Hypokalemia, its contributing factors and renal outcomes in patients with chronic kidney disease

Abstract

Background: In the chronic kidney disease (CKD) population, the impact of serum potassium (sK) on renal outcomes has been controversial. Moreover, the reasons for the potential prognostic value of hypokalemia have not been elucidated.

Design participants & measurements: 2500 participants with CKD stage 1-4 in the Integrated CKD care program Kaohsiung for delaying Dialysis (ICKD) prospective observational study were analyzed and followed up for 2.7 years. Generalized additive model was fitted to determine the cutpoints and the U-shape association between sK and end-stage renal disease (ESRD). sK was classified into five groups with the cutpoints of 3.5, 4, 4.5 and 5 mEq/L. Cox proportional hazard regression models predicting the outcomes were used.

Results: The mean age was 62.4 years, mean sK level was 4.2±0.5 mEq/L and average eGFR was 40.6 ml/min per 1.73 m(2). Female vs male, diuretic use vs. non-use, hypertension, higher eGFR, bicarbonate, CRP and hemoglobin levels significantly correlated with hypokalemia. In patients with lower sK, nephrotic range proteinuria, and hypoalbuminemia were more prevalent but the use of RAS (renin-angiotensin system) inhibitors was less frequent. Hypokalemia was significantly associated with ESRD with hazard ratios (HRs) of 1.82 (95% CI, 1.03-3.22) in sK <3.5mEq/L and 1.67 (95% CI,1.19-2.35) in sK = 3.5-4 mEq/L, respectively, compared with sK = 4.5-5 mEq/L. Hyperkalemia defined as sK >5 mEq/L conferred 1.6-fold (95% CI,1.09-2.34) increased risk of ESRD compared with sK = 4.5-5 mEq/L. Hypokalemia was also associated with rapid decline of renal function defined as eGFR slope below 20% of the distribution range.

Conclusion: In conclusion, both hypokalemia and hyperkalemia are associated with increased risk of ESRD in CKD population. Hypokalemia is related to increased use of diuretics, decreased use of RAS blockade and malnutrition, all of which may impose additive deleterious effects on renal outcomes.

Figure 1. Serum Potassium Distribution by Chronic Kidney Disease (CKD) Stages.

Figure 2. The Relationships between Serum Potassium and Other Predictive Covariates.

Figure 2A. Percentages of malnutrition indices including serum albumin lower than 3.5 mg/dL and body mass index (BMI) less than 20 kg/m² across potassium groups. Figure 2B. Proportions of diuretics use (Thiazide and/or Furosemide use), anti-hypertensive (anti-HTN) medication and mean blood pressure (MBP) across potassium groups. Figure 2C. Proportions of ACEI, ARB and proteinuria with nephrotic range across potassium groups. ACEI, angiotensin-converting enzyme inhibitor; ARB, angiotensin II receptor blocker; UPCR, Urine protein-to-creatinine ratio. P-values were generated by chi-square tests.

Figure 3. Restricted Cubic Spline Regression Plot of the U-shape Association between sK and the Risk for End Stage Renal Disease.

Covariates included in the model were the same as the Cox regression in Table 4. Serum potassium (sK), body mass index, mean blood pressure and C-reactive protein were treated as restricted cubic spline functions. The solid line represents the log transformed multivariable-adjusted hazard ratio of ESRD. The dashed lines indicate the 95% confidence intervals. sK below 4.03 and above 5.11 mEq/L were associated with higher hazard (log hazard ratio >0). Tick marks on the x-axis indicate individual observations at corresponding levels of sK.