HYPERKALEMIA: OVERVIEW OF A CHRONIC RISK

Hyperkalemia can be an asymptomatic condition, with potentially serious outcomes1-3

Hyperkalemia can be an asymptomatic condition with serious risks that include ventricular arrhythmias and increased mortality.1-3 While the exact incidence of hyperkalemia, specifically in community-based medical practice, is unknown, the documented prevalence rate is between 1% and 10% in hospitalized patients.4

Diagnosis can be difficult because the clinical presentation of the patient with hyperkalemia is variable. Some patients may be asymptomatic, while others may report non-specific symptoms; additionally, hyperkalemia can occur without typical ECG changes.1,5 Therefore, hyperkalemia may go unnoticed until it reaches unsafe levels that require immediate treatment.2,3

The profile of a hyperkalemic event depends on a number of factors: degree of hyperkalemia, rapidity of onset, transmembrane compartmental shift versus inability to excrete potassium,3 and coexisting medical conditions and/or medications.1,2

A balance of gastrointestinal intake and renal potassium excretion is responsible for more long-term potassium balance.6 As the decline of kidney function compromises the kidney’s ability to properly excrete potassium (K+), recurrent hyperkalemia is most commonly seen in patients with chronic kidney disease (CKD). It may also be seen in patients with hypertension, type 2 diabetes mellitus, and/or heart failure.7-10

Compounding risk factors—of progressive kidney disease and use of medicines that are important for kidney and cardiac outcomes but elevate K+ levels3,4—create a situation where hyperkalemia can be a chronic risk for the CKD and heart failure patient.3,9-11 (See more on chronic risk.)

Clinical data mine: Explore rates of hyperkalemia among high-risk patient populations

(Click on any link below to expand and view clinical evidence.)

There is a strong correlation between kidney function and rates of hyperkalemia:

Jain et al: Advanced CKD is a key predictor of hyperkalemia

In a retrospective analysis, risk factors for hyperkalemia were examined in 15,803 patients with CVD who were also being treated with ACEi, ARBs, and potassium-sparing diuretics. Results indicate that the most important risk factors for hyperkalemia in patients with established CVD were advanced CKD, DM, CAD, and PVD, along with ACEi, ARBs, and potassium-sparing diuretics. Furthermore, these were all found to be independent predictors of hyperkalemia.12

PREDICTORS OF HYPERKALEMIA: LOGISTIC REGRESSION ANALYSIS OF PREDICTORS OF HYPERKALEMIA IN ALL PATIENTS AND IN THOSE WITH ADVANCED CKD (STAGES 3-5)12

Einhorn et al: Significance of GFR in the incidence of hyperkalemia in CKD patients

In this retrospective analysis of a national cohort of more than 2 million medical records of >245,000 veterans, patients had ≥1 hospitalization and ≥1 serum K+ value measured and recorded during either an inpatient or outpatient visit. Einhorn supports that impaired K+ excretion and increased risk of hyperkalemia is highly correlated to decreased glomerular filtration rate (GFR). In patients with GFRs of 30-59 mL/min/1.73 m2, approximately 21% of patients had at least 1 incident of hyperkalemia within a year, while 42% of patients with reduced GFR of 15-29 mL/min/1.73 m2 experienced hyperkalemia at least once within a year.8

THE ASSOCIATION OF CHRONIC HYPERKALEMIA WITH IMPAIRED GLOMERULAR FILTRATION RATE (GFR) AND RAASi USE8a
This bar graph shows the percentage of patients on a RAASi  diagnosed with hyperkalemia increasing as glomerular filtration rates decrease and the stage of chronic kidney disease increases

aStage 3, GFR ≥30-59 mL/min/1.73 m2; Stage 4, GFR ≥15-29 mL/min/1.73 m2; Stage 5, GFR <15 mL/min/1.73 m2.

bNumber of patients with hyperkalemia divided by number of patients in each respective cohort. Reproduced with permission from Einhorn LM, Zhan M, Hsu VD, et al. The frequency of hyperkalemia and its significance in chronic kidney disease. Arch Intern Med. 2009;169(12):1156-1162.

Moranne et al: As modified glomerular filtration rates decreased, the prevalence of hyperkalemia increased

An analysis of 1038 adult patients with Stage 2 through Stage 5 CKD who were not on dialysis studied the occurrence of metabolic complications. As modified glomerular filtration rate (mGFR) decreased from 90 to 60 to < 20 mL/min/1.73 m2, the prevalence of hyperkalemia increased from 2% to 42%.11

TIMING OF ONSET OF CKD-RELATED HYPERKALEMIA11
This bar graph shows the prevalence of hyperkalemia increasing as modified glomerular filtration rate decreases

Reproduced with permission from Moranne O, Froissart M, Rossert J, et al; for NephroTest Study Group. Timing of onset of CKD-related metabolic complications. J Am Soc Nephrol. 2009;(20)1:164-171.

Khosla et al: Baseline serum K+ and eGFR were strong predictors of hyperkalemia

In a 2-center study of 46 patients with resistant hypertension and Stage 2 or Stage 3 CKD (mean estimated glomerular filtration rate [eGFR] was 56.5 ± 16.2 mL/min/1.73 m2) receiving treatment for high blood pressure (BP), Khosla et al show that baseline serum K+ and eGFR are strong predictors for hyperkalemia. While the primary endpoint was change in systolic BP, change in serum K+, creatinine, and eGFR were predetermined secondary endpoints. The mean increase in serum K+ was 0.4 mEq/L above baseline (P=0.001), with 17.3% of patients experiencing hyperkalemia (defined in this study as >5.5 mEq/L). There was a higher correlation between hyperkalemia in patients with a baseline eGFR of ≤45 mL/min/1.73 m2 and baseline serum K+ of >4.5 mEq/L, despite properly dosed medications.13

CHANGE FROM BASELINE IN SERUM K+ CORRELATING TO BASELINE eGFR13
This bar grows shows a pronounced increase in serum potassium levels as estimated glomerular filtration rates decreased

Reproduced with permission from Khosla N, Kalaitzidis R, Bakris GL. Predictors of hyperkalemia risk following hypertension control with aldosterone blockade. Am J Nephrol. 2009;30:418-424.

Furthermore, hyperkalemia was demonstrated to be a recurring condition in high-risk patients:

Einhorn et al: Patients with CKD and using RAASi had multiple hyperkalemic events per year

While studies of chronic hyperkalemia are limited, Einhorn et al establishes that recurrent hyperkalemia has been documented in patients with renal insufficiency. In this retrospective analysis of a national cohort of more than 2 million medical records of >245,000 veterans, patients had ≥1 hospitalization and ≥1 serum K+ value measured and recorded during either an inpatient or outpatient visit. The adjusted rate of hyperkalemia (≥5.5 mEq/L) was higher in patients with CKD taking a RAASi than in those without CKD taking a RAASi. Approximately 50% of patients who experienced hyperkalemia had 2 or more events within a year. Some patients had as many as >20 episodes within a year.8

AASK Trial: Multiple factors drive recurrent hyperkalemia in CKD patients

Chronic hyperkalemia appears to be closely related to renal insufficiency and RAASi use.9 In the African American Study of Kidney Disease and Hypertension (AASK) trial, a study of 1094 non-diabetic patients with hypertensive CKD, those with lower baseline GFR treated with antihypertensives were more likely to experience hyperkalemic events than those with greater GFR and low renal insufficiency.14

HYPERKALEMIA EVENT RATE PER 100 PATIENT-YEARS14
This table shows the hyperkalemic event rate per 100 patients-years according to baseline glomerular  filtration rate. As GFR decreases, the event rate increases.

Several clinical trials have also shown that RAASi use is highly associated with hyperkalemia in patients with kidney disease14-17

There is significant evidence highlighting the association between commonly used medications for CKD and heart failure and an increased risk for hyperkalemia (see more on medications). In particular, the impact of RAASi has been the focus of many of these studies because of their prevalent use in these patient populations and the considerable risk they pose. It is well established that RAASi use compounds the risk for increased serum K+ and hyperkalemia, especially in patients with impaired renal function.14-18

A REPRESENTATIVE SELECTION OF CLINICAL TRIALS THAT ASSOCIATE RAASi USE WITH INCREASED RISK OF HYPERKALEMIA14-17
This table shows a representation selection of clinical trials that have drawn an association between the use of a renin-angiotensin-aldosterone system inhibitor and an increased risk of hyperkalemia.

aAASK = African American Study of Kidney Disease and Hypertension.

bJ-LIGHT = Japanese Losartan Therapy Intended for the Global Renal Protection in Hypertensive Patients.

cRENAAL = Reduction of Endpoints in NIDDM (noninsulin-dependent diabetes mellitus) with the Angiotensin II Antagonist Losartan.

dIDNT = Irbesartan Diabetic Nephropathy Trial.