Parathyroid hormone suppression by intravenous 1,25-dihydroxyvitamin D. A role for increased sensitivity to calcium.

Numerous in vitro studies in experimental animals have demonstrated a direct suppressive effect of 1,25-dihydroxyvitamin D (1,25(OH)2D) on parathyroid hormone (PTH) synthesis. We therefore sought to determine whether such an effect could be demonstrated in uremic patients undergoing maneuvers designed to avoid changes in serum calcium concentrations. In addition, the response of the parathyroid gland in patients undergoing hypercalcemic suppression (protocol I) and hypocalcemic stimulation (protocol II) before and after 2 wk of intravenous 1,25(OH)2D was evaluated. In those enlisted in protocol I, PTH values fell from 375 +/- 66 to 294 +/- 50 pg (P less than 0.01) after 1,25(OH)2D administration. During hypercalcemic suppression, the "set point" (PTH max + PTH min/2) for PTH suppression by calcium fell from 5.24 +/- 0.14 to 5.06 +/- 0.15 mg/dl (P less than 0.05) with 1,25(OH)2D. A similar decline in PTH levels after giving intravenous 1,25(OH)2D was noted in protocol II patients. During hypocalcemic stimulation, the parathyroid response was attenuated by 1,25(OH)2D. We conclude that intravenous 1,25(OH)2D directly suppresses PTH secretion in uremic patients. This suppression, in part, appears to be due to increased sensitivity of the gland to ambient calcium levels.

Does strict phosphorus control precipitate renal osteomalacia?

Hyperphosphatemia leads to the development of osteitis fibrosa in patients with chronic renal failure. In contrast, crippling osteomalacia may appear in uremic patients who are hypophosphatemic or aluminum intoxicated or who undergo total or subtotal parathyroidectomy. Thus, strict phosphorus control by use of aluminum-containing gels may ameliorate renal osteitis fibrosa, but may potentiate the development of osteomalacia. To evaluate this possibility, we compared the bone histologies of 10 chronic renal hemodialysis patients who consistently maintained predialysis phosphorus levels between 4-5 mg/dl (Strict-P) to those of 46 randomly selected dialysis patients (Random-P). We found that the Strict-P group had lower circulating immunoreactive PTH (P less than 0.02) and alkaline phosphatase (P less than 0.05) levels and, as expected, less evidence of hyperparathyroid bone disease. On the other hand, the Strict-P patients had osteomalacia, as evidenced by moderate osteoid accumulation and reduced capacity of bone to assume a fluorescent tetracycline label. Furthermore, all Strict-P patients had histological evidence of bone aluminum accumulation. We conclude that maintenance of normal serum P levels with aluminum-containing gels in hemodialysis patients prevents severe hyperparathyroid bone disease. Such treatment, however, is also attended by a moderate degree of aluminum-associated osteomalacia.

The metabolic and psychological effects of exercise training in hemodialysis patients.

The effect of exercise training on metabolic abnormalities and psychological function was assessed in seven hemodialysis patients. Their initial work capacity was low and improved after 8 months of training. Exercise was associated with a reduction in the dose of antihypertensive medications in four patients and a decrease in phosphate binder therapy in three patients. There was also a rise in hematocrit levels (% delta = 34 +/- 20%, P less than 0.03) and the hemoglobin concentration (% delta = 37 +/- 23%, P less than 0.05) of five males. Plasma glucose levels fell (-5 +/- 2%, P less than 0.05, n = 5) and the glucose disappearance rate improved (20 +/- 7%, P less than 0.02), while hyperinsulinism decreased (-36 +/- 20%, P less than 0.02, n = 5) during training. There was no change in body weight or diet. Exercise lowered plasma triglyceride levels (-41 +/- 28%, P less than 0.02, n = 6) and raised the high-density lipoprotein cholesterol concentration (20 +/- 21%, P less than 0.05, n = 6). Psychological testing (n = 4) demonstrated that exercise training was associated with an improvement in depression, hostility, anxiety, social interaction, and outlook for the future. These results suggest that exercise can improve some of metabolic abnormalities and psychological dysfunction which exists in some dialysis patients.

Insulin-like growth factor 1 enhances renal function in a patient with chronic renal failure on peritoneal dialysis.

Insulin-like growth factor 1 (IGF1) has been shown to improve renal function in healthy subjects, as well as those with chronic renal failure. To our knowledge, IGF1 has not been shown to be efficacious in patients who were already undergoing dialysis. We present the case of a 70-year-old woman with end-stage renal disease (ESRD) and overt uremic symptoms treated with IGF1 after peritoneal dialysis was discontinued because of complications. There was a significant improvement in her inulin clearance during the course of treatment. The patient remained well and did not require dialytic support for 19 weeks. Although further data are necessary, we believe this case shows that IGF1 may be a short-term alternative to dialysis in patients with ESRD.

Studies on the role of the liver and splanchnic tissues in the production of carbohydrate intolerance in uremia.

The potential contribution of the splanchnic tissues to the carbohydrate intolerance of uremia was studied in fasted, partially nephrectomized rats. The livers of sham operated (C) and partially nephrectomized (Nx) rats were perfused with physiologic concentrations of potential gluconeogenic substrates using a nonrecirculating perfusion apparatus. Glucose release was slightly greater in the livers of Nx rats as compared to C rats. The portal vein concentrations of the potential gluconeogenic precursors were not different in the two groups. Moreover, there were no differences in the net hepatic extraction of alanine, glutamine or glutamate between the two groups of rats. There was also no difference in the production of glucose from U14C alanine. The livers of Nx rats, however, demonstrated less net extraction of lactate and released greater concentrations of betahydroxybutyrate. The increased release of glucose by livers of Nx rats may be at least partially due to their greater hepatic glycogen content.

Therapeutic benefits of exercise training for hemodialysis patients.

Twenty-five hemodialysis patients were randomized into comparable exercising (E, N = 14) and sedentary control (N = 11) groups. After baseline testing, training was 3 to 5 times weekly for a mean of 12 +/- 4 (SD) months. Maximal aerobic capacity increased 21% (P less than 0.01), and the durations for the graded exercise stress test improved 19% (P less than 0.01) in E, but did not change in controls (8 +/- 4 months). Declining blood pressures in 8 hypertensive E led to reductions in antihypertensive medications; no changes occurred in 9 hypertensive controls. Exercise lowered plasma total triglyceride levels 33% (280 +/- 258 to 175 +/- 95 mg/dl; P less than 0.01), but no change occurred in total and low-density lipoprotein cholesterol concentrations. High-density lipoprotein cholesterol levels rose 16% in E (31 +/- 9 to 36 +/- 12 mg/dl; P less than 0.02), but did not change in controls. An increase in the affinity of insulin for receptors on mononuclear cells was associated with a 20% decrease in fasting plasma insulin levels (24 +/- 7 to 19 +/- 2 microU/ml, N = 8; P less than 0.05) and a 42% improvement in glucose disappearance rates (1.9 +/- 1.0 to 2.6 +/- 1.2% per min, N = 6) in E. There were no changes in the body weights or diets of the patients. A 27% increase in red blood cell mass (P less than 0.02) with no change in plasma volume resulted in a 27% increase in hematocrit (24 +/- 3% to 31 +/- 5%, P less than 0.01) and a 20% increase in hemoglobin (8 +/- 1 to 10 +/- 2 g/dl; P less than 0.01) in E.(ABSTRACT TRUNCATED AT 250 WORDS)

Comparison of survival of an expanded polytetrafluoroethylene graft designed for early cannulation to standard wall polytetrafluoroethylene grafts.

BACKGROUND: Placement and maintenance of a well-functioning vascular access are essential for delivery of adequate hemodialysis. Newly placed polytetrafluoroethylene (PTFE) arteriovenous grafts require a period of wound healing and incorporation of fibrous tissue before use, a period typically lasting two to three weeks. An ideal PTFE graft would be one that can be used for vascular access immediately, obviating the need for temporary dialysis catheters. Recently an expanded PTFE (ePTFE) graft with a mesh cannulation segment (Diastat graft) has been proposed for early cannulation. STUDY DESIGN: This is a retrospective single-center study comparing ePTFE graft survival to contemporaneously placed standard wall PTFE (GORE-TEX) grafts. RESULTS: Forty-seven consecutive new or established patients receiving chronic hemodialysis had grafts (25 ePTFE, 22 standard PTFE) placed between November 1994 and July 1995. There were no significant differences between the groups in age, race, gender, incidence of diabetes mellitus, or peripheral vascular disease. By the end of the study, 21 of 25 ePTFE grafts had clotted, compared with 11 of the 22 patients receiving a standard PTFE graft. Median time to first clotting was 53 days for the ePTFE grafts and 164 days for the standard PTFE grafts (p < 0.0001). Nine patients with ePTFE grafts required a temporary catheter after their first clotting episode. CONCLUSIONS: The ePTFE grafts thrombosed at a significantly higher rate than standard wall PTFE grafts. Further experience with the Diastat graft might improve graft survival. However, early experience does not suggest that the avoidance of short-term temporary access outweighs the problem of high clotting rate, and its attendant morbidity.

A controlled trial of the early treatment of secondary hyperparathyroidism with calcitriol in hemodialysis patients.

BACKGROUND: Calcitriol is widely used in conjunction with phosphorus-binders containing calcium to treat secondary hyperparathyroidism in dialysis patients. Its efficacy in patients with severe hyperparathyroidism is diminished, in part, due to glandular hyperplasia associated with decreased calcitriol and calcium receptors. SUBJECTS AND METHODS: We, therefore, developed a prospective, randomized trial comparing i.v. calcitriol plus calcium carbonate (CaCO3) compared to CaCO3 alone (control) in patients with mild to moderate hyperparathyroidism who were within the first year of initiating hemodialysis. Patients underwent calcium (Ca) suppression/stimulation testing at baseline and after six and twelve months of treatment to indirectly assess parathyroid gland hyperplasia. RESULTS: In the calcitriol group, the amino-terminal parathyroid hormone (N-PTH) decreased significantly from a baseline value of 70 +/- 12 pg/ml at month zero to 22 +/- 7 and 19 +/- 6 pg/ml at months 6 and 12, respectively (the conversion factor of amino-terminal PTH to intact PTH is 6, i.e., 10 pg/ml N-PTH equals 60 pg/ml intact PTH). In contrast, the N-PTH levels in the CaCO3 alone group did not change. The change in nadir N-PTH levels at month 12 compared to month zero decreased by 14 +/- 7% in the calcitriol group but increased by 96 +/- 59% in the control group (p < 0.05). In addition, the increment in N-PTH levels during hypocalcemic stimulation decreased by 68 +/- 6% at month 12 compared to month zero but increased by 61 +/- 42% in the control group. Although total calcium and phosphorus levels were not different between the two groups, ionized calcium values were higher in the calcitriol group. The incidence of hypercalcemia was the same in both groups and the episodes were asymptomatic. CONCLUSION: Pulse calcitriol therapy is effective in preventing progression of secondary hyperparathyroidism in hemodialysis patients with mild to moderate disease. Based on Ca suppression/stimulation tests, calcitriol was more successful in preventing gland growth than CaCO3 alone. Further studies are needed to determine if the strategy of early treatment of mild to moderate hyperparathyroidism by pulse calcitriol is safe and effective in hemodialysis in patients.

Removal of phosphorus by peritoneal dialysis.

Substantial evidence exists that peritoneal dialysis, as currently practiced, cannot alone remove adequate amounts of phosphorus in well-nourished patients. Current efforts should address the possibility of developing improved nontoxic oral phosphorus binders and/or different compositions of dialysate fluid.

Control of mineral metabolism in CAPD patients.

The purpose of this article is to review the basic pathophysiological events leading to renal osteodystrophy and how continuous ambulatory peritoneal dialysis may alter these processes. This form of therapy has significant effects on mineral homeostasis and may, under some circumstances, alter vitamin D and parathyroid hormone metabolism. Some short-term studies suggest that there may be an improvement in bone histology during treatment. Although much remains to be learned about renal osteodystrophy and continuous ambulatory peritoneal dialysis, enough information is currently available to allow implementation of a rational plan of therapy that should optimize mineral metabolism.

Hyperphosphatemia: its consequences and treatment in patients with chronic renal disease.

Control of phosphorus accumulation in chronic renal insufficiency is crucial to the prevention of secondary hyperparathyroidism and metastatic calcification. In early renal failure, calcitriol levels are normal and parathyroid hormone levels are elevated. The phosphorus levels are maintained in the normal range by the phosphaturia induced by hyperparathyroidism. In this situation, dietary phosphorus restriction increases calcitriol levels and suppresses parathyroid hormone secretion. As renal failure progresses into late stages, hyperphosphatemia is evident along with low levels of calcitriol and worsening hyperparathyroidism. Phosphorus restriction will not affect calcitriol concentrations, yet parathyroid levels may decline. During long-term dialysis, urinary excretion of phosphorus is usually minimal. Therefore, phosphorus balance is determined primarily by the net amount absorbed by the bowel and the quantity removed during dialytic therapy. Given an adequate diet, no form of conventional dialysis is able to fully compensate for the gastrointestinal absorption of phosphorus. Hence, compounds that bind phosphorus in the bowel are often necessary. With the realization that the use of phosphorus binders containing aluminum leads to aluminum accumulation and its sequelae: osteomalacia, dementia, myopathy, and anemia, other phosphorus binders have been evaluated. Calcium carbonate has been investigated the most thoroughly and is in wide use. It is inexpensive and contains a high percent of elemental calcium. However, it is only modestly potent in the binding of phosphorus, and large doses are often necessary to attain satisfactory control of phosphorus. This may lead to hypercalcemia. One approach to this problem is to decrease the concentration of calcium in the dialysate. Alternatively, a more effective phosphorus binder may be used. Calcium acetate has been shown in acute studies to have twice the binding capacity of phosphorus per calcium absorbed than calcium carbonate. Whether use of this compound decreases the incidence of hypercalcemia is unproven. Calcium citrate increases the gastrointestinal absorption of aluminum and offers no advantage over calcium carbonate. Other compounds, such as calcium ketoacids and calcium alginate, have not been extensively studied and are not generally available. The use of phosphorus binders containing magnesium in conjunction with a dialysate low in magnesium may be efficacious. Large doses of magnesium will cause diarrhea and thus limit its use as a single agent. Reasons for failure to control hyperphosphatemia include poor compliance, improper prescription of binders, poor dissolution rates seen with some generic brands of calcium carbonate, and the presence of severe hyperparathyroidism. Optimal control of serum phosphorus in dialysis patients should always be viewed in the context of adequate nutrition and protein intake.

Hemodialysis prescription and delivery in a metropolitan community. The St. Louis Nephrology Study Group.

The National Cooperative Dialysis Study attempted to determine adequacy of hemodialysis based on kinetic modeling of urea. Based on this study, it has been recommended that a dimensionless term quantitating the amount of dialysis delivered (KT/V) be greater than 1.0 to avoid adverse outcomes. With the declining duration of dialysis treatments in the United States, there has been concern that a significant proportion of patients may be receiving inadequate therapy. The purpose of this study was to survey hemodialysis practices and treatment outcomes in our metropolitan area. Sixteen area nephrologists volunteered to study their outpatient hemodialysis patients (N = 617). Demographic data and urea kinetic modeling results were then analyzed at the lead center. The mean length of dialysis was 3.2 +/- 0.4 (SD) hours with dialysis blood flow rates of 333 +/- 74 ml/min. The mean KT/V was 1.03 +/- 0.25 with nearly half of patients failing to attain a KT/V of 1.0. In 55% of patients the reason for a low KT/V was the prescription of an insufficient amount of dialysis treatment. In the remainder, insufficient delivery of prescribed dialysis contributed to the low KT/V. Only 1 of 33 patients undergoing dialysis twice a week achieved the recommended quantity of treatment on a weekly basis. Patients undergoing dialysis in non-profit units had a higher KT/V than those treated in proprietary units (1.1 +/- 0.26 vs. 0.92 +/- 0.22, P less than 0.001). In addition, patients dialyzed in units that performed urea kinetic modeling on all or selected patients had a higher KT/V compared to those in units where urea kinetics were not done (1.12 +/- 0.25 vs. 0.95 +/- 0.23, P less than 0.001). If these findings reflect practices elsewhere in the United States, many hemodialysis patients fail to receive the current recommended quantity of treatment.

Pathogenesis of secondary hyperparathyroidism.

Hyperplasia of the parathyroid glands and increased concentrations of immunoreactive parathyroid hormone are among the earlier alterations of mineral metabolism in patients with chronic renal failure. In the past five years several investigators have demonstrated that phosphorus retention plays a key role in the development of secondary hyperparathyroidism and chief cell hyperplasia of the parathyroid glands. Since phosphorus regulates the production of 1,25D3 by altering the enzyme 1-alpha-hydroxylase it is possible that the effect of phosphorus retention is mediated by a decrease in the synthesis of 1,25D3. This has been shown in patients with early renal insufficiency. However, in patients with advanced renal failure the reduced renal mass may limit the production of 1,25D3. It is clear now that phosphorus per se independent of the levels of ionized calcium and 1,25D3 can increase the synthesis and secretion of PTH in vivo and in vitro. The abnormalities in vitamin D metabolism are not only characterized by low levels 1,25D3 but by low number of vitamin D receptors. Thus, the parathyroid glands are resistant to the action of 1,25D3 and high pharmacological concentrations of 1,25D3 in blood are necessary to suppress the levels of parathyroid hormone in advanced renal failure. The development of monoclonal changes in glands obtained from patients with secondary hyperparathyroidism further complicates the treatment of secondary hyperparathyroidism in patients maintained on haemodialysis. Thus, correction of serum phosphorus is imperative for the success of 1,25D3 to control the levels of parathyroid hormone. Currently several laboratories are studying at the molecular level the mechanisms by which dietary phosphorus induces chief cell hyperplasia.

Effects of prazosin in the control of blood pressure in hypertensive dialysis patients.

Twenty-two chronic hemodialysis patients with hypertension were treated with prazosin. Eight patients had volume-responsive hypertension, 11 volume-indpendent, and 3 high-renin hypertension. Blood pressure fell in all volume-responsive patients from a predialysis level of 175 +/- 5/100 +/- 3 to 148 +/- 4/75 +/- 3 mm Hg (p less than 0.001) after 3 months of therapy. Prazosin alone was effective in volume responsive patients at a dose of 5 +/- 1.0 mg daily. The blood pressure fell in volume-indpendent patients from 192 +/- 7/105 +/- 2 mm Hg predialysis to 155 +/- 6/80 +/- 3 after 3 months (p less than 0.001). Two were controlled on prazosin alone at a dose of 12 +/- 2 mg daily. Nine required 27 +/- 5 mg of prazosin daily as well as additional antihypertensive treatment. The blood pressure fell from 183 +/- 3/109 +/- 6 mm Hg predialysis to 173 +/- 17/85 +/- 3 mm Hg in high-renin patients after 3 months. One patient was controlled on 40 mg of prazosin daily. Two required 40 mg of prazosin daily as well as additional antihypertensive medication. Eleven patients described transient dizziness within the first month of therapy. One patient had recurrent syncope necessitating prazosin withdrawal; Prazosin is an effective antihypertensive agent which can be used in all types of hypertensive dialysis patients either alone or in combination with minimal side effects.