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2001 40: 533CLIN PEDIATRKarl S. Roth and James C. M. Chan

Renal Tubular Acidosis: A New Look at an Old Problem

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Renal Tubular Acidosis: A New Look

at an Old Problem

Karl S. Roth, MDJames C. M. Chan, MD

Summary: Although the definition of renal tubular acidosis (RTA) is simple, understanding thephysiologic basis underlying the various types of this clinical entity is much more difficult. Thepathophysiology of this disorder is reviewed using the normal acid-base functions of the involvedsegments of the nephron as a guide to understanding. Clinical and laboratory features of thesubtypes of RTA are addressed, and diagnosis and treatment discussed. New developments in theknowledge and understanding of the associated growth disturbances, mineral metabolism, and mol-ecular biology of RTA are also reviewed to provide the most current view of this relatively commonpediatric entity. Clin Pediatr. 2001;40:533-543

Introduction

M aintenance of a normalpH of body fluids is ofcritical importance to

virtually all cell processes. Theability of changes in hydrogen ionconcentration to affect the physi-cal conformation and thus the bi-ologic function of protein mole-cules, is a familiar example of thekey role of pH. Moreover, the hu-man organism produces substan-tial quantities of anions, such as,

sulfate, phosphate, and lactate.These materials are collectivelytermed "unmeasured anions,"and they must be excreted by the

kidney; accumulation of one or

more causes an increased plasmaanion gap ([Na+]-{ [Cl-] + [HCO3-]D.Generally, such accumulation re-

sults from increased production(e.g., inborn errors of metabo-lism), so that absent such condi-tions most patients with metabolicacidosis have an anion gap of lessthan 16. Although the gut makes a

significant contribution to elec-trolyte and fluid reabsorption, it isthe renal tubular epithelium that isresponsible for defense against ac-

cumulation of hydrogen ion. Ac-cordingly, when there is clinical ev-

idence of metabolic acidosis withno increase in the anion gap, a

Departments of Pediatrics and Biochemistry & Molecular Biophysics, Virginia CommonwealthUniversity, MCV Campus, Richmond, Virginia.

Reprint requests and correspondence to: Karl S. Roth, MD, MCV Campus, P0 Box 980239,Richmond, VA 23298-0239.

2001 Westminster Publications, Inc., 708 Glen Cove Avenue, Glen Head, NY 11545, U.S.A.

search for renal disease is a priority.* Clinically, renal tubular acido-

sis (RTA) is characterized by a

normal anion gap, hyper-chloremic metabolic acidosis, andassociated failure to thrive sec-

ondary to growth failure as well as

anorexia. Polyuria and constipa-tion can also be seen, althoughneither may be apparent in theneonatal period. Hyperchloremicmetabolic acidosis in pediatricpractice is most often associatedwith diarrheal disease. Both diar-rhea and RTA result in hy-pokalemia; in a young infant withdiarrhea and underlying RTA, thetrue diagnosis may be obscured.Thus, inordinately slow resolu-tion of hyperchloremic metabolicacidosis following diarrheal dis-ease should suggest the possibilityof an underlying primary RTA.

Beyond the difficulties inher-ent in delineating RTA, RTA can

be subcategorized into differentdisorders with distinctly differentprognoses. The diagnostic cata-

O

OCTOBER 2001 CLINICAL PEDIATRICS 533



Roth, Chan

loguing of RTA is important be-cause of these varied outcomesand is based on the underlyingpathophysiology. Thus, we beginwith a review of the normalprocesses for renal handling ofanacid load and progress from thisto a discussion of the pathophysi-ology underlying the differenttypes of RTA. Following this, we

provide an updated review ofmin-eral metabolism in RTA and endwith a discussion of our current

understanding of the molecularbiology of the disorder.

Physiology andPathophysiology

Proximal TubuleIn a functional sense, the

nephron regulates acid-basehomeostasis by simultaneousprocesses of bicarbonate reab-sorption and hydrogen ion secre-

tion. For purposes of simplifica-tion we have chosen to representthese as base reabsorption and acidsecretion (Figure 1). Conceptually,the proximal tubule is chargedwith the task of reclaiming fil-tered base (-85% of the total);failure of this process leads to re-

duction in systemic base, resultingin metabolic acidosis. Isolatedproximal RTA of genetic origin isuncommon and is generally seen

in association with other aspectsof tubular dysfunction. The nor-

mal process of base salvage pro-

ceeds in the proximal tubule with-out generation of a significant pHgradient. The threshold for bicar-bonate reabsorption in neonatesis reduced, despite an eventualnormal adult reabsorptive capac-

ity." 2 The threshold is increasedgradually during maturation,which is reflected in increasingserum bicarbonate concentra-tions with age. In the normaladult, the proximal tubular sys-

H',HCO -,Na',HPO -2 K1pH 7.4

Acid (H+)NH_ secreton

Na4+HCO 4-H+ Distal

Na++pC073 4 0 {Ht J X tubulepH 7.4 Base

reabsorptDonProximal

tubule

pH 7.4

Figure 1. The nephron in base reabsorption, acid secretion and generation of an acid urine. Bloodat pH 7.4 enters the glomerular capillaries, where the ionic constituents shown are filtered and en-

ter the proximal tubular lumen, still at pH 7.4. There is a net reabsorption in the proximal tubuleof Na+ and HC03- with no change in luminal pH. Urine passing through the lumen exits the loopof Henle still at pH 7.4 and enters the distal tubule. Again, as described in the text, the generationof ammonia and the net secretion of H+ occur in this segment, with consequent elaboration of an

acidic urine in a pH range of 4.5 to 8.0. The distal tubule is able to secrete hydrogen against a gra-

dient as high as 1000:1 using an active transport system.

tem results in recovery of >6000mEq of bicarbonate/day. Filteredsodium is actively transportedacross the luminal membrane us-

ing a Na+-H+ carrier molecule(NHE-3) driven by the concentra-tion gradient for sodium gener-

ated by Na+-K+ ATPase located atthe antiluminal surface of the cell(Figure 2). The expelled H+rapidly associates with filtered lu-minal bicarbonate to form H2CO3

(membrane-bound carbonic anhy-drase, CA MV), which just as rapidlydissociates and liberates CO2 andwater. The CO2 diffuses into thecell, where it is enzymatically (car-bonic anhydrase, CA II) rehydratedto form carbonic acid, whichagain dissociates with the forma-tion ofH+ and HCO3-. CA II, or cy-

tosolic carbonic anhydrase, is thepredominant (95%) renalisozyme and is found in large pro-

534 CLINICAL PEDIATRICSOCTOBER

2001534 CLINICAL PEDIATRICS OCTOBER 2001



Renal Tubular Acidosis

0 Na+- HCO3 Cotransporter

Figure 2. The process of proximal tubular base reabsorption. There are three key features of theproximal tubular epithelial cell that enable the ability to reabsorb base: 1) active transport of lu-minal sodium as part of the Na+-K+ ATPase system; 2) luminal surface and intracellular carbonicanhydrase capable of producing large quantities of bicarbonate; 3) a sodium-bicarbonate ex-

changer (NBC-1) at the inner basolateral surface. It should be noted that although bicarbonate ap-

pears to be synthesized in order for its reabsorption to occur, there is no net contribution of bi-carbonate made to the amount originally filtered; thus, there is net reabsorption. Used withpermission from Cohn RM, Roth KS. Biochemistry and Disease: Bridging Basic Science and Clin-ical Medicine. Baltimore: Williams & Wilkins; 1996.

portion in the proximal tubules.3Bicarbonate exits across the anti-luminal membrane for two rea-

sons: 1) mass action, because thebicarbonate concentration islower in the interstitial space thanin the cytosol; and 2) carrier-me-diated cotransport (NBC-1) alongan electrochemical gradient, gen-

erated by expulsion of the posi-tively-charged Na+ cation into thisspace by the ion pump. While theeconomy of the system is mar-

velous, the net result is sodiumand bicarbonate reabsorption butno net elimination of H+.

A traditional view of proximalrenal tubular acidosis holds thatthe tubular maximum (Tm) for bi-

carbonate is reduced, thus lower-ing the plasma concentration andpermitting a greater proportionthan normal of the filtered HCO3-to escape into the urine. At firstglance, this is an adequate expla-nation for the clinical observa-tions; a closer look leaves us withthe difficulty of explaining howthe tubular maximum (Tm) isphysically lowered and why pa-

tients with type 2 RTA often can

produce an acid urine. Modernmolecular biology has helped us

to address the central issue of re-

duction in the Tm.Contrary to the natural ten-

dency to conceive a reduced Tm as

impairment of transport across

the brushborder surface, the realdefect is almost certainly locatedin the carrier for Na+-HCO3- co-transport across the antiluminalor basolateral surface. This mole-cule, NBC-1 (Na+-bicarbonate co-transporter), is a protein consist-ing of approximately 1000 aminoacid residues and undergoes func-tional changes with varying pHconditions.4 Human gene cloningexperiments have revealed the ex-istence of three molecular iso-forms in kidney (NBC-1, NBC-2,and NBC-3); it is unclear at pre-sent what the precise functionaldistinctions are between each ofthe three isoforms.5 It is also notyet apparent whether the cause (s)for the varying clinical severity oftype 2 RTA can be attributed tomixed heterozygosity of muta-tions in these three isoforms be-cause of limited access to tissuefor study. Nonetheless, it appearsthat the mechanism underlyingthe reduced tubular maximumfor bicarbonate is actually re-duced transport out of the proxi-mal tubular cell with increasedbackflow (efflux) of cytosolic bi-carbonate into the tubular lumen.

The inability of the proximaltubule to achieve net hydrogenion elimination renders the bicar-bonate buffer system vulnerableto an impairment in the processof bicarbonate reclamation. Insuch circumstances, the result is anon-anion gap metabolic acido-sis. This is because the body'smetabolic processes generatenonvolatile, or fixed acids, whichmust be buffered by the bloodand eliminated through the kid-neys. The laws of electrical neu-trality also demand that eachmole of bicarbonate that is lost beaccompanied by a mole of cation,usually potassium and, to a lesserextent, sodium. The sodium lossprovokes a blood volume contrac-tion and a secondary release of al-

OCTOBER 2001CLINICAL PEDIATRICS 535

LUMEN

PROXIMAL TUBULE

CELL BLOOD

Na*

* Carbonic Anhydrase

OCTOBER 2001 CLINICAL PEDIATRICS 535



Roth, Chan

dosterone, which exacerbates theurinary potassium loss and cre-

ates a significant hypokalemia, al-though this is generally mild anddoes not require treatment. Theseare the phenomena underlyingthe clinical entity termed proxi-mal or type 2 RTA, defined as a sys-

temic acidosis deriving from a rel-ative decrease in the ability of thetubule to reclaim base.

Finally, while bicarbonaturiamay be expected to produce alka-line urine, this is not necessarilythe case in clinical practice. Al-though the ability of the proximaltubule to reclaim base is impairedin proximal RTA, the ability of thenephron to eliminate H+ remainsunaffected. Thus, patients withtype 2 RTA and systemic acidosismay produce urine with an acidpH, rendering urine pH alone an

inaccurate diagnostic test for dis-tinction between types I and IIRTA. Since the bicarbonatethreshold increases with age, therelative reduction in bicarbonateTm in the neonate often con-

tributes to a picture of hyper-chloremic metabolic acidosis andacid urine pH, which disappearsas the infant develops. Notwith-standing its disappearance, how-ever, this situation may require al-kali therapy in early life to avoidanorexia and permit normalgrowth.

Distal TubuleAs noted, base reabsorption is

handled primarily in the proxi-mal tubule, which is physiologi-cally unequipped to form a hy-drogen ion gradient between theblood and the tubular lumen withwhich to regulate blood pH. Thistask falls to the distal tubule,where hydrogen ion is secretedwith the generation of a steep H+gradient. Thus, the role of the dis-tal tubule in acid-base homeosta-sis may be conceptualized as one

of acid secretion, in contrast tothe proximal tubule, which serves

as a major site for reabsorption of

base. It is this difference in rolesthat also accounts for the differ-ences in clinical severity betweendisturbances of proximal and dis-tal tubular functions. Hence, al-though increased loss of basefrom the proximal tubule causes

development of a systemic acido-sis, the degree of the acidosis ismitigated considerably by theability of the distal tubule to elim-inate hydrogen ion. In contrast,however, when the distal tubule isnot capable of normal H+ elimi-nation, there is a major acid-basedisequilibrium resulting in severe

acidosis.

The key to the ability of thedistal tubule to cause net acid se-

cretion is the capacity to directlysecrete H+ into the tubular lumenindependent of sodium, using a

H+-ATPase pump.6 Other featuresdistinct to the distal tubule in-clude the following: nonleakytightjunctions permitting genera-

tion of very steep concentrationgradients, and the generation ofammonia (Figure 3). It is impor-tant to understand that the hydro-gen ion that is expelled is gener-

ated by the action of carbonicanhydrase on water and C02, so

that the remaining HC03- can beexchanged at the basal surface fora chloride ion. The deficit left byexpulsion of the hydrogen ion isaddressed by diffusion of a

sodium ion, which exits with thebicarbonate in exchange for a K+.The simultaneous production ofNH3 from glutamine and its diffu-sion into the lumen captures thehydrogen ion by formation ofam-monium radical and combinationwith filtered phosphate. It is theformation of these acid salts thatcomprises titratable acid and ren-

ders the ability of the distal tubuleto produce an acid urine.

Remarkably, there is a directsimilarity between the moleculardefects in proximal and distalRTA. As in type 2 RTA, the defectin type 1 RTA lies not in thebrushborder H+-ATPase, whichmight be an intuitive assumption,but rather in the Cl- - HC03- ex-

changer at the antiluminal sur-

face7 (see Figure 3). This has beendefinitively demonstrated inthose individuals showing an au-

tosomal dominant transmissionpattern,8 but is less clear in thosewith the autosomal recessive vari-ety, in which some patients are

thought to have a defect in thebrushborder H+-ATPase.9 Thefailure of chloride-bicarbonateexchange leads to accumulationof intracellular carbonic acid thatimpedes further synthesis as wellas dissociation into hydrogen ionand bicarbonate. Sodium-potas-sium exchange will be adverselyaffected as well, since sodium nor-

mally exits into the pericapillaryspace along with bicarbonate.Since less hydrogen ion is formedby dissociation, there is less ex-

pelled into the lumen to formacid salts and the urine pH tendstoward the neutral range.

As in proximal RTA, the di-minished sodium reabsorptioncauses a volume contraction, re-

duced body sodium, and a sec-

ondary hyperaldosteronism. Theresulting potassium loss leads tohypokalemia, often of a rather se-

vere degree. However, there is a

divergent response of the hy-pokalemia to therapy between thetwo forms of RTA; with volumeand pH correction there is a de-crease in aldosterone and a cor-

rection of potassium wasting indistal RTA. By contrast, in proxi-mal RTA the potassium wastingincreases with volume correction,because there is increased deliv-ery of sodium bicarbonate to thedistal tubule, which is charged

536 CLINICAL PEDIATRICSOCTOBER 2001

536 CLINICAL PEDIATRICS OCTOBER 2001




DISTAL TUBULE

CEL L BLOOD

= Carbonic Anhydrase O Na'- K+-ATPase

0 Chloride-Bicarbonate Exchanger

Figure 3. The process of net H+ excretion in the distal tubule. There are four key features of thedistal tubule that contribute to the acidification of the urine: 1) a brushborder H+ ATPase; 2) intra-

cellular carbonic anhydrase; 3) a basolateral Cl- - HCO3- exchanger; 4) ability to synthesize NH3.Details are contained in the text. Modified and used with permission from Cohn RM, Roth KS. Bio-chemistry and Disease: Bridging Basic Science and Clinical Medicine. Baltimore: Williams &

Wilkins, 1996.

with sodium-potassium exchange.A review of this discussion now al-lows explanation for the clinicalfindings of polyuria and constipa-tion in affected patients. The re-

duction in volume causes upregu-

lation of the renin-angiotensinsystem; increased angiotensin II

has a direct effect on the thirstcenter in the brain,10 while de-creased interstitial potassium anddecreased chloride exchange di-minishes concentrating ability inthe renal loop of Henle with thetwo phenomena combining to

cause polyuria. The constipationis a direct consequence of hy-pokalemia, with consequent de-crease in gut motility.

A final pathogenic issue inboth forms of RTA is that of cal-cium-phosphorus metabolismand secondary effects on the kid-ney. Common to both proximaland distal RTA is a state of chronicmetabolic acidosis, requiring thatH+ be both buffered and excretedby alternative means. The most di-rect effect of acidosis is the dis-placement of protein-bound cal-cium by hydrogen in the blood,thereby increasing both theamount of ionized calciumll,"2and its filtration by the glomeru-lus. However, chronic acidosisprovokes divergent responses to

this increased calcium load in theproximal and distal segments, in-

creasing reabsorption in the for-mer and inhibiting it in the latter.The net effect is to cause hyper-calciuria, which can reach strikingproportions in the distal RTAform but usually remains of noconsequence in isolated type 2disease. Type 1 RTA is due to fail-ure to eliminate hydrogen ion,while type 2 is a consequence ofdiminished base reabsorption;thus, the marked difference in de-gree of systemic acidosis may alsoplay a role.

The severe acidosis of type 1disease also inhibits productionand release of mitochondrial cit-rate,13 which is normally presentto react with calcium and en-hance its solubility. 14 Increasedfiltered load and inhibited reab-sorption causes severe hyper-calciuria, while the reduction insolubility leads to a marked ten-dency toward nephrocalcinosis.Moreover, the need to maintainserum calcium necessitates in-creased turnover of bone matrixand results in osteomalacia. Incontrast, bone disease in type 2RTA is relatively mild, generallyresulting from phosphate loss andsecondary hyperparathyroidism.Phosphate, a major urinarybuffer, is filtered by the glomeru-lus and enters the proximal tubu-lar lumen where it becomes avail-able to buffer hydrogen ions.However, ammoniagenesis is sub-maximal in chronic acidosis,which restricts the usefulness ofNH3 as a urinary buffer, especiallyin an alkaline urine such as thatproduced in type 1 RTA. In addi-tion, this reduced synthetic ratelimits cations required for fixedacid excretion and obligatesother cations, such as Ca++, to actin its place.

Rate-Dependent Distal RTAConditions that alter transep-

ithelial voltage in the distal seg-


LUMEN

CLINICAL PEDIATRICS 537OCTOBER 2001



Roth, Chan

ment, such as impaired sodiumuptake, can also alter the rate atwhich H+ is secreted into the lu-men, and are etiologically distinctfrom the genetically transmitteddisorder already discussed. Strifeand associatesl5 have demon-strated in children with distal RTAthat differentiation of the classicaldisease from rate-dependent dis-tal RTA on clinical grounds will bedifficult. In rate-dependent distalRTA the kidney can elaborateurine with a pH less than 4.5, lead-ing to misdiagnosis of proximal

RTA. Determination of the differ-ence between urine and bloodpartial pressure of CO2 will aid indifferentiation, since all patientswith distal RTA will have a differ-ence of less than 20 mm Hg, whilenormal subjects and children withproximal RTA will have a differ-ence greater than 20 mm Hg.15

Diagnostic Approach

Identification and appropri-ate categorization of patients withRTA require consideration of an

extensive list of differential diag-noses (Figure 4). The initial task isto determine the presence of a hy-perchloremic metabolic acidosisand absence of any significantplasma anion gap ([sodium] -

[bicarbonate] + [chloride]). Thedifferential list of entities fittingthis description is presented inTable 1.

The most common cause ofthis situation in pediatrics is acutediarrheal disease. Potassiumlosses can be substantial enoughin either RTA or diarrheal diseaseto cause hypokalemia, making thetwo difficult to distinguish fromeach other when they coexist inthe infant. The most direct meansto approach a differential in sus-

pected RTA is by determinationof the urinary anion gap, defined

Metabolic Acidosis

Evaluate Serum Anion Gap

Elevated Normal (10-12 meq/1)

Work up forhigh aniongap acidosis

Evaluate Urinary Anion Gap

Normal (small to negative)R/O Type II RTA

EvaluateUrine pHSerum K+

Fractional Excretion HCOJ

Elevated (positive)

Serum K+

Low HighR/O Type I RTA R/O Type IV RTA

Evaluate Evaluate

Urine pH Urine pH

Urine: Blood pCO2 Uine: BloodPCO2

Figure 4. Algorithm for diagnosis of RTA. From Hanna JD, Santos F, Chan JCM. Renal tubular aci-dosis. In Kher KK, Makker SP (eds): Pediatric Renal Disease: Diagnosis and Management. NewYork: McGraw-Hill, 1992, pp. 665-668.

somewhat differently from theserum anion gap, as the sum of(urine [Na+] + urine [K+]) - urine[C1-]. Ammonium excretion isusually increased as acidosis de-velops, most commonly in theform of chloride salts, althoughurinary ammonium is considered

an unmeasured cation. Thus, in a

state of acidosis, the urinary an-

ion gap should decrease as thechloride excretion increases inconcert with ammonium. Theutility of this calculation reflects

the fact that ammonium genera-

tion by the kidney occurs in thedistal tubule, so that in all formsof distal RTA it would be antici-pated that no decrease in urineanion gap would be seen. In con-

trast, a normal renal response to

gastrointestinal bicarbonatelosses, or in a kidney affected byType II RTA, would be increasedammonium production, in-

creased chloride excretion, andhence, a decreased value of theurinary anion gap.

538 CLINICAL PEDIATRICS 2001~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~OCTOBER 2001538 CLINICAL PEDIATRICS




ExamplesNormal Type I RTA Type II RTA

Cl >Na+K+ ClV>Na+K+ ClV>Na+K+100+5-150-45 100+5-150-45 100+5-200--95

The use of this parameter inchildren has been discussed;16 it isadvisable to use caution in inter-preting the uirine anion gap inchildren, and especially inneonates since ammonium gener-ation matures during postnataldevelopment.

In children with a relativelymild degree of systemic acidosis(a serum bicarbonate concentra-tion no lower than 17 mEq/L), itmay be helpful to perform anacid-loading test. The classicalmethod for this has been an oral

load of NH4Cl; recently, the intra-venous arginine hydrochlorideinfusion test (100-150 mEqH+/m2 body surface area) hasbeen used.'7 The overall purposeof these tests is to create systemicconditions that will maximize re-nal hydrogen ion excretion, andto determine systemic and urinepH under these circumstances. Ifurine pH falls below 5.5, the pa-tient can be assumed not to havedistal RTA. Some patients withproximal RTA can achieve a nor-mal urine pH response underthese circumstances, so that typeII RTA cannot be ruled out by thistechnique.

Another test of the ability ofthe distal tubule to secrete H+ is to

alkalinize the urine and measurethe secretory capacity along a hy-drogen ion gradient where bloodpH should be less than urine pH.Classically this was achieved usingan oral sodium bicarbonate dose,but oral acetazolamide as a uri-nary alkalinizing agent (17mg/Kg) has been found to bemore efficient.18 Distally secretedhydrogen ions enter the tubularlumen and combine with bicar-bonate anions to form carbonicacid, which slowly dehydrates intowater and CO2 because of the ab-sence of luminal membrane car-bonic anhydrase in distal tubularcells. Accumulation of luminalCO2 because of delayed dehydra-tion of carbonic acid is further en-hanced by diminished diffusiondue to an unfavorable volume tosurface area relationship in themedullary collecting duct.'7 As aresult of these two factors, thepCO2 of the urine increases and,measured in sufficiently alkalineurine, it can be used as a reliableindex of distal hydrogen ion se-cretion. Under these conditions,normal individuals are capable ofincreasing urine pCO2 above 70mm Hg and achieving a pCO2 dif-ference between urine and bloodof 25 to 30 mm Hg. Given thesame conditions, a difference ofless than 20 mm Hg strongly sug-gests diminished H+ secretory ca-pacity, which is characteristic ofdistal RTA.

Normal individuals givenfurosemide (1-2 mg/kg) gener-ate a markedly acid urine and asignificant increase in net acid ex-cretion within 2 to 3 hours. Thiseffect is based on furosemide-in-duced increased sodium deliveryto and inhibition of chloride re-absorption in the distal tubule. Asa consequence, the increasedsodium load results in greater ex-change for H+ and the greaterpresence of chloride induces a

CLINICAL PEDIATRICS 539OCTOBER 2001



Roth, Chan

higher degree of luminal elec-tronegativity. Thus, patients withRTA should show concordant re-

sponses to a furosemide test. Inpatients suspected of having type4 RTA in whom hyperkalemiacould become hazardous withacid loading, furosemide can pro-

vide a useful and safe alternative.

Growth Failure in RTA

Disturbances of growth are

typically associated with RTA of alltypes and with chronic metabolicacidosis in general. The effects ofacidosis appear to fall into twoseparate categories: direct (bycommitting calcium as a bufferfor H+) and indirect (through thegrowth hormone-IGF axis). In theclassical view, the pathophysio-logic response to chronic acidosisleads to increase in the ionizedfraction in serum, a resultant in-crease in glomerular filtrationand a consequent enhanced uri-nary loss as calcium salts. The netresult of this is osteomalacia withbowing of the long bones, partic-ularly those in the lower extremi-ties, and growth failure. We havealready examined the tubularprocesses leading to these effects,so that this mechanism for the ad-verse impact of acidosis upon

growth should be clear.In 1981, McSherry and associ-

ates19 reported a blunted growthhormone release in children withRTA, although no data were in-cluded on frequency, quantity, or

other aspects of growth hormonesecretion. To update this report,Challa and co-workers20 recentlydemonstrated that pulse ampli-tude and area, as well as totalgrowth hormone secretion were

diminished in acidotic rats, com-

pared to control and pair-fed ani-mals, while the pulse frequencyremained unaffected in the aci-

dotic animals. Other findings in-cluded suppressed serum IGF, he-patic IGF-1 mRNA and hepaticgrowth hormone receptormRNA, as well as gene expressionof IGF at the growth plate of thelong bones in these animals. Thechanges in IGF-1 mRNA andgrowth hormone receptors seem

to be specific to the cellular effectsof acidosis. Taken together, thesefindings are representative of an

additional mechanism for the ad-verse impact of chronic acidosisupon growth, although they willneed confirmation in humans.

Genetics andMolecular Genetics

Until recently, elucidation ofthe genetic aspects of types 1 and2 RTA was hampered by confus-ing clinical associations (e.g.,

deafness, Fanconi syndrome) andfamilial, inherited, and sporadicpatterns of occurrence for each.However, with the advent of mole-cular genetics, many of the previ-ously puzzling aspects of these dis-orders are now coming into

sharper focus. The transient,neonatal form of RTA may becaused by relative immaturity ofthe apical Na+-H+ exchanger mol-ecule (NHE-3), which is known toundergo postnatal developmentin animals.21,22 The gene forNHE-3 has been mapped to

5pl5.3.23 With respect to genetictype 2 RTA, the molecular basisfor an inherited defect is now inhand with the cloning of the twohuman genes for the Na+ - HCO3-cotransporter (NBC) proteinmolecules. The gene for NBC-1has been mapped to 4p2I.24 How-ever, it may require developmentof diagnostic technology to ascer-

tain the presence of an abnormalNBC-1 transporter gene in non-

renal tissue from affected individ-

uals, since renal biopsy in type 2RTA is difficult to rationalize. Thevast majority of cases of proximalRTA are seen in association withother genetic disorders, in whichthe acid-base disturbance is sim-ply a part of a generalized proxi-mal tubular dysfunction calledthe renal Fanconi syndrome.25,26In these individuals, the geneticsof the RTA follows the pattern ofthe underlying disorder, almostalways an autosomal recessivetrait. It is worth noting that type 2RTA due to a carbonic anhydrase(CA II) deficiency occurs in asso-

ciation with osteopetrosis andcerebral calcification as an auto-somal recessive trait, as well.27 CAII deficiency may also cause a

mixed type I-type II RTA, origi-nally designated type III, a termno longer in use. CA II has beenmapped to 8q22; use of a CA1I-deficient mouse model hasprovided the basis for successful,but temporary gene therapy.28

In contrast, distal RTA occurs

with the greatest frequency as an

isolated defect, often transmittedas an autosomal dominant traitdue to a mutation at 17q21-q22.29The molecular abnormality inthese cases is an impaired Cl--HC03- exchanger within the cellat the antiluminal surface, as pre-

viously discussed. Norman and as-

sociates30 studied two pedigreesin which clinically affected indi-viduals were shown to be hypoci-traturic; other, asymptomaticmembers of the pedigree with in-complete distal RTA were foundto be hypocitraturic and were alsoshown to have an abnormal re-

sponse to acid loading. These ob-servations are entirely consistentwith an autosomal dominant trait.In addition, distal RTA can be in-herited as an autosomal recessivetrait, with or without associatedsensorineural hearing loss. Thoseindividuals without hearing de-

540 CLINICAL PEDIATRICS OCTOBER 2001540 CLINICAL PEDIATRICS OCTOBER 2001




fects carry mutations at 7q33-q34.9 Distal RTA in associationwith hearing loss has been shownto involve the gene (ATP6B1)coding for the B-subunit of theH+-ATPase,8 which is normally re-

sponsible for the secretion of hy-drogen ion into the lumen. Sig-nificantly, neither of the two

recessive forms of distal RTA in-volves a locus even remotely con-

nected with that which deter-mines the chloride-bicarbonateexchanger defect in the domi-nant trait. Thus, there are clearlyat least three distinct abnormali-ties of the genome which can ad-versely affect urinary acidificationin the distal tubule. While a gooddeal of work remains to be doneon the molecular biology of RTA,the data are already beginning tohelp us to understand the clinicalgenetics as well as the pathophysi-ology to a degree not possible 20years ago.

Variation on the Theme

In past literature on the sub-ject, RTA nomenclature hadevolved to a degree of confusionvastly out of proportion to its un-derlying pathophysiologic com-

plexity. The more recent litera-ture on the subject dealsessentially with three types: 1, 2,and 4. It is now clearly recog-

nized that type 4, also called hy-perkalemic distal RTA to distin-guish it from classical type 1, is anacquired defect generally due toeither aldosterone deficiency or

relative aldosterone resistance.31The first situation often pertainsin cases of congenital adreno-genital syndrome, while the sec-

ond may be seen whenever renalmass is diminished (e.g., obstruc-tive uropathy, diabetic nephropa-thy). Although chronic renal fail-ure is a prominent cause of type

4 RTA in adults, it is rarely seen

in children. The mechanism be-hind the hyperkalemia is plainlyan impaired or inhibited ex-

change of potassium for sodium,a process regulated in the distaltubule by aldosterone. The same

applies to the systemic accumula-tion of H+, since secretion of hy-drogen ion is linked to the same

process that is impaired in theabsence of normal aldosteroneregulation.

Incidence

The relative incidence of thethree types of RTA was reportedby Brennen and associates32shortly after the initial descrip-tion of type 4 RTA. These work-ers suggested that type 1 was

most common, followed by type4, with type 2 the least commonof all. This order is, however, un-

likely because genetic defectsrarely, if ever, outnumber ac-

quired ones. Thus, the numberof elderly males with prostatic hy-pertrophy and patients of all ageswith obstructive uropathy whobecome relatively resistant to al-dosterone and in whom type 4RTA develops are clearly more

numerous than individuals withmutations for a chloride-bicar-bonate exchanger (type 1). Al-though it is certain that every in-fant is born with a lowerbicarbonate threshold than itsparents, most newborns do not

develop systemic acidosis in rela-tion to their age cohorts as a con-

sequence. Nonetheless, it is atleast arguable that type 2, due toa physiologic immaturity, ap-

pears in the general populationmore frequently than geneticallydetermined type 1. However, it iscertain that after infancy, iso-lated type 1 is seen far more com-

monly than isolated type 2.

Treatment

The basis for treatment of a

patient with any form of RTA isthe resulting metabolic acidosis,which all patients experience. Inproximal RTA, where the funda-mental physiologic abnormality,as we have defined it, is in base re-

absorption, it stands to reason

that base replacement would betherapeutic. Thus, base replace-ment as sodium bicarbonate or

the more palatable alternative,citrate or Shohl's solution (2-14mEq/kg/day in divided doses33)is utilized to maintain plasma bi-carbonate higher than the re-

duced Tm and offset the increasedurinary losses. In both forms ofdistal RTA, notwithstanding thedifferent underlying mechanismcompared to type 2 RTA, the clin-ical problem remains a systemicmetabolic acidosis. Citrate re-

placement has been used as an ef-fective mainstay of treatment in

type 1 RTA. Finally, in treatmentof type 4 RTA, it is essential to de-termine the underlying mecha-nism, whether hypoaldostero-nism vs end-organ resistance. Forthe former state, mineralocorti-coid replacement is effective, butthe patient should be monitoredfor sodium retention and volumeoverload. For the latter, generallyresulting from chronic renal dis-ease, administration offurosemide (2 mg/kg/day) ishighly effective and avoids theproblem of volume overload bypromoting sodium excretion.

Conclusions

We presented a conception ofthe two major types of RTA basedon the characteristic functionaldeficit of each. In the case of type2 (proximal) RTA, the underlyinggenetic defect in sodium-bicar-


OCTOBER 2001 CL17VICAL PEDIATRICS 541



Roth, Chan

bonate cotransporter molecule(NBC-1) results in a deficit inbase reabsorption. Thus, proxi-mal RTA results in reducedplasma bicarbonate and systemicmetabolic acidosis on this basis.By contrast, type 1 (distal) RTA hasbeen presented as a failure to elim-inate hydrogen ion, a concept am-ply supported by the moleculardefinition of a genetic deficiency

of the chloride-bicarbonate ex-

changer molecule impairing thedistal tubule's ability to secreteH+. The utility of this conceptual-ization lies primarily in the factthat it emphasizes both the nor-

mal and abnormal function ofeach of the two involved seg-

ments, while also helping to ex-

plain the physiologic basis for theclinical presentations.

The marked abnormalities oflinear growth, particularly evi-dent in distal RTA, are under-stood as the result of at least twoseparate sets of events: osteoma-lacia and bowing of the lower ex-

tremities due to calcium loss;and, the acidosis-inducedchanges in the growth hormone-IGF axis. Our knowledge of thelatter influence is still in the mostrudimentary stages, althoughtechniques of molecular biologyprovide the promise of rapid ad-vances in the near future. Themolecular genetics of RTA hasprogressed dramatically in thepast decade, providing evidenceof the actual molecular defects intypes 1 and 2 RTA and furtheringour understanding of the under-lying cellular events. These ob-servations have also helpedgreatly in our delineation of theinheritance patterns of bothproximal and distal RTA. Thus,the progress in the past twodecades has been dramatic andholds direct implications for clin-ical care of patients affected byRTA.

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533 tubularacidosis 0na+-hco3 cotransporter figure 2. the process of proximal tubular base...

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