Excretion of Cyclic 3', 5'-Adenosine Monophosphate in Renal Insufficiency and Primary Hyperparathyroidism after Stimulation with Parathyroid Hormone

295

112

A B S T R A C T Nephrogenous cyclic AMP (NcAMP), total cyclic AMP excretion (UcAMP), and plasma immunoreactive parathyroid hormone (iPTH), determined with a multivalent antiserum, were prospectively measured in 55 control subjects, 57 patients with primary hyperparathyroidism (10 HPT), and 10 patients with chronic hypoparathyroidism.In the group with 1°HPT, NcAMP was elevated in 52 patients (91%), and similar elevations were noted in subgroups of 26 patients with mild (serum calcium c 10.7 mg/dl) or intermittent hypercalcemia, 19 patients with mild renal insufficiency (mean glomerular filtration rate, 64 mllmin), and 10 patients with moderate renal insufficiency (mean glomerular filtration rate, 43 ml/min). Plasma iPTH was increased in 41 patients (73%).The development of a parametric expression for UcAMP was found to be critically important in the clinical interpretation of results for total cAMP excretion. Because of renal impairment in a large number of patients, the absolute excretion rate of cAMP correlated poorly with the hyperparathyroid state. Expressed as a function of creatinine excretion, UcAMP was elevated in 81% of patients with 10 HPT, but the nonparametric nature of the expression led to a number of interpretive difficulties. The expression of cAMP excretion as a function of glomerular filtration rate was developed on the basis of the unique features of cAMP clearance in man, and this expression, which provided elevated values in 51 (89%) ofthe patients with 10 HPT, avoided entirely the inadequacies of alternative expressions.Results for NcAMP and UcAMP in nonazotemic and azotemic patients with hypoparathyroidism confirmed An abstract ofthis work appeared in 1976. Clin. Res. 24: 456A.

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confidence: 73%

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confidence: 99%

Nephrogenous Cyclic Adenosine Monophosphate as a Parathyroid Function Test

Broadus¹,

Mahaffey²,

Bartter³

et al. 1977

295

112

“…The majority of these reports (5,6,9,10,(31)(32)(33) Resistance to PTH has been provoked in rats by hypercalcemia (36), hypermagnesemia (37), and hypokalemia (38), and in both rats and chicks by hypocalcemia associated with either vitamin D deficiency or a calcium-deficient diet (27,39). Humans with chronic renal failure (5, 9), vitamin D deficiency (32), and some patients with primary hyperparathyroidism (6)(7)(8)(9) are also refractory to stimulation by exogenous PTH.…”

Section: Resultsmentioning

confidence: 99%

“…"Resistance" or tachyphylaxis to the effects of PTH follows sustained or repetitive exposure to the hormone in animal studies in vitro (2,3) and in vivo (4). For human beings, chronic endogenous PTH excess (primary or secondary) is associated with reduction of the urinary cAMP response to stimulation by exogenous PTH in some patients (5)(6)(7)(8)(9)(10)(11).…”

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confidence: 99%

Rapid development of renal resistance to low doses of synthetic bovine parathyroid hormone fragment 1-34. Dissociation of urinary cyclic adenosine monophosphate, phosphaturic, and calciuric responses.

Law¹,

Heath²

1983

A B S T R A C T The designing of parathyroid hormone (PTH)-renal dose-response studies in human beings is complicated by the possibility of rapid homologous receptor down-regulation, a phenomenon that is clearly shown to occur in vitro. Large amounts of PTH given to human subjects as serial injections or prolonged infusions cause decreased urinary 3',5'-cyclic adenosine monophosphate (cAMP) responses to subsequent PTH doses, but it is uncertain whether lower doses given over shorter periods similarly cause renal tachyphylaxis to PTH action. Thus, in seven water-loaded adults, we infused in ascending order 10, 30, 75, 150, and 300 U of synthetic bovine PTH fragment (bPTH 1-34) per 70 kg body wt over 15 min on widely separated days ("separate day administration"). On another day, each subject received all five 15-min doses in ascending order at 75-min intervals ("single day administration"). Urine collection intervals were control, 0-30 min (including the PTH infusion), and 30-60 min. Peak nephrogenous cAMP (NcAMP, nmol/100 ml glomerular filtrate) response was linearly related to the dose of PTH (separate day study, r = 0.94, P < 0.001; single day study, r = 0.88, P < 0.001). However, the slope of NcAMP responses plotted against PTH dose for the single day study was only 36% of that derived from separate day administration of the same PTH doses (P < 0.001). After only 40 U (10 + 30) of bPTH 1-34/70 kg, the NcAMP response to 75 U was reduced 44%, and the effect of 300 U/70 kg, when given as the last of the sequential single day infusions, was 64% less than the response to 300 U of bPTH 1-34 given alone (P < 0.001). The phosphaturic response (fractional excretion of phosphorus, FEP [percent]) was also linearly related to bPTH 1-34 dose, but combined administration of the PTH infusions on one day increased FEP at each dose identically with the effects of separate day administration. A transient, dose-related, early hypercalciuric response to bPTH 1-34 also occurred, and was of equal magnitude in both protocols. These studies demonstrate that significant blunting of the NcAMP response to bPTH 1-34 occurs rapidly and follows brief exposure to relatively low doses of hormone. In contrast, there is no effect of recent PTH administration on the phosphaturic and early hypercalciuric actions of bPTH 1-34. This seeming dissociation of PTH effects makes unclear the physiologic importance of PTH-induced cAMP tachyphylaxis in the regulation of final PTH actions. In any case, studies of NcAMP responses in which the occurrence of tachyphylaxis would be undesirable should be designed to avoid prolonged or closely spaced administrations of the hormone. INTRODUCTION The acute administration of exogenous parathyroid hormone (PTH)' causes increased urinary excretion of

“…Hyperparathyroid states in man are often associated with renal and skeletal resistance to the action of exogenous parathyroid hormone (PTH)l (1)(2)(3)(4)(5). The renal resistance is manifested by blunting of the phosphaturic and urinary cyclic (c)AMP responses to exogenous PTH, and appears to be related to the level of endogenous PTH (2).…”

Section: Introductionmentioning

confidence: 99%

Canine renal receptors for parathyroid hormone. Down-regulation in vivo by exogenous parathyroid hormone.

Mahoney¹,

Nissenson²

1983

A B S T R A C T Chronic elevation of circulating parathyroid hormone (PTH) is associated with decreased target cell responsiveness to PTH. To study the subcellular mechanism of this phenomenon we evaluated PTH receptors and adenylate cyclase activity in renal cortical membranes prepared before and after infusion of bovine parathyroid gland extract (PTE) into thyroparathyroidectomized dogs. PTE infusion resulted in a 53% decrease in the number of high-affinity receptors (P < 0.01) associated with a 66% decrease in PTH-stimulated adenylate cyclase (P < 0.01) relative to paired base-line values. Both the equilibrium constant of dissociation (KD) for PTH binding and the concentration of PTH that caused half-maximal stimulation of adenylate cyclase were in the range of 1 to 4 nM, and were unaffected by the PTE infusion. Responsiveness of the renal adenylate cyclase to sodium fluoride was 88% of base-line values. Infusion of the PTE vehicle alone did not affect PTH receptor number or blunt the adenylate cyclase response to PTH.Pretreatment of the membranes made after PTE infusion with guanosine triphosphate (GTP), which is known to produce dissociation of receptor-bound PTH, failed to restore either receptor number or PTH-stimulated adenylate cyclase. This finding was not due to a lack of efficacy of the GTP pretreatment, because identical GTP pretreatment restored PTH incubation with PTH in vitro. Thus, simple residual occupancy of PTH receptors by the infused hormone did not appear to account for the observed receptor loss.The results of this study suggest that target cell resistance to PTH in patients with hyperparathyroidism might occur, at least in part, due to down-regulation of PTH receptors by circulating hormone.