BACKGROUND:Hyperkalemia can be detected by point-of-care (POC) blood testing and by artificial intelligence- enabled electrocardiography (ECG). These 2 methods of detecting hyperkalemia have not been compared. OBJECTIVE:To determine the accuracy of POC and ECG potassium measurements for hyperkalemia detection in patients with critical illness. METHODS:This retrospective study involved intensive care patients in an academic medical center from October 2020 to September 2021. Patients who had 12-lead ECG, POC potassium measurement, and central laboratory potassium measurement within 1 hour were included. The POC potassium measurements were obtained from arterial blood gas analysis; ECG potassium measurements were calculated by a previously developed deep learning model. Hyperkalemia was defined as a central laboratory potassium measurement of 5.5 mEq/L or greater. RESULTS:Fifteen patients with hyperkalemia and 252 patients without hyperkalemia were included. The POC and ECG potassium measurements were available about 35 minutes earlier than central laboratory results. Correlation with central laboratory potassium measurement was better for POC testing than for ECG (mean absolute errors of 0.211 mEq/L and 0.684 mEq/L, respectively). For POC potassium measurement, area under the receiver operating characteristic curve (AUC) to detect hyperkalemia was 0.933, sensitivity was 73.3%, and specificity was 98.4%. For ECG potassium measurement, AUC was 0.884, sensitivity was 93.3%, and specificity was 63.5%. CONCLUSIONS:The ECG potassium measurement, with its high sensitivity and coverage rate, may be used initially and followed by POC potassium measurement for rapid detection of life-threatening hyperkalemia.

Abstract Background Hyperthyroidism is frequently under-recognized and leads to heart failure and mortality. Timely identification of high-risk patients is a prerequisite to effective antithyroid therapy. Since the heart is very sensitive to hyperthyroidism and its electrical signature can be demonstrated by electrocardiography, we developed an artificial intelligence model to detect hyperthyroidism by electrocardiography and examined its potential for outcome prediction. Methods The deep learning model was trained using a large dataset of 47,245 electrocardiograms from 33,246 patients at an academic medical center. Patients were included if electrocardiograms and measurements of serum thyroid-stimulating hormone were available that had been obtained within a three day period. Serum thyroid-stimulating hormone and free thyroxine were used to define overt and subclinical hyperthyroidism. We tested the model internally using 14,420 patients and externally using two additional test sets comprising 11,498 and 596 patients, respectively. Results The performance of the deep learning model achieves areas under the receiver operating characteristic curves (AUCs) of 0.725–0.761 for hyperthyroidism detection, AUCs of 0.867–0.876 for overt hyperthyroidism, and AUC of 0.631–0.701 for subclinical hyperthyroidism, superior to a traditional features-based machine learning model. Patients identified as hyperthyroidism-positive by the deep learning model have a significantly higher risk (1.97–2.94 fold) of all-cause mortality and new-onset heart failure compared to hyperthyroidism-negative patients. This cardiovascular disease stratification is particularly pronounced in subclinical hyperthyroidism, surpassing that observed in overt hyperthyroidism. Conclusions An innovative algorithm effectively identifies overt and subclinical hyperthyroidism and contributes to cardiovascular risk assessment.

Context: Abnormal serum calcium concentrations affect the heart and may alter the electrocardiogram (ECG), but the detection of hypocalcemia and hypercalcemia (collectively dyscalcemia) relies on blood laboratory tests requiring turnaround time.Objective: The study aimed to develop a bloodless artificial intelligence (AI)-enabled (ECG) method to rapidly detect dyscalcemia and analyze its possible utility for outcome prediction. Methods: This study collected 86,731 development, 15,611 tuning, 11,105 internal validation, and 8401 external validation ECGs from electronic medical records with at least 1 ECG associated with an albumin-adjusted calcium (aCa) value within 4 h. The main outcomes were to assess the accuracy of AI-ECG to predict aCa and follow up these patients for all-cause mortality, new-onset acute myocardial infraction (AMI), and new-onset heart failure (HF) to validate the ability of AI-ECG-aCa for previvor identification.Results: ECG-aCa had mean absolute errors (MAE) of 0.78/0.98 mg/dL and achieved an area under receiver operating characteristic curves (AUCs) 0.9219/0.8447 and 0.8948/0.7723 to detect severe hypercalcemia and hypocalcemia in the internal/external validation sets, respectively. Although < 20 % variance of ECG-aCa could be explained by traditional ECG features, the ECG-aCa was found to be associated with more complications. Patients with ECG-hypercalcemia but initially normal aCa were found to have a higher risk of subsequent all -cause mortality [hazard ratio (HR): 2.05, 95 % conference interval (CI): 1.55-2.70], new-onset AMI (HR: 2.88, 95 % CI: 1.72-4.83), and new-onset HF (HR: 2.02, 95 % CI: 1.38-2.97) in the internal validation set, which were also seen in external validation.Conclusion: The AI-ECG-aCa may help detecting severe dyscalcemia for early diagnosis and ECG-hypercalcemia also has prognostic value for clinical outcomes (all-cause mortality and new-onset AMI and HF).

Dyskalemias are common electrolyte disorders associated with high cardiovascular risk. Artificial intelligence (AI)-assisted electrocardiography (ECG) has been evaluated as an early-detection approach for dyskalemia. The aims of this study were to determine the clinical accuracy of AI-assisted ECG for dyskalemia and prognostic ability on clinical outcomes such as all-cause mortality, hospitalizations, and ED revisits. This retrospective cohort study was done at two hospitals within a health system from May 2019 to December 2020. In total, 26,499 patients with 34,803 emergency department (ED) visits to an academic medical center and 6492 ED visits from 4747 patients to a community hospital who had a 12-lead ECG to estimate ECG-K+ and serum laboratory potassium measurement (Lab-K+) within 1 h were included. ECG-K+ had mean absolute errors (MAEs) of ≤0.365 mmol/L. Area under receiver operating characteristic curves for ECG-K+ to predict moderate-to-severe hypokalemia (Lab-K+ ≤3 mmol/L) and moderate-to-severe hyperkalemia (Lab-K+ ≥ 6 mmol/L) were >0.85 and >0.95, respectively. The U-shaped relationships between K+ concentration and adverse outcomes were more prominent for ECG-K+ than for Lab-K+. ECG-K+ and Lab-K+ hyperkalemia were associated with high HRs for 30-day all-cause mortality. Compared to hypokalemic Lab-K+, patients with hypokalemic ECG-K+ had significantly higher risk for adverse outcomes after full confounder adjustment. In addition, patients with normal Lab-K+ but dyskalemic ECG-K+ (pseudo-positive) also exhibited more co-morbidities and had worse outcomes. Point-of-care bloodless AI ECG-K+ not only rapidly identified potentially severe hypo- and hyperkalemia, but also may serve as a biomarker for medical complexity and an independent predictor for adverse outcomes.

Context: Thyrotoxic periodic paralysis (TPP) characterized by acute weakness, hypokalemia, and hyperthyroidism is a medical emergency with a great challenge in early diagnosis since most TPP patients do not have overt symptoms. Objective: This work aims to assess artificial intelligence (AI)-assisted electrocardiography (ECG) combined with routine laboratory data in the early diagnosis of TPP. Methods: A deep learning model (DLM) based on ECG12Net, an 82-layer convolutional neural network, was constructed to detect hypokalemia and hyperthyroidism. The development cohort consisted of 39 ECGs from patients with TPP and 502 ECGs of hypokalemic controls; the validation cohort consisted of 11 ECGs of TPP patients and 36 ECGs of non-TPP individuals with weakness. The AI-ECG-based TPP diagnostic process was then consecutively evaluated in 22 male patients with TTP-like features. Results: In the validation cohort, the DLM-based ECG system detected all cases of hypokalemia in TPP patients with a mean absolute error of 0.26 mEq/L and diagnosed TPP with an area under curve (AUC) of approximately 80%, surpassing the best standard ECG parameter (AUC = 0.7285 for the QR interval). Combining the AI predictions with the estimated glomerular filtration rate and serum chloride boosted the diagnostic accuracy of the algorithm to AUC 0.986. In the prospective study, the integrated AI and routine laboratory diagnostic system had a PPV of 100% and F-measure of 87.5%. Conclusion: An AI-ECG system reliably identifies hypokalemia in patients with paralysis, and integration with routine blood chemistries provides valuable decision support for the early diagnosis of TPP.

BackgroundThe detection of dyskalemias—hypokalemia and hyperkalemia—currently depends on laboratory tests. Since cardiac tissue is very sensitive to dyskalemia, electrocardiography (ECG) may be able to uncover clinically important dyskalemias before laboratory results. ObjectiveOur study aimed to develop a deep-learning model, ECG12Net, to detect dyskalemias based on ECG presentations and to evaluate the logic and performance of this model. MethodsSpanning from May 2011 to December 2016, 66,321 ECG records with corresponding serum potassium (K+) concentrations were obtained from 40,180 patients admitted to the emergency department. ECG12Net is an 82-layer convolutional neural network that estimates serum K+ concentration. Six clinicians—three emergency physicians and three cardiologists—participated in human-machine competition. Sensitivity, specificity, and balance accuracy were used to evaluate the performance of ECG12Net with that of these physicians. ResultsIn a human-machine competition including 300 ECGs of different serum K+ concentrations, the area under the curve for detecting hypokalemia and hyperkalemia with ECG12Net was 0.926 and 0.958, respectively, which was significantly better than that of our best clinicians. Moreover, in detecting hypokalemia and hyperkalemia, the sensitivities were 96.7% and 83.3%, respectively, and the specificities were 93.3% and 97.8%, respectively. In a test set including 13,222 ECGs, ECG12Net had a similar performance in terms of sensitivity for severe hypokalemia (95.6%) and severe hyperkalemia (84.5%), with a mean absolute error of 0.531. The specificities for detecting hypokalemia and hyperkalemia were 81.6% and 96.0%, respectively. ConclusionsA deep-learning model based on a 12-lead ECG may help physicians promptly recognize severe dyskalemias and thereby potentially reduce cardiac events.

Background: Teaching the practice of high-value care (HVC) is an increasingly important function of graduate medical education but best practices and long-term outcomes remain unknown. Objective: Whether a multimodal curriculum designed to address specific drivers of low-value care would affect resident attitudes, skills, and performance of HVC as tested by the Internal Medicine In-Training Exam (ITE). Methods: In 2012, we performed a baseline needs assessment among internal medicine residents at a community program regarding drivers of healthcare utilization. We then created a multimodal curriculum with online interactive worksheets, lectures, and faculty buy-in to target specific skills, knowledge, and culture deficiencies. Perceived drivers of care and performance on the Internal Medicine ITE were assessed yearly through 2016. Results: Fourteen of 27 (52%) residents completed the initial needs assessment while the curriculum was eventually seen by at least 24 of 27 (89%). The ITE was taken by every resident every year. Long-term, 3-year follow-up demonstrated persistent improvement in many drivers of utilization (patient requests, reliance on subspecialists, defensive medicine, and academic curiosity) and improvement with sustained high performance on the high-value component of the ITE. Conclusion: A multimodal curriculum targeting specific drivers of low-value care can change culture and lead to sustained improvement in the practice of HVC.

BACKGROUND: Uncovering the correct diagnosis of chronic hypokalemia with potassium ( K+) wasting from the kidneys or gut can be fraught with challenges. We identified clinical and laboratory parameters helpful for differentiating the causes of chronic hypokalemia.METHODS: Normotensive patients referred to our tertiary academic medical center for the evaluation of chronic hypokalemia were prospectively enrolled over 5 years. Clinical features, laboratory examinations-including blood and spot urine electrolytes, acid-base status, biochemistries, and hormones-as well as genetic analysis, were determined.RESULTS: Ninety-nine patients with chronic normotensive hypokalemia (serum K+ 2.8 +/- 0.4 mmol/L, duration 4.1 +/- 0.9 years) were enrolled. Neuromuscular symptoms were the most common complaints. Although Gitelman syndrome (n = 33), Bartter syndrome (n = 10), and distal renal tubular acidosis (n = 12) were the predominant renal tubular disorders, 44 patients (44%) were diagnosed with anorexia/bulimia nervosa (n = 21), surreptitious use of laxatives (n = 11), or diuretics ( n = 12). Patients with gastrointestinal causes and surreptitious diuretics use exhibited a female predominance, lower body mass index, and less K+ supplementation. High urine K+ excretion (transtubular potassium gradient > 3, urine K+/Cr > 2 mmol/mmol) was universally present in patients with renal tubular disorders, but also found in > 50% patients with gastrointestinal causes. Of interest, while urine sodium (Na+) and chloride (Cl (-)) excretions were high and coupled (urineNa(+)/ Cl (-) ratiow1) in renal tubular disorders and "on" diuretics use, skewed or uncoupled urineNa(+) andCl (-) excretions were found in anorexia/bulimia nervosa and laxatives abuse (urine Na+/Cl (-) ratio: 5.0 +/- 2.2, 0.4 +/- 0.2, respectively) and lowurineNa(+) andCl (-) excretions with fixed Na+/Cl (-) ratios ( 0.9 +/- 0.2) when "off" diuretics.CONCLUSION: Besides body mass index, sex, and blood acid-base status, integrated interpretation of the urine Na+: Cl (-) excretion and their ratio is important to make an accurate diagnosis and treatment plan for patients with chronic normotensive hypokalemia. (C) 2017 Elsevier Inc. All rights reserved.

Inactivation of the thiazide-sensitive sodium chloride cotransporter (NCC) due to genetic mutations in Gitelman's syndrome (GS) or pharmacological inhibition with thiazide diuretics causes hypocalciuria and increased bone mineral density (BMD) with unclear extrarenal calcium (Ca2+) regulation. We investigated intestinal Ca2+ absorption and bone Ca2+ metabolism in nonsense Ncc Ser707X (S707X) homozygous knockin mice (Ncc(S707X/S707X) mice). Compared to wild-type and heterozygous knockin littermates, Ncc(S707X/S707X) mice had increased intestinal absorption of Ca-45(2+) and expression of the active Ca2+ transport machinery (transient receptor potential vanilloid 6, calbindin-D-9K, and plasma membrane Ca2+ ATPase isoform 1b). Ncc(S707X/S707X) mice had also significantly increased Ca2+ content accompanied by greater mineral apposition rate (MAR) in their femurs and higher trabecular bone volume, cortical bone thickness, and BMD determined by CT. Their osteoblast differentiation markers, such as bone alkaline phosphatase, procollagen I, osteocalcin, and osterix, were also significantly increased while osteoclast activity was unaffected. Analysis of marrow-derived bone cells, either treated with thiazide or directly cultured from Ncc S707X knockin mice, showed that the differentiation of osteoblasts was associated with increased phosphorylation of mechanical stress-induced focal adhesion kinase (FAK) and extracellular signal-regulated kinase (ERK). In conclusion, NCC inhibition stimulates duodenal Ca2+ absorption as well as osteoblast differentiation and bone Ca2+ storage, possibly through a FAK/ERK dependent mechanism. (c) 2014 American Society for Bone and Mineral Research.

Hormonally inactive adrenocortical carcinoma (ACC) is a rare disease where abdominal discomfort and back pain are common presenting symptoms due to mass effect from a large tumor. Acute kidney injury (AKI) from retroperitoneal tumors has rarely been reported. The most common etiologies include venous thrombosis, ureteral compression, or both. Here, we described a man who presented with AKI from a large retroperitoneal tumor, which was finally diagnosed as a non-functional ACC. The inferior vena cava (IVC) was nearly completely compressed by the large retroperitoneal tumor leading to venous outflow obstruction and AKI. After surgical resection, his urine output increased and renal function recovered. Unfortunately, AKI recurred 2 months later due to recurrence of the tumor. Treatment with a tyrosine kinase inhibitor stabilized his tumor size, and hemodialysis was started. IVC-compression-associated AKI can be the presenting scenario for ACC, a rare but prognostically important aggressive neoplasm.

BACKGROUND: Hypokalemic nonperiodic paralysis represents a group of heterogeneous disorders with a large potassium (K+) deficit. Rapid diagnosis of curable causes with appropriate treatment is challenging to avoid the sequelae of hypokalemia. We prospectively analyzed the etiologies and therapeutic characteristics of hypokalemic nonperiodic paralysis.METHODS: Over an 8-year period, patients with hypokalemic nonperiodic paralysis were enrolled by excluding those with hypokalemic periodic paralysis due to acute shift of K+ into cells. Blood and spot urine samples were collected for the measurements of electrolytes, pH, and biochemistries. Intravenous potassium chloride (KCl) at a rate of 10-20 mmol/h was administered until muscle strength recovered.RESULTS: We had identified 58 patients with hypokalemic nonperiodic paralysis from 208 consecutive patients with hypokalemic paralysis, and their average K+ concentration was 1.8 +/- 0.2 mmol/L. Among patients with low urinary K+ excretion (n = 17), chronic alcoholism, remote diuretic use, and anorexia/bulimia nervosa were the most common causes. Among patients with high urinary K+ excretion (n = 41) and metabolic acidosis, renal tubular acidosis and chronic toluene abuse were the main causes, while primary aldosteronism, Gitelman syndrome, and diuretics were the leading diagnoses with metabolic alkalosis. The average KCl dose needed to restore muscle strength was 3.8 +/- 0.8 mmol/kg. Initial lower plasma K+, volume depletion, and high urinary K+ excretion were associated with higher recovery KCl dosage. During therapy, patients with paradoxical hypokalemia (n = 32) who required more KCl supplementation than patients without (4.1 +/- 0.7 vs 3.4 +/- 0.7 mmol/kg, P < 0.001) often exhibited significantly higher plasma renin activity and received a higher volume of normal saline before its appearance.CONCLUSIONS: Understanding the common etiologies of hypokalemic nonperiodic paralysis may aid in early diagnosis. Patients with initial lower plasma K+, renal K+ wasting, and hypovolemia required higher recovery K+ dosage. Paradoxical hypokalemia is prone to develop in hypovolemic patients even during K+ supplementation with volume repletion. (C) 2015 Elsevier Inc. All rights reserved.

To the Editor: An 86-year-old man presented with recurrent fatigue and exertional dyspnea for 2 months. He had a history of diabetic nephropathy with Stage V chronic kidney disease (CKD) (creatinine, 4.7 mg/dL; estimated glomerular filtration rate, 12.6 mL/min per 1.73 m2), congestive heart failure, and benign prostatic hyperplasia. His regular medications included clopidogrel, aspirin, terazosin, furosemide, digoxin, and insulin. Two months earlier, he had received phenazopyridine 100 mg three times a day for 10 days to treat lower urinary tract symptoms. He was then admitted with severe anemia (hemoglobin, 6 g/dL; baseline, 9 g/dL), presumably secondary to advanced renal failure and treated with blood transfusions followed by regular erythropoietin administration (6,000 IU subcutaneously weekly). Ten days before the present admission, he had resumed phenazopyridine 100 mg three times daily to treat lower urinary tract symptoms. On physical examination, he had pale conjunctiva without sclera icterus. The remainder of the physical examination was unremarkable. Pertinent laboratory studies showed severe anemia (hemoglobin, 6.0 g/dL), high lactate dehydrogenase (LDH; 354 U/L), low haptoglobin (22 mg/dL), and a negative Coomb's test. Stool examination was negative for occult blood. His serum levels of C-reactive protein, albumin, C3, C4, antinuclear antibody, and tumor markers were normal. Results of relevant laboratory studies are shown in Table 1. Peripheral blood smear revealed hypochromic red blood cells, schistocytes, and bite cells. Hemolytic anemia was diagnosed because of a sudden fall in the hemoglobin, high LDH, and the abnormal peripheral smear. Glucose-6-phosphate dehydrogenase level was normal. After phenazopyridine and blood transfusions were stopped, his hemoglobin level remained stable at approximately 9 g/dL, without fragmented red blood cells on the blood smear. His serum creatinine concentration remained at approximately 4.9 mg/dL over the following 3 months. This elderly man with diabetes mellitus with exertional dyspnea and fatigue was found to have acute anemia. Acute hemolytic anemia was established because of the lack of gastrointestinal blood loss or acute inflammation and the appearance of red blood cell fragments on blood smear, high serum LDH, low haptoglobin, and hemoglobinuria. Phenazopyridine-induced hemolytic anemia was diagnosed because of the extended use of phenazopyridine without dose adjustment for CKD and resolution of the hemolytic anemia upon withdrawal of the offending agent. Phenazopyridine has been long been approved for the relief of dysuria because of its local anesthetic effect on the urinary tract mucosa. It is also frequently used as brief adjuvant therapy with antibiotics for the treatment of urinary tract infections. In many countries, it is available over the counter. It is primarily eliminated through the kidneys and has a blood half-life of 7.35 hours in individuals with normal renal function.1 The recommended dose of phenazopyridine is 200 mg three times daily in adults with normal renal function. The dose must be lower in individuals with impaired renal function, although specific dose adjustment based on renal function is not available. Because of its oxidizing properties,2 overdose of phenazopyridine causes devastating complications such as methemoglobinemia and acute renal failure.3 Although phenazopyridine-induced hemolysis was first reported four decades ago,4 this serious adverse effect has been reported in only four individuals with advanced CKD, including this man. Phenazopyridine may overwhelm the red blood cell's reductase enzyme systems, which normally provide the reduced glutathione that protects the sulfhydryl groups of hemoglobin from oxidation. The depleted glutathione may thus precipitate red blood cell hemolysis. Furthermore, advanced CKD per se may deplete other endogenous intracellular and extracellular antioxidant systems5 in addition to reducing the elimination of drugs that cause oxidative hemolysis. The current case of phenazopyridine-induced hemolysis is a prime example of drug-induced hemolytic anemia. Other drugs, including ribavirin, a renally eliminated antiviral drug for hepatitis C, can accumulate without dose adjustment in advanced CKD and cause similar hemolytic anemia by inhibition of glutathione.6 The management of phenazopyridine-induced hemolytic anemia relies on early recognition with prompt withdrawal of the drug. Because of its vague symptoms and other causes of anemia in individuals with CKD, the diagnosis may be easily overlooked, as was initially the case here. Supportive blood transfusions are often needed to maintain hemoglobin levels because there is no direct antidote for phenazopyridine overdose. Given its small molecular weight of 249.7 kD and high water solubility (15.9 g/L), phenazopyridine may be effectively removed from the blood using hemodialysis. Phenazopyridine, a renally eliminated, commonly used urinary tract analgesic, should not be viewed as an innocuous drug, especially in CKD. This case reinforces the importance of a detailed drug history, including over-the-counter medications, and dose adjustment of renally cleared medications. Phenazopyridine- and other drug-induced hemolytic anemias should be kept in mind as a cause of worsening anemia in individuals with advanced CKD. Conflict of Interest: None. Author Contributions: All authors were involved in management of the case in the Tri-Service General Hospital. All authors were involved in review of the literature on drug-induced hemolytic anemia and in writing the manuscript. Sponsor's Role: None.

A 15-year-old Chinese girl presented to the emergency department with muscle paralysis of bilateral lower extremities over the course of 1 day. She had a 2-year history of polyuria, nocturia, and rampant dental caries and calculi. She denied vomiting, diarrhea, or use of alcohol, laxatives, or diuretics, and her family history was unremarkable. Her pulse rate was 90/min, blood pressure 112/72 mmHg, and body temperature 36.4 °C. Physical examination revealed severe dental caries and calculi (Fig. 1a) with dry oral mucosa. Her thyroid gland was not enlarged. Neurologic examination disclosed symmetric flaccid paralysis with areflexia of both lower extremities. The remainder of the physical examination was unremarkable. The most striking biochemical abnormalities were profound hypokalemia (1.8 mEq/l) and hyperchloremic metabolic acidosis (pH 7.28, HCO3 – 16.6, Na 141 and Cl 114 mEq/l). Her renal, liver, and thyroid function were all normal (creatinine 0.9 mg/dl). Urinalysis revealed proteinuria (1+), low urine specific gravity (1.010), high K excretion (transtubular K gradient 5, 24-h urine K 38 mEq/day), positive urine anion gap (Na 43, K 16 and Cl 39 mEq/l) and persistent alkaline urine (pH 7–7.5). Electrocardiogram revealed prolonged PR interval with flattened T wave. Abdominal ultrasonography showed bilaterally medullary nephrocalcinosis (Fig. 1b). Questions:

BackgroundA comprehensive analysis has not been performed on patients with thyrotoxic periodic paralysis (TPP) characterized by acute hypokalemia and paralysis in the setting of thyrotoxicosis.PurposeThe aim of this study was to analyze the detailed symptomatology of thyrotoxicosis and precipitating factors for the attack in a large cohort of TPP patients.Patients and methodsA prospective observational study enrolled patients with TPP consecutively over 10 years at an academic medical center. Clinical features, including signs/symptoms of thyrotoxicosis and precipitating factors, were analyzed. The Wayne's index was used to assess the severity of thyrotoxicosis at presentation. Patients who agreed to receive an oral glucose-loading test after recovery were evaluated.ResultsAmong the 135 TPP patients (male:female, 130:5), 70% of paralytic attacks occurred in the morning, especially during the seasons of summer and fall. Two-thirds of patients did not have a known family or personal history of hyperthyroidism. Only 17% of TPP patients manifested overt signs/symptoms of thyrotoxicosis (Wayne's index >19). A clear precipitating factor, such as high carbohydrate load, acute upper respiratory tract infection, strenuous exercise, high-salt diet, or the use of steroids or bronchodilators, was identified in only 34% of TPP patients. A glucose load to stimulate insulin secretion induced acute hypokalemia (K+2.47±0.6 mmol/l) with reparalysis in only 18% (10/55) of TPP patients.ConclusionsMost TPP patients have only subtle clinical signs/symptoms of thyrotoxicosis and only a small fraction has clear precipitating factors. In addition to the effects of hyperinsulinemia, other insulin-independent mechanisms may participate in the pathogenesis of TPP.

Stimulation of the OSR1 (Oxidative stress-responsive kinase-1)/SPAK [STE20 (sterile 20)/SPS1-related proline/alanine-rich kinase]-NCC (Na(+)-Cl(-) cotransporter) signaling cascade plays an important role in the WNK [With-No-Lysine (K)] kinase 4 D561A knock-in mouse model of pseudohypoaldosteronism type II (PHA II) characterized by salt-sensitive hypertension and hyperkalemia. The aim of this study was to investigate the respective roles of Osr1 and Spak in the pathogenesis of PHA II in vivo. Wnk4 (D561A/+) mice were crossed with kidney tubule-specific (KSP) Osr1 knockout (KSP-Osr1 (-/-)) and Spak knockout (Spak (-/-)) mice. Blood pressure, plasma and urine biochemistries, and the relevant protein expression in the kidneys were examined. Wnk4 (D561A/+), KSP-Osr1 (-/-), and Spak (-/-) mice recapitulated the phenotypes of PHA II, Bartter-like syndrome, and Gitelman syndrome, respectively. Wnk4 (D561A/+).KSP-Osr1 (-/-) remained phenotypically PHA II while Wnk4 (D561A/+).Spak (-/-) mice became normotensive and lacked the PHA II phenotype. Phosphorylated Spak and Ncc were similarly increased in both Wnk4 (D561A/+) and Wnk4 (D561A/+).KSP-Osr1 (-/-) mice while phosphorylated Ncc normalized in Wnk4 (D561A/+).Spak (-/-) mice. Furthermore, Wnk4 (D561A/+).KSP-Osr1 (-/-) mice exhibited exaggerated salt excretion in response to thiazide diuretics while Wnk4 (D561A/+).Spak (-/-) mice exhibited normal responses. Wnk4(D561A/+).Spak (-/-).KSP-Osr1 (-/-) triple mutant mice had low blood pressure and diminished phosphorylated Ncc. Both SPAK and OSR1 are important in the maintenance of blood pressure but activation of SPAK-NCC plays the dominant role in PHA II. SPAK may be a therapeutic target for disorders with salt-sensitive hypertension related to WNK4 activation.

Ertapenem, a novel carbapenem with long-acting antimicrobial activity, is predominantly eliminated by the kidneys. Acute prolonged neurotoxicity associated with recommended doses of ertapenem in patients with advanced renal failure not yet on dialysis has not been reported. Two patients with Stage 5 chronic kidney disease (CKD) developed progressive hallucinations, asterixis, myoclonic jerks, and cognitive impairment after receiving the recommended dose reduction for CKD of ertapenem (500 mg/d) for 4 days (Case 1: acute cholecystitis) and 5 days (Case 2: arteriovenous fistula infection). Exhaustive diagnostic workups were non-revealing. Plasma ertapenem level measured 24 h after the last dose in Patient 2 was 53.7 mg/l, much higher than the therapeutic MIC90 (2 mg/l). Despite the cessation of ertapenem and initiation of high-flux hemodialysis, their neurologic manifestations lasted for 2 weeks. The structural and pharmacokinetic characteristics of ertapenem such as its high lipophilicity, central nervous penetration, and volume of distribution contributed to sustained neurotoxicity even with significant reduction in plasma ertapenem levels by high-flux hemodialysis. Although ertapenem 500 mg/d has been recommended in patients with glomerular filtration rate less than 30 ml/min/1.73 m2, our 2 cases highlight that this dosage might be excessive for patients with Stage 5 CKD, especially those not yet on dialysis.

A T60M mutation in the thiazide-sensitive sodium chloride cotransporter (NCC) is common in patients with Gitelman's syndrome (GS). This mutation prevents Ste20-related proline and alanine-rich kinase (SPAK)/oxidative stress responsive kinase-1 (OSR1)-mediated phosphorylation of NCC and alters NCC transporter activity in vitro. Here, we examined the physiologic effects of NCC phosphorylation in vivo using a novel Ncc T58M (human T60M) knock-in mouse model. Ncc(T58M/T58M) mice exhibited typical features of GS with a blunted response to thiazide diuretics. Despite expressing normal levels of Ncc mRNA, these mice had lower levels of total Ncc and p-Ncc protein that did not change with a low-salt diet that increased p-Spak. In contrast to wild-type Ncc, which localized to the apical membrane of distal convoluted tubule cells, T58M Ncc localized primarily to the cytosolic region and caused an increase in late distal convoluted tubule volume. In MDCK cells, exogenous expression of phosphorylation-defective NCC mutants reduced total protein expression levels and membrane stability. Furthermore, our analysis found diminished total urine NCC excretion in a cohort of GS patients with homozygous NCC T60M mutations. When Wnk4(D561A/+) mice, a model of pseudohypoaldosteronism type II expressing an activated Spak/Osr1-Ncc, were crossed with Ncc(T58M/T58M) mice, total Ncc and p-Ncc protein levels decreased and the GS phenotype persisted over the hypertensive phenotype. Overall, these data suggest that SPAK-mediated phosphorylation of NCC at T60 regulates NCC stability and function, and defective phosphorylation at this residue corrects the phenotype of pseudohypoaldosteronism type II.