Discussion
The major finding of this study is that low serum potassium concentration is a risk factor for the development of CKD in Japanese subjects. Moreover, we identified that serum potassium concentration below 4 mmol/l is a predictor of CKD. This finding is of clinical importance because most physicians consider serum potassium concentrations of 3.5–3.9 mmol/l to be within normal limits. In fact, 149 subjects with serum potassium concentration of 3.5–3.9 mmol/l developed CKD (33.6%), which was more frequently than that with serum potassium concentration of equal to or above 4 mmol/l (16.1%; p < 0.0001).
Previous studies have reported the association between potassium and CVD or mortality. Intake of potassium reduced the risk of stroke or all-cause mortality, low potassium intake increased the risk of mortality from CVD and low serum potassium concentration increased the risk of CVD. However, the relationship between serum potassium concentration and the development of CKD has not been investigated. In this study, multiple regression analysis revealed that low serum potassium concentration could be a predictor of CKD after adjustment for the known risk factors. Recent studies reported that CKD was associated with increased CVD and all-cause mortality. Therefore, it is important to identify predictor of CKD. To our knowledge, this is the first report to identify serum potassium concentration as a possible predictor of CKD in healthy subjects.
Under normal conditions, serum potassium concentration is maintained within the narrow range of 3.5–5.0 mmol/l despite great variations in water and food intake and interplays with neurohormonal pathways, blood pressure and sodium homeostasis. Although a mechanism that could explain the association between serum potassium concentration and development of CKD has not been clear, there are some studies which support the protective effect of potassium from the development of CKD. Increase in potassium concentration reduces cultured vascular smooth muscle cell proliferation, inhibits free radical formation from vascular endothelial cells and macrophages, and inhibits platelet aggregation and arterial thrombosis, all of which lead to protect from the development of CKD. Raising extracellular potassium concentration by 1 mmol/l caused a highly significant decrease in free radical formation, smooth muscle proliferation and thrombus formation. Furthermore, elevation of potassium concentration reduces renal vascular resistance and increases glomerular filtration rate. Higher serum potassium concentration is associated with reduced activity of renin-angiotensin-aldosterone system or use of renin-angiotensin-aldosterone system antagonists such as angiotensin-converting enzyme inhibitor or angiotensin II receptor blocker, which has been shown to slow progression of CKD. However, none of the subjects in this study were taking any medications known to affect serum potassium concentration. In addition, potassium depletion or low potassium intake could play a pivotal role in blood pressure regulation. However, serum potassium concentration was an independent predictor of CKD after adjustment of systolic blood pressure in this study.
In general, we pay little attention to serum potassium concentration among normal range as a risk factor for progression of CKD. Therefore, it is important to clarify the role of serum potassium concentration in the progression of CKD. We suggest that examination of the low serum potassium concentration can be practical screening tool of CKD and it is beneficial to recognise segment of the population whose serum potassium concentration is low. Furthermore, potassium supplementation could be one of the treatments to protect the development of CKD in subjects with low serum potassium concentration. Replication of this study and additional studies are suggested.
This study has several strengths, including the community-based sample, and long duration of follow-up. Nevertheless, several limitations may affect the interpretation of these results. First, we have used eGFR < 60 ml/min/1.73 m as a clinical end-point rather than urinary protein excretion. It was supported by the reports that a reduced eGFR was associated with increased risks of death, cardiovascular events and hospitalisation, which was independent of the presence of documented proteinuria. However, we believe it is worthy of note that low serum potassium concentration could be a predictor of CKD in outpatient and routine medical check-up setting. Second, we have not measured activity of renin-angiotensin-aldosterone system. Third, we did not have information about supplements or herbal medicine, which may lower serum potassium concentration. Last, the study population consisted of Japanese men and women, therefore, it is uncertain whether these findings are generalised in other ethnic groups. Interventional studies are also needed to evaluate the effectiveness of potassium supplementation to protect the development of CKD in subjects with low serum potassium concentration.