Low dialysate [K+] decreases efficiency of hemodialysis and increases urea rebound.

In a previous study, it was reported that hemodialysis with dialysate [K+] (KD) of 1.0 or 2.0 mmol/L caused an increase in BP shortly after completion of treatment due to arteriolar constriction. With this background, it was hypothesized that a low KD might decrease dialysis efficiency by a similar mechanism. To evaluate this hypothesis, paired observations of two consecutive 3-h treatments, with KD of 1.0 or 3.0 mmol/L, were performed in 14 stable end-stage renal disease patients. A KD of 1.0 mmol/L resulted in lower values for both urea reduction ratio and Kt/V evaluated at completion of dialysis and 1 h thereafter. Values at equilibrium were urea reduction ratio 42+/-1% versus 47+/-2% (P < 0.02), Kt/V 0.65+/-0.03 versus 0.73+/-0.03 (P < 0.02) for KD 1.0 or 3.0 mmol/L, respectively. The mechanisms responsible for the observed differences in dialysis efficiency were examined using a urea kinetics model that predicts urea sequestration caused by impaired blood flow to urea-rich tissues. For this purpose, urea rebound and its effect on Kt/V (by means of deltaKt/V, calculated as equilibrated minus single pool value) with KD 1.0 and 3.0 mmol/L were assessed. Greater urea rebound, 12.8+/-1.6% versus 8.6+/-1.4% (P < 0.001), and larger deltaKt/V, 0.12+/-0.01 versus 0.10+/-0.02 (P < 0.02), were observed with KD 1.0 mmol/L compared with 3.0 mmol/L. The theoretical model accurately predicted the deltaKt/V observed with KD 1.0 mmol/L. It is concluded that a low KD decreases dialysis efficiency. This effect is likely caused by reduced blood perfusion to nonvisceral organs, largely skeletal muscle. Conversely, hemodialysis with KD 3.0 mmol/L facilitates tissue perfusion, minimizes urea trapping in poorly perfused areas, and improves the efficiency of this treatment modality.

Endothelin-1 increases rat distal tubule acidification in vivo.

Because endothelin receptor inhibition blunts increased distal tubule acidification induced by dietary acid, we examined whether endothelin-1 (ET-1) increases acidification of in vivo perfused distal tubules of anesthetized rats. ET-1 was infused intraaortically (1.4 pmol x kg(-1) x min[-1]) into control animals and into those with increased distal tubule HCO3 secretion induced by drinking 80 mM NaHCO3 solution for 7-10 days. ET-1 increased distal tubule acidification in both control and NaHCO3 animals. Increased acidification in control animals was mediated by increased distal tubule H+ secretion (23.7+/-2.2 vs. 18.7 +/- 1.7 pmol x mm(-1) x min(-1), P < 0.05) with no changes in HCO3 secretion. By contrast, ET-1 increased distal tubule acidification in NaHCO3 animals predominantly by decreasing HCO3 secretion (-9.5 +/- 1.0 vs. -18.7 +/-1.8 pmol x mm(-1) x min(-1), P < 0.001) with less influence on H+ secretion. When indomethacin was infused (83 microg x kg(-1) x min[-1]) to inhibit synthesis of prostacyclin, an agent previously shown to increase HCO3 secretion in the distal tubule, ET-1 increased distal tubule H+ secretion in both control (24.3 +/-2.2 vs. 15.7 +/- 1.6 pmol x mm(-1) x min(-1), P < 0.02) and NaHCO3 (20.0 +/- 2.0 vs. 13.6 +/- 1.4 pmol x mm(-1) x min(-1), P < 0.05) without affecting HCO3 secretion. The data show that ET-1 increases distal tubule acidification in vivo and can do so by increasing H+ secretion and by decreasing HCO3 secretion when the latter is augmented by dietary NaHCO3.

Vascular relaxation probably mediates the antihypertensive effect of a high-potassium diet: a role for enhanced vascular Na,K-ATPase activity.

OBJECTIVE: to evaluate the effect of dietary potassium on blood pressure and vascular contractility in adult rats of two strains, spontaneously hypertensive rats (SHR) and normotensive Wistar-Kyoto (WKY) rats. DESIGN: 'Potassium-induced relaxation' was evaluated in aortic rings as a functional measure of Na,K-ATPase activity in the vascular wall. The rats were fed one of three diets: regular (American Institute of Nutrition-76 rat chow); high-sodium (7% sodium chloride) or high-sodium plus potassium (7% sodium chloride and 13.4% potassium citrate) for 12 +/- 1 weeks. RESULTS: SHR fed the high-sodium diet had a mean blood pressure of 157 +/- 8 mmHg, as compared with 130 +/- 9 mmHg for those on a regular diet (P < 0.01). SHR fed the potassium-supplemented diet had a blood pressure of 122 +/- 9 mmHg (P < 0.01 versus the high-sodium diet group). The mean blood pressure of WKY rats was 78 +/- 3 mmHg and did not differ among the dietary groups. The 'potassium-induced relaxation' response of aortic rings from SHR and WKY rats fed a potassium-supplemented diet was significantly higher (P < 0.05) than that in animals in the corresponding high-sodium dietary group. This observation in potassium-supplemented rats is interpreted as indicative of increased Na,K-ATPase activity in the vascular wall. CONCLUSIONS: A potassium-rich diet in SHR receiving a high sodium intake was associated with lower blood pressure and higher vascular Na,K-ATPase activity. A similar effect of this diet on vascular Na,K-ATPase was observed in WKY. We propose that the antihypertensive effect of a potassium-rich diet is mediated, at least in part, by stimulation of vascular Na,K-ATPase activity.

Acute decreases in serum potassium augment blood pressure.

Potassium depletion is a risk factor for cardiovascular diseases, including hypertension, and frequently is encountered in patients with end-stage renal disease. Since the treatment of end-stage renal disease might result in K+ depletion and postdialysis hypokalemia, we investigated the relationship between acute K+ removal by hemodialysis and changes in blood pressure at the completion of treatment compared with predialysis and 1-hour postdialysis blood pressure. The effects of three different dialysate potassium concentrations ([K+]d; 1.0, 2.0, and 3.0 mmol/L) were investigated in 11 patients. Hemodialysis-induced K+ removal, serum [K+], total body K+, and blood pressure were measured. The use of 1.0, 2.0, or 3.0 mmol/L [K+]d resulted in the removal of 77.0 +/- 6.5, 54.5 +/- 7.9, and 42.5 +/- 9.9 mmol of K+ per treatment, respectively (P < 0.05, [K+]d 1.0 v [K+]d 3.0). Predialysis and postdialysis serum [K+] were 4.9 +/- 0.2 and 3.6 +/- 0.1 mEq/L for 1.0 mmol/L [K+]d, 5.1 +/- 0.3 and 3.9 +/- 0.1 mEq/L for 2.0 mmol/L [K+]d, and 5.3 +/- 0.3 and 4.2 +/- 0.2 mEq/L for 3.0 mmol/L [K+]d, respectively (P < 0.001 for each [K+]d). The baseline total body K+ corrected for gender, age, and race was 92% of predicted normal level and did not change significantly with the use of different [K+]d. Blood pressure decreased during hemodialysis as excess fluid was removed, regardless of [K+]d. Significant increases in blood pressure did occur 1 hour postdialysis compared with levels measured at the completion of treatment ("rebound hypertension") when hemodialysis was performed with 1.0 and 2.0 mmol/L, but not with 3.0 mmol/L [K+]d.(ABSTRACT TRUNCATED AT 250 WORDS)

Rhabdomyolysis and acute renal failure during high-dose haloperidol therapy.

Severe adverse reactions to neuroleptic medications are not uncommon and include the neuroleptic malignant syndrome, rhabdomyolysis, and acute renal failure. The neuroleptic malignant syndrome consists of hyperthermia, diaphoresis, tachycardia, tachypnea, abnormal blood pressure, alteration of consciousness, and extrapyramidal rigidity. Rhabdomyolysis--which might be due to hyperthermia, muscle rigidity, and/or metabolic changes in skeletal muscle function--results in acute renal failure. We report a patient with rhabdomyolysis and acute renal failure that developed after large doses of haloperidol were given, but without muscle rigidity or hyperthermia. This patient's presentation illustrates that high-dose haloperidol therapy might cause rhabdomyolysis and acute renal failure without significant rigidity or hyperthermia.

Identification of GTP-binding proteins in turtle urinary bladder epithelial cells.

Water and electrolyte transport in turtle urinary bladder closely resembles that present in the mammalian collecting tubule. Although cAMP is known to participate in the control of mucosal transport processes, the GTP-binding inhibitory Gi and stimulatory Gs proteins which link receptors on the cell surface to the adenylate cyclase system remain to be identified in this urinary epithelium. To this end, individual cells harvested from the mucosal surface of the turtle bladder were isolated using a discontinuous density Ficoll gradient. Examination by electron microscopy of the material from the different layers of the Ficoll gradient confirmed that bands II and III contained carbonic anhydrase-rich cells and granular cells, respectively. Identification of Gi and Gs in carbonic anhydrase-rich and granular cells was accomplished using pertussis (PT) and cholera toxins to promote [32P] ADP ribosylation of the proteins. Separation of Gi and Gs from other cell proteins was accomplished using polyacrylamide gel electrophoresis and autoradiography. Pretreatment of cells with 0.2% triton X-100 substantially magnified the ADP-ribosylation of Gi by PT. A doublet form of Gi was present in the 40-kD region and indicated heterogeneity of the PT substrate in granular and carbonic anhydrase-rich cells. Gs was observed as a single polypeptide at the 42-kD region in both cell types. A distinct 45-kD peptide not present in mammalian collecting tubule was identified by both toxins in granular cells and by cholera toxin in carbonic anhydrase-rich cells. In summary, this investigation identified and characterized Gi and Gs proteins in carbonic anhydrase-rich and granular cells from the mucosa of turtle urinary bladder.(ABSTRACT TRUNCATED AT 250 WORDS)

Enhanced HCO3 secretion by distal tubule contributes to NaCl-induced correction of chronic alkalosis.

Free-flow micropuncture studies show depressed net HCO3 reabsorption in the surface distal tubule of rats undergoing correction of chronic metabolic alkalosis induced by NaCl infusion. The present studies used in vivo microperfusion of the rat distal tubule to investigate whether the described reduction in net HCO3 reabsorption was due to decreased luminal H+ secretion or to increased HCO3 secretion. Animals with correcting alkalosis had higher HCO3 secretion in this nephron segment than did animals with maintained alkalosis regardless of whether the perfusing solution was initially Cl free (-27.6 vs. -16.6 pmol.mm-1.min-1, P < 0.01) or contained 40 mM Cl (-31.5 vs. -23.0 pmol.mm-1.min-1, P < 0.01); H+ secretion was not different between animals with correcting and maintained alkalosis. Animals without alkalosis (control) demonstrated no differences in H+ or HCO3 secretion in response to NaCl infusion. These studies demonstrate that enhanced HCO3 secretion mediates the depressed net HCO3 reabsorption observed in the distal tubule of rats undergoing NaCl-induced correction of chronic metabolic alkalosis.

Demonstration of an apical chloride conductive pathway in granular cells of toad urinary bladder.

Chloride electrodiffusion across the apical membrane of granular cells from toad urinary bladder, an analogue of mammalian principal cells, was examined using the patch clamp technique. A chloride conductance was demonstrated in cell-attached membrane patches exposed to barium chloride pipette solutions. A change in the pipette chloride concentration from 30 to 100 mM caused a shift in the current voltage curve which demonstrated chloride selectivity. The chloride conductance was also examined in excised, inside out membrane patches using choline chloride solutions (chloride:choline selectivity ratio was 18:1). A closed and two open chloride conductive states were found (states A and B, 10.1 +/- 1.0 and 17.2 +/- 5.5 pS, respectively, p < 0.01). Incubation of the preparation with arginine vasopressin, dibutyryl-cAMP, or 8-bromo-cAMP approximately doubled chloride conductance to 16.6 +/- 1.7 pS (p < 0.01). The enhanced electrodiffusion was accounted for by a shift in the channel kinetics from the closed state C to the high conductance state B (p < 0.05, n = 9). 4,4'-Diisothio-cyanatostilbene- 2,2'-disulfonic acid (DIDS) and 9-anthracene-carboxylic acid (9-AC) failed to block the chloride currents. In conclusion, the regulated apical chloride conductance described would balance the sodium and potassium electrodiffusive pathways and maintain a stable membrane potential, facilitating overall conductive transport by these cells.

Luminal membrane potassium conductance of rabbit proximal straight tubules.

Potassium channels have been found in the apical and basolateral membranes of renal proximal straight tubules, but the fraction of apical membrane conductance due to or associated with potassium has not been reported. Therefore, the transepithelial conductance of rabbit pars recta was measured and the portion of conductance which was inhibited by barium determined. The mean control transepithelial voltage and conductance were -5.6 +/- 0.7 mV and 106 +/- 10 mS/cm2, respectively. The addition of barium to the luminal perfusing solution decreased transepithelial conductance to 93 +/- 9 mS/cm2. This decrease of 13 +/- 2% from control (p < 0.001, n = 20) cannot be explained solely by inhibition of an apical potassium conductance. It is proposed that the apical potassium channels found in the pars recta facilitate transepithelial conductive transport by sodium and other ions.

Maximal proton secretory rate of rat distal tubules is higher during chronic metabolic alkalosis.

In vivo microperfusion studies show augmented proton secretion in the distal tubule of rats with chronic metabolic alkalosis. The present studies used the same technique to determine whether this augmented proton secretion is due predominantly to an increase in substrate affinity or alternatively to a predominant increase in the maximal proton secretory rate. Surface distal tubules of alkalotic and control rats were microperfused in vivo with solutions containing increasing concentrations of HCO3. Proton secretion was determined as the difference between measured net HCO3 reabsorption and passive HCO3 transport calculated by use of the permeability derived from perfusing with a HCO3-free solution. Proton secretion was expressed as a function of the initial luminal HCO3 concentration and was assumed to follow saturable Michaelis-Menten kinetics. Alkalotic animals had a significantly higher Km (33.9 vs. 21.6 mM, P less than 0.03) and Vmax (223.8 vs. 99.1 pmol.mm-1.min-1, P less than 0.001) compared with control. These data are consistent with the augmented proton secretion in the distal tubule of alkalotic animals as predominantly due to an increased maximal proton secretory rate rather than to increased substrate affinity.

Augmented bidirectional HCO3 transport by rat distal tubules in chronic alkalosis.

Free-flow micropuncture studies show both augmented net HCO3 reabsorption in the distal tubule of rats with chronic metabolic alkalosis and higher HCO3 delivery to this nephron segment. The present studies in rats used in vivo microperfusion of surface distal tubules to investigate whether the augmented net reabsorption 1) was due to decreased HCO3 secretion and/or to increased proton secretion or 2) depended on the higher HCO3 delivery to the distal tubule. Artificial perfusates were designed to simulate in situ deliveries of HCO3 to the distal tubules of both alkalotic and control animals and to represent extremes of in situ Cl deliveries. Rather than being decreased, both measured and calculated HCO3 secretion were higher in the alkalotic animals for each perfusate used. Similarly, calculated proton secretion (difference between net HCO3 reabsorption and calculated HCO3 secretion) was higher for the alkalotic animals using each HCO3-containing perfusate. Augmented net HCO3 reabsorption by alkalotic animals was more clearly demonstrated using higher HCO3 deliveries and Cl-free perfusates. These studies demonstrate that both the reabsorptive and secretory components of net HCO3 transport are increased in the distal tubule of animals with chronic metabolic alkalosis.

Electrolyte abnormalities before and after the onset of acute renal failure.

The chemical composition of body fluids, which is regulated by the kidneys, may affect renal function. Conversely, the onset of acute renal failure (ARF) interrupts the normal regulation of the volume and content of the body fluids. In order to further study these relationships and determine the epidemiology and consequences of ARF in a tertiary-care setting, the computerized hospital data base was used to identify and obtain laboratory data on patients with ARF. 9,276 patients, encountered over a 90-day period, were surveyed and 96 were found to have developed ARF in the hospital (3.1% of admissions). The majority of the patients with ARF were found on the medicine service (68%), and sepsis with aminoglycoside use was the single most common of multiple etiologic factors. Patients with ARF experienced an increase in morbidity, as evidenced by an increase in the hospital length of stay and frequent need for ICU care. Mortality (29%) was due to the patients' underlying illnesses, and not uremia. Serum levels of the electrolytes prior to the onset of ARF were within the normal range with the exception of the creatinine (2.04 +/- 0.25 mg/dl) and bicarbonate (22.9 +/- 0.6 meq/l). After the development of ARF (mean creatinine 3.91 +/- 0.03) sodium, chloride, and bicarbonate were decreased, and phosphate, uric acid, and the anion gap were increased (p less than 0.05 for all values). The decrease in serum calcium became significant (p less than 0.05) in those patients whose creatinine increased by a factor of 2 or more.

Relationship among parathyroid hormone, cAMP, and calcium on proximal tubule sodium transport.

Parathyroid hormone (PTH), through the generation of cAMP, inhibits the transport of sodium, bicarbonate, and water in the proximal convoluted tubule. The present studies were designed to determine whether the response to PTH or dibutyryl cAMP by proximal renal tubules requires an influx of calcium into the cells or an alteration in the cytosolic concentration of calcium. O2 consumption was determined in an enriched suspension of rabbit proximal convoluted tubules, and the ouabain-sensitive component of O2 consumption was taken as a measure of sodium transport. PTH (1 IU/ml) inhibited the ouabain-sensitive component of O2 consumption from 14.2 +/- 1.6 to 8.9 +/- 1.1 nmol O2 X min-1 X mg protein-1 (P less than 0.005). Dibutyryl cAMP (10(-4) M) inhibited ouabain-sensitive O2 consumption from 12.0 +/- 1.1 to 8.4 +/- 0.8 nmol O2 X min-1 X mg protein-1 (P less than 0.005). In the presence of lanthanum (5-50 microM) or verapamil (20-200 microM), PTH inhibited ouabain-sensitive O2 consumption by 21.3 +/- 3.4% (P less than 0.025) and 33.9 +/- 5.5% (P less than 0.025), respectively. Dibutyryl cAMP inhibited the ouabain-sensitive O2 consumption by 22.6 +/- 7.1% (P less than 0.025) in the presence of lanthanum and 35.4 +/- 3.1% (P less than 0.01) in the presence of verapamil. To more directly assess the cytosolic concentration of calcium, the fluorescent intensity of quin 2-loaded tubules was determined. As compared with timed controls, exposure to PTH resulted in a lower cytosolic concentration of calcium over the 10 min of incubation. Dibutyryl cAMP had a similar effect.(ABSTRACT TRUNCATED AT 250 WORDS)

Parathyroid hormone and dibutyryl cAMP inhibit Na+/H+ exchange in renal brush border vesicles.

Parathyroid hormone (PTH) and cAMP inhibit sodium, water, and bicarbonate reabsorption in the proximal tubule. We wished to determine whether these agents directly inhibit proximal tubular Na+/H+ exchange. A suspension of rabbit proximal tubules was prepared by enzymatic digestion and Ficoll gradient centrifugation. Oxygen consumption at 37 degrees C was stable over 60 min, averaged 20 nmol X mg protein-1 X min-1, and was inhibited 60% by ouabain. Over 96% of cells excluded trypan blue. From this suspension, brush border membrane vesicles were isolated. The vesicles were enriched 12.7 times in alkaline phosphatase relative to a cortical homogenate and demonstrated pH gradient-stimulated, amiloride-sensitive Na+/H+ countertransport and sodium-phosphate and sodium-D-glucose cotransport. When the tubule suspension was exposed to PTH or dibutyryl cAMP, the activity of Na+/H+ countertransport in the resultant brush border vesicles was inhibited. Neither PTH nor dibutyryl cAMP affected the amiloride-insensitive component of sodium transport or sodium-phosphate or sodium-D-glucose cotransport. The effect of PTH on Na+/H+ counter-transport could not be explained by an alteration in fluidity of the brush border membrane. These experiments demonstrate that PTH and dibutyryl cAMP directly inhibit Na+/H+ countertransport in the brush border membrane of the rabbit proximal tubule.