F. John Gennari

Disorders of potassium homeostasis Hypokalemia and hyperkalemia

This article reviews the diagnosis and management of clinical disorders of potassium balance, with particular attention to the critically ill patient. The normal regulation of potassium balance is reviewed as a background for understanding these disorders, followed by a discussion of the causes and management of hypo- and hyperkalemia. Practical guidelines are presented for acute and chronic management.

Assessing acid-base disorders

Effective management of acid-base disorders depends on accurate diagnosis. Three distinct approaches are currently used in assessing acid-base disorders: the physiological approach, the base-excess approach, and the physicochemical approach. There are considerable differences among the three approaches. In this review, we first describe the conceptual framework of each approach, and comment on its attributes and drawbacks. We then highlight the application of each approach to patient care. We conclude with a brief synthesis and our recommendations for choosing an approach.

Role of the kidney in potassium homeostasis: Lessons from acid-base disturbances

Potassium homeostasis in man is normally accomplished by appropriate changes in the renal excretion of this cation in response to random variations in intake. Although this physiologic feedback system normally functions to maintain potassium balance well within tolerable limits, it has long been known that potassium excretion can be influenced importantly by numerous factors unrelated to total body potassium content [1]. A detailed understanding, however, of the interaction between the interests of potassium homeostasis and the constraints imposed by other physiologic priorities remains to be defined. A highly promising focal point for further investigation into the renal regulation of potassium balance has emerged recently from experimental observations using renal micropuncture techniques; these observations have provided major new insights into the nature of the tubular mechanisms through which the many diverse influences on renal potassium excretion operate [2]. The purpose of this editorial is to utilize these new insights in an attempt to explain the well-documented effects on potassium excretion that stem from the common disturbances of acid-base equilibrium. In so doing, it is hoped that a better understanding will emerge not only of the interplay among the numerous factors impinging on renal potassium handling, but also of the renal adaptive mechanisms called into play by persistent acid-base disorders.

Acid-Base Homeostasis in End-Stage Renal Disease

In end-stage renal disease, acid-base homeostasis is accomplished by the transfer of bicarbonate (or an organic anion) across the dialysis membrane rather than by hydrogen ion or ammonium excretion by the kidney. Although the rate of base addition during dialysis is completely indifferent to body pH, a new equilibrium is nonetheless achieved which is driven by endogenous acid production, just as in individuals with functioning kidneys (1-3). This equilibrium occurs because the physical principles of diffusion dictate that HC03addition or removal during dialysis is determined by the transmembrane concentration gradient (Fig. 1 ) . Because bath bicarbonate concentration ([HCO,-I) is maintained constant by design, the variable component of this gradient is serum [HCO,-]. In patients receiving dialysis therapy, serum [HCO,-] is determined jointly by the rate of endogenous acid production and by the characteristics of the dialysis prescription. This dynamic situation creates a new feedback loop between acid production and alkali addition. If endogenous acid production increases, serum [HCO,-] falls, allowing for more alkali addition during dialysis (Fig. 1 ) . If endogenous acid production falls (or Hf is lost from the body), [HCO,-] rises and less alkali is added. This iterative process establishes a new equilibrium between acid production and alkali addition, and sets the predialysis serum [HCO,-]. Given this feedback loop between acid production and alkali addition and the fairly uniform nature of the dialysis prescription, two questions emerge: 1. Why does serum [HCO,-] vary so widely from patient to patient? 2. Why can’t we easily devise a hemodialysis prescription that will normalize serum [HCO,-] in all our patients?

Effect of Dietary Protein Intake on Serum Total CO2 Concentration in Chronic Kidney Disease: Modification of Diet in Renal Disease Study Findings

Metabolic acidosis is a feature of chronic kidney disease (CKD), but whether serum bicarbonate concentration is influenced by variations in dietary protein intake is unknown. For assessing the effect of diet, data that were collected in the Modification of Diet in Renal Disease study were used. In this study, patients with CKD were enrolled into a baseline period, then randomly assigned to follow either a low- or a usual-protein diet (study A, entry GFR 25 to 55 ml/min) or a low- or very low-protein diet, the latter supplemented with ketoanalogs of amino acids (study B, entry GFR 13 to 24 ml/min). Serum [total CO2] and estimated protein intake (EPI) were assessed at entry (n = 1676) and again at 1 yr after randomization, controlling for changes in GFR and other key covariates (n = 723). At entry, serum [total CO2] was inversely related to EPI (1.0 mEq/L lower mean serum [total CO2]/g per kg body wt increase in protein intake/d; P = 0.009). In an intention-to-treat analysis, the reduction in mean EPI in the low-protein group as compared with the usual-protein group (0.41 g/kg body wt per d) was independently associated with a 0.9-mEq/L increase in serum [total CO2], after adjustment for covariates (P < 0.001). No such effect was evident in study B, in which the very low-protein diet group received dietary supplements. Serum [total CO2] is inversely correlated with dietary protein intake in patients with CKD. A reduction in protein intake results in an increase in serum [total CO2].

Acid-Base Disorders in End-Stage Renal Disease: Part I

Detection and management of acid-base disorders in patients with end-stage renal disease presents a special challenge. In these patients, one indicator of acid-base status, serum bicarbonate (or total COZ) concentration, is regulated by the dialysis treatment itself rather than responding in the expected manner to acid or base challenges. As a first step in diagnosing acid-base disorders, one must define a new range of normal for this parameter, which will vary depending on the particular mode of dialysis therapy. Armed with a knowledge of the normal or expected value in a given patient, and with a knowledge of the manner in which bicarbonate is affected by the dialysis treatment, diagnosis, and management of acid-base disorders becomes a straightforward process. In the first part of this review we briefly discuss the determinants of normal acid balance in dialysis patients, and then turn to the features of metabolic acidosis in these patients. The second part of this review will complete consideration of the cardinal acid-base abnormalities and touch upon methods for diagnosing mixed disorders in patients with endstage renal disease.

Pathophysiology of Metabolic Alkalosis: A New Classification Based on the Centrality of Stimulated Collecting Duct Ion Transport

Metabolic alkalosis is a unique acid-base disorder because it can be induced and sustained by functional alterations in renal ion transport. This review summarizes more than 50 years of research into the pathophysiologic processes causing this disorder. The evidence reviewed supports the hypothesis that virtually all forms of metabolic alkalosis are sustained by enhanced collecting duct hydrogen ion secretion, induced by stimulation of sodium uptake through the epithelial sodium channel (ENaC). Enhanced collecting duct hydrogen ion secretion in metabolic alkalosis occurs most commonly secondary to changes in ion transport earlier along the nephron, but also can occur as the result of primary stimulation of ENaC. In both these settings, potassium secretion is stimulated, and abnormal potassium losses cause depletion of body potassium stores. Potassium depletion has a key role in sustaining metabolic alkalosis by stimulating renal hydrogen ion secretion, enhancing renal ammonium production and excretion, and downregulating sodium reabsorption in the loop of Henle and early distal tubule. A new classification of the causes of metabolic alkalosis is proposed based on these pathophysiologic events rather than response to treatment.

Acute Electrolyte and Acid-Base Disorders in Patients With Ileostomies: A Case Series

BACKGROUND Patients with ileostomies are well known to be susceptible to extracellular fluid volume depletion as a result of fluid and solute losses that are greater than intake. However, electrolyte and acid-base disorders accompanying these episodes of volume depletion are not well delineated. STUDY DESIGN Case series. SETTING & PARTICIPANTS 7 patients with hospitalization because of acute acid-base disturbances at an academic medical center. OUTCOMES In all patients, serum and urine creatinine and electrolytes were measured. In 2 patients, arterial blood pH and Pco(2) and ileal drainage electrolytes also were measured. RESULTS 2 patients presented with severe metabolic alkalosis, and the remaining 5 patients had low serum total carbon dioxide values in association with hyperkalemia. All 7 had acute renal failure. Pathophysiological characteristics, diagnosis, and management of these disorders are discussed, along with considerations for long-term management of fluid and electrolyte balance. LIMITATIONS This report illustrates electrolyte and acid-base disorders encountered in patients with ileostomies from our clinical experience. We have no data about the incidence of these disorders. CONCLUSION Patients with ileostomies can develop diverse and potentially life-threatening acute electrolyte and acid-base disorders when ileostomy drainage increases. Either metabolic acidosis or metabolic alkalosis can occur, depending on the nature and duration of the losses. These cases emphasize the need to be aware of the variety of acute electrolyte and acid-base disorders that can occur in this group of patients and to intervene rapidly when they develop.

Very Low and High Predialysis Serum Bicarbonate Levels are Risk Factors for Mortality: What are the Appropriate Interventions?

Adjustment of bath [HCO3−] to “normalize” predialysis serum [HCO3−] in patients receiving intermittent hemodialysis has been advocated to prevent the adverse effects of metabolic acidosis. However, when mortality risk has been evaluated in hemodialysis patients in relation to their nadir serum [HCO3−], an increase in risk is noted both with very low values (<18 mmol/l) and very high values (>27 mmol/l). If mortality risk is adjusted for comorbidity, age and effectiveness of dialysis, as well as for nutritional and inflammatory factors, very low predialysis values remain an independent risk factor, but the risk for high values virtually disappears. Patients with mild predialysis metabolic acidosis (serum [HCO3−] 18–23 mmol/l) have the lowest mortality risk. Metabolic acidosis has adverse effects on bone and muscle metabolism in patients receiving hemodialysis but, unless the acidosis is severe, these effects appear to be overshadowed by nutritional and inflammatory influences. This commentary reviews the principles of acid–base homeostasis in patients receiving intermittent hemodialysis and the studies that have addressed the adverse effects of metabolic acidosis in this patient population. It concludes that high predialysis serum [HCO3−] values are likely a marker for malnutrition and comorbidity, whereas very low values may be an indication for direct treatment. The latter should be addressed using strategies to increase predialysis values, whereas the former need attention directed to nutritional factors and comorbidity.

ACID-BASE IN RENAL FAILURE: Acid-Base Balance in Dialysis Patients

Acid‐base balance in dialysis patients is achieved by a unique interaction between the patient and the particular mode of renal replacement therapy. The prevailing serum HCO3− in these patients is determined not only by endogenous acid production but also by the nature of the dialysis prescription and, in particular, by the bicarbonate (or lactate) concentration of the bath solution. Despite the technical advances in dialysis therapy, pre‐dialysis serum HCO3− remains lower than normal in most patients receiving hemodialysis and in many patients receiving peritoneal dialysis. A central question is whether even a mild degree of acidosis increases morbidity and mortality in patients with end‐stage renal disease. This article reviews the nature of the acid‐base equilibrium achieved in patients receiving hemodialysis or peritoneal dialysis, addresses the question of whether correction of acidosis is beneficial, and reviews the techniques for increasing serum HCO3− in these patients. Based on the information available, it is clear that the patient with a serum HCO3− less than 19 mEq/L should be assessed to determine the cause of the low value and steps undertaken to correct the acidosis. Whether patients with steady‐state values between 19 and 24 mEq/L require specific attention remains an issue for further investigation.