The Urine Anion Gap: Common Misconceptions.

Two papers, one in 1986 and another one in 1988, reported a strong inverse correlation between urinary anion gap (UAG) and urine ammonia excretion (UNH4) in patients with metabolic acidosis and postulated that UAG could be used as an indirect measure of UNH4 This postulation has persisted until now and is widely accepted. In this review, we discuss factors regulating UAG and examine published evidence to uncover errors in the postulate and the design of the original studies. The essential fact is that, in the steady state, UAG reflects intake of Na, K, and Cl. Discrepancy between intake and urinary output of these electrolytes (i.e, UAG) indicates selective extrarenal loss of these electrolytes or nonsteady state. UNH4 excretion, which depends, in the absence of renal dysfunction, mainly on the daily acid load, has no consistent relationship to UAG either theoretically or in reality. Any correlation between UAG and UNH4, when observed, was a fortuitous correlation and cannot be extrapolated to other situations. Furthermore, the normal value of UAG has greatly increased over the past few decades, mainly due to increases in dietary intake of potassium and widespread use of sodium salts with anions other than chloride as food additives. The higher normal values of UAG must be taken into consideration in interpreting UAG.

L-lactic acidosis: pathophysiology, classification, and causes; emphasis on biochemical and metabolic basis.

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.

Alkali delivery in chronic hemodialysis: Would more acetate be helpful?

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.

The key to halting progression of CKD might be in the produce market, not in the pharmacy.

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.

Management of hyponatremia and clinical use of vasopressin antagonists.

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.

A hypothesis for mechanism for brain oedema due to glycine.

Death following the use the glycine distension solution in transurethral prostatectomy (TURP) or hysteroscopic surgery has been attributed to the toxic effect of glycine on the brain through the glycine receptors and hyperammonemia, contending that glycine-associated hyponatremia is isosmotic and therefore would not cause brain oedema. Here we propose a hypothesis that the mechanism of brain oedema and death is actually osmotic brain oedema caused by selective diffusion of glycine into the brain while sodium cannot diffuse out of the brain despite favourable concentration gradient because of the absence of sodium transporter on the cerebral capillaries needed for the exit of sodium from the brain. The mechanism for unidirectional diffusion of solutes into the brain in glycine-associated hyponatremia is explained.

Colon Necrosis Due to Sodium Polystyrene Sulfonate with and without Sorbitol: An Experimental Study in Rats.

INTRODUCTION: Based on a single rat study by Lillemoe et al, the consensus has been formed to implicate sorbitol rather than sodium polystyrene sulfonate (SPS) as the culprit for colon necrosis in humans treated with SPS and sorbitol. We tested the hypothesis that colon necrosis by sorbitol in the experiment was due to the high osmolality and volume of sorbitol rather than its chemical nature. METHODS: 26 rats underwent 5/6 nephrectomy. They were divided into 6 groups and given enema solutions under anesthesia (normal saline, 33% sorbitol, 33% mannitol, SPS in 33% sorbitol, SPS in normal saline, and SPS in distilled water). They were sacrificed after 48 hours of enema administration or earlier if they were very sick. The gross appearance of the colon was visually inspected, and then sliced colon tissues were examined under light microscopy. RESULTS: 1 rat from the sorbitol and 1 from the mannitol group had foci of ischemic colonic changes. The rats receiving SPS enema, in sorbitol, normal saline, distilled water, had crystal deposition with colonic necrosis and mucosal erosion. All the rats not given SPS survived until sacrificed at 48 h whereas 11 of 13 rats that received SPS in sorbitol, normal saline or distilled water died or were clearly dying and sacrificed sooner. There was no difference between sorbitol and mannitol when given without SPS. CONCLUSIONS: In a surgical uremic rat model, SPS enema given alone or with sorbitol or mannitol seemed to cause colon necrosis and high mortality rate, whereas 33% sorbitol without SPS did not.

What can we learn from the saga of chitosan gums in hyperphosphatemia therapy?

Control of high serum phosphorus, a marker of poor outcome, is still a poorly achieved goal in dialysis therapy. Therefore, the 2009 study (Savica et al., J Am Soc Nephrol 20: 639-644, 2009) showing a significant drop of serum phosphate (2.35 mg/dl) after only 2 weeks of chewing a chitosan-containing gum two times per day was received with great hopes by the renal community. Chitosan is a polymer of glucosamine, similar to sevelamer, which allegedly would bind phosphate present in high concentrations in the saliva of renal patients. Recent randomized studies, however, have been unable to duplicate these results. A systematic and detailed quantitative analysis of the available data was performed. It concluded that the amount of chitosan contained in the chewing gum (20 mg) is too little to account for the originally observed reduction in serum phosphate and be of any use as a phosphate binding agent in the management of hyperphosphatemia. It was postulated that the original marked drop in serum phosphate may have been caused by the Hawthorne effect, which is frequently observed in nonrandomized clinical trials. Two important lessons derived from this analysis are emphasized. The first lesson is the demonstration of the importance of randomized, placebo-controlled studies in clinical research. If randomization had been performed in the original study, the Hawthorne effect would have been detected. The second lesson is showing the importance of quantitative analysis, which in this case, would have avoided the time and effort expended in several randomized clinical trials that eventually concluded the ineffectiveness of the chitosan-containing chewing gums as a phosphate binder.

Inevitability of balance restoration.

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.

Uncoventional views on certain aspects of toxin-induced metabolic acidosis.

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 (<30 mOsm/L), the starting dose of ethanol should be far less than the usual recommended dose. One can take advantage of the high vapor pressure of methanol in the treatment of methanol poisoning when hemodialysis is not readily available. Profuse sweating with increased water ingestion can be highly effective in reducing methanol levels. Impaired production of ammonia by the proximal tubule of the kidney plays a major role in the development of metabolic acidosis in pyroglutamic acidosis. Glycine, not oxalate, is the main final end product of ethylene glycol metabolism. Metabolism of ethylene glycol to oxalate, albeit important clinically, represents less than 1% of ethylene glycol disposal. Urine osmolal gap would be useful in the diagnosis of ethylene glycol poisoning, but not in methanol poisoning. Hemodialysis is important in the treatment of methanol poisoning and ethylene glycol poisoning with renal impairment, with or without fomepizole or ethanol treatment. Severe leucocytosis is a highly sensitive indicator of ethylene glycol poisoning. Uncoupling of oxidative phosphorylation by salicylate can explain most of the manifestations of salicylate poisoning.

Mechanisms to concentrate the urine: an opinion.

PURPOSE OF REVIEW: Our goal is to suggest how the renal concentrating mechanism is regulated in vivo. RECENT FINDINGS: The majority of descending thin limbs of the loop of Henle lack aquaporin-1 water channels, and loops of Henle in the inner medulla lack urea transporters. SUMMARY: Lack of water permeability in the descending thin limbs of the loop of Henle offers several advantages. First, since much less water is added to the outer medullary interstitial compartment, inhibitory control mechanisms on sodium and chloride reabsorption from the medullary thick ascending of loop of Henle initiated by water addition from the medullary collecting duct can be effective. Second, recycling of urea is efficient, as little urea will be washed out of the medulla. Third, delivery of a larger volume of filtrate to the medullary thick ascending limb of the loop of Henle permits both an appreciable reabsorption of sodium along with only a small fall in the luminal concentration of sodium in each of these liters. Hence there need be only a small lumen positive voltage in the medullary thick ascending limb of the loop of Henle. The absence of urea transporters in the loop of Henle in the inner medulla is required for a passive mechanism of sodium and chloride reabsorption in the inner medulla. Control of urea reabsorption from the medullary collecting duct is needed to prevent excessive oliguria in electrolyte-poor urine.

Pathogenesis and diagnosis 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.

Pathogenesis and treatment of hypernatremia.

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.

Bartter's, Gitelman's, and Gordon's syndromes. From physiology to molecular biology and back, yet still some unanswered questions.

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.

Reevaluation of the criteria for the clinical diagnosis of Gitelman syndrome.

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.