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Kamada A, Hirose T, Sato S, Takahashi C, Kaburaki T, Sato K, Ishikawa R, Endo A, Ito H, Oba-Yabana I, Nakamura H, Matsuyama M, Mori T. Construction of arginine vasopressin receptor 2-deficient rats by the rGONAD method. Clin Exp Nephrol 2025:10.1007/s10157-025-02652-5. [PMID: 40102322 DOI: 10.1007/s10157-025-02652-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/16/2024] [Accepted: 02/28/2025] [Indexed: 03/20/2025]
Abstract
BACKGROUND Congenital nephrogenic diabetes insipidus (NDI) is a hereditary disease characterized by a reduced response to arginine vasopressin in the renal collecting duct. NDI is primarily caused by mutations in the arginine vasopressin receptor 2 (AVPR2). Several animal models have been developed for congenital NDI; however, the appropriate models are limited. Thus, we constructed a novel Avpr2-deficient rat model using gene-editing technology to study the pathophysiological mechanisms of NDI. METHODS Avpr2-deficient rats were generated via a novel genome editing approach termed the rat Genome-editing via Oviductal Nucleic Acid Delivery (rGONAD) method. The phenotypes were analyzed using biological, molecular, and histological examinations. The effects of hydrochlorothiazide (40 mg/kg/d) on 24-h water intake, urine volume, and urine osmolality were evaluated in a metabolic cage. RESULTS Avpr2-deficient rats were born and weaned under normal rearing conditions and exhibited symptoms similar to those of human congenital NDI, such as polydipsia, polyuria, and growth retardation. Although they exhibited hydronephrosis-like kidneys, no glomerular or tubular damage was observed. Aquaporin-2 was retained in the cytoplasm of collecting duct cells, and its phosphorylation was suppressed. Administration of hydrochlorothiazide decreased urine volume and improved urine osmolality in Avpr2-deficient rats. CONCLUSIONS Avpr2-deficient rats are a reliable model of congenital NDI for elucidating the underlying mechanisms and identifying therapeutic targets.
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Affiliation(s)
- Ayaka Kamada
- Division of Nephrology and Endocrinology, Faculty of Medicine, Tohoku Medical and Pharmaceutical University, 1-15-1, Fukumuro, Miyagino, Sendai, 983-8536, Japan
| | - Takuo Hirose
- Division of Nephrology and Endocrinology, Faculty of Medicine, Tohoku Medical and Pharmaceutical University, 1-15-1, Fukumuro, Miyagino, Sendai, 983-8536, Japan.
- Division of Integrative Renal Replacement Therapy, Faculty of Medicine, Tohoku Medical and Pharmaceutical University, Sendai, Japan.
| | - Shigemitsu Sato
- Division of Integrative Renal Replacement Therapy, Faculty of Medicine, Tohoku Medical and Pharmaceutical University, Sendai, Japan
| | - Chika Takahashi
- Division of Integrative Renal Replacement Therapy, Faculty of Medicine, Tohoku Medical and Pharmaceutical University, Sendai, Japan
| | - Takahito Kaburaki
- Division of Nephrology and Endocrinology, Faculty of Medicine, Tohoku Medical and Pharmaceutical University, 1-15-1, Fukumuro, Miyagino, Sendai, 983-8536, Japan
| | - Kaori Sato
- Division of Nephrology and Endocrinology, Faculty of Medicine, Tohoku Medical and Pharmaceutical University, 1-15-1, Fukumuro, Miyagino, Sendai, 983-8536, Japan
| | - Risa Ishikawa
- Division of Nephrology and Endocrinology, Faculty of Medicine, Tohoku Medical and Pharmaceutical University, 1-15-1, Fukumuro, Miyagino, Sendai, 983-8536, Japan
| | - Akari Endo
- Division of Nephrology and Endocrinology, Faculty of Medicine, Tohoku Medical and Pharmaceutical University, 1-15-1, Fukumuro, Miyagino, Sendai, 983-8536, Japan
| | - Hiroki Ito
- Division of Nephrology and Endocrinology, Faculty of Medicine, Tohoku Medical and Pharmaceutical University, 1-15-1, Fukumuro, Miyagino, Sendai, 983-8536, Japan
| | - Ikuko Oba-Yabana
- Division of Nephrology and Endocrinology, Faculty of Medicine, Tohoku Medical and Pharmaceutical University, 1-15-1, Fukumuro, Miyagino, Sendai, 983-8536, Japan
| | - Hannah Nakamura
- Division of Nephrology and Endocrinology, Faculty of Medicine, Tohoku Medical and Pharmaceutical University, 1-15-1, Fukumuro, Miyagino, Sendai, 983-8536, Japan
| | - Makoto Matsuyama
- Division of Molecular Genetics, Shigei Medical Research Institute, Okayama, Japan
| | - Takefumi Mori
- Division of Nephrology and Endocrinology, Faculty of Medicine, Tohoku Medical and Pharmaceutical University, 1-15-1, Fukumuro, Miyagino, Sendai, 983-8536, Japan.
- Division of Integrative Renal Replacement Therapy, Faculty of Medicine, Tohoku Medical and Pharmaceutical University, Sendai, Japan.
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Jin X, Ding N, Guo HY, Hu Q. Macrocyclic-based strategy in drug design: From lab to the clinic. Eur J Med Chem 2024; 277:116733. [PMID: 39098132 DOI: 10.1016/j.ejmech.2024.116733] [Citation(s) in RCA: 2] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/05/2024] [Revised: 07/24/2024] [Accepted: 07/25/2024] [Indexed: 08/06/2024]
Abstract
Macrocyclic compounds have emerged as potent tools in the field of drug design, offering unique advantages for enhancing molecular recognition, improving pharmacokinetic properties, and expanding the chemical space accessible to medicinal chemists. This review delves into the evolutionary trajectory of macrocyclic-based strategies, tracing their journey from laboratory innovations to clinical applications. Beginning with an exploration of the defining structural features of macrocycles and their impact on drug-like characteristics, this discussion progresses to highlight key design principles that have facilitated the development of diverse macrocyclic drug candidates. Through a series of illustrative representative case studies from approved macrocyclic drugs and candidates spanning various therapeutic areas, particular emphasis is placed on their efficacy in targeting challenging protein-protein interactions, enzymes, and receptors. Additionally, this review thoroughly examines how macrocycles effectively address critical issues such as metabolic stability, oral bioavailability and selectivity. Valuable insights into optimization strategies employed during both approved and clinical phases underscore successful translation of promising leads into efficacious therapies while providing valuable perspectives on harnessing the full potential of macrocycles in drug discovery and development endeavors.
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Affiliation(s)
- Xin Jin
- Department of Obstetrics and Gynaecology, Shengjing Hospital of China Medical University, Shenyang, China
| | - Ning Ding
- Department of Obstetrics and Gynaecology, Shengjing Hospital of China Medical University, Shenyang, China
| | - Hong-Yu Guo
- Department of Obstetrics and Gynaecology, Shengjing Hospital of China Medical University, Shenyang, China
| | - Qing Hu
- Department of Obstetrics and Gynaecology, Shengjing Hospital of China Medical University, Shenyang, China.
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Warren AM, Grossmann M, Christ-Crain M, Russell N. Syndrome of Inappropriate Antidiuresis: From Pathophysiology to Management. Endocr Rev 2023; 44:819-861. [PMID: 36974717 PMCID: PMC10502587 DOI: 10.1210/endrev/bnad010] [Citation(s) in RCA: 38] [Impact Index Per Article: 19.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/02/2022] [Revised: 02/19/2023] [Accepted: 03/27/2023] [Indexed: 03/29/2023]
Abstract
Hyponatremia is the most common electrolyte disorder, affecting more than 15% of patients in the hospital. Syndrome of inappropriate antidiuresis (SIAD) is the most frequent cause of hypotonic hyponatremia, mediated by nonosmotic release of arginine vasopressin (AVP, previously known as antidiuretic hormone), which acts on the renal V2 receptors to promote water retention. There are a variety of underlying causes of SIAD, including malignancy, pulmonary pathology, and central nervous system pathology. In clinical practice, the etiology of hyponatremia is frequently multifactorial and the management approach may need to evolve during treatment of a single episode. It is therefore important to regularly reassess clinical status and biochemistry, while remaining alert to potential underlying etiological factors that may become more apparent during the course of treatment. In the absence of severe symptoms requiring urgent intervention, fluid restriction (FR) is widely endorsed as the first-line treatment for SIAD in current guidelines, but there is considerable controversy regarding second-line therapy in instances where FR is unsuccessful, which occurs in around half of cases. We review the epidemiology, pathophysiology, and differential diagnosis of SIAD, and summarize recent evidence for therapeutic options beyond FR, with a focus on tolvaptan, urea, and sodium-glucose cotransporter 2 inhibitors.
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Affiliation(s)
- Annabelle M Warren
- Department of Medicine, University of Melbourne, Victoria 3010, Australia
- Department of Endocrinology, The Austin Hospital, Victoria 3084, Australia
| | - Mathis Grossmann
- Department of Medicine, University of Melbourne, Victoria 3010, Australia
- Department of Endocrinology, The Austin Hospital, Victoria 3084, Australia
| | - Mirjam Christ-Crain
- Department of Endocrinology, Diabetology and Metabolism, University Hospital Basel, Basel 4031, Switzerland
- Department of Clinical Research, University of Basel and University Hospital Basel, Basel 4031, Switzerland
| | - Nicholas Russell
- Department of Medicine, University of Melbourne, Victoria 3010, Australia
- Department of Endocrinology, The Austin Hospital, Victoria 3084, Australia
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Krisanapan P, Tangpanithandee S, Thongprayoon C, Pattharanitima P, Kleindienst A, Miao J, Craici IM, Mao MA, Cheungpasitporn W. Safety and Efficacy of Vaptans in the Treatment of Hyponatremia from Syndrome of Inappropriate Antidiuretic Hormone Secretion (SIADH): A Systematic Review and Meta-Analysis. J Clin Med 2023; 12:5483. [PMID: 37685548 PMCID: PMC10488023 DOI: 10.3390/jcm12175483] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/12/2023] [Revised: 08/20/2023] [Accepted: 08/21/2023] [Indexed: 09/10/2023] Open
Abstract
The utilization of vasopressin receptor antagonists, known as vaptans, in the management of hyponatremia among patients afflicted with the syndrome of inappropriate antidiuretic hormone (SIADH) remains a contentious subject. This meta-analysis aimed to evaluate the safety and efficacy of vaptans for treating chronic hyponatremia in adult SIADH patients. Clinical trials and observational studies were identified by a systematic search using MEDLINE, EMBASE, and Cochrane Database from inception through September 2022. The inclusion criteria were the studies that reported vaptans' safety or efficacy outcomes compared to placebo or standard therapies. The study protocol was registered with the International Prospective Register of Systematic Reviews (PROSPERO; CRD 42022357307). Five studies were identified, comprising three RCTs and two cohort studies, enrolling a total of 1840 participants. Regarding short-term efficacy on days 4-5, vaptans exhibited a significant increase in serum sodium concentration from the baseline in comparison to the control group, with a weighted mean difference of 4.77 mmol/L (95% CI, 3.57, 5.96; I2 = 34%). In terms of safety outcomes, the pooled incidence rates of overcorrection were 13.1% (95% CI 4.3, 33.6; I2 = 92%) in the vaptans group and 3.3% (95% CI 1.6, 6.6; I2 = 27%) in the control group. Despite the higher correction rate linked to vaptans, with an OR of 5.72 (95% CI 3.38, 9.70; I2 = 0%), no cases of osmotic demyelination syndrome were observed. Our meta-analysis comprehensively summarizes the efficacy and effect size of vaptans in managing SIADH. While vaptans effectively raise the serum sodium concentration compared to placebo/fluid restriction, clinicians should exercise caution regarding the potential for overcorrection.
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Affiliation(s)
- Pajaree Krisanapan
- Division of Nephrology and Hypertension, Department of Medicine, Mayo Clinic, Rochester, MN 55905, USA; (S.T.); (C.T.); (J.M.); (I.M.C.)
- Division of Nephrology, Department of Internal Medicine, Faculty of Medicine, Thammasat University, Pathum Thani 12120, Thailand;
- Division of Nephrology, Department of Internal Medicine, Thammasat University Hospital, Pathum Thani 12120, Thailand
| | - Supawit Tangpanithandee
- Division of Nephrology and Hypertension, Department of Medicine, Mayo Clinic, Rochester, MN 55905, USA; (S.T.); (C.T.); (J.M.); (I.M.C.)
- Chakri Naruebodindra Medical Institute, Faculty of Medicine Ramathibodi Hospital, Mahidol University, Samut Prakan 10540, Thailand
| | - Charat Thongprayoon
- Division of Nephrology and Hypertension, Department of Medicine, Mayo Clinic, Rochester, MN 55905, USA; (S.T.); (C.T.); (J.M.); (I.M.C.)
| | - Pattharawin Pattharanitima
- Division of Nephrology, Department of Internal Medicine, Faculty of Medicine, Thammasat University, Pathum Thani 12120, Thailand;
| | - Andrea Kleindienst
- Department of Neurosurgery, Friedrich-Alexander-University Nürnberg-Erlangen, 91054 Erlangen, Germany;
| | - Jing Miao
- Division of Nephrology and Hypertension, Department of Medicine, Mayo Clinic, Rochester, MN 55905, USA; (S.T.); (C.T.); (J.M.); (I.M.C.)
| | - Iasmina M. Craici
- Division of Nephrology and Hypertension, Department of Medicine, Mayo Clinic, Rochester, MN 55905, USA; (S.T.); (C.T.); (J.M.); (I.M.C.)
| | - Michael A. Mao
- Division of Nephrology and Hypertension, Department of Medicine, Mayo Clinic, Jacksonville, FL 32224, USA;
| | - Wisit Cheungpasitporn
- Division of Nephrology and Hypertension, Department of Medicine, Mayo Clinic, Rochester, MN 55905, USA; (S.T.); (C.T.); (J.M.); (I.M.C.)
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Fratangelo L, Nguyen S, D'Amelio P. Hyponatremia and aging-related diseases: key player or innocent bystander? A systematic review. Syst Rev 2023; 12:84. [PMID: 37173774 PMCID: PMC10182618 DOI: 10.1186/s13643-023-02246-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/06/2022] [Accepted: 04/24/2023] [Indexed: 05/15/2023] Open
Abstract
BACKGROUND Hyponatremia is frequent in older age; whether it is a key player, a surrogate marker, or an innocent bystander in age-related diseases is still unclear. OBJECTIVE To understand the role of hyponatremia in falls, osteoporosis, fractures, and cognitive impairment in old patients. METHOD Eligibility criteria for study inclusions were: written in English, peer-reviewed observational and intervention studies, clinical trial, prospective and retrospective controlled cohort studies, and case-controlled studies without limitations regarding the date of publication. INFORMATION SOURCES Protocol available on the International Prospective Register of Systematic Reviews (PROSPERO, CRD42021218389). MEDLINE, Embase, and PsycINFO were searched. Final search done on August 8, 2021. Risk-of-bias assessment: Risk-of-Bias Assessment tool for Non-randomized Studies (RoBANS) and the Bradford Hill's criteria for causality. RESULTS Includes studies: One-hundred thirty-five articles retained for the revision. Synthesis of results - Falls: Eleven studies were included. Strong association between hyponatremia and falls in all the studies was found. Osteoporosis and fractures: nineteen articles were included. The association between hyponatremia and osteoporosis is unclear. Cognitive impairment: Five articles were included. No association between hyponatremia and cognitive impairment was found. DISCUSSION Interpretation: Falls, osteoporosis, and fractures are multifactorial. Hyponatremia is not temporally related with the outcomes; we suggest that hyponatremia may be regarded as a marker of unhealthy aging and a confounder instead of a causal factor or an innocent bystander for falls and fractures. Concerning cognitive impairment, there are no evidence supporting a real role of hyponatremia to be regarded as an innocent bystander in neurodegeneration.
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Affiliation(s)
- Luigia Fratangelo
- Service of Geriatric Medicine & Geriatric Rehabilitation, Department of Medicine, Lausanne University Hospital and University of Lausanne, Lausanne, Switzerland.
| | - Sylvain Nguyen
- Service of Geriatric Medicine & Geriatric Rehabilitation, Department of Medicine, Lausanne University Hospital and University of Lausanne, Lausanne, Switzerland
| | - Patrizia D'Amelio
- Service of Geriatric Medicine & Geriatric Rehabilitation, Department of Medicine, Lausanne University Hospital and University of Lausanne, Lausanne, Switzerland
- Department of Medical Science, Geriatric Unit, University of Torino, 10126, Turin, Italy
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Iijima Y, Mizoguchi T, Ishikawa M, Iwai S, Motono N, Uramoto H. Impacts of perioperative hyponatremia relevant to outcomes and prognosis of non-small cell lung cancer in octogenarians. Surgery 2023; 173:1476-1483. [PMID: 37045621 DOI: 10.1016/j.surg.2023.03.004] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/24/2022] [Revised: 01/28/2023] [Accepted: 03/08/2023] [Indexed: 04/14/2023]
Abstract
BACKGROUND A recent study reported the effect of preoperative hyponatremia on postoperative outcomes of patients with non-small cell lung cancer. However, the influence of postoperative hyponatremia on postoperative outcomes has not been completely investigated. METHODS We retrospectively studied 75 octogenarians who underwent pulmonary surgery for non-small cell lung cancer between 2009 and 2018. We divided them into hyponatremic and non-hyponatremic groups, depending on preoperative and immediate postoperative serum sodium levels, and investigated their clinicopathological characteristics and outcomes. Disease-specific survival and cumulative incidence of relapse rates between the two groups were calculated and compared using the stratified Kaplan-Meier method. Univariable and multivariable analyses were performed to identify prognostic factors. RESULTS Preoperative hyponatremia was associated with 66.7% of postoperative respiratory and 88.9% of non-cardiovascular complications. The long-term prognosis of the postoperative hyponatremic group was significantly worse than that of their counterpart. The 3-year disease-specific survival and 3-year cumulative incidence of relapse rate were 55.9% and 46.2%, respectively, and the median observation period after surgery was 37.4 (interquartile range, 23.7-51.0) months for the entire cohort. Kaplan-Meier curves showed that hyponatremia was associated with worse disease-specific survival and cumulative incidence of relapse. Multivariable analysis identified hyponatremia as a factor that predicted unfavorable disease-specific survival and cumulative incidence of relapse. CONCLUSIONS Immediate postoperative hyponatremia is an independent predictor of non-small cell lung cancer outcomes among octogenarians. Preoperative hyponatremia was associated with a high frequency of postoperative respiratory and non-cardiovascular complications. Surgical indications in older patients with hyponatremia should be carefully considered with follow-up.
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Affiliation(s)
- Yoshihito Iijima
- Department of Thoracic Surgery, Kanazawa Medical University, Ishikawa, Japan.
| | - Takaki Mizoguchi
- Department of Thoracic Surgery, Kanazawa Medical University, Ishikawa, Japan
| | - Masahito Ishikawa
- Department of Thoracic Surgery, Kanazawa Medical University, Ishikawa, Japan
| | - Shun Iwai
- Department of Thoracic Surgery, Kanazawa Medical University, Ishikawa, Japan
| | - Nozomu Motono
- Department of Thoracic Surgery, Kanazawa Medical University, Ishikawa, Japan
| | - Hidetaka Uramoto
- Department of Thoracic Surgery, Kanazawa Medical University, Ishikawa, Japan
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Reddy P. Clinical Approach to Euvolemic Hyponatremia. Cureus 2023; 15:e35574. [PMID: 37007374 PMCID: PMC10063237 DOI: 10.7759/cureus.35574] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/09/2023] [Accepted: 02/27/2023] [Indexed: 03/04/2023] Open
Abstract
Euvolemic hyponatremia is frequently encountered in hospitalized patients and the syndrome of inappropriate antidiuretic hormone secretion (SIADH) is the most common cause in most patients. SIADH diagnosis is confirmed by decreased serum osmolality, inappropriately elevated urine osmolality (>100 mosmol/L), and elevated urine sodium (Na) levels. Patients should be screened for thiazide use and adrenal or thyroid dysfunction should be ruled out before making a diagnosis of SIADH. Clinical mimics of SIADH like cerebral salt wasting and reset osmostat should be considered in some patients. The distinction between acute (<48 hours) versus chronic (>48 hours or without baseline labs) hyponatremia and clinical symptomatology are important to initiate proper therapy. Acute hyponatremia is a medical emergency and osmotic demyelination syndrome (ODS) occurs commonly when rapidly correcting any chronic hyponatremia. Hypertonic (3%) saline should be used in patients with significant neurologic symptoms and maximal correction of serum Na level should be limited to <8 mEq over 24 hours to prevent the ODS. Simultaneous administration of parenteral desmopressin is one of the best ways to prevent overly rapid Na correction in high-risk patients. Free water restriction combined with increased solute intake (e.g., urea) is the most effective therapy to treat patients with SIADH. 0.9% saline acts as a hypertonic solution in patients with hyponatremia and should be avoided in the treatment of SIADH due to rapid fluctuations in serum Na levels. Dual effects of 0.9% saline resulting in rapid correction of serum Na during infusion (inducing ODS) and post-infusion worsening of serum Na levels are described in the article with clinical examples.
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The Potential of Self-Assessment and Associated Factors for Delayed Symptomatic Hyponatremia Following Transsphenoidal Surgery: A Single Center Experience. J Clin Med 2022; 12:jcm12010306. [PMID: 36615106 PMCID: PMC9821286 DOI: 10.3390/jcm12010306] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/15/2022] [Revised: 12/12/2022] [Accepted: 12/26/2022] [Indexed: 01/03/2023] Open
Abstract
(1) Background: We identified screening parameters and associated factors for delayed, symptomatic hyponatremia (DSH) following inpatient discharge after transsphenoidal surgery (TSS). (2) Methods: In this prospective, monocentric study, 108 patients who underwent TSS for pituitary pathologies were included, provided with a questionnaire and instructed to document urine specific gravity, fluid intake/urine output, body weight and clinical symptoms for every of five days following discharge from hospital. (3) Results: The overall incidence of DSH within 14 days following discharge from the hospital was 14.8% (n = 9). Symptomatic patients presented on average 8.6 days after surgery. Mild DSH was present in 3.3% of the patients, moderate in 1.6% and severe hyponatremia in 9.8% of patients. Female sex (p = 0.02) and lower BMI (p = 0.02), as well as nausea (66.7%; p < 0.01) and emesis (33.3%; p < 0.05), were associated with DSH. A significant weight delta between morning and afternoon weight two days before the event of DSH between both groups (1.26 kg (n = 5) vs. 0.79 kg (n = 52), p < 0.05) was detected. (4) Conclusions: Handing out a symptom questionnaire at discharge seems to be an easy and feasible tool for the detection of DSH after hospital discharge.
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Pineyro MM, Diaz L, Guzzetti M, Risso M, Pereda J. Acute Sheehan's Syndrome Presenting with Hyponatremia Followed by a Spontaneous Pregnancy. Case Rep Endocrinol 2022; 2022:9181365. [PMID: 36465526 PMCID: PMC9718624 DOI: 10.1155/2022/9181365] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/05/2022] [Revised: 11/05/2022] [Accepted: 11/07/2022] [Indexed: 09/24/2023] Open
Abstract
BACKGROUND Acute Sheehan's syndrome is rare, as well as hyponatremia as its initial manifestation. In addition, spontaneous pregnancy in patients after Sheehan's syndrome is unusual. To our knowledge, no cases of spontaneous pregnancy after acute Sheehan's syndrome have been reported. We describe a case of Sheehan's syndrome that presented with acute hyponatremia and a spontaneous pregnancy. CASE A 34-year-old female developed blood loss during delivery, which required a blood transfusion. On day seven postpartum, she presented with headaches, lethargy, and difficulty in breastfeeding. The workup showed hyponatremia (118 mEq/l), secondary hypothyroidism, and low prolactin levels. Magnetic resonance imaging showed pituitary necrosis. She was treated with NaCl, hydrocortisone (cortisol results were not available), and levothyroxine. Laboratory tests six weeks after discharge showed low IGF-1 and 8 AM cortisol and normal FT4, LH, FSH, and PRL levels. She was able to partially breastfeed until 4 months postpartum. Regular menstrual cycles started three months later. She became spontaneously pregnant one year later. CONCLUSION Acute Sheehan's syndrome should be considered in the evaluation of postpartum patients with suggestive symptoms. Physicians should be aware that hyponatremia could be an initial manifestation of Sheehan's syndrome, which requires a high index of suspicion for diagnosis. Spontaneous pregnancy can occur after acute Sheehan's syndrome.
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Affiliation(s)
- Maria M. Pineyro
- Clinica de Endocrinología y Metabolismo, Hospital de Clínicas, Facultad de Medicina, Universidad de la República, Montevideo, Uruguay
| | - Leonardo Diaz
- Clinica de Endocrinología y Metabolismo, Hospital de Clínicas, Facultad de Medicina, Universidad de la República, Montevideo, Uruguay
| | - Macarena Guzzetti
- Clinica de Endocrinología y Metabolismo, Hospital de Clínicas, Facultad de Medicina, Universidad de la República, Montevideo, Uruguay
| | - Mariana Risso
- Clinica de Endocrinología y Metabolismo, Hospital de Clínicas, Facultad de Medicina, Universidad de la República, Montevideo, Uruguay
| | - Jimena Pereda
- Clinica de Endocrinología y Metabolismo, Hospital de Clínicas, Facultad de Medicina, Universidad de la República, Montevideo, Uruguay
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Lah S, Wahab A, Wakil A. Case report: Primary empty Sella causing secondary adrenal insufficiency and severe yet asymptomatic hyponatremia. Clin Case Rep 2022; 10:e6125. [PMID: 35957779 PMCID: PMC9359028 DOI: 10.1002/ccr3.6125] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/17/2022] [Revised: 06/23/2022] [Accepted: 06/28/2022] [Indexed: 11/12/2022] Open
Abstract
A 61-year-old man presented with incidental hyponatraemia to 118 mmol/L, to which he was asymptomatic. Diagnostic workup revealed a partially empty sella turcica on magnetic resonance imaging. He had associated secondary adrenal insufficiency but other hormonal axes were relatively unaffected. Treatment with cortisol replacement promptly resolved the hyponatraemia.
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Affiliation(s)
| | - Almas Wahab
- Royal North Shore HospitalSt LeonardsNSWAustralia
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Rohrscheib M, Sam R, Raj DS, Argyropoulos CP, Unruh ML, Lew SQ, Ing TS, Levin NW, Tzamaloukas AH. Edelman Revisited: Concepts, Achievements, and Challenges. Front Med (Lausanne) 2022; 8:808765. [PMID: 35083255 PMCID: PMC8784663 DOI: 10.3389/fmed.2021.808765] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/03/2021] [Accepted: 12/13/2021] [Indexed: 11/13/2022] Open
Abstract
The key message from the 1958 Edelman study states that combinations of external gains or losses of sodium, potassium and water leading to an increase of the fraction (total body sodium plus total body potassium) over total body water will raise the serum sodium concentration ([Na]S), while external gains or losses leading to a decrease in this fraction will lower [Na]S. A variety of studies have supported this concept and current quantitative methods for correcting dysnatremias, including formulas calculating the volume of saline needed for a change in [Na]S are based on it. Not accounting for external losses of sodium, potassium and water during treatment and faulty values for body water inserted in the formulas predicting the change in [Na]S affect the accuracy of these formulas. Newly described factors potentially affecting the change in [Na]S during treatment of dysnatremias include the following: (a) exchanges during development or correction of dysnatremias between osmotically inactive sodium stored in tissues and osmotically active sodium in solution in body fluids; (b) chemical binding of part of body water to macromolecules which would decrease the amount of body water available for osmotic exchanges; and (c) genetic influences on the determination of sodium concentration in body fluids. The effects of these newer developments on the methods of treatment of dysnatremias are not well-established and will need extensive studying. Currently, monitoring of serum sodium concentration remains a critical step during treatment of dysnatremias.
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Affiliation(s)
- Mark Rohrscheib
- Department of Medicine, University of New Mexico School of Medicine, Albuquerque, NM, United States
| | - Ramin Sam
- Department of Medicine, Zuckerberg San Francisco General Hospital and Trauma Center, University of California San Francisco School of Medicine, San Francisco, CA, United States
| | - Dominic S Raj
- Department of Medicine, George Washington University, Washington, DC, United States
| | - Christos P Argyropoulos
- Department of Medicine, University of New Mexico School of Medicine, Albuquerque, NM, United States
| | - Mark L Unruh
- Department of Medicine, University of New Mexico School of Medicine, Albuquerque, NM, United States
| | - Susie Q Lew
- Department of Medicine, George Washington University, Washington, DC, United States
| | - Todd S Ing
- Department of Medicine, Stritch School of Medicine, Loyola University Chicago, Maywood, IL, United States
| | - Nathan W Levin
- Mount Sinai Icahn School of Medicine, New York, NY, United States
| | - Antonios H Tzamaloukas
- Research Service, Department of Medicine, Raymond G. Murphy Veterans Affairs Medical Center and University of New Mexico School of Medicine, Albuquerque, NM, United States
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12
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Memon W, Akram A, Popli K, Spriggs JB, Rehman S, Gipson G, Gehr T. Cerebral Salt-Wasting Syndrome in a Patient With Active Pulmonary Tuberculosis. Cureus 2022; 14:e21202. [PMID: 35165637 PMCID: PMC8840384 DOI: 10.7759/cureus.21202] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 01/13/2022] [Indexed: 11/24/2022] Open
Abstract
A 37-year-old female with a medical history of recently diagnosed active pulmonary tuberculosis and a new intracranial lesion presented with altered mental status, nausea, and vomiting for two days. An initial physical examination revealed that the patient was euvolemic. Laboratory findings revealed a serum sodium concentration of 105 mEq/L. During her admission, she was initially managed with lactated ringer solution in the emergency department, followed by 3% normal saline in the intensive care unit, and, eventually, on oral sodium chloride and fluid restriction on discharge. Once she was stabilized, she had episodes of dizziness, and concerns were raised about the salt-wasting syndrome.
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13
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Kumar A, Ghosh M, Jacob JJ. Prevalence of adrenal insufficiency among patients with euvolemic hyponatremia. Endocr Connect 2021; 10:1623-1631. [PMID: 34788227 PMCID: PMC8679923 DOI: 10.1530/ec-21-0500] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/29/2021] [Accepted: 11/17/2021] [Indexed: 01/02/2023]
Abstract
BACKGROUND The diagnosis of syndrome of inappropriate anti-diuresis requires the exclusion of secondary adrenal insufficiency (AI) among patients with euvolemic hyponatremia (EuVHNa). Studies have suggested that about 2.7-3.8% of unselected patients presenting to the emergency room with EuVHNa have undiagnosed AI and it is as high as 15% among patients admitted to specialized units for evaluation of hyponatremia. OBJECTIVE To study the prevalence of AI among in-patients with EuVHNa in a general medical ward setting. METHODS This was a prospective, single-center observational study conducted among general medical in-patients with EuVHNa, defined as patients with a serum sodium <135 mmol/L, clinical euvolemia and urine spot sodium >30 mmol/L. Additionally, patients with recent vomiting, current renal failure, diuretic use and those with uncontrolled hyperglycemia were excluded. Adrenal functions were assessed by a modified adrenocorticotropic hormone (ACTH) stimulation test called the Acton Prolongatum™ stimulation test (APST). A cut-off cortisol value of <18 mg/dL after 60 min of ACTH injection was used to diagnose AI. RESULTS One hundred forty-one patients were included and underwent an APST. APST suggested 20/141 (14.2%) had undiagnosed AI. The commonest cause of AI (9/20) was secondary AI because of the use of steroids including inhaled steroids and indigenous medicines contaminated with steroids. In 5 (3.5%) patients hypopituitarism was newly diagnosed. Despite primary AI (PAI) not commonly presenting as EuVHNa, 2/20 patients had PAI. CONCLUSIONS AI is much commoner in our country, among in-patients with EuVHNa primarily driven by exogenous steroid use and undiagnosed hypopituitarism.
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Affiliation(s)
- Amit Kumar
- Department of Medicine, Christian Medical College and Hospital, Ludhiana, Punjab, India
| | - Maria Ghosh
- Department of Biochemistry, Christian Medical College and Hospital, Ludhiana, Punjab, India
| | - Jubbin Jagan Jacob
- Department of Endocrinology, Christian Medical College and Hospital, Ludhiana, Punjab, India
- Correspondence should be addressed to J J Jacob:
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14
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Arzhan S, Lew SQ, Ing TS, Tzamaloukas AH, Unruh ML. Dysnatremias in Chronic Kidney Disease: Pathophysiology, Manifestations, and Treatment. Front Med (Lausanne) 2021; 8:769287. [PMID: 34938749 PMCID: PMC8687113 DOI: 10.3389/fmed.2021.769287] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/01/2021] [Accepted: 11/04/2021] [Indexed: 12/29/2022] Open
Abstract
The decreased ability of the kidney to regulate water and monovalent cation excretion predisposes patients with chronic kidney disease (CKD) to dysnatremias. In this report, we describe the clinical associations and methods of management of dysnatremias in this patient population by reviewing publications on hyponatremia and hypernatremia in patients with CKD not on dialysis, and those on maintenance hemodialysis or peritoneal dialysis. The prevalence of both hyponatremia and hypernatremia has been reported to be higher in patients with CKD than in the general population. Certain features of the studies analyzed, such as variation in the cut-off values of serum sodium concentration ([Na]) that define hyponatremia or hypernatremia, create comparison difficulties. Dysnatremias in patients with CKD are associated with adverse clinical conditions and mortality. Currently, investigation and treatment of dysnatremias in patients with CKD should follow clinical judgment and the guidelines for the general population. Whether azotemia allows different rates of correction of [Na] in patients with hyponatremic CKD and the methodology and outcomes of treatment of dysnatremias by renal replacement methods require further investigation. In conclusion, dysnatremias occur frequently and are associated with various comorbidities and mortality in patients with CKD. Knowledge gaps in their treatment and prevention call for further studies.
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Affiliation(s)
- Soraya Arzhan
- Department of Internal Medicine, University of New Mexico School of Medicine, Albuquerque, NM, United States
| | - Susie Q. Lew
- Department of Medicine, George Washington University, Washington, DC, United States
| | - Todd S. Ing
- Department of Medicine, Stritch School of Medicine, Loyola University Chicago, Maywood, IL, United States
| | - Antonios H. Tzamaloukas
- Department of Internal Medicine, University of New Mexico School of Medicine, Albuquerque, NM, United States
- Research Service, Raymond G. Murphy Veteran Affairs (VA) Medical Center, Albuquerque, NM, United States
| | - Mark L. Unruh
- Department of Internal Medicine, University of New Mexico School of Medicine, Albuquerque, NM, United States
- Medicine Service, Division of Nephrology, Raymond G. Murphy Veteran Affairs (VA) Medical Center, Albuquerque, NM, United States
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15
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Mansoor F, Kumar J, Kaur N, Sultan S, Tahir H, Dilip A, Khan F, Kumar N, Khalid H, Talpur AS. Frequency of Electrolyte Imbalance in Patients Presenting With Acute Stroke. Cureus 2021; 13:e18307. [PMID: 34725581 PMCID: PMC8553280 DOI: 10.7759/cureus.18307] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 09/27/2021] [Indexed: 11/05/2022] Open
Abstract
Introduction Electrolyte disturbances are commonly reported in acute stroke in studies conducted in the western world. Presently, the data available about the prevalence of electrolyte disturbance in patients with stroke are not sufficient, especially from developing countries. The purpose of our study is to determine the frequency of occurrence of electrolyte imbalance in patients presenting with acute stroke in a tertiary care hospital. Methods This descriptive cross-sectional study was conducted in the department of internal medicine and neurology in a tertiary care hospital, Pakistan, from December 2019 to March 2021. A total of 300 patients, aged between 30 and 70 years, with either ischemic or hemorrhagic stroke, as diagnosed on contrast tomography (CT) scan of the head or magnetic resonance imaging (MRI) of the brain, were enrolled in the study. The biochemical analysis of the stroke patients was done. Results Out of the 300 participants, 139 (46.3%) participants were from the ischemic stroke group while 161 (53.7%) were from the hemorrhagic stroke group. The mean sodium level was significantly lower in the ischemic group as compared to the hemorrhagic group (129.41 ± 3.12 mEq/L vs. 134.42 ± 3.46 mEq/L; p-value: <0.0001). Potassium level was significantly higher in the hemorrhagic group compared to the ischemic group (6.27 ± 1.12 mmol vs. 4.31 ± 0.71 mmol; p-value: <0.0001). Conclusion Patients coming to emergency with stroke should be screened immediately for electrolyte imbalance. Early identification of rapid imbalances of serum electrolytes may aid in prompt medical intervention and resultant improved outcomes in stroke patients. It is crucial that electrolyte imbalances in these patients are closely monitored to avoid any complications.
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Affiliation(s)
- Farah Mansoor
- Internal Medicine, Jinnah Sindh Medical University, Karachi, PAK
| | - Jitesh Kumar
- Internal Medicine, Ghulam Muhammad Mahar Medical College, Sukkur, PAK
| | - Navneet Kaur
- Internal Medicine, Adesh Institute of Medical Sciences and Research, Buchu Kalan, IND
| | - Sandresh Sultan
- Internal Medicine, Jinnah Sindh Medical University, Karachi, PAK
| | - Hamza Tahir
- Internal Medicine, Allama Iqbal Medical College, Lahore, PAK
| | - Anum Dilip
- Internal Medicine, Jinnah Sindh Medical University, Karachi, PAK
| | - Faryal Khan
- Internal Medicine, Jinnah Sindh Medical University, Karachi, PAK
| | - Narindar Kumar
- Internal Medicine, Bhitai Dental and Medical College, Mirpur Khas, PAK
| | - Haya Khalid
- Internal Medicine, Jinnah Sindh Medical University, Karachi, PAK
| | - Abdul Subhan Talpur
- Internal Medicine, Liaquat University of Medical and Health Sciences, Jamshoro, PAK
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16
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Mulyani EY, Hardinsyah, Briawan D, Santoso BI, Jus'at I. Effect of dehydration during pregnancy on birth weight and length in West Jakarta. J Nutr Sci 2021; 10:e70. [PMID: 34527228 PMCID: PMC8411261 DOI: 10.1017/jns.2021.59] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/06/2021] [Revised: 07/20/2021] [Accepted: 07/22/2021] [Indexed: 11/25/2022] Open
Abstract
Nutrition and maternal behavior are critical factors in fetal development. Maternal water intake is necessary to regulate metabolism and may influence fetal growth. This study aims to determine the effect of dehydration during pregnancy on birth weight and length. This cohort-prospective study took place in the area of Kebon Jeruk District Health Centre. A total of 38 subjects of pregnant women in their second trimester were examined. Subject characteristics were collected through direct measurements and interviews. Urine and blood samples were collected at the sixth trimester (32-34 and 35-37 weeks) to determine hydration status. Nutritional status was collected through food recall, while birth weight and length were obtained from the anthropometric measurements 30 min after birth. From a total of 38 subjects, 20 were dehydrated, and 18 were well hydrated. There was a significant relationship between hydration status and water intake, birth weight and length, head circumference, and chest circumference. After being corrected to the level of water intake, the difference in birth weight and length between the two groups were 500⋅6 g and 0⋅4 cm, and 0⋅8 cm and 1⋅4 cm for the head circumference and chest circumference (P < 0⋅05). It is recommended for mothers to monitor their weight and ensure fluid intake of 3⋅0 l per day. Further research requires more subjects to observe the effects of chronic maternal dehydration on pregnancy output and a cohort study that monitors infant development in the first six months of life.
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Affiliation(s)
- Erry Y. Mulyani
- Department of Nutrition, Faculty of Health Sciences, Esa Unggul University, Jalan Arjuna Utara No.9, Kebon Jeruk11510, West Jakarta, Indonesia
| | - Hardinsyah
- Department of Community Nutrition, Faculty of Human Ecology, Bogor Agricultural University, Bogor, Indonesia
| | - Dodik Briawan
- Department of Community Nutrition, Faculty of Human Ecology, Bogor Agricultural University, Bogor, Indonesia
| | - Budi I. Santoso
- Department of Obstetrics and Gynaecology, Faculty of Medicine, University of Indonesia - Dr. Cipto Mangunkusumo General Hospital, Depok, Indonesia
| | - Idrus Jus'at
- Department of Nutrition, Faculty of Health Sciences, Esa Unggul University, Jalan Arjuna Utara No.9, Kebon Jeruk11510, West Jakarta, Indonesia
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Wang R, Wu ST, Yang X, Qian Y, Choi JP, Gao R, Song S, Wang Y, Zhuang T, Wong JJ, Zhang Y, Han Z, Lu HA, Alexander SI, Liu R, Xia Y, Zheng X. Pdcd10-Stk24/25 complex controls kidney water reabsorption by regulating Aqp2 membrane targeting. JCI Insight 2021; 6:e142838. [PMID: 34156031 PMCID: PMC8262504 DOI: 10.1172/jci.insight.142838] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/11/2020] [Accepted: 05/12/2021] [Indexed: 11/17/2022] Open
Abstract
PDCD10, also known as CCM3, is a gene found to be associated with the human disease cerebral cavernous malformations (CCMs). PDCD10 forms a complex with GCKIII kinases including STK24, STK25, and MST4. Studies in C. elegans and Drosophila have shown a pivotal role of the PDCD10-GCKIII complex in maintaining epithelial integrity. Here, we found that mice deficient of Pdcd10 or Stk24/25 in the kidney tubules developed polyuria and displayed increased water consumption. Although the expression levels of aquaporin genes were not decreased, the levels of total and phosphorylated aquaporin 2 (Aqp2) protein in the apical membrane of tubular epithelial cells were decreased in Pdcd10- and Stk24/25-deficient mice. This loss of Aqp2 was associated with increased expression and membrane targeting of Ezrin and phosphorylated Ezrin, Radixin, Moesin (p-ERM) proteins and impaired intracellular vesicle trafficking. Treatment with Erlotinib, a tyrosine kinase inhibitor promoting exocytosis and inhibiting endocytosis, normalized the expression level and membrane abundance of Aqp2 protein, and partially rescued the water reabsorption defect observed in the Pdcd10-deficient mice. Our current study identified the PDCD10-STK-ERM signaling pathway as a potentially novel pathway required for water balance control by regulating vesicle trafficking and protein abundance of AQP2 in the kidneys.
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Affiliation(s)
- Rui Wang
- Department of Pharmacology, School of Basic Medical Sciences, Tianjin Medical University, China
| | - Shi-Ting Wu
- Department of Pharmacology, School of Basic Medical Sciences, Tianjin Medical University, China
| | - Xi Yang
- Department of Pharmacology, School of Basic Medical Sciences, Tianjin Medical University, China
| | - Yude Qian
- Department of Pharmacology, School of Basic Medical Sciences, Tianjin Medical University, China
| | - Jaesung P Choi
- Lab of Cardiovascular Signaling, Centenary Institute, and Sydney Medical School, University of Sydney, Sydney, Australia
| | - Rui Gao
- Department of Pharmacology, School of Basic Medical Sciences, Tianjin Medical University, China
| | - Siliang Song
- Department of Pharmacology, School of Basic Medical Sciences, Tianjin Medical University, China
| | - Yixuan Wang
- Department of Pharmacology, School of Basic Medical Sciences, Tianjin Medical University, China
| | - Tao Zhuang
- Key Laboratory of Arrhythmias of the Ministry of Education of China, Research Center for Translational Medicine, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, China
| | - Justin Jl Wong
- Epigenetics and RNA Biology Program Centenary Institute and Sydney Medical School, University of Sydney, Sydney, Australia
| | - Yuzhen Zhang
- Key Laboratory of Arrhythmias of the Ministry of Education of China, Research Center for Translational Medicine, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, China
| | - Zhiming Han
- State Key Laboratory of Stem Cell and Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing, China
| | - Hua A Lu
- Division of Nephrology, Department of Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, USA
| | - Stephen I Alexander
- Department of Pediatric Nephrology, The Children's Hospital at Westmead and Centre for Kidney Research, Sydney Medical School, University of Sydney, Sydney, Australia
| | - Renjing Liu
- Vascular Epigenetics Laboratory, Victor Chang Cardiac Research Institute, Sydney, Australia
| | - Yin Xia
- School of Biomedical Sciences, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong, China
| | - Xiangjian Zheng
- Department of Pharmacology, School of Basic Medical Sciences, Tianjin Medical University, China.,Lab of Cardiovascular Signaling, Centenary Institute, and Sydney Medical School, University of Sydney, Sydney, Australia
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18
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Tagetti A, Marcon D, Moghetti P, Spiazzi G, Fava C, Minuz P. Onset of Addison Disease appeared during the first trimester of a twin pregnancy: A case report. Clin Case Rep 2021; 9:e03784. [PMID: 34026120 PMCID: PMC8117816 DOI: 10.1002/ccr3.3784] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/02/2020] [Revised: 10/04/2020] [Accepted: 12/24/2020] [Indexed: 11/29/2022] Open
Abstract
Addison Disease is an uncommon, life‐threatening condition affecting people at any age, including women during pregnancy. If left untreated, the disease can be rapidly fatal, but the prognosis is good if promptly recognized and hormones are replaced.
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Affiliation(s)
- Angela Tagetti
- Department of Medicine Section of General Medicine and Hypertension University of Verona Verona Italy
| | - Denise Marcon
- Department of Medicine Section of General Medicine and Hypertension University of Verona Verona Italy
| | - Paolo Moghetti
- Department of Medicine Section of Endocrinology, Diabetes and Metabolic Disease University of Verona Verona Italy
| | - Giovanna Spiazzi
- Department of Medicine Section of Endocrinology, Diabetes and Metabolic Disease University of Verona Verona Italy
| | - Cristiano Fava
- Department of Medicine Section of General Medicine and Hypertension University of Verona Verona Italy
| | - Pietro Minuz
- Department of Medicine Section of General Medicine and Hypertension University of Verona Verona Italy
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19
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Rosinger AY, Bethancourt H, Swanson ZS, Nzunza R, Saunders J, Dhanasekar S, Kenney WL, Hu K, Douglass MJ, Ndiema E, Braun DR, Pontzer H. Drinking water salinity is associated with hypertension and hyperdilute urine among Daasanach pastoralists in Northern Kenya. THE SCIENCE OF THE TOTAL ENVIRONMENT 2021; 770:144667. [PMID: 33515884 PMCID: PMC7969420 DOI: 10.1016/j.scitotenv.2020.144667] [Citation(s) in RCA: 28] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/06/2020] [Revised: 11/20/2020] [Accepted: 12/15/2020] [Indexed: 05/30/2023]
Abstract
Water salinity is a growing global environmental health concern. However, little is known about the relation between water salinity and chronic health outcomes in non-coastal, lean populations. Daasanach pastoralists living in northern Kenya traditionally rely on milk, yet are experiencing socioecological changes and have expressed concerns about the saltiness of their drinking water. Therefore, this cross-sectional study conducted water quality analyses to examine how water salinity, along with lifestyle factors like milk intake, was associated with hypertension (blood pressure BP ≥140 mm Hg systolic or ≥90 mm Hg diastolic) and hyperdilute urine (urine specific gravity <1.003 g/mL, indicative of altered kidney function). We collected health biomarkers and survey data from 226 non-pregnant adults (46.9% male) aged 18+ from 134 households in 2019 along with participant observations in 2020. The salinity (total concentration of all dissolved salts) of reported drinking water from hand-dug wells in dry river beds, boreholes, and a pond ranged from 120 to 520 mg/L. Water from Lake Turkana and standpipes, which was only periodically used for consumption when no other drinking sources are available, ranged from 1100 to 2300 mg/L. Multiple logistic regression models with standard errors clustered on households indicate that each additional 100 mg/L of drinking water salinity was associated with 45% (95% CI: 1.09-1.93, P = 0.010) increased odds of hypertension and 33% (95% CI: 0.97-1.83, P = 0.075) increased odds of hyperdilute urine adjusted for confounders. Results were robust to multiple specifications of the models and sensitivity analyses. Daily milk consumption was associated with 61-63% (P < 0.01) lower odds of both outcomes. This considerable protective effect of milk intake may be due to the high potassium, magnesium, and calcium contents or the protective lifestyle considerations of moving with livestock. Our study results demonstrate that drinking water salinity may have critical health implications for blood pressure and kidney function even among lean, active pastoralists.
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Affiliation(s)
- Asher Y Rosinger
- Department of Biobehavioral Health, Pennsylvania State University, University Park, PA, United States of America; Department of Anthropology, Pennsylvania State University, State College, PA, United States of America.
| | - Hilary Bethancourt
- Department of Biobehavioral Health, Pennsylvania State University, University Park, PA, United States of America
| | - Zane S Swanson
- Department of Evolutionary Anthropology, Duke University, Durham, NC, United States of America
| | | | - Jessica Saunders
- Department of Evolutionary Anthropology, Duke University, Durham, NC, United States of America
| | - Shiva Dhanasekar
- Department of Anthropology, Emory University, Atlanta, GA, United States of America
| | - W Larry Kenney
- Department of Kinesiology, Pennsylvania State University, University Park, PA, United States of America
| | - Kebin Hu
- Department of Medicine, Pennsylvania State University, Hershey, PA, United States of America
| | - Matthew J Douglass
- College of Agricultural Sciences and Natural Resources and Agricultural Research Division, University of Nebraska-Lincoln, Lincoln, NE, United States of America
| | - Emmanuel Ndiema
- Department of Earth Sciences, National Museums of Kenya, Nairobi, Kenya
| | - David R Braun
- Center for the Advanced Study of Human Paleobiology, Department of Anthropology, The George Washington University, Washington, DC, United States of America; Department of Human Evolution, Max Planck Institute of Evolutionary Anthropology, 04103 Leipzig, Germany
| | - Herman Pontzer
- Department of Evolutionary Anthropology, Duke University, Durham, NC, United States of America; Global Health Institute, Duke University, Durham, NC, United States of America
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20
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Abstract
TRPC3 is a Ca2+-permeable cation channel commonly activated by the G-protein coupled receptors (GPCR) and mechanical distortion of the plasma membrane. TRPC3-mediated Ca2+ influx has been implicated in a variety of signaling processes in both excitable and non-excitable cells. Kidneys play a commanding role in maintaining whole-body homeostasis and setting blood pressure. TRPC3 is expressed abundantly in the renal vasculature and in epithelial cells, where it is well positioned to mediate signaling and transport functions in response to GPCR-dependent endocrine stimuli. In addition, TRPC3 could be activated by mechanical forces resulting from dynamic changes in the renal tubule fluid flow and osmolarity. This review critically analyzes the available published evidence of the physiological roles of TRPC3 in different parts of the kidney and describes the pathophysiological ramifications of TRPC3 ablation. We also speculate how this evidence could be further translated into the clinic.
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Affiliation(s)
- Naghmeh Hassanzadeh Khayyat
- Department of Integrative Biology and Pharmacology, The University of Texas Health Science Center at Houston, Houston, TX, USA
| | - Viktor N. Tomilin
- Department of Integrative Biology and Pharmacology, The University of Texas Health Science Center at Houston, Houston, TX, USA
| | - Oleg Zaika
- Department of Integrative Biology and Pharmacology, The University of Texas Health Science Center at Houston, Houston, TX, USA
| | - Oleh Pochynyuk
- Department of Integrative Biology and Pharmacology, The University of Texas Health Science Center at Houston, Houston, TX, USA
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21
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Clinical management of patients with Cushing syndrome treated with mifepristone: consensus recommendations. Clin Diabetes Endocrinol 2020; 6:18. [PMID: 33292727 PMCID: PMC7596972 DOI: 10.1186/s40842-020-00105-4] [Citation(s) in RCA: 21] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/10/2020] [Accepted: 09/01/2020] [Indexed: 12/17/2022] Open
Abstract
BACKGROUND While surgery is the first-line treatment for patients with endogenous hypercortisolism (Cushing syndrome [CS]), mifepristone has been shown to be a beneficial medical treatment option, as demonstrated in the SEISMIC (Study of the Efficacy and Safety of Mifepristone in the Treatment of Endogenous Cushing Syndrome) trial. Mifepristone is a competitive glucocorticoid receptor antagonist and progesterone receptor antagonist that is associated with several treatment effects and adverse events that clinicians need to be aware of when considering its use. The objective of this review was to provide updated clinical management recommendations for patients with CS treated with mifepristone. METHODS A panel of endocrinologists from the US with extensive experience in treating patients with CS, including with mifepristone, convened as part of a clinical advisory board to develop a consensus on the practical, real-world clinical management of patients on mifepristone. RESULTS Comprehensive considerations and recommendations are provided for managing mifepristone-associated effects, including symptoms of cortisol withdrawal, hypokalemia, and change in thyroid function; effects related to its antiprogesterone activity; and rash. Additional management strategies to address concomitant medications and special clinical situations, such as surgery and use in specific populations, are also provided. CONCLUSION Safe and effective use of mifepristone requires clinical judgment and close patient monitoring to ensure optimal clinical outcomes. These consensus recommendations provide useful, practical guidance to clinicians using mifepristone.
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22
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Nkengne A, Robic J, Lua BL. Self-perceived and objective measurements of facial puffiness in Chinese women. Skin Res Technol 2020; 27:385-392. [PMID: 33089925 DOI: 10.1111/srt.12955] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/10/2020] [Revised: 07/23/2020] [Accepted: 09/07/2020] [Indexed: 11/27/2022]
Abstract
BACKGROUND Facial puffiness, caused by mild or normal fluid retention, commonly experienced by women, may not pose a health risk, but it can be a cause of cosmetic concern. The objectives of this study were to determine whether self-perceived facial puffiness can be measured objectively. MATERIALS AND METHODS A total of 151 Chinese women between 20 and 68 years of age were recruited. Facial water content, skin thickness, and elasticity were measured at two time points within a day (visit one occurred when the participants perceived they had facial puffiness; visit two occurred when the participants perceived their facial puffiness had subsided). Participants were also given a rating scale to self-evaluate their puffiness and firmness at different regions of the face. RESULTS The participants could perceive a difference in facial puffiness between the two visits. Water content and skin thickness were significantly higher in all regions of the face for all participants during the first visit. Skin elasticity was also significantly different between visits one and two. There was a significant increase in water content and skin thickness in the lower eyelid region in women who were older than 40 years. CONCLUSION This is the first study to show that self-perceived facial puffiness can be measured objectively and that skin elasticity can change significantly when facial puffiness subsides.
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Abstract
The recent demonstration of the significant reduction in mortality in patients with septic shock treated with adjunctive glucocorticoids combined with fludrocortisone and the effectiveness of angiotensin II in treating vasodilatory shock have renewed interest in the role of the mineralocorticoid axis in critical illness. Glucocorticoids have variable interactions at the mineralocorticoid receptor. Similarly, mineralocorticoid receptor-aldosterone interactions differ from mineralocorticoid receptor-glucocorticoid interactions and predicate receptor-ligand interactions that differ with respect to cellular effects. Hyperreninemic hypoaldosteronism or selective hypoaldosteronism, an impaired adrenal response to increasing renin levels, occurs in a subgroup of hemodynamically unstable critically ill patients. The suggestion is that there is a defect at the level of the adrenal zona glomerulosa associated with a high mortality rate that may represent an adaptive response aimed at increasing cortisol levels. Furthermore, cross-talk exists between angiotensin II and aldosterone, which needs to be considered when employing therapeutic strategies.
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Morla L, Shore O, Lynch IJ, Merritt ME, Wingo CS. A noninvasive method to study the evolution of extracellular fluid volume in mice using time-domain nuclear magnetic resonance. Am J Physiol Renal Physiol 2020; 319:F115-F124. [PMID: 32475134 DOI: 10.1152/ajprenal.00377.2019] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022] Open
Abstract
Maintaining water homeostasis is fundamental for cellular function. Many diseases and drugs affect water balance and plasma osmolality. Water homeostasis studies in small animals require the use of invasive or terminal methods that make intracellular fluid volume and extracellular fluid volume (ECF) monitoring over time stressful and time consuming. We examined the feasibility of monitoring mouse ECF by a noninvasive method using time-domain nuclear magnetic resonance (TD-NMR). This technique allows differentiation of protons in a liquid environment (free fluid) from protons in soft tissues containing a majority of either small molecules (lean) or large molecules (fat). Moreover, this apparatus enables rapid, noninvasive, and repeated measurements on the same animal. We assessed the feasibility of coupling TD-NMR analysis to a longitudinal metabolic cage study by monitoring mice daily. We determined the effect of 24-h water deprivation on mouse body parameters and detected a sequential and overlapping decrease in free fluid and lean mass during water deprivation. Finally, we studied the effect of mineralocorticoids that are known to induce a transient increase in ECF but for which no direct measurements have been performed in mice. We showed, for the first time, that mineralocorticoids induced a transient ~15% increase in free fluid in conscious mice. TD-NMR is, therefore, the first method to allow direct measurement of discrete changes in ECF in conscious small animals. This method allows analysis of kinetic changes to stimuli before investigating with terminal methods and will allow further understanding of fluid disorders.
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Affiliation(s)
- Luciana Morla
- Centre de Recherche des Cordeliers, Institut National de la Santé et de la Recherche Médicale, Sorbonne Université, USPC, Université Paris Descartes, Université Paris Diderot, Paris, France.,Centre National de la Recherche Scientifique, ERL 8228, Laboratoire de Physiologie Rénale et Tubulopathies, Paris, France
| | - Oliver Shore
- North Florida/South Georgia Veterans Health System, Gainesville, Florida.,Department of Medicine, University of Florida, Gainesville, Florida
| | - I Jeanette Lynch
- North Florida/South Georgia Veterans Health System, Gainesville, Florida.,Department of Medicine, University of Florida, Gainesville, Florida
| | - Matthew E Merritt
- Department of Biochemistry and Molecular Biology, University of Florida, Gainesville, Florida
| | - Charles S Wingo
- North Florida/South Georgia Veterans Health System, Gainesville, Florida.,Department of Medicine, University of Florida, Gainesville, Florida
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25
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Schiara LAM, Moirano G, Grosso E, Richiardi L, Tibaldi M, Spertino E, Vezza C, Isaia GC, Massaia M, D'Amelio P. Hyponatremia, Hypokalemia, and Fragility Fractures in Old Patients: More than an Association? Calcif Tissue Int 2020; 106:599-607. [PMID: 32076748 DOI: 10.1007/s00223-020-00675-6] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/25/2019] [Accepted: 02/08/2020] [Indexed: 12/11/2022]
Abstract
PURPOSE Hyponatremia and hypokalemia are common among elderly and have been associated with osteoporosis, we evaluate the role of these electrolytes as risk for fragility fractures. METHODS This study is divided in two parts: one retrospective and one prospective. We retrospectively collected data on urgently admitted patients for femoral fragility fractures (Fx) or for acute myocardial infarction (AMI), and patients admitted for elective hip/knee replacement surgery for osteoarthrosis (OA). Age, sex, serum sodium, potassium, creatinine, and comorbidities were recorded. We enrolled prospectively in-patients from our unit: age, sex, comorbidities, drugs, and fragility fractures were recorded. Blood electrolytes were measured. Cognitive function, nutrition, muscular strength, and balance were evaluated by standard tests. The mortality rate was recorded with a follow-up after hospital discharge. RESULTS The retrospective study included 2166 subjects: 702 Fx and 1464 controls (907 AMI, 557 OA): the prevalence of hyponatremia was similar in Fx and AMI, whereas it was higher in Fx with respect to OA (p < 0.001) as well as hypokalemia (p < 0.001). Sodium decrease was associated with higher fracture risk. Among the 284 subjects included in the prospective study, 50 patients were hyponatremic, more likely malnourished, and presented a higher prevalence of fragility fractures (p = 0.008). They had a higher mortality after hospital discharge (HR = 1.80, p = 0.005), however, this association disappears after correction for confounding variables. CONCLUSIONS We suggest that hyponatremia and hypokalemia have to be considered as a marker of poor health more than an independent fracture risk.
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Affiliation(s)
- Laura Anna Maria Schiara
- Gerontology Section, Department of Medical Science, University of Torino, Corso Bramante 88/90, 10126, Torino, Italy
| | - Giovenale Moirano
- Cancer Epidemiology Unit-CERMS, Department of Medical Science, University of Torino and CPO-Piemonte, Via Santena 7, 10126, Torino, Italy
| | - Elena Grosso
- Department of Orthopedics, Traumatology, City of Health and Science Hospitals, Via Zuretti 29, 10126, Torino, Italy
| | - Lorenzo Richiardi
- Cancer Epidemiology Unit-CERMS, Department of Medical Science, University of Torino and CPO-Piemonte, Via Santena 7, 10126, Torino, Italy
| | - Michela Tibaldi
- Gerontology Section, Department of Medical Science, University of Torino, Corso Bramante 88/90, 10126, Torino, Italy
| | - Elena Spertino
- Gerontology Section, Department of Medical Science, University of Torino, Corso Bramante 88/90, 10126, Torino, Italy
| | - Carlotta Vezza
- Gerontology Section, Department of Medical Science, University of Torino, Corso Bramante 88/90, 10126, Torino, Italy
| | - Giovanni Carlo Isaia
- Gerontology Section, Department of Medical Science, University of Torino, Corso Bramante 88/90, 10126, Torino, Italy
| | - Massimiliano Massaia
- Gerontology Section, Department of Medical Science, University of Torino, Corso Bramante 88/90, 10126, Torino, Italy
| | - Patrizia D'Amelio
- Gerontology Section, Department of Medical Science, University of Torino, Corso Bramante 88/90, 10126, Torino, Italy.
- Centre Hospitalier Universitaire Vaudoise (CHUV) Service de Gériatrie, Mont Paisible 16 CH, 1011, Lausanne, Switzerland.
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26
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Ibrahim IA, Hassan EA, Ali TZ, Brockmann JG, Aleid HA. Severe hyponatremia after donor nephrectomy. SAUDI JOURNAL OF KIDNEY DISEASES AND TRANSPLANTATION 2020; 31:515-520. [PMID: 32394926 DOI: 10.4103/1319-2442.284028] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/04/2022] Open
Abstract
Living kidney donation is safe and established but can lead to short- and long-term complications. Hyponatremia is the most common disorder of body fluid and electrolyte balance in clinical practice, associated with increased morbidity, mortality, and the length of hospital stay. A correct diagnosis of the etiology of hyponatremia is critical, both to determine correct management and prognosis. Here, we present a case of a severe hyponatremia following left- sided donor nephrectomy with a physical examination suggestive of mild hypovolemia. Laboratory tests revealed high urine osmolality and sodium concentration mimicking syndrome of inappropriate antidiuretic hormone secretion (SIADH), in the setting of abnormally blunted response to Synacthen. The patient responded well to hydrocortisone replacement. Differentiating between primary adrenal insufficiency and SIADH as a cause of severe hyponatremia was the key to successfully treating this patient. Hyponatremia following donor nephrectomy is unusual and could be explained in this case by hypocortisolism.
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Affiliation(s)
- Ihab A Ibrahim
- Department of Kidney Transplantation, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia
| | - Ehab A Hassan
- Department of Kidney Transplantation, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia
| | - Tariq Z Ali
- Department of Kidney Transplantation, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia
| | - Jens G Brockmann
- Department of Kidney Transplantation, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia
| | - Hassan A Aleid
- Department of Kidney Transplantation, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia
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27
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Cheung PW, Bouley R, Brown D. Targeting the Trafficking of Kidney Water Channels for Therapeutic Benefit. Annu Rev Pharmacol Toxicol 2020; 60:175-194. [PMID: 31561739 PMCID: PMC7334826 DOI: 10.1146/annurev-pharmtox-010919-023654] [Citation(s) in RCA: 22] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/21/2023]
Abstract
The ability to regulate water movement is vital for the survival of cells and organisms. In addition to passively crossing lipid bilayers by diffusion, water transport is also driven across cell membranes by osmotic gradients through aquaporin water channels. There are 13 aquaporins in human tissues, and of these, aquaporin-2 (AQP2) is the most highly regulated water channel in the kidney: The expression and trafficking of AQP2 respond to body volume status and plasma osmolality via the antidiuretic hormone, vasopressin (VP). Dysfunctional VP signaling in renal epithelial cells contributes to disorders of water balance, and research initially focused on regulating the major cAMP/PKA pathway to normalize urine concentrating ability. With the discovery of novel and more complex signaling networks that regulate AQP2 trafficking, promising therapeutic targets have since been identified. Several strategies based on data from preclinical studies may ultimately translate to the care of patients with defective water homeostasis.
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Affiliation(s)
- Pui W. Cheung
- Center for Systems Biology, Program in Membrane Biology, and Division of Nephrology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts 02114, USA
| | - Richard Bouley
- Center for Systems Biology, Program in Membrane Biology, and Division of Nephrology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts 02114, USA
| | - Dennis Brown
- Center for Systems Biology, Program in Membrane Biology, and Division of Nephrology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts 02114, USA
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28
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Zhou N, Yang C. A case of extreme hyponatremia without neurologic symptoms. Clin Case Rep 2019; 7:1874-1879. [PMID: 31624600 PMCID: PMC6787862 DOI: 10.1002/ccr3.2383] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/13/2019] [Revised: 07/02/2019] [Accepted: 07/28/2019] [Indexed: 12/25/2022] Open
Abstract
Our case report highlights that profound hyponatremia with sodium level 101 mmol/L could have no CNS symptoms, and drugs and endocrine disorders are relatively common causes and should be considered in the differential diagnosis of hyponatremia. Standard dose trimethoprim-sulfamethoxazole-induced hyponatremia is rare but still worth close attention in clinical practice.
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Affiliation(s)
- Na Zhou
- Kidney Research ClinicUniversity of Utah School of MedicineSalt Lake CityUtah
| | - Chang Yang
- Apogee Hospital MedicinePassavant Area HospitalJacksonvilleIllinois
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29
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Wiśniewski K, Qi S, Kraus J, Ly B, Srinivasan K, Tariga H, Croston G, La E, Wiśniewska H, Ortiz C, Laporte R, Rivière PJM, Neyer G, Hargrove DM, Schteingart CD. Discovery of Potent, Selective, and Short-Acting Peptidic V 2 Receptor Agonists. J Med Chem 2019; 62:4991-5005. [PMID: 31022340 DOI: 10.1021/acs.jmedchem.9b00132] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/30/2022]
Abstract
The vasopressin analogue desmopressin (desamino-d-arginine8 vasopressin, dDAVP, 1) is a potent vasopressin 2 (V2) receptor (V2R) agonist approved in many countries for the treatment of diabetes insipidus, primary nocturnal enuresis, nocturia, and coagulation disorders. Since 1 is primarily excreted via the kidneys, an age-related decline in kidney function leads to slower elimination, prolonged antidiuresis, and hyponatremia. In search of novel, potent, selective, and short-acting peptidic V2R agonists, we synthesized a series of C-terminally truncated analogues of [Val4]dDAVP, 2, modified in positions 2, 3, and 7 and/or at the disulfide bridge. The peptides were evaluated for in vitro potency at the human V2 receptor, selectivity versus the related receptors (human vasopressin 1a receptor, human vasopressin 1b receptor, and human oxytocin receptor), and pharmacokinetic profiles in rodents and other higher species. The truncated analogues show excellent potency at the V2R, increased systemic clearance, and shorter half-life in rats. Two compounds 19 (c(Bua-Cpa-Thi-Val-Asn-Cys)-Pro-Agm) and 38 (c(Bua-Cpa-Thi-Val-Asn-Cys)-Pro-d-Arg-NEt2) have been selected for clinical development for nocturia.
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Affiliation(s)
| | - Steve Qi
- Ferring Research Institute Inc. , San Diego , California 92121 , United States
| | - John Kraus
- Ferring Research Institute Inc. , San Diego , California 92121 , United States
| | - Brian Ly
- Ferring Research Institute Inc. , San Diego , California 92121 , United States
| | - Karthik Srinivasan
- Ferring Research Institute Inc. , San Diego , California 92121 , United States
| | - Hiroe Tariga
- Ferring Research Institute Inc. , San Diego , California 92121 , United States
| | - Glenn Croston
- Ferring Research Institute Inc. , San Diego , California 92121 , United States
| | - Erin La
- Ferring Research Institute Inc. , San Diego , California 92121 , United States
| | - Halina Wiśniewska
- Ferring Research Institute Inc. , San Diego , California 92121 , United States
| | - Carlos Ortiz
- Ferring Research Institute Inc. , San Diego , California 92121 , United States
| | - Régent Laporte
- Ferring Research Institute Inc. , San Diego , California 92121 , United States
| | - Pierre J-M Rivière
- Ferring Research Institute Inc. , San Diego , California 92121 , United States
| | - Gebhard Neyer
- Ferring Research Institute Inc. , San Diego , California 92121 , United States
| | - Diane M Hargrove
- Ferring Research Institute Inc. , San Diego , California 92121 , United States
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30
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Lee ES, Sohn JA, Kim HS, Heo JS, Lee JA. Risk Factors for Brain Damage in Preterm Infants After Late-Onset Circulatory Collapse Events. NEONATAL MEDICINE 2019. [DOI: 10.5385/nm.2019.26.1.55] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/01/2022] Open
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31
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Nagae M, Egi M, Furushima N, Okada M, Makino S, Mizobuchi S. The impact of intravenous isotonic and hypotonic maintenance fluid on the risk of delirium in adult postoperative patients: retrospective before-after observational study. J Anesth 2019; 33:287-294. [PMID: 30806785 DOI: 10.1007/s00540-019-02626-4] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/21/2018] [Accepted: 02/22/2019] [Indexed: 11/28/2022]
Abstract
PURPOSE To assess the impact of intravenous isotonic and hypotonic maintenance fluid on the risk of delirium in adult postoperative patients, we conducted retrospective before-after study in a tertiary teaching hospital. METHODS We examined all adult patients admitted ICU after an elective operation for head and neck cancer, or esophageal cancer from February 2014 to January 2017. From February 2014 to July 2015, patients were administered hypotonic fluid (sodium; 35 mmol/L) as the National Institute for Health and Care Excellence (NICE) have recommended. From August 2015 to January 2017, patients were administered isotonic fluid (sodium; 140 mmol/L). We defined the incidence of delirium as the primary outcome. The delirium was defined as the Intensive Care Delirium Screening Checklist during the ICU stay ≥ 4. A propensity score-matched model was used to adjust confounders. RESULTS As postoperative intravenous maintenance fluid, hypotonic fluid was administered to 119 patients and isotonic fluid was administered to 92 patients. Among those total cohorts, the incidence of postoperative delirium in the hypotonic group was 21.8%, which was significantly higher than that (9.8%) in the isotonic group (p = 0.019). After propensity score matching, we selected 77 patients in each group. The incidence of delirium during the ICU stay in the hypotonic group was 26.0%, which was significantly higher than the incidence of 11.7% in the isotonic group (p = 0.023). CONCLUSIONS In this study, the use of postoperative hypotonic maintenance fluid was associated with a higher risk of postoperative delirium than that when isotonic maintenance fluid was used.
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Affiliation(s)
- Masaharu Nagae
- Department of Anesthesiology, Kobe University Hospital, 7-5-2 Kusunoki-cho, Chuo-ku, Kobe city, 650-0017, Japan
| | - Moritoki Egi
- Department of Anesthesiology, Kobe University Hospital, 7-5-2 Kusunoki-cho, Chuo-ku, Kobe city, 650-0017, Japan.
| | - Nana Furushima
- Department of Anesthesiology, Kobe University Hospital, 7-5-2 Kusunoki-cho, Chuo-ku, Kobe city, 650-0017, Japan
| | - Masako Okada
- Department of Anesthesiology, Kobe University Hospital, 7-5-2 Kusunoki-cho, Chuo-ku, Kobe city, 650-0017, Japan
| | - Shohei Makino
- Department of Anesthesiology, Kobe University Hospital, 7-5-2 Kusunoki-cho, Chuo-ku, Kobe city, 650-0017, Japan
| | - Satoshi Mizobuchi
- Department of Anesthesiology, Kobe University Hospital, 7-5-2 Kusunoki-cho, Chuo-ku, Kobe city, 650-0017, Japan
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32
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Practical document on the management of hyponatremia in critically ill patients. Med Intensiva 2019; 43:302-316. [PMID: 30678998 DOI: 10.1016/j.medin.2018.12.002] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/21/2018] [Revised: 11/29/2018] [Accepted: 12/09/2018] [Indexed: 02/06/2023]
Abstract
Hyponatremia is the most prevalent electrolyte disorder in Intensive Care Units. It is associated with an increase in morbidity, mortality and hospital stay. The majority of the published studies are observational, retrospective and do not include critical patients; hence it is difficult to draw definitive conclusions. Moreover, the lack of clinical evidence has led to important dissimilarities in the recommendations coming from different scientific societies. Finally, etiopathogenic mechanisms leading to hyponatremia in the critical care patient are complex and often combined, and an intensive analysis is clearly needed. A study was therefore made to review all clinical aspects about hyponatremia management in the critical care setting. The aim was to develop a Spanish nationwide algorithm to standardize hyponatremia diagnosis and treatment in the critical care patient.
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33
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Change in natremia as a prognostic marker in patients with acute heart failure. Int J Cardiol 2018; 269:222-223. [DOI: 10.1016/j.ijcard.2018.07.028] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/28/2018] [Accepted: 07/03/2018] [Indexed: 11/18/2022]
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Windpessl M, Karrer A, Schwarz C. Acute Hyponatremia in Puerperium: Sheehan's Syndrome. Am J Med 2018; 131:e147-e148. [PMID: 29253367 DOI: 10.1016/j.amjmed.2017.11.032] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/13/2017] [Revised: 11/17/2017] [Accepted: 11/17/2017] [Indexed: 11/18/2022]
Affiliation(s)
- Martin Windpessl
- Nephrology Section, Fourth Department of Internal Medicine, Klinikum Wels-Grieskirchen, Wels, Austria.
| | - Andreas Karrer
- Department of Radiology, Klinikum Wels-Grieskirchen, Wels, Austria
| | - Christoph Schwarz
- First Department of Internal Medicine, Landeskrankenhaus Steyr, Steyr, Austria
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Bryant JL, Guda PR, Ray S, Asemu G, Sagi AR, Mubariz F, Arvas MI, Khalid OS, Shukla V, Nimmagadda VKC, Makar TK. Renal aquaporin-4 associated pathology in TG-26 mice. Exp Mol Pathol 2018; 104:239-249. [PMID: 29608911 DOI: 10.1016/j.yexmp.2018.03.005] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/04/2018] [Accepted: 03/29/2018] [Indexed: 12/15/2022]
Abstract
Human immunodeficiency virus-associated nephropathy (HIVAN) is a leading cause of end-stage renal disease in HIV patients, which is characterized by glomerulosclerosis and renal tubular dysfunction. Aquaporin-4 (AQP-4) is a membrane bound water channel protein that plays a distinct role in water reabsorption from renal tubular fluid. It has been proven that failure of AQP-4 insertion into the renal tubular membrane leads to renal dysfunction. However, the role of AQP-4 in HIVAN is unclear. We hypothesize that impaired water reabsorption leads to renal injury in HIVAN, where AQP-4 plays a crucial role. Renal function is assessed by urinary protein and serum blood urea nitrogen (BUN). Kidneys from HIV Transgenic (TG26) mice (HIVAN animal model) were compared to wild type mice by immunostaining, immunoblotting and quantitative RT-PCR. TG26 mice had increased proteinuria and BUN. We found decreased AQP-4 levels in the renal medulla, increased endothelin-1, endothelin receptor A and reduced Sirtuin1 (SIRT-1) levels in TG26 mice. Also, oxidative and endoplasmic reticulum stress was enhanced in kidneys of TG26 mice. We provide the first evidence that AQP-4 is inhibited due to induction of HIV associated stress in the kidneys of TG26 mice which limits water reabsorption in the kidney which may be one of the cause associated with HIVAN, impairing kidney physiology. AQP-4 dysregulation in TG26 mice suggests that similar changes may occur in HIVAN patients. This work may identify new therapeutic targets to be evaluated in HIVAN.
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Affiliation(s)
- Joseph L Bryant
- Institute of Human Virology, University of Maryland, Baltimore, MD, United States
| | | | - Sugata Ray
- Department of Neurology, University of Maryland, Baltimore, MD, United States
| | - Girma Asemu
- Institute of Human Virology, University of Maryland, Baltimore, MD, United States
| | - Avinash R Sagi
- Department of Neurology, University of Maryland, Baltimore, MD, United States
| | - Fahad Mubariz
- Department of Neurology, University of Maryland, Baltimore, MD, United States
| | - Muhammed I Arvas
- Department of Neurology, University of Maryland, Baltimore, MD, United States
| | - Omar S Khalid
- Department of Neurology, University of Maryland, Baltimore, MD, United States
| | - Vivek Shukla
- Department of Neurology, University of Maryland, Baltimore, MD, United States
| | - Vamshi K C Nimmagadda
- Department of Neurology, University of Maryland, Baltimore, MD, United States; VA Medical Center, Baltimore, MD, United States
| | - Tapas K Makar
- Department of Neurology, University of Maryland, Baltimore, MD, United States; VA Medical Center, Baltimore, MD, United States.
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Faerch M, Schroeder MK, Mahler BT, Christensen JH, Kamperis K, Rittig S. Determination of the renal concentration capacity following intravenous administration of dDAVP in healthy humans. Scandinavian Journal of Clinical and Laboratory Investigation 2018; 78:114-119. [PMID: 29361858 DOI: 10.1080/00365513.2017.1420215] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 10/18/2022]
Abstract
The synthetic AVP analogue 1-desamino-8-d-arginine-vasopressin (dDAVP) is used for treatment of polyuric disorders. Lack of commercially available assays limits the usefulness of dDAVP as a diagnostic tool in the assessment of renal concentrating capacity. We aimed to develop a specific radioimmunoassay (RIA) for determination of plasma dDAVP (pdDAVP) in order to investigate the relationship between pdDAVP levels and urine osmolality (Uosm). Further, we aimed to determine the onset, duration, and maximum concentrating capacity following intravenous (i.v.) bolus dDAVP injection. The dDAVP assay was based on a well-established RIA for measurements of AVP. Fourteen healthy subjects (aged 15-18 years) participated. Blood and urine samples were collected prior to and after i.v. bolus of 0.03 µg/kg dDAVP. Diuresis and Uosm was measured for nine hours following dDAVP administration. PdDAVP and Uosm were analyzed.We established a specific RIA for the measurement of pdDAVP. All subjects reached maximal pdDAVP concentration (Cmax) 30 minutes following infusion, and a rise in Uosm after 60 minutes. Maximal Uosm varied between subjects, with no direct correlation to the achieved pdDAVP levels. We found no significant intra-individual variation between two dDAVP infusions and the effect was reproducible in terms of Cmax and maximal Uosm. We characterized the relationship between pdDAVP and Uosm after dDAVP bolus injection in healthy adolescents using our dDAVP assay. Maximal Uosm achieved correlated with the baseline Uosm levels and seemed unrelated to achieved pdDAVP levels. The urine concentrating response was maintained at least eight hours.
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Affiliation(s)
- Mia Faerch
- a Department of Pediatrics , Aarhus University Hospital , Aarhus , Denmark
| | - Marie K Schroeder
- b Pediatric Research Laboratory , Aarhus University Hospital , Aarhus , Denmark
| | - Birgitte T Mahler
- a Department of Pediatrics , Aarhus University Hospital , Aarhus , Denmark
| | - Jane H Christensen
- b Pediatric Research Laboratory , Aarhus University Hospital , Aarhus , Denmark.,c Department of Biomedicine , Aarhus University , Aarhus , Denmark
| | | | - Soren Rittig
- a Department of Pediatrics , Aarhus University Hospital , Aarhus , Denmark
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Roumelioti ME, Glew RH, Khitan ZJ, Rondon-Berrios H, Argyropoulos CP, Malhotra D, Raj DS, Agaba EI, Rohrscheib M, Murata GH, Shapiro JI, Tzamaloukas AH. Fluid balance concepts in medicine: Principles and practice. World J Nephrol 2018; 7:1-28. [PMID: 29359117 PMCID: PMC5760509 DOI: 10.5527/wjn.v7.i1.1] [Citation(s) in RCA: 58] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/14/2017] [Revised: 11/16/2017] [Accepted: 11/27/2017] [Indexed: 02/06/2023] Open
Abstract
The regulation of body fluid balance is a key concern in health and disease and comprises three concepts. The first concept pertains to the relationship between total body water (TBW) and total effective solute and is expressed in terms of the tonicity of the body fluids. Disturbances in tonicity are the main factor responsible for changes in cell volume, which can critically affect brain cell function and survival. Solutes distributed almost exclusively in the extracellular compartment (mainly sodium salts) and in the intracellular compartment (mainly potassium salts) contribute to tonicity, while solutes distributed in TBW have no effect on tonicity. The second body fluid balance concept relates to the regulation and measurement of abnormalities of sodium salt balance and extracellular volume. Estimation of extracellular volume is more complex and error prone than measurement of TBW. A key function of extracellular volume, which is defined as the effective arterial blood volume (EABV), is to ensure adequate perfusion of cells and organs. Other factors, including cardiac output, total and regional capacity of both arteries and veins, Starling forces in the capillaries, and gravity also affect the EABV. Collectively, these factors interact closely with extracellular volume and some of them undergo substantial changes in certain acute and chronic severe illnesses. Their changes result not only in extracellular volume expansion, but in the need for a larger extracellular volume compared with that of healthy individuals. Assessing extracellular volume in severe illness is challenging because the estimates of this volume by commonly used methods are prone to large errors in many illnesses. In addition, the optimal extracellular volume may vary from illness to illness, is only partially based on volume measurements by traditional methods, and has not been determined for each illness. Further research is needed to determine optimal extracellular volume levels in several illnesses. For these reasons, extracellular volume in severe illness merits a separate third concept of body fluid balance.
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Affiliation(s)
- Maria-Eleni Roumelioti
- Division of Nephrology, Department of Medicine, University of New Mexico School of Medicine, Albuquerque, NM 87131, United States
| | - Robert H Glew
- Department of Surgery, University of New Mexico School of Medicine, Albuquerque, NM 87131, United States
| | - Zeid J Khitan
- Division of Nephrology, Department of Medicine, Joan Edwards School of Medicine, Marshall University, Huntington, WV 25701, United States
| | - Helbert Rondon-Berrios
- Division of Renal and Electrolyte, Department of Medicine, University of Pittsburgh School of Medicine, Pittsburgh, PA 15260, United States
| | - Christos P Argyropoulos
- Division of Nephrology, Department of Medicine, University of New Mexico School of Medicine, Albuquerque, NM 87131, United States
| | - Deepak Malhotra
- Division of Nephrology, Department of Medicine, University of Toledo School of Medicine, Toledo, OH 43614-5809, United States
| | - Dominic S Raj
- Division of Renal Disease and Hypertension, Department of Medicine, George Washington University, Washington, DC 20037, United States
| | - Emmanuel I Agaba
- Division of Nephology, Department of Medicine, Jos University Medical Center, Jos, Plateau State 930001, Nigeria
| | - Mark Rohrscheib
- Division of Nephrology, Department of Medicine, University of New Mexico School of Medicine, Albuquerque, NM 87131, United States
| | - Glen H Murata
- Research Service, Raymond G Murphy VA Medical Center and University of New Mexico School of Medicine, Albuquerque, NM 87108, United States
| | | | - Antonios H Tzamaloukas
- Research Service, Raymond G Murphy VA Medical Center and University of New Mexico School of Medicine, Albuquerque, NM 87108, United States
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Arystarkhova E, Bouley R, Liu YB, Sweadner KJ. Impaired AQP2 trafficking in Fxyd1 knockout mice: A role for FXYD1 in regulated vesicular transport. PLoS One 2017; 12:e0188006. [PMID: 29155857 PMCID: PMC5695786 DOI: 10.1371/journal.pone.0188006] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/18/2017] [Accepted: 10/30/2017] [Indexed: 01/08/2023] Open
Abstract
The final adjustment of urine volume occurs in the inner medullary collecting duct (IMCD), chiefly mediated by the water channel aquaporin 2 (AQP2). With vasopressin stimulation, AQP2 accumulation in the apical plasma membrane of principal cells allows water reabsorption from the lumen. We report that FXYD1 (phospholemman), better known as a regulator of Na,K-ATPase, has a role in AQP2 trafficking. Daytime urine of Fxyd1 knockout mice was more dilute than WT despite similar serum vasopressin, but both genotypes could concentrate urine during water deprivation. FXYD1 was found in IMCD. In WT mice, phosphorylated FXYD1 was detected intracellularly, and vasopressin induced its dephosphorylation. We tested the hypothesis that the dilute urine in knockouts was caused by alteration of AQP2 trafficking. In WT mice at baseline, FXYD1 and AQP2 were not strongly co-localized, but elevation of vasopressin produced translocation of both FXYD1 and AQP2 to the apical plasma membrane. In kidney slices, baseline AQP2 distribution was more scattered in the Fxyd1 knockout than in WT. Apical recruitment of AQP2 occurred in vasopressin-treated Fxyd1 knockout slices, but upon vasopressin washout, there was more rapid reversal of apical AQP2 localization and more heterogeneous cytoplasmic distribution of AQP2. Notably, in sucrose gradients, AQP2 was present in a detergent-resistant membrane domain that had lower sedimentation density in the knockout than in WT, and vasopressin treatment normalized its density. We propose that FXYD1 plays a role in regulating AQP2 retention in apical membrane, and that this involves transfers between raft-like membrane domains in endosomes and plasma membranes.
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Affiliation(s)
- Elena Arystarkhova
- Laboratory of Membrane Biology, Dept. of Neurosurgery, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, Unites States of America
- * E-mail: (EA); (KJS)
| | - Richard Bouley
- Center for Systems Biology, Program in Membrane Biology and Division of Nephrology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, United States of America
| | - Yi Bessie Liu
- Laboratory of Membrane Biology, Dept. of Neurosurgery, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, Unites States of America
| | - Kathleen J. Sweadner
- Laboratory of Membrane Biology, Dept. of Neurosurgery, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, Unites States of America
- * E-mail: (EA); (KJS)
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Abstract
OBJECTIVES Hyponatremic encephalopathy, symptomatic cerebral edema due to a low osmolar state, is a medical emergency and often encountered in the ICU setting. This article provides a critical appraisal and review of the literature on identification of high-risk patients and the treatment of this life-threatening disorder. DATA SOURCES, STUDY SELECTION, AND DATA EXTRACTION Online search of the PubMed database and manual review of articles involving risk factors for hyponatremic encephalopathy and treatment of hyponatremic encephalopathy in critical illness. DATA SYNTHESIS Hyponatremic encephalopathy is a frequently encountered problem in the ICU. Prompt recognition of hyponatremic encephalopathy and early treatment with hypertonic saline are critical for successful outcomes. Manifestations are varied, depending on the extent of CNS's adaptation to the hypoosmolar state. The absolute change in serum sodium alone is a poor predictor of clinical symptoms. However, certain patient specific risks factors are predictive of a poor outcome and are important to identify. Gender (premenopausal and postmenopausal females), age (prepubertal children), and the presence of hypoxia are the three main clinical risk factors and are more predictive of poor outcomes than the rate of development of hyponatremia or the absolute decrease in the serum sodium. CONCLUSIONS In patients with hyponatremic encephalopathy exhibiting neurologic manifestations, a bolus of 100 mL of 3% saline, given over 10 minutes, should be promptly administered. The goal of this initial bolus is to quickly treat cerebral edema. If signs persist, the bolus should be repeated in order to achieve clinical remission. However, the total change in serum sodium should not exceed 5 mEq/L in the initial 1-2 hours and 15-20 mEq/L in the first 48 hours of treatment. It has recently been demonstrated in a prospective fashion that 500 mL of 3% saline at an infusion rate of 100 mL per hour can be given safely. It is critical to recognize the early signs of cerebral edema (nausea, vomiting, and headache) and intervene with IV 3% sodium chloride as this is the time to intervene rather than waiting until more severe symptoms develop. Cerebral demyelination is a rare complication of overly rapid correction of hyponatremia. The principal risk factors for cerebral demyelination are correction of the serum sodium more than 25 mEq/L in the first 48 hours of therapy, correction past the point of 140 mEq/L, chronic liver disease, and hypoxic/anoxic episode.
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Affiliation(s)
- Steven G Achinger
- 1Department of Nephrology, Watson Clinic LLP, Lakeland, FL. 2Renal Consultants of Houston, Department of Research, Houston, TX. 3Department of Nephrology, Hospital Italiano, Buenos Aires, Argentina. 4Department of Nephrology, Hospital Austral, Austral University, Buenos Aires, Argentina. 5Department of Nephrology, University of California, Irvine, CA
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Shchekochikhin DY, Kozlovskaya NL, Kopylov FY, Syrkin AL, Shilov EM. Hyponatremia: A clinical approach. TERAPEVT ARKH 2017; 89:134-140. [DOI: 10.17116/terarkh2017898134-140] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/15/2023]
Abstract
Hyponatremia is the most common electrolyte metabolic abnormality in clinical practice. The unfavorable course of many diseases is associated with hyponatremia. Acute severe hyponatremia is life-threatening because cerebral edema may develop. Less obvious chronic hyponatremia increases the risk of balance problems, falls and fractures, especially in elderly patients. In any occasion, hyponatremia should not be now regarded only as a laboratory phenomenon in critically ill patients, but it necessitates a thorough clinical analysis of each individual case and appropriate therapy. The paper presents approaches to diagnosing and treating hyponatremia in various clinical situations.
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Nagarur A, Axelrod L, Dighe AS. Case 9-2017. A 27-Year-Old Woman with Nausea, Vomiting, Confusion, and Hyponatremia. N Engl J Med 2017; 376:1159-1167. [PMID: 28328333 DOI: 10.1056/nejmcpc1616024] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/19/2022]
Affiliation(s)
- Amulya Nagarur
- From the Departments of Medicine (A.N., L.A.) and Pathology (A.S.D.), Massachusetts General Hospital, and the Departments of Medicine (A.N., L.A.) and Pathology (A.S.D.), Harvard Medical School - both in Boston
| | - Lloyd Axelrod
- From the Departments of Medicine (A.N., L.A.) and Pathology (A.S.D.), Massachusetts General Hospital, and the Departments of Medicine (A.N., L.A.) and Pathology (A.S.D.), Harvard Medical School - both in Boston
| | - Anand S Dighe
- From the Departments of Medicine (A.N., L.A.) and Pathology (A.S.D.), Massachusetts General Hospital, and the Departments of Medicine (A.N., L.A.) and Pathology (A.S.D.), Harvard Medical School - both in Boston
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Abstract
Sheehan syndrome or postpartum hypopituitarism is a condition characterized by hypopituitarism due to necrosis of the pituitary gland. The initial insult is caused by massive postpartum haemorrhage (PPH), leading to impaired blood supply to the pituitary gland, which has become enlarged during pregnancy. Small sella turcica size, vasospasms (caused by PPH) and/or thrombosis (associated with pregnancy or coagulation disorders) are predisposing factors; autoimmunity might be involved in the progressive worsening of pituitary functions. Symptoms are caused by a decrease or absence of one or more of the pituitary hormones, and vary, among others, from failure to lactate and nonspecific symptoms (such as fatigue) to severe adrenal crisis. In accordance with the location of hormone-secreting cells relative to the vasculature, the secretion of growth hormone and prolactin is most commonly affected, followed by follicle-stimulating hormone and luteinizing hormone; severe necrosis of the pituitary gland also affects the secretion of thyroid-stimulating hormone and adrenocorticotropic hormone. Symptoms usually become evident years after delivery, but can, in rare cases, develop acutely. The incidence of Sheehan syndrome depends, to a large extent, on the occurrence and management of PPH. Sheehan syndrome is an important cause of hypopituitarism in developing countries, but has become rare in developed countries. Diagnosis is based on clinical manifestations combined with a history of severe PPH; hormone levels and/or stimulation tests can confirm clinical suspicion. Hormone replacement therapy is the only available management option so far.
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Affiliation(s)
- Züleyha Karaca
- Department of Endocrinology, Erciyes University Medical School, 38039, Kayseri, Turkey
| | - Bashir A Laway
- Department of Endocrinology, Sher-I-Kashmir Institute of Medical Sciences (SKIMS), Srinagar, Jammu and Kashmir, India
| | - Hatice S Dokmetas
- Department of Endocrinology, Istanbul Medipol University Medical School, Istanbul, Turkey
| | - Hulusi Atmaca
- Department of Endocrinology, Ondokuz Mayıs University Medical School, Samsun, Turkey
| | - Fahrettin Kelestimur
- Department of Endocrinology, Erciyes University Medical School, 38039, Kayseri, Turkey
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Raimann JG, Tzamaloukas AH, Levin NW, Ing TS. Osmotic Pressure in Clinical Medicine with an Emphasis on Dialysis. Semin Dial 2016; 30:69-79. [PMID: 27611901 DOI: 10.1111/sdi.12537] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/28/2022]
Abstract
Since the beginning of life of the first multicellular organisms, the preservation of a physiologic milieu for every cell in the organism has been a critical requirement. A particular range of osmolality of the body fluids is essential for the maintenance of cell volume. In humans the stability of electrolyte concentrations and their resulting osmolality in the body fluids is the consequence of complex interactions between cell membrane functions, hormonal control, thirst, and controlled kidney excretion of fluid and solutes. Knowledge of these mechanisms, of the biochemical principles of osmolality, and of the relevant situations occurring in disease is of importance to every physician. This comprehensive review summarizes the major facts on osmolality, its relation to electrolytes and other solutes, and its relevance in physiology and in disease states with a focus on dialysis-related considerations.
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Affiliation(s)
- Jochen G Raimann
- Research Division, Renal Research Institute, New York City, New York
| | - Antonios H Tzamaloukas
- Raymond G. Murphy VA Medical Center/University of New Mexico School of Medicine, Albuquerque, New Mexico
| | - Nathan W Levin
- Research Division, Renal Research Institute, New York City, New York
| | - Todd S Ing
- Stritch School of Medicine, Loyola University Chicago, Maywood, Illinois
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Efe O, Klein JD, LaRocque LM, Ren H, Sands JM. Metformin improves urine concentration in rodents with nephrogenic diabetes insipidus. JCI Insight 2016; 1:88409. [PMID: 27478876 DOI: 10.1172/jci.insight.88409] [Citation(s) in RCA: 38] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/17/2022] Open
Abstract
Urine concentration is regulated by vasopressin. Congenital nephrogenic diabetes insipidus (NDI) is caused by vasopressin type 2 receptor (V2R) mutations. We studied whether metformin could improve urine concentration in rodent models of congenital NDI by stimulating AMPK. To block the V2R in rats, tolvaptan (10 mg/kg/d) was given by oral gavage with or without metformin (800 mg/ kg/d). Control rats received vehicle with or without metformin. Tamoxifen-induced V2R KO mice were given metformin (600 mg/kg) or vehicle twice daily. Urine osmolality in tolvaptan-treated rats (1,303 ± 126 mOsM) was restored to control levels by metformin (2,335 ± 273 mOsM) within 3 days and was sustained for up to 10 days. Metformin increased protein abundance of inner medullary urea transporter UT-A1 by 61% and aquaporin 2 (AQP2) by 44% in tolvaptan-treated rats, and immunohistochemistry showed increased membrane accumulation of AQP2 with acute and chronic AMPK stimulation. Outer medullary Na+-K+-2Cl- cotransporter 2 (NKCC2) abundance increased (117%) with AMPK stimulation in control rats but not in V2R-blocked rats. Metformin increased V2R KO mouse urine osmolality within 3 hours, and the increase persisted for up to 12 hours. Metformin increased AQP2 in the V2R KO mice similar to the tolvaptan-treated rats. These results indicate that AMPK activators, such as metformin, might provide a promising treatment for congenital NDI.
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Affiliation(s)
- Orhan Efe
- Renal Division, Department of Medicine, Emory University School of Medicine, Atlanta, Georgia, USA
| | - Janet D Klein
- Renal Division, Department of Medicine, Emory University School of Medicine, Atlanta, Georgia, USA.,Department of Physiology, Emory University, Atlanta, Georgia, USA
| | - Lauren M LaRocque
- Renal Division, Department of Medicine, Emory University School of Medicine, Atlanta, Georgia, USA
| | - Huiwen Ren
- Renal Division, Department of Medicine, Emory University School of Medicine, Atlanta, Georgia, USA
| | - Jeff M Sands
- Renal Division, Department of Medicine, Emory University School of Medicine, Atlanta, Georgia, USA.,Department of Physiology, Emory University, Atlanta, Georgia, USA
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Mamenko M, Dhande I, Tomilin V, Zaika O, Boukelmoune N, Zhu Y, Gonzalez-Garay ML, Pochynyuk O, Doris PA. Defective Store-Operated Calcium Entry Causes Partial Nephrogenic Diabetes Insipidus. J Am Soc Nephrol 2016; 27:2035-2048. [PMID: 26574044 PMCID: PMC4926963 DOI: 10.1681/asn.2014121200] [Citation(s) in RCA: 29] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/09/2014] [Accepted: 09/23/2015] [Indexed: 12/12/2022] Open
Abstract
Store-operated calcium entry (SOCE) is the mechanism by which extracellular signals elicit prolonged intracellular calcium elevation to drive changes in fundamental cellular processes. Here, we investigated the role of SOCE in the regulation of renal water reabsorption, using the inbred rat strain SHR-A3 as an animal model with disrupted SOCE. We found that SHR-A3, but not SHR-B2, have a novel truncating mutation in the gene encoding stromal interaction molecule 1 (STIM1), the endoplasmic reticulum calcium (Ca(2+)) sensor that triggers SOCE. Balance studies revealed increased urine volume, hypertonic plasma, polydipsia, and impaired urinary concentrating ability accompanied by elevated circulating arginine vasopressin (AVP) levels in SHR-A3 compared with SHR-B2. Isolated, split-open collecting ducts (CD) from SHR-A3 displayed decreased basal intracellular Ca(2+) levels and a major defect in SOCE. Consequently, AVP failed to induce the sustained intracellular Ca(2+) mobilization that requires SOCE in CD cells from SHR-A3. This effect decreased the abundance of aquaporin 2 and enhanced its intracellular retention, suggesting impaired sensitivity of the CD to AVP in SHR-A3. Stim1 knockdown in cultured mpkCCDc14 cells reduced SOCE and basal intracellular Ca(2+) levels and prevented AVP-induced translocation of aquaporin 2, further suggesting the effects in SHR-A3 result from the expression of truncated STIM1. Overall, these results identify a novel mechanism of nephrogenic diabetes insipidus and uncover a role of SOCE in renal water handling.
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Affiliation(s)
| | - Isha Dhande
- Institute of Molecular Medicine, The University of Texas Health Science Center at Houston, Houston, Texas; and
| | - Viktor Tomilin
- Department of Integrative Biology and Pharmacology, and Institute of Cytology, Russian Academy of Sciences, St. Petersburg, Russia
| | - Oleg Zaika
- Department of Integrative Biology and Pharmacology, and
| | | | - Yaming Zhu
- Institute of Molecular Medicine, The University of Texas Health Science Center at Houston, Houston, Texas; and
| | - Manuel L Gonzalez-Garay
- Institute of Molecular Medicine, The University of Texas Health Science Center at Houston, Houston, Texas; and
| | | | - Peter A Doris
- Institute of Molecular Medicine, The University of Texas Health Science Center at Houston, Houston, Texas; and
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Grammatiki M, Rapti E, Mousiolis AC, Yavropoulou M, Karras S, Tsona A, Daniilidis M, Yovos J, Kotsa K. Patient With Severe Hyponatremia Caused by Adrenal Insufficiency Due to Ectopic Posterior Pituitary Lobe and Miscommunication Between Hypothalamus and Pituitary: A Case Report. Medicine (Baltimore) 2016; 95:e2872. [PMID: 26962783 PMCID: PMC4998864 DOI: 10.1097/md.0000000000002872] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/26/2022] Open
Abstract
Hyponatremia may be one of the clinical manifestations of adrenal insufficiency (AI) and during the diagnostic workup of hyponatremic patients investigation of AI should be included.We report the case of an 82-year-old patient who was admitted to our hospital with clinical symptoms and laboratory findings of hyponatremia. Following the diagnostic algorithm of hyponatremia we reached the diagnosis of AI. Clinician's attention must focus on the underlying cause of AI which in this case was hidden in a miscommunication between hypothalamus and pituitary due to an ectopic posterior pituitary lobe and became apparent by a pituitary magnetic resonance imaging (MRI) scan. Treatment with oral hydrocortisone resulted in full clinical recovery and electrolyte balance, which was maintained after 7 months of follow-up.Secondary AI is related with hyponatremia through increased ADH secretion. Although a hyponatremic episode may be the first presentation of AI, clinical suspicion is of high importance in order to place the right diagnosis. Disruption of communication between hypothalamus and pituitary is a rare but considerable cause of AI.
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Affiliation(s)
- Maria Grammatiki
- From the Department of Endocrinology and Metabolism - Diabetes Center, 1st Clinic of Internal Medicine (MG, ER, ACM, MY, SK, JY, KK); and 1st Department of Internal Medicine, AHEPA University Hospital, Thessaloniki, Greece (AT, MD)
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47
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Abstract
Hyponatremia is the most common electrolyte abnormality in clinical practice, and a differential diagnosis of the etiologic disorders is crucial because hyponatremia is associated with many different disease states including malignancies. Although only a few cases of hyponatremia with hepatocellular carcinoma (HCC) have been previously reported, the abnormal expression of arginine vasopressin (AVP) in tumor cells has not been demonstrated. We herein present a rare case of hyponatremia associated with the aberrant expression of AVP in tumor cells of HCC. This case suggests that an extensive diagnostic work-up is needed in patients with hyponatremia because hyponatremia may provide diagnostic clues for the presence of other underlying disorders.
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Affiliation(s)
- Seong Kwon Ma
- Department of Internal Medicine, Chonnam National University Medical School, Korea
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Rafat C, Flamant M, Gaudry S, Vidal-Petiot E, Ricard JD, Dreyfuss D. Hyponatremia in the intensive care unit: How to avoid a Zugzwang situation? Ann Intensive Care 2015; 5:39. [PMID: 26553121 PMCID: PMC4639545 DOI: 10.1186/s13613-015-0066-8] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/02/2015] [Accepted: 09/02/2015] [Indexed: 12/11/2022] Open
Abstract
Hyponatremia is a common
electrolyte derangement in the setting of the intensive care unit. Life-threatening neurological complications may arise not only in case of a severe (<120 mmol/L) and acute fall of plasma sodium levels, but may also stem from overly rapid correction of hyponatremia. Additionally, even mild hyponatremia carries a poor short-term and long-term prognosis across a wide range of conditions. Its multifaceted and intricate physiopathology may seem deterring at first glance, yet a careful multi-step diagnostic approach may easily unravel the underlying mechanisms and enable physicians to adopt the adequate measures at the patient’s bedside. Unless hyponatremia is associated with obvious extracellular fluid volume increase such as in heart failure or cirrhosis, hypertonic saline therapy is the cornerstone of the therapeutic of profound or severely symptomatic hyponatremia. When overcorrection of hyponatremia occurs, recent data indicate that re-lowering of plasma sodium levels through the infusion of hypotonic fluids and the cautious use of desmopressin acetate represent a reasonable strategy. New therapeutic options have recently emerged, foremost among these being vaptans, but their use in the setting of the intensive care unit remains to be clarified.
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Affiliation(s)
- Cédric Rafat
- AP-HP, Service de Réanimation Médico-Chirurgicale, Hôpital Louis Mourier, Colombes, France. .,AP-HP, Urgences Néphrologiques et Transplantation Rénale, Hôpital Tenon, Paris, France.
| | - Martin Flamant
- AP-HP, Service de Physiologie Rénale, Hôpital Bichat, Paris, France. .,Université Paris Diderot, Sorbonne Paris Cité, Paris, France. .,INSERM, U1149, Centre de Recherche sur l'Inflammation, Paris, France.
| | - Stéphane Gaudry
- AP-HP, Service de Réanimation Médico-Chirurgicale, Hôpital Louis Mourier, Colombes, France. .,Université Paris Diderot, Sorbonne Paris Cité, Paris, France. .,ECEVE UMR 1123, ECEVE, Paris, France.
| | - Emmanuelle Vidal-Petiot
- AP-HP, Service de Physiologie Rénale, Hôpital Bichat, Paris, France. .,Université Paris Diderot, Sorbonne Paris Cité, Paris, France. .,INSERM, U1149, Centre de Recherche sur l'Inflammation, Paris, France.
| | - Jean-Damien Ricard
- AP-HP, Service de Réanimation Médico-Chirurgicale, Hôpital Louis Mourier, Colombes, France. .,Université Paris Diderot, Sorbonne Paris Cité, Paris, France. .,INSERM UMR 1137, IAME, Paris, France.
| | - Didier Dreyfuss
- AP-HP, Service de Réanimation Médico-Chirurgicale, Hôpital Louis Mourier, Colombes, France. .,Université Paris Diderot, Sorbonne Paris Cité, Paris, France. .,INSERM UMR 1137, IAME, Paris, France.
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Boon AC, Lam AK, Gopalan V, Benzie IF, Briskey D, Coombes JS, Fassett RG, Bulmer AC. Endogenously elevated bilirubin modulates kidney function and protects from circulating oxidative stress in a rat model of adenine-induced kidney failure. Sci Rep 2015; 5:15482. [PMID: 26498893 PMCID: PMC4620450 DOI: 10.1038/srep15482] [Citation(s) in RCA: 32] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/27/2015] [Accepted: 09/28/2015] [Indexed: 12/13/2022] Open
Abstract
Mildly elevated bilirubin is associated with a reduction in the presence and progression of chronic kidney disease and related mortality, which may be attributed to bilirubin's antioxidant properties. This study investigated whether endogenously elevated bilirubin would protect against adenine-induced kidney damage in male hyperbilirubinaemic Gunn rats and littermate controls. Animals were orally administered adenine or methylcellulose solvent (vehicle) daily for 10 days and were then monitored for 28 days. Serum and urine were assessed throughout the protocol for parameters of kidney function and antioxidant/oxidative stress status and kidneys were harvested for histological examination upon completion of the study. Adenine-treated animals experienced weight-loss, polyuria and polydipsia; however, these effects were significantly attenuated in adenine-treated Gunn rats. No difference in the presence of dihydroadenine crystals, lymphocytic infiltration and fibrosis were noted in Gunn rat kidneys versus controls. However, plasma protein carbonyl and F2-isoprostane concentrations were significantly decreased in Gunn rats versus controls, with no change in urinary 8-oxo-7,8-dihydro-2'-deoxyguanosine or kidney tissue F2-isoprostane concentrations. These data indicated that endogenously elevated bilirubin specifically protects from systemic oxidative stress in the vascular compartment. These data may help to clarify the protective relationship between bilirubin, kidney function and cardiovascular mortality in clinical investigations.
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Affiliation(s)
- Ai-Ching Boon
- Heart Foundation Research Centre, Menzies Health Institute Queensland, Griffith University, Gold Coast, Australia
| | - Alfred K Lam
- School of Medicine and Cancer Molecular Pathology, Menzies Health Institute Queensland, Griffith University, Gold Coast, Australia.,Pathology Queensland, Gold Coast University Hospital, Gold Coast, Australia
| | - Vinod Gopalan
- School of Medicine and Cancer Molecular Pathology, Menzies Health Institute Queensland, Griffith University, Gold Coast, Australia
| | - Iris F Benzie
- Department of Health Technology &Informatics, The Hong Kong Polytechnic University, Hong Kong
| | - David Briskey
- School of Human Movement and Nutrition Sciences, University of Queensland, St Lucia, Australia
| | - Jeff S Coombes
- School of Human Movement and Nutrition Sciences, University of Queensland, St Lucia, Australia
| | - Robert G Fassett
- School of Human Movement and Nutrition Sciences, University of Queensland, St Lucia, Australia
| | - Andrew C Bulmer
- Heart Foundation Research Centre, Menzies Health Institute Queensland, Griffith University, Gold Coast, Australia
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