Reduced Glomerular Filtration Rate Can Maintain a

Am. J. Nephrol. 7: 450-454 (1987)

Reduced Glomerular Filtration Rate Can Maintain a Rise in Plasma Bicarbonate Concentration in Humans Antonio Vaz Carneiro, Anthony Sebastian, Martin G. Cogan General Clinical Research Center. Department of Medicine, and Cardiovascular Research Institute. University of California, San Francisco. Calif., USA

Key Words. Hyperbicarbonatemia • Gastric alkalosis • Bicarbonate reabsorption • Acidification • Potassium depletion • Chloride depletion

Introduction The elevated plasma bicarbonate concentration of chronic metabolic alkalosis persists because the kidney reabsorbs essentially all of the filtered bicarbonate. Two pathophysiological mechanisms might prevent bicarbon ate escape into the urine: (a) without change in glomeru lar filtration rate, the absolute rate of renal bicarbonate reabsorption increases commensurate with the increased filtered bicarbonate load, or (b) the glomerular filtration rate (GFR) decreases, such that the filtered bicarbonate

load remains unchanged, so that the absolute rate of renal bicarbonate reabsorption need not increase [1-3]. In the rat, most evidence supports the second mecha nism [4. 5]. In a previous study in humans, however, we found that a reduction in GFR did not completely offset the rise in plasma bicarbonate concentration during chronic metabolic alkalosis induced by gastric hydroch loric acid removal. Rather, both a reduction in GFR and an increase in renal bicarbonate reabsorption contrib uted to the maintenance of the alkalotic state, in a ratio of 40/60%, respectively [6],

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Abstract. In humans, deficiency of chloride and potassium were found to perpetuate the hyperbicarbonatemia that attends metabolic alkalosis induced by gastric aspiration partly by increasing renal bicarbonate reabsorption, commensurate with the attendant increase in filtered bicarbonate load, and partly by decreasing glomerular filtration rate (GFR), which minimizes the degree of which the filtered bicarbonate load increases and thereby minimizes the requisite increase in bicarbonate reabsorption. The relative contribution of stimulated renal bicarbonate reabsorp tion might increase, however, if the supply of extrarenal bicarbonate is increased, in which case a greater degree of hyperbicarbonatemia would be sustained. To investigate that possibility, we reexamined the mechanism of perpe tuation of gastric alkalosis in normal subjects eating a low NaCl diet supplemented with bicarbonate salts. Prior to gastric aspiration, plasma bicarbonate concentration ([HCOyjp) and pH were higher than in similarly studied sub jects not receiving bicarbonate: 29.9 ± 0.6 vs. 25.3 ± 0.1 and 7.43 ± 0.008 vs. 7.41 ± 0.002 ntEq/1, respectively. With continued bicarbonate supplementation, gastric aspiration induced a further significant increase (p < 0.05) in [HCOjjp of 10.8%, to values not significantly different from those in nonbicarbonate-loaded subjects with gastric alkalosis: 33.2 ± 1.2 mEq/1. GFR decreased significantly by 8.4% (from 98 ± 4 to 90 ± 3 ml/min. p < 0.025). offsetting nearly commensurately the increase in [HCOyjp so that total renal bicarbonate reabsorption was not significantly increased (2.90 ± 0.12 vs. 2.97 ± 0.19 mEq/min, p = NS). Thus, in humans ingesting a low NaCl diet, when bicarbonate availability is not rate-limiting, bicarbonate reabsorption appears to be maximal and docs not increase in response to gastric aspiration; the increment in [HCO^Jp induced by gastric aspiration is perpetuated predominantly by a reduction in GFR.

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GFR and Metabolic Alkalosis

Methods General Techniques All studies were performed using standard balance techniques at the General Clinical Research Center of MolTm Hospital. Univer sity of California. San Francisco. Research was carried out accord ing to the principles of the Declaration of Helsinki. Approval was obtained from the institutional Committee on Human Research and informed consent was obtained from each subject. Balance tech niques and analytical methods used in this laboratory' have been reported previously [7], Studies were performed in 4 healthy, nonsmoking male volun teers (ages 29-53 years). During the entire protocol, low NaCl whole food diet ingested was identical to the previous study [6], providing per kg of body weight: 43.7 keal. 1.4 g protein, 0.15 mEq sodium, 0.88 mEq potassium. 3.4 mg calcium. 12.3 mg phosphorus, and 50 ml distilled water. Throughout the study, patients were given I mEq/kg body weight per day each of sodium bicarbonate and potas sium bicarbonate. Study Design A precontrol period of 10 days was allowed to obtain a steady state value for plasma and urine acid-base and electrolyte composi tion. During the subsequent 4-day control period, daily afternoon sets of iothalamale clearances were performed and arterialized blood gases were obtained. Following this period of control mea surements, an increment in plasma bicarbonate concentration was induced over the next 10 days [6, 8], During this period. 3-5 gastric aspirations were performed by nasogastric or orogastric intubation.

Each gastric aspiration lasted 3-4.5 h. Pentagastrin (6 pg/kg body weight s.c.) was administered after insertion of the tube and at 1.5 and 3 h. None of the subjects developed plasma potassium concen tration < 2 .6 mEq/l that would have required termination of the gastric aspiration. At the end of this period, the amount of sodium aspirated was returned (as sodium chloride) to each subject. Follow ing observation for at least 48 h, iothalamatc clearances and arteri alized blood gases were remeasured for 4 successive days as pre viously outlined. Clearance Techniques A water diuresis was established and baseline collections of urine and plasma were obtained 2.5 h after lunch. A loading dose of meglumine iothalamate (Conray 60, 30 mg/kg body weight of iodine) was administered intravenously followed by a maintenance infusion of 0.18-0.28 mg/min per kg body weight to achieve a plasma iodine level of approximately 15 mg/dl (the individual main tenance infusions were based on each subject's body weight and creatinine clearance) [9], After an equilibration period of 1 h, five sequential 45-min urine collections commenced. Plasma samples were obtained at the mid-point of each urine collection. Each sub ject remained supine except to urinate. One arterialized blood sam ple was obtained midway during the clearance periods for estima tion of arterial pH, pCO; and total COj. Measurements and calculations were identical to the ones used and reported in the previous study [6], Statistical Analysis Measurements were pooled to obtain an average value for each subject in each period and are expressed as mean ± SEM for the 4 subjects. Significance was assessed by the paired (two-tailed) Stu dent’s t test.

Results The administration of bicarbonate was successful in inducing a constant level of urinary bicarbonate excre tion during the control period averaging 60.0 ± 7.2 mEq/day. Net acid excretion was therefore negative (-52.0 ± 5.9 mEq/day). This bicarbonate supplementa tion caused a mild metabolic alkalosis during the control period: arterial blood pH was 7.43 ± 0.008, pCOi was 46.2 ± 0.5 mm Hg, and plasma bicarbonate concentra tion was 29.9 ± 0.6 mEq/l. These values were all signif icantly greater than those that had previously been ob tained on a similar low salt diet without bicarbonate sup plementation (7.41 ± 0.002, 41.0 ± 0.4 mm Hg, and 25.3 ± 0.1 mEq/l, respectively) [6], With gastric aspira tion, a significantly more severe metabolic alkalosis de veloped than in the control period. Arterial blood pH increased to 7.48 ± 0.01 (p < 0.025) and plasma bicar bonate concentration increased to 33.2 ± 1.2 mEq/l (p < 0.05). This further severity of alkalosis occurred with the concurrent development of hypokalemia (3.5 ±


In our previous study, the potential of the human kid ney to increase bicarbonate reabsorption in the mainte nance of chronic metabolic alkalosis might not have been fully realized because gastric bicarbonate genera tion may not have produced sufficient bicarbonate to saturate bicarbonate reabsorptive capacity, thereby re stricting the degree of metabolic alkalosis. That is, if more bicarbonate of extrarenal origin had been avail able, a further increase in plasma bicarbonate might have been achieved by a reserve of bicarbonate reabsorp tive capacity. The present study was designed to assess the relative roles of a decrease in GFR versus an increase in renal bicarbonate reabsorption in maintaining chronic meta bolic alkalosis when the availability of bicarbonate from extrarenal sources was not rate-limiting for attaining the maximal degree of hyperbicarbonatemia. A dietary sup plement of bicarbonate was given in a control state as well as following gastric aspiration to induce persistent bicarbonaturia so that the highest possible rates of bicar bonate reabsorption could be defined in each period. We then could assess whether a greater degree of hyperbicar bonatemia could be sustained than in our previous study.

Va/. Carneiro/Scbaslian/Cogan

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Fig. 1. Effect of gastric aspiration on plasma bicarbonate concentration, GFR, and total renal acidification in 4 subjects maintained on a low N a d diet supplemented with bicarbonate (2 mEq/ kg body weight).

APIasma [HCOj] % With supplemental HCOj [present study] Low salt diet 18 Gastric aspiration 10 Without supplemental HCOj [6] Low salt diet and gastric aspiration 27

AGFR %

-8

-1 0

AHCOj reabsorption %

2

17

- = Not measured.

0.1 to 3.0 ± 0.2 mEq/1, p < 0.05). Similar to our pre vious study, cumulative balances of potassium and chlo ride were -7 8 ± 28 and -2 0 ± 58 mEq, respectively, and weight loss of 0.3 kg (p = NS). Bicarbonaturia (60.8 ± 8.3 mEq/day) and negative net acid excretion (-51.0 ± 8.1 mEq/day) continued. Associated with the 10.8% rise in plasma bicarbonate concentration there was a 8.4% fall in GFR, from 98 ± 4 to 90 ± 3 ml/min com pared with the control period (p < 0.025), as shown in figure 1. Because the changes in plasma bicarbonate con centration and GFR were almost inversely proportional, total renal acidification changed only slightly (2.4%), from 2.90 ± 0.12 to 2.97 ± 0 . 1 9 mEq/min (p = NS). Thus, despite bicarbonate supplementation, the incre

ment in plasma bicarbonate concentration induced by gastric aspiration was maintained primarily by a reduc tion in GFR, rather than by an increase in renal bicar bonate reabsorption, due to the attendant chloride and/or potassium deficiencies.

Discussion In humans with experimentally induced gastric alka losis, we studied the mechanisms perpetuating alkalosis under conditions in which bicarbonate availability from extrarenal sources is not rate-limiting for renal bicarbon ate reabsorption. We found that renal bicarbonate reab sorption did not increase in response to gastric aspira tion; the increment in plasma bicarbonate concentration due to gastric aspiration persisted predominantly be cause GFR decreased as a consequence of the accompa nying chloride and/or potassium deficiencies. In the control period prior to gastric aspiration, a higher steady state plasma bicarbonate concentration existed than had prevailed in the control period of our previous study carried out under similar conditions ex cept for bicarbonate supplementation [10], On compara ble low salt diets, steady state plasma bicarbonate regu lated at 29.9 ± 0.6 mEq/I with bicarbonate supplements compared to 25.3 ± 0.1 mEq/1 without supplements [6]. Thus, bicarbonate supplementation revealed a pre viously unexpressed ability of the kidney to regulate the plasma bicarbonate concentration at a higher set point.


Table I. Maintenance of hyperbicarbonatemia by réduction in GFR and rise in rénal bicarbonate reabsorption

453

GFR and Metabolic Alkalosis

not increase as a consequence of an approximately com mensurate reduction in GFR (table I). The previous study was not designed to isolate the first of this two-step sequence, so that both steps occurred concurrently, and a mixture of GFR reduction and bicarbonate reabsorptive augmentation resulted in maintenance of the increased plasma bicarbonate concentration (25-32 mEq/1). In conclusion, under conditions of bicarbonate sup plementation, gastric aspiration associated with chloride and potassium deficiencies caused an increment in ar terial bicarbonate concentration to be maintained with out an increase in filtered or reabsorbed bicarbonate owing to the simultaneous reduction in GFR. These results support the concept that an increment in plasma bicarbonate concentration can be maintained by en hanced renal bicarbonate reabsorption when reabsorp tive capacity is not saturated, but when it is, mainte nance of a further increase in bicarbonate concentration requires that GFR be reduced.

Acknowledgements The excellent technical assistance of Ms. Joan Colman is grate fully acknowledged. These studies were supported in pan by the Division of Research Resources of the National Institutes of Health (RR-79). by grants (AM 21605 and AM 37423) and Clinical Inves tigator Award (AM 01015) from the National Institute of Diabetes. Digestive and Kidney Diseases, and by a grant from the Research Evaluation and Education Committee of the University of Califor nia, San Francisco. Dr. C'arnciro was supported by funds from the National Kidney Foundation of Northern California and the Divi sion of Nephrology, San Francisco General Hospital.

References 1 Cogan, M.G.; Rector. F.C.: Acid-base disorders; in Brenner, Rector. The kidney; 3rd ed. (Saunders. Philadelphia 1986). 2 Cogan. M.G.; Liu, F.-Y.; Berger. B.E.: Sebastian. A.; Rector. F.C.: Metabolic alkalosis. Med. Clins N. Am. 67: 903-914 (1983). 3 Scldin, D.W.; Rector. F.C.: The generation and maintenance of metabolic alkalosis. Kidney int. /: 306-321 (1972). 4 Maddox. D.A.; Gennari, F.J.: Proximal tubular bicarbonate reabsorption and pC02 in chronic metabolic alkalosis in the rat. J. clin. Invest. 72: 1385-1395 (1983). 5 Cogan. M.G.; L.iu. F.-Y.: Metabolic alkalosis in the rat. Evidence that reduced glomerular filtration rather than enhanced tubular bicarbonate rcabsorption is responsible for maintaining the alkalotic state. J. clin. Invest. 71: 1141-1160(1983). 6 Berger. B E.: Cogan. M.G.: Sebastian, A.: Reduced glomerular filtration and enhanced bicarbonate rcabsorption maintain met abolic alkalosis in humans. Kidney int. 26: 205-208 ( 1984). 7 Joncs. J.W.; Sebastian. A.: Hultcr. H.N.: Schambelan. M.: Sut-


although the mechanism responsible (reduced GFR or increased bicarbonate reabsorption) was not defined. We had not expected this rather striking alkalosis-producing effect of bicarbonate supplementation since previous studies in humans predicted little change (