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L-lactic acidosis (L-LA) is the most common cause of metabolic acidosis in the critical care setting, which has been associated with a large increase in mortality. The purpose of this article is to provide clinicians with an overview of the biochemical and metabolic background required to understand the different pathophysiological mechanisms that may lead to the development of L-LA. We propose a classification based on whether the pathophysiology of L-LA is due predominantly to increased production or decreased removal of L-lactic acid. In this article, we provide an overview of the biochemical and metabolic aspects of glucose oxidation, the production and removal of L-lactic acid, and a discussion of the pathophysiology of the various causes of L-LA.

The dialysate alkali used in hemodialysis to replace low body alkali levels in end stage renal disease (ESRD) patients has changed over time from bicarbonate to acetate and finally back to bicarbonate with a small addition of acetate. The ideal way to replace alkali in dialysis patients remains uncertain. Elsewhere in this issue of the journal, Sargent and Gennari, who have contributed greatly to our understanding of dialysis and acid-base kinetics, suggest that decreasing the currently used concentration of bicarbonate while increasing concentration of acetate in the dialysate may be a much more physiological approach to alkali delivery during hemodialysis. These recommendations are based on results from a series of hemodialysis simulations using mathematical theoretical methods, with the assumption that acetate metabolism will be sufficiently delayed with the higher acetate dialysate and reduce the rate of correction of metabolic acidosis during dialysis. Although valuable in calling attention to the issues surrounding alkali repletion during hemodialysis, these postulations should be tested in clinical trials. We believe, however, that the available evidence suggests that the rate of gain of bicarbonate during dialysis with the higher acetate dialysate would not be slower and that the replacement of some dialysate bicarbonate with acetate will not alter alkali accretion or intradialytic pH.

Prolonged imbalance between input and output of any element in a living organism is incompatible with life. The duration of imbalance varies, but eventually balance is achieved. This rule applies to any quantifiable element in a compartment of finite capacity. Transient discrepancies occur regularly, but given sufficient time, balance is always achieved, because permanent imbalance is impossible, and the mechanism for eventual restoration of balance is foolproof. The kidney is a central player for balance restoration of fluid and electrolytes, but the smartness of the kidney is not the reason for perfect balance. The kidney merely accelerates the process. The most crucial element of the control system is that discrepancy between intake and output inevitably leads to a change in total content of the element in the system, and uncorrected balance has a cumulative effect on the overall content of the element. In a living organism, the speed of restoration of balance depends on the permissible duration of imbalance without death or severe disability. The three main factors that influence the speed of balance restoration are: magnitude of flux, basal store, and capacity for additional storage. For most electrolytes, total capacity is such that a substantial discrepancy is not possible for more than a week or two. Most control mechanisms correct abnormality partially. The infinite gain control mechanism is unique in that abnormality is completely corrected upon completion of compensation.

Hyponatremia, the most common electrolyte disorder in hospitalized patients, has been associated with high rate of mortality among both this population and nonhospitalized patients. This review describes briefly the classification and pathogenesis of hyponatremia, and, in greater detail, the management of hyponatremia with a particular emphasis on the clinical pharmacology of arginine vasopressin (AVP) antagonists. This review includes more in-depth discussion on the pharmacology of conivaptan, an AVP antagonist recently approved by the United States Food and Drug Administration.

In vitro, experimental, and clinical work suggests that metabolic acidosis, either directly or indirectly, can promote the progression of chronic kidney disease (CKD). Goraya et al. demonstrate that both oral alkali supplementation and a diet rich in fruits and vegetables are equally effective at decreasing urinary excretion of markers of renal injury in patients with stage 2 CKD. Although this study is promising, the short duration and use of only urinary markers as a surrogate outcome weaken the conclusions.

Item does not contain fulltext A 16-year-old female had mutations in both alleles of the gene encoding her sodium-chloride cotransporter; one of these mutations is newly described. Her clinical findings were not typical because of the absence of hypocalciuria in 24-h urine samples, her maximum urine osmolality (U(osm)) was only 802 mosmol/kg H(2)O, and her plasma magnesium (Mg) concentration (P(Mg)) was easily maintained in the normal range with oral Mg supplements for 1 month. In detailed studies, the calcium/creatinine ratio in spot urines with a U(osm) >700 mosmol/kg H(2)O was very low, except during Mg therapy. Renal medullary function did not appear to be compromised because she had a non-urea U(osm)of approximately 600 mosmol/kg H(2)O, reflecting a very high non-urea osmole excretion rate (due to KCl supplements). At age 18 years, her P(Mg) became persistently low despite Mg therapy. We conclude that the clinical criteria for a provisional diagnosis of Gitelman syndrome should be revised. Hypocalciuria may only be evident initially in concentrated spot urine samples. Urine concentrating ability should include an analysis of the non-urea U(osm), especially when patients are taking large KCl supplements.

The molecular basis of many of the inherited disorders of potassium homeostasis has become much clearer in the last two decades. Despite these new insights into the physiology of renal potassium handling, a number of questions remain to be answered. The examples we use to illustrate these issues are Gordon’s syndrome, Bartter’s syndrome, and Gitelman’s syndrome. Our objective is to integrate these new insights into an understanding of the pathophysiology of renal potassium handling. We also propose different ways to think about some of the unresolved issues in this area.

Two aspects of hypernatremia are emphasized in this discussion: pathogenesis and treatment. Hypernatremia rarely develops with increased water loss alone; there must be a mechanism that interferes with water intake. In treating hypernatremia, the speed of correction is important because the volume regulation mechanisms restore the brain volume to normal when hypernatremia is chronic. Thus, too rapid correction of chronic hypernatremia results in brain edema. The calculation of fluid volume needed to correct hypernatremia can be obtained with use of various formulae described here for the fluid that contains dextrose in water or for hypotonic saline solution. Accurate prediction of the fluid volume requirement demands the knowledge of urine output and its electrolyte content, but when the information is not available, urine may be assumed to be isotonic in its electrolyte content.

In uremic patients, hyperphosphatemia is associated with cardiovascular calcification and increased cardiovascular mortality. Despite the use of phosphate binders, only half of hemodialysis (HD) patients achieve recommended serum phosphate levels. A hyperphosphoric salivary content, which correlates linearly with serum phosphate, has been reported in HD patients. We hypothesized that binding salivary phosphate during periods of fasting in addition to using phosphate binders with meals could improve the treatment of hyperphosphatemia. We assessed the phosphate-binding capacity of the natural polymer chitosan by (31)P nuclear magnetic resonance and established that 10 and 20% (wt/vol) middle viscosity chitosan solutions bind 30 and 50% of the phosphate contained in PBS, respectively. Thirteen HD patients with serum phosphate levels6.0 mg/dl despite treatment with sevelamer hydrochloride chewed 20 mg of chitosan-loaded chewing gum twice daily for 2 wk at fast in addition to their prescribed phosphate-binding regimen. Salivary phosphate and serum phosphate significantly decreased during the first week of chewing; by the end of 2 wk, salivary phosphate decreased 55% from baseline (73.21 +/- 19.19 to 33.19 +/- 6.53; P0.00001), and serum phosphate decreased 31% from baseline (7.60 +/- 0.91 to 5.25 +/- 0.89 mg/dl; P0.00001). Salivary phosphate returned to baseline by day 15 after discontinuing the chewing gum, whereas serum phosphate levels took 30 d to return to baseline. Parathyroid hormone and serum calcium concentrations were not affected by the gum. In conclusion, adding salivary phosphate binding to traditional phosphate binders could be a useful approach for improving treatment of hyperphosphatemia in HD patients.

This review will cover two main areas of acid-base balance, both of which are attended with much misconception and misunderstanding. One is the external balance of acids and alkali; the other is the contribution of bone buffering in acute and chronic metabolic acidosis.

It is widely believed that the cerebral salt-wasting syndrome (CSWS) exists as an entity distinct from the syndrome of inappropriate ADH secretion, and that it is characterized by evidence of severe renal salt wasting that results in volume depletion and hyponatremia. Proof of the existence of CSWS as an entity requires documentation of renal salt wasting and volume depletion. The present review has been undertaken to examine the evidence that the CSWS is a separate entity. In this effort, we have discussed various methods of documentation of volume depletion, and then reviewed reported cases of CSWS to determine whether volume depletion and renal salt wasting have been clearly demonstrated. Our review has led us to conclude that not one case of purported CSWS has demonstrated clear evidence of volume depletion and renal salt wasting. If renal salt wasting had been proven in these cases, we would conclude that the likely site of renal salt transport was the proximal tubule. The proximal site of salt transport defect has been suggested by the absence of hyperreninemia and hypokalemia, which would be a distinguishing feature of Bartter’s syndrome and Gitelman’s syndrome.

This report describes a case of d-lactic acidosis observed by the authors and then reviews all case reports of d-lactic acidosis in the literature in order to define its clinical and biochemical features and pathogenetic mechanisms. The report also reviews the literature on metabolism of d-lactic acid in humans. The clinical presentation of d-lactic acidosis is characterized by episodes of encephalopathy and metabolic acidosis. The diagnosis should be considered in a patient who presents with metabolic acidosis and high serum anion gap, normal lactate level, negative Acetest, short bowel syndrome or other forms of malabsorption, and characteristic neurologic findings. Development of the syndrome requires the following conditions 1) carbohydrate malabsorption with increased delivery of nutrients to the colon, 2) colonic bacterial flora of a type that produces d-lactic acid, 3) ingestion of large amounts of carbohydrate, 4) diminished colonic motility, allowing time for nutrients in the colon to undergo bacterial fermentation, and 5) impaired d-lactate metabolism. In contrast to the initial assumption that d-lactic acid is not metabolized by humans, analysis of published data shows a substantial rate of metabolism of d-lactate by normal humans. Estimates based on these data suggest that impaired metabolism of d-lactate is almost a prerequisite for the development of the syndrome.

Renal stone formation is uncommon in patients with type IV renal tubular acidosis (RTA). This study was undertaken to explore the urinary biochemical and physicochemical factors in patients with type IV RTA in order to elucidate the mechanisms that protect them from renal stone formation. Twelve subjects with type IV RTA and 12 matched subjects with a similar degree of kidney impairment but without RTA were studied. Both groups of patients had low urinary excretion of calcium, phosphorus, uric acid, and citrate, probably reflective of kidney impairment. Patients with type IV RTA had a significantly lower urinary pH and urinary excretion of calcium than their matched controls. Hypocitraturia was present in both groups without any significant difference between them. This study suggests that the major protection from renal stone formation in type IV RTA results from impaired renal function and ensuing reduction in renal excretion of stone-forming substances, such as calcium and uric acid.

This discussion will highlight the following 9 specific points that related to metabolic acidosis caused by various toxins. The current recommendation suggests that alcohol dehydrogenase inhibitor fomepizole is preferred to ethanol in treatment of methanol and ethylene glycol poisoning, but analysis of the enzyme kinetics indicates that ethanol is a better alternative. In the presence of a modest increase in serum osmolal gap (

Discussion of abnormal plasma sodium concentrations with an emphasis on the pathogenesis, diagnosis, and treatment.Relevant literature in the English language and the authors' clinical experience.No special study has been carried out for the present discussion.The information from the literature and the data from the authors' clinical experience have been used to illustrate important points in the discussion.A most important aspect in the approach to hypernatremia is determination of the mechanism responsible for impaired water intake. Various mechanisms of abnormal water loss can be determined from measurement of urine osmolality. Hypernatremia is treated by water replacement and measures to reduce abnormal water loss. In most instances, hyponatremia is caused by inappropriate concentration of urine because of either appropriate or inappropriate antidiuretic hormone secretion. The determination of appropriateness of antidiuretic hormone secretion requires the assessment of effective arterial volume. Treatment depends on the pathogenetic mechanism.Abnormal plasma sodium concentration results from abnormal water intake or water output. Treatment is guided by determining the pathogenetic mechanism.

The present communication seeks to resolve the mechanism of metabolic acidosis that persists after ketonemia has cleared; the reason for the approximate equality of excess anion gap and reduction in serum bicarbonate at the time of admission despite substantial prior urinary loss of ketone anions; the mechanism of transformation of normochloremic acidosis to hyperchloremic acidosis during the recovery phase of DKA

The purpose of the present investigation was to determine whether dexamethasone, an agent known to preserve the blood-brain barrier, and colchicine, an agent that impairs mobilization of macrophages, can prevent demyelinating lesions associated with rapid correction of hyponatremia in the experimental animal. Hyponatremia was induced in rats with Pitressin and water. After 4 days hyponatremic rats received hypertonic saline alone or hypertonic saline plus dexamethasone or colchicine. All of the 9 rats that received only 5% NaCl developed demyelinating disease, while 3 of 6 rats treated with dexamethasone and 5 of 15 rats treated with colchicine showed no CNS abnormality. The results of our investigation might help understand the pathogenetic mechanism of central pontine myelinolysis in humans, a disease attributed to rapid correction of hyponatremia.

This discussion emphasizes two aspects of hyponatremia: classification according to effective osmolality of the body fluid, and distinction between appropriate and inappropriate ADH secretion. Assessment of the effective osmolality is important because the main deleterious effect of hyponatremia is cell overhydration, which occurs only when the effective osmolality is reduced. Since most cases of hyponatremia are associated with low effective osmolality, cell overhydration is a hallmark of acute hyponatremia. On the other hand, one must be aware of other types of hyponatremia in which effective osmolality is either normal or even increased. Inappropriateness of ADH secretion is defined as ADH secretion that occurs despite low effective osmolality and normal or expanded effective vascular volume. ADH secretion that occurs in hyponatremia is deemed appropriate if the effective vascular volume is low. The use of laboratory parameters is much more reliable in determining effective vascular volume than is careful physical examination.

The effect of meals on the physiological and physicochemical actions of potassium citrate was examined in 8 patients with nephrolithiasis maintained on a constant metabolic dietary regimen. Potassium citrate (20mEq. 3 times per day), whether given with food or on an empty stomach, significantly increased urinary pH, citrate and potassium, and decreased urinary calcium and ammonium. Moreover, potassium citrate decreased urinary saturation of calcium oxalate and uric acid, although it slightly increased that of brushite. However, there was no significant difference in these measures when the drug was given with meals from the time when it was given on an empty stomach. Thus, the effect of potassium citrate on urinary risk factors is unaffected by food.

We describe a case of renal hypouricemia due to increased tubular secretion of urate associated with absorptive hypercalciuria. This association has been described in the past, but this is the first time that high plasma levels of 1,25-dihydroxyvitamin D have been reported. A possible cause-and-effect relation between altered uric acid transport and altered vitamin D metabolism in the proximal tubule is suggested.

Sir, A 32‐year‐old African‐American male construction worker and martial arts student presented to the emergency room complaining of generalized weakness that was more pronounced in the lower extremities and confined him to bed. Weakness began about 12 h after vigorous physical exercise and ingestion of a high carbohydrate diet. He had no significant personal or family medical history. Initial blood pressure was 220/60 mmHg and resting pulse rate was regular at 98–104/min. His blood pressure normalized after 8 h without treatment (120/70 mmHg). Physical examination revealed a diffusely enlarged palpable thyroid gland and motor power of 3/5 in upper and 1–2/5 in the lower extremities. The rest of the examination was normal. In the emergency room the concentration of electrolytes were potassium 2.3 mEq/l (range 3.5–5.0 mEq/l), magnesium 2.2 mEq/l, calcium 9.5 mEq/l, phosphate 3.5 mEq/l. Serum creatinine phosphokinase (CPK) level was 474 U/L (24–195 U/L) and the blood pH was 7.45. Urine pH was 7.5 and specific gravity was 1.025. Concentrations of spot urine electrolytes were: potassium 13 mEq/l, sodium 177 mEq/l and chloride 132 mEq/l. Electrocardiogram showed mild sinus tachycardia (rate of 100/min) and U‐waves in …

Potassium filtered at the glomerulus is almost completely reabsorbed before the distal tubule; it must therefore be secreted into the collecting duct. The rate of potassium secretion is determined by a number of factors, notably aldosterone, distal sodium delivery, and serum potassium. Normal serum potassium is maintained by the interplay of passive leak of potassium from the cells and its active return to the cells. Transmembrane potassium distribution is influenced largely by acid-base equilibrium and hormones including insulin and catecholamines. In the diabetic with ketoacidosis hyperkalemia, in the face of potassium depletion, is attributable to reduced renal function, acidosis, release of potassium from cells due to glycogenolysis, and lack of insulin. Chronic hyperkalemia in diabetics is most often attributable to hyporeninemic hypoaldosteronism but other conditions including urinary tract obstruction may also contribute. A variety of clinical situations (e.g., volume depletion) and drugs (e.g., nonsteroidal antiinflammatory agents, and heparin) may acutely provoke hyperkalemia in susceptible individuals.

The present study is an investigation of the role of acetate metabolism in dialysis-induced hypoxemia and of the relative roles of acetate metabolism, bicarbonate loss, and CO2 gas (g) loss

A group of patients whose dietary potassium was unrestricted and who received 12-18 h of Kiil dialysis twice weekly against a bath containing no potassium, had body potassium concentrations (total body potassium/intracellular volume) of 7.6% lower than normal. Despite marked hypokalemia at the end of dialysis, suprisingly few electrocardiographic changes were seen. Another group of subjects, dialyzed fro 5-6 h thrice weekly against a bath containing 1 mEq/liter of potassium in a Dow dialyzer, showed more marked electrocardiographic abnormalities despite smaller alterations in transmembrane potassium gradients. Rapidity of establishment of potassium gradients is important as well as magnitude. The following changes occur in a single dialysis: 100 mEq of cell potassium and 20 mEq of extracellular potassium leave the body; 100 mEq of extracellular sodium enter the cells and 415 mEq of extracellular sodium leave the body; 3.5 liters of water leave the extracellular fluid, 2.5 liters into the bath and 1 liter into the cells.

A 77-year-old diabetic man with a creatinine clearance of 23--27 ml/min developed hyperkalemia while receiving heparin for peripheral arterial insufficiency. Discontinuation of this agent led to resolution of hyperkalemia as the plasma aldosterone concentration multiplied by sixfold. Renal insufficiency may have predisposed this patient to the development of hyperkalemia when heparin therapy suppressed aldosterone synthesis.

Isotonic saline is the fluid most commonly used for treatment of asymptomatic hypotonic dehydration, but as shown in the case presented in this article, rapid increase in serum sodium may follow administration of isotonic saline, leading to the development of central pontine myelinolysis (CPM). Because the necessity of rapid correction is less, whereas the risk of CPM is greater with chronic asymptomatic hyponatremia than with acute hyponatremia, use of a half normal saline might be more appropriate than normal saline for treating certain patients with hypotonic dehydration with asymptomatic hyponatremia. The calculations indicate that half normal saline will expand the extracellular volume quite effectively, but the rate of increase in serum sodium will be considerably slower than that with normal saline.

A 56-year-old woman received a kidney transplant and presented subsequently with evidence of volume contraction, hyponatremia and hyperkalemia. Urinary sodium excretion was inappropriately high for the degree of volume contraction and urinary potassium excretion inappropriately low for the degree of hyperkalemia. Marked elevation of plasma renin activity and plasma aldosterone suggested that the renal tubules were unresponsive to mineralocorticoids. The defect was shown to be transient. The mechanisms leading to the defect are discussed.

Bartter's syndrome is generally attributed to a primary defect in salt reabsorption either in the ascending limb of Henle's loop or in the proximal tubule. 2 siblings presented here have all the clinical and biochemical features of Bartter's syndrome but seem to have defective salt reabsorption in the distal convoluted tubule. A surreptitious use of diuretics was ruled out. Free water clearance was reduced in both patients and also was low after the addition of furosemide when compared with controls. Urine osmolalities following overnight dehydration were 883 and 1,000 mosm/l. The reduced maximal free water clearance argues against a proximal defect, and the normal urine concentration against a Henle's loop defect. Low free water clearance after furosemide suggests a defect in the distal convoluted tubule.

WE have recently studied a patient who had short-bowel syndrome that presented with peculiar neurologic manifestations and severe metabolic acidosis. The anion gap was increased, but the identity of the abnormal anion was not readily apparent. By several chemical technics the agent responsible for metabolic acidosis was found to be D-lactic acid — a cause of metabolic acidosis familiar to veterinarians but not to physicians. Case History The patient, a 30-year-old man, was in good health until July, 1975, when a superior mesenteric-vein thrombosis of unknown cause resulted in gangrene of most of the small intestine. After emergency jejunoileostomy with . . .

The proper approach to diagnosis and management in patients with a first episode of a calcium-containing kidney stone is controversial, and we have reviewed the literature in a search for objective information. Six large retrospective studies show the "natural cumulative recurrence rate of renal stones" to be 14% at 1 year, 35% at 5 years, and 52% at 10 years. Randomized studies of the use of either thiazides or allopurinol suggest a modest beneficial effect of about 35% over placebo. Considering that the risk of this specific therapy is about 5%, the morbidity associated with renal stones is limited, and relatively less invasive procedures can often replace nephrolithotomy, we conclude that use of specific drug therapy, namely thiazides or allopurinol, is not warranted in patients with a first kidney stone and, therefore, that extensive metabolic evaluation is unnecessary.