Bone mass and structure in adolescents with type 1 diabetes compared to healthy peers.

SUMMARY: We measured bone mass and structure using pQCT and DXA in adolescents with Type 1 diabetes and compared the results with those of healthy peers. Our results showed that diabetes is associated with reduced bone mass and smaller bones. The diabetes-associated deficits seemed to concern male adolescents more than females. INTRODUCTION: The aim of this study was to compare bone mass and structure between adolescents with type 1 diabetes and their healthy peers. METHODS: Peripheral quantitative computed tomography (pQCT) at radius and tibia, and dual-energy X-ray absorptiometry (DXA) at lumbar spine and proximal femur were performed for 48 adolescents, 26 girls and 22 boys, with type 1 diabetes, and for healthy peers matched for age, sex, body height and weight, and pubertal maturity. RESULTS: Diabetes was associated with reduced bone mineral content (BMC) and smaller bone cross-sectional size. Diabetic boys seemed to be more affected than diabetic girls. Among the boys, the mean deficit in BMC of all measured skeletal sites was more than 10%, while among the girls it was less than 5%. CONCLUSION: In conclusion, type 1 diabetes is associated with reduced BMC and appears to affect bone cross-sectional size and cortical rigidity. The diabetes-related skeletal deficits seemed to concern male adolescents more than females. Whether diabetes-related deficits would contribute to an increased risk of fractures in adulthood or later in life remains to be confirmed.

Treatment of hyperphosphatemia, secondary hyperparathyroidism and hypocalcemia with calcium carbonate favorably modulates vaccination response in uremic rats.

AIMS: Immune dysfunction is characteristic of renal failure, leading to suboptimal antibody generation and increased susceptibility to infections. We tested whether the treatment of uremic phosphate retention by increased calcium carbonate intake will beneficially influence vaccination response in 5/6-nephrectomized rats. METHODS: The nephrectomized (uremic) and sham-operated (control) rats were either fed 0.3% calcium diet (NTX and Sham groups, respectively) or 3% high-calcium diet (Ca-NTX and Ca-Sham groups). All rats were immunized with tetanus toxoid 6 weeks after the operations, and antitoxin levels were measured 7 weeks later. RESULTS: Plasma creatinine was significantly elevated after the nephrectomy: the values (mean +/- SD) in the NTX (n = 16), Ca-NTX (n = 11), Sham (n = 14) and Ca-Sham (n = 8) groups were 97 +/- 14, 93 +/- 17, 66 +/- 7, and 69 +/- 8 micromol/l, respectively. The NTX group developed phosphate retention and secondary hyperparathyroidism, which were completely prevented by the high calcium diet. The mean tetanus antitoxin concentrations of the groups were: NTX 0.25 +/- 0.32; Ca-NTX 0.45 +/- 0.44; Sham 0.58 +/- 0.24 and Ca-Sham 0.64 +/- 0.25 IU/ml (log of geometric mean concentration). The antibody response in the NTX group was significantly lower, i.e. 43% of that in the Sham group (p = 0.003), while the response in the Ca-NTX group was not different from that in the Sham group. The tetanus response of all the uremic rats inversely correlated with the plasma levels of phosphate (r = 0.447, p = 0.02), parathormone (r = -0.409, p = 0.03) and creatinine (r = 0.578, p = 0.002). DISCUSSION: We conclude that renal failure impairs vaccination response in rats, the impairment of which can be favorably modulated by phosphate-binding and PTH-suppressing high-calcium diet.

Time course of serum prolactin and sex hormones following successful renal transplantation.

BACKGROUND: Chronic renal failure is commonly associated with disturbances in hypothalamic-pituitary-gonadal function. METHODS: The gonadotrophins, prolactin and estradiol or testosterone levels were measured immediately before renal transplantation, at discharge from the transplantation unit (19 +/- 8 days after Tx) and 6 months after transplantation in 21 patients, 7 females and 14 males, age range 21-60 years. RESULTS: The mean prolactin level was high during uremia and decreased rapidly after transplantation, from 441 to 167 mU/l in males and from 1,057 to 521 mU/l in females. Hypergonadotrophism was seen in most uremic patients, with the mean LH and FSH levels of 14.2 and 6.0 U/l in males and 14.7 and 4.0 U/l in females, respectively. A temporary change to hypogonadotrophic hypogonadism took place 2-3 weeks after transplantation and was followed by normalization of the hypothalamic-gonadal function. The levels of circulating sex steroids were suppressed when the patients were discharged from the transplantation unit but returned to the normal range at 6 months. CONCLUSIONS: We conclude that renal transplantation corrects the hyperprolactinemia induced by uremia and is followed by rapid onset of restoration of the hypothalamic-pituitary-gonadal axis.

Thyroid hormone substitution therapy rapidly enhances left-ventricular diastolic function in hypothyroid patients.

OBJECTIVE: Alterations in thyroid status may lead to changes in both systolic and diastolic function of the heart. Pulsed Doppler echocardiography is a reliable non-invasive means of assessing left-ventricular (LV) diastolic function. The aim of the present study was to evaluate LV diastolic function in patients with primary hypothyroidism receiving thyroxine therapy. METHODS: Twelve patients (all females, mean age 47 +/- 17, range 16-69 years) with primary hypothyroidism were studied by pulsed Doppler echocardiography. The first examination was made before the start of thyroxine substitution and the second at 37-68 (mean 53 +/- 10) days after commencing thyroxine treatment (mean dose 136 +/- 22 microg/day). RESULTS: During thyroxine substitution therapy, the hypothyroid patients became clinically euthyroid and serum T4 increased from 51 +/- 21 to 119 +/- 24 nmol/l; TSH decreased from 50.4 +/- 55.3 to 1.2 +/- 1.5 mU/l. During therapy, heart rate increased from 61 +/- 8 to 68 +/- 10 (p = 0.05). The LV posterior wall (7.8 +/- 1.0 mm) and interventricular septum thickness (8.0 +/- 1.4 mm) were significantly greater in hypothyroid patients than in the control subjects (6.4 +/- 1.0 mm, p = 0.007 and 6.8 +/- 1.0 mm, p = 0.04, respectively). There was no significant change in LV dimensions and wall thickness during follow-up. E/A(max) increased significantly during treatment (from 1.679 +/- 0.432 to 1.947 +/- 0.335, p = 0.006). The isovolumic relaxation time shortened significantly (from 88 +/- 23 ms to 75 +/- 24 ms, p = 0.005). CONCLUSIONS: The present study shows that LV diastolic function as assessed by pulsed Doppler echocardiography in hypothyroid patients is enhanced by thyroxine therapy during a rather short follow-up period.

Constant, but not pulsed calcitriol suppresses hemodialysis patients' antigen-induced lymphocyte proliferation.

BACKGROUND/AIMS: In vitro constant calcitriol [1,25-(OH)(2)D(3)] inhibits healthy individuals' T lymphocyte proliferation at supraphysiological concentrations. In contrast, among hemodialysis patients, intravenous 1,25-(OH)(2)D(3) pulse therapy of secondary hyperparathyroidism has been shown to be even immunostimulatory. We studied the effect of in vitro constant and intermittent 1, 25-(OH)(2)D(3) on lymphocyte antigen response of hemodialysis patients. METHODS: Twelve hemodialysis patients' peripheral blood mononuclear cells were stimulated with purified protein derivative of tuberculin (12.5, 25 and 50 mg/l) or tetanus toxoid (TT; 1,000, 5, 000 and 10,000 Lf/l, limit of flocculation) for 7 days. Constant 1, 25-(OH)(2)D(3) was added to all cultures at concentrations of 0, 10(-10) or 0.25 x 10(-9) mol/l (0, 42 and 105 ng/l) and to half of the cultures additionally as a 0.75 x 10(-9) mmol/l (315-ng/l) pulse on the 5th culture day. RESULTS: TT-induced lymphocyte proliferation was statistically related to a constant 1,25-(OH)(2)D(3) concentration (p = 0.001, analysis of variance). With constant 1, 25-(OH)(2)D(3) concentrations of 0, 42 and 105 ng/l, the TT-induced responses were 1.53, 1.44 and 1.40 log cpm, respectively (mean of TT concentrations). The responses of the (additionally) pulse-treated cells [1.65, 1.50 and 1.40 log cpm; concentrations of constant 1, 25-(OH)(2)D(3) as above] were similar to those of the nonpulsed cells. Thus constant, but not pulsed 1,25-(OH)(2)D(3) decreased the TT responses. On the purified protein derivative of tuberculin response, neither constant nor pulsed 1,25-(OH)(2)D(3) had any significant effect. CONCLUSIONS: The decline of TT response with constant 1,25-(OH)(2)D(3) corresponds with findings on immunosuppressive action of 1,25-(OH)(2)D(3) in previous studies done on normal subjects' cells. This was not seen with intermittently applied 1,25-(OH)(2)D(3). These results support the previous concept that intermittent 1,25(OH)(2)D(3) therapy is not immunosuppressive in hemodialysis patients.

Adequate seroresponse to influenza vaccination in dialysis patients.

BACKGROUND: Hemodialysis (HD) patients are immunocompromised, and they have been shown to react suboptimally to recommended vaccinations. Advances in dialysis therapy and other supportive measures may theoretically result in better immune system functions. Clinical evidence supporting this theory has, however, not been presented. With influenza vaccination response, we tried to address this question. METHODS: 42 HD and 15 continuous ambulatory peritoneal dialysis (CAPD) patients were vaccinated with a trivalent influenza vaccine, and the seroresponses at 5 weeks were measured. The results were compared with those of similarly vaccinated 20 nephrology outpatient clinic patients with varying degrees of renal insufficiency and those of 31 cardiac patients with normal renal function. RESULTS: The dialysis patients had higher prevaccination titers of hemagglutination-inhibiting (HI) antibodies to all three vaccine virus antigens than the other groups due to more frequent previous vaccinations. The dialysis patients exhibited lower antibody increases, but an almost comparable proportion of them reached a protective antibody level (HI titers > or =40) 5 weeks after vaccination [A/H3N2: 61% (cardiac patients), 35% (nephrology outpatient clinic patients), 67% (CAPD), and 36% (HD); A/H1N1: 71, 70, 80 and 60; B: 97, 90, 80, and 76%, respectively]. Among the HD group, all patients receiving parenteral calcitriol except 1 (83%), but only 50% of the other HD patients produced protective antibody titers at least to two out of three vaccine virus antigens. No other patient- or HD treatment-associated parameter was significantly related to the vaccination-induced antibody response. CONCLUSIONS: We conclude that influenza vaccination of dialysis patients according to current recommendations may be effective. Additionally, our results suggest that parenteral calcitriol treatment may augment the immune response of HD patients even in a clinically relevant way, an effect so far shown only in in vitro studies.

QTc dispersion increases during hemodialysis with low-calcium dialysate.

BACKGROUND: The risk of ventricular arrhythmias is known to increase during hemodialysis (HD) treatment, but the cause of this phenomenon has remained unidentified. QT dispersion (= QTmax - QTmin) reflects heterogeneity of cardiac repolarization, and increased dispersion is known to predispose the heart to ventricular arrhythmias and sudden cardiac death. METHODS: We studied the effect of dialysate calcium concentration on cardiac electrical stability during HD treatment in 23 end-stage renal disease patients. Three HD treatments were applied with dialysate Ca++ concentrations of 1.25 mmol/L (dCa++1.25), 1.5 mmol/L (dCa++1.5), and 1.75 mmol/L (dCa++1.75). The QTc interval and QTc dispersion were measured before and after the three sessions. RESULTS: With the dCa++1.5 and dCa++1.75 dialyses, serum Ca++ increased and the QTc interval remained stable (dCa++1.5) or decreased (dCa++1.75), but no significant change was noted in QTc dispersion. With dCa++1.25 HD, serum Ca++ decreased (1.24 +/- 0.11 vs. 1.20 +/- 0.09 mmol/L, P < 0. 05), and both the QTc interval (403 +/- 27 vs. 419 +/- 33 ms, P < 0. 05) and QTc dispersion increased (38 +/- 19 vs. 49 +/- 18 ms, P < 0. 05). The change in the QTc interval correlated inversely with the change in serum Ca++ (r = -0.68, P < 0.0001). Except for serum Ca++ and plasma intact parathyroid hormone, predialysis and postdialysis values in other blood chemistry, blood pressure, heart rate, body weight, and total ultrafiltration were equal in the three dialysis sessions. CONCLUSION: This study is the first, to our knowledge, to demonstrate that HD increases QTc dispersion if a low-calcium (dCa++1.25) dialysate is used. This indicates that the use of low-calcium dialysate may predispose HD patients to ventricular arrhythmias and that perhaps it should be avoided, at least when treating patients with pre-existing cardiac disease.

Hemodialysis with high-calcium dialysate impairs cardiac relaxation.

BACKGROUND: During hemodialysis (HD), serum ionized calcium is directly related to the dialysate calcium concentration. We have recently shown an acute induction of hypercalcemia to impair left ventricular (LV) relaxation. In the current study we sought to establish whether changes in serum Ca++ also affect LV function during HD. METHODS: We echocardiographically examined the LV relaxation and systolic function of 12 patients with end-stage renal disease before and after three HD treatments with dialysate Ca++ concentrations of 1.25 mmol/liter (dCa++1.25), 1.5 mmol/liter (dCa++1.50), and 1.75 mmol/liter (dCa++1.75), respectively. Age- and sex-matched healthy controls were also examined echocardiographically. RESULTS: The LV posterior wall thickness and the interventricular septum thickness, and the LV end-diastolic dimension and the end-systolic dimensions were significantly greater in the patients when compared with the controls, and the LV fractional shortening, the ratio of peak early to peak late diastolic velocities (E/Amax), and the isovolumic relaxation time (IVRT) showed impairment of LV relaxation and systolic function in the patients. Serum ionized calcium increased significantly during the dCa++1.5 HD (1.24 +/- 0.10 vs. 1.34 +/- 0.06 mmol/liter, P = 0. 004) and dCa++1.75 HD (1.19 +/- 0.10 vs. 1.47 +/- 0.06 mmol/liter, P = 0.002), and plasma intact parathyroid hormone decreased significantly during the dCa++1.75 HD (medians 8.2 vs. 2.7 pmol/liter, P = 0.002). LV systolic function was not altered during any of the treatments. The changes in E/Amax and IVRT suggested impairment of relaxation during all sessions, but only during the dCa++1.75 HD was the impairment statistically significant (E/Amax 1. 153 +/- 0.437 vs. 0.943 +/- 0.352, P < 0.05; IVRT 147 +/- 29 vs. 175 +/- 50 msecond, P < 0.05). CONCLUSION: HD with high-calcium (dCa++1. 75 mmol/liter) dialysate impairs LV relaxation when compared with lower calcium dialysate (dCa++1.25 and dCa++1.5 mmol/liter) treatments.

Pharmacokinetics of clodronate in peritoneal dialysis patients.

OBJECTIVE: To study the pharmacokinetics of clodronate in patients on continuous ambulatory peritoneal dialysis (CAPD). DESIGN: A single intravenous dose pharmacokinetic study. SETTING: University hospital. PATIENTS: Ten CAPD patients (3 female, 7 male, age 39-79 year, median 55). METHODS: Clodronate disodium in serum, urine, and dialysate was collected for 24 hours and analyzed by capillary gas chromatography with mass-selective detection. RESULTS: Only 7% of the infused dose of clodronate was eliminated through peritoneal dialysis during 24 hours. Clearance via CAPD (CL[CAPD]) was 2.4 +/- 0.6 mL/min, which was less than 10% of the total serum clearance (CL(tot), 26.0 +/- 19.3 mL/min). Even the kidneys were a more important route of elimination than CAPD in those patients with residual diuresis of more than 500 mL/24 hr. However, in all patients most of the clodronate serum clearance (77% +/- 13%) took place via routes other than peritoneal dialysis or kidneys, that is, via nonrenal-non-CAPD clearance (CL[NRD]). CL(NRD) most likely represents the part of the drug deposited in the skeleton. There was a positive correlation between CL(NRD) and the plasma intact parathyroid hormone concentration. CONCLUSIONS: CAPD removed clodronate poorly from the circulation. Most clearance took place via routes other than CAPD or kidneys. This CL(NRD) most likely represents the skeletal deposition of the drug, and this is related to the severity of hyperparathyroidism. When treating CAPD patients with hyperparathyroid bone disease, the administration of clodronate should be adjusted as in those subjects with severe renal failure.

Calcium infusion and left ventricular diastolic function in patients with chronic renal failure.

BACKGROUND: Left ventricular (LV) function is sensitive to disorders in calcium metabolism. Most previous reports have focused on the effects of calcium on systolic performance. We studied the acute effect of calcium infusion on LV diastolic function in patients with moderate to severe chronic renal failure (CRF) and secondary hyperparathyroidism (SHP). METHODS: We infused calcium gluconate at a constant rate of 45 mumol/kg/h to 14 patients with severe to moderate CRF and SHP. Our aim was to reach slightly supranormal levels of serum ionized calcium (1.35-1.45 mmol/l). LV diastolic function was assessed by pulsed Doppler echocardiography before and after the calcium infusion. The echocardiographic indices were compared to those of 14 age- and sex-matched healthy controls. RESULTS: Before calcium infusion the patients had significantly greater LV dimensions than the controls, but there was no differences in the diastolic indices. During calcium infusion, serum ionized calcium increased from 1.18 +/- 0.03 to 1.40 +/- 0.03 mmol/l (P < 0.0001) and plasma intact PTH decreased from 38.6 +/- 5.6 to 9.0 +/- 2.2 pmol/l (P < 0.0001). Calcium infusion did not affect the LV dimensions or fractional shortening. The peak early diastolic velocity (Emax) decreased and peak late diastolic velocity (Amax) increased, and their relationship decreased significantly (1.552 +/- 0.586 vs 1.414 +/- 0.535 m/s, P = 0.03). These changes reflect impairment of LV diastolic function. CONCLUSIONS: Induction of acute hypercalcaemia by calcium infusion impairs LV diastolic function in patients with CRF and SHP.

Measurement of serum ionized magnesium in CAPD patients.

OBJECTIVE: To evaluate the magnesium status of continuous ambulatory peritoneal dialysis (CAPD) patients using a new method for assessing the level of the ionized fraction of serum magnesium. DESIGN: Serum ionized magnesium was measured in CAPD patients using the ion-selective electrode for Mg2+. SETTING: The Dialysis Unit of Tampere University Hospital. PATIENTS: Twenty-six patients on CAPD (age: 21-81 years, mean 54 +/- 16 years; duration of CAPD: 3-52 months, mean 13 months), and 26 sex- and age-matched healthy controls. RESULTS: Both serum ionized magnesium (0.73 +/- 0.11 mmol/L vs 0.56 +/- 0.07 mmol/L, p < 0.001) and total magnesium (1.11 +/- 0.22 vs 0.81 +/- 0.08 mmol/L, p < 0.01) were higher in CAPD patients than in sex- and age-matched controls. The ionized magnesium fraction of total magnesium was slightly lower in dialysis patients in spite of the fact that 16/26 patients had serum albumin less than 36 g/L. Hypermagnesemia (mean serum ionized magnesium 0.78 +/- 0.10 mmol/L) was observed in the 13 of 26 patients with 0.75 mmol/L Mg2+ dialysate; those with lower magnesium dialysate (Mg2+ 0.50 mmol/L in 10/26 and Mg2+ 0.25 mmol/L in 3/26) had mean serum ionized magnesium at the upper normal margin (0.69 +/- 0.10 mmol/L). CONCLUSION: In CAPD patients with Mg2+ 0.5-0.75 mmol/L in their dialysis fluid, both serum ionized and total magnesium concentrations were higher but the ionized/total magnesium ratio was lower than in healthy control subjects. Use of ion-selective electrodes to measure ionized magnesium may be a more useful methodology than measuring total magnesium in the evaluation of magnesium status of CAPD patients, because it is not influenced by hypoalbuminemia or increased complexed fraction of magnesium often present in dialysis patients.

Sequential changes in vitamin D and calcium metabolism after successful renal transplantation.

A prospective study was made of sequential changes in the metabolism of vitamin D and calcium in 19 allograft recipient during the first year after successful renal transplantation. All but one of the patients received cyclosporine A combined with corticosteroids and azathioprine as immunosuppressive therapy. Shortly after transplantation most patients showed transient hypocalcemia and hypophosphatemia. At the time of transplantation 17 of 19 patients had an elevated plasma intact parathyroid hormone (PTH) level, and at the close of follow-up one in four patients. In six other patients intact PTH was within the reference range, but high in relation to simultaneously measured serum ionized calcium. According, one year after transplantation less than half of the patients showed complete resolution of hyperparathyroidism. The change towards normal in the metabolism of vitamin D began within the first post-transplantation week irrespective of the onset of diuresis. One to two weeks after transplantation 1,25(OH)2D3 and 24,25(OH)2D3 reached the lower limit of normal range. In these renal allograft recipients who received cyclosporine A the long-term values of serum 1,25(OH)2D3 did not differ from those of normal subjects.