Acidosis Tubular Review

8/7/2019 Acidosis Tubular Review

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Abstract The diagnosis and classification of renal tubu-lar acidosis (RTA) have traditionally been made on thebasis of functional studies. On these grounds, RTA has

been separated into three main categories: (1) proximalRTA, or type 2; (2) distal RTA, or type 1; and (3) hyper-kalemic RTA, or type 4. In recent years significant ad-vances have been made in our understanding of the sub-cellular mechanisms involved in renal bicarbonate(HCO3

) and H+ transport. Application of molecular bi-ology techniques has also opened a completely new per-spective to the understanding of the pathophysiology ofinherited cases of RTA. Mutations in the gene SLC4A4,encoding Na+-HCO3

cotransporter (NBC-1), have beenfound in proximal RTA with ocular abnormalities; in thegene SLC4A1, encoding Cl-HCO3

exchanger (AE1), inautosomal dominant distal RTA; in the gene ATP6B1,encoding B1 subunit of H+-ATPase, in autosomal reces-sive distal RTA with sensorineural deafness; and in thegene CA2, encoding carbonic anhydrase II, in autosomalrecessive osteopetrosis. Syndromes of aldosterone resis-tance have been also characterized molecularly and mu-tations in the gene MLR, encoding mineralocorticoid re-ceptor, and in the genes SNCC1A, SNCC1B, andSCNN1G, encoding subunits of the epithelial Na+ chan-nel, have been found in dominant and recessive forms ofpseudohypoaldosteronism type 1, respectively. It can beconcluded that, although functional studies are still nec-essary, a new molecular era in the understanding of dis-orders of renal acidification has arrived.

Key words Renal tubular acidosis Pseudohypoaldosteronism H+-ATPase NBC-1 AE1 Carbonic anhydrase Mineralocorticoid receptor

Epithelial Na+

channel

Introduction

To date classification of renal tubular acidosis (RTA) hasbeen exclusively based on clinical and functional stud-ies. On these grounds RTA has been separated into threemain categories: (1) proximal RTA, or type 2; (2) distalRTA, or type 1; and (3) hyperkalemic RTA, or type 4 [1,2, 3]. In the past few years the rapidly expanding knowl-edge about the molecular abnormalities involved in thedisturbed bicarbonate (HCO3

) and H+ transport in thesepatients has opened a completely new perspective for theunderstanding of the pathophysiology of this entity. Al-though RTA may occur in a number of etiologies, bothinherited and acquired, in this review we shall limit com-ments to the molecular biology of the primary forms ofRTA (Table 1).

Physiology of renal acidification

Renal acid-base homeostasis may be broadly divided in-to two processes: (1) reabsorption of filtered HCO3

,which occurs fundamentally in the proximal convolutedtubule, and (2) excretion of fixed acids through the titra-tion of urinary buffers and the excretion of ammonium,which takes place primarily in the distal nephron.

Proximal HCO3 reabsorption

The mechanisms for proximal reabsorption of about80%90% of filtered HCO3

are shown in Fig. 1 [4]. Theforemost processes occurring in this segment are H+ se-cretion at the luminal membrane via a specific Na+-H+

exchanger (NHE-3) and HCO3 transport at the basolat-

J. Rodrguez-Soriano ()Department of Pediatrics, Hospital de Cruces, Plaza de Cruces s/n,Baracaldo, 48903 Vizcaya, Spaine-mail: [email protected].: +34-94-6006357, Fax: +34-94-6006044/+34-94-4850148

J. Rodrguez-SorianoDivision of Pediatric Nephrology, Department of Pediatrics,Hospital de Cruces and Basque University School of Medicine,Bilbao, Pas Vasco, Spain

Pediatr Nephrol (2000) 14:11211136 IPNA 2000

I N V I T E D R E V I E W

Juan Rodrguez-Soriano

New insights into the pathogenesis of renal tubular acidosis

from functional to molecular studies

Received: 10 February 2000 / Revised: 7 April 2000 / Accepted: 7 April 2000


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eral membrane via a Na+-HCO3 cotransporter (NBC-1).

In the proximal tubules, carbonic acid (H2CO3) is formedwithin the cell by the hydration of CO2, a reaction cata-lyzed by a soluble cytoplasmic carbonic anhydrase (CAII). The H

2CO

3ionizes and the H+ is secreted in ex-

change for luminal Na+. This mechanism is electroneu-tral, driven by a lumen-to-cell Na+ gradient, stimulatedby intracellular acidosis and inhibited by high concentra-tions of amiloride.

HCO3 generated within the cell leaves across the ba-

solateral membrane by passive 1 Na+-3 HCO3 cotrans-

port. The secreted H+ reacts with filtered HCO3 to form

luminal H2CO3, which quickly dissociates into CO2 andwater by the luminal action of membrane-bound carbon-ic anhydrase (CA IV). Luminal CO2 can freely diffuseback into the cell to complete the reabsorption cycle.

Both CA II and CA IV are markedly stimulated duringchronic metabolic acidosis.

A substantial fraction of proximal HCO3 reabsorption

is mediated by vacuolar H+-ATPase, thus mutations ofgenes encoding the protein subunits of this transportermight lead to proximal RTA. However, it is possible thatproximal HCO3

reabsorption through Na+-H+ exchangemay fully compensate for defective H+-mediated reab-sorption. Also, about 20% of filtered HCO3

is reabsorbedby passive back-diffusion along the paracellular pathway.

A second major function of the proximal tubule cell isammonia (NH3) formation from glutamine, a reactionwhich is rate-limited by the enzymes glutaminase andphosphoenolpyruvate carboxylase. Chronic acidosis up-regulates the activity of both enzymes.

In recent years important advances have been madeconcerning the molecular biology of these transportersand enzymes . Na+-H+ exchangers (NHE) belong to acommon family of transport proteins and perform elec-troneutral 1:1 exchange of Na+ and H+ [5]. To date, fiveisoforms of NHE have been cloned in mammals [6, 7].They share a similar predicted structure with approxi-mately 800 amino acids and 12 transmembrane domainsand two cytoplasmic termini (Fig. 2). The carboxy-terminal half of the protein is mainly regulatory in func-tion and contains phosphorylation sites that are targetsfor protein kinases, and domains that bind to various reg-ulatory cofactors [8]. NHE-1 and NHE-3 are the princi-pal isoforms involved in renal function. NHE-1 is ubiq-uitous and is immunolocalized at the basolateral mem-brane. NHE-3 is kidney specific and is apically localizedin proximal tubule and TALH cells. The human NHE-3gene (SLC9A3) is encoded at 5p15.3 [9].

There are three Na+-HCO3 cotransporters (NBC-1,-2, and -3) belonging to a superfamily of HCO3

trans-

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Table 1 Genetics of primary renal tubular acidosis (RTA) (NBC-1 Na+-HCO3 cotransporter, NHE-3 Na+-H+ exchanger, AE1 Cl

HCO3 exchanger,ENaCepithelial Na+ channel)

Syndrome Gene localization Locus symbol Gene product

Primary proximal RTA (type 2)Autosomal dominant ? ? ?Autosomal recessive with ocular abnormalities 4q21 SLC4A4 NBC-1Sporadic in infancy Immaturity of NHE-3?

Primary distal RTA (type 1)Autosomal dominant 17q2122 SLC4A1 AE1Autosomal recessive with deafness (rdRTA1) 2p13 ATP6B1 B1 subunit of H+-ATPaseAutosomal recessive without deafness (rdRTA2) 7q3334 ? ?

Combined proximal and distal RTA (type 3)Autosomal recessive with osteopetrosis 8q22 CA2 Carbonic anhydrase II

Hyperkalemic distal RTA (type 4)Pseudohypoaldosteronism type 1Autosomal dominant renal form 4q31.1 MLR Mineralocorticoid receptorAutosomal recessive multiple organ form 16p12 SNCC1B, SCNN1G and ENaCAutosomal recessive multiple organ form 12p13 SNCC1A ENaCEarly childhood hyperkalemia Immaturity of

mineralocorticoid receptor?Pseudohypoaldosteronism type 2 (Gordon syndrome) 1q3142,17p11-q21 ? ?

Fig. 1 Schematic model of bicarbonate (HCO3) reabsorption in

proximal convoluted tubule. The processes occurring are H+ secre-tion at the luminal membrane via a specific Na+-H+ exchanger(NHE-3) and HCO3

transport at the basolateral membrane via a1 Na+-3 HCO3

cotransporter (NBC-1). Cytoplasmic carbonic an-hydrase II (CA II) and membrane-bound carbonic anhydrase IV(CA IV) are necessary to reabsorb HCO3


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porters, which also includes Cl-HCO3 exchangers and

K+-HCO3 cotransporters [10]. NBC-1 is formed by

1,035 amino acids, it contains ten transmembrane do-mains and two cytoplasmic termini, and is present inkidney, brain, eye, pancreas, heart, prostate, epididymis,stomach, and intestine (Fig. 3) There are two isoforms:kNBC-1 (from kidney) and p(h)NBC-1 (from pancreasand heart). NBC-1 is expressed mainly at the basolateralmembrane of proximal tubule, with only traces found inmedullary thick ascending limb of Henle. In the kidney,NBC-1 is up-regulated by metabolic acidosis, K+ deple-tion and glucocorticoid excess and is down-regulated byHCO3

loading or metabolic alkalosis. There are at leasttwo genes encoding the NBC proteins. The human NBC-1 gene (SLC4A4) is located at 4p21 [11].

The carbonic anhydrases (CA) are a family of at least14 zinc metalloenzymes (CA I-XIV) that catalyze the re-versible hydration of CO2 in the reaction CO2+H2O=HCO3

+H+. The isoenzymes vary in physicochemicaland enzymatic properties, in sensitivities to various in-hibitors, and in subcellular localizations. Cytoplasmic(CA I, II, III, and VII), extracellular (CA IV, VI, IX, XII,and XIV), and mitochondrial (CA V) isoenzymes have

been described [12, 13]. In the kidney more than 95% ofCA activity is located in the cytosol and is attributable toCA II. It is primarily found in proximal tubular cells andin intercalated cells of the cortical and outer medullarycollecting tubules [14]. Membrane-bound CA IV repre-sents approximately 5% of total kidney CA activity andalthough it is mainly localized at the apical side of proxi-mal and medullary tubular cells, its presence in the baso-

lateral membrane has been also demonstrated. The hu-man CA II gene (CA2) maps to 8q22, whereas the hu-man CA IV gene (CA4) maps to 17q23 [15]. A low pHis required for bone resorption, hence CA II is also ex-pressed in osteoclasts, where it generates protons for aspecific vacuolar H+-ATPase [16].

Proximal HCO3 reabsorption is influenced by lumi-

nal HCO3 concentration and flow rate, extracellular flu-

id volume, peritubular HCO3 concentration and PCO2,

Cl, K+, Ca2+, phosphate, parathyroid hormone, gluco-corticoids, -adrenergic tone, and angiotensin II [17].

Distal urinary acidification

Urinary acidification takes place in the distal nephron bythree related processes: (1) reclamation of the small frac-tion of filtered HCO3

that escapes reabsorption proxi-mally (10%20%); (2) titration of divalent basic phos-phate (HPO4

2), which is converted to the monovalentacid form (H2PO4

) or titrable acid; and (3) accumulationof NH3 intraluminally, which buffers H

+ to form non-dif-fusible ammonium (NH4

+).The thick ascending limb of loop of Henle reabsorbs

about 15% of the filtered HCO3 load by a mechanism

similar to that present in the proximal tubule, i.e.,

through Na+

-H+

apical exchange. It also participates inNH3 transport. Absorption of NH4+ in the apical mem-

brane of the loop of Henle occurs by substitution for K+

both in the Na+ K+ 2Cl cotransport system and in theK+-H+ antiport system. The medullary thick ascendinglimb has a low permeability to NH3, limiting back-diffu-sion. A NH4

+ medullary concentration gradient is gener-ated and amplified by countercurrent multiplicationthrough NH4

+ secretion into the proximal tubule andpossibly into the thin descending limb of the loop ofHenle. The accumulation of NH3 in the medullary inter-stitium increases the driving force for diffusional entryof NH3 into the collecting tubule, a process facilitated bythe high acidity of the tubular fluid at this level. Abnor-malities in this complex process of NH3/NH4

+ synthesisand transport may lead to impaired distal urinary acidifi-cation.

Distal urinary acidification occurs mainly in the col-lecting tubules [18]. In the cortical collecting tubule, theintercalated cells are involved in both H+ and HCO3

se-cretion, while the principal cells are in charge of Na+ re-absorption and K+ secretion. There are two populationsof intercalated cells that differ both functionally andstructurally. The -cell is responsible for H+ secretion,and the -cell is responsible for HCO3

secretion. The

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Fig. 2 Membrane topology of Na+-H+ exchangers (NHE). Theyshare a similar structure with 12 transmembrane domains and cy-toplasmic amino- and carboxy-termini

Fig. 3 Membrane topology of Na+-HCO3 cotransporters (NBC).

NBC-1 is present in the kidney and contains 10 transmembranedomains and cytoplasmic amino- and carboxy-termini


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cellular mechanisms involved in distal acidification are

shown in Fig. 4. The main pump for luminal H+

secre-tion in the type intercalated cell is a vacuolar H+-ATPase, but it is also highly influenced by the luminalelectronegativity caused by active Na+ transport takingplace in the principal cells. A second ATPase, the H+,K+-ATPase, is also involved in H+ secretion, but itsphysiological role is probably more related to K+ than toacid-base homeostasis. Intracellularly formed HCO3

leaves the cell by an electroneutral mechanism involvingCI-HCO3

exchange, facilitated by an anion exchanger(AE1 or band 3 protein).

H+ secretion proceeds in the outer medullary collect-ing tubule, which is a unique segment that does not reab-

sorb Na+

or secrete K+

and whose only function is thetransport of H+ [19]. The medullary collecting tubule islumen positive and H+ must be secreted against the elec-trochemical gradient via an electrogenic, Na+-indepen-dent process modulated by the vacuolar H+-ATPase. H+

secretion is not inhibited by agents that block Na+ trans-port, but is influenced by aldosterone, through a mecha-nism which is independent of Na+ delivery or reabsorp-tion. The terminal part, the inner medullary collectingduct, also plays an important role in distal acidification[20]. The cellular process involved in mediating H+ se-cretion appears to be similar to the process described in-intercalated cells, but its importance in overall renalH+ secretion remains to be determined. All segments ofthe collecting tubule are very rich in cytosolic carbonicanhydrase II, but membrane-bound, luminal carbonic an-hydrase IV is also present in both outer and inner seg-ments of the medullary collecting duct. The luminal CAIV seems to play an important role for HCO3

absorptionin this segment [21].

The vacuolar H+-ATPase (V-ATPase) is one of themost-fundamental enzymes in nature [22]. It functions inalmost every eukaryotic cell and energizes a wide varietyof organelles and membranes. Its primary function isATP-dependent proton transfer. V-ATPases have similar

structure and mechanism of action as F-ATPases, but

these latter enzymes are confined to mitochondria, andthe primary function is to form ATP at the expense of theproton-motif force. The structure of vacuolar H+-ATP-ases has been mainly elucidated in yeast [23, 24]. Genet-ic screening has lead to the identification of 14 genes en-coding subunits of the enzyme complex. Several addi-tional genes have been identified that encode proteinsthat are not part of the final V-ATPase complex yet arerequired for its assembly. The complex is organized intotwo major domains, V0 and V1 (Fig. 5). The intracellu-lar, catalytic V1 segment is formed by three A subunitsand three B subunits. There are two isoforms (B1 andB2), encoded by different genes (ATP6B1 and ATP6B2)

and showing different patterns of expression. The B2isoform is widely distributed while the B1 isoform hasbeen exclusively detected in -intercalated cells of thedistal nephron, placenta, and inner ear [25]. The humanATP6B1 gene is located at 2p13 and contains 14 exons.

The H+, K+-ATPases comprise a group of integralmembrane proteins that belong to the P cation-transport-ing ATPases [26]. The other important member of thisfamily is Na+, K+-ATPase. Both consist of two trans-membrane subunits, the larger of which (catalytic -sub-unit) has ten domains and exchanges K+ against intracel-lular Na+ or H+, at the expense of ATP hydrolysis. The-subunit seems to be necessary for the correct packingand stable membrane insertion of the -subunit [27](Fig. 6). Differences in the functional properties andadaptability of the H+, K+-ATPases in different tissuescan partly be explained by the existence of isoforms ofthe enzyme components. The isoforms of the -subunit(HK) were initially specified according to their originaltissue origin, gastric or colonic. Recently, there is agree-ment that the HK subunits should be assigned accord-ing to their order of discovery: HK1 (gastric), HK2(colonic), HK3, and HK4. The ATP4A andATP1AL1genes code for HK1 and HK2, respectively. The hu-man ATP1AL1 gene, formed by 23 exons, has been

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Fig. 4 Schematic model of H+ secretion in cortical collecting tu-bule. The main pump for luminal H+ secretion in the -type inter-calated cell is a vacuolar H+-ATPase. A H+, K+-ATPase is also in-volved in H+ secretion. Intracellularly formed HCO3

leaves thecell via Cl-HCO3 exchange, facilitated by an anion exchanger(AE1). Cytoplasmic CA II is necessary to secrete H+

Fig. 5 Membrane topology of the vacuolar H+-ATPase. VacuolarH+-ATPase is a complex of different protein subunits organized intwo major domains, V0 and Vl. The intracellular, catalytic Vl seg-ment is formed by three A subunits and three B subunits


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cloned [28]. At least three different pumps containing

the HK1, HK2, and HK3 subunits have been detect-ed in rabbit kidney. The HK protein associates withHK1 in gastric tissue, but in the kidney the main roleseems to be played by HK2-HK isoforms [29]. Futurework should elucidate the activity and pharmacologicalproperties of different H+, K+-ATPases, depending on thepresence of HK2 variants and the interaction with dif-ferent HK subunits.

Anion exchangers (AE) interchange Cl and HCO3 at

cell membranes and belong to a superfamily of transporterswhich also includes Na+-HCO3

and K+-HCO3 cotrans-

porters [30]. There are three isoforms: AE1, AE2, andAE3. The red cell AE1, or band 3 protein, contributes to

cytoskeletal structure and is important for the respiratoryfunction by interchanging Cl and HCO3 at red cell mem-

branes. In the kidney, AE1 interchanges anions at basolat-eral membranes of type intercalated cells of cortical andmedullary collecting ducts [31]. AE2 is also expressed inthe kidney, especially in medullary thick ascending limb[32]. AE3 is mainly expressed in cardiac muscle and brain.AE1 has 911 amino acids and it was formerly believed thatit was made up of 14 transmembrane domains and two cy-toplasmic termini. Recent studies, however, have shownthat human AE1 of erythrocyte membranes is composed of13 typical transmembrane segments, while the regionAsp807-His834 is membrane embedded but does not havethe usual -helical conformation [33] (Fig. 7). The AE1gene (SLC4A1) is located at 17q2122 and the AE2 gene(SLC4A2) has been localized to 7q35-36.

Distal urinary acidification is influenced by blood pHand PCO2, distal Na

+ transport and transepithelial poten-tial difference, aldosterone, and K+. Aldosterone influ-ences distal acidification through several mechanisms(Fig. 8). Firstly it enhances Na+ transport in the late dis-tal and cortical collecting tubules, and thereby increasesthe lumen-negative potential difference across epitheli-um, so favoring both H+ and K+ secretion. This action isearly mediated by activation of pre-existing epithelial

Na+ channels (ENaC) and pumps (Na+, K+- ATPase), andsubsequently mediated by increasing the overall trans-port capacity of the renal tubular cells [34]. Aldosteroneseems to be responsible for the specific localization ofthe ENaC in the apical membrane of principal cells ofdistal and cortical collecting tubules [35]. Both early reg-ulatory and late anabolic-type actions depend on thetranscriptional regulation exerted by hormone-activatedmineralocorticoid receptors (MR). However, the regula-tory pathways that link the transcriptional action of aldo-sterone to these Na+ transport proteins are still largelyunknown [36]. In addition to the genomic action of aldo-sterone, rapid effects involving second messengers, suchas calcium and cAMP, have been also observed inknockout mice lacking the MR [37].

Aldosterone also enhances H+-ATPase activity in cor-tical and medullary collecting tubules, an effect that isindependent of plasma K+ levels. However, the stimula-tion of H+, K+-ATPase, which is also observed in aldo-sterone excess, depends predominantly on the stimulusexerted by accompanying hypokalemia [38]. 3) Aldo-sterone also affects NH4

+ excretion by increasing NH3synthesis, both as a direct action and as a consequence ofsimultaneous changes in K+ homeostasis [39].

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Fig. 6 Membrane topology of the H+, K+-ATPase. It is formed bytwo transmembrane subunits, the larger of which (catalytic subunit) has 10 domains and exchanges K+ against intracellular H+, atthe expense of ATP hydrolysis. The -subunit seems to be neces-sary for the correct packing and stable membrane insertion of the-subunit

Fig. 7 Membrane topology of the AE1 exchanger. It is formed by13 membrane-spanning domains, an atypical intramembranous re-gion (Asp807-His834), and intracellular amino- and carboxy-termini

Fig. 8 Schematic representation of aldosterone action in distal andcortical collecting tubules. Once aldosterone is bound to the min-eralocorticoid receptor, it penetrates into the nucleus and activatesspecific genes. The result is stimulation of Na+ entry and both H+

and K+ exit at the luminal membrane, and of K+ entry and Na+ exitat the basolateral membrane


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The MR is a protein of 984 amino acids belonging tothe superfamily of steroid receptors. It contains an im-munogenic domain, a zinc finger DNA-binding domain,and a hormone-binding domain. Unlike the glucocorti-coid receptor, which is almost ubiquitous, MR expres-sion is restricted to specific cells of kidney distal andcollecting tubules, colonic epithelium, and sweat and sal-ivary gland ducts. In all these epithelia aldosterone stim-ulates Na+ reabsorption [40]. The structure of the geneencoding the human MR (MLR) has been elucidated. Itis formed by nine exons and is located at 4q31.1[41].Two different isoforms have been identified. Eachisoform is expressed at an approximately equivalent lev-

el in kidney, colon, and sweat glands [42].The epithelial Na+ channel (ENaC) is formed bythree subunit proteins (, , and ), having short cytosol-ic termini, two transmembrane domains, and a large ex-tracellular loop [43]. The -subunit appears to be re-quired for the assembly or function of the whole com-plex. The three ENaC subunits are homologous to eachother and have about 35% amino acid identity. There is apossible membrane topology of the heterotetramericcomplex formed by 2 , 1 , and 1 subunits, since thiscomplex maintains a high amiloride sensitivity and avery Na+ selective pore [44] (Fig. 9 ). The ENaC is notonly present in the kidney but also in other organs suchas lung, colon, exocrine glands, skin, and hair follicle.Both genes encoding the (SNCC1B) and -subunits(SNCC1G) are located in 16p12, while the gene encod-ing the -subunit (SNCC1A) is located in 12p13 [45].

Ontogeny of renal acidification

lt is well known that during early postnatal life there is amaturational increase in proximal tubular reabsorption ofHCO3

[46]. The immaturity of this process is still moreapparent in preterm newborn infants [47]. Classic func-

tional studies in puppies and rabbits have shown that therate of reabsorption in neonatal proximal tubules is ap-proximately one-third of that observed in mature seg-ments, and that normalization only occurs after a periodof several weeks [48, 49]. Recent investigations haveshown that several transporters and enzymes involved inHCO3

transport are insufficiently expressed during theearly neonatal period. The functioning of apical NHE-3,

either studied as Na+

-H+

antiporter activity in microvil-lus membrane vesicles prepared from cortex of fetal andnewborn lambs [50] or as expression of NHE-3 mRNAin cortex from neonatal rabbits [51, 52], is clearly im-paired. NBC-1 activity at the basolateral membrane isalso decreased in neonatal rabbits, but this activity is rel-atively more mature than the NHE-3 activity at the api-cal membrane [53]. Maturation of CA II and CA IV ac-tivities may also play an important role, since these en-zymes are insufficiently expressed during the first 2weeks of life in rat and rabbit kidneys, respectively [54,55]. The maturational increase of proximal tubular reab-sorption of HCO3

takes place pari passu with parallel

increases in proximal tubular basolateral surface areaand Na+, K+-ATPase activity [56, 57, 58].lt is of great interest that administration of glucocor-

ticoids accelerates the maturation of both Na+-H+ anti-porter activity [59] and expression of NHE-3 mRNA[51, 52]. These experimental findings have an importanthuman correlate because administration of prenatal ste-roids is also associated with earlier maturation of glom-erular filtration rate and tubular Na+ reabsorption [60,61].

The process of distal tubular acidification appears tomature earlier than proximal tubular transport. In fact,the ability to excrete an acid load is not different in in-

fancy than later in life [46]. Premature infants, however,do present an inability to acidify the urine as a conse-quence of insufficient ammoniagenesis [62, 63]. Gluta-mine uptake, NH3 production, and excretion into the tu-bular fluid are lower in neonatal rats after an acid load[64].

There are few molecular biology studies related to on-togeny of distal H+ transport. They show that the varioustransporters involved are all expressed in post-S-shapestages, suggesting that microanatomical differentiationof the developing distal nephron to some degree pre-cedes the tubular expression of specific transport-relatedgene product [65]. It should be noted that intercalatedcells are fully developed in the fetal rat kidney and thatthe entire population of these cells present in the medul-lary collecting duct are eliminated, by programmed celldeath, during the development of the collecting duct[66]. However, in the cortical collecting duct of the rab-bit, intercalated cells are reduced in number and are alsofunctionally immature. They undergo postnatal prolifera-tion and maturation to attain adult function severalweeks postnatally [67].

It is well known that, in contrast to term newborn in-fants, preterm newborn infants born before 35 weeks ofgestational age present an obligatory Na+ loss despite

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Fig. 9 Membrane topology of the epithelial Na+ channel. The pro-posed model is a heterotetrameric structure formed by two -sub-units, one -subunit, and one -subunit Each subunit is formed bytwo membrane spanning-domains, a large extracellular loop, andcytoplasmic amino- and carboxy-termini


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very elevated plasma levels of renin and aldosterone.This situation is especially observed in the context ofhigh water intake and is caused by deficient proximaland distal tubular Na+ reabsoption [68].

The various proteins implicated in the function of al-dosterone target cells, such as MR and ENaC, are al-ready fully expressed in the terminal part of the nephronand the collecting duct [69]. The aldosterone unrespon-

siveness present during development may be thereforerelated to a low density of mineralocorticoid receptorsand apical epithelial Na+ channels [70, 71].

Proximal RTA (type 2)

Proximal RTA (type 2) is caused by an impairment ofHCO3

reabsorption in the proximal tubule and is char-acterized by a decreased renal HCO3

threshold. Distalacidification mechanisms are intact and when plasmaHCO3

concentration diminishes to sufficiently low lev-els these patients may lower urine pH below 5.5 and ex-

crete adequate amounts of NH4+

. In children, proximalRTA is most frequently observed in the Fanconi syn-drome, but it may also occur as a primary or inheritedentity.

Autosomal dominant proximal RTA

This form has been exclusively described in nine mem-bers of a Costa Rican family by Brenes et al. [72]. Theage of the patients varied between 2 and 27 years andclinical signs were limited to the presence of growth re-tardation. The presence of the disorder in several genera-

tions suggested an autosomal dominant transmission.Molecular biology studies have not yet been reported inthis family, but one may speculate about a possible can-didate gene, such as SLC9A3, encoding the NHE-3 trans-porter.

A mouse model in which the gene SLC9A3 has beenabated using gene targeting strategies has been devel-oped [73]. These knock-out mice lack NHE-3 activityand have combined renal and intestinal absorptive de-fects. Microperfusion and micropuncture studies show asignificant decrease in HCO3

reabsorption in the proxi-mal tubule [74, 75]. However, the mice only exhibit amild degree of metabolic acidosis, due to a compensato-ry increase in HCO

3

reabsorption in more distal neph-ron segments [76]. Kidney expression of renin and dif-ferent transporters such as NBC1, AE1, and HK2 is in-creased [73]. It will be of interest to determine the clini-cal findings of surviving animals and specifically wheth-er they exhibit growth retardation.

Autosomal recessive proximal RTAwith ocular abnormalities

Primary proximal RTA has also been reported as an auto-somal recessive entity in association with other anoma-lies, such as mental retardation and ocular abnormalities[77, 78, 79]. Igarashi et al. [80] have reported molecularbiology studies in two unrelated girls, of 22 and 11 years

of age, presenting with short stature, mental retardation,bilateral glaucoma, cataracts, band keratopathy, and per-manent isolated proximal RTA. Both girls had homozy-gous missense mutations (Arg298Ser in patient 1,Arg510His in patient 2) in the gene SLC4A4, encodingNBC-1. These findings are of great interest since theyare the first showing that loss-of-function mutations ofSLCA4A4 may cause permanent primary proximal RTAwith ocular abnormalities.

The involvement of the corneal epithelium may beexplained by the fact that it transports fluids, Na+, andHCO3

out of the corneal stroma into the aqueous humorto maintain corneal transparency. The function of NBC-1

in this process is of great importance and NBC1 is high-ly expressed in corneal epithelium [81]. In mutated pa-tients, the increase in HCO3

concentration in the cornealstroma may facilitate calcium deposition and develop-ment of band keratopathy.

Sporadic isolated proximal RTA

A non-familial and transient type of isolated proximalRTA has been described in infancy [82, 83]. Affected in-dividuals present with an isolated defect in renal and in-testinal HCO3

absorption, without any identifiable

cause or evidence of other abnormality. The presentingsymptoms are growth retardation and persistent vomitingin early infancy. Alkali therapy induces a rapid increasein growth and can be discontinued after several yearswithout reappearance of symptoms. The transient natureof this entity suggests the persistence beyond the neona-tal period of a decreased HCO3

threshold, possibly as acontinued immaturity of NHE-3 function.

Distal RTA (type 1)

This type of RTA is caused by impaired distal acidificat-ion and is characterized by the inability to lower urinepH maximally (below 5.5) under the stimulus of system-ic acidemia. The impaired excretion of NH4

+ is second-ary to this defect. Distal RTA is almost always observedin children as a primary entity inherited in both autoso-mal dominant and recessive patterns. In adults, distalRTA is generally acquired and is often seen in the con-text of an immune-mediated disease. Prominent clinicalfeatures include impairment of growth, polyuria, hyper-calciuria, nephrocalcinosis, lithiasis, and K+ depletion.Progression of nephrocalcinosis may lead to the develop-

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ment of chronic renal failure. If detected early in life,therapeutic correction of the acidosis by continuous alka-li administration may induce resumption of normalgrowth, arrest of nephrocalcinosis, and preservation ofrenal function.

Autosomal dominant distal RTA

In a few reported families the presence of the disorder inseveral generations suggests an autosomal dominanttransmission [84, 85]. Although clinical findings are notdifferent from those observed in autosomal recessive orsporadic cases, in these patients the disease may be diag-nosed later or manifest with milder symptomatology.Autosomal dominant distal RTA has been found to be as-sociated in several kindreds with mutations in theSLC4A1 gene encoding the CI/HCO3

exchanger AEI[86, 87, 88]. Neither morphological abnormalities nor in-creased fragility are present in the erythrocytes, in con-trast with an autosomal recessive AEI nonsense mutation

found in cattle which is associated with systemic acido-sis, severe anemia, and red cell fragility [89].The abnormalities described in patients with autoso-

mal dominant distal RTA mostly include missense muta-tions in codon Arg589 (Arg589His, Arg589Ser,Arg589Cys) found in various unrelated families, theSer613Phe and Gly1766A1a mutations found in twofamilies, and an 11-amino acid deletion at the carboxyterminus found in another family [86, 87, 88]. One ofour patients presented a de novo Arg589His mutation[88]. The frequent involvement of codon Arg589 indi-cates the critical importance of this residue in the normalacidification process. Arg589 lies at the intracellular bor-

der of the sixth transmembrane domain of the protein,adjacent to Lys590. These basic residues are conservedin all the known vertebrate exchanger isoforms and mayform part of the site of intracellular anion binding.

The few mutations described in distal RTA contrastwith the great number of AE1 mutations present in redcell diseases such as hereditary spherocytosis and South-east Asian ovalocytosis, where more than 20 differentmissense, nonsense, and frameshift mutations have beendescribed [90]. A remarkable fact is that these hereditaryred cell disorders are not generally associated with distalRTA. Administration of an acid load to ten patients fromseven unrelated families with hereditary spherocytosisand AE1 deficiency revealed that uniquely two patientsfrom one family had an acidification defect [91]. Also,the presence of distal RTA in hereditary ovalocytosis[92] or elliptocytosis [93, 94] has been only exceptional-ly described.

How can one explain either the absence of red cell ab-normalities in patients with distal RTA or the rarity ofdefects in distal urinary acidification in patients with he-matological disorders, when in both circumstances muta-tions in the same SLC4A1 gene are present?. Functionalanalysis of the Arg589His mutation has revealed only amodest reduction in AE1-mediated 36C1 transport when

expressed in Xenopus oocytes or of sulfate transport inpatients' red cells [86]. It is therefore possible that thisand other AE1 mutations do not lead to defective distalacidification through a loss-of-function of the protein butthrough an intracellular misrouting. Lack of insertion ofAE1 exchanger into the basolateral membrane or errone-ous insertion into the apical membrane would interferewith H+ secretion. The finding of high urine PCO2 val-

ues in an adult patient with distal RTA and ovalocytosisfavors the possibility that -type intercalated cells se-crete HCO3

instead of H+ due to the erroneous presenceof AE1 in the apical membrane [92]. This hypothesis isalso supported by the findings in two affected siblingswith a homozygous, loss-of-function mutation,Gly701Asp [95]. AE1-Gly701Asp loss-of-function wasaccompanied by impaired trafficking to the Xenopus oo-cyte surface. Glycophorin A rescued both AE1-mediatedCl transport and AE1 surface expression in oocytes. Inconclusion, normal erythroid anion transport may bepresent when the AE1 mutation leads to disrupted intra-cellular trafficking rather than to significant loss-of-func-

tion of AE1. Conversely, in hematological disorders dueto AE1 mutations, remaining function of the exchangerin the heterozygous carriers may be insufficient to pre-serve the integrity of red cell membranes but sufficientto maintain, with a few exceptions, normal distal H+ se-cretion.

Autosomal recessive distal RTAwith sensorineural deafness

An important fraction of cases of sporadic or autosomalrecessive distal RTA develop sensorineural deafness.

This association was first noted by Royer and Broyer in1967 [96], and to date some 50 cases have been de-scribed [97]. Clinical findings, other than deafness, areidentical to those present in patients with sporadic or au-tosomal recessive distal RTA and normal hearing. Thereis great variation in the presentation of deafness, frombirth to late childhood, it is progressive and does notameliorate after alkali therapy.

Karet et al. [98] have recently demonstrated that mostpatients with distal RTA and nerve deafness have muta-tions in the gene ATP6B1 encoding the B1-subunit ofH+-ATPase. These represent the first genetic abnormali-ties described in autosomal recessive distal RTA(rdRTA1). They found 15 different mutations in 20 pa-tients belonging to 15 kindreds. The nonsense mutation,Ala31Stop, was found in three unrelated patients, frame-shift mutations were identified in 4 patients, and 7 differ-ent missense mutations were identified in 9 patients. Fi-nally, mutations altering the highly conserved splice do-nor (GT) or splice acceptor (CAG) sequences were iden-tified in 4 patients. The mutations were distributedacross theATP6B1 gene and not clustered in the proteinstructure, suggesting that alterations in many parts of thishighly conserved molecule may result in loss of func-tion.

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er, not all mutant animals with osteopetrosis evidenceabnormalities in osteoclastic acid secretion and there areat least four osteopetrotic mutations in the rat showingnormal osteoclastic CA II and H+-ATPase functions[120]. CA II is present in oligodendrocytes and astro-cytes and its deficiency may delay brain maturation andresult in mental retardation and cerebral calcification[121].

The development of mutant mice (CAR2n

) exhibitinga loss-of-function point mutation in the CA2 gene hasbeen of great help in studying the pathogenesis of CA IIdeficiency. This mutant mouse is generated by exposureto N-ethyl-nitrosourea and transmission of the mutationto the progeny [122]. The most-interesting study per-formed in this mouse has been the correction of the acid-ification defect by gene therapy. Lai et al. [123] per-formed retrograde injection into the intrarenal pelvicaly-ceal system of cationic liposome-complexed plasmidcontaining human CA II cDNA under the control of thecytomegalovirus early promoter. Expression of CA2mRNA was highest by day 3 after treatment, but re-

mained undetectable after 1 month. After gene therapyCA II-deficient mice had restored ability to acidify theurine, but this ability was progressively lost by 6 weeks.This study represents the first successful gene therapy ofa genetic renal disease and opens a completely new wayfor treating other hereditary renal tubular disorders.

Hyperkalemic RTA (type 4)

Hyperkalemic RTA (type 4) accompanies a large numberof hyperkalemic states: the acidification defect is mainlycaused by impaired renal ammoniagenesis. It is charac-

terized by a normal ability to acidify the urine after anacid load, but net acid excretion remains subnormal dueto a very low rate of NH4

+ excretion. Although the de-crease in NH3 production is mainly caused by hyperkale-mia itself, aldosterone deficiency or resistance may alsoplay important contributory roles [124]. HyperkalemicRTA of hereditary origin is most frequently observed inchildren with primary pseudohypoaldosteronism.

Pseudohypoaldosteronism type 1

Pseudohypoaldosteronism type 1 (PHA1) is a hereditarycondition characterized by salt wasting, hyperkalemia,and metabolic acidosis in the presence of markedly ele-vated plasma renin activity and aldosterone concentra-tion. Since its first description by Check and Perry in1958 [125], many cases have been reported. In recentyears, it has become clear that PHA1 is a heterogeneoussyndrome that includes at least two clinically and geneti-cally distinct entities with either renal or multiple targetorgan defects [126].

The autosomal dominant renal form represents themost frequently encountered form of PHA1. These pa-tients present with salt wasting, metabolic acidosis, and

hyperkalemia, but do not have pulmonary, sweat glands,or any other organ involvement. Clinical features are ex-tremely variable, from severe neonatal sodium loss andmenacing hyperkalemia to lack of symptoms throughoutlife [127]. Although the primary defect persists forever,improvement may occur beyond 1 or 2 years of age, dueto maturation of proximal tubular transport, developmentof salt appetite, and improvement in the renal tubular re-

sponse to mineralocorticoids [128].The pathogenesis of renal PHA1 has been greatlyclarified with the identification of heterozygous muta-tions in the mineralocorticoid receptor gene in one spo-radic and four dominant kindreds with this disease [129].The mutations found included two frameshift mutations,which resulted in deletion of a single base pair in exon 2,one premature stop codon in exon 2 at codon 537, and asingle pair deletion in the intron 5 splice donor site. Intwo patients no mutations in the MRL gene could bedemonstrated, indicating either the existence of othermutations in additional genes or the implication of non-genetic factors.

The observation that many adult gene carriers haveelevated aldosterone levels but no history of clinical dis-ease raises the possibility that only a fraction of suchcarriers develop clinically evident disease [130]. Thereasons for the phenotype differences are unknown, butmay be related to intercurrent volume-depleting eventsor to dietary habits of salt ingestion.

The coexistence of polymorphisms or mutations inthe gene encoding ENaC could also play a potential con-tributory role. Polymorphisms and mutations which leadto either loss-of-function or gain-of-function of the epi-thelial Na+ channel may aggravate or attenuate, respec-tively, the consequences of deficient mineralocorticoid

receptor function [131, 132, 133].Mineralocorticoid receptor-deficient mice have beengenerated by gene targeting technology [134]. TheseMRL knock-out mice develop symptoms of pseudohypo-aldosteronism soon after birth, which can be compensat-ed by abundant sodium chloride administration [135].The renin-angiotensin-aldosterone system is greatlystimulated with maximal expression of renin mRNA inkidney and adrenal gland [136].

A few kindreds have been reported with PHA1 due tomultiple target organ resistance (kidney, colon, sweatand salivary glands) since its original description [137].This variant is inherited as an autosomal recessive disor-der, with uniform expression. The parents of affectedchildren are asymptomatic and evidence normal plasmaaldosterone levels. This autosomal recessive formpresents with more-severe salt wasting and has a pooreroutcome than the renal form. Patients manifest salt wast-ing episodes early after birth, and death may ensue dur-ing the neonatal period. Sweat and salivary electrolytesare markedly elevated. The high incidence of lower res-piratory tract involvement may contribute to the confu-sion with cystic fibrosis [138, 139].

lt has recently been demonstrated that this entity iscaused by loss-of-function mutations of genes encoding

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one of the three constitutive subunits (, , and ) of theENaC. Conversely, Liddle syndrome is caused by gain-of-function mutations of only the genes encoding thesubunits and of the ENaC [140]. In the recessiveform, homozygous mutations have been identified in allthree ENaC subunits and include frameshift, missense,and premature stop codons [141, 142, 143, 144]. Criticalhot spots for loss-of-function mutations seem to be the

cysteine-rich domains in the large extracellular loop ofthe proteins [145].Multiple target organ PHA1 is due to defective Na+

transport in many organs containing the ENaC: kidney,lung, colon, and exocrine glands. Insights into pathogen-esis have been facilitated by the development of trans-genic mouse models in which expression of the , , or subunits of ENaC has been abated. Interestingly, only theENaC-deficient mice have marked failure to clear thefetal lung fluid that leads to early neonatal death [146]. lfthe mice are "rescued" from death by the engineered ex-pression of the -subunit gene in the lung, they developa full-blown picture of pseudohypoaldosteronism, with

salt wasting and hyperkalemia [147]. The ENaC- andENaC-deficient mice do not die of neonatal respiratoryfailure and develop from birth a very severe picture ofneonatal salt wasting and hyperkalemia, similar to hu-man PHA1 [148, 149, 150].

The neonatal lung findings present in ENaC-defi-cient mice are only exceptionally observed in humans[151], despite impressive truncations of the -subunit insome kindreds. Bonny et al. [143] tried to explain thisdiscrepancy by demonstrating that the tetrameric struc-ture of ENaC (), although formed in humans bytwo mutated -subunits, maintains a low but sufficientNa+ transport activity to absorb the fetal pulmonary flu-

id. However, some impairment in Na+

transport acrossairway epithelia may persist throughout life. In fact, pul-monary symptoms in patients with autosomal recessivePHA1 are not always related to infection and may besecondary, especially in young patients, to failure to ab-sorb liquid from airway surfaces [144, 152]. The defectin Na+ transport can be demonstrated by measurement oftransepithelial voltage across the nasal epithelium [153].

Early childhood hyperkalemia

A transient syndrome of hyperkalemia and metabolic ac-idosis, without clinical salt wasting, has been describedin infancy. Plasma renin activity and aldosterone excre-tion were consistently normal or elevated [154, 155].This entity has been called early-childhood hyperkale-mia and represents a variant of the renal form of PHA1probably due to a maturation disorder in the number orfunction of mineralocorticoid receptors. This hypothesis,however, remains highly speculative because it does notexplain the absence of salt wasting.

Pseudohypoaldosteronism type 2(Gordon syndrome)

An autosomal dominant syndrome of arterial hyperten-sion, hyperkalemia, metabolic acidosis, and suppressedplasma renin activity was characterized as a new clinicalentity by Gordon et al. in 1970 [156]. Less than 50 caseswith so-called Gordon syndrome have been reported in

the literature [157]. Hypertension represents a featurelimited to adolescent or adult individuals. A similar con-dition has been reported in children with short stature,hyperkalemia, and metabolic acidosis but with normalblood pressure (Spitzer-Weinstein syndrome) [158, 159].The name of chloride-shunt syndrome has been alsoproposed, according to the hypothesis that the primaryabnormality is a tubular hyper-reabsorption of sodiumchloride in the thick ascending loop of Henle or earlydistal tubule that leads to impaired K+ and H+ secretionin cortical collecting duct as a consequence of a voltage-shunting defect [160].

The genetic defect persists unknown. Linkage analy-

sis in eight affected families showing autosomal domi-nant transmission demonstrated locus heterogeneity ofthe trait with involvement of chromosomes 1q3142 and17p11-q21 [161]. Therefore, gain-of-function mutationsat the genes encoding bumetanide-sensitive Na-K-2Clcotransporter, thiazide-sensitive Na-Cl cotransporter andchloride channel ClC-Kb can be readily excluded. An at-tractive hypothesis is that the syndrome results fromgain-of-function mutations of a carrier protein governingsodium chloride passage across the paracellular tightjunctions of the thick ascending loop of Henle. However,the existence of such a carrier protein remains to beproved.

Future perspectives

Molecular biology studies have opened completely newinsights into the pathogenesis of RTA. At present only afew genes controlling renal H+, HCO3

, and Na+ trans-port have been implicated, but soon other candidategenes will surely join the spectrum of genetic causes ofprimary RTA. However, loss-of-function resultingfrom observed mutations has been experimentally dem-onstrated in only a few cases. Over the next few yearsfunctional studies with the mutant genes expressed in aheterologous system such as the Xenopus oocyte will benecessary to demonstrate the functional consequences ofspecific mutations. Also, molecular studies will also helpto better understand cases of secondary RTA. Immuno-histochemical techniques using mono- or polyclonal an-tibodies against specific renal transporters have alreadybeen used to clarify the pathogenesis of distal RTA asso-ciated with immune-mediated diseases such as thyroidi-tis, systemic lupus erythematosus nephritis, and Sjgrensyndrome [162, 163]. Direct study in renal tissue of geneexpression of such transporters will soon ensue. Unfortu-nately, these molecular studies do not offer any obvious

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advantage with regard to therapy, since gene transfer inthe kidney is only expected to be clinically available inthe distant future, and be initially oriented to more-com-mon renal disorders, such as transplantation, polycysticdisease or cancer [164]. Fortunately, the therapeuticneeds of most patients with primary RTA are easily cov-ered with alkali therapy. Nevertheless, application ofgene therapy to generalized disorders such as CA II defi-

ciency or autosomal recessive pseudohypoaldosteronismtype 1 remains a prospect for the future.

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L I T E R AT U R E A B S T R A C T S

H. Kaul M. Girndt U. Sester M. Sester H. Kohler

Initiation of hemodialysis treatment leads

to improvement of T-cell activation in patients

with end-stage renal disease

Am J Kidney Dis (2000) 35:611616

Patients with chronic renal failure show an immunodeficiencycharacterized by frequent infectious complications and a low re-sponse to vaccinations. This is paralleled in vitro by a low T-cellproliferation on mitogenic stimuli because of an impaired costim-ulation by accessory cells. Furthermore, alterations of the cytokineprofile are correlated with impaired immune function. The im-mune system is influenced by both uremia and renal replacementtherapy. To evaluate the influence of hemodialysis on immune pa-rameters, we studied patients before and after the initiation ofchronic hemodialysis therapy. Fourteen patients with end-stage re-nal failure were tested before dialysis initiation and during the first6 weeks of hemodialysis treatment. We determined the in vitro T-cell proliferation, as well as plasma levels of interleukin-6 (IL-6)

and the release of IL-6 and IL-10 into culture supernatant post-stimulation with lipopolysaccharide. After 6 weeks of intermittenthemodialysis, in vitro T-cell proliferation on stimulation improvedsignificantly (stimulation index, 21.6 +/ 18.5 versus 58.1+/ 45.5; P < 0.01). This improvement occurred regardless ofwhether synthetic dialyzers or cellulosic membranes were used forthe initiation of dialysis. Plasma IL-6 levels, as well as IL-6 andIL-10 secretion, did not change during the study period. In pa-tients with end-stage renal disease, the initiation of hemodialysisled to a significant improvement of in vitro T-cell proliferation.This effect may have a role for an improvement of immune func-tion in vivo. The expected normalization of IL-6 and IL-10 pro-duction may be masked by cytokine induction through hemodialy-sis membranes.

D.K. Wilson D.A. Sica S.B. Miller

Effects of potassium on blood pressure

in salt-sensitive and salt-resistant black

adolescents

Hypertension (1999) 34:181186

This study examined the effects of increasing dietary potassium onambulatory blood pressure nondipping status (/=5 mm Hg from the low to high sodium diet. Sixteen salt-sensi-tive and 42 salt-resistant subjects were then randomly assigned to

either a 3-week high potassium diet (80 mmol/24 h) or usual dietcontrol group. Urinary potassium excretion significantly increasedin the treatment group (35+/7 to 57+/21 mmol/24 h). At base-line, a significantly greater percentage of salt-sensitive (44%)compared with salt-resistant (7%) subjects were nondippers on thebasis of diastolic blood pressure classifications (P

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