On the mechanism of renal potassium wastingin renal tubular acidosis associated with theFanconi syndrome (type 2 RTA)

Anthony Sebastian, … , Elisabeth McSherry, R. Curtis MorrisJr.

J Clin Invest. 1971;50(1):231-243. https://doi.org/10.1172/JCI106479.

The mechanism of renal potassium wasting in renal tubular acidosis associated with theFanconi syndrome (type 2 RTA) was investigated in 10 patients, each of whom hadimpaired proximal renal tubular reabsorption of bicarbonate as judged from a greater than15-20% reduction of renal tubular bicarbonate reabsorption (THCO3

-) at normal plasma

bicarbonate concentrations. When the plasma bicarbonate concentration ([HCO3-]p) was

experimentally increased to normal levels in three patients with a fractional potassiumexcretion (CK/Cin) of less than 1.0 during acidosis, CK/Cin and urinary potassium excretion(UKV/Cin) increased strikingly and concurrently with a striking increase in urinary sodium

(UNaV/Cin) and bicarbonate (UHCO3-V/Cin) excretion. When [HCO3

-]p was increased to

normal levels in two patients with a CK/Cin of greater than 1.0 during acidosis and in whomUNaV/Cin and UHCO3

-V/Cin were already markedly increased, CK/Cin did not increase

further. When [HCO3-]p was decreased to subnormal levels in a patient given ammonium

chloride, UKV/Cin, CK/Cin, and UHCO3-V/Cin decreased concurrently. In the six patients in

whom [HCO3-]p was maintained at normal levels (oral alkali therapy) for 2 months or longer,

CK/Cin was directly related to the urinary excretion rates of sodium and bicarbonate, hence

was directly related to the magnitude of reduction of THCO3- at normal [HCO3

-]p; CK/Cinwas greater than 0.55 in all six patients and greater than 1.0 in four.

In eight patients […]

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On the Mechanism of Renal Potassium Wasting

in Renal Tubular Acidosis

Associated with the Fanconi Syndrome (Type 2 RTA)

ANTHoNYSEBASTLN, ELISABETH McSHERRY,and R. CURTSMORRMS,JR.From the Departments of Medicine and Pediatrics, University of California,San Francisco, California 94122

A B S T R A C T The mechanism of renal potassium wast-ing in renal tubular acidosis associated with the Fanconisyndrome (type 2 RTA) was investigated in 10 patients,each of whom had impaired proximal renal tubularreabsorption of bicarbonate as judged from a greaterthan 15-20% reduction of renal tubular bicarbonatereabsorption (THCO3-) at normal plasma bicarbonateconcentrations. When the plasma bicarbonate concentra-tion ([HCOs-]p) was experimentally increased to nor-mal levels in three patients with a fractional potassiumexcretion (CK/Cin) of less than 1.0 during acidosis,CK/Ci. and urinary potassium excretion (UKV/CIU) in-creased strikingly and concurrently with a striking in-crease in urinary sodium (UNaV/Cin) and bicarbonate(UHcos-V/Cin) excretion. When [HCOs-]p was in-creased to normal levels in two patients with a CK/Cinof greater than 1.0 during acidosis and in whomUNaV/Cln and UHCOI-V/CIU were already markedly in-creased, CK/CIn did not increase further. When[HCOi-]p was decreased to subnormal levels in a patientgiven ammonium chloride, UKV/CGI, CK/CIn, andUHCO3-V/CIn decreased concurrently. In the six patientsin whom [HCOj-]p was maintained at normal levels(oral alkali therapy) for 2 months or longer, CK/Cinwas directly related to the urinary excretion rates ofsodium and bicarbonate, hence was directly related tothe magnitude of reduction of THCOi- at normal[HCOs-]p; CK/Cin was greater than 0.55 in all sixpatients and greater than 1.0 in four.

In eight patients with classic RTA (type 1 RTA),proximal renal tubular reabsorption of bicarbonate was

Dr. Sebastian and Dr. McSherry were recipients of Bankof America-Giannini Foundation Fellowships. Dr. McSherryis currently recipient of a National Institutes of HealthSpecial Fellowship.

Received for publication 28 April 1970 and in revised form23 September 1970.

largely intact as judged from a trivial reduction ofTHCO3- at normal [HCO3-]p. When [HCOj-]p waseither increased from subnormal to normal levels, ordecreased from normal to subnormal levels, U1co,-V/Ci.remained essentially constant, and UKV/Cin did notchange significantly. When correction of acidosis wassustained, UIJcOs-V/Cin remained a trivial fraction ofthat filtered, and CK/Cin was consistently less than 0.55.

These results provide evidence that renal potassiumwasting in type 2 RTA is physiologically separable fromthat in type 1 RTA and in part the result of a reductionin the rate at which the proximal tubule reabsorbs bi-carbonate and the distal delivery of supernormal amountsof sodium bicarbonate. With an increased stimulus todistal sodium reabsorption, indicated by the finding ofhyperaldosteronism, delivery to the distal nephron ofsupernormal amounts of sodium with the relativelyimpermeant bicarbonate anion would be expected toincrease intraluminal negativity in the distal nephron,and as a consequence, increase potassium secretion andpromote renal potassium wasting.

INTRODUCTIONRenal potassium wasting' is a common complication ofthe clinical syndrome of renal tubular acidosis (RTA)(1-8). Both in patients with so-called classic RTA(type 1 RTA, "distal" or "gradient" RTA) and inpatients with RTA associated with the Fanconi syn-drome (type 2 RTA, "proximal" or "rate" RTA), ithas been inferred that renal potassium wasting is areversible consequence of the renal acidification defect(1, 4, 8, 9-13). In patients with type 1 RTA, this infer-

'Renal potassium wasting is defined as the continued uri-nary excretion of more than 40 mEq of potassium daily inthe face of potassium depletion of severity sufficient toproduce hypokalemia.

The Journal of Clinical Investigation Volume 50 1971 231

ence is based on the observation that correction of sys-temic acidosis with alkali therapy can lead to a reductionin urinary potassium excretion and correction of hypo-kalemia (1, 2, 13). In patients with type 2 RTA, thisresponse to corrective alkali therapy has been assumed(12) but apparently never documented (3, 5, 6).

In patients with type 2 RTA, however, the physio-logic character of the underlying renal acidificationdefect suggests the possibility that renal potassiumwasting might be augmented rather than corrected bycorrection of systemic acidosis (14). In these patients,the renal acidification defect is characterized by com-plete, or nearly complete, renal tubular reabsorption ofbicarbonate at subnormal plasma bicarbonate concentra-tions but by a greater than 15-20% reduction in tubularreabsorption of bicarbonate at normal plasma bicar-bonate concentrations, a finding indicating that the rateof bicarbonate reabsorption in the proximal nephron isreduced (15, 16). Accordingly, raising the plasma bi-carbonate concentration from subnormal to normal lev-els has the immediate and sustained effect of swampingthe distal nephron with massive amounts of NaHCO3.In the presence of a continued stimulus for sodiumreabsorption, the delivery to the distal nephron of suchsupernormal amounts of NaHCO3might be expected toincrease intraluminal negativity, augment potassium se-cretion, and thereby promote renal potassium wasting(17-20).

To investigate this possibility and to compare theeffects of correction of acidosis on renal potassiumwasting in patients. with type 1 and 2 RTA, we mea-sured urinary potassium excretion and fractional potas-sium excretion in the two groups (a) at plasmabicarbonate concentrations progressively increased fromsubnormal to normal levels by intravenous administra-tion of NaHCO3and (b) at normal plasma bicarbonateconcentrations sustained for 2 months or longer. Theresults of these investigations indicate that in type 2RTA, the physiologic character of renal potassium wast-ing is distinct from that in type 1 RTA and support thehypothesis that in type 2 RTA renal potassium wastingresults in part from the delivery of supernormal amountsof NaHCO3to the distal nephron.

METHODSA total of 29 clearance studies were carried out on thefollowing 23 subjects: 8 patients with type 1 RTA; 10patients with type 2 RTA; and 5 normal subjects.

All studies were performed in the early morning with thepatients lying comfortably supine. Breakfast was withheldbut free access to water was permitted before and duringthe studies. Spontaneously voided urine (men, boys) orurine from an indwelling Foley catheter (women, infants)was collected under a layer of mineral oil at 15- to 30-minintervals for immediate determination of pH and carbondioxide content and for subsequent determination of sodium,

potassium, and chloride. At appropriate intervals arterializedblood was drawn from a superficial vein on the back ofthe hand that had been heated with an electric heatingmuffler to at least 450C for more than 60 min for determina-tion of blood pH and carbon dioxide tension and serumsodium and potassium concentrations. Inulin clearance wasmeasured throughout each study period.

NaHCOs infusion. 10 studies were designed to examinethe effect on urinary potassium excretion (UKV/Cin) andfractional potassium excretion (CK/C In) of progressivelyincreasing the plasma bicarbonate concentration from sub-normal to normal levels by intravenous infusion of sodiumbicarbonate. The subj ects were five patients with type 2RTA (R. A., R. G., R. Y., G. F., A. M.) and four patientswith type 1 RTA (C. V., Le. S., La. S., P. B.) (Table I).When studied, each patient had been in a spontaneous stateof mild or moderate systemic acidosis for at least 3 days.In each study plasma bicarbonate was increased by approxi-mately 2 mmoles/liter per hr by the intravenous administra-tion of a 3.75%o solution of sodium bicarbonate at ratesranging from 0.25 to 3.8 ml/min. In most studies the rateof infusion remained constant throughout; in some studieson the patients with type 2 RTA, it was necessary toincrease the rate of infusion at the higher plasma bicar-bonate concentrations.

Sustained correction of acidosis. 17 studies were designedto compare fractional potassium excretion in type 1 andtype 2 RTA during prolonged correction of systemic acido-sis. The subjects were six patients with type 2 RTA (R. G.,M. P., M. H., M. N., E. S., B. L.), six patients with type1 RTA (C. V., Le. S., B. Mc., N. A., K. E., L. C. S.)(Table I), and five normal subjects ranging in age from27 to 46 yr. For at least 2 months immediately preceding thestudies, normal plasma bicarbonate concentrations (22-26mmoles/liter) had been maintained in each patient by appro-priate alkali therapy (Table I). Two to six consecutive 15-to 30-min urine collections were obtained for determinationof fractional potassium excretion. In some studies, urinecollections were obtained over a narrow range of nor-mal plasma bicarbonate concentrations (1-3 mmoles/liter)achieved by intravenous infusion of small amounts of sodiumbicarbonate.

NH4Cl loading. In a patient with type 2 RTA (R. A.)and in a patient with type 1 RTA (L. C. S.), paired studieswere performed to compare the effect on UKV/Cin andCK/CIn of progressively decreasing the plasma bicarbonateconcentration from normal to subnormal levels. The plasmabicarbonate concentration was decreased by oral administra-tion of ammonium chloride; after an initial dose of 6 g(R. A.) or 2 g (L. C. S.), each patient received 5 g individed doses over the subsequent 2 hr.

Laboratory methods. Laboratory determinations were car-ried out as described previously (15, 21).

RESULTS

Table I summarizes clinical and physiologic data on the18 patients with RTA obtained during earlier studies.

NaHCOsinfusion. In base line determinations duringacidosis on five patients with type 2 RTA, urinary potas-sium excretion (UKV/CIn) varied from 0.78 to 7.27AEq/ml, and fractional potassium excretion (CK/CIn)varied from 0.16 to 2.03 at plasma bicarbonate concen-trations ranging from 13.3 to 20.0 mmoles/liter (Table

232 A. Sebastian, E. McSherry, and R. C. Morris, Jr.

II, Figs. 1 and 2). Five studies were begun at similarplasma bicarbonate concentrations (16.5-20.0 mmoles/liter); in these, the base line values of UKV/Cln andCK/CiU varied directly with the magnitude of urinarysodium and bicarbonate excretion (Table II). Whenthe plasma bicarbonate concentration was progressivelyincreased from subnormal to normal or near normallevels by intravenous infusion of sodium bicarbonate,UKV/Cln and CK/CIn increased progressively in R. A.(two studies), in G. F., and in A. M., concomitant witha progressive and striking increase in urinary sodiumand bicarbonate excretion (Tables II and III, Figs. 1and 2). In R. G. and R. Y., in whom the base linevalues of UKV/Cin and CK/Cin were already considera-bly greater than the maximal values attained in A. M.,G. F., and R. A. during sodium bicarbonate infusion,UKV/Cin and CK/Cin did not increase further (TableII, Fig. 1). In R. Y., the only patient with type 2 RTAin whom the serum potassium concentration decreased tolevels below 3.0 mEq/liter during sodium bicarbonateinfusion, UKV/Cin actually decreased slightly (from7.27 to 5.02 iEq/ml) but fractional potassium excretionremained essentially constant (2.03-1.85, Table II, Fig.1). Throughout, as before NaHCO3infusion, UKV/Clnand CK/Cin varied directly with the magnitude of uri-nary sodium and bicarbonate excretion (Table II).

In base line determinations during acidosis on fourpatients with type 1 RTA, UKV/Cin varied from 0.70to 2.12 /LEq/ml, and CK/Cln varied from 0.18 to 0.51 atplasma bicarbonate concentrations ranging from 18.0to 19.7 mmoles/liter (Fig. 1, Table II). Only in C. V.were the base line values of UKV/Cin and CK/Cin ashigh as any of those observed in the patients with type2 RTA (Table II). No correlation was apparent be-tween the base line values of UKV/Cin and CK/Cin andthe corresponding values of urinary sodium or bicar-bonate (Table II). When the plasma bicarbonate con-centration was progressively increased to normal levelsby intravenous infusion of sodium bicarbonate, UKV/Clninvariably decreased slightly and CK/Cin either remainedconstant (P. B., Le. S., La. S.) or tended to decrease(C. V.) (Table II, Figs. 1 and 2).

Sustained correction of acidosis. In six patients withtype 2 RTA studied after prolonged correction of sys-temic acidosis, fractional potassium excretion variedfrom 0.53 to 3.47 at serum potassium concentrationsranging from 2.5 to 4.5 mEq/liter (Fig. 3). In twopatients (M. N., M. P.), CK/Cin was less than 1.0; andin four patients (R. G., E. S., M. H., B. L.), CK/Cinwas consistently greater than 1.0 at plasma bicarbonateconcentrations ranging from 22 to 26 mmoles/liter. Thevalues of CK/Cin varied directly and nearly linearlywith the urinary excretion rates of bicarbonate (Fig. 3)and sodium. In general, CK/Cin varied inversely with

the glomerular filtration rate (GFR) (Fig. 4). While asimilar inverse relationship between CK/Cin and GFRoccurs in chronic renal disease of diverse etiology, thevalues of CK/Cin in the patients with type 2 RTA were,in comparison, consistently higher at any given GFR(Fig. 4) (27). That the disproportionately greaterfractional potassium excretion reflects in fact "renalpotassium wasting" in the patients with type 2 RTA isindicated by the presence of frank hypokalemia (2.5 <K. < 3.8) in four of the patients (M. P., M. N., R. G.,E. S.) despite the provision of potassium supplementsas well as a normal dietary potassium intake. In unpub-lished balance studies on three of these patients (M. P.,R. G., E. S.), the total daily potassium requirementnecessary to maintain serum potassium concentratrons inthe low-normal range exceeded 2 mEq/Kg, even thoughglomerular filtration rate was reduced.

In the six patients with type 1 RTA studied afterprolonged correction of acidosis, fractional potassiumexcretion varied from 0.17 to 0.39 at serum potassiumconcentrations ranging from 3.5 to 4.2 mEq/liter (Fig.3). No correlation was apparent between CK/Cin andurinary sodium excretion (UNaV/Cin) or betweenCK/Cin and urinary bicarbonate excretion (UHCO3-V/Cin).An inverse relationship between fractional potassiumexcretion and GFR was not apparent (Fig. 4). Thefollowing values of CK/Cin were essentially the same asthose observed in five normal subjects: 0.10-0.33 (mean0.22) at normal plasma bicarbonate concentrations andserum potassium concentrations ranging from 4.1 to4.6 mEq/liter.

NH4Cl loading studies. When the plasma bicarbonateconcentration was progressively decreased from 22.8 to12.9 mmoles/liter in a patient with type 2 RTA (R. A.),UKV/Cin and CK/Cin decreased progressively from 3.46to 1.75 /Eq/ml and 0.82 to 0.42, respectively, concomi-tant with a progressive decrease in UHCo3-V/Cin from4.59 to 0.68 imoles/ml and an increase in urinary chlo-ride excretion (Uc1V/CI.) from 1.56 to 3.10 AEq/ml(Table IV). The greatest reduction in UKV/Cin, CK/Cln,and UHco3-V/Ct. occurred as the plasma bicarbonateconcentration decreased to 16.6 mmoles/liter. In con-trast, when the plasma bicarbonate concentration wasprogressively decreased from 22.8 to 16.7 mmoles/literin a patient with type 1 RTA (L. C. S.), UKV/Cin,CK/Cin, UHCo3-V/Cin, and UCI-V/Cin remained essen-tially constant (Table IV). No significant change inurinary sodium excretion occurred in either study.

Urinary aldosterone. Table V summarizes the dailyurinary excretion rates of aldosterone in six of thepatients with RTA associated with the Fanconi syn-drome. The urine collections were obtained during pro-longed correction of the patients' acidosis and whensodium intake had been normal or supernormal for at

Renal Potassium Wasting in Type 2 RTA 233

TABLE I

Clinical and Physiologic Data in Patients with Renal Tubuksr Acidosis (RAI)

THCOs-(Plasma Urinary excretion

Urinary acidification* [HCOs-IPatient, 22-24 Alkali a-Aminoage (yr), U.Rmin mmoles/ require- N/crea-

sex Clinical diagnosis Cin (CO2) UTAVE= U~NH4Vm liter) ment4 a-Amino N tinine N Glucose

-m/min pE/min mmoles/ mmoles/ mg/24 hr g/gper 100 ml kg per

1.73 m2 GF 24 hrNormal values

Adult subjects <5.31 >25.0 >39.0 50-150Children (a)

(b)Infants

<5.60 >13.9<5.90 >31

4.90 62 -44.9RRenal tubular acidosis associated with the Fanconi syndrome (type 2 RTA)

>45.7>27

57 :14.3

0.30-0.62

M. P. Multiple myeloma63M

R. A. Siogren's syndrome58F

R. G. Idiopathic Fanconi20 syndromeM

R. Y. Cystinosis9-M

B. L. Cystinosis8M

M. H. Idiopathic type 2 RTA8M

M. N. Lowe's syndrome7M

E. S. Cystinosis5M

G. F. Idiopathic Fanconi4 syndromeF

A. M. CystinosisifM

Classic renal tubular acidosis (type 1 RTA)N. A. Siogren's syndrome56F

C. V. Idiopathic RTA,51 nephrocalcinosisF

Le. S. Familial RTA,38 nephrocalcinosisF

B. Mc. Idiopathic hypergamma-32 globulinemia,F nephrocalcinosis

K. E. Lupoid hepatitis,22 nephrocalcinosisF

74.3 5.83 18.3(14.0)

30.7 6.81 7.6(12.2)

22.3 5.24 35.0(15.3)

23.7 5.0 -(10)

21.5 6.67 23.2(18.8)

34.7 5.93 28.9(17.5)

83.0 5.83 33.8(18.1)

36.4 5.29 70.3(13.3)

122 5.04 47.3(21.0)

92.0 5.13 62.0(13.3)

55.0 6.68 22.0(17.2)

48.8 6.48 12.9(13)

71.9 6.59 14.3(15.5)

45.0 6.80 13.0(17)

82.1 7.10 4.3(20.1)

68.7 2.0 3-4 333

6.4 1.6 3-4 366

20.8 1.6 3 640

- 1.3 10

17.3 1.5 5-6

35.9 2.0 4

49.5 1.7 7-8

75.0 1.9 6

70.4 2.0 4

56.0 2.0 20

11.2 2.24 1 59.5

28.1 2.36 1-11 89.6

59.1 2.29 1-1l 132

14.0 2.36 <1 76.0

16.4 1 67

234 A. Sebastian, E. McSherry, and R. C. Morims, Jr.

0

0

1.69 +

1.8-2.6 0

0.3 0

4.9 +

1.3 +

0.7-1.3 0

13.9-15.3 +

0

0

TABLE I-( Continued)

THCOs-(Plasma Urinary excretion

Urinary acidification* [HCOs-3Patient, 22-24 Alkali a-Aminoage (yr), UHmin mmoles/ require- N/crea-

sex Clinical diagnosis Cin (COO) UTAVmuz UNH4Vmaz liter) ment* a-Amino N tinine N Glucose

mil/min pEqlmin mmolesi mmolesi mg/24 hr g/gPer 100 ml kg per

1.73 mn GF 24 hrLi. S. Familial RTA, 89.3 6.79 7.7 23.1 2.32 2-3 78 019 nephrocalcinosis (16.5)F

La. S. Familial RTA 85.7 6.17 26.9 62.2 2.29 <1 0.42-.44 014 (17.5)M

P. B. Idiopathic RTA 86.8 7.13 - 63.9 2.18 2-3 0.7-1.6 01 (11.4)F

Ci, inulin clearance; Upsmin, minimal urinary pH (numerals in parentheses indicate lowest measured serum C02 content in mmoles/liter); UTAVmDxandUNN4Vax1, maximal rates of excretion of titratable acid and ammonium, respectively (values in infants and children were corrected to a standard bodysurface area of 1.73 mi); THCOs-, tubular reabsorption of bicarbonate (values in infants, children, and adults were determined at plasma bicarbonateconcentrations of 22, 23, and 24 mmoles/liter, respectively); GF, glomerular filtrate.* Renal acidification response to existent or NHiCl-induced acidosis; procedure of Wrong and Davies (22). Normal values for adults were established in aprevious study (23); normal values for children and infants, corrected to 1.73 mi, were derived by measurements (a) on the last day of a 3-5 day periodof NH4Cl-induced acidosis in children aged 1-16 yr (24). and (b) after a single oral dose of NH4Cl (75 mEq/m2) in children aged 4-13 yr (25) and in infants(26) (values in infants are mean dsE).* Total daily alkali requirement (administered orally in divided doses) necessary to maintain plasma bicarbonate concentration in the range of 22-26mmoles/liter (adults, children) or 21-24 mmoles/liter (infants).

least 2 wk. Except in M. P., who was potassium depletedwhen the urine collection was obtained, the urinaryexcretion rates of aldosterone were supernormal (nor-mal values: 4-17 /Ag/24 hr).

DISCUSSIONAccording to current views (16, 28), the syndrome ofrenal tubular acidosis can reflect two physiologically dis-tinct disorders of renal acidification. In patients withso-called classic RTA (type 1 RTA, "distal" or "gradi-ent" RTA), the urinary pH remains inappropriatelyhigh during mild as well as severe degrees of acidosisand persisting bicarbonaturia is characteristic. Theamount of bicarbonate excreted, however, remains atrivial fraction of that filtered both at subnormal and atnormal plasma bicarbonate concentrations, a findingwhich indicates no substantial reduction in the rate atwhich the proximal (or distal) nephron reabsorbs bi-carbonate (4, 9). In contrast, in patients with RTA as-sociated with the Fanconi syndrome (type 2 RTA,"proximal" or "rate" RTA), the amount of bicarbonateexcreted at normal plasma bicarbonate concentrations ismore than 15% of that filtered, indicating that the rateof reabsorption of bicarbonate in the proximal nephronis reduced (15, 16). Prototypically in patients with type2 RTA, the urinary pH is inappropriately high, and bi-carbonaturia occurs only during mild or moderate de-grees of acidosis; during more severe degrees of acidosis,

bicarbonaturia disappears and the urinary pH decreasesto normal minima (15, 28, 29).

The results of the present study provide evidence thatrenal potassium wasting in type 2 RTAis physiologicallyseparable from that in type 1 RTAand in part the resultof a reduction in the rate at which the proximal nephronreabsorbs bicarbonate and the consequent delivery to thedistal nephron of supernormal amounts of NaHCOs. Ineach of the 10 patients studied with type 2 RTA, bi-carbonate reabsorption in the proximal nephron was al-most certainly impaired, since at normal plasma bicarbo-nate concentrations renal bicarbonate reabsorption wasinvariably reduced by more than 15% (Table I). Infour studies on three patients with type 2 RTA, urinarypotassium excretion (UaV) and fractional potassiumexcretion (CK/Cin) increased strikingly when the plasmabicarbonate concentration was progressively increasedfrom subnormal to normal or near normal levels by in-travenous infusion of NaHCOs. As would have beenpredicted from the physiological character of the renalacidification defect in these patients, urinary sodium andbicarbonate excretion also increased strikingly and con-comitantly. In the two patients in whom fractional po-tassium excretion did not increase when the plasma bi-carbonate concentration was increased to normal levels,the base line values of fractional potassium excretionduring acidosis were already considerably greater thanthe maximal values observed in the other three patients

Renal Potassium Wasting in Type 2 RTA 235

a U

A . "~~~~~

18 20 22 24 26 :Plosma HCOIS (mmoles/liter )

FIGURE 1 Effect of experimentally increasing plasma bicarbonateconcentration (intravenous administration of sodium bicarbonate)on fractional potassium excretion and urinary bicarbonate excre-tion in four patients with renal tubular acidosis associated withthe Fanconi syndrome (closed symbols) and in three patientswith classic renal tubular acidosis (open symbols). 0, A, R. A.;*, R. G.; *, R. Y.; 7, G. F.; 0, C. V.; O, La. S.; A, Le. S.

at normal plasma bicarbonate concentrations, and thebase line values of urinary sodium and bicarbonate ex-

cretion were more than twice the base line values inthese three patients. In the one patient in whom theplasma bicarbonate concentration was acutely decreasedby the administration of ammonium chloride, UKV andCK/CIn decreased concurrently with a decrease in urinarybicarbonate excretion. In six patients in whomcorrectionof acidosis was sustained for 2 months or longer, frac-tional potassium excretion was consistently greater than0.55, usually greater than 1.0, and varied directly withthe urinary excretion rates of both sodium and bicarbo-nate, hence varied directly with the magnitude of reduc-tion in tubular reabsorption of sodium and bicarbonate.It might be argued that the fractional excretion rates of

potassium were high in these patients because their glo-merular filtration rates were reduced, but in each patientin whom GFRwas reduced, fractional potassium excre-

tion was disproportionately high relative to the degreeof reduction of glomerular filtration rate, despite theoccurrence in some cases of hypokalemia.

These characteristics of urinary potassium excretionin patients with type 2 RTA can be explained in part as

a consequence of increased intraluminal negativity in thedistal nephron resulting from the combination of an in-creased distal delivery of sodium with the relatively im-permeant bicarbonate anion and an increased stimulusfor renal sodium reabsorption. In the rat, under a va-

riety of metabolic conditions that increase potassium ex-

cretion, including the administration of a poorly perme-

236 A. Sebastian, E. McSherry, and R. C. Morris, Jr.

29 .-0

1.6-

1

1WFCKCin 0.8

0.6

0.2H_

a

UHCO-EVCin

(Mmoles /ml)

0.4 _

ant anion (sulfate) in a sodium-deficient state and theinhibition of carbonic anhydrase (dichlorphenamide),the degree of intraluminal negativity in the distal neph-ron is a critical determinant of the net rate of potas-sium secretion in the distal nephron and, as a conse-quence, of urinary potassium excretion (18-20). In ratsstimulated to reabsorb sodium avidly, increasing thedelivery of sodium and bicarbonate to the distal nephronresults in a substantial increase in intraluminal nega-tivity (17). In the patients with type 2 RTA, the stimu-lus for renal sodium reabsorption was undoubtedly in-creased since, in the six patients in whom urinary al-dosterone was measured, it was either increased (fivepatients) or effectively increased relative to the degreeof potassium depletion (one patient) (30, 31).

In the two patients with type 2 RTA in whom CK/Cinwas greater than 1.5, the finding that urinary excretionof potassium did not increase further when acidosis wascorrected does not indicate that the delivery of abnor-mally large amounts of NaHCOs to the distal nephronwas not an important determinant of their renal potas-

0.50

0.40

CKCin

0.30

0.20

0.10

sium wasting. Because of the marked impairment ofrenal bicarbonate reabsorption in these two patients, uri-nary sodium and bicarbonate excretion during acidosiswas already greatly increased. Hence, the maximal po-tassium secretory response of the distal nephron mayhave already been elicited.

In the patient with type 2 RTA in whom the plasmabicarbonate concentration was decreased by the adminis-tration of ammonium chloride, the finding that urinarysodium excretion did not decrease as urinary potassiumexcretion decreased does not indicate that the initiallyhigh urinary excretion rates of potassium were not theresult of increased distal delivery of NaHCOs. Since inthis study the reduction in urinary excretion of bicarbo-nate was accompanied by an increase in urinary excre-tion of chloride, it can be inferred that the delivery ofHC03- and Cl- to the distal nephron decreased and in-creased, respectively. For a given delivery of sodium tothe distal nephron and a given stimulus for renal sodiumreabsorption, the combination of an increased distal de-livery of the highly permeant anion, chloride, and a

1. r

UHCO-VCmoles/m3 0.6Cin

(ii moles/ml) O.A

He

0.2k-

9~~~~~

I /I I I I

I

12 14 16 18 20 22 24 26 28Plasmo HCO3(mmoles/I;ter)

FIGURE 2 Effect of experimentally increasing plasma bicarbonateconcentration (intravenous administration of sodium bicarbonate) onfractional potassium excretion and urinary bicarbonate excretion inan infant with renal tubular acidosis associated with the Fanconi syn-drome (A. M., closed symbols) and in an infant with classic renaltubular acidosis (P. B., open symbols).

Renal Potassium Wasting in Type 2 RTA 237

OL

TABLE I ISummary of Results of Sodium Bicarbonate Infusion Studies*

Plasma UKV CK UN.V UHCO:aVPatient HCOs- Serum K Cin Cin CGD Cin

mmoles/lWter mEqiliter oEq/ml 1&Eqiml pmoles/ml

Type 2 RTAA. M. 13.3 3.5 0.92 0.26 1.38 0

18.9 3.0 1.39 0.46 2.57 0.80G. F. 20.0 4.8 0.78 0.16 1.82 0.41

23.5 4.1 2.20 0.54 4.50 3.39R. A.i 19.0 4.3 2.30 0.54 3.12 1.65

27.9 3.5 3.67 1.04 7.22 7.30R. A.2 17.9 4.4 3.43 0.78 3.89 1.94

22.5 4.3 4.43 1.03 8.37 7.09R. G. 19.0 3.9 5.53 1.45 8.28 4.10

27.2 3.7 5.38 1.44 18.2 12.0R. Y. 16.5 3.6 7.27 2.03 19.5 4.80

26.2 2.7 5.02 1.85 29.7 13.2

Type 1 RTAP. B. 19.7 3.4 0.75 0.22 0.72 0.14

26.3 2.8 0.62 0.22 2.96 0.92La. S. 19.3 3.9 0.70 0.18 2.77 0.07

27.2 3.5 0.58 0.16 2.45 0.58Le. S. 18.1 4.0 0.78 0.20 2.22 0.24

25.1 3.5 0.76 0.22 4.65 1.96C. V. 18.0 4.1 2.12 0.51 2.46 0.28

28.9 3.0 1.17 0.38 6.42 0.88

Cin, inulin clearance; CK, potassium clearance; UKV, UN.V, and UHCO3-V, urinaryexcretion rates of potassium, sodium, and bicarbonate, respectively.* For each patient, the initial and final values obtained during NaHCO3infusionare shown as vertical pairs.

TABLE I I IRepresentative Study of the Effect of Intravenous Bicarbonate Infusion on Urinary Potassium Excretion in a

Patient with Renal Tubular Acidosis Associated with the Fanconi Syndrome (Type 2 RTA) (R. A.)

Urine Arterial SerumUHOOaWV UxV CK

Time Flow Na K HCOa- pH Cin Cin Cin Cin HCOs- PCoo pH K Na

mil/min Eq/min jsmoks/min pmoles/ml pEq/ml ml/min mmoies/ mmHgliter

mEqlliter

Priming infusion: 25 ml of 10% inulin over 5 min period intravenously.Constant infusion 1: 5% inulin at 0.191 ml/min intravenously at 0 time.

151-174 5.61 83.0 61.1 44.0 7.04 1.65 2.30 0.535 26.6 17.9 35.9 7.319 4.3 141174-191 5.65 71.6 50.9 37.3 7.01 1.66 2.27 0.531 22.4 18.8 36.7 7.332 4.3 137

Constant infusion 2: 3.75% sodium bicarbonate at 3.82 ml/min intravenously.191-218 5.75 81.6 57.0 55.2 7.09 1.93 1.99 0.481 28.6 20.4 35.8 7.379 4.1 138218-244 3.00 82.1 63.9 68.4 7.46 3.08 2.88 0.725 22.2 23.4 38.5 7.405 4.0 138244-263 4.25 137.2 100.8 124.2 7.57 3.87 3.14 0.828 32.1 24.3 38.0 7.428 3.8 139263-291 3.39 135.7 88.8 127.9 7.65 4.98 3.46 0.939 25.7 27.2 40.4 7.450 3.7 141291-315 4.55 210.0 106.9 222.2 7.71 7.30 3.67 1.04 29.1 28.6 40.6 7.470 3.5 141

238 A. Sebastian, E. McSherry, and R. C. Morris, Jr.

Cin, inulin clearance; Uoog-V and UkV. urinary excretion rates of bicarbonate and potassium, respectively; CK. potassium clearance; Pco2, carbon dioxidetension.

decreased distal delivery of the relatively impermeantanion, bicarbonate, would be expected to reduce intra-luminal negativity in the distal nephron and the stimu-lus for potassium secretion and excretion (17-20). Theimportance of the anion accompanying sodium as a de-terminant of potassium excretion was specifically ex-amined by Bank and Schwartz (32). In dogs stimulatedto conserve sodium avidly, a constant intravenous infu-sion of sodium phosphate was abruptly replaced by aconstant infusion of sodium chloride. Potassium excre-tion first increased as sodium and phosphate excretionincreased. When, however, the infusion of sodium phos-phate was replaced by that of sodium chloride, potassium

excretion decreased as phosphate excretion decreasedand chloride excretion increased, despite a further in-crease in the rate of sodium excretion.

The results of the present investigation do not ex-clude the possibility that in patients with type 2 RTA,renal potassium wasting results in part from impairedproximal tubular reabsorption of potassium. The findingin some patients, however, that CK/Cin was greater than1.5 indicates that even complete suppression of potas-sium reabsorption in the proximal nephron would nothave been sufficient to account for the degree of renalpotassium wasting (18, 19).

In the patients with type 1 RTA, delivery of super-

K3.0o_

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FIGURE 3 Relationship between fractional potassium excretion (CK/Cln) and urinary bicar-bonate excretion (UHco3-V/Cin) in patients with renal tubular acidosis associated with theFanconi syndrome (closed and three-quarter closed symbols) and in patients with classic renaltubular acidosis (open and three-quarter open symbols) in whom the plasma bicarbonate con-centration was maintained at normal levels (22-26 mmoles/liter) for more than 2 months(closed and open symbols) or was rapidly increased to normal levels (intravenous adminis-tration of sodium bicarbonate) (three-quarter closed and three-quarter open symbols; datafrom Fig. 1). Like geometric symbols represent measurements made in a single patient. Thenear overlap of UHCO-V/C1. in patients represented by * and V reflects the fact that in *THCO3- was the least reduced of the Fanconi group and UHcoo-V/CG1 was measured at thelowest normal plasma bicarbonate concentrations (22.2 mmoles/liter) while in V THCO8- wasthe most reduced of the classic RTA group and UHcoS-V/CIR was measured at the highestnormal plasma bicarbonate concentrations (25.5 mmoles/liter).

Renal Potassium Wasting in Type 2 RTA 239

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240 A. Sebastian, E. McSherry, and R. C. Morris, Jr.

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GFR (ml /minFIGURE 4 Relationship between fractional potassium excretion (CK/CI.) and glomeru-lar filtration rate (GFR) in patients with renal tubular acidosis associated with theFanconi syndrome (closed and three-quarter closed symbols), in patients with classicrenal tubular acidosis (open and three-quarter open symbols), and in patients withchronic renal insufficiency of diverse etiology (shaded area) (27). See Fig. 3 forexplanation of symbols.

normal amounts of NaHCOsto the distal nephron couldnot be supported as a cause of renal potassium wasting.In each of the eight patients studied, the rate of bicarbo-nate reabsorption in the proximal nephron could not havebeen substantially reduced since tubular reabsorption ofbicarbonate at normal plasma bicarbonate concentrationswas nearly complete (Table I). In the four patientswith type 1 RTA in whom the plasma bicarbonate con-centration was progressively increased from subnormalto normal levels by intravenous infusion of NaHCOs,UKV and CK/Ciu remained essentially constant or de-creased. As would have been predicted from the physio-logical character of the renal acidification defect inthese patients, urinary bicarbonate excretion also re-mained essentially constant until normal or supernormalplasma bicarbonate concentrations were reached. In theone patient in whom the plasma bicarbonate concentra-tion was rapidly decreased by the administration of am-monium chloride, UKV and CK/Ci. remained essentiallyconstant, as did urinary sodium and bicarbonate excre-tion. In the six patients with type 1 RTA maintained atnormal plasma bicarbonate concentrations for 2 monthsor longer, fractional potassium excretion was consistently

less than 0.55 and did not correlate with the urinary ex-cretion rates of either sodium or bicarbonate.

In patients with type 2 RTA but not in patients withtype 1 RTA, the results of the present studies permit theprediction that renal potassium wasting will occur in-variably and even worsen when systemic acidosis is cor-rected with alkali therapy. Conceivably, during pro-

TABLE VUrinary Aldosterone in Patients with Renal Tubular Acidosis

Associated with the Fanconi Syndrome (Type 2 RTA)

Urinary Sodium SerumPatient aldosterone* intake* potassium

Ag/24 hr mEq/24 hr mEqlilerR. A. 39.3 95 4.5M. P. 9.1 >100 3.7R. G. 30.5 85 4.1M. H.* 159.4 >200 3.8A. M.* 105.9 157 4.5E. S.* 148.6 275 3.6

$ Values in children aged < 12 yr corrected to 1.73 M2.

Renal Potassium Wasting in Type 2 RTA 241

longed NaHCOstherapy, the severity of renal potassiumwasting in some patients might diminish as a conse-quence of a reduction in aldosterone secretion. But inthree patients in whom serial measurements of urinaryaldosterone were made, hyperaldosteronism persisteddespite sustained correction of acidosis with alkalitherapy and despite normal or supernormal sodium intakeand no measured reduction of plasma volume (unpub-lished observations).

ACKNOWLEDGMENTS

We gratefully acknowledge our debt to Dr. Edward G.Biglieri for the determinations of urinary aldosterone. Wewish to thank the following physicians for referring patients:Ralph Alexander, Maurice Fox, Edwin Henning, MalcolmHolliday, Felix Kolb, Bruce Marshall, Carolyn Piel, andRalph Wallerstein.

These studies were supported by U. S. Public HealthService Grants HE-10044, HD00182, and CA11067; byCancer Research Coordinating Committee Funds and Schoolof Medicine Edwards Fund, University of California, SanFrancisco; and by a grant from the California Division ofthe American Cancer Society. Studies were carried out onthe General Clinical Research Center Ward, University ofCalifornia, San Francisco, with funds provided by theDivision of Research Resources, RR-79, U. S. Public HealthService.

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16. Morris, R. C., Jr. 1969. Renal tubular acidosis: mecha-nisms, classification and implications. N. Engl. J. Med.281: 1405.

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Renal Potassium Wasting in Type 2 RTA 243