Effect of eplerenone on blood pressure and the renin-angiotensin-aldosterone system in oligo-anuric chronic hemodialysis patients - a pilot study.

INTRODUCTION AND AIMS: Recent studies have suggested that aldosterone has many effects in addition to its ability to cause the kidney to retain sodium. To test the hypothesis that aldosterone can cause hypertension in a manner that does not involve renal sodium retention, we administered eplerenone, a specific aldosterone antagonist, to oligo-anuric chronic hemodialysis patients who had HTN. METHODS: 220 chronic hemodialysis patients underwent initial screening. Of these, 8 patients were followed for 8 weeks and their blood pressure, weight, plasma potassium, aldosterone levels and plasma renin activity were recorded. After a 4 week run in period, each patient received eplerenone 25 mg twice daily for another 4 weeks. RESULTS: Administration of eplerenone for 4 weeks decreased predialysis systolic blood pressure from 166 ± 14 to 153 ± 10 mmHg (p < 0.05). Eplerenone had no effect on diastolic blood pressure, potassium, predialysis weight, intradialytic weight gain, plasma aldosterone or PRA. CONCLUSION: Eplerenone significantly reduces systolic blood pressure in oligo-anuric hypertensive hemodialysis patients without effect on plasma aldosterone concentrations or plasma renin activity. Plasma potassium increases minimally after 4 weeks of therapy, a finding that raises some concern for long-term eplerenone use in chronic hemodialysis.

High dose urokinase for restoration of patency of occluded permanent central venous catheters in hemodialysis patients.

BACKGROUND: Catheter thrombosis is common and results in inadequate dialysis treatment and, frequently, in catheter loss. Since dialysis treatment runs on a strict schedule, occluded catheters need to be restored in a timely and cost effective manner. We present a new shortened protocol of urokinase infusion that allows hemodialysis to be performed within 90 minutes. METHODS: To chronic hemodialysis patients, who developed complete catheter occlusion, urokinase was infused simultaneously through both lumens of the catheter (125,000 units to each lumen) over 90 minutes. Technical success was defined as restoring blood pump speed to at least 250 ml/min. We determined the average time from catheter placement to first clot event (primary patency PP), recurrent clot event after urokinase treatment (secondary patency SP), catheter salvage rate and cause for removal. RESULTS: 37 catheters developed total thrombosis and urokinase was used to restore patency one or more times (total 47 treatments). Catheter salvage rate was 97 %. The average time of PP was 152 ± 56 days (7 - 784 days). Nine patients (30%) developed recurrent occlusion and the average time of SP was 64 ± 34 days (2 - 364 days). One catheter was removed because of dysfunction due to thrombosis. Other catheters were removed due to infection, fistula maturation or fell out spontaneously. Hemodialysis was performed immediately after treatment with blood speed of 250 ml/min in all patients. CONCLUSION: Our protocol is highly effective, short, and allows to restore patency of totally occluded central venous catheters with minimal disruption of the dialysis session.

EGF inhibits muscarinic receptor-mediated calcium signaling in a human salivary cell line.

The effects of epidermal growth factor (EGF) on intracellular calcium ([Ca(2+)](i)) responses to the muscarinic agonist carbachol were studied in a human salivary cell line (HSY). Carbachol (10(-4) M)-stimulated [Ca(2+)](i) mobilization was inhibited by 40% after 48-h treatment with 5 x 10(-10) M EGF. EGF also reduced carbachol-induced [Ca(2+)](i) in Ca(2+)-free medium and Ca(2+) influx following repletion of extracellular Ca(2+). Under Ca(2+)-free conditions, thapsigargin, an inhibitor of Ca(2+) uptake to internal stores, induced similar [Ca(2+)](i) signals in control and EGF-treated cells, indicating that internal Ca(2+) stores were unaffected by EGF; however, in cells exposed to thapsigargin, Ca(2+) influx following Ca(2+) repletion was reduced by EGF. Muscarinic receptor density, assessed by binding of the muscarinic receptor antagonist L-[benzilic-4,4'-(3)HCN]quinuclidinyl benzilate ([(3)H]QNB), was decreased by 20% after EGF treatment. Inhibition of the carbachol response by EGF was not altered by phorbol ester-induced downregulation of protein kinase C (PKC) but was enhanced upon PKC activation by a diacylglycerol analog. Phosphorylation of mitogen-activated protein kinase (MAP kinase) and inhibition of the carbachol response by EGF were both blocked by the MAP kinase pathway inhibitor PD-98059. The results suggest that EGF decreases carbachol-induced Ca(2+) release from internal stores and also exerts a direct inhibitory action on Ca(2+) influx. A decline in muscarinic receptor density may contribute to EGF inhibition of carbachol responsiveness. The inhibitory effect of EGF is mediated by the MAP kinase pathway and is potentiated by a distinct modulatory cascade involving activation of PKC. EGF may play a physiological role in regulating muscarinic receptor-stimulated salivary secretion.

Predicting HIV disease progression in children using measures of neuropsychological and neurological functioning. Pediatric AIDS clinical trials 152 study team.

BACKGROUND: Neuropsychological testing and 2 measures of neurological status, cortical atrophy, and motor dysfunction were assessed for their usefulness in predicting human immunodeficiency virus (HIV) disease progression in infants, children, and adolescents who participated in Pediatric AIDS Clinical Trials Group Protocol 152 (PACTG 152). METHODS: A cohort of 722 antiretroviral therapy-naive children with symptomatic HIV infection were assessed at study entry and at later intervals. Assessments included neurodevelopmental testing, neuroradiologic imaging, and neurological examination of motor function. CD4 cell count and plasma RNA viral load also were measured. RESULTS: Children with the lowest neuropsychological functioning (IQ < 70) at baseline had the highest risk for later HIV disease progression (56%), compared with those with borderline/low (IQ = 70-89) functioning (26%), or with average or above (IQ > 90) functioning (18%). This was also true of week 48 neuropsychological functioning. Motor dysfunction (especially reduced muscle mass) at entry also predicted disease progression. Furthermore, motor dysfunction and week 48 neuropsychological functioning provided predictive information beyond that obtainable from surrogate markers of HIV disease status (eg, CD4 count, HIV RNA level). Children with cortical atrophy also were at higher risk for later disease progression, but when CD4 count and RNA viral load were known, cortical atrophy information provided no additional predictive information. CONCLUSIONS: Measures of neuropsychological and motor function status provide unique information regarding pediatric HIV disease progression. As such, these findings have important implications for predicting long-term outcomes (eg, longevity) in pediatric patients.

Neurologic, neurocognitive, and brain growth outcomes in human immunodeficiency virus-infected children receiving different nucleoside antiretroviral regimens. Pediatric AIDS Clinical Trials Group 152 Study Team.

OBJECTIVES: To compare the impact of three different nucleoside reverse transcriptase inhibitor regimens, zidovudine (ZDV) monotherapy, didanosine (ddI) monotherapy, and ZDV plus ddI combination therapy, on central nervous system (CNS) outcomes in symptomatic human immunodeficiency virus (HIV)-infected children. METHODS: Serial neurologic examinations, neurocognitive tests, and brain growth assessments (head circumference measurements and head computed tomography or magnetic resonance imaging studies) were performed in 831 infants and children who participated in a randomized double-blind clinical trial of nucleoside reverse transcriptase inhibitors. The Pediatric AIDS Clinical Trials Group study 152 conducted between 1991 and 1995 enrolled antiretroviral therapy-naive children. Subjects were stratified by age (3 to <30 months of age or 30 months to 18 years of age) and randomized in equal proportions to the three treatment groups. RESULTS: Combination ZDV and ddI therapy was superior to either ZDV or ddI monotherapy for most of the CNS outcomes evaluated. Treatment differences were observed within both age strata. ZDV monotherapy showed a modest statistically significant improvement in cognitive performance compared with ddI monotherapy during the initial 24 weeks, but for subsequent protection against CNS deterioration no clear difference was observed between the two monotherapy arms. CONCLUSIONS: Combination therapy with ZDV and ddI was more effective than either of the two monotherapies against CNS manifestations of human immunodeficiency virus disease. The results of this study did not indicate a long-term beneficial effect for ZDV monotherapy compared with ddI monotherapy.

Modulation by food restriction of intracellular calcium signaling in parotid acinar cells of aging Fischer 344 rats.

Previous studies suggest that alpha 1-adrenergic (alpha 1-AR)-induced intracellular calcium ([Ca2+]i) mobilization in rat parotid acinar cells declines with age. In this study, we examined the effects of food restriction on alpha 1-AR and muscarinic-stimulated [Ca2+]i mobilization in parotid acinar cells during aging. [Ca2+]i levels in response to the alpha 1-AR agonist epinephrine and the muscarinic agonist carbachol were evaluated in Fura-2-loaded parotid acinar cells from ad libitum-fed (AL) and food-restricted (FR) Fischer 344 male rats at 4, 6, 14, and 24 months of age. [Ca2+]i responses to epinephrine and carbachol (10 microM) were significantly reduced (48% and 35%, respectively; p < .05) in cells from 24-month-old AL rats as compared to younger AL rats. In contrast, no significant reduction of epinephrine and carbachol responses was observed in 24-month-old FR animals. An age-related increase in basal [Ca2+]i (peak around 14 months; p < .02) was observed in both AL and FR rats. In addition, basal [Ca2+]i was higher in FR than in AL rats at 14 and 24 months of age (p < .02). These studies suggest that FR partially attenuates or delays age-related impairments in alpha 1-AR- and muscarinic-cholinergic signal transduction systems of parotid acinar cells. Basal [Ca2+]i also appears to be altered during aging and by FR.

Clinical and laboratory characteristics of a large cohort of symptomatic, human immunodeficiency virus-infected infants and children. AIDS Clinical Trials Group Protocol 152 Study Team.

BACKGROUND: A large cohort of antiretroviral therapy-naive, symptomatic, HIV-infected children were enrolled into a controlled therapeutic trial (AIDS Clinical Trials Group Protocol 152), providing an opportunity to describe their clinical and laboratory characteristics and determine age-related distinctions. METHODS: Study entry evaluations for 838 of 839 enrolled children were analyzed. Weight, head circumference (if < 30 months of age), neuroradiologic imaging of the head, developmental or cognitive status and neurologic examination were assessed. Laboratory studies included hemoglobin, absolute neutrophil count, CD4 cell count, serum amylase, alanine aminotransaminase, p24 antigen and HIV blood culture. Data were categorized by age (3 to < 12 months, 12 to < 30 months, 30 months to 6 years and > or = 6 years). RESULTS: Younger children had significantly higher rates of abnormalities before antiretroviral therapy, especially factors relating to growth and neurologic or cognitive function. Lower CD4+ cell counts and percentages as well as a positive serum p24 antigen correlated with lower weight-for-age Z scores and developmental indices. CONCLUSIONS: These data provide a description of the clinical characteristics of HIV-infected US children at the time antiretroviral therapy is initiated for HIV-related symptoms. The high rate of abnormalities of growth, development and cognitive ability that were observed in children < 30 months of age demonstrates that treatment strategies should be developed for earlier intervention.

Protein kinase C differentially modulates PTH- and PGE2-sensitive adenylate cyclase in osteoblast-like cells.

The effects of phorbol 12-myristate 13-acetate (PMA), a known activator of protein kinase C, on receptor-mediated stimulation of adenylate cyclase were evaluated in a rat osteosarcoma cell line (UMR-106) with the osteoblast phenotype. Pretreatment of UMR-106 cells with PMA increased parathyroid hormone (PTH)-stimulated adenylate cyclase activity and inhibited prostaglandin E2 (PGE2)-responsive enzyme activity. In addition, PMA enhanced enzyme activation by forskolin, which is thought to exert a direct stimulatory action on the catalytic subunit of adenylate cyclase. The regulatory effects of PMA were concentration dependent and of rapid onset (less than or equal to 1 min). Treatment with PMA also resulted in translocation of protein kinase C activity from the cytosol to the particulate cell fraction. Pertussis toxin, which attenuates inhibition of adenylate cyclase mediated by the inhibitory guanine nucleotide-binding regulatory protein (Gi), augmented PTH-sensitive adenylate cyclase activity and reduced the incremental increase in PTH response produced by PMA. The results suggest that activation of protein kinase C increases PTH-stimulated adenylate cyclase activity by actions on Gi and/or the catalytic subunit and decreases PGE2 responsiveness by a mechanism involving the PGE2 receptor.

An exploratory study of the structure and validity of pediatric examination of educational readiness (PEER) factors.

The Pediatric Examination of Educational Readiness (PEER) is an assessment instrument specifically designed for use by pediatricians in assessing the development of preschool children. The present study investigated the psychometric properties of the PEER. Specifically, factor analyses of items from the Developmental Attainment and Associated Observation components of the test were performed. The PEER was administered to 69 preschool children. Three major factors were identified as making up the Developmental Attainment portion of the test: perceptual-motor, verbal-cognitive, and gross motor. The Associated Observations component was found to be composed of only one factor, attention. Children's performance on only two of these four factors was associated with their performance on the McCarthy Scales, the Woodcock-Johnson skills cluster, and the Minnesota Child Development Inventory. Discussion focused on the validity and utility of the PEER.

Nonhandicapped very-low-birth-weight infants at one year of age: developmental profile.

The developmental profile of 61 very-low-birth-weight infants without major cognitive, motor, or sensory deficits was compared with that of 28 term infants at 1 year chronologic age. The groups significantly differed in two ways on the Revised Gesell Developmental Schedules. First, very-low-birth-weight infants were more likely than term infants to have significant discrepancies between either their fine motor or language abilities and their early problem-solving skills as measured by the Adaptive scale of the Gesell. Second, across all fields of behavior (adaptive, gross motor, fine motor, language, and personal/social), very-low-birth-weight infants scored significantly below term infants. The very-low-birth-weight infant's motor performance significantly correlated with bronchopulmonary dysplasia, intracranial hemorrhage, and number of days spent in the hospital. Language performance significantly correlated with intracranial hemorrhage, birth weight, and sex. These findings underscore the limitations of global developmental scores to describe adequately the developmental performance of very-low-birth-weight infants. Instead, a comprehensive assessment of all fields of behavior is necessary to provide an accurate profile of this high-risk group.

Monoclonal antibody ELISA for cotinine in saliva and urine of active and passive smokers.

The value of a monoclonal antibody-based ELISA for measuring cotinine in saliva and urine of active and passive smokers was assessed. Cotinine (mean +/- SEM) was detected in all 26 saliva (392 +/- 74 ng/ml) and 27 urine (4264 +/- 508 ng/mg creatinine; 2566 +/- 364 ng/ml) samples from smoking parents, but in only two of 36 salivas and one of 37 urines from nonsmokers (P less than 0.001). Similarly, mean cotinine levels in 30 salivas (4.67 +/- 1.10 ng/ml) and 33 urines (35.5 +/- 8.8 ng/mg creatinine; 25.3 +/- 8.1 ng/ml) from passively exposed children were significantly higher (P less than 0.001) than in fluids of 36 unexposed children. Children's levels showed a strong correlation (P less than 0.001) with the number of cigarettes smoked in the home, but only when data from nonsmoking households were included in the analysis. In adult smokers there was a positive correlation between salivary and urinary cotinine (P = 0.002) and a close relationship between urinary cotinine and cigarettes smoked per day (P = 0.066). The ELISA gives a reliable quantitative measure of cotinine as an indicator of active and passive exposure to tobacco smoke. However, correlations with cotinine can be overestimated if large numbers of nonsmokers are included in the comparison.

B2-microglobulin and associated amyloidosis presenting as bilateral popliteal tumors.

Chronic hemodialysis has led to the prolongation of life in many patients with end-stage renal disease, but has also allowed for the development of new diseases that are a consequence of this clinical setting. B2-microglobulin accumulation leading to systemic amyloidosis may be the most recent disease in this category. This case report documents the development of bilateral popliteal tumors in a patient undergoing chronic hemodialysis for 9 years. Removal of one of the tumors and pathological examination demonstrated amyloid that was positive for B2-microglobulin by specific antibody testing. This case adds further support to the suggestion that B2-microglobulin amyloidosis in chronic hemodialysis patients is truly a systemic disorder. The development of popliteal tumors, particularly in proximity to joints, in a chronic hemodialysis patient, must include amyloidosis in the differential diagnosis.

Prostaglandins and the urinary concentrating defect in potassium-depleted rabbits.

Urinary prostaglandin E (UPGE) excretion increased significantly after 1 and 2 wk of potassium depletion (KD) in female New Zealand White rabbits on ad libitum water intake [UPGE control, 21.3 +/- 4.6 ng PGE/mg creatinine; 1 wk KD, 40.4 +/- 6.1 ng PGE/mg creatinine (P less than 0.01); 2 wk KD, 31.9 +/- 14.9 ng PGE/mg creatinine (P less than 0.05)]. In vivo prostaglandin inhibition with indomethacin or meclofenamate significantly increased urinary osmolality after 12 h of dehydration and exogenous vasopressin (1.25 U) from 794 +/- 59 to 1,163 +/- 113 mosmol/kgH2O (P less than 0.01). In vitro prostaglandin inhibition with indomethacin or meclofenamate corrected the antidiuretic hormone (ADH) unresponsiveness of isolated perfused cortical collecting tubules (CCTs) from KD rabbits. Furthermore, preincubation with pertussis toxin, an agent that inactivates the guanine nucleotide inhibitory (Ni) subunit of adenylate cyclase, normalized the ADH response of KD CCTs, suggesting that prostaglandins may attenuate ADH action on the CCT through activation of Ni and contribute to the urinary concentrating defect associated with KD.

Renal eicosanoids as determinants of renal function in liver disease.

The available data suggest that alterations in renal prostaglandin metabolism participate in the pathogenesis of at least two prominent renal complications of liver disease: (a) sodium retention and (b) HRS. Although the data are highly suggestive, additional studies, including experimental manipulations that augment vasodilatory prostaglandins while diminishing vasoconstrictor metabolites of arachidonic acid, will be required to establish the role of prostaglandins or other arachidonic acid metabolites in mediating these renal abnormalities. The clinical caveat emerging from these observations is that every attempt should be made to avoid prescribing drugs which possess cyclooxygenase inhibitory activity to patients with decompensated liver disease who are sodium-avid.

Contribution of AV3V region in anephric NaCl-induced hypertension in the rat.

The role of the anteroventral third ventricle (AV3V) region in mediating hypertonic sodium chloride-induced pressor responses was investigated in conscious rats. Sham- and AV3V-lesioned rats were prepared with femoral artery and vein catheters and subjected to bilateral nephrectomy under gaseous anesthesia. After recovery, animals were infused intravenously with isotonic (0.5 meq/kg) or hypertonic (10 meq/kg) saline at a rate of 0.0103 ml/min over 2 h. Isotonic saline infusion did not affect arterial pressure or heart rate in either group of rats. Hypertonic saline increased arterial pressure 35 +/- 3 mmHg in sham-lesioned rats and only 10 +/- 4 mmHg in AV3V-lesioned animals (P less than 0.0005). Sham-lesioned rats infused with hypertonic saline had a greater vasopressin-dependent component maintaining arterial pressure than the other groups of rats. Conversely, the sympathetic nervous system-dependent component of blood pressure was suppressed in the hypertonic saline-infused sham-lesioned animals compared with the other animals. However, when the vasopressin receptors were blocked, the neurally mediated portion of blood pressure was similar in all four groups of rats. These results emphasize that circulating vasopressin is important for the rise in arterial pressure accompanying the osmotic stimulus. Furthermore, this study demonstrates that the AV3V region is necessary for vasopressin-dependent pressor responses caused by an osmotic stimulus.

Suprofen-related nephrotoxicity. A distinct clinical syndrome.

We describe a unique clinical syndrome of flank pain and acute renal failure that is associated with suprofen, a nonsteroidal anti-inflammatory drug that has recently been made available in the United States. In the initial 6 months of the drug's distribution in this country, at least 16 patients developed this syndrome. All 16 had acute flank pain and 13 developed mild reversible renal failure within 12 hours of ingestion of one to three suprofen capsules. This syndrome is unlike other nephrotoxic syndromes related to nonsteroidal anti-inflammatory drugs. The mechanism is not known.