Disturbances of Na/K Balance

Pseudohypoaldosteronism (PHA) is a heterogenous syndrome resulting from the inability for aldosterone to produce one of its physiologic effects, namely the promotion of potassium and hydrogen secretion. It is thus characterized by three essential features: (1) hyperkalemia, (2) metabolic acidosis, and (3) abnormally elevated plasma aldosterone concentrations. It has been classified by Kuhnle (1) into three distinct diseases or types (Table 1).Table 1: The three types of pseudohypoaldosteronismaType I PHA Type I PHA is characterized by early and severe manifestations of salt-wasting, life-threatening hyperkalemia, metabolic acidosis, dehydration, and activation of the renin-angiotensin-aldosterone system (RAAS) associated with normal adrenal function. Plasma aldosterone concentrations are elevated, as is plasma renin activity, thus demonstrating the peripheral resistance of target tissues to these hormones. Treatment by the potent mineralocorticoid fludrocortisone is without effect. Salt supplementation alone is sufficient to compensate for sodium wasting. Type I PHA is heterogeneous and was divided into at least two entities on the basis of inheritance and phenotype of the disease (2). The identification of two distinct genetic defects strengthened this subdivision. Type II PHA PHA II is also known as familial hyperkalemia and hypertension or Gordon syndrome (3,4). The classification of this heterogeneous syndrome as PHA is, however, controversial because plasma aldosterone concentrations are highly variable, usually almost normal, and patients respond adequately to mineralocorticoid hormone (5). The hallmarks of PHA II are hypertension, hyperkalemia, and correction of these abnormalities by low doses of thiazide diuretics (6). Mild hyperchloremia, metabolic acidosis, and suppressed plasma renin activity are also associated with the syndrome. The GFR and adrenal function are normal. An autosomal dominant inheritance has been reported in these families. Three loci were linked to the disease, demonstrating the genetic heterogeneity of the syndrome, which underscores the heterogeneity of the clinical phenotype. Moreover, additional pedigrees with PHA II could not be linked to these loci, implying a wider genetic heterogeneity of the syndrome (7). One locus is on chromosome 1 (8); a second locus is on chromosome 12 (6); the third is on chromosome 17 (6). Interestingly, this latter locus overlaps with a syntenic segment of rat chromosome 10 that contains a BP quantitative trait locus (8). Online Mendelian Inheritance in Man (OMIM) proposes to symbolize the chromosome 1q31-q42 locus involved in type II PHA as PHA2A, the chromosome 17p11-q21 locus as PHA2B, and the locus on chromosome 12p13 by PHA2C. Thanks to the study of a large PHA II kindred, the molecular basis of the syndrome was recently elucidated (9). Mutations or deletions in two members of the WNK serine-threonine kinase family (WNK1 and WNK4) were identified. The precise pathogenic mechanisms by which these mutations or deletions lead to the PHA II phenotype are not yet understood. The deletions (22 and 41 kb) of the intron 1 of the WNK1 gene lead to fivefold overexpression of the WNK1 transcript in leukocytes of affected patients. The WNK1 protein was localized in the cytoplasm of the cells bordering the distal convoluted tubule (DCT), the cortical collecting duct (CC,D) and the medullary collecting duct. Four missense mutations of the WNK4 gene involve a highly conserved coil-coiled region of the protein. Interestingly, the WNK4 protein is expressed both in cytoplasm and at intercellular junctions in the CCD and exclusively in the tight junction complex in the DCT. Further studies are needed for a better understanding of the pathogenesis of this syndrome. Type III PHA Type III PHA is transient and secondary to different pathologies related to kidneys or other organs (Table 1). Rare cases of major intestinal resection (10) or sweat gland dysfunction associated with excessive loss of sodium (11) have been described as leading to PHA III. However, renal causes are encountered more frequently. Nephropathies such as obstructive uropathy (12) or urinary tract infections (13) were reported as causes of transient aldosterone resistance (1). The main characteristic of this type of PHA is a decreased GFR. The mechanism of the renal aldosterone resistance is not well understood, but a relationship between the increase in amounts of transforming growth factor–β (TGF-β) produced in inflammatory states and the known inhibitory effect of TGF-β on the sensitivity of the collecting duct to aldosterone has been suggested (5,14). PHA-1 and PHA III share common features and are primarily salt-losing syndromes. PHA II is a salt-retaining syndrome with a hypertensive phenotype. As discussed below, we propose to abandon this classification and restrict the discussion to PHA as a salt-losing syndrome with strong activation of RAAS. In this review, we will focus on PHA-1, and we will discuss the molecular basis of the disease in describing the relevant molecular mechanisms that allow mineralocorticoid-dependent Na/K balance that takes place in CCD. We will then discuss the genetic basis of the two forms of PHA-1 in an attempt to understand the pathogenic mechanisms of the disease. Sodium and Potassium Balance: Aldosterone Control The final concentration of sodium and potassium in urine is determined during its passage through the collecting duct; this process is mainly controlled by aldosterone (15). In the collecting duct, sodium is reabsorbed from the urinary lumen into the extracellular compartment through a tight epithelium formed by principal and intercalated cells. Aldosterone-dependent, amiloride-sensitive electrogenic sodium transport takes place in the principal cell and is generated by the selective entry of sodium trough an epithelial sodium channel (ENaC) located at the apical membrane. Sodium is then actively extruded out of the cell by the sodium pump or to the membrane. electrogenic sodium transport is the for the of potassium through a selective potassium channel at the apical with The of the mechanism of aldosterone in tight proposes the aldosterone the plasma and to its the mineralocorticoid or and are from by of plasma or to the of which the into an that is to to or The complex is to the with the region of target or or or an increase in sodium are produced by the activation of transport (15). We will discuss and as the two in aldosterone that are in PHA-1 and the main features relevant to understand the of the disease. of have recently been in this We will essential features of the and the function of the mineralocorticoid that are to understand the of are two types of the type 1 or mineralocorticoid and the type or which are highly The hormone in to with a that is to that of the mineralocorticoid hormone aldosterone aldosterone to the with a that is to that of of the and mineralocorticoid the of and of common and a of in with the of the The gene a protein of with a molecular of and are the and The contains the which is involved in The the or which is for and of the It of two and the highly conserved of the which the or also contains that are involved in and with The of different is known The has not yet been but has been on the basis of the and the for on the relationship of the and on the for or to an the a major of are for and have been by and by the of a leading to a a severe hypertensive phenotype in of is a for to in the region of the target In aldosterone target is with and has been that with more in the physiologic to or but the in of the to be Sodium (ENaC) is characterized by a for sodium a low and and a for the diuretics and The for were by for are members of the family that involved in epithelial sodium or for and is a protein of three and three share at the and the with two and and a large extracellular to of the protein three are expressed in the to a The of the is Four or were for for a related of the gene the sodium channel in has been of in the three are and in the not have the function. alone in the the but amiloride-sensitive sodium alone are to or are in the the sodium and of but with a in the of the In with and but amiloride-sensitive sodium are to of with a to with a between the of channel at the and the expressed in the cell for and alone with could be on with or studies have that the a in the of the channel to the cell or in its to the with and to with and has been in expressed in the with and an and to sodium with with the The sensitivity is and of sodium is The is mainly expressed in the and to in the was in and of epithelial sodium channel in the were with or and were by a In the the to the are for the In the of a for the to of the channel for In the a highly conserved region the is involved in the of the channel The of this on is not between of the region is the of that these on the and be and are the of the reported that a on the rat could a in the of the the was reported to be involved in channel as for the The extracellular is the of the by different in with the or the which are by one It contains and are also in the contains and that between 1 and in the and and 12 in the second are for channel to the cell membrane. an in the extracellular but its is by and the of the in the and the mutations that the sensitivity on the three recently the molecular of the and a of the of the The contains involved in the of the of at the cell is on three but not on the or missense of this on the and are in patients affected by the syndrome, its in channel In syndrome, the channel is because of two an of at the cell and an activity of that the is the target of a which to the through its The the of and its In syndrome, this between and the of the and is and this to a of at the cell for An for the of the of at the cell was out by propose that the a as of is and but not were to be on the of and in the channel were expressed in cells In these aldosterone and of the and but not the However, the are not yet and the not a in the of the that a was involved in the with an of the could a in the of the channel at the cell and of three are expressed in the main target cells or namely the of the in the in the distal in the of and sweat and in the could be expressed the However, in one or two are leading to the of the channel and physiologic function. In the the alone is as well as in the and the In the the was in different but its function In the the is alone as as aldosterone concentrations are low and and are The is expressed in the and are in the rat in and in the urinary of the rat could a in In the three are expressed in and sodium transport through and that be involved in cell in the is by as well as by extracellular or activity by and for concentration of sodium by a mechanism is in expressed in the but this is understood. low has a inhibitory as by the on have been in the of In the was to increase activity and the of at the cell this effect is by the of could also a in function. and were reported to function. sodium concentrations have been described to by and the by an extracellular but the molecular mechanisms of effect have not yet been and Sodium in The of to the that a of hypertension, namely the syndrome, was by mutations the in the of the or the a syndrome in PHA-1, was also to be by genetic defects in the three for the the of in and that or mutations could on the and lead to of in tight of of extracellular and BP has a of and out and its as involved in sensitivity and resistance Pseudohypoaldosteronism Type 1 Type 1 PHA dominant of inheritance is associated with a renal phenotype characterized by salt-wasting, hyperkalemia, and metabolic It has a and are of such and mutations in the gene for the mineralocorticoid or leading to a mineralocorticoid a missense in a family with autosomal dominant PHA-1 to a of the function. an in a of renal PHA-1, leading to a from to for the Interestingly, one described by and the of are that cases could be in the is the that one of the mineralocorticoid is sufficient to lead to the renal phenotype. for the mineralocorticoid and a renal phenotype with a severe dehydration, and a 10 severe phenotype is not in at could be by the a of of these with this and with as in is the the is to sodium and in is to compensate the renal In that in of the in the between and could the Type 1 PHA The of type I PHA as an autosomal is characterized by a renal phenotype as in the renal autosomal dominant However, is In other organs kidneys defects in and this is the this is abnormalities were described as infections or which are characterized by and are but and and were in the of the in PHA-1 patients and an of more the normal. that the could lumen that thus the phenotype. The of in the of these patients from an of electrogenic sodium transport as by of the Interestingly, was associated with this of PHA-1 patients are with normal of syndrome has been associated to However, features of this are with an the was a and is well that are more to syndrome without a genetic well and to a mineralocorticoid which is an for phenotype and of the were not The was not the in a affected by a of and the of an amiloride-sensitive mutations were on for but the is affected by the of in PHA could from in other was described and with with cases reported with or were associated with the of The of other and with the syndrome are not yet the other of in tissues or that other clinical have to be or One also of to plasma aldosterone in the of plasma aldosterone has been associated with but is this to the effect of aldosterone or to BP which Mutations and the Type I PHA PHA-1 was linked to chromosome and in three mutations in from (Table were from and have the of the of on the to a at in the extracellular of the a the second and the missense in a highly conserved in the of the genetic heterogeneity of was by the of a on the leading to that in a protein or into the of conserved by a one mutations were described by different of are on the thus the of this in the function of mutations of the syndrome were in the of the and mutations the autosomal of mutations on the for the were reported in PHA-1 more in the of the trait In these PHA-1 patients not autosomal but also as is the we to the associated to as the and not the autosomal also reported on the for and suggested that could be related to type I PHA associated with in the gene for the mineralocorticoid on that not lead to a but associated with on other could be of a excessive and a on the region of the which was associated to in a large The was associated with an in BP and with a of In a in and that the was associated with a of the activity of with the the of in the region of to However, the clinical of the patients the were not and we are not have a a aldosterone concentration or other features of PHA-1 patients reported in the have not been that not cases of PHA-1 are to mutations of In the of mutations were on of In the of was in of of the of cases of PHA-1 could be the of a low sensitivity of the for the or could from mutations of the or of that were by the we could mutations on or the mineralocorticoid from the mineralocorticoid to for the involved in the of could be and for PHA-1 or Further studies will in this in of the PHA-1 mutations were in (Table is the but cell or have been will focus on by of in different Mutations in the on the the mutations for syndrome are on the and of the mutations in patients affected by PHA-1 are on the gene for the (Table the of the in the channel Mutations of the are mainly or In two missense mutations were one is and the other is a associated with a on the other mutations the and lead to and The effect of mutations on is The of are not and are produced the of are decreased and are In PHA-1 studies on were reported the of the and the of a activity of the protein. clinical has a sufficient to the of a in the function be in the of the in the were in that system (Table We the described by with and rat and the to amiloride-sensitive of the however, from with and and mutations were recently in the system and to and of the activity, We were by such a activity, the second of the the channel is We that the is with and and that three are at the cell to a The of the of these expressed in the was to the decreased of at the cell was by the channel which was was the that channel activity was expressed a and has the as the that could have a by these that of an of one of the more of the activity could be in the activity could be of in the at the of and the of syndrome at The missense was in a The to the of the extracellular The of the extracellular is the of two of the the extracellular are conserved from different that are involved in these by and the as a of a of essential for the channel to the plasma membrane. these a at the on the rat in the that the is of the at and of the at The of was in the The is also were at the to a of the amiloride-sensitive by at the The of this the of these of the extracellular in the of the protein and in the to the plasma membrane. three mutations in patients (Table One of these mutations is by a common for these PHA-1 patients. One missense is of for two the is a missense in the second to in and this latter was by that this is the of the of the in the channel is and potassium were in a of the channel was in the was to the inability of the channel to to the as by a and this is of because was to be associated with the was described by and was in of a normal with essential hypertension was and increase in amiloride-sensitive was of the into However, an increase in the activity of the rat We not the of the from channel in of the in the system to be However, is to the in PHA-1 patients with by a of the in between and will or could be to a activity to or to the activity of the with and for the were by that the of the of the in the were to have and which between to were to be normal for which and with The of the was in the with or thus the of the as amiloride-sensitive of activity was in that is in the for amiloride-sensitive electrogenic sodium also of associated with a in function in the that is not to the but also to resulting from to to have more activity in PHA-1 in a of PHA-1 patients different mutations on and three were not but the was to of the normal and of not the Moreover, a with mutations of the a that of a normal and this one was not affected by that with of the have almost more activity in as by the leading to an and to the characteristic that or with and a in the However, the activity of the be sufficient to at of the phenotype of and of a in which the for the was not are also to that to a activity in the but without syndrome. these that a low amiloride-sensitive sodium is sufficient to of at and of the mutations on the also be through the study of the that in of the protein was described in a cell and in a loss of channel activity expressed in the two other in resulting from the of in the junction of and and to a of the at or to of in the extracellular the was in the with and amiloride-sensitive could be In the reported the of an and a of this that a protein. In rat two and were reported both of are to the protein. Interestingly, the was at the cell as determined by a on but amiloride-sensitive could be in However, the physiologic function of these is not yet in but is suggested that could a in a has been that in the region of the In the with and amiloride-sensitive were of with the The and the were and was a in the of of the protein at the that the in the of the and rat a in the of the activity of expressed of the leading to in a cell in an at the junction of III and from in the of an leading to a and a protein from the rat and lead to a of the at the junction between and as a of an in the these that mutations of the in PHA-1 patients lead to a of However, a for activity is encountered in the different a activity, and a in salt-wasting, hyperkalemia, metabolic acidosis, and The is more to a decreased activity, and the of the in a phenotype in the but not in were in patients with severe of the Mutations in the mutations were described in the The is a missense a highly conserved in a the segment clinical of the that are The at clinical of PHA-1 was with plasma aldosterone concentration was at the of the normal and the was In this a PHA-1, but we are not of the clinical of this The phenotype was by the in the The in amiloride-sensitive is a between the activity associated with a PHA-1 phenotype and the are of We have for that In for an the decreased function to that that the is with and and that the of at the was with Moreover, the was by the The suggested that a in the the in the and thus this as the of the However, the of this for the of the channel to be variable, on the the is on the the function is to The on the to a activity of more the is mainly by the and a missense in that to lead to a more phenotype the one on the the Interestingly, an to was in a gene of the family involved in the of the to a of that gene and a thus the of the mechanism of of through the mutations and were in a described by the phenotype and the reported in are to the in the extracellular of the and the of the protein. in a of the the activity could be to which were to have the as the channel in the is of the 1). are in that of hyperkalemia and metabolic acidosis, that the is essential for the function in In to not of and not an but increase in was but was the increase reported for is is that the phenotype is in the the these the phenotype is the as in other patients affected by the PHA-1 with mutations on the for However, the phenotype is not to from this Mutations in the reported a on the in three families. the the third of with the of two to two with three highly conserved by a one or a from to recently reported a of type mutations of the were The a in at the leading to a from this to the is and The a of the of on of the the could the that the in the the the function of these mutations of the in a the mutations the a activity be to in to of the channel 1). are different or rat are have the sensitivity and the for potassium or sodium as the rat are to and are more selective between sodium and with the rat is also We have for these but were also with and the PHA-1 channel The of hyperkalemia, metabolic acidosis, and phenotype that three are needed for a at least in the as have a renal phenotype. a but of the but syndrome, by to of the a by by to activity could be to or to a function of the associated to and In PHA-1 patients a we are not of but phenotype were not the of mutations to a heterogeneity of clinical (Table the PHA-1 or is between mutations on the or between patients the missense on the known to by the activity of the channel with the almost the and leading to a are to because we have reported patients with clinical and The be on that better the in PHA-1 patients and for and be of the of a of the clinical phenotype. In could be from the discussed and clinical could the of the of a or its function in a system such as the are also not as of the as we could as by the The by a of in the which out to be also in and The of the molecular mechanisms of type 1 a clinical the of this heterogeneous syndrome into two main the renal autosomal dominant and the autosomal the of has genetic studies that have in the identification of as for the syndrome, the phenotype of affected by autosomal PHA-1 were and mutations were on the three for these mutations were in such as or that lead to a in The between and not PHA-1 patients have for disease. Salt is not sufficient to the loss to the disease, and Moreover, the of of these patients is to better understand the disease and be In that an syndrome be to the of mutations linked to these It and phenotype and to the Moreover, the of for to in of patients affected by one of these is the in a better of these is the of a of the of the of is by a of the and We and for of the