Secondary Hyperparathyroidism In Chronic Renal Failure Research Articles

Secondary hyperparathyroidism: present and future therapeutic implications

Secondary Hyperparathyroidism: Present and Future Therapeutic Implications was the first programme in a series of clinically oriented Masterclasses in Nephrology which took place in Vienna, Austria in November 2001. Designed to heighten awareness and understanding within specific areas of nephrology, this masterclass examined issues surrounding the pathogenesis, epidemiology, health consequences and medical management of secondary hyperparathyroidism (HPT) in patients with chronic renal failure (CRF). The pathogenesis of secondary HPT in CRF is associated with disturbances of calcium and phosphate metabolism. The three major factors involved in triggering an increase in parathyroid hormone (PTH) secretion appear to be low plasma calcitriol, hypocalcaemia and hyperphosphataemia. A low calcitriol level prevents the inhibition of preproPTH gene transcription. Hypocalcaemia and hyperphosphataemia result in the stabilization of PTH mRNA, leading to an increase in PTH synthesis. Epidemiological studies investigating the incidence of parathyroidectomy (PTx) among uraemic patients have provided conflicting results. The Lombardy epidemiological study [1] found that the prevalence and incidence of PTx in Lombardy was lower than that previously reported for Europe and Italy, probably because of improvements in the monitoring and management of dialysis patients. However, in more recent years as the Lombardy study has continued, no additional decrease in the incidence of PTx has been observed. One major health consequence of secondary HPT is renal osteodystrophy (ROD). ROD includes bone remodelling disorders, where bone quality is altered, and bone loss disorders, where bone mass is reduced; both abnormalities being potentially associated. Adynamic bone disease is now the most common bone remodelling disorder found in patients with end-stage renal disease [2], while osteoporosis is a significant risk factor for both pre-dialysis and dialysis patients. The dose requirements of recombinant human erythropoietin (rHuEpo) in patients with CRF vary considerably, and many patients do not achieve recommended target haemoglobin levels of )11 gudl. Some evidence suggests that HPT may have an inhibitory effect on erythropoiesis. However, other factors, such as inflammation and iron deficiency, might play a more predominant role in rHuEpo hyporesponsiveness. Control of hyperphosphataemia and maintenance of normocalcaemia form the basis of medical management of secondary HPT. Novel approaches include the use of non-calcium-based phosphate binders, different dialysis modalities, new vitamin D metabolites, second-generation calcimimetics and advances in surgical techniques.

Central nervous dysfunction in uremia

The mechanisms of central nervous system dysfunction in uremia are multifactorial and only partially characterized. Studies using sealed presynaptic nerve terminals (synaptosomes) for in vitro ion transport and metabolism of neurotransmitter in chronic renal failure (CRF) neuronal cell culture and in vivo brain structure microdialysis generated significant new information. An increase in total calcium content of the cerebral cortex accompanied by increased levels of cytosolic calcium ([Ca2+]i) in synaptosomes are common findings in rats with CRF. Mechanisms leading to the increase in [Ca2+]i include increased calcium uptake mediated by parathyroid hormone and decreased activity of Na+,K+-adenosine triphosphatase (ATPase) and Ca2+-ATPase of synaptosomes in CRF rats. Moreover, these synaptosomes respond inappropriately to depolarization, which can impair neurotransmitter metabolism. Brain γ-aminobutyric acid content, norepinephrine, and acetylcholine release uptake and degradation are affected by uremia. These may lead to certain somatic, behavioral, and motor dysfunctions in uremia. Many derangements of the central nervous system in uremia appear to be mediated by secondary hyperparathyroidism of CRF because parathyroidectomy of animals with CRF prevented the increase in basal levels of [Ca2+]i and derangements in neurotransmitter metabolism. The role of other neurotoxins, such as guanidinosuccinic acid, are also reviewed. © 2001 by the National Kidney Foundation, Inc.

Does hypophosphataemia induce hypoparathyroidism in pre-dialysis patients?

renal osteodystrophy [10]. The group included 15males (65%) and eight females (35%), with a mean ageIt has long been recognized that phosphorus retentionof 51.1±12.6 years (mean±standard deviation) andand low concentrations of calcitriol are the two majorcreatinine clearance of 20.8±13.3 ml/min/1.73 m2. Thepathogenetic mechanisms responsible for the develop-undecalcified bone biopsy showed three patients withment of secondary hyperparathyroidism in chronicrenal failure [1–3]. Support for the major role of hyperparathyroid bone disease (13%), eight with mixedphosphorus retention has been provided by several bone disease (34.8%), four with osteomalacia (OM;investigators who have found that a decrease in the 17.4%) and eight with ABD (34.8%). No stainableamount of phosphorus in the diet, in proportion to aluminium or iron was detected at the bone surface.the decrease in the glomerular filtration rate, prevents They had not taken any vitamin D or calcium supple-[1] or ameliorates [4] secondary hyperparathyroidism. ment, phosphate binders, anti-convulsants or corticos-In patients with moderate renal insuYciency, restric- teroids. When compared with the other histologicaltion of dietary phosphorus increases the production of subgroups, ABD patients showed a more preservedcalcitriol and decreases the concentrations of para- renal function (creatinine clearance=32.8±14

Direct in vivo assessment of parathyroid hormone-calcium relationship curve in renal patients

Secondary hyperparathyroidism (SHP) is a well documented finding even in the early stages of chronic renal failure (CRF). A sigmoidal relationship, fitting a four parameter model, links PTH secretion rate and calcium concentration changes. To our knowledge, PTH secretory parameters have only been studied in uremic patients who are in dialysis treatment. As a result of these studies, a possible role for derangement in setpoint values (that is, the serum calcium concentration corresponding to the mid-range value on the sigmoidal curve) has been suggested in the pathogenesis of SHP in CRF. Our study was undertaken to gain insight into the calcium-PTH relationship curve in the first course of CRF and to assess whether a change in any of the secretory parameters is related to the beginning of SHP. We studied 27 male renal patients with a variable degree of renal function (creatinine clearance 12 to 164 ml/min) and 9 control subjects. In all patients and controls the following parameters were evaluated: (1) basal 1,25(OH)2 vitamin D, 25(OH)vitamin D, calcitonin (CT), intact PTH; (2) GFR by Cr51EDTA clearance; (3) the sigmoidal PTH-ionized calcium relation curve, by means of a hypocalcemic stimulating test (Na2-EDTA 37 mg/kg body weight/2 hr) and a hypercalcemic test (Ca gluconate giving 8 mg/kg of body weight/2 hr of Ca element), performed on two consecutive days.(ABSTRACT TRUNCATED AT 250 WORDS)

Abnormal leucine-induced insulin secretion in chronic renal failure.

Chronic renal failure (CRF) is associated with a sundry of abnormalities in pancreatic islets including a rise in their cytosolic calcium, reduced ATP content, and impaired glucose-induced insulin secretion. The latter is also stimulated by amino acids (such as leucine), and the cellular processes involved in leucine-induced insulin secretion are different from those responsible for glucose-induced insulin release. The present study examined whether leucine-induced insulin secretion is also impaired in CRF and investigated the cellular derangements for such a potential abnormality. The results showed that leucine-induced insulin secretion is markedly reduced by islets from CRF animals, and this defect was prevented by parathyroidectomy (PTX) of the CRF animals or by their treatment with verapamil, an agent that blocks the action of parathyroid hormone (PTH) on the pancreatic islets. Both leucine uptake and alpha-ketoisocaproic acid-induced insulin secretion by islets from CRF rats are normal; however, both the activation of glutamate dehydrogenase (GLDH) by leucine or by 2-aminobicyclo-[2-2-1]-haptene and the utilization of alpha-ketoglutarate are impaired, and the maximal reaction rate (Vmax) of glutaminase is reduced. These derangements are corrected by PTX of CRF rats or by their treatment with verapamil. The data demonstrate that 1) CRF is associated with impaired leucine-induced insulin secretion, 2) this defect is due to the state of secondary hyperparathyroidism of CRF, and 3) the cellular derangements responsible for this defect involve abnormalities in the metabolism of leucine and derangements in the leucine-GLDH-alpha-ketoglutarate-glutaminase pathway of the islets.

Chronic Renal Failure is a State of Cellular Calcium Toxicity

Studies on the metabolic profile of many cells have shown that chronic renal failure (CRF) is associated with a significant elevation in the basal levels of cytosolic calcium ([Ca2+]i). This latter abnormality is, in major part, responsible for the organ dysfunction in CRF. The initial step leading to the eventual increase in the basal level of [Ca2+]i is parathyroid hormone (PTH)-mediated increased calcium influx into cells. This is followed by decreased extrusion of calcium out of cells due to reduced activity of the enzymes responsible for pumping calcium out of the cells. The combination of increased entry and decreased exit of calcium results in elevation of [Ca2+]i. Prevention of secondary hyperparathyroidism in CRF or blocking of the effect of PTH by a calcium channel blocker results in normalization of [Ca2+]i and restoration of cell function. Thus, the available data are consistent with the notion that CRF is a state of cellular calcium toxicity, which underlies many of the metabolic and functional derangements in CRF.

Decreased O2 consumption by PMNL from humans and rats with CRF: role of secondary hyperparathyroidism.

Bactericidal ability of polymorphonuclear leukocytes (PMNL) is impaired in chronic renal failure (CRF). This function of PMNL is mediated by the generation of oxidizing radicals and the latter event requires O2 consumption by these cells. The present study examined both basal and FMLP-stimulated rise in cytosolic calcium ([Ca2+]i) and O2 consumption of PMNL from normal subjects and hemodialysis patients and from CRF rats, and evaluated the potential role of secondary hyperparathyroidism of CRF on these properties of PMNL. Basal levels of [Ca2+]i were significantly higher, and FMLP-induced increments in [Ca2+]i were significantly lower in PMNL of both humans and rats with CRF than in normals. Basal and FMLP-stimulated O2 consumption were significantly lower in CRF subjects and rats than in normals. These derangements were prevented by prior parathyroidectomy of CRF rats or by their treatment with verapamil from day one of CRF. Also, therapy of rats with pre-existing CRF with this drug reversed the abnormalities in [Ca2+]i and in O2 consumption of PMNL. The data indicate that: (1) CRF is associated with derangements in the homeostasis of [Ca2+]i of PMNL and their oxygen consumption, (2) these abnormalities are, most likely, mediated by the state of secondary hyperparathyroidism of CRF, and (3) verapamil, which blocks the PTH-induced entry of calcium into cells, and prevents as well as reverses these PMNL dysfunctions. These results implicate the excess PTH of CRF in the genesis of the defective bactericidal function of PMNL, and assign a new dimension to PTH toxicity in CRF.