Nephrol. Dial. Transplant.-2001-Gagnon-1280-4

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					Nephrol Dial Transplant (2001) 16: 1280±1284

Interesting Case

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

Raymonde F. Gagnon1 and Mitchell L. Halperin2

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

Keywords: adrenal insuf®ciency; aldosterone; anion                  absence of aldosterone and to suggest a possible
gap; cortical collecting duct; hyponatraemia; potassium             explanation that hinges on an unexpectedly high distal
                                                                    delivery of Kq to the cortical collecting duct (CCD).

Introduction                                                        Case

In a patient with Addison's disease, the major clinical             A 64-year-old male from India sought medical atten-
manifestations are due to a lack of glucocorticoid and              tion because of orthostatic hypotension 12 days prior
mineralocorticoid hormonal actions. The combina-                    to establishing a diagnosis of Addison's disease.
tion of hyponatraemia, hyperkalaemia, mild hyper-                   His past medical history revealed weakness, fatigue,
chloraemic metabolic acidosis, and modest elevations                anorexia, a rare episode of diarrhoea, and a 35-pound
in the plasma creatinine, BUN, and haematocrit are                  weight loss over the past 3 months. Salt craving, a salty
classical ®ndings w1x. Although almost one-third of                 taste in his mouth, and a distaste of sweet foods that he
a large series of patients with Addison's disease did not           previously enjoyed were also noted. He denied vomit-
have hyperkalaemia on admission w2x, insuf®cient data               ing and the use of natriuretic agents. On physical
were provided to ensure that there was a de®ciency of               examination, his blood pressure was 100u60 mmHg
aldosterone and that the intake of potassium (Kq) was               and his heart rate was 76umin; he was afebrile (36.48C).
not abnormally low.                                                 He had a low jugular venous pressure and poor skin
   Because Addison's disease is a chronic condition,                turgor. Hyperpigmentation of his skin and mucus
all the Kq ingested must be excreted to maintain a                  membranes was dif®cult to assess because of ethnicity.
steady state. To have the needed urinary Kq excretion                  On laboratory examination,            hyponatraemia
in the absence of aldosterone, hyperkalaemia is usually             (112 mmolul, Table 1) was a striking ®nding. A pre-
required w3x. The absence of hyperkalaemia could be                 sumptive diagnosis of the syndrome of inappropriate
anticipated if there were an isolated de®ciency of                  secretion of antidiuretic hormone (SIADH) was
cortisol or if there were another reason for excessive              made because the patient's urine osmolality was
renal excretion of Kq (e.g. protracted vomiting) w4x or             394 mOsmukg H2O and it was felt that both hypo-
an acute shift of Kq into cells.                                    thyroidism and adrenal insuf®ciency (because of
   We report data from a patient who had bio-                       normokalaemia and a high Kqucreatinine ratio on
chemically proven Addison's disease and aldosterone                 a spot urine sample, Table 1) were not present. When
de®ciency, in whom 18 of 20 plasma Kq values were                   he was ¯uid restricted and given a small quantity of
within the normal range in the week prior to establish-             hypertonic saline, the plasma sodium (Naq) concen-
ing this diagnosis. An estimate of urinary excretion                tration rose to the low À120 mmolul range in 48 h,
of Kq (Kqucreatinine ratio w5x) in a random urine                   but the plasma Kq concentration remained in the
sample did not suggest that the rate of renal Kq                    normal range during the ®rst hospital admission (16 of
excretion was very low. This patient did not have an                the ®rst sequential values in Figure 1).
obvious mechanism that maintained his usual rate of                    There were laboratory ®ndings to suggest that the
excretion of Kq. This prompted us to review the renal               patient's extracellular ¯uid (ECF) volume was con-
mechanisms involved in Kq homeostasis in the                        tracted due to a defect in renal Naq conservation.
                                                                    His initial haemoglobin was elevated (15.2 gudl);
                                                                    both haemoglobin and plasma albumin (3.9 gudl)
Correspondence and offprint requests to: M. L. Halperin MD          fell to 13.4 gudl and 3.1 gudl respectively, over the
FRCP(C), Division of Nephrology, St Michael's Hospital, 38 Shuter   ®rst 16 h. The initial urine Naq and ClÀ concentra-
Street, Toronto, Ontario, Canada M5B 1A6.                           tions were high before therapy (118 and 143 mmolul

#   2001 European Renal Association±European Dialysis and Transplant Association
Absence of hyperkalaemia in Addison's disease                                                                                            1281
Table 1. Plasma and urine values

                                        Admission                                                                  9 months later

                                        First (day 1)                       Second (day 7)                         Plasma              Urine

                                        Plasma             Urine            Plasma              Urine

Naq (mmolul)                            112.0              118              121.0               143                140.0               177
Kq (mmolul)                               4.3               28                4.5                63                  4.1                71
ClÀ (mmolul)                             84.0              134               86.0               125                 99.0               231
HCOÀ (mmolul)
     3                                   22.0              ±                 26.0               ±                   29.0                 0
Anion gap (mEqul)                         6.0              ±                  9.0               ±                   12.0               ±
BUN (mgudl)                              13.0              ±                 27.0               ±                   14.0               ±
Creatinine (mgudl)                        0.9               41                1.2               ±                    1.0               ±
Glucose (mgudl)                          70.0              ±                116.0               ±                   71.0               Neg
Albumin (gudl)                            3.9              ±                ±                   ±                    4.2               Neg
Haemoglobin (gudl)                       15.2              ±                 13.5               ±                   43.5               ±
Osmolality (mOsmukg H2O)                ±                  394              ±                   710                ±                   902
KuCreat (mmolug)                        ±                   68              ±                   ±                  ±                   ±

The plasma samples before diagnosis are the initial values on his ®rst admission and upon discharge from the emergency room. The urine
samples represent random urine collections during these 2 days. To estimate excretion rates, divide the concentrations by the urine creatinine
and express results per gram creatinine in urine.

                                                                        When seen by the Nephrology Service 6 days later, his
                                                                        blood pressure was low (75±85u50 mmHg), his pulse
                                                                        rate was 96umin, his jugular venous pressure was low
                                                                        and his skin turgor was poor. Although the last
                                                                        available value for plasma Kq concentration was
                                                                        4.5 mmolul (day 7), several hours later, hyperkalaemia
                                                                        (6.2 and 6.5 mmolul) was present (Figure 1). 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 Kq concentration.
                                                                        This impression was con®rmed by ®nding very low
                                                                        plasma aldosterone (2.4 ngudl, normal 3.1±16.1 ngudl)
Fig. 1. Sequential values for the wKqx and the anion gap in plasma.     and cortisol level (5.8 mgudl, normal 6.9±25 mgudl). The
The solid circles represent the plasma Kq concentration with a
normal range of 3.5±5.0 mmolul shown in the lower shaded area.          plasma adrenocorticotrophic hormone (ACTH) was
Most of the sequentially drawn blood values before diagnosis            markedly elevated (1314 pguml (normal 9±50 pguml))
(on day 12, indicated by the vertical line) fell within this normal     and there was no rise in the plasma cortisol level
range (18 of 20 measurements). The second hospital admission            (5.3 mgudl) in response to an infusion of ACTH. The
begins with sample number 16. The open circles represent the plasma
anion gap with the normal range of 10À14 mEqul shown in the upper
                                                                        thyroid-stimulating hormone (TSH) level was in
shaded area. In one determination (day 3), the plasma anion gap         the normal range (1.8 mUul, normal 0.5±4.0 mUul).
was normal, but the plasma Naq concentration at that time was              The patient was treated initially with 100 mg
)10 mmolul higher than in the preceding and succeeding samples,         of solucortef q8h for the ®rst 24 h; he also received
raising the possibility of a laboratory error in that one sample.       a bolus of l litre and a steady infusion of 125 mluh of
Arrows indicate the time of the ®rst and second hospital admissions
and the intervening visit to the emergency room (ER).                   isotonic saline. There was a rapid clinical as well
                                                                        as biochemical improvement. The patient remains well
respectively, Table 1) while the `effective' blood                      9 months later on daily cortisol (25 mg q am and
volume was probably low. An unexplained ®nding                          12.5 mg q pm) and 9-a ¯udrocortisone (50±100 mg qd)
was a very low plasma anion gap when viewed in                          (Table 1). The plasma anion gap rose to 12 mEqul and
conjunction with his plasma albumin level (Figure 1,                    remained in this range after the other laboratory data
Table 1).                                                               had become normal.
  The day after discharge, the patient again presented
to our emergency room with similar symptoms.
His blood pressure and pulse rate were essentially                      Discussion
unchanged from his ®rst admission. Laboratory exam-
ination revealed hyponatraemia (121 mmolul) and                         There were several factors that could be ruled out as
normokalaemia (Figure 1, sample numbers 19, 20).                        explanations for the near absence of hyperkalaemia
1282                                                                                                      R. F. Gagnon and M. L. Halperin

from the data available in this patient. First, if a low                in our patient, angiotensin II levels should have been
dietary intake of Kq were a valid explanation for the                   very high w8x. At the stage of adrenal insuf®ciency
absence of hyperkalaemia, there must be a very low                      before cells of the glomerulosa completely disappeared,
rate of excretion of Kq. If the rate of excretion of                    this stimulus for the release of aldosterone might
creatinine occurs at a near constant rate in a chronic                  permit the ambient aldosterone level to be suf®cient
condition w6x, one can obtain a reasonable impression                   to cause the excretion of enough Kq to avoid the
of the Kq excretion rate by examining the urinary                       development of hyperkalaemia. A 24-h aldosterone
Kqucreatinine ratio (equation 1) w5x. This value is                     excretion rate rather than a single plasma aldosterone
70 mmol Kq per 1.15 g of creatinine in an adult eating                  level would be a better test of this hypothesis.
a typical diet. One must also estimate the creatinine                   Unfortunately, aldosterone excretion rates were not
excretion rate (20 mgubody weight) w6x. Because the                     measured in this patient
patient was thin, his rate of excretion of creatinine                      It is possible that the patient had a high rate of Kq
could have been somewhat less than 1 guday; however,                    excretion because of a high CCD ¯ow rate. This ¯ow
the estimated rate of excretion of Kq (68 mmolug creat-                 rate is directly proportional to the osmole excretion
inine) casts doubt on the presence of an exceedingly                    rate when vasopressin acts w9x because the osmolality in
low rate of excretion of Kq.                                            the lumen of the CCD is equal to that in the cortical
                                                                        interstitial compartment (equal to the plasma osmolal-
Kq excretion ˆ …‰Kq Šurine 3Volumeurine †u
                                                                        ity (Posm), equation 2). In this patient, the osmole excre-
                   …‰CreatinineŠurine 3Volumeurine †                    tion rate was 961 mOsmolug creatinine (394 mOsmul
                ˆ ‰Kq Šurine u‰CreatinineŠurine            …Eqn 1†      divided by 0.41 g creatinine per litre), a value that is in
                                                                        the normal range. This implies a near normal osmole
   Another possible cause for a higher than expected                    excretion rate w9x. Nevertheless, he could have had
rate of excretion of Kq would be a very low cortisol                    a somewhat higher than expected ¯ow rate in the
level without a parallel decline in aldosterone. Since                  CCD because of the severe degree of hyponatraemia
the patient's plasma aldosterone level was very low,                    (112 mmolul) on the ®rst admission. This low plasma
this cannot explain the normokalaemia. Other causes                     Naq concentration would cause a much lower Posm
for a high rate of renal excretion of Kq such as                        (228 mOsmukg H2O) and thereby a 25% higher ¯ow
vomiting and diuretics were not present (vomiting was                   rate in the terminal CCD for any given osmole
denied, the urine pH was not alkaline, the urine                        excretion rate (equation 2). This should only make
was not chloride (ClÀ) poor, and alkalaemia was not                     a minor contribution to the degree of kaliuresis.
present). Similarly, tubulopathies such as Bartter's,                   Flow rateCCD ˆ # Urine osmoles=Posm                        …Eqn 2†
Gitelman's, or Liddle's syndromes could not explain
the absence of hyperkalaemia because the patient was                      To evaluate a possible role of a higher rate of deliv-
normokalaemic after hormone replacement therapy.                        ery of Kq to the CCD, micropuncture data from the
Therefore, other factors that might have augmented                      nephron of the rat will be used to re¯ect events in a
the renal Kq excretion rate will be explored.                           human. A 70-kg human eating a typical Western
   When adrenal cortical granulosa cells have                           diet excretes close to 1 mmol Kq per kg body weight
decreased in number, a higher concentration of one                      (or 70 mmol) w10x. This does not mean that 70 mmol
of the secretagogues for aldosterone release would be                   of Kq must be secreted in the CCD because 36 mmol
needed to defend the ECF volume anduor excrete                          of Kq should be delivered daily to the CCD
suf®cient Kq to avoid hyperkalaemia w7x. The two                        (24 litresuday 3 1.5 mmol Kqul, the concentration of
secretagogues for the release of aldosterone are angio-                 Kq in ¯uid in the early distal tubule w11x, Figure 2).
tensin II and hyperkalaemia. Therefore, because the                     If there were little Kq reabsorbed in the distal
degree of ECF volume contraction was very profound                      convoluted tubule or the connecting tubules, the net

Fig. 2. Delivery of Kq to the cortical collecting duct. The ®gure depicts a stylized nephron modi®ed 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 Kqmust be excreted daily, there is a need for
more net secretion of Kq in the CCD when the GFR is reduced.
Absence of hyperkalaemia in Addison's disease                                                                                1283
                q                                       q
secretion of K would be 34 instead of 70 mmol of K
per day.
   The glomerular ®ltration rate (GFR) could, in
theory, in¯uence the delivery of Kq to the distal
nephron. When the GFR declines, the volume deliv-
ered to the distal nephron will be smaller. In this
setting, there should be an even larger demand for net
Kq secretion in the CCD to excrete the usual dietary
Kq 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         Fig. 3. Possible factors contributing to a low distal delivery of Kq.
                                                             For details, see text. The ®gure depicts factors that might lower the
a lower Donnan effect secondary to the low plasma            amount of active Naq reabsorption in the mTAL of the loop of
anion gap (Figure 1). Second, if the severe degree of        Henle. When this reabsorption is inhibited, the osmolality in the
hyponatraemia was due in part to water gain, the             interstitial compartment is decreased, which reduces the volume of
volume of water retained in the ECF compartment              ¯uid reabsorbed in the DtL of the loop of Henle. Possible causes
could diminish the degree of ECF volume contraction          include the effect of hyponatraemia to lower the luminal concentra-
                                                             tion of Naq, and a cationic ligand to block the ROM-K channel.
and thereby help maintain the blood pressure. While
true in theory, we doubt that these factors were
suf®ciently important on their own to account for the        When occupied, the ROM-K channel in the luminal
relatively high rate of excretion of Kq.                     membrane would be inhibited w16x. This will depress
   If the volume of ¯uid reabsorbed in upstream              NaCl reabsorption because Kq entry into the lumen of
nephron segments were diminished, this should                the mTAL is needed both for the Naq, Kq, 2 C1À
increase distal volume delivery. With a contracted           cotransporter and for the generation of a lumen-
ECF volume and the absence of renal glucosuria or            positive voltage to drive Naq reabsorption via the
bicarbonate wasting, it is unlikely that there was a         paracellular route w17x. The very low plasma anion gap
reduced reabsorption of Naq and water in the pro-            (Figure 1) may suggest the presence of a circulating
ximal convoluted tubule. Therefore if distal delivery        cationic substance w18x. Since the patient's plasma
were higher than expected, there would need to be a          anion gap is currently in the normal range, it is possible
lower volume of ®ltrate reabsorbed in the loop of            that there was a more cationic circulating protein that
Henle (LOH). Water is reabsorbed in its descending           was transient in nature.
thin limb (DtL) because this nephron segment is
permeable to water and the medullary interstitium
osmolality is higher than that in its lumen w12x. Because
the patient's urine osmolality on ®rst admission was         Concluding remarks
only 394 mOsmukg H2O, and if this re¯ected the medul-
lary interstitial osmolality at that time, the volume        The absence of hyperkalaemia and a reasonable
reabsorbed in the DtL would be much less than normal         estimated rate of renal Kq excretion raised doubt
(rise in osmolality was less than twofold as against the     initially concerning the diagnosis of Addison's disease.
usual ratio of almost threefold w13x). Therefore a lower     Nevertheless, Addison's disease should have been sus-
osmolality in the medullary interstitial compartment         pected because of renal salt wasting. Because he had
could help increase the volume delivery and thereby          a suf®cient rate of excretion of Kq to avoid the devel-
the quantity of Kq to the distal nephron despite a decline   opment of hyperkalaemia along with aldosterone de®-
in GFR and an enhanced proximal reabsorption of              ciency, factors controlling the excretion of Kq were
Naq. With a more severe decline in GFR on his visit to       examined to help explain these unanticipated ®ndings.
the ER (higher plasma creatinine and BUN, Table 1),
there might now be a lower delivery of Kq and a need         Acknowledgements. We are extremely grateful to Dr S. Cheema-
                                                             Dhadli and Dr Kamel S. Kamel for very helpful discussions
for more secretion of Kq in his CCD to excrete the           and suggestions during the preparation of this manuscript. We
daily Kq load.                                               are also indebted to Stella Tang and Chee Kiong Chong for
   Because the patient could achieve a urine osmolal-        expert technical assistance, and to Jolly Mangat for outstanding
ity of 710 mOsmukg H2O on his visit to the ER,               secretarial assistance.
the basis for the lower initial medullary interstitial
osmolality was reversible. Although downregulation of
aquaporin (AQP)-2 water channels in the MCD might            Appendix
be a partial explanation for a low urine osmolality
w14x, another possibility is that a more severe degree
                                                             Hyponatraemia may cause a lower osmolality of the
of hyponatraemia diminished the osmolality in the
                                                             medullary interstitial compartment
medullary interstitial compartment (see Appendix).
   A cationic substance in plasma could produce a            Our purpose was to explore whether a more severe
`frusemide-like' lesion if bound to the calcium receptor     degree of hyponatraemia might lead to an increased
on the basolateral surface of the medullary thick            delivery of Kq to the distal nephron. If more volume is
ascending limb of the LOH (mTAL) w15x (Figure 3).            delivered distally, more Kq will be delivered as well if
1284                                                                                        R. F. Gagnon and M. L. Halperin
there is little change in the luminal K concentration      in the mTAL with hyponatraemia, less Naq would
in ¯uid entering this portion of the nephron. It follows   be reabsorbed in the mTAL. It is interesting to
that when a smaller volume is reabsorbed in the            note that this patient's plasma Naq concentra-
LOH, a larger volume (and Kq) should be delivered          tion was 112 mmolul and his urine osmolality was
to the distal nephron. The main factor controlling         394 mOsmukg H2O on the ®rst admission and these
volume reabsorbed in the LOH (actually, its DtL, the       values rose to 121 mmolul and 710 mOsmukg H2O
water permeable segment) is the medullary interstitial     respectively, on the second admission (Table 1).
osmolality. This osmolality could be lower if either
more osmole-free water was reabsorbed from the
MCD anduor less Naq and ClÀ ions were reabsorbed
in the mTAL.                                               References
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                                                           Received for publication: 28.11.00
                                                           Accepted in revised form: 11.1.01

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