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.

Factors associated with the prevalence of arteriovenous fistulas in hemodialysis patients in the HEMO study. Hemodialysis (HEMO) Study Group.

BACKGROUND: Arteriovenous (AV) fistulas are the vascular access of choice for hemodialysis patients, but only about 20% of hemodialysis patients in the United States dialyze with fistulas. There is little information known about the factors associated with this low prevalence of fistulas. METHODS: Multiple logistic regression analysis was used to evaluate the independent contribution of factors associated with AV fistula use among patients enrolled in the HEMO Study. The analysis was conducted in 1824 patients with fistulas or grafts at 45 dialysis units (15 clinical centers). RESULTS: Thirty-four percent of the patients had fistulas. The prevalence of fistulas varied markedly from 4 to 77% among the individual dialysis units (P < 0.001). Multiple regression analysis revealed five demographic and clinical factors that were each independently associated with a lower likelihood of having a fistula, even after adjustment for dialysis unit. Specifically, the prevalence of fistulas was lower in females than males [adjusted odds ratio (AOR) 0.37, 95% CI, 0.28 to 0.48], lower in patients with peripheral vascular disease than in those without (AOR 0.55, 95% CI, 0.38 to 0.79), lower in blacks than in non-blacks (AOR 0.64, 95% CI, 0.46 to 0.89), lower in obese patients (AOR per 5 kg/m(2) body mass index, 0.76, 95% CI, 0.65 to 0.87), and lower in older patients (AOR per 10 years, 0.85, 95% CI, 0.78 to 0.94). The differences in the prevalence of fistulas among the dialysis units remained statistically significant (P < 0.001) after adjustment for these demographic and clinical factors. Finally, there were substantial variations in the prevalence of fistulas even among dialysis units in a single metropolitan area. CONCLUSIONS: Future efforts to increase the prevalence of fistulas in hemodialysis patients should be directed at both hemodialysis units and patient subpopulations with a low fistula prevalence.

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.

Bone disease in long-term dialysis.

We reviewed the clinical features, laboratory findings, and skeletal abnormalities of six patients who have been on dialysis therapy for 12 to 20 years (average, 16.7 years). Hemodialysis has been the major therapeutic modality in five of the six individuals. Ages of the patients ranged from 28 to 67 years (mean, 44.5). Bone biopsy specimens were available for five of the patients. In three of these, the predominant changes in bone were those of osteitis fibrosa. In two patients with severe osteitis fibrosa, there was a decrease in height. Two patients had predominantly osteomalacia, but in one of these, the condition was noted before the initiation of 13 years of chronic ambulatory peritoneal dialysis, supplanted 2 years ago by hemodialysis. Total parathyroidectomies with implants of parathyroid tissue in the forearm were performed in four of the six patients. All four had, and continue to have, markedly elevated levels of parathyroid hormone (PTH). Symptoms and signs of amyloidosis of bone have occurred in all six patients, including carpal tunnel syndrome in two, bone cysts in three, and presumptive tendon involvement of the shoulder in one patient. The pathogenesis of hyperparathyroidism is described briefly, and appropriate treatment is summarized.

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.

Magnesium carbonate as a phosphorus binder: a prospective, controlled, crossover study.

The use of calcium carbonate (CaCO3) to bind phosphorus (P) in chronic hemodialysis patients has been a popular tactic in the past decade. Nonetheless, problems with hypercalcemia decrease its usefulness, particularly in patients treated with calcitriol. A P binder not containing calcium (Ca) would be of value in these circumstances. In short-term studies, we showed that magnesium carbonate (MgCO3) was well-tolerated and controlled P and Mg levels when given in conjunction with a dialysate Mg of 0.6 mg/dl. We, therefore, performed a prospective, randomized, crossover study to evaluate if the chronic use of MgCO3 would allow a reduction in the dose of CaCO3 and yet achieve acceptable levels of Ca, P, and Mg. We also assessed whether the lower dose of CaCO3 would facilitate the use of larger doses of calcitriol. The two phases were MgCO3 plus half the usual dose of CaCO3 and CaCO3 alone given in the usual dose. It was found that MgCO3 (dose, 465 +/- 52 mg/day elemental Mg) allowed a decrease in the amount of elemental Ca ingested from 2.9 +/- 0.4 to 1.2 +/- 0.2 g/day (P < 0.0001). The Ca, P, Mg levels were the same in the two phases. The maximum dose of i.v. calcitriol without causing hypercalcemia was 1.5 +/- 0.3 micrograms/treatment during the MgCO3 phase and 0.8 +/- micrograms/treatment during the Ca phase (P < 0.02). If these studies are confirmed, the use of MgCO3 and a dialysate Mg of 0.6 mg/dl may be considered in selected patients who develop hypercalcemia during treatment with i.v. calcitriol and CaCO3.

Impaired delivery of dialysis: diagnosis and correction.

Hemodialysis treatments yielding inadequate amounts of dialysis, as defined by urea kinetic modeling, are partially responsible for considerable mortality and morbidity in the United States. In almost 50% of dialysis treatments resulting in a Kt/V of < 1.0, the culprit is impaired delivery of the prescribed amount of dialysis. The factors involved in impaired delivery of dialysis are many and often elusive. If present and widespread, a search for the cause of the problem entails careful examination of the equipment and nursing procedures. If impaired delivery is a sporadic and infrequent event, a patient-specific investigation should be undertaken. In either circumstance, a clear understanding of the principles and practical aspects of hemodialysis greatly assists the nephrologist as a sleuth.

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.

Modulation of renal osteodystrophy by extrarenal production of calcitriol.

We report a patient with severe chronic renal failure who developed spontaneous bone fractures. He was found to have hypercalcemia, normal calcitriol levels (probably due to extrarenal production by noncaseating granulomas), and functional hypoparathyroidism. The bone biopsy showed low bone turn-over and the presence of noncaseating granulomas. Treatment with corticosteroids decreased the calcium and calcitriol levels and the parathyroid hormone levels rose. No further fractures occurred. A repeat bone biopsy revealed the presence of osteitis fibrosa. Renal osteodystrophy may be modulated by extrarenal production of calcitriol. In this case, excessive suppression of parathyroid hormone by endogenous calcitriol presumably caused an adynamic bone lesion and spontaneous fractures.

Acute effects of different concentrations of dialysate magnesium during high-efficiency dialysis.

It has been suggested that magnesium carbonate (MgCO3) may be an effective and safe alternative to calcium carbonate in binding phosphorus in dialysis patients. In these studies, the concentration of magnesium in the dialysate was either very low or zero. To date, only patients undergoing conventional dialysis have been reported. The primary purpose of the present study was to determine the fluxes of magnesium using dialysate magnesium concentrations of 0 mg/dL, 0.6 mg/dL, and 1.8 mg/dL in eight patients undergoing high-efficiency hemodialysis. The net removal of magnesium was 486 +/- 44 mg, 306 +/- 69 mg, and 56 +/- 50 mg, with the use of dialysate magnesium concentrations of 0 mg/dL, 0.6 mg/dL, and 1.8 mg/dL, respectively (P = 0.001). Plasma magnesium levels significantly decreased from 3.3 +/- 0.2 mg/dL to 1.6 +/- 0.2 mg/dL and from 3.4 +/- 0.3 mg/dL to 2.1 +/- 0.2 mg/dL during the dialysis sessions using 0 mg/dL and 0.6 mg/dL magnesium dialysates, respectively. Plasma magnesium remained unchanged when 1.8 mg/dL dialysate magnesium was used. A significant independent correlation was found between the total magnesium removed and both the dialysate concentration used (P < 0.001) and the predialysis plasma magnesium level (P < 0.001). The measured magnesium removal exceeded the estimated predialysis extracellular fluid (ECF) magnesium pool with the use of magnesium-free dialysate. This was not found with dialysate magnesium concentrations of either 0.6 mg/dL or 1.8 mg/dL. A secondary purpose of the study was to determine the acute clinical tolerance of the low and magnesium-free dialysates.(ABSTRACT TRUNCATED AT 250 WORDS)

The successful treatment of recurrent nephrotic syndrome with the MOPP regimen in a patient with a remote history of Hodgkin's disease.

The association of Hodgkin's disease and minimal-change nephrotic syndrome is well established. We describe a gentleman who developed Hodgkin's disease that was treated successfully. Two years later, he developed minimal-change nephrotic syndrome that responded to steroids. Over the next 9 years, the patient experienced two episodes of nephrotic syndrome due to focal segmental glomerulonephritis that were successfully treated with the mustard/vincristine/prednisone/procarbazine (MOPP) regimen. There was no evidence of recurrence of Hodgkin's lymphoma during any episode of nephrotic syndrome.

Pathogenesis of secondary hyperparathyroidism.

The past 20 years has witnessed a dramatic improvement in our understanding of the factors involved in the pathogenesis of secondary hyperparathyroidism in chronic renal insufficiency. The major causes are retention of phosphorus, relatively low levels of serum calcium, and decreased 1,25-(OH)2D3 (calcitriol) levels. Abnormalities in vitamin D metabolism are responsible for a series of events that result in a state of abnormal calcium-regulated parathyroid hormone (PTH) secretion. In patients with a moderate degree of renal insufficiency, phosphate restriction suppresses PTH secretion by increasing serum calcitriol. However, studies in patients and dogs with advanced renal insufficiency have clearly demonstrated that phosphate per se, independent of the levels of calcitriol or ionized calcium, has an important effect on the secretion of PTH. In addition, low levels of calcitriol, characteristically seen in patients with advanced renal insufficiency, may affect the response of the parathyroid glands to serum ionized calcium. A shift in the set-point for calcium-regulated PTH secretion requires a much higher concentration of serum calcium to suppress the release of PTH. Studies evaluating the administration of intravenous calcitriol have clearly demonstrated that the parathyroid glands become more sensitive to calcium and the suppression of PTH secretion can be achieved with physiologic levels of ionized calcium. In addition, the number of calcitriol receptors in the parathyroid glands of patients and experimental animals with advanced renal failure is low. Investigators have shown that the administration of calcitriol to normal rats increases the mRNA of the vitamin D receptor. Thus, calcitriol upregulates the number of its own receptor.(ABSTRACT TRUNCATED AT 250 WORDS)

Factors affecting delivery of high-efficiency dialysis using temporary vascular access.

The effectiveness of hemodialysis depends, in part, on the delivery of the prescribed rate of blood flow and the amount of blood recirculation. Studies evaluating the magnitude of recirculation in double-lumen catheters at blood flow rates > or = 300 mL/min have not been performed. We therefore examined the effects of prescribed blood flow rate and placement site on measure blood flow, recirculation and effective clearance using double-lumen catheters in 17 patients. Double-lumen catheters were placed in the internal jugular (12.5 cm), subclavian (20 cm), and femoral veins (15 cm and 24 cm). Recirculation studies were performed in triplicate with a two-needle method at blood flow rates of 250, 300, 350, and 400 mL/min. Blood flow rate was measured with an ultrasonic flow meter placed on the venous line. The arterial line pressure was continuously monitored. Mean arterial line pressure was -105 +/- mm Hg at 250 mL/min and -231 +/- mm Hg at 400 mL/min prescribed blood flow rates in the internal jugular, subclavian, and 15-cm femoral vein catheters. Patients with 24-cm femoral catheters had a mean arterial line pressure of -196 +/- mm Hg at 250 mL/min and -327 +/- mm Hg at 400 mL/min. In spite of the change in arterial line pressure, measured blood flow rate increased appropriately at all set blood flows and with all catheter sites studied.(ABSTRACT TRUNCATED AT 250 WORDS)

Cardiac troponin I. A marker with high specificity for cardiac injury.

BACKGROUND: Levels of MBCK can be increased in patients with skeletal muscle injury or renal failure in the absence of myocardial injury, causing diagnostic confusion. This study was designed to determine whether measurement of cardiac troponin I (cTnI), a myocardial regulatory protein with comparable sensitivity to MBCK, has sufficient specificity to clarify the etiology of MBCK elevations in patients with acute or chronic skeletal muscle disease or renal failure. METHODS AND RESULTS: Of the patients (n = 215) studied, 37 had acute skeletal muscle injury, 10 had chronic muscle disease, nine were marathon runners, and 159 were chronic dialysis patients. Patients were evaluated clinically, by ECG, and by two-dimensional echocardiography. Total creatine kinase (normal, < 170 IU/L) was determined spectrophotometrically, and cTnI (normal, < 3.1 ng/mL) and MBCK (normal, < 6.7 ng/mL) were determined with specific monoclonal antibodies. Values above the upper reference limit were considered "elevated." Elevations of total creatine kinase were common, and elevations of MBCK occurred in 59% of patients with acute muscle injury, 78% of patients with chronic muscle disease and marathon runners, and 3.8% of patients with chronic renal failure. Some of the patients were critically ill; five patients were found to have had myocardial infarctions and one had a myocardial contusion. cTnI was elevated only in these patients. CONCLUSIONS: Elevations of cTnI are highly specific for myocardial injury. Use of cTnI should facilitate distinguishing whether elevations of MBCK are due to myocardial or skeletal muscle injury.