From finch to fish to man: role of aquaporins in body fluid and brain water regulation.

Charles Darwin, in his Origin of the Species, noted that different species of finches on the Galapagos Islands had adapted their beak size based on where they sought their food. Homer Smith, in his book From Fish to Philosopher, discussed the evolution of the nephron from a single conduit in salt water vertebrates, to nephrons with large glomerular capillaries and proximal and distal tubules in fresh water vertebrates, to smaller glomerular capillaries in amphibians, to nephrons with loops of Henle to allow for urinary concentration and dilution in mammals. The kidney with its million nephrons has emerged as the vital organ for regulating body fluid composition and volume. With the recent discovery of aquaporin water channels, our understanding of volume regulation has been greatly enhanced. This article reviews current knowledge regarding: 1) the unifying hypothesis of body fluid volume regulation; 2) brain aquaporins and their role in pathophysiologic states; and 3) function and regulation of renal aquaporins in the syndrome of inappropriate antidiuretic hormone secretion (SIADH).

Chronic NOS inhibition reverses systemic vasodilation and glomerular hyperfiltration in pregnancy.

The chronic role of nitric oxide (NO), independent of prostaglandin synthesis, in the primary peripheral vasodilation, increased glomerular filtration rate (GFR), and renal plasma flow (RPF) in normal pregnancy remains to be defined. The purpose of the present study was to chronically inhibit NOS to return systemic vascular resistance (SVR), cardiac output (CO), GFR, and RPF to nonpregnant values. Pregnant rats received the nitric oxide synthase (NOS) inhibitor, nitro-L-arginine methyl ester (L-NAME), orally from gestational days 7 through 14. Results were compared with nonpregnant and untreated pregnant rats. At 14 days gestation, CO significantly increased in pregnant vs. nonpregnant rats (187 +/- 17 vs. 125 +/- 10 ml/min, P < 0.05) as SVR decreased (0.64 +/- 0.08 vs. 1.08 +/- 0.08 mmHg. ml(-1). min, P < 0.05) and mean arterial pressure was unchanged (117 +/- 5 vs. 125 +/- 2 mmHg, not significant). Pregnant rats also demonstrated increased GFR (3,015 +/- 33 vs. 2,165 +/- 136 microl/min, P < 0.01) and RPF (7,869 +/- 967 vs. 5,507 +/- 290 microl/min, P < 0.05) vs. nonpregnant rats. L-NAME-treated pregnant rats had values for CO (118 +/- 7 ml/min), SVR (1.09 +/- 0.07 mmHg. ml(-1). min), GFR (2,264 +/- 150 microl/min), and RPF (5,777 +/- 498 microl/min), which were no different than nonpregnant animals. In summary, similar to human pregnancy, primary peripheral vasodilation occurs early in rat pregnancy. Furthermore, the hyperdynamic circulation and glomerular hyperfiltration of normal rat midterm pregnancy can be chronically reversed by NOS inhibition. These findings suggest a role for endothelial damage and decreased NO in the pathogenesis of preeclampsia.

Pathogenesis and management of sodium and water retention in cardiac failure and cirrhosis.

The kidneys play the crucial role in the maintenance of the body fluid volume homeostasis. Several hypotheses have been introduced to explain sodium and water retention leading to edematous states in such pathologic conditions as congestive heart failure (CHF) and cirrhosis. We have suggested a unifying arterial underfilling hypothesis, explaining the development of edema in these conditions. Arterial underfilling, caused by decreased cardiac output or peripheral arterial vasodilation, leads to activation of the sympathetic nervous system, renin-angiotensin-aldosterone system, and nonosmotic vasopressin release. This review discusses the pathophysiologic mechanisms resulting in renal sodium and water retention, impaired mineralocorticoid escape, and resistance to atrial natriuretic peptide in patients with CHF and cirrhosis. Furthermore, the basis of current therapies in these disorders is discussed, including beta-blockers, angiotensin-converting enzyme inhibitors, angiotensin-receptor blockers, aldosterone antagonists, and diuretics in CHF and cirrhosis, as well as new approaches to treatment of water retention with vasopressin V(2) receptor antagonists.

Water-losing and water-retaining states: role of water channels and vasopressin receptor antagonists.

Alterations in water metabolism are present in conditions such as diabetes insipidus, syndrome of inappropriate antidiuretic hormone secretion, cardiac failure, cirrhosis, and pregnancy. Recent advances in molecular biology have enhanced our understanding of disordered water metabolism in these conditions. This review examines the roles of central vasopressin synthesis and release and collecting duct vasopressin V2 receptor and aquaporin-2 water channel regulation in water-losing and water-retaining states.

Pathophysiology of sodium and water retention in heart failure.

Heart failure is a leading cause of morbidity and mortality. In the United States, there are more than 5 million patients with heart failure and over 500,000 newly diagnosed cases each year. Numerous advances have been made in our understanding of the pathophysiologic mechanisms contributing to sodium and water retention in this condition. Important alterations in the sympathetic nervous system and the renin-angiotensin-aldosterone system have been described in heart failure, allowing the use of mechanism-specific treatments such as beta-adrenergic receptor antagonism and angiotensin-converting enzyme inhibition. As our understanding of the roles of the natriuretic peptides and the arginine vasopressin-aquaporin-2 system in the pathophysiology of heart failure evolves, treatments directed toward the alterations in these systems in heart failure can be further developed.

Neuronal nitric oxide synthase and systemic vasodilation in rats with cirrhosis.

Cirrhosis is typically associated with a hyperdynamic circulation consisting of low blood pressure, low systemic vascular resistance (SVR), and high cardiac output. We have recently reported that nonspecific inhibition of nitric oxide synthase (NOS) with nitro-L-arginine methyl ester reverses the hyperdynamic circulation in rats with advanced liver cirrhosis induced by carbon tetrachloride (CCl(4)). Although an important role for endothelial NOS (eNOS) is documented in cirrhosis, the role of neuronal NOS (nNOS) has not been investigated. The present study was carried out to specifically investigate the role of nNOS during liver cirrhosis. Specifically, physiological, biochemical, and molecular approaches were employed to evaluate the contribution of nNOS to the cirrhosis-related hyperdynamic circulation in CCl(4)-induced cirrhotic rats with ascites. Cirrhotic animals had a significant increase in water and sodium retention. In the aorta from cirrhotic animals, both nNOS protein expression and cGMP concentration were significantly elevated compared with control. Treatment of cirrhotic rats for 7 days with the specific nNOS inhibitor 7-nitroindazole (7-NI) normalized the low SVR and mean arterial pressure, elevated cardiac index, and reversed the positive sodium balance. Increased plasma arginine vasopressin concentrations in the cirrhotic animals were also repressed with 7-NI in association with diminished water retention. The circulatory changes were associated with a reduction in aortic nNOS expression and cGMP. However, 7-NI treatment did not restore renal function in cirrhotic rats (creatinine clearance: 0.76 +/- 0.03 ml. min(-1). 100 g body wt(-1) in cirrhotic rats vs. 0.79 +/- 0.05 ml. min(-1). 100 g body wt(-1) in cirrhotic rats+7-NI; P NS. ). Taken together, these results indicate that nNOS-derived NO contributes to the development of the hyperdynamic circulation and fluid retention in cirrhosis.

Cystic renal lymphangiectasia presenting as renal insufficiency in childhood.

Cystic renal lymphangiectasia is an unusual cause of cystic renal disease in childhood. We present a case of bilateral cystic renal lymphangiectasia in a 7-year-old boy who presented with asymptomatic renal insufficiency and anemia with decreased erythropoietin production. The clinical features of this condition and the diagnostic approach are reviewed. Although rare, this disorder should be considered in the differential diagnosis of cystic renal disease.

Hypocomplementemic urticarial vasculitis: report of a pediatric case.

Hypocomplementemic urticarial vasculitis syndrome (HUVS) is well described in adults but is quite rare in children. We report a pediatric case of HUVS initially diagnosed as juvenile rheumatoid arthritis and then as Henoch-Schönlein purpura. Beginning at 3 years of age, our patient developed polyarthritis with hypocomplementemia. She subsequently experienced an intermittent purpuric rash beginning at age 4 years, and she continued to have episodic arthritis and rash for years. Hematuria and proteinuria were noted at 12 years of age; renal biopsy revealed membranoproliferative glomerulonephritis with membranous features. Serum complement evaluation revealed activation of the classical pathway, consistent with HUVS. Therapy with oral dapsone led to improvement in proteinuria. HUVS should be considered in the differential diagnosis of pediatric patients with glomerulonephritis, urticarial rash, arthritis/arthralgias, and obstructive pulmonary disease.

Infection and cholestasis in neonates with intestinal resection and long-term parenteral nutrition.

OBJECTIVES: This retrospective study was conducted to determine the incidence of cholestasis and liver failure in patients with intestinal resection in the neonatal period who subsequently become dependent on parenteral nutrition support and to assess the significance of associated clinical factors--gestational age, birth weight and length; length of bowel resected; presence of ileocecal valve; enteral feeding history; and infection--to the incidence and severity of cholestasis. METHODS: Retrospective chart review of all patients in a single institution from May 1984 to February 1997 with neonatal small intestinal resection dependent on parenteral nutrition for at least 3 months. RESULTS: Forty-two patients fitting the inclusion criteria were the subjects of this review. Cholestasis developed in 28 (67%) while they were receiving parenteral nutrition (direct serum bilirubin more than 2 mg/dl). In 21, the elevated direct bilirubin normalized while patients continued to receive parenteral nutrition. Seven patients progressed to liver failure. In 14 patients, serum direct bilirubin nerve rose above 2 mg/dl. The cholestatic patients did not differ from the noncholestatic in gestational age, birth weight, and length; primary diagnosis; length of bowel resected; or presence of ileocecal valve. The duration of dependence on parenteral nutrition was longer in noncholestatic (33.2 +/- 9 months) than in cholestatic patients progressing to liver failure (19.4 +/- 3 months) or in cholestatic patients who recovered (16.1 +/- 1.9 months) (p < 0.05). Invasive fungal or bacterial infections occurred in all but one noncholestatic patient. The number of infections per patient was similar in all groups. The mean age (days) at first infection was significantly younger in cholestatic patients progressing to liver failure (28.5 +/- 5) and cholestatic patients who recovered (48.2 +/- 14.2) than in noncholestatic patients (167 +/- 43.2) (p < 0.01). Infection preceded the onset of cholestasis in all but 3 patients by an average of 13.5 days. Infecting organisms and site of first infection were similar in all patients. CONCLUSIONS: Cholestasis is common in infants with neonatal intestinal resection. Liver failure develops in 16.6%. Bacterial infection early in life characterized the cholestatic patients, and cholestasis developed shortly after the first infection in 90% of patients.

Predicting the duration of dependence on parenteral nutrition after neonatal intestinal resection.

OBJECTIVE: To determine whether there are clinical or physical factors that could be used to predict the duration of dependence on parenteral nutrition (PN) in infants who have undergone resection of small intestine in the neonatal period. STUDY DESIGN: Medical records of 44 patients who had small intestinal resection as neonates from 1985 to 1996 and who were dependent on PN for at least 3 months were reviewed. Statistical evaluation of patient variables and their impact on duration of dependence on PN were determined by using the Cox Proportional Hazard model. RESULTS: Twenty-seven patients became independent of PN before the age of 36 months. Seven patients between 40 and 129 months of age are permanently dependent on PN. Outcome could not be determined in 10 patients, four of whom died of hepatic failure while still receiving PN and six of whom are still receiving PN but are younger than 36 months of age. Small bowel length after initial surgery and the percent of daily energy intake received by the enteral route at 12 weeks' adjusted age were significantly related to the duration of dependence on PN. Gestational age, presence of the ileocecal valve, and development of cholestasis were not significantly related. With the use of the Cox Proportional Hazards survival model, a formula was generated to allow estimation of the duration of dependence on PN. CONCLUSIONS: The duration of dependence on PN can be predicted at an early age in neonatal short bowel syndrome by using two patient variables: the length of residual small bowel after initial surgery and the percent of daily energy intake tolerated through the enteral route.

Increased nosocomial infection in neutropenic low birth weight (2000 grams or less) infants of hypertensive mothers.

The neutropenia often seen in infants of hypertensive mothers (IHMs) at < 12 hours of age has been associated with nosocomial infection in the first 18 days of life. To assess maternal hypertension as an independent factor for nosocomial infection, we compared 101 low birth weight (< or = 2.00 kg) IHMs to a concurrent birth weight-matched group of infants of normotensive mothers (INMs). Infants without differential leukocyte counts at < 12 hours of age were excluded, leaving 93 IHMs and 98 INMs. The incidence of neutropenia at < 12 hours among IHMs was not significantly different from that among INMs (42/92 (45%) vs 37/98 (38%)). Nosocomial infection was more frequent in neutropenic IHMs than in neutropenic INMs (12/42 vs 2/37; p = 0.007). Infection in IHMs included omphalitis (2 infants), pneumonia (4), and sepsis with or without meningitis (6); INMs had cellulitis (1) and sepsis (1). The underlying mechanism(s) for this predisposition remains to be elucidated, although limited data suggest that neutropenia may be more severe and prolonged among IHMs.