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The bone disease seen in our aging dialysis population is a complex mixture of osteoporosis and renal osteodystrophy. Attention must be paid to both of these issues. Hip fractures are increased with aging and this increase is further aggravated by renal failure. Preventive management with Vitamin D and bisphosphonates is reviewed.

We have previously shown that pamidronate, when given within 10 days of burn injury, preserves lumbar spine bone mineral content from admission to discharge in 6-8 weeks and at 6 months increases both lumbar spine and total body bone mineral content (BMC) over placebo. We followed patients unblinded after 6 months every 3 months up to 2 years post-burn to see if the effects of pamidronate were sustained. Additionally, we assessed bone remodeling at 1 year post-burn by iliac crest bone biopsy. We enrolled 57 subjects who were initially randomized to pamidronate (n=32) and placebo (n=25). After 2 years, 21 subjects (pamidronate=8, placebo=13) remained. Analysis of bone densitometry by dual energy X-ray absorptiometry revealed an effect of both treatment (p<0.012 for total body BMC, p<0.001 for lumbar spine BMC, p<0.014 for lumbar spine bone area and p<0.003 for lumbar spine bone density (BMD)) and time (p<0.0003 on total body BMC, p<0.001 on lumbar spine BMC, p<0.001 on lumbar spine bone area, and no significant difference on lumbar spine BMD). There was no interaction between treatment and time. Results for bone histomorphometry revealed no effect of treatment on either static or dynamic parameters but did show an effect of time on osteoid area (p=0.004, surface p<0.001, and width, p<0.001). We conclude that acute administration of pamidronate resulted in sustained therapeutic effect on bone and that this type of administration may serve as a useful adjunct to other therapies in the preservation and augmentation of bone mass following severe burns.

Adynamic bone disease (ABD) is increasingly recognized, especially in dialysis patients treated with oral calcium carbonate, vitamin D supplements, or supraphysiological dialysate calcium. We undertook this study to assess the effect of lowering dialysate calcium on episodes of hypercalcemia, serum parathyroid hormone (PTH) levels as well as bone turnover. Fifty-one patients treated with peritoneal dialysis and biopsy-proven ABD were randomized to treatment with control calcium, 1.62 mM, or low calcium, 1.0 mM, dialysate calcium over a 16-month period. In the low dialysate calcium group, 14 patients completed the study. This group experienced a decrease in serum total and ionized calcium levels, and an 89% reduction in episodes of hypercalcemia, resulting in a 300% increase in serum PTH values, from 6.0+/-1.6 to 24.9+/-3.6 pM (P<0.0001). Bone formation rates, all initially suppressed, at 18.1+/-5.6 microm2/mm2/day rose to 159+/-59.4 microm2/mm2/day (P<0.05), into the normal range (>108 microm2/mm2/day). In the control group, nine patients completed the study. Their PTH levels did not increase significantly, from 7.3+/-1.6 to 9.4+/-1.5 pM and bone formation rates did not change significantly either, from 13.3+/-7.1 to 40.9+/-11.9 microm2/mm2/day. Lowering of peritoneal dialysate calcium reduced serum calcium levels and hypercalcemic episodes, which resulted in increased PTH levels and normalization of bone turnover in patients with ABD.

Background: First-generation immunometric assays for "intact" parathyroid hormone (iPTH) also measure large N-terminally truncated PTH fragments, whereas second-generation assays, such as the "bio-intact" PTH (biPTH) assay, measure only full-length biologically active PTH(1-84). This study compared iPTH and biPTH assays during cinacalcet treatment in subjects with secondary HPT receiving dialysis., Methods: Four hundred and ten subjects were enrolled in a 26-week randomized, double-blind, placebo-controlled trial of oral cinacalcet (or placebo), 30 to 180 mg once daily, and efficacy was assessed using biPTH and iPTH assays., Results: Compared with control treatment, cinacalcet improved the management of secondary HPT. Both biPTH and iPTH decreased by 38%+/- 3% during weeks 13 to 26 in the cinacalcet group; biPTH increased by 23%+/- 4% and iPTH increased by 9.5%+/- 3% in the control group (P < 0.001). Fifty-six percent of cinacalcet subjects and 10% of control subjects had a > or = 30% reduction in biPTH, and 61% and 11%, respectively, had a > or = 30% reduction in iPTH. Significant correlations between biPTH and iPTH levels were observed throughout the study. Both assays correlated similarly with bone-specific alkaline phosphatase levels. The ratio of biPTH to iPTH was maintained at 56% +/- 1% after treatment in both treatment groups. Increasing serum calcium levels were associated with a decreasing ratio of biPTH to (iPTH-biPTH)., Conclusion: These data show that PTH can be monitored with either iPTH or biPTH assays during therapy with cinacalcet, and that cinacalcet therapy does not exert a major influence on the ratio between PTH(1-84) and large, N-terminally truncated PTH fragments.

Bone loss is a known complication of severe burn injury. It is, in part, due to increased endogenous glucocorticoids that contribute to the reduction in bone formation and osteoblast differentiation, hypercalciuria secondary to hypoparathyroidism, and vitamin D deficiency. In this study we attempted to prevent post-burn bone loss by acute intravenous administration of the bisphosphonate pamidronate. We enrolled 43 children, with burns of > 40% total body surface area, in a randomized, double-blind, placebo-controlled study, administering the study drug within 10 days of burn injury and again 1 week later. Dual energy X-ray absorptiometry was performed prior to drug therapy, at hospital discharge and at 6 months post-burn. Urine specimens were obtained at baseline and discharge for determination of calcium and free deoxypyridinoline. Blood was obtained along with the urine specimens for measurement of intact parathyroid hormone (iPTH) and ionized calcium (Ca) levels. Following doxycycline labeling, intra-operative iliac crest bone biopsies were obtained, and bone histomorphometry was determined. At time of discharge there were no differences in total body bone mineral content (BMC), but lumbar spine BMC was significantly higher in the pamidronate group (P < 0.005). By 6 months post-burn the differences in lumbar spine BMC persisted, but, now, total body BMC was significantly higher in the pamidronate group (P < 0.05). Bone histomorphometry and levels of urine Ca and free deoxypyridinoline failed to show significant increases in bone formation or decreases in bone resorption. Pamidronate did not exacerbate the hypocalcemia in burn patients. In summary, acute intravenous pamidronate administration following burns may help to preserve bone mass, perhaps by inhibiting the glucocorticoid-induced apoptosis of osteoblasts and osteocytes.

Background: The National Kidney Foundation's Kidney Disease Outcomes Quality Initiative (NKF-K/DOQItrade mark) has established guidelines for treatment of secondary hyperparathyroidism (HPT). The ability of cinacalcet HCl (Sensipartrade mark) treatment to improve achievement of target levels of parathyroid hormone (PTH), calcium, phosphorus, and calcium-phosphorus product (Ca x P) was investigated in subjects on dialysis with secondary HPT., Methods: Data were combined from three placebo-controlled, double-blind, 26-week studies with similar design that randomized 1136 subjects on dialysis to receive traditional therapy plus cinacalcet or placebo. Oral cinacalcet was titrated from 30 to 180 mg/day. Achievement of K/DOQI goals was determined for each treatment group overall and for subgroups defined by baseline intact PTH (iPTH) and Ca x P levels., Results: Cinacalcet-treated subjects were more likely to achieve a mean iPTH

Elevated serum phosphate levels have been linked with vascular calcification and mortality among dialysis patients. The relationship between phosphate and mortality has not been explored among patients with chronic kidney disease (CKD). A retrospective cohort study was conducted from eight Veterans Affairs' Medical Centers located in the Pacific Northwest. CKD was defined by two continuously abnormal outpatient serum creatinine measurements at least 6 mo apart between 1999 and 2002. Patients who received chronic dialysis, those with a present or previous renal transplant, and those without a recent phosphate measurement were excluded. The primary end point was all-cause mortality. Secondary end points were acute myocardial infarction and the combined end point of myocardial infarction plus death. A total of 95,619 veterans with at least one primary care or internal medicine clinic contact from a Northwest VA facility and two or more outpatient measurements of serum creatinine, at least 6 mo apart, between January 1, 1999, and December 31, 2002, were identified. From this eligible population, 7021 patients met our definition of CKD. After exclusions, 6730 CKD patients were available for analysis, and 3490 had a serum phosphate measurement during the previous 18 mo. After adjustment, serum phosphate levels >3.5 mg/dl were associated with a significantly increased risk for death. Mortality risk increased linearly with each subsequent 0.5-mg/dl increase in serum phosphate levels. Elevated serum phosphate levels were independently associated with increased mortality risk among this population of patients with CKD.

Background: Secondary hyperparathyroidism (SHPTH) is highly prevalent among persons with end-stage renal disease (ESRD). SHPTH has been linked to uremic bone disease, vascular calcification, and a higher risk of death. Parathyroidectomy (PTX) can dramatically reduce parathyroid hormone (PTH) and phosphate levels; however, the relationship between PTX and survival is not known., Methods: We conducted an observational matched cohort study utilizing data from the United States Renal Database System (USRDS) in which 4558 patients undergoing a first PTX while on hemodialysis or peritoneal dialysis were individually matched by age, race, gender, cause of ESRD, dialysis duration, prior transplantation status, and dialysis modality to 4558 control patients who did not undergo PTX. Patients were followed from the date of PTX until they died or were lost to follow-up., Results: The 30-day postoperative mortality rate following PTX was 3.1%. Long-term relative risks of death among patients undergoing PTX were estimated to be 10% to 15% lower than those of matched control patients not undergoing surgery. Survival curves between the 2 groups crossed 587 days following PTX. Median survival was 53.4 months (95% CI: 51.2-56.4) in the PTX group, and 46.8 months (95% CI: 44.7-48.9) in the control group., Conclusion: PTX was associated with higher short-term, and lower long-term, mortality rates among U.S. patients receiving chronic dialysis. Measures to attenuate SHPTH may play an important role in reducing mortality among patients with end-stage renal disease.

Children burned > or =40% total body surface area suffer acute bone loss. The reason(s) for this is uncertain. In order to determine whether high endogenous glucocorticoid production can contribute to the bone loss, we sequentially studied a total of 14 pediatric burn patients for bone histomorphometry; 7 of these patients and 4 controls were studied for characteristics of corticosteroid-induced bone loss, including decreased osteoblasts and down-regulation of the glucocorticoid receptor in bone. We then studied 4 of the burn patients and three controls for a decrease in markers of osteoblast differentiation, another feature of glucocorticoid toxicity. Bone biopsies were taken from each of the 14 burn patients a mean of 3 weeks post-burn. Histomorphometry was performed on one specimen ( n=7) and either glucocorticoid and mineralocorticoid receptor, collagen and alkaline phosphatase expression by RT-PCR ( n=7) or marrow stromal cell culture ( n=4) on the other. Patients were permitted a maximum of two biopsies for study. One biopsy was obtained intra-operatively from normal subjects during elective iliac crest alveolar bone grafting and compared with burn specimens for glucocorticoid receptors and marrow stromal cell culture. A 24 h urine specimen was obtained for free cortisol ( n=7). Histomorphometry revealed low osteoblast and osteoid surfaces and few detectable osteoblasts. Resorptive surfaces were also reduced. Glucocorticoid receptor alpha mRNA (GRalpha) was not decreased; however, there was a trend toward inverse relationships between urine free cortisol and GRalpha and type-1 collagen mRNA, r=-0.61 and -0.64, respectively, and a significantly lower mRNA for type-1 collagen in bone in burn vs control patients by the median test, lambda(2)=7.6 ( p<0.01). Markers of osteoblast differentiation, core-binding factor (cbf)a1, bone morphogenetic protein (BMP)-2, type-I collagen, and alkaline phosphatase were reduced in burn cell cultures compared with controls ( p<0.05). The eightfold elevation of urinary free cortisol excretion, low osteoblast number, decreased resorptive surface, and reduced markers of osteoblast differentiation are all consistent with an acute glucocorticoid effect on bone.

Background: Medical therapy for secondary hyperparathyroidism (SHPTH) has evolved considerably during the past decade. It is not known how changes in medical therapy might impact the parathyroidectomy (PTX) rate among dialysis patients. Relatively low parathyroid hormone (PTH) levels have been found among elderly dialysis patients and those with diabetes. Clinical factors associated with differing PTX rates among United States dialysis patients have not been reported. We report PTX rates in the United States from 1990 to 1999 among persons with end-stage renal disease, accounting for changes in patient characteristics., Methods: Data from the United States Renal Database were utilized. Patients insured by Medicare or Medicaid and receiving renal replacement therapy between January 1, 1990, and December 31, 1999 were considered for analysis. PTX was determined by ICD-9 procedure codes. Multivariate Poisson models were used to estimate adjusted PTX rates., Results: The overall observed PTX rate in the study sample was 7.16 per 1000 person-years at risk. After a slight rise during the early 1990s, adjusted PTX rates declined by approximately 30% between 1995 and 1999. Adjusted PTX rates were higher among patients who were younger, female, nondiabetic, receiving peritoneal dialysis, and those with a longer cumulative duration of dialysis., Conclusion: PTX rates have recently decreased in the United States, independent of changes in patient characteristics. The effectiveness of medical therapy in targeting secondary hyperparathyroidism may be improving. Younger, nondiabetic patients with a longer cumulative dialysis burden are at particularly high risk for PTX.

Current treatment of secondary hyperparathyroidism in chronic kidney failure with calcium and active vitamin D is potentially limited by hypercalcemia and hyperphosphatemia. AMG 073 represents a new class of compounds for the treatment of hyperparathyroidism known as calcimimetics, which reduce parathyroid hormone (PTH) synthesis and secretion by increasing the sensitivity of the parathyroid calcium-sensing receptor (CaR) to extracellular calcium. The current study evaluates the efficacy and safety of AMG 073 when added to conventional treatment of secondary hyperparathyroidism in end-stage renal disease (ESRD). Seventy-one hemodialysis patients with uncontrolled secondary hyperparathyroidism, despite standard therapy with calcium, phosphate binders, and active vitamin D sterols, were treated in this 18-wk, dose-titration study with single daily oral doses of AMG 073/placebo up to 100 mg. Changes in plasma PTH, serum calcium, serum phosphorus, and calcium x phosphorus levels were compared between AMG 073 and placebo groups. Mean PTH decreased by 33% in the AMG 073 patients compared with an increase of 3% in placebo patients (P = 0.001). A significantly greater proportion of AMG 073 patients (44%) had a mean PTH < or = 250 pg/ml compared with placebo patients (20%; P = 0.029). Also, a significantly greater proportion of AMG 073 patients (53%) had a decrease in PTH > or =30% compared with placebo patients (23%; P = 0.009). Calcium x phosphorus levels decreased by 7.9% in AMG 073 patients compared with an increase of 11.3% in placebo patients (P = 0.013). Adverse event rates were low and mostly mild to moderate in severity; however, the incidence of vomiting was higher in AMG 073 patients. In this study, the calcimimetic AMG 073 at doses up to 100 mg for 18 wk provided a safe and effective means to attain significant reductions in PTH and calcium x phosphorus levels in ESRD patients. AMG 073 represents a novel and promising therapy to improve the management of secondary hyperparathyroidism.

Background: Patients with end-stage renal disease are subject to a broad range of thrombotic complications. Low molecular weight heparins (LMWHs) are effective antithrombotic agents; however, they are cleared largely by renal mechanisms, raising uncertainty about their use in renally impaired patients., Methods: Twelve chronic hemodialysis subjects were administered two single doses of the LMWH tinzaparin, 75 IU/kg, 2 weeks apart: subcutaneously (SC) on an off-dialysis day and intravenously (IV) just before dialysis., Results: Mean maximal anti-factor Xa (anti-Xa) activity was 0.33 IU/mL 4.0 hours after SC administration and 1.33 IU/mL 0.25 hours after IV administration. Anti-Xa half-lives were 3.89 and 2.31 hours, respectively. Anti-Xa activity returned to baseline within 24 hours of administration by either route. Consistent with population pharmacokinetic analyses of clinical study subjects with severe renal impairment, anti-Xa clearance after tinzaparin administration was reduced 28% relative to subjects with normal renal function. All 12 study subjects completed hemodialysis without requiring additional anticoagulation. One subject had minimal clotting in the dialyzer drip chamber, and one subject had mild prolonged bleeding at the vascular access site after dialysis needle removal. No major bleeding events occurred., Conclusion: Tinzaparin, 75 IU/kg, SC on an off-dialysis day and IV just before dialysis is well tolerated in chronic hemodialysis patients. The weight-based regimen of 75 IU/kg IV just before dialysis provides adequate anticoagulation. SC weight-based dosing on off-dialysis days is a feasible regimen for further clinical thromboprophylaxis efficacy studies in hemodialysis patients. The risk for clinical overdose in severely renally impaired patients using this weight-based regimen of tinzaparin is unlikely., (Copyright 2002 by the National Kidney Foundation, Inc.)

Background: Studies have shown that protein-energy malnutrition (PEM) is a strong predictor of total mortality among patients with end-stage renal disease (ESRD). The aim of this study is to assess the relationship between nutritional indices and cardiovascular (CV) mortality among patients with ESRD by using data from the US Renal Data System (USRDS) Dialysis Morbidity and Mortality Study Wave I (DMMS-1)., Methods: Demographic and medical data were abstracted from 5,058 patients who participated in the USRDS DMMS-1. Nutritional measurements of interest included subjective assessment of malnutrition, serum albumin level, body mass index (BMI), and cholesterol level. The USRDS provided follow-up data on mortality through July 1998. The Cox proportional hazard model was used to estimate the risk for CV death associated with nutritional markers., Results: The risk for CV death was 39% greater for each 1-g/dL (10-g/L) decrement in serum albumin level (95% confidence interval [CI], 1.20 to 1.60; P < 0.001). A care provider's assessment of malnutrition was associated with a 27% greater risk for CV mortality (95% CI, 1.08 to 1.50; P < 0.004). For each one-unit decrement in BMI, the risk for CV disease (CVD) was 6% greater (95% CI, 1.00 to 1.13; P < 0.046). Among patients without CVD at the study start, serum albumin level remained a significant risk factor for CV death (adjusted relative risk = 1.39 per 1-g/dL (10-g/L) increment; P = 0.026). In addition, change in albumin levels over time was significantly associated with CV mortality. For each 0.1-g/dL (1-g/L) decrement in albumin level per month, the risk for CV death was 2.24-fold greater (95% CI, 1.65 to 3.02; P < 0.001) among the entire cohort and 3.86-fold greater (95% CI, 1.96 to 7.60; P < 0.010) among those without a known history of CVD at the study start., Conclusion: Both PEM at baseline and worsening PEM over time are associated with a greater risk for CV death. This finding persists among dialysis patients without preexisting CVD at baseline., (Copyright 2002 by the National Kidney Foundation, Inc.)

Background: Patients on dialysis suffer from alarming rates of cardiovascular disease. While calcium channel blockers (CCBs) are prescribed widely to patients with end-stage renal disease (ESRD) for the treatment of hypertension, the long-term outcomes associated with the use of these medications are not known. We sought to determine the association between CCB use and mortality among a cohort of ESRD patients., Methods: Data were utilized from the United States Renal Data System Dialysis Morbidity and Mortality Wave II, a randomly selected prospective cohort of 4065 ESRD patients who began dialysis in 1996. Clinical data, including medication information, were collected 60 days after the start of dialysis. Subsequent survival status and cause of death were ascertained. The Cox proportional hazards model was used to estimate the relative risk of death associated with CCB use., Results: Data from 3716 patients (91.4%) were available for analysis. Fifty-one percent of the study patients were prescribed a CCB. The use of a CCB was associated with a 21% lower risk of total mortality (RR 0.79, CI 0.69 to 0.90) and a 26% lower risk of cardiovascular specific mortality (RR 0.74, CI 0.60 to 0.91). For patients with pre-existing cardiovascular disease, CCB use was associated with a 23% (RR 0.77, CI 0.65 to 0.91) and 32% (RR 0.68, CI 0.53 to 0.87) lower risk of total and cardiovascular mortality, respectively., Conclusion: After controlling for known risk factors and potential confounders, CCBs were found to be associated with a lower risk of mortality among ESRD patients.

Background: Although serum albumin is a marker for malnutrition and associated with a higher mortality in adult patients with end-stage renal disease (ESRD), the risk of death associated with serum albumin is unknown in pediatric patients with ESRD. We evaluated the association between serum albumin and death among pediatric patients initiating dialysis., Methods: Data from the United States Renal Data System (USRDS) were used to identify all patients under the age of 18 who initiated dialysis between January 1, 1995 and December 31, 1998. Using the Cox proportional hazards models, the association between serum albumin obtained 45 days prior to dialysis initiation and death was estimated, controlling for demographic factors, dialysis modality, and anthropometric measures., Results: Of 1723 patients included in the analysis, there were 93 deaths over 2953 patient-years of observation. The multivariate analysis demonstrated that each -1 g/dL difference in serum albumin between patients was associated with a 54% higher risk of death [adjusted relative risk (aRR), 1.54; 95% confidence interval (CI), 1.15 to 1.85; P=0.002]. This was independent of glomerular causes for their ESRD and other potential confounding variables., Conclusions: Pediatric patients initiating dialysis with hypoalbuminemia are at a higher risk for death. This finding persists after adjusting for glomerular causes for ESRD and other potential confounding variables. Low serum albumin at dialysis initiation is an important marker of mortality risk in pediatric ESRD patients.

Unlabelled: BACKGROUND.: Patients with end-stage renal disease (ESRD) suffer from markedly higher rates of cardiovascular disease than the general population. Although therapy with 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors ("statins") has been demonstrated to reduce the mortality from cardiovascular disease in patients without ESRD, only 10% of patients on dialysis are treated with these medications by day 60 of ESRD. We determined whether the use of statins is associated with a reduction in cardiovascular-specific death and total mortality in ESRD patients., Methods: Data were analyzed from the U.S. Renal Data System Dialysis Morbidity and Mortality Wave-2 study, a cohort of randomly selected patients who were initiating dialysis in 1996. Information about the use of statins as well as other baseline characteristics was abstracted from the patients' dialysis records by dialysis personnel. Cox proportional hazards models were developed to determine the association between use of statins at baseline and subsequent risk of mortality, with adjustment for known mortality risk factors., Results: Follow-up data were available for 3716 patients through July 1998. At baseline, 362 (9.7%) of patients were using statins. These patients had a mortality rate of 143/1000 person-years, compared with a rate of 202/1000 person-years for patients not using statins. Statin use was independently associated with a reduced risk of total mortality [relative risk (RR)=0.68, 95% confidence interval (CI)=0.54, 0.87] as well as cardiovascular-specific mortality (RR=0.64, 95% CI=0.45, 0.91). In contrast, the use of fibrates was not associated with reduced mortality (RR=1.29)., Conclusions: Statin use was associated with a reduction in cardiovascular-specific death and total mortality in patients on dialysis.

Objective: The study's aim was to evaluate access patency and incidence of revisions in patients initiating hemodialysis and to determine differences in access performance by type of access among patient subgroups., Methods: The study used data from the United States Renal Data System Dialysis Morbidity and Mortality Study Wave 2, which contained a random sample of dialysis patients initiating dialysis in 1996 and early 1997. Failures and revisions were evaluated among 2247 newly placed hemodialysis accesses by using Cox proportional hazards regression model and Poisson regression. Primary and secondary patency rates were estimated using the Kaplan-Meier method., Results: Fifteen hundred seventy-four prosthetic grafts, 492 simple autogenous fistulas, and 181 venous transposition fistulas were available for evaluation. Prosthetic grafts had a 41% greater risk of primary failure compared with simple fistulas (relative risk, 1.41; 95% CI, 1.22-1.64; P < .001) and a 91% higher incidence of revision (relative risk, 1.91; 95% CI, 1.60-2.28; P <.001). At 2 years, autogenous fistulas demonstrated superior primary patency (39.8% versus 24.6%, P < .001) and equivalent secondary patency (64.3% versus 59.5%, P = .24) compared with prosthetic grafts. When compared with simple fistulas, vein transpositions demonstrated equivalent secondary patency at 2 years (61.5% versus 64.3%, P = .43) but inferior primary patency (27.7% versus 39.8%, P = .008) and had a 32% increased incidence of revision (P = .04). Autogenous fistulas had superior primary patency compared with prosthetic grafts in all patient subgroups except for patients with previously failed access. Vein transpositions showed the greatest benefit in terms of patency and incidence of revision in women and in patients with previously failed access., Conclusions: The preferential placement of autogenous fistulas may increase primary patency and decrease the incidence of revisions. Vein transpositions had similar secondary patency compared with simple fistulas, but required more revisions. The greatest benefit of a vein transposition fistula was seen in women and in patients with a history of access failure.

Background: The aim of this study was to evaluate the determinants of access patency and revision, including the effects of reducing the placement of prosthetic hemodialysis access., Methods: A retrospective cohort study of all hemodialysis accesses placed at the Veteran's Administration Puget Sound Health Care System between 1992 and 1999 was conducted. A policy was instituted in 1996 that maximized the use of autogenous hemodialysis access. The impacts of the policy change, demographics, and comorbid factors on access type and patency, were examined. Primary and secondary patency rates were examined using the Kaplan--Meier method, and factors associated with failure and revision were examined using Cox proportional hazard models and Poisson regression., Results: During the study, 104 accesses (61 prosthetic grafts and 43 autogenous fistulas) were placed prior to 1996, and 118 (31 prosthetic grafts and 87 autogenous fistulas) were placed after 1996. There was a significant increase in autogenous fistulas placed after 1996 (87 out of 118) compared with before 1996 (43 out of 104, P < 0.001). At one year, autogenous fistulas demonstrated superior primary patency (56 vs. 36%, P = 0.001) and secondary patency (72 vs. 58%, P = 0.003) compared with prosthetic grafts. After adjustment for age, race, side of access placement, and history of prior access placement, patients with a prosthetic graft were estimated to experience a 78% increase in the risk of primary access failure when compared with similar patients having an autogenous access [adjusted relative risk (aRR) = 1.78, 95% CI 1.21--2.62, P = 0.003)]. Similarly, the adjusted relative risk of secondary access failure for comparing prosthetic grafts with autogenous fistulas was estimated to be 2.21 (95% CI 1.38--3.54, P = 0.001). The adjusted risk of access revision was 2.89-fold higher for prosthetic grafts than for autogenous fistulas (95% CI 1.88--4.44, P < 0.001)., Conclusions: Autogenous conduits demonstrated superior performance when compared with prosthetic grafts in terms of primary and secondary patency and number of revisions. A policy emphasizing the preferential placement of autogenous fistulas over prosthetic grafts may result in improved patency and a reduction in the number of procedures required to maintain dialysis access patency.

The incidence and course of bone density abnormalities following hematopoietic stem cell transplantation are poorly understood and complicated by the impact of multiple factors. Hip, spine, and wrist bone mineral densities (BMDs) were measured in 104 adults (54 women, 54 men; mean age, 40 years [range, 18-64 years]) at 3 and 12 months after allogeneic transplantation. Clinical and laboratory variables were evaluated using univariate and multivariate analyses to determine risk factors for osteoporosis, fracture, and avascular necrosis. At 3 months posttransplantation, combined (male and female) hip, spine, and wrist z scores were -0.35, -0.42, and +0.04 standard deviations, respectively. At 12 months both men and women experienced significant loss of hip BMD (4.2%, P < .0001); changes in the spine and wrist were minimal. The cumulative dose and number of days of glucocorticoid therapy and the number of days of cyclosporine or tacrolimus therapy showed significant associations with loss of BMD; age, total body irradiation, diagnosis, and donor type did not. Nontraumatic fractures occurred in 10.6% of patients and avascular necrosis in 9.6% within 3 years posttransplantation. The decrease in height between pretransplantation and 12 months posttransplantation was significant (P = .0001). Results indicate that loss of BMD after allogeneic stem cell transplantation is common and accelerated by the length of immunosuppressive therapy and cumulative dose of glucocorticoid. An increased incidence of fracture and avascular necrosis may adversely impact long-term quality of life. Prevention of bone demineralization appears warranted after stem cell transplantation.

Background: Although bone disease is well described among end-stage renal disease (ESRD) patients, little attention has been paid to the occurrence of fracture. We sought to identify factors that are associated with hip fracture among ESRD patients., Methods: Data from patients who participated in the United States Renal Data System Dialysis Morbidity and Mortality Study Wave 1 were used for this study. Hip fractures occurring among these patients between 1993 and 1996 were identified from Medicare claims data available from the United States Renal Data System. Cox proportional hazards models were used to estimate the risk of hip fracture associated with demographic and medical variables., Results: Of the 4952 patients included in this analysis, 103 sustained a hip fracture. In the multivariate analysis, age (per increasing decade, RR = 1.40, 95% CI 1.20, 1.64), female gender (RR = 2.26, 95% CI 1.48, 3.44), race (blacks compared with whites, RR = 0.58, 95% CI 0.37, 0.91), body mass index (per 1 unit increase, RR 0.89, 95% CI 0.86, 0.93), and the presence of peripheral vascular disease (RR 1.94, 95% CI 1.29, 2.92) were independently associated with hip fracture. Serum intact parathyroid hormone (iPTH), aluminum, diabetes, and bicarbonate levels did not appreciably influence the risk of hip fracture., Conclusions: Demographic and other characteristics that predict risk of hip fracture in the population at large also do so in ESRD patients. However, we could identify no characteristics of ESRD or its treatment that were independently related to hip fracture incidence.

We evaluated the association between anthropometric measurements and death among pediatric patients with end-stage renal disease (ESRD) using data from the Pediatric Growth and Development Special Study (PGDSS) from the US Renal Data System. Height, growth velocity, and body mass index (BMI) were used for the analysis of 1,949 patients in the PGDSS. To standardize these measurements, SD scores (SDSs) were calculated using population data from the Third National Health and Nutrition Examination Survey. Using Cox proportional hazards models, we assessed the association between anthropometric measures and death, controlling for demographic factors and stratifying by age. Multivariate analysis showed that each decrease by 1 SDS in height was associated with a 14% increase in risk for death (adjusted relative risk [aRR], 1.14; 95% confidence interval [CI], 1.02 to 1.27; P = 0.017). For each 1 SDS decrease in growth velocity among patients in our sample, the risk for death increased by 12% (aRR, 1.12; 95% CI, 1.00 to 1.25; P = 0.043). There was a statistically significant U-shaped association between BMI and death (P = 0.001), with relatively low and high BMIs associated with an increased risk for death. In children with ESRD, growth delay and extremes in BMI are associated with an increased risk for mortality.

Background: Although patients with end-stage renal disease (ESRD) are at increased risk for bone loss, the risk of hip fracture in this population is not known. We compared the risk of hip fracture among dialysis patients with the general population., Methods: We used data from the United States Renal Data System (USRDS) to identify all new Caucasian dialysis patients who began dialysis between January 1, 1989, and December 31, 1996. All hip fractures occurring during this time period were ascertained. The observed number of hip fractures was compared with the expected number based on the experience of residents of Olmstead County (MN, USA). Standardized incidence ratios were calculated as the ratio between observed and expected. The risk attributable to ESRD was calculated as the difference between the observed and expected rate of hip fracture per 1000 person-years., Results: The number of dialysis patients was 326,464 (55.9% male and 44.1% female). There were 6542 hip fractures observed during the follow-up period of 643, 831 patient years. The overall incidence of hip fracture was 7.45 per 1000 person years for males and 13.63 per 1000 person years for females. The overall relative risk for hip fracture was 4.44 (95% CI, 4.16 to 4.75) for male dialysis patients and 4.40 (95% CI, 4.17 to 4.64) for female dialysis patients compared with people of the same sex in the general population. While the age-specific relative risk of hip fracture was highest in the youngest age groups, the added risks of fracture associated with dialysis rose steadily with increasing age. The relative risk of hip fracture increased as time since first dialysis increased., Conclusions: The overall risk of hip fracture among Caucasian patients with ESRD is considerably higher than in the general population, independent of age and gender.

The phenomenon of hypercalcemia in immobilization is well known, but there is limited awareness of the potential for this complication in patients with end-stage renal disease (ESRD) on maintenance hemodialysis with reduced capacity for disposition of calcium. We describe such a patient who showed a calcemic response to just 3 days of immobilization in the setting of an acute illness marked by coma. Despite intensive initial therapy for hypercalcemia, including withdrawal of all calcium products and daily hemodialysis treatments using low calcium baths, her serum calcium rose to 14.0 mg/dL during the hospitalization; this metabolic abnormality appeared to perpetuate her stuporous state. Mobilization as an outpatient was the most effective therapy. Extensive testing was performed to rule out other causes for this patient's hypercalcemia. Greater recognition of acute hypercalcemia in patients with ESRD immobilized by various illnesses would preclude unnecessarily expensive and invasive testing for other causes of hypercalcemia.

Background: We undertook a population-based study of hemodialysis (HD) patients to determine which factors are important in predicting the type of permanent access initially placed and if a functional permanent access is in place at the start of HD., Methods: Selected characteristics were abstracted from the United States Renal Data System (USRDS) Dialysis Morbidity and Mortality Study (DMMS) Wave 2. Logistic regression was used to estimate the independent contribution of specific characteristics in predicting whether the initial permanent access placed was an arteriovenous (AV) fistula compared with a polytetrafluoroethylene (PTFE) graft, and in predicting whether permanent access (fistula or graft) was in place at the initiation of dialysis., Results: Sixty-seven percent of the patients had an AV graft placed as their first permanent access. Characteristics important in predicting if a fistula was initially placed included age (per decade; aOR = 0.84, P < 0.001), female gender (aOR = 0.52, P < 0.001), body mass index (per standard deviation; aOR = 0.70, P = 0.09), avoiding blood draws (aOR = 1.96, P < 0.001), ability to ambulate (aOR = 2.24, P = 0.008), underlying renal disease (glomerular compared with diabetes, aOR = 2.19, P = 0.009), college education (aOR = 1.72, P = 0.002), and sharing in decision making (aOR = 1.50, P = 0.02). Thirty-four percent of patients (34.4%) had functional permanent access at the start of HD. Characteristics important in predicting which patients had functional permanent access included serum albumin (per 1 mg/dL increase, aOR =1.55, P = 0.003), erythropoietin prior to starting HD (aOR = 1.79, P = 0.002), fewer predialysis nephrologist visits (aOR = 0.21, P < 0.001), and when the patient was told they had renal disease (aOR = 0.33, P = 0.002)., Conclusions: PTFE grafts were the most common initial permanent access. The majority of patients did not have permanent access at the start of dialysis. Factors that are thought to compromise identification of adequate veins were important predictors of PTFE graft placement. Permanent access at the start of HD was largely a function of early patient education and early referral to a nephrologist.

Aluminum accumulation in plasma and tissues is a well-described complication among persons undergoing peritoneal dialysis or hemodialysis. Excess bone aluminum is associated with low bone formation rates and increased risk for fractures. Current recommendations for care of patients with end-stage renal disease include screening for aluminum toxicity with plasma aluminum levels; patients with levels below 40 microg/L are considered to be at low risk for aluminum bone disease (ABD). We examined data from the Toronto Renal Osteodystrophy Study to evaluate the performance of plasma aluminum levels in screening for ABD. Two hundred fifty-eight unselected patients undergoing peritoneal dialysis (n = 143) or hemodialysis (n = 115) underwent diagnostic bone biopsy and measurement of plasma aluminum level. Sixty-nine patients (26.7%) were identified as having ABD, defined as low or normal bone formation rates with 25% or more bone surface aluminum staining. Plasma aluminum level was strongly associated with the presence of ABD; the odds ratio was 1.4 for each increase of 10 microg/L (95%CI, 1.2, 1.6). However, only 50.1% of patients with a plasma aluminum level of 40 microg/L or greater had ABD, whereas 14.2% of patients with a level below this threshold also had ABD. Using this cutoff level of 40 microg/L, the sensitivity and specificity were 65.2% and 76.7%, respectively. We conclude that although there is a correlation between high aluminum levels and ABD, a patient's plasma aluminum level does not predict well the presence of ABD in spite of a relatively high prevalence of disease.

The purpose of the present study is to investigate whether an ethnic difference exists in the incidence of renal osteodystrophy between Asian and Western countries in end-stage renal disease (ESRD) patients. We evaluated bone histology in 58 pre-dialysis patients (28 male, 30 female; mean age: 47.7 years). All patients had bone biopsies with quantitative histomorphometry and serological parameters such as intact PTH, osteocalcin, total alkaline phosphatase, and basal and deferoxamine-stimulated serum aluminum levels. We observed that 91.4% of all evaluated patients showed renal osteodystrophy before the start of dialytic therapy. Mild osteitis fibrosa were observed in 21 patients (36.2%), severe osteitis fibrosa in 5 patients (8.6%), mixed lesions in 7 patients (12.1%), osteomalacia in 6 patients (10.3%), aplastic bone disease in 14 patients (24.1%), and normal bone in 5 patients (8.6%). Among the bone histomorphometric parameters, fibrosis area rate (%) showed the best correlation with intact PTH, and osteocalcin and osteoid area rate (%) with total alkaline phosphatase. Aluminum-related bone disease was not observed. Among patients with aplastic bone disease, only 14.3% showed aluminum deposition of any significance (5% < stainable bone surface aluminum < 25%). In the diabetic patients, aplastic bone disease was most common, but no case was related to aluminum intoxication. In conclusion, the distribution of renal osteodystrophy in our study was different from that of Western countries in pre-dialysis patients. Our patients tended to have more mild-form osteitis fibrosa and normal findings, and less severe-form osteitis fibrosa and aplastic bone disease. Aluminum-related bone disease was not observed.

The control of hyperparathyroidism in patients with chronic renal failure continues to be a problem, particularly when parathyroid hormone (PTH) suppression becomes refractory to calcitriol activation of parathyroid cell 1,25-dihydroxyvitamin D receptors. To evaluate whether parathyroid cell calcium receptor activation may be useful in suppressing PTH levels, we tested the safety and effectiveness of a novel calcimimetic agent in dialysis patients with hyperparathyroidism. In a prospective, dose finding study, the calcimimetic agent, NPS R-568, was administered orally to seven patients at the start of a hemodialysis session and again 24 hours later. Plasma PTH, calcitonin and ionized calcium levels were measured over a 48 hour period and patients were observed for adverse events. Plasma PTH levels fell abruptly in all patients after a single dose of the compound, with the maximum suppression occurring within one to two hours after its administration. Following the administration of low doses (40 or 80 mg), the suppressed PTH levels rose to baseline values over 48 hours, whereas in patients who received high doses (120 or 200 mg) the mean PTH level remained 51% below baseline. Plasma calcitonin increased after the administration of both low and high doses (peak effect within 4 to 6 hr), with levels always returning to baseline by 48 hours. There were no episodes of hypocalcemia and no adverse effects were reported. We conclude that the activation of parathyroid cell calcium receptors by a novel calcimimetic compound is safe and effective in acutely suppressing PTH secretion in dialysis patients with hyperparathyroidism. Whether concomitant stimulation of calcitonin secretion will provide added beneficial effects on bone remodeling remains to be determined in long-term studies.

The role of specific immunosuppressive agents in the development of avascular necrosis (AVN) following hematopoietic stem cell and solid organ transplantation remains unclear. To further explore this question, we conducted a case-control study of patients who underwent bone marrow transplantation (BMT) at the Fred Hutchinson Cancer Research Center. 96 of 1939 long-term survivors transplanted between May 1976 and October 1993 were identified as having AVN. Eight patients were excluded because AVN developed before transplant and one was excluded due to restrictions on reviewing follow-up records. The remaining 87 patients developed AVN a mean of 26.3 +/- 2 months posttransplant and were matched for age, gender, and date of transplant to other BMT recipients. Records were reviewed for corticosteroid and cyclosporine use, pretransplant conditioning with total body irradiation (TBI), and other information including disease for which the transplant was indicated, type of transplant, the occurrence of acute and chronic graft-vs.-host disease, and steroid use prior to transplant. Adjusted odds ratios (ORs) were obtained from conditional logistic regression for 87 matched pairs. Posttransplant steroid use was a risk factor for the occurrence of AVN (adjusted OR, 14.4; 95% CI, 2.8-73.2), with the greatest risk associated with those receiving steroids at the time of diagnosis of AVN (adjusted OR, 31.9; 95% CI, 4.4-248.9). There was no further increasing risk associated with increasing duration of steroid use. Conditioning with TBI was also associated with the occurrence of AVN (adjusted OR, 3.2; 95% CI, 1.1-9.7); however, cyclosporine was not a risk factor for AVN (adjusted OR, 0.5; 95% CI, 0.1-1.9). Our results support the hypothesis that AVN following BMT has a strong association with the administration of corticosteroids. TBI may be an additional risk factor, and cyclosporine does not appear to contribute to an increased incidence of AVN.

There has been controversy regarding the initial pathogenic events involved with the hyperparathyroidism of chronic renal failure (CRF). Low serum levels of 1,25-dihydroxyvitamin D in uremic patients are postulated by some as having a role in permitting higher parathyroid hormone (PTH) secretion. However, recent animal and in vitro studies strongly suggest that phosphate has a direct effect on parathyroid cells to enhance PTH secretion. To evaluate the relationships among serum phosphate, calcium, PTH, and 1,25-dihydroxyvitamin D in uremic humans, we performed a cross-sectional analysis of 84 patients with varying levels of CRF. Using stepwise regression analysis after adjusting for multiple comparisons, we found that serum phosphate correlated directly with serum PTH (r = 0.62, P < 0.01) in patients with mild to moderate CRF (creatinine < or = 3.0 mg/dL), independent of serum calcium and 1,25-dihydroxyvitamin D levels. In patients with more severe renal failure (creatinine > 3.0 mg/dL), only the serum calcium correlated with serum PTH (r = -0.47, P < 0.01). While serum 1 ,25-dihydroxyvitamin D showed no correlations with PTH, phosphate, or calcium at any stage of renal failure, the mean 1,25-dihydroxyvitamin D level in patients with mild CRF was lower than that in age-matched controls (24 +/- 3 pg/mL v 37 +/- 2 pg/mL; P < 0.01), suggesting that low 1,25-dihydroxyvitamin D was permissive for enhanced PTH secretion. These data demonstrate an independent association of serum phosphate with PTH in patients with CRF and suggest that phosphate may directly enhance PTH secretion in this setting. This study supports recent animal studies showing a direct parathyroid cell effect of phosphate on PTH secretion.

Statement of Problem: Little information has been reported with regard to the dimensional accuracy of improved dental stone materials for reproduction of an entire arch form., Purpose: The purpose of this study was to evaluate the ability of an epoxy resin die material and a type IV dental stone to dimensionally reproduce an entire arch form., Material and Methods: Models were fabricated and measurements were made of reference marks to calculate dimensions from first molar to the midline bilaterally and between first molars. Each measurement was repeated three times and the mean measurement and percent relative change was calculated for each dimension., Results: The results revealed that the difference in the relative change in two dimensions was statistically significant for the epoxy resin group (p < 0.05)., Conclusions: The materials provided a similar degree of dimensional accuracy in reproducing a complete arch when used with addition silicone impression material.

We evaluated vasectomy as a potential risk factor for urolithiasis. Vasectomy is a common method of contraception among otherwise healthy men. This is also the population at highest risk for urolithiasis. We conducted a case-control study of patients in a large prepaid health maintenance organization. Cases were men experiencing initial episodes of urolithiasis, ascertained by reviewing radiology logs and medical records. The age-matched controls were men with no history of urolithiasis. In logistic regression models, the relative risk of urolithiasis for men with vasectomies compared with men without vasectomies was 1.9 for men younger than 46 years of age (95% confidence interval = 1.2 to 3.1, P = 0.005), and the relative risk was 0.9 (95% confidence interval = 0.5 to 1.5, P > 0.8) for men who were at least 46 years old. The relative risk of urinary calculi was 2.0 (95% confidence interval 1.0 to 4.1, P < 0.05) for men with vasectomies 0 to 4 years before evaluation compared with men without vasectomies, and the excess risk persisted as long as 14 years postvasectomy. Vasectomy was associated with a twofold increased risk for urolithiasis in men younger than 46 years of age. This increased risk may persist for up to 14 years postvasectomy. Given the large number of men who undergo vasectomy worldwide each year, the increased risk for urolithiasis among vasectomized men may result in substantial excess morbidity.

Statement of Problem: Improved dental stone has been widely used for producing dies for the fabrication of restorations with the lost-wax technique. Improved dental stone is used for several reasons, but it is selected most often because of its reasonable cost, ease of use, and ability to produce consistent results., Purpose: This study evaluated the ability of an epoxy resin die material and a type IV dental stone to dimensionally reproduce a custom-fabricated metal die., Material and Methods: Dies were fabricated and measurements were made from three reference lines. Measurements were repeated three times for the master die and for the specimen dies. A mean measurement and percent relative change for each dimension was calculated., Results: A significant difference in the relative change for die height was found between the groups studied (p < 0.003)., Conclusions: This epoxy die system will provide a degree of dimensional accuracy comparable to gypsum when used with addition silicone impression material.

Few studies have examined urolithiasis in primary care populations, and limited data are available on non-drug interventions to reduce the risk for urinary calculi. Therefore, we conducted a case control study of patients enrolled in a large prepaid health maintenance organization. The 240 study cases were men experiencing initial episodes of urolithiasis, ascertained by reviewing radiology procedure logs and medical records. The 392 controls were age-matched men with no history of urolithiasis chosen from a list of randomly selected men. Data were collected using standardized telephone interviews. Odds ratios were calculated for potential risk factors. In logistic regression analyses the risk for urinary tract calculi was related to both consumption variables, such as a low-fat or weight reduction diet (adjusted odds ratio, 0.41; P < 0.0005) and beer drinking (adjusted odds ratio, 0.41; P < 0.0001), and to demographic variables, such as African-American ethnicity (adjusted odds ratio, 0.29; P = 0.03) and a positive family history (adjusted odds ratio, 2.22; P < 0.001). These findings suggest the need to evaluate appropriate behavioral interventions to reduce the morbidity associated with urolithiasis. Prospective studies should evaluate the possibilities that beer drinking, even in modest amounts, and a low-fat or weight reduction diet are associated with substantial reductions in risk.

Abnormal calcium metabolism has been implicated in human hypertension. Caffeine consumption may contribute to hypertension since it increases urinary calcium excretion. Nineteen hypertensive subjects (HTN) and nineteen age and gender matched normotensive controls (NTC) who habitually consumed at least 175 mg caffeine daily were studied before and after abstinence from all caffeine (CAF) consumption for 2 weeks. Caffeine abstinence (CAF-) increased fasting serum ultrafiltrable calcium in HTN and NTC, but not serum total calcium. Parathyroid hormone (PTH) levels decreased after CAF abstinence in 14 of 18 HTN subjects, including all seven subjects consuming less than 700 mg calcium daily. Three day dietary calcium intakes and 72 h urinary excretion of calcium were not different between CAF+ and CAF- or between HTN and NTC. A morning caffeine dose of 6 mg/kg lean body mass increased urinary Ca/creatinine ratios similarly for 2 h after beverage consumption in both HTN and NTC. Caffeine consumption stresses calcium metabolism in hypertensive individuals, especially those consuming less than 700 mg calcium daily.

That bone disease accompanies renal failure has been known for over 100 years. This bone disease (renal osteodystrophy) has been variously attributed to hyperparathyroidism, vitamin D deficiency, aluminium toxicity, iron toxicity, uraemia, and a host of other aetiologies. In addition, the form the bone disease takes has been variously described as osteitis fibrosa, osteomalacia, mixed uraemic osteodystrophy and the aplastic (adynamic) lesion. In this manuscript we will focus on the aetiology, consequences, diagnosis and possible management of the aplastic form of the disease. The renal osteodystrophy study was a prospective, cross-sectional study of renal bone disease in a largely unselected population of patients receiving dialysis in three hospitals in Toronto. A variety of non-invasive data (parathyroid hormone (PTH), aluminium, etc.) and bone histology were obtained and analysed to assess pathogenesis, diagnostic criteria and management. We have defined the aplastic lesion as having low bone formation without a marked increase in unmineralized osteoid (i.e. excluding osteomalacia). We have noted that it may be associated with increased aluminium or little to no aluminium. With increased aluminium the patients have a poorer prognosis both with regards to bone disease and mortality, and they should be managed appropriately to alleviate aluminium toxicity. With lesser amounts of aluminium, morbidity and mortality are less severely impacted, but not normal. We have shown that the low bone formation, of the aplastic lesion without aluminium may be "normalized' by increasing PTH levels. It is concluded that aplastic bone disease carries adverse consequences both in terms of bone problems and survival. In the absence of aluminium toxicity the stimulation of PTH effectively corrects the bone formation abnormality. Whether this will alleviate the adverse consequences will be difficult to study. Avoiding the problem by not over-suppressing PTH seems a reasonable approach at this point.