Machine learning for prediction of chronic kidney disease progression: Validation of the Klinrisk model in the CANVAS Program and CREDENCE trial.

AIM: To validate the Klinrisk machine learning model for prediction of chronic kidney disease (CKD) progression in patients with type 2 diabetes in the pooled CANVAS/CREDENCE trials. MATERIALS AND METHODS: We externally validated the Klinrisk model for prediction of CKD progression, defined as 40% or higher decline in estimated glomerular filtration rate (eGFR) or kidney failure. Model performance was assessed for prediction up to 3 years with the area under the receiver operating characteristic curve (AUC), Brier scores and calibration plots of observed and predicted risks. We compared performance of the model with standard of care using eGFR (G1-G4) and urine albumin-creatinine ratio (A1-A3) Kidney Disease Improving Global Outcomes (KDIGO) heatmap categories. RESULTS: The Klinrisk model achieved an AUC of 0.81 (95% confidence interval [CI] 0.78-0.83) at 1 year, and 0.88 (95% CI 0.86-0.89) at 3 years. The Brier scores were 0.020 (0.018-0.022) and 0.056 (0.052-0.059) at 1 and 3 years, respectively. Compared with the KDIGO heatmap, the Klinrisk model had improved performance at every interval (P < .01). CONCLUSIONS: The Klinrisk machine learning model, using routinely collected laboratory data, was highly accurate in its prediction of CKD progression in the CANVAS/CREDENCE trials. Integration of the model in electronic medical records or laboratory information systems can facilitate risk-based care.

Adverse effects during treatment with renin-angiotensin-aldosterone system inhibitors; should we stay or should we stop?

PURPOSE OF REVIEW: To discuss recent evidence on the benefits and harms of stopping therapy with renin-angiotensin-aldosterone system inhibitors (RAASi) after the occurrence of adverse events or in patients with advanced chronic kidney disease (CKD). RECENT FINDINGS: RAASi may result hyperkalemia or acute kidney injury (AKI), particularly in persons with CKD. Guidelines recommend to temporarily stop RAASi until the problem is resolved. However permanent discontinuation of RAASi is common in clinical practice with the potential to heighten subsequent cardiovascular disease (CVD) risk. A series of studies evaluating the consequences of stopping RAASi (vs. continuing) after an episode of hyperkalemia or AKI consistently report worse clinical outcomes, both higher risk of death and cardiovascular events. The STOP-angiotensin converting enzyme inhibitors (ACEi) trial and two large observational studies also favor the decision to continue ACEi/ angiotensin receptor blockers in advanced CKD, refuting old observations that use of these medications can accelerate the risk of kidney replacement therapy. SUMMARY: Available evidence suggests continuing with RAASi after the occurrence of adverse events or in patients with advanced CKD, primarily attributed to sustained cardioprotection. This is in line with current guideline recommendations.

The association between dual RAAS inhibition and risk of acute kidney injury and hyperkalemia in patients with diabetic kidney disease: a systematic review and meta-analysis.

BACKGROUND AND OBJECTIVES: Dual renin-angiotensin-aldosterone system (RAAS) blockade involves dual therapy with a combination of angiotensin-converting enzyme inhibitors (ACEis), angiotensin-receptor blockers (ARBs), direct renin inhibitors (DRIs), or mineralocorticoid receptor antagonists (MRAs). It is hypothesized that dual RAAS blockade would result in a more complete inhibition of the RAAS cascade. However, large clinical trials on dual RAAS inhibition have shown increased risk of acute kidney injury (AKI) and hyperkalemia without additional benefit on mortality, cardiovascular events, or chronic kidney disease (CKD) progression compared to RAAS inhibitor monotherapy in patients with diabetic kidney disease (DKD). The development of newer, more selective non-steroidal MRAs as cardiorenal protective therapies has created a new opportunity for dual RAAS inhibition. We conducted a systematic review and meta-analysis of the risks of AKI and hyperkalemia with dual RAAS blockade in patients with DKD. DESIGN, SETTING, PARTICIPANTS, AND MEASUREMENTS: This is a systematic review and meta-analysis of the randomized controlled trials (RCT) published from 1 January 2006 to 30 May 2022. The study population included adult patients with DKD receiving dual RAAS blockade. A total of 31 RCTs and 33 048 patients were included in the systematic review. Pooled risk ratios (RRs) and 95% confidence intervals (CIs) were calculated using random effects. RESULTS: There were 208 AKI events in 2690 patients on ACEi + ARB versus 170 in 4264 patients with ACEi or ARB monotherapy (pooled RR 1.48, 95% CI: 1.23-1.39). There were 304 hyperkalemia events in 2818 patients on ACEi + ARB versus 208 in 4396 patients with ACEi or ARB monotherapy (pooled RR 1.97, 95% CI: 1.32-2.94). A non-steroidal MRA + ACEi or ARB showed no increase in the risk of AKI (pooled RR 0.97, 95% CI: 0.81-1.16) compared to ACEi or ARB monotherapy but had a 2-fold higher risk of hyperkalemia with 953 events in 7837 patients in dual therapy versus 454 events in 6895 patients in monotherapy (pooled RR 2.05, 95% CI: 1.84-2.28). A steroidal MRA + ACEi or ARB had a 5-fold higher risk of hyperkalemia with 28 events in 245 at risk in dual therapy versus five events in 248 at risk in monotherapy (pooled RR 5.42 95% CI: 2.15-13.67). CONCLUSION: Dual therapy with RAASi is associated with an increased risk of AKI and hyperkalemia compared to RAASi monotherapy. Conversely, dual therapy with RAAS inhibitors and non-steroidal MRAs have no additional risk of AKI but a similar risk of hyperkalemia, which is lower than dual therapy with RAAS inhibitors and steroidal MRAs.

Can chronic kidney disease lead to chronic heart failure, and does worsening chronic heart failure lead to chronic kidney disease progression.

PURPOSE OF REVIEW: The objective of this review is to discuss if chronic kidney disease (CKD) leads to chronic heart failure (CHF), and does worsening CHF lead to CKD progression and how a new medication class can modify the risk of both outcomes. RECENT FINDINGS: Sodium-glucose cotransporter 2 (SGLT2) inhibitors are similarly effective on cardiovascular (CV) - and kidney-related outcomes in the presence of CV and CKD. SUMMARY: SGLT2 inhibitors can reduce the risk of CHF events and CKD progression, and may have synergistic effects in patients with cardiorenal syndrome.

Hyperkalemia-Related Discontinuation of Renin-Angiotensin-Aldosterone System Inhibitors and Clinical Outcomes in CKD: A Population-Based Cohort Study.

RATIONALE & OBJECTIVE: Renin-angiotensin-aldosterone system (RAAS) inhibitors are evidence-based therapies that slow the progression of chronic kidney disease (CKD) but can cause hyperkalemia. We aimed to evaluate the association of discontinuing RAAS inhibitors after an episode of hyperkalemia and clinical outcomes in patients with CKD. STUDY DESIGN: Retrospective cohort study. SETTING & PARTICIPANTS: Adults in Manitoba (7,200) and Ontario (n = 71,290), Canada, with an episode of de novo RAAS inhibitor-related hyperkalemia (serum potassium ≥ 5.5 mmol/L) and CKD. EXPOSURE: RAAS inhibitor prescription. OUTCOME: The primary outcome was all-cause mortality. Secondary outcomes were cardiovascular (CV) mortality, fatal and nonfatal CV events, dialysis initiation, and a negative control outcome (cataract surgery). ANALYTICAL APPROACH: Cox proportional hazards models examined the association of RAAS inhibitor continuation (vs discontinuation) and outcomes using intention to treat approach. Sensitivity analyses included time-dependent, dose-dependent, and propensity-matched analyses. RESULTS: The mean potassium and mean estimated glomerular filtration rate were 5.8 mEq/L and 41 mL/min/1.73 m2, respectively, in Manitoba; and 5.7 mEq/L and 41 mL/min/1.73 m2, respectively, in Ontario. RAAS inhibitor discontinuation was associated with a higher risk of all-cause mortality (Manitoba: HR, 1.32 [95% CI, 1.22-1.41]; Ontario: HR, 1.47 [95% CI, 1.41-1.52]) and CV mortality (Manitoba: HR, 1.28 [95% CI, 1.13-1.44]; and Ontario: HR, 1.32 [95% CI, 1.25-1.39]). RAAS inhibitor discontinuation was associated with an increased risk of dialysis initiation in both cohorts (Manitoba: HR, 1.65 [95% CI, 1.41-1.85]; Ontario: HR, 1.11 [95% CI, 1.08-1.16]). LIMITATIONS: Retrospective study and residual confounding. CONCLUSIONS: RAAS inhibitor discontinuation is associated with higher mortality and CV events compared with continuation among patients with hyperkalemia and CKD. Strategies to maintain RAAS inhibitor treatment after an episode of hyperkalemia may improve clinical outcomes in the CKD population.

Opioids and the Risk of Motor Vehicle Collision: A Systematic Review.

Background: Opioid analgesics are among the most commonly prescribed medications, but questions remain regarding their impact on the day-to-day functioning of patients including driving. We set out to perform a systematic review on the risk of motor vehicle collision (MVC) associated with prescription opioid exposure. Method: We searched Medline, PubMed, EMBASE, Scopus, and TRID from January 1990 to August 31, 2021 for primary studies assessing prescribed opioid use and MVCs. Results: We identified 14 observational studies that met inclusion criteria. Among those, 8 studies found an increased risk of MVC among those participants who had a concomitant opioid prescription at the time of the MVC and 3 found no significant increase of culpability of fatal MVC. The 3 studies that evaluated the presence of a dose-response relationship between the dose of opioids taken and the effects on MVC risk reported the existence of a dose-response relationship. Due to the heterogeneity of the different studies, a quantitative meta-analysis to sum evidence was deemed unfeasible. Our review supports increasing evidence on the association between motor vehicle collisions and prescribed opioids. This research would guide policies regarding driving legislation worldwide. Conclusion: Our review indicates that opioid prescriptions are likely associated with an increased risk of MVCs. Further studies are warranted to strengthen this finding, and investigate additional factors such as individual opioid medications, opioid doses and dose adjustments, and opioid tolerance for their effect on MVC risk.

The impact of epilepsy and its treatment in patients with end-stage renal disease.

Patients with end-stage renal disease requiring dialysis and persons with epilepsy are at increased risk of death. However, there is little information related to the risk of death when the 2 conditions co-exist. In this issue, Waddy et al. determined that among patients with end-stage renal disease, those with a diagnose of epilepsy or seizures have a higher risk of all-cause mortality compared with those who do not have an epilepsy or seizure diagnosis. This association was further modified by neurology consultation, with a lower risk in persons who had received a consultation. Among antiseizure medications, only gabapentin was associated with a higher risk of death.

New therapies for hyperkalemia.

PURPOSE OF REVIEW: Although renin-angiotensin aldosterone system (RAAS) inhibitors have become the mainstay treatment for patients with chronic diseases, hyperkalemia is a major contributory deterrent to their use in patients with chronic kidney disease (CKD) and heart failure. For the first time in 50 years, two new therapies (patiromer and ZS-9) have recently emerged for the concomitant treatment of hyperkalemia in these patients. The objective of this review is to discuss the efficacy and safety of these new agents. RECENT FINDINGS: Patiromer effectively reduces serum potassium in patients with CKD and heart failure, even with the concomitant use of RAAS inhibitors. The most common adverse events in clinical trials were gastrointestinal events. ZS-9 (Lokelma) rapidly reduces serum potassium levels and to a greater magnitude, and has a role in the acute management of hyperkalemia. Despite having more adverse events than patiromer, ZS-9 is overall well tolerated. SUMMARY: These new therapies show promising results for the chronic management of hyperkalemia, whilst also potentially allowing for the concomitant use of RAAS inhibitors at optimal doses. More research is needed to examine the benefits of continuation of RAAS inhibitors after an episode of hyperkalemia in patients with CKD and heart failure.

Validation of the Klinrisk chronic kidney disease progression model in the FIDELITY population.

Background: Chronic kidney disease (CKD) affects >800 million individuals worldwide and is often underrecognized. Early detection, identification and treatment can delay disease progression. Klinrisk is a proprietary CKD progression risk prediction model based on common laboratory data to predict CKD progression. We aimed to externally validate the Klinrisk model for prediction of CKD progression in FIDELITY (a prespecified pooled analysis of two finerenone phase III trials in patients with CKD and type 2 diabetes). In addition, we sought to identify evidence of an interaction between treatment and risk. Methods: The validation cohort included all participants in FIDELITY up to 4 years. The primary and secondary composite outcomes included a ≥40% decrease in estimated glomerular filtration rate (eGFR) or kidney failure, and a ≥57% decrease in eGFR or kidney failure. Prediction discrimination was calculated using area under the receiver operating characteristic curve (AUC). Calibration plots were calculated by decile comparing observed with predicted risk. Results: At time horizons of 2 and 4 years, 993 and 1795 patients experienced a primary outcome event, respectively. The model predicted the primary outcome accurately with an AUC of 0.81 for 2 years and 0.86 for 4 years. Calibration was appropriate at both 2 and 4 years, with Brier scores of 0.067 and 0.115, respectively. No evidence of interaction between treatment and risk was identified for the primary composite outcome (P = .31). Conclusions: Our findings demonstrate the accuracy and utility of a laboratory-based prediction model for early identification of patients at the highest risk of CKD progression.

Ticagrelor as Compared to Clopidogrel Following Percutaneous Coronary Intervention for Acute Coronary Syndrome.

Dual antiplatelet therapy with acetylsalicylic acid and a P2Y12 inhibitor has become a mainstay of therapy after percutaneous coronary intervention (PCI) for acute coronary syndrome (ACS). Although higher-potency P2Y12 inhibitors are preferred over clopidogrel in major society guidelines, recent evidence has questioned the extent of the benefit. It is important to evaluate the relative efficacy and safety of P2Y12 inhibitors in a real-world setting. This is a retrospective cohort study of all patients who underwent PCI for ACS in a Canadian province from January 1, 2015 to March 31, 2020. Baseline characteristics, including co-morbidities, medications, and bleeding risk, were obtained. Propensity matching was used to compare patients who received ticagrelor versus clopidogrel. The primary outcome was occurrence of major adverse cardiovascular events (MACEs) at 12 months, defined as death, nonfatal myocardial infarction, or unplanned revascularization. Secondary outcomes included all-cause mortality, major bleeding, stroke, and all-cause hospitalization. A total of 6,665 patients were included; 2,108 received clopidogrel and 4,214 received ticagrelor. Patients who received clopidogrel were older, had more co-morbidities, including cardiovascular risk factors, and had a higher bleeding risk. In 1.925 propensity score-matched pairs, ticagrelor was associated with a significantly lower risk of MACE (hazard ratio 0.79, 0.67 to 0.93, p <0.01) and hospitalization (hazard ratio 0.85, 0.77 to 0.95, p <0.01). No difference was observed in the risk of major bleeding. A statistically nonsignificant trend toward reduced risk of all-cause mortality was noted. In conclusion, in a real-world high-risk cohort, ticagrelor was associated with decreased risk of MACE and all-cause hospitalization compared with clopidogrel after PCI for ACS.

Use of Wearable and Wireless Technology in Real-World Clinical Settings to Improve Patient Outcomes in Chronic Kidney Disease: A Mixed Methods Pilot Prospective Trial.

Background: During the 30-day period prior to initiating dialysis, there is a 10-fold rise in emergency department visits and hospitalizations related to kidney failure. Objective: The Virtual Ward Incorporating Electronic Wearables (VIEWER) trial implemented a home telemonitoring system to track changes in patients' vitals and assess their adherence and the acceptability of telemonitoring in a chronic kidney disease (CKD) population. Design: A pilot prospective clinical trial using a mixed methods approach was performed. Setting: The research was conducted in Winnipeg, Manitoba. Participants: There were 2 phases: Phase 1 was a 2-week-long pilot trial consisting of 10 participants. Phase 2 was a 3-month-long trial with a total of 26 participants. Patients with an estimated glomerular filtration rate <15 and a >40% risk of beginning dialysis in the next 2 years according to the kidney failure risk equation were eligible to participate in the study. Methods: The primary quantitative outcome was adherence, defined as the proportion of daily self-assessments completed using VIEWER over the follow-up period. The usability and acceptability of VIEWER was assessed qualitatively at the end of the trial through structured questionnaires and focus groups. Results: Phase 1 participants (n = 10) had a median adherence of 77.17% for the 2-week observation period. Phase 2 participants (n = 26) showed a lower median adherence of 36% for the 3-month period. Focus group participants (n = 11) identified many positive aspects of VIEWER, including increased awareness and empowerment over health, simplicity of the data platform, and the ability to show clinical staff their health trends. Some challenges identified with VIEWER were connectivity issues with the Bluetooth, perceived inconvenience, and negative thoughts toward their health. Limitations: Limitations of the study include a small sample size, which limited our ability to measure quantitative outcomes. In addition, patients agreeing to participate in any trial are generally more highly motivated and engaged in their care than those declining participation. Therefore, our results may not be generalizable to individuals who are not interested in self-management of their health. Conclusion: Our results suggest that home telemonitoring in patients with advanced CKD is feasible using a CKD-specific platform like VIEWER. We anticipate that improved functionality with incorporation of feedback from this study will result in greater long-term adherence. A future randomized clinical trial is planned.

Contexte: Les visites aux urgences et les hospitalisations en lien avec l'insuffisance rénale augmentent d'environ dix fois dans les 30 jours qui précèdent le début de la dialyse. Objectif: L'essai VIEWER a mis en œuvre un système de télésurveillance à domicile qui permet de suivre les changements dans les paramètres vitaux des patients atteints d'insuffisance rénale chronique (IRC). L'essai permet également d'évaluer l'observance et l'acceptabilité de la télésurveillance dans cette population. Conception: Un essai clinique pilote prospectif utilisant une approche par méthodes mixtes. Cadre: Les recherches ont été menées à Winnipeg, au Manitoba. Sujets: L'essai s'est déroulé en deux phases: un essai pilote de deux semaines avec 10 participants (phase 1) et un essai de trois mois avec un total de 26 participants (phase 2). Étaient admissibles à participer: les patients présentant un DFGe inférieur à 15 ml/kg/1,73 m2 et une probabilité d'au moins 40 % d'amorcer des traitements de dialyse dans les deux ans, selon l'équation KFRE (kidney failure risk equation). Méthodologie: Le principal critère d'évaluation quantitatif était l'observance, définie par la proportion d'auto-évaluations réalisées quotidiennement à l'aide VIEWER au cours de la période de suivi. La facilité d'utilisation et l'acceptabilité de VIEWER ont été évaluées qualitativement à la fin de l'essai au moyen de questionnaires structurés et de groupes de discussion. Résultats: Les participants à la phase 1 (n=10) ont montré une observance médiane de 77,17 % pendant les deux semaines d'observation. Les participants à la phase 2 (n=26) ont montré une observance médiane inférieure, soit de 36 %, pendant les trois mois du suivi. Les participants au groupe de discussion (n=11) ont identifié plusieurs aspects positifs de VIEWER, notamment: une sensibilisation et une responsabilisation accrues à l'égard de la santé, la simplicité de la plateforme de données, et le fait de pouvoir montrer leurs tendances de santé au personnel clinique. Parmi les défis identifiés figurent des problèmes de connectivité avec Bluetooth, des désagréments perçus à son utilisation et des pensées négatives à l'égard de la santé. Limites: La faible taille des échantillons a limité notre capacité à mesurer les résultats quantitatifs. En outre, les patients qui acceptent de participer à un essai clinique sont généralement plus motivés et impliqués dans leurs soins que ceux qui refusent de participer. Par conséquent, nos résultats pourraient ne pas être généralisables aux personnes qui ne sont pas intéressées par l'autogestion de leur santé. Conclusion: Nos résultats suggèrent que la télésurveillance des patients atteints d'IRC avancée est réalisable par le biais d'une plateforme spécifique à l'IRC comme VIEWER. Nous pensons que l'amélioration de sa fonctionnalité, découlant des résultats de cette étude, se traduira par une plus grande observance à long terme. Un futur essai clinique randomisé est prévu.

A Randomized Trial Examining the Impact of Timing of Intradialytic Cycling on Intradialytic Hypotension.

Introduction: Intradialytic cycling is often performed during the first half of hemodialysis because of concerns regarding increased frequency of intradialytic hypotension (IDH) late in hemodialysis. This increases exercise program resource needs and limits utility of intradialytic cycling to treat dialysis-related symptoms. Methods: This multicenter, randomized, crossover trial compared IDH rate when cycling during the first half versus the second half of hemodialysis in 98 adults on maintenance hemodialysis. Group A cycled during the first half of hemodialysis for 2 weeks and subsequently during the second half for 2 weeks. In group B, the cycling schedule was reversed. Blood pressure (BP) was measured every 15 minutes throughout hemodialysis. Primary outcome was IDH rate (systolic BP [SBP] decrease of >20 mm Hg or SBP <90 mm Hg). Secondary outcomes included symptomatic IDH rate and time to recover post hemodialysis. Data were analyzed using negative binomial and gamma distribution mixed regression. Results: Mean age 64.7 (SD 12.0) and 64.7 (SD 14.2) years in group A (n = 52) and group B (n = 46), respectively. Proportions of females were 33% in group A and 43% in group B. Median time on hemodialysis was 4.1 (interquartile range [IQR] 2.5, 6.1]) years in group A and 3.9 years (IQR 2.5, 6.7) in group B. IDH rate per 100 hemodialysis hours (95% confidence interval [CI]) was 34.2 (26.4, 42.0) and 36.0 (28.9, 43.1) during early and late intradialytic cycling, respectively (P = 0.53). Timing of intradialytic cycling was not associated with symptomatic IDH (relative risk [RR]: 1.07 [0.75-1.53]) or time to recover post hemodialysis (odds ratio: 0.99 [0.79-1.23]). Conclusion: We found no association between the rate of overall or symptomatic IDH and the timing of intradialytic cycling in patients enrolled in an intradialytic cycling program. Increased use of cycling late in hemodialysis may optimize intradialytic cycling program resource use and should be studied as a possible treatment for symptoms common in late hemodialysis.

Prescription patterns of sodium and calcium polystyrene sulfonate in patients with hyperkalemia and chronic kidney disease receiving RAAS inhibitors.

Background: Sodium and calcium polystyrene sulfonate (SPS/CPS) cation-exchange resins have had long-standing clinical use for hyperkalemia in patients with chronic kidney disease (CKD). However, uncertainty exists regarding the real-world usage of SPS/CPS for acute and chronic management of hyperkalemia. We evaluated the prescription patterns of SPS/CPS and their impact on renin-angiotensin-aldosterone system inhibitor (RAASi) treatment in patients with CKD Stages G3-G5 after an episode of de novo hyperkalemia. Methods: We conducted a retrospective cohort study using population-level administrative databases in Manitoba, Canada, which included adults with CKD and a RAASi prescription who had an episode of de novo hyperkalemia (≥5.5 mmol/L) between January 2007 and December 2017. Results: A total of 10 009 individuals were included in our study cohort. Among the study population, 4% received an SPS/CPS prescription within 30 days of their hyperkalemia episode. Of those, 22% received a 1-day supply of SPS/CPS and 7% received a prescription for more than 30 days. There were 8145 patients using RAASi at baseline who survived 90 days after their first hyperkalemia episode. Of those, 1447 (18%) discontinued their RAAS inhibitor and 339 (5%) received a prescription of SPS/CPS. Also, the proportion of patients who discontinued their RAASi was similar among those who did and did not receive a prescription of SPS/CPS. Conclusion: In patients with CKD receiving RAASi therapy, there is a low frequency of SPS/CPS prescription after an episode of hyperkalemia. RAASi discontinuation or downtitration is the most used pharmacologic approach for the management of hyperkalemia, a strategy that deprives patients of the cardiac and renal protective benefits of RAASi. New options for the management of hyperkalemia in this population are needed.

Hyperkalemia and its Association With Mortality, Cardiovascular Events, Hospitalizations, and Intensive Care Unit Admissions in a Population-Based Retrospective Cohort.

INTRODUCTION: Hyperkalemia is a common, potentially life-threatening condition in patients with chronic kidney disease (CKD). We studied the association between hyperkalemia and mortality, cardiovascular events, hospitalizations, and intensive care unit (ICU) admissions. METHODS: We performed a retrospective cohort study using administrative databases in Manitoba, Canada. All adults (≥18 years of age) with potassium tests between January 2007 and December 2016 were included, with follow-up until March 31, 2017. Propensity score matching was performed among patients with de novo hyperkalemia (serum potassium ≥ 5.0 mmol/l) and patients who were nonhyperkalemic. The association between hyperkalemia and normokalemia and mortality was assessed using multivariate Cox proportional hazards regression models, adjusting for patient characteristics in a 1:1 propensity score-matched sample. Secondary outcomes included cardiovascular events, hospitalizations, and ICU admissions. A sensitivity analysis was performed with hyperkalemia defined as serum potassium ≥ 5.5 mmol/l. RESULTS: Of 93,667 patients with de novo hyperkalemia, 36% had diabetes mellitus (DM), 28% had CKD, and 21% had heart failure (HF). In the propensity score-matched sample of 177,082 individuals, hyperkalemia was associated with an increased risk for all-cause mortality (hazard ratio [HR] 1.15 [95% confidence interval {CI} 1.13-1.18], P < 0.001), cardiovascular events (HR 1.20 [95% CI 1.14-1.26], P < 0.001), short-term mortality (odds ratio [OR] 1.29 [95% CI 1.24-1.34], P < 0.001), hospitalizations (OR 1.71 [95% CI 1.68-1.74]), and ICU admissions (OR 3.48 [95% CI 3.34-3.62], P < 0.001). Findings were unchanged when a threshold of serum potassium ≥ 5.5 mmol/l was used. CONCLUSION: Hyperkalemia was an independent risk factor for all-cause mortality, cardiovascular events, hospitalizations, and ICU admissions. This finding expands our understanding of important clinical outcomes associated with hyperkalemia.

Ambulatory Treatments for RAAS Inhibitor-Related Hyperkalemia and the 1-Year Risk of Recurrence.

BACKGROUND AND OBJECTIVE: The optimal ambulatory management of renin-angiotensin-aldosterone system inhibitor (RAASi)-related hyperkalemia to reduce the risk of recurrence is unknown. We examined the risk of hyperkalemia recurrence on the basis of outpatient pharmacologic changes following an episode of RAASi-related hyperkalemia. DESIGN: We performed a population-based, retrospective cohort study of older adults (n=49,571; mean age 79 years) who developed hyperkalemia (potassium ≥5.3 mEq/L) while on a RAASi and were grouped as follows: no intervention, RAASi discontinuation, RAASi dose decrease, new diuretic, diuretic dose increase, or sodium polystyrene sulfonate within 30 days. The primary outcome was hyperkalemia recurrence, with secondary outcomes of cardiovascular events and all-cause mortality within 1 year. RESULTS: Among patients who received a pharmacologic intervention (23% of the cohort), RAASi discontinuation was the most commonly prescribed strategy (74%), followed by RAASi decrease (15%), diuretic increase (7%), new diuretic (3%), and sodium polystyrene sulfonate (1%). A total of 16,977 (34%) recurrent hyperkalemia events occurred within 1 year. Compared with no intervention (35%, referent), the cumulative incidence of recurrent hyperkalemia was lower with RAASi discontinuation (29%; hazard ratio, 0.82; 95% confidence interval, 0.78 to 0.85), whereas there was no difference with RAASi dose decrease (36%; hazard ratio, 0.94; 95% confidence interval, 0.86 to 1.02), new diuretic (32%; hazard ratio, 0.95; 95% confidence interval, 0.78 to 1.17), or diuretic increase (38%; hazard ratio, 0.99; 95% confidence interval, 0.87 to 1.12) and a higher incidence with sodium polystyrene sulfonate (55%; hazard ratio, 1.30; 95% confidence interval, 1.04 to 1.63). RAASi discontinuation was not associated with a higher risk of 1-year cardiovascular events (hazard ratio, 0.96; 95% confidence interval, 0.91 to 1.02) or all-cause mortality (hazard ratio, 1.05; 95% confidence interval, 0.96 to 1.15) compared with no intervention. CONCLUSIONS: Among older adults with RAASi-related hyperkalemia, RAASi discontinuation is associated with the lowest risk of recurrent hyperkalemia, with no apparent increase in short-term risks for cardiovascular events or all-cause mortality.

Initial and Recurrent Hyperkalemia Events in Patients With CKD in Older Adults: A Population-Based Cohort Study.

BACKGROUND: The risk of hyperkalemia is elevated in chronic kidney disease (CKD); however, the initial and recurrent risk among older individuals is less clear. OBJECTIVES: We set out to examine the initial and 1-year recurrent risk of hyperkalemia by level of kidney function (estimated glomerular filtration rate, eGFR) in older adults (≥66 years old). DESIGN: Population-based, retrospective cohort study. SETTINGS: Ontario, Canada. PARTICIPANTS: 905 167 individuals (≥66 years old) from 2008 to 2015. MEASUREMENTS: Serum potassium values. METHODS: Individuals were stratified by eGFR (≥90, 60-89, 30-59, 15-29 mL/min/1.73 m2) and examined for the risk of incident hyperkalemia (K ≥ 5.5 mEq/L) using adjusted Cox proportional hazards models. The 1-year risk of recurrent hyperkalemia was examined using multivariable Andersen-Gill models. RESULTS: Among a population of 905 167 individuals (15% eGFR ≥ 90, 58% eGFR 60-89, 25% eGFR 30-59, 3% eGFR 15-29) with a potassium measurement, there were a total of 18 979 (2.1%) individuals with hyperkalemia identified. The event rate (per 1000 person-years) and adjusted hazard ratio (HR) of hyperkalemia was inversely associated with eGFR (mL/min; eGFR >90 mL/min: 8.8, referent, 60-89 mL/min: 11.8 HR 1.41; eGFR 30-59: 39.8, HR 4.37; eGFR 15-29: 133.6, 13.65) and with an increasing urine albumin-to-creatinine ratio (ACR, mg/mmol; ACR< 3: 14, referent, ACR 3-30: 35.1, HR 1.98; ACR >30: 93.7, 4.71). The 1-year event rate and adjusted risk of recurrent hyperkalemia was similarly inversely associated with eGFR (eGFR ≥ 90: 10.1, referent, eGFR 60-89: 14.4, HR 1.47; eGFR 30-59: 54.8, HR 4.90; eGFR 15-29: 208.0, HR 12.98). Among individuals with a baseline eGFR of 30 to 59 and 15 to 29, 0.9 and 3.8% had greater than 2 hyperkalemia events. The relative risk of initial and recurrent hyperkalemia was marginally higher with RAAS blockade. Roughly 1 in 4 individuals with hyperkalemia required hospitalization the day of or within 30 days after their hyperkalemia event. LIMITATIONS: Limited to individuals aged 66 years and above. CONCLUSIONS: Patients with low eGFR are at a high risk of initial and recurrent hyperkalemia. TRIAL REGISTRATION: N/A.

CONTEXTE: Le risque d'hyperkaliémie est élevé en contexte d'insuffisance rénale chronique (IRC). On en sait cependant peu sur le risque initial et récurrent d'hyperkaliémie chez les patients âgés. OBJECTIF: Nous avons examiné le risque initial d'hyperkaliémie et le risque de récurrence sur une année selon le niveau de fonction rénale (débit de filtration glomérulaire estimé [DFGe]) chez les patients âgés (plus de 66 ans). TYPE D'ÉTUDE: Étude de cohorte rétrospective basée sur une population. CADRE: Ontario, Canada. SUJETS: L'étude porte sur un total de 905 167 individus (âgés de 66 ans et plus) entre 2008 et 2015. MESURES: Les valeurs de potassium sérique. MÉTHODOLOGIE: Les individus ont été stratifiés en fonction du DFGe (≥90, 60-89, 30-59, 15-29 ml/min/1.73m2) et examinés pour le risque d'hyperkaliémie incidente (K ≥ 5,5 mEq/L) à l'aide de modèles de risques proportionnels de Cox corrigés. Le risque de récurrence sur un an a été examiné avec des modèles multivariés d'Andersen-Gill. RÉSULTATS: Parmi les 905 167 individus disposant d'une mesure de potassium sérique (15 % avec un DFGe ≥ 90; 58 % avec un DFGe de 60-89; 25 % avec un DFGe de 30-59; et 3 % avec un DFGe de 15-29), on a recensé 18 979 individus (2,1 %) présentant une hyperkaliémie. Le taux d'événements (pour 1 000 années-personnes) et le rapport de risque corrigé (RR) de l'hyperkaliémie étaient inversement associés au DFGe (ml/min). Ainsi, un DFGe > 90 ml/min a été associé à 8,8 événements pour 1 000 années-personnes (EV) et constituait le référent pour le RR; ces valeurs pour les autres niveaux de DFGe étaient les suivantes: 11,8 EV (RR = 1,41) pour un DFGe 60-89; 39,8 EV (RR = 4,37) pour un DFGe de 30-59; et 133,6 EV (RR = 13,65) pour un DFGe de 15-29. L'accroissement de ces valeurs a également été associé à un accroissement du rapport albumine/créatinine dans l'urine (RAC mg/mmol). Ainsi, un RAC < 3 a été associé à 14 EV et constituait le référent pour le RR, tandis que 35,1 EV (RR = 1,98) ont été observés pour un RAC de 3-30; et que ce nombre passait à 93,7 EV (RR=4,71) pour un RAC > 30. Le taux d'événements sur un an et le risque corrigé d'hyperkaliémie récidivante étaient eux aussi inversement associés au DFGe: 10,1 EV (RR = valeur de référence) pour un DFGe ≥ 90; 14,4 EV (RR=1,47) pour un DFGe 60-89; 54,8 EV (RR=4,90) pour un DFGe 30-59; et 208,0 EV (RR=12,98) pour un DFGe 15-29. Parmi les individus présentant un DFGe initial de 30-59 et de 15-29 ml/min/1,73m2, un certain nombre de patients avaient vécu plus de deux événements d'hyperkaliémie (respectivement 0,9 % et 3,8 %). Le risque relatif d'hyperkaliémie initiale et récurrente était légèrement plus élevé avec le blocage du SRAA. Environ une personne sur quatre atteinte d'hyperkaliémie a dû être hospitalisée le jour de l'événement ou dans les 30 jours suivant celui-ci. LIMITES: L'étude a été limitée aux personnes âgées de 66 ans et plus. CONCLUSION: Les patients présentant un faible taux de DFGe présentent un risque élevé d'hyperkaliémie initiale et récurrente.

The Use of Renin-Angiotensin System Inhibitors in Patients With Chronic Kidney Disease.

Chronic kidney disease (CKD) is a growing public health issue worldwide. It is acknowledged that CKD is associated with increased risk of cardiovascular disease, which is the leading cause of morbidity and mortality in this population. The role of the renin-angiotensin-aldosterone system in the pathophysiology of hypertension, and cardiovascular and kidney diseases is well known and the renin-angiotensin-aldosterone system is a major regulator of blood pressure through its effect on body fluids and electrolyte homeostasis. For 2 decades, renin-angiotensin system inhibitors have been the mainstay of treatment for CKD. Clinical trials have shown that prescription of monotherapy with angiotensin-converting enzyme inhibitors or angiotensin receptor blockers reduces albuminuria and slows the progression of nephropathy in patients with diabetes. In clinical practice guidelines, renin-angiotensin system inhibitors are recommended as the antihypertensive drug of choice in patients with CKD with or without diabetes. Moreover, renin-angiotensin system inhibitors have been shown to offer cardiovascular protection beyond those resulting after blood pressure control. However, the benefits of renin-angiotensin system inhibitor prescriptions for patients with advanced CKD remain controversial. Patients with advanced CKD or who undergo dialysis are under-represented in clinical trials, and studies in this population are urgently needed.