Pseudohypoaldosteronism Type II: History, Arguments, Answers, and Still Some Questions John K. Healy Hypertension. 2014;63:648-654; originally published online January 6, 2014; doi: 10.1161/HYPERTENSIONAHA.113.02187 Hypertension is published by the American Heart Association, 7272 Greenville Avenue, Dallas, TX 75231 Copyright © 2014 American Heart Association, Inc. All rights reserved. Print ISSN: 0194-911X. Online ISSN: 1524-4563

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Brief Review Pseudohypoaldosteronism Type II History, Arguments, Answers, and Still Some Questions John K. Healy • Online Data Supplement

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seudohypoaldosteronism type I (PHAI) is sometimes dominantly inherited and is characterized by mutations causing a near-absence of mineralocorticoid receptors in the kidneys.1 This leads to salt-wasting and hyperkalemia, despite increased aldosterone levels. It starts in infancy but eases toward adulthood. There is also a recessive form2 of PHAI that is more severe, associated with loss of function mutations of epithelial sodium (Na+) channels (ENaC) in the late distal tubules (DTs), the connecting tubule and collecting ducts, and also in other tissues expressing the ENaC. It starts in the newborn, with lifethreatening salt-wasting and hyperkalemia. Salt supplements of ≤45 g/d are required indefinitely, together with control of hyperkalemia. More than 100 cases of these forms of PHAI have by now been described. PHAII is also inherited, but can be sporadic, in which hyperkalemia despite a normal glomerular filtration rate is the cardinal presenting feature. There is also acidosis and a low plasma renin level and a high incidence of hypertension. Plasma aldosterone levels are low to mildly but inadequately increased. This disease was named PHAII by Schambelan et al,3 but it has also been known as Familial Hyperkalemia and Hypertension, Gordon Syndrome, and Chloride Shunt Syndrome. The first case was described in 1964 by Paver and Pauline.4 In 1968, their patient, a white man aged 18 years, came under my care. He had a plasma potassium (K+) of 8.2 mmol/L, a normal glomerular filtration rate, acidosis, and a blood pressure of 180/120 mm Hg.5 Although Paver and Pauline4 found that he had an extreme cold pressor response, we did not find it so in 1968, but meanwhile it may have been affected by treatment. Renal biopsy was normal. Plasma renin level was low, and plasma aldosterone was low normal. A 4-day balance study on a stable intake of 78 mmol/d of K+ showed a positive K+ balance of 113 mmol but only a 5-mmol positive balance of Na+. His renal K+ secretory ability was then stimulated with intravenous sodium sulfate (Na2SO4) on 2 occasions, which >90 minutes caused a negligible rise in urinary K+ output (UKV) when compared with the same test in 2 normal control subjects (Figure S1 in the online-only Data Supplement). After 90 minutes of Na2SO4 infusion, a dose of

acetazolamide intravenous caused a modest increase in UKV. The procedure was repeated twice after salt depletion and other stimuli to K+ secretion. Then UKV rose and approached, but did not equal the response of controls given this protocol (Figure S2). On the basis of the balance study and the Na2SO4 studies, we concluded that there was a primary defect in the patient’s distal nephron K+ secretion. By now, ≈100 to 200 cases similar to ours have arisen3–29 (Table S1), many dominantly inherited in large families. About the cause of hyperkalemia, 3 views have emerged: first, the possibility of directly reduced activity of the K+ secretory mechanism; second, there was a secondary deficiency in K+ secretion because of a lack of chloride (Cl–) reaching the ENaC; and third, there was a lack of Na+ reaching the ENaC for adequate exchange for K+ (Figure). With regard to possible direct suppression of K+ secretion, the DT capacity in this regard can be tested by infusion of the poorly reabsorbed anions (PRAN) sulfate or the more effective30 bicarbonate (HCO3–), which stimulates K+ secretion. PRAN increase the lumen negativity at the ENaC, while supplying copious Na+ ions that can diffuse down a chemical gradient into the cells, which in turn stimulates the basolateral Na+/K+ exchange with more K+ entry into principal cells.31 PRAN use is a practical test of DT K+ secretory capacity, primarily as a test of the ENaC. Emphasizing this, as will be seen below in genetics, upregulation of the ENaC in a mouse model of PHAII was associated with an exaggerated kaliuretic response to Na2SO4.32 A protocol for the use of PRAN has been provided by DeFronzo et al33 with control data from 5 normal subjects, but it has not always been used, many authors assuming that any increase in K+ secretion is a normal response. Some quantitation is needed. The degree of response to PRAN has been assessed by comparison with control subjects, in the absence of abnormal Na+ or K+ intakes or mineralocorticoid administration or other K+ stimulatory substances.5,7,20 The data provided reveal that the average maximum K+ excretion reached during Na2SO4 infusion in PHAII subjects relative to the average maximum control values was 18.2%5 and 51.2%.20 For NaHCO3 infusion, it was 46.0%7 and 66.7%20 of average maximum controls. Another author8 reported no change in urinary or plasma

Received August 5, 2013; first decision August 15, 2013; revision accepted December 11, 2013. From the Princess Alexandra Hospital Brisbane, Brisbane, Queensland, Australia; and Renal Unit, Royal Brisbane Hospital, Brisbane, Queensland, Australia. Current address: Emeritus Fellow, Wesley Hospital, Brisbane, Queensland, Australia. The online-only Data Supplement is available with this article at http://hyper.ahajournals.org/lookup/suppl/doi:10.1161/HYPERTENSIONAHA. 113.02187/-/DC1. Correspondence to John K. Healy, 3 Lytham St, Indooroopilly, Brisbane, Queensland 4068, Australia. E-mail [email protected] (Hypertension. 2014;63:648-654.) © 2014 American Heart Association, Inc. Hypertension is available at http://hyper.ahajournals.org

DOI: 10.1161/HYPERTENSIONAHA.113.02187

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Healy   Pseudohypoaldosteronism Type II   649 Figure. Theories about disturbances in Na+ and K+ handling in the distal tubule in pseudohypoaldosteronism type II (PHAII) as at the end of the 20th century before genetic revelations. Combinations of these theories are not excluded. Both increased Na+–Cl– cotransporter (NCC) activity (derived from the effect of thiazides) and mildly depressed function of the epithelial sodium (Na+) channels (ENaC; derived from the effect of poorly reabsorbed anions) are considered likely in all 3 theories. Normal: Relevant normal electrolyte handling in principal cells of the distal nephron. PHAII Theory 1: Depression of renal outer medullary K+ (ROMK) channels is proposed as the main reason for hyperkalemia. PHAII Theory 2: Increased Cl– reabsorption via the paracellular pathway results in less negativity at the ENaC, depression of which is proposed as the main cause of hyperkalemia. PHAII Theory 3: Increased NCC activity results in less Na+ reaching the ENaC for reabsorption, depression of which is proposed as the main cause of hyperkalemia. Thiazide inhibits the NCC.

K+ during a NaHCO3 infusion. As will be discussed below, we now know that there are 5 levels of severity of PHAII so that the response to PRAN may differ between individual cases. Given the hyperkalemia of these patients, one might have expected even a supranormal response to PRAN as seen below in the mouse model of PHAII.32 PRAN were used in 11 of the studies surveyed here and although some had a reduced kaliuretic response, in none was there a response greater than the normal controls.3,5,7–9,11–13,17,19,20 Therefore, given the hyperkalemia, these results indicate a mild degree of depression of ENaC function. This might have been expected to lead to a compensatory increase in activity of the major K+ secretory mechanism, the renal outer medullary K+ (ROMK) channels.34,35 This might imply that ROMK also was not functioning normally (Figure, Theory 1). Another factor that could have suppressed the K+ secretion, particularly ROMK,31 was the acidosis, which is known to be because of hyperkalemia in PHAII.5,7,11,12 If PHAII is reversed by drug treatment (thiazide) and the drug is stopped, the hyperkalemia returns in 10 days before a return of the acidosis at 17 days,8 indicating the primacy of the hyperkalemia. If the ENaC is compromised to a degree, this period without acidosis would provide ROMK with a window of opportunity to control the rising plasma K+; this clearly does not happen. DeFronzo et al33 studied K+ secretion in sickle cell disease that damages the renal papillae and the medulla. They found a negligible response in K+ secretion to PRAN, yet hyperkalemia did not occur (average plasma K+, 3.78±0.01 mmol/L). This difference from PHAII might be explained by the fact that although ROMK shares the late DT, the connecting tubule and the collecting duct sites with ENaC, functioning isoforms ROMK 2 and 3 are present as well in the whole of the distal convoluted tubule (DCT).34 Therefore, in sickle cell disease, these isoforms may have been intact in the DCT before the late DCT but perhaps not so in PHAII. PHAII and sickle cell disease cannot be compared pathologically, but these results reflect on the way the effects of PRAN are interpreted because they show that a negligible response in K+ secretion to PRAN is not obligatorily associated with hyperkalemia in humans.

Finally, Golbang et al26 (see below) have described a father and son with PHAII caused by a mutant gene shown by genetic testing to inhibit ROMK substantially. The second view of the cause of hyperkalemia in PHAII is that a Cl– shunt may play a role3 by increasing paracellular Cl– absorption in the early DT (Figure, Theory 2). Schambelan et al3 in 1981 showed that with mineralocorticoid pretreatment, intravenous Na2SO4 and NaHCO3 could both invoke an increase in K+ excretion in PHAII, but that intravenous sodium chloride (NaCl) was much less able to do so. They postulated that a Cl– shunt proximal to the ENaC would result in less Cl– delivery and thus less negativity at the ENaC, resulting in decreased K+ secretion. Support for this came from other authors12,19,20 and also from genetic studies (below) although mathematical modeling36 of the DCT and connecting tubule function has not demonstrated a need for a Cl– shunt to explain PHAII. The third concept (Figure, Theory 3) that excessive Na+ reabsorption occurs in a region before the ENaC was based on the effectiveness of thiazides in reversing the features of PHAII.6,10,14,27,37,38 This part of the DT was later found to be the site of the electroneutral thiazide-sensitive Na+–Cl– cotransporter (NCC).39 Excess salt retention at the NCC may cause hypertension in PHAII but is insufficient to lead to edema. In 1970, Gordon et al6 hypothesized that increased Na+ reabsorption before the distal nephron Na+/K+ exchange site would result in decreased Na+ delivery to that site and so suppression of K+ secretion. However, they did not test their theory in any of their cases6,14,18 by the use of PRAN. Others did so, as mentioned above, and in 3 controlled studies increased Na+ delivery with PRAN revealed a reduced kaliuretic response when compared with controls.5,7,20 In 1990, Gordon et al did find correction of hyperkalemia with a saline infusion in 2 patients with mild hyperkalemia with PHAII40 but only after 33 days of a low K+ diet (50 mmol K+/d), which could have affected results,41,42 and 12 days of severe Na+ restriction (10 mmol/d). Their protocol involved 2 L of normal saline in 2 hours with no normal controls, making the results difficult to interpret. Salt depletion in others’ studies caused a reduction,11,15 no change,4,9,10,12,21 or an increase17,37 in plasma K+.

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650   Hypertension   April 2014 Gordon et al6 also reported normalization of plasma K+ with 5 months of moderate (50 mmol/d) Na+ restriction, but this study was unsatisfactory because pre- and poststudy plasma K+ levels were not given, only a plasma K+ level of 5.2 mmol/L after a further week of severe Na+ restriction (10 mmol/d) at the end of the 5-month study. This study followed a year of investigation and possible treatment, and the plasma K+ at its start may not have been the same as at original presentation. Dietary K+ intake, which was not stated, may have been reduced and can have a marked effect on UKV in man41 and animals.42 As Perez et al43 and Sanjad et al11 point out, reduction of plasma K+ with salt restriction does not rule out a defect in K+ secretion. There is nevertheless convincing evidence in genetic studies (below), as well as from the effects of thiazides, that the NCC is causing increased salt absorption in PHAII, and this may decrease the supply of Na+ to the ENaC, reducing K+ secretion, but its relative role in PHAII is hard to assess. Therefore, we have evidence that all 3 of these hypotheses on the hyperkalemia might operate in PHAII, and although the author favors inhibition of ROMK as the most important, firm quantitation is not possible. It is generally agreed that hypertension in PHAII relates to NaCl retention. The hypertension is often severe but may be absent in ≈20% of cases,24,29 discussed later. However, a diagnostic problem arises in distinguishing the hypertension in PHAII from low renin hypertension. Low renin hypertension is characterized by a suppressed plasma renin and normal plasma aldosterone level, together with saltsensitive hypertension and possible relative volume expansion.44 Plasma K+ is usually normal, but levels of ≤5.3 mmol/L have been reported.45 There is a good response to thiazides. If PHAII is suspected, plasma K+ and blood pressure of all relatives may help. The obvious distinction clinically between low renin hypertension and PHAII should be the hyperkalemia of the latter, together with the acidosis. Upper normal value of plasma K+ for adults is 4.6 mmol/L, but for children is 5.6 mmol/L and for newborn infants is 5.7 mmol/L46 although many laboratories allow ≤5.0 mmol/L for adults. In 3 of the 27 studies of PHAII reported here, plasma K+ reached H) in the acidic motif of the WNK4 gene. Hypertension. 2005;46:295–300. 27. Proctor G, Linas S. Type 2 pseudohypoaldosteronism: new insights into renal potassium, sodium, and chloride handling. Am J Kidney Dis. 2006;48:674–693. 28. Mayan H. Melnikov S, Novikov I, Holtzmann EJ, Farfel Z. Familial hyperkalemia and hypertension: pathogenic insights based on lithium clearance. J Clin Endo & Meta. 2009;94:3010–3016. 29. Farfel A, Mayan H, Melnikov S, Holtzman EJ, Pinhas-Hamiel O, Farfel Z. Effect of age and affection status on blood pressure, serum potassium and stature in familial hyperkalaemia and hypertension. Nephrol Dial Transplant. 2011;26:1547–1553. 30. Carlisle EJ, Donnelly SM, Ethier JH, Quaggin SE, Kaiser UB, Vasuvattakul S, Kamel KS, Halperin ML. Modulation of the secretion of potassium by accompanying anions in humans. Kidney Int. 1991;39:1206–1212. 31. Giebisch G. Renal potassium transport: mechanisms and regulation. Am J Physiol. 1998;274(5 Pt 2):F817–F833. 32. Yang SS, Morimoto T, Rai T, Chiga M, Sohara E, Ohno M, Uchida K, Lin SH, Moriguchi T, Shibuya H, Kondo Y, Sasaki S, Uchida S. Molecular pathogenesis of pseudohypoaldosteronism type II: generation and analysis of a Wnk4(D561A/+) knockin mouse model. Cell Metab. 2007;5:331–344. 33. DeFronzo RA, Taufield PA, Black H, McPhedran P, Cooke CR. Impaired renal tubular potassium secretion in sickle cell disease. Ann Intern Med. 1979;90:310–316. 34. Boim MA, Ho K, Shuck ME, Bienkowski MJ, Block JH, Slightom JL, Yang Y, Brenner BM, Herbert SC. ROMK inwardly rectifying ­ ATP-sensitive K+ channel II. Cloning and distribution of alternative forms. Am J Physiol Ren FL & Electrol Physiol. 1995;268:F1132–F1140. 35. Kohda Y, Ding W, Phan E, Housini I, Wang J, Star RA, Huang CL. Localization of the ROMK potassium channel to the apical membrane of distal nephron in rat kidney. Kidney Int. 1998;54:1214–1223.

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Correction In the Hypertension article by Healy (Healy JK. Pseudohypoaldosteronism Type II: History, Arguments, Answers, and Still Some Questions. Hypertension. 2014;63:648–654), several corrections were needed. 1. On page 651, first column, in the third paragraph, the first sentence read, “Further work was done by Chiga et al66 with mice triple knocked-in for the same Wnk D564A mutation....” It has been changed to read, “Further work was done by Chiga et al66 with mice triple knocked-in for the same Wnk D561A mutation….” The publisher apologizes for the error. 2. On page 651, first column, in the fifth paragraph, the first 2 sentences read, “In another example, Ohta et al67 developed mice hypomorphic for Wnk. These Wnk hypomorphs exhibited salt- sensitive hypotension.” They have been changed to read, “In another example, Ohta et al67 developed mice hypomorphic for Wnk4. These Wnk4 hypomorphs exhibited salt-sensitive hypotension.” The author apologizes for the error. These corrections have been made to the current online version of the article, which is available at http://hyper.ahajournals.org/content/63/4/648.full.

(Hypertension. 2014;63:e174.) © 2014 American Heart Association, Inc. Hypertension is available at http://hyper.ahajournals.org

DOI: 10.1161/HYP.0000000000000009

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             PSEUDOHYPOALDOSTERONISM TYPE II:   HISTORY, ARGUMENTS, ANSWERS, AND STILL SOME QUESTIONS    John K Healy                                              Short  title: Pseudohypoaldosteronism Type II        Dr.  J  K  Healy  MB  BS  (Hons)  (FRACP)  is  a  former  LIONS  Renal  Research  Fellow,  Princess  Alexandra  Hospital  Brisbane  and,  Consultant  Nephrologist,  Renal  Unit,  Royal  Brisbane  Hospital (retrd.)                                        e‐Mail:   [email protected]   Word Count: Manuscript 4352; figure 719; references 2244; total 7316.  Mail address: Dr J.K.Healy, 3 Lytham St., Indooroopilly, QLD. 4068, Australia     Key Words: pseudohypoaldosteronism type II; mutations; hypertension;  hyperkalemia; thiazides; vasopressin      

Data Supplement On‐line for HYPE201302187  1. Abstract.   In the search for the basis of essential hypertension, rare genetic disorders have been studied. 

Pseudohypoaldosteronism is an example. There are two types: Type I is outlined, and Type II  fully reviewed. Type II is characterized by marked hyperkalemia in spite of a normal  glomerular filtration rate, low renin levels and usually hypertension. Differentiation from  low renin hypertension is discussed. The hyperkalemia in pseudohypoaldosteronism Type II    may be due to direct inhibition of distal tubular potassium secretory mechanisms, or to  indirect inhibition of epithelial sodium channels from lack of chloride or sodium reaching  them. There is clinical and genetic evidence for all three theories, but their relative  contributions are not established. Genetic evidence confirms over‐activity of the thiazide‐ sensitive sodium chloride co‐transporter, explaining the therapeutic efficacy of this drug.  Inheritance of this condition is usually dominant, occasionally recessive. Five levels of  severity have been found. In some patients vasopressin has resolved the hyperkalemia.  Thiazide causes mild chronic hypovolemia, which might raise the vasopressin level. This  could be a factor in the response of the hyperkalemia to thiazides, as vasopressin is known  to directly stimulate potassium secretion.   2. How acetazolamide stimulates K+ secretion.  Acutely, acetazolamide decreases proximal tubular bicarbonate absorption, thus increasing  bicarbonate delivery to the distal tubule causing increased K+ secretion.  3. The K+‐Cl‐ co‐transporter.  Poorly reabsorbed anions, sulphate and bicarbonate (PRAN), can be used to stimulate K+  secretion. An unexpected factor has arisen in the response to PRAN from micro‐puncture  studies by Amorim et al.1, in which some K+ secretion remained after the lumen negativity  was collapsed by amiloride.  An electro‐neutral K+‐CL‐ co‐transporter was proposed as an  explanation. However, from a physiological viewpoint, this transporter would only be  operative in patients on a low salt diet or with a metabolic alkalosis, so PRAN can be used as  a test of K+ secretion in PHAII in patients on a normal diet with acidosis.   4. PPARγ  In relation to hypertension, some comments were made regarding this relatively new topic.  A recent report showing that dominant negative (DN) mutation in the nuclear hormone  receptor peroxisome proliferator‐activated receptor gamma (PPARγ) cause hypertension.  DN PPARγ increases Rho‐A and Rho‐kinase activity which increase vascular tone. Their  inhibitors decrease tone. These authors also found that cullin‐3 correlated with increased  Rho‐A levels, but their suggestion that cullin‐3 regulates arterial pressure needs further 

confirmation, notably with direct evidence from manipulation of cullin‐3. If so, it could lead  to an interesting association with CUL‐3 mutations2.     References.  1. Amorim JBO, Bailey MA, Musa‐Aziz R,Giebisch G. Role of luminal anion and pH in distal  tubule potassium secretion. Am J Physiol. 2003:284:F381‐F388.   2. Pelham CJ, Ketsawatsomkrom P, Groh S, Grobe JL,de Lange WJ, Iveawuchi SC, Keen HL,  Weatherford ET, Faraci FM, Sigmund CD. Cullin‐3 regulates vascular smooth muscle function  and arterial blood pressure via PPARamma and Rho‐A/Rho‐kinase. Cell Metab.2012;16:462‐ 472. 

Plasma   Aldosterone 

Response to  thiazides 

Plasma   volume  

Blood volume  ml/m2 S.A. 

ECF volume  ml/m2 S.A. 

Total body   ENa+ 

Total body  K+   mmol/kg  B.W.or total 

Urinary Ca2  (stone) 

180/ 120 

++ 

116 



L N. 

+++ 

‐ 

‐ 

‐ 

‐ 

43.5 







23 

S  6.0 

113 

21 

136/ 82 

‐ 

146 







‐ 

‐ 

‐ 

‐ 

‐ 







10 

S  8.5 

117 

14 

160/ 110 

++ 

100 



‐ 

++ 

‐ 

‐ 

‐ 

‐ 

‐ 

‐ 





11 

S  7.3 

114 

16 

110/ 70 

‐ 



‐ 

‐ 

+++ 

‐ 

‐ 

‐ 

‐ 

50.0 

‐ 







S  6.2 

111

18

105/ 65



106



L N 

++











ST



52 

F  6.2 

110

23

200/ 100



130

L



















(4)  1  1 

20 

S  6.6 

109 

20 

220/ 95 

‐ 

130 



L N  

+++ 

‐ 

‐ 

3220

4177 

‐ 





13 

S  8.6 

105 

14 

240/ 140 

‐ 

133 



‐ 



31.8 *  ‐ 

‐ 

‐ 

‐ 

‐ 





26 

F  6.9 

112 

19 

120/ 72 

‐ 

130 





++ 

‐ 

‐ 

‐ 

‐ 

‐ 





(5)  1  1 

22 

S  6.3 

106 

20 

160/ 110 

‐ 

131 





++ 

‐ 

‐ 

‐ 

‐ 

‐ 

‐ 





48 

S  7.0 

116 

21 

176/ 130 

‐ 

L N 

L N 

++ 

‐ 

‐ 

‐ 

‐ 

‐ 

‐ 





15 

S  7.4 

112 

18 

240/ 140 

‐ 

85‐ 100  N 



‐ 

+++ 

46.3

‐ 

‐ 

‐ 

‐ 

‐ 

Plasma  Renin 

20 

GFR ml/min 

109 

Cold Pressor  Response 

S  8.2 

BP mmHg 

15 

P.HCO2— mmol/l 



P.Cl—mmol/l 

Fam/ Sporadic 



P.K+ mmol/l 

Age 

10    11    12    13    14    15 

# of subjects 

4,5    3    6    7    8    9 

Male/Female 

Reference # 

TABLE S1. Characteristics of Patients in 25 Reports of Pseudohypoaldosteronism Type II. 

16    17    18 a    18b    19    20a    20b    20c    21a    21b    21c    22    23    24    25 









++

++

*  54.0 *  ‐











L N 

‐ 

‐ 

‐ 

‐ 

‐ 

‐ 

‐ 



L N  

‐ 

‐ 

‐ 

‐ 

‐ 

‐ 

‐ 

109 





++ 

‐ 

‐ 

‐ 

‐ 

‐ 

++ 

‐ 

78 





‐ 

‐ 

‐ 

‐ 

‐ 

‐ 

‐ 

166/ 104 

‐ 

90 





+++ 

‐ 

‐ 

‐ 

‐ 

‐ 

‐ 

19 

140/ 100 

‐ 

90 





‐ 

‐ 

‐ 

‐ 

‐ 

‐ 

‐ 

116 

18 

150/ 100 

‐ 

105 





++ 

‐ 

‐ 

F  6.1 

107

18

160/ 100



95

L

L N 

++





33 

F  6.0 

110

18

140/ 100



108





++







26 

S  6.6 

115 

19 

180/ 100 

‐ 

91 

L N 



++ 

‐ 

‐ 





40 

F  6.0 

‐ 

21 

190/115 

‐ 

95 



L N 

++ 

‐ 

‐ 

‐ 

‐ 

 

M  F  F 

8  9  1 

13‐  F  5.7  71  41  S  6.0 

107 

25 

146/ 89 

‐ 

‐ 



L N 

‐ 

‐ 

‐ 

‐ 

‐ 

‐ 

ST  ++  ‐ 



‐ 

160/ 95 

‐ 







‐ 

‐ 

‐ 

‐ 

‐ 

‐ 

‐ 





14 

S  7.9 

117

15

160/ 110



119

L



++





13 

S  6.8 

113

18

106/ 64



103

L







40 

F  6.7 

119 

‐ 



++ 

‐ 







38 

F  7.7 

‐ 

‐ 

160/ 100 

++ 

‐ 







S  6.7 

109 

17 

100/ 65 

‐ 



50 

F  6.8 

114 

17 

150/ 90 



(5)  1  1 

24 

F  8.1 

115 

21 





21 

F  7.6 

114 





39 

F  6.0 





43 







1130 1753

9500 

1286 +‐  1170 1955 9879 1375 +  1062 1809 10157 1371 +  ‐  ‐  ‐  ‐ 

  26a  M  1  26  F  8.2  119 16 150/ 95 ‐ ‐ L L N  ++ ‐ ‐ ‐ ‐ ‐ ‐   26b  M  1  4  F  6.7  110 13 100/ 60 ‐ N L L  ++ ‐ ‐ ‐ ‐ ‐ ‐   27  M  1  28  S  8.2  108  22  140/ 88  ‐  N  L  N  ‐  ‐  ‐  ‐  ‐  ‐  ‐    F=familial, S=sporadic; cold pressor response ++=increased; plasma renin and aldosterone not numerical due to varying methodologies, L=low,  N=normal, H=high; plasma volume *=ml/kg BW, otherwise ml/m2 SA on normal salt intake; ENa=total body exchangeable Na, mmol/kg BW,  except reference 21 where mmol/m2 SA. In reference 24 average results given. ST = renal stone former. ++ = hypercalciuria.    References 28 & 29 (omitted) involve varying average figures. 

 

  Figure S1. 

The effect of IV sodium sulphate for 90 minutes, then an injection of  acetazolamide (Diamox) IV, on urinary K+ excretion.  Performed on two  occasions in patient and in two separate control subjects. Time periods 30‐40  minutes.  

   

 

  Figure S2. 

The effect of IV sodium sulphate for 90 minutes, then an injection of  acetazolamide performed twice on the patient after 3 days of NaCl restriction  (30 mmol/day), ethacrynic acid, and 9α fluorohydrocortisone. Two control  subjects were given the same protocol. Time periods 30‐40 minutes. 

 

 

  Figure S3.  The effect of thiazide on Na+ and K+ homeostasis in PHA II. Acutely there is  significant fluid loss and plasma vasopressin very likely increases but even in long‐term use,  mild hypovolemia persists and plasma vasopressin might be elevated. 

Pseudohypoaldosteronism type II: history, arguments, answers, and still some questions.

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