Increased Urine Osmolality Research Articles

Disturbed Homeostasis in Sodium-Restricted Mice Heterozygous and Homozygous for Aldosterone Synthase Gene Disruption

We have determined that differences in expression of aldosterone synthase (AS) affect responses to a low-salt diet. In AS-null mice (AS(-/-)), but not in wild-type, low salt significantly decreased plasma sodium and increased potassium. The increased urine volume (1.5xwild-type) and decreased urine osmolality (0.7xwild-type), present in AS(-/-) mice on normal salt, became more severe (2.3xwild-type and 0.5xwild-type) on low salt, but neither changed in wild-type. In both genotypes, plasma vasopressin was similar on normal and low salt, and desmopressin injection significantly increased urine osmolality. Renal mRNA levels for aquaporin 1 and 3 were unchanged by genotype or diet and epithelial sodium channel and Na(+)-K(+)-2Cl(-)-cotransporter by genotype. In AS(-/-) mice, aquaporin 2 mRNA increased on normal salt, whereas Na(+)Cl(-)-cotransporter and cortex K(+) channel mRNAs decreased on both diets. The low blood pressure of AS(-/-) mice was decreased further by low salt, despite additional increases in renin, intrarenal arterial wall thickness, and macula densa cyclogenase-2 mRNA. In AS(+/-) mice on normal salt, adrenal AS mRNA was slightly decreased (0.7xwild-type), but blood pressure was normal. On low salt, their blood pressure was less than wild-type (101+/-2 mm Hg versus 106+/-2 mm Hg), even though renin mRNA increased to 2xwild-type. We conclude that aldosterone is critical for urine concentration and maintenance of blood pressure and even a mild reduction of AS expression makes blood pressure sensitive to low salt, suggesting that genetic differences of AS levels in humans may influence how blood pressure responds to dietary salt.

Pathogenesis and treatment of autosomal-dominant nephrogenic diabetes insipidus caused by an aquaporin 2 mutation.

Frame-shift mutations within the C terminus of aquaporin 2 (AQP2) cause autosomal-dominant nephrogenic diabetes insipidus (AD-NDI). To identify the molecular mechanism(s) of this disease in vivo and to test possible therapeutic strategies, we generated a mutant AQP2 (763-772 del) knockin mouse. Heterozygous knockin mice showed a severely impaired urine-concentrating ability. However, they were able to slightly increase urine osmolality after dehydration. This milder phenotype, when compared with autosomal-recessive NDI, is a feature of AD-NDI in humans, thus suggesting successful establishment of an AD-NDI mouse model. Immunofluorescence of collecting duct cells in the AD-NDI mouse revealed that the mutant AQP2 was missorted to the basolateral instead of apical plasma membrane. Furthermore, the mutant AQP2 formed a heterooligomer with wild-type AQP2 and showed a dominant-negative effect on the normal apical sorting of wild-type AQP2 even under dehydration. Using this knockin mouse, we tested several drugs for treatment of AD-NDI and found that rolipram, a phosphodiesterase 4 inhibitor, was able to increase urine osmolality. Phosphodiesterase inhibitors may thus be useful drugs for the treatment of AD-NDI. This animal model demonstrates that a mutant monomer gains a dominant-negative effect that reverses the normal polarized sorting of multimers.

Renal function in transgenic rats expressing an angiotensin-(1–7)-producing fusion protein

Transgenic rats [TGR(A1–7)3292] present a chronic 2.5-fold increase in plasma Angiotensin-(1–7) [Ang-(1–7)] concentration. In the present study, we investigated the effects of this chronic elevation on renal function, vasopressin levels, kidney morphology, expression of Ang-(1–7) and vasopressin receptors in TGR(A1–7)3292. Urine volume and water intake were measured for 24 h. At the end of this period, plasma and urine samples were collected to evaluate renal function parameters and circulating vasopressin levels. Expression of renal V 2 receptors and Mas was assessed by ribonuclease protection assay. Renal slices were processed for histological analysis. The urine flow of TGR(A1–7)3292 was significantly lower in comparison with Sprague–Dawley rats. The reduced urine volume of TGR(A1–7)3292 was accompanied by a significant increase in urinary osmolality and decrease free water clearance. Glomerular filtration rate, urinary sodium and potassium excretion were similar in both strains. No significant changes were observed in vasopressin levels as well as in V 2 receptor and Mas mRNA expression in renal tissue. No changes in kidney structure of TGR(A1–7)3292 were detected. These data suggest that changes in circulating renin–angiotensin system produced by chronic increase of Ang-(1–7) levels can lead to adjustments in the water balance that are independent of vasopressin release and V 2 receptor expression.

Acquired Nephrogenic Diabetes Insipidus

Nephrogenic diabetes insipidus (NDI) is defined as the inability of the kidney to concentrate urine owing to the insensitivity of the distal nephron to the antidiuretic hormone, arginine vasopressin. NDI can be either a congenital or an acquired disorder. Acquired NDI most commonly is secondary to drugs such as lithium or metabolic disturbances, such as hypokalemia and hypercalcemia. Disturbance of the aquaporin-2 shuttle is the underlying molecular basis of acquired NDI. NDI is diagnosed with the help of a water-deprivation test. Patients with the disorder will have a urinary osmolality of less than 300 mosm/kg H2O despite water deprivation. On administration of aqueous vasopressin, patients with NDI will show little or no increase in urine osmolality. Therapy consists of identifying and correcting the underlying disorder, or withdrawing the offending drug. Other treatment options that may be beneficial include diuretics, nonsteroidal anti-inflammatory drugs, decreased dietary solute intake, and desmopressin (DDAVP).

Extracellular Signal–Regulated Kinase Inhibition Slows Disease Progression in Mice with Polycystic Kidney Disease

The expression of mitogen-activated protein kinases (MAPK) in DBA/2-pcy/pcy (pcy) mice, a murine model of polycystic kidney disease was investigated. Proliferating cell nuclear antigen-positive cells were recognized in cyst epithelium from embryonic day 14.5 to 25 wk of age. Extracellular signal-regulated kinase (ERK) was expressed in the renal tubules of control and pcy mice, but stronger immunostaining was observed in cyst epithelium. Phosphorylated ERK was detected only in pcy mice and was localized predominantly in the cysts. p38 MAPK (p38) was no longer expressed after birth in controls but was detected in the cyst epithelium and in occasional tubular cells of pcy mice at all stages examined. c-Jun N-terminal kinase (JNK) was expressed in all tubular segments of controls after neonatal day 7, whereas in pcy kidneys, tubules became positive for JNK after 8 wk, and the cysts expressed little JNK. Administration of an oral MAP/ERK kinase inhibitor, PD184352, 400 mg/kg per d, to 10-wk-old pcy mice daily for the first week and then every third day for 6 additional weeks significantly decreased BP, kidney weight, serum creatinine level, and water intake and significantly increased urine osmolality. The cystic index and expression of phosphorylated ERK and ERK were significantly lower in PD184352-treated pcy mice. These results demonstrate that the expression of MAPK is dysregulated in cyst epithelium and that inhibition of ERK slowed the progression of renal disease in pcy mice.

Effect of Carbamazepine on Urinary Volume and Osmolality, Water Clearance, and Serum Osmolality in Patients with Primary Enuresis

ObjectiveIn this study we investigate the effects of carbamazepine (CBZ) on urinary volume, frequency of micturition, serum and urine osmolality, osmotic and creatinine clearance, and free water clearance in patients with primary nocturnal enuresis. This information might help in our understanding of the mechanism of action of CBZ in management of patients with enuresis. Patients and methodsThe study comprised eight patients with primary enuresis (age range, 8–14 yr) who wet at night on a daily basis. Enuretics were given, CBZ 200mg each night; urine volume, urinary osmolality and electrolytes, serum osmolality and electrolytes, osmotic clearance, fractional excretion of sodium, and free water clearance were assayed before CBZ treatment and after 15 d of treatment. Frequencies of bed-wetting and dry nights were observed during treatment. ResultsMean number (±SD) of dry nights was increased from zero dry nights (daily bed-wetting) to 9.7 (2.8) per 15 d of treatment (65%). CBZ decreased the 24-h urinary volume by 41%, the night volume by 45%, the day volume by 38%, and frequency of micturition by 28%. CBZ increased the 24-h urinary osmolality by 43%. Serum osmolality changed significantly from 283.7mOsm/l to 277.2mOsm/l. CBZ decreased osmotic clearance by 37% and free water clearance by 34%. Creatinine clearance was decreased by 19% after CBZ treatment (p<0.05). ConclusionCBZ reduced urine volume, increased urine osmolality, and decreased the free water clearance, the osmotic clearance, and the frequency of micturition in enuretics; this might help in understanding its mechanism of action.

Pharmacologic Chaperones as a Potential Treatment for X-Linked Nephrogenic Diabetes Insipidus

In many mendelian diseases, some mutations result in the synthesis of misfolded proteins that cannot reach a transport-competent conformation. In X-linked nephrogenic diabetes insipidus, most of the mutant vasopressin 2 (V2) receptors are trapped in the endoplasmic reticulum and degraded. They are unable to reach the plasma membrane and promote water reabsorption through the principal cells of the collecting ducts. Herein is reported two types of experiments: In vivo studies to assess clinically a short-term treatment with a nonpeptide V1a receptor antagonist (SR49059) and in vitro studies in cultured cell systems. In patients, SR49059 decreased 24- h urine volume (11.9 +/- 2.3 to 8.2 +/- 2.0 L; P = 0.005) and water intake (10.7 +/- 1.9 to 7.2 +/- 1.6 L; P < 0.05). Maximum increase in urine osmolality was observed on day 3 (98 +/- 22 to 170 +/- 52 mOsm/kg; P = 0.05). Sodium, potassium, and creatinine excretions and plasma sodium were constant throughout the study. In vitro studies indicate that the nonpeptide V1a receptor antagonist SR49059 and the V1a/V2 receptor antagonist YM087 (Conivaptan) rescued cell surface expression and function of mutant V2 receptors. Mutant V2 receptors with nonsense mutations were not affected by the treatment. Misfolded V2 receptor mutants were rescued in vitro and also in vivo by nonpeptide antagonists. This therapeutic approach could be applied to the treatment of several hereditary diseases that result from errors in protein folding and kinesis.

Physiological acclimation of a desert antelope, Arabian oryx (Oryx leucoryx), to long-term food and water restriction

Desert mammals often experience scarcity of drinking water and food for prolonged periods. In this study, the first long-term acclimation experiment in a non-domesticated desert-adapted ungulate, we investigated the mechanisms used by the Arabian oryx Oryx leucoryx, to adjust its physiology to progressive food and water restriction over 5 months, an experimental regimen and time course chosen to mimic what it typically experiences between spring and late summer in the desert. At the end of the acclimation period, oryx consumed less than one and half of food and water of animals in the control group and lost 8.2+/-2.6% of their initial body mass. Experimental animals reduced their mass-specific resting metabolic rate (RMR) and total evaporative water loss (TEWL) by 16.2 and 25.7%, respectively, and maintained a digestive efficiency of about 70%. We found no support for the idea that reduced RMR in oryx correlated with a decreased thyroid hormone concentration in plasma. At the end of the 5 months acclimation, oryx continued to mobilize fatty acids to fuel metabolism, and did not use protein breakdown as a major source of gluconeogenesis. Oryx in the experimental group reduced their water intake by 70% and maintained constant plasma osmolality. They adjusted their water budget by reducing mass-specific TEWL, increasing urine osmolality and reducing urine volume by 40%, and excreting feces with <50% water content. Oryx have an unusually low TEWL compared with other arid-zone ungulates; both hydrated and water-deprived individuals have TEWL values, 51.7 and 39.3%, respectively, of allometric predictions for arid-zone ungulates.

Hypotension inNKCC1null mice: role of the kidneys

NKCC1 null mice are hypotensive, in part, from the absence of NKCC1-mediated vasoconstriction. Whether these mice have renal defects in NaCl and water handling which contribute to the hypotension is unexplored. Therefore, we asked 1) whether NKCC1 (-/-) mice have a defect in the regulation of NaCl and water balance, which might contribute to the observed hypotension and 2) whether the hypotension observed in these mice is accompanied by endocrine abnormalities and/or downregulation of renal Na+ transporter expression. Thus we performed balance studies, semiquantitative immunoblotting, and immunohistochemistry of kidney tissue from NKCC1 (+/+) and NKCC1 (-/-) mice which consumed either a high (2.8% NaCl)- or a low-NaCl (0.01% NaCl) diet for 7 days. Blood pressure was lower in NKCC1 (-/-) than NKCC1 (+/+) mice following either high or low dietary NaCl intake. Relative to wild-type mice, NKCC1 null mice had a lower plasma ANP concentration, a higher plasma renin and a higher serum K+ concentration with inappropriately low urinary K+ excretion, although serum aldosterone was either the same or only slightly increased in the mutant mice. Expression of NHE3, the alpha-subunit of the Na-K-ATPase, NCC, and NKCC2 were higher in NKCC1 null than in wild-type mice, although differences were generally greater during NaCl restriction. NKCC1 null mice had a reduced capacity to excrete free water than wild-type mice, which resulted in hypochloremia following the NaCl-deficient diet. Hypochloremia did not occur from increased aquaporin-1 (AQP1) or 2 protein expression or from redistribution of AQP2 to the apical regions of principal cells. Instead, NKCC1 null mice had a blunted increase in urinary osmolality following vasopressin administration, which should increase free water excretion and attenuate the hypochloremia. In conclusion, aldosterone release is inappropriately low in NKCC1 null mice. Moreover, the action of aldosterone and vasopressin is altered within kidneys of NKCC1 null mice, which likely contributes to their hypotension. Increased Na+ transporter expression, increased plasma renin, and reduced plasma ANP, as observed in NKCC1 null mice, should increase vascular volume and blood pressure, thus minimizing hypotension.

A case of lymphocytic hypophysitis with masked diabetes insipidus unveiled by glucocorticoid replacement

Lymphocytic hypophysitis may involve the pituitary gland and various hormonal abnormalities. A 72-year-old man presented with euvolemic hyponatremia caused by glucocorticoid deficiency. After glucocorticoid replacement, hypernatremia in the presence of dilute urine was found. Central diabetes insipidus (DI) was confirmed later by a significant increase in urine osmolality after vasopressin administration. Brain magnetic resonance imaging showed a pituitary mass and loss of hyperintense signal in the posterior pituitary gland on T1-weighted imaging. The patient underwent a transsphenoidal adenectomy, and pathological examination of dissected tissues showed a typical finding of lymphocytic hypophysitis. Two months after surgery, the patient's central DI had resolved sufficiently that 1-desamino-8- d -arginine vasopressin therapy was discontinued without polyuria. However, he was kept on glucocorticoid and levothyroxine therapy. In conclusion, lymphocytic hypophysitis may feature a concealed central DI caused by glucocorticoid deficiency-associated hyponatremia.

Residual Urinary Concentrating Ability and AQP2 Expression in a Rat Model for Chronic Renal Failure

Background: In chronic renal failure (CRF), a defect in urinary concentrating ability develops gradually as the renal failure progresses. Although several molecular mechanisms associated with renal urinary concentration are reported to be impaired in a rat model for renal failure, the mechanisms underlying residual urinary concentration ability in CRF remain to be elucidated. Methods: Rats that underwent an 8-week recovery period after 5/6 nephrectomy were used as the model for CRF. Urinary concentration was induced by 24-hour water restriction. Plasma osmolality and arginine vasopressin (AVP) were measured from blood sampled by inserting a catheter into the femoral artery before and after the water restriction. AQP2 mRNA expression in the inner medulla was examined by competitive PCR and in situ hybridization, and protein expression, by Western blotting. Rats that underwent sham operation were used as control. Results: Water restriction significantly reduced urine volume and increased urine osmolality in CRF rats, although such changes were much less than those in sham-operated rats. Plasma AVP was elevated at the basal condition, and further elevation was noted after water restriction. AQP2 mRNA signals were significantly intensified by water restriction even in CRF rats, although the increase was limited as in the case of urine osmolality. Western blotting also showed a small but significant enhancement of protein signals in response to water restriction in CRF rats. Conclusions: We noted a weak but significant response of AQP2 expression to dehydration in CRF rats. This response in the collecting duct may be one of the factors contributing to residual urinary concentrating ability in CRF.

Nonpeptide AVE 0991 is an angiotensin-(1-7) receptor Mas agonist in the mouse kidney.

It has been described recently that the nonpeptide AVE 0991 (AVE) mimics the effects of angiotensin-(1-7) [Ang-(1-7)] in bovine endothelial cells. In this study, we tested the possibility that AVE is an agonist of the Ang-(1-7) receptor Mas, in vitro and in vivo. In water-loaded C57BL/6 mice, AVE (0.58 nmol/g body weight) produced a significant reduction in urinary volume (0.06+/-0.03 mL/60 min [n=9] versus 0.27+/-0.05 [n=9]; P<0.01), associated with an increase in urinary osmolality. The Ang-(1-7) antagonist A-779 completely blocked the antidiuretic effect of AVE. As observed previously for Ang-(1-7), the antidiuretic effect of AVE after water load was blunted in Mas-knockout mice (0.37+/-0.10 mL/60 min [n=9] versus 0.27+/-0.03 mL/60 min [n=11] AVE-treated mice). In vitro receptor autoradiography in C57BL/6 mice showed that the specific binding of 125I-Ang-(1-7) to mouse kidney slices was displaced by AVE, whereas no effects were observed in the binding of 125I-angiotensin II or 125I-angiotensin IV. Furthermore, AVE displaced the binding of 125I-Ang-(1-7) in Mas-transfected monkey kidney cells (COS) cells (IC50=4.75x10(-8) mol/L) and of rhodamine-Ang-(1-7) in Mas-transfected Chinese hamster ovary (CHO) cells. It also produced NO release in Mas-transfected CHO cells blocked by A-779 but not by angiotensin II type-1 (AT1) and AT2 antagonists. Contrasting with these data, the antidiuretic effect of AVE was totally blocked by AT2 antagonists and partially blocked (approximately 60%) by AT1 antagonists. The binding data, the results obtained in Mas-knockout mice and in Mas-transfected cells, show that AVE is a Mas receptor agonist. Our data also suggest the involvement of AT2/AT1-related mechanisms, including functional antagonism, oligomerization or cross-talk, in the renal responses to AVE.

Chronic COX-2 inhibition reduces medullary HSP70 expression and induces papillary apoptosis in dehydrated rats

Papillary cells adapt to their hyperosmotic environment by accumulating organic osmolytes and by enhanced synthesis of heat shock protein 70 (HSP70), which protect against high-solute concentrations. Because cyclooxygenase-2 (COX-2) is expressed abundantly in the renal papilla and is induced by dehydration, and because HSP70 expression is stimulated by specific prostaglandins, COX-2 inhibition may interfere with cellular osmoadaptation. In vivo, rats received rofecoxib before water deprivation. Medullary expression of several tonicity-responsive genes was analyzed and apoptosis was monitored by transferase-mediated dUTP nick-end labeled (TUNEL) staining and determination of papillary caspase-3 activity. In vitro, inner medullary collecting duct 3 (IMCD3) cells were exposed to hypertonic medium containing a COX-2-specific inhibitor. Thereafter, expression of tonicity-responsive genes was analyzed and resistance to high-solute concentrations was examined. Further, the effect of Delta 12-PGJ2, a urinary prostaglandin, and of HSP70 overexpression on resistance against high urea concentration, was evaluated. Rofecoxib treatment significantly increased urine osmolality due to higher urea concentrations, but reduced papillary HSP70 abundance by 50%. TUNEL staining showed numerous apoptotic cells in the papilla, associated with increased caspase-3 activity. These in vivo results were confirmed by experiments on cultured IMCD3 cells, in which COX-2 inhibition impaired the tonicity-induced up-regulation of HSP70 expression and rendered the cells susceptible to high urea concentrations. Furthermore, Delta 12-PGJ2 increased both HSP70 expression and resistance against high urea, which was causally linked to higher HSP70 levels. These observations support the view that chronic COX-2 inhibition reduces medullary HSP70 expression, thus rendering papillary cells susceptible to damage by high urea concentrations, especially when accompanied by dehydration.

Water and electrolyte salvage in an animal model of dehydration and malnutrition.

Recently, a new oral rehydration solution (ORS) called Resomal has been designed specifically for children with severe malnutrition. The aim of this study was to assess the effect of malnutrition on renal and intestinal responses to dehydration, and to compare intestinal water and electrolyte absorption from Resomal and from the standard World Health Organization-Oral Rehydration Solution (WHO-ORS). Malnutrition was achieved in a rabbit model by feeding the animals daily for 30 days with half the amount of food that a well-nourished group of control animals had consumed on the previous day. Dehydration was achieved by water deprivation for 46 hours in both control and malnourished rabbits. At 46 hours, dehydration was assessed by changes in body weight, urinary volume and osmolarity, and blood urea nitrogen concentration. At that time active colonic and jejunal mucosal electrolyte transport in Ussing chambers was also measured. Small intestinal absorption of water, sodium, and potassium was measured in vivo during intestinal perfusion of the two ORSs and in vitro by measurement of mucosal electrogenic glucose-stimulated sodium absorption across intestinal patches. Compared to controls (C), well-nourished but dehydrated (C+D) animals lost 12% of their body weight, with an 87% reduction in urine volume, a 110% increase in urine osmolality, and a 94% increase in blood urea nitrogen. In the colon of C+D animals, short-circuit current (Isc) and net sodium transepithelial flux (JNa+ net) were increased. Almost identical results were obtained in malnourished and dehydrated (M+D) animals. In the jejunum, net in vivo absorption of water (JWater), sodium (JNa+), and potassium (JK+) were increased during standard ORS infusion in both dehydrated groups. During Resomal infusion, water absorption was the same as seen with WHO-ORS, but sodium absorption was reduced, and potassium absorption was increased in both well-nourished and malnourished dehydrated animals. In vitro, compared to controls, the glucose-stimulated short-circuit current (DeltaIsc), JNa+ net and G were increased in both dehydrated groups. During experimental dehydration, the kidney and large intestine salvage water and electrolytes, thus reducing the consequences of dehydration. These findings indicate that jejunal water absorption from Resomal and WHO-ORS is increased during dehydration, but Resomal allows for less sodium and more potassium to be absorbed, both in well-nourished and malnourished dehydrated rabbits.

Water and Electrolyte Salvage in an Animal Model of Dehydration and Malnutrition

ABSTRACTBackground and aimRecently, a new oral rehydration solution (ORS) called Resomal has been designed specifically for children with severe malnutrition. The aim of this study was to assess the effect of malnutrition on renal and intestinal responses to dehydration, and to compare intestinal water and electrolyte absorption from Resomal and from the standard World Health Organization‐Oral Rehydration Solution (WHO‐ORS).MethodsMalnutrition was achieved in a rabbit model by feeding the animals daily for 30 days with half the amount of food that a well‐nourished group of control animals had consumed on the previous day. Dehydration was achieved by water deprivation for 46 hours in both control and malnourished rabbits. At 46 hours, dehydration was assessed by changes in body weight, urinary volume and osmolarity, and blood urea nitrogen concentration. At that time active colonic and jejunal mucosal electrolyte transport in Ussing chambers was also measured. Small intestinal absorption of water, sodium, and potassium was measured in vivo during intestinal perfusion of the two ORSs and in vitro by measurement of mucosal electrogenic glucose‐stimulated sodium absorption across intestinal patches.ResultsCompared to controls (C), well‐nourished but dehydrated (C+D) animals lost 12% of their body weight, with an 87% reduction in urine volume, a 110% increase in urine osmolality, and a 94% increase in blood urea nitrogen. In the colon of C+D animals, short‐circuit current (Isc) and net sodium transepithelial flux (JNa+ net) were increased. Almost identical results were obtained in malnourished and dehydrated (M+D) animals. In the jejunum, net in vivo absorption of water (JWater), sodium (JNa+), and potassium (JK+) were increased during standard ORS infusion in both dehydrated groups. During Resomal infusion, water absorption was the same as seen with WHO‐ORS, but sodium absorption was reduced, and potassium absorption was increased in both well‐nourished and malnourished dehydrated animals. In vitro, compared to controls, the glucose‐stimulated short‐circuit current (ΔIsc), JNa+ net and G were increased in both dehydrated groups.ConclusionDuring experimental dehydration, the kidney and large intestine salvage water and electrolytes, thus reducing the consequences of dehydration. These findings indicate that jejunal water absorption from Resomal and WHO‐ORS is increased during dehydration, but Resomal allows for less sodium and more potassium to be absorbed, both in well‐nourished and malnourished dehydrated rabbits.

Clinical characteristics of eight patients with congenital nephrogenic diabetes insipidus.

Congenital nephrogenic diabetes insipidus (NDI) is characterized by the insensitivity of the distal nephron to arginine vasopressin. Clinical knowledge of this disease is based largely on case reports. For this study, we investigated the clinical findings of eight patients in terms of age at onset, age at diagnosis, main complaint, results of physical examination, the diagnosis, the effect of treatment, kidney function, and presence or absence of gene defects. The main complaints of all eight cases at initial examination were unknown fever, failure to thrive, and short stature. Polyuria and polydipsia are not always the chief complaints with congenital NDI. In one case, diabetes insipidus could be diagnosed based only on the results of a 5% hypertonic saline test. In six cases, we found abnormalities in the V2 receptor gene. Initially, trichlormethiazide therapy was shown to have a significant effect on polyuria; however, this effect decreased over time. In one patient with partial NDI, the addition of trichlormethiazide twice a day to 1-desamino-8-D-arginine vasopressin increased urine osmolality in the morning and caused nocturia to disappear. Results of 99mTc-diethylenetriamine pentaacetic acid kidney scintigraphy revealed a slight decrease in glomerular filtration rate in three patients. No patient experienced serious renal dysfunction.

Upregulation of collecting duct aquaporin-2 by metabolic acidosis: role of vasopressin.

Metabolic acidosis is associated with alteration in fluid and electrolyte reabsorption in a number of nephron segments. However, the effects of metabolic acidosis on urine osmolality and aquaporin-2 (AQP-2) remain poorly understood. In these studies, we examined the effects of chronic metabolic acidosis on water handling by the kidney. Rats were placed in metabolic cages and subjected to water (control) or 280 mM NH(4)Cl loading for 120 h to induce metabolic acidosis. The results indicated a significant increase in urine osmolality with no change in urine volume or urinary Na(+) excretion in acid-loaded animals. This effect was independent of alteration in fluid intake or salt/Cl(-) loading. Immunoblotting and Northern hybridization studies indicated that AQP-2 protein abundance and mRNA expression levels increased significantly along the collecting duct system of NH(4)Cl-but not NaCl-loaded animals. RIA results indicated that metabolic acidosis was associated with a fourfold increase in circulating levels of vasopressin (AVP) and a significant increase in brain AVP mRNA expression levels. In conclusion, metabolic acidosis upregulates the expression levels of AQP-2 and increases urine osmolality, suggesting an adaptive increase in water reabsorption in the collecting duct. A concomitant increase in AVP synthesis and secretion likely plays an essential role in the adaptation of AQP-2 in metabolic acidosis.

Role of urea in the postprandial urine concentration cycle of the insectivorous bat Antrozous pallidus

Insectivorous bats, which feed once daily, produce maximally concentrated urine only after feeding. The role of urea as an osmolyte in this process was investigated in pallid bats ( Antrozous pallidus) in the laboratory. Following a 24-h fast, plasma and urine were sampled before and 2 h after feeding in postprandial (PP) animals and before and 2 h after similar treatment without feeding in nonfed (NF) animals. Food consumption by PP animals and handling of NF animals had no effect on blood water content as measured by hematocrit and plasma oncotic pressure. Food consumption increased both plasma osmolality ( P osm) and plasma urea ( P urea) by as much as 15%. Food consumption also increased urine osmolality ( U osm) and urine urea ( U urea) by 50–100%. Feeding increased U osm regardless of changes in P osm, and elevation of U osm resulted primarily from increased U urea. In NF bats, P osm and P urea were unchanged, while U osm and U urea increased by as much as 25%. Again, increased U osm resulted primarily from increased U urea. The PP urine concentration cycle of pallid bats resulted from increased urea excretion in response to apparent rapid urea synthesis. Bats rapidly metabolized protein and excreted urea following feeding when body water was most plentiful.

Effects of Cadmium Ingestion on Plasma and Osmoregulatory Hormone Concentrations in Male and Female Pekin Ducks

Effects of ingested cadmium (Cd) on body mass and plasma, urine, salt-gland secretion, and osmoregulatory hormone concentrations were assessed in male and female Pekin ducks, Anas platyrhynchos, acclimated to 450 mM NaCl over 6 wk and then held an additional 13 wk on 300 mM NaCl (prolonged saline exposure). Groups of six birds ate diets containing 0 (control), 50 (low-Cd diet), or 300 (high Cd diet) w g Cd/g food. Ducks that ingested Cd, especially females, lost body mass. Cadmium ingestion did not affect salt-gland secretion concentration. Control males had higher plasma osmolality and lower relative plasma volume. These increased in both sexes during saline acclimation. The high-Cd diet suppressed the increase in plasma osmolality in both sexes, but a rise in relative plasma volume occurred only in females. Following prolonged exposure to saline, plasma osmolality and relative plasma volume were reduced in control ducks but further elevated in ducks on the high-Cd diet. Cadmium ingestion suppressed the increase in urine osmolality that occurred in control ducks during saline acclimation. Neither saline acclimation nor Cd ingestion affected plasma concentrations of arginine vasotocin or prolactin. Arginine vasotocin was not correlated with plasma osmolality; prolactin was negatively correlated with plasma osmolality, but only in males. Cadmium suppressed the increase in angiotensin II that occurred at higher salinities in control and low-Cd males. This study examined the effects of gradually increasing body cadmium content on osmotic homeos-tasis. Cadmium affected plasma and urine, but not salt-gland secretion, concentrations and some of these responses were sexually disparate. Cadmium did not affect osmoregulatory hormones (arginine vasotocin and prolactin) by which observed changes in plasma concentration might have been influenced.

Transient gestational diabetes insipidus: report of two cases and review of pathophysiology and treatment

Gestational diabetes insipidus is a rare disorder characterized by polyuria and polydipsia due to the inability of the kidneys to concentrate urine. We report two cases of transient gestational diabetesinsipidus in which patients responded to intranasal DDAVP® (1-deamino-8-D-arginine vasopressin) with greater than 50% increase in urine osmolality and marked reduction in urine output. IntranasalDDAVP was discontinued after their discharge and both patients maintained normal urine output and appropriate urine osmolality. In determining whether diabetes insipidus is present in a patient who is polyuricand hypernatremic, a urine osmolality below that of the plasma suggests the presence of diabetes insipidus. Understanding of the pathophysiology may soon lead to improved methods of prevention, diagnosisand treatment.