HARMONIZE Asia: A Phase III Randomized Study to Investigate the Efficacy and Safety of Sodium Zirconium Cyclosilicate in Patients with Hyperkalemia in China.

PURPOSE: Sodium zirconium cyclosilicate (SZC) is an oral potassium (K+)-lowering therapy for adults with hyperkalemia. HARMONIZE Asia (ClinicalTrials.gov identifier: NCT03528681) evaluated the efficacy and safety of SZC in Chinese patients with hyperkalemia. METHODS: This Phase III, randomized, double-blind, placebo-controlled study recruited patients with serum K+ (sK+) ≥5.1 mmol/L at 35 sites in China. Patients received SZC 10 g three times daily (TID) for 24 or 48 hours during an open-label initial phase (OLP). Those patients achieving normokalemia (sK+ 3.5-5.0 mmol/L inclusive) entered a 28-day randomized (2:2:1) treatment phase (RTP) and received SZC 5 g, SZC 10 g, or placebo once daily. The primary endpoint was mean sK+ during RTP Days 8 to 29. Secondary endpoints included mean change in sK+ during the OLP, the proportion of patients who achieved normokalemia at the end of the OLP, the proportion that maintained normokalemia during the RTP, and time to recurrence of hyperkalemia. FINDINGS: In total, 270 patients received SZC 10 g TID during the OLP; 256 (94.8%) completed the OLP. During the OLP, mean sK+ decreased by 1.1 mmol/L from baseline (5.9 mmol/L; P < 0.001) and 87.4% of patients achieved normokalemia. During the RTP, SZC 5 g and 10 g reduced mean sK+ versus placebo in a dose-dependent manner (each P < 0.001); least-squares means (95% confidence interval [CI]) sK+ were 4.9 mmol/L (4.7, 5.0), 4.4 mmol/L (4.3, 4.6), and 5.2 mmol/L (5.1, 5.4) for SZC 5 g, 10 g, and placebo, respectively. At RTP end, the proportions of patients who maintained normokalemia were 58.8% (SZC 5 g; odds ratio vs placebo, 2.5 [95% CI: 1.1, 6.1; P = 0.035]), 76.5% (SZC 10 g; odds ratio vs placebo, 6.3 [95% CI: 2.6, 15.3; P < 0.001]), and 36.8% for placebo. Risk of recurrent hyperkalemia was reduced by 61.0% and 84.0% with SZC 5 g and SZC 10 g, respectively, versus placebo (each P < 0.001). During the RTP, the incidence of adverse events was numerically higher with SZC 5 g (50.0% of patients) and 10 g (44.0%) versus placebo (36.0%); driven primarily by peripheral edema and constipation. IMPLICATIONS: Both SZC doses demonstrated clinically relevant and statistically significant, dose-dependent efficacy in managing sK+ levels in Chinese patients with hyperkalemia, compared with placebo. SZC tolerability was broadly aligned with the known safety profile of SZC.

Atypical Normokalemic Case of Thyrotoxic Periodic Paralysis in a Pediatric Patient.

Thyrotoxic periodic paralysis (TPP) is a rare complication of hyperthyroidism characterized by typical muscular symptoms, ranging from paresis to complete paralysis, commonly associated with low potassium blood levels (<3 mmol/l). It is more commonly reported in adult Asian individuals and can lead to life-threatening situations. Therefore, early clinical diagnosis and targeted therapy are of crucial importance. In this article, we report the case of a 17-year-old adolescent with a Vietnamese background and known Graves' disease who was admitted with typical TPP-related symptoms but no hypokalemia. After treatment with an antithyroid medication and oral potassium supplementation, no new episode of TPP was observed. Using next-generation sequencing, a genetic analysis of TPP-related ion channel genes (KCNJ2, KCNJ18, KCNE3, SCN4A, and CACNA1S) found no known/likely pathogenic variants or variants of unknown significance. To the best of our knowledge, this is only the second reported case of quite normokalemic TPP in the pediatric population. Prompt diagnosis of TPP is essential to prevent harmful complications. Supplementation with potassium appears to be successful alongside non-selective beta-blockers. Normalization of thyroid function should be pursued to prevent new attacks, which is considered the best preventive measure.

A rare case of thyrotoxic periodic paralysis revealing Graves' disease in a young Malian.

Sporadic thyrotoxic periodic paralysis (TPP) is a rare muscle disorder that manifests with abrupt muscle weakness and hypokalemia associated with hyperthyroidism. It is mostly reported in the Asian population, and rare in Caucasians. Only few cases have been reported in people with black ancestry. Here, we report a rare case of thyrotoxic periodic paralysis revealing Graves' disease in a young Malian. A 17-year-old man was admitted in the Neurology clinic with rapid proximal tetraplegia that started after strenuous physical activities at the school. Clinical examination confirmed the proximal weakness. In addition, he had bilateral ptosis, exophthalmia, and horizontal ophthalmoplegia. Laboratory testing showed normal serum potassium and creatinine, low calcium and TSH levels. However, CK, FT4, thyroid stimulating hormone antibody, and acetylcholine receptor antibody levels were high. In addition, electrocardiogram was normal while thyroid Doppler-ultrasound showed heterogeneous, hypoechogenic, hypertrophic, and hyper vascularized gland. Patient had completely recovered his limb weakness within the following hours with symptomatic treatment. The clinical findings were consistent with Graves' disease, and he was put on Neomercazole. He did not present another episode of paralysis after 4-years of follow up. This is a first case of thyrotoxic periodic paralysis reported in Mali and one of the rare cases in sub-Saharan Africa. Despite its scarcity, all patients with acute weakness consecutive to effort, whether recurring or not, should be screened for TPP.

A Real-World Experience of Hyperkalemia Management Using Sodium Zirconium Cyclosilicate in Chronic Hemodialysis: A Multicenter Clinical Audit.

INTRODUCTION:  Hyperkalemia, a common condition among hemodialysis (HD) patients, is associated with adverse health outcomes. Evidence of the safety and efficacy of a potassium-binder, sodium zirconium cyclosilicate (SZC), has been limited among Asian (HD) patients beyond phase 3 trials. This article demonstrates real-world evidence of SZC usage in an Asian cohort of HD patients. METHODS:  A retrospective clinical audit was conducted among 293 patients who received maintenance HD at community-based dialysis centers in Singapore. Patients received SZC for either management of hyperkalemia or hyperkalemia prevention during anticipated disruption to dialysis, such as during traveling. Among patients treated for hyperkalemia (N = 147), serum potassium (K+) prior to SZC initiation and at the endpoint was compared using a paired Student's t-test. Changes in K+ from baseline to endpoint were compared across various categories within each demographic and health-related variables using either Student's t-test or one-way ANOVA. Patients who experienced adverse events after SZC initiation or were deceased during the audit were reviewed to provide a descriptive account. RESULTS:  Among patients who received SZC for hyperkalemia treatment, SZC use was associated with a significant reduction of 0.812 mmol/L in serum potassium. Patients with ethnicities other than Chinese, Malay, or Indian had a nominal reduction in K+ of 0.7 mmol/L and this can be accounted for the small sample size of this sub-group. The three main ethnicities which represented more than 95% of the sample showed a significant reduction in K+ levels (all three p<0.001). This is consistent with other studies with SZC which showed efficacy across various ethnicities. Patients who received SZC for hyperkalemia treatment or prevention had a significant lowering of mortality rate. This mortality reduction may have inherent biases and confounders, due to the retrospective clinical audit study design.  Conclusions: Overall, SZC was safe and effective among the audited patients. The efficacy in the real-world setting was similar to previous trials. The novel use of SZC to manage serum potassium when HD sessions are missed, such as during traveling, warrants further investigation due to potentially significant life-saving implications.

A Novel Frameshift Mutation of SCNN1G Causing Liddle Syndrome with Normokalemia.

BACKGROUND: Liddle syndrome (LS) is an autosomal dominant disorder caused by single-gene mutations of the epithelial sodium channel (ENaC). It is characterized by early-onset hypertension, spontaneous hypokalemia and low plasma renin and aldosterone concentrations. In this study, we reported an LS pedigree with normokalemia resulting from a novel SCNN1G frameshift mutation. METHODS: Peripheral blood samples were collected from the proband and eight family members for DNA extraction. Next-generation sequencing and Sanger sequencing were performed to identify the SCNN1G mutation. Clinical examinations were used to comprehensively evaluate the phenotypes of two patients. RESULTS: Genetic analysis identified a novel SCNN1G frameshift mutation, p.Arg586Valfs*598, in the proband with LS. This heterozygous frameshift mutation generated a premature stop codon and deleted the vital PY motif of ENaC. The same mutation was present in his elder brother with LS, and his mother without any LS symptoms. Biochemical examination showed normokalemia in the three mutation carriers. The mutation identified was not found in any other family members, 100 hypertensives, or 100 healthy controls. CONCLUSIONS: Our study identified a novel SCNN1G frameshift mutation in a Chinese family with LS, expanding the genetic spectrum of SCNN1G. Genetic testing helped us identify LS with a pathogenic mutation when the genotypes and phenotype were not completely consistent because of the hypokalemia. This case emphasizes that once a proband is diagnosed with LS by genetic testing, family genetic sequencing is necessary for early diagnosis and intervention for other family members, to protect against severe cardiovascular complications.