Kidney International, Vol. 26 (1984), pp. 88—97

NEPHROLOGY FORUM

Metabolic alkalosis

Principal discussant: JOHN T. HARRINGTON

New England Medical Center, Boston, Massachusetts

Case presentation

A 59-year-old woman was transferred to New England MedicalCenter (NEMC) for evaluation of carcinoma of the lung, profoundhypokalemia, and metabolic alkalosis. The patient, who smoked onepack of cigarettes daily for 25 years, was well until 4 months prior toadmission, when she developed bilateral ankle edema, nocturia, dysp-nea on exertion, and facial puffiness. She gained 20 pounds in onemonth and also suffered from progressive muscle weakness. Sheconsulted her physician, who prescribed 5 mg of methychlothiazide(Enduron) daily; her weight fell and ankle edema lessened, but the othersymptoms did not improve.

She was admifted to a local hospital, where the following laboratorydata were obtained: serum sodium, 146 mEq/liter; serum potassium, 1.2mEq/liter; serum chloride, 67 mEq/liter; total CO2, 66 mmol/liter; bloodpH, 7.65; and PaCO2, 60 mm Hg (Table 1). She was treated withpotassium chloride orally and intravenously, but by the second hospitalday the serum potassium had increased to only 1.7 mEq/liter, and the24-hour urinary potassium excretion was 218 mEq; urine sodium was257 mEq. Over the next 3 weeks serum potassium averaged 2.6 mEq/liter, although the patient was receiving large doses of potassiumchloride (Fig. 1).

Plain chest films showed a left lower lobe infiltrate and collapse and aleft pleural effusion. An obstructing endobronchial lesion of the left

Presentation of the Forum is made possible by grants from CIBAPharmaceutical Company and GEIGY Pharmaceuticals.

© 1984 by the International Society of Nephrology

lower lobe bronchus was biopsied during bronchoscopy. The patientwas given 100 mg/day of spironolactone as well as the oral potassiumsupplements and was referred to NEMC for further evaluation.

On examination she was deeply tanned, appeared chronically ill, andhad hyperpigmentation of the palmar creases. Blood pressure was 140/80mm Hg; pulse, 70; respiratory rate, 24/mm; and temperature, 37.3°C.Head and neck examination were unremarkable. Chest examinationrevealed dullness to percussion at both bases with poor air entrybilaterally. Inspiratory and expiratory rhonchi were heard over the rightlung field. Examination of the heart disclosed an S4 and normal Sl andS2 sounds; a grade TI/VT systolic murmur was present at the apex.Abdominal examination revealed the liver edge to be at the costalmargin. She had 1+ pitting edema in the legs. Diffuse muscularweakness was present. Laboratory data were: sodium, 143 mEq/liter;potassium, 2.5 mEq/liter; chloride, 94 mEq/liter; total CO2, 45 mmol/liter; BUN, 15 mg/dl; creatinine, 0.6 mg/dl; pH, 7.54; Pa02, 54 mm Hg(on room air); PaCO2, 50 mm Hg; blood glucose, 171 mg/dl; serumalbumin, 2.9 g/dl; white blood cell count, 15,400/mm3; hemoglobin, 11.9g/dl; hematocrit, 37%; platelet count, 284,000/mm3; and serum calcium,7.8 mg/dl. Urinalysis revealed a pH of 7.0; specific gravity, 1.014; atrace of protein; 3+ glucose; and 1 to 3 white cells per high-power field.Electrocardiogram was normal and chest radiographs showed a smallleft pleural effusion. Plasma ACTH was 3887 pglml (normal up to 100pg/mI) and plasma aldosterone was 43.3 ng/dl (normal 5 to 30 ng/dl).Morning plasma cortisol measured 35.0 mg/dl; evening plasma cortisol,42.4 mg/dl; urinary 17-hydroxycorticosteroids, 127 mg/24 hr (normal 3to 10 mg/24 hr); urinary free cortisol, 14,957 mg/24 hr (normal 100 to 375mg/24 hr).

The biopsy showed a small cell, undifferentiated carcinoma compati-ble with oat cell carcinoma of the lung. Brain, bone, and liver scansshowed no evidence of metastatic disease. A CT scan of the chestrevealed a large left hilar tumor compressing the left main stembronchus and the bronchus of the left lower lobe with metastases tomediastinal lymph nodes.

The patient was treated with CCNU, methotrexate, and cyclosphos-phamide, which she tolerated well. She also was given a dietarypotassium supplement (40 mEq orally 4 times daily) and spironolactone,200 mg, 3 times daily; her dietary sodium was restricted to 1 g/day. Thisregimen sustained serum potassium at 4.5 mEq/liter and total CO2content at approximately 35 mmol/liter.

Discussion

DR. JOHN T. HARRINGTON (Professor of Medicine, TuftsUniversity School of Medicine, and Chief, General MedicineDivision, New England Medical Center, Boston, Mass.). Meta-bolic alkalosis, defined as a primary increment in plasmabicarbonate concentration, has been a subject of intense inter-est to acid-base physiologists and to clinicians over the lastseveral decades, and it remains so [1—91. I plan to discussseveral aspects of the patient presented, especially the initiallyelevated PaCO2, review present concepts regarding the mainte-nance of both chloride-resistant and chloride-responsive chronic

88

EditorsJORDAN J. COHENJOHN T. HARRINGTONJEROME P. KASSIRERNIcoLAos E. MADIAS

Managing EditorCHERYL J. ZLJSMAN

Michael Reese Hospital and Medical CenterUniversity of Chicago Pritzker School of Medicine

andNew England Medical Center

Tufts University School of Medicine

brought to you by COREView metadata, citation and similar papers at core.ac.uk

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Metabolic alkalosis 89

Table 1. Selected laboratory data

Days following first hospitalization

0 1 2 3

Serum potassium(mEqiliter) 1.2 1.7 2.3 2.3

Blood pH 7.65 7.63 7.59 7.57PaCO2

(mm Hg) 60 57 53 53Plasma HCO3

(mEqiliter) 65 58 49 47PaCO2* 0.5 0.5 0.5 0.6

HC03

* Represents the ratio of the increase above the normal PaCO2 of 40mm Hg and the normal bicarbonate concentration of 24 mEq/liter.

metabolic alkalosis [11, examine some new physiologic observa-tions on experimental metabolic alkalosis, and conclude with abrief synopsis of the treatment of metabolic alkalosis.

The metabolic alkalosis was severe in this patient, as werethe hypokalemia and the adaptive or secondary hypercapnia.The diagnosis of chloride-resistant metabolic alkalosis due to anACTH-secreting bronchogenic carcinoma could easily havebeen made given the information available within the first fewdays of her admission to the local hospital. The precise cause ofmetabolic alkalosis in an individual patient usually is identifiedon the basis of the medical history and clinical setting, andelaborate laboratory testing generally is not required. Diureticuse or abuse and gastric acid loss secondary either to vomitingor nasogastric drainage account for the vast majority of in-stances of severe metabolic alkalosis. For today's purposes, Iwill ignore the special case of metabolic alkalosis due to excessalkali ingestion or administration [101; we then can convenientlycategorize metabolic alkalosis as either chloride-responsive orchloride-resistant. Table 2 lists the common causes of metabolicalkalosis in each of these categories. Although in this patient wedo not have the critical laboratory determination—that is, theurinary chloride concentration—I am confident that the urinechloride would have considerably exceeded 20 mEq/liter, evenii the small dose of thiazides had been stopped. I say thisbecause the patient was receiving large amounts of potassiumchloride with little or no change in potassium or plasma chlorideconcentration and without effect on the metabolic alkalosis.Second, the glomerular filtration rate was normal, as measuredby a serum creatinine of 0.6 mgldl. We can surmise that thepatient was in a steady state and in chloride balance, that is, alladministered chloride was being excreted in the urine. Thus wecan reasonably conclude that this patient had chloride-resistantalkalosis.

The differential diagnosis of chloride-resistant metabolic al-kalosis comprises the disorders listed in the bottom half ofTable 2. Primary aldosteronism is not a consideration in thispatient because she was not hypertensive and because theplasma bicarbonate concentration was much higher than thattypically seen in primary aldosteronism. Bartter's syndrome, arare disorder in adults, could have caused the acid-base abnor-mality noted. Extensive endocrinologic investigation is neededto definitively distinguish Bartter's syndrome from primaryaldosteronism and Cushing's syndrome, but determination of

plasma renin activity is a readily available method for makingthis distinction. Increased renin secretion is a sine qua non forpatients with Bartter's syndrome, whereas in patients withprimary aldosteronism or Cushing's syndrome (who are volumeexpanded), the renin level is suppressed. Although plasma reninwas not measured, there is no evidence to support a diagnosisof Bartter's syndrome. Moreover, we have a better reason forthe chloride-resistant alkalosis.

In the patient we are discussing, the long history of smoking,the finding of severe metabolic alkalosis resistant to chlorideadministration, and the results of bronchoscopy virtually con-firm the diagnosis of an ACTH-secreting bronchogenic carcino-ma [Il, 121 even without special endocrinologic studies. Afterthe lesion was diagnosed, treatment was instituted both for themajor disorder in this patient—the bronchogenic carcinoma—aswell as for the paraneoplastic problem of interest to us today. 1should reiterate that aggressive, conventional, oral and intrave-nous treatment with potassium and chloride failed to totallycorrect the alkalosis and the hypokalemia.

The greatly elevated plasma bicarbonate concentration in thispatient with Cushing's syndrome secondary to an ACTH-secreting tumor is intriguing. In a recent review of extrememetabolic alkalosis, we found that plasma bicarbonate concen-trations greater than 60 mmol/liter virtually never occur save inpatients with chloride-responsive gastric alkalosis [1]. Whataccounts for the plasma bicarbonate concentration of 66 mmol/liter when this patient was first examined? The first possibilityis that hypersecretion of steroids explains the unusual eleva-tion. The data in this patient suggest excess aldosterone secre-tion, a finding that is not typical of Cushing's syndrome due to amalignancy 13]. The excess aldosterone secretion, whatever itscause, could have contributed to the rise in the plasma bicar-bonate concentration. A second possibility is that the patienthas a mixed metabolic alkalosis: in addition to having metabolicalkalosis due to the demonstrated ACTH excess, she hadgastric or diuretic-induced alkalosis as well. She had no historyof vomiting or nasogastric drainage, however, and I cannotadvance this possibility further. The third possibility is thatsevere potassium deficiency contributed to the genesis andmaintenance of this patient's chloride-resistant metabolic alka-losis. We will return to this issue later.

The hypercapnia of metabolic alkalosisI would like to address a series of questions regarding the

elevated PaCO2 when the patient was admitted to a localhospital. First, what degree of hypercapnia should be anticipat.ed for a given rise in plasma bicarbonate concentration inpatients with metabolic alkalosis? A related question, did thispatient have hypercapnia of a magnitude greater than thatattributed to metabolic alkalosis alone? Finally, how helpfulwas the rise in PaCO2 in defending against severe alkalemia?

The quantitative aspects of the human ventilatory response tometabolic alkalosis remain poorly defined. Experimental stud-ies in dogs and rats have shown that as plasma bicarbonateconcentration rises, PaCO2 also increases. In animals, thechange in PaCO2 with respect to the change in plasma bicarbon-ate (PaCO2/XHCO3), varies from 0.55 to 0.70 mm Hg/mEq/liter [14—17], Limited data in humans, including observations indialyzed patients [18], indicate that the relationship approxi-mates 0.7 mm Hg/mEq/liter for plasma bicarbonate concentra-

90 Nephrology Forum

Days after first hospital admission

Primary aldosteronismBartter' s syndromeCushing's syndromeDisorders that simulate adrenocortical excessIdiopathic

tions up to 40 mEq/liter [1]. To define the APaCO2/HCO3relationship for levels of plasma bicarbonate greater than 40mEq/Iiter, we carefully selected from the literature patientswith plasma bicarbonate concentrations of 40 to 75 mEq/liter[1]. Patients with respiratory disease or other factors known tosuppress ventilation were excluded from the analysis. Theevidence that the patients had only metabolic alkalosis and nota complicating respiratory acidosis derives from two compellingobservations: (1) when plasma bicarbonate concentration wasrestored to normal, PaCO2 also fell to normal; and (2) pulmo-nary function tests carried out after correction of the metabolicalkalosis were normal. Figure 2 represents acid-base data fromthe 19 selected patients; the open circles represent their acid-base data. Even at extreme levels of alkalosis, there is increas-ing hypercapnia; that is, the iPaCO2/HCO3 relationship doesnot appear to reach a plateau. Values for PaCO2 even greater

IHCO3I m Eq/I

Fig. 2: Respiratory adaptation in metabolic alkalosis. The dashed linerepresents the mean "whole-body titration" response approximatedfrom available data and defines the increment in PaCO2 attributable toincrements in plasma bicarbonate concentration. On average, eachmEq/liter rise in plasma bicarbonate is associated with a 0.7 mm Hg risein PaCO2. The dashed line is not extended beyond a bicarbonateconcentration of 40 mEq/liter because no systematic observations areavailable at higher levels (open circles represent the acid-base data fromthe 19 selected patients) (from Ref. 46).

than 70 mm Hg have been observed, and respiratory failure hasbeen reported. Thus, in answer to my first question, the meanslope of the PaCO2/HCO3 relationship in humans withmetabolic alkalosis and with plasma HC03 concentrations lessthan 40 mEq/liter is approximately 0.7 mm Hg per mEq/liter [11.The data from the 19 patients suggest, but do not prove, that theslope of the relationship remains at approximately 0.7 even inpatients with plasma bicarbonate concentrations greater than 40mEq/liter.

The principal receptors responsible for the rise in PaCO2 (that

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Table 2. Causes of metabolic alkalosis

Fig. 1: Clinical course of patient during monthafter first hospital admission. Daily doses ofspironolactone, potassium citrate, andpotassium chloride are shown above, andserial TCO2 contents and serum potassiumlevels are plotted below PaCO2.

A. Chloride-responsive alkalosis

Gastric fluid lossesDiuretic therapyPosthypercapnic stateStool losses

Congenital chloridorrheaVillous adenoma

B. Chloride-resistant alkalosis

80

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4024 36 48 60 72

Metabolic alkalosis 91

Fig. 3: Effects of persistent, secondaryhypercapnia on plasma bicarbonateConcentration during chronic diuretic-inducedmetabolic alkalosis. Steady-state values forPaCO2 are shown on the left and forbicarbonate concentration on the right. Eachpoint represents the average of 3 observationsobtained on consecutive days in a single dog(from Ref. 19).

is, the decrease in ventilation) in metabolic alkalosis reside inthe central nervous system. Clear evidence in the dog indicatesthat cerebrospinal fluid bicarbonate concentration rises asplasma bicarbonate concentration rises; no change in the usualCSF-arterial PCO2 gradient occurs [15]. As a consequence,CSF acidity decreases, in turn resulting in a depression ofminute ventilation. Limited data in humans with severe meta-bolic alkalosis suggest that a similar degree of CSF alkalinityoccurs, thus accounting for the secondary hypercapnia [1].

Table 1 shows that the PaCO2/HCO3 ratio in this patientvaried between 0.5 and 0.6 for the first 3 days of observation.These findings are close to the ratio of 0.7 I have just presented.Although pulmonary function tests were not performed in thispatient, no evidence of clinically significant respiratory diseasewas apparent from the medical history or physical examination.Thus I believe that metabolic alkalosis was a sufficient explana-tion for the patient's hypercapnia.

I have not yet answered the final question: was the strikingincrease in PaCO2 entirely beneficial to the patient? Most of us,I believe, have accepted the intuitively attractive notion that therise in PaCO2 in metabolic alkalosis is salutary with respect tothe body's hydrogen ion concentration. Although logical, thisconcept is now known to be only partially correct. Recentstudies show that hypercapnia causes the kidney to increaseacid excretion and to generate new bicarbonate—not only inprimary respiratory acidosis, but also in the secondary hyper-capnia associated with metabolic alkalosis [19]. To demonstratethis effect, metabolic alkalosis was induced in dogs by theadministration of ethacrynic acid and a chloride-free diet. Aftera steady state of plasma composition had been achieved, thesecondary hypercapnia of metabolic alkalosis was abolished byhypoxemia-induced hyperventilation. The PaCO2 fell to controlvalues; observations were continued over the next severaldays, and the animals then were allowed to recover. Figure 3documents the effect of the secondary hypercapnia on plasmabicarbonate concentration in this model of diuretic-inducedmetabolic alkalosis [19]. The PaCO2 was 36 mm Hg andbicarbonate 23 mEq/liter in the control period. When metabolicalkalosis was produced, the plasma bicarbonate concentrationrose to 31 mEq/liter and the PaCO2 rose, as anticipated, to 41

Room air 13% 02 Room airControl 1Metabolic alkalosis—

mm Hg; when secondary hypercapnia was abolished by hypox-emia, the PaCO2 fell to its control value of 36 mm Hg and, inresponse, the plasma bicarbonate concentration decreased to 27mEq/liter. No change in plasma lactate was noted. Whensecondary hypercapnia was reestablished in the final period,the plasma bicarbonate concentration again rose to 31 mEq/literin concert with the return of the PaCO2 to its previous level.

These studies indicated that fully 40% of the change in plasmabicarbonate in this model of chronic metabolic alkalosis is not aconsequence of the "metabolic" abnormality per Se, but is dueto a direct effect of the secondary change in PaCO2 on renal acidexcretion and bicarbonate reabsorption. The alteration in plas-ma bicarbonate concentration in chronic metabolic alkalosisthus has a dual genesis. One element of the hyperbicarbonate-mia is related to the factor that generated the alkalosis initially,whereas a second element is related to the "maladaptive" renalresponse to the secondary hypercapnia [191. Because the stud-ies of the secondary hypercapnia of metabolic alkalosis werelimited to a small increase in plasma bicarbonate, it is difficult toextrapolate quantitatively from those experimental data tospecific clinical situations. Nevertheless, one can assume fromthese data that some fraction of the increment in plasmabicarbonate concentration in the patient under discussion todaywas due to the secondary hypercapnia. I conclude that whilethe rise in PaCO2 does mitigate severe changes in pH in patientswith chronic metabolic alkalosis and is beneficial, its salutaryimpact is dampened by the "maladaptive" renal response.

This direct impact of a rise in PaCO2, whether primary orsecondary, on renal acid excretion gains credence from analo-gous studies in metabolic acidosis. Figure 4 shows the majorfindings in a study designed to divorce the effect of hydrochloricacid feeding per se on plasma bicarbonate concentration fromthe potential effect of the secondary hypocapnia that usuallyaccompanies metabolic acidosis [201. First, in the controlsetting, PaCO2 was 36 mm Hg and plasma bicarbonate 21 mEq/liter, typical values for normal dogs. With hydrochloric acidfeeding (7 mmol/kglday), but with secondary hypocapnia pre-vented by an elevated ambient CO2 concentration, plasmabicarbonate concentration fell from 21 mEq/liter to 16 mEq/liter, a reduction less than that commonly observed in this

PaCO2mm Hg

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40

35

30

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Room air 13% 02 Room airControl —Metabolic alkalosis

92 Nephrology Forum

Fig. 4: Effects of persistent spontaneous hypocapnia on plasma bicar-bonate concentration during chronic HCI acidosis. Steady-state valuesfor PaCO2 are shown on the left and for bicarbonate concentration onthe right. Each point represents the average of three observationsobtained on consecutive days in a single dog. PaCO2 was maintained atcontrol levels during eucapnic HCI acidosis but fell significantly duringthe period of spontaneous hypocapnia (mean PaCO2 6 mm Hg).Reproduced from The Journal of Clinical Investigation, 1977, vol. 60,pp. 1393—1401, by copyright permission of the American Society forClinical Investigation.

experimental model of metabolic acidosis [211. However, whenthe PaCO2 was allowed to fall from 36 to 30 mm Hg—thespontaneous hypocapnia of metabolic acidosis—plasma bicar-bonate concentration fell further from 16 mEq/liter to 13 mEq/liter. The data thus demonstrate quite clearly that the decline inplasma bicarbonate concentration in chronic HCI acidosis hastwo components: one element of the decline results from theacid load itself, but a substantial portion, some 40% of thedecrement, results from the effect of PaCO2 on plasma bicar-bonate concentration. This is remarkably similar to the 40%increase in plasma bicarbonate concentration due to the sec-ondary hypercapnia of experimental, diuretic-induced metabol-ic alkalosis. It is apparent from these studies that the kidneysets its rate of bicarbonate reclamation by the prevailing PaCO2and that it does so whether the change in PaCO2 is a primary orsecondary phenomenon.

Mechanisms of persistent hyperbicarbonatemia in metabolicalkalosis

I have just concluded that some portion of the elevatedplasma bicarbonate concentration in this patient was related tothe secondary hypercapnia—but that clearly is not the wholestory. Something has to raise plasma bicarbonate concentrationin the first place, and then some factors must act in concert tomaintain the elevated level [22]. Why didn't this patient simplyexcrete the excess bicarbonate in the urine, as a normalindividual would if sufficient sodium bicarbonate were adminis-tered to raise plasma bicarbonate? This remains the criticalquestion in understanding persistent metabolic alkalosis. Overthe years, persistent alkalosis has been attributed to sodium

depletion, potassium depletion, chloride depletion, excess glu-cocorticoid, excess mineralocorticoid, or a combination ofthese factors [1]. Recently it was suggested that a reduction inglomerular filtration rate is necessary for the maintenance ofmetabolic alkalosis in at least one experimental model [23].Before discussing this issue in detail, I would like briefly toreview the maintenance of the two major types of metabolicalkalosis, chloride-responsive and chloride-resistant alkalosis.

Chloride-responsive alkalosis. Studies in the l960s using anexperimental model of one of the common types of metabolicalkalosis, that due to loss of acid gastric juice, demonstratedthat the increased renal hydrogen ion secretion required tomaintain an elevated plasma bicarbonate concentration couldbe attributed to a combination of sodium avidity and diminishedchloride availability [6—91. I stress sodium avidity; overt sodiumdepletion is not required either in experimental animals or innormal human volunteers.

After selective depletion of hydrochloric acid in normalhumans (produced by gastric acid drainage and replacement ofany NaC1 and KCI removed), plasma bicarbonate concentrationrose to 40 mEq/liter or more, and plasma chloride concentrationfell in a reciprocal fashion [81. Substantial negative chloride (viagastric losses) and potassium (via renal losses) balance ensuedand persisted as long as the diet remained chloride free. Onecan correct the gastric alkalosis by administering either NaClwithout potassium or KC1 without sodium. These normalindividuals lost less than 100 mEq of sodium in the urine, had noevidence of volume contraction, and maintained inulin clear-ances during the period of alkalosis at levels unchanged fromcontrol [81. These latter observations are particularly notewor-thy in light of the recent study by Cogan and Liu [23], whoconclude that a decline in GFR is critical to the persistence ofmetabolic alkalosis. The observation by Cohen that diuretic-induced metabolic alkalosis in the dog could be corrected byrapid infusion of a solution that mimicked the plasma composi-tion of the alkalemic animals gives further weight to thehypothesis that both sodium avidity and chloride depletion arerequired to perpetuate metabolic alkalosis [24].

Chloride-resistant alkalosis. In the patient under discussion,chloride depletion cannot account for the persistent hyperbicar-bonatemia. But what does maintain the alkalosis in this group ofpatients? Unfortunately, we do not know. Increased secretionof glucocorticoids (in this patient, secondary to ACTH produc-tion by the bronchogenic carcinoma), increased secretion ofmineralocorticoids, and severe potassium depletion have beenconsidered the agents or factors most likely to be responsible[1]. In this patient, the severe potassium depletion (serumpotassium was 1.2 mEq/liter) might have contributed to themaintenance of the alkalosis. Hulter, Licht, and Sebastian haveshown that potassium depletion potentiates the effect of miner-alocorticoids on renal acid excretion [25]. Clinically, extremehypokalemia has been found in a small but interesting group ofpatients with so-called idiopathic chloride-resistant alkalosis.Plasma bicarbonate concentration in these patients varies from35 to 47 mEq/liter, and potassium concentrations range fromless than 1.0 to 2,1 mEq/liter. One patient, studied duringrecovery from the alkalosis, retained nearly 1000 mEq ofpotassium, emphasizing the profound degree of potassiumdepletion present in these unusual patients [26].

I should point out that experimental studies of isolatedpotassium depletion (produced by dietary restriction) conflict.

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Metabolic alkalosis 93

Although potassium depletion causes net acid excretion to fallin dogs and in humans, plasma bicarbonate rises slightly inhumans [27] and actually falls slightly in dogs [281. In neitherspecies can severe metabolic alkalosis be produced by purepotassium depletion.

Role of GFR in the persistence of metabolic alkalosis

If the glomerular filtration rate always were depressed inmetabolic alkalosis, as it probably is in alkalotic patients salt-depleted from vomiting or taking diuretics, one could argue thatthe fall in GFR and the consequent decrease in filtered bicar-bonate load might be sufficiently great to perpetuate the alkalo-sis without the need for invoking enhanced absolute tubularbicarbonate reabsorption. As I mentioned, Cogan and Liu haveclaimed recently that just such a reduction in GFR does occurand is critical to the maintenance of metabolic alkalosis [23].They carried out a series of micropuncture and clearanceexperiments in rats with chronic metabolic alkalosis and vary-ing degrees of potassium and chloride deficiency [23] andcompared their results to those obtained in previous studies innormal rats [29]. Metabolic alkalosis was induced by feeding theanimals an electrolyte-deficient diet supplemented with sodiumsulfate and sodium bicarbonate, and by injecting deoxycorticos-terone acetate. Severe metabolic alkalosis was produced; pHwas 7.57 and total CO2 41 mmollliter. In these animals, whole-kidney and single-nephron glomerular filtration rate declinedsufficiently to leave the filtered load of HCO3 unchanged ascompared to the non-current, unpaired euvolemic controls [29].Similarly, absolute proximal HC03 reabsorption and distalHC03 delivery did not differ in the two groups. The authorsconcluded that the demonstrated fall in GFR permitted normalrates of renal tubular hydrogen ion secretion to maintain thealkalotic state. Isohydric expansion in an additional 10 rats withmetabolic alkalosis produced an increase in GFR and a de-crease in fractional proximal HC03 reabsorption.

The data are interesting and the authors' conclusions provoc-ative, but let us examine the interpretation of these data. Usingthe clearance data, Cogan and Liu demonstrate only a correla-tion between the changes in single-nephron GFR and thechanges in plasma bicarbonate concentration; they do not showthat one is causally related to the other. More important,individual data points are not shown, simply the means, andindividual data points are crucial for determining whether theGFR is the critical determinant of the elevated plasma bicarbon-ate concentration in chronic metabolic alkalosis. The authorsdo demonstrate that alterations in proximal tubular renal acidifi-cation seem not to be regulated by changes in systemic pH; thisview is consistent with the hypothesis advanced by Schwartzand Cohen [301.

Studies by two different groups help to shed light on the roleof GFR in the maintenance of metabolic alkalosis. First, thestudies of Maddox and Gennari [31] conflict with those ofCogan and Liu. Metabolic alkalosis was produced in rats byprovision of a chloride-free and potassium-restricted diet, injec-tion of furosemide, and administration of sodium bicarbonate inthe drinking water. Animals with metabolic alkalosis had astable elevated plasma bicarbonate concentration throughout a2-week observation period. At 11 to 14 days, single-nephronGFR was 24 nl/min, a figure not significantly different fromcontrol. In addition, whole-kidney GFR, initially 1.2 mI/mm,

SNGFR(ni/mm)

Fig. 5: Relationship between SNGFR and APRHCO3 in control rats(open symbols and dotted line) and in rats with CMA (filled symbolsand solid line). The lines drawn through the data points were obtainedby least-squares analysis. The two lines have similar slopes, butsignificantly different intercepts (p < 0.01) by covariance analysis.Reproduced from The Journal of Clinical Investigation, 1983, vol. 72,pp. 1385—1395 by copyright permission of The American Society forClinical investigation.

was 1,0 ml/min (not significantly different from control) at 11 to14 days. When filtered bicarbonate load was plotted againstabsolute plasma bicarbonate concentration at 11 to 14 days, ahigher rate of proximal bicarbonate reabsorption was found in 5of 7 rats in which single-nephron GFR was not different fromcontrol.

Maddox and Gennari plotted absolute proximal bicarbonatereabsorption (APRHCO3) against single-nephron GFR(SNGFR) in control animals and in animals with chronicmetabolic alkalosis (CMA) and obtained two parallel lines (Fig.5). They thus demonstrated that proximal bicarbonate reab-sorption is simply delivery related, a situation entirely analo-gous to the proximal tubular control of sodium reabsorption[32]. These data suggest that glomerular filtration rate andluminal bicarbonate concentration are not the critical factors; itappears that it does not matter how bicarbonate delivery isincreased; it is the increased bicarbonate delivery per se that isimportant.

Galla, Bonduris, and Luke also studied the impact of volumeexpansion and changes in GFR on correction of metabolicalkalosis [33]. These investigators studied the relative impor-tance of volume expansion versus the availability of chloride inthe correction of experimental metabolic alkalosis induced byperitoneal dialysis. In experimental rats, provision of chloridewith either sodium or choline corrected the alkalosis despite acontinued negative potassium balance. Volume expansion didnot occur in the choline chloride-treated animals, and Galla et althus concluded that chloride depletion accounted for the main-tenance of the metabolic alkalosis [33—35]. Although single-nephron GFR was not determined in their study [331, it seemsunlikely that the correction phase was associated with anincrease in SNGFR, given the absence of volume expansion inthe choline chloride-treated animals.

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94 Nephrology Forum

Treatment of metabolic alkalosisTreatment of the common type of chloride-sensitive metabol-

ic alkalosis usually requires only correction of chloride deple-tion, restoration of extracellular volume (if depleted), and theprovision of an adequate amount of potassium. Most patientswith metabolic alkalosis respond rapidly to intravenous infu-sions of 2 to 3 liters/day of normal saline with 40 to 60 mEq ofKCI in each liter. When alkalosis is severe (arbitrarily definedas a plasma bicarbonate concentration of 40 mEq/liter), moreaggressive measures are required, including treatment withammonium chloride, arginine hydrochloride, hydrochloric acid,or acetazolamide. Even hemodialysis has been proposed. Myown practice in these unusual circumstances—and I have donethis usually in patients with severe secondary hypercapnia ordigitalis intoxication from concomitant hypokalemia—has beeneither to infuse 0.1 N hydrochloric acid through a central vein,or argininc hydrochloride through a peripheral vein, monitoringserum potassium carefully. Recently Knutsen showed that theadministration of hydrochloric acid through a peripheral line isfeasible by adding 0.15 N hydrochloric acid to an amino acidsolution and fat emulsion [361. This approach has the advantageof not requiring a central venous catheter and should beconsidered in the unusually severe case of metabolic alkalosis.

Treatment of chloride-resistant metabolic alkalosis is muchmore difficult, as demonstrated by the patient under discussiontoday. Therapy consists of the administration of large amountsof KC1, the use of spironolactone in maximal doses in hyperad-renal states, and an attack on the root cause of the alkalosis.Examples include surgical treatment of primary aldosteronismand treatment with prostaglandin synthetase inhibitors in pa-tients with Bartter's syndrome.

Questions and answers

DR. JEROME P. KASSIRER: I would like to make two com-ments on the pathogenesis of metabolic alkalosis. First, Iassumed that a reduction in GFR had been dismissed as animportant factor in the pathogenesis of persistent alkalosis bythe extensive studies by Schwartz and colleagues in animalsand humans. Both in gastric alkalosis in dogs and humans and insodium nitrate-induced alkalosis in humans, inulin or creatinineclearances performed during steady-state alkalosis are un-changed as compared to controls [7, 8, 37]. These observationsin intact animals and humans argue strongly against a fall inGFR as a necessary pathogenetic element. I continue to believethat in gastric and diuretic-induced alkalosis, the principalmechanism for persistent alkalosis is the disproportion betweensodium reabsorption and chloride availability.

My second comment relates to the pathogenesis of steroid-induced metabolic alkalosis. The question is whether there isany relevance between experimental steroid-induced alkalosisand the clinical alkalosis that occurs in primary aldosteronismor Cushing's syndrome. In all the experimental forms of steroidalkalosis, some nonphysiologic combination of diet and electro-lyte supplement is required to produce alkalosis; in the case ofthe studies by Cogan and Liu [23], Hulter and colleagues [25],and us [38], either sodium sulfate or bicarbonate must be givenwith the steroids, or else plasma bicarbonate rises little. In fact,if one administers large quantities of aldosterone to normalindividuals ingesting a normal diet for as long as 3 months,plasma bicarbonate increases 2 or 3 mEq/liter after a few daysand does not increase thereafter [39]. Thus we are stuck with

the dilemma that manipulations not relevant to human alkalosisare needed in these experimental models. Presumably thesteroid itself influences renal hydrogen secretion, but a modelto test this hypothesis has not yet surfaced.

DR. HARRINGTON: I fully agree with your comments, whichseem to contain one basic question: How analogous to gastricalkalosis in humans are the models of metabolic alkalosis inrats? The answer is that they aren't analogous at all. To performmicropuncture studies and determine whether and where alongthe nephron enhanced bicarbonate reabsorption occurs, it isnecessary to work with these complex models. I should pointout that in the Maddox and Gennari study [311, administrationof bicarbonate in the drinking water was required to sustain themetabolic alkalosis induced by furosemide. It is a lyric leapfrom these kinds of experimental models to real-world gastricalkalosis. Dr. Gennari, do you want to comment?

DR. F. JOHN GENNARI (Professor of Medicine, and Chief,Renal Division, Univ. of Vermont College of Medicine, Burling-ton, Vermont): Yes. First, I agree with Dr. Kassirer. Theexperiments he and Dr. Schwartz carried out provide definitiveevidence that a reduction in GFR is not required for themaintenance of chloride depletion alkalosis in humans [8]. IfGFR doesn't change, and the plasma bicarbonate concentrationis maintained at 40 mEq/liter, the kidneys are obviously reab-sorbing much more bicarbonate than normal. In the two micro-puncture studies in the rat that were discussed in this Forum,the fall in GFR is most likely due to a concomitant fall inextracellular fluid volume [23, 31]. In contrast to the experi-ments reported by Kassirer and Schwartz, NaCl losses werenot specifically replaced in either study. In their model ofmetabolic alkalosis in the rat, Cogan and Liu found a closecorrelation between the degree of chloride depletion and themagnitude of the fall in GFR [23]. To go from this closecorrelation to the conclusion that a fall in GFR is a necessarycondition for maintenance of the metabolic alkalosis, however,is unjustified. The demonstration by these investigators thatchloride repletion (induced by acute isometric expansion) bothincreases GFR and reduces bicarbonate reabsorption providesinsight into recovery from metabolic alkalosis, but not into themaintenance of this acid-base disorder.

The observations Dr. Maddox and I made in a somewhatdifferent model of metabolic alkalosis in the rat are generally inaccord with the results of Cogan and Liu. The GFR tended tofall in the chloride-depleted alkalotic rats, and mean proximaltubular and overall renal bicarbonate reabsorption was notsignificantly increased above control. In our study, however,the rate of proximal bicarbonate reabsorption was higher thanthe highest control value in 5 rats with metabolic alkalosis inwhich GFR did not fall. If a reduction in GFR is truly critical forthe maintenance of alkalosis in the rat, we should not have seenthis finding. In both Cogan and Liu's study and ours, proximalbicarbonate reabsorption varied in direct relation to the filteredload in chronic metabolic alkalosis, and the relationship wasindistinguishable from that seen in control animals. I find itinteresting that neither severe hypokalemia nor alkalemia influ-enced the pattern of proximal bicarbonate reabsorption in therats with chronic metabolic alkalosis. Instead, the filtered loadappears to be the overriding influence determining the rate ofproximal bicarbonate reabsorption. Given this relationship, it isapparent that proximal bicarbonate reabsorption may be in-creased, unchanged, or decreased as compared to control in

Metabolic alka/osis 95

chronic metabolic alkalosis, depending on the extent to whichGFR has fallen. Our data suggest that when GFR is not notablyreduced, metabolic alkalosis in the rat is maintained, at least inpart, by a load-dependent increase in proximal bicarbonatereabsorption.

DR. NIcoLAos E. MADIAS: I should like to point out anotherimportant discrepancy between the results of Cogan and Liu intheir complex model of metabolic alkalosis in the rat and thoseof Cohen in ethacrynic acid-induced metabolic alkalosis in thedog [24, 40]. As Dr. Harrington mentioned, Cohen showed thatinfusion of alkalotic animals with a solution isometric to plasma(with respect to major electrolytes), while preventing filteredload from increasing by means of an aortic clamp, led tosuppression of absolute bicarbonate reabsorption, to bicarbona-tuna, and to selective renal chloride retention. These dataclearly indicate that correction of metabolic alkalosis in the dogdoes not depend on an increment in glomerular filtration rate.

In regard to mineralocorticoid-induced metabolic alkalosis, Ishould like to reemphasize that prior potassium restrictionallows the generation of moderate degrees of hyperbicarbonate-mia in the dog in the absence of co-administration of bicarbon-ate [251. However, even this degree of metabolic alkalosis ismuch less severe than the one usually occurring in patients withprimary aldosteronism [391. The pathogenesis of human mm-eralocorticoid-induced metabolic alkalosis remains unclear.

DR. RONALD D. PERR0NE (Division of Nephrology, NEMC):In Dr. Gennari's slide (Fig. 5), there is the same relationshipbetween absolute proximal bicarbonate reabsorption and fil-tered load in controls and animals with metabolic alkalosis,although there seems to be a higher set point in metabolicalkalosis. Could you explain that?

DR. GENNARI: The two parallel lines that emerge whenproximal bicarbonate reabsorption is plotted against single-nephron GFR in control animals and animals with metabolicalkalosis simply underscore the fact that plasma bicarbonateconcentration is higher in rats with metabolic alkalosis. Al-though this relationship indicates that bicarbonate reabsorptionis higher for any given level of GFR in metabolic alkalosis, Idon't believe that bicarbonate reabsorption is stimulated. Thefiltered load, that is, SNGFR x Bowman's space [HC03], isjust higher in these animals. As indicated earlier, bicarbonatereabsorption appears to be determined primarily by the filteredload both under control conditions and during chronic metabol-ic alkalosis. Our data indicate that the proximal tubule isindifferent to whether the filtered load is altered by changes inGFR or in bicarbonate concentration. Bicarbonate reabsorptionin the accessible portion of proximal tubule remains at about80% to 85% of the filtered load regardless of whether plasmabicarbonate concentration or SNGFR is altered in our studies.It should be noted that this relationship between bicarbonatedelivery and reabsorption can be altered by acute changes inextracellular volume and by acute alkalemia [41—45]. In micro-perfusion experiments, potassium depletion also appears to be amodifying influence [45]. For reasons that remain unclear, ourresults suggest that alkalemia, hypokalemia, and extracellularvolume are not very important influences (or else they areexactly counterbalanced) in chronic metabolic alkalosis.

Turning away from the GFR issue, let me ask Dr. Madias aquestion. We know that the increase in bicarbonate concentra-tion induced by chronic hypercapnia is a function of the

bicarbonate concentration prior to hypercapnia. Thus, I suspectthat the secondary hypercapnia in this patient increased plasmabicarbonate concentration only slightly. Can you comment onthis point?

DR. MADIAS: As Dr. Harrington indicated, in our studies withethacrynic acid-induced metabolic alkalosis of moderate sever-ity ([HCO3] of 7.7 mEq/liter), some 40% of the bicarbonateincrement was attributed not to the associated chloride andvolume deficits but to the renal response to the accompanyingsecondary hypercapnia. The observed [HCO3]/PaCO2slope was 0.61 mEq liter1 mm Hg [19]. Studies withgraded degrees of metabolic alkalosis will be required toquantitatively answer Dr. Gennari's question.

DR. KASSIRER: I suspect that the higher the plasma bicarbon-ate, the smaller fractional contribution there is to this maladapt-ive phenomenon. The incremental PaCO2-induced increase inplasma bicarbonate probably has a much larger impact onadaptation when the bicarbonate is slightly elevated and lesswhen the bicarbonate is very high. Clearly these are specula-tions that require further evaluation.

DR. MADIA5: The overall utility of the ventilatory response tometabolic acid-base disorders for the living organism warrantsredefinition in view of our recent findings, summarized by Dr.Harrington, that drew a sharp distinction between the impact ofPaCO2 changes on plasma acidity in acute versus chronicderangements [19, 201. These observations brought into focusthe basic principle that a deviation in plasma pH resulting froma primary change in plasma bicarbonate concentration is offsetto a maximal degree by a given secondary change in PaCO2 onlyso long as plasma bicarbonate is not further altered. Wepreviously showed that this situation only prevails in acutemetabolic acid-base disorders, in which the observed ventila-tory response does little to further alter the plasma bicarbonateconcentration. By contrast, in chronic metabolic acid-basedisorders, the potential benefits of the ventilatory adaptation instabilizing extracellular acidity are greatly undermined by amaladaptive renal response to the changes in PaCO2 culminat-ing in substantial, secondary changes in plasma bicarbonateconcentration. Our use of the term "maladaptive" refers to thefact that this renal response clearly diminishes the degree towhich systemic acidity is protected by the ventilatory responseacutely. Indeed, experimental conditions can be arranged suchthat the kidney's response to so-called "compensatory" hyper-ventilation actually results in more severe acidemia than wouldoccur in the complete absence of secondary hypocapnia [201.Because of these findings, we previously suggested that thetime-honored terms "compensatory hypercapnia or hypocap-nia" be discarded in favor of the descriptive terms "secondary(or adaptive) hypercapnia or hypocapnia."

DR. KASSIRER: Although it is true that the mechanismsdescribed by Dr. Madias do reduce the effectiveness of theadaptive response, we should not lose sight of the strikingprotective effect conferred by secondary hypercapnia. Figure 6,reprinted from Acid-Base [46], shows the protective effect ofhypercapnia as compared to no adaptation, assuming the slopeof the PaCO2/HCO3 relationship to be 0.7: even withexteme alkalosis, that is, plasma bicarbonate concentrations of60 to 70 mEq/liter, the adaptive increase in PaCO2 prevents pHfrom rising above 7.6.

96 Nephrology Forum

I

Plasma LHCO3I (mEq//)

Fig. 6: Beneficial effect of respiratory adaptation on pH and hydrogenion concentration in metabolic alkalosis. See text (from Ref. 46).

DR. DAVID CAHAN (Chief of Nephrology, Faulkner Hospital,Boston): Does hypokalemia enhance hydrogen ion secretion bythe nephron?

DR. HARRINGTON: The information we have reviewed today,including Cogan and Liu's study and the Maddox and Gennaristudy, shows that the degree of potassium depletion has noimpact on the relationship between SNGFR and absoluteproximal bicarbonate reabsorption. As I mentioned earlier,potassium depletion in humans causes plasma bicarbonate torise only slightly [271 and in dogs causes mild but definitemetabolic acidosis [281.

DR. KASSIRER: Dr. Gennari, would you comment about therelationship between potassium deficiency and ammonia pro-duction? In particular, what is the effect on steady-state acid-base equilibrium of an increase in ammonia production conse-quent to potassium deficiency?

DR. GENNARI: The evidence is clear that potassium depletionstimulates ammonia production [47]. Despite this change, acidbalance is unaffected; urine pH rises and titratable acid excre-tion falls so that net acid excretion is unchanged. Potassiumdepletion, per se, has no effect in plasma bicarbonate concen-tration in humans, except perhaps where it is severe enough toreduce potassium concentration to below 2 mEq/liter. In thedog, it produces metabolic acidosis; in the rat it producesmetabolic alkalosis [48, 49]. The potassium depletion-inducedincrease in bicarbonate concentration in the rat is thought to berelated to transcellular shifts rather than to direct stimulation ofbicarbonate reabsorption or to an increase in acid excretion.

DR. MADIAS: Recent studies in the isolated rabbit proximalconvoluted tubule perfused in vitro have shown that when bathpotassium concentration is progressively lowered, sodiumtransport, as reflected by volume absorption, and acidification,as reflected by net total CO2 absorption, are both inhibitedproportionately [50].

DR. FERGUS MOYLAN (Dept. of Pediatrics, Boston FloatingHospital, NEMC): Dr. Harrington, do we still need to beconcerned about metabolic alkalosis in neonates being fed low-chloride formulas?

DR. HARRINGTON: Yes and no. A few years ago, a number ofinvestigators reported metabolic alkalosis in several normoten-sive infants fed a commercial soybean formula [5 1—53]. Thecritical clinical observation in these patients was that the urinechloride concentration was extraordinarily low; the chlorideconcentration of the soybean formula was less than 2 mEqlliterin contrast to a chloride concentration of 10 to 18 mEq/liter inotherformulas and in human breast milk in most instances. Thistype of alkalosis has disappeared with provision of adequatechloride in the formula. So you don't have to concern yourselfregarding that type of metabolic alkalosis. However, the identi-cal syndrome was observed recently in 2 infants fed only breastmilk. In these patients, the chloride content of the mother'sbreast milk was found to be near zero for unknown reasons [54,55]. Chloride-responsive metabolic alkalosis also has beenfound, not too surprisingly, to be a significant clinical problemin the current epidemic of anorexia nervosa [56].

DR. VINCENT CANZANELLO (Fellow, Division of Nephrolo-gy, NEMC): You did not comment on the increased "aniongap" in metabolic alkalosis. Can you describe its origin?

DR. HARRINGTON: Most of the elevation of the anion gap inmetabolic alkalosis derives from an increase in the net anioniccharge of plasma proteins, due both to their titration (from thealkalemia per se) and to the elevated concentration of plasmaproteins consequent to extracellular volume depletion [57, 58].The clinical relevance of this observation is that a modestincrease in the anion gap in this setting should not force theclinician to assume that a coexistent "hidden" degree ofmetabolic acidosis is present. Metabolic acidosis thus is not theonly cause of an elevated anion gap.

Reprint requests to Dr. J. Harrington, Box 212, New EnglandMedical Center, 171 Harrison Avenue, Boston, Massachusetts 02111,USA

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