Metabolic alkalosis.

Metabolic alkalosis is a primary pathophysiologic event characterized by the gain of bicarbonate or the loss of nonvolatile acid from extracellular fluid. The kidney preserves normal acid-base balance by two mechanisms: bicarbonate reclamation mainly in the proximal tubule and bicarbonate generation predominantly in the distal nephron. Bicarbonate reclamation is mediated mainly by a Na-H antiporter and to a smaller extent by the H-ATPase. The principal factors affecting HCO 3 reabsorption include effective arterial blood volume, glomerular filtration rate, chloride, and potassium. Bicarbonate regeneration is primarily affected by distal Na delivery and reabsorption, aldosterone, arterial pH, and arterial pCO2. To generate metabolic alkalosis, either a gain of base or a loss of acid, must occur. The loss of acid may be via the GI tract or by the kidney. Excess base may be gained by oral or parenteral HCO 3 administration or by lactate, acetate, or citrate administration. Factors that help maintain metabolic alkalosis include decreased glomerular filtration rate (GFR), volume contraction, hypokalemia, hypochloremia, and aldosterone excess. Clinical states associated with metabolic alkalosis are vomiting, mineralocorticoid excess, the adrenogenital syndrome, licorice ingestion, diuretic administration, and Bartter's and Gitelma's Syndromes. The effects of metabolic alkalosis on the body are varied and include effects on the central nervous system, myocardium, skeletal muscle, and the liver. Treatment of this disorder is simple, once the pathophysiology of the cause is delineated. Therapy consists of reversing the contributory factors promoting alkalosis and in severe cases, administration of carbonic anhydrase inhibitors, acid infusion, and low bicarbonate dialysis.

Nephritic edema.

Nephritic edema results from the primary retention of salt. Acute glomerulonephritis is the prototypical form of the disorder. The stimulus for the salt retention arises within the kidney by an unknown mechanism. As effective arterial blood volume (EABV) was normal at the start of the disease process, it becomes expanded as salt and water are added to it. The pathophysiological sequelae of this process are compared with those which follow the salt retention of congestive heart failure (CHF). The latter is a syndrome in which salt retention is secondary, driven by the contraction of EABV which is at the heart of CHF. Finally, mechanisms responsible for the salt retention of nephrosis are considered. It is possible, and even likely, that most patients with nephrotic edema have primary salt retention, rather than secondary edema. If this view is correct, salt is retained not because of urinary protein loss and its consequent hypoalbuminemia, but rather because of the glomerulopathy which caused the syndrome in the first place.

Metabolic alkalosis.

Metabolic alkalosis is a primary pathophysiologic event characterized by the gain of bicarbonate or the loss of nonvolatile acid from extracellular fluid. The kidney preserves normal acid-base balance by two mechanisms: bicarbonate reclamation, mainly in the proximal tubule, and bicarbonate generation, predominantly in the distal nephron. Bicarbonate reclamation is mediated mainly by a Na(+)-H(+) antiporter and to a smaller extent by the H(+)-ATPase (adenosine triphosphate-ase). The principal factors affecting HCO3(-) reabsorption include effective arterial blood volume, glomerular filtration rate, chloride, and potassium. Bicarbonate regeneration is primarily affected by distal Na(+) delivery and reabsorption, aldosterone, arterial pH, and arterial partial pressure of carbon dioxide. To generate metabolic alkalosis, either a gain of base or a loss of acid must occur. The loss of acid may be via the gastrointestinal tract or via the kidney. Excess base may be gained by oral or parenteral HCO3(-) administration or by lactate, acetate, or citrate administration. Factors that help maintain metabolic alkalosis include decreased glomerular filtration rate, volume contraction, hypokalemia, hypochloremia, and aldosterone excess. Clinical states associated with metabolic alkalosis are vomiting, mineralocorticoid excess, the adrenogenital syndrome, licorice ingestion, diuretic administration, and Bartter's and Gitelman's syndromes. The effects of metabolic alkalosis on the body are variable and include effects on the central nervous system, myocardium, skeletal muscle, and liver. Treatment of this disorder is simple, once the pathophysiology of the cause is delineated. Therapy consists of reversing the contributory factors that are promoting the alkalosis and, in severe cases, administration of carbonic anhydrase inhibitors, acid infusion, and low bicarbonate dialysis.

Biochemical and genetic advances in distal renal tubular acidosis.

Distal renal tubular acidosis is a constellation of syndromes arising from different derangements of tubular acid transport. Recent advances in the biology of urinary acidification have allowed us to discern various molecular mechanisms responsible for these syndromes. This article relates clinical disorders of distal acidification to the underlying defective mechanisms responsible for them. A clinical classification of these disorders is presented which integrates each disorder with the prevailing serum potassium concentration. That distal renal tubular acidosis can be associated with low, normal, or high serum potassium concentration is now explainable by identifying the specific defect in transport causing each syndrome.

Renal tubular acidosis syndromes.

Renal tubular acidosis is a constellation of syndromes arising from different derangements of tubular acid transport. Recent advances in the biology of urinary acidification have allowed us to discern various molecular mechanisms responsible for these syndromes. This report relates clinical disorders of acidification to the underlying defective mechanisms responsible for them. A clinical classification of these disorders is presented, integrating each disorder with the prevailing serum potassium concentration. That renal tubular acidosis can be associated with low, normal, or high serum potassium concentration is now explainable by identifying the specific defect in transport causing each syndrome.

Anemia and cardiovascular complications: iron and EPO impact.

Management of end-stage renal disease (ESRD) has been revolutionized by the advent of erythropoietin replacement. We briefly review its characteristics and clinical use. Also emphasized is the importance of iron deficiency in limiting the clinical response to erythropoietin therapy. Iron-replacement therapy in ESRD patients is briefly discussed.

Studies on the mechanism of trimethoprim-induced hyperkalemia.

We examined the effects of trimethoprim (TMP) on metabolic parameters and renal ATPases in rats after a 90 minute infusion (9.6 mg/hr/kg body wt, i.v.) and after 14 days (20 mg/kg body wt/day, i.p.). After one dose of TMP, plasma electrolytes, arterial pH and aldosterone levels were normal, but a natriuresis, bicarbonaturia, and decreased urinary potassium excretion occurred. Na-K-ATPase activity in microdissected segments from these animals was decreased by 36 +/- 0.9% in proximal convoluted tubule (PCT) (P < 0.005); decreases of 50 +/- 2.1% and 40 +/- 1.1% were seen in cortical and medullary collecting tubules (CCT and MCT), respectively (P < 0.005). Na-K-ATPase activity was unaffected in medullary thick ascending limb (MTAL). H-ATPase (in PCT and collecting duct) and H-K-ATPase (in CCT and MCT)-activities were not changed. Following chronic TMP administration, plasma potassium increased as compared to control (5.16 +/- 0.05 mEq/liter vs. 3.97 +/- 0.05 mEq/liter, P < 0.05), however, acid-base status and plasma aldosterone levels were normal. Na-K-ATPase activity was decreased by 45 +/- 2.6% in PCT (P < 0.005), 73 +/- 2.0% in CCT (P < 0.001), and 53 +/- 2.5% in MCT (P < 0.005). Na-K-ATPase, activity in MTAL and H-K-ATPase activity in CCT and MCT were unchanged. H-ATPase activity in PCT and MTAL was normal, but in the collecting tubule (CCT and MCT) it was decreased by approximately 25% (P < 0.05). TMP inhibited Na-K-ATPase activity in a dose-dependent fashion in PCT, CCT, and MCT when tubules from normal animals were incubated in vitro with the drug; TMP in vitro did not affect H-ATPase or H-K-ATPase activity. These results suggest that TMP-induced hyperkalemia may result from decreased urinary potassium excretion caused by inhibition of distal Na-K-ATPase, in the face of intact H-K-ATPase activity.

Acid-base disorders in medicine.

The practice of internal medicine involves daily exposure to abnormalities of acid-base balance. A wide variety of disease states either predispose patients to develop these conditions or lead to the use of medications that alter renal, gastrointestinal, or pulmonary function and secondarily alter acid-base balance. In addition, primary acid-base disease follows specific forms of renal tubular dysfunction (renal tubular acidosis). We review the acid-base physiologic functions of the kidney and gastrointestinal tract and the current understanding of acid-base pathophysiologic conditions. This includes a review of whole animal and renal tubular physiologic characteristics and a discussion of the current knowledge of the molecular biology of acid-base transport. We stress an approach to diagnosis that relies on knowledge of acid-base physiologic function, and we include discussion of the appropriate treatment of each disorder considered. Finally, we include a discussion of the effects of acidosis and alkalosis on human physiologic functions.

Renal ATPases twenty-four hours after uninephrectomy: the role of IGF-1.

We studied the effect of 24 h of uninephrectomy and somatostatin analogue, an inhibitor of growth hormone secretion, in microdissected nephron segment H-ATPase, H-K ATPase and Na-K ATPase activities. Systemic acid-base status, plasma and tissue electrolytes, and aldosterone levels in the uninephrectomized rats were similar to controls. Uninephrectomy increased fractional sodium, potassium, and bicarbonate excretion (p < 0.05). After 24 h the solitary kidney weighted the same as the single kidney from sham-operated controls. Protein content of the microdissected nephron segments studied enzymatically did not differ from control. Insulin-like growth factor-1 (IGF-1) levels in plasma and kidney were also similar. By contrast, ATPase values in uninephrectomized animals were markedly elevated: H-ATPase was increased by 91 +/- 5% in proximal convoluted tubule (PCT) (p < 0.005), 65 +/- 3% in medullary thick ascending limb of Henle's loop (MTAL) (p < 0.01), 92 +/- 9% in cortical collecting tubule (CCT) (p < 0.005), and 94 +/- 8% in medullary collecting tubule (MCT) (p < 0.005). In these same animals, H-K ATPase activity was also increased: 88 +/- 6% in CCT (p < 0.005) and 92 +/- 5% in MCT (p < 0.005). Uninephrectomy also decreased Na-K ATPase activity in PCT, MTAL and CCT, but enzyme activity in MCT remained unchanged. Somatostatin analogue administration to animals with one kidney had no effect on metabolic parameters or plasma and kidney IGF-1 concentrations nor did it prevent the alterations in renal ATPase activities observed with uninephrectomy done. The analogue alone had no effect in control animals. While the mechanisms responsible for the increase in renal ATPases seen after uninephrectomy are not known, they are independent of aldosterone, potassium, or IGF-1.

The renal adenosine triphosphatases: functional integration and clinical significance.

The ion-transporting ATPases determine the chemical composition of cells both directly and through their secondary effects. The Na,K-ATPase generates the transmembrane sodium gradient which provides the primary energy for uptake and extrusion of a wide variety of solutes by renal tubular epithelia. The H-ATPase and the H,K-ATPase acidify the urine, and also generates bicarbonate for excretion by the cortical collecting duct. Calcium ATPase regulates the intracellular calcium, which in turn impacts on the myriad of cellular functions for which calcium serves as an intracellular messenger. If one considers the impact of potential pump dysfunction in a purely speculative mode, the list of disorders which might be potentially ascribed to 'pump disease' would be enormous. This article reviews those disorders of renal transport already considered to be 'pump diseases'.

Insights into the biochemical mechanism of maleic acid-induced Fanconi syndrome.

Maleic acid administration is known to produce the Fanconi syndrome, although the biochemical mechanism is incompletely understood. In this study the effect of a single injection of maleic acid (50 mg/kg body wt, i.v.) on the rat renal ATPases was examined. Maleic acid rapidly caused bicarbonaturia, natriuresis, and kaliuresis. When nephron segments were microdissected, there was an 81 +/- 2% reduction in proximal convoluted tubule (PCT) Na-K-ATPase activity (P < 0.005) and a 48 +/- 4% reduction in PCT H-ATPase activity (P < 0.01). Enzyme activity (Na-K-ATPase, H-ATPase, H-K-ATPase) in the medullary thick ascending limb of Henle's loop and distal nephron segments was normal. In vitro, maleic acid (1 and 10 mM) inhibited Na-K-ATPase in PCT, but it had no effect on H-ATPase in PCT. Prior phosphate infusion to maleic acid-treated rats attenuated urinary bicarbonate wastage by 50% (P < 0.05); activity of proximal tubule Na-K-ATPase and H-ATPase activities were partially protected as compared to the animals given maleic acid alone (P < 0.05). Renal cortical ATP levels were not altered at the concentration of maleic acid used in this study (that is, 50 mg/kg body wt), but higher doses of maleic acid (that is, 500 and 1000 mg/kg body wt) caused ATP levels to fall. Maleic acid did not affect cortical medullary total phosphate concentration, however, P32 turnover (1 and 24 hr) was altered by prior phosphate infusion. A protective effect of prior phosphate loading on the membrane bound Pi pool (insoluble) was seen while the cytosolic Pi pool (soluble) was not different from control. Thus, maleic acid-induced "Fanconi" syndrome likely results from both direct inhibition of proximal tubule Na-K-ATPase activity and membrane-bound phosphorus depletion. The former mechanism would reduce activity of the sodium-dependent transporters (that is, Na/H antiporter), while the latter would inhibit the electrogenic proton pump (H-ATPase). The combination of reduced proximal tubule Na-H exchange and H-ATPase activities would markedly inhibit bicarbonate reabsorption and result in the metabolic acidosis universally seen in the Fanconi syndrome.

Effects of pH on calcium transport in turtle bladder.

This study was designed to examine the effect of apical and basolateral (ie, mucosal and serosal) pH on calcium (Ca) transport in turtle bladder, a nonmammalian analog of the distal nephron. Unidirectional Ca45 fluxes were measured when serosal pH was 6.4, 7.4, or 8.4 (mucosal pH, 7.4) in the presence and absence of ouabain. When serosal pH was 8.4, M-->S Ca45 flux increased significantly, and when it was 6.4, M-->S Ca45 flux decreased markedly. Changes in serosal pH did not affect the S-->M Ca45 flux. When 5 x 10(-4) mol/L ouabain was added to inhibit sodium transport, M-->S Ca45 flux, at pH 7.4, was 221.6 +/- 27.4 pmol/mg/h (n = 10), and low pH again inhibited this flux (approximately 50%). Lowering mucosal pH (with serosal pH 7.4) also decreased M-->S Ca45 flux. In stripped bladders, Ca45 uptake increased linearly as medium pH was increased from 4.4 to 8.4. Total tissue Ca concentration did not change when serosal pH was varied, except at the extreme of pH 4.4, where tissue Ca decreased. By contrast, when apical pH was 6.4, tissue Ca rose substantially (approximately 1.5-fold). these results demonstrate that extracellular pH directly affects Ca homeostasis in the turtle bladder. Lowering the pH of either the serosal or mucosal medium directly inhibits apical Ca permeability. This change in Ca permeability is seen in the presence of ouabain. By contrast, alkalization of the serosal medium enhances apical permeability, but this effect is, in some manner, related to sodium transport.(ABSTRACT TRUNCATED AT 250 WORDS)