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Charles R Nolan
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ABSTRACT: In 2003, more than 320,000 people in the United States were receiving dialysis for ESRD, with predicted increases to 650,000 by 2010 and 2 million by 2030. Mortality from cardiovascular disease (CVD) in patients with ESRD is 10 to 30 times higher than in the general population. The exact mechanism of accelerated CVD in patients with kidney disease is unknown. Treatment costs for ESRD are in excess of $14 billion annually (6.4% of Medicare budget). Strategies to improve long-term outcomes include aggressive risk factor modification, minimization of dialysis complications, and kidney transplantation. Because abnormalities of mineral metabolism contribute to mortality risk, phosphate binder therapy is fundamental. More expensive non-calcium-containing phosphate binders such as sevelamer have been recommended to reduce cardiovascular calcification. However, the lack of outcome data and the $2 to $3 billion annual cost make it difficult to justify widespread utilization of newer binders as first-line therapy. Conversely, kidney transplantation is known to improve survival in ESRD. Progression of atherosclerosis and CVD in patients with renal failure is largely due to loss of renal function per se, and provision of a functioning kidney through renal transplantation halts the progression of CVD and dramatically reduces mortality. Despite this fact, many patients lose Medicare funding for immunosuppressive therapy 3 yr posttransplantation. To achieve the goal of prevention of cardiovascular mortality in patients with ESRD, it clearly would be more prudent, efficacious, and cost-effective to use Medicare prescription drug dollars to provide full coverage for life-long immunosuppressive drug therapy after renal transplantation.
Journal of the American Society of Nephrology 12/2005; 16 Suppl 2:S120-7. · 9.66 Impact Factor
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Charles R Nolan
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ABSTRACT: Hyperphosphatemia in patients with chronic kidney disease leads to secondary hyperparathyroidism and renal osteodystrophy, and it is independently associated with mortality risk. The exact mechanism by which hyperphosphatemia increases mortality risk is unknown, but it may relate to enhanced cardiovascular calcification. The National Kidney Foundation Kidney Disease Outcomes Quality Initiative (K/DOQI) Clinical Practice Guidelines for Bone Metabolism and Disease in Chronic Kidney Disease recommends maintenance of serum phosphorus below 5.5 mg/dL, calcium-phosphorus (Ca x P) product less than 55 mg(2)/dL(2), intact parathyroid hormone (iPTH) 150 pg/mL to 300 pg/mL, and bicarbonate (HCO(3)) greater than 22 mEq/L. Although calcium-based phosphate binders (CBPB) are cost effective, there are long-term safety concerns pertaining to their postulated role in the progression of cardiovascular calcification. Sevelamer hydrochloride has been recommended as an alternative noncalcium phosphate binder. Results from the Calcium Acetate Renagel Evaluation (CARE) study indicate that calcium acetate is more effective than sevelamer hydrochloride in controlling serum phosphorous, Ca x P product, and HCO(3) in hemodialysis patients. In the Treat-to-Goal study, dialysis patients treated with sevelamer hydrochloride had slower progression of coronary and aortic calcification than patients treated with CBPB. The mechanism underlying the beneficial effect of sevelamer hydrochloride is unknown but may relate to decreased calcium loading, or to dramatic reductions in low-density lipoprotein (LDL) cholesterol in sevelamer hydrochloride-treated patients. At present, evidence incriminating CBPB in the progression of cardiovascular calcification in end-stage renal disease (ESRD) remains largely circumstantial. As calcium acetate is more efficacious and cost effective than sevelamer hydrochloride, it remains an accepted first-line phosphate binder. This review examines these issues and provides rational guidelines for the use of CBPB in patients on maintenance hemodialysis.
Kidney international. Supplement 08/2005;
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ABSTRACT: Cardiovascular calcification (CVC) is common and severe in patients with end-stage renal disease on dialysis. However, the prevalence and severity of CVC is less well documented in patients with chronic kidney disease (CKD) not yet on dialysis.
Fifty-eight nondialyzed HA with type 2 diabetes and CKD were enrolled. They comprise 29 patients with stages 1 and 2 CKD (early CKD group) and 26 patients with stages 4 and 5 CKD (advanced CKD group). Coronary artery calcification (CAC) was measured by ultrafast spiral computed tomography, while peripheral artery calcification (PAC) was evaluated by plain x-ray of the chest, pelvis, thighs, and lower extremities.
The prevalence of CAC and PAC were significantly higher in the advanced CKD group compared to the early CKD group (73% vs. 38%; P < 0.01 and 85% vs. 35%; P < 0.0001, respectively). The median CAC scores were 18-fold greater in the advanced CKD group (138.9 vs. 7.8, respectively). By linear regression analysis, a strong association was found between the level of renal function and ln total volume of CAC.
Our data indicate that CAC and PAC are common and severe in HA diabetic patients with CKD not previously treated with dialysis, calcium-based phosphate binders, or vitamin D analogues. Lower level of renal function is associated with increased burden of vascular calcification in predialysis patients with CKD.
Kidney International 07/2005; 68(1):271-7. · 6.61 Impact Factor
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ABSTRACT: Treatment of hyperphosphatemia in patients with chronic kidney disease on maintenance hemodialysis. Hyperphosphatemia in patients with ESRD leads to secondary hyperparathyroidism, renal osteodystrophy, and is independently associated with mortality risk. The exact mechanism by which hyperphosphatemia increases mortality risk is unknown, but it may relate to enhanced cardiovascular calcification. National Kidney Foundation K/DOQI bone metabolism and disease guidelines recommend maintenance of serum phosphorus (P) below 5.5 mg/dL, and Ca x P product less than 55 mg(2)/dL(2). Although calcium-based phosphate binders (CBPB) are cost effective, long-term safety concerns relate to their postulated role in progression of cardiovascular calcification. Sevelamer hydrochloride has been recommended as an alternative noncalcium phosphate binder. Results from the Calcium Acetate Renagel Evaluation (CARE study) indicate that calcium acetate is more effective than sevelamer in controlling serum phosphorous and Ca x P product in hemodialysis patients. In the Treat-to-Goal study, dialysis patients treated with sevelamer had slower progression of coronary and aortic calcification than patients treated with CBPB. The mechanism underlying the beneficial effect of sevelamer is unknown, but may relate to decreased calcium loading or to dramatic reductions in LDL cholesterol in sevelamer-treated patients. At present, evidence incriminating CBPB in the progression of cardiovascular calcification in ESRD remains largely circumstantial. As calcium acetate is more efficacious and cost effective than sevelamer, it remains an accepted first-line phosphate binder. In this review, we will examine these issues and provide rational guidelines for the use of calcium-based phosphate binders in patients on maintenance hemodialysis.
Kidney international. Supplement 07/2005;
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Kidney International 05/2005; 67(4):1636-7. · 6.61 Impact Factor
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ABSTRACT: Most patients with end-stage renal disease develop hyperphosphatemia because their dietary intake exceeds phosphorus elimination by intermittent thrice-weekly dialysis. Inadequately treated hyperphosphatemia plays a central role in the pathogenesis of secondary hyperparathyroidism and extraosseous calcification. Moreover, in the last 15 years, this biochemical abnormality has become increasingly important following the publication of two epidemiologic studies that demonstrated an association between elevated serum phosphorus and increased mortality risk in patients with end-stage renal disease. As a result, the National Kidney Foundation Kidney Disease Outcome and Quality Initiative (K/DOQI) Bone Metabolism and Chronic Kidney Disease Guidelines recommend that serum phosphorus levels be maintained between 3.5 and 5.5 mg/dL. Unfortunately, cross-sectional studies have shown a mean serum phosphorus of 6.2 mg/dL in the maintenance hemodialysis population in the United States. An alarming 60% of patients have serum phosphorus in excess of the 5.5 mg/dL level recommended by K/DOQI guidelines. In order to achieve this new target for serum phosphorus, the most efficacious and cost-effective phosphate binders currently available should be utilized. In this review, we discuss the results of the Calcium Acetate Renagel Evaluation (CARE study), which clearly demonstrated the superiority of calcium acetate over sevelamer hydrochloride for controlling serum phosphorus and calcium-phosphate product to the levels recommended by the K/DOQI guidelines.
Kidney international. Supplement 10/2004;
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ABSTRACT: Short-term and long-term studies indicate that patients treated with sevelamer hydrochloride have lower serum bicarbonate levels than patients treated with calcium-containing phosphate binders. This observation has previously been attributed to withdrawal of a source of base with discontinuation of calcium carbonate or calcium acetate. However, understanding of the chemistry of sevelamer hydrochloride suggests at least three potential mechanisms whereby it might induce a dietary acid load. Moreover, preliminary results from an animal model demonstrate that treatment with sevelamer hydrochloride results in a fall in urine pH, as well as an increase in urinary ammonium and calcium excretion consistent with an increase in net acid excretion. Chronic metabolic acidosis in maintenance dialysis patients is associated with major systemic effects. It is independently associated with an increased risk of death in dialysis patients. Metabolic acidosis has both catabolic and antianabolic effects that may lead to a net negative nitrogen balance and total body protein balance. Metabolic acidosis also leads to physiochemical dissolution of bone and promotes cell-mediated bone resorption due to enhanced osteoclast activity and reduced osteoblast activity. It may also exacerbate secondary hyperparathyroidism and renal osteodystrophy. Given the long-term risks of chronic metabolic acidosis in maintenance dialysis patients, Kidney/Dialysis Outcome Quality Initiative (K/DOQI) guidelines have recently recommended maintaining predialysis serum levels of CO2 above 22 mmol/L in order to improve bone histology, and to ameliorate excess protein catabolism.
Kidney international. Supplement 10/2004;
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Wajeh Y Qunibi,
Robert E Hootkins,
Laveta L McDowell,
Micah S Meyer,
Matthias Simon,
Rodolfo O Garza,
Russell W Pelham,
Mark V B Cleveland,
Larry R Muenz,
David Y He, Charles R Nolan
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ABSTRACT: Hyperphosphatemia underlies development of hyperparathyroidism, osteodystrophy, extraosseous calcification, and is associated with increased mortality in hemodialysis patients.
To determine whether calcium acetate or sevelamer hydrochloride best achieves recently recommended treatment goals of phosphorus </=5.5 mg/dL and Ca x P product </=55 mg(2)/dL(2), we conducted an 8-week randomized, double-blind study in 100 hemodialysis patients.
Comparisons of time-averaged concentrations (weeks 1 to 8) demonstrated that calcium acetate recipients had lower serum phosphorus (1.08 mg/dL difference, P= 0.0006), higher serum calcium (0.63 mg/dL difference, P < 0.0001), and lower Ca x P (6.1 mg(2)/dL(2) difference, P= 0.022) than sevelamer recipients. At each week, calcium acetate recipients were 20% to 24% more likely to attain goal phosphorus [odds ratio (OR) 2.37, 95% CI 1.28-4.37, P= 0.0058], and 15% to 20% more likely to attain goal Ca x P (OR 2.16, 95% CI 1.20-3.86, P= 0.0097). Transient hypercalcemia occurred in 8 of 48 (16.7%) calcium acetate recipients, all of whom received concomitant intravenous vitamin D. By regression analysis hypercalcemia was more likely with calcium acetate (OR 6.1, 95% CI 2.8-13.3, P < 0.0001). Week 8 intact PTH levels were not significantly different. Serum bicarbonate levels were significantly lower with sevelamer hydrochloride treatment (P < 0.0001).
Calcium acetate controls serum phosphorus and calcium-phosphate product more effectively than sevelamer hydrochloride. Cost-benefit analysis indicates that in the absence of hypercalcemia, calcium acetate should remain the treatment of choice for hyperphosphatemia in hemodialysis patients.
Kidney International 06/2004; 65(5):1914-26. · 6.61 Impact Factor
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ABSTRACT: Hyperphosphatemia in patients with end-stage renal disease leads to secondary hyperparathyroidism and renal osteodystrophy, and is independently associated with mortality risk. How hyperphosphatemia increases mortality risk is unknown but it may promote cardiovascular calcification. It is recommended that dialysis patients be treated to maintain normal serum phosphorus. Although calcium-based phosphate binders are cost-effective, their long-term safety has been questioned because of their postulated role in progression of cardiovascular calcification. In this regard, sevelamer hydrochloride has been recommended as an alternative phosphate binder. In this review, we will examine these issues and provide rational guidelines for the use of calcium-based phosphate binders.
Results from the calcium acetate Renagel evaluation study indicate that calcium acetate is more effective than sevelamer in controlling serum phosphorus and calcium x phosphorus product in hemodialysis patients. However, in the Treat-to-Goal study dialysis patients treated with sevelamer had less progression of coronary and aortic calcification than patients treated with calcium-containing binders. The mechanism underlying the slower rate of progression of cardiovascular calcification in sevelamer-treated patients remains uncertain but may relate to decreased calcium loading or to dramatic reductions in LDL cholesterol.
At present, evidence incriminating calcium-containing phosphate binders in the progression of cardiovascular calcification in end-stage renal disease remains largely circumstantial. As calcium acetate is more efficacious and cost-effective than sevelamer, it remains an accepted first-line drug. Treatment with sevelamer hydrochloride should be considered for patients with persistent hypercalcemia during calcium-based binder therapy despite appropriate adjustment of vitamin D therapy.
Current Opinion in Nephrology and Hypertension 08/2003; 12(4):373-9. · 4.33 Impact Factor
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Kidney International 02/2003; 63(1):383; author reply 383-4. · 6.61 Impact Factor
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Seminars in Dialysis 15(5):315-28. · 2.27 Impact Factor
