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Metabolic Alkalosis, Bedside and Bench Melvin E Metabolic Alkalosis, Bedside and Bench Melvin E. Laski and Sandra Sabatini Although significant contributions to the understanding of metabolic alkalosis have been made recently, much of our knowledge rests on data from clearance studies performed in humans and animals many years ago. This article reviews the contributions of these studies, as well as more recent work relating to the control of renal acid-base transport by mineralocorticoid hormones, angiotensin, endothelin, nitric oxide, and pottasium balance. Finally, clinical aspects of metabolic alkalosis are considered. Semin Nephrol 26:404-421 © 2006 Elsevier Inc. All rights reserved. KEYWORDS metabolic alkalosis, acid-base regulation, bicarbonate transport, urinary acidifi- cation, endothelin, angiotensin, aldosterone t is always interesting to observe how many of the young ing clinical studies in many cases defined the human condi- Iphysicians interviewing for nephrology fellowship posi- tion in acid-base disorders earlier than the animal studies that tions report that their interest in the field is based on a per- outlined the underlying physiology. sonal delight in the complexities of acid-base and electrolyte problems. It is with sadness that we explain to them that (1) consulting nephrologists, whether in private practice or in an Early Studies Relating academic setting, receive few, if any, requests to evaluate to Metabolic Alkalosis acid-base or electrolyte problems, and that (2) their (the ap- plicants) dreams of a career in clinical research investigating The outstanding studies of Pitts et al1,2 outlined for nephrolo- acid-base physiology probably would go unfulfilled in the gists the integrated result of the renal transport of bicarbonate absence of significant basic skills in molecular biology and a in the human being before the diverse mechanisms by which willingness to spend large amounts of time at the bench and bicarbonate transport occurred were ever elucidated in ani- an even greater amount of time dealing with regulation and mal models. These investigators infused themselves with bi- bureaucracy. carbonate to achieve increasing serum bicarbonate concen- The situation was considerably different in the decades of tration and carefully quantified the resulting urinary the 1960s and 1970s, when a great number of significant bicarbonate excretion. The results defined a curve for re- clinical studies of acid-base physiology were performed. The nal bicarbonate handling in the human being that dis- techniques of the beginning of that era were astute history played a steady increase in reabsorption until it reached its taking, careful physical examination, arterial and/or venous maximum when the serum bicarbonate concentration ex- blood gas determination, acid and alkali titration of blood ceeded 28 mmol/L. The kidney then maintained an appar- and urine, and clinical chemistry. The designs of choice were ent maximal rate of absorption, or tubular maximum the balance study and the clearance study. Virtually any grad- (Tm); the further infusion of bicarbonate only increased uate of an accredited medical school was equipped to con- the rate at which bicarbonate escaped the kidney and was tribute to the research effort. No long period of additional excreted. These studies defined a relationship between special training was required. Those with an interest and a bicarbonate load and reabsorption, and carry within them keen intellect could readily participate. An additional aspect the seed of the relationship between volume and the main- of this period is that the research proceeded in such a way tenance phase of metabolic alkalosis, that is, the kidney that the clinical answers sometimes came first. Groundbreak- can support and maintain increased blood bicarbonate concentration if the product of the glomerular filtration rate and the bicarbonate concentration is less than the Tm From the Departments of Internal Medicine and Physiology, Texas Tech for bicarbonate. University Health Sciences Center, Lubbock, TX. 3 Address reprint requests to Melvin E. Laski, MD, TTUHSC, Department of Cohen performed a critical study of metabolic alkalosis in Internal Medicine, Mail Stop 9410, 3601 4th St, Lubbock, TX 79413. 1968 when he examined the effect of volume expansion with E-mail: [email protected] isometric fluids (defined by having concentrations of so- 404 0270-9295/06/$-see front matter © 2006 Elsevier Inc. All rights reserved. doi:10.1016/j.semnephrol.2006.09.001 Metabolic alkalosis 405 dium, chloride, bicarbonate, and potassium identical to that The administration of chloride per se is not needed to already present in the blood) in dogs with metabolic alkalosis increase bicarbonate excretion. The volume expansion of induced by diuretics and a low-chloride diet. In this classic dogs with isotonic bicarbonate resulted in a natriuresis (frac- balance study, Cohen3 showed that replacement of lost vol- tional excretion of sodium ϭ 16.8%), bicarbonaturia, and ume corrected an increased blood bicarbonate concentra- depressed the reabsorption of bicarbonate. By contrast, dogs tion, even when fluid with a bicarbonate concentration that given bicarbonate after induction of absolute volume con- did not differ from that seen in the alkalemic animals was traction by hemorrhage increased their rate of bicarbonate administered. Thus, as volume was administered, the kidney reabsorption and developed a markedly increased serum bi- responded by adjusting the composition of the blood to re- carbonate concentration. Similar results were obtained when turn the acid-base state to normal. dogs were given bicarbonate in the presence of ligation of the It was in this context that Dr. Neil Kurtzman6 published an thoracic vena cava, another experimental model marked by a article that can reasonably be said to have launched his aca- severe decrease in effective arterial blood volume. Both the demic career. While working at the Metabolic Burn Unit of hemorrhage group and the caval ligation group showed low the Brooke Army Medical Center under the guidance of Colo- sodium and chloride excretion. When the caval ligation was nel Basil Pruitt, MD, Dr. Kurtzman developed an intense released and effective arterial blood volume was restored, interest in the problems of the renal response to perturba- sodium and chloride excretion increased rapidly, and bicar- tions of acid-base balance and of volume. In particular, the bonaturia developed. relationship between extracellular volume, specifically “the The earlier-described results were interpreted by effective arterial blood volume” and the renal handling of Dr. Kurtzman6 to indicate a relationship between bicarbonate bicarbonate became his question of the day. Clinical obser- reabsorption and effective arterial blood volume, and the vations already had been made. The administration of so- groups exposed to isotonic sodium bicarbonate infusion dium chloride was known to increase the excretion of bicar- showed that bicarbonate excretion could be increased with- bonate in patients, but whether this was caused by chloride out the infusion of chloride. Kurtzman6 further showed that itself, by the effect on blood pressure, by the sodium that the infusion of sodium bicarbonate did not increase bicar- accompanied the chloride, or by some other process was not bonate or sodium excretion if volume expansion was pre- certain. Kassirer et al4,5 already had outlined the clinical treat- vented. ment of metabolic alkalosis: provision of chloride, and, in The clearance studies by Kurtzman6 in dogs and the con- addition, correction of hypokalemia when deficits were seri- temporaneous studies of Purkerson et al7 in rats clearly es- ous. Thus, the physician of that day did not know exactly tablished that there was a relationship between bicarbonate what went on in the black box that was the kidney, but reabsorption and volume; and, by extension, explained the recognized the conditions that cause metabolic alkalosis and previously observed response of metabolic alkalosis to the what needed to be performed to correct it. In short, although infusion of saline. Kurtzman8 further linked the increase in the cause and the treatment of metabolic alkalosis were bicarbonate reabsorption observed in acute hypercapnia to known, the debate concerned why treatment worked. changes in blood pressure, effective arterial blood volume, In the seminal paper of 1970, Kurtzman6 investigated how glomerular filtration rate, and filtered load of bicarbonate. dogs responded to the administration of isotonic sodium bi- When blood pressure and filtered load were supported, the carbonate, isotonic sodium chloride, and hypertonic sodium increase in bicarbonate reabsorption that accompanied hy- bicarbonate plus isotonic saline. The results indicated that percarbia was grossly blunted. dogs given hypertonic bicarbonate initially developed an in- These observations were confirmed and extended as phys- crease of the plasma bicarbonate level (metabolic alkalemia) iologic techniques increased in sophistication. The studies of but rapidly excreted the excess bicarbonate when infused bicarbonate transport performed after re-emergence of renal with isotonic saline. The bicarbonaturia occurred in concert micropuncture in several laboratories,9-13 and the efforts of with a massive increase in the fractional sodium excretion McKinney and Burg14 and Burg and Green15 to develop in and an increase in potassium excretion that induced marked vitro tubular microperfusion allowed the careful dissection of hypokalemia. Additional
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