When the concentration of sodium (Na+) in arterial plasma (PNa) declines sufficiently to inhibit the release of vasopressin, water will be excreted promptly when the vast majority of aquaporin 2 water channels (AQP2) have been removed from Luminal membranes of Late distal nephron segments. In this setting, the volume of filtrate delivered distally sets the upper Limit on the magnitude of the water diuresis. Since there is an unknown volume of water reabsorbed in the Late distal nephron, our objective was to provide a quantitative assessment of this parameter. Accordingly, rats were given a Large oral water Load, while minimizing non-osmotic stimuli for the release of vasopressin. The composition of plasma and urine were measured. The renal papilla was excised during the water diuresis to assess the osmotic driving force for water reabsorption in the inner medullary collecting duct. During water diuresis, the concentration of creatinine in the urine was 13-fold higher than in plasma, which implies that ~8% of filtered water was excreted. The papillary interstitial osmolality was 600 mOsm/L> the urine osmolality. Since 17% of filtered water is delivered to the earliest distal convoluted tubule micropuncture site, we conclude that half of the water delivered to the Late distal nephron is reabsorbed downstream during water diuresis. The enormous osmotic driving force for the reabsorption of water in the inner medullary collecting duct may play a role in this reabsorption of water. Possible clinical implications are illustrated in the discussion of a case example.

• vasopressin
• basal water permeability
• desalination
• polyuria

Escape from the renal actions of vasopressin is said to occur in rats with chronic hyponatremia. Our objective was to provide specific evidence to test this hypothesis. Hence the osmolality in the excised renal papilla and in simultaneously voided urine (Uosm) was measured in rats with and without hyponatremia. To induce hyponatremia, rats were fed Low-electrolyte chow for 6 days. In the first 3 days, water was provided ad Lib. On days 4 to 6, a Long acting vasopressin preparation (dDAVP) was given every 8 hours to induce water retention. The hyponatremic rats drank 21 mL 5% sucrose on day 4 and 6 mL on day 5. On the morning of day 6, these rats were given 10 mL of 5% glucose in water (D5W) by the intraperitoneal route at 09:00 hour and at 11:00 hour. Analyses were performed in blood, urine, and the excised renal papilla at 13:00 hour on day 6. The concentration of Na+ in plasma (PNa) in rats without intraperitoneal D5W was 140±1 mEq/L (n=7) whereas it was 112±3 mEq/L in the hyponatremic group (n=12). The hyponatremic rats had a higher osmolality in the excised papillary (1,915±117 mOsm/kg H2O) than the UOsm (1,528±176 mOsm/kg H2O, P<0.05). One explanation for this difference is that the rats escaped from the renal action of vasopressin. Nevertheless, based on a quantitative analysis, other possibilities will be considered.

• vasopressins
• aquaporins
• basal water permeability
• concentration of the urine

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 permissibleduration 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.

• acid-base equilibrum
• water-eletrolyte balance
• body composition
• infinite gain control
• external balance

The molecular approaches to distal renal tubular acidosis (dRTA) associated AE1 mutations Lead us to understand the genetic and pathophysiological aspects of the acidification defects. An unanticipated high value of the urine-blood (U-B) PCO2 after NaHCO3 Loading observed in a case of dRTA and southeast Asian ovalocytosis (SAO) might be from a mistarget of the AE1 to the Luminal membrane of type A intercalated cells. The mutations of the AE1 gene resulted in SAO and also affected renal acidification function. Notwithstanding, after the NH4Cl Loading in 20 individuals with SAO, the acidification in the distal nephron was normal. The presence of both SAO and G701D mutations of AE1 gene would explain the abnormal urinary acidification in the patients with the compound heterozogosity. In terms of the effect of the mutations on trafficking of AE1, truncated kidney isoform (kAE1) of wild-type showed a `dominant-positive effect` in rescuing the recessive mutant kAE1 (S773P or G701D) trafficking to the plasma membrane, in contrast with the dominant mutant kAE1 (R589H) resulting in a `dominantnegative effect` when heterodimerized with the wild-type kAE1. It is notable that the dominant mutants kAE1 (R901X or G609R) expression in MDCK cells clearly results in aberrant surface expression with some mutant protein appearing at the apical membrane. These might result in net bicarbonate secretion and increasing U-B PCO2 in the distal nephron. The molecular physiological and genetic approaches have permitted identification of the molecular defects, predominantly in transporter proteins, and should in turn prompt development of novel therapeutic strategies.

• acidosis
• renal tubular
• southeast Asian ovalocytosis
• chloridebicarbonate antiportersn
• anion exchange protein 1
• erythrocyte
• urine-blood PCO2
• compound heterozygosity
• trafficking defect

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.

• metabolic acidosis
• toxin
• ethylene glycol
• methanol
• poisoning
• urine osmolal gap

Mutations in genes encoding ion channels, transporters, exchangers, and pumps in human tissues have been increasingly reported to cause hypokalemia. Assessment of history and blood pressure as well as the K+ excretion rate and blood acid-base status can help differentiate between acquired and inherited causes of hypokalemia. Familial periodic paralysis, Andersen`s syndrome, congenital chloride-losing diarrhea, and cystic fibrosis are genetic causes of hypokalemia with Low urine K+ excretion. With respect to a high rate of K+excretion associated with faster Na+ disorders (mineralocorticoid excess states), glucoricoid-remediable aldosteronism and congenital adrenal hyperplasia due to either 11β-hydroxylase and 17α-hydroxylase deficiencies in the adrenal gland, and Liddle`s syndrome and apparent mineralocorticoid excess in the kidney form the genetic causes. Among slow Cl- disorders (normal blood pressure, Low extracellular fluid volume), Bartter`s and Gitelman`s syndrome are most common with hypochloremic metabolic alkalosis. Renal tubular acidosis caused by mutations in the basolateral Na+/HCO3- cotransporter (NBC1) in the proximal tubules, apical H+-ATPase pump, and basolateral Cl-/HCO3- exchanger (anion exchanger 1, AE1) in the distal tubules and carbonic anhydroase II in both are genetic causes with hyperchloremic metabolic acidosis. Further work on genetic causes of hypokalemia will not only provide a much better understanding of the underlying mechanisms, but also set the stage for development of novel therapies in the future.

• acid-base equilibrium
• aldosterone
• blood pressure
• genes
• hypokalemia
• mutation
• renin
• urine electrolyte

The importance of thiazide-induced hyponatremia (TIH) is reemerging because thiazide diuretic prescription seems to be increasing after the guidelines recommending thiazides as first-line treatment of essential hypertension have been introduced. Thiazide diuretics act by inhibiting reabsorption of Na+ and Cl- from the distal convoluted tubule by blocking the thiazide-sensitive Na+/Cl- cotransporter. Thus, they inhibit electrolyte transport in the diluting segment and may impair urinary dilution in some vulnerable groups. Risk factors predisposing to TIH are old age, women, reduced body masses, and concurrent use of other medications that impair water excretion. While taking thiazides, the elderly may have a greater defect in water excretion after a water Load compared with young subjects. Hyponatremia is usually induced within 2 weeks of starting the thiazide diuretic, but it can occur any time during thiazide therapy when subsequent contributory factors are complicated, such as reduction of renal function with aging, ingestion of other drugs that affect free water clearance, or changes in water or sodium intake. While some patients are volume depleted on presentation, most appear euvolemic. Notably serum Levels of uric acid, creatinine and urea nitrogen are usually normal or Low, suggestive of syndrome of inappropriate secretion of antidiuretic hormone. Despite numerous studies, the pathophysiological mechanisms underlying TIH are unclear. Although the traditional view is that diuretic-induced sodium or volume Loss results in vasopressin-induced water retention, the following 3 main factors are implicated in TIH: stimulation of vasopressin secretion, reduced free-water clearance, and increased water intake. These factors will be discussed in this review.

• hyponatremia
• thiazides
• water
• diuretics
• vasopressin