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It has been acknowledged for years that compounds containing sulfur (S) are an important source of endogenous acid production. In the metabolism, S is oxidized to sulfate, and therefore the mEq sulfate excreted in the urine is counted as acid retained in the body. In this study we show that pH in fluids with constant [Na] and [HEPES] declines as sulfate ions are added, and we show that titratable acidity increases exactly with the equivalents of sulfate. Therefore, sulfate excretion in urine is also acid excretion per se. This is in accordance with the down-regulation of proximal sulfate reabsorption under acidosis and the observation that children with distal renal tubular acidosis may be sulfate depleted. These results are well explained using charge-balance modeling, which is based only on the three fundamental principles of electroneutrality, conservation of mass, and rules of dissociation as devised from physical chemistry. In contrast, the findings are in contrast to expectations from conventional narratives. These are unable to understand the decreasing pH as sulfate is added since no conventional acid is present. The results may undermine the traditional notion of endogenous acid production since in the case of sulfur balance, S oxidation and its excretion as sulfate exactly balance each other. Possible clinical correlates with these findings are discussed.

Rational treatment and thorough diagnostic classification of acid-base disorders requires quantitative understanding of the mechanisms that generate and dissipate loads of acid and base. A natural precondition for this tallying is the ability to quantify the acid content in any specified fluid. Physical chemistry defines the pH-dependent charge on any buffer species, and also on strong ions on which, by definition, the charge is pH-invariant. Based, then, on the requirement of electroneutrality and conservation of mass, it was shown in 1914 that pH can be calculated and understood on the basis of the chemical composition of any fluid. Herein we first show that this specification for [H+] of the charge-balance model directly delivers the pH-dependent buffer-capacity as defined in the literature. Next, we show how the notion of acid transport as proposed in experimental physiology can be understood as a change in strong ion difference, ΔSID. Finally, based on Brønsted-Lowry theory we demonstrate that by defining the acid content as titratable acidity, this is equal to SIDref–SID, where SIDref is SID at pH 7.4. Thereby, any chemical situation is represented as a curve in a novel diagram with titratable acidity = SIDref–SID as a function of pH. For any specification of buffer chemistry, therefore, the change in acid content in the fluid is path invariant. Since constituents of SID and titratable acidity are additive, we thereby, based on first principles, have defined a new framework for modeling acid balance across a cell, a whole organ, or the whole-body.

Objective: The effects of a dose-reduction intervention of biological disease-modifying anti-rheumatic drugs (bDMARDs) in patients in remission were analysed with epidemiology and health economics strategies. The aims were to analyse changes in bDMARD dosage, evaluate potential disease worsening, and estimate cost reduction. Method: This uncontrolled single-centre observational study analysed bDMARD-treated patients with rheumatoid arthritis (RA), psoriatic arthritis (PsA), and spondyloarthritis (SpA). bDMARD expenditure constituted a proxy for bDMARD doses, which enabled group-level analysis. Interrupted time-series regression was used to analyse changes in treatment cost due to the dose reduction. Disease activity and treatment durations were monitored to investigate disease worsening. Results: In total, 997 biological treatment cases were analysed. This involved 527 bDMARD patients, where an unknown fraction of patients was given reduced doses. Disease activity of RA and PsA patients decreased from 2001 to 2009 and remained stable after that, while disease activity for SpA patients was unchanged, indicating no disease worsening from the intervention. The dose tapering resulted in decreased bDMARD expenditure, indicating a decrease in bDMARD consumption, which led to an accumulated cost reduction of 4 178 000 EUR. Conclusions: The results suggest that dose reduction can be safely performed in patients in treatment remission on a group level without compromising treatment efficacy. Subcutaneous bDMARDs, including abatacept, adalimumab, and etanercept, were observed to be well suited to customizing dosage. This study highlights the potential for individualized and personalized rheumatic medicine by providing dose reduction to individual patients, while monitoring disease activity.

Objectives: We designed a novel respiratory dialysis system to remove Co2 from blood in the form of bicarbonate. We aimed to determine if our respiratory dialysis system removes Co2 at rates comparable to low-flow extracorporeal Co2 removal devices (blood flow < 500 mL/min) in a large animal model. Design: Experimental study. Setting: Animal research laboratory. Subjects: Female Yorkshire pigs. Interventions: Five bicarbonate dialysis experiments were performed. Hypercapnia (Pco2 90–100 mm Hg) was established in mechanically ventilated swine by adjusting the tidal volume. Dialysis was then performed with a novel low bicarbonate dialysate. Measurements and Main Results: We measured electrolytes, blood gases, and plasma-free hemoglobin in arterial blood, as well as blood entering and exiting the dialyzer. We used a physical-chemical acid-base model to understand the factors influencing blood pH after bicarbonate removal. During dialysis, we removed 101 (±13) mL/min of Co2 (59 mL/min when normalized to venous Pco2 of 45 mm Hg), corresponding to a 29% reduction in Paco2 (104.0 ± 8.1 vs 74.2 ± 8.4 mm Hg; p < 0.001). Minute ventilation and body temperature were unchanged during dialysis (1.2 ± 0.4 vs 1.1 ± 0.4 L/min; p = 1.0 and 35.3°C ± 0.9 vs 35.2°C ± 0.6; p = 1.0). Arterial pH increased after bicarbonate removal (7.13 ± 0.04 vs 7.21 ± 0.05; p < 0.001) despite no attempt to realkalinize the blood. Our modeling showed that dialysate electrolyte composition, plasma albumin, and plasma total Co2 accurately predict the measured pH of blood exiting the dialyser. However, the final effluent dose exceeded conventional doses, depleting plasma glucose and electrolytes, such as potassium and phosphate. Conclusions: Bicarbonate dialysis results in Co2 removal at rates comparable with existing low-flow extracorporeal Co2 removal in a large animal model, but the final dialysis dose delivered needs to be reduced before the technique can be used for prolonged periods. Objectives: We designed a novel respiratory dialysis system to remove Co2from blood in the form of bicarbonate. We aimed to determine if our respiratory dialysis system removes Co2at rates comparable to low-flow extracorporeal Co2removal devices (blood flow < 500 mL/min) in a large animal model. Design: Experimental study. Setting: Animal research laboratory. Subjects: Female Yorkshire pigs. Interventions: Five bicarbonate dialysis experiments were performed. Hypercapnia (Pco290-100 mm Hg) was established in mechanically ventilated swine by adjusting the tidal volume. Dialysis was then performed with a novel low bicarbonate dialysate. Measurements and Main Results: We measured electrolytes, blood gases, and plasma-free hemoglobin in arterial blood, as well as blood entering and exiting the dialyzer. We used a physical-chemical acid-base model to understand the factors influencing blood pH after bicarbonate removal. During dialysis, we removed 101 (±13) mL/min of Co2(59 mL/min when normalized to venous Pco2of 45 mm Hg), corresponding to a 29% reduction in Paco2(104.0 ± 8.1 vs 74.2 ± 8.4 mm Hg; p < 0.001). Minute ventilation and body temperature were unchanged during dialysis (1.2 ± 0.4 vs 1.1 ± 0.4 L/min; p = 1.0 and 35.3°C ± 0.9 vs 35.2°C ± 0.6; p = 1.0). Arterial pH increased after bicarbonate removal (7.13 ± 0.04 vs 7.21 ± 0.05; p < 0.001) despite no attempt to realkalinize the blood. Our modeling showed that dialysate electrolyte composition, plasma albumin, and plasma total Co2accurately predict the measured pH of blood exiting the dialyser. However, the final effluent dose exceeded conventional doses, depleting plasma glucose and electrolytes, such as potassium and phosphate. Conclusions: Bicarbonate dialysis results in Co2removal at rates comparable with existing low-flow extracorporeal Co2removal in a large animal model, but the final dialysis dose delivered needs to be reduced before the technique can be used for prolonged periods.

© 2019, Springer Science+Business Media, LLC, part of Springer Nature. Background: In our metabolomics studies we have noticed that repeated NMR acquisition on the same sample can result in altered metabolite signal intensities. Aims: To investigate the reproducibility of repeated NMR acquisition on selected metabolites in serum and plasma from two large human metabolomics studies. Methods: Two peak regions for each metabolite were integrated and changes occurring after reacquisition were correlated. Results: Integral changes were generally small, but serum citrate signals decreased significantly in some samples. Conclusions: Several metabolite integrals were not reproducible in some of the repeated spectra. Following established protocols, randomising analysis order and biomarker validation are important.

Introduction: Progressive chronic kidney disease (CKD) is an important cause of morbidity and mortality. It has a long asymptomatic phase, where routine blood tests cannot identify early functional losses, and therefore identifying common mechanisms across the many etiologies is an important goal. Objectives: Our aim was to characterize serum, urine and tissue (kidney, lung, heart, spleen and liver) metabolomics changes in a rat model of CKD. Methods: A total of 17 male Wistar rats underwent 5/6 nephrectomy, whilst 13 rats underwent sham operation. Urine samples were collected weekly, for 6 weeks; blood was collected at weeks 0, 3 and 6; and tissue samples were collected at week 6. Samples were analyzed on a nuclear magnetic resonance spectroscopy platform with multivariate and univariate data analysis. Results: Changes in several metabolites were statistically significant. Allantoin was affected in all compartments. Renal asparagine, creatine, hippurate and trimethylamine were significantly different; in other tissues creatine, dimethylamine, dimethylglycine, trigonelline and trimethylamine were significant. Benzoate, citrate, dimethylglycine, fumarate, guanidinoacetate, malate, myo-inositol and oxoglutarate were altered in urine or serum. Conclusion: Although the metabolic picture is complex, we suggest oxidative stress, the gut-kidney axis, acid–base balance, and energy metabolism as promising areas for future investigation.

Dysregulation of capillary blood flow seems associated with a number of diseases, but the majority of measurements of capillary flow distributions have been performed in brain or muscle capillary b...

What is the central question of this study? The brain response to acute hyponatraemia is usually studied in rodents by intraperitoneal instillation of hypotonic fluids (i.p. model). The i.p. model is described as 'dilutional' and 'syndrome of inappropriate ADH (SIADH)', but the mechanism has not been explored systematically and might affect the brain response. Therefore, in vivo brain and muscle response were studied in pigs. What is the main finding and its importance? The i.p. model induces hypovolaemic hyponatraemia attributable to sodium redistribution, not dilution. A large reduction in brain sodium is observed, probably because of the specific mechanism causing the hyponatraemia. This is not accounted for in current understanding of the brain response to acute hyponatraemia. Hyponatraemia is common clinically, and if it develops rapidly, brain oedema evolves, and severe morbidity and even death may occur. Experimentally, acute hyponatraemia is most frequently studied in small animal models, in which the hyponatraemia is produced by intraperitoneal instillation of hypotonic fluids (i.p. model). This hyponatraemia model is described as 'dilutional' or 'syndrome of inappropriate ADH (SIADH)', but seminal studies contradict this interpretation. To confront this issue, we developed an i.p. model in a large animal (the pig) and studied water and electrolyte responses in brain, muscle, plasma and urine. We hypothesized that hyponatraemia was induced by simple water dilution, with no change in organ sodium content. Moderate hypotonic hyponatraemia was induced by a single i.v. dose of desmopressin and intraperitoneal instillation of 2.5% glucose. All animals were anaesthetized and intensively monitored. In vivo brain and muscle water was determined by magnetic resonance imaging and related to the plasma sodium concentration. Muscle water content increased less than expected as a result of pure dilution, and muscle sodium content decreased significantly (by 28%). Sodium was redistributed to the peritoneal fluid, resulting in a significantly reduced plasma volume. This shows that the i.p. model induces hypovolaemic hyponatraemia and not dilutional/SIADH hyponatraemia. Brain oedema evolved, but brain sodium content decreased significantly (by 21%). To conclude, the i.p. model induces hypovolaemic hyponatraemia attributable to sodium redistribution and not water dilution. The large reduction in brain sodium is probably attributable to the specific mechanism that causes the hyponatraemia. This is not accounted for in the current understanding of the brain response to acute hyponatraemia.

Quantitative modeling of acid-base is possible from a notion of charge balance. The chapter demonstrates how this explains findings from classical physiology and makes possible an understanding of clinical disorders. A complete and explicit model is derived and substantiated, obviating with notions of dependent and independent variables, and solidly based on physical chemistry. The model is presented in detail and links to code provided to confirm and extend the findings.

Disorders of sodium (Na+) and water balance commonly are encountered in critically ill patients. Critical illness, multiple-organ dysfunction, fluid therapy, and the numerous additional interventions applied in the routine care of patients admitted to the intensive care unit can interfere with the complex mechanisms that maintain total body sodium and water homeostasis. Sodium is the principal osmolyte in the extracellular fluid and hence determines the size of the extracellular volume. Loss of sodium and water can cause life-threatening hypovolemia, and resuscitation with sodium-containing fluids is essential. In contrast, gain of sodium and water expands the extracellular volume and can cause significant morbidity because of respiratory, circulatory, and renal failure. Besides the effect on extracellular volume, sodium and water balance determines extracellular tonicity. Cells are bathed in salt water, and normonatremia—normal tonicity—is pivotal for optimal cell size and function. Disorders of sodium and water balance disturb the cellular environment by causing hyponatremia or hypernatremia. Hyponatremia and hypernatremia are frequent in the critically ill patient and associated with significant morbidity and mortality. A rapid change in serum sodium concentration can result in brain damage and death because of brain edema or osmotic demyelination. Addressing disorders of sodium and water balance, including the safe treatment of patients admitted to the intensive care unit and the prevention of fluid and electrolyte imbalances, is essential in critical care therapy. To achieve this, clinicians must have a solid understanding of what determines serum sodium concentration in the individual patient.

ObjectiveWe aimed to investigate the impact of hyponatremia severity on mortality risk and assess any evidence of a dose–response relation, utilizing prospectively collected data from population-based registries.DesignCohort study of 279 508 first-time acute admissions to Departments of Internal Medicine in the North and Central Denmark Regions from 2006 to 2011.MethodsWe used the Kaplan–Meier method (1 – survival function) to compute 30-day and 1-year mortality in patients with normonatremia and categories of increasing hyponatremia severity. Relative risks (RRs) with 95% CIs, adjusted for age, gender and previous morbidities, and stratified by clinical subgroups were estimated by the pseudo-value approach. The probability of death was estimated treating serum sodium as a continuous variable.ResultsThe prevalence of admission hyponatremia was 15% (41 803 patients). Thirty-day mortality was 3.6% in normonatremic patients compared to 7.3, 10.0, 10.4 and 9.6% in patients with serum sodium levels of 130–134.9, 125–129.9, 120–124.9 and ConclusionsHyponatremia is highly prevalent among patients admitted to Departments of Internal Medicine and is associated with increased 30-day and 1-year mortality risk, regardless of underlying disease. This risk seems independent of hyponatremia severity.

IgA nephropathy (IgAN) is characterized by a variable clinical course and multifaceted pathophysiology. There is substantial evidence to suggest that complement activation plays a pivotal role in the pathogenesis of the disease. Therefore, complement inhibition using the humanized anti-C5 monoclonal antibody eculizumab could be a rational treatment. We report here a 16-year-old male with the vasculitic form of IgAN who failed to respond to aggressive conventional therapy including high-dose steroids, cyclophosphamide and plasma exchange and who was treated with four weekly doses of 900 mg eculizumab followed by a single dose of 1200 mg. He responded rapidly to this treatment and has had a stable creatinine around 150 µmol/L (1.67 mg/dL) for >6 months. However, proteinuria was unabated on maximal conventional anti-proteinuric treatment, and a repeat renal biopsy 11 months after presentation revealed severe chronic changes. We believe this case provides proof of principle that complement inhibition may be beneficial in IgAN but also that development of chronicity may be independent of complement.

The textbook account of whole body acid-base balance in terms of endogenous acid production, renal net acid excretion, and gastrointestinal alkali absorption, which is the only comprehensive model around, has never been applied in clinical practice or been formally validated. To improve understanding of acid-base modeling, we managed to write up this conventional model as an expression solely on urine chemistry. Renal net acid excretion and endogenous acid production were already formulated in terms of urine chemistry, and we could from the literature also see gastrointestinal alkali absorption in terms of urine excretions. With a few assumptions it was possible to see that this expression of net acid balance was arithmetically identical to minus urine charge, whereby under the development of acidosis, urine was predicted to acquire a net negative charge. The literature already mentions unexplained negative urine charges so we scrutinized a series of seminal papers and confirmed empirically the theoretical prediction that observed urine charge did acquire negative charge as acidosis developed. Hence, we can conclude that the conventional model is problematic since it predicts what is physiologically impossible. Therefore, we need a new model for whole body acid-base balance, which does not have impossible implications. Furthermore, new experimental studies are needed to account for charge imbalance in urine under development of acidosis.

The demonstration of impaired C regulation in the thrombotic microangiopathy (TMA) atypical hemolytic uremic syndrome (aHUS) resulted in the successful introduction of the C inhibitor eculizumab into clinical practice. C abnormalities account for approximately 50% of aHUS cases; however, mutations in the non-C gene diacylglycerol kinase-ε have been described recently in individuals not responsive to eculizumab. We report here a family in which the proposita presented with aHUS but did not respond to eculizumab. Her mother had previously presented with a post-renal transplant TMA. Both the proposita and her mother also had Charcot-Marie-Tooth disease. Using whole-exome sequencing, we identified a mutation in the inverted formin 2 gene (INF2) in the mutational hotspot for FSGS. Subsequent analysis of the Newcastle aHUS cohort identified another family with a functionally-significant mutation in INF2 In this family, renal transplantation was associated with post-transplant TMA. All individuals with INF2 mutations presenting with a TMA also had aHUS risk haplotypes, potentially accounting for the genetic pleiotropy. Identifying individuals with TMAs who may not respond to eculizumab will avoid prolonged exposure of such individuals to the infectious complications of terminal pathway C blockade.

BACKGROUND:: Hyponatremia is associated with increased mortality and is frequently induced by diuretic use. It is uncertain whether diuretic use is linked to mortality risk in patients with hyponatremia. STUDY QUESTION:: To measure the prognostic impact of diuretic use on 30-day mortality among patients hospitalized with hyponatremia. STUDY DESIGN:: Using population-based registries, we identified all patients with a serum sodium measurement

Aim: To test the effects of dietary NaCl and carbohydrate content on urine volume in diabetic rats. Methods: Streptozotocin-induced diabetic rats were subjected to NaCl restriction using either a NaCl-deficient carbohydrate-rich synthetic diet (Altromin C1036) supplemented to contain 0.16% NaCl (C1036 + lowNaCl) or a modified normal cereal-based diet (Altromin 1320) containing 0.086% NaCl (lowNaCl-1320). Normal diet contained 0.2683% NaCl. Results: Using the C1036 + lowNaCl diet, earlier reported paradoxical increases in water intake and urine volume of diabetic rats were reproduced. However, water intake and urine volume also increased in diabetic rats offered the synthetic C1036 diet supplemented with NaCl to normal levels. Using the lowNaCl-1320 diet, water intake and urine volume were markedly reduced. Highly significant correlations between urine volume and both osmotic output and urinary glucose excretion were found in diabetic rats on normal diet, but these correlations were absent in diabetic rats on synthetic diet, which showed higher urine volumes than expected from the correlations. In contrast, urine volume was significantly correlated with carbohydrate intake in diabetic rats, irrespective of the diet. Conclusions: (i) The synthetic diet dramatically increases the urine volume in STZ-DM rats irrespectively of NaCl content. (ii) Rats with STZ-DM on a normal diet show reduced water intake and urine volume in response to dietary NaCl restriction. (iii) A shift to high carbohydrate diet induces polyuria in STZ-DM rats. (iv) Urine volume in all STZ-DM rats only shows correlation with dietary carbohydrate intake. (v) Glucose-driven osmotic diuresis is unlikely to explain the carbohydrate-induced polyuria.

Udgivelsesdato: 2009-Aug Congenital obstructive nephropathy accounts for a major proportion of renal insufficiency in infancy and childhood. In an earlier investigation we demonstrated that bilateral complete ureteral obstruction (BUO) in rats is associated with inadequate urinary acidification [Am J Physiol Renal Physiol. 295(2):F497-506, 2008]. The aim of the study reported here was to determine whether this defect is also associated with unilateral ureteral obstruction (UUO), which is clinically more common than BUO. The time-course of the changes in protein expression levels of major renal acid-base transporters was examined at 7 and 14 weeks in rats with neonatally induced partial unilateral ureteral obstruction (PUUO), which was performed within the first 48 h of life. We observed that protein expression of the renal acid-base transporters NHE3, NBC1, NBCn1, pendrin and Na(+)-K(+)-ATPase was increased in both obstructed and non-obstructed kidneys 7 weeks after the induction of neonatal PUUO. This was confirmed by immunocytochemistry. In contrast, 14 weeks after the induction of PUUO, there was a significant downregulation of the renal acid-base transporters NBC1, NBCn1 and Na(+)-K(+)-ATPase in the obstructed kidneys. These time/age-dependent changes in protein expression were associated with parallel changes in renal function resulting in urine acidification in response to exogenous acid loading. In conclusion, these results show that downregulation of protein expression is a time/age-dependent response to PUUO, which could contribute to the decreased net acid excretion and development of metabolic acidosis in neonatal rats with PUUO.

What is the central question of this study? The brain response to acute hyponatraemia is usually studied in rodents by intraperitoneal instillation of hypotonic fluids (i.p. model). The i.p. model is described as 'dilutional' and 'syndrome of inappropriate ADH (SIADH)', but the mechanism has not been explored systematically and might affect the brain response. Therefore, in vivo brain and muscle response were studied in pigs. What is the main finding and its importance? The i.p. model induces hypovolaemic hyponatraemia attributable to sodium redistribution, not dilution. A large reduction in brain sodium is observed, probably because of the specific mechanism causing the hyponatraemia. This is not accounted for in current understanding of the brain response to acute hyponatraemia. Hyponatraemia is common clinically, and if it develops rapidly, brain oedema evolves, and severe morbidity and even death may occur. Experimentally, acute hyponatraemia is most frequently studied in small animal models, in which the hyponatraemia is produced by intraperitoneal instillation of hypotonic fluids (i.p. model). This hyponatraemia model is described as 'dilutional' or 'syndrome of inappropriate ADH (SIADH)', but seminal studies contradict this interpretation. To confront this issue, we developed an i.p. model in a large animal (the pig) and studied water and electrolyte responses in brain, muscle, plasma and urine. We hypothesized that hyponatraemia was induced by simple water dilution, with no change in organ sodium content. Moderate hypotonic hyponatraemia was induced by a single i.v. dose of desmopressin and intraperitoneal instillation of 2.5% glucose. All animals were anaesthetized and intensively monitored. In vivo brain and muscle water was determined by magnetic resonance imaging and related to the plasma sodium concentration. Muscle water content increased less than expected as a result of pure dilution, and muscle sodium content decreased significantly (by 28%). Sodium was redistributed to the peritoneal fluid, resulting in a significantly reduced plasma volume. This shows that the i.p. model induces hypovolaemic hyponatraemia and not dilutional/SIADH hyponatraemia. Brain oedema evolved, but brain sodium content decreased significantly (by 21%). To conclude, the i.p. model induces hypovolaemic hyponatraemia attributable to sodium redistribution and not water dilution. The large reduction in brain sodium is probably attributable to the specific mechanism that causes the hyponatraemia. This is not accounted for in the current understanding of the brain response to acute hyponatraemia.

EPO and α-MSH prevent ischemia/reperfusion-induced down-regulation of AQPs and sodium transporters in rat kidney. Background Ischemia-induced acute renal failure (ARF) is known to be associated with significant impairment of urinary concentrating ability and down-regulation of renal aquaporins (AQPs) and sodium transporters in rats. We tested whether treatment with erythropoietin (EPO) or α-melanocyte-stimulating hormone (α-MSH) in combination with EPO reduces the renal ischemia/reperfusion (I/R) injury and prevents the down-regulation of renal AQPs and major sodium transporters. Methods I/R-induced ARF was established in rats by 40-minute temporary bilateral obstruction of renal arteries, and rats were kept in metabolic cages for urine measurements. After 2 or 4 days following EPO and/or α-MSH treatment, kidneys were removed to determine the expression levels of AQPs and sodium transporters by semiquantitative immunoblotting. Results Rats with ARF showed significant renal insufficiency, increased urine output, and high fractional excretion of urinary sodium. Consistent with this, immunoblotting and immunocytochemistry revealed that the kidney expression of AQPs (AQP-1, -2 and -3) and sodium transporters [Na,K-ATPase, rat type 1 bumetanide-sensitive Na-K-2Cl cotransporter (BSC-1), Na/H exchanger type 3 (NHE3), and thiazide-sensitive sodium chloride cotransporter (TSC)] in ARF rats was significantly decreased compared to sham-operated control rats. In contrast, EPO treatment at the time of ischemia of rats with ARF significantly prevented the ischemia-induced down-regulation of renal AQPs and sodium transporters and in parallel improved the urinary concentrating capability and renal sodium reabsorption. Importantly, similar effects were observed following the initiation of EPO or α-MSH treatment 4 hours after the onset of ischemia injury. Moreover, the combination of EPO with α-MSH potentiated the beneficial effects of single compound treatment. Conclusion EPO and/or α-MSH treatment significantly prevent I/R-induced injuries such as urinary-concentrating defects and down-regulation of renal AQPs and sodium transporters.

Item does not contain fulltext A 16-year-old female had mutations in both alleles of the gene encoding her sodium-chloride cotransporter; one of these mutations is newly described. Her clinical findings were not typical because of the absence of hypocalciuria in 24-h urine samples, her maximum urine osmolality (U(osm)) was only 802 mosmol/kg H(2)O, and her plasma magnesium (Mg) concentration (P(Mg)) was easily maintained in the normal range with oral Mg supplements for 1 month. In detailed studies, the calcium/creatinine ratio in spot urines with a U(osm) >700 mosmol/kg H(2)O was very low, except during Mg therapy. Renal medullary function did not appear to be compromised because she had a non-urea U(osm)of approximately 600 mosmol/kg H(2)O, reflecting a very high non-urea osmole excretion rate (due to KCl supplements). At age 18 years, her P(Mg) became persistently low despite Mg therapy. We conclude that the clinical criteria for a provisional diagnosis of Gitelman syndrome should be revised. Hypocalciuria may only be evident initially in concentrated spot urine samples. Urine concentrating ability should include an analysis of the non-urea U(osm), especially when patients are taking large KCl supplements.

We present a report of what we believe was an extremely rare case of hyperacute respiratory failure caused by first time exposure to cyclophosphamide in a 40-year-old woman with systemic lupus erythematosus. The patient was extensively evaluated for alternative etiologies with negative results. Treatment with methylprednisolone and high doses of human immunoglobulin resulted in gradual improvement of the patient's condition. We review the literature with regard to cyclophosphamide-induced lung toxicity.

The following is the abstract of the article discussed in the subsequent letter: The presence of negatively charged, impermeant proteins in the plasma space alters the distribution of diffusible ions in the plasma and interstitial fluid (ISF) compartments to preserve electroneutrality. We have derived a new mathematical model to define the quantitative interrelationship between the Gibbs-Donnan equilibrium, the osmolality of body fluid compartments, and the plasma water Na+ concentration ([Na+]pw) and validated the model using empirical data from the literature. The new model can account for the alterations in all ionic concentrations (Na+ and non-Na+ ions) between the plasma and ISF due to Gibbs-Donnan equilibrium. In addition to the effect of Gibbs-Donnan equilibrium on Na+ distribution between plasma and ISF, our model predicts that the altered distribution of osmotically active non-Na+ ions will also have a modulating effect on the [Na+]pw by affecting the distribution of H2O between the plasma and ISF. The new physiological insights provided by this model can for the first time provide a basis for understanding quantitatively how changes in the plasma protein concentration modulate the [Na+]pw. Moreover, this model defines all known physiological factors that may modulate the [Na+]pw and is especially helpful in conceptually understanding the pathophysiological basis of the dysnatremias.

OBJECTIVE: To examine the validity of the International Classification of Diseases, 10th revision (ICD-10) codes for hyponatraemia in the nationwide population-based Danish National Registry of Patients (DNRP) among inpatients of all ages.DESIGN: Population-based validation study.SETTING: All somatic hospitals in the North and Central Denmark Regions from 2006 through 2011.PARTICIPANTS: Patients of all ages admitted to hospital (n=819 701 individual patients) during the study period. The patient could be included in the study more than once, and our study did not restrict to patients with serum sodium measurements (total of n=2 186 642 hospitalisations).MAIN OUTCOME MEASURE: We validated ICD-10 discharge diagnoses of hyponatraemia recorded in the DNRP, using serum sodium measurements obtained from the laboratory information systems (LABKA) research database as the gold standard. One sodium value RESULT: An ICD-10 code for hyponatraemia was recorded in the DNRP in 5850 of the 2 186 642 hospitalisations identified. According to laboratory measurements, however, hyponatraemia was present in 306 418 (14%) hospitalisations. Sensitivity of hyponatraemia diagnoses was 1.8% (95% CI 1.7% to 1.8%). For sodium values CONCLUSIONS: ICD-10 codes for hyponatraemia in the DNRP have high specificity but very low sensitivity. Laboratory test results, not discharge diagnoses, should be used to ascertain hyponatraemia.

Item does not contain fulltext Nephronophthisis is an autosomal recessive cystic kidney disease that leads to renal failure in childhood or adolescence. Most NPHP gene products form molecular networks. Here we identify ANKS6 as a new NPHP family member that connects NEK8 (NPHP9) to INVS (NPHP2) and NPHP3. We show that ANKS6 localizes to the proximal cilium and confirm its role in renal development through knockdown experiments in zebrafish and Xenopus laevis. We also identify six families with ANKS6 mutations affected by nephronophthisis, including severe cardiovascular abnormalities, liver fibrosis and situs inversus. The oxygen sensor HIF1AN hydroxylates ANKS6 and INVS and alters the composition of the ANKS6-INVS-NPHP3 module. Knockdown of Hif1an in Xenopus results in a phenotype that resembles loss of other NPHP proteins. Network analyses uncovered additional putative NPHP proteins and placed ANKS6 at the center of this NPHP module, explaining the overlapping disease manifestation caused by mutation in ANKS6, NEK8, INVS or NPHP3. 6 p.

To the Editor: Bankir and Yang1 provided a very thought-provoking account of renal physiology, linking structural and functional details in a new and important way. Their arguments in favor of active urea secretion in pars recta of the proximal tubule seem particularly convincing. As clinicians, we have been used to assessing the relative change of concentrations of urea and creatinine to help in distinguishing pre-renal failure from acute tubular necrosis (ATN). Bankir and Yang1 now state that in the case of ATN, blood urea nitrogen (BUN) rises significantly more than plasma creatinine in comparison with pre-renal failure. This is not the common interpretation. In a Nephrology Forum in the Journal in 1998, RC Blantz discussed the pathophysiology of pre-renal azotemia and wrote that pre-renal failure in comparison with ATN was characterized by a high ratio of BUN to serum creatinine.2 Dr Blantz analyzed the overall situation in pre-renal failure as one in which glomerular filtration rate (GFR) and oxygen consumption in the proximal tubule was reduced, citing the concept of Thurau of ‘acute renal success’ in which the tubuloglomerular feedback protected overworked oxygen-deprived tubules by reducing GFR. Hence, it is entirely consistent with generalized inhibition of active urea secretion as described in the paper by Bankir and Yang. Also, as actual tubular necrosis is in fact a rare finding in ‘acute tubular necrosis,’3 it is to be anticipated that the active urea transport could be less inhibited in the presence of ATN as compared with pre-renal failure. As previously reported,4, 5 this is in fact what has been observed: a low fractional excretion of urea in pre-renal failure ( 40%).

Hyponatraemia with cerebral symptoms is a medical emergency. Prompt management of airway, breathing and circulation together with repeated boluses of 2 ml/kg 3% NaCl constitute a rational treatment. The goal is remission of symptoms. After the initial correction, the main concern is to avoid overcorrection, thus reducing the risk of osmotic demyelination. P-[Na(+)] and diuresis must be measured frequently together with diuresis. Definitive treatment should be directed toward the aetiology.

To the Editor: Holtkamp et al.1 recently reported a slower decline in renal function after an initial decrease in estimated glomerular filtration rate (eGFR) in patients assigned to angiotensin receptor blockers (ARBs). This was interpreted to indicate a favorable response, and thus ARBs should be continued with various precautions. From Table 3, however, a very robust increase in probability of reaching study end point as a function of initial decrease in eGFR can be deduced (P

to the editor: Wesson and coworkers ([4][1]) make a commendable attempt at explaining the interesting beneficial effect of alkali administration to ameliorate progressive renal failure. They conclude that patients with moderately reduced renal function already have proton retention, which may have

Brain edema is suggested to be the principal mechanism underlying the symptoms in acute hyponatremia. Identification of the mechanisms responsible for global and regional cerebral water homeostasis during hyponatremia is, therefore, of utmost importance. To examine the osmotic behavior of different brain regions and muscles, in vivo-determined water content (WC) was related to plasma sodium concentration ([Na+]) and brain/muscle electrolyte content. Acute hyponatremia was induced with desmopressin acetate and infusion of a 2.5% glucose solution in anesthetized pigs. WC in different brain regions and skeletal muscle was estimated in vivo from T1 maps determined by magnetic resonance imaging (MRI). WC, expressed in gram water per 100 g dry weight, increased significantly in slices of the whole brain [342(SD = 14) to 363(SD = 21)] (6%), thalamus [277(SD = 13) to 311(SD = 24)] (12%) and white matter [219(SD = 7) to 225(SD = 5)] (3%). However, the WC increase in the whole brain and white mater WC was less than expected from perfect osmotic behavior, whereas in the thalamus, the water increase was as expected. Brain sodium content was significantly reduced. Muscle WC changed passively with plasma [Na+]. WC determined with deuterium dilution and tissue lyophilzation correlated well with MRI-determined WC. In conclusion, acute hyponatremia induces brain and muscle edema. In the brain as a whole and in the thalamus, regulatory volume decrease (RVD) is unlikely to occur. However, RVD may, in part, explain the observed lower WC in white matter. This may play a potential role in osmotic demyelination.

to the editor: pH was predicted based on preequilibrium quantities. I show here that Stewart and an equivalent formula published in 1990 by Herman et al. ([2][1]) can predict the measured pH equally well, but much easier from these initial values. However, clarification is needed on exactly how

Acute hyponatremia is a serious condition, which poses major challenges. Of particular importance is what determines plasma sodium concentration ([Na+]). Edelman introduced an explicit model to describe plasma [Na+] in a population as [Na+] = α·(exchangeable Na++ exchangeable K+)/(total body water) − β. Evidence for the clinical utility of the model in the individual and in acute hyponatremia is sparse. We, therefore, investigated how the measured plasma [Na+] could be predicted in a porcine model of hyponatremia. Plasma [Na+] was estimated from in vivo-determined balances of water, Na+, and K+, according to Edelman's equation. Acute hyponatremia was induced with desmopressin acetate and infusion of a 2.5% glucose solution in anesthetized pigs. During 480 min, plasma [Na+] and osmolality were reduced from 136 (SD 2) to 120 mmol/l (SD 3) and from 284 (SD 4) to 252 mosmol/kgH2O (SD 5), respectively. The following interpretations were made. First, Edelman's model, which, besides dilution, takes into account Na+and K+, fits plasma [Na+] significantly better than dilution alone. Second, a common value of α = 1.33 (SD 0.08) and β = −13.04 mmol/l (SD 7.68) for all pigs explains well the plasma [Na+] in the individual animal. Third, measured exchangeable Na+and calculated exchangeable Na++ K+per weight in the pigs are close to Edelman's findings in humans, whereby the methods are cross-validated. In conclusion, plasma [Na+] can be explained in the individual animal by external balances, according to Edelman's construct in acute hyponatremia.

Udgivelsesdato: 2009-10-28 PURPOSE: Unilateral ureteral obstruction is a common clinical problem that is often associated with a urinary acidification defect caused by decreased net H(+) secretion and/or HCO(3)(-) reabsorption. To clarify the molecular mechanisms of these defects we examined expression levels of key acid-base transporters along the renal nephron segments and collecting duct. MATERIALS AND METHODS: Wistar rats (Møllegard Breeding Centre, Eiby, Denmark) underwent 24-hour unilateral ureteral obstruction, unilateral ureteral obstruction release followed for 4 days or unilateral ureteral obstruction release followed for 4 days plus experimental acidosis induced by NH(4)Cl oral administration. After sacrifice kidneys were processed for immunoblotting and immunohistochemistry. RESULTS: Semiquantitative immunoblotting revealed that unilateral ureteral obstruction caused significant mean +/- SE down-regulation of type 3 Na(+)/H(+) exchanger to 53% +/- 9%, electrogenic Na(+)/HCO(3)(-) cotransporter to 60% +/- 9%, type 1 bumetanide sensitive Na(+)-K(+)(NH(4)(+)) -2Cl(-) cotransporter to 64% +/- 7%, electroneutral Na(+)/HCO(3)(-) cotransporter to 43% +/- 4% and anion exchanger (pendrin) to 53% +/- 10% in the obstructed kidney, which was confirmed by immunohistochemistry. After release of unilateral ureteral obstruction down-regulation of these transporters persisted together with marked down-regulation of H(+)-adenosine triphosphatase in the obstructed kidney. In rats with unilateral ureteral obstruction release followed for 4 days with experimental acidosis induced by NH(4)Cl oral administration plasma pH and HCO(3)(-) were dramatically decreased in response to NH(4)Cl for 2 days compared with those in sham operated rats with acid loading, indicating a defect in H(+) excretion and HCO(3)(-) reabsorption after obstruction release. Expression of these transporters did not change in the contralateral nonobstructed kidney of rats with unilateral ureteral obstruction and unilateral ureteral obstruction release followed for 4 days. CONCLUSIONS: The expression of renal acid-base transporters is markedly decreased in the obstructed kidney, which may be responsible for the contribution of impaired renal H(+) excretion and HCO(3)(-) reabsorption to the urinary acidification defect in response to unilateral ureteral obstruction.