Metabolic Alkalosis, Bedside and Benchmedlib.yu.ac.kr/eur_j_oph/sem_nephrol/sem_n_pdf/... · Metabolic Alkalosis, Bedside and Bench Melvin E. Laski and Sandra Sabatini Although signiﬁcant

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etabolic Alkalosis, Bedside and Benchelvin E. Laski and Sandra Sabatini

Although significant contributions to the understanding of metabolic alkalosis have beenmade recently, much of our knowledge rests on data from clearance studies performed inhumans and animals many years ago. This article reviews the contributions of thesestudies, as well as more recent work relating to the control of renal acid-base transport bymineralocorticoid hormones, angiotensin, endothelin, nitric oxide, and pottasium balance.Finally, clinical aspects of metabolic alkalosis are considered.Semin Nephrol 26:404-421 © 2006 Elsevier Inc. All rights reserved.

KEYWORDS metabolic alkalosis, acid-base regulation, bicarbonate transport, urinary acidifi-cation, endothelin, angiotensin, aldosterone

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t is always interesting to observe how many of the youngphysicians interviewing for nephrology fellowship posi-

ions report that their interest in the field is based on a per-onal delight in the complexities of acid-base and electrolyteroblems. It is with sadness that we explain to them that (1)onsulting nephrologists, whether in private practice or in ancademic setting, receive few, if any, requests to evaluatecid-base or electrolyte problems, and that (2) their (the ap-licants) dreams of a career in clinical research investigatingcid-base physiology probably would go unfulfilled in thebsence of significant basic skills in molecular biology and aillingness to spend large amounts of time at the bench and

n even greater amount of time dealing with regulation andureaucracy.The situation was considerably different in the decades of

he 1960s and 1970s, when a great number of significantlinical studies of acid-base physiology were performed. Theechniques of the beginning of that era were astute historyaking, careful physical examination, arterial and/or venouslood gas determination, acid and alkali titration of bloodnd urine, and clinical chemistry. The designs of choice werehe balance study and the clearance study. Virtually any grad-ate of an accredited medical school was equipped to con-ribute to the research effort. No long period of additionalpecial training was required. Those with an interest and aeen intellect could readily participate. An additional aspectf this period is that the research proceeded in such a wayhat the clinical answers sometimes came first. Groundbreak-

rom the Departments of Internal Medicine and Physiology, Texas TechUniversity Health Sciences Center, Lubbock, TX.

ddress reprint requests to Melvin E. Laski, MD, TTUHSC, Department ofInternal Medicine, Mail Stop 9410, 3601 4th St, Lubbock, TX 79413.

iE-mail: [email protected]

04 0270-9295/06/$-see front matter © 2006 Elsevier Inc. All rights reserved.doi:10.1016/j.semnephrol.2006.09.001

ng clinical studies in many cases defined the human condi-ion in acid-base disorders earlier than the animal studies thatutlined the underlying physiology.

arly Studies Relatingo Metabolic Alkalosishe outstanding studies of Pitts et al1,2 outlined for nephrolo-ists the integrated result of the renal transport of bicarbonaten the human being before the diverse mechanisms by whichicarbonate transport occurred were ever elucidated in ani-al models. These investigators infused themselves with bi-

arbonate to achieve increasing serum bicarbonate concen-ration and carefully quantified the resulting urinaryicarbonate excretion. The results defined a curve for re-al bicarbonate handling in the human being that dis-layed a steady increase in reabsorption until it reached itsaximum when the serum bicarbonate concentration ex-

eeded 28 mmol/L. The kidney then maintained an appar-nt maximal rate of absorption, or tubular maximumTm); the further infusion of bicarbonate only increasedhe rate at which bicarbonate escaped the kidney and wasxcreted. These studies defined a relationship betweenicarbonate load and reabsorption, and carry within themhe seed of the relationship between volume and the main-enance phase of metabolic alkalosis, that is, the kidneyan support and maintain increased blood bicarbonateoncentration if the product of the glomerular filtrationate and the bicarbonate concentration is less than the Tmor bicarbonate.

Cohen3 performed a critical study of metabolic alkalosis in968 when he examined the effect of volume expansion with

sometric fluids (defined by having concentrations of so-

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Metabolic alkalosis 405

ium, chloride, bicarbonate, and potassium identical to thatlready present in the blood) in dogs with metabolic alkalosisnduced by diuretics and a low-chloride diet. In this classicalance study, Cohen3 showed that replacement of lost vol-me corrected an increased blood bicarbonate concentra-ion, even when fluid with a bicarbonate concentration thatid not differ from that seen in the alkalemic animals wasdministered. Thus, as volume was administered, the kidneyesponded by adjusting the composition of the blood to re-urn the acid-base state to normal.

It was in this context that Dr. Neil Kurtzman6 published anrticle that can reasonably be said to have launched his aca-emic career. While working at the Metabolic Burn Unit ofhe Brooke Army Medical Center under the guidance of Colo-el Basil Pruitt, MD, Dr. Kurtzman developed an intense

nterest in the problems of the renal response to perturba-ions of acid-base balance and of volume. In particular, theelationship between extracellular volume, specifically “theffective arterial blood volume” and the renal handling oficarbonate became his question of the day. Clinical obser-ations already had been made. The administration of so-ium chloride was known to increase the excretion of bicar-onate in patients, but whether this was caused by chloride

tself, by the effect on blood pressure, by the sodium thatccompanied the chloride, or by some other process was notertain. Kassirer et al4,5 already had outlined the clinical treat-ent of metabolic alkalosis: provision of chloride, and, in

ddition, correction of hypokalemia when deficits were seri-us. Thus, the physician of that day did not know exactlyhat went on in the black box that was the kidney, but

ecognized the conditions that cause metabolic alkalosis andhat needed to be performed to correct it. In short, although

he cause and the treatment of metabolic alkalosis werenown, the debate concerned why treatment worked.In the seminal paper of 1970, Kurtzman6 investigated how

ogs responded to the administration of isotonic sodium bi-arbonate, isotonic sodium chloride, and hypertonic sodiumicarbonate plus isotonic saline. The results indicated thatogs given hypertonic bicarbonate initially developed an in-rease of the plasma bicarbonate level (metabolic alkalemia)ut rapidly excreted the excess bicarbonate when infusedith isotonic saline. The bicarbonaturia occurred in concertith a massive increase in the fractional sodium excretion

nd an increase in potassium excretion that induced markedypokalemia. Additional dogs given isotonic saline withoutrior bicarbonate infusion developed significant bicarbona-uria despite initially normal, and, later, low serum bicarbon-te levels. Bicarbonaturia even developed after volume ex-ansion in dogs with low serum bicarbonate inducedeliberately with infusion of HCl. Although a Tm seeminglyeveloped at a blood bicarbonate concentration in the 26 to8 mEq/L range in normal dogs given bicarbonate, the vol-me-expanded dogs appeared to show a Tm at serum bicar-onate concentrations as low as 16 to 18 mEq/L. Thus, salinexpansion increased bicarbonate loss to the urine regardlessf the initial bicarbonate concentration; something about thenfusion of volume, sodium, or chloride resulted in bicar-
onaturia. c
The administration of chloride per se is not needed toncrease bicarbonate excretion. The volume expansion ofogs with isotonic bicarbonate resulted in a natriuresis (frac-ional excretion of sodium � 16.8%), bicarbonaturia, andepressed the reabsorption of bicarbonate. By contrast, dogsiven bicarbonate after induction of absolute volume con-raction by hemorrhage increased their rate of bicarbonateeabsorption and developed a markedly increased serum bi-arbonate concentration. Similar results were obtained whenogs were given bicarbonate in the presence of ligation of thehoracic vena cava, another experimental model marked by aevere decrease in effective arterial blood volume. Both theemorrhage group and the caval ligation group showed lowodium and chloride excretion. When the caval ligation waseleased and effective arterial blood volume was restored,odium and chloride excretion increased rapidly, and bicar-onaturia developed.The earlier-described results were interpreted by

r. Kurtzman6 to indicate a relationship between bicarbonateeabsorption and effective arterial blood volume, and theroups exposed to isotonic sodium bicarbonate infusionhowed that bicarbonate excretion could be increased with-ut the infusion of chloride. Kurtzman6 further showed thathe infusion of sodium bicarbonate did not increase bicar-onate or sodium excretion if volume expansion was pre-ented.

The clearance studies by Kurtzman6 in dogs and the con-emporaneous studies of Purkerson et al7 in rats clearly es-ablished that there was a relationship between bicarbonateeabsorption and volume; and, by extension, explained thereviously observed response of metabolic alkalosis to the

nfusion of saline. Kurtzman8 further linked the increase inicarbonate reabsorption observed in acute hypercapnia tohanges in blood pressure, effective arterial blood volume,lomerular filtration rate, and filtered load of bicarbonate.hen blood pressure and filtered load were supported, the

ncrease in bicarbonate reabsorption that accompanied hy-ercarbia was grossly blunted.These observations were confirmed and extended as phys-

ologic techniques increased in sophistication. The studies oficarbonate transport performed after re-emergence of renalicropuncture in several laboratories,9-13 and the efforts ofcKinney and Burg14 and Burg and Green15 to develop in

itro tubular microperfusion allowed the careful dissection ofenal tubular reabsorption. In vivo micropuncture studiesstablished that bicarbonate reabsorption was almost exclu-ively a proximal tubule phenomenon with high capacity.lpern and Cogan et al16-20 used micropuncture and the fur-

her refinement of in vivo microperfusion to redefine the Tmn terms of maximum rates of reabsorption by subsegmentsf the proximal tubule, passive reabsorptive processes relatedo concentration gradients and solvent drag, and back leak oficarbonate from the blood to the tubule lumen as intralu-inal bicarbonate concentrations decreased.21 Bank et al22

rst suggested that the earliest portion of the proximalubule, the S1 segment, contained a proton pump (an-adenosine triphosphatase [ATPase]), a hypothesis later

onfirmed definitively as molecular biologic techniques

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406 M.E. Laski and S. Sabatini

ere applied to the question.23 The greater portion ofroximal tubule bicarbonate absorption in the S2 segmentas shown to be sodium dependent and mediated by arush-border membrane sodium-proton exchanger, laterefined as the NHE3 antiporter, one of a large family ofodium-proton exchangers.24,25 Beyond the reach of inivo techniques, the S3 segment was found to again have aroton pump, but reabsorptive capacity was balanced by

ncreased back leak in this segment. The final bicarbonateoncentration achieved at the end of the proximal tubule,hich is inaccessible to in vivo techniques, has been esti-ated to be approximately 7 to 8 mmol/L.When the control of proximal nephron bicarbonate reab-

orption was investigated with micropuncture and microper-usion, multiple critical factors were identified, including theffects of extracellular volume, bicarbonate delivery, peritu-ular bicarbonate and pH, carbon dioxide tension, tubularuid flow rate, angiotensin II (AII), catecholamines, insulin,arathyroid hormone, and other hormones.25 The modula-ors of proximal tubule bicarbonate reabsorption are listed inable 1.The advent of microperfusion techniques also has per-itted the evaluation of acid-base transport in the loop ofenle. The mechanisms found in the loop include Na/H

xchange and ammonium transport; in addition, the H-TPase is found in the apical membrane of cells in the

hick ascending loop. When bicarbonate and inulin con-entrations at the end-accessible superficial proximal tu-ule and the early distal convoluted tubule (DCT) areompared, 10% to 20% of the bicarbonate leaving theroximal tubule is found to be reabsorbed. However, mi-ropuncture and in vivo microperfusion do not permit oneo determine the quantitative contribution of the proximaltraight tubule versus the thick ascending loop with regardo this reabsorption. In vivo microperfusion studies per-ormed in rats with metabolic acidosis show increased

able 1 Factors Controlling Proximal Bicarbonate Reabsorption

UpregulatingFactors

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peritubular [HCO3], pH 1 peritubular [HCO3], pHperitubular CO2 2 peritubular CO2

hronic acidosis(systemic)

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luminal [HCO3] Parathyroid hormoneluminal fluid flow rateHCO3 delivery

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otassium depletionypercalcemia

icarbonate reabsorption between the end proximal and c

arly distal tubule; reabsorption also was increased in re-ponse to acute but not chronic metabolic alkalosis.26,27

ood28 studied the medullary thick ascending loop usingn vitro microperfusion and found that both in vivo met-bolic acidosis and in vivo bicarbonate loading of the ratsrom which tubules were obtained increased the reabsorp-ion of total CO2 and ammonium by this segment. The rolef this segment in generation and maintenance of meta-olic alkalosis thus remains open to question.The physiology of the DCT and the collecting duct in renal

cid-base transport and metabolic alkalosis is complex. Thearliest studies that localized a decrease in pH to the collect-ng duct were performed by Ullrich and Eigler,29 using a

icrocatheter advanced up the papilla to obtain samples inhe golden hamster. That the distal nephron and collectinguct system had a role in acidifying the urine were confirmedurther by measurement of transport in the distal tubule, andlso could be imputed from the pH and bicarbonate of thenal urine relative to values at the most distal accessibleortion of the DCT.The distal nephron, including the collecting duct system,

as identified clearly as a major contributor to bicarbonateandling as microtechniques permitted the segmental dissec-ion of renal transport. Studies over the past 20 years definedhe DCT and the cortical collecting duct as sites of greatdaptability of bicarbonate transport. The DCT, a complexosaic of cells with a wide variety of physiologic capacity,

ppears to both secrete and reabsorb bicarbonate at all times,ith alteration of what is generally net bicarbonate reabsorp-

ion as a result. The early distal tubule appears to secreterotons by a sodium-proton exchange mechanism (NHE2),he late distal tubule may show the H,K-ATPase pumps, andhe H-ATPase is seen throughout the segment.30-32 Bicarbon-te secretion occurs in the later portions of the distal tu-ule.33-35 Careful dissection of the unilateral vectors of bicar-onate movement under a variety of acid-base conditions byesson32 and Wesson and Dolson34,36 has shed some light

n this difficult segment, with the most important recentevelopment being the identification of endothelin, a hor-one involved in regulation of blood pressure and volume

esponses, as a significant modulator of bicarbonate trans-ort. Bicarbonate loading served to increase bicarbonate se-retion without decreasing proton secretion; when chlorideas excluded from the luminal fluid, proton secretion was

ound to be enhanced in chronic metabolic alkalosis.34,37

cid loading of animals reduced the rate of bicarbonate se-retion without increasing the rate of proton secretion.38

tudies also showed that endothelin concentrations increaseuring acid loading, that endothelin stimulates the rate ofcid secretion and thus shifts the balance of transport to neteabsorption. Inhibitors (ET1b) of endothelin blunt the re-ponse to acidosis.36 More recently, examination of bidirec-ional bicarbonate flux in rats with chronic alkalosis has in-icated that in this model, there is increased activity of thea-H antiporter and the H,K-ATPase in the DCT, but no

hange in the activity of the H-ATPase.32

Both net bicarbonate reabsorption and net bicarbonate se-
retion have been observed in the collecting duct, depending

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n the pretreatment of the experimental animal.39-41 Bicar-onate secretion in this segment appears to be sensitive toyclic adenosine monophosphate (cAMP)-mediated stimulin the short term and was affected by chloride presence in theumen and chloride gradients across the epithelium.42,43 Bi-arbonate reabsorption mediated by proton secretion by an-ATPase and an H,K-ATPase also varied, with control of the-ATPase by aldosterone and control of the H,K-ATPase byotassium balance.44-46 In the long term, the adaptation ofoth proton-secreting type A intercalated cells and bicarbon-te-secreting type B intercalated cells appeared to play a sig-ificant role. Whether such cells merely undergo a shift be-ween activated and quiescent states or actually totally shiftolarity from proton secretion to bicarbonate secretion hasever been resolved completely. The deeper collecting ductegments show only proton secretion. The medullary collect-ng duct responds to mineralocorticoid hormone by increas-ng H-ATPase activity, and to potassium depletion by in-reasing H,K-ATPase activity.46 Table 2 outlines the knownodulators of acid-base transport in the DCT and the col-

ecting duct system.The importance of the collecting ducts in metabolic alka-

osis lies in the response of these segments to mineralocorti-oid hormone. Desoxycorticosterone acetate was noted tonduce an increase in serum bicarbonate concentration in

able 2 Factors Regulating Distal Nephron Acidification of th

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2 luminal1 luminalMetabolicMineraloco

H-ATPase–mediated H� secretion Mineraloco1 peritubu2 peritububuffer deliv1 Na reab2 luminalmetabolic

H,K-ATPase–mediated H� secretion PotassiumCDH-ATPase–mediated H� secretion Mineraloco

1 peritubu2 peritubu2 luminalMetabolic

H,K-ATPase–mediated H� secretion HypokalemPotassium

uman beings 50 years ago.47 However, in the absence ofther confounders, the effect of mineralocorticoid on serumicarbonate is mild. The administration of exogenous aldo-terone results in only a 1 to 3 mEq/L increase in serumicarbonate level.48 On the other hand, an increase of min-ralocorticoid hormone levels increases urinary potassiumxcretion and thus contributes to potassium depletion, a ma-or influence in metabolic alkalosis.

linical Relevancef Metabolic Alkalosis

here is no accurate estimate of the incidence or prevalencef metabolic alkalosis. To quote many, metabolic alkalosis isot an overwhelming issue in public health. Most patientsho have mild acute or chronic metabolic alkalosis are notospitalized; even fewer of these individuals are ever specif-

cally diagnosed. Most patients with metabolic alkalosisever have the requisite laboratory testing, which includes anrterial blood gas measurement, to make a certain diagnosis.ertainly the only estimates of epidemiology that can be gen-rated would need to be based on the frequency of metaboliclkalosis as an inpatient diagnosis. Our ability to generateccurate estimates of secondary diagnoses was lost long ago

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hen discharge diagnosis lists became irretrievably en-eshed with billing issues. A patient who develops metabolic

lkalosis as a result of diuretic administration for the treat-ent of congestive heart failure and vomiting related to liverysfunction consequent to passive congestion may be dis-harged with diagnoses of congestive heart failure, passiveongestion of the liver, emesis, and arrhythmias, but will notikely bear diagnoses of contraction of effective arterial bloodolume, hypokalemia, potassium depletion, or metabolic al-alosis. The Center for Medicare and Medicaid Services limitshe number of diagnoses to be reported. Billing clerks rou-inely look for the most lucrative diagnoses and the Diseaseelated Group payment for metabolic alkalosis is not lucra-

ive. Furthermore, if metabolic alkalosis is a result of priorreatment with diuretics, emesis as a result of medications, ornattention to volume status then the diagnosis may beiewed as a red flag for potential lawsuit, and the attention itould bring could prevent one from highlighting its occur-

ence.When one considers the causes of metabolic alkalosis

isted previously, it is obvious that many patients (all thoseho develop metabolic alkalosis after nasogastric suction,

hose on diuretics, and those developing posthypercapniclkalemia) have the disorder on the basis of therapeutic mis-dventure. To these also must be added the growing inci-ence of alkalosis resulting from the use of citrate anticoag-lation during chronic renal replacement therapy, andlkalosis caused by the increasing use of calcium carbonate toreat bone disorders in the aging. The exact percentage ofases of metabolic alkalosis that are iatrogenic remains un-nown.Alkalosis and alkalemia are important because they alterorbidity and mortality. Increase of blood pH increases car-iac arrhythmia, probably through mechanisms involving aecrease in ionized calcium concentration and potassiumhifts.49 Other effects include alteration of consciousness, in-reased seizure activity, decreased oxygen release to tissuerom hemoglobin, tetany secondary to hypocalcemia, in-reased ammonia generation by the kidney, and, in somenstances, depression of the respiratory drive.50-53 Althoughhe data regarding this issue are far from plentiful, Luke54

ecently reviewed in detail the incidence and impact of met-bolic alkalosis. Metabolic alkalosis has been reported to ac-ount for more than half of all acid-base disorders in anntensive care setting, and also was associated with high mor-ality rates.55-57 Because mortality is especially high when aH in excess of 7.6 develops, intervention at a pH of 7.55 andreater has been recommended.58 Data regarding hospital-zed patients outside the intensive care setting are not avail-ble and likely will never be forthcoming.

etabolic Alkalosisn Clinical Practicet is useful to begin a discussion of clinical metabolic alkalosisith a precise definition of terms, even when one presumes a

eadership with significant knowledge of medicine and ne- p

hrology. The clinical term alkalemia defines a pathophysio-ogic state in which there is an observed increase in the pH ofhe blood that is greater than normal. By contrast, the termlkalosis here defines a pathophysiologic process that tends toncrease the relative amount of base, or alkali, in the body. Inhe case of metabolic alkalosis, the pathophysiologic pro-esses that tend to increase the net amount of alkali in theody are either the loss of fixed acid derived from metabolicources to the external environment, or the ingestion of base.ecause any number of acid-base abnormalities may co-exist

n a single patient, the presence of alkalosis does not presumehat alkalemia also is present. For instance, a patient withetabolic alkalosis may have an ongoing state of metabolic

cidosis, as in the case of a patient who initially has metaboliclkalosis caused by vomiting, and then develops diabetic ke-oacidosis as a result of a failure to take insulin. If the keto-cidosis is severe, the arterial blood pH may be well belowormal, but the initial metabolic alkalosis still would beresent.Regardless of differences in opinion arising from the inter-

retation of study results relative to the relative importance ofolume, chloride, and potassium, it generally is agreed thatetabolic alkalosis is divisible into 2 phases, a generation

hase during which the relative concentration of alkali withinhe body increases or tends to increase, and a maintenancehase during which the increased bicarbonate is retained.hese 2 phases are each considered later.

he Generationf Metabolic Alkalosisxcess Alkali Administration or Intakehe simplest way to increase serum bicarbonate concentra-

ion is to administer excessive amounts of base to the patient.lthough this is never performed purposefully to create met-bolic alkalosis, several common clinical errors by patients orhysicians may produce this result. The milk-alkali syn-rome once was seen commonly when peptic ulcer diseaseas treated with calcium carbonate and the Sippy diet.59 The

requency at which it was diagnosed decreased markedlyith the introduction of H2 blockers and H,K-ATPase inhib-

tors, especially since the recognition of Helicobacter pylori ashe cause of ulcer led to the development of curative triple-rug therapy. However, the number of cases may be in-reased most recently because of the emphasis on the use ofairy and calcium supplementation for prevention or thereatment of osteoporosis and, recently, the promotion ofeight loss, especially if vitamin D also is taken. The condi-

ion is more likely to develop if renal insufficiency isresent.60

Excess administration of base also may arise as a result ofvertreatment of metabolic acidosis resulting from adminis-ration of bicarbonate in the treatment of diabetic ketoacido-is or lactic acidosis, and the misinterpretation of the de-ressed serum bicarbonate in respiratory alkalosis as a sign ofetabolic acidosis in the absence of measurement of arterial
H. Finally, the introduction of citrate anticoagulation in

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hronic renal replacement therapy has led to the occurrencef metabolic alkalosis as a result of the large quantities oficarbonate precursor during treatment61,62 If completelyonverted, each millimole of citrate given produces 3 mmolf bicarbonate. If adjustments are not made in replacementuids and dialysate, severe metabolic alkalosis may develop,ven in patients with renal failure.

astric Alkalosisastric loss of acid is a common cause of metabolic alkalosis.

t may result from emesis or from the use of nasogastricuction or drainage. The concentration of acid in gastric juices significant; the pH generally is less than 2.0. A liter ofastric juice at a pH of 1.0 has a proton concentration equal-ng 100 mEq/L; up to 4 L/d of gastric juice may be lost touction in the presence of outlet obstruction. Lesser amountsre lost if some of the stomach’s output reaches the duode-um to react with secreted bicarbonate. The maximum lossf acid by this route is therefore 400 mEq/d of acid. Notably,ecause it is hydrochloric acid that is lost, this involves the

oss of up to 400 mEq of chloride. Thus, in the presence ofevere vomiting or continuous suction, significant volumeoss accompanies the ongoing loss of acid. If volume loss isot monitored carefully and replaced appropriately, signifi-ant volume depletion will occur, triggering the secretion ofldosterone.

Gastric alkalosis almost always is associated with the de-elopment of potassium depletion, but the potassium loss isot a direct consequence of emesis. Rather, the increase ofineralocorticoid levels in response to volume depletion

timulates renal potassium secretion at the distal nephronnd collecting duct.

The risk of developing gastric alkalosis can be minimizedy the use of antiemetics when indicated, limiting the use ofasogastric suction, by careful attention to volume losses andppropriate replacement of ongoing losses, and by reductionf gastric acid secretion in the presence of nasogastric suc-ion.63 In the absence of concurrent use of diuretics, the urinehloride can be used to determine when the volume stateeturns to normal.

iuretic-Induced Alkalosishat diuretics may induce metabolic alkalosis has been real-

zed since the introduction of effective diuretic agents over aalf a century ago. Loop diuretics and thiazides have 3 im-ortant effects relative to the generation of metabolic alkalo-is. First, they increase acid excretion by the kidneys. Netcid excretion increases markedly in response to both typesf diuretics. Loop diuretics also decrease urine pH, indicatingncreased acid excretion, a property used in the furosemideest for renal tubular acidosis.64 Because both loop diureticsnd thiazides work beyond the proximal tubule, they haveittle direct effect on bicarbonate reabsorption. However,oth types of diuretics induce chloriuresis and natriuresis. Inddition, the loop diuretics, which inhibit the Na-K-2Cl co-ransporter of the loop of Henle, directly increase potassium
rinary potassium loss. g
The volume depletion that develops in response to diureticse results in the stimulation of aldosterone secretion. Again,ldosterone, by increasing apical membrane sodium perme-bility and the basolateral membrane Na,K-ATPase activity inrincipal cells of the cortical collecting duct and in distalephron cells, causes an increase in the luminal negativity ofhese segments. Potassium secretion, a passive process re-ponsive to the epithelial potential, is increased. In addition,his passive secretory process is sensitive to the rate at whichubular fluid flows past the collecting ducts. As diureticsncrease flow, potassium secretion increases directly.

Other diuretic agents have opposing effects. Although rarelysed as diuretics per se, carbonic anhydrase inhibitors effec-ively limit the reabsorption of bicarbonate in the proximalubule and also inhibit acid secretion in the distal nephronnd collecting duct. Thus, their use routinely results in theevelopment of hypobicarbonatemia and metabolic acidosis.owever, by increasing distal delivery of sodium, increasing

he delivery of a nonreabsorbable anion (bicarbonate is non-eabsorbable in the distal nephron after carbonic anhydrasenhibition), and increasing flow rate, carbonic anhydrase in-ibitors can cause significant potassium wasting. This is ofome importance when these agents are used to induce di-resis and bicarbonate loss in patients with so-called posthy-ercapnic metabolic acidosis.Spironolactone, eplerenone, amiloride, and triamterene all

educe acid excretion and potassium loss by interfering withineralocorticoid action in the distal tubule and the collect-

ng duct. These agents are not associated with metabolic al-alosis, rather they tend to induce a mild hyperchloremicetabolic acidosis.

rimary Mineralocorticoid Excessldosterone and other adrenal hormones with mineralocor-

icoid activity stimulate sodium reabsorption in the DCT andhe cortical collecting duct by increasing the apical mem-rane sodium permeability of principal cells and increasinga,K-ATPase activity in these cells as well. As sodium reab-

orption increases in these segments via the apical membraneodium channel (ENaC), there is a resulting increase in theumen negative electrical potential across these epithelia. Theegative potential increases the passive transfer of potassium

nto the tubule lumen, producing a kaliuresis. In addition,he lumen negativity reduces the work required for activeroton secretion by the electrogenic H-ATPase found in bothites. Proton secretion subsequently is enhanced.

In addition to stimulating the Na,K-ATPase, aldosteronelso stimulates the electrogenic H-ATPase. The rate of protonransport increases, but the power of the pump does nothange, suggesting that more pumps are made available inhe membrane. H-ATPase is increased in the medullary col-ecting duct and the previously mentioned segments.

There are several syndromes of primary mineralocorti-oid excess associated with hypokalemia and alkalosis.hese include primary aldosteronism (Conn’s syndrome,drenal hyperplasia, and adrenal carcinoma), the adreno-
enital syndrome (11�- and 17�-hydroxylase deficiency),

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ia and alkalosis may be seen as well in secondary states ofypermineralocorticoidism unassociated with volume de-letion (unilateral renal artery stenosis, tumor of the jux-aglomerular apparatus).

rimary Glucocorticoid Excessdrenal hyperactivity, whether primary or secondary, has

ong been associated with metabolic alkalosis. Several mech-nisms appear to be involved.

Although mineralocorticoid hormones have been showno stimulate acid secretion in the collecting duct, glucocorti-oid hormones appear to exert primary effects on the proxi-al tubule and loop of Henle.65-68 Both Na/H exchange anda,K-ATPase activity appear to be stimulated by these hor-ones; theoretically the proximal reabsorption of volume

nd bicarbonate should be increased. However, the directdministration of glucocorticoids does not result in the de-elopment of metabolic alkalosis.69 This being said, why doatients with Cushing’s disease develop metabolic alkalosis?ost do not have increased aldosterone levels. However,

onaldosterone mineralocorticoid hormones are found in aignificant number, and glucocorticoid hormones do exertineralocorticoid-like effects.70-72 The mineralocorticoid-

ike effects include not only increased acid excretion, but alsoncreased potassium secretion and the development of potas-ium depletion.

enal Tubular Disorders Associatedith Alkalosis and Potassium Wasting

everal renal tubular disorders are associated with both po-assium wasting and metabolic alkalosis. These include Bar-ter syndrome, Gitelman’s syndrome, and Liddle syndrome.

Bartter syndrome is characterized by the presence of pro-ound hypokalemia, metabolic alkalosis, volume depletionith low blood pressure, and the development of renal fail-re caused by tubulointerstitial scarring. Its cause was long aystery. The metabolic aspects of the disorder resembledineralocorticoid excess, but blood pressure was low and

olume depletion could be severe. Kurtzman and Guitier-ez73 once suggested that a chloride leak was the most likelyause because of the resemblance of the condition to surrep-itious use of loop diuretics with secondary hyperaldosteron-sm. The true nature of the defect in Bartter syndrome was notnderstood until after the mechanisms of chloride, sodium,nd potassium reabsorption in the loop of Henle was de-ned.74,75 Recent studies have indicated that the disorderay result from any one of several genetic defects involving

he following: (1) the Na-K-2Cl cotransporter in type I,76 (2) theuminal potassium channel (ROMK) in type II,77 (3) the baso-ateral membrane chloride channel (CLCNKB) in type III,78

nd, (4) a subunit of the Cl channel called barttin in type IV.79

he type IV patients also are afflicted with sensorineural deaf-ess. Although the individual mechanisms differ, in every

nstance the result is potassium loss with volume depletion. i

n type I it occurs by direct inhibition of Na, K, and Clransport and in type II it is caused by secondary failure of theotransporter consequent to a primary defect of potassiumecirculation. In types III and IV the failure of basolateralhloride exit results in the secondary failure of Na-K-2Clptake. The volume depletion that follows the sodium chlo-ide loss induces aldosterone secretion, which results in fur-her acid and potassium secretion by the collecting duct.

Gitelman’s syndrome closely resembles Bartter syndromeut it also is associated with the presence of significant uri-ary magnesium wasting and hypomagnesemia. Gitelman’syndrome also presents with hypercalcemia and hypocalci-ria. It has been shown to be caused by any one of severalefects affecting the thiazide-sensitive Na-Cl cotransporter ofhe distal tubule.80,81 The genetic defect thus clearly explainshe similarity of the disease physiology to the effects of thia-ide diuretics. The failure of NaCl cotransport results in con-inual natriuresis, chloruresis, and volume depletion. Theres subsequent aldosterone release and further potassium loss,nd urinary proton secretion follow. Hypercalcemia and hy-ocalciuria are a consequence of inhibition of NaCl uptakefter thiazide diuretic use. The mechanism of magnesium losss not well understood.

Not all cases of Bartter and Gitelman’s syndromes are clearlyistinguishable, and additional genetic defects have been lo-ated with syndromes closely resembling each.82 If the clini-al phenotype strongly suggests one or the other syndrome isresent, the absence of the expected genotype should lead tosearch for additional defects rather than the abandonmentf the diagnosis.Liddle syndrome more closely resembles pure mineralo-

orticoid excess than either Bartter or Gitelman’s syndromes.n Liddle syndrome metabolic alkalosis and potassium defi-iency is associated with hypertension in the presence of lowldosterone levels. Molecular genetic studies defined theause of Liddle syndrome to be an abnormal � subunit of theistal nephron ENaC that causes the channel to remain in itspen configuration for a greater percentage of time than nor-al.83 The effect is thus to mimic mineralocorticoid stimula-

ion of sodium entry at this site. Potassium wastage and ex-essive proton secretion result from increased sodiumeabsorption and transepithelial potential. The effect of thencreased luminal negativity is enhancement of passive po-assium secretion, and also increased proton secretion.

ereditary Chloride-Losing Diarrheaost nephrologists have heard of this entity but very few

ave ever seen it. Children with the disorder lack normall-bicarbonate exchange in the ileum, resulting in continu-us loss of chloride in the stool.84 Volume depletion resultsnd there is a compensatory increase in aldosterone secretionith subsequent effects on potassium handling producingypokalemia. It has been treated classically by replenishingolume and potassium losses. More recently, proton pump
nhibitors have been advanced as therapy.85

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ubular Adenomaetabolic alkalosis resulting from secretion of electrolytes byvillous adenoma of the colon was first reported in 1961.86

hese otherwise benign tumors secrete varying amounts ofhloride and bicarbonate, and generally secrete sodium andotassium at high concentrations. Volume loss may approachL/d. Because volume depletion will increase aldosterone

evels and subsequently lead to renal potassium secretion,lkalosis may result even if potassium is not secreted by theumor. Potassium secretion by the tumor increases the risk oferious metabolic alkalosis.

icorice Ingestionlycyrrhizinic acid is a naturally occurring compound found

n licorice. Although it originally was believed to cause ex-essive potassium secretion by the distal nephron because itunctioned as a mineralocorticoid, later studies found glycyr-hizinic acid to be a competitive inhibitor of 11�-hydroxys-eroid dehydrogenase.87 Carbenoxolone appears to share thisehavior.

otassium Depletionenal potassium transport and renal acidification of the urine

nteract on multiple levels. Potassium depletion and excesslter aldosterone release. Mineralocorticoid stimulation ofhe distal nephron and collecting duct increases both protonecretion (by increasing H-ATPase activity) and sodium re-bsorption. The increased sodium reabsorption increases theumen-negative transepithelial potential in the cortical col-ecting duct and thus reduces the work of proton secretion.he increased potential also increases the passive secretion ofotassium. Potassium and hydrogen ion transport in the col-

ecting duct also are linked at the H,K-ATPase. Here, obvi-usly, the ions move in opposite directions. The luminal,K-ATPase is stimulated markedly by potassium depletion,

esulting in reclamation of intraluminal potassium, but lossf acid. Unlike the H-ATPase, the H,K-ATPase does not ap-ear to respond to mineralocorticoid hormone directly.Additional links between potassium homeostasis and acid-

ase balance exist. Potassium balance is a critical regulator ofmmonium metabolism. Potassium depletion stimulates am-onium production and excretion, a response of consider-

ble consequence in patients with liver disease, and a possi-le mediator of interstitial renal fibrosis in chronic potassiumeficiency. Excess potassium and hyperkalemia inhibits am-onium production and excretion, an effect of considerable

mportance in the management of renal acidosis.Potassium depletion and hypokalemia affect proximal tu-

ule acidification directly through stimulation of transport-rs and alteration of intracellular pH as shown by the effectsf K depletion on proximal tubules studied in vivo.88-90 Thus,otassium depletion and hypokalemia may increase proxi-al reabsorption of bicarbonate and help maintain a state ofetabolic alkalosis.Potassium depletion also has been shown to significantly

lter glomerular hemodynamics and it increases renin and
II levels.90-93 These effects have been implicated in the de- t
elopment of volume-resistant (ie, chloride-resistant) meta-olic alkalosis.Clinical reports indicate that, in human beings, severe po-

assium depletion results in mild metabolic alkalosis.94 Bothenal and nonrenal mechanisms have been inferred, and theondition is not related to chloride depletion.

onreabsorbable Anionshe reabsorption of sodium in the distal tubule and corti-al collecting duct is associated with the development andaintenance of a lumen-negative electrical potential thatay both increase passive potassium secretion and in-

rease proton secretion by reducing the total gradientgainst which the H-ATPase pump must work. The elec-rical potential is the result of the difference between so-ium and chloride movement across the membrane. Theotential generated by the reabsorption of sodium de-ends on the conductance of the anion that travels withodium. (Conductance is the reciprocal of resistance; it iselated to chemical permeability and ionic charge.) Sub-tituting an anion less permeable than chloride for chlo-ide increases the electrical potential generated by theransport of sodium. Examples of relatively nonpermeablenions include phosphate and sulfate, which may be usedo stimulate acidification of the urine in tests of distalcidification.

Clinically, the substances usually involved in the develop-ent of metabolic alkalosis as a result of enhancement ofotassium and proton secretion by impermeable anions arehe penicillins and cephalosporins.95,96 The key factors arehat the anion is impermeable and that the drug appears inuantity in the urine.

ostmetabolic Acidosisetabolic alkalosis may appear in the wake of treated meta-

olic acidosis as the result of 2 general mechanisms. First, thereating physician may overestimate the amount of bicarbon-te required to correct the acidosis. Second, the treating phy-ician may underestimate how much base will be producedrom bicarbonate precursors when the underlying cause ofverproduction acidosis is corrected in ketoacidosis and lac-ic acidosis.97,98 Usually, the metabolic alkalosis will be mildecause the additional bicarbonate will be excreted in therine when volume and potassium deficits have been cor-ected.

lkalosis Posthypercapnicespiratory Acidosishe response of the carbon dioxide/carbonic acid/bicarbon-te/carbonate buffer system to the addition of carbon dioxides to increase the plasma bicarbonate concentration. In addi-ion, hypercarbia stimulates proton secretion by cells in-olved in renal acidification causing acid loss to the urine;ypercarbia also decreases blood pressure and glomerularltration rate, which reduces the bicarbonate filtered loadnd supports an increased serum bicarbonate concentra-
ion.8 All these events are part of metabolic compensation in

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espiratory acidosis, and they serve to maintain blood pH at aevel much nearer to normal than might be expected from thencrease in carbon dioxide tension. Although the bicarbonateevel is increased, this increase is not truly metabolic alkalo-is.

When respiratory failure is corrected, the carbon dioxideension may decrease rapidly. This is especially true in in-tances in which patients are placed on ventilator support. Ashe partial pressure of carbon dioxide decreases, serum pHncreases and alkalemia may develop. The situation shoulde self-correcting. When the effects of respiratory acidosis onroximal bicarbonate reabsorption and on glomerular filtra-ion have been removed, the resulting increase in filtered loadnd decrease in proximal reabsorption should lead to rapidxcretion of excess bicarbonate. This process should occurithin 48 hours of the restoration of normal ventilation.ithin this period, the increased bicarbonate is expected,

nd little additional intervention is needed. However, in thelinical setting, the patient with respiratory failure often isiven diuretics in an attempt to improve respiratory function.he result of this intervention is further contraction of theffective arterial volume, increase of aldosterone levels, andotassium loss. If this has occurred, the patient may be un-ble to undergo the anticipated bicarbonatriuresis. An ex-ended period of metabolic alkalosis may ensue. Treatment iso restore volume and circulation, and to repair any potas-ium deficits that may have occurred.

We add 2 additional notes of caution. First, when onedministers saline to a patient such as the one just described,ne potential result is that the resulting bicarbonaturia serveso deliver a nonreabsorbable anion (bicarbonate is a nonre-bsorbable anion in the presence of alkalemia) to a distalubule and cortical collecting duct primed for potassium se-retion by aldosterone. As a result, large amounts of potas-ium then may be lost in the urine, resulting in potassiumeficiency, which renders the metabolic alkalosis chlorideesistant. Second, the use of acetazolamide to induce bicar-onatriuresis will induce even greater potassium losses. Theotassium deficits inherent in the posthypercapnic state muste corrected. Both volume and potassium are required in thisondition.

oststarvation Alkalosisefeeding carbohydrates after starvation is an unusual butell-documented cause of metabolic alkalosis. Mechanisms

re not certain, but may include conversion of circulatingetoacids to bicarbonate after significant losses of ketoacids

n the urine.99

aintenance Phasef Metabolic Alkalosis

he preceding discussion has outlined both common andncommon mechanisms by which metabolic alkalosis is gen-rated. One of 2 processes occurs. Metabolic alkalosis is ei-her generated by the net gain of alkali (as in the case of
icarbonate administration or calcium carbonate ingestion) l
r by the net loss of acid (as in emesis/nasogastric suction orenal loss of acid during stimulation by mineralocorticoidormones). When either of these processes occurs in theresence of normal or increased effective arterial volume, theesulting metabolic alkalosis is limited. Metabolic alkalosisends to dissipate if its generating mechanism is interruptednd kidney function and volume status are normal.

The most common clinically relevant examples of meta-olic alkalosis are marked not only by a generation phase, butlso by the presence of a definable maintenance phase. Threeajor factors classically underlie the maintenance phase ofetabolic alkalosis in most clinical situations. These are as

ollows: (1) changes in circulating volume (volume deple-ion), generalized hemodynamics (heart failure), and intrare-al hemodynamics (alteration of preglomerular and postglo-erular resistance and filtration fraction) that combine to

educe the filtered load of bicarbonate traversing the proxi-al tubule despite the increase of plasma bicarbonate con-

entration; (2) increased aldosterone secretion, which occursecondary to diminished volume and increased AII concen-ration, that stimulates renal acid secretion; and (3) potas-ium depletion and hypokalemia, which alter glomerular he-odynamics, stimulate the renal H,K-ATPase, and

econdarily increase renal acid secretion in the presence ofldosterone. A terse summary of these effects could simplytate that the regulation of bicarbonate concentration and pHs sacrificed to preserve volume and potassium stores. If vol-me and potassium balance are normal, metabolic alkalosiself-corrects.

The mechanisms by which metabolic alkalosis is main-ained are regulated by the actions of several mediators.hese are divisible into those classically recognized to be

mportant to metabolic alkalosis, primarily renin, angioten-in, and aldosterone, and those more recently recognized,rimarily endothelin and nitric oxide. The role of the renin-ngiotensin-aldosterone axis in the maintenance of metaboliclkalosis has long been recognized and need not be reviewedn depth here. The stimuli for renin release include inputrom stretch-sensing renal baroreceptors, the composition ofubular fluid at the macula densa, central nervous systemnput, circulating or local prostaglandins, and cAMP-medi-ted circulating hormones. Decreased circulating volume,ecreased salt delivery to the macula densa, and changes inentral nervous system input all may act to increase reninelease when volume is depressed. The primary result of in-reased renin release is enhanced production of angiotensin Irom angiotensinogen (renin substrate). The conversion ofngiotensin I to AII is mediated by converting enzyme. AIIncreases blood pressure by increasing arterial vasoconstric-ion, which increases postglomerular resistance, thereby in-reasing filtration fraction and glomerular filtration rate. Itcts on the proximal tubule to increase bicarbonate reabsorp-ion, and stimulates the adrenal gland to increase aldosteroneelease. Aldosterone in turn acts on the distal nephron toncrease the apical membrane sodium conductance and theasolateral membrane Na,K-ATPase activity in sodium-reab-orbing principal cells and the H-ATPase of type A interca-
ated cells. This produces increased sodium absorption, in-

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reased transepithelial potential, and directly increasesroton secretion. The increase in transepithelial potentialrives passive potassium secretion and enhances electrogenicrinary acidification medicated by the H-ATPase. Thus, throughhe actions of AII on the proximal tubule, and actions ofldosterone on the distal nephron, proximal bicarbonate re-bsorption is stimulated, and distal proton and potassiumecretion are enhanced. The renin-angiotensin-aldosteronexis irretrievably links the maintenance of volume to acid-ase and potassium homeostasis. Newer aspects of angioten-in and aldosterone action and the actions of nitric oxide andndothelin are considered later.

ecentevelopments Impactingn our Understandingf Metabolic Alkalosisngiotensin IIur concepts regarding the diversity of AII effects have ex-anded markedly in the past decade. This comes in part fromhe recognition that all of the cellular machinery for local AIIroduction and/or AII receptors exists in widely diverse tis-ues, including the heart, jejunum, liver, and lungs. It is nowlear that the renal proximal tubule synthesizes AII and thatII receptors are found on both brush-border and basolateralembranes. In the S1 segment of the proximal tubule AII

inding is 10-fold higher than the S2 segment; binding den-ity in the pars recta (S3) is minimal. All later tubule segmentsontain AII receptors, with the lowest density noted in theortical collecting duct.

Type 1 angiotensin receptors mediate most tubular trans-ort and hemodynamic effects of AII. In the proximal tubuleiu and Cogan100 found that systemic infusion of AII, whichid not change blood pressure, was associated with a 50%

ncrease in bicarbonate reabsorption in the S1 segment of thearly proximal tubule and a significant, although lesser, in-rease in flux in the late proximal convoluted tubule. Subse-uent studies have shown that AII can be released at the

uminal membrane by perfused tubules and by culturedroximal tubular cells, documenting its importance as a reg-lator of transport in the renal cortex.101,102 This apical mem-rane release is detectable despite the presence of largemounts of degrading angiotensinases in the apical brushorder. Approximately 90% of an infused arterial dose of AII

s degraded after a single pass through kidney.103 Seikaly etl102 further examined the importance of luminal membraneII release in glomerular ultrafiltrate using micropuncture

echniques and found intraluminal AII concentrations to be,000-fold higher than that in plasma.The nonhemodynamic effects of AII in the kidney areany; some are more well known than others. In proximal

ubular cells AII stimulates H3-thymidine incorporation (hy-ertrophy), as well as actin and collagen synthesis, and itnhances the action of epidermal growth factor.104,105 AII also
irectly stimulates the release of several peptides involved in e
ell proliferation (hyperplasia) and fibrosis (progressive renalnjury). These peptides include endothelin, platelet-derivedrowth factor, and transforming growth factor-�.106 AII alsotimulates ammoniagenesis, a phenomenon long associatedith hypokalemia, and a further stimulus to renal hypertro-hy. In acid-base balance, one thus could postulate that AIIets the scene for the unchecked maintenance of metaboliclkalosis. Coupled with its action to decrease urinary nitricxide secretion (a potent renal vasodilator) and cause a de-rease in glomerular filtration rate, these effects of AII act as aositive feedback and drive a relentless increase in bicarbon-te retention.107 Kwon et al108 showed that if AII was given toats for 7 days, apical NHE3 labeling was increased markedlyn the medullary thick limb (inner stripe of the outer me-ulla) and in the proximal convoluted tubule. By contrast,all et al109 showed that AII at 10-8 mol/L in the surrounding

ath decreased acid excretion in the rat medullary collectingubule.

The best-studied mechanism of AII action is its stimulationf aldosterone release from the zona glomerulosa of the ad-enal cortex. Classic theory states that in response to a de-rease in pressure, pH, or distal salt delivery to the maculaensa, renin is released from the juxtaglomerular cells. Reninhen enzymatically converts angiotensinogen to angiotensin Iith the latter converted to AII. AII then stimulates the re-

ease of aldosterone. Hyperkalemia is also a potent stimuluso aldosterone release but probably not via the renin-AIIechanisms just described.110 Given all the new information

btained using a variety of techniques such as knock-out andverexpression studies, molecular and microarray investiga-ions, and human genetic profiling, it is time to reassess thelassic theory. For 2.5 decades we have recognized the im-ortance of autocrine and paracrine (cross-talk) elementsithin cells. We are now just beginning to discover the com-lexity of this issue with regard to AII.

ldosteronen the past decade new studies have uncovered several newiologic actions of the mineralocorticoid hormone aldoste-one, some of which are nongenomic. These actions occuruickly, at times within minutes in the kidney and in non-raditional target tissues and will be considered here first. Theull relevance of these new actions to hypokalemic metaboliclkalosis in human pathophysiology remains to be elucidatedut these new data provoke significant questions.Terada et al111 identified aldosterone receptors in cultured

at mesangial cells and glomeruli and showed that aldoste-one stimulates c-Raf and certain components of the cell-ycle pathway, notably cyclin D1 and cyclin A promoter ac-ivities, as well as their protein and mitogen-activatedinases. These actions may adversely affect glomerular filtra-ion rate with time, in a manner analogous to the deleterioushanges induced by aldosterone in the heart, where the aldo-terone antagonists (eg, spironolactone) have been proven toe clinically beneficial.Quinkler et al112 recently provided evidence for excess min-

ralocorticoid receptor abundance in human renal biopsy tis-

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ues with a significant increase in the response of inflammatoryediators such as renal transforming growth factor-�1 messen-

er RNA (mRNA) (3-fold increase), interleukin-6 mRNA (2-foldncrease), and macrophage chemoattractant protein-1 (7-foldncrease). In renal tubular cells, Cha et al113 found that mac-ophage chemoattractant protein-1, connective tissue growthactor, and nuclear factor-� B were increased in abundancefter incubation with aldosterone and that spironolactoneretreatment prevented this response. In rat renal fibroblasts,ldosterone treatment resulted in rapid phosphorylation ofxtracellular signal-regulated kinases 1/2 followed by a sub-equent increase in collagen (types I, III, IV).114 The spirono-actone antagonist eplerenone blocked these actions (ibid).114

uman mesangial cells115 showed that AII stimulated aldo-terone synthesis and that the addition of low-density li-oprotein synergistically increased the rate of synthesis.In the medullary thick ascending limb 1 nmol/L aldoste-

one rapidly decreases bicarbonate reabsorption by 30%.his action was preserved when maneuvers were used to

nhibit basolateral NHE1 activity. Similar results were ob-ained in medullary thick ascending limbs from NHE1nockout mice. By using inhibitors to block an apical protononductance and apical K-HCO3 cotransport, Good et al116

oncluded that aldosterone must modulate the apical NHE3xchanger.

In the collecting duct aldosterone increases Na reabsorp-ion by stimulating basolateral Na,K-ATPase activity and theNaC. These effects occur after 4 hours and result from gene

ranscription. In the cortical collecting duct proton secretionH-ATPase) is stimulated in �-intercalated cells via a Na-ependent mechanism, whereas in the medullary collectinguct aldosterone action is Na-independent. Aldosterone doesot appear to directly affect the collecting duct H,K-ATPase,owever, the H,K-ATPase is stimulated to reabsorb potas-ium and to secrete protons during potassium-depletedtates.46

In studies performed in our laboratory,46 we showed thathe most severe metabolic alkalosis occurred when rats givenharmacologic amounts of aldosterone were simultaneouslylaced on a low-potassium diet (see Table 3).46 In a series ofgroups (only 8 of which could be studied) we showed that

n vivo chronic aldosterone excess (delivered via osmoticinipump) to animals on a low-potassium diet developed

able 3 Effect of Body Potassium Stores and Plasma Aldo-terone on Plasma HCO3 (mEq/L) and Collecting Tubule-ATPase and H, K-ATPase

Low-PotassiumDiet

High-PotassiumDiet

ero aldosterone 21 mEq/L 16 mEq/LH-ATPase � 0 H-ATPase � 0H,KATPase 11 H,KATPase � 0

igh aldosterone 46 mEq/LH-ATPase 111H,K-ATPase 11

ormal potassium diet, normal aldosterone. and sham groups not
rshown.44
he most severe metabolic alkalosis with a plasma bicar-onate averaging 46 mEq/L. When collecting tubules fromhese animals were dissected and the H-ATPase and H,K-TPase activities were measured using radiolabeled ATP,

his same group had the highest levels of activity of bothnzymes. The lowest H-ATPase activity was found in the 3roups given no aldosterone, regardless of whether theyere on a low-, normal, or high-potassium diet. The high-

st activity of H,K-ATPase was found in the 3 groups ofnimals on the low-potassium diet, confirming the find-ngs of Wingo117 in the isolated perfused tubule. (In theow-potassium groups the H,K-ATPase activity was unaf-ected by the amount of aldosterone given via osmoticinipump.) Although these effects are thought to reflect

vents occurring in the intercalated cells of the distalephron, the close association of intercalated cells to thea-reabsorbing principal cells could allow regulators of

odium transport to influence the 2 enzymes in a paracrineashion.

Rozansky118 recently reviewed the aldosterone-sensitiveathways and the perturbations resulting within collectinguct Na-reabsorbing cells during aldosterone stimulation.rom the effect of aldosterone to enhance basolateral surfacerea and Na, K-ATPase activity to the hormone’s action toncrease ENaC surface cell expression (and, in the late DCT toncrease the thiazide-sensitive NaCl cotransporter), it is clearhat many aldosterone-sensitive genes are involved and 3 to 4econdary intracellular messengers are synthesized. Whetherhese act only within one cell type or are capable of subse-uently acting on closely surrounding cells (or releasing yetther mediators) remains to be elucidated.In Figure 1 the effect of aldosterone (lower right corner)

n some of these intracellular actions is shown. Serum andlucocorticoid-inducible kinase 1 (SGK1) mRNA is stim-lated within 30 minutes of incubation with aldoste-one.118 It subsequently phosphorylates specific serinend threonine residues, including, in the principal cells,hose on the Nedd4 to 2 protein. This then allows ENaC toncrease at the apical cell surface and hence stimulate Naeabsorption. SGK1 back-diffuses to the basolateral mem-rane and stimulates the Na,K-ATPase. SGK1 functionequires activation by phosphatidylinositol 3 kinase, annzyme activated by insulin and other mediators.119,120

he WNK proteins, another family of serine-threonineinases, also are stimulated by aldosterone, at least kid-ey-specific WNK1. This isoform may modulate SGK1.ther WNK isoforms may affect ROMK channels121 in thea-reabsorbing cells. Although Figure 1 outlines the in-

racellular effects of aldosterone on sodium reabsorption,omparable mechanisms may be involved in the protonecretory cells.

Gumz et al122 has shown that early transcriptional effects ofldosterone include stimulation of preproendothelin in addi-ion to SGK. By using microarray technology these investiga-ors also report that a number of other transcripts are upregu-ated by aldosterone, including connective tissue growthactor, a prostaglandin E–receptor subtype, a retinoic acid–
esponsive transcript, and claudin-1. How these and other

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ndothelinn the past 15 years the endothelins (ET) have been recognizedo play an important role in both proximal and distal urinarycidification. This 3-member 21-amino acid polypeptide familyET-1, ET-2, and ET-3) is synthesized in diverse cell types in aide variety of tissues including vascular endothelial cells, heart,

iver, gut, gonads, neurons, adrenal medulla, and the eye. ETsre best known for causing smooth muscle contraction (they are0 times more potent than AII), but now it is clear that one or allre involved in stimulation of growth, myocardial fibrosis, and

Figure 1 Regulatory mechanisms initiated by aldosterotransport. Darkened shapes represent key signaling moltext. Pointed arrows represent movement of the molecubrane vesicles. Circle-end arrows represent stimulatory manisms. Stippled lines with nearby “?” indicate unresolvreabsorption from the apical to the basolateral compart

eural crest migration. l

ll 3 ETs (or theirRNAs or Binding Sites)re Found in the Kidney

T-1 is the best understood of the ETs. It is synthesized byhe glomerulus, proximal tubule, the thick ascending limb,nd the medullary collecting duct (outer and inner). ET-2RNA and protein have been detected in human proximal

ubules; ET-3 has been found in the cortical collecting duct inddition to those sites noted earlier for ET-1.

ET-1 alters hemodynamics and decreases the glomerularltration rate. ET-1 also stimulates Na reabsorption in theroximal tubule and inhibits Na reabsorption in the medul-

DO) in DCT2 cells to increase transepithelial sodiumof the pathway that are discussed in greater detail in thethin the cell’s nucleus, cytoplasm, or subsurface mem-isms, diamond-end arrows represent inhibitory mech-ractions. Dashed arrows indicate the direction of Na�

Reprinted with permission from Rozansky.118

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One of the first reports on ET-1 and renal acidification ishat of Eiam-Ong et al.123 These investigators showed thatT-1 (10�8 to 10�11 mol/L) increased Na/H antiporter activ-

ty in rabbit brush-border membrane vesicles. They furtherhowed that when basolateral membrane vesicles were incu-ated with ET-1, the Na:3HCO3 cotransporter was stimu-

ated. These important findings suggest that in the proximalubule ET-1 stimulation of the apical membrane proton se-retion and its attendant basolateral bicarbonate flux couldct in metabolic acidosis to preserve acid-base homeostasis. Itould just as well be involved pathophysiologically to main-ain metabolic alkalosis (eg, under circumstances when ET-1as released to produce intense vasoconstriction). It subse-uently was shown by Guntupalli et al124 that NHE-3 activityas enhanced in renal cortical slices by ET-1; similar resultsave been documented in cultured renal cells. A calcium-edicated mechanism has been suggested.125,126

The effects of the ETs are mediated by either the ETA or ETB

eceptor, both of which have domains characteristic of G-oupled receptors (ie, Ca-mediated). The receptors have sig-ificant homology; however, their binding affinities are suchhat ET-3 is an EB-selective agonist whereas ET-1 is nonse-ective for both receptors. Brush-border membrane vesiclesontain both receptors, but binding studies suggest that ETB

s found at higher abundance.Chu et al126 overexpressed both ET receptors in opossum

idney cells in culture and showed that after a 5-minutencubation with ET-1, those cells that overexpressed the ETB

eceptor, increased NHE-3 activity by approximately 25%.his stimulation of proton flux was inhibited by the selectiveTB-receptor blocker BQ-788. In subsequent studies in miceroximal tubule suspensions, ET-1 and ET-3 enhancedHE-3 activity. To examine this further they repeated the

xperiments in mice in which the ETB receptor had been dis-upted genetically and compared the results with those res-ued by a transgene. (This was performed in a model of toxicegacolon showing the role of the ETB receptor in mice.127)

aghmani et al128 showed that ET-1 increased NHE-3 activityignificantly in the rescued mice proximal tubules whereas inhe receptor-deficient suspensions there was no such effect.

Precisely how ET-1 affects proximal acidification has beenhown by Laghmani et al.128 As stated earlier, one of theirbservations suggested that a Ca-mediated mechanism126

as present, but that study did not elucidate the steps in-olved. In a series of elegant studies from their laboratory itppears that with a decrease in cell pH, the pH sensor praline-ich tyrosine kinase 2 is activated and this in turn activates-Src by phosphorylation of tyrosine 416 in its catalytic do-ain. There is a downstream increase in c-fos/c-Jun expres-

ion and activator protein 1 activity. This then results in anncrease in cortical cell preproET-1 mRNA (and a decrease inreproET-3 mRNA), and an increase in proET-1, followed bystimulation in cellular ET-1. The interaction of ET-1 with

he ETB receptor phosphorylates and moves NHE-3 from its
ubapical localization in the intracellular pool to the plasma i
embrane. This involves cytoplasmic microfilaments and islocked by latrunculin B, an inhibitor of microfilament orga-ization and the actin cytoskeleton. There appears to be noole for protein kinase A, protein kinase G, cyclo-oxygenase,ipoxygenase, or cytochrome P450 pathways; there is someontroversy over the role of protein kinase C.126,128 Impor-antly, there is a link between the ETB receptor and nitricxide formation in the kidney.A second major mechanism of proton secretion, and hence

icarbonate reabsorption in the proximal tubule, is the vac-olar H-ATPase. As discussed, roughly one third of acidifica-ion occurs via this enzyme. There is no information support-ng a direct action of endothelin on the vacuolar H-ATPase.oubtless, information regarding the role of endothelin wille forthcoming with the transgenic models described earlier.Table 4 summarized some of the factors known to stimu-

ate the synthesis and release (or action) of endothelin. Ofarticular interest here and to the possible generation and/oraintenance of metabolic alkalosis are volume contraction,ypokalemia, hypoxia/hypercarbia, renal ischemia, medul-

ary osmolarity, congestive heart failure, and shock, as well asII. Although the triggering mechanisms may seem obvious

n most cases (ie, an absolute or effective decrease in arterialolume), there are some disease states in which the mecha-ism stimulating ET-1 release is not so clear.During hypokalemia, the marked decrease in muscle

lood flow and subsequent tissue anoxia probably releasesndothelin from those vascular beds. Renal ischemia results

able 4 Factors Stimulating Endothelin

Volume contraction*Hypokalemia*ErythropoietinHypoxia/?hypercarbia*Acute renal ischemia*Increased renal medullary osmolarity*Radiocontrast dyesCyclosporineET-secreting hemangioendotheliomalDisease states

Hypertension (some forms)Endotoxin shock*Congestive heart failure*Cardiogenic shock*AtherosclerosisProgressive glomerulopathiesHepatorenal syndrome

Humoral mediatorsAII*Arginine vasopressinInsulinThrombinInterleukin-1Transforming growth factor-bTumor necrosis factorBradykinin

Factors that may generate or maintain metabolic alkalosis.

n ET release from mesangial cells of the glomerulus, the

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ame site thought to be involved in the hepatorenal syn-rome and in chronic progressive glomerulopathies.Precisely how increased medullary tonicity results in ET

elease is not clear. It should be noted that nitric oxide, atrialatriuretic peptide, and prostacyclin inhibit ET action, eithery affecting synthesis or release.In the distal nephron, from the bend of the loop of Henle to

he medullary collecting duct, far less is known about ET-1nd its role in the maintenance of metabolic alkalosis. Theouse thick ascending limb contains the apparatus for en-othelin biosynthesis and receptors for ET-1 action. In bothedullary and cortical thick limb 1 � 10�8 MET-1 (the

hreshold was 1 � 10�13 mol/L) added to either the lumen orhe bath significantly inhibited net chloride flux (JCl) by3%.129 This inhibition was partially reversible with time andas abolished completely with the addition of BQ-788, indi-

ating the effect was via the ETB receptor. ET-1 did not affectasal or vasopressin-stimulated cAMP content; and prosta-landin inhibition, as assessed in the presence of 3 � 10�6

ol/L ibuprofen, did not alter the effect of ET on JCl. ET-1 didot increase cytosolic Ca concentration in the mouse thick

imb, whereas it did after other maneuvers, including 1 �0�8 mol/L AII. The action of ET-1 on JCl appears to beelated to protein kinase C activation in that diacylglyceroleproduced the effect.129 These findings suggest a role forT-1 on salt transport in the thick ascending limb and mayontribute to natriuresis.

The medullary thick ascending limb also absorbs bicar-onate via an apical membrane Na/H antiporter NHE-3.130

ood et al131 showed that the isolated perfused medullaryhick ascending limb vasopressin inhibits bicarbonate reab-orption via a cAMP-mediated mechanism. Hyperosmolalitylso inhibits bicarbonate reabsorption. By contrast, hypoos-olality stimulates medullary thick limb bicarbonate reab-

orption. This occurs via phosphatidylinositol 3-kinase be-ause inhibitors of this pathway (ie, wortmannin andY294002) completely block the effect.131 Such a phospha-idylinositol 3-kinase mechanism has been shown for Na/Hntiporter activity induced by epidermal growth factor inntestinal epithelia cells.131 Should ET-1 affect thick limbicarbonate transport, one could predict it would stimulatehe bicarbonate transport in this segment.

In isolated tubule studies the various segments typicallyre bathed and perfused in a solution containing 25 mmol/LCO3, equilibrated with 95% O2–5% CO2 (pH 7.45), withighly stylized chemicals. It seems unlikely that the thick

imb sees this concentration of bicarbonate in the intactammal under most circumstances. It is difficult at this time

o place a defect in thick ascending limb bicarbonate trans-ort into a pathophysiologic schema because there is no dis-ase resulting in bicarbonate waste from this site. The 2 ex-mples known to occur, administration of loop diuretics andartter syndrome, stimulate urinary acidification. Indeed,iving furosemide to human beings with metabolic alkalosisakes the alkalosis worsen, whereas acetazolamide adminis-

ration ameliorates it.In the distal convoluted and connecting tubules, ET-1

ncreases acidification in both control rats and those given b

0 mmol/L NaHCO3 drinking solution for 7 to 10 days tonduce chronic metabolic alkalosis and a maneuver known toeduce distal acidification. In these in vivo micropuncturetudies the effect of ET-1 in both groups of animals occurredithout a significant change in plasma pH or partial pressuref carbon dioxide. In the control animals ET-1 primarilyecreased distal tubule proton secretion whereas in the alka-

otic animals the polypeptide decreased HCO3 secretion.his latter finding lends support to a role of ET in the main-

enance of metabolic alkalosis, particularly if its release istimulated by one or more of the factors listed in Table 4.

In the collecting tubule, the 2 major enzymes involved inhe maintenance of metabolic alkalosis are the vacuolar H-TPase and the P-type H,K-ATPase. Stimulation of either oroth of these enzymes would result in bicarbonate regenera-ion and loss of protons into the tubular lumen. There are noirect data regarding the effects of ET on the biochemicalctivity of these 2 important enzymes.

itric Oxideitric oxide (NO) is metabolized from L-arginine by 1 of 3itric oxide synthase (NOS) isoform enzymes, all of whichave been found in the kidney.132 Inducible NOS (iNOS)iffers from the other 2 forms in that it binds calmodulin atesting cytosolic Ca concentrations, and the gene encoding its found on chromosome 17. There is functional evidence forNOS action in the proximal tubule after inflammatory insult.he endothelial NOS gene is found on chromosome 7, and itsrotein has been found in proximal tubule, thick limb, andollecting duct in addition to the endothelial lining the arte-ioles (afferent and efferent) and vasa recta. Neuronal NOS,hose gene is localized to chromosome 12, has been local-

zed to the collecting duct and the macula densa, and isxpressed after maneuvers that stimulate inflammation. Therecise regulators within the kidney that determine which ofhe NOS isoforms is turned on or off are not yet known.

All of the renal isoforms can be inhibited by endogenouslyroduced dimethyl arginines. These compounds are in-reased in chronic renal failure and in states associated withndothelial dysfunction (eg, hypertension, heart failure, ath-rosclerosis). They can prevent the diverse actions of NO, theest known of which is vasodilation. Excessive production ofO appears to contribute to a number of inflammatory

tates, including tubulointerstitial disease, glomerulonephri-is, obstructive uropathy, and transplant rejection.

Both neuronal NOS and iNOS play a role in solute anduid transport in the kidney. In neuronal NOS knockoutice, proximal bicarbonate reabsorption and fluid transport

re decreased and metabolic acidosis results133; in iNOSnockout mice, a decrease in JHCO3 and water reabsorptionf one-third has been noted.134 Neither of these effects wasound in endothelial NOS knockout mice. Application of NOo proximal tubules has been shown to stimulate JHCO3 andater flux and to directly inhibit Na/H antiporter activity135

nd Na,K-ATPase activity.136,137 There is no information as tohe effect of NO on the vacuolar H-ATPase in proximal tu-
ule.

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In the distal nephron, NO inhibits bicarbonate reabsorp-ion probably by a direct effect to block both the apical Na/Hxchanger and the Na-K-2Cl cotransporter.138-140

Tojo et al141 showed that in the collecting duct NO inhibitshe H-ATPase in intercalated cells. This finding, all otherhings being equal, would result in impaired proton secretionnd the tendency to mitigate the maintenance of metaboliclkalosis and decrease the action of aldosterone. It would bef interest to examine H-ATPase activity throughout the en-ire nephron in the 2 knockout mice just described. In addi-ion, the interaction of NO with endothelins and Ang IIhould be examined carefully because the latter plays a sig-ificant role as regards to aldosterone action, and, hence, theaintenance of metabolic alkalosis.

reatmentn the vast majority of patients, the treatment of metaboliclkalosis has been relatively constant for decades. If there isvidence of volume depletion, whether in terms of total bodyolume or effective arterial blood volume, the treatment re-uires that the deficit be repaired. In practice, this most ofteneans the administration of normal saline. There have long

een debates about whether it is the sodium or the chloridehat leads to a decrease in proximal bicarbonate reabsorption,nd whether chloride delivery or volume is responsible forhe effect, but the clinician’s answer is the same: saline shoulde given in metabolic alkalosis with evidence of volume de-letion. This group of patients includes those with persistentmesis or nasogastric suction, the milk alkali syndrome, andther forms of volume depletion.When the patient is compromised by congestive heart fail-

re and suffers from a decrease in effective arterial bloodolume while suffering an excess of total body salt and waterespite the use of diuretics aggressive enough to produceetabolic alkalosis, care must be exercised if saline is given.

ndeed, the point of treatment will generally be to improveardiac output by some other means that produces signifi-ant improvement in renal blood flow, and changes filtrationraction and glomerular filtration rate. Similar situations mayxist in the nephrotic individual who has compromised cir-ulation as a result of intravascular depletion while againuffering from peripheral fluid overload, and more rarely, inhe cirrhotic patient with ascites who has been diuresed tooggressively. More often, these individuals have developedetabolic alkalosis as a result of the effects of diuretics andill be better treated by the provision of potassium chlorideecause their prior treatments will have more likely than notendered them potassium deplete.

Posthypercapnic metabolic alkalosis usually presents aombination of alkali overload, some degree of volume de-letion, and, most often, serious potassium depletion. Care-ul volume expansion may be needed, but more often, the keys potassium supplementation.

The major new developments in the treatment of meta-olic alkalosis involve the treatment of metabolic alkalosis inhe case of Liddle syndrome, in which instance the knowl-
dge that the mechanism of disease is an abnormally open
odium channel directs therapy. Amiloride or triamtereneay be used to inhibit the channel; spironolactone offers no

enefit. Bartter and Gitelman’s syndromes remain difficult toreat. One must provide salt and water to restore volume,eplace potassium chloride, and, in the case of Gitelman’syndrome, provide magnesium, but the overall response isost often disappointing. Amiloride, triamterene, and spi-

onolactone may be used as adjuncts in Bartter syndromeecause there is secondary hyperaldosteronism and subse-uent potassium and proton secretion in the collectinguct.142,143 However, these drugs do not alter the potassium

oss in the loop and DCT related to the inherited or acquiredefects in the NaK2Cl, ROMK, and CCl2, transporters. An-iotensin-converting enzyme inhibitors also have been usedo prevent the stimulation of aldosterone release, but use isimited by hypotensive effects.144,145 The observation thatrostaglandins are increased has led to the use of nonsteroi-al anti-inflammatory drugs with some success.146 Similarly,

n Gitelman’s syndrome some success has been achieved byhe addition of inhibitors of collecting duct sodium reabsorp-ion.147 The use of the other adjuncts mentioned with regardo Bartter syndrome may be tried.

onclusionas the Bench Caught up to the Bedside?s a result of the work of nephrologists, biochemists, andolecular biologists, we now know the precise and varied

auses of Bartter syndrome, Gitelman’s syndrome, and Liddleyndrome, but only in Liddle syndrome has our knowledgeed to better treatment (amiloride). Considerable knowledgeas certainly been added in regard to the diagnosis and treat-ent of abnormalities of steroid metabolism. Nevertheless, if

ne were to transport the Robert Pitts of 1950 to the presentay and confront him with a case of a patient with metaboliclkalosis caused by gastrointestinal losses or the use of diuret-cs, the most common causes of the disorder, he wouldoubtless be able to diagnose the condition, outline itsauses, and recommend the administration of normal sa-ine and potassium for its correction. The contemporariesf Dr. Kurtzman would similarly be able to offer a fully ra-ionalized explanation of the effectiveness of the treatmentased on an understanding of the basic relationship of theeabsorption of volume and bicarbonate in the proximal tu-ule, and the effect of aldosterone and sodium delivery in theistal nephron. Much has been added to define the fineoints of these interactions and to explain the basic mecha-isms of reabsorption along what is now viewed as a muchore complex nephron, but the original insights remain cor-

ect and continue to serve medicine well.

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