LAUSR

According to our recently published guideline [1], we choose first-line antihypertensives from among three major classes, thiazide diuretics, calcium channel blockers, and renin-angiotensin inhibitors, unless the patients have specific organ damage. By using these three classes of drugs, we target blood pressure. These three classes of drugs are supported by large amounts of clinical data showing that they effectively lower blood pressure and protect organs from hypertension. Nevertheless, we know that not all patients respond to these drugs equally; some are responsive to diuretics, and some are not. It is said that salt-sensitive individuals and those who are consuming a high-salt diet are more likely to respond to thiazide. It has been reported that plasma renin activity (PRA) can predict blood pressure responses to thiazide diuretics [2]. However, plasma renin activity varies depending on the sampling conditions. It is well known that upright posture increases PRA, and in clinical settings, it is difficult to standardize the postural status in outpatient phlebotomy labs [3]. Advancing age decreases PRA; therefore, the cutoff value of PRA should be set according to age. Females have lower PRA than males. In addition to these preanalytical factors, cryoactivation of PRA is an another important preanalytical factor. When the sampled blood is kept at low temperature, PRA increases. Once the plasma is separated, it should be frozen rapidly and kept frozen until analysis. PRA is also affected by analytical factors, such as pH and the abundance of angiotensinogen. Therefore, PRA is not yet recommended as a biomarker for thiazide usage. To overcome these difficulties in using PRA as a marker for thiazide sensitivity, genetic analysis and liquid biopsy have been investigated. Some genetic markers for thiazide effectiveness [4, 5] have been reported, and in this issue of Hypertension Research, Huang et al. [6] successfully found candidate biomarkers for thiazide sensitivity in an Asian cohort. Their research reproduced the investigations in Caucasian and Black individuals [7, 8]. They claimed that sphingolipids can serve as a biomarker to predict thiazide sensitivity, and a possible mechanism is that those sphingolipids alter the ability of the drug to bind to NCC. We must pay attention to the interpretation of these studies. First, the observational period is substantially different between Huang6 and other studies [7, 8], 2 weeks and 9 weeks. The blood pressure-lowering effect of thiazide is biphasic, and in the early stage, thiazide decreases blood volume and lowers blood pressure; later, thiazide lowers vascular resistance rather than controlling blood volume [9]. The blood pressure-lowering effect of thiazide may differ between these two periods. In the early phase, when Huang’s observations were conducted, thiazide mainly blocks NCC, and the interaction of sphingolipids and thiazides in terms of binding ability might explain the causeeffect relationship. Second, Shahin et al. [7] claimed that the sphingolipid level was determined genetically and that Huang6 did not evaluate the genetic background. Sphingolipid levels are regulated not only by genetic background but also by environmental factors such as inflammation [10]. Sphingolipid is degraded to ceramide by sphingomyelinase, which is activated under high inflammation conditions. I assume that patients with high inflammation might be resistant to thiazide after several weeks of treatment, which is possibly related to the effect of thiazide on the vasculature. We often experience changes in responsiveness to drugs in the same patient. This is possibly due to changes in pharmacodynamics, such as drug metabolism, absorption, or distribution, as well as drug interactions. In addition to these drugs’ per se effect, the pathophysiological condition of the patients should also be considered. For example, long-term use of thiazide activates the renin–angiotensin–aldosterone axis to lead to activation of pendrin at the collecting duct in the kidney to increase sodium reuptake and results in thiazide resistance [11]. We often use receptor antagonists, and * Tatsuo Shimosawa [email protected]