Effects of sevelamer and calcium-based phosphate binders on mortality in hemodialysis patients.

Elevated serum phosphorus and calcium are associated with arterial calcification and mortality in dialysis patients. Unlike calcium-based binders, sevelamer attenuates arterial calcification but it is unknown whether sevelamer affects mortality or morbidity. In a multicenter, randomized, open-label, parallel design trial we compared sevelamer and calcium-based binders on all-cause and cause-specific mortality (cardiovascular, infection, and other) in prevalent hemodialysis patients. A total of 2103 patients were initially randomized to treatment and 1068 patients completed the study. All-cause mortality rates and cause-specific mortality rates were not significantly different. There was a significant age interaction on the treatment effect. Only in patients over 65 years of age was there a significant effect of sevelamer in lowering the mortality rate. There was a suggestion that sevelamer was associated with lower overall, but not cardiovascular-linked, mortality in older patients. We suggest that further research is needed to confirm these findings.

Renal hemodynamic effects of nabumetone, sulindac, and placebo in patients with osteoarthritis.

We assessed the effects of nabumetone, sulindac, and placebo on renal function and renal excretion of vasodilatory prostaglandins in older female patients (age >50 years) with osteoarthritis and normal renal function. Using a prospective, crossover design, we compared the effects of nabumetone 2000 mg/d and sulindac 400 mg/d with placebo on glomerular filtration rate (GFR), renal plasma flow (RPF), and urinary excretion of prostaglandin E2 and 6-keto-prostaglandin F1alpha in 12 patients. Urinary excretion of vasodilatory prostaglandins was not decreased after 14 days of treatment with either nabumetone or sulindac. Likewise, treatment with nabumetone or sulindac did not significantly alter renal function compared with placebo. There were no differences in mean changes in GFR or RPF from baseline after treatment with nabumetone or sulindac compared with placebo. The mean (+/- SD) changes in GFR from baseline were 0%+/-8% in patients receiving nabumetone, -8%+/-15% in patients receiving sulindac, and -7%+/-15% in patients receiving placebo. The results of this study demonstrate that treatment with nabumetone or sulindac caused no deterioration in renal function in older female patients with osteoarthritis and normal renal function.

Hypertension and renal disease in Puerto Ricans.

Hypertension and end-stage renal disease (ESRD) constitute a major health threat to Puerto Ricans in the United States and in the Commonwealth. In the Hispanic population of the United States, Puerto Ricans seem to have a worse health status than Mexican- and Cuban Americans. Poverty, language, and lack of education increase the risk of less-than-adequate diagnosis and treatment of hypertension. In the Commonwealth, hypertension is a common problem. Deaths caused by heart disease continue to increase on the island. Although the health care system in Puerto Rico continues to improve, changes in diet, increased social stress, and the high prevalence of diabetes mellitus and obesity may add to the increased death rate from cardiovascular causes. The incidence and prevalence of ESRD in Puerto Rico is as high as in the United States; however, diabetes mellitus seems to be the primary diagnosis in a larger number of patients with ESRD than in the U.S. Preventive and control measures must be urgently taken by public health officials to minimize the impact of these disorders in the health of Puerto Ricans.

Altered lens short-circuit current in adult cataract-prone Dahl hypertensive rats.

We assessed components of lenticular short-circuit current in adult hypertensive Dahl salt-sensitive rats (DS) during chronic control (0.4% sodium) versus high (3% sodium) dietary NaCl intake begun at the age of 4 weeks until rats were studied. We also evaluated the influence of barium, a potassium channel blocker, and ouabain, a specific inhibitor of Na+, K(+)-ATPase activity, by adding them to the anterior lens surface, thus measuring barium-sensitive, ouabain-sensitive, and barium- and ouabain-in-sensitive short-circuit currents. During control NaCl intake, short-circuit current in DS and their control group, Dahl salt-resistant rats (DR), did not differ significantly. DS were subclassified into cataract-prone rats and rats unlikely to develop cataracts on the basis of their initial pressor response to the change from a normal to high NaCl diet during the first weeks of age. Although only transparent lenses were studied, total lens short-circuit current was already markedly decreased in the cataract-prone subgroup compared with DS unlikely to develop cataracts and control DR. This was in sharp contrast to the increase in short-circuit current previously reported in Sprague-Dawley rats and now observed in control DR in response to high dietary NaCl. The decrease in lens short-circuit current in cataract-prone rats was associated with lower absolute values of barium- and ouabain-sensitive short-circuit currents as well as with low barium- and ouabain-insensitive short-circuit current. Although the barium- and ouabain-sensitive components of the short-circuit current were similar in DS unlikely to develop cataracts and DR, the barium- and ouabain-insensitive component of the short-circuit current was lower in DS unlikely to develop cataracts than values in DR. Interestingly, this component of lens short-circuit current also increased in DR during chronic high NaCl, whereas the opposite change occurred in cataract-prone DS and DS unlikely to develop cataracts. Thus, the barium- and ouabain-insensitive short-circuit current may be a mechanism that protects the normal lens from developing cataracts. Possible candidates for this short-circuit current component are voltage-dependent potassium channels, calcium-activated potassium channels, or both. Our studies show altered lens short-circuit current in response to high NaCl intake in cataract-prone DS and suggest the possibility of altered lens potassium transport during sustained hypertension but before loss of lens transparency.

Increased dietary NaCl intake influences lens transport properties in Sprague-Dawley rats.

Several years ago, we reported a high frequency of cataracts in Dahl salt-sensitive rats (DS) which led us to carry out a series of studies, such as longitudinal ouabain-sensitive lens 86Rb uptake measurements. Yet, throughout all of our work, we used the Dahl salt-resistant rat (DR) as our control group, despite the fact that DR is a strain resistant to even experimental hypertension such as that resulting from renal cellophane wrapping. Thus, in the present study we assessed lens short-circuit current (Isc) in adult Sprague-Dawley rats (SD) from which DS and DR were derived. Sprague-Dawley rats were studied during chronic normal vs high NaCl intake. These studies showed that basal Isc and calculated translenticular potential difference (PDt) were nearly doubled by this dietary regimen. Sequential addition of BaCl2 and ouabain to the isolated lens anterior surface bath also revealed increased BaCl2-sensitive as well as BaCl2- and ouabain-insensitive lens Isc in SD kept on a high NaCl diet. There was a statistically insignificant tendency for lens ouabain-sensitive Isc to increase in SD given a high NaCl diet. These findings were unrelated to levels of arterial blood pressure which were not altered by chronic high NaCl intake in adult SD. Our data suggest the possibility of increased lens barium and ouabain insensitive ionic permeabilities combined with possibly increased lens fiber potassium concentration, as a response to chronic high dietary NaCl in the normal rat. The nature of the barium and ouabain insensitive component of the lens Isc that rises during chronic high NaCl intake requires elucidation.(ABSTRACT TRUNCATED AT 250 WORDS)

Hypertension in Hispanic Americans.

BACKGROUND: People of Hispanic origin constitute a fast-growing segment of the US population. OBJECTIVE: To review the incidence and prevalence of hypertension in Hispanic Americans. SUMMARY: Some 22.4 million Hispanics live in the United States, but they are not a homogeneous group: Puerto Ricans appear to have a worse health status than Mexicans and Cubans, but different studies have yielded conflicting results. Only approximately half of hypertensive Hispanic Americans know that they have high blood pressure, and only approximately one fourth of these have their blood pressure under control. The prevalence of hypertension among Hispanic Americans falls between that of blacks and non-Hispanic whites, but appears to increase with the process of acculturation. In addition, the prevalence of hypertension and other cardiovascular risk factors increases with decreasing socioeconomic status. Although cardiovascular mortality is declining in the US population at large, it is declining more slowly for Hispanics than it is for blacks and non-Hispanic whites. CONCLUSIONS: Hypertension is a major health threat in the Hispanic community. Barriers to care posed by poverty, language, and lack of education increase the risk of less-than-adequate diagnosis and treatment.

Deoxycorticosterone hypertension in the intact weanling rat without salt loading.

Deoxycorticosterone (DOC) hypertension in the rat is generally induced in rats at an age of approximately 3 months. Both uninephrectomy and a high sodium diet are necessary, however, to induce DOC hypertension. Considering the inability of the developing kidney to adequately excrete a sodium load, we studied the possibility that DOC alone might induce hypertension when treatment is initiated in rats at the age of 21 days. The contribution of volume expansion as a factor mediating the pressor response to DOC was assessed in rats given a high sodium diet instead of DOC. Systolic blood pressure increased in DOC-treated rats within 3 weeks. Although systolic blood pressure also increased in rats on a high sodium diet, the increase was transient and of a lesser magnitude than that observed in DOC-treated rats. The rise in blood pressure in both groups of rats was associated with suppression of plasma renin activity and aldosterone concentration. Furthermore, extracellular fluid volume was similarly increased in DOC-treated rats and rats given a high sodium diet. Consistent with these data, DOC-treated rats showed an exaggerated natriuretic response to acute saline loading as compared with a vehicle-treated control group. Discontinuation of DOC treatment after 5 weeks led to normalization of all variables studied including blood pressure. Yet, when DOC was continued for 8 weeks, stopping treatment did not lower blood pressure despite normalization of the renin-angiotensin-aldosterone system and the natriuretic response to saline loading. In contrast, discontinuation of the high sodium diet after 8 weeks normalized blood pressure.(ABSTRACT TRUNCATED AT 250 WORDS)

Lenticular rubidium uptake and plasma renin activity in weanling cataract-prone salt-sensitive rats.

Our earlier studies of cataracts in Dahl salt-sensitive (DS) rats suggested the possibility of altered lens ion transport as a contributing factor in cataractogenesis in this genetic model. We also observed that those weanling DS rats with the greatest pressor response to a high salt diet eventually developed cataracts, and that changes in salt intake modified cataract formation. In the present studies, we measured lens 86Rb uptake as an index of sodium-potassium adenosine triphosphatase [(Na+,K+)-ATPase] activity in weanling DS rats before the development of cataracts or sustained hypertension. Additionally, plasma renin activity was measured to indirectly assess our hypothesis that the difference between cataract-prone DS rats and DS rats unlikely to develop cataracts might be a difference in degree of salt sensitivity. At the age of 4 weeks, 50 DS and 25 salt-resistant (DR) rats were given a high sodium diet for 2 weeks, at which time the rats were divided into three groups based on the systolic blood pressure response, that is, cataract-prone DS rats with systolic blood pressure equal to or greater than 155 mm Hg, DS rats unlikely to develop cataracts with systolic blood pressure less than or equal to 125 mm Hg, and DR rats. Lens and aqueous humor Na+ and K+, lens dry weight, and water content were not significantly different among the three groups of weanling rats. Plasma renin activity was lowest in cataract-prone DS rats and low in DS rats unlikely to develop cataracts when compared with values in DR rats.(ABSTRACT TRUNCATED AT 250 WORDS)

Prevention and reversal of cataracts in genetically hypertensive rats through sodium restriction.

We previously described the Dahl salt-sensitive rat as a potential model of cataractogenesis in which cataract formation is associated with hypertension. Cataractous lesions were characterized by a marked lenticular and aqueous humor electrolyte imbalance. In the present study the effects of chronic dietary sodium restriction on cataract formation were evaluated in salt-sensitive rats to determine whether or not modification of the hypertensive process might reduce the incidence of cataracts in this genetic model. In addition, the possibility that early cataractous lesions in adult hypertensive salt-sensitive rats might be reversed by acute sodium restriction was evaluated. Chronic dietary sodium restriction modified the development of hypertension and prevented cataract formation in salt-sensitive rats. Furthermore, acute dietary sodium restriction (1 week) completely and consistently reversed early cataractous lesions (pinpoint opacities) in adult hypertensive salt-sensitive rats. Both the prevention and reversal of cataracts were associated with normalization of the lenticular and aqueous humor parameters measured. These data suggest that cataractogenesis is not the consequence of sustained arterial hypertension, but rather that initiation of both hypertension and cataract formation in this genetic model may be the result of extracellular fluid volume state.

A new model of genetic hypertension in rats with superficial glomeruli.

Despite renal involvement in the genesis of hypertension, the precise renal hemodynamic events prior to and during development of hypertension have not been obtainable by direct study in the available rat models of genetic hypertension. We have developed a model of genetic salt-sensitive hypertension in rats with superficial glomeruli, using the protocol described by Dahl to develop the Brookhaven model. Adult Munich Wistar rats were purchased from Charles River and bred in our laboratory. Offspring were allowed to mature without intervention. Systolic blood pressure and body weight were measured weekly to determine the normal longitudinal changes with increasing age for this strain. Balance studies were also carried out longitudinally, and during these studies plasma renin activity (PRA) was determined. When the rats were 16 weeks old, the availability of superficial glomeruli was assessed under microscopic examination and only those rats with numerous superficial glomeruli/field were mated. The offspring of these breeders were used as the zero generation (F0) of salt-sensitive rats, and were treated as described by Dahl. Systolic blood pressure, body weights and balance studies were carried out in this and in all subsequent generations. Sibling breeding was maintained and rats were bred for salt-sensitivity (systolic blood pressure greater than 155 mmHg at the age of 2 months) and availability of superficial glomeruli. Those rats with systolic blood pressure of less than 120 mmHg were bred in an attempt to develop a salt-resistant strain, and untreated Munich Wistar rats were bred to provide another control.(ABSTRACT TRUNCATED AT 250 WORDS)

Lenticular rubidium uptake in hypertensive 'cataract-prone' salt-sensitive rats.

We have previously reported a high incidence of cataract formation in adult hypertensive salt-sensitive rats, suggesting that hypertension may be an important cataractogenic risk factor. Weanling salt-sensitive rats that eventually developed cataracts showed a marked increase in the pressor response to a high-sodium diet compared to salt-sensitive rats that did not develop cataracts. A lens and aqueous fluid electrolyte imbalance occurred in all adult salt-sensitive rats examined, but was greater in the salt-sensitive rats that developed cataracts, suggesting an alteration in lens and/or ciliary ion transport in cataracts associated with hypertension. In the present study, lens 86Rb uptake was measured in adult hypertensive salt-sensitive rats prior to cataract formation. 'Cataract-prone' salt-sensitive hypertensive rats (increased pressor response to a high sodium diet given at weanling age), salt-sensitive hypertensive rats unlikely to develop cataracts and control salt-resistant rats were studied at the age of 16 weeks. Total and ouabain-insensitive lens 86Rb uptake were measured for the determination of ouabain-sensitive uptake, an index of Na+,K+-ATPase activity. Lens ouabain-sensitive 86Rb uptake was low in adult hypertensive cataract-prone salt-sensitive rats before cataract formation compared with values in control resistant rats. Intermediate values were observed in hypertensive salt-sensitive rats unlikely to develop cataracts. These data suggest that altered ion transport may play a pivotal role in cataractogenesis associated with this model of hypertension. The data are also consistent with the concept of a generalized defect in epithelial ion transport, at least in salt-sensitive hypertension.

Pathogenesis of systemic hypertension and glomerular injury in the spontaneously hypertensive rat.

Weanling and young spontaneously hypertensive rats (SHRs) demonstrate higher plasma renin activity and plasma aldosterone concentration than age-matched normotensive Wistar-Kyoto (WKY) control rats. In addition, this age group exhibits a salt-retaining tendency not seen in WKYs. Nevertheless, when they reach adulthood, these differences between SHRs and WKYs are all but abolished, yet hypertension persists in SHRs. The possible mechanisms leading to these changes in SHRs and to the differences seen with advancing age are discussed. Results of micropuncture studies that help elucidate the glomerular hemodynamic adaptations to elevation in systemic blood pressure in young SHRs are also presented. Evidence is advanced suggesting that increased intraglomerular pressure is responsible for the histologic lesions characteristic of untreated severe hypertension. The salutary effects of treatment with vasodilator drugs that reduce intraglomerular pressure are emphasized.

Cataracts and hypertension in salt-sensitive rats. A possible ion transport defect.

In previous unrelated studies, we observed a 35 to 50% incidence of cataract formation in several groups of Dahl salt-sensitive hypertensive rats (DS) over a 4-year period. In the present study we evaluated longitudinal changes in blood pressure in DS in which cataracts eventually developed and those in which cataracts did not develop when all animals were maintained on a high sodium diet. Lenses were evaluated by slit-lamp microscopy to determine if cataractous lesions were similar among rats, to classify lesion types, and to define the age at which cataracts were detectable in DS. The possible participation of several cataractogenic risk factors as major influences on cataract formation also was evaluated. Finally, aqueous humor concentrations and lenticular content of sodium and potassium were determined to evaluate the possibility that a defect in ion transport at the lens epithelium and ciliary body might play a role in cataractogenesis in DS, since ion transport defects have been shown to lead to lens opacification in other models of genetic and experimental cataracts. Parallel studies were performed in Dahl salt-resistant control rats (DR). A high incidence of cataract formation was found in DS. Although systolic blood pressure was not consistently greater in adult DS with cataracts compared with values in age-matched DS without cataracts, the initial pressor response to a high salt diet was greatest in weanling DS in which cataractous lesions later developed. Slit-lamp analysis revealed that cataracts in this genetic model were cortical, with one mixed cortical, nuclear lesion. Posterior subcapsular lesions were not observed, suggesting that lesions were not steroid-induced.(ABSTRACT TRUNCATED AT 250 WORDS)

High vanadate interferes with the Fiske-Subbarow determination of inorganic phosphate.

We evaluated the possibility that oxyions of vanadium might react with molybdate and, in that manner, interfere with the Fiske-Subbarow colorimetric determination of inorganic phosphate. Phosphate (Pi) standard curves were prepared (0.03-0.30 mumole/ml) in the presence and absence of oxyvanadium solutions (2 X 10(-4) M) prepared from ortho- and metavanadate. Molybdate prepared in 5 N sulfuric acid was added to each standard. Upon addition of a reducing agent to develop color of the phosphomolybdate complex, a less intense color was observed at any given Pi concentration in the presence of oxyvanadium species. The slope of the regression line for the Pi standard curve in the presence of 2 X 10(-4) M oxyvanadium species was markedly depressed. The effect of oxyvanadium was similar when solutions were prepared from ortho- and metavanadate, despite differences in pH of these solutions. In addition, in the final reaction the pH was similar in the presence and absence of oxyvanadium, independent of the source of vanadate used to prepare solutions. Thus, interference by oxyvanadium did not appear to be related to changes in pH of samples containing vanadium oxyions. Interference was concentration dependent and the minimal concentration of vanadium oxyions that interfered was 5 X 10(-5) M. The effects of oxyvanadium (2 X 10(-4) M) on Mg+2-dependent and Na+-K+-ATPase activities in a renal microsomal preparation were then evaluated through the measurement of inorganic phosphate generation. Enzyme activities were determined with and without correction for interference by oxyvanadium with the method of Fiske and Subbarow. A significant artifactual depression of Mg+2 ATPase activity, but not Na+-K+-ATPase activity, was consistently observed when enzyme activities were not corrected for interference by oxyvanadium with the measurement of inorganic phosphate. These data indicate that when effects of high vanadate concentrations (5 X 10(-5) M) on ATP hydrolyzing enzymes are evaluated through changes in Pi generation, artifactual depression of enzyme activity may occur.

Renal Na+-K+-ATPase in weanling and adult spontaneously hypertensive rats.

The interrelationships among plasma renin activity (PRA, ng AI/ml plasma/hr), aldosterone concentration (ng%), and renal Na+-K+-ATPase activity (mumole PO4/mg protein/hr) were studied in 9 weanling normotensive spontaneously hypertensive rats (SHR), 9 adult hypertensive SHR, and 9 weanling and 9 adult normotensive Wistar-Kyoto rats (WKY). All groups were placed on a normal (0.4% sodium) diet. PRA and plasma aldosterone, measured in samples drawn from the ether-anesthetized rat, were higher in weanling SHR (15.2 +/- 2.0, 37 +/- 4.2) than in WKY. PRA measured in samples collected from a separate group of unanesthetized weanling SHR was also greater than in age-matched WKY. In adult SHR, PRA (6.1 +/- 0.9) and plasma aldosterone (20.0 +/- 2.7) were decreased. During the weanling period Na+-K+-ATPase activity in SHR was not only greater than in age-matched WKY but was also increased compared to adult normotensive and hypertensive rats (137 +/- 9 weanling SHR, 89 +/- 7 weanling WKY, 73 +/- 11 adult SHR, 84 +/- 17 adult WKY). Thus, during the weanling period the renin-angiotensin-aldosterone (R-A-A) system and renal Na+-K+-ATPase activity are activated in SHR. The elevation of Na+-K+-ATPase activity may be due to increased aldosterone levels. It was noted, however, that plasma aldosterone was similar in adult WKY and weanling SHR, while Na+-K+-ATPase activity was higher in SHR. These findings involving R-A-A and renal Na+-K+-ATPase activity prior to the elevation of blood pressure suggest that the kidneys may play a role in the initiation of hypertension in SHR.

Circadian rhythms of plasma renin levels in the anesthetized rat.

Circadian rhythms of plasma renin activity (PRA) is described in the ether anesthetized rat. PRA values are significantly higher than corresponding values previously reported in the awake rat. Peak activity was observed at 12.00 and 16.00 h, similar to the pattern of diurnal rhythm established in the conscious rat. The reproducibility of PRA in the anesthetized rat is demonstrated by relatively constant values obtained from a separate group of rats bled at the same hour every other week. In addition, each sample was also incubated with excess renin substrate for the determination of relative plasma renin concentration (PRC). The pattern obtained for PRC is similar to that of PRA, indicating that the circadian rhythms result from variations of plasma renin rather than changes in renin substrate. Furthermore, although ether anesthesia raises the basal levels of PRA, it does not interfere with the demonstration of the normal pattern of circadian rhythms.