Kidney transplant patients frequently have hypertension irrespective of their native kidney diseases. It is important to control blood pressure after kidney transplantation (KT) because uncontrolled hypertension is associated with earlier graft failure and higher cardiovascular mortality in the recipients [1]. Notably, salt sensitivity has a role in the pathogenesis of hypertension associated with chronic kidney disease (CKD) [2] and the use of calcineurin inhibitors [3]. Thus, diuretic therapy would be helpful to control hypertension in kidney transplant recipients.

Cicletanine (Tenstaten; Daewoong, Seoul, Korea) is an antihypertensive agent, synthetized by Esanu et al in 1986, and has been widely used in European countries [4]. It has been commercially available in Korea since 1992 and is used for the treatment of hypertension because it has effects of natriuresis and vasodilation without reflex tachycardia [5]. Although previous studies reported on the efficacy and safety of cicletanine in the treatment of hypertension [6], [7], adverse effects of electrolyte imbalance induced by cicletanine have yet to be investigated.

Considering that the action of cicletanine is associated with natriuresis and kaliuresis [8], we postulated that cicletanine may produce side effects of hyponatremia and hypokalemia similar to those of thiazide diuretics. A few previous studies have shown that cicletanine has a milder natriuretic effect [9] and less kaliuresis [8] than thiazide diuretics in a small number of patients with essential hypertension. However, whether hyponatremia and hypokalemia are induced by cicletanine has not been investigated in patients with CKD. This study was undertaken to characterize cicletanine-induced hyponatremia and hypokalemia in kidney transplant patients.

We conducted a retrospective analysis of adult patients who underwent KT in Hanyang University Seoul Hospital and were prescribed cicletanine >2 weeks for the treatment of hypertension from January 2001 to April 2008. The patients who returned to hemodialysis or peritoneal dialysis after KT were excluded. We also excluded patients whose serum sodium and potassium levels were previously lower than 135 and 3.5 mmol/L, respectively.

Laboratory data, including serum electrolytes, blood urea nitrogen (BUN), and serum creatinine before and after cicletanine administration, were reviewed. To evaluate patient characteristics, demographic data including comorbidities and concurrent medications were also collected. The dose and duration of cicletanine use were estimated. Estimated glomerular filtration rate (eGFR) was calculated using the Chronic Kidney Disease Epidemiology Collaboration equation.

Cicletanine-induced hyponatremia and hypokalemia were defined as having follow-up serum sodium concentration of < 135 mmol/L and serum potassium concentration of < 3.5 mmol/L. Accordingly, the incidence of cicletanine-induced hyponatremia and hypokalemia was estimated. To compare patient characteristics, patients were divided into those with and without cicletanine-induced hyponatremia or hypokalemia.

Data are expressed as mean ± standard deviation or frequency (and proportion). Two groups were compared using the Mann–Whitney U test for continuous variables and the chi-square test for categorical variables. Two-tailed P < 0.05 was considered statistically significant. All statistical analyses were performed using StatView software (version 5.0 for Windows; SAS Institute Inc., Cary, USA).

In this study, we demonstrated that cicletanine induced hyponatremia and hypokalemia while it was used for the treatment of hypertension in kidney transplant patients. Hyponatremia was more frequently associated with cicletanine than hypokalemia, and extended use of cicletanine may increase the risk of hyponatremia.

The mechanisms of action by which cicletanine exerts antihypertensive effects are unclear. However, one possibility is a direct action on the vascular wall because cicletanine, a furopyridine-derivative drug, is believed to stimulate the synthesis of prostaglandin I₂ (also called prostacyclin) [5] and inhibit sympathetic nerve activity [10]. Another possibility is the natriuretic activity of the drug, resulting from the action of the sulfoconjugated metabolite of cicletanine [4].

Whether cicletanine acts like thiazide diuretics in the distal convoluted tubule is controversial. According to Greven [11], cicletanine has a tubular site of action similar to thiazide diuretics, so despite the disparity in chemical structure between these drugs, there is speculation that cicletanine has adverse effects similar to thiazides. However, Monroy et al [12] demonstrated that the natriuretic metabolite of cicletanine (cicletanine sulfate) was unable to inhibit thiazide-sensitive NaCl cotransporters in the distal convoluted tubule. Cicletanine may act on different transporters than those targeted by thiazides, such as the apical Na⁺-dependent Cl⁻/HCO₃⁻ anion exchanger in the distal convoluted tubule [4]. Thus, cicletanine may not act like thiazide diuretics.

Despite these pharmacologic clues, clinical studies on electrolyte disorders induced by cicletanine were not previously reported. According to Tarrade et al [6], hematologic and biochemical values are not affected by cicletanine. Adverse effects reported during the use of cicletanine were gastrointestinal disorders, fatigue, pruritus, headache, vertigo, and lower limb edema, so it was concluded that cicletanine had no toxic or serious adverse effects. Passa [13] reported that cicletanine administered at 150–200 mg/d did not significantly influence serum sodium and potassium levels.

However, the ability to concentrate or dilute urine is diminished in CKD, ultimately leading to changes in the serum sodium concentration [14]. As a result, KT recipients can be susceptible to hyponatremia, especially when thiazide-like diuretics are administered.

In this study, hyponatremia occurred in 11 patients (16.2%) among 68 kidney transplant recipients who used cicletanine for the treatment of hypertension. We believe that a causative relationship was present between hyponatremia and use of cicletanine because hyponatremia appeared after using cicletanine and was relieved by the discontinuance of the drug. The incidence of cicletanine-induced hyponatremia that we observed appears to be similar to that of thiazide-induced hyponatremia, although previous studies have shown variable incidences of thiazide-induced hyponatremia. Gross et al [15] reported an estimated incidence of 11% in 114 elderly patients. According to Clayton et al [16], the incidence was 13.7% in 951 adult patients. Interestingly, a population-based study reported a higher prevalence (32.4%) of thiazide-associated hyponatremia [17].

In comparison with hyponatremia, cicletanine-induced hypokalemia in our patients was less frequent (11.8%) and milder in severity. The association between hypokalemia and use of cicletanine was also clear. The simultaneous occurrence of hyponatremia and hypokalemia suggests that the diuretic property of cicletanine induces natriuresis and kaliuresis. Consistently, Wagner et al [8] reported that both hydrochlorothiazide and cicletanine had more natriuretic, diuretic, and kaliuretic effects than placebo. However, they showed that 150 mg of cicletanine had less kaliuresis than 25 mg of hydrochlorothiazide, a finding that is compatible with our results. According to Singer et al [9], cicletanine has milder natriuretic effects than thiazides and is relatively safer than thiazides with lower risk of developing hypokalemia. These findings suggest that cicletanine is a favorable and well-tolerated option for the treatment of hypertension, compared to hydrochlorothiazide [8], [9].

Advanced age, female gender, and low body weight were known to be risk factors of thiazide-induced hyponatremia [16], [18]. However, these factors were not significantly associated with cicletanine-induced hyponatremia in our study. As expected, patients with hyponatremia had a longer duration of cicletanine administration. It is not clear why patients with cicletanine-induced hyponatremia had lower levels of serum protein than those without hyponatremia. In patients with cicletanine-induced hypokalemia, the serum chloride level was decreased, most likely due to hypokalemic metabolic alkalosis. However, we did not find that the serum total CO₂ level was significantly different between patients with and without hypokalemia.

This study has limitations because it involved clinical data from a small number of patients that were retrospectively analyzed. The chance of observation may increase in parallel with the duration of medication. Only some of the patients had urine electrolyte data, but they were all compatible with diuretic-induced hyponatremia and hypokalemia [19], [20]. We excluded patients who had histories of electrolyte imbalance before cicletanine administration. Importantly, most of our patients with cicletanine-induced hyponatremia and hypokalemia recovered within 2 weeks of discontinuation of the drug (17 of 19 patients, 89.5%).

In conclusion, we documented cicletanine-induced hyponatremia and hypokalemia in kidney transplant patients. To the best of our knowledge, there have been no clinical studies on cicletanine-associated electrolyte disorders. It may be emphasized that patients using cicletanine need to be monitored for electrolyte disturbance as in cases with thiazide diuretic use. Further studies are required to determine conclusively whether cicletanine induces hyponatremia or hypokalemia in other scenarios of CKD and in a population with normal kidney function.

All authors have no conflicts of interest to declare.