RESUMEN
We have used homologous recombination to disrupt the mouse gene coding for the NaK2Cl cotransporter (NKCC2) expressed in kidney epithelial cells of the thick ascending limb and macula densa. This gene is one of several that when mutated causes Bartter's syndrome in humans, a syndrome characterized by severe polyuria and electrolyte imbalance. Homozygous NKCC2-/- pups were born in expected numbers and appeared normal. However, by day 1 they showed signs of extracellular volume depletion (hematocrit 51%; wild type 37%). They subsequently failed to thrive. By day 7, they were small and markedly dehydrated and exhibited renal insufficiency, high plasma potassium, metabolic acidosis, hydronephrosis of varying severity, and high plasma renin concentrations. None survived to weaning. Treatment of -/- pups with indomethacin from day 1 prevented growth retardation and 10% treated for 3 weeks survived, although as adults they exhibited severe polyuria (10 ml/day), extreme hydronephrosis, low plasma potassium, high blood pH, hypercalciuria, and proteinuria. Wild-type mice treated with furosemide, an inhibitor of NaK2Cl cotransporters, have a phenotype similar to the indomethacin-rescued -/- adults except that hydronephrosis was mild. The polyuria, hypercalciuria, and proteinuria of the -/- adults and furosemide-treated wild-type mice were unresponsive to inhibitors of the renin angiotensin system, vasopressin, and further indomethacin. Thus absence of NKCC2 in the mouse causes polyuria that is not compensated elsewhere in the nephron. The NKCC2 mutant animals should be valuable for uncovering new pathophysiologic and therapeutic aspects of genetic disturbances in water and electrolyte recovery by the kidney.
Asunto(s)
Síndrome de Bartter/genética , Proteínas Portadoras/genética , Proteínas de la Membrana/fisiología , Poliuria/etiología , Animales , Síndrome de Bartter/patología , Síndrome de Bartter/fisiopatología , Calcio/orina , Proteínas Portadoras/fisiología , Modelos Animales de Enfermedad , Electrólitos/sangre , Hidronefrosis/genética , Hidronefrosis/fisiopatología , Indometacina/farmacología , Intrones , Riñón/metabolismo , Riñón/patología , Proteínas de la Membrana/deficiencia , Proteínas de la Membrana/genética , Ratones , Ratones Endogámicos , Ratones Noqueados , Poliuria/genética , Poliuria/patología , Potasio/sangre , Regiones Promotoras Genéticas , Proteinuria , Renina/sangre , Simportadores de Cloruro de Sodio-PotasioRESUMEN
We have measured serum aluminium and urinary aluminium/creatinine ratios in 235 aluminium workers and 44 controls to examine the association between occupational exposure to airborne aluminium and aluminium absorption. Serum and urine samples were taken before and after a 3- to 5-day work shift. Occupational exposure was estimated from aluminium measurements of respirable and total particulates in air. Median exposure values were 25 and 100 micrograms m-3, respectively. Serum aluminium and urinary aluminium/creatinine ratios did not change significantly during the shift; however, both pre-shift and post-shift serum aluminium and urinary aluminium/creatinine ratios were increased in the exposed group. Occupational exposure was associated with serum aluminium increments of 1.32 micrograms l.-1 (P = 0.01) pre-shift, and 0.96 micrograms l.-1) (P = 0.08) post-shift. Greater and more significant differences were seen between exposed and controls for the urinary aluminium/creatinine ratios [5.67 micrograms g-1 (P < 0.01) pre-shift; 8.01 micrograms g-1 (P < 0.01) post-shift]. Urinary aluminium/creatinine ratios were greater in plants with higher aluminium exposures. These results are consistent with the systemic absorption of aluminium from occupational exposure and suggest the presence of a sensitive uptake process for airway aluminium.
Asunto(s)
Aluminio/sangre , Aluminio/orina , Metalurgia , Exposición Profesional/análisis , Análisis de Varianza , Creatinina/orina , Femenino , Humanos , MasculinoRESUMEN
Occupational exposure to aluminum can be associated with increases in both urinary aluminum excretion and serum aluminum. In most studies, the increases in urinary aluminum are proportionately greater than the changes in serum aluminum. A similar pattern of response follows increases in dietary aluminum intake. Thus, there is ample evidence for systemic aluminum absorption from occupational exposure to airborne aluminum as well as dietary intake. Although both circumstances are accompanied by a similar renal response, there is little information explaining how normal kidneys augment renal excretion with only trivial changes in serum aluminum concentrations. In addition, it is not understood how airborne exposure to microgram amounts of aluminum produces significant increases in urinary aluminum. The latter observation suggests the presence of a sensitive uptake process for aluminum from airway exposure.
Asunto(s)
Contaminantes Ocupacionales del Aire/farmacocinética , Contaminantes Ocupacionales del Aire/orina , Aluminio/farmacocinética , Aluminio/orina , Contaminantes Ocupacionales del Aire/sangre , Aluminio/sangre , Animales , Humanos , Masculino , RatasRESUMEN
Recent physiologic information concerning the renal response to potassium deprivation has been used to reevaluate potassium wasting in Bartter's syndrome. Experimental patient data support the notion that failure of potassium conservation is due to an imbalance between tubular secretory and reabsorptive processes. Suggestions are presented for the further evaluation of potassium reabsorptive pathways in the distal tubule.
Asunto(s)
Síndrome de Bartter/fisiopatología , Potasio/metabolismo , Síndrome de Bartter/terapia , HumanosRESUMEN
We have compared the renal handling of silicon in 16 patients with renal insufficiency to 14 normal individuals. Silicon, phosphate and creatinine were measured in plasma and urine samples. The renal insufficiency group showed significant increases in plasma silicon (1.28 +/- 0.19 vs. 0.17 +/- 0.03 mg/liter), creatinine (5.19 +/- 0.85 vs. 0.89 +/- 0.03 mg/dl) and phosphate (1.33 +2- 0.11 vs. 1.07 +/- 0.4 mmol/liter). Fractional phosphate excretion was increased in the renal insufficiency group (0.55 +/- 0.07 vs. 0.14 +/- 0.01). In contrast, the fractional excretion of ultrafiltrable silicon was not significantly different between groups (0.78 +/- 0.07 vs. 0.87 +/- 0.06). It is concluded that renal insufficiency does not alter the tubular handling of silicon and that regulatory control of silicon excretion is unlikely.
Asunto(s)
Riñón/metabolismo , Insuficiencia Renal/metabolismo , Silicio/metabolismo , Creatinina/sangre , Femenino , Humanos , Masculino , Fosfatos/metabolismoRESUMEN
Plasma silicon measurements have been obtained in patients with end-stage renal disease on chronic dialysis therapy. The mean +/- SE values for normal plasma silicon concentrations are .15 +/- .02 mg/L. All dialysis groups showed marked elevations in their plasma silicon that correlated with the silicon content of their respective dialysis fluids. The values of two different hemodialysis groups and a peritoneal dialysis group were 4.6 +/- .4, 2.5 +/- .2, and 1.9 +/- 1.2 mg/L, respectively. The silicon content of their respective dialysis fluids were 4.0 +/- .7, 0.5 +/- .4, and 0 +/- .1 mg/L. The ultrafiltrability of plasma silicon through Cuprophane membranes was 79 +/- 2%. Hemodialysis patients drinking high-silicon well water showed significantly higher plasma silicon levels than patients drinking lower silicon municipal water. It is concluded that use of dialysis fluid with elevated silicon levels and the consumption of water containing high concentrations of silicon are two important determinants of silicon levels in a dialysis population. We observed no overt effects of silicon accumulation on the health status of our dialysis patients.
Asunto(s)
Fallo Renal Crónico/sangre , Diálisis Renal , Silicio/sangre , Soluciones para Diálisis/análisis , Femenino , Humanos , Fallo Renal Crónico/terapia , Masculino , Persona de Mediana Edad , Silicio/análisis , Abastecimiento de Agua/análisisAsunto(s)
Alcalosis/patología , Síndrome de Bartter/patología , Calcio/orina , Hipopotasemia/patología , Deficiencia de Magnesio/patología , Diagnóstico Diferencial , Humanos , Aparato Yuxtaglomerular/patología , Enfermedades Renales/patología , Túbulos Renales/patología , Síndrome , Terminología como AsuntoRESUMEN
Swelling-activated [K-Cl] cotransport and shrinkage-activated Na/H exchange were studied in dog red cells with altered internal Mg or Li content. The two pathways responded in a coordinated fashion. When cells were depleted of Mg, [K-Cl] cotransport was stimulated and Na/H exchange was inhibited. Raising internal Mg had the opposite effect: [K-Cl] cotransport was inhibited and Na/H exchange was stimulated. Li loading, previously shown to stimulate Na/H exchange, inhibited [K-Cl] cotransport. From these reciprocal effects and from other evidence, we surmise that the regulation of Na/H exchange and [K-Cl] cotransport is conducted and coordinated by a discrete mechanism that responds to changes in cell volume and is sensitive to cytoplasmic Mg and Li concentrations.
Asunto(s)
Proteínas Portadoras/sangre , Cloruros/sangre , Eritrocitos/metabolismo , Potasio/sangre , Simportadores , Animales , Calcimicina/farmacología , Perros , Cinética , Litio/farmacología , Magnesio/farmacología , Intercambiadores de Sodio-Hidrógeno , Cotransportadores de K ClRESUMEN
The observation of higher plasma flouride levels in our hemodialysis (HD) patients than our continuous ambulatory peritoneal dialysis (CAPD) patients (4.0 +/- 0.5 mumol/L [n = 17] v 2.5 +/- 0.3 mumol/L [n = 17], P less than 0.005) prompted an evaluation of fluoride metabolism during HD. We found that serum fluoride was completely ultrafiltrable across cuprophane membranes (99% +/- 4%) and that HD produced acute changes in plasma fluoride levels that correlated well with the fluoride gradient between plasma and dialysis fluid at the start of dialysis. Our HD fluids contained significantly higher fluoride concentrations than were present in commercially prepared peritoneal dialysis fluid. Our fluids are prepared from fluoridated tap water that is purified by reverse osmosis (RO). We conclude that the different concentrations of fluoride in our dialysis fluids account for the differences in the plasma flouride concentrations between our dialysis groups. Since many HD units rely on RO systems to purify fluoridated tap water, it is likely that many HD patients are being exposed inadvertently to increased concentrations of fluoride.
Asunto(s)
Soluciones para Diálisis/análisis , Fluoruros/sangre , Fallo Renal Crónico/terapia , Diálisis Renal , Femenino , Fluoruración , Fluoruros/análisis , Humanos , Fallo Renal Crónico/sangre , Masculino , Persona de Mediana Edad , Diálisis Peritoneal Ambulatoria ContinuaRESUMEN
An automated procedure for the determination of fluoride in biological fluids that uses silicone-facilitated diffusion at room temperature to separate fluoride from other sample constituents is described. Fluoride is measured by its ability to quench the fluorescence of a morin-thorium complex. The procedure appears to be free of significant interferences and is capable of measuring fluoride in the submicromolar range.
Asunto(s)
Difusión , Fluoruros/análisis , Siliconas , Animales , Flavonoides , Humanos , Reproducibilidad de los Resultados , Soluciones , TorioRESUMEN
Depleting dog red cells of Mg prevents activation of Na-H exchange by cell shrinkage but has no effect on activation by acidification of the cytosol. Replacing cell Mg restores the activation of Na-H exchange by cell shrinking. We conclude that Mg is required, not for the transport process per se, but for the transduction of the volume stimulus.
Asunto(s)
Proteínas Portadoras/sangre , Eritrocitos/metabolismo , Magnesio/fisiología , Amilorida/farmacología , Animales , Calcimicina/farmacología , Perros , Ácido Edético/farmacología , Concentración de Iones de Hidrógeno , Magnesio/farmacología , Concentración Osmolar , Sodio/sangre , Intercambiadores de Sodio-HidrógenoRESUMEN
An improved electrothermal atomic absorption spectrometric method for determination of aluminum in serum is described. An ammonium hydroxide/sulfuric acid diluent is used to control matrix effects from serum constituents. Because serum produces no apparent matrix effects with this diluent, one can accurately calibrate the procedure with aqueous standards.
Asunto(s)
Aluminio/sangre , Aluminio/normas , Matriz Extracelular , Humanos , Espectrofotometría AtómicaRESUMEN
To examine the influence of osteoblast function on aluminum-induced neo-osteogenesis in the mammalian species, we compared the effects of aluminum in sham-operated and thyroparathyroidectomized (TPTX) beagles. TPTX dogs received sufficient calcium carbonate and calcitriol to maintain normal plasma calcium and calcitriol levels, but developed evidence of decreased osteoblast recruitment and activity, including diminished osteoid-covered trabecular bone surface (3.22 +/- 0.21 vs. 10.95 +/- 1.30%) and a decreased osteoblast number (27.8 +/- 8.1 vs. 139.0 +/- 26.0/mm). Administration of aluminum (1.25 mg/kg i.v., three times/wk) increased the serum aluminum levels in both sham (1,087.0 +/- 276.0 vs. 2.7 +/- 0.8 micrograms/liter) and TPTX animals (2,786.0 +/- 569.0 vs. 3.6 +/- 0.8 micrograms/liter) above normal but did not alter the plasma calcium, creatinine, or PTH from control levels in either sham or TPTX dogs. After 8 wk of therapy, however, bone biopsies from sham-operated beagles displayed evidence of neo-osteogenesis including an increased bone volume (47.0 +/- 1.0 vs. 30.4 +/- 0.9%) and trabecular number (4.1 +/- 0.2 vs. 3.2 +/- 0.2/mm). Much of the enhanced volume resulted from deposition of poorly mineralized woven bone (9.9 +/- 2.7%). In contrast, biopsies from aluminum-treated TPTX animals exhibited significantly less evidence of ectopic bone formation. In this regard, bone (35.5 +/- 1.7%) and woven tissue volume (1.4 +/- 0.8%) as well as trabecular number (3.3 +/- 0.1/mm) were significantly less than those of the aluminum-treated controls. These observations illustrate that aluminum reproducibly stimulates neo-osteogenesis and induces a positive bone balance. However, this effect apparently depends on the availability of a functional osteoblast pool which, if depleted by TPTX, limits the expression of aluminum-induced new bone formation.
Asunto(s)
Aluminio/administración & dosificación , Hormona Paratiroidea/fisiología , Animales , Huesos/patología , Recuento de Células , Perros , Inyecciones Intravenosas , Masculino , Osteoblastos/patología , Osteoblastos/fisiología , Osteogénesis , Glándulas Paratiroides/cirugía , TiroidectomíaRESUMEN
This report describes a patient who developed the hemolytic uremic syndrome while undergoing chemotherapy with cisplatin, bleomycin, and vincristine, for metastatic squamous cell cancer of the floor of the mouth. In spite of dialysis and plasmapheresis, the patient died. This complication has rarely been reported in association with cisplatin, bleomycin, or vincristine therapy. The etiology of this syndrome is uncertain but may be related to scleroderma-like endothelial injury and vasospasm caused by bleomycin combination chemotherapy. It is notable that the development of the hemolytic uremic syndrome in conjunction with this combination of agents has been fatal in all patients over the age of 50 with squamous cell cancers.
Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Carcinoma de Células Escamosas/tratamiento farmacológico , Síndrome Hemolítico-Urémico/inducido químicamente , Suelo de la Boca , Neoplasias de la Boca/tratamiento farmacológico , Bleomicina/efectos adversos , Cisplatino/efectos adversos , Síndrome Hemolítico-Urémico/sangre , Humanos , Masculino , Persona de Mediana Edad , Vincristina/efectos adversos , Factor de von Willebrand/metabolismoRESUMEN
To define the primary effects of aluminum on bone in the mammalian species, we examined the dose/time-dependent actions of aluminum in normal beagles. Administration of low dose aluminum (0.75 mg/kg) significantly elevated the serum aluminum (151.7 +/- 19.9 micrograms/liter) compared with that in controls (4.2 +/- 1.35 micrograms/liter) but did not alter the calcium, creatinine, or parathyroid hormone. After 8 wk of therapy, bone biopsies displayed reduced bone resorption (2.6 +/- 0.63 vs. 4.5 +/- 0.39%) and osteoblast covered bone surfaces (2.02 +/- 0.51 vs. 7.64 +/- 1.86%), which was indicative of low turnover. In contrast, prolonged treatment resulted in increased bone volume and trabecular number (38.9 +/- 1.35 vs. 25.2 +/- 2.56% and 3.56 +/- 0.23 vs. 2.88 +/- 0.11/mm) which was consistent with uncoupled bone formation. Administration of higher doses of aluminum (1.20 mg/kg) increased the serum aluminum further (1242.3 +/- 259.8 micrograms/liter) but did not affect calcium, creatinine, or parathyroid hormone. However, after 8 wk of treatment, bone biopsies displayed changes similar to those after long-term, low-dose therapy. In this regard, an increased trabecular number (3.41 +/- 0.18/mm) and bone volume (36.5 +/- 2.38%) again provided evidence of uncoupled bone formation. In contrast, in this instance poorly mineralized woven bone contributed to the enhanced bone volume. High-dose treatment for 16 wk further enhanced bone volume (50.4 +/- 4.61%) and trabecular number (3.90 +/- 0.5/mm). These observations illustrate that aluminum may stimulate uncoupled bone formation and induce a positive bone balance. This enhancement of bone histogenesis contrasts with the effects of pharmacologic agents that alter the function of existing bone remodeling units.
Asunto(s)
Aluminio/farmacología , Desarrollo Óseo/efectos de los fármacos , Osteogénesis/efectos de los fármacos , Animales , Análisis Químico de la Sangre , Huesos/anatomía & histología , Perros , Relación Dosis-Respuesta a DrogaAsunto(s)
Aluminio/toxicidad , Trastorno Mineral y Óseo Asociado a la Enfermedad Renal Crónica/inducido químicamente , Osteomalacia/inducido químicamente , Diálisis Renal/efectos adversos , Animales , Huesos/patología , Trastorno Mineral y Óseo Asociado a la Enfermedad Renal Crónica/patología , Humanos , Fallo Renal Crónico/complicaciones , Osteomalacia/patologíaRESUMEN
The successful application of any analytical technique involves a balance between the performance characteristics of the method and the data requirements of the problem. As has been discussed, the electrothermal procedure for the determination of aluminum imposes some constraints on the clinical application of the methodology. These include detection limits in the same range as normal serum values, the possibility of interference from sample constituents, and the potential for contamination. In addition, reference standards are not currently available. Nevertheless, electrothermal procedures have received broad acceptance. This can be attributed to several factors. Electrothermal procedures tend to be inherently simple. Second, an understanding of the potential limitations of the technique has led to procedures that minimize these negative aspects and provide accurate measurements of aluminum in biological fluids. These factors, in conjunction with the reliability and relative ease of application of the technique, have led to an acceptance of electrothermal atomic absorption as the method of choice for the measurement of aluminum in biological samples.
Asunto(s)
Aluminio/análisis , Espectrofotometría Atómica/métodos , Aluminio/sangre , Humanos , Estándares de ReferenciaRESUMEN
Although aluminum excess is an apparent pathogenetic factor underlying osteomalacia in dialysis-treated patients with chronic renal failure, the mechanism by which aluminum impairs bone mineralization is unclear. However, the observation that aluminum is present at osteoid-bone interfaces in bone biopsies of affected patients suggests that its presence at calcification fronts disturbs the cellular and/or physiochemical processes underlying normal mineralization. Alternatively, aluminum at osteoid-bone interfaces may reflect deposition in preexistent osteomalacic bone without direct effects on the mineralization process. We investigated whether aluminum accumulates preferentially in osteomalacic bone and, if so, whether deposition of aluminum occurs at calcification fronts and specifically inhibits mineralization. Aluminum chloride (1 mg/kg) was administered intravenously three times per week for 3 wk to five normal and five vitamin D-deficient osteomalacic dogs. Before administration of aluminum the vitamin D-deficient dogs had biochemical and bone biopsy evidence of osteomalacia. Bone aluminum content in the osteomalacic dogs (15.1 +/- 2.2 micrograms/g) and the plasma aluminum concentration (10.4 +/- 2.1 micrograms/liter) were no different than those of normal dogs (10.5 +/- 3.5 micrograms/g and 11.9 +/- 1.2 microgram/liter, respectively). After the 3 wk of aluminum administration the plasma phosphorus, parathyroid hormone, and 25-hydroxyvitamin D concentrations were unchanged in normal and vitamin D-deficient dogs. Similarly, no alteration in bone histology occurred in either group. In contrast, bone aluminum content increased to a greater extent in the vitamin D-deficient dogs (390.3 +/- 24.3 micrograms/g) than in the normal dogs (73.6 +/- 10.6 micrograms/g). Moreover, aluminum localized at the osteoid-bone interfaces of the osteomalacic bone in the vitamin D-deficient dogs, covering 42.9 +/- 9.2% of the osteoid-bone surface. Further, in spite of continued aluminum chloride administration (1 mg/kg two times per week), vitamin D repletion of the vitamin D-deficient dogs for 11 wk resulted in normalization of their biochemistries. In addition, while normal dogs maintained normal bone histology during the period of continued aluminum administration, vitamin D repletion of the vitamin D-deficient dogs induced healing of their bones. Indeed, the appearance of aluminum in the cement lines of the healed bones indicated that mineralization had occurred at sites of prior aluminum deposition. These observations illustrate that aluminum deposition in osteomalacic bone may be a secondary event that does not influence bone mineralization. Thus, although aluminum may cause osteomalacia in chronic renal failure, its presence at mineralization fronts may not be the mechanism underlying this derangement.