) Statistical analysis Differences among patient subgroups Male, n (%) 593 (63.9) 248 (60.5) were evaluated by using chi-squared test or t test, as Race, n (%) appropriate. Mean serum potassium level at each visit White 449 (48.4) 198 (48.3) during follow-up, as well as the proportion of patients with Black 161 (17.3) 40 (9.8) month 6 potassium level ≥5.0 mmol/l and ≥5.5 mmol/l was Hispanic 144 (15.5) 98 (23.9) calculated in both the losartan and placebo group. To Asian 163 (17.6) 68 (16.6) identify the predictors of increased serum potassium at Other 11 (1.2) 6 (1.5) month 6, a multivariate logistic regression model was used. Systolic BP (mmHg) 152.1 (19.2) 153.2 (19.7) Baseline characteristics that showed an association with Diastolic BP (mmHg) 82.9 (10.5) 81.3 (10.1) serum potassium ≥5.0 mmol/l (p<0.2) at univariate analysis Urinary ACR (mg/mmol), 129 (59–263) 155 (76–327) were selected for the multivariate logistic model. The median (IQR) multivariate logistic model was adjusted for age, treatment Serum creatinine (μmol/l) 161 (41.6) 173 (42.9) assignment, serum potassium, diastolic blood pressure, –1 –2 b eGFR (mlmin 1.73 m ) 40.9 (12.2) 37.0 (11.9) estimated glomerular filtration rate (eGFR), month 6 HbA , (%) 8.4 (1.6) 8.4 (1.6) 1c change in eGFR from baseline, urinary albumin:creatinine Haemoglobin (g/l) 127 (18) 121 (18) ratio (ACR), prescription of α-blockers, thiazide diuretics, Serum potassium (mmol/l) 4.5 (0.5) 4.9 (0.4) loop diuretics, and haemoglobin. To assess the association Serum potassium ≥5.0 140 (15.1) 187 (45.6) between change in serum potassium from baseline to mmol/l, n (%) month 6 and renal outcomes, a multivariate Cox proportional Treatment, n (%) hazard model was used. The linearity of baseline and follow- Losartan 416 (44.8) 259 (63.2) up continuous variables was assessed. If the linearity was not Thiazide diuretics 161 (17.3) 45 (11.0) demonstrated, the variable was recoded as a categorical K-sparing diuretics 24 (2.6) 7 (1.7) variable. In the final Cox model we adjusted for the following Loop diuretics 426 (45.9) 177 (43.2) baseline variables: age, sex, race, treatment, eGFR, follow-up Calcium channel blocker 679 (73.2) 291 (71.0) systolic blood pressure, diastolic blood pressure, ACR. We α-Blockers 239 (25.8) 81 (19.8) checked for an interaction between serum potassium levels at β-Blockers 173 (18.6) 76 (18.5) month 6 and eGFR. To ensure that our results are not affected Month 6 characteristics by baseline renal function and other important predictors of Systolic BP (mmHg) 149.3 (19.8) 150.1 (20.4) renal outcomes, such as blood pressure and urinary albumin b Diastolic BP (mmHg) 81.2 (10.7) 79.3 (10.4) excretion we performed a sensitivity analysis in which we Urinary ACR (mg/mmol), 1095 (407-22-5) 1228 (454-2571) matched patients based on their propensity score of developing median (IQR) –1 –2 b eGFR (mlmin 1.73 m ) 38.1 (14.2) 32.9 (13.2) serum potassium ≥5.0 mmol/l. The propensity score was obtained by performing a logistic regression model with serum Data are presented as means (SD) unless otherwise indicated. potassium ≥5.0 mmol/l as an outcome. The risk of renal p<0.05 between patients with K ≥5.0 mmol/l and those with K outcomes was presented by hazard ratios (HR) with 95% <5.0 mmol/l at month 6. confidence intervals (95% CI). Analyses were conducted with BP, blood pressure; IQR, interquartile range SPSS version 16.0 software. remained relatively stable during follow-up (Fig. 1). In Results contrast, in the placebo group, the mean potassium level decreased gradually from 4.62 mmol/l at baseline to Serum potassium over time and characteristics of the study 4.56 mmol/l at month 6, and remained relatively stable population In the whole population at month 6, 928 thereafter. (69.4%) patients had a serum potassium <5.0 mmol/ The percentage of patients with month 6 serum potassium l (normal value) while 410 (30.6%) patients had month 6 levels ≥5.0 mmol/l and ≥5.5 mmol/l increased from 167 serum potassium ≥5.0 mmol/l (Table 1). In the losartan (22.2%) at baseline to 259 (38.4%) and 22 (2.9%) at baseline group, mean potassium level significantly increased from to 73 (10.8%) at month 6, respectively in patients on losartan, 4.59 mmol/l at baseline to 4.79 mmol/l at month 6, and while in those on placebo it decreased from 200 (26.2%) to Diabetologia (2011) 54:44–50 47 4.9 Table 2 Baseline multivariate predictors of incident drug induced serum potassium ≥5.0 mmol/l at month 6 4.8 Risk marker OR (95% CI) χ p value 4.7 Losartan treatment 2.80 (2.02–3.88) 38.3 <0.001 Serum potassium (mmol/l) 2.30 (1.53–3.44) 26.2 <0.001 4.6 –1 –2 eGFR, (mlmin 1.73 m ) 0.98 (0.97–0.99) 6.2 0.013 α-Blocker use 0.68 (0.46–1.01) 3.6 0.058 4.5 Loop diuretic use 0.75 (0.53–1.04) 3.0 0.085 Month 6 change eGFR 1.02 (0.99–1.05) 2.9 0.086 4.4 –1 –2 0 6 12 18 24 30 36 42 48 (mlmin 1.73 m ) Time of study (months) Age (years) 1.02 (0.99–1.04) 2.2 0.141 Haemoglobin (g/l) 0.94 (0.85–1.04) 1.5 0.228 Fig. 1 Mean serum potassium level during follow-up among patients Diastolic blood pressure 0.99 (0.98–1.01) 1.3 0.252 who were assigned to receive losartan or placebo. Bars represent (mmHg) standard errors. Continuous line, losartan; dashed line, placebo Log-transformed ACR, 1.06 (0.89–1.26) 0.4 0.541 log unit mg/mmol 151 (22.8%) and from 35 (4.6%) to 34 (5.1%), respectively Thiazide use 0.82 (0.53–1.27) 0.8 0.372 (Fig. 2a, b). Predictors are ordered by decreasing significance based on χ values Patients with serum potassium levels ≥5.0 mmol/l at Presented risk markers were selected for multivariate analysis if an month 6 were more likely to have higher baseline serum association with serum potassium ≥5.0 mmol/l was demonstrated in potassium levels, higher ACR, lower diastolic blood univariate analyses. Risk markers are ordered according the χ values pressure and lower haemoglobin levels compared with patients with serum potassium <5.0 mmol/l (Table 1). The use of losartan was more common, while the use of thiazide from serum potassium ≥5.0 mmol/l and further increased at diuretics and α-blockers was less common in patients with serum potassium ≥5.5 mmol/l during follow-up (HR 1.39; serum potassium ≥5.0 mmol/l. 95% CI 1.07–1.80 and HR 1.77; 95% CI 1.22–2.56, respectively). However several other factors also explained Predictors of incident serum potassium ≥5.0 mmol/l at the progressive loss of renal function such as age, eGFR, month 6 In testing in multivariate analysis which baseline and ACR. The most important question was therefore variables are related to increased serum potassium whether the progressive nature of renal endpoints in ≥5.0 mmol/l at month 6, we found that the strongest patients with serum potassium ≥5.0 mmol/l is independent baseline predictors were losartan therapy (OR 2.81; 95% CI of other factors, and most importantly, by the prevailing 2.03–3.89) and serum potassium (OR 2.26; 95% 1.51– renal function, as patients with low eGFR are more prone to 3.37). In contrast, a decreased eGFR was associated with an develop high serum potassium levels. After adjustment for increased risk of high serum potassium (Table 2). other risk factors, month 6 serum potassium ≥5.0 mmol/l was associated with a 22% increased risk for developing Month 6 serum potassium and renal outcomes Serum adverse renal outcomes (HR 1.22; 95% CI 1.00–1.50). potassium level was associated with a higher risk of the Further analysis revealed that this increased risk was merely composite renal outcome of DSCR or ESRD. As observed attributed to patients with persistent drug-induced serum in Fig. 3a, the risk already started to significantly increase potassium ≥5.0 mmol/l both at month 6 and month 9 (HR 1.56; 95% CI 1.09–2.21) (Table 3). In the second approach we assessed the association ab between the mean serum potassium level during follow-up 40 with renal outcomes. The relationship between the mean serum potassium level during follow-up displayed a similar 25 pattern with renal outcomes as the month 6 serum potassium level (Fig. 3b). After controlling for potential 10 confounders, the analyses revealed that patients who achieved a mean serum potassium ≥5.0 mmol/l during 0 0 Losartan Placebo Losartan Placebo follow-up had a 43% higher risk of the composite endpoint of DSCR or ESRD (HR 1.36; 95% CI 1.11–1.67). Fig. 2 Proportion of patients with serum potassium ≥5.0 mmol/l (a) The sensitivity analysis in 712 patients matched per and ≥5.5 mmol/l (b) at baseline (black bars) and month 6 (white bars) among patients assigned to losartan and placebo propensity score showed similar detrimental effects of Patients with serum potassium Serum potassium (mmol/l) ≥5.0 mmol/l (n) Patients with serum potassium ≥5.0 mmol/l (n) 48 Diabetologia (2011) 54:44–50 a and counteract the beneficial renoprotective effects of losartan. The increase in the renal risk appeared to be 2.5 independent of other important renal risk factors, such as blood pressure, eGFR and ACR. Thus, although the RENAAL trial has clearly shown that losartan is a renopro- 1.5 tective drug, under this protection a renal damaging effect is hiding in those individuals in whom losartan induces high serum potassium levels. 0.5 The effects of the ARB losartan on serum potassium are in line with other studies. In patients with diabetes, either <3.5 3.5–4.0 4.0–4.5 4.5–5.0 5.0–5.5 ≥5.5 addition or administration of an ARB increases the n=25 n=149 n=361 n=474 n=246 n=83 Serum potassium at month 6 (mmol/l) incidence of hyperkalaemia, independent of renal function 4 [8]. Also, in patients with heart failure, addition of an ARB or aldosterone antagonist to baseline RAAS inhibitor 3.5 therapy increases the risk of hyperkalaemia [9, 12]. In contrast, in non-diabetic patients addition of RAAS- 2.5 inhibitors poses a minimal risk of hyperkalaemia as long as renal function is relatively preserved [13–17]. It appears 1.5 that the risk of hyperkalaemia is particularly elevated in patients with underlying predisposing disorders, such as 0.5 diabetes and renal insufficiency, and in patients who receive 0 combined RAAS therapy. <3.5 3.5–4.0 4.0–4.5 4.5–5.0 5.0–5.5 ≥5.5 n=11 n=110 n=404 n=606 n=303 n=48 The mechanism via which ARB treatment induces elevations in serum potassium levels has already been Mean serum potassium during follow-up(mmol/l) Fig. 3 Month 6 serum potassium level (a) and mean serum potassium (b) and the risk for the composite renal endpoint (DSCR or ESRD). Table 3 Persistent and single elevated serum potassium ≥5.0 mmol/l Bars represent 95% CI and their association with the risk for DSCR or ESRD Risk factors HR (95% CI) χ p value increased serum potassium ≥5.0 mmol/l on renal outcomes b Drug induced persistent serum 1.54 (1.07–2.22) 5.4 0.020 (HR 1.32; 1.03–1.70). There was no heterogeneity between potassium ≥5.0 mmol/l (month 6 and 9) increased serum potassium and eGFR (p=0.132). Single elevated serum potassium 1.26 (0.93–1.70) 2.2 0.142 ≥5.0 mmol/l (month 6 or 9) Effect of serum potassium ≥5.0 mmol/l on the renoprotection Age 0.97 (0.96–1.00) 2.3 0.126 induced by losartan To examine to what extent the increase Race (reference: White) –– – in potassium influences the renoprotective effect afforded Black 2.13 (146–3.10) 15.6 <0.001 by losartan, we analysed the impact of an increase in serum Asian 1.42 (1.01–1.99) 4.0 0.046 potassium on the losartan treatment effect. When the Other 1.62 (1.18–2.21) 9.0 0.003 treatment effect on losartan was adjusted for the residual eGFR 0.96 (0.95–0.97) 46.6 <0.001 potassium level (last potassium level measured prior to the Systolic blood pressure 1.01 (1.00–1.02) 7.2 0.008 renal endpoint), the treatment effect of losartan on the Diastolic blood pressure 0.99(0.98–1.01) 1.4 0.233 DSCR or ESRD endpoint increased from 21% (6–34%) to ACR 3.75 (3.12–4.51) 196.8 <0.001 35% (20–48%). This finding suggests that the effect of Treatment (losartan/placebo) 0.92 (0.71–1.20) 0.4 0.538 losartan on serum potassium offsets the renoprotective effect of losartan. Essentially similar results were obtained for the individual compo- nents of the endpoint (data not shown) Persistent elevated serum potassium defined as drug induced serum potassium ≥5.0 mmol/l at month 6 and 9 Discussion Single elevated measurement defined as serum potassium ≥5.0 mmol/l at month 6 or 9 In this study, we showed that treatment with losartan There was no interaction between treatment groups and high increased the serum potassium concentration. We further- potassium at month 6 and 9 (p=0.284) indicating that the association more demonstrated that the occurrence of high serum between high potassium and renal outcome are consistent across both treatment groups potassium levels increased the risk of adverse renal outcomes HR for DSCR or ESRD HR for DSCR or ESRD Diabetologia (2011) 54:44–50 49 described [6]. In short, potassium excretion is mainly individuals with high serum potassium at both visit 6 and 9. regulated by serum aldosterone and sodium delivery to This implies that elevation in serum potassium level needs the distal nephron. Blocking the effects of angiotensin II by particular attention and appropriate management if it is RAAS inhibitors decreases aldosterone production and confirmed at a follow-up visit. In addition, our data on the consequently induces hyperkalaemia. Patients with diabetes relationship between the mean potassium level during are particularly susceptible to the hyperkalaemic effects of follow-up, which reflects the exposure to a high serum RAAS inhibitors as their RAAS activity is already sup- potassium load during a definitive period of time more pressed. Several factors may account for this, such as an accurately than a single value, and renal outcomes displayed impaired conversion of pro-renin to renin [18] or volume a similar association between increased serum potassium and expansion with subsequent increase in circulating atrial adverse renal outcomes. These results are in clear contrast to natriuretic peptide levels and suppression of plasma renin a recent report from Weir et al. who suggested that the activity [19]. changes in serum potassium concentration observed during In previous studies no data are available on the effect of RAAS therapy are unlikely to be clinically significant [23]. high serum potassium levels on renal outcomes. Our study We recommend not down-playing modest changes in serum showed for the first time that increased serum potassium potassium as they independently indicate increased risk for concentrations ≥5.0 mmol/l is associated with a clearly renal outcomes in the long-term. increased risk of DSCR or ESRD, independent of renal Hyperkalaemia is usually defined by a serum potassium function and other important predictors of renal outcomes. concentration ≥5.5 mmol/l. Our results demonstrated a The pathophysiological mechanism whereby increased distinct risk of adverse renal events in not only patients serum potassium levels affect renal outcomes is not well with serum potassium concentration ≥5.5 mmol/l, but also known. It is likely that individuals with persistent drug in patients with potassium concentrations ≥5.0 mmol/l induced hyperkalaemia are resistant against the kaliuretic during follow-up and at month 6. These results have important effects of aldosterone. It has indeed been shown that the consequences for clinical practice as they indicate that the risk trans-tubular potassium gradient, as measure for aldosterone for renal events already starts to increase within ranges that are bioactivity with respect to its kaliuretic response, is currently considered to be normal. Particular caution is needed decreased in individuals with drug induced hyperkalaemia when prescribing a second RAAS agent as the combination of despite increased plasma aldosterone levels [20]. Conse- RAAS inhibitors may lead to even higher serum potassium quently, these individuals are continuously exposed to the levels [24, 25]. In patients with high potassium levels at start deleterious effects of aldosterone on renal tissue. Another of ARB therapy, it may be initiated with a low dose, and potential mechanism could be that a vicious cycle exits increased to a higher dose if serum potassium levels do not increase above a therapeutic threshold. between renal function and potassium levels that usually takes place in disorders that affect both tubular dysfunction Would improved management of high serum potassium and release of renin. On the one hand, a decrease in renal levels lead to better renal outcomes associated with RAAS perfusion and the start of tubulointerstitial damage may blockade? Our study does not directly answer this question. impair renal potassium excretion, even though renal However, when we adjusted the treatment effects by the function is only mildly depressed. This situation may lead residual serum potassium levels measured prior to the renal to an imbalance in renal potassium/sodium handling that endpoint the renoprotective effects associated with losartan may further damage the tubules, thereby subsequently use markedly improved. It is therefore tempting to contributing to a further decline in renal function [7]. speculate that management of high serum potassium levels Several reports have drawn attention to spurious hyper- improves the renoprotective effects of losartan. Further kalaemia (pseudohyperkalaemia) as a common problem in prospective randomised controlled trials are needed to clinical care [21, 22]. The reasons for spurious hyper- confirm this finding. kalaemia are multiple, such as inappropriate phlebotomy Our study has some limitations. First, this is a post-hoc technique (e.g. requesting patient to fist clench to facilitate analysis, and as such may be subject to confounding. To venesection), improper sample storage (i.e. cold storage or control for confounding we adjusted for a wide range of too long storage causing deterioration of the sample speci- clinical variables, both at baseline and follow-up. It is men) or contamination with anticoagulant from another nevertheless possible that residual confounding remained sample (ethylene diamine tetra-acetic acid [EDTA]contami- even in our multivariate adjusted analysis. Also, we nation) [21, 22]. As it is unlikely that individuals with a performed two additional sensitivity analyses matching single erroneous potassium measurement are at increased patients on their eGFR and propensity score to ensure that risk, we classified patients in those who had persistent high renal events are independent of important predictors of serum potassium levels at month 6 and 9. As expected, the increased serum potassium. Second, although the RENAAL increased risk for renal outcomes was particularly marked in trial included a broad range of patients with type 2 diabetes 50 Diabetologia (2011) 54:44–50 10. Brenner BM, Cooper ME, de Zeeuw D et al (2000) The losartan and nephropathy, the findings cannot be extrapolated to renal protection study—rationale, study design and baseline other populations. characteristics of RENAAL (Reduction of Endpoints in NIDDM In conclusion, in this study we found that treatment with with the Angiotensin II Antagonist Losartan). J Renin Angiotensin the ARB losartan is associated with a high risk of serum Aldosterone Syst 1:328–335 11. Kratz A, Ferraro M, Sluss PM, Lewandrowski KB (2004) Case potassium level elevation in patients with type 2 diabetes records of the Massachusetts General Hospital. Weekly clinico- and nephropathy. This elevated serum potassium level is in pathological exercises. Laboratory reference values. N Engl J Med turn associated with an increased risk of renal outcomes and 351:1548–1563 offsets the renoprotective effects of losartan. Whether 12. Pitt B, Bakris G, Ruilope LM, DiCarlo L, Mukherjee R (2008) Serum potassium and clinical outcomes in the Eplerenone Post- additional management of elevated serum potassium would Acute Myocardial Infarction Heart Failure Efficacy and Survival further increase the renal protective properties of losartan is Study (EPHESUS). Circulation 118:1643–1650 an important clinical question. 13. Weinberg JM, Appel LJ, Bakris G et al (2009) Risk of hyperkalemia in nondiabetic patients with chronic kidney disease Acknowledgements We acknowledge the supportive role of all receiving antihypertensive therapy. Arch Intern Med 169:1587– RENAAL investigators, support staff and participating patients. 1594 14. 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Ann renin–angiotensin–aldosterone system: balancing risk and benefit. Clin Biochem 45:266–269 Circulation 118:1609–1611 22. Cornes MP, Ford C, Gama R (2008) Spurious hyperkaliemia due 6. van Nieuwkoop C, Ijpelaar DH, Bolk JH (2007) Treating to EDTA contamination: common and not always easy to identify. proteinuria in a diabetic patient despite hyperkaliemia due to Ann Clin Biochem 45:601–603 hyporeninaemic hypoaldosteronism. Neth J Med 65:75–77 23. Weir MR, Rolfe M (2010) Potassium homeostasis and renin– 7. Palmer BF (2004) Managing hyperkalemia caused by inhibitors of angiotensin–aldosterone system inhibitors. Clin J Am Soc the renin–angiotensin–aldosterone system. N Engl J Med 351: Nephrol 5:531–548 24. Vogt L, Navis G, de Zeeuw D (2005) Individual titration for 585–592 maximal blockade of the renin-angiotensin system in proteinuric 8. Takaichi K, Takemoto F, Ubara Y, Mori Y (2007) Analysis of patients: a feasible strategy? J Am Soc Nephrol 16(Suppl 1):S53– factors causing hyperkalemia. Intern Med 46:823–829 S57 9. Desai AS, Swedberg K, McMurray JJ et al (2007) Incidence and 25. Frimodt-Moller M HNA, Strandgaard S, Kamper AL (2009) predictors of hyperkalemia in patients with heart failure: an Feasibility of combined treatment with enalapril and candesartan analysis of the CHARM Program. J Am Coll Cardiol 50:1959– 1966 in advanced chronic kidney disease. Nephrol Dial Transplant http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Diabetologia Pubmed Central

Increased serum potassium affects renal outcomes: a post hoc analysis of the Reduction of Endpoints in NIDDM with the Angiotensin II Antagonist Losartan (RENAAL) trial

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Diabetologia (2011) 54:44–50 DOI 10.1007/s00125-010-1922-6 ARTICLE Increased serum potassium affects renal outcomes: a post hoc analysis of the Reduction of Endpoints in NIDDM with the Angiotensin II Antagonist Losartan (RENAAL) trial Y. Miao & D. Dobre & H. J. Lambers Heerspink & B. M. Brenner & M. E. Cooper & H-H. Parving & S. Shahinfar & D. Grobbee & D. de Zeeuw Received: 24 June 2010 /Accepted: 1 September 2010 /Published online: 30 September 2010 # The Author(s) 2010. This article is published with open access at Springerlink.com Abstract NIDDM with the Angiotensin II Antagonist Losartan Aims/hypothesis To assess the effect of an angiotensin (RENAAL) study. Renal outcomes were defined as a compos- receptor blocker (ARB) on serum potassium and the effect ite of doubling of serum creatinine or end-stage renal disease. of a serum potassium change on renal outcomes in patients Results At month 6, 259 (38.4%) and 73 (10.8%) patients with type 2 diabetes and nephropathy. in the losartan group and 151 (22.8%) and 34 (5.1%) patients Methods We performed a post hoc analysis in patients with in the placebo group had serum potassium ≥5.0 mmol/l and type 2 diabetes participating in the Reduction of Endpoints in ≥5.5 mmol/l, (p<0.001), respectively. Losartan was an independent predictor for serum potassium ≥5.0 mmol/l at month 6 (OR 2.8; 95% CI 2.0–3.9). Serum potassium at : : : Y. Miao D. Dobre H. J. Lambers Heerspink (*) D. de Zeeuw month 6 ≥ 5.0 mmol/l was in turn associated with increased Department of Clinical Pharmacology, risk for renal events (HR 1.22; 95% CI 1.00–1.50), University Medical Centre Groningen, independent of other risk factors. Adjustment of the overall Antonius Deusinglaan 1, 9713 AV Groningen, the Netherlands treatment effects for serum potassium augmented losartan’s e-mail: [email protected] renoprotective effect from 21% (6–34%) to 35% (20–48%), suggesting that the renoprotective effects of losartan are B. M. Brenner offset by its effect on serum potassium. Brigham and Women’s Hospital and Harvard School of Medicine, Boston, MA, USA Conclusions/interpretation In this study, we found that treatment with the ARB losartan is associated with a high M. E. Cooper risk of increased serum potassium levels, which is in turn Baker IDI Heart and Diabetes Research Institute, associated with an increased risk of renal outcomes in Melbourne, VIC, Australia patients with diabetes and nephropathy. Whether additional H.-H. Parving management of high serum potassium would further Department of Medical Endocrinology, increase the renal protective properties of losartan is an University Hospital of Copenhagen, important clinical question. Copenhagen, Denmark H.-H. Parving . . Keywords Angiotensin receptor blocker Losartan The Faculty of Health Science, Aarhus University, . . Nephropathy Potassium Type 2 diabetes Aarhus, Denmark S. Shahinfar Abbreviations Shahinfar Consulting, The Children’s Hospital of Philadelphia, Philadelphia, PA, USA ACR Albumin:creatinine ratio ARB Angiotensin receptor blocker D. Grobbee CV Cardiovascular Julius Center for Health Science and Primary Care, DSCR Doubling of serum creatinine University Medical Center Utrecht, Utrecht, the Netherlands ESRD End-stage renal disease Diabetologia (2011) 54:44–50 45 eGFR Estimated glomerular filtration rate 250 centres in 28 countries and involved 1,513 patients. NIDDM Non-insulin-dependent diabetes mellitus The study design, the inclusion/exclusion criteria, and the RAAS Renin–angiotensin–aldosterone system treatment protocol have been reported previously [3, 10]. In RENAAL Reduction of Endpoints in NIDDM with the short, after a 6-week screening phase, patients were Angiotensin II Antagonist Losartan randomised to either losartan 50 mg (titrated to 100 mg after 4 weeks) or placebo. Additional antihypertensive medications (calcium channel blockers, β-blockers, centrally Introduction acting agents, and diuretics, excluding angiotensin- converting enzyme inhibitors or other angiotensin receptor Diabetic nephropathy is the leading cause of end-stage renal antagonists) were permitted to reach the blood pressure goal disease (ESRD) in western societies. As the prevalence of of <140/90 mmHg (systolic/diastolic). All patients signed diabetes is increasing, ESRD accounts for substantial informed consent before enrolment, and the local Institutional morbidity and mortality [1, 2]. Review Board of each participating centre approved the Angiotensin receptor blockers (ARBs) have several study. The mean duration of follow-up was 3.4 years. Blood important beneficial effects in patients with diabetes and pressure, serum potassium level, serum creatinine and nephropathy, such as decreasing systemic blood pressure albumin:creatinine ratio were measured at first month, third and reducing albuminuria. These effects are related to long- month, and then every 3 months until the end of the study. term renal protection [3, 4]. However, these beneficial effects are accompanied by a so-called side effect of ARBs, Change in serum potassium and outcomes In this study, we induction of a rise in serum potassium levels even leading performed a post hoc analysis of all individuals with to hyperkalaemia. This situation may in turn lead to potassium measurements included in the RENAAL trial. detrimental long-term effects [5]. The risk of hyperkalaemia We assessed the relationship between serum potassium is particularly high in patients with diabetes as these level and renal outcomes in two ways. First, we assessed patients already have reduced aldosterone production the relationship between serum potassium and renal out- secondary to renin deficiency, the so-called hyporeninemic comes at month 6. The month 6 values were chosen as the hypoaldosteronism syndrome [6, 7]. Diabetes, low renal treatment effects were considered to be fully present and function and use of renin–angiotensin–aldosterone system relatively few renal events occurred before month 6. The (RAAS) inhibitors are independent factors that increase month 6 serum potassium level was classified into two serum potassium level. In combination, these factors pose categories: <5.0 mmol/l (reference, and ≥5.0 mmol/l [11]. patients at even higher risk of hyperkalaemia [8]. We selected this threshold (instead of the clinical accepted Increased serum potassium levels are associated with value of 5.5 mmol/l) because the risk of adverse renal increased risk for cardiovascular (CV) morbidity and outcomes started to increase from 5.0 mmol/l, and a small mortality. Hyperkalaemia as a result of ARB therapy has number of patients reached serum potassium levels been related to worse CV outcomes [9]. However, the ≥5.5 mmol/l in our population. As a single elevated relationship between change in serum potassium levels in potassium measurement may be an erroneous finding, we response to RAAS therapy and renal outcomes is not well also assessed the relationship between persistent drug- established. Therefore, we assessed the relationship be- induced serum potassium at months 6 and 9 and its tween ARB treatment, serum potassium levels and renal association with renal outcome. These individuals were outcomes in patients with type 2 diabetes and nephropathy either compared with those with a single elevated serum participating in the Reduction of Endpoints in NIDDM with potassium measurement at month 6 or 9, or compared with the Angiotensin II Antagonist Losartan (RENAAL) trial those without increases in serum potassium above (Clinical trials.gov identifier: NCT 00308347). 5.0 mmol/l during the first 9 months of follow-up. In the second approach, we calculated the average serum potassium concentration during follow-up and explored the Methods relationship between the average serum potassium level during follow-up with renal outcomes. The average serum Study design The RENAAL trial was a multinational, potassium concentration, as well as average levels of other randomised, double-blind trial that compared the effects of relevant covariates was calculated as the mean of the first losartan vs placebo in addition to conventional anti- month and each consecutive third month potassium value hypertensive medication in patients with type 2 diabetes until the occurrence of the renal event. This approach was and nephropathy. Patients had serum creatinine levels chosen as it more accurately reflects the risk of a participant between 115 and 265 μmol/l (133 to 265 μmol/l for men to exposure to a high serum potassium load for a definite weighing more than 60 kg). The study was performed in period of time than a single elevated measure. Renal out- 46 Diabetologia (2011) 54:44–50 Table 1 Baseline and month 6 characteristics of the whole population comes were defined as a composite of doubling of serum creatinine (DSCR) or ESRD, and as DSCR and ESRD Serum potassium at month 6 (mmol/l) individually. All endpoints were adjudicated by a blinded Baseline characteristic <5.0 (n=928) ≥5.0 mmol/l (n=410) endpoint committee using rigorous guideline definitions. Age ( years) 60.0 (7.6) 60.4 (7.1) Statistical analysis Differences among patient subgroups Male, n (%) 593 (63.9) 248 (60.5) were evaluated by using chi-squared test or t test, as Race, n (%) appropriate. Mean serum potassium level at each visit White 449 (48.4) 198 (48.3) during follow-up, as well as the proportion of patients with Black 161 (17.3) 40 (9.8) month 6 potassium level ≥5.0 mmol/l and ≥5.5 mmol/l was Hispanic 144 (15.5) 98 (23.9) calculated in both the losartan and placebo group. To Asian 163 (17.6) 68 (16.6) identify the predictors of increased serum potassium at Other 11 (1.2) 6 (1.5) month 6, a multivariate logistic regression model was used. Systolic BP (mmHg) 152.1 (19.2) 153.2 (19.7) Baseline characteristics that showed an association with Diastolic BP (mmHg) 82.9 (10.5) 81.3 (10.1) serum potassium ≥5.0 mmol/l (p<0.2) at univariate analysis Urinary ACR (mg/mmol), 129 (59–263) 155 (76–327) were selected for the multivariate logistic model. The median (IQR) multivariate logistic model was adjusted for age, treatment Serum creatinine (μmol/l) 161 (41.6) 173 (42.9) assignment, serum potassium, diastolic blood pressure, –1 –2 b eGFR (mlmin 1.73 m ) 40.9 (12.2) 37.0 (11.9) estimated glomerular filtration rate (eGFR), month 6 HbA , (%) 8.4 (1.6) 8.4 (1.6) 1c change in eGFR from baseline, urinary albumin:creatinine Haemoglobin (g/l) 127 (18) 121 (18) ratio (ACR), prescription of α-blockers, thiazide diuretics, Serum potassium (mmol/l) 4.5 (0.5) 4.9 (0.4) loop diuretics, and haemoglobin. To assess the association Serum potassium ≥5.0 140 (15.1) 187 (45.6) between change in serum potassium from baseline to mmol/l, n (%) month 6 and renal outcomes, a multivariate Cox proportional Treatment, n (%) hazard model was used. The linearity of baseline and follow- Losartan 416 (44.8) 259 (63.2) up continuous variables was assessed. If the linearity was not Thiazide diuretics 161 (17.3) 45 (11.0) demonstrated, the variable was recoded as a categorical K-sparing diuretics 24 (2.6) 7 (1.7) variable. In the final Cox model we adjusted for the following Loop diuretics 426 (45.9) 177 (43.2) baseline variables: age, sex, race, treatment, eGFR, follow-up Calcium channel blocker 679 (73.2) 291 (71.0) systolic blood pressure, diastolic blood pressure, ACR. We α-Blockers 239 (25.8) 81 (19.8) checked for an interaction between serum potassium levels at β-Blockers 173 (18.6) 76 (18.5) month 6 and eGFR. To ensure that our results are not affected Month 6 characteristics by baseline renal function and other important predictors of Systolic BP (mmHg) 149.3 (19.8) 150.1 (20.4) renal outcomes, such as blood pressure and urinary albumin b Diastolic BP (mmHg) 81.2 (10.7) 79.3 (10.4) excretion we performed a sensitivity analysis in which we Urinary ACR (mg/mmol), 1095 (407-22-5) 1228 (454-2571) matched patients based on their propensity score of developing median (IQR) –1 –2 b eGFR (mlmin 1.73 m ) 38.1 (14.2) 32.9 (13.2) serum potassium ≥5.0 mmol/l. The propensity score was obtained by performing a logistic regression model with serum Data are presented as means (SD) unless otherwise indicated. potassium ≥5.0 mmol/l as an outcome. The risk of renal p<0.05 between patients with K ≥5.0 mmol/l and those with K outcomes was presented by hazard ratios (HR) with 95% <5.0 mmol/l at month 6. confidence intervals (95% CI). Analyses were conducted with BP, blood pressure; IQR, interquartile range SPSS version 16.0 software. remained relatively stable during follow-up (Fig. 1). In Results contrast, in the placebo group, the mean potassium level decreased gradually from 4.62 mmol/l at baseline to Serum potassium over time and characteristics of the study 4.56 mmol/l at month 6, and remained relatively stable population In the whole population at month 6, 928 thereafter. (69.4%) patients had a serum potassium <5.0 mmol/ The percentage of patients with month 6 serum potassium l (normal value) while 410 (30.6%) patients had month 6 levels ≥5.0 mmol/l and ≥5.5 mmol/l increased from 167 serum potassium ≥5.0 mmol/l (Table 1). In the losartan (22.2%) at baseline to 259 (38.4%) and 22 (2.9%) at baseline group, mean potassium level significantly increased from to 73 (10.8%) at month 6, respectively in patients on losartan, 4.59 mmol/l at baseline to 4.79 mmol/l at month 6, and while in those on placebo it decreased from 200 (26.2%) to Diabetologia (2011) 54:44–50 47 4.9 Table 2 Baseline multivariate predictors of incident drug induced serum potassium ≥5.0 mmol/l at month 6 4.8 Risk marker OR (95% CI) χ p value 4.7 Losartan treatment 2.80 (2.02–3.88) 38.3 <0.001 Serum potassium (mmol/l) 2.30 (1.53–3.44) 26.2 <0.001 4.6 –1 –2 eGFR, (mlmin 1.73 m ) 0.98 (0.97–0.99) 6.2 0.013 α-Blocker use 0.68 (0.46–1.01) 3.6 0.058 4.5 Loop diuretic use 0.75 (0.53–1.04) 3.0 0.085 Month 6 change eGFR 1.02 (0.99–1.05) 2.9 0.086 4.4 –1 –2 0 6 12 18 24 30 36 42 48 (mlmin 1.73 m ) Time of study (months) Age (years) 1.02 (0.99–1.04) 2.2 0.141 Haemoglobin (g/l) 0.94 (0.85–1.04) 1.5 0.228 Fig. 1 Mean serum potassium level during follow-up among patients Diastolic blood pressure 0.99 (0.98–1.01) 1.3 0.252 who were assigned to receive losartan or placebo. Bars represent (mmHg) standard errors. Continuous line, losartan; dashed line, placebo Log-transformed ACR, 1.06 (0.89–1.26) 0.4 0.541 log unit mg/mmol 151 (22.8%) and from 35 (4.6%) to 34 (5.1%), respectively Thiazide use 0.82 (0.53–1.27) 0.8 0.372 (Fig. 2a, b). Predictors are ordered by decreasing significance based on χ values Patients with serum potassium levels ≥5.0 mmol/l at Presented risk markers were selected for multivariate analysis if an month 6 were more likely to have higher baseline serum association with serum potassium ≥5.0 mmol/l was demonstrated in potassium levels, higher ACR, lower diastolic blood univariate analyses. Risk markers are ordered according the χ values pressure and lower haemoglobin levels compared with patients with serum potassium <5.0 mmol/l (Table 1). The use of losartan was more common, while the use of thiazide from serum potassium ≥5.0 mmol/l and further increased at diuretics and α-blockers was less common in patients with serum potassium ≥5.5 mmol/l during follow-up (HR 1.39; serum potassium ≥5.0 mmol/l. 95% CI 1.07–1.80 and HR 1.77; 95% CI 1.22–2.56, respectively). However several other factors also explained Predictors of incident serum potassium ≥5.0 mmol/l at the progressive loss of renal function such as age, eGFR, month 6 In testing in multivariate analysis which baseline and ACR. The most important question was therefore variables are related to increased serum potassium whether the progressive nature of renal endpoints in ≥5.0 mmol/l at month 6, we found that the strongest patients with serum potassium ≥5.0 mmol/l is independent baseline predictors were losartan therapy (OR 2.81; 95% CI of other factors, and most importantly, by the prevailing 2.03–3.89) and serum potassium (OR 2.26; 95% 1.51– renal function, as patients with low eGFR are more prone to 3.37). In contrast, a decreased eGFR was associated with an develop high serum potassium levels. After adjustment for increased risk of high serum potassium (Table 2). other risk factors, month 6 serum potassium ≥5.0 mmol/l was associated with a 22% increased risk for developing Month 6 serum potassium and renal outcomes Serum adverse renal outcomes (HR 1.22; 95% CI 1.00–1.50). potassium level was associated with a higher risk of the Further analysis revealed that this increased risk was merely composite renal outcome of DSCR or ESRD. As observed attributed to patients with persistent drug-induced serum in Fig. 3a, the risk already started to significantly increase potassium ≥5.0 mmol/l both at month 6 and month 9 (HR 1.56; 95% CI 1.09–2.21) (Table 3). In the second approach we assessed the association ab between the mean serum potassium level during follow-up 40 with renal outcomes. The relationship between the mean serum potassium level during follow-up displayed a similar 25 pattern with renal outcomes as the month 6 serum potassium level (Fig. 3b). After controlling for potential 10 confounders, the analyses revealed that patients who achieved a mean serum potassium ≥5.0 mmol/l during 0 0 Losartan Placebo Losartan Placebo follow-up had a 43% higher risk of the composite endpoint of DSCR or ESRD (HR 1.36; 95% CI 1.11–1.67). Fig. 2 Proportion of patients with serum potassium ≥5.0 mmol/l (a) The sensitivity analysis in 712 patients matched per and ≥5.5 mmol/l (b) at baseline (black bars) and month 6 (white bars) among patients assigned to losartan and placebo propensity score showed similar detrimental effects of Patients with serum potassium Serum potassium (mmol/l) ≥5.0 mmol/l (n) Patients with serum potassium ≥5.0 mmol/l (n) 48 Diabetologia (2011) 54:44–50 a and counteract the beneficial renoprotective effects of losartan. The increase in the renal risk appeared to be 2.5 independent of other important renal risk factors, such as blood pressure, eGFR and ACR. Thus, although the RENAAL trial has clearly shown that losartan is a renopro- 1.5 tective drug, under this protection a renal damaging effect is hiding in those individuals in whom losartan induces high serum potassium levels. 0.5 The effects of the ARB losartan on serum potassium are in line with other studies. In patients with diabetes, either <3.5 3.5–4.0 4.0–4.5 4.5–5.0 5.0–5.5 ≥5.5 addition or administration of an ARB increases the n=25 n=149 n=361 n=474 n=246 n=83 Serum potassium at month 6 (mmol/l) incidence of hyperkalaemia, independent of renal function 4 [8]. Also, in patients with heart failure, addition of an ARB or aldosterone antagonist to baseline RAAS inhibitor 3.5 therapy increases the risk of hyperkalaemia [9, 12]. In contrast, in non-diabetic patients addition of RAAS- 2.5 inhibitors poses a minimal risk of hyperkalaemia as long as renal function is relatively preserved [13–17]. It appears 1.5 that the risk of hyperkalaemia is particularly elevated in patients with underlying predisposing disorders, such as 0.5 diabetes and renal insufficiency, and in patients who receive 0 combined RAAS therapy. <3.5 3.5–4.0 4.0–4.5 4.5–5.0 5.0–5.5 ≥5.5 n=11 n=110 n=404 n=606 n=303 n=48 The mechanism via which ARB treatment induces elevations in serum potassium levels has already been Mean serum potassium during follow-up(mmol/l) Fig. 3 Month 6 serum potassium level (a) and mean serum potassium (b) and the risk for the composite renal endpoint (DSCR or ESRD). Table 3 Persistent and single elevated serum potassium ≥5.0 mmol/l Bars represent 95% CI and their association with the risk for DSCR or ESRD Risk factors HR (95% CI) χ p value increased serum potassium ≥5.0 mmol/l on renal outcomes b Drug induced persistent serum 1.54 (1.07–2.22) 5.4 0.020 (HR 1.32; 1.03–1.70). There was no heterogeneity between potassium ≥5.0 mmol/l (month 6 and 9) increased serum potassium and eGFR (p=0.132). Single elevated serum potassium 1.26 (0.93–1.70) 2.2 0.142 ≥5.0 mmol/l (month 6 or 9) Effect of serum potassium ≥5.0 mmol/l on the renoprotection Age 0.97 (0.96–1.00) 2.3 0.126 induced by losartan To examine to what extent the increase Race (reference: White) –– – in potassium influences the renoprotective effect afforded Black 2.13 (146–3.10) 15.6 <0.001 by losartan, we analysed the impact of an increase in serum Asian 1.42 (1.01–1.99) 4.0 0.046 potassium on the losartan treatment effect. When the Other 1.62 (1.18–2.21) 9.0 0.003 treatment effect on losartan was adjusted for the residual eGFR 0.96 (0.95–0.97) 46.6 <0.001 potassium level (last potassium level measured prior to the Systolic blood pressure 1.01 (1.00–1.02) 7.2 0.008 renal endpoint), the treatment effect of losartan on the Diastolic blood pressure 0.99(0.98–1.01) 1.4 0.233 DSCR or ESRD endpoint increased from 21% (6–34%) to ACR 3.75 (3.12–4.51) 196.8 <0.001 35% (20–48%). This finding suggests that the effect of Treatment (losartan/placebo) 0.92 (0.71–1.20) 0.4 0.538 losartan on serum potassium offsets the renoprotective effect of losartan. Essentially similar results were obtained for the individual compo- nents of the endpoint (data not shown) Persistent elevated serum potassium defined as drug induced serum potassium ≥5.0 mmol/l at month 6 and 9 Discussion Single elevated measurement defined as serum potassium ≥5.0 mmol/l at month 6 or 9 In this study, we showed that treatment with losartan There was no interaction between treatment groups and high increased the serum potassium concentration. We further- potassium at month 6 and 9 (p=0.284) indicating that the association more demonstrated that the occurrence of high serum between high potassium and renal outcome are consistent across both treatment groups potassium levels increased the risk of adverse renal outcomes HR for DSCR or ESRD HR for DSCR or ESRD Diabetologia (2011) 54:44–50 49 described [6]. In short, potassium excretion is mainly individuals with high serum potassium at both visit 6 and 9. regulated by serum aldosterone and sodium delivery to This implies that elevation in serum potassium level needs the distal nephron. Blocking the effects of angiotensin II by particular attention and appropriate management if it is RAAS inhibitors decreases aldosterone production and confirmed at a follow-up visit. In addition, our data on the consequently induces hyperkalaemia. Patients with diabetes relationship between the mean potassium level during are particularly susceptible to the hyperkalaemic effects of follow-up, which reflects the exposure to a high serum RAAS inhibitors as their RAAS activity is already sup- potassium load during a definitive period of time more pressed. Several factors may account for this, such as an accurately than a single value, and renal outcomes displayed impaired conversion of pro-renin to renin [18] or volume a similar association between increased serum potassium and expansion with subsequent increase in circulating atrial adverse renal outcomes. These results are in clear contrast to natriuretic peptide levels and suppression of plasma renin a recent report from Weir et al. who suggested that the activity [19]. changes in serum potassium concentration observed during In previous studies no data are available on the effect of RAAS therapy are unlikely to be clinically significant [23]. high serum potassium levels on renal outcomes. Our study We recommend not down-playing modest changes in serum showed for the first time that increased serum potassium potassium as they independently indicate increased risk for concentrations ≥5.0 mmol/l is associated with a clearly renal outcomes in the long-term. increased risk of DSCR or ESRD, independent of renal Hyperkalaemia is usually defined by a serum potassium function and other important predictors of renal outcomes. concentration ≥5.5 mmol/l. Our results demonstrated a The pathophysiological mechanism whereby increased distinct risk of adverse renal events in not only patients serum potassium levels affect renal outcomes is not well with serum potassium concentration ≥5.5 mmol/l, but also known. It is likely that individuals with persistent drug in patients with potassium concentrations ≥5.0 mmol/l induced hyperkalaemia are resistant against the kaliuretic during follow-up and at month 6. These results have important effects of aldosterone. It has indeed been shown that the consequences for clinical practice as they indicate that the risk trans-tubular potassium gradient, as measure for aldosterone for renal events already starts to increase within ranges that are bioactivity with respect to its kaliuretic response, is currently considered to be normal. Particular caution is needed decreased in individuals with drug induced hyperkalaemia when prescribing a second RAAS agent as the combination of despite increased plasma aldosterone levels [20]. Conse- RAAS inhibitors may lead to even higher serum potassium quently, these individuals are continuously exposed to the levels [24, 25]. In patients with high potassium levels at start deleterious effects of aldosterone on renal tissue. Another of ARB therapy, it may be initiated with a low dose, and potential mechanism could be that a vicious cycle exits increased to a higher dose if serum potassium levels do not increase above a therapeutic threshold. between renal function and potassium levels that usually takes place in disorders that affect both tubular dysfunction Would improved management of high serum potassium and release of renin. On the one hand, a decrease in renal levels lead to better renal outcomes associated with RAAS perfusion and the start of tubulointerstitial damage may blockade? Our study does not directly answer this question. impair renal potassium excretion, even though renal However, when we adjusted the treatment effects by the function is only mildly depressed. This situation may lead residual serum potassium levels measured prior to the renal to an imbalance in renal potassium/sodium handling that endpoint the renoprotective effects associated with losartan may further damage the tubules, thereby subsequently use markedly improved. It is therefore tempting to contributing to a further decline in renal function [7]. speculate that management of high serum potassium levels Several reports have drawn attention to spurious hyper- improves the renoprotective effects of losartan. Further kalaemia (pseudohyperkalaemia) as a common problem in prospective randomised controlled trials are needed to clinical care [21, 22]. The reasons for spurious hyper- confirm this finding. kalaemia are multiple, such as inappropriate phlebotomy Our study has some limitations. First, this is a post-hoc technique (e.g. requesting patient to fist clench to facilitate analysis, and as such may be subject to confounding. To venesection), improper sample storage (i.e. cold storage or control for confounding we adjusted for a wide range of too long storage causing deterioration of the sample speci- clinical variables, both at baseline and follow-up. It is men) or contamination with anticoagulant from another nevertheless possible that residual confounding remained sample (ethylene diamine tetra-acetic acid [EDTA]contami- even in our multivariate adjusted analysis. Also, we nation) [21, 22]. As it is unlikely that individuals with a performed two additional sensitivity analyses matching single erroneous potassium measurement are at increased patients on their eGFR and propensity score to ensure that risk, we classified patients in those who had persistent high renal events are independent of important predictors of serum potassium levels at month 6 and 9. As expected, the increased serum potassium. Second, although the RENAAL increased risk for renal outcomes was particularly marked in trial included a broad range of patients with type 2 diabetes 50 Diabetologia (2011) 54:44–50 10. Brenner BM, Cooper ME, de Zeeuw D et al (2000) The losartan and nephropathy, the findings cannot be extrapolated to renal protection study—rationale, study design and baseline other populations. characteristics of RENAAL (Reduction of Endpoints in NIDDM In conclusion, in this study we found that treatment with with the Angiotensin II Antagonist Losartan). J Renin Angiotensin the ARB losartan is associated with a high risk of serum Aldosterone Syst 1:328–335 11. Kratz A, Ferraro M, Sluss PM, Lewandrowski KB (2004) Case potassium level elevation in patients with type 2 diabetes records of the Massachusetts General Hospital. Weekly clinico- and nephropathy. This elevated serum potassium level is in pathological exercises. Laboratory reference values. N Engl J Med turn associated with an increased risk of renal outcomes and 351:1548–1563 offsets the renoprotective effects of losartan. Whether 12. Pitt B, Bakris G, Ruilope LM, DiCarlo L, Mukherjee R (2008) Serum potassium and clinical outcomes in the Eplerenone Post- additional management of elevated serum potassium would Acute Myocardial Infarction Heart Failure Efficacy and Survival further increase the renal protective properties of losartan is Study (EPHESUS). Circulation 118:1643–1650 an important clinical question. 13. Weinberg JM, Appel LJ, Bakris G et al (2009) Risk of hyperkalemia in nondiabetic patients with chronic kidney disease Acknowledgements We acknowledge the supportive role of all receiving antihypertensive therapy. Arch Intern Med 169:1587– RENAAL investigators, support staff and participating patients. 1594 14. Mitterbauer C, Heinze G, Kainz A, Kramar R, Horl WH, Duality of interest The RENAAL study was funded by Merck & Oberbauer R (2008) ACE-inhibitor or AT2-antagonist therapy of Co. B.M. Brenner, M.E. Cooper, D. de Zeeuw, H-H. Parving have renal transplant recipients is associated with an increase in received financial support from Merck for their participation in the serum potassium concentrations. Nephrol Dial Transplant Steering Committee. S. Shahinfar has been an employee of Merck. 23:1742–1746 15. Maddirala S, Khan A, Vincent A, Lau K (2008) Effect of angiotensin converting enzyme inhibitors and angiotensin receptor Open Access This article is distributed under the terms of the blockers on serum potassium levels and renal function in Creative Commons Attribution Noncommercial License which per- ambulatory outpatients: risk factors analysis. Am J Med Sci 336: mits any noncommercial use, distribution, and reproduction in any 330–335 medium, provided the original author(s) and source are credited. 16. Han SW, Won YW, Yi JH, Kim HJ (2007) No impact of hyperkaliemia with renin-angiotensin system blockades in main- tenance haemodialysis patients. Nephrol Dial Transplant 22:1150– References 17. Einhorn LM, Zhan M, Hsu VD et al (2009) The frequency of hyperkalemia and its significance in chronic kidney disease. Arch 1. Keane WF, Brenner BM, de Zeeuw D et al (2003) The risk of Intern Med 169:1156–1162 developing end-stage renal disease in patients with type 2 diabetes 18. Lush DJ, King JA, Fray JC (1993) Pathophysiology of low renin and nephropathy: the RENAAL study. Kidney Int 63:1499–1507 syndromes: sites of renal renin secretory impairment and prorenin 2. Raine AE (1993) Epidemiology, development and treatment of overexpression. Kidney Int 43:983–999 end-stage renal failure in type 2 (non-insulin dependent) diabetic 19. 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J Am Soc Nephrol 16(Suppl 1):S53– factors causing hyperkalemia. Intern Med 46:823–829 S57 9. Desai AS, Swedberg K, McMurray JJ et al (2007) Incidence and 25. Frimodt-Moller M HNA, Strandgaard S, Kamper AL (2009) predictors of hyperkalemia in patients with heart failure: an Feasibility of combined treatment with enalapril and candesartan analysis of the CHARM Program. J Am Coll Cardiol 50:1959– 1966 in advanced chronic kidney disease. Nephrol Dial Transplant

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Diabetologia – Pubmed Central

Published: Sep 30, 2010

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