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Previous studies have shown that with important decisions, unconscious thought has surprisingly led to better choices than conscious thought. The present study challenges this so-called 'deliberation-without-attention effect' in the medical domain. In a computerized study, physicians and medical students were asked, after either conscious or unconscious thought, to estimate the 5-year survival probabilities of four fictitious patients with varying medical characteristics. We assumed that experienced physicians would outperform students as a result of their superior knowledge. The central question was whether unconscious thought in this task would lead to better performance in experts or novices, in line with the deliberation-without-attention effect. We created four fictitious male 60-year-old patients, each of whom with signs and symptoms related to likely prognosis, from 12 (Complex) or 4 (Simple) categories. This manipulation resulted in objectively different life expectancies for these patients. Participants (86 experienced physicians and 57 medical students) were randomly allocated to the Simple or Complex condition. Statements were randomly presented for 8 s. Next, each participant assessed the life expectancies after either conscious or unconscious thought. As expected, experienced physicians were better in assessing life expectancies than medical students. No significant differences were found in performance between conscious and unconscious thought, nor did we detect a significant interaction between expertise level and mode of thought. In a medical decision task, unconscious thought did not lead to better performance of experienced physicians or medical students than conscious thought. Our findings do not support the deliberation-without-attention effect.

Despite advances in preventive therapy, prognosis in chronic kidney disease (CKD) is still grim. Clinical cohorts of CKD patients provide a strategic resource to identify factors that drive progression in the context of clinical care and to provide a basis for improvement of outcome. The combination with biobanking, moreover, provides a resource for fundamental and translational studies. In 2007, the Dutch government initiated and funded the String of Pearls Initiative (PSI), a strategic effort to establish infrastructure for disease-based biobanking in the University Medical Centres (UMCs) in the Netherlands, in a 4-year start-up period. CKD was among the conditions selected for biobanking, and this resulted in the establishment of the Biobank of Nephrological Diseases-NL (BIND-NL) cohort. Patients with CKD Stages 1-4 are eligible. The data architecture is designed to reflect routine care, with specific issues added for enrichment, e.g. questionnaires. Thus, the collected clinical and biochemical data are those required by prevailing guidelines for routine nephrology care, with a minimal dataset for all patients, and diagnosis-specific data for the diagnostic categories of primary and secondary glomerular disorders and adult dominant polycystic kidney disease, respectively. The dataset is supplemented by a biobank, containing serum, plasma, urine and DNA. The cohort will be longitudinally monitored, with yearly follow-up for clinical outcome. Future linking of the data to those from the national registries for renal replacement therapy is foreseen to follow the patients' lifeline throughout the different phases of renal disease and different treatment modalities. In the design of the data architecture, care was taken to ensure future exchangeability of data with other CKD cohorts by applying the data harmonization format of the Renal DataSHaPER, with a dataset based upon standardized indicator sets to facilitate collaboration with other CKD cohorts. Enrolment started in 2010, and over 2200 eligible patients have been enrolled in the different UMCs. Follow-up of enrolled patients has started, and enrolment will continue at a slower rate. The aggregation and standardization of clinical data and biosamples from large numbers of CKD patients will be a strategic resource not only for clinical and translational research, but also by its basis in routine clinical care for clinical governance and quality improvement projects., (© The Author 2013. Published by Oxford University Press on behalf of ERA-EDTA. All rights reserved.)

Hyponatraemia, defined as a serum sodium concentration <135 mmol/l, is the most common disorder of body fluid and electrolyte balance encountered in clinical practice. It can lead to a wide spectrum of clinical symptoms, from subtle to severe or even life threatening, and is associated with increased mortality, morbidity and length of hospital stay in patients presenting with a range of conditions. Despite this, the management of patients remains problematic. The prevalence of hyponatraemia in widely different conditions and the fact that hyponatraemia is managed by clinicians with a broad variety of backgrounds have fostered diverse institution- and speciality-based approaches to diagnosis and treatment. To obtain a common and holistic view, the European Society of Intensive Care Medicine (ESICM), the European Society of Endocrinology (ESE) and the European Renal Association - European Dialysis and Transplant Association (ERA-EDTA), represented by European Renal Best Practice (ERBP), have developed the Clinical Practice Guideline on the diagnostic approach and treatment of hyponatraemia as a joint venture of three societies representing specialists with a natural interest in hyponatraemia. In addition to a rigorous approach to methodology and evaluation, we were keen to ensure that the document focused on patient-important outcomes and included utility for clinicians involved in everyday practice.

Purpose: Because most population-based studies on the epidemiology of chronic kidney disease (CKD) are cross-sectional, there is, except for end-stage renal disease, hardly any information on incidence rates., Methods: We conducted a retrospective cohort study in a dynamic population, using data of 784,563 adult participants retrieved from the Integrated Primary Care Information database, a primary care database containing the complete electronic longitudinal medical records. CKD (both incidence and prevalence) was based on (1) an increased urine albumin-to-creatinine ratio, (2) a decreased estimated glomerular filtration rate, or (3) explicit statement in the medical record. Results were stratified by age according to the WHO standard population, sex, and diabetes mellitus., Results: Based on a single measurement only, the incidence rate of CKD in adults was 1,213 per 100,000 person-years, and 6.7 percent of the adult population had a prevalent diagnosis of CKD. The incidence rate increased by age and was the highest in participants with diabetes with an incidence of 25,000 per 100,000 person-years, affecting over 75 percent of participants with diabetes., Conclusions: This is the first study to report the incidence rates of all stages of CKD for the entire adult population, stratified by sex, 5-year age groups, and diabetes. Our data demonstrate that the incidence of CKD increases with age and is the highest in participants with diabetes mellitus.

Background: There are limited therapeutic options to slow the progression of autosomal dominant polycystic kidney disease (ADPKD). Recent clinical studies indicate that somatostatin analogues are promising for treating polycystic liver disease and potentially also for the kidney phenotype. We report on the design of the DIPAK 1 (Developing Interventions to Halt Progression of ADPKD 1) Study, which will examine the efficacy of the somatostatin analogue lanreotide on preservation of kidney function in ADPKD., Study Design: The DIPAK 1 Study is an investigator-driven, randomized, multicenter, controlled, clinical trial., Setting & Participants: We plan to enroll 300 individuals with ADPKD and estimated glomerular filtration rate (eGFR) of 30-60 mL/min/1.73 m(2) who are aged 18-60 years., Intervention: Patients will be randomly assigned (1:1) to standard care or lanreotide, 120 mg, subcutaneously every 28 days for 120 weeks, in addition to standard care., Outcomes: Main study outcome is the slope through serial eGFR measurements starting at week 12 until end of treatment for lanreotide versus standard care. Secondary outcome parameters include change in eGFR from pretreatment versus 12 weeks after treatment cessation, change in kidney volume, change in liver volume, and change in quality of life., Measurements: Blood and urine will be collected and questionnaires will be filled in following a fixed scheme. Magnetic resonance imaging will be performed for assessment of kidney and liver volume., Results: Assuming an average change in eGFR of 5.2 ± 4.3 (SD) mL/min/1.73 m(2) per year in untreated patients, 150 patients are needed in each group to detect a 30% reduction in the rate of kidney function loss between treatment groups with 80% power, 2-sided α = 0.05, and 20% protocol violators and/or dropouts., Limitations: The design is an open randomized controlled trial and measurement of our primary end point does not begin at randomization., Conclusions: The DIPAK 1 Study will show whether subcutaneous administration of lanreotide every 4 weeks attenuates disease progression in patients with ADPKD., (Copyright © 2014 National Kidney Foundation, Inc. Published by Elsevier Inc. All rights reserved.)

Hyponatraemia is a common but complex electrolyte disorder. This clinical lesson, based on two case histories, illustrates how asking the right questions will not only lead to the correct diagnosis and treatment of hyponatraemia but can also indicate how the condition is endangering the patient.

SLC12A3 encodes the thiazide-sensitive sodium chloride cotransporter (NCC), which is primarily expressed in the kidney, but also in intestine and bone. In the kidney, NCC is located in the apical plasma membrane of epithelial cells in the distal convoluted tubule. Although NCC reabsorbs only 5 to 10% of filtered sodium, it is important for the fine-tuning of renal sodium excretion in response to various hormonal and non-hormonal stimuli. Several new roles for NCC in the regulation of sodium, potassium, and blood pressure have been unraveled recently. For example, the recent discoveries that NCC is activated by angiotensin II but inhibited by dietary potassium shed light on how the kidney handles sodium during hypovolemia (high angiotensin II) and hyperkalemia. The additive effect of angiotensin II and aldosterone maximizes sodium reabsorption during hypovolemia, whereas the inhibitory effect of potassium on NCC increases delivery of sodium to the potassium-secreting portion of the nephron. In addition, great steps have been made in unraveling the molecular machinery that controls NCC. This complex network consists of kinases and ubiquitinases, including WNKs, SGK1, SPAK, Nedd4-2, Cullin-3, and Kelch-like 3. The pathophysiological significance of this network is illustrated by the fact that modification of each individual protein in the network changes NCC activity and results in salt-dependent hypotension or hypertension. This review aims to summarize these new insights in an integrated manner while identifying unanswered questions.

Background: The aldosterone-to-renin ratio (ARR) is a widely used screening test for primary aldosteronism. Current guidelines recommend a cut-off value of 91  pmol/mU. Studies on its sensitivity, specificity, reproducibility and the role of medication have been conflicting. We prospectively assessed the test characteristics of the ARR and the effect of combination antihypertensive treatment., Methods: In 178 patients with persistent hypertension despite the use of at least two antihypertensives, plasma renin and aldosterone were assessed twice within an interval of 4 weeks. All patients underwent an intravenous salt loading test. A posttest plasma aldosterone exceeding 235  pmol/l was considered diagnostic for primary aldosteronism. ARR was repeated after 4 weeks of standardized treatment with a calcium channel blocker and/or α-adrenergic-receptor blocker., Results: The prevalence of primary aldosteronism was 15.2%. The median ARR was 35.0 (interquartile range 16.2-82.0) in primary aldosteronism versus 7.1 (2.2-17.5) pmol/mU in essential hypertensive patients (P < 0.001). Under random medication, the ARR had 22.2% sensitivity and 98.7% specificity. On standardized treatment, the ARR rose from 9.6 (2.5-24.8) to 21.4 (10.8-52.1) (P < 0.001). Multivariate regression showed that angiotensin-converting enzyme (ACE)-inhibitors and angiotensin II-receptor blockers were responsible for the lower ARR during random treatment. The area under the receiver operating characteristic curve was, however, similar under random and standardized treatment (84 vs. 86%, respectively, P = 0.314). Bland-Altman plots showed an almost five-fold difference in ARR values taken under the same conditions., Conclusion: ARR sensitivity for primary aldosteronism is low when the recommended cut-off is used. Reproducibility is also poor, stressing the need for alternative screening tests.

During hypovolemia and hyperkalemia, the kidneys defend homeostasis by Na(+) retention and K(+) secretion, respectively. Aldosterone mediates both effects, but it is unclear how the same hormone can evoke such different responses. To address this, we mimicked hypovolemia and hyperkalemia in four groups of rats with a control diet, low-Na(+) diet, high-K(+) diet, or combined diet. The low-Na(+) and combined diets increased plasma and kidney ANG II. The low-Na(+) and high-K(+) diets increased plasma aldosterone to a similar degree (3-fold), whereas the combined diet increased aldosterone to a greater extent (10-fold). Despite similar Na(+) intake and higher aldosterone, the high-K(+) and combined diets caused a greater natriuresis than the control and low-Na(+) diets, respectively (P < 0.001 for both). This K(+)-induced natriuresis was accompanied by a decreased abundance but not phosphorylation of the Na(+)-Cl(-) cotransporter (NCC). In contrast, the epithelial Na(+) channel (ENaC) increased in parallel with aldosterone, showing the highest expression with the combined diet. The high-K(+) and combined diets also increased WNK4 but decreased Nedd4-2 in the kidney. Total and phosphorylated Ste-20-related kinase were also increased but were retained in the cytoplasm of distal convoluted tubule cells. In summary, high dietary K(+) overrides the effects of ANG II and aldosterone on NCC to deliver sufficient Na(+) to ENaC for K(+) secretion. K(+) may inhibit NCC through WNK4 and help activate ENaC through Nedd4-2.

Background: Encapsulating peritoneal sclerosis (EPS) is a rare complication of peritoneal dialysis (PD). It is characterized by encapsulation of the bowel, causing symptoms of intestinal obstruction. Exclusive involvement of parts of the bowel may occur and may be more common than previously thought. Our main objective was to investigate and report on patients with localized EPS., Methods: Between July 2002 and December 2011, 9 of 17 EPS patients were referred to our department of surgery for a diagnostic laparotomy. Three of the 9 cases showed localized encapsulation of the small bowel and were selected for the purpose of this study., Results: All 3 patients presented with an acute inflammatory state and symptoms of bowel obstruction. In 2 patients, EPS became clinically overt after kidney transplantation; the third patient was diagnosed while on hemodialysis. All shared a history of PD ranging from 31 to 101 months. In none of the patients was radiologic examination conclusive, although 2 showed peritoneal thickening and ascites. Each patient underwent laparotomy, confirming EPS. In all cases, a thickened peritoneal membrane became apparent, predominantly covering the ileocecal region of the intestine. In addition, a constrictive membrane at the level of the terminal ileum was noted. In 2 cases, the patients underwent enterolysis and dissection of the constricting fibrotic peritoneal membrane (peritonectomy) without bowel resection. The 3rd patient was managed with parenteral nutrition and tamoxifen. The postoperative course in 1 patient was complicated by infected ascites that resolved with antibiotic treatment. Eventually, all patients were doing well, with adequate oral intake and without the need for repeat surgery., Conclusions: Localized EPS may be more common than previously thought. It has a predilection for the level of the terminal ileum. We believe that an elective diagnostic laparotomy should be considered early, because this procedure offers both diagnostic opportunities and therapeutic options. Localized EPS cases may benefit most from enterolysis and peritonectomy.

Disorders of calcium and magnesium balance are physiologically interesting and clinically challenging. In this review, we attempt to bridge the gap between physiology and practice by providing a physiology-based approach to understanding hypocalcemia, hypercalcemia and hypomagnesemia. Calcium and, to a lesser extent, magnesium balance is achieved through a complex interplay between the parathyroid gland, bone, the intestine and the kidney. Our understanding of the molecular physiology of calcium and magnesium balance has grown considerably following the discovery of the calcium-sensing receptor (CaSR) and the main intestinal and renal transporters for calcium and magnesium, namely, the transient receptor potential channels TRPV5, TRPV6 and TRPM6. The regulation of parathyroid hormone (PTH) secretion by CaSR and the subsequent effects of PTH and vitamin D on TRPV5 constitute an increasingly characterized regulatory loop. In contrast, no truly magnesiotropic hormones have been identified, although the recently established interactions between the epidermal growth factor and TRPM6 suggest a possible candidate. Overall, the aim of this review is to illustrate the clinical disorders of calcium and magnesium balance from the perspective of their integrated physiology.

Background and Objectives: Critically ill patients with AKI necessitating renal replacement therapy (RRT) have high in-hospital mortality, and survivors are at risk for kidney dysfunction at hospital discharge. The objective was to evaluate the association between impaired kidney function at hospital discharge with long-term renal and overall survival., Design, Setting, Participants, & Measurements: Degree of kidney dysfunction in relation to long-term effects on renal survival and patient mortality was investigated in a retrospective cohort study of 1220 adults admitted to an intensive care unit who received continuous RRT between 1994 and 2010., Results: After hospital discharge, median follow-up of survivors (n=475) was 8.5 years (range, 1-17 years); overall mortality rate was 75%. Only 170 (35%) patients were discharged with an estimated GFR (eGFR) >60 ml/min per 1.73 m(2). Multivariate proportional hazards regression analysis demonstrated that age, nonsurgical type of admission, preexisting kidney disease, malignancy, and eGFR of 29-15 ml/min per 1.73 m(2) (hazard ratio [HR], 1.62; 95% confidence interval [CI], 1.01 to 2.58) and eGFR <15 ml/min per 1.73 m(2) (HR, 1.93; 95% CI, 1.23 to 3.02) at discharge were independent predictors of increased mortality. Renal survival was significantly associated with degree of kidney dysfunction at discharge. An eGFR of 29-15 ml/min per 1.73 m(2) (HR, 26.26; 95% CI, 5.59 to 123.40) and <15 ml/min per 1.73 m(2) (HR, 172.28; 95% CI, 37.72 to 786.75) were independent risk factors for initiation of long-term RRT., Conclusions: Most critically ill patients surviving AKI necessitating RRT have impaired kidney function at hospital discharge. An eGFR <30 ml/min per 1.73 m(2) is a strong risk factor for decreased long-term survival and poor renal survival.

Acute hyponatremia can cause death if cerebral edema is not treated promptly. Conversely, if chronic hyponatremia is corrected too rapidly, osmotic demyelination may ensue, which also potentially is lethal. However, these severe complications of hyponatremia are relatively uncommon and often preventable. More commonly, hyponatremia predicts mortality in patients with advanced heart failure or liver cirrhosis. In these conditions, it generally is assumed that hyponatremia reflects the severity of the underlying disease rather than contributing directly to mortality. The same assumption holds for the recently reported associations between hyponatremia and mortality in patients with pulmonary embolism, pulmonary hypertension, pneumonia, and myocardial infarction. However, recent data suggest that chronic and mild hyponatremia in the general population also are associated with mortality. In addition, hyponatremia has been associated with mortality in long-term hemodialysis patients without residual function in whom the underlying disease cannot be responsible for hyponatremia. These new data raise the question of whether hyponatremia by itself can contribute to mortality or it remains a surrogate marker for other unknown risk factors. We review hyponatremia and mortality and explore the possibility that hyponatremia perturbs normal physiology in the absence of cerebral edema or osmotic demyelination., (Copyright © 2013 National Kidney Foundation, Inc. Published by Elsevier Inc. All rights reserved.)

Background: Recent studies suggest that overanticoagulation impairs renal function in patients on warfarin therapy, due to renal tubular obstruction from glomerular hemorrhage., Methods: Data from the Rotterdam Study (The Netherlands), a prospective population-based cohort study of patients 55 years and older, were used for this study. Information on vitamin K antagonist (VKA) therapy was obtained from the regional anticoagulation clinic, where prothrombin times were monitored every 1-6 weeks depending on target level and stability of the international normalized ratio (INR). Linear regression was performed to study the association between the cumulative number of instances of overanticoagulation (defined as a measurement of an INR >6.0) and the change in renal function between baseline and third examination round based on estimated glomerular filtration rate (CKD-EPI equation). Age, sex, baseline renal function, baseline and incident heart failure, and indication for VKA therapy were included as potential confounders., Results: Information was available for analysis on 2,802 study participants in whom overanticoagulation was significantly associated with a decline in renal function, after adjustment for confounding by age, sex, heart failure, baseline glomerular filtration rate and indication for VKA therapy (-0.180 ml/min per 1.73 m(2) per year per event for INR >6.0, p = 0.030)., Conclusions: Overanticoagulation (INR >6.0) is associated with a decline in renal function. Further studies are needed to evaluate the causal role of different degrees of overanticoagulation, including transient effects, in high-risk groups, and the association with the new oral anticoagulants.

Electrolyte disorders are common and often challenging in terms of differential diagnosis and appropriate treatment. To facilitate this, the first Dutch guideline was developed in 2005, which focused on hypernatraemia, hyponatraemia, hyperkalaemia, and hypokalaemia. This guideline was recently revised. Here, we summarise the key points of the revised guideline, including the major complications of each electrolyte disorder, differential diagnosis and recommended treatment. In addition to summarising the guideline, the aim of this review is also to provide a practical guide for the clinician and to harmonise the management of these disorders based on available evidence and physiological principles.

Recent interest focuses on urinary renin and angiotensinogen as markers of renal renin-angiotensin system activity. Before concluding that these components are independent markers, we need to exclude that their presence in urine, like that of albumin (a protein of comparable size), is due to (disturbed) glomerular filtration. This review critically discusses their filtration, reabsorption and local release. Given the close correlation between urinary angiotensinogen and albumin in human studies, it concludes that, in humans, urinary angiotensinogen is a filtration barrier damage marker with the same predictive power as urinary albumin. In contrast, in animals, tubular angiotensinogen release may occur, although tubulus-specific knockout studies do not support a functional role for such angiotensinogen. Urinary renin levels, relative to albumin, are >200-fold higher and unrelated to albumin. This may reflect release of renin from the urinary tract, but could also be attributed to activation of filtered, plasma-derived prorenin and/or incomplete tubular reabsorption.

Purpose: Identification of risk factors for impaired renal function at hospital discharge in critically ill patients with acute kidney injury (AKI) requiring renal replacement therapy (RRT)., Methods: A single-center retrospective cohort study was performed evaluating demographic and clinical parameters as potential risk factors for a modest to severely impaired renal function at hospital discharge in patients with AKI requiring RRT in the intensive care unit., Results: Of the 353 patients in our cohort, 90 (25.5%) patients had pre-existing chronic kidney disease (CKD). An estimated glomerular filtration rate (eGFR) ≤60 mL min(-1) 1.73 m(-2) at hospital discharge occurred in 64.0% of which 63.7% without known renal impairment before hospital admission and 8.2% of all cases left the hospital dialysis-dependent. Multivariable logistic regression showed that age (OR = 1.051, P < .001), serum creatinine concentration at start of RRT (OR = 1.004, P < .001) and administration of iodine-containing contrast fluid (OR = 0.830, P = .045) were associated with an eGFR ≤60 mL min(-1) 1.73 m(-2). Furthermore, a medical history of CKD (OR = 5.865, P < .001) was associated with dialysis dependence., Conclusions: Elderly and patients with pre-existing CKD are at a high risk for modest to severely impaired renal function at hospital discharge after AKI requiring RRT., (Copyright © 2013 Elsevier Inc. All rights reserved.)

Background: Electrolyte disorders have been studied mainly in hospitalized patients, whereas data in the general population are limited. The aim of this study was to determine the prevalence and risk factors of common electrolyte disorders in older subjects recruited from the general population., Methods: A total of 5179 subjects aged 55 years or more were included from the population-based Rotterdam Study. We focused on hyponatremia, hypernatremia, hypokalemia, hyperkalemia, and hypomagnesemia. Multivariable logistic regression was used to study potential associations with renal function, comorbidity, and medication. The adjusted mortality also was determined for each electrolyte disorder., Results: A total of 776 subjects (15.0%) had at least 1 electrolyte disorder, with hyponatremia (7.7%) and hypernatremia (3.4%) being most common. Diabetes mellitus was identified as an independent risk factor for hyponatremia and hypomagnesemia, whereas hypertension was associated with hypokalemia. Diuretics were independently associated with several electrolyte disorders: thiazide diuretics (hyponatremia, hypokalemia, hypomagnesemia), loop diuretics (hypernatremia, hypokalemia), and potassium-sparing diuretics (hyponatremia). The use of benzodiazepines also was associated with hyponatremia. Hyponatremic subjects who used both thiazides and benzodiazepines had a 3 mmol/L lower serum sodium concentration than subjects using 1 or none of these drugs (P < .001). Hyponatremia and hypomagnesemia were independently associated with an increased mortality risk., Conclusions: Electrolyte disorders are common among older community subjects and mainly associated with diabetes mellitus and diuretics. Subjects who used both thiazides and benzodiazepines had a more severe degree of hyponatremia. Because even mild electrolyte disorders were associated with mortality, monitoring of electrolytes and discontinuation of offending drugs may improve outcomes., (Copyright © 2013 Elsevier Inc. All rights reserved.)

Background: Add-on therapy with aldosterone receptor antagonists has been reported to lower blood pressure (BP) in patients with uncontrolled hypertension. We assessed potential predictors of this response., Methods: In essential hypertensive patients with uncontrolled BP, despite the use of at least two antihypertensives, plasma renin and aldosterone concentrations and the transtubular potassium gradient (TTKG) were measured. Patients were treated with eplerenone 50 mg daily on top of their own medication. The office and ambulatory BP response and biochemical changes were evaluated after 1 week and 3 months of treatment and 6 weeks after discontinuation. Potential predictors for the change in 24-h ambulatory BP were tested in a multivariate regression model., Results: One hundred and seventeen patients with a mean age of 50.5 ± 6.6 years were included. Office BP decreased from 149/91 to 142/87 mmHg (P < 0.001) and ambulatory BP from 141/87 to 132/83 mmHg after 3 months of treatment (P < 0.001). Six weeks after discontinuation of eplerenone, office and ambulatory BP measurements returned to baseline values. Treatment resulted in a small rise in serum potassium and creatinine, and a small decrease in the TTKG. In a multivariate model, neither renin, aldosterone, or their ratio, nor the TTKG predicted the BP response. Only baseline ambulatory SBP predicted the BP response, whereas the presence of left ventricular hypertrophy was associated with a smaller BP reduction., Conclusion: Add-on therapy with eplerenone effectively lowers BP in patients with difficult-to-treat primary hypertension. This effect is unrelated to circulating renin-angiotensin-aldosterone system activity and renal mineralocorticoid receptor activity as assessed by the TTKG.

Purpose of Review: The aim is to review the recently reported effects of angiotensin II (Ang II) on sodium and potassium transport in the aldosterone-sensitive distal nephron, including the signaling pathways between receptor and transporter, and the (patho)physiological implications of these findings., Recent Findings: Ang II can activate the sodium chloride cotransporter (NCC) through phosphorylation by Ste20-related, proline-alanine rich kinase (SPAK), an effect that is independent of aldosterone but dependent on with no lysine kinase 4 (WNK4). A low-sodium diet (high Ang II) activates NCC, whereas a high-potassium diet (low Ang II) inhibits NCC. NCC activation also contributes to Ang-II-mediated hypertension. Ang II also activates the epithelial sodium channel (ENaC) additively to aldosterone, and this effect appears to be mediated through protein kinase C and superoxide generation by nicotinamide adenine dinucleotide phosphate oxidase. While aldosterone activates the renal outer medullary potassium channel (ROMK), this channel is inhibited by Ang II. The key kinase responsible for this effect is c-Src, which phosphorylates ROMK and leaves WNK4 unphosphorylated to further inhibit ROMK., Summary: The effects of Ang II on NCC, ENaC, and ROMK help explain the renal response to hypovolemia which is to conserve both sodium and potassium. Pathophysiologically, Ang-II-induced activation of NCC appears to contribute to salt-sensitive hypertension.

Urinary exosomes are vesicles derived from renal tubular epithelial cells. Exosomes often contain several disease-associated proteins and are thus useful targets for identifying biomarkers of disease. Here, we hypothesized that the phosphorylated (active) form of the sodium chloride cotransporter (pNCC) or prostasin could serve as biomarkers for aldosteronism. We tested this in 2 animal models of aldosteronism (aldosterone infusion or low-sodium diet) and in patients with primary aldosteronism. Urinary exosomes were isolated from 24-hour urine or spot urine using ultracentrifugation. In rats, a normal or a high dose of aldosterone for 2, 3, or 8 days increased pNCC 3-fold in urinary exosomes (P<0.05 for all). A low-sodium diet also increased pNCC in urinary exosomes approximately 1.5-fold after 4 and after 8 days of treatment. The effects of these maneuvers on prostasin in urinary exosomes were less clear, showing a significant 1.5-fold increase only after 2 and 3 days of high-aldosterone infusion. In urinary exosomes of patients with primary aldosteronism, pNCC was 2.6-fold higher (P<0.05) while prostasin was 1.5-fold higher (P=0.07) than in patients with essential hypertension. Urinary exosomal pNCC and, to a lesser extent, prostasin are promising markers for aldosteronism in experimental animals and patients. These markers may be used to assess the biological activity of aldosterone and, potentially, as clinical biomarkers for primary aldosteronism.

We and others have recently shown that angiotensin II can activate the sodium chloride cotransporter (NCC) through a WNK4-SPAK-dependent pathway. Because WNK4 was previously shown to be a negative regulator of NCC, it has been postulated that angiotensin II converts WNK4 to a positive regulator. Here, we ask whether aldosterone requires angiotensin II to activate NCC and if their effects are additive. To do so, we infused vehicle or aldosterone in adrenalectomized rats that also received the angiotensin receptor blocker losartan. In the presence of losartan, aldosterone was still capable of increasing total and phosphorylated NCC twofold to threefold. The kinases WNK4 and SPAK also increased with aldosterone and losartan. A dose-dependent relationship between aldosterone and NCC, SPAK, and WNK4 was identified, suggesting that these are aldosterone-sensitive proteins. As more functional evidence of increased NCC activity, we showed that rats receiving aldosterone and losartan had a significantly greater natriuretic response to hydrochlorothiazide than rats receiving losartan only. To study whether angiotensin II could have an additive effect, rats receiving aldosterone with losartan were compared with rats receiving aldosterone only. Rats receiving aldosterone only retained more sodium and had twofold to fourfold increase in phosphorylated NCC. Together, our results demonstrate that aldosterone does not require angiotensin II to activate NCC and that WNK4 appears to act as a positive regulator in this pathway. The additive effect of angiotensin II may favor electroneutral sodium reabsorption during hypovolemia and may contribute to hypertension in diseases with an activated renin-angiotensin-aldosterone system.

This article reviews the current understanding of the mechanisms of calcineurin inhibitor-induced hypertension. Already early after the introduction of cyclosporine in the 1980s, vasoconstriction, sympathetic excitation and sodium retention by the kidney had been shown to play a role in this form of hypertension. The vasoconstrictive effects of calcineurin inhibitors are related to interference with the balance of vasoactive substances, including endothelin and nitric oxide. Until recently, the renal site of the sodium-retaining effect of calcineurin inhibitors was unknown. We and others have shown that calcineurin inhibitors increase the activity of the thiazide-sensitive sodium chloride cotransporter through an effect on the kinases WNK and SPAK. Here, we review the pertinent literature on the hypertensinogenic effects of calcineurin inhibitors, including neural, vascular and renal effects, and we propose an integrated model of calcineurin inhibitor-induced hypertension.

Background: Hyponatremia is the most common electrolyte disorder, but a lack of well-characterized cohorts is hindering a full appreciation of this complex and heterogeneous disorder., Methods: During 4 months, clinical, biochemical, treatment and outcome data were collected for patients presenting with hyponatremia (serum sodium =130 mmol/L) to an urban university hospital., Results: Forty-three patients were included (serum sodium 126.6 ± 3.7 mmol/L). The most common causes of hyponatremia were diuretics (n=12), syndrome of inappropriate antidiuretic hormone secretion (n=11) and heart or liver disease (n=5). Renal insufficiency was frequent (n=18, 42%), and usually represented acute kidney injury (AKI; n=14, 78%). In patients with AKI, admission serum creatinine was 271 ± 252 µmol/L (3.4 ± 3.1-fold increase from baseline) and the origin was usually prerenal (12/14, 86%, fractional sodium excretion 0.54% ± 0.38%). Of these, patients with potentially reversible causes (salt loss or sepsis, n=7) had more favorable outcomes than patients with severe underlying disease (heart or liver disease, n=5), despite similar predictions using the RIFLE criteria. Survivors recovered with fluid resuscitation only. No overly rapid correction of hyponatremia was observed., Conclusions: AKI is common in patients presenting with hyponatremia and is usually of prerenal origin. The concurrence of AKI and hyponatremia has previously not been emphasized, but is important pathophysiologically and to plan rational management for both disorders. In this cohort, isotonic fluid replacement corrected both disorders and did not lead to overly rapid correction of hyponatremia.

In this article, an ethical analysis of an educational programme on renal replacement therapy options for patients and their social network is presented. The two main spearheads of this approach are: (1) offering an educational programme on all renal replacement therapy options ahead of treatment requirement and (2) a home-based approach involving the family and friends of the patient. Arguments are offered for the ethical justification of this approach by considering the viewpoint of the various stakeholders involved. Finally, reflecting on these ethical considerations, essential conditions for carrying out such a programme are outlined. The goal is to develop an ethically justified and responsible educational programme.

Hyponatremia is the most common electrolyte disorder and is mainly known for its neurological complications. New studies suggest previously unrecognized complications of hyponatremia, including falls, osteoporosis and fractures. Because these novel associations are mainly derived from epidemiological studies, it remains unclear whether hyponatremia has a direct effect on bone or whether it is a surrogate marker of another etiology. However, one animal and one in vitro study now show that hyponatremia can have direct effects on bone, mainly via activation of osteoclasts. The association between hyponatremia and fractures appears to be independent of osteoporosis (defined as low BMD). Also, data suggest that this association cannot be fully explained by the possibility that hyponatremia predisposes to falls. Hyponatremia, therefore, also has an effect on bone quality that is not captured by BMD. Here, the emerging relationship between hyponatremia and bone is reviewed, with special emphasis on possible mechanisms, unanswered questions and clinical implications.

Aims: Considering the growing relevance of fibroblast growth factor-23 (FGF-23) in the pathogenesis of chronic kidney disease bone and mineral disorder (CKD-MBD), an analysis was performed to determine the relative importance of C-terminal (cFGF-23) and intact (iFGF-23) assays in assessing CKD-MBD status in the first place and the relationship between FGF-23 and mortality as a secondary aim., Methods: In 77 patients (15 peritoneal dialysis and 62 hemodialysis), levels of calcium, phosphate, parathyroid hormone (PTH), 25-hydroxyvitamin- D (25D), 1,25D, FGF-23 (C-terminal and intact molecule) were measured and their correlations were analyzed. The relationship between FGF-23 levels and patient survival was also analyzed., Results: A significant correlation was found between cFGF-23 and 1,25D, PTH and 25D while iFGF-23 was significantly correlated with phosphate, 25D and PTH. PTH and 1,25D were independent predictors of cFGF-23, while for iFGF-23 independent predictors were phosphate and 25D. No significant relationship was found between FGF-23 and mortality., Conclusions: C-terminal or intact FGF-23 levels are weakly correlated and thus not clearly indicative of FGF-23 effects on PTH, P and vitamin D metabolism in dialysis patients. Assays for cFGF-23 and iFGF-23 showed a good correlation, but the intact molecule was not superior in defining interactions with CKD-MBD molecules. Measuring FGF-23 on a regular basis with the current assays in CKD and dialysis patients does not yet seem clinically useful.

Recent studies suggest that mild hyponatremia is associated with fractures, but prospective studies are lacking. We studied whether hyponatremia is associated with fractures, falls, and/or bone mineral density (BMD). A total of 5208 elderly subjects with serum sodium assessed at baseline were included from the prospective population-based Rotterdam Study. The following data were analyzed: BMD, vertebral fractures (mean follow-up 6.4 years), nonvertebral fractures (7.4 years), recent falls, comorbidity, medication, and mortality. Hyponatremia was detected in 399 subjects (7.7%, 133.4 ± 2.0 mmol/L). Subjects with hyponatremia were older (73.5 ± 10.3 years versus 70.0 ± 9.0 years, p < .001), had more recent falls (23.8% versus 16.4%, p < .01), higher type 2 diabetes mellitus prevalence (22.2% versus 10.3%, p < .001), and more often used diuretics (31.1% versus 15.0%, p < .001). Hyponatremia was not associated with lower BMD but was associated with increased risk of incident nonvertebral fractures [hazard ratio (HR) =1.39, 95% confidence interval (CI) 1.11-1.73, p = .004] after adjustment for age, sex, and body mass index. Further adjustments for disability index, use of diuretics, use of psycholeptics, recent falls, and diabetes did not modify results. In the fully adjusted model, subjects with hyponatremia also had increased risk of vertebral fractures at baseline [odds ratio (OR) = 1.78, 95% CI 1.04-3.06, p = .037] but not at follow-up. Finally, all-cause mortality was higher in subjects with hyponatremia (HR = 1.21, 95% CI 1.03-1.43, p = .022). It is concluded that mild hyponatremia in the elderly is associated with an increased risk of vertebral fractures and incident nonvertebral fractures but not with BMD. Increased fracture risk in hyponatremia also was independent of recent falls, pointing toward a possible effect on bone quality., (Copyright © 2011 American Society for Bone and Mineral Research.)

Objective: Encapsulating peritoneal sclerosis (EPS) is a serious complication of peritoneal dialysis (PD) with a multifactorial pathophysiology and possible increasing incidence. The aim of the present study was to evaluate the independent associations of PD duration, age, dialysis fluids, and kidney transplantation with EPS., Methods: A multicenter case-control study was performed in the Netherlands from 1 January 1996 until 1 July 2007. The population comprised 63 patients with EPS and 126 control patients. Control patients were selected from the national registry and were matched for date of PD start. Associations were analyzed using a log linear regression model. Primary outcome was appearance of EPS., Results: Compared with control patients, patients with EPS were younger at the start of PD (34.7 ± 15.4 years vs. 51.5 ± 14.7 years, p < 0.0001). The cumulative period on PD was longer in EPS patients than in control patients (78.7 ± 37.8 months vs. 32.8 ± 24 months, p < 0.0001), and the cumulative period on icodextrin was also longer in EPS patients (32.7 ± 23.3 months vs. 18.1 ± 15.7 months, p = 0.006). Compared with control patients, more EPS patients underwent kidney transplantation (47 vs. 59, p < 0.0001). With regard to the period after transplantation, the yearly probability of EPS increased in the year after transplantation to 7.5% from 1.75%. In multivariate regression analysis, cumulative PD duration, age at PD start, transplantation, time from last transplantation to EPS, calendar time, time on icodextrin, and ultrafiltration failure were independently associated with EPS. Transfer from PD to hemodialysis for reasons other than suspected EPS could not be identified as a risk factor for EPS., Conclusions: Duration of PD, age at PD start, kidney transplantation, time since last transplantation, ultrafiltration failure, and time on icodextrin were associated with a higher risk of EPS.

Background: A 57-year-old woman was referred to a nephrology clinic because of chronic hypokalemia. She had a history of polycystic kidney disease, resistant hypertension, atrial fibrillation, type 2 diabetes, stroke, and end-stage renal disease, and had received a kidney transplant from a deceased donor at the age of 48 years. At presentation, the patient described symptoms of chronic fatigue and muscle aches, but she did not report pareses. Her medications included four antihypertensive agents, glucose-lowering drugs, immunosuppressants, digoxin, a coumarin derivative, and potassium chloride., Investigations: Full history, physical examination, laboratory testing of blood and urine, including aldosterone-torenin ratio, and a saline infusion test., Diagnosis: Primary aldosteronism., Management: Treatment with spironolactone resulted in prompt control of hypertension and hypokalemia, allowing discontinuation of potassium chloride and reduction in antihypertensive medication.

The antidiuretic hormone vasopressin is crucial for regulating free water clearance in normal physiology. However, it has also been hypothesized that vasopressin has deleterious effects on the kidney. Vasopressin is elevated in animals and patients with chronic kidney disease. Suppression of vasopressin activity reduces proteinuria, renal hypertrophy, glomerulosclerosis and tubulointerstitial fibrosis in animal models. The potential detrimental influence of vasopressin is probably mediated by its effects on mesangial cell proliferation, renin secretion, renal hemodynamics, and blood pressure. In this review, we discuss the increasing body of evidence pointing towards the contribution of vasopressin to chronic kidney disease progression in general and to autosomal dominant polycystic kidney disease in particular. These data allude to the possibility that interventions directed at lowering vasopressin activity, for example by the administration of vasopressin receptor antagonists or by drinking more water, may be beneficial in chronic kidney disease., (Copyright © 2011 S. Karger AG, Basel.)

We studied here the independent roles of angiotensin II and aldosterone in regulating the sodium chloride cotransporter (NCC) of the distal convoluted tubule. We adrenalectomized three experimental and one control group of rats. Following surgery, the experimental groups were treated with either a high physiological dose of aldosterone, a non-pressor, or a pressor dose of angiotensin II for 8 days. Aldosterone and both doses of angiotensin II lowered sodium excretion and significantly increased the abundance of NCC in the plasma membrane compared with the control. Only the pressor dose of angiotensin II caused hypertension. Thiazides inhibited the sodium retention induced by the angiotensin II non-pressor dose. Both aldosterone and the non-pressor dose of angiotensin II significantly increased phosphorylation of NCC at threonine-53 and also increased the intracellular abundance of STE20/SPS1-related, proline alanine-rich kinase (SPAK). No differences were found in other modulators of NCC activity such as oxidative stress responsive protein type 1 or with-no-lysine kinase 4. Thus, our in vivo study shows that aldosterone and angiotensin II independently increase the abundance and phosphorylation of NCC in the setting of adrenalectomy; effects are likely mediated by SPAK. These results may explain, in part, the hormonal control of renal sodium excretion and the pathophysiology of several forms of hypertension.

Although hyponatremia is a recognized complication of several inflammatory diseases, its pathophysiology in this setting has remained elusive until recently. A growing body of evidence now points to an important role for interleukin-6 in the non-osmotic release of vasopressin. Here, we review this evidence by exploring the immuno-neuroendocrine pathways connecting interleukin-6 with vasopressin. The importance of these connections extends to several clinical scenarios of hyponatremia and inflammation, including hospital-acquired hyponatremia, postoperative hyponatremia, exercise-associated hyponatremia, and hyponatremia in the elderly. Besides insights in pathophysiology, the recognition of the propensity for antidiuresis during inflammation is also important with regard to monitoring patients and selecting the appropriate intravenous fluid regimen, for which recommendations are provided., (Copyright © 2010 S. Karger AG, Basel.)

Background: Hyponatremia is a common diagnostic challenge., Methods: An index case is presented to discuss the diagnostic approach to chronic and unexplained hyponatremia., Results: The index case concerns a 60-year-old man with chronic hepatitis C and previous alcohol use who was referred because of weight loss, poor dietary intake, dizzy spells, and unexplained hyponatremia (serum sodium 124-129 mmol/l). A low urine sodium concentration (20 mmol/l) and a low fractional sodium excretion (0.07%) were observed repeatedly, while urine osmolality was high (>400 mosm/kg). The central questions in this case are: what is the differential diagnosis, which tests are needed to confirm or exclude a diagnosis, and how would you proceed if no obvious cause is found?, Conclusions: The diagnosis of this case of unexplained hyponatremia was unexpected, but important because it was treatable. The challenges and caveats of the diagnostic approach to hyponatremia are discussed. A diagnostic algorithm to guide clinicians who are confronted with similar cases is presented., (Copyright © 2011 S. Karger AG, Basel.)

Despite a crucial role in body fluid homeostasis, elevated vasopressin levels can also be pathological in conditions such as congestive heart failure, liver cirrhosis and the syndrome of inappropriate antidiuretic hormone secretion. The result of elevated vasopressin is renal water retention and hyponatremia, a low serum sodium concentration. Hyponatremia is associated with excess morbidity and mortality. Nonpeptide vasopressin-receptor antagonists represent a new drug class of small molecules that competitively inhibit one or more of the vasopressin receptors. There are three vasopressin receptors in humans, including V1a, V1b and V2. Selective V2- and combined V1a/V2-receptor antagonists have been developed for the treatment of hyponatremia resulting from congestive heart failure, liver cirrhosis and the syndrome of inappropriate antidiuretic hormone secretion. Two nonpeptide vasopressin-receptor antagonists, conivaptan and tolvaptan, have recently been approved by American and European drug authorities for clinical use. This article aims to provide a succinct and clinical update on nonpeptide vasopressin-receptor antagonists, including their mechanism of action, performance in randomized clinical trials and current clinical status.

Proton pump inhibitor (PPI)-induced hypomagnesemia has been recognized since 2006. Our aim was to further characterize the clinical consequences and possible mechanisms of this electrolyte disorder using 4 cases. Two men (aged 63 and 81 years) and 2 women (aged 73 and 62 years) had been using a PPI (esomeprazole, pantoprazole, omeprazole, and rabeprazole, 20-40 mg) for 1-13 years. They developed severe hypomagnesemia (magnesium, 0.30 +/- 0.28 mEq/L; reference, 1.40-2.10 mEq/L) with hypocalcemia (calcium, 6.4 +/- 1.8 mg/dL), relative hypoparathyroidism (parathyroid hormone, 43 +/- 6 pg/mL), and extremely low urinary calcium and magnesium excretion. One patient was admitted with postanoxic encephalopathy after a collapse likely caused by arrhythmia. The others had electrocardiogram abnormalities (prolonged QT interval, ST depression, and U waves). Concomitant hypokalemia (potassium, 2.8 +/- 0.1 mEq/L) was considered the trigger for these arrhythmias. Hypomagnesemia-induced kaliuresis (potassium excretion, 65 +/- 24 mEq/L) was identified as the cause of hypokalemia. This series of PPI-induced hypomagnesemia shows that this is a generic effect. It also indicates that hypomagnesemia may occur within 1 year of PPI therapy initiation and can have serious clinical consequences, likely triggered by the associated hypokalemia. A high index of suspicion is required in PPI users for unexplained hypomagnesemia, hypocalcemia, hypokalemia, or associated symptoms.

Background: Hyponatraemia (serum sodium < 135 mmol/L) has long been recognized as a complication of malaria. However, few studies have been done in non-immune adult populations. It has not been investigated previously how hyponatraemia is distributed among the various Plasmodium species, and its association with malaria severity is unknown.The aim of this retrospective cohort study was to determine the prevalence of hyponatraemia and its association with malaria severity in a large cohort of patients with imported malaria caused by various Plasmodium species., Methods: All patients that were diagnosed with malaria in the Harbour Hospital and Institute for Tropical Diseases in Rotterdam in the period 1999-2009 and who had available serum sodium on admission were included. Severe malaria was defined according to the modified WHO criteria. Prevalence of hyponatraemia and its association with malaria severity were investigated by univariate comparison, ROC analysis and multivariate logistic regression analysis., Results: A total of 446 patients with malaria (severe falciparum malaria n = 35, non-severe falciparum malaria n = 280, non-falciparum malaria n = 131) was included. Hyponatraemia was present in 207 patients (46%). Prevalence and severity of hyponatraemia were greatest in severe falciparum malaria (77%, median serum sodium 129 mmol/L), followed by non-severe falciparum malaria (48%, median serum sodium 131 mmol/L), and non-falciparum malaria (34%, median serum sodium 132 mmol/L). Admission serum sodium < 133 mmol/L had a sensitivity of 0.69 and a specificity of 0.76 for predicting severe malaria. Multivariate logistic regression showed that serum sodium < 131 mmol/L was independently associated with severe falciparum malaria (odds ratio 10.4, 95% confidence interval 3.1-34.9). In patients with hyponatraemia, hypovolaemia did not appear to play a significant role in the development of hyponatraemia when prerenal azotaemia and haematocrit were considered as surrogate markers for hypovolaemia., Conclusions: Hyponatraemia is common in imported malaria and is associated with severe falciparum malaria. From a clinical point of view, the predictive power of hyponatraemia for severe malaria is limited. The precise pathophysiological mechanisms of hyponatraemia in malaria require further study.

Water balance disorders after neurosurgery are well recognized, but detailed reports of the triphasic response are scarce. We describe a 55-year-old woman, who developed the triphasic response with severe hyper- and hyponatraemia after resection of a suprasellar meningioma. The case illustrates how sudden and dramatic the changes in water balance after neurosurgery can be. The biochemical profile suggested central diabetes insipidus and the syndrome of inappropriate antidiuretic hormone secretion. The underlying pathophysiology was further analysed using fractional excretions, measurements of renin, aldosterone and vasopressin and a metyrapone test. Diagnostic, therapeutic and preventive strategies for these intriguing but complex cases are proposed.

Dehydration is an important cause of morbidity and mortality for children and the elderly. Acute loss of weight is the most reliable measure of dehydration. In addition, a range of physical diagnostic findings are used for measuring dehydration; separate clinical findings have very little predictive value. In clinical practice the need for further investigation and rehydration treatment can be assessed by combining history and physical examination.

Background: In clinical practice, discriminating between glomerular and nonglomerular causes of hematuria is often difficult. Dysmorphic red blood cells (dRBC) in the urinary sediment are claimed to be effective, but the cutoff points in the literature vary. This follow-up study aimed to determine the diagnostic value of dRBC., Methods: We investigated 134 hematuria patients in the departments of nephrology and urology. To diagnose the origin of hematuria, urological and/or nephrological examination was performed and the %dRBC identified by microscopy. Follow-up was performed after 3.5 years., Results: The cause of hematuria was proven in 68 patients (35% glomerular; 65% nonglomerular). Patients with glomerular disease had significantly more albuminuria and dRBC than patients with nonglomerular disease, but the %dRBC ranged from 1 to 50% and no optimal cutoff could be identified. Logistic regression analysis showed that %dRBC had a predicted probability to diagnose glomerular disease of 77.9% (area under the curve, AUC, 0.85). When %dRBC was combined with other risk factors such as serum creatinine, sex, age, dipstick erythrocyte or proteinuria score and number of casts, the predictive probability increased to 90.6% (AUC 0.97). Follow-up of the included patients showed no benefit of dRBC to identify patients at risk for glomerular disease., Conclusions: The diagnostic value of routinely collected urinary dRBC to diagnose glomerular disease in patients presenting with hematuria is modest. However, including dRBC with other variables, such as age and erythrocyte score on dipstick testing may increase the sensitivity, but needs to be confirmed in another, preferably larger, population., (Copyright 2010 S. Karger AG, Basel.)

The syndrome of inappropriate antidiuretic hormone secretion (SIADH) remains a challenging disorder to diagnose and treat. Three cases are presented to illustrate these challenges. The first two cases had drug-induced SIADH secondary to a selective serotonin reuptake inhibitor (for depression) or carbamazepine (for trigeminal neuralgia). The third case had SIADH possibly secondary to bronchiectasis. The lowest serum sodium concentrations ranged between 118 and 124 mmol/L in the three cases. Hyponatraemia was not acute and severe symptoms were absent. However, several mild neurological symptoms were present. In the first case, hyponatraemia likely contributed to a fall, which resulted in a fracture of the odontoid process of the axis. The other two cases also had gait disturbances, in addition to nausea, headache, impaired memory, difficulty concentrating and confusion. In at least two of the cases, the underlying cause of SIADH was impossible to reverse. Traditional treatment for SIADH with fluid restriction and demeclocycline failed, caused side effects or increased duration of hospital stay. These examples suggest a need for better treatment options. The introduction of the vasopressin-receptor antagonists for SIADH may be a welcome new therapy to overcome some of these challenges.

Background: The aim was to investigate the unknown mechanism of osmomediated natriuresis. This is the phenomenon by which hypertonic saline (HS) produces a larger natriuresis than isotonic saline (IS), despite the same sodium content., Methods: Seven healthy volunteers first received HS and then IS (both 3.85 mmol sodium/kg). To investigate the role of calcium metabolism, four patients received HS, two with an activating mutation (ADH) and two with an inactivating mutation (FHH) of the calcium-sensing receptor (CaSR)., Results: In healthy volunteers, HS produced mild hypernatraemia, a 4-fold rise in vasopressin (to 2.2 +/- 0.85 pg/mL) and a 3-fold rise in natriuresis compared with a 1.5-fold rise with IS (P = 0.002). This confirmed osmomediated natriuresis. HS caused calciuresis to increase 1.4-fold and then reduced it 1.4-fold, whereas IS failed to increase calciuresis and caused it to fall 3.7-fold (P = 0.05). Natriuresis and calciuresis in ADH patients were similar to healthy volunteers receiving HS, whereas a blunted response was seen in FHH patients. Patient vasopressin levels did not exceed 1.3 pg/mL and changes from baseline were variable. In one FHH patient, a 3-fold rise in vasopressin did not prevent the blunted natriuresis and calciuresis. In one ADH patient, natriuresis and calciuresis were similar to healthy volunteers despite a 1.7-fold fall in vasopressin., Conclusions: Our data suggest that not only vasopressin (possibly via its V1a receptor), but also the CaSR (which is sensitive to high sodium concentrations) may play a role in osmomediated natriuresis. These results shed new light on osmomediated natriuresis and suggest roles for the CaSR beyond calcium regulation.

The treatment of hyponatraemia due to SIADH is not always as straightforward as it seems. Although acute treatment with hypertonic saline and chronic treatment with fluid restriction are well established, both approaches have severe limitations. These limitations are not readily overcome by addition of furosemide, demeclocycline, lithium or urea to the therapy. In theory, vasopressin-receptor antagonists would provide a more effective method to treat hyponatraemia, by virtue of their ability to selectively increase solute-free water excretion by the kidneys (aquaresis). In this review we explore the limitations of the current treatment of SIADH and describe emerging therapies for the treatment of SIADH-induced hyponatraemia.

The vasopressin-receptor antagonists have received approval for the treatment of hyponatraemia secondary to the syndrome of inappropriate antidiuretic hormone secretion (SIADH). It is therefore necessary that physicians encountering hyponatraemia focus on SIADH. Recent studies show that hyponatraemia is often poorly managed-insufficient diagnostic tests are ordered and patients are undertreated. At the same time, it has become clear that chronic hyponatraemia causes neurological symptoms such as gait disturbances and attention deficits. However, physicians often tolerate chronic hyponatraemia as if it were benign, or as if its treatment would cause significant morbidity. Therefore, physicians must reconsider the diagnostic and therapeutic approaches to hyponatraemia and SIADH.