James A. Delmez

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

BackgroundLevels 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 ResultsOf 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%o 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. ConclusionElevations 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.

Effect of clopidogrel on early failure of arteriovenous fistulas for hemodialysis: a randomized controlled trial.

CONTEXT The arteriovenous fistula is the preferred type of vascular access for hemodialysis because of lower thrombosis and infection rates and lower health care expenditures compared with synthetic grafts or central venous catheters. Early failure of fistulas due to thrombosis or inadequate maturation is a barrier to increasing the prevalence of fistulas among patients treated with hemodialysis. Small, inconclusive trials have suggested that antiplatelet agents may reduce thrombosis of new fistulas. OBJECTIVE To determine whether clopidogrel reduces early failure of hemodialysis fistulas. DESIGN, SETTING, AND PARTICIPANTS Randomized, double-blind, placebo-controlled trial conducted at 9 US centers composed of academic and community nephrology practices in 2003-2007. Eight hundred seventy-seven participants with end-stage renal disease or advanced chronic kidney disease were followed up until 150 to 180 days after fistula creation or 30 days after initiation of dialysis, whichever occurred later. INTERVENTION Participants were randomly assigned to receive clopidogrel (300-mg loading dose followed by daily dose of 75 mg; n = 441) or placebo (n = 436) for 6 weeks starting within 1 day after fistula creation. MAIN OUTCOME MEASURES The primary outcome was fistula thrombosis, determined by physical examination at 6 weeks. The secondary outcome was failure of the fistula to become suitable for dialysis. Suitability was defined as use of the fistula at a dialysis machine blood pump rate of 300 mL/min or more during 8 of 12 dialysis sessions. RESULTS Enrollment was stopped after 877 participants were randomized based on a stopping rule for intervention efficacy. Fistula thrombosis occurred in 53 (12.2%) participants assigned to clopidogrel compared with 84 (19.5%) participants assigned to placebo (relative risk, 0.63; 95% confidence interval, 0.46-0.97; P = .018). Failure to attain suitability for dialysis did not differ between the clopidogrel and placebo groups (61.8% vs 59.5%, respectively; relative risk, 1.05; 95% confidence interval, 0.94-1.17; P = .40). CONCLUSION Clopidogrel reduces the frequency of early thrombosis of new arteriovenous fistulas but does not increase the proportion of fistulas that become suitable for dialysis. Trial Registration clinicaltrials.gov Identifier: NCT00067119.

Calcium Carbonate as a Phosphate Binder in Patients with Chronic Renal Failure Undergoing Dialysis

Phosphate binders that contain aluminum are frequently prescribed to treat hyperphosphatemia in patients with chronic renal failure, but an accumulation of aluminum can lead to osteomalacia. To evaluate the efficacy of calcium carbonate as an alternative phosphate binder, we studied 20 patients maintained on dialysis during three consecutive periods. In period 1, the patients took aluminum hydroxide for a month (mean dose, 5.6 g per day; range, 1.5 to 14.0). In period 2, they took no phosphate binders for a month, and in period 3, they took calcium carbonate (Os-Cal) for two months (mean dose, 8.5 g per day; range, 2.5 to 17). The mean (+/- SE) serum calcium level during period 1 was 9.6 +/- 0.2 mg per deciliter; this decreased slightly (to 9.3 +/- 0.1) during period 2 and increased to 10.0 +/- 0.2 during period 3. The mean (+/- SE) serum phosphorus level during period 1 was 4.8 +/- 0.1 mg per deciliter; this increased to 7.3 +/- 0.3 during period 2, but returned to the control value (4.8 +/- 0.2) during period 3. Six of the 20 patients continued to need aluminum hydroxide during period 3 for satisfactory control of hyperphosphatemia. Calcium carbonate successfully lowered serum phosphorus levels and raised serum calcium levels in the majority of our patients, thereby confirming that this agent may be a satisfactory substitute for traditional phosphate binders that contain aluminum. The possibility that long-term treatment could cause such side effects as metastatic calcification will require further investigation.

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.

Prevention of Thrombosis in Patients on Hemodialysis by Low-Dose Aspirin

Since platelet cyclo-oxygenase is much more sensitive to inactivation by aspirin than is the enzyme in the arterial wall and low doses of aspirin may prevent thrombosis by blocking thromboxane synthesis, we conducted a randomized, double-blind trial of aspirin (160 mg per day) vs. placebo in 44 patients on chronic hemodialysis. The study was continued until there were 24 patients with thrombi and both groups had been under observation for a mean of nearly five months. Thrombi occurred in 18 of 25 (72 per cent) of patients given placebo and 16 of 19 (32 per cent) of those given aspirin (P less than 0.01). The incidence of thrombosis was reduced from 0.46 thrombi per patient month in the placebo group to 0.16 thrombi per patient month in the aspirin group (p less than 0.005). A dose of 160 mg of aspirin per day is an effective, nontoxic antithrombotic regimen in patients on hemodialysis.

Effect of Dipyridamole plus Aspirin on Hemodialysis Graft Patency

BACKGROUND Arteriovenous graft stenosis leading to thrombosis is a major cause of complications in patients undergoing hemodialysis. Procedural interventions may restore patency but are costly. Although there is no proven pharmacologic therapy, dipyridamole may be promising because of its known vascular antiproliferative activity. METHODS We conducted a randomized, double-blind, placebo-controlled trial of extended-release dipyridamole, at a dose of 200 mg, and aspirin, at a dose of 25 mg, given twice daily after the placement of a new arteriovenous graft until the primary outcome, loss of primary unassisted patency (i.e., patency without thrombosis or requirement for intervention), was reached. Secondary outcomes were cumulative graft failure and death. Primary and secondary outcomes were analyzed with the use of a Cox proportional-hazards regression with adjustment for prespecified covariates. RESULTS At 13 centers in the United States, 649 patients were randomly assigned to receive dipyridamole plus aspirin (321 patients) or placebo (328 patients) over a period of 4.5 years, with 6 additional months of follow-up. The incidence of primary unassisted patency at 1 year was 23% (95% confidence interval [CI], 18 to 28) in the placebo group and 28% (95% CI, 23 to 34) in the dipyridamole-aspirin group, an absolute difference of 5 percentage points. Treatment with dipyridamole plus aspirin significantly prolonged the duration of primary unassisted patency (hazard ratio, 0.82; 95% CI, 0.68 to 0.98; P=0.03) and inhibited stenosis. The incidences of cumulative graft failure, death, the composite of graft failure or death, and serious adverse events (including bleeding) did not differ significantly between study groups. CONCLUSIONS Treatment with dipyridamole plus aspirin had a significant but modest effect in reducing the risk of stenosis and improving the duration of primary unassisted patency of newly created grafts. (ClinicalTrials.gov number, NCT00067119.)

Diverticular Disease in Patients with Chronic Renal Failure Due to Polycystic Kidney Disease

Twelve patients with chronic renal failure and polycystic kidney disease represent 8% of the 151 hemodialysis patients followed up at the Chromalloy American Kidney Center, Washington University School of Medicine. Ten (83%) of these patients have diverticulosis, and four of these patients developed gross colonic perforation secondary to diverticulitis. Barium enemas on 31 chronic renal failure patients without polycystic kidney disease revealed diverticulosis in 10 (32%). None had diverticulitis. Barium enemas in 120 age-matched non-renal failure control patients revealed diverticulosis in 45 (38%). None had diverticulitis. These findings suggest that patients with chronic renal failure due to polycystic kidney disease have a high incidence of diverticulosis and diverticulitis, that diverticulosis occurs in patients with chronic renal failure without polycystic kidney disease at a rate similar to that in the general population, and that diverticulitis should be an initial consideration in the differential diagnosis of abdominal pain in patients with polycystic kidney disease.

Pathogenesis of Secondary Hyperparathyroidism

Secondary hyperparathyroidism is a universal complication in patients with chronic renal failure. Hyperplasia of the parathyroid glands is typically seen in these patients. In early renal failure, alteration in vitamin metabolism, decreased levels of calcitriol and moderate decreases in ionized calcium may allow greater synthesis and secretion of PTH. As the disease progresses, there is a decrease in the number of vitamin D receptors (VDR) and calcium receptors (CaR). The decreased number of VDR and CaR makes the parathyroid glands more resistant to calcitriol and calcium. Phosphorus induces hyperplasia of the parathyroid glands independent of calcium and calcitriol, and by a post-transcriptional mechanism increases PTH synthesis and secretion. Experimental work in uremic rats demonstrated that if the animals are fed a high-phosphorus diet, they not only developed secondary hyperparathyroidism but parathyroid cell hyperplasia. If the diet is then reduced in phosphorus, the levels of PTH return to normal. However, the parathyroid cell hyperplasia persists and no apoptosis is seen. Thus, the control of the three most important factors, calcium, calcitriol and phosphorus, is critical to prevent the development of secondary hyperparathyroidism and hyperplasia of the parathyroid glands.

Exercise training reduces coronary risk and effectively rehabilitates hemodialysis patients

This study examines the effects of 12 months of endurance exercise training (cycling, walking and jogging) on lipid profiles, glucose metabolism, blood pressure, anemia and psychological function in 14 hemodialysis patients. Maximal aerobic capacity (VO2max) increased 18% in the exercisers (p less than 0.01), but did not change in 11 controls. This was associated with a reduction in depression, a decrease in dosages of antihypertensive medications, a significant increase in hematocrit and hemoglobin levels (red cell mass rose, plasma volume did not change), a decrease in plasma triglyceride by 23% (p less than 0.05) and an increase in high-density lipoprotein cholesterol (HDL-C) levels by 21% (p less than 0.01) (both HDL-C and triglyceride levels worsened in the sedentary controls), and an 18% increase in glucose disappearance rates (p less than 0.05) in spite of a 52% decrease in fasting insulin levels (p less than 0.01), suggesting that insulin sensitivity improved. These results demonstrate that some of the complications present in hemodialysis patients may be caused by their sedentary life-style, rather than endstage renal disease itself. This suggests that rehabilitation through exercise is possible for these patients. By reducing coronary risk factors in hemodialysis patients, exercise training may also decrease their heightened morbidity and mortality from atherosclerotic complications. These possibilities need to be examined in a longitudinal study.

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)