Q J Med 2004; 97: 167-178
QJM vol. 97 no. 3 (c) Association of Physicians 2004; all rights reserved.
Masterclasses in medicine |
Anorexia nervosa and chronic renal insufficiency: a prescription for disaster
From the 1Division of Nephrology, St. Michael's Hospital, University of Toronto, Toronto, Canada, and 2Nephrology Unit and Department of Internal Medicine, Stellenbosch University, Cape Town, South Africa
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Summary |
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 Top Summary IntroductionThe consultationAnalysis of issues concerning...Analysis of the salt...Acid-base issuesIntegrative physiologyConcluding remarksReferences |
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Our imaginary consultant, Professor McCance, is asked to explain the basis for four major acute electrolyte abnormalities in a young woman with long-standing anorexia nervosa. She has a severe degree of hypokalaemia (2.0 mmol/l) with renal potassium wasting, a contracted extracellular fluid volume with renal NaCl wasting, hyponatraemia (118 mmol/l) while excreting hypoosmolar urine, and metabolic acidosis with a normal plasma anion gap (pH 7.20, bicarbonate 9 mmol/l). McCance begins his discussion by considering the basis for hypokalaemia, as this electrolyte disorder is potentially life-threatening. Its pathophysiology is linked to the other major findings, using principles of integrative physiology together with a deductive and quantitative analysis. Nevertheless, to reach his final diagnosis, he requires information about newer molecular discoveries. Not only is he able to suggest a likely diagnosis, but he also devises a novel long-term plan for therapy.
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Introduction |
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TopSummaryIntroductionThe consultationAnalysis of issues concerning...Analysis of the salt...Acid-base issuesIntegrative physiologyConcluding remarksReferences |
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In our continuing series on applying integrative physiology at the bedside, we present another problem in the fluid, electrolyte, acid–base, and/or energy metabolism area. Once again, we are guided by our imaginary consultant, the integrative physiologist Professor McCance, whom we transport to the present to help with the management of an actual case. As always, he begins with an analysis of the most pressing abnormality—his emphasis is on concepts rather than details. Facts are revealed only when they advance the understanding of key issues. Elements that could contribute to the diagnosis and treatment become evident once the issues are considered from the perspective of whole-body physiology. When Professor McCance is made aware of recent molecular discoveries, he suggests an unanticipated diagnosis, and suggests a novel form of therapy.
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The consultation |
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TopSummaryIntroductionThe consultationAnalysis of issues concerning...Analysis of the salt...Acid-base issuesIntegrative physiologyConcluding remarksReferences |
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On the morning post-intake ward round, Professor McCance was shown a 37-year-old woman with four similar hospital admissions in the past 6 months. On each admission, there had been a period of one week where she became progressively ill. She was not febrile, and her respirations were neither rapid nor deep. Although her blood pressure was 110/70 mmHg and her pulse rate 80 bpm lying flat, her ECF volume appeared to be contracted, because her jugular venous pressure was well below the sternal angle (regrettably, postural changes in blood pressure and pulse rate were not recorded before therapy). From the laboratory data, three important medical problems were identified: hypokalaemia (2.0 mmol/l), hyponatraemia (118 mmol/l), and metabolic acidosis with a normal plasma anion gap (pH 7.20 and a plasma bicarbonate
concentration (PHCO3) of 9 mmol/l, Table 1).
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Noting that the junior staff found it difficult to decide where to begin their analysis, Professor McCance asked, ‘What are the potential medical emergencies in this patient?’ The house officers agreed that their first step should be to identify the most serious threat to survival.
Question 1. What are the potential medical emergencies in this patient?
The medical registrars were prepared—they provided Professor McCance with their list of potential medical emergencies (Table 2). It began with her plasma potassium (K+) concentration (PK), because the hypokalaemia was severe in degree and could pose an immediate threat to her life.
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Analysis of issues concerning potassium |
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Five issues with respect to her PK were identified. First, a major cardiac threat was unlikely for the moment, because of the absence of serious EKG changes, and there was no evidence of underlying heart disease or the intake of drugs that could have increased the likelihood of a cardiac rhythm disturbance. Second, weakness was not serious enough to compromise breathing to a major extent because her arterial PCO2 was close to the appropriate range for her pH and PHCO3 (Table 1). Third, the renal excretion of K+ was higher than expected if hypokalaemia were due simply to a low intake of K+ or non-renal losses (she excreted 30–40 mmol of K+/day rather than the expected 10 mmol/day1). Fourth, she had retained 120 mmol of the K+ that was administered overnight, but her PK rose from 2.0 mmol/l to only 2.7 mmol/l, suggesting that there was a large total body K+ deficit. Fifth, after discharge from hospital on previous admissions, her PK was in the normal range (3.9 mmol/l) while she was no longer taking K+ supplements. Therefore she had an acquired, intermittent renal K+ wasting disorder. And so they turned to Professor McCance asking, ‘What could compromise renal conservation of K+? ’
Question 2. What could compromise renal conservation of K+?
Physiology principle 1: Regulation of excretion occurs in the last nephron segment where a specific compound, ion or water is secreted or reabsorbed
Professor McCance shared his ideas about the regulation of K+ excretion. First, K+ is one of the few major constituents of the urine that requires a secretory process to achieve a high excretion rate. This secretion occurs in the distal nephron (Figure 1). Second, because secretion of K+ is linked to the reabsorption of Na+, this distal nephron site must have a sufficient delivery of Na+ to permit the excretion of all the dietary K+ that our ancestors were likely to consume (as high as 500 mmol/day2). Moreover, the most important control mechanisms likely developed in response to demands in prehistoric times.3 Therefore, it is not surprising that regulation of K+ secretion occurs primarily in a distal nephron site with a delivery of close to 500 mmol of Na+, the cortical collecting duct (CCD).4 On the other hand, when the intake of K+ is very low, the kidney must conserve K+ maximally.1 Hence when there is a K+ deficit, not only must there be virtually no secretion of K+ in the CCD, but a downstream nephron segment (the medullary collecting duct, MCD) must be able to reabsorb almost all of the K+ delivered to it.
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Return to the bedside: There are two major processes to evaluate to understand why our patient excreted more than the expected 10 mmol of K+ per day—an abnormally high secretion of K+ in the CCD and/or a diminished capacity to reabsorb K+ in the MCD. Professor McCance chose to begin his analysis with the reabsorption of K+ in the MCD, calling on the Renal Fellow to supply the details of the modern molecular advances in K+ physiology.
Physiology principle 2: K+ is reabsorbed in the MCD
For K+ to be reabsorbed in the MCD, the major process must be electroneutral, because an appreciable transtubular lumen-positive voltage difference is not observed in the MCD.5 The mechanism involves a 1:1 exchange of cations—K+ ions are reabsorbed while H+ ions are secreted—by an H+/K+ ATPase6 (Figure 2).
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or NH3. Return to the bedside: Professor McCance emphasized that this system for K+ reabsorption needs H+ acceptors that are already in the tubular lumen (
or 
), or which must enter the luminal fluid in an electroneutral fashion. In the latter category, he included the entry of NH3 or an electroneutral exchange of (entry) for Cl- (reabsorbed). Focusing on our patient, he pointed out that delivery of should be low (provided the metabolic acidosis was not due to impaired reabsorption of NaHCO3 in her proximal convoluted tubule, or PCT). Similarly, at a urine pH close to 6.0, most of the inorganic phosphate is already in its 
form. He added that a patient with a poor dietary intake could be expected to have a low total phosphate excretion. He also anticipated a low rate of NH3 availability when told that her plasma creatinine was elevated at least 5-fold, because 
excretion is typically very low in patients with a very low GFR.7 Hence he suspected that K+ reabsorption would be low in our patient. Because the clinical story did not suggest an inherited defect in the K+ excretion system (her PK remained in the normal range between episodes without K+ supplements), he asked, ‘Did she take a drug that might inhibit K+ reabsorption in the MCD? ’
Question 3. Did she take a drug that might inhibit K+ reabsorption in the MCD?
Professor McCance was informed that the major H+ pump in the stomach is an H+/K+-ATPase, and that this patient was taking two gastric H+/K+-ATPase inhibitors, one prescribed by her gastrointestinal consultant (for gastro-oesophageal reflux), and the other by her endocrine consultant (for osteoporosis) (Table 3). Nevertheless, there seemed to be different requirements (and problems) for the H+/K+-ATPase in the stomach and the MCD that might suggest different types of regulation. The problem in the stomach seemed to be with H+ affinity for its H+ binding site. Inside gastric parietal cells, the pH is close to 7, whereas the pH is close to 1 in the stomach lumen. Hence a change in affinity for bound H+ of 106-fold was needed in the stomach. Perhaps an electrical force (binding of K+) changed this affinity for H+. In contrast, there is a much smaller affinity problem for H+ in the MCD (luminal fluid pH is usually > 5.0). Here, the major function of the H+/K+-ATPase is to reabsorb K+, and the problem is finding enough luminal H+ acceptors while not causing metabolic alkalosis. With the different functions in these two locations, our Professor was not sure that the inhibitors of gastric H+/K+-ATPase would have an important renal effect, but if they did, the setting where one might see this loss of function was one where K+ reabsorption was the major renal action in the distal nephron. In fact, this was just the function that our patient needed. Her list of medications is provided in Table 3.
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In summary, there were many possible reasons why the patient could have reduced K+ reabsorption in her MCD. But when told that the K+ concentration in the urine (UK) was in the 10–20 mmol/l range, he was virtually certain that reduced K+ reabsorption in the MCD was not the sole explanation for her large K+ deficit. ‘What made him think there was enhanced secretion of K+ in the CCD? ’
Question 4. What made him think there was enhanced secretion of K+ in the CCD?
Knowing that Professor McCance placed so much emphasis on a quantitative analysis, our team performed a calculation to determine how many litres of urine had to be excreted to develop a K+ deficit that exceeded 120 mmol. This was a minimum estimate because her PK rose only to 2.7 mmol/l with a positive balance of 120 mmol of K+. If there were no intake of K+ and a UK of 12 mmol/l, she would have to excrete 10 l of urine to create a 120 mmol K+ deficit (12 mmol/l x 10 l).
If this urine also contained its usual sodium (Na+) concentration (
40 mmol/l, Table 1), she would need to excrete close to 400 mmol Na+. This amount of Na+ represented more than 25% of her entire ECF Na+ content of 1400 mmol (10 l x 140 mmol/l). Together with a possible loss of NaHCO3 to cause her metabolic acidosis (Table 1) and that there should be low Na+ intake in a patient with anorexia nervosa, her deficit of Na+ would have to be extremely large.
In summary, he suspected she would have excessive secretion of K+ in her CCD, but only early when her PK was normal or slightly reduced. He would return to the problem of the Na+ deficit when considering the other electrolyte abnormalities.
Physiology principle 3: Regulation of K+ secretion occurs primarily in the CCD
Two elements are required for net secretion of K+ in the CCD: an electrical driving force (lumen-negative voltage) and open K+ channels in its luminal membrane (Figure 3). K+ channels are usually abundant and have a high ‘open-probability’, so they are not likely to be the cause of a high rate of secretion of K+. To generate this lumen-negative electric driving force, Na+ must be reabsorbed faster than the reabsorption of its accompanying anion, Cl-—this is called ‘electrogenic’ reabsorption of Na+ (Figure 3). Hence any cause for faster Na+ reabsorption or slower Cl- reabsorption in the CCD will increase the lumen-negative voltage to drive the net secretion of K+.8 Na+ reabsorption in the CCD occurs via a specific Na+ channel in the luminal membrane of principal cells (ENaC). Aldosterone is the major hormone that causes more ENaC to be present in an open configuration in the luminal membrane of the CCD.9
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Return to the bedside: Patients with K+ depletion due simply to a low intake of K+ should have a similar K+ concentration in the lumen of the CCD ([K]CCD) and the plasma.10 Because her UK was 5-fold higher than her PK, McCance deduced that she probably had a larger than expected lumen-negative voltage to drive K+ secretion in her CCD. This electrical driving force had to be generated by reabsorbing Na+ faster than Cl-. The possibility that Na+ was delivered without Cl- was immediately ruled out because her urine contained abundant Cl- (UCl 44 mmol/l, Table 1). The Renal Fellow then suggested that Cl- reabsorption might be inhibited by
in the lumen of the CCD,11 but he condeded that this might not be a satisfactory explanation, because her urine pH was 5.9 and that there are abundant H+ pumps in the MCD.12 Could it be that Cl- was being delivered to the CCD at a rate faster than it could be reabsorbed? Professor McCance guessed that this was a distinct possibility. He suspected that electrogenic reabsorption of Na+ was due to a high delivery of Na+ + Cl- to the CCD, in a setting where Na+ reabsorption by ENaC was stimulated by aldosterone (released in response to her low effective blood volume). To assess which upstream nephron segment had failed to reabsorb Na+ and Cl- adequately, he looked for signs of compromised function of the PCT, the loop of Henle (LOH) and/or the distal convoluted tubule (DCT). Because of the absence of defects in the renal reabsorption of glucose and phosphate, and the fact that her PHCO3 was normal between admissions, he doubted that there was a major defect in her PCT. In contrast, he suspected a defect in the function of the LOH, because the past medical records revealed that her maximum urine osmolality (Uosm) when vasopressin was administered was only 350 mOsm/kg H2O. Had she been able to concentrate her urine, he would have looked for a major defect in Na+ and Cl- reabsorption in her DCT.
The renal fellow added the following statements that were consistent with the deductions of Professor McCance. First, her excretion of calcium (Ca) was much higher than normal, a feature consistent with a lesion in the LOH. He added that had hypocalciuria and/or hypomagnesaemia been present, these findings would have suggested that a defect in Na+ and Cl- reabsorption was likely to be present in her DCT.13 Because the housestaff also suspected a lesion in her LOH, her urine had been tested for loop diuretics on this and previous admissions. Every urine sample tested was negative for loop diuretics.
In summary, the patient likely had an acquired and possibly transient defect in Na+ and Cl- reabsorption in her LOH that was not due to conventional loop diuretics. The excessive delivery of Na+ and Cl- to her CCD led to the renal K+ wasting, because she seemed to have had the capacity to reabsorb Na+ faster than Cl- in this nephron segment. Our Professor was not yet happy with this explanation and asked, ‘What else is needed to cause a high [K+]CCD other than excessive delivery of Na+ and Cl- to the CCD? ’
Question 5. What else is needed to cause a high [K+]CCD other than excessive delivery of Na+ and Cl- to the CCD?
Return to the bedside: One should always look for ways to disprove a hypothesis, because the scientific process can never prove it to be correct. If one exception is found in a flawless experiment, the hypothesis must be abandoned.14 With this in mind, Professor McCance stated that renal K+ wasting does not result from an excessive delivery of Na+ and Cl- to the CCD if the latter is caused by a large dietary NaCl intake. He pointed out the major difference between a high distal delivery of Na+ and Cl- due to a high salt diet and that due to a loop diuretic—the ECF volume is expanded with the NaCl load and contracted with a loop diuretic. A contracted ECF volume likely contributed to the renal K+ wasting in our patient—aldosterone, a stimulator of ENaC, caused a ‘faster Na+ reabsorption’ in her CCD. He expected that aldosterone would be released (through activation of the renin–angiotensin system) because her ECF volume was contracted.9
Professor McCance returned to a previous comment, the need for a higher rate of K+ excretion earlier in her illness. One registrar offered a speculation that might be tested in a research laboratory. Perhaps K+ channels in the luminal membrane of principal cells in her CCD were more abundant and/or more open when her PK was close to normal. In contrast, with a large K+ deficit, perhaps fewer open luminal K+ channels might now be present. Hence the lumen-negative driving force would no longer be capable of causing such a high rate of secretion of K+. Professor McCance thanked the registrar for that intriguing thought—he wondered whether it might help explain why patients with aldosterone-producing tumours do not usually develop extremely low PK levels.
In summary, a LOH lesion should cause a high delivery of Na+ and Cl- to the CCD. Na+ will be reabsorbed faster than Cl+ when ENaC is activated by aldosterone. This electrogenic reabsorption of Na+ in the CCD could provide the electrical driving force to augment K+ secretion. Hence a LOH lesion would explain her hypokalaemia with renal K+ wasting, her hypovolemia with renal Na+ and Cl- wasting, her renal concentration defect, and her hypercalciuria. While the cause of her LOH lesion was not yet defined, attention turned for the moment to the need to define the basis for her low PNa and its treatment.
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Analysis of the salt and water issues |
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The housestaff reviewed the information concerning her PNa to focus the discussion on a few selected issues (Table 4). First, the duration of her illness suggested that her hyponatraemia was not acute, so the main danger would be osmotic demyelination (ODS), rather than acute brain cell swelling.15 The danger was even greater in this patient, because she had both a severe degree of hypokalaemia16 and was malnourished.17 Second, the danger of ODS was an immediate concern because she was excreting a hypo-osmolar urine (Table 1). Third, she clearly had a Na+ deficit in her ECF compartment. Fourth, she likely had an expanded ICF volume if one were to judge solely by her low PNa.
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Physiology principle 4. Hyponatraemia can be due to a gain of water and/or to a deficit of Na+
The quantitative analysis of the housestaff illustrated these points. If her ECF volume were normal (10 l) and her plasma Na+ concentration (PNa) was reduced by 22 mmol/l (140–118 mmol/l), her Na+ deficit in the ECF compartment would be 220 mmol. Moreover, since her ECF volume was low on clinical grounds, this was a minimum estimate of her Na+ deficit. With a PNa that was reduced by close to 15% (118 mmol/l, Table 1), her ICF volume (if the normal value was 20 l) might also be expanded by roughly 15% or 3 l in absolute terms. When they saw the smile fade on their Professor's face, they hastened to add that this latter calculation depended on having no change in the number of ‘effective’ osmoles in the ICF compartment. Because she was both malnourished and had a large deficit of K+, the ICF particle number might be significantly reduced and the surplus of water in her ICF compartment might not actually be that large. Taken together with her ECF volume contraction, she might not have an appreciable total body water surplus.
In summary, the main basis of her low PNa was probably a negative balance of Na+. What was still to be explained was how her blood pressure was maintained, and why her initial and all subsequent Uosm values were close to 150 mOsm/kg H2O (Table 1). In fact, this low Uosm seemed to be a consistent finding in her previous hospital admissions. So our Professor asked, ‘What could cause hyponatraemia with a Uosm that was consistently close to 150 mOsm/kg H2O? ’
Question 6. What could cause hyponatraemia with a Uosm that was consistently close to 150 mOsm/kg H2O?
Physiology principle 5: The permeability of the late DCT, CCD, and MCD to water is increased when vasopressin acts
The osmotic driving force for movement of water is large (19 mmHg per mOsm/l). Hence when vasopressin causes open water channels to be inserted into the luminal membrane of the CCD, the Uosm should equal the plasma osmolality (Posm), if there is no medullary function, or be higher than the Posm if there is some medullary concentrating ability.18
Return to the bedside: Because her Uosm (150 mOsm/kg H2O) was lower than her Posm, there was either very little vasopressin in plasma (central diabetes insipidus, DI) and/or the kidney could not respond to this hormone (nephrogenic DI). Professor McCance was not content with an explanation that this was simply the effect of a loop diuretic-like agent. He recommended that she be given a small dose of vasopressin to assess whether there was a low bioavailability of vasopressin. If vasopressin acted, her rate of excretion of electrolyte-free water would decline, lessening the danger of too rapid a rate of rise in her PNa. Because her Uosm rose to 350 mOsm/kg H2O after dDAVP was given, this excluded nephrogenic DI. Nevertheless, he was curious why her Uosm was consistently close to 150 mOsm/kg H2O before giving this hormone. He doubted that vasopressin release by her hypothalamus could be so precise that it led to this near-constant Uosm when she was acutely ill. He also recalled that she did not suffer from polyuria between admissions. His differential diagnosis for a persistently low Uosm is shown in Table 5. He could readily rule out two of these diagnostic categories. First, a reset osmostat that attempts to defend a given, low PNa was unlikely, because the patient continued to excrete hypoosmolar urine when her PNa rose progressively over several days to the 130–135 mmol/l range. Second, it is unlikely that the patient had a form of nephrogenic DI, because Uosm rose two-fold when dDAVP was given. Therefore he was drawn to the conclusion that vasopressin release might be suppressed by her low PNa. He hastened to add that while this explanation was consistent with the other findings, he had some reservations, because he expected that a low ECF volume might have stimulated the release of vasopressin.18 He continued: to explain why her Uosm was 150 instead of 50 mOsm/kg H2O, he suspected that a LOH defect would impair Na+ and Cl- reabsorption in its cortical thick ascending limb (TAL). He pointed out that reduced Na+ and Cl- reabsorption in a nephron segment that was responsible for dilution of the urine would cause the excretion of urine with a higher Uosm when vasopressin was not acting on the kidney.
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Physiology principle 6: The major danger during the treatment of chronic hyponatraemia is the development of osmotic demyelination
The discussion now switched from diagnostic issues to therapeutic considerations. The plan for therapy was summarized by the team. Their first objective was to re-expand her ECF volume without changing her PNa. This could be accomplished by infusing saline that was isotonic to the patient. The initial 0.5 l of isotonic saline and 0.5 l of half-isotonic saline would be given relatively quickly. Decisions about the subsequent rate of infusion would be made on clinical grounds. They also stressed that K+ must be included when calculating the tonicity of the infusate. Therefore they would replace much of the Na+ in the infusate with K+. The second objective was to avoid osmotic demyelination in her brain. To achieve this aim, the rate of rise in her PNa was monitored closely and the targets for this rise were set. Their rationale was that the rate of rise in PNa should be lower than values reported in every patient who did develop osmotic demyelination. Given her hypokalaemia and poor nutritional state, the maximum rise in her PNa was set at 4 mmol/l/day rather than the values of 8–12 mmol/l/day recommended in otherwise normal patients.19 A lesser daily rise in her PNa might be an even better goal for this therapy. A positive balance for Na+ + K+ rather than a negative balance for water was their preferred option to raise her PNa. In quantitative terms, the patient needed a positive balance of close to 120 mmol of Na+ + K+ (4 mmol/l x 30 l of TBW) to achieve this daily rise in PNa. To prevent an excessive rise in her PNa, the volume and Na+ + K+ concentration infused should match urine excretions after the 120 mmol positive balance for K+ + Na+ was achieved. Issues concerning the anions that accompany the infused Na+ + K+ will be considered in the section on acid-base to follow.
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Acid–base issues |
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Professor McCance was pleased with their logical and thoughtful therapeutic analysis, so he turned his attention to the metabolic acidosis. Of note, her anion gap in plasma was elevated only for the first few hours in the Emergency Department, even when this value was adjusted for her plasma albumin concentration. Therefore he asked, ‘What is the basis for metabolic acidosis in a patient who has no elevation in her plasma anion gap? ’
Question 9. What is the basis for metabolic acidosis in a patient who has no elevation in her plasma anion gap?
The team summarized their views on the acid–base abnormality in their patient. They had come to the conclusion that her laxative use and renal insufficiency (low 
excretion) might have contributed in a major way to the rather severe degree of metabolic acidosis on admission (Table 2). There was no evidence of added acids, the ‘footprints’ of which would be new unmeasured anions in plasma or the urine—the anion gap was appropriately low in the urine and only elevated transiently in plasma. Thus they concluded that a loss of NaHCO3 was the most likely basis for the metabolic acidosis. Taken together with the hypokalaemia and laxative use, diarrhoea seemed to be a likely cause of the metabolic acidosis in the absence of an alternative explanation. At this point, the intern who admitted the patient reported that the patient had denied having diarrhoea, saying that she took laxatives because of extremely troublesome constipation. In fact, she had not had a bowel movement for several days. They asked Professor McCance, ‘Could the metabolic acidosis be due to something other than diarrhoea?’
Question 10. Could the metabolic acidosis be due to something other than diarrhoea?
Professor McCance doubted that she had ingested HCl or a similar compound. If the basis for the NaHCO3 loss was not via diarrhoea or in the urine, he suspected that vomiting might be the cause of her metabolic acidosis. He quickly added that vomiting usually causes metabolic alkalosis in adults, because of loss of gastric HCl.20 In this case, however, the use of inhibitors of gastric HCl secretion (Table 2), together with reflux of secretions containing NaHCO3 from the small intestine to the stomach, could lead to a net loss of NaHCO3 via vomiting. Our Professor added that in very young children who do not have pyloric obstruction, vomiting often causes the net loss of NaHCO3.
While all were impressed with this hypothesis for the metabolic acidosis, a new member of the housestaff was uncomfortable with part of this story. He would have expected that the patient should have a major haemodynamic collapse if she had renal NaCl wasting, GI NaHCO3 wasting, hypoalbuminaemia and a degree of anaemia. Support for his view was gaining strength, until one of the senior registrars reminded them of a previous intriguing suggestion by Professor McCance.21 The PNa was 118 mmol/l and this should be associated with cell swelling. Not only would this increase the red blood cell volume, but it would also raise the interstitial tissue pressure in organs with capsules or dense connective tissue sheaths, squeezing the interstitial fluid back into the vascular bed (Figure 4). It was therefore possible that her hyponatraemia was helping to defend her intravascular volume. Another housestaff asked, given the severe degree of metabolic acidosis, what are the risks for this patient?
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Question 11. What are the risks of metabolic acidosis in this patient?
Physiology principle 7: Many of the risks of acidosis are related to changes in the charge when H+ ions bind to proteins22
A change in the net charge on proteins may disrupt cellular function, because enzymes, transporters, and contractile elements are proteins. To minimize this risk, the
buffer system selectively removes H+, providing that the tissue PCO2 can fall appreciably. Two factors could contribute to poor buffering of H+ in this patient. First, a contracted ECF volume can lead to a lower blood flow rate and thereby to a high capillary and intracellular PCO2. Second, although most ICF buffering occurs in skeletal muscle, our patient was emaciated. Therefore her proportion of muscle in the body was very low, and thus her buffer capacity was markedly reduced. This probably led to a more severe degree of acidemia for a given deficit of NaHCO3. Bearing this in mind, it was advisable to treat her metabolic acidosis with isotonic (to the patient) saline to remove the limitation of a high tissue PCO2 on her ICF buffer system. Later, when an extreme degree of hypokalaemia is less of a threat, she will require therapy with NaHCO3 because of her low rate of excretion (renal insufficiency). Professor McCance thanked the group for their comments, with which he entirely concurred. Nevertheless, the picture was not yet complete. It was not clear what caused her LOH lesion and the low GFR. He therefore turned to the Renal Fellow, to know if there was new information in the modern literature to help explain these findings, or if any of the drugs that were ingested could have led to these defects.
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Integrative physiology |
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TopSummaryIntroductionThe consultationAnalysis of issues concerning...Analysis of the salt...Acid-base issuesIntegrative physiologyConcluding remarksReferences |
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Hypercalcaemia, said the Renal Fellow, could not only contribute to the development of a low GFR by directly causing arteriolar and mesangial contraction, it could also cause renal Na+, K+, and Cl- wasting via a loop diuretic-like effect. Pleased that his colleagues appeared suitably impressed, he continued. Hypercalcaemia might lead to a LOH or Bartter's-like lesion, because of occupancy of the newly-discovered ionized calcium (Ca2+)-sensing receptor on the basolateral aspect of cells of the thick ascending limb of the LOH (Figure 5).23 When Ca2+ or other polyvalent cations occupy this interesting receptor, the ROM-K ion channel in the luminal membrane is inhibited, and the lumen lacks K+ as well as its usual positive voltage. As a result, there is less reabsorption of Na+ and Cl- as well as Ca2+ in the LOH. The consequences of the reabsorptive defect could lead to findings akin to those seen with the use of loop diuretics or the ROM-K defect subtype of Bartter's syndrome with wasting of Na+, Cl-, K+, and calcium in the urine. ‘Well done!’ exclaimed Professor McCance, ‘But why is there hypercalcaemia in the first place?’
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Question 12. Why is there hypercalcaemia in the first place?
Physiology principle 8: A rise in plasma Ca2+ concentration (PCa2+) must be due either to an increased input into this body pool and/or a decrease in the output
The presence of a high renal excretion of Ca2+ would thus imply that her high PCa2+ was due to a large input of Ca2+.
Return to the bedside: The source of input of Ca2+ could either be bone, or a high rate of GI absorption. There were no clinical clues pointing to malignancy with bone reabsorption (parathyroid hormone levels were not measured), and the elevated PCa2+ was self-limited, so attention switched to the possibility of increased GI absorption of the Ca2+. The intake of CaCO3 seemed to be the obvious culprit. Their excitement at having solved the entire case was, however, short-lived as the nursing sister who had joined the ward round asked, ‘I take CaCO3 regularly for heartburn; will I develop an elevated PCa2+ as well?’ Our team was dumb-struck. The fact that thousands of people take CaCO3 regularly without developing a high PCa2+ seemed to destroy the case they had so carefully crafted! As usual, it was left to Professor McCance to save the day.
Question 13. What protects us from excessive GI Ca2+ absorption?
Physiology principle 9: Ca2+ is reabsorbed primarily by a regulated transcellular pathway in the early small bowel, and by a passive paracellular route in the large intestine
There are two pathways for GI Ca2+ absorption, said the learned Professor. Both pathways require ionized Ca2+ for absorption to occur. The well-known pathway in the duodenum and proximal small bowel is vitamin-D-dependent and saturable. Once alkaline pancreatic juice enters the bowel lumen, Ca2+ is precipitated as insoluble CaCO3, and absorption stops.
There is a less well-known second pathway for absorption of Ca2+ over a large area of the distal GI tract that is not vitamin-D-dependent, not saturable, and simply depends on the availability of ionized Ca2+ in its lumen (Figure 6). Should CaCO3 reach the distal GI tract, it may be re-dissolved by H+ formed by GI bacteria—this releases ionized Ca2+ for absorption.24 What protects those of us who ingest lots of Ca2+ is that most calcium-containing foods contain even more phosphate, and when phosphate binds Ca2+ in the GI tract distal to the stomach, this results in the formation of a Ca3(PO4)2 precipitate. In fact, the intestinal pH never falls sufficiently to re-dissolve it, and the minute Ca3(PO4)2 precipitate is excreted in the stool. We can speculate, concluded Professor McCance, that more dietary Ca2+ could be absorbed if there was a relatively greater availability of Ca2+ than phosphate in the lumen of the GI tract. This might indeed be the case in our patient with anorexia nervosa who ingested CaCO3, but very little phosphate in her diet.
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Our Professor went on to use this simple analysis based on principles of chemistry to define her future therapy. If our patient cannot be relied upon to abstain from using calcium and magnesium-containing antacids and/or laxatives, measures need to be taken to prevent the excessive absorption of these divalent cations from her GI tract. Using the principles outlined above, he suggested that she be given a small dose of inorganic phosphate on a daily basis (Figure 7). The dose had to be small enough to avoid unwanted complications from a high plasma concentration of phosphate because of her renal insufficiency. He added that measuring a random urine and plasma sample for calcium, magnesium, phosphate, and creatinine might be the way to determine whether this therapy offered more benefits than risks.
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Concluding remarks |
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TopSummaryIntroductionThe consultationAnalysis of issues concerning...Analysis of the salt...Acid-base issuesIntegrative physiologyConcluding remarksReferences |
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The team thanked Professor McCance for his help. His explanations for the basis of the four major electrolyte abnormalities in a young woman with longstanding anorexia nervosa provided much ‘food for thought’. The link between these disorders and her prescribed medications was one neither they nor her physicians had recognized beforehand. The importance of applying principles of integrative physiology together with a deductive and quantitative analysis at the bedside was very clearly illustrated and insightful. It did not go unnoticed, however, that to reach his final diagnosis, their Professor required information about newer molecular discoveries. When interpreted together, a novel long-term plan for therapy could be devised. Careful follow-up would nonetheless be essential.
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Footnotes |
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Address correspondence to Professor M.L. Halperin, University of Toronto, St. Michael's Hospital Annex, Lab #1, Research Wing, 38 Shuter Street, Toronto, Ontario, M5B 1A6, Canada. e-mail: mitchell.halperin{at}utoronto.ca
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References |
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1. Huth EJ, Squires RD, Elkinton JR. Experimental potassium depletion in normal human subjects. II. Renal and hormonal factors in the development of extracellular alkalosis during depletion. J Clin Invest 1959; 38:1149–65.[Web of Science][Medline]
2. Rabelink TJ, Koomans HA, Hené RJ, Dorhout Mees EJ. Early and late adjustment to potassium loading in humans. Kidney Int 1990; 38:942–7.[Web of Science][Medline]
3. Schreiber MS, Halperin ML. Paleolithic curriculum: Figure it out (with the help of experts). Advances Physiol Education 1998; 20:S185–94.
4. Giebisch G. Renal potassium transport: mechanisms and regulation. Am J Physiol 1998; 274:F817–33.[Web of Science][Medline]
5. Backman KA, Hayslett JP. Role of the medullary collecting duct in potassium conservation. Pflugers Arch 1983; 396:297–300.[CrossRef][Web of Science][Medline]
6. Silver RB, Soleimani M. H+-K+-ATPases: regulation and role in pathophysiological states. Am J Physiol 1999; 276:F799–811.[Web of Science][Medline]
7. Halperin ML, Jungas RL, Pichette C, Goldstein MB. A quantitative analysis of renal ammoniagenesis and energy balance: a theoretical approach. Can J Physiol Pharmacol 1982; 60:1431–5.[Web of Science][Medline]
8. Halperin ML, Kamel KS. Potassium. Lancet 1998; 352:135–42.[Web of Science][Medline]
9. Verrey F, Hummler E, Schild L, Rossier BC. Control of Na+ transport by aldosterone. In: Seldin DE, Giebisch G, eds. The Kidney: Physiology & Pathophysiology. Philadelphia, Lippincott Williams & Wilkins, 2000:1441–72.
10. Ethier JH, Kamel KS, Magner PO, Lemann JJ, Halperin ML. The transtubular potassium concentration in patients with hypokalemia and hyperkalemia. Am J Kidney Dis 1990; 15:309–15.[Web of Science][Medline]
11. Carlisle EJF, Donnelly SM, Ethier J, Quaggin SE, Kaiser U, Vasuvattakul S, et al. Modulation of the secretion of potassium by accompanying anions in humans. Kidney Int 1991; 39:1206–12.[Web of Science][Medline]
12. Alpern RJ. Cell mechanisms of proximal tubule acidification. Physiol Rev 1990; 70:79–114.
13. Friedman PA. Renal calcium metabolism. In: Seldin DW, Giebisch G, eds. The Kidney: Physiology & Pathophysiology. Philadelphia PA, Lippincott Williams & Wilkins, 2000:1749–90.
14. Beveridge. Art of Scientific Thinking. Penguin Books, 1951.
15. Sterns RH, Clark EC, Silver SM. Clinical consequences of hyponatremia and its correction. In: Seldin DW, Giebisch G, eds. Clinical Disturbances of Water Metabolism. New York, Raven Press, 1993:225–36.
16. Lohr JW. Osmotic demyelination syndrome following correction of hyponatremia: association with hypokalemia. Am J Med 1994; 96:408–13.[CrossRef][Web of Science][Medline]
17. Bahr M, Sommer N, Peterson D, Wietholter H, Dichgans J. Central pontine myelinolysis associated with low potassium levels in alcoholism. J Neurol 1990; 237:275–6.[CrossRef][Web of Science][Medline]
18. Robertson GL. Vasopressin. In: Seldin DW, Giebisch G, eds. The Kidney: Physiology & Pathophysiology. Philadelphia PA, Lippincott Williams & Wilkins, 2000:1133–52.
19. Oh MS, Kim HJ, Carroll HJ. Recommendations for treatment of symptomatic hyponatremia. Nephron 1995; 70:143–50.[Web of Science][Medline]
20. Kassirer JP, Schwartz WB. The response of normal man to selective depletion of hydrochloric acid. Am J Med 1966; 40:10–18.[CrossRef][Web of Science][Medline]
21. Cherney DZI, Davids MR, Edoute Y, Halperin ML. The importance of thirst for the development of hyponatraemia when 3,4-methylnedioxymethamphetamine (‘Ecstasy’) is ingested. Q J Med 2002; 95:475–83.
22. Vasuvattakul S, Warner LC, Halperin ML. Quantitative role of the intracellular bicarbonate buffer system in response to an acute acid load. Am J Physiol 1992; 262:R305–9.[Web of Science][Medline]
23. Hebert SC. Extracellular calcium-sensing receptor: Implications for calcium and magnesium handling in the kidney. Kidney Int 1996; 50:2129–39.[Web of Science][Medline]
24. Lin S-H, Lin Y-F, Cheema-Dhadli S, Davids MR, Halperin ML. Hypercalcaemia and metabolic alkalosis with betel nut chewing: emphasis on its integrative pathophysiology. Nephrol Dial Transplant 2002; 17:708–14.
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