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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.

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.

A 46-year-old female had a history of recurrent uric acid stone formation, but the reason why uric acid precipitated in her urine was not obvious, because the rate of urate excretion was not high, urine volume was not low, and the pH in her 24-h urine was not low enough. In his discussion of the case, Professor McCance provided new insights into the pathophysiology of uric acid stone formation. He illustrated that measuring the pH in a 24-h urine might obscure the fact that the urine pH was low enough to cause uric acid to precipitate during most of the day. Because he found a low rate of excretion of NH(4)(+) relative to that of sulphate anions, as well as a high rate of citrate excretion, he speculated that the low urine pH would be due to a more alkaline pH in proximal convoluted tubule cells. He went on to suspect that there was a problem in our understanding of the function of renal medullary NH(3) shunt pathway, and he suggested that its major function might be to ensure a urine pH close to 6.0 throughout the day, to minimize the likelihood of forming uric acid kidney stones.

A 22-year-old male developed a severe degree of metabolic acidosis (plasma pH 7.20, bicarbonate 8 mmol/l), with a large increase in the plasma anion gap (26 mEq/l). Ketoacidosis was suspected because of the odour of acetone on his breath and a positive qualitative test for acetone in plasma (to a 1:4 dilution). Later, his plasma beta-hydroxybutyrate concentration was found to be 4.5 mmol/l. After receiving an infusion of 1 l of half-isotonic saline and 1 l of 5% dextrose in water over 24 h, as well as curtailing his large oral intake of sweetened beverages, all blood tests became normal. Diabetic ketoacidosis, alcoholic ketoacidosis, starvation ketosis and hypoglycaemic ketoacidosis were all ruled out, and his toxin screen was negative for salicylates. Finding another possible cause for ketoacidosis became the focus of this case.

Osmotic demyelination of the brain (ODS) is a dreaded complication that typically occurs several days after aggressive therapy for chronic hyponatraemia, but is eminently avoidable. In this teaching exercise, Professor McCance, an imaginary consultant, is asked to explain how he would have treated a 28-year-old female who had hyperkalaemia, hypoglycaemia, hypotension and hyponatraemia (118 mM) to prevent the development of ODS. He begins with a review of the physiology, including his own landmark work on chronic hyponatraemia associated with a contracted extracellular fluid volume. Adding quantitative analysis, the cause of the excessive rise in plasma sodium concentration is revealed, and a better plan for therapy is proposed.

The aim of this masterclass is to develop a rational plan of therapy to deal with a severe degree of hyponatraemia (90 mmol/l) and hyperglycaemia (100 mmol/l) that occurred 100 min after the start of laproscopic surgery in a young woman. The lavage fluid used in this procedure was 10% dextrose.H(2)O in water (505 mmol glucose/l). To focus attention on specific issues, three questions are posed to the reader, as they were to a panel of 59 modern-day experts. Two imaginary consultants from the past were asked the same (and additional) questions. Their responses were restricted to knowledge available before the molecular era, to show the power of integrative physiology at the bedside. An analysis of intracellular events was helpful in answering the first question: 'Is an infusion of hypertonic saline required to treat her acute hyponatremia?' Similarly, a quantitative analysis of changes in the composition of the extracellular fluid compartment was helpful in answering the second question: 'Is an infusion of isotonic saline required to treat her hypotension?' A metabolic analysis was used to answer the third question, 'Should insulin be administered?'

Background Events in the gastrointestinal tract that might contribute to a high absorption of calcium were simulated in vitro to evaluate why only a small proportion of individuals who ingest alkaline calcium salts develop hypercalcaemia, hypokalaemia and metabolic alkalosis. Methods A patient who chewed and swallowed around 40 betel nuts daily developed hypercalcaemia, metabolic alkalosis, hypokalaemia with renal potassium wasting, and renal insufficiency. The quantities of calcium and alkali per betel nut preparation were measured. Factors that might increase intestinal absorption of calcium were evaluated. Results Hypercalcaemia in the index case was accompanied by a high daily calcium excretion (248 mg, 6.2 mmol). Circulating levels of 1,25-dihydroxyvitamin D(3) and parathyroid hormone were low. Hypokalaemia with a high transtubular K(+) concentration gradient, metabolic alkalosis, a low excretion of phosphate and a very low glomerular filtration rate were prominent features. Conclusions Possible explanations for the pathophysiology of metabolic alkalosis and hypokalaemia are provided. We speculate that a relatively greater availability of ionized calcium than inorganic phosphate in the lumen of the intestinal tract could have enhanced dietary calcium absorption.