Possible mechanisms to explain the absence of hyperkalaemia in Addison's disease

Raymonde F. Gagnon1 and Mitchell L. Halperin2,

Renal Divisions, 1 Montreal General Hospital, McGill University, Montreal, Quebec; 2 St Michael's Hospital, University of Toronto, Toronto, Ontario, Canada

Keywords: adrenal insufficiency; aldosterone; anion gap; cortical collecting duct; hyponatraemia; potassium

Introduction

In a patient with Addison's disease, the major clinical manifestations are due to a lack of glucocorticoid and mineralocorticoid hormonal actions. The combination of hyponatraemia, hyperkalaemia, mild hyperchloraemic metabolic acidosis, and modest elevations in the plasma creatinine, BUN, and haematocrit are classical findings [1]. Although almost one-third of a large series of patients with Addison's disease did not have hyperkalaemia on admission [2], insufficient data were provided to ensure that there was a deficiency of aldosterone and that the intake of potassium (K+) was not abnormally low.

Because Addison's disease is a chronic condition, all the K+ ingested must be excreted to maintain a steady state. To have the needed urinary K+ excretion in the absence of aldosterone, hyperkalaemia is usually required [3]. The absence of hyperkalaemia could be anticipated if there were an isolated deficiency of cortisol or if there were another reason for excessive renal excretion of K+ (e.g. protracted vomiting) [4] or an acute shift of K+ into cells.

We report data from a patient who had biochemically proven Addison's disease and aldosterone deficiency, in whom 18 of 20 plasma K+ values were within the normal range in the week prior to establishing this diagnosis. An estimate of urinary excretion of K+ (K+/creatinine ratio [5]) in a random urine sample did not suggest that the rate of renal K+ excretion was very low. This patient did not have an obvious mechanism that maintained his usual rate of excretion of K+. This prompted us to review the renal mechanisms involved in K+ homeostasis in the absence of aldosterone and to suggest a possible explanation that hinges on an unexpectedly high distal delivery of K+ to the cortical collecting duct (CCD).

Case

A 64-year-old male from India sought medical attention because of orthostatic hypotension 12 days prior to establishing a diagnosis of Addison's disease. His past medical history revealed weakness, fatigue, anorexia, a rare episode of diarrhoea, and a 35-pound weight loss over the past 3 months. Salt craving, a salty taste in his mouth, and a distaste of sweet foods that he previously enjoyed were also noted. He denied vomiting and the use of natriuretic agents. On physical examination, his blood pressure was 100/60 mmHg and his heart rate was 76/min; he was afebrile (36.4°C). He had a low jugular venous pressure and poor skin turgor. Hyperpigmentation of his skin and mucus membranes was difficult to assess because of ethnicity.

On laboratory examination, hyponatraemia (112 mmol/l, Table 1Go) was a striking finding. A presumptive diagnosis of the syndrome of inappropriate secretion of antidiuretic hormone (SIADH) was made because the patient's urine osmolality was 394 mOsm/kg H2O and it was felt that both hypothyroidism and adrenal insufficiency (because of normokalaemia and a high K+/creatinine ratio on a spot urine sample, Table 1Go) were not present. When he was fluid restricted and given a small quantity of hypertonic saline, the plasma sodium (Na+) concentration rose to the low -120 mmol/l range in 48 h, but the plasma K+ concentration remained in the normal range during the first hospital admission (16 of the first sequential values in Figure 1Go).


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Table 1. Plasma and urine values

 


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Fig. 1. Sequential values for the [K+] and the anion gap in plasma. The solid circles represent the plasma K+ concentration with a normal range of 3.5–5.0 mmol/l shown in the lower shaded area. Most of the sequentially drawn blood values before diagnosis (on day 12, indicated by the vertical line) fell within this normal range (18 of 20 measurements). The second hospital admission begins with sample number 16. The open circles represent the plasma anion gap with the normal range of 10- 14 mEq/l shown in the upper shaded area. In one determination (day 3), the plasma anion gap was normal, but the plasma Na+ concentration at that time was > 10 mmol/l higher than in the preceding and succeeding samples, raising the possibility of a laboratory error in that one sample. Arrows indicate the time of the first and second hospital admissions and the intervening visit to the emergency room (ER).

 
There were laboratory findings to suggest that the patient's extracellular fluid (ECF) volume was contracted due to a defect in renal Na+ conservation. His initial haemoglobin was elevated (15.2 g/dl); both haemoglobin and plasma albumin (3.9 g/dl) fell to 13.4 g/dl and 3.1 g/dl respectively, over the first 16 h. The initial urine Na+ and Cl- concentrations were high before therapy (118 and 143 mmol/l respectively, Table 1Go) while the ‘effective’ blood volume was probably low. An unexplained finding was a very low plasma anion gap when viewed in conjunction with his plasma albumin level (Figure 1Go, Table 1Go).

The day after discharge, the patient again presented to our emergency room with similar symptoms. His blood pressure and pulse rate were essentially unchanged from his first admission. Laboratory examination revealed hyponatraemia (121 mmol/l) and normokalaemia (Figure 1Go, sample numbers 19, 20). When seen by the Nephrology Service 6 days later, his blood pressure was low (75–85/50 mmHg), his pulse rate was 96/min, his jugular venous pressure was low and his skin turgor was poor. Although the last available value for plasma K+ concentration was 4.5 mmol/l (day 7), several hours later, hyperkalaemia (6.2 and 6.5 mmol/l) was present (Figure 1Go). His plasma anion gap, although rising over the past week, remained low.

Since the patient's ECF volume was low and renal NaCl wasting was present, a presumptive clinical diagnosis of Addison's disease was made without knowledge of the current plasma K+ concentration. This impression was confirmed by finding very low plasma aldosterone (2.4 ng/dl, normal 3.1–16.1 ng/dl) and cortisol level (5.8 µg/dl, normal 6.9–25 µg/dl). The plasma adrenocorticotrophic hormone (ACTH) was markedly elevated (1314 pg/ml (normal 9–50 pg/ml)) and there was no rise in the plasma cortisol level (5.3 µg/dl) in response to an infusion of ACTH. The thyroid-stimulating hormone (TSH) level was in the normal range (1.8 mU/l, normal 0.5–4.0 mU/l).

The patient was treated initially with 100 mg of solucortef q8h for the first 24 h; he also received a bolus of l litre and a steady infusion of 125 ml/h of isotonic saline. There was a rapid clinical as well as biochemical improvement. The patient remains well 9 months later on daily cortisol (25 mg q am and 12.5 mg q pm) and 9-{alpha} fludrocortisone (50–100 µg qd) (Table 1Go). The plasma anion gap rose to 12 mEq/l and remained in this range after the other laboratory data had become normal.

Discussion

There were several factors that could be ruled out as explanations for the near absence of hyperkalaemia from the data available in this patient. First, if a low dietary intake of K+ were a valid explanation for the absence of hyperkalaemia, there must be a very low rate of excretion of K+. If the rate of excretion of creatinine occurs at a near constant rate in a chronic condition [6], one can obtain a reasonable impression of the K+ excretion rate by examining the urinary K+/creatinine ratio (equation 1) [5]. This value is 70 mmol K+ per 1.15 g of creatinine in an adult eating a typical diet. One must also estimate the creatinine excretion rate (20 mg/body weight) [6]. Because the patient was thin, his rate of excretion of creatinine could have been somewhat less than 1 g/day; however, the estimated rate of excretion of K+ (68 mmol/g creatinine) casts doubt on the presence of an exceedingly low rate of excretion of K+.


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Another possible cause for a higher than expected rate of excretion of K+ would be a very low cortisol level without a parallel decline in aldosterone. Since the patient's plasma aldosterone level was very low, this cannot explain the normokalaemia. Other causes for a high rate of renal excretion of K+ such as vomiting and diuretics were not present (vomiting was denied, the urine pH was not alkaline, the urine was not chloride (Cl-) poor, and alkalaemia was not present). Similarly, tubulopathies such as Bartter's, Gitelman's, or Liddle's syndromes could not explain the absence of hyperkalaemia because the patient was normokalaemic after hormone replacement therapy. Therefore, other factors that might have augmented the renal K+ excretion rate will be explored.

When adrenal cortical granulosa cells have decreased in number, a higher concentration of one of the secretagogues for aldosterone release would be needed to defend the ECF volume and/or excrete sufficient K+ to avoid hyperkalaemia [7]. The two secretagogues for the release of aldosterone are angiotensin II and hyperkalaemia. Therefore, because the degree of ECF volume contraction was very profound in our patient, angiotensin II levels should have been very high [8]. At the stage of adrenal insufficiency before cells of the glomerulosa completely disappeared, this stimulus for the release of aldosterone might permit the ambient aldosterone level to be sufficient to cause the excretion of enough K+ to avoid the development of hyperkalaemia. A 24-h aldosterone excretion rate rather than a single plasma aldosterone level would be a better test of this hypothesis. Unfortunately, aldosterone excretion rates were not measured in this patient

It is possible that the patient had a high rate of K+ excretion because of a high CCD flow rate. This flow rate is directly proportional to the osmole excretion rate when vasopressin acts [9] because the osmolality in the lumen of the CCD is equal to that in the cortical interstitial compartment (equal to the plasma osmolality (Posm), equation 2). In this patient, the osmole excretion rate was 961 mOsmol/g creatinine (394 mOsm/l divided by 0.41 g creatinine per litre), a value that is in the normal range. This implies a near normal osmole excretion rate [9]. Nevertheless, he could have had a somewhat higher than expected flow rate in the CCD because of the severe degree of hyponatraemia (112 mmol/l) on the first admission. This low plasma Na+ concentration would cause a much lower Posm (228 mOsm/kg H2O) and thereby a 25% higher flow rate in the terminal CCD for any given osmole excretion rate (equation 2). This should only make a minor contribution to the degree of kaliuresis.


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To evaluate a possible role of a higher rate of delivery of K+ to the CCD, micropuncture data from the nephron of the rat will be used to reflect events in a human. A 70-kg human eating a typical Western diet excretes close to 1 mmol K+ per kg body weight (or 70 mmol) [10]. This does not mean that 70 mmol of K+ must be secreted in the CCD because 36 mmol of K+ should be delivered daily to the CCD (24 litres/dayx1.5 mmol K+/l, the concentration of K+ in fluid in the early distal tubule [11], Figure 2Go). If there were little K+ reabsorbed in the distal convoluted tubule or the connecting tubules, the net secretion of K+ would be 34 instead of 70 mmol of K+ per day.



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Fig. 2. Delivery of K+ to the cortical collecting duct. The figure depicts a stylized nephron modified for illustrative purposes with the circle representing the glomerulus. The volumes are in litres per day. The left-hand portion represents the normal state with a GFR of 180 litres per day and the right-hand portion depicts events with a 50% reduction in GFR. When 70 mmol of K+must be excreted daily, there is a need for more net secretion of K+ in the CCD when the GFR is reduced.

 
The glomerular filtration rate (GFR) could, in theory, influence the delivery of K+ to the distal nephron. When the GFR declines, the volume delivered to the distal nephron will be smaller. In this setting, there should be an even larger demand for net K+ secretion in the CCD to excrete the usual dietary K+ load. The GFR in our patient could have been higher than expected for two theoretical reasons. First, the colloid osmotic pressure could be low because of a lower Donnan effect secondary to the low plasma anion gap (Figure 1Go). Second, if the severe degree of hyponatraemia was due in part to water gain, the volume of water retained in the ECF compartment could diminish the degree of ECF volume contraction and thereby help maintain the blood pressure. While true in theory, we doubt that these factors were sufficiently important on their own to account for the relatively high rate of excretion of K+.

If the volume of fluid reabsorbed in upstream nephron segments were diminished, this should increase distal volume delivery. With a contracted ECF volume and the absence of renal glucosuria or bicarbonate wasting, it is unlikely that there was a reduced reabsorption of Na+ and water in the proximal convoluted tubule. Therefore if distal delivery were higher than expected, there would need to be a lower volume of filtrate reabsorbed in the loop of Henle (LOH). Water is reabsorbed in its descending thin limb (DtL) because this nephron segment is permeable to water and the medullary interstitium osmolality is higher than that in its lumen [12]. Because the patient's urine osmolality on first admission was only 394 mOsm/kg H2O, and if this reflected the medullary interstitial osmolality at that time, the volume reabsorbed in the DtL would be much less than normal (rise in osmolality was less than twofold as against the usual ratio of almost threefold [13]). Therefore a lower osmolality in the medullary interstitial compartment could help increase the volume delivery and thereby the quantity of K+ to the distal nephron despite a decline in GFR and an enhanced proximal reabsorption of Na+. With a more severe decline in GFR on his visit to the ER (higher plasma creatinine and BUN, Table 1Go), there might now be a lower delivery of K+ and a need for more secretion of K+ in his CCD to excrete the daily K+ load.

Because the patient could achieve a urine osmolality of 710 mOsm/kg H2O on his visit to the ER, the basis for the lower initial medullary interstitial osmolality was reversible. Although downregulation of aquaporin (AQP)-2 water channels in the MCD might be a partial explanation for a low urine osmolality [14], another possibility is that a more severe degree of hyponatraemia diminished the osmolality in the medullary interstitial compartment (see Appendix).

A cationic substance in plasma could produce a ‘frusemide-like’ lesion if bound to the calcium receptor on the basolateral surface of the medullary thick ascending limb of the LOH (mTAL) [15] (Figure 3Go). When occupied, the ROM-K channel in the luminal membrane would be inhibited [16]. This will depress NaCl reabsorption because K+ entry into the lumen of the mTAL is needed both for the Na+, K+, 2 C1- cotransporter and for the generation of a lumen-positive voltage to drive Na+ reabsorption via the paracellular route [17]. The very low plasma anion gap (Figure 1) may suggest the presence of a circulating cationic substance [18]. Since the patient's plasma anion gap is currently in the normal range, it is possible that there was a more cationic circulating protein that was transient in nature.



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Fig. 3. Possible factors contributing to a low distal delivery of K+. For details, see text. The figure depicts factors that might lower the amount of active Na+ reabsorption in the mTAL of the loop of Henle. When this reabsorption is inhibited, the osmolality in the interstitial compartment is decreased, which reduces the volume of fluid reabsorbed in the DtL of the loop of Henle. Possible causes include the effect of hyponatraemia to lower the luminal concentration of Na+, and a cationic ligand to block the ROM-K channel.

 

Concluding remarks

The absence of hyperkalaemia and a reasonable estimated rate of renal K+ excretion raised doubt initially concerning the diagnosis of Addison's disease. Nevertheless, Addison's disease should have been suspected because of renal salt wasting. Because he had a sufficient rate of excretion of K+ to avoid the development of hyperkalaemia along with aldosterone deficiency, factors controlling the excretion of K+ were examined to help explain these unanticipated findings.

Appendix

Hyponatraemia may cause a lower osmolality of the medullary interstitial compartment
Our purpose was to explore whether a more severe degree of hyponatraemia might lead to an increased delivery of K+ to the distal nephron. If more volume is delivered distally, more K+ will be delivered as well if there is little change in the luminal K+ concentration in fluid entering this portion of the nephron. It follows that when a smaller volume is reabsorbed in the LOH, a larger volume (and K+) should be delivered to the distal nephron. The main factor controlling volume reabsorbed in the LOH (actually, its DtL, the water permeable segment) is the medullary interstitial osmolality. This osmolality could be lower if either more osmole-free water was reabsorbed from the MCD and/or less Na+ and Cl- ions were reabsorbed in the mTAL.

More reabsorption of water in the MCD
With the same medullary osmolality, more water might be reabsorbed in the MCD if a larger volume were delivered to the terminal CCD when vasopressin acts. Consider the following quantitative example to illustrate the potential impact of hyponatraemia on this ‘dilution’ of the medullary interstitial compartment. Assume that 24 litres are delivered daily to the early distal convoluted tubule with an osmolality of 100 mOsm/kg H2O. Close to 2/3 (16 litres) would be reabsorbed normally by the time this fluid reaches the terminal CCD because its luminal osmolality rose threefold higher (equal to the Posm, or close to 300 mOsm/kg H2O) [9]. In contrast, with a severe degree of hyponatraemia (100 instead of 140 mmol/l), the Posm would now be close to 200 mOsm/kg H2O. If everything else remained constant and vasopressin acted, one-half of the 24 litres (12 litres) would be reabsorbed when this fluid reached the terminal CCD in our hyponatraemic individual (twofold rise in Posm). Hence an extra 4 litres per day would be delivered to the MCD for reabsorption with this degree of hyponatraemia.

Less reabsorption of Na+ in the mTAL
Our rationale is that hyponatraemia might cause a decreased reabsorption of Na+ and Cl- in the mTAL if an additional stimulus for its Na+ reabsorption was not present. If less Na+ were reabsorbed from the mTAL, the osmolality of the medullary interstitial compartment would decline. Consider a quantitative example where there is a twofold rise in medullary interstitial osmolality. Enough water will be reabsorbed from the DtL to raise its luminal Na+ concentration at the bend of the LOH by twofold as compared to its end-proximal value (equal to the plasma Na+ concentration). Therefore, with hyponatraemia, the concentration of Na+ will be lower at the bend of the LOH (double a smaller value). If the percentage decline in luminal Na+ concentration were the same when hyponatraemia was present (same lumen-positive voltage), the absolute quantity of Na+ reabsorption in the mTAL would be reduced. Therefore if there were not a greater stimulus for Na+ reabsorption in the mTAL with hyponatraemia, less Na+ would be reabsorbed in the mTAL. It is interesting to note that this patient's plasma Na+ concentration was 112 mmol/l and his urine osmolality was 394 mOsm/kg H2O on the first admission and these values rose to 121 mmol/l and 710 mOsm/kg H2O respectively, on the second admission (Table 1Go).

Acknowledgments

We are extremely grateful to Dr S. Cheema-Dhadli and Dr Kamel S. Kamel for very helpful discussions and suggestions during the preparation of this manuscript. We are also indebted to Stella Tang and Chee Kiong Chong for expert technical assistance, and to Jolly Mangat for outstanding secretarial assistance.

Notes

Correspondence and offprint requests to: M. L. Halperin MD FRCP(C), Division of Nephrology, St Michael's Hospital, 38 Shuter Street, Toronto, Ontario, Canada M5B 1A6. Back

References

  1. Orth DN, Kovacs WJ. The adrenal cortex. In: Wilson JD, Foster DW, Kronenberg HM, Larsen PR, eds. Williams Textbook of Endocrinology. WB Saunders Company Philadelphia, PS, 1998; 550, Table 512–558
  2. Nerup J. Addison's disease—clinical studies. A report of 108 cases. Acta Endocrinol1974; 76: 127–141[ISI][Medline]
  3. Muto S, Sansom S, Giebisch G. Effects of a high potassium diet on electrical properties of cortical collecting ducts from adrenalectomized rabbits. J Clin Invest1988; 8l: 376–380
  4. Adrogué HJ, Madias NE. Changes in plasma potassium concentration during acute acid–base disturbances. Am J Med1981; 71: 456–466[ISI][Medline]
  5. Kamel KS, Ethier JH, Richardson RMA, Bear RA, Halperin ML. Urine electrolytes and osmolality: when and how to use them. Am J Nephrol1990; 10: 89–102[ISI][Medline]
  6. Cockcroft DW, Gault MH. Prediction of creatinine clearance from serum creatinine. Nephron1976; 16: 31–41[ISI][Medline]
  7. Halperin ML, Kamel KS. Dynamic interactions between integrative physiology and molecular medicine: The key to understand the mechanism of action of aldosterone in the kidney. Can J Physiol Pharm2000; 78: 587–594[ISI][Medline]
  8. Hollenberg NK, Williams GH. Abnormal renal function, sodium-volume homeostasis and renin system behavior in normal-renin essential hypertension: the evolution of the non-modulator concept. In: Laragh JH, Brenner BM, eds. Hypertension: Pathophysiology, Diagnosis, and Management. Raven Press, New York, 1995; 1837–1856
  9. Steele A, deVeber H, Quaggin SE et al. What is responsible for the diurnal variation in potassium excretion? Am J Physiol1994; 36: R554–560
  10. 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 Invest1959; 38: 1149–1165[ISI][Medline]
  11. Vallon V, Osswald H, Blantz, RC, Thomson S. Potential role of luminal potassium in tubuloglomerular feedback. J Am Soc Nephrol1997; 8: 1831–1837[Abstract]
  12. Knepper MA, Rector FCJ. Urinary concentration and dilution. In: Brenner BM, ed. Brenner and Rector's, The Kidney. Saunders, Philadelphia, 1996; 532–570
  13. Oh MS, Halperin ML. The mechanisms of urine concentration in the inner medulla. Nephron1997; 75: 384–393[ISI][Medline]
  14. Ecelbarger CA, Nielsen S, Olson BR et al. Role of renal aquaporins in escape from vasopressin-induced antidiuresis in rat. J Clin Invest1997; 99: 1852–1863[Abstract/Free Full Text]
  15. Hebert SC. Extracellular calcium-sensing receptor: Implications for calcium and magnesium handling in the kidney. Kidney Int1996; 50: 2129–2139[ISI][Medline]
  16. Hebert SC. Roles of Na-K-2Cl and Na-Cl cotransporters and ROMK potassium channels in urinary concentrating mechanism. Am J Physiol1998; 275: F325–327[ISI][Medline]
  17. Molony DA, Reeves WE, Andreoli TE. Na+K+2Cl- cotransporter and the thick limb. Kidney Int1989; 36: 418–425[ISI][Medline]
  18. Murray T, Long W, Narins RG. Multiple myeloma and the anion gap. N Engl J Med1975; 292: 574–575[ISI][Medline]
Received for publication: 28.11.00
Revision received 11. 1.01.