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We evaluated annual productivity and carbon fluxes over the Fontainebleau forest, a large heterogeneous forest region of 17,000 ha, in terms of species composition, canopy structure, stand age, soil type and water and mineral resources. The model is a physiological process-based forest ecosystem model coupled with an allocation model and a soil model. The simulations were done stand by stand, i.e., 2992 forest management units of simulation. Some input parameters that are spatially variable and to which the model is sensitive were calculated for each stand from forest inventory attributes, a network of 8800 soil pits, satellite data and field measurements. These parameters are: (1) vegetation attributes: species, age, height, maximal leaf area index of the year, aboveground biomass and foliar nitrogen content; and (2) soil attributes: available soil water capacity, soil depth and soil carbon content. Main outputs of the simulations are wood production and carbon fluxes on a daily to yearly basis. Results showed that the forest is a carbon sink, with a net ecosystem exchange of 371 g C m–2 year–1. Net primary productivity is estimated at 630 g C m–2 year–1 over the entire forest. Reasonably good agreement was found between simulated trunk relative growth rate (2.74%) and regional production estimated from the National Forest Inventory (IFN) (2.52%), as well as between simulated and measured annual wood production at the forest scale (about 71,000 and 68,000 m3 year–1, respectively). Results are discussed species by species. [ABSTRACT FROM AUTHOR]

Introduction: Factor (F) XI deficiency is an inherited bleeding disorder with increased prevalence in Ashkenazi Jews where it is mainly caused by two variants, p.Glu135* (type II, leading to a null allele) and p.Phe301Leu (type III, missense variant). Inhibitor development is rare, and only seen in severe FXI deficiency (<20 IU/dL) upon exposure to plasma-based products. We report our experience of a large cohort of patients with severe FXI deficiency, including seven patients who developed FXI alloinhibitors, their presentation, natural history and subsequent perioperative management., Methods: A single-centre retrospective database review of patients with FXI deficiency, including those who have subsequently developed inhibitors, and extraction of clinical, laboratory and genotype data, including operative management records., Results: A total of 682 patients were identified with FXI deficiency, of whom 113 had FXI < 20 IU/dL and 42 had FXI ≤ 1 IU/dL. Factor XI inhibitors were seen in seven patients, six of whom were homozygous for the type II variant (prevalence of inhibitor with this genotype of 30%, risk of inhibitor upon plasma exposure 50%). FXI inhibitors were not seen, despite similar exposures, in patients with other genotypes. No alteration in bleeding phenotype occurred after inhibitor development and subsequent surgery was managed on 13 occasions with recombinant factor VIIa (rFVIIa), including low doses (15-30 µg/kg), with good haemostasis. The inhibitor spontaneously disappeared in four of seven patients over 1-22 years., Conclusion: FXI inhibitors were only observed in severe FXI deficient patients homozygous for p.Glu135* (null allele) upon plasma or FXI concentrate exposure, with a 30% prevalence. The bleeding phenotype was not altered and inhibitors may disappear with time. Adequate haemostasis in the perioperative setting is achievable with low doses of rFVIIa., (© 2024 John Wiley & Sons Ltd.)

Competing Interests: Competing interests:: None declared.

International guidelines designed to minimize the risk of complications that can occur when correcting severe hyponatremia have been widely accepted for a decade. On the basis of the results of a recent large retrospective study of patients hospitalized with hyponatremia, it has been suggested that hyponatremia guidelines have gone too far in limiting the rate of rise of the serum sodium concentration; the need for therapeutic caution and frequent monitoring of the serum sodium concentration has been questioned. These assertions are reminiscent of a controversy that began many years ago. After reviewing the history of that controversy, the evidence supporting the guidelines, and the validity of data challenging them, we conclude that current safeguards should not be abandoned. To do so would be akin to discarding your umbrella because you remained dry in a rainstorm. The authors of this review, who represent 20 medical centers in nine countries, have all contributed significantly to the literature on the subject. We urge clinicians to continue to treat severe hyponatremia cautiously and to wait for better evidence before adopting less stringent therapeutic limits., (Copyright © 2023 The Authors. Published by Wolters Kluwer Health, Inc. on behalf of American Society of Nephrology.)

We discuss the use of urine electrolytes and urine osmolality in the clinical diagnosis of patients with fluid, electrolytes, and acid-base disorders, emphasizing their physiological basis, their utility, and the caveats and limitations in their use. While our focus is on information obtained from measurements in the urine, clinical diagnosis in these patients must integrate information obtained from the history, the physical examination, and other laboratory data., (© 2021 International Society of Nephrology. Published by Elsevier Inc.)

L-lactic acidosis (L-LA) is the most common cause of metabolic acidosis in the critical care setting, which has been associated with a large increase in mortality. The purpose of this article is to provide clinicians with an overview of the biochemical and metabolic background required to understand the different pathophysiological mechanisms that may lead to the development of L-LA. We propose a classification based on whether the pathophysiology of L-LA is due predominantly to increased production or decreased removal of L-lactic acid. In this article, we provide an overview of the biochemical and metabolic aspects of glucose oxidation, the production and removal of L-lactic acid, and a discussion of the pathophysiology of the various causes of L-LA., (Copyright © 2019 International Society of Nephrology. Published by Elsevier Inc. All rights reserved.)

We summarize the current understanding of the physiology of the renal handling of potassium (K + ), and present an integrative view of the renal response to K + depletion caused by dietary K + restriction. This renal response involves contributions from different nephron segments, and aims to diminish the rate of excretion of K + as a result of: decreasing the rate of electrogenic (and increasing the rate of electroneutral) reabsorption of sodium in the aldosterone-sensitive distal nephron (ASDN), decreasing the abundance of renal outer medullary K + channels in the luminal membrane of principal cells in the ASDN, decreasing the flow rate in the ASDN, and increasing the reabsorption of K + in the cortical and medullary collecting ducts. The implications of this physiology for the association between K + depletion and hypertension, and K + depletion and formation of calcium kidney stones are discussed., (Copyright © 2017 International Society of Nephrology. Published by Elsevier Inc. All rights reserved.)

Diabetic ketoacidosis (DKA), a common cause of severe metabolic acidosis, remains a life-threatening condition due to complications of both the disease and its treatment. This Acid-Base and Electrolyte Teaching Case discusses DKA management, emphasizing complications of treatment. Because cerebral edema is the most common cause of mortality and morbidity, especially in children with DKA, we emphasize its pathophysiology and implications for therapy. The risk for cerebral edema may be minimized by avoiding a bolus of insulin, excessive saline resuscitation, and a decrease in effective plasma osmolality early in treatment. A goal of fluid therapy is to lower muscle venous Pco 2 to ensure effective removal of hydrogen ions by bicarbonate buffer in muscle and diminish the binding of hydrogen ions to intracellular proteins in vital organs (such as the brain). In patients with DKA and a relatively low plasma potassium level, insulin administration may cause hypokalemia and cardiac arrhythmias. It is suggested in these cases to temporarily delay insulin administration and first administer potassium chloride intravenously to bring the plasma potassium level close to 4mmol/L. Sodium bicarbonate administration in adult patients should be individualized. We suggest it be considered in a subset of patients with moderately severe acidemia (pH<7.20 and plasma bicarbonate level < 12mmol/L) who are at risk for worsening acidemia, particularly if hemodynamically unstable. Sodium bicarbonate should not be administered to children with DKA, except if acidemia is very severe and hemodynamic instability is refractory to saline administration., (Copyright © 2016 National Kidney Foundation, Inc. Published by Elsevier Inc. All rights reserved.)

Background and Objectives: Hyperkalemia is a common electrolyte disorder that can result in fatal cardiac arrhythmias. Despite the importance of insulin as a lifesaving intervention in the treatment of hyperkalemia in an emergency setting, there is no consensus on the dose or the method (bolus or infusion) of its administration. Our aim was to review data in the literature to determine the optimal dose and route of administration of insulin in the management of emergency hyperkalemia., Design, Setting, Participants, & Measurements: We searched several databases from their date of inception through February 2015 for eligible articles published in any language. We included any study that reported on the use of insulin in the management of hyperkalemia., Results: We identified eleven studies. In seven studies, 10 units of regular insulin was administered (bolus in five studies, infusion in two studies), in one study 12 units of regular insulin was infused over 30 minutes, and in three studies 20 units of regular insulin was infused over 60 minutes. The majority of included studies were biased. There was no statistically significant difference in mean decrease in serum potassium (K+) concentration at 60 minutes between studies in which insulin was administered as an infusion of 20 units over 60 minutes and studies in which 10 units of insulin was administered as a bolus (0.79±0.25 mmol/L versus 0.78±0.25 mmol/L, P = 0.98) or studies in which 10 units of insulin was administered as an infusion (0.79±0.25 mmol/L versus 0.39±0.09 mmol/L, P = 0.1). Almost one fifth of the study population experienced an episode of hypoglycemia., Conclusion: The limited data available in the literature shows no statistically significant difference between the different regimens of insulin used to acutely lower serum K+ concentration. Accordingly, 10 units of short acting insulin given intravenously may be used in cases of hyperkalemia. Alternatively, 20 units of short acting insulin may be given as a continuous intravenous infusion over 60 minutes in patients with severe hyperkalemia (i.e., serum K+ concentration > 6.5 mmol/L) and those with marked EKG changes related to hyperkalemia (e.g., prolonged PR interval, wide QRS complex) as an alternative to 10 units of short acting insulin. Because the risk of hypoglycemia is increased with using large insulin doses, sufficient glucose (60 grams with the administration of 20 units of insulin and 50 grams with the administration of 10 units) should be given to prevent hypoglycemia, and plasma glucose should be frequently monitored.

Our purpose is to integrate new insights in potassium (K(+)) physiology to understand K(+) homeostasis and illustrate some of their clinical implications. Since control mechanisms that are essential for survival were likely developed in Paleolithic times, we think the physiology of K(+) homeostasis can be better revealed when viewed from what was required to avoid threats and achieve balance in Paleolithic times. Three issues will be highlighted. First, we shall consider the integrative physiology of the gastrointestinal tract and the role of lactic acid released from enterocytes following absorption of sugars (fruit and berries) to cause a shift of this K(+) load into the liver. Second, we shall discuss the integrative physiology of WNK kinases and modulation of delivery of bicarbonate to the distal nephron to switch the aldosterone response from sodium chloride retention to K(+) secretion when faced with a K(+) load. Third, we shall emphasize the role of intra-renal recycling of urea in achieving K(+) homeostasis when the diet contains protein and K(+).

Background: Potassium (K(+)) input occurs after meals or during ischemic exercise and is accompanied by a high concentration of L-lactate in plasma (P(L-lactate))., Methods: We examined whether infusing 100 μmol L-lactic acid/min for 15 min would lead to a fall in the arterial plasma K(+) concentration (P(K)). We also aimed to evaluate the mechanisms involved in normal rats compared with rats with acute hyperkalemia caused by a shift of K(+) from cells or a positive K(+) balance., Results: There was a significant fall in P(K) in normal rats (0.25 mM) and a larger fall in P(K) in both models of acute hyperkalemia (0.6 mM) when the P(L-lactate) rose. The arterial P(K) increased by 0.8 mM (p < 0.05) 7 min after stopping this infusion despite a 2-fold rise in the concentration of insulin in arterial plasma (P(Insulin)). There was a significant uptake of K(+) by the liver, but not by skeletal muscle. In rats pretreated with somatostatin, P(Insulin) was low and infusing L-lactic acid failed to lower the P(K)., Conclusions: A rise in the P(L-lactate) in portal venous blood led to a fall in the P(K) and insulin was permissive. Absorption of glucose by the Na(+)-linked glucose transporter permits enterocytes to produce enough ADP to augment aerobic glycolysis, raising the P(L-lactate) in the portal vein to prevent postprandial hyperkalemia., (Copyright © 2012 S. Karger AG, Basel.)

Background/aims: Since furosemide (FS) inhibits active Na(+) reabsorption by medullary thick ascending limb (mTAL) in the renal outer medulla, it may decrease its work during periods of low O2 supply to deep in the renal outer medulla. This study was designed to demonstrate that there may be a dose of FS would reduce its metabolic work while preventing the excessive loss of magnesium (Mg(2+)). Mg(2+) is important because the ATP needed to perform work must have bound Mg(2+) to it., Methods: Rats were injected intraperitoneally with a range of doses of FS. The measured outcomes were urine flow rate and parameters of functions of the mTAL (i.e. urine and renal papillary osmolality and urinary excretion of Na(+), Cl(-), K(+) and Mg(2+), and concentrations of Mg(2+) in serum)., Results: The urine flow rate increased significantly starting at 2.4 mg FS/kg. The renal papillary osmolality decreased at ≥0.4 mg FS/kg, and the large detectable natriuresis started at 1.6 mg FS/kg. At this latter dose, the urinary excretion of Mg(2+) rose significantly., Conclusion: In rats, the non-natriuretic dose of FS may reduce the work of the mTAL. The earliest indicator of reduced work in the mTAL appears to be a decrease in urine osmolality rather than a rise in urine flow rate. Higher doses of FS should be avoided, as they induce high rates of Mg(2+) excretion, which can deplete the body of this essential electrolyte., (Copyright © 2013 S. Karger AG, Basel.)

Purpose of Review: This review aims to illustrate why urea recycling may play an important role in potassium (K⁺) excretion and to emphasize its potential clinical implications., Recent Findings: A quantitative analysis of the process of intrarenal urea recycling reveals that the amount of urea delivered to the distal convoluted tubule is about two-fold larger than the quantity of urea excreted in the urine. As the number of osmoles delivered to the late cortical distal nephron (CCD) determines its flow rate when aquaporin 2 water channels have been inserted in the luminal membrane of principal cells, urea recycling may play an important role in regulating the rate of excretion of K⁺ when the distal delivery of electrolytes is not very high., Summary: Urea recycling aids the excretion of K⁺; this is especially important in patients with disorders or those who are taking drugs that lead to a less lumen-negative voltage in the CCD. As a large quantity of urea is reabsorbed daily in the inner medullary collecting duct, the assumption made in the calculation of the transtubular K concentration gradient that there is no appreciable reabsorption of osmoles downstream CCD is not valid.

When the concentration of sodium (Na(+)) in arterial plasma (P(Na)) declines sufficiently to inhibit the release of vasopressin, water will be excreted promptly when the vast majority of aquaporin 2 water channels (AQP2) have been removed from luminal membranes of late distal nephron segments. In this setting, the volume of filtrate delivered distally sets the upper limit on the magnitude of the water diuresis. Since there is an unknown volume of water reabsorbed in the late distal nephron, our objective was to provide a quantitative assessment of this parameter. Accordingly, rats were given a large oral water load, while minimizing non-osmotic stimuli for the release of vasopressin. The composition of plasma and urine were measured. The renal papilla was excised during the water diuresis to assess the osmotic driving force for water reabsorption in the inner medullary collecting duct. During water diuresis, the concentration of creatinine in the urine was 13-fold higher than in plasma, which implies that ~8% of filtered water was excreted. The papillary interstitial osmolality was 600 mOsm/L > the urine osmolality. Since 17% of filtered water is delivered to the earliest distal convoluted tubule micropuncture site, we conclude that half of the water delivered to the late distal nephron is reabsorbed downstream during water diuresis. The enormous osmotic driving force for the reabsorption of water in the inner medullary collecting duct may play a role in this reabsorption of water. Possible clinical implications are illustrated in the discussion of a case example.

Escape from the renal actions of vasopressin is said to occur in rats with chronic hyponatremia. Our objective was to provide specific evidence to test this hypothesis. Hence the osmolality in the excised renal papilla and in simultaneously voided urine (U(Osm)) was measured in rats with and without hyponatremia. To induce hyponatremia, rats were fed low-electrolyte chow for 6 days. In the first 3 days, water was provided ad lib. On days 4 to 6, a long acting vasopressin preparation (dDAVP) was given every 8 hours to induce water retention. The hyponatremic rats drank 21 mL 5% sucrose on day 4 and 6 mL on day 5. On the morning of day 6, these rats were given 10 mL of 5% glucose in water (D5W) by the intraperitoneal route at 09:00 hour and at 11:00 hour. Analyses were performed in blood, urine, and the excised renal papilla at 13:00 hour on day 6. The concentration of Na(+) in plasma (P(Na)) in rats without intraperitoneal D5W was 140±1 mEq/L (n=7) whereas it was 112±3 mEq/L in the hyponatremic group (n=12). The hyponatremic rats had a higher osmolality in the excised papillary (1,915±117 mOsm/kg H(2)O) than the U(Osm) (1,528±176 mOsm/kg H(2)O, P<0.05). One explanation for this difference is that the rats escaped from the renal action of vasopressin. Nevertheless, based on a quantitative analysis, other possibilities will be considered.

Despite its probable importance in health and disease, the elastic tissue in the trachea has rarely been investigated. In addition, various aspects of the trachealis muscle are controversial. The aim of this study was to clarify this clinically relevant anatomy. Ten cadaveric tracheobronchial specimens (age range 68-101 years; seven males; no major airway pathology) were qualitatively investigated by microdissection. Serial histologic sections from multiple sites in three specimens were analyzed after staining for elastin. Findings were correlated with observations from video tracheobronchoscopies. An extensive and prominent meshwork of elastic tissue was found within the trachea and bronchi. Elastic fibers were predominantly longitudinal and aggregated into discrete bundles within the membranous wall of the trachea and main bronchi; a discrete fibroelastic membrane bridging the membranous wall of the trachea; and vertical laminae connecting the ends of successive cartilages. The longitudinal elastic bundles continued into the segmental bronchi, becoming thinner and more circumferentially distributed. Trachealis consisted of a transverse layer of smooth muscle deep to the fibroelastic membrane of the membranous wall of the trachea, together with scattered longitudinal muscle bundles, mostly embedded within the fibroelastic membrane in the distal half of the trachea. In conclusion, there is an extensive but relatively neglected elastic framework within the tracheobronchial tree. This is likely to have major clinical relevance to the pathophysiology of respiratory disease and ageing. The trachealis muscle is more complex than previously stated.

Most morphometric studies of the human trachea have relied on plain radiographs with their attendant limitations. Reports using computed tomography (CT) have focused on the growing trachea or one particular dimension. The aim of this study was to document the morphometry of the adult trachea in vivo using high-resolution chest CT scans, supplemented by data from cadavers. Sixty anonymised high-resolution chest CT scans (aged 22-88 years, 40 males) were analyzed. Scans were performed using a standardized breath-holding technique in patients with no distorting intrathoracic pathology. Standardized tracheal measurements included: length, maximum antero-posterior and transverse diameters, volume, subcarinal angle, and carinal position in relation to the tracheal midline. Measurements were also made in 10 cadaver tracheas (aged 68-101 years, 7 males). CT data showed that mean tracheal length (males 105.1 +/- 9.8 mm, females 98.3 +/- 8.7 mm), maximum antero-posterior and transverse diameters, and tracheal volume (males 35.6 +/- 6.8 cm3, females 24.7 +/- 6.1 cm3) were all significantly greater in men (P < or = 0.01). The subcarinal angle was very variable (mean 78 +/- 20 degrees , range 36-121 degrees ) and showed no correlation with age or gender. The carina was sited to the left of the tracheal midline in 49 (81%) patients. Cadaver tracheas had 14-19 tracheal rings and the posterior membranous trachea was wider in men (17.7 +/- 4.4 mm vs. 11.8 +/- 3.0 mm, P = 0.07). In conclusion, there is marked sexual dimorphism in the morphometry of the human trachea. The variation in adult tracheal dimensions in vivo is greater than in standard descriptions. These data may be valuable when interpreting chest CT scans and when calculating respiratory dead space., (Copyright 2009 Wiley-Liss, Inc.)

There are four themes in this teaching exercise for Professor McCance. The first challenge was to explain how a premature infant with Bartter's syndrome could survive despite having such a severe degree of renal salt wasting. Second, the medical team wanted to know why there was such a dramatic decrease in the natriuresis in response to therapy, despite the presence of a permanent molecular defect that affected the loop of Henle. Third, Professor McCance was asked why this patient seemed to have a second rare disease, AQP2 deficiency type of nephrogenic diabetes insipidus. The fourth challenge was to develop a diagnostic test to help the parents of this baby titrate the dose of indomethacin to ensure an effective dose while minimizing the likelihood of developing nephrotoxicity. The missing links in this interesting story emerge during a discussion between the medical team and its mentor.

In this teaching exercise, the goal is to demonstrate how an application of principles of physiology can reveal the basis for a severe degree of acidaemia (pH 6.81, bicarbonate <3 mmol/l (P(HCO(3))), PCO(2) 8 mmHg), why it was tolerated for a long period of time, and the issues for its therapy in an 8-year-old female with diabetic ketoacidosis. The relatively low value for the anion gap in plasma (19 mEq/l) suggested that its cause was both a direct and an indirect loss of NaHCO(3). Professor McCance suggested that ileus due to hypokalaemia might cause this direct loss of NaHCO(3), and that an excessive excretion of ketoacid anions without NH(4)(+) in the urine accounted for the indirect loss of NaHCO(3). In addition, he suspected that another factor also contributing to the severity of the acidaemia was a low input of alkali. He was also able to explain why there was a 16-h delay before there was a rise in the P(HCO(3)) once therapy began. The missing links in this interesting story, including a possible basis for the hypokalaemia, emerge during the discussion between the medical team and Professor McCance.

In the traditional approach to buffering of H(+) during metabolic acidosis, the sole focus is on lowering the H(+) concentration, but this overlooks several important points. First, increased binding of H(+) to proteins changes their charge, shape, and possibly function. Second, organs in which buffering of H(+) occurs is not assessed even though it would be advantageous to spare brain proteins in this process. Third, only the arterial and not the capillary PCO(2) of individual organs is considered. This article provides a "brain protein-centered" view, which leads to different conclusions concerning the way H(+) are removed physiologically.

Background: Patients with CaHPO(4) kidney stones belong to a diagnostic category that has a high urine pH as its common feature. Our objective was to provide a new clinical approach to examine the basis for this high pH., Methods: The study group consisted of 26 CaHPO(4) stone formers and 28 normal volunteers. Urine was collected q2h plus an overnight sample to identify patients with a urine pH > 6.5 for 12/24 h. Urine ammonium (U(NH4)), sulphate (U(SO4)) and citrate were measured and diet net alkali was calculated., Results: Of the 26 patients, 13 had persistently alkaline urine. In 7/13, U(NH4) (68 +/- 13 mEq/day) and U(SO4) (57 +/- 7 mEq/day) were both high. In 6/13 patients, U(NH4) was the usual 31 +/- 3 mEq/day; in 4/6, U(NH4)/U(SO4) was 0.9 +/- 0.1; the cause of the alkaline urine pH seemed to be a dietary alkali load because the rise in urine pH was episodic and coincided with a high net diet alkali load and peak citrate excretion rates. The remaining two patients had a high U(NH4)/U(SO4) (2.2 and 1.6). Citrate excretion was very low in the male, but not in the female patient., Conclusions: There are heterogeneous causes for a persistently high urine pH. Two of the patients had a possible molecular basis: the lesion could be a low proximal convoluted tubule cell pH in the male and an increased entry of NH(3) into the late distal nephron in the female.

This teaching exercise demonstrates how the application of principles of physiology can identify the cause of a severe degree of hyperglycaemia (plasma glucose concentration 80 mmol/l) in a very young patient with newly diagnosed diabetes mellitus, determine whether the patient has diabetic ketoacidosis, and highlight the potential risks for this patient on admission and during initial therapy. A consultation with Professor McCance was sought to determine whether this patient had an unusual degree of 'insulin resistance'. There were also uncertainties regarding the acid-base diagnosis. The patient did not appear to have an important degree of metabolic acidosis as judged from his pH of 7.39 and plasma bicarbonate concentration of 20 mmol/l in arterial blood; hence the diagnostic impression was that he had a hyperglycaemic hyperosmolar state. However, his plasma anion gap was significantly elevated, and remained so for 60 h, despite the administration of insulin. Issues in management concerning the basis for this severe degree of hyperglycaemia and how to minimize the risk of developing cerebral oedema are addressed. The missing links in this interesting story emerge during a discussion between the medical team and their mentor, Professor McCance.

Two processes permit the urine pH and the medullary interstitial pH to remain in an "ideal range" to minimize the risk of forming kidney stones. First, a medullary shunt for NH(3) maintains the urine pH near 6.0 to minimize uric acid precipitation when distal H(+) secretion is high. Second, excreting dietary alkali excreting alkali as a family of organic anions--including citrate--rather than as bicarbonate maintains the urine pH near 6.0 while urinary citrate chelates ionized calcium, which minimizes CaHPO(4) precipitation. In patients with idiopathic hypercalciuria and recurrent calcium oxalate stones, the initial nidus is a calcium phosphate precipitate on the basolateral membrane of the thin limb of the loop of Henle (Randall's plaque). Formation of this precipitate requires medullary alkalinization; K(+) -depletion and augmented medullary H(+)/K(+) -ATPase may be predisposing factors.

The PO2 at this site where erythropoietin release is regulated should vary only when the hemoglobin concentration changes in capillary blood. The kidney cortex is an ideal location for this O2 sensor for four reasons. First, it extracts a small proportion of the oxygen that is delivered in each liter of blood; this makes the PO2 signal easier to recognize. Second, there is a constant ratio of the work performed (consumption of O2) to the renal blood flow rate (delivery of O2). Third, the high renal blood flow rate improves diffusion of O2 from capillaries to this O2 receptor. Fourth, a high renal cortical PCO2 prevents an additional shift of the O2:hemoglobin dissociation curve by other factors from being a confounding variable. This suggests that the GFR and the renal blood flow rate should be examined in patients with unexplained anemia or erythrocytosis.

This teaching exercise demonstrates how principles of physiology might help in identifying the cause of a particularly severe case of metabolic acidosis and making appropriate decisions about therapy. The patient's plasma pH was 7.00 and their plasma bicarbonate concentration was 2 mmol/l. Because the time course of the patient's illness was believed to be <24 h, this suggested that a large quantity of acid had been added to the body in this short time period, but the medical team managing the case could not identify any acid that could have been produced rapidly by endogenous processes, or was ingested by the patient. Moreover, there was a question about how such a very low arterial PCO(2) (8 mmHg) could be sustained. Even once the diagnosis was made, there were issues to resolve concerning therapy. These included questions about how much sodium bicarbonate to administer, and what dangers might arise during this therapy. The missing links in this interesting story emerge during a discussion between the medical team and their imaginary mentor, Professor McCance.

Control mechanisms for potassium (K(+)) excretion in humans developed in Palaeolithic times when diets were sodium poor and episodically K(+) rich. Nevertheless, our understanding of the regulation of K(+) excretion comes from experiments in rats with large sodium and K(+) intakes. Our objective was to identify how K(+) excretion was regulated when rats consumed a low NaCl diet to reflect Palaeolithic conditions. Rats that were given mineralocorticoids plus either NaCl, mannitol, or NaHCO(3) had a small kaliuresis. In contrast, KCl load induced a large kaliuresis and a near-maximal luminal [K(+)] in the terminal cortical collecting duct ([K(+)](CCD)). The time course of events was important. The rise in the [K(+)](CCD) was prompt, but the initial kaliuresis was only modest. Over the next 4 h, kaliuresis increased markedly due solely to a higher calculated distal flow rate, which appeared to be due to diminished reabsorption of NaCl in the loop of Henle; of note, the measured papillary [K(+)] rose. In summary, the increase in the [K(+)](CCD) in rats given KCl is likely to be due to an increase in the number of luminal K(+) channels rather than to mechanisms that are known to induce a lumen-negative voltage in cortical distal nephron segments. The higher distal flow rate might be due to a higher interstitial [K(+)], which inhibited NaCl reabsorption in the loop of Henle. Thus, to understand which of the potential control mechanisms are operating, one must look very closely at the conditions imposed by the experimental setting.

Clinicians should identify life-threatening issues in patients with metabolic acidosis. These threats may be present before therapy begins and/or anticipated after therapy commences. By adding four amendments, short-comings in the commonly used clinical approaches for the diagnosis of metabolic acidosis can be overcome. First, a definition of metabolic acidosis should consider not only the concentration of bicarbonate but also the content of bicarbonate in the extra cellular fluid compartment. The latter requires a quantitative estimate of the ECF volume, which can be obtained using the hematocrit and/or the total protein concentration in plasma. Second, to determine if the basis for metabolic acidosis was the addition of acids or the loss of NaHCO 3 , one must hunt for new anions, not only in plasma, but also in the urine. Third, it is important to measure the venous as well as the arterial PCO2 to assess the capacity to buffer H+ while minimizing H + binding to intracellular proteins. Fourth, to assess the role of the kidney in a patient with metabolic acidosis, the urine osmolal gap and the concentration of creatinine in the urine should be measured to provide an estimate of the rate of excretion of ammonium.