Renal osteodystrophy and aging.

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.

Pamidronate preserves bone mass for at least 2 years following acute administration for pediatric burn injury.

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.

First- and second-generation immunometric PTH assays during treatment of hyperparathyroidism with cinacalcet HCl.

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.

Achieving NKF-K/DOQI bone metabolism and disease treatment goals with cinacalcet HCl.

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

The efficacy of acute administration of pamidronate on the conservation of bone mass following severe burn injury in children: a double-blind, randomized, controlled study.

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.

Serum phosphate levels and mortality risk among people with chronic kidney disease.

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.

Survival following parathyroidectomy among United States dialysis patients.

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.

Evidence supporting a role of glucocorticoids in short-term bone loss in burned children.

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.

Parathyroidectomy rates among United States dialysis patients: 1990-1999.

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.

The calcimimetic AMG 073 as a potential treatment for secondary hyperparathyroidism of end-stage renal disease.

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.

Parathyroid hormone (PTH), PTH-derived peptides, and new PTH assays in renal osteodystrophy.

Parathyroid hormone (PTH), PTH-derived peptides, and new PTH assays in renal osteodystrophy. Reliable measurements of parathyroid hormone (PTH) concentrations in serum or plasma are critical for the appropriate diagnosis and management of patients with renal osteodystrophy. With the introduction of second generation immunometric assays for PTH, it is now possible to measure exclusively full-length, biologically active PTH(1-84). In contrast, first generation immunometric assays that have been used widely for many years detect not only PTH(1-84), but also other large amino-terminally-truncated, PTH-derived peptides. This development will require a careful re-evaluation of PTH measurements, as determined by either first or second generation immunometric assays, and their relationship to bone histology and bone remodeling rates in patients with end-stage renal disease (ESRD). Such information is essential for proper clinical management, but only limited bone biopsy data are available to guide the interpretation of PTH results using second generation PTH assays. The different performance characteristics of first and second generation immunometric PTH assays also makes it possible to quantify the plasma levels of amino-terminally-truncated, PTH-derived peptides, which may accumulate disproportionately in patients with ESRD. Recent experimental evidence indicates that one or more of these peptides can modify bone cell activity and skeletal remodeling, possibly by interacting with a PTH receptor distinct from the type I PTH receptor that binds to the amino-terminal portion of PTH and mediates the classical biological actions of the hormone. The putative C-PTH receptor interacts with mid- and/or carboxyterminal regions of PTH and other amino-terminally-truncated PTH-derived peptides; signaling through it may contribute to the skeletal resistance to PTH that characterizes ESRD. The current review discusses certain aspects of the molecular structure of PTH and its interaction with various receptors, briefly comments about selected components of PTH secretion, highlights recent technical advances in PTH assays, and summarizes the effects of various PTH-derived peptides on bone cells and on skeletal metabolism.

Intravenous and subcutaneous weight-based dosing of the low molecular weight heparin tinzaparin (Innohep) in end-stage renal disease patients undergoing chronic hemodialysis.

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.

Increased risk for cardiovascular mortality among malnourished end-stage renal disease patients.

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.

Calcium channel blocker use and mortality among patients with end-stage renal disease.

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.

Hypoalbuminemia and risk of death in pediatric patients with end-stage renal disease.

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.

HMG-CoA reductase inhibitors are associated with reduced mortality in 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.