Regulation of renal calbindin-D28K.

Calbindin-D28k is an intracellular protein with high affinity for calcium. In the kidney, this protein is exclusively localized in the distal tubule and in the proximal part of the collecting ducts. Functionally, calbindin-D28k is supposed to be involved in the regulation of the reabsorption of calcium and possibly magnesium in the distal nephron though the exact regulatory mechanisms are not yet known. Thus, several theories regarding the functional role of calbindin-D28k have been proposed: The carrier theory describes calbindin-D28k as a transport protein which binds calcium and then transports it from the luminal to the basolateralcell membrane. The buffer theory assumes that calbindin-D28k functions by binding calcium ions to prevent intracellular calcium concentrations from reaching toxic levels. The activator theory describes that calbindin-D28k increases the activity of calcium channels or the enzymatic activity of the Ca++-Mg++-ATPase in the luminal membrane and thereby increases the tubular reabsorption of calcium. The renal calbindin-D28k is dependent upon vitamin D. Pharmacological doses of the active vitamin D metabolite 1,25-(OH)2D increases the concentrations of renal calbindin-D28k, whereas the concentration of calbindin-D28k is low in conditions with reduced levels of circulating 1,25-(OH)2D. Likewise, plasma calcium concentrations, uremia and hypertension affect calbindin-D28k expression. However, several studies have rendered probable the effect of additional factors in the regulation of renal calbindin-D28k. The aim of the present dissertation therefore was to examine the regulation of renal calbindin-D28k in a series of physiological and pathophysiological conditions established in vivo in the rat. A possible correlation between hypertension and calbindin-D28k was examined in three models of experimental hypertension: the genetically defined spontaneous hypertensive rat, the salt-sensitive Dahl rat and the renovascular hypertensive rat. These three models clearly demonstrated three separate patterns in the calcium metabolism, but the studies were unable to support a role for calbindin-D28k in the development of hypertension. In all three models the development of hypertension caused an increased plasma 1,25-(OH)2D. This increase was accompanied by either unaltered or reduced levels of renal calbindin-D28k possibly secondary to a cellular resistance against 1,25-(OH)2D. Magnesium binds to calbindin-D28k with a relatively high affinity. The regulation of urinary magnesium excretion takes place in the distal tubule where calbindin-D28k is found in high concentrations. Therefore, a possible relation between magnesium and calbindin-D28k was examined. The studies demonstrated not previously known connections between magnesium intake, urinary magnesium excretion and renal calbindin-D28k which suggests that this protein is involved in the regulation of magnesium homeostasis by the kidney. Calcitonin increases the reabsorption of calcium in the distal tubule. Therefore, the effect ofcalcitonin on renal calbindin-D28k was examined both by eliminating the endogeneous calcitonin production by a selective thyroidectomy followed by an autotransplantation of the parathyroid glands and further by infusion of calcitonin. These studies demonstrated unchanged concentrations of renal calbindin-D28k. It was concluded that the increased calcium reabsorption induced by calcitonin in the distal tubule is not mediated by calbindin-D28k. Urinary calcium excretion is in part regulated by the action of PTH on calcium reabsorption in the distal nephron. Previous reports of increased expression of renal calbindin-D28k in uremic rats led us to suggest that secondary hyperparathyroidism associated with uremia induced the synthesis of renal calbindin-D28k. Therefore, the effect of PTH was examined in a study comprising selective parathyroidectomy and infusions of PTH, PTHrP, 1,25-(OH)2D and calcium. (ABSTRACT TRUNCATED)

Bi-level positive airway pressure treatment of obstructive sleep apnoea syndrome.

We evaluated the effect of non-invasive nocturnal ventilation with the bi-level positive airway pressure (BiPAP) ventilator in 12 overweight patients with verified obstructive sleep apnoea syndrome (OSAS) and nocturnal hypercapnia. All patients exhibited subsequently less overnight CO2 accumulation (p < 0.0001), the desaturation event frequency was reduced (p < 0.002), daytime O2 tension rose (p < 0.001), daytime CO2 tension was reduced (p < 0.01), and apnoeas were eliminated. All symptoms characterising the syndrome, when present at the beginning of the therapy, were eliminated during the treatment. Patient compliance was high. This study showed that OSAS patients with hypercapnia can be effectively treated by BiPAP ventilation during sleep.

The effect of 1,25-vitamin D3 on calbindin-D and calcium-metabolic variables in the rat.

Intraperitoneal injection of 1,25-(OH)2D3 4 micrograms/kg was given to 84 calcium- and vitamin D-repleted Wistar rats and samples of plasma, duodenal mucosa and renal tissue were taken after 0, 3, 6, 12, 24, 48 and 96 hr (n = 12 at each time interval). Plasma-ionized Ca increased after 6 hr, reached a maximum after 24 hr and returned to the initial values after 96 hr. The concentrations of renal calbindin-D28k and intestinal calbindin-D9k did not increase until 48 hr after injection and remained elevated until 96 hr after. Therefore, significantly elevated concentrations of the cytosolic calbindin-D were found at a time with normal values of plasma Ca. The present data suggest that calbindin-D does not alone increase the transcellular Ca transport and, therefore, supports the view that calbindin-Ds may serve as Ca buffer proteins.

Urinary calcium excretion and renal calbindin-D28k.

The present investigation examined the possible influence of urinary calcium excretion on the concentration of renal calbindin-D28k. Thiazide diuretics stimulate calcium transport across the epithelial cells of the distal tubule, which express calbindin-D28k in high concentrations. Calbindin-D28k is assumed to facilitate transcellular Ca diffusion. Reduced urine calcium excretion and increased urine output were induced in Wistar rats by infusion of bendroflume-thiazide 1 mg/kg/day. The two control groups had infusions of either furosemide 20 mg/kg/day or vehicle, n = 8 in each group. Urinary Ca excretion was reduced to 10% in the thiazide group and increased by 50% in the furosemide group. Renal concentrations of calbindin-D28 showed no difference between vehicle, thiazide- and furosemide-treated rats. No differences in plasma concentrations of calcium, magnesium, phosphorus, urea, PTH, calcitonin and 1,25-(OH)2D were found between the groups. The present study describes that urine calcium excretion selectively can be manipulated without accompanying changes in renal calbindin-D28k concentrations. The data, therefore, suggest that urinary calcium excretion is not a significant determinator of cytosolic concentrations of renal calbindin-D28k.

Effect of vitamin D metabolites and analogs on renal and intestinal calbindin-D in the rat.

The effects on renal and intestinal calbindin-D of vitamin D3 metabolites and synthetic 20-epi-vitamin D3 analogs with different calcemic actions were examined in Wistar rats. The compounds were administered intraperitoneally once daily for 5 days. The dosages of the metabolites were 1,25-(OH)2D3 0.01, 0.05, 0.1, and 0.4 microg/kg x d, 24,25-(OH)2D3 0.1, 1 and 10 microg/kg x d, and 25-(OH)D3 10 and 400 microg/kg x d. The dosage of the synthetic analogs were MC903 0. 1, 10, and 100 microg/kg x d, EB1213 0.1 and 10 microg/kg x d, KH1060 0.1 and 0.4 microg/kg x d, and GS1725 0.01 and 0.1 microg/kg x d. Two control groups had either vehicle alone or no treatment. N = 8 in each group. 1,25-(OH)2D3 increased renal and intestinal calbindin-D levels, induced hypercalcemia, and suppressed plasma PTH and magnesium concentrations. 24,25-(OH)2D3 increased intestinal calbindin-D9k and plasma calcium, but had no effect on renal calbindin-D28k, plasma PTH, and magnesium. The dosage of 24, 25-(OH)2D3 that was required to increase plasma calcium was larger than the dosage required to increase intestinal calbindin-D9k. 25-(OH)D3 did not change the calcium metabolic parameters. MC903, a low calcemic analog with a relative high affinity for the vitamin D receptor and a short half-life, increased renal calbindin-D28k without increasing ionized calcium or intestinal calbindin-D9k. EB1213, an analog with a reduced calcemic action and short half-life, increased renal calbindin-D28k and ionized calcium without increasing intestinal calbindin-D9k. The effect of the high calcemic vitamin D analogs KH1060 and GS1725 on calbindin-D was directly related to their calcemic activity. In conclusion, these results demonstrate that 24,25-(OH)2D3 increases intestinal calbindin-D9k, but has no effect on renal calbindin-D28k, that low calcemic analogs may increase renal calbindin-D28k without increasing intestinal calbindin-D9k, and that the effect of high calcemic analogs on calbindin-D is directly related to their calcemic activity.

Effect of parathyroid hormone on renal calbindin-D28k.

The present investigation was conducted to examine the effects of parathyroid hormone (PTH) and parathyroid hormone related peptide (PTHrP) on renal calbindin-D28k in rats. Four groups of studies were performed: (1) parathyroidectomy (PTX) or a sham operation followed by infusion of 1,25-dihydroxyvitamin D (1,25[OH]2D) or vehicle; (2) infusions of PTH(1-34), PTH(1-84), 1,25(OH)2D, or vehicle; (3) infusion of PTHrP(1-34), PTHrP (1-86), PTH(1-34), or vehicle; and (4) injections of calcium or vehicle. PTX reduced renal calbindin-D28k levels even when plasma concentrations of 1,25(OH)2D were kept constant by infusion of 1,25(OH)2D. Infusions of PTH(1-34), PTH(1-84), and 1,25(OH)2D all increased renal calbindin-D28k and plasma calcium, whereas PTHrP(1-34) and PTHrP(1-86) increased renal calbindin-D28k before an increase of plasma calcium took place. Hypercalcemia induced by the injection of calcium did not affect the levels of renal calbindin-D28k. The present data suggest that PTH and PTHrP exert a direct effect on renal calbindin-D28k, which is not mediated by changes of 1,25(OH)2D or calcium.

Regulation of renal calbindin-D28K: the role of calcitonin.

Infusion of calcitonin lowers circulating calcium, but in the distal tubule of the kidney, pharmacological doses of calcitonin increase the active calcium reabsorption. Calbindin-D28k plays a significant role in the calcium reabsorption in the distal convoluted tubule of the kidney. The effect of calcitonin on renal calbindin-D28k in relation to calcium metabolic changes was therefore examined. In study 1, thyroparathyroidectomy followed by autotransplantation of the parathyroid glands (TX) was compared with a sham operation in rats. TX reduced plasma calcitonin from 54 +/- 2 to 9 +/- 1 pg/ml (P < 0.001), whereas ionized calcium and parathyroid hormone were returned to the control value after an initial decrease, indicating a successful implantation of the parathyroid glands. No changes were seen in calbindin-D or plasma 1,25(OH)2D. In study 2, subcutaneous infusion of salmon calcitonin 2.5 U/kg/hour via osmotic pumps was compared with infusion of vehicle in rats. Ionized calcium was reduced from 1.37 +/- 0.01 to 1.33 +/- 0.02 mmol/liter (P < 0.05), whereas no changes were seen in renal or intestinal calbindin-D or in plasma 1,25(OH)2D. After TX, only calcitonin decreased whereas the other calcium metabolic parameters showed no change. This indicates that in rats, selective elimination of calcitonin does not influence other parameters of the calcium metabolism and that the effect of calcitonin on calcium transport in the distal tubule is not mediated via an increase in renal calbindin-D28k.

Comparison of straight and curled Tenckhoff peritoneal dialysis catheters implanted by percutaneous technique: a prospective randomized study.

OBJECTIVE: To examine the impact of peritoneal dialysis catheter configuration, curled or straight catheter, on catheter survival and mechanical and infectious complications. DESIGN: Prospective randomized trial. SETTING: Department of Nephrology of a single university hospital. PATIENTS: Seventy-two consecutive patients initiating peritoneal dialysis were randomized to receive either a single cuff straight catheter or a single cuff curled catheter, implanted by percutaneous technique. RESULTS: Significantly higher (p < 0.01) survival rate of the curled as compared to the straight catheter. The difference in catheter survival was due to a significantly higher (p < 0.01) incidence of drainage failure associated with catheter tip migration of the straight catheter than of the curled catheter. No difference in infectious complication between the two types of catheters was seen. Catheter survival at 12 months was 77% for the curled catheter and 36% for the straight catheter. CONCLUSION: This study demonstrates superiority of the curled Tenckhoff peritoneal dialysis catheter survival as compared to the straight catheter. This difference in catheter survival is due to the higher displacement rate of the straight catheter.

Calcium metabolic changes and calbindin-D in experimental hypertension.

OBJECTIVE: To examine renal and intestinal calbindin-D in relation to calcium metabolic changes in three different models of experimental hypertension. DESIGN: Spontaneously hypertensive rats (SHR), hypertension-prone Dahl salt-sensitive (Dahl-S) rats and the Goldblatt two-kidney, one clip rat model of renovascular hypertension were examined. RESULTS: Both prehypertensive and hypertensive SHR had significantly lower concentrations of both renal calbindin-D28k and intestinal calbindin-D9k than Wistar control rats. This was accompanied by hypocalcaemia, hypomagnesaemia and increased plasma 1,25(OH)2 vitamin D levels. Induction of hypertension in Dahl-S rats reduced intestinal calbindin-D9k and increased plasma levels of 1,25(OH)2 vitamin D, while renal calbindin-D28k levels, plasma calcium levels and plasma magnesium levels were unchanged. Renovascular hypertension was associated with a significant increase in the intestinal calbindin-D9k, plasma 1,25(OH)2 vitamin D, parathyroid hormone and magnesium levels, while renal calbindin-D2k, plasma calcium and phosphorus levels were unaffected. CONCLUSIONS: These three models of experimental hypertension have clearly demonstrated three separate patterns in the regulation of renal and intestinal calbindin-D, which relate to different alterations of factors involved in calcium and magnesium metabolism. In all three models hypertension was accompanied by a significant increase in plasma concentrations of 1,25(OH)2 vitamin D. Only rats with renovascular hypertension showed increased intestinal calbindin-D9k levels, whereas reduced concentrations were found in the SHR and in the hypertensive Dahl-S rats. This indicates the existence of a resistance at the cellular level to 1,25(OH)2 vitamin D affecting the expression of calbindin-D in both SHR and Dahl-S rats.

Ketamine in the treatment of bronchospasm during mechanical ventilation.

The effect of ketamine on bronchospasm during mechanical ventilation was evaluated in a prospective, placebo-controlled, double-blind trial. Fourteen mechanically ventilated patients with bronchospasm were randomly allocated to either ketamine 1 mg/kg or saline placebo. In the ketamine-treated patients, PO2 increased from 10.5 (+/- 0.5) kPa to 16.4 (+/- 2.7) kPa (P < .05), whereas PO2 in the placebo-treated patients remained unchanged. The PCO2 was constant in the ketamine group, although it increased from 5.6 (+/- 0.9) kPa to 6.1 (+/- 0.9) kPa in the placebo group (P < .05). The pulmonary stethoscopic bronchospasm improved immediately after the administration of ketamine, whereas the thoracic compliance remained unchanged. In conclusion, the ketamine-treated patients showed an improvement by stethoscopic examination, in PO2 and in PCO2, suggesting that ketamine might be useful in the treatment of bronchospasm during mechanical ventilation. However, further studies are required to decide whether ketamine should be considered the drug of choice in patients with severe bronchospasm during ventilator treatment.

Effects of magnesium on renal and intestinal calbindin-D.

The possible effects of magnesium on the vitamin D-dependent renal and intestinal calbindin-D were investigated. In a low magnesium model 70 Wistar rats were allocated to either a normomagnesemic diet (Mg 3.2 g/kg) or a Mg-deficient diet (Mg 0.18 g/kg) for 10 or 24 days. The rats had intraperitoneal injections of 1,25-(OH)2 vitamin D3 0.2 microgram, MgSO4 100 mumol or placebo daily for the last 4 days. In a high magnesium model 60 Wistar rats were allocated to three groups on a normomagnesemic diet supplied with intraperitoneal MgSO4 20 mumol, 100 mumol or placebo daily. Half of the animals in each group were further supplied with intraperitoneal 1,25-(OH)2 vitamin D3 0.2 micrograms daily. The concentrations of intestinal calbindin-D9k increased on the low Mg diet from 1.6 (1.1-2.0) to 2.7 (2.0-2.9) micrograms/mg protein (p < 0.02), but were unchanged in the high Mg groups. Vitamin D treatment raised the levels of calbindin-D9k in the normomagnesemic group (p < 0.01), but not significantly in the low Mg group. Administration of MgSO4 to the low Mg rats normalized the elevated levels of intestinal calbindin-D9k (p < 0.05). The concentrations of renal calbindin-D28k were not changed by the low Mg diet, but were lower in the high Mg group [0.8 (0.6-1.1) micrograms/mg protein] than in the control group [1.5 (1.1-1.8) micrograms/mg protein; p < 0.05]. Animals in the low, high and normal magnesium group showed no differences in plasma concentrations of 1,25-(OH)2 vitamin D.(ABSTRACT TRUNCATED AT 250 WORDS)

Peritonitis incidence on a disconnect CAPD-system with or without the use of iodine clamp shields.

The purpose of the study was to review a single center's experience with the disconnect system for continuous ambulatory peritoneal dialysis (CAPD), and to evaluate peritonitis incidence with and without use of iodine-containing clamp shields. The retrospective review of patients using the disconnect system lasted from January 1991 throughout March 1993, evaluating the peritonitis incidence with and without use of iodine clamp shields. In the observation period, a total of 103 patients were evaluated. Of these, 42 patients were treated with iodine clamp shields until July 1992 and then were instructed not to use the iodine clamp shields, thus acting as their own controls. We found an overall peritonitis incidence of 0.411 episodes/patient/year (= 29.2 patient-months/episode) on disconnect CAPD-system (Baxter), in spite of the fact that more than 60% of our dialysis population is treated with peritoneal dialysis. We found no difference in peritonitis rates with or without the use of iodine clamp shields. Peritonitis rates with clamp shields were 0.400 episodes/patient/year and, without clamp shields, were 0.400 episodes/patient/year. The introduction of a disconnect system provided a system with low incidence of peritonitis. No difference in peritonitis rates was observed with or without the use of iodine clamp shields, allowing us to reduce the cost of treatment and to simplify training procedures.

[Complications of spinal anesthesia compared to general anesthesia. A prospective study of 408 consecutive orthopedic patients]. / Komplikationer ved spinal anaestesi sammenlignet med generel anaestesi. En prospektiv undersøgelse omfattende 408 konsekutive ortopaedkirurgiske patienter.

UNLABELLED: In this prospective study the preoperative risk classification and pulmonary status was compared to postoperative mortality and morbidity, following either spinal or general anaesthesia. We studied 408 consecutive orthopaedic patients. Comparing the anaesthetic methods we found no differences in mortality or in frequency of cardiac complications, while the non-cardiac complications were seen more frequently in patients who had undergone spinal anaesthesia (p < 0.05). Patients from the lower risk groups with a preoperative abnormal pulmonary status had a higher frequency of postoperative pulmonary complications following spinal anaesthesia than following general anaesthesia (p = 0.015). IN CONCLUSION: 1) We find no difference in postoperative mortality depending on the anaesthetic method chosen, 2) the predictive value of the Boston Cardiac Risk index is identical for the two anaesthetic methods, and 3) the anaesthetic method of choice for the pulmonary disabled patient has not yet been established.

The effect of oral ondansetron in the prevention of postoperative nausea and vomiting after major gynaecological surgery performed under general anaesthesia.

The efficacy and safety of ondansetron in preventing postoperative nausea and vomiting following major gynaecological surgery was evaluated in this multicentre, double-blind study. A total of 243 patients were randomised to receive three doses of oral ondansetron 8 mg or matching placebo at 8-hourly intervals, with the first dose being given an hour before surgery. A standard general anaesthetic technique was employed throughout. Nausea, vomiting and safety assessments were performed continuously during the 24 h postrecovery period. Of the 237 patients evaluated for efficacy, significantly fewer ondansetron 8 mg treated patients (65/117; 56%) experienced postoperative nausea and/or vomiting compared with placebo-treated patients (94/120; 78%) during the study period (p < 0.001). In addition, ondansetron 8 mg reduced the severity of nausea (p < 0.001) and the total number of vomiting episodes experienced (p < 0.001). Overall, ondansetron 8 mg was well tolerated and effective in preventing postoperative nausea and vomiting in this surgical setting.

Intravenous ketamine for prevention of severe hypotension during spinal anaesthesia.

Spinal block causes paralysis of preganglionic sympathetic fibres, while ketamine induces activation of the sympathetic nervous system. Hypotension is a frequent complication during spinal anaesthesia and is associated with an increased risk of postoperative mortality. The aim of our study was to compare circulatory changes in patients who received either fentanyl or ketamine during spinal anaesthesia. Thirty patients (ASA I-III) scheduled to undergo spinal anaesthesia for osteosynthesis of hip fractures were allocated to receive either ketamine or fentanyl intravenously during the procedure. Immediately before anaesthesia, 7 ml/kg BW of an isotonic NaCl solution was administered i.v. Patients received either fentanyl 1.5 mg/kg BW i.v. before anaesthesia, or ketamine 0.7 mg/kg BW i.v. before anaesthesia, and 0.35 mg/kg BW 15 and 30 min after the first dose. No prophylactic vasopressor was used. During the first 40 min of anaesthesia a fluid load of 14 ml/kg BW was given i.v. If the mean arterial pressure (MAP) fell more than 20%, the infusion rate was increased. If the reduction in MAP exceeded 33% or if the systolic pressure decreased to less than 80 mmHg, patients were registered as haemodynamically unstable. In both groups the spinal anaesthesia caused a reduction in MAP. The MAP was lower in the fentanyl group than in the ketamine group at all times. In the fentanyl group six subjects developed a haemodynamically unstable condition, while only one subject in the ketamine group was registered as such (P less than 0.05). There was no significant change in heart rate in either group. We conclude that during spinal anaesthesia patients can in part be kept haemodynamically stable by intravenous administration of ketamine.

CVP catheter electrocardiography: an alternative to radiographic control after cannulation of central veins?

We evaluated 160 electrocardiograms taken after placement of central venous catheters (CVC) to determine their locations. Usable recordings were obtained in 154 patients. Subsequent radiographs revealed 30 misplaced catheters. Twenty-five of those were detected by CVC electrocardiograms. There were five false positive and five false negative traces. The sensitivity of CVC electrocardiography was 96%, the specificity 83.3%, and the total predictive power 93.5%. Electrocardiograms obtained from guide-wires were of significantly better quality than those from 0.9% NaCl filled catheters. The technique is accurate, safe and easy to learn. It may reduce the need for routine radiographic control to less than 10% of patients.

[Indomethacin enema in treatment of postoperative pain after knee arthrotomy. A double-blind controlled trial]. / Indometacin-klysma til behandling af postoperative smerter efter knaeartrotomi. En dobbeltblind kontrolleret undersøgelse.

Twenty-three patients subjected to arthrotomy of the knee were in a double-blind trial randomly allocated to either: 1) Indomethacin 100 mg (Confortid) administered as an enema immediately before induction of anaesthesia and repeated morning and evening for the next two days, or: b) a placebo. The patients' demand for postoperative pain treatment were registered. Survival analysis was applied to the time passed from recovery from anaesthesia until patients first asked for postoperative pain treatment. A significant difference was found (p less than 0.05). The indomethacin treated group required significantly less postoperative pain treatment than did the placebo group. 36% of the patients in the indomethacin group had no additional pain treatment during the two days of observation. Indomethacin as an enema proved to be an easy and effective way of reducing postoperative pain.

[Risk and hemodynamic instability in spinal anesthesia]. / Risiko og haemodynamisk instabilitet ved spinal anaestesi.

We investigated 131 consecutive patients who were submitted to orthopaedic surgical interventions under spinal anaesthesia during a period of 12 months. Prior to operation, all of the patients were classified according to the Boston Cardiac Risk Index. Immediately before operation, approximately 500 ml sodium chloride solution was infused. Patients were registered as haemodynamically unstable when a peroperative fall in the mean arterial pressure of more than 30% occurred or when the systolic blood pressure fell to less than 80 mmHg. In 40 patients, haemodynamically unstable conditions developed peroperatively while 91 were haemodynamically stable. In Boston group III, 67% of the patients were haemodynamically unstable peroperatively which was significantly more than in the Boston group I (25%) and the Boston group II (32%) (p less than 0.005). The postoperative mortality was significantly higher (13%) among the total number of peroperatively haemodynamically unstable patients than among the peroperatively stable patients (3%) (p less than 0.05). In Boston group III, the postoperative mortality was 42% as compared with 1% and 7% in the Boston groups I and II, respectively (p less than 0.05). It is concluded that the risk of fall in blood pressure during spinal anaesthesia may be predicted by the Boston Cardiac Risk Index and that patients who develop haemodynamic instability during spinal anaesthesia have an increased risk of developing complications. These patients should be offered maximal postoperative observation and care.