Common Causes of Metabolic Alkalosis in the Elderly

Alterations in Acid-Base Homeostasis with Aging Naureen Tareen, MD; Ashraf Zadshir, MD; David Martins, MD; Glenn Nagami, MD; Barton Levine, MD; and Keith C. Norris, MD Los Angeles, California

Key words: acid-base * aging U renal funcfion m metabolic acidosis metabolic alkalosis respiratory acidosis U respiratory alkalosis © 2004. From the Departments of Medicine at the West Los Angeles, Veterans Affairs Greater Los Angeles Healthcare System (Tareen, Nagami, Levine), Chardes R. Drew University of Medicine and Science (Tareen, Zadshir, Martins, Norris) and UCLA School of Medicine (Nagami, Levine, Norris). Send correspondence and reprint requests for J NatI Med Assoc. 2004; 96:921-926 to: Keith Norris, Charles R. Drew University of Medicine and Science, Department of Internal Medicine, 1731 E. 120th St., Los Angeles, CA 90059; e-mail: [email protected]

INTRODUCTION Acid-base disorders are commonly encountered in clinical practice and can have a substantial impact on a patient's prognosis and outcome. The elderly are more prone to develop acid-base disturbances than the young. With age, the kidney undergoes structural and functional changes that limit the adaptive mechanisms responsible for maintaining acidbase homeostasis in response to dietary and environmental changes. In addition to a decrease in glomerular filtration rate (GFR), the capacity of the kidneys to handle electrolyte alterations and excrete an acid load is diminished with advancing age. Therefore, an improved recognition of these disorders and underlying causes will improve our ability to better manage elderly patients. In this review we have summarized age-related changes in acid-base homeostasis that may impact clinical outcomes.

INTRINSIC RENAL CHANGES WITH AGING Several changes occur in glomerular number, function, and the GFR with advancing age. By the seventh decade, there is a 30-50% reduction in the number of glomeruli' and a reduction in proximal renal tubule volume and glomerular surface area.2 There is also a progressive fall in total renal plasma flow34 and the cortical component of blood flow.5 Commensurate with the decline in the number of JOURNAL OF THE NATIONAL MEDICAL ASSOCIATION

glomeruli is an average decline in GFR of about 1% per year or 10% per decade after age 40.5,6 Despite the fall in GFR, serum creatinine levels remain unchanged in most instances due to a proportional reduction in muscle mass and endogenous creatinine production.67 The common assumption of normal kidney function on the basis of normal serum creatinine level predisposes older patients to many iatrogenic complications, including but not limited to acute renal failure, drug toxicities, and a variety of acid-base and electrolyte abnormalities.8-'0 The Cockcroft and Gault" formula has been used for many years to estimate GFR with adjustment for body weight and age. Using this formula, a serum creatinine of 1.2 mg/dl in a 20-year-old, 80-kg male reflects a GFR of 111 ml/min., while a serum creatinine of 1.2 mg/dl in a 70-year-old, 60-kg female reflects a GFR of 41 ml/min., a nearly three-fold difference. Thus, the importance of a more accurate assessment of GFR in an older patient cannot be overestimated. A new formula derived from the Modification ofDiet in Renal Disease (MDRD) study has been reported to be even more accurate than CockcroftGault formula in predicting GFR as measured by 1251-iothalamate clearance'2 (see Table 1 for GFR estimation formulas; easy-to-use programs are available on websites and PDAs that need only serum creatinine level, and patient age, gender, and race).

ACID-BASE DISORDERS Serum [H+] is maintained within a narrow range through a series of reversible chemical buffers and physiologic pulmonary and renal responses. Although the pH of the extracellular fluid (ECF) is maintained between 7.38-7.42 in the elderly, there is evidence to suggest this occurs at the expense of a reduced serum HCO3 reserve. A recent review noted a significant increase in the steady-state blood [H+] and a reduction in steady-state serum HCO3 from subjects aged 20-100 years, suggesting a progressive age-related, low-level metabolic acidosis."3 The homeostatic responses to chronic metabolic acidosis VOL. 96, NO. 7, JULY 2004 921

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in aging may engender pathologic consequences, such as nephrolithiasis, bone demineralization, and muscle protein breakdown. These maladaptive changes, which may reflect subtle degrees of acidosis or the intermittent nature of the acidosis, suggest a "eubicarbonatemic" metabolic acidosis may exist in older patients and emphasizes the importance of recognition and treatment of even mild acid loads to prevent these maladaptive homeostatic responses.'4 This eubicarbonatemic metabolic acidosis with aging appears to be most directly related to a decline of renal function and possibly an age-related, lowgrade, diet-dependent metabolic acidosis.'5 In addition to the normal physiologic changes that occur with aging, the increased frequency of comorbid conditions and/or medications which may further impact upon both pulmonary and renal function increase the susceptibility towards the development of acid-base disturbances.

Approach to Acid-Base Disorders Acidosis is a process that, if left unopposed, results in acidemia (pH 7.42). The physiologic response to changes in pH involves changes in alveolar ventilation (pCO2), renal acid excretion and/or HCO3 reclamation. The full respiratory response to metabolic acidosis requires hours, while the maximal renal response to respiratory disturbances usually requires three-to-four days. A rough guide to determining the appropriate physiologic response to a given primary disturbance is shown in Table 2.

METABOLIC ACIDOSIS Metabolic acidosis is a process that results in excessive generation of H+ or consumption of serum HCO3. It may or may not be associated with acidemia (low plasma pH). This can occur by the addition of an acid, direct loss of bicarbonate from the gastrointestinal tract or the kidney, or rapid dilution of the ECF by a nonbicarbonate-containing solution. The physiologic response to acidemia is an increase in ventilation that returns serum pH towards normal (Table 2). In clinical practice, metabolic acidosis is divided into two functional categories-increased anion gap and normal anion gap

(Table 3). With high anion gap acidosis, it is important to measure the serum osmolality and compare it to the estimated osmolality (Calculated osm = 2 x plasma Na + [Glucose]/1 8 + BUN/2.8). A markedly elevated serum osmolal gap (the difference between the actual and calculated serum osmolality) >10 mosm would indicate the presence of unaccounted osmoles, suggesting ethylene glycol or methanol as possible causes. If the osmolal gap is less than 10 mosm in the setting of a high-anion-gap acidosis, the differential diagnosis primarily consists of ketoacidosis, lactic acidosis, renal failure, salicylate ingestion, and D-lactic acidosis. By contrast, normal anion-gap metabolic acidosis is related to a loss or reduced synthesis of bicarbonates either through the gastrointestinal tract (e.g., diarrhea) or the kidney (e.g., renal tubular acidosis), rather than generation or addition of acid (with the exception of chloride-based acid, such as HCL or arginine HCL in total parenteral nutrition supplements). A helpful step to the diagnosis of renal vs. nonrenal cause of normal anion-gap metabolic acidosis is the measurement of random urinary electrolytes and calculating the urinary anion gap, the difference between positive and negative charges (UNa+UK-UC1). An excess ofnegative charges (a negative urinary anion gap) suggests high levels of ammonium excretion. Ammonium is cation that is excreted with chloride in the urine. A negative urinary anion gap indicates an intact renal response, suggesting a nonrenal cause for the acidosis (e.g., GI bicarbonate loss with diarrhea). The absence of excess calculated negative charges indicates a renal origin to the acidosis since the kidney is not able to acidify the urine through generation of ammonium. The differential diagnosis is then narrowed to renal tubular acidosis, early stages of chronic kidney disease, use of carbonic anhydrase inhibitor, and ureteral diversion.

CLINICAL PRESENTATION The patient with mild acidemia may exhibit no acute symptoms. With severe acidemia nausea, vomiting, anorexia, lethargy, and Kussmaul respirations may develop. Severe acidemia is associated with decreased myocardial contractility, hypotension, pulmonary edema, and tissue hypoxia.6 These affects are less well-tolerated in older individuals and are more likely to lead to acute medical emergencies. Chronically, it can produce

Table 1. Commonly Used Formula for Estimaftng Glomerular Filtration Rate A. Cockcroft and Gault Estimated GFR (ml/min) = (140- age in years) x lean body mass in Kg *(x 0.85 if female) 72 x Serum Creatinine (mg/dl)

B. Abbreviated Modification of Diet in Renal Disease (MDRD) Study Formula Estimated GFR (ml/min) = 186.3 * (sCr)l' '54* age -.3 * (0.742 if female) * (1.21 if African-American)

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a negative nitrogen balance and result in bone loss, which may exacerbate osteopenia and osteoporosis. Animal studies suggest acidemia associated myocardial impairment is more severe with advancing age."7

Therapy Initial treatment is directed toward correcting the underlying disease process. Oral HCO3 or precursors, such as citrate, can be administered to treat mild and chronic metabolic acidosis. Severe acidemia, pH