Parathyroid hormone and growth in children with chronic renal failure

BACKGROUND: In pediatric chronic renal failure (CRF) optimal parathyroid hormone (PTH) concentrations that minimize renal osteodystrophy and maximize growth are unknown. The search for optimum concentrations has been complicated as currently used "intact" PTH (iPTH) assays cross-react with long carboxyl-terminal PTH fragments (C-PTH), which antagonize the biologic actions of 1-84 PTH. The purpose of this study was to investigate the relationship between PTH, the 1-84 PTH:C-PTH ratio and growth rate in children with CRF. METHODS: A total of 162 patients, median (range) age 9.9 years (0.3 to 17.1 years), were recruited: 136 with a glomerular filtration rate (GFR) <60 mL/min/1.73 m(2)[96 managed conservatively (CRF group) and 40 transplanted patients], and 26 dialysis patients. Over a median (range) period of 1.1 years (0.5 to 1.7 years), children attended five (three to 15) clinics at which iPTH, cyclase-activating PTH (CAP-PTH), and height were measured. RESULTS: Mean PTH concentrations were within the normal range for both assays for the CRF group and up to twice the upper limit of normal for the dialysis group; CAP-PTH 24.8 pg/mL and 59.9 pg/mL (normal range 5 to 39 pg/mL), iPTH 37.1 pg/mL, and 102.6 pg/mL, respectively (normal range 14 to 66 pg/mL). The patients grew normally (change in height standard deviation score per year (DeltaHtSDS) =-0.01). There was no relationship between PTH concentrations and DeltaHtSDS in any patient group. The 1-84 PTH:C-PTH ratio was lower in dialyzed patients (P= 0.003), with worsening renal function (P= 0.047) and with PTH concentrations outside the normal range (P= 0.01). There was a weak correlation between the 1-84 PTH:C-PTH ratio and the DeltaHtSDS (r= 0.2, P= 0.01). CONCLUSION: Normal range PTH concentrations are appropriate, allowing normal growth in children with CRF managed conservatively. C-PTH may be of clinical significance.     

Parathyroid hormone and its fragments in children with chronic renal failure

Parathyroid hormone (PTH) immunoradiometric assays (IRMA) exhibit cross-reactivity between 1-84 PTH and long carboxyl-terminal-PTH (C-PTH) molecules. C-PTH antagonizes the biological actions of 1-84 PTH and circulates in excess in chronic renal failure (CRF), partially explaining why supra-physiological PTH levels are recommended to maintain bone turnover. Furthermore, the ratio 1-84 PTH/C-PTH may be related to bone turnover. This study characterizes the 1-84 PTH/C-PTH ratio in children with varying severity of CRF and levels of PTH. Two hundred and forty-one children with CRF, managed with the aim of preventing the development of hyperparathyroidism, had PTH measured by intact IRMA and a new more specific Cyclase-Activating-PTH (CAP) IRMA. C-PTH levels were calculated by subtracting CAP-IRMA from intact IRMA. Fifty-three controls with normal renal function were also recruited. Mean intact IRMA correlated with CAP-IRMA (r=0.98), but was higher (P<0.001). The mean 1-84 PTH/C-PTH ratio was lower than controls in dialysis patients (P=0.022) and those with a glomerular filtration rate <30 ml/min per m² (P=0.033). This ratio was comparable to controls when the PTH level was normal, but was lower with PTH levels outside the normal range (P<0.01). These data suggest that CAP-IRMA gives a more accurate assessment of actual PTH levels than intact IRMA in CRF. Maintenance of normal PTH levels throughout the course of CRF permits the maintenance of a normal 1-84 PTH/C-PTH ratio, the clinical significance of which requires further investigation in children.     

Parathyroid hormone inhibits B cell proliferation: implications in chronic renal failure

B cell proliferation is impaired in patients with chronic renal failure, but the mechanisms underlying this defect are not known. Lymphocytes have receptors for parathyroid hormone, and it is possible that the state of secondary hyperparathyroidism of renal failure is responsible for the B cell defect. Our studies were designed to (a) examine T cell-independent B cell proliferation [3H)thymidine incorporation) induced by Staphylococcus aureus Cowan 1 after 5 days of culture, (b) evaluate the effect of parathyroid hormone on S. aureus Cowan I-induced B cell proliferation, and (c) investigate the mechanisms through which parathyroid hormone may exert its effect on B cell proliferation. Lymphocytes were obtained from 37 normal subjects and 21 dialysis patients. S. aureus Cowan I induced significant stimulation (P less than 0.01) of the proliferation of B cells from both groups, but the effect was smaller on B cells from dialysis patients (10.0 x 10(3) +/- 1.4 x 10(3) cpm) than on those from normal subjects (21.8 x 10(3) +/- 2.0 x 10(3) cpm). Both the intact molecule of parathyroid hormone (1-84 PTH) and its amino-terminal fragment (1-34 PTH) caused significant inhibition of proliferation of B cells from normal subjects in a dose-dependent manner, with the effect being significantly greater (P less than 0.01) with an equimolar concentration of 1-84 PTH than that of 1-34 PTH. Inactivation of 1-84 PTH by oxidation abolished most of its inhibitory effect on B cell proliferation.(ABSTRACT TRUNCATED AT 250 WORDS)     

Parathyroid hormone, vitamin D, and cardiovascular disease in chronic renal failure.

BACKGROUND: Parathyroid hormone and vitamin D have been shown to influence cardiac and vascular growth and function experimentally in human subjects with normal renal function. Because of the increased prevalence of hyperparathyroidism and altered vitamin D status in chronic renal failure, these alterations have been considered to contribute to the increased prevalence of cardiovascular disease and hypertension seen in this patient population. Methods and Results. In this article, we review experimental and clinical literature on the cardiovascular effects of parathyroid hormone and vitamin D and relate them to the development of cardiac and vascular dysfunction in uremia, such as: cardiomyopathy, myocardial hypertrophy, and fibrosis, as well as to myocardial ischemia; uremic glucose intolerance, dyslipidemia, and atherosclerosis; hypertension; and vascular and cardiac calcifications. CONCLUSIONS: The hyperparathyroid state and altered vitamin D status found in uremia contribute to the cardiovascular pathology seen clinically in uremia and also to the excess mortality from cardiovascular causes found in this patient group. The therapeutic implications of these observations are also discussed.     

Parathyroid pathology in hyperparathyroidism secondary to chronic renal failure

Weights and histopathological changes in parathyroid glands were evaluated in relation to clinical and biochemical parameters in 42 patients who underwent parathyroidectomy for hyperparathyroidism (HPT) secondary to chronic renal failure. There was a positive relation (r = 0.71, p less than 0.01) between duration of renal insufficiency and total parathyroid glandular weight. The glandular weight was also closely related to the serum levels of parathyroid hormone (r = 0.67, p less than 0.01). No correlation was found between total parathyroid glandular weight or histopathological findings and clinical symptoms, serum levels of calcium, phosphate, alkaline phosphatases, calcium X phosphorus product or radiological evidence of bone disease. The enlargement of the glands was mostly uniform in the individual patient and all patients showed multiple gland involvement. This indicates that when parathyroid surgery is performed in patients with uraemia and secondary HPT, a radical approach, i.e. total parathyroidectomy with autotransplantation or subtotal parathyroidectomy, should always be used. In smaller glands only diffuse hyperplasia of parenchymal cells was generally found; fat cells were present in near-normal amounts. With increasing glandular weight, fat cells were more sparse and nodularity was common. In general, the proportion of oxyphil cells increased parallel with the total glandular weight, suggesting that this cell type is sensitive to stimulation. As a group, patients undergoing conservative renal treatment had suffered longer with renal disease, had larger parathyroid glands with more nodularity, and had more oxyphil cells than those undergoing parathyroidectomy while on haemodialysis.     

Parathyroid hormone as a marker for the differential diagnosis of acute and chronic renal failure

It is often difficult to distinguish acute renal failure clinically from chronic renal failure, especially in patients who do not have records of their medical history. We investigated the magnitude of iPTH increase in ARF and the potential role of iPTH as a marker for differential diagnosis of ARF and CRF in new patients referred to our renal unit. We prospectively analyzed 122 (ARF n = 64, CRF n = 58) patients referred to our renal unit with serum creatinine higher than 2 mg/dL. ROC curve analysis was performed to investigate role of iPTH for differentiating ARF from CRF. The sensitivity, specificity, and positive predictive value of iPTH in discrimination of ARF and CRF were calculated. There was no statistically significant difference regarding the means of age, sex distribution, and serum chemistry between patients with ARF or CRF. But serum iPTH (p < 0.0001) levels were lower in patients with ARF than in those with CRF. A cutoff, set at 170 pg/mL for iPTH to discriminate patients with CRF, yielded a sensitivity of 88% and a specificity of 89%. This study confirms that the iPTH measurement is of clinical value in differentiating acute from chronic renal failure.     

Parathyroid hormone metabolites in renal failure: bioactivity and clinical implications

Non-(1-84) parathyroid hormones (PTHs) are large circulating carboxyl-terminal PTH (C-PTH) fragments with a partially preserved amino-terminal structure. They were discovered during high-performance liquid chromatography (HPLC) analysis of circulating PTH molecular forms detected by an intact PTH (I-PTH) assay. Like other C-PTH fragments, they accumulate in blood in renal failure and account for up to 50% of I-PTH. They are secreted by the parathyroid glands in humans, and are generated by the peripheral metabolism of hPTH(1-84) in rats. The exact structure of non-(1-84)PTH fragments is not known. To study the possible role of non-(1-84) in PTH biology, hPTH(7-84) has been used as a surrogate, being the only large C fragment available on the market. In anesthetized, thyroparathyroidectomized rats, hPTH(7-84) caused hypocalcemia beyond that induced by surgery. It also blocked the calcemic response to hPTH(1-84) or hPTH(1-34). Other smaller C-PTH fragments, such as hPTH(39-84) and hPTH(53-84), were synergistic to hPTH(7-84) effects. hPTH(7-84) did not bind to the PTH/PTHrP receptor, but only to the C-PTH receptor in ROS 17/2.8 clonal cells, and did not stimulate cyclic adenosine monophosphate (cAMP) production by the same cells, suggesting that its hypocalcemic action was mediated via a receptor different from the PTH/PTHrP receptor, and that the calcium concentration resulted from the sum of the positive effect of hPTH(1-84) on the PTH/PTHrP receptor and of the negative effect of hPTH(7-84) and of C-PTH fragments on the C-PTH receptor. These data will change our understanding of circulating calcium regulation, which must now be viewed as the end result of opposite actions on two PTH receptors. PTH immunoheterogeneity, a highly regulated phenomenon, contributes to this dual biological effect, generating an agonist for the two different receptors. Clinically these results could have some implications in our knowledge of the PTH resistance of renal failure, of renal osteodystrophy, and of certain aspects of the uremic syndrome.     

Parathyroid carcinoma in a case of chronic renal failure on dialysis

The combination of chronic renal failure plus parathyroid adenocarcinoma is very rare. A 53-year-old female had been on hemodialysis for chronic renal failure for 7 years. For 2 years she has had bilateral knee joint pain, hypercalcemia and an increased parathyroid hormone level. Swelling of parathyroid gland was diagnosed and it was excised. Histological examinations of the excised right lower parathyroid gland revealed adenocarcinoma and the left lower gland showed hyperplasia.     

Effect of a simultaneous potassium and carbohydrate load on extrarenal K homeostasis in end-stage renal failure

Patients with chronic renal failure (CRF) are continuously exposed to hyperkalemia. In these patients the extrarenal disposal of a potassium load may be very important to determine the plasma potassium levels. We studied the effect of a combined oral load of potassium (0.5 mEq/kg body weight) and carbohydrate (0.5 g/kg body weight) to mimic normal ingestion of potassium. Eight CRF patients and 5 control subjects were studied. The maximal increase in plasma potassium levels achieved was significantly higher in the patients (1.07 +/- 0.1 mEq/l) than in controls (0.39 +/- 0.05 mEq/l). Basal insulin levels were higher in the CRF patients and increased with the oral potassium and carbohydrate load in both controls and patients. In the CRF patients only 58.9 +/- 3% of the potassium load was translocated to the intracellular space compared to 81 +/- 6% in the controls. No correlation was found between the acid base status and maximal potassium increase. We conclude that patients with CRF exhibit an impaired extrarenal handling of potassium and that this abnormality does not appear to be related to insulin secretion or acid base status.     

Paradoxical potassium depletion: a renal mechanism for extrarenal potassium adaptation

Following nephrectomy and acute potassium loading, animals previously maintained on a high potassium diet have a smaller increment in plasma potassium than do animals on a control diet. The mechanism of this "extrarenal potassium adaptation" is not known. To explore the role of potassium depletion in this process, we studied rats adapted to either a high potassium (HK) or control (C) diet. When dietary potassium was withdrawn, urinary potassium losses in HK rats greatly exceeded those in C rats for at least two days, leading to greater potassium depletion in HK than C animals. A smaller increment in plasma potassium in HK compared to C rats was seen only after prolonged fasting preceded nephrectomy and acute potassium loading. Correction of potassium depletion incurred during fasting abolished extrarenal potassium adaptation. We conclude: after withdrawal of dietary potassium, urinary potassium losses are much greater in HK than in C rats; if the duration of dietary potassium deprivation is sufficient, these urinary potassium losses will cause potassium-adapted animals to paradoxically become more potassium depleted than controls; and this paradoxical potassium depletion may be responsible for extrarenal potassium adaptation.     

Impaired renal and extrarenal potassium adaptation in old rats

Young (3 to 4 months) and old (21 to 22 months) rats were fed either a regular or high potassium (K) diet. After acute potassium chloride infusion, the fraction of infused K excreted (K efficiency) was similar in rats on a normal diet (57 +/- 3%, young, vs. 61 +/- 2%, old). With high K feeding there was a significant increase in the young, 69 +/- 4%, but not in the old rats, 62 +/- 2%. Na-K ATPase activity was markedly reduced in the renal medulla of old rats on a regular or high K diet. In addition, the response to acute K loading was compared in acutely nephrectomized rats. In the young rats on a regular diet plasma K increased from 3.72 +/- 0.09 to 5.28 +/- 0.16 mEq/liter while with K ingestion the increase was significantly less, 3.62 +/- 0.07 to 4.75 +/- 0.12 mEq/liter. In the old rats plasma K increased similarly on a regular or high K diet, 3.68 +/- 0.10 to 5.68 +/- 0.33 mEq/liter and 3.76 +/- 0.06 to 5.97 +/- 0.30 mEq/liter, respectively. Thus, old rats have impaired renal and extrarenal adaptation, but they have a normal response to an acute K challenge. A reduction in Na-K ATPase may account for the defect in renal adaptation in the aged rats.     

Somatic and renal effects of growth hormone in rats with chronic renal failure

Recombinant human growth hormone (rhGH) has been widely used to improve growth in children with chronic renal failure (CRF). However, there has been great concern that GH may aggravate renal disease and hasten the progression to end-stage renal failure. We therefore investigated the effect of prolonged administration of rhGH at various doses on somatic growth and renal function and structure in rats with CRF, divided into four groups based on rhGH dose (vehicle, 0.4, 2.0, and 10.0 IU/day). rhGH was administered subcutaneously daily for 8 weeks. The mean growth was significantly greater in rats treated with high-dose rhGH (10.0 IU) than those treated with low-dose rhGH (P = 0.0089) or vehicle (P = 0.0011). Body weight gain increased in parallel with body length (Creatinine clearance at the end of the experiment was significantly lower in rats on high or medium-dose rhGH than those on low-dose rhGH and controls (P <0.05). The glomerular sclerosing index was greater in rats treated with higher doses of rhGH. There were significant differences between rats treated with high-dose rhGH and controls (P = 0.0144) and also between rats on medium-dose rhGH and controls (P = 0.0065). Although there was no significant difference, rats treated with higher doses of rhGH tended to excrete more protein. Renal insulin-like growth factor-I (IGF-I) content and circulating IGF-I and IGF-II levels did not significantly differ among groups. We conclude that: (1) GH improves somatic growth failure in rats with CRF, but prolonged administration of GH dose-dependently induces deterioration in renal function and structure and (2) this effect was induced neither via circulating IGF-I and IGF-II nor by local production of IGF-I, but seems to be direct. Received June 7, 1996; received in revised form and accepted November 19, 1996     

Parathyroid surgery in patients with renal failure.

A subtotal parathyroidectomy was performed in 32 patients with hyperparathyroidism and renal dysfunction. Minimal long-term sequelae were observed [two patients with recurrent hyperparathyroidism (6.2%), one patient with persistent hypoparathyroidism (3.1%)]. This experience is compared with reports in the literature advocating total parathyroidectomy and autotransplantation. A subtotal parathyroidectomy remains the preferred approach at this institution. Patients with elevated alkaline phosphatase levels before surgery should be monitored carefully for early postoperative hypocalcemia. The low incidence (3.2%) of hyperparathyroidism observed in patients following successful renal transplantation indicates that hypercalcemic allograft recipients should be observed for at least 4 months before contemplating surgical intervention.     

Adrenergic modulation of extrarenal potassium disposal in men with end-stage renal disease.

In normal subjects, beta-adrenergic stimulation lowers the serum potassium, whereas alpha-stimulation raises it. Epinephrine, a mixed alpha and beta agonist, acutely lowers the blood potassium in normal subjects, but not in patients with end-stage renal disease. This study was designed to determine whether the resistance to the hypokalemic effect of epinephrine in dialysis patients is due to a blunted beta-adrenergic response, or to an augmented alpha-adrenergic response. The infusion of epinephrine at low doses (0.01 microgram/kg/min) produced a significant increase in serum potassium in hemodialysis patients (+0.21 +/- 0.07 mmol/liter, P less than 0.05), as compared to a nonsignificant decrease (-0.06 +/- 0.04 mmol/liter) in normal subjects. Epinephrine at high physiologic doses (0.04 microgram/kg/min) failed to significantly change the serum potassium in the dialysis patients (-0.10 +/- 0.14 mmol/liter), but substantially lowered serum potassium in the controls (-0.64 +/- 0.10 mmol/liter, P less than 0.001). There was no significant correlation (r = 0.03) between the baseline serum potassium concentration and the magnitude of change during epinephrine infusion. Epinephrine infusion (0.04 microgram/kg/min) during beta-blockade with propranolol produced a greater rise in serum potassium in the dialysis patients as compared to the controls (+0.69 +/- 0.11 vs. +0.32 +/- 0.11 mmol/liter, P less than 0.05). Epinephrine infusion (0.01 microgram/kg/min) during alpha-blockade with phentolamine resulted in similar changes in serum potassium in dialysis patients and in normal control (-0.10 +/- 0.12 vs. -0.10 +/- 0.06 mmol/liter). Moreover, phentolamine reversed the increase in serum potassium observed in dialysis patients during the infusion of epinephrine following beta-blockade.(ABSTRACT TRUNCATED AT 250 WORDS)     

Increased secretion of potassium in the rectum of humans with chronic renal failure

Previous studies have shown that the intestinal excretion of potassium increases in patients with renal failure and serves to guard against severe potassium retention. It is not known, however, whether the rise in intestinal potassium excretion occurs because of an increase in intestinal potassium secretion or a reduction in potassium absorption. Therefore, studies were performed to evaluate the rate of potassium secretion in the human rectum of controls and subjects with renal insufficiency, using a dialysis bag technique. The results demonstrate that net potassium secretion was increased in subjects with renal failure (-5.2 +/- 0.9 microEq X min-1) compared with the control value of -2.0 +/- 0.4 microEq (P less than .05). This change in intestinal secretion of potassium was shown to be independent of the passive effects of plasma potassium. The rise in potassium secretion, however, correlated directly with an increase in transepithelial potential difference (lumen-negative). Although plasma aldosterone levels were higher in patients than in controls, the scatter of data precludes an assessment of the role of aldosterone in the mechanism of the rise in potassium secretion. These data suggest that augmented intestinal potassium excretion in patients with chronic renal insufficiency is caused by increased net potassium secretion in the large intestine, and highlight the role of the intestine in maintaining potassium balance.     

Parathyroid function in chronic vitamin D deficiency in man: A model for comparison with chronic renal failure

Summary It has become obvious, from the elegantin vitro studies of Cohnet al. (3) and of others, that calcium may act at various steps in the biosynthesis, storage, degradation and secretory release of parathyroid hormone. It would be premature to attempt to interpret our simple clinical observations in terms of these still incompletely defined mechanisms. These clinical studies have, however, identified several different components in the overall pattern of parathyroid response in chronic vitamin D deficiency. In significantly hypocalcaemic patients there was an inverse proportional relationship between serum calcium and serum iPTH, both in the steady-state (9) and during calcium infusion (Fig. 2A); a similar pattern was seen in primary hyperparathyroidism (Fig. 2B). One is tempted to regard this relationship as reflecting an action of calcium on hormonal biosynthesis. There is the further suggestion that profound hypocalcaemia in vitamin D deficiency might limit the capacity of the parathyroid gland to release its hormone (Figs. 3, 4). In the majority of cases of chronic vitamin D deficiency, the serum calcium is maintained close to normal but varying between 8.1 and 11.1 mg/dl in different individual patients of the present series; and in all these cases there is very obvious evidence of increased parathyroid activity. In such patients, it appears that the serum iPTH represents the maximum rate of secretion that the parathyroid gland can currently produce; and the level of serum calcium reflects the extent to which that parathyroid secretion compensates for lack of vitamin D action on gut, bone and kidney. If this equilibrium state is disturbed by an induced, barely detectable, increment in serum calcium there appears to be an immediate inhibition of parathyroid secretion (Fig. 5). There is nothing in the data to suggest that a direct action of vitamin D on the parathyroid glands is required for any of these patterns of parathyroid response, since all were observed in patients with clinical vitamin D deficiency. Only the very slow decay in the steady-state concentration of serum iPTH after correction of vitamin D deficiency in the two hypercalcaemic patients (Fig. 6) suggests a possible direct action of vitamin D on the parathyroid glands. The very slowness of this decay must imply a process of structural involution. Is it possible that vitamin D is involved in some way in coupling the calcium dependent processes of hormonal synthesis and secretion with a calcium dependent mechanism controlling cell division? At present one can do little more than ask the question and wonder it it is a disturbance of such coupling that permits the development of hypercalcaemic secondary hyperparathyroidism.