Rate dependence of acute PTH release and association between basal plasma calcium and set point of calcium-PTH curve in dialysis patients.

BACKGROUND: In vivo, the control of calcium-mediated acute PTH release during induced hypo- or hypercalcaemia is linked not only to plasma calcium concentration per se but also to the rate and direction of calcium change. In fact, during induced hypocalcaemia, the predominant mechanism that causes PTH to be released is the reduction of plasma Ca(2+) irrespective of the absolute starting concentration of ionized calcium. This mechanism, which is rate-dependent and even activated in conditions of hypercalcaemia, may be involved in the association, reported in several papers, between the basal Ca(2+) and the set point of the calcium-PTH curve. METHODS: The calcium-PTH relationship was studied in 12 dialysis patients under conditions of induced low and high predialysis plasma Ca(2+). At each level of basal Ca(2+), dynamic tests were conducted using two methodological approaches. In method A patients underwent low (0.5 mmol/l) calcium dialysis in the stimulation test and high (2 mmol/l) calcium dialysis in the inhibition test, while the dialysate calcium (CaD) was kept constant during each test. In this way a higher but variable rate of change in plasma Ca(2+) was achieved. In method B, CaD was progressively decreased (stimulation test) and increased (inhibition test) during the tests in order to obtain a lower but more constant rate of change in plasma Ca(2+). Consequently, for each patient, four calcium-PTH curves were produced: low basal Ca(2+) with methods A and B, and high basal Ca(2+) with methods A and B. RESULTS: Basal plasma Ca(2+) was similar in A and B at low (1.16+/-0.02 vs 1.15+/-0.02 mmol/l) and high (1.25+/-0.02 vs 1.26+/-0.02 mmol/l) basal plasma Ca(2+). The set point was higher in A than in B both at low (1.12+/-0.02 vs 1.10+/-0.02 mmol/l, P=0.01) and high (1.20+/-0.02 vs 1.16+/-0.02 mmol/l, P=0.03) basal Ca(2+) as was the slope (542+/-41 vs 426+/-44%/mmol, P=0.02; 615+/-73 vs 389+/-25%/mmol, P=0.01). No significant difference was found between A and B as regards minimal PTH and plasma Ca(2+) at minimal PTH (Camin) in both calcaemic states. Maximal PTH was slightly higher in B at low (510+/-97 vs 548+/-107 pg/ml, P=NS) and high basal plasma Ca(2+) (410+/-97 vs 464+/-108 pg/ml, P=0.02). Plasma calcium at maximal PTH (Camax) was significantly higher in A (1.1+/-0.03 vs 0.99+/-0.02 mmol/l, P=0.001) at high basal plasma Ca(2+). The set point was strictly related to basal plasma Ca(2+) in both methods, but the slope of the linear regression was significantly steeper with method A. The set point was predicted to increase by 0.881 (CI 0.772-0.990) mmol/l for each mmol/l of increase in basal plasma Ca(2+) with method A and by 0.641 (CI 0.546-0.737) mmol/l for each mmol/l of increase in basal plasma Ca(2+) with method B. CONCLUSIONS: (i) Higher and variable rates of change in plasma Ca(2+) produce a higher set point value and a steeper slope of the calcium-PTH curve when compared to lower and more constant rates of calcium change. (ii) The different slope of the linear correlations between basal plasma Ca(2+) and set point in the two methods suggests that the rate-dependent mechanism of acute PTH release plays a significant role in the association between set point and basal plasma Ca(2+). (iii) The significance of the set point is questionable when the calcium-PTH curve is carried out in vivo.     

Dynamics of secretion and metabolism of PTH during hypo- and hypercalcaemia in the dog as determined by the 'intact' and 'whole' PTH assays.

BACKGROUND: Recent evidence has shown that the assay for 'intact' parathyroid hormone (I-PTH) not only reacts with 1-84 PTH but also with large non-1-84 PTH fragments, most of which is probably 7-84 PTH. As a result, an assay specific for 1-84 PTH named 'whole' PTH (W-PTH) has been developed. The present study was designed: (i) to determine whether the W-PTH assay reliably measures PTH values in the dog; (ii) to evaluate differences between the W-PTH and I-PTH assays during hypo- and hypercalcaemia; and (iii) to assess the peripheral metabolism of W-PTH and I-PTH. METHODS :In normal dogs, hypocalcaemia was induced by EDTA infusion and was followed with a 90 min hypocalcaemic clamp. Hypercalcaemia was induced with a calcium infusion. RESULTS: I-PTH and W-PTH values increased from 36+/-8 and 13+/-3 pg/ml (P=0.01) at baseline to a maximum of 158+/-40 and 62+/-15 pg/ml (P=0.02 vs I-PTH) during hypocalcaemia. The W-PTH/I-PTH ratio, 38+/-4% at baseline, did not change during the induction of hypocalcaemia, but sustained hypocalcaemia increased (P<0.05) this ratio. During hypercalcaemia, maximal suppression for I-PTH was 2.0+/-0.5 and only 5.7+/-0.6 pg/ml for W-PTH, due to a decreased sensitivity of the W-PTH assay at values <5 pg/ml. The disappearance rate of PTH was determined in five additional dogs which underwent a parathyroidectomy (PTX). At 2.5 min after PTX, W-PTH was metabolized more rapidly, with a value of 25+/-2% of the pre-PTX value vs 30+/-3% for I-PTH (P<0.05). CONCLUSIONS: (i) The W-PTH/I-PTH ratio is less in the normal dog than in the normal human, suggesting that the percentage of non-1-84 PTH measured with the I-PTH assay is greater in normal dogs than in normal humans; (ii) the lack of change in the W-PTH/I-PTH ratio during acute hypocalcaemia is different from the situation observed in humans; and (iii) the dog appears to be a good model to study I-PTH and W-PTH assays during hypocalcaemia.     

PTH pulsatility but not calcium sensitivity is restored after total parathyroidectomy with heterotopic autotransplantation

In healthy humans, parathyroid hormone (PTH) is secreted via basal mode with superimposed oscillatory bursts every 8 to 12 min. Amplitude and frequency changes mediate the instantaneous response of the parathyroids to changes in ambient Ca(2+) concentrations. The parathyroid gland tetrad may be synchronized by autonomic innervation. This study investigated the effect of total parathyroidectomy and heterotopic autotransplantation of parathyroid tissue (PTX) on PTH secretion patterns in nine patients with end-stage renal disease. Intact-PTH versus time concentration profiles were obtained early (1 to 8 wk, n = 4) or late (15 to 33 mo, n = 5) after PTX. In four patients late after PTX, Ca(2+) responsiveness of PTH secretion was additionally investigated by citrate and calcium clamp studies. The nonrandomness of plasma PTH fluctuations was assessed by the approximate entropy (ApEn) statistic, and secretion characteristics by multiparametric deconvolution analysis. Results were compared with those of matched normal subjects and chronic renal failure (CRF) patients without PTX. PTH burst frequency was 2.9 +/- 0.1 h(-1) early and 7 +/- 0.4 h(-1) late after PTX as compared with 8.1 +/- 0.4 h(-1) in CRF and 7 +/- 0.3 h(-1) in healthy controls. Fractional pulsatile PTH secretion was diminished after PTX (18 +/- 2%) compared with healthy controls (32 +/- 5%, P < 0.05) and CRF patients (25 +/- 4%, P = 0.05). The orderliness of PTH release was significantly reduced after PTX (ApEn: 1.59 +/- 0.03 versus 1.41 +/- 0.09 in healthy and 1.46 +/- 0.03 in CRF controls, P < 0.01). Acute hypocalcemia elicited a lesser increase in pulsatile PTH secretion in PTX patients (147 +/- 134%) than in the CRF (500 +/- 92%, P = 0.05) and healthy controls (1410 +/- 290%, P < 0.05), mainly due to a diminished mass of PTH secreted per burst. Pulsatile PTH secretion was also resistant to hypercalcemia, wherein the suppression of burst mass was significantly reduced compared with that in healthy controls. In conclusion, pulsatile PTH secretion is partially restored within 2 yr of PTX. However, the capacity of the autotransplanted tissue to adapt to changes in ionized calcium remains profoundly disturbed.     

Effect of Direction and Rate of Change of Calcium on Parathyroid Hormone Secretion in Uraemia

We have studied the control of amino-terminal parathyroid hormone(PTH) secretion in haemodialysis patients in response to slowor fast calcium infusion and during acute hypocalcaemia. Innine patients, fast calcium infusion (0.4 mmol/kg bodyweightper hour) for 15 min increased ionised calcium and reduced PTH,with an initial t of 12.8 min. After the infusion had ceased,calcium decreased steadily, and PTH increased, mean PTH reachingbaseline values when calcium was still significantly greaterthan pre-infusion values. During slow calcium infusion for 2.5h (0.1 mmol/kg bodyweight per hour), parathyroid suppressionwas evident at 15 min, when the calcium increment was only 0.03mM. After 60 min, PTH did not decrease further despite progressivehypercalcaemia. Hypocalcaemic haemodialysis led to rapid increasesin PTH. After 15 min, the mean calcium decrement was 0.09 mM(P<0.01) and the mean PTH increment was 283 pg/ml (P<0.01).The parathyroid response was maximal at 30 min, and did notincrease subsequently, despite progressive hypocalcaemia fora further 90 min. During recovery from hypocalcaemia, PTH reducedand, despite comparable hypocalcaemia, PTH during periods ofincreasing calcium was always lower at a given calcium concentrationthan while calcium was decreasing. This influence of the directionof change of calcium was not seen during hypocalcaemia. Theresults showed that even in advanced renal disease, the parathyroidglands are highly responsive to small initial increments (0.03mM) and decrements (0.09 mM) in blood calcium, though less soto further perturbation of blood calcium. During hypocalcaemia,the parathyroid glands respond to both the absolute value ofblood calcium and also to the direction of change of calcium.     

Suppression of PTH and decreased action on bone are partially responsible for the low calcemic activity of 22-oxacalcitriol relative to 1,25-(OH)2D3.

We previously showed that OCT, an analog of 1,25-(OH)2D3 with little calcemic activity, can decrease PTH mRNA levels in normal rats and inhibit PTH secretion in cultured bovine parathyroid cells with the same potency as 1,25-(OH)2D3 and that in normal rats fed a normal calcium diet, administration of OCT (500 ng) for 5 days did not increase plasma Ca. Thus, to determine if PTH suppression by OCT contributes to its lack of calcemic activity and to further characterize the effects of OCT on Ca metabolism, we performed several studies in parathyroidectomized (PTX) rats. PTX rats, maintained on a normal diet (0.9% Ca), received daily injections of vehicle, 1,25-(OH)2D3 (200 ng/day), or OCT (200 ng/day) for 6 days. Plasma Ca was measured daily. Plasma Ca in control rats stayed between 6.60 and 7.40 mg/dl, whereas Ca increased to 12.9 +/- 0.42 mg/dl in 1,25-(OH)2D3-treated rats and to 9.53 +/- 0.35 mg/dl in OCT-treated rats after 6 days. With a Ca-deficient diet, control rats maintained a plasma Ca between 4.25 and 4.60 mg/dl, but Ca increased to 13.7 +/- 0.24 mg/dl with 1,25-(OH)2D3 and to 7.29 +/- 0.17 mg/dl with OCT. Since the elevation in Ca by OCT was similar with both diets, OCT appears to act primarily on bone. PTX rats were infused with PTH (1.84 micrograms/kg/day) via an Alzet pump to achieve normal plasma Ca and then treated daily with either vehicle or OCT (200 ng/day). After 6 days, OCT increased serum Ca to 10.7 +/- 0.21 mg/dl over a control value of 8.58 +/- 0.29 mg/dl.(ABSTRACT TRUNCATED AT 250 WORDS)     

Decreased renal transplant function after parathyroidectomy.

BACKGROUND: Persistent secondary hyperparathyroidism after renal transplantation may require parathyroidectomy (PTX). Clinical experience suggests that these patients commonly develop decreased renal function thereafter. METHODS: To test this notion, we evaluated 76 transplant patients who underwent pararhyroidectomy between 1997 and 2003. RESULTS: In half the patients (47%), creatinine clearance decreased >20% (before vs after PTX, 57 +/- 21 vs 38 +/- 17 ml/min, P = 0.001). The patients with decreased creatinine clearance had higher parathyroid hormone (PTH) concentrations before and lower values after PTX compared with those who did not (594 +/- 392 vs 447 +/- 234 pg/ml before PTX, P = 0.03; 35 vs 123 pg/ml thereafter, P = 0.002). They also had lower serum calcium concentrations after PTX (2.0 vs 2.2 mmol/l, P = 0.005) and they required more calcium and vitamin D analogues. These patients also more commonly underwent total PTX with autotransplantation, compared with subtotal (75 vs 50%, P = 0.03). However, in multivariate analysis, only the delta PTH decline (%) after PTX was a significant predictor of deteriorating renal function (P = 0.005) and was correlated with the creatinine clearance decrease (R = 0.369, P = 0.001). Prospectively measured inulin and para-amino-hippuric acid (PAH) clearance decreased significantly after PTX in a subgroup of 19 patients (inulin before vs after PTX 67 vs 55 ml/min/1.73 m(2), P = 0.001; PAH 360 vs 289 ml/min/1.73 m(2), P = 0.001). Transplant biopsies revealed calcification in 70% of biopsied cases. CONCLUSION: Since PTH has a known positive regulatory effect on renal perfusion and glomerular filtration rate, we conclude that relative hypoparathyroidism after PTX is the main mechanism contributing to decreased renal function in these patients. There was no difference in 10-year-graft survival between the deteriorating and the non-deteriorating group.     

PTH secretion in patients with chronic renal failure assessed by a modified CiCa clamp method: effects of 1-year calcitriol therapy

BACKGROUND: Secondary hyperparathyroidism (secondary HPT) in patients with chronic renal failure (CRF) is characterized by parathyroid gland hyperplasia and an intrinsic defect in the recognition of parathyroid hormone (PTH) secretion. Conflicting results have been reported regarding the set point for calcium-regulated PTH release and its modification by calcitriol therapy in hemodialysis patients. Additionally, the effect of calcitriol on the calcium/PTH relationship in predialysis CRF patients with early secondary HPT has not been investigated. Our objective in this controlled study was to investigate the calcium/PTH relationship and to determine the calcium set point in patients with early stages of CRF before and after a 1-year treatment with calcitriol and in normal volunteers. METHODS: Nine patients with an early stage of CRF (GFR between 20 and 50 ml/min x 1.73 m2 b.s.) aged 35-77 years and 13 healthy volunteers (HV) aged 26-60, years were included in the study. All participants were investigated by sequential lowering and raising of serum calcium levels comprising the following phases: blood-ionized calcium (Ca2+) was lowered by about 0.2 mmol/l (3 steps), steady-state hypocalcemia of Ca2+ 0.2 mmol/l below the baseline (step 4), stop of the infusion for 5 minutes (step 5), Ca2+ was raised to about 0.2 mmol/l above baseline (steps 6 and 7), and a steady state hypercalcemia of Ca2+ 0.2 mmol/l above baseline (step 8). Ionized calcium and intact PTH (iPTH) were measured at 30 time points during 240 minutes. The calcium set point was determined using the classical 4-parameter model. The CiCa clamp test was performed before and after a 1-year treatment with 0.5 microg of calcitriol thrice weekly. RESULTS: No differences in the set point were observed between HV and CRF patients with early secondary HPT. Four of 9 patients responded to calcitriol treatment with a decrease in basal serum iPTH levels ("responders"). There was no difference between renal function (GFR 18 +/- 6 vs. 17 +/- 8 ml/min x 1.73 m2 b.s.), set point (Ca2+ 1.07 +/- 0.13 vs. 1.07 +/- 0.06 mmol/l) and suppressibility of PTH secretion (PTHmin% 7.3 +/- 1.6 vs. 8.2 +/- 2.9) in responders vs non-responders, nor did these values change after treatment with calcitriol. PTHmin% decreased significantly in the whole group after treatment (10.4 +/- 8.5 vs. 7.8 +/- 2.4). CONCLUSIONS: Although the calcium set point was not different in predialysis CRF patients with early secondary HPT compared to HV, calcitriol treatment improved the calcium-related suppression of PTH secretion (PTHmin%).     

Effects of calcitriol on parathyroid function and on bone remodelling in secondary hyperparathyroidism.

BACKGROUND: Secondary hyperparathyroidism (2HPT) develops in chronic renal failure due to disturbances of calcium, phosphorus and vitamin D metabolism. It is characterized by high turnover bone disease and an altered calcium-parathyroid hormone (PTH) relationship. Calcitriol has been widely used for the treatment of 2HPT. However, it remains controversial whether calcitriol is capable of inducing changes of the calcium-PTH curve. The aim of the present study was to examine this issue and to determine the effect of calcitriol on bone remodelling in patients with severe 2HPT. METHODS: We evaluated 16 chronic haemodialysis patients with severe 2HPT (PTH 899+/-342 pg/ml). Each patient underwent a dynamic parathyroid function test (by infusion of calcium gluconate and sodium citrate) and a bone biopsy before and after a 6 month period of i.v. calcitriol therapy (CTx). RESULTS: After treatment, eight patients were identified as calcitriol responders and the other eight as non-responders, based on plasma PTH level (<300 pg/ml for responders and >300 pg/ml for non-responders). The first group had higher plasma 25OHD(3) levels (39+/-8 vs 24+/-7 ng/ml, P<0.005). As to the calcium-PTH curve, we found differences in slope (-12.7+/-5.2 vs -21.7+/-11.4, P=0.05), basal/maximum PTH ratio (48.8+/-14.9 vs 71.05+/-20.1%, P=0.01) and time to achieve hypocalcaemia (79.0+/-13.5 vs 94.3+/-13.7 min, P<0.001). Initial histomorphometric parameters did not allow identification of the different groups. After the 6-month CTx, alterations in the calcium-PTH curve were clearly seen in responders [a drop in maximum PTH (from 1651+/-616 to 938+/-744 pg/ml, P<0.05) and minimum PTH (from 163+/-75.4 to 102.2+/-56.7 pg/ml, P<0.005)], associated with an increase in minimum/basal PTH ratio (from 23.3+/-11.6 to 34.5+/-20.4%, P<0.05) and maximum calcium (from 0.99+/-0.07 to 1.1+/-0.09 mmol/l, P<0.05). Set point and slope were not altered after calcitriol treatment, in responders (set point=1.17+/-0.08 vs 1.15+/-0.1 mmol/l, ns; slope=-12.7+/-5.2 vs -12.9+/-9.3, ns) or non-responders (set point=1.21+/-0.05 vs 1.21+/-0.2 mmol/l, ns; slope=-21.7+/-11.4 vs -17.3+/-8.4, ns). Bone formation parameters were reduced in all patients [osteoid surface (OS/BS)=from 57.1+/-21.6 to 41.6+/-26%, P<0.05 for responders, and from 76.7+/-12 to 47.1+/-15%, P<0.001 in non-responders], but non-responders had increased bone resorption [eroded surface (ES/BS)=7.1+/-3.4 vs 16.6+/-4.9, P<0.05]. CONCLUSION: Calcitriol had non-uniform effects on parathyroid function and bone remodelling in uraemic patients. Non-responders exhibited a decoupled remodelling process that could further influence mineral balance or possibly also bone structure. To avoid such undesirable effects, early identification of non-responder patients is crucial when using calcitriol for the treatment of 2HPT.     

Bone mineral density and biochemical markers of bone turnover in patients with predialysis chronic renal failure.

BACKGROUND: Metabolic bone disease might commence early in the course of renal failure. This study therefore examined the frequency and severity of the skeletal changes in predialysis chronic renal failure by measurements of bone mineral density (BMD), biochemical markers of bone turnover (osteocalcin, bone-specific alkaline phosphatase, carboxy terminal propeptide of type I collagen, and carboxy-terminal telopeptide of type I collagen), parathyroid hormone (PTH), ionized calcium (Ca++), phosphate (P), and vitamin D metabolites. METHODS: The study was performed in 113 patients (male/female: 82/31) with chronic renal diseases [mean glomerular filtration rate (GFR) of 37 ml/min] and in 89 matched, normal control subjects. RESULTS: The patients had significantly (P<0.05) reduced BMD in the spine (-6.3%), the femur (-12.1%), the forearm (-5.7%), and the total body (-4.2%) as compared with the control subjects. Dividing the patients into quartiles according to GFR revealed that BMD decreased with the gradual decline in renal function at all the measured skeletal sites, but was most pronounced in the femur: 0.63+/-0.03, 0.74+/-0.02, 0.77+/-0.02, and 0.82+/-0.03 g/cm2 in each quartile from lowest to highest GFR compared with 0.82+/-0.02 g/cm2 in the control group (P<0.0001). All of the measured bone markers showed increasing plasma levels with the more advanced stages of renal failure. Serum PTH and serum P levels increased, whereas serum Ca++ and 1,25-dihydroxyvitamin D decreased. BMD Z-scores of the femur and of the forearm correlated to the biochemical markers and to PTH (P<0.05 to P<0.0001). The biochemical markers all showed strong correlations to PTH, also when corrected for the effect of the decline in GFR (r = 0.40 to 0.92, P<0.01 to P< 0.0001). CONCLUSION: Skeletal changes are initiated at an early stage of chronic renal failure, as estimated from reduced BMD and elevated levels of PTH and from the biochemical markers of both bone formation and bone resorption.     

Long-term suppression of secondary hyperparathyroidism by intravenous 1 alpha-hydroxyvitamin D3 in patients on chronic hemodialysis.

The effect of intravenous 1 alpha-hydroxyvitamin D3 [1 alpha(OH)D3] on circulating levels of intact parathyroid hormone (PTH 1-84) and COOH-terminal immunoreactive PTH(PTH 53-84) was examined in 13 patients on chronic hemodialysis. Thirteen patients were treated for 300 days (10 months), 9 patients for 520 days (14 months) and 6 patients for 720 days (2 years) with increasing doses of 1 alpha(OH)D3 intravenously under careful control of plasma Ca2+. Blood samples were obtained 1 week before start of treatment and then at every 2nd week. None of the patients had previously been treated with oral vitamin D metabolites. Intact PTH levels were maximally suppressed after 27-33 weeks of treatment by approximately 73%. At the end of the study periods, PTH 1-84 was still suppressed by 78 +/- 4.3% after 300 days, 78 +/- 8.8% after 520 days and 85 +/- 6.5% after 720 days. Plasma Ca2+ was kept within normal levels, but showed an initial increase from 1.14 +/- 0.03 to 1.27 +/- 0.15 mmol/l, and an adjustment of the doses of 1 alpha(OH)D3 was necessary. The present investigation demonstrated (1) that intravenous administration of the 1-hydroxylated vitamin D metabolite 1 alpha(OH)D3 induced a significant decrease in circulating levels of biologically active intact PTH, and (2) that it was possible to maintain the marked suppression of PTH secretion by intravenous treatment of 1 alpha (OH)D3 for up to 2 years. Hypercalcemia could be avoided by careful monitoring of plasma Ca2+ and adjustment of the doses of 1 alpha(OH)D3.     

Regulation of 1,25-dihydroxyvitamin D3 by calcium in the parathyroidectomized, parathyroid hormone-replete rat

Parathyroid hormone (PTH) is a major stimulus for the renal production of 1,25-dihydroxyvitamin D3 [1,25-(OH)2D3]. Elevated arterial blood ionized calcium ([Ca2+]) depresses serum 1,25-(OH)2D3 in nonparathyroidectomized rats even when serum PTH is maintained at high levels by infusion. However, suppression by [Ca2+] of endogenous PTH, causing the fall in 1,25-(OH)2D, cannot be excluded. To determine whether [Ca2+] regulates 1,25-(OH)2D3 in the absence of a variation in PTH, we parathyroidectomized (PTX) rats (post-PTX calcium levels less than 7.0 mg/dl), inserted arterial and venous catheters, and then replaced PTH using an osmotic pump. We varied [Ca2+] by infusing either 75 mM sodium chloride (control), 0.61 mumol/min of EGTA (EGTA), or calcium chloride at 0.61 mumol/min (low calcium) or 1.22 mumol/min (high calcium) for 24 h 5 days after surgery. Blood was then drawn from the rat through the arterial catheter. Compared with the control, [Ca2+] fell with EGTA, remained constant with the low-calcium infusion, and rose with the high-calcium infusion. 1,25-(OH)2D3 was correlated inversely with [Ca2+] in all four groups together (r = -0.635, n = 34, p less than 0.001), within the control group alone (r = -0.769, n = 11, p less than 0.002), and within the EGTA group alone (r = -0.774, n = 10, p less than 0.003). Serum phosphorus, PTH, and arterial blood pH were not different in any group, and none correlated with serum 1,25-(OH)2D3. We conclude that 1,25-(OH)2D3 levels are regulated by [Ca2+] independently of serum PTH, phosphorus, and acid-base status, all of which support the hypothesis that [Ca2+] is a principal regulator of serum 1,25-(OH)2D3 in the rat.     

Serum intact parathyroid hormone as a predictor of hypocalcaemia after total thyroidectomy

BACKGROUND: Hypocalcaemia from hypoparathyroidism is a complication of total thyroidectomy. The aim of the present study was to determine whether an early postoperative level of serum parathyroid hormone (PTH) after total thyroidectomy predicts the development of significant hypocalcaemia and the need for treatment. METHODS: Patients undergoing total thyroidectomy had their serum level of intact PTH checked 1 h after removal of the thyroid gland. Serum calcium level was checked on the following morning. Oral calcium and/or calcitriol was commenced if the patient developed hypocalcaemic symptoms, or if the corrected serum calcium level was <2.0 mmol/L. RESULTS: Seventy-nine patients were included in the present study. Thirteen patients had symptoms of hypocalcaemia on postoperative days 1 or 2 and 66 patients remained asymptomatic. The postoperative intact PTH, day 1 calcium and day 2 calcium was 0.32 +/- 0.60 pmol/L, 2.01 +/- 0.11 mmol/L, and 2.02 +/- 0.16 mmol/L, respectively, for the symptomatic group and 1.98 +/- 1.25, 2.21 +/- 0.13, and 2.19 +/- 0.14, respectively, for the asymptomatic group. Calcium support was given to 25 patients, of whom 14 also required calcitriol. CONCLUSION: Serum PTH 1-h after total thyroidectomy is a reliable predictor of hypocalcaemia and can allow safe early discharge of patients from hospital.     

Acute Responses of Parathyroid Hormone and 1,25 Dihydroxyvitamin D3 to Unilateral Nephrectomy in Healthy Donors

Plasma immunoreactive parathyroid hormone (iPTH), 1,25(OH)₂D3calcium and phosphate and urinary creatinine, calcium and phosphatewere measured before and following unilateral nephrectomy insix kidney donors. Unexpectedly, plasma calcium rose, from 2.27±0.02mmol/l (mean±SEM) to 2.41±0.03 mmol/l on day 7and to 2.37±0.02 mmol/l on day 30 (P<0.02). A parallelrise in iPTH occurred, from 0.61±0.16 ng/ml initially,to 1.83±0.54 ng/ml on day 7 (P<0.05) and to 1.18±0.18on day 30 (P<0.01). The ratio of maximal tubular reabsorptionof phosphate to GFR (TmP/GFR) fell by day 2 (P<0.001), remainingreduced on day 30 (P<0.05). The significance of elevated iPTH in renal insufficiency wasfurther assessed by determining the time course of the disappearanceof iPTH after parathyroidectomy in three haemodialysis subjects.Fifty per cent baseline iPTH level occurred after an averageof 104.7 min, suggesting that the assay did not predominantlyrecognize C-terminal PTH fragments. By day 2, plasma 1,25(OH)₂D3had fallen from 34.3±4.5 pg/ml to 22.8±3.8 pg/ml(P<0.001), but by day 4 had regained its pre-nephrectomyvalue. Our results suggest that hypocalcaemia may not be thesole stimulus to parathyroid hormone secretion. It is speculatedthat reduction in circulating 1,25(OH)₂D3 may be involved.     

Surgery for hyperparathyroidism: does morphology or function matter most?

BACKGROUND: With minimally invasive parathyroidectomy (MIP) not all enlarged parathyroid glands are necessarily removed, and intraoperative measurement of parathyroid hormone levels (IO-PTH) does not necessarily predict multiple enlarged glands. The aim of this study was to compare morphology with function, using Ca(2+)-regulated PTH secretion. METHODS: PTH secretion was determined by perifusion: (1) cells from 12 normal parathyroids were compared with 14 parathyroid adenomas; (2) functional characteristics (PTH secretion, sestamibi uptake, IO-PTH decrease) were correlated with morphologic characteristics; (3) PTH secretion as a predictor of IO-PTH decrease was determined in 7 patients with 2 enlarged parathyroids. RESULTS: (1) There were significant differences between normal and pathological parathyroid cells consistent with reduced sensitivity to Ca(2+). Maximum secretion rates for normal and adenomatous cells were, respectively, 3.9 +/- 0.4 fg min(-1) cell(-1) and 2.0 +/- 0.4 fg min(-1) cell(-1) (P = .002) and minimum secretion rates, 0.7 +/- 0.1 fg min(-1) cell(-1) and 0.4 +/- 0.1 fg min(-1) cell(-1) (P = .008). However, the IC(50) value for Ca(2+) was elevated in adenomatous cells indicating an apparent loss of extracellular Ca(2+) sensitivity being 1.1 +/- 0.02 mmol/L for normal and 1.2 +/- 0.02 mmol/L for adenomatous cells (P = .02). (2) There was no overall correlation between PTH secretion and gland morphology. (3) In 5 of 7 cases, PTH secretion correctly predicted the decrease in IO-PTH. CONCLUSION: Parathyroid adenomas generally exhibit abnormal PTH secretory function; however, enlarged parathyroid glands that do not contribute to the biochemical changes of hyperparathyroidism do exist, and, in these cases, cellular secretory function is a useful predictor of IO-PTH dynamics.     

Primary in vivo oscillations of metabolism in the pancreas

The role of metabolism in the generation of plasma insulin oscillations was investigated by simultaneous in vivo recordings of oxygen tension (pO(2)) in the endocrine and exocrine pancreas and portal blood insulin concentrations in the anesthetized rat. At the start of the experiment, the blood glucose concentration of seven rats was 6.2 +/- 0.1 mmol/l and the arterial blood pressure was 116 +/- 5 mmHg. These values did not differ from those obtained at the end of the experiment. Islet pO(2) was measured by impaling superficially located islets with a miniaturized Clark electrode. The pO(2) measurements revealed slow (0.21 +/- 0.03 min(-1)) with superimposed rapid (3.1 +/- 0.3 min(-1)) oscillations. The average pO(2) was 39 +/- 5 mmHg. Simultaneous recordings of pO(2) in the exocrine pancreas were significantly lower (16 +/- 6 mmHg), but showed a slow and a rapid oscillatory activity with similar frequencies as seen in the endocrine pancreas. Corresponding measurements of portal insulin concentrations revealed insulin oscillations at a frequency of 0.22 +/- 0.02 min(-1). The results are the first in vivo recordings of an oscillatory islet parameter with a frequency corresponding to that of plasma insulin oscillations; they support a primary role of metabolic oscillations in the induction of plasma insulin oscillations.     

Influence of parathyroidectomy and calcium on rat renal function.

Parathyroid hormone (PTH) has multiple effects on water and electrolyte transport along the nephron. However, the influences of PTH and calcium on the urinary concentration ability are not fully understood. In this study, clearance and microperfusion studies were performed in thyroparathyroidectomized (TPTX) rats either supplemented (TPTX+Ca(2+)) or not with calcium added to the ingested food as CaCl(2) (1.6 g/100 g). Acid-base data and renal functional parameters were measured in TPTX and TPTX+Ca(2+) rats. Additional studies were performed in the isolated inner medullary collecting tubules of intact and TPTX rats to evaluate the osmotic permeability of this segment in the presence of 10(-6) M PTH added to the bath. In these experiments the possible influence of PTH on antidiuretic hormone induced changes of the osmotic permeability in TPTX and TPTX+Ca(2+) rats was also investigated. In the TPTX+Ca(+) group, the glomerular filtration rate increased significantly when compared to the TPTX group (6.04 +/- 0.42 vs. 4.88 +/- 0.20 ml.min(-1).kg(-1); p < 0.05), but the U/P inulin ratio remained lower than control values (30.8 +/- 1.48 vs. 54.0 +/- 3.5; p < 0.05), which suggests that normal levels of PTH are necessary to maintain the concentrating ability. In a group of TPTX rats, an acute infusion of PTH (0.5 microg.min(-1).kg(-1)) significantly decreased the urinary flow and increased the renal plasma flow, results that agree with the vasomodulator action of this hormone on the renal vasculature. A significant increase in the fractional K(+) excretion observed in the TPTX+Ca(2+) group as compared with both control and TPTX, groups suggests that the excreted load of Ca(2+) may interfere with tubular K(+) handling in the absence of PTH. PTH (10(-6) M) added to the bath of the isolated inner medullary collecting tubules did not change the osmotic permeability, of intact, TPTX, and TPTX+Ca(2+) rats. Furthermore, it did not modify the antidiuretic hormone induced changes in the osmotic permeability. These results suggest that this segment of the nephron is PTH insensitive as far as water and ion transport are concerned.     

Differential effects of intermittent PTH(1-34) and PTH(7-34) on bone microarchitecture and aortic calcification in experimental renal failure

PTH(1-84) and PTH(7-84) are elevated in chronic kidney disease (CKD). These peptides, as their shorter analogs PTH(1-34) and PTH(7-34) both promote PTH receptor (PTH1R) internalization but only PTH(1-34) and PTH(1-84) activate the receptor. Here, we examined the effects of intermittent administration of PTH(1-34) and PTH(7-34) on mineral ion metabolism, bone architecture, and vascular calcification in rats with experimental CKD. CKD with or without parathyroidectomy (PTX) was established by 5/6 nephrectomy (NPX) in rats. Animals were divided into 4 groups: Sham PTX+ sham NPX (Sham); PTX+ sham NPX (PTX); Sham PTX+NPX (NPX); PTX+NPX (PTX/NPX). Rats were treated with single daily doses of 40 microg/kg PTH(1-34), PTH(7-34), or vehicle. Creatinine was higher in NPX and Ca lower in PTX and PTX/NPX groups than in Sham or NPX rats. Plasma phosphate was higher in PTX, NPX and PTX/NPX than in Sham rats. PTH(1-34) was more hypercalcemic than PTH(7-34) in PTX rats. Fractional bone volume in rats treated with PTH(1-34) increased significantly in all groups compared to that of vehicle treatment. In addition, trabecular number, thickness and volumetric bone density increased in rats treated with PTH(1-34). In contrast, PTH(1-34) diminished vascular calcification. Bone and renal PTH1R mRNA expression was reduced as much or more in PTX/NPX rats as in NPX alone, whereas PTH(7-34) had no effect on PTH1R expression. Renal but not bone PTH1R mRNA increased in response to PTH(1-34). These findings suggest that PTH(1-34) exerts greater hypercalcemic and anabolic effects in parathyroidectomized and/or nephrectomized rats than does PTH(7-34). There was no evidence for significant bone or vascular actions of PTH(7-34). We conclude that PTH(1-34) protects against vascular calcification and bone demineralization in experimental renal failure.     

High-normal calcium (1.35 mmol/I) dialysate in patients on CAPD: efficient and safe long-term control of plasma calcium, phosphate, and parathyroid hormone

AIM.: The aim of the present study was to examine the long-term efficacyand safety of treatment with a high-normal calcium dialysatewith a calcium concentration of 1.35 mmol/l in patients on CAPD.This dialysate calcium concentration is close to the high-normalplasma ionized calcium level aimed at in dialysis patients inorder to suppress the parathyroid hormone secretion. The end-pointsof the study were (1) plasma ionized calcium (iCa) and phosphate(P) levels, (2) plasma intact parathyroid hormone (PTH) levels,(3) doses of calcium carbonate and alfacalcidol, (4) requirementsof Al-containing phosphate binders, and (5) bone mineral density(BMD). RESULTS.: Thirty-seven non-selected patients on CAPD treatment were followedfor an average of 10 months after switching from a dialysateCa of 1.75 to 1.35 mmol/l. After 1 week, a significant decreaseof mean iCa from 1.26±0.01 to 1.23±0.01 mmol/l(P<0.05) and an increase of median PTH from 80 to 135 pg/ml(P<0.01) were seen. From the 2nd week and onwards, however,basal levels of iCa and PTH were restored and remained stable.Mean plasma iCa was kept within 1.23–1.31 mmol/l; meanplasma P below 1.65 mmol/l and median PTH within 52–135pg/ml. Episodes of hypercalcaemia were few (1.2 cases of plasmaiCa>1.45 mmol/l per 100 treatment weeks), and the need forAl-containing P binders low with only five patients requringthis treatment for isolated and four patients for repeated episodesof hyperphosphataemia or hypercalcaemia. After switching froma dialysate Ca of 1.75 to 1.35 mmol/l, the doses of calciumcarbonate and alfacalcidol could be significantly increased.Furthermore, using the dialysate Ca of 1.35 mmol/l made it possibleto induce a controlled increase of PTH levels to 80–100pg/ml by a temporarily discontinuation of alfacalcidol and/ora reduction of calcium carbonate dosage in the patients wherePTH had become suppressed to levels below the upper normal limit.The intention of the treatment was to maintain PTH levels within1.5–2.5 times the upper normal limit for non-uraemic patients.Pre-study BMD of the vertebral bodies L2–L4 and of thefemoral neck were normal and not significantly different frompost-study measurements. CONCLUSIONS.: The present study demonstrated that when using a high-normaldialysate Ca concentration of 1.35 mmol/l in non-selected patientson CAPD treatment, high-normal plasma iCa and near-normal plasmaP levels could be readily achieved with a minimal risk of incidentalhypercalcaemia despite use of calcium carbonate as the mainP binder. As a consequnce of the tight Ca and P regulation,minimal doses of alfacalcidol were required to keep PTH withinacceptable limits. We recommend this dialysate Ca concentrationas a first-choice therapy for the majority of patients startingon CAPD treatment.     

Parathyroid hormone is not required for normal milk composition or secretion or lactation-associated bone loss in normocalcemic rats

To determine if parathyroid hormone (PTH) is essential for lactation in rats, the parathyroid glands were removed surgically during the first week of lactation and the rats were given a diet containing a high calcium-phosphorus ratio to maintain a normal serum calcium concentration. Lactating rats were placed on diet containing 1.2% calcium (Ca) and 0.8, 0.6, or 0.4% phosphorus (P) on day 2 postpartum (PP) and were parathyroidectomized (PTX) at 4-6 days PP. At 10 days PP serum Ca was 10.5 +/- 0.2 mg/dl (mean +/- SEM) for PTX rats and 10.4 +/- 0.3 mg/dl in sham-operated lactating rats when the diet contained 0.6% P. When the diet P was 0.8%, the litters gained little or no weight and serum Ca fell to 6.9 +/- 0.6 mg/dl by day 10 PP in PTX rats compared with 10.2 +/- 0.2 mg/dl in sham rats. PTX rats fed the diet containing 1.2% Ca and 0.6% P maintained a normal serum Ca level until at least day 18 PP, but their serum P levels fell gradually from approximately 5 mg/dl at 10 days to 3 mg/dl at 18 days PP. In spite of this hypophosphatemia, the litters of PTX and sham rats had gained the same amount of weight by age 16 days, indicating equal milk production in the two groups. Milk Ca, P, and total solids were not significantly different between PTX and sham rats on day 11 PP.(ABSTRACT TRUNCATED AT 250 WORDS)