Association of Familial Hyperkalemia and Hypertension with Proximal Renal Tubular Acidosis and Epileptic Seizures.

INTRODUCTION: Familial hyperkalemic hypertension (FHHt) is an inherited disease characterized by hyperkalemia, hypertension, and hyperchloremic acidosis (HCA). The primary defect is a hyperactive sodium chloride co-transporter, expressed in the renal distal tubule. FHHt is caused by mutation in either WNK1, WNK4, KLHL3, or Cul3. The mechanism of HCA is not completely understood. METHODS: Clinical and genetic data were collected from the largest family with FHHt described in the literature. Urine ammonia was measured in 26 family members. Epilepsy was diagnosed clinically. RESULTS: Of the 85 family members, 44 are affected by the Q565E WNK4 mutation, and 28 are newly described. In genetically engineered mice, urinary ammonium was decreased. In our study, urine ammonium did not change. In 11 unaffected subjects, urine ammonia per creatinine was 8.013 ± 3.620 mm/mm, and in 15 subjects affected by FHHt, it was 8.990 ± 4.300 mm/mm (p = 0.546, not significant). Due to the large family size and prolonged follow-up, rare conditions can be identified. Indeed, two children have genetic generalized epilepsy and one child has migraine. The prevalence of epilepsy is 4.545% (2/44) much higher than in the general population (0.681%). This difference is statistically significant (χ2 with Yates correction = 5.127, p = 0.023). CONCLUSIONS: We provide further evidence that the origin of HCA in FHHt lies in the proximal renal tubule. The association of FHHt with epilepsy leads us to speculate that the raised serum K in susceptible subjects may cause a rise in CSF K, and extracellular cerebral K, leading to epilepsy.

Comparison of the Mortality of Non-COVID Hospitalized Patients during the COVID Pandemic: A Retrospective Cohort Study in a Tertiary Medical Center in Israel.

BACKGROUND: At the beginning of 2020, the coronavirus disease 2019 (COVID-19) pandemic presented a new burden on healthcare systems. OBJECTIVES: To evaluate the impact of the COVID-19 pandemic on the outcome of non-COVID patients in Israel. METHODS: We conducted a retrospective observational cohort study at a tertiary medical center in Israel. From December 2018 until June 2022, 6796 patients were hospitalized in the internal medicine wards. Patients were grouped based on their admission date: admitted during COVID waves (waves group), admitted between waves (interim group), and admitted during the same months in the previous year (former-year group). RESULTS: Mortality during hospitalization and 30-day mortality were higher in the waves group compared to the interim and former-year groups (41.4% vs. 30.5% and 24%, 19.4% vs. 17.9% and 12.9%, P < 0.001). In addition, 1-year mortality was higher in the interim group than in the waves and former-year group (39.1 % vs. 32.5% and 33.4%, P = 0.002). There were significant differences in the readmissions, both at 1 year and total number. The waves group had higher rates of mechanical ventilation and noradrenaline administration during hospitalization. Moreover, the waves group exhibited higher troponin levels, lower hemoglobin levels, and more abnormalities in liver and kidney function. CONCLUSIONS: Hospitalized non-COVID patients experienced worse outcomes during the peaks of the pandemic compared to the nadirs and the preceding year, perhaps due to the limited availability of resources. These results underscore the importance of preparing for large-scale threats and implementing effective resource allocation policies.

Process of drug registration in Israel: the correlation between the number of discussions within the Ministry of Health and postapproval variations by EMA and/or FDA.

OBJECTIVES: US FDA and EMA allow facilitated regulatory pathways to expedite access to new treatments. Limited supportive data may result in major postapproval variations. In Israel, partly relying on Food and Drug Administration (FDA) and European Medicines Agency (EMA), clinical data are reviewed independently by the Advisory Committee of Drug Registration (ACDR). In this study, the correlation between the number of discussions at the ACDR and major postapproval variations is examined. DESIGN: This is an observational retrospective comparative cohort study. SETTING: Applications with FDA and/or EMA approval at time of assessment in Israel were included. The timeframe was chosen to allow a minimum of 3 years of postmarketing approval experience for potential major label variations. Data regarding the number of discussions at ACDR were extracted from protocols. Data on postapproval major variations were extracted from the FDA and EMA websites. RESULTS: Between 2014 and 2016, 226 (176 drugs) applications, met the study criteria. 198 (87.6%) and 28 (12.4%) were approved following single and multiple discussions, respectively. A major postapproval variation was recorded in 129 (65.2%) compared with 23 (82.1%) applications approved following single and multiple discussions, respectively (p=0.002). Increased risk for major variation was found for medicines approved following multiple discussions (HR=1.98, 95% CI: 1.26 to 3.09) with a median time of 1.2 years, applications approved based on phase II trials (HR=2.58, 95% CI: 1.72 to 3.87), surrogate endpoints (HR=1.99, 95% CI: 1.44 to 2.74) and oncologic indications (HR=2.48, 95% CI: 1.78 to 3.45). CONCLUSIONS: Multiple ACDR discussions associated with limited supportive data are predictive for major postapproval variations. Moreover, our findings demonstrate that approval by the FDA and/or EMA does not pave the way to automatic approval in Israel. In a substantial per cent of the cases, submission of the same clinical data resulted in different safety and efficacy considerations, requiring additional supporting data in some cases or even rejection of the application in others.

Prevalence and clinical implication of thrombocytopenia and heparin-induced thrombocytopenia in patients who are critically ill with COVID-19.

As the COVID-19 pandemic continues to evolve, different clinical manifestations are better understood and studied. These include various haematologic disorders that have been shown to be associated with increased morbidity and mortality. We studied the prevalence of one unusual manifestation, heparin-induced thrombocytopenia (HIT) and its clinical implications in patients who are severely ill with COVID-19 in a single tertiary centre in Israel. The presence of thrombocytopenia, disseminated intravascular coagulation (DIC) and HIT, and their association with clinical course and outcomes were studied. One-hundred and seven patients with COVID-19 were included. Fifty-seven (53.2%) patients developed thrombocytopenia, which was associated with the worst outcomes (ventilation, DIC and increased mortality). Sixteen (28.0%) patients with thrombocytopenia were positive for HIT, all of which were supported by extracorporeal devices. HIT was independently associated with ventilation days, blood product transfusions, longer hospitalisation and mortality.Platelet abnormalities and HIT are common in patients who are critically ill with COVID-19 and are associated with the worst clinical outcomes. The mechanisms underlying HIT in COVID-19 are yet to be studied; HIT may contribute to the dysregulated immunologic response associated with COVID-19 critical illness and may play a significant part in the coagulopathy seen in these patients. As many patients with COVID-19 require aggressive thromboprophylaxis, further understanding of HIT and the implementation of appropriate protocols are important.

Autoimmune Neutropenia Associated With HHV-6 Virus Infection: A Case Report.

Background: Autoimmune neutropenia (AIN) is divided into primary and secondary forms. The former is more prevalent in children and is usually a self-limiting disease. Secondary AIN is more common in adults and often occurs in the setting of another autoimmune disorder or secondary to infections, malignancies or medications. Several viral and bacterial pathogens were described to trigger AIN. Here we report a case of AIN in an adult woman associated with human herpesvirus-6 (HHV-6) infection. Case Presentation: We report a case of AIN in an adult woman associated with HHV-6 infection. The patient presented to the emergency department with fever and painful genital ulcers. Upon arrival, her laboratory workup demonstrated severe neutropenia and elevated inflammatory markers. She was hospitalized and underwent a thorough infectious, hematological, autoimmune and inflammatory workup. Malignancy was also excluded using an advanced whole body radiological scan. Serological tests confirmed the presence of both acute and chronic types of HHV-6 antibodies, at very high titers. Polymerase chain reaction demonstrated a numerous copies of the virus in the patient's blood. Specific immunofluorescence test confirmed the diagnosis of autoimmune neutropenia. Conclusion: Secondary AIN is a rare disease that may affect all range of ages. The adult type is a challenging disorder that has different etiologies and may be triggered by a variable infectious pathogen. The finding of HHV-6 as a possible culprit pathogen may warrant physicians into widening the evaluation and include HHV-6 in the analysis.

[ETHICAL CHALLENGES IN TREATING CRITICAL CORONAVIRUS PATIENTS: EXPERIENCE FROM THE SHEBA MEDICAL CENTER ON THE FIRST COVID-19 PANDEMIC OUTBREAK].

INTRODUCTION: As the coronavirus pandemic emerged in late 2019, a task force was founded in the Sheba Medical Center and began preparing for the arrival of the pandemic to Israel. Several wards were put in charge of isolated COVID-19 patients. A new intensive care unit was formed for the most critical COVID-19 patients, requiring mechanical ventilation and multi-organ treatment. The Corona ICU began operating in March 2020, with a multi-disciplinary team, gathered from ICU units, an internal medicine ward, an anesthesiology department, social workers and psychologists. Simultaneously, the routine medical center functions in non-corona sections were maintained, as much as possible. The coronavirus pandemic entails challenges of many aspects: an unfamiliar pathogen causing an unknown illness, a necessity for social distancing, ambiguity regarding the risk factors for contamination and illness severity, and medical crews put at risk. Consequently, the pandemic involves ethical, social, economic and moral aspects, affecting the medical crew members and system, the patients and their families, and our society as a whole. In this article we review our joint experience in the Sheba Medical Center Corona ICU, of the medical, ethical and moral dilemmas that emerged from the first COVID-19 wave.

Automated processing of thermal imaging to detect COVID-19.

Rapid and sensitive screening tools for SARS-CoV-2 infection are essential to limit the spread of COVID-19 and to properly allocate national resources. Here, we developed a new point-of-care, non-contact thermal imaging tool to detect COVID-19, based on advanced image processing algorithms. We captured thermal images of the backs of individuals with and without COVID-19 using a portable thermal camera that connects directly to smartphones. Our novel image processing algorithms automatically extracted multiple texture and shape features of the thermal images and achieved an area under the curve (AUC) of 0.85 in COVID-19 detection with up to 92% sensitivity. Thermal imaging scores were inversely correlated with clinical variables associated with COVID-19 disease progression. In summary, we show, for the first time, that a hand-held thermal imaging device can be used to detect COVID-19. Non-invasive thermal imaging could be used to screen for COVID-19 in out-of-hospital settings, especially in low-income regions with limited imaging resources.

The Association between Health and Culture: The Perspective of Older Adult Hospital In-Patients in Israel.

People from different cultures are often hospitalized while the staff treating them do not have sufficient knowledge about the attitudes and feelings of the patients regarding culture and health. To fill this gap, the aim of this study was to examine the perspective of Israeli older adult hospital in-patients regarding the association between health and culture and to understand the meaning of the participants' experiences with regards to the medical staff's attitude towards them. This study was carried out using qualitative methodology that followed the interpretive interactionism approach. The research participants were 493 (mean age 70.81, S.D.: 15.88) in-patients at internal care departments at a hospital in Israel who answered an open-ended question included in the questionnaire as part of a wide study held during 2017 to 2018. Two main themes were found: (1) a humane attitude of respect and the right to privacy and (2) beliefs, values, and traditional medicine that are passed down through generations. The findings highlighted the issue of the patients' cultural heritage and ageist attitudes they ascribed to the professional staff. This study provided recommendations for training the in-patient hospital workforce on the topic of cultural competence, beginning from the stage of diagnosis through treatment and to discharge from the hospital, in order to improve the service.

Human Kidney Spheroids and Monolayers Provide Insights into SARS-CoV-2 Renal Interactions.

BACKGROUND: Although coronavirus disease 2019 (COVID-19) causes significan t morbidity, mainly from pulmonary involvement, extrapulmonary symptoms are also major componen ts of the disease. Kidney disease, usually presenting as AKI, is particularly severe among patients with COVID-19. It is unknown, however, whether such injury results from direct kidney infection with COVID-19's causative virus, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), or from indirect mechanisms. METHODS: Using ex vivo cell models, we sought to analyze SARS-CoV-2 interactions with kidney tubular cells and assess direct tubular injury. These models comprised primary human kidney epithelial cells (derived from nephrectomies) and grown as either proliferating monolayers or quiescent three-dimensional kidney spheroids. RESULTS: We demonstrated that viral entry molecules and high baseline levels of type 1 IFN-related molecules were present in monolayers and kidney spheroids. Although both models support viral infection and replication, they did not exhibit a cytopathic effect and cell death, outcomes that were strongly present in SARS-CoV-2-infected controls (African green monkey kidney clone E6 [Vero E6] cultures). A comparison of monolayer and spheroid cultures demonstrated higher infectivity and replication of SARS-CoV-2 in actively proliferating monolayers, although the spheroid cultures exhibited high er levels of ACE2. Monolayers exhibited elevation of some tubular injury molecules-including molecules related to fibrosis (COL1A1 and STAT6) and dedifferentiation (SNAI2)-and a loss of cell identity, evident by reduction in megalin (LRP2). The three-dimensional spheroids were less prone to such injury. CONCLUSIONS: SARS-CoV-2 can infect kidney cells without a cytopathic effect. AKI-induced cellular proliferation may potentially intensify infectivity and tubular damage by SARS-CoV-2, suggesting that early intervention in AKI is warranted to help minimize kidney infection.

Unprovoked pulmonary embolism in older adults: incidence and prognosis.

INTRODUCTION: Unprovoked pulmonary embolism (UPE) is not rare and it is associated with an unfavorable prognosis in adults. However, the incidence and the prognosis of UPE in older adults have never been studied. MATERIAL AND METHODS: This was a historical prospective study. We reviewed all the medical charts of all older adults (aged 70 years or more) with UPE, provoked pulmonary embolism (PPE), and malignancy-associated PE (MAPE), admitted to a tertiary medical center between 2010 and 2012. The all-cause 3-year mortality rates and cumulative survival following admission were compared between the groups. RESULTS: The final cohort included 249 patients with PE: 161 (64.7%) were women; the mean age was 79.8 ±5.7 years. Overall, 36 (14.5%) patients had UPE, 81 (32.5%) patients had MAPE, and 132 (53.0%) patients had PPE. Overall, 39 (15.7%) patients died within 30 days, 76 (30.5%) patients died within 6 months, 101 (40.6%) patients died within 1 year, and 136 (54.6%) patients died within 3 years of admission. Relative to PPE and MAPE patients, the cumulative survival was significantly higher in UPE patients at each time point within 1 year of admission (p < 0.05 and p < 0.001, respectively). However, 3 years after admission, the cumulative survival was comparable between PPE patients and UPE patients, and was significantly lower in MAPE patients (p < 0.001). CONCLUSIONS: UPE is not rare in older adults with PE, and it is associated with a favorable prognosis within 1 year of admission in this population.

Publisher Correction: Pyroglutamic acidosis as a cause for high anion gap metabolic acidosis: a prospective study.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Pyroglutamic acidosis as a cause for high anion gap metabolic acidosis: a prospective study.

5-oxoprolinemia (pyroglutamic acid, PGA) in the absence of acetaminophen use has been rarely reported as a cause for high anion gap metabolic acidosis. We investigated the prevalence and risk factors for elevated PGA concentrations among hospitalized patients with high anion gap metabolic acidosis: We prospectively enrolled patients with high anion gap metabolic acidosis hospitalized in the department of medicine. For each patient we collected the main diagnosis, concurrent medications and laboratory parameters. Spot urine samples were tested for PGA concentration. Levels ≥63 µmol/mmol creatinine were considered elevated. Overall, forty patients were prospectively followed. Mean age was 66.9 (17.9) years. Four (6.3%) patients had a high urine PGA level and demonstrated also lower blood pH (7.2 vs 7.3, p = 0.05) and lower serum lactate concentration (17.5 mg/dl vs 23.0 mg/dl, p = 0.04). Additionally, the high PGA level group consisted of more patients with septic shock [2/4 (50%) vs 3/36 (8.3%)] with a trend towards significance (p = 0.07). In conclusion, PGA might have a role in patients with septic shock and acidosis. Being a treatable condition, PGA should be taken into consideration particularly when no other cause for high anion gap is identified.

Renal Mg handling, FXYD2 and the central role of the Na,K-ATPase.

This article examines the central role of Na,K-ATPase (α1ß1FXYD2) in renal Mg handling, especially in distal convoluted tubule (DCT), the segment responsible for final regulation of Mg balance. By considering effects of Na,K-ATPase on intracellular Na and K concentrations, and driving forces for Mg transport, we propose a consistent rationale explaining basal Mg reabsorption in DCT and altered Mg reabsorption in some human diseases. FXYD2 (γ subunit) is a regulatory subunit that adapts functional properties of Na,K-ATPase to cellular requirements. Mutations in FXYD2 (G41R), and transcription factors (HNF-1B and PCBD1) that affect FXYD2 expression are associated with hypomagnesemia with hypermagnesuria. These mutations result in impaired interactions of FXYD2 with Na,K-ATPase. Renal Mg wasting implies that Na,K-ATPase is inhibited, but in vitro studies show that FXYD2 itself inhibits Na,K-ATPase activity, raising K0.5 Na. However, FXYD2 also stabilizes the protein by amplifying specific interactions with phosphatidylserine and cholesterol within the membrane. Renal Mg wasting associated with impaired Na,K-ATPase/FXYD2 interactions is explained simply by destabilization and inactivation of Na,K-ATPase. We consider also the role of the Na,K-ATPase in Mg (and Ca) handling in Gitelman syndrome and Familial hyperkalemia and hypertension (FHHt). Renal Mg handling serves as a convenient marker for Na,K-ATPase activity in DCT.

Gender differences in mortality among statin users aged 80 years or more.

BACKGROUND: Little is known about the prognosis associated with statin therapy and its gender differences in older adults aged ≥80 years. OBJECTIVE: To study the mortality and survival associated with statin therapy and their gender differences in older adults aged ≥80 years. METHOD: This was a historical prospective study conducted at a tertiary medical center. The medical charts of all older adults aged ≥80 years who had been admitted to a single internal medicine department during 1 year were reviewed. All-cause 3­year mortality and survival rates following hospital admission in men and in women using statins were investigated. RESULTS: The final cohort included 216 patients: 122 (56.5%) women, mean age 85.3 ± 3.9 years. Overall, 66 (53.2%) women and 58 (46.8%) men used statins for 3 years or more following hospital admission. During this time 48 (39.3%) women and 48 (51.1%) men died. The all-cause 3­year mortality rates were significantly lower only in women who had used statins compared with women who had not used statins (24.2% vs. 57.1%; relative risk = 0.2; 95% confidence interval 0.1-0.5; p < 0.0001). The 3­year cumulative survival rates were significantly higher in women who had used statins as part of primary as well as secondary cardiovascular prevention (p < 0.0001 and p = 0.014, respectively). A Cox regression analysis showed that statin therapy was independently associated with low 3­year cumulative mortality rates in women (hazard ratio=0.3; 95% confidence interval=0.1-0.6; p = 0.001). CONCLUSION: In older adults aged ≥80 years, statin therapy is associated with high 3­year cumulative survival rates only in women.

Hypermagnesuria in Humans Following Acute Intravenous Administration of Digoxin.

BACKGROUND: Hypomagnesemia is a known predisposing condition for the appearance of digitalis toxicity. The detection of a genetic form of Mg urinary wasting with hypomagnesemia being caused by a mutation in the γ subunit (FXYD2) of the Na,K-ATPase, the pharmacological target of Digoxin, prompted us to investigate whether Digoxin administration increases urinary Mg excretion. METHODS: Two groups of subjects, with rapid atrial fibrillation, received intravenous Digoxin (n = 9) or verapamil (n = 8), for heart rate control. During the following 4 h, blood and urinary creatinine, sodium, potassium, calcium, and magnesium levels were determined, and fractional excretion (Fex) values for Na, K, Ca, and Mg were calculated. RESULTS: In the Digoxin group, at 60 min Fex Mg rose from 3.07 ± 1.21 to 7.58 ± 2.51% (an increase of 269 ± 107% of baseline, p < 0.001), and at 240 min to 6.05 ± 2.30% (204 ± 56% of baseline, p < 0.01). No significant change was observed for Fex Na, Fex K, and Fex Ca. A striking correlation was found between individual values of Fex Mg and serum Digoxin concentration (r = 0.678, p < 0.0001). No significant correlation was found between Fex Na or Fex K and serum Digoxin. A correlation of borderline significance was found between Fex Ca and serum Digoxin (r = 0.349, p = 0.073). CONCLUSIONS: The hypermagnesuric effect of acute Digoxin treatment is reminiscent of the effect of the missense mutation in FXYD2, which assumes that FXYD2 is a positive regulator of Na,K-ATPase in the distal convoluted tubule (DCT). The borderline calciuric effect of Digoxin may point to an additional site of action, more proximal to the DCT, that is, the thick ascending limb.

Familial Hyperkalemia and Hypertension (FHHt) and KLHL3: Description of a Family with a New Recessive Mutation (S553L) Compared to a Family with a Dominant Mutation, Q309R, with Analysis of Urinary Sodium Chloride Cotransporter.

BACKGROUND: Familial hyperkalemia and hypertension (FHHt) is an inherited disorder manifested by hyperkalemia and hypertension. The following four causative genes were identified: WNK1, WNK4, CUL3, and KLHL3. For the first 3 genes, inheritance is autosomal dominant. For KLHL3, inheritance is mostly dominant. A few cases with autosomal recessive disease were described. The mechanism of these 2 modes of inheritance is not clear. In the recessive form, the phenotype of heterozygotes is not well described. METHODS: Clinical and genetic investigation of members of 2 families was performed, one with recessive FHHt, and the other, an expansion of a family with Q309R KLHL3 dominant mutation, previously reported by us. Urinary exosomal sodium chloride cotransporter (NCC) was measured. RESULTS: A family with recessive FHHt caused by a new KLHL3 mutation, S553L, is described. This consanguineous Jewish family of Yemenite extraction, included 2 homozygous and 7 heterozygous affected subjects. Increased urinary NCC was found in the affected members of the family with dominant Q309R KLHL3 mutation. In the recessive S553L family, homozygotes appeared to have increased urinary NCC abundance. Surprisingly, heterozygotes seemed to have also increased urinary NCC, though at an apparently lower degree. This was not accompanied by a clinical phenotype. CONCLUSIONS: A new recessive mutation in KLHL3 (S553L) was identified in FHHt. Increased urinary NCC was found in affected members (heterozygous) with dominant KLHL3 Q309R, and in affected members (homozygous) of the recessive form. Unexpectedly, in the recessive disease, heterozygotes seemed to have increased urinary NCC as well, apparently not sufficient quantitatively to produce a clinical phenotype.