Hyperkalemia in pediatric chronic kidney disease.

BACKGROUND: While hyperkalemia is well described in adult chronic kidney disease (CKD), large studies evaluating potassium trends and risk factors for hyperkalemia in pediatric CKD are lacking. This study aimed to characterize hyperkalemia prevalence and risk factors in pediatric CKD. METHODS: Cross-sectional analysis of Chronic Kidney Disease in Children (CKiD) study data evaluated median potassium levels and percentage of visits with hyperkalemia (K ≥5.5 mmoL/L) in relation to demographics, CKD stage, etiology, proteinuria, and acid-base status. Multiple logistic regression was used to identify risk factors for hyperkalemia. RESULTS: One thousand and fifty CKiD participants with 5183 visits were included (mean age 13.1 years, 62.7% male, 32.9% self-identifying as African American or Hispanic). A percentage of 76.6% had non-glomerular disease, 18.7% had CKD stage 4/5, 25.8% had low CO2, and 54.2% were receiving ACEi/ARB therapy. Unadjusted analysis identified a median serum potassium level of 4.5 mmol/L (IQR 4.1-5.0, p <0.001) and hyperkalemia in 6.6% of participants with CKD stage 4/5. Hyperkalemia was present in 14.3% of visits with CKD stage 4/5 and glomerular disease. Hyperkalemia was associated with low CO2 (OR 7.72, 95%CI 3.05-19.54), CKD stage 4/5 (OR 9.17, 95%CI 4.02-20.89), and use of ACEi/ARB therapy (OR 2.14, 95%CI 1.36-3.37). Those with non-glomerular disease were less frequently hyperkalemic (OR 0.52, 95%CI 0.34-0.80). Age, sex, and race/ethnicity were not associated with hyperkalemia. CONCLUSIONS: Hyperkalemia was observed more frequently in children with advanced stage CKD, glomerular disease, low CO2, and ACEi/ARB use. These data can help clinicians identify high-risk patients who may benefit from earlier initiation of potassium-lowering therapies. A higher resolution version of the Graphical abstract is available as Supplementary information.

Implications of differences between point-of-care blood gas analyser and laboratory analyser potassium results on hyperkalaemia diagnosis & treatment.

BACKGROUND: Hyperkalaemia is managed in the emergency department (ED) following measurement of potassium results by blood gas analysers (BGA) or laboratory analysers (LAB). AIMS: To determine the prevalence of clinically significant differences between BGA and LAB potassium results and the impact on ED hyperkalaemia management. METHODS: Retrospective analysis of time-matched ED BGA and LAB potassium samples from 2019 to 2020 (taken within 15 min, one or both results ≥6.0 mmol/L). Mean differences and 95% limits of agreement (LoA) were determined for pairs with one or both results ≥6.0 mmol/L and a separate 500 consecutive sample pairs. RESULTS: Four hundred eighty-eight matched BGA and LAB samples met the inclusion criteria. Of these, 201 (41.2%) differed by ≤0.5 mmol/L, 169 (34.6%) included a haemolysed LAB sample, and 12 (2.5%) had an unreportable BGA sample. One hundred six (21.7%) pairs differed by >0.5 mmol/L, and 60/106 (57%) had normal LAB potassium results, but BGA indicated moderate/severe hyperkalaemia (two of these pairs received hyperkalaemia treatment). Of patients with a haemolysed LAB sample, or where pairs differed by >0.5 mmol, 48 were treated with insulin and five (10.4%) experienced hypoglycaemia. Mean differences and LoA for pairs with LAB results <6.0 mmol/L but BGA ≥6.0 mmol/L demonstrated unacceptable agreement, with 18 (25.7%) BGA results exceeding 8.0 mmol/L. CONCLUSIONS: Potentially significant discordance may occur between BGA and LAB potassium results. Clinicians need to be aware of factors impacting both analytical methods' accuracy (such as poor venepuncture or sample handling, (K) EDTA interference) and undetectable haemolysis with BGA measurements. We recommend BGA hyperkalaemia be confirmed with LAB results using a non-haemolysed sample where time permits.

Outcomes in patients with cardiometabolic disease who develop hyperkalemia while treated with a renin-angiotensin-aldosterone system inhibitor.

BACKGROUND: Many patients with indications for renin-angiotensin-aldosterone system inhibitor (RAASi) therapy are not receiving these medications. Concern about hyperkalemia is thought to contribute to this lack of evidence-based therapy. METHODS: A retrospective cohort study included adult patients in primary care practices affiliated with an integrated health care delivery system treated with RAASi between 2000 and 2019 for any of the following indications: (a) coronary artery disease (CAD); (b) heart failure (HF) with a left ventricle ejection fraction ≤ 40%; (c) diabetes mellitus (DM) with proteinuria; or (d) chronic kidney disease (CKD) with proteinuria. Relationship between hyperkalemia (K > 5.0 mEg/L) over the first 12 months of follow-up and a composite end point of cardiovascular events, renal dysfunction, and all-cause mortality was evaluated. RESULTS: Among 82,732 study patients, 7,727 (9.34%) developed hyperkalemia. Patients with hyperkalemia were older (69.0 vs 64.6) and more likely to have CAD (57.8 vs 53.7%), CKD (57.3 vs 51.1%), HF (19.3 vs 9.7%), and DM (45.3 vs 33.3%) (P < .001 for all). Five-year cumulative risk of the primary outcome was higher in patients who did (63.9%; 95% CI: 62.8%-65.1%) versus did not (37.2%; 95% CI: 36.8%-37.6%) develop hyperkalemia. Five-year cumulative risk of ED visit or hospitalization for hyperkalemia was 15.6% (14.7%-16.6%) for patients with versus 2.7% (95% CI: 2.6-2.9) for patients without hyperkalemia, rising to 25.9% (95% CI: 22.4-29.9) for patients with severe (K > 6.0 mEq/dL) hyperkalemia. Patients who experienced hyperkalemia were more likely (34.4%) than patients who did not (29.2%) to deintensify RAASi therapy (P < .001). Five-year cumulative risk of the primary outcome was higher in patients who lowered RAASi dose (50.4%; 95% CI: 48.5%-52.4%) or stopped RAASi therapy completely (49.3%; 95% CI: 48.5%-50.1%), compared to patients who continued RAASi therapy (36.1%; 95% CI: 25.7-36.5). Similar findings were observed in multivariable analyses and for individual components of the primary outcome. CONCLUSIONS: Hyperkalemia is a common complication of RAASi therapy and is associated with an increased risk of multiple adverse outcomes. Patients who have their RAASi medications deintensified after a hyperkalemic event have higher incidence of cardiovascular events, renal dysfunction and death.

High- Versus Low-dose Losartan and Serum Potassium: An Analysis From HEAAL.

BACKGROUND: Patients with heart failure (HF) experience frequent alterations of serum potassium. Despite the high risk of events associated with hypokalemia, hyperkalemia is feared by clinicians and often leads to interruption or discontinuation of renin-angiotensin-aldosterone system inhibitors. Data on serum potassium of patients treated with different doses of renin-angiotensin-aldosterone system inhibitors are scarce. METHODS AND RESULTS: The effects of high-dose vs low-dose losartan on clinical outcomes in patients with heart failure (HEAAL) trial randomized 3834 patients with HFrEF intolerant to angiotensin-converting enzyme inhibitors to losartan 150 mg/d (high dose) vs 50 mg/d (low dose). We studied the associations of serum potassium (baseline and time updated) with study outcomes and the effect of the randomized treatment on serum potassium. Patients with higher baseline potassium were older, had diabetes, poorer renal function, and used mineralocorticoid receptor antagonists more frequently. In time-updated models, hyperkalemia (>5.0 or ≥5.5 mmol/L) was not associated with cardiovascular death or the composite of cardiovascular death or HF hospitalization. Hypokalemia (serum potassium of ≤3.5 mmol/L, in particular) was associated with a higher risk of the composite of cardiovascular death or HF hospitalization (hazard ratio [HR] 1.58, 95% confidence interval [CI] 1.19-2.08), all-cause death (HR 1.68, 95% CI 1.26-2.24), and sudden cardiac death or resuscitated cardiac arrest (HR 1.74, 95% CI 1.11-2.73). High-dose losartan decreased the risk of hypokalemia (HR 0.77, 95% CI 0.63-0.92) and increased the risk of hyperkalemia (HR 1.21, 95% CI 1.05-1.39). High-dose losartan decreased the composite of cardiovascular death or HF hospitalizations consistently across the full spectrum of serum potassium at baseline (interaction P = .85). CONCLUSIONS: In patients with HF with reduced ejection fraction intolerant to angiotensin-converting enzyme inhibitors and treated with either high- or low-dose losartan, incident hypokalemia had a stronger association with poor outcomes than incident hyperkalemia. High-dose losartan reduced the incidence of hypokalemia, and its benefits were maintained across the full spectrum of serum potassium.

Adverse Events After Initiating Angiotensin-Converting Enzyme Inhibitor/Angiotensin II Receptor Blocker Therapy in Individuals with Heart Failure and Multimorbidity.

BACKGROUND: Current clinical practice guidelines recommend routine kidney function and serum potassium testing within 30 days of initiating angiotensin-converting enzyme inhibitor (ACEI) or angiotensin II receptor blocker (ARB) therapy. However, evidence is lacking on whether routine follow-up testing reduces therapy-related adverse events in adults with heart failure and if multimorbidity influences the association between laboratory testing and these adverse events. METHODS: We conducted a retrospective cohort study among adults with heart failure from 4 US integrated health care delivery systems. Multimorbidity was defined using counts of chronic conditions. Patients with outpatient serum creatinine and potassium tests in the 30 days after starting ACEI or ARB therapy were matched 1:1 to patients without follow-up tests. We evaluated the association of follow-up testing with 30-day all-cause mortality and hospitalization with acute kidney injury or hyperkalemia using Cox regression. RESULTS: We identified 3629 matched adults with heart failure initiating ACEI or ARB therapy between January 1, 2005, and December 31, 2012. Follow-up testing was not significantly associated with 30-day all-cause mortality (adjusted hazard ratio [aHR] 0.45, 95% confidence interval [CI] 0.14; 1.39) and hospitalization with hyperkalemia (aHR 0.73, 95% CI, 0.33; 1.61). However, follow-up testing was significantly associated with hospitalization with acute kidney injury (aHR, 1.40, 95% CI, 1.01; 1.94). Interaction between multimorbidity burden and follow-up testing was not statistically significant in any of the outcome models examined. CONCLUSIONS: Routine laboratory monitoring after ACEI or ARB therapy initiation was not associated with risk of 30-day all-cause mortality or hospitalization with hyperkalemia across the spectrum of multimorbidity burden in a cohort of patients with heart failure.

Population kinetic-pharmacodynamic analysis of serum potassium in patients receiving sulfamethoxazole/trimethoprim.

Since trimethoprim (TMP) dose-dependently inhibits the excretion of potassium, a population kinetic-pharmacodynamic analysis was performed to establish an adequate dosing schedule and characterize factors of hyperkalaemia. Dataset was constructed using a retrospective observational cohort of hospitalized patients (>18 years) with oral sulfamethoxazole/trimethoprim formulation. The model integrated a kinetic model for TMP, a urinary TMP concentration-response curve and a kinetic model for serum potassium using an indirect response model. The model was a function of body weight, renal function, serum potassium levels and TMP dosing schedule. We evaluated covariates by the stepwise forward and backward selection methods. The Monte Carlo simulation determined the probability of hyperkalaemia (>5.5 or >6.0 meq/L) according to the dosing schedule, renal function and covariates. This study included 317 patients [age 62 (42-72) years] with 4359 serum potassium levels. The significant covariate was non-steroidal anti-inflammatory drugs (NSAIDs), with a 72.3% reduction in 50% inhibitory concentration. Monte Carlo simulation revealed that high-dose TMP (400 mg thrice daily) co-administered with NSAIDs led to mild hyperkalaemia (>10%) and severe hyperkalaemia (approximately 5%), regardless of renal function. In conclusion, clinicians should pay attention to hyperkalaemia with TMP high-dose and co-administered NSAIDs.

Comparative Safety and Effectiveness of Aldosterone Antagonists Versus Beta-Blockers as Fourth Agents in Patients With Apparent Resistant Hypertension.

BACKGROUND: Limited evidence exists regarding long-term effectiveness and safety of aldosterone antagonists (AAs) versus beta blockers (BBs) as fourth-line antihypertensive agents in patients with resistant hypertension (RH). We evaluated the comparative effectiveness and safety of aldosterone AA versus BB. METHODS: We conducted a real-world retrospective cohort study using IBM MarketScan commercial claims and Medicare Supplemental claims (2007-2019). Patients with RH entered the cohort (ie, index date) when they newly initiated either AA or BB. The effectiveness outcome was major adverse cardiovascular events. Safety outcomes were hyperkalemia, gynecomastia, and kidney function deterioration. Potential confounding was addressed by adjustment for baseline characteristics via stabilized inverse probability of treatment weighting (SIPTW) based on propensity scores. Cox proportional hazards regression with SIPTWs were used to estimate adjusted hazard ratio (aHR) and 95% CI comparing risk for outcomes between AA and BB groups. RESULTS: We identified 80 598 patients with RH (mean age: 61 years, 51% males), of which 6626 initiated AA and 73 972 initiated BB as the fourth antihypertensive agent. Among patients with RH, initiation of AA as a fourth-line antihypertensive agent did not significantly reduce major adverse cardiovascular event risk relative to BB initiation (aHR, 0.77 [95% CI, 0.50-1.19]) but did substantially increase the risk of hyperkalemia (aHR, 3.86 [95% CI, 2.78-5.34]), gynecomastia (aHR, 9.51 [95% CI, 5.69-15.89]), and kidney function deterioration (aHR, 1.63 [95% CI, 1.34-1.99]). CONCLUSIONS: Long-term clinical trials powered to assess major adverse cardiovascular events are necessary to understand the risk-benefit trade-off of AA as fourth-line therapy for RH.

Real-world clinical burden and economic assessment associated with hyperkalaemia in a large integrated healthcare system: a retrospective analysis.

BACKGROUND: Hyperkalaemia (HK) is a serious and potentially life-threatening condition. Both acute and chronic conditions may alter potassium homeostasis. Our aim is to describe HK incidence, clinical outcomes, and associated resource use within a large, integrated healthcare system. METHODS: Adult patients seen at Intermountain Healthcare facilities with a serum potassium (sK) result between January 1, 2003 and December 31, 2018 were retrospectively studied. Descriptive assessment of a population with detected HK, defined by any sK > 5.0 mmol/L and HK frequency and severity to associated resource use and characteristics of HK predictors were made. Multivariable Cox hazard regression was used to evaluate HK to outcomes. RESULTS: Of 1,208,815 patients included, 13% had HK. Compared to no-HK, HK patients were older (60 ± 18 vs 43 ± 18 years, P < 0.001), male (51% vs 41%, P < 0.001), and had greater disease burden (Charlson Comorbidity Index 3.5 ± 2.8 vs 1.7 ± 1.4, P < 0.001). At 3 years, more HK patients experienced major adverse cardiovascular events (MACEs) (19 vs 3%, P < 0.001), persisting post-adjustment (multivariable hazard ratio = 1.60, P < 0.001). They incurred higher costs for emergency department services ($552 ± 7,574 vs $207 ± 1,930, P < 0.001) and inpatient stays ($10,956 ± 93,026 vs $1,477 ± 21,423, P < 0.001). HyperK Risk Scores for the derivation and validation cohorts were: 44% low-risk, 45% moderate-risk, 11% high-risk. Strongest HK predictors were renal failure, dialysis, aldosterone blockers, diabetes, and smoking. CONCLUSION: Within this large system, HK was associated with a large clinical burden, affecting over 1 in 10 patients; HK was also associated with increased 3-year MACE risk and higher medical costs. Although risk worsened with more severe or persistently recurring HK, even mild or intermittent HK episodes were associated with significantly greater adverse clinical outcomes and medical costs. The HyperK Score predicted patients who may benefit from closer management to reduce HK risk and associated costs. It should be remembered that our assumptions are valid only for detected HK and not HK per se.

A single-center experience of parathyroidectomy in 1500 cases for secondary hyperparathyroidism: a retrospective study.

BACKGROUND: Chronic kidney disease (CKD) is a global public health problem. With the deterioration of renal function, a certain proportion of CKD patients enter the uremic stage, and secondary hyperparathyroidism (SHPT) becomes a challenge. For refractory hyperparathyroidism, parathyroidectomy (PTX) plays a key role in reducing mortality and improving prognosis. Nevertheless, no consensus has been reached on the optimal surgical method. We aimed to provide evidence for the effectiveness of surgical treatment by summarizing the experience from our center. METHODS: Clinical data from 1500 patients undergoing parathyroidectomy were recorded, which included 1419 patients in a total parathyroidectomy without autotransplantation (tPTX) group, 54 patients in a total parathyroidectomy plus autotransplantation (tPTX + AT) group, and 27 patients in the other group. Perioperative basic data, intact parathyroid hormone (i-PTH) levels, serum calcium levels, serum phosphorus levels, pathological reports, coexisting thyroid diseases, short-term outcomes and complications were analyzed. Moreover, postoperative complications were compared between the tPTX and tPTX + AT groups. RESULTS: Parathyroid hormone, serum calcium and phosphorus levels decreased significantly post-surgery. Two patients died during the perioperative period. As the two most common complications, the incidences of severe hypocalcemia and hyperkalemia were 36.20% (543 cases) and 24.60% (369 cases), respectively. Pre-iPTH levels (OR = 1.001, 95% CI: 1.001-1.001, p < 0.01), serum alkaline phosphatase (ALP) levels (OR = 1.002, 95% CI: 1.001-1.002, p < 0.01) and the mass of excised parathyroid gland (OR = 3.06, 95% CI: 1.24-7.55, p = 0.02) were positively associated with postoperative severe hypocalcemia, while age and serum calcium were negatively associated with it. Pathological reports of resected parathyroid and thyroid glands indicated that 96.49% had parathyroid nodular hyperplasia, 13.45% had thyroid nodular hyperplasia, and 4.08% had thyroid papillary carcinoma. CONCLUSIONS: Parathyroidectomy is a safe and effective treatment for refractory secondary hyperparathyroidism. Severe hypocalcemia is the main complication, and coexistent thyroid diseases should never be neglected.

Dyskalemia risk associated with fixed-dose anti-hypertensive medication combinations.

A model-based meta-analysis quantified comparative dyskalemia risk (hyper- or hypo-kalemia) in hypertensive patients treated with angiotensin receptor blockers (ARBs), a calcium channel blocker (CCB) and/or a thiazide diuretic (hydrochlorothiazide; HCTZ) as monotherapy or as fixed-dose combinations. Among 15 randomized controlled trials in a US Food and Drug Administration regulatory review database, dyskalemia events were reported by five trials (24 treatment arms, 11,030 subjects, 8-week median follow up time). The five trials evaluated monotherapy (ARB or HCTZ) alongside dual (ARB + HCTZ, ARB + CCB, or HCTZ + CCB) or triple fixed-dose combinations (ARB + CCB + HCTZ). Hypo- and hyper-kalemia rates were analyzed jointly to account for correlation. Significant drug class, drug, or dose effects were included in the final model. Effect on various drug- and dose combinations on dyskalemia risk were simulated and compared with model-estimated placebo arm dyskalemia risk. After a typical follow-up of 8 weeks, fixed-dose combinations of ARB with a high dose (25 mg) of HCTZ were associated with a higher hypokalemia risk difference (RD) from placebo (e.g.,Valsartan + HCTZ: 2.52%[95%CIs:1.17, 4.38%]). However, when ARB was combined with a lower, 12.5 mg dose of HCTZ, hypokalemia RD from placebo was not significant (Valsartan + HCTZ: -0.03%[-0.80, 0.71%]). ARB monotherapy raised hyperkalemia RD from placebo (1.3%[0.3, 3.6%]). Hyperkalemia risk was not appreciably higher than placebo for any FDC that combined ARB with HCTZ (Valsartan + HCTZ: 0.06%[-1.48, 1.64%]). In uncomplicated hypertensive patients, ARB + 12.5 mg HCTZ fixed-dose combinations are safer with respect to dyskalemia than either ARB or HCTZ monotherapy for initial antihypertensive treatment.

Effect of senna glycoside on serum potassium levels among patients on maintenance hemodialysis: A randomized controlled trial.

BACKGROUND: Hyperkalemia is common among end-stage renal disease (ESRD) patients, and consequently contributes to an increased risk of cardiac arrhythmia. Senna glycoside may decrease colonic transit time and potassium colonic reabsorption. METHODS: Patients on hemodialysis were randomized to receive either oral senna glycoside (n = 37) or control (n = 36) for 8 weeks. The primary outcomes were predialysis serum potassium and prevalence of hyperkalemia. RESULTS: At the end of the study, significantly reduced serum potassium concentrations were observed in the senna glycoside compared with the control (-0.32 [95%CI -0.43, -0.04] vs. -0.02 [95%CI -0.12, 0.05] mEq/L, p < 0.001, respectively). The prevalence of hyperkalemia during the study occurred at 13.8% in the control and 5.4% in the senna glycoside (p = 0.309). No serious adverse events were observed. CONCLUSION: Among patients with ESRD on hemodialysis, senna glycoside significantly decreases serum potassium level. Senna glycoside is a safe and possibly effective alternative treatment for hyperkalemia in ESRD.

[Validation of a hyperkalemia prediction model in chronic kidney disease].

Objective: To validate the accuracy and consistency of a previously established prediction model for the occurrence of hyperkalemia in non-dialytic chronic kidney disease (CKD) patients. Methods: All patients diagnosed with CKD from Outpatient Department of Shanghai Changzheng Hospital during the 4th quarter of 2020 were recruited. Demographic data, clinical characteristics and prediction model-related parameters of the patients were collected and analyzed. Receiver operating characteristic (ROC) curve was drawn to evaluate the effectiveness of the model, and the specificity and sensitivity were calculated based on the cut-off value of 4 obtained from the previous model. The improved Hanley method was used to compare the area under the curve (AUC) between the previously established model and current validation dataset. The calibration curve was drawn to verify the model calibration degree. Results: A total of 434 patients diagnosed with non-dialytic CKD were enrolled, among whom 233 were males and 201 were females, with an average age of (55±16) years. According to the measured serum potassium values, the prevalence of hyperkalemia was 7.6%. And 33 patients were allocated to the hyperkalemia group and 401 patients were to the normal potassium group. There was no significant difference in age and sex between the two groups (both P>0.05). A combination of hyperkalemia and heart failure (27.3% vs 3.7%, P<0.001), diabetes (42.4% vs 19.7%, P=0.002), and acidosis (51.5% vs 7.0%, P<0.001) were more frequently in the hyperkalemia group, compared with the normal serum potassium group. Patients in the hyperkalemia group were more likely to have a past history of serum potassium ≥5.0 mmol/L (48.5% vs 2.5%, P<0.001). For the drugs that could increase serum potassium levels, there was a significant correlation between Chinese herbal medicine and the occurrence of hyperkalemia, while renin-angiotensin-aldosterone system inhibitor (RAASi) and potassium supplementation showed no significant difference between the two groups. The results of ROC curve analysis showed that the AUC was 0.914, with the sensitivity of 84.8% and the specificity of 79.8% with the cut-off value of 4. The difference of AUC between the previously established risk assessment model of hyperkalemia in patients with non-dialytic CKD and current validation dataset was not statistically significant (Z=1.924, P=0.054), indicating the good accuracy and consistency of the prediction model. In the calibration curve, when the predicted risk of patients was below 0.4 or above 0.6, the prediction effect of the model was better. Conclusion: The previously-constructed hyperkalemia prediction model in non-dialytic CKD patients had good accuracy and consistency, and could be used to evaluate the risk of hyperkalemia in all stages of non-dialytic CKD patients.

Effect of high-dose sulfamethoxazole/trimethoprim and glucocorticoid use on hyperkalemic event: A retrospective observational study.

INTRODUCTION: Sulfamethoxazole/trimethoprim causes hyperkalemia; however, the effect of sulfamethoxazole/trimethoprim dose and co-administered glucocorticoids on hyperkalemia has not been clarified. METHODS: This single-center, retrospective, observational cohort, chart review study involving patients (>20 years) who were treated with sulfamethoxazole/trimethoprim was conducted at Tokyo Women's Medical University, Medical Center East from June 2015 to May 2019. Multivariate Cox proportional hazard model was used to identify risk factors for hyperkalemia (serum potassium level > 5.5 mEq/L). Additionally, Kaplan-Meier curve analyzed the cumulative incidence of hyperkalemia focusing on sulfamethoxazole/trimethoprim dose and concomitant use of glucocorticoids with mineralocorticoid activity. RESULTS: Among 333 patients, 44 (13%) patients developed hyperkalemia associated with sulfamethoxazole/trimethoprim use for over 49 (interquartile range; 17-233) days. We found associations between the time to hyperkalemia development and sulfamethoxazole/trimethoprim dose (hazard ratio 1.238, 95% confidence interval 1.147-1.338, p < 0.001) and glucocorticoid use (hazard ratio 0.678, 95% confidence interval 0.524-0.877, p = 0.003). Interestingly, the Kaplan-Meier curves revealed that the concomitant use of glucocorticoids did not attenuate the risk of hyperkalemia in patients receiving high-dose sulfamethoxazole/trimethoprim (p = 0.747), whereas concomitant use of glucocorticoids significantly reduced the risk of hyperkalemia in patients receiving non-high dose sulfamethoxazole/trimethoprim (p < 0.001). CONCLUSIONS: High-dose sulfamethoxazole/trimethoprim is a significant predictor of hyperkalemia. The effect of glucocorticoids on hyperkalemia varies depending on the sulfamethoxazole/trimethoprim dose.

Hyperkalaemia and hypokalaemia outpatient management: a survey of 500 French general practitioners.

AIMS: How general practitioners (GPs) manage dyskalaemia is currently unknown. This study aimed at describing GP practices regarding hypokalaemia or hyperkalaemia diagnosis and management in their outpatients. METHODS AND RESULTS: A telephone survey was conducted among French GPs with a 20-item questionnaire (16 closed-ended questions and 12 open-ended questions) regarding their usual management of hypokalaemia or hyperkalaemia patients, both broadly and more specifically in patients with heart failure and/or chronic kidney disease and/or in patients treated with angiotensin-converting enzyme/angiotensin receptor blockers or mineralocorticoid receptor antagonists. We aimed to interview 500 GPs spread geographically throughout France. This descriptive survey results are presented as mean ± standard deviation (if normally distributed or as median and inter-quartile range if the distribution was skewed). Categorical variables are expressed as frequencies and proportions (%). A total of 500 GPs participated in the study. Dyskalaemia thresholds (for diagnosis and intervention) and management patterns were highly heterogeneous. The mean ± SD (range) potassium level leading to 'intervene' was 5.32 ± 0.34 mmol/L (4.5-6.5) for hyperkalaemia and 3.23 ± 0.34 mmol/L (2.0-6.5) for hypokalaemia. Potassium levels leading to refer the patient to the emergency department (ED) were 6.14 ± 0.55 (4.5-10) and 2.69 ± 0.42 mmol/L (1-4), respectively. Potassium binders (51-65%) or potassium supplements (67-74%) were frequently used to manage hyperkalaemia or hypokalaemia. GPs uncommonly referred their dyskalaemic patients to cardiologists or nephrologists (or to the emergency department, if the latter was deemed necessary owing to the severity of the dyskalaemia). We identified an association between the close vicinity of GP office from an ED and 'referring a heart failure patient' (19.2% with ED vs. 8.6% without ED) and referring a heart failure and chronic kidney disease patient on mineralocorticoid receptor antagonist (16.7% with ED vs. 9.3% without ED). Although the majority (67%) of GPs had an electrocardiogram on hand, it was rarely used (14%) in dyskalaemic patients. Subgroup analyses considering gender, age of the participating GPs, and high-income/low-income regions did not identify specific patterns regarding the multidimensional aspect of dyskalaemia management. CONCLUSIONS: Owing to the considerable heterogeneity of French GP practices toward dyskalaemia diagnosis and management approaches, there is a likely need to standardize (potentially enabled by therapeutic algorithms) practices.

Predictors of Hyperkalemia and Hypokalemia in Individuals with Diabetes: a Classification and Regression Tree Analysis.

BACKGROUND: Both hyperkalemia and hypokalemia can lead to cardiac arrhythmias and are associated with increased mortality. Information on the predictors of potassium in individuals with diabetes in routine clinical practice is lacking. OBJECTIVE: To identify predictors of hyperkalemia and hypokalemia in adults with diabetes. DESIGN: Retrospective cohort study, with classification and regression tree (CART) analysis. PARTICIPANTS: 321,856 individuals with diabetes enrolled in four large integrated health care systems from 2012 to 2013. MAIN MEASURES: We used a single serum potassium result collected in 2012 or 2013. Hyperkalemia was defined as a serum potassium ≥ 5.5 mEq/L and hypokalemia as < 3.5 mEq/L. Predictors included demographic factors, laboratory measurements, comorbidities, medication use, and health care utilization. KEY RESULTS: There were 2556 hypokalemia events (0.8%) and 1517 hyperkalemia events (0.5%). In univariate analyses, we identified concordant predictors (associated with increased probability of both hyperkalemia and hypokalemia), discordant predictors, and predictors of only hyperkalemia or hypokalemia. In CART models, the hyperkalemia "tree" had 5 nodes and a c-statistic of 0.76. The nodes were defined by prior potassium results and eGFRs, and the 5 terminal "leaves" had hyperkalemia probabilities of 0.2 to 7.2%. The hypokalemia tree had 4 nodes and a c-statistic of 0.76. The hypokalemia tree included nodes defined by prior potassium results, and the 4 terminal leaves had hypokalemia probabilities of 0.3 to 17.6%. Individuals with a recent potassium between 4.0 and 5.0 mEq/L, eGFR ≥ 45 mL/min/1.73m2, and no hypokalemia in the previous year had a < 1% rate of either hypokalemia or hyperkalemia. CONCLUSIONS: The yield of routine serum potassium testing may be low in individuals with a recent serum potassium between 4.0 and 5.0 mEq/L, eGFR ≥ 45 mL/min/1.73m2, and no recent history of hypokalemia. We did not examine the effect of recent changes in clinical condition or medications on acute potassium changes.

Rationale and Design of a Randomized Placebo-Controlled Clinical Trial Assessing the Renoprotective Effects of Potassium Supplementation in Chronic Kidney Disease.

BACKGROUND/AIMS: Dietary potassium (K+) has beneficial effects on blood pressure and cardiovascular (CV) outcomes. Recently, several epidemiological studies have revealed an association between urinary K+ excretion (as proxy for dietary intake) and better renal outcomes in subjects with chronic kidney disease (CKD). To address causality, we designed the "K+ in CKD" study. METHODS: The K+ in CKD study is a multicenter, randomized, double blind, placebo-controlled clinical trial aiming to include 399 patients with hypertension, CKD stage 3b or 4 (estimated glomerular filtration rate [eGFR] 15-44 mL/min/1.73 m2), and an average eGFR decline > 2 mL/min/1.73 m2/year. As safety measure, all included subjects will start with a 2-week open-label phase of 40 mmol potassium chloride daily. Patients who do not subsequently develop hyperkalemia (defined as serum K+ >5.5 mmol/L) will be randomized to receive potassium chloride, potassium citrate (both K+ 40 mmol/day), or placebo for 2 years. The primary end point is the difference in eGFR after 2 years of treatment. Secondary end points include other renal outcomes (> 30% decrease in eGFR, doubling of serum creatinine, end-stage renal disease, albuminuria), ambulatory blood pressure, CV events, all-cause mortality, and incidence of hyperkalemia. Several measurements will be performed to analyze the effects of potassium supplementation, including body composition monitoring, pulse wave velocity, plasma renin and aldosterone concentrations, urinary ammonium, and intracellular K+ concentrations. CONCLUSION: The K+ in CKD study will demonstrate if K+ sup-plementation has a renoprotective effect in progressive CKD, and whether alkali therapy has additional beneficial effects.

Hyperkalaemia in people with diabetes: occurrence, risk factors and outcomes in a Danish population-based cohort study.

AIMS: To examine the incidence, risk factors and clinical outcomes of hyperkalaemia in people with diabetes in a real-world setting. METHODS: Using Danish health registries, we identified a population-based cohort of people with first-time drug-treated diabetes, in the period 2000-2012. First, the cumulative incidence of hyperkalaemia, defined as first blood test with potassium level >5.0 mmol/l after diabetes treatment initiation, was ascertained. Second, in a case-control analysis, risk factors were compared in people with vs without hyperkalaemia. Third, clinical outcomes were assessed among individuals with hyperkalaemia in a before-after analysis, and among people with and without hyperkalaemia in a matched cohort analysis. RESULTS: Of 68 601 individuals with diabetes (median age 62 years, 47% women), 16% experienced hyperkalaemia (incidence rate 40 per 1000 person-years) during a mean follow-up of 4.1 years. People who developed hyperkalaemia had a higher prevalence of chronic kidney disease [prevalence ratio 1.74 (95% CI 1.68-1.81)], heart failure [prevalence ratio 2.35 (95% CI 2.18-2.54)], use of angiotensin-converting enzyme inhibitors [prevalence ratio 1.24 (95% CI 1.20-1.28)], use of spironolactone [prevalence ratio 2.68 (95% CI 2.48-2.88)] and potassium supplements [prevalence ratio 1.59 (95% CI 1.52-1.67)]. In people with diabetes who developed hyperkalaemia, 31% were acutely hospitalized within 6 months before hyperkalaemia, increasing to 50% 6 months after hyperkalaemia [before-after risk ratio 1.67 (95% CI 1.61-1.72)]. The 6-month mortality rate after hyperkalaemia was 20%. Compared with matched individuals without hyperkalaemia, the hazard ratio for death was 6.47 (95% CI 5.81-7.21). CONCLUSIONS: One in six newly diagnosed people with diabetes experienced a hyperkalaemic event, which was associated with severe clinical outcomes and death.

Elevated potassium levels in patients with chronic kidney disease: occurrence, risk factors and clinical outcomes-a Danish population-based cohort study.

Background: Data on the true burden of hyperkalemia (HK) in patients with chronic kidney disease (CKD) in a real-world setting are scarce. Methods: The incidence rate of HK [first blood test with an elevated blood potassium level level >5.0 mmol/L] in primary or hospital care was assessed in a population-based cohort of all newly diagnosed CKD patients [second estimated glomerular filtration rate (eGFR) measurement <60 mL/min/1.73 m2 or hospital diagnosis] in northern Denmark. Risk factors and clinical outcomes were compared for CKD patients with HK and matched CKD patients without HK. Results: Of 157 766 patients with CKD, 28% experienced HK, for an overall HK incidence rate of 70/1000 person-years. Among patients with Stage 3A, 3B, 4 or 5 CKD, 9, 18, 31 and 42%, respectively, experienced HK within the first year. Important HK risk factors included diabetes {prevalence ratio [PR] 1.74 [95% confidence interval (CI) 1.69-1.79]}, heart failure [PR 2.31 (95% CI 2.23-2.40)] and use of angiotensin-converting enzyme inhibitors [PR 1.45 (95% CI 1.42-1.48)], potassium supplements [PR 1.59 (95% CI 1.55-1.62)] or spironolactone [PR 2.53 (95% CI 2.44-2.63)]. In CKD patients who developed HK, 34% had any acute hospitalization 6 months before the HK event, increasing to 57% 6 months after HK [before-after risk ratio 1.72 (95% CI 1.69-1.74)]. The 6-month mortality following HK was 26%, versus 6% in matched non-HK patients. Compared with non-HK patients, 6-month hazard ratios for any acute hospitalization in HK patients were 2.11-fold higher, including hazard ratios of 2.07 for cardiac diagnoses, 2.29 for ventricular arrhythmias, 3.26 for cardiac arrest, 4.77 for intensive care and 4.85 for death. Conclusions: More than one in four CKD patients develops HK. Patients with severe CKD, diabetes, heart failure or use of spironolactone are at high risk. HK is associated with severe clinical outcomes.

Contralateral suppression of aldosterone at adrenal venous sampling predicts hyperkalemia following adrenalectomy for primary aldosteronism.

BACKGROUND: We aimed to determine whether a greater degree of contralateral suppression of aldosterone secretion at adrenal venous sampling predicted the development of postoperative hyperkalemia after unilateral adrenalectomy for primary aldosteronism. METHODS: A retrospective analysis of patients undergoing unilateral adrenalectomy for primary aldosteronism between 2004-2015 was performed. Clinical and biochemical parameters of patients who developed hyperkalemia (≥5.2 mmol/L) after unilateral adreanlectomy were compared with those who remained normokalemic. The contralateral suppression index was defined as the aldosterone-to-cortisol ratio from the nondominant adrenal vein divided by the aldosterone-to-cortisol ratio from the external iliac vein. RESULTS: Of 192 patients who met criteria for inclusion, 12 (6.3%) developed hyperkalemia (median serum potassium 5.5 mmol/L, range 5.2-6.2 mmol/L), with a median time to onset of 13.5 days (range 7-55 days). Five patients had transiently increased serum potassium concentrations that normalized spontaneously. Four patients received mineralocorticoid replacement therapy with fludrocortisone. On univariate analysis, hyperkalemic patients had slightly greater preoperative serum creatinine levels (1.2 vs 1.0 mg/dL, P = .01), higher postoperative creatinine (1.3 vs 1.0 mg/dL, P = .02), lesser median contralateral suppression index (0.14 vs 0.27, P = .03), and larger adenomas (1.9 vs 1.4 cm, P = .02). On multivariable logistic regression, the contralateral suppression index remained the only significant predictor of postoperative hyperkalemia (P = .04) with an optimal cut-off of <0.47. CONCLUSION: Hyperkalemia after unilateral adrenalectomy for primary aldosteronism is uncommon and usually transient, but may require mineralocorticoid supplementation. Patients with a contralateral suppression index of <0.47 require meticulous follow-up and monitoring of serum potassium concentrations after unilateral adrenalectomy.

Experience using high-dose glucose-insulin-potassium (GIK) in critically ill patients.

PURPOSE: To audit the use of GIK in terms of safety, haemodynamic effects, and impact on catecholamine dosage. MATERIALS AND METHODS: A retrospective, descriptive, evaluative audit of GIK use within the adult ICU of a London teaching hospital was conducted. Rescue therapy of GIK (up to 1.0Unitsinsulin/kg/h) was administered to improve cardiac function. Outcomes were ICU survival, change in cardiac index (CI) and blood lactate levels, events of hypoglycaemia, hyperglycaemia, hypokalaemia and hyperkalaemia, and discontinuation time of catecholamine inotropes. RESULTS: Of 85 patients treated with GIK, 13 (15.3%) survived their ICU stay and 9 (10.5%) were discharged home. In patients surviving until 72h, a trend of improved CI and lactate levels was seen, often with reductions in catecholamine dosing. Inotropes were discontinued in 35 (54%) patients. Severe hypoglycaemia (<2mmol/l), hyperglycaemia (>20mmol/l), hypokalaemia (<2.5mmol/l) and hyperkalaemia (>7mmol/l) during GIK affected 1, 6, 8 and 1 patients, respectively. These abnormalities were quickly identified. No measurable harm was noted. CONCLUSIONS: High-dose GIK can be safely used in critically ill patients, though blood glucose and potassium levels must be monitored frequently. GIK was associated with improved CI and blood lactate levels. Impact on survival requires prospective evaluation.