Atrasentan and renal events in patients with type 2 diabetes and chronic kidney disease (SONAR): a double-blind, randomised, placebo-controlled trial.

BACKGROUND: Short-term treatment for people with type 2 diabetes using a low dose of the selective endothelin A receptor antagonist atrasentan reduces albuminuria without causing significant sodium retention. We report the long-term effects of treatment with atrasentan on major renal outcomes. METHODS: We did this double-blind, randomised, placebo-controlled trial at 689 sites in 41 countries. We enrolled adults aged 18-85 years with type 2 diabetes, estimated glomerular filtration rate (eGFR) 25-75 mL/min per 1·73 m2 of body surface area, and a urine albumin-to-creatinine ratio (UACR) of 300-5000 mg/g who had received maximum labelled or tolerated renin-angiotensin system inhibition for at least 4 weeks. Participants were given atrasentan 0·75 mg orally daily during an enrichment period before random group assignment. Those with a UACR decrease of at least 30% with no substantial fluid retention during the enrichment period (responders) were included in the double-blind treatment period. Responders were randomly assigned to receive either atrasentan 0·75 mg orally daily or placebo. All patients and investigators were masked to treatment assignment. The primary endpoint was a composite of doubling of serum creatinine (sustained for ≥30 days) or end-stage kidney disease (eGFR <15 mL/min per 1·73 m2 sustained for ≥90 days, chronic dialysis for ≥90 days, kidney transplantation, or death from kidney failure) in the intention-to-treat population of all responders. Safety was assessed in all patients who received at least one dose of their assigned study treatment. The study is registered with ClinicalTrials.gov, number NCT01858532. FINDINGS: Between May 17, 2013, and July 13, 2017, 11 087 patients were screened; 5117 entered the enrichment period, and 4711 completed the enrichment period. Of these, 2648 patients were responders and were randomly assigned to the atrasentan group (n=1325) or placebo group (n=1323). Median follow-up was 2·2 years (IQR 1·4-2·9). 79 (6·0%) of 1325 patients in the atrasentan group and 105 (7·9%) of 1323 in the placebo group had a primary composite renal endpoint event (hazard ratio [HR] 0·65 [95% CI 0·49-0·88]; p=0·0047). Fluid retention and anaemia adverse events, which have been previously attributed to endothelin receptor antagonists, were more frequent in the atrasentan group than in the placebo group. Hospital admission for heart failure occurred in 47 (3·5%) of 1325 patients in the atrasentan group and 34 (2·6%) of 1323 patients in the placebo group (HR 1·33 [95% CI 0·85-2·07]; p=0·208). 58 (4·4%) patients in the atrasentan group and 52 (3·9%) in the placebo group died (HR 1·09 [95% CI 0·75-1·59]; p=0·65). INTERPRETATION: Atrasentan reduced the risk of renal events in patients with diabetes and chronic kidney disease who were selected to optimise efficacy and safety. These data support a potential role for selective endothelin receptor antagonists in protecting renal function in patients with type 2 diabetes at high risk of developing end-stage kidney disease. FUNDING: AbbVie.

Baseline characteristics and enrichment results from the SONAR trial.

AIM: The SONAR trial uses an enrichment design based on the individual response to the selective endothelin receptor antagonist atrasentan on efficacy (the degree of the individual response in the urinary albumin-to-creatinine ratio [UACR]) and safety/tolerability (signs of sodium retention and acute increases in serum creatinine) to assess the effects of this agent on major renal outcomes. The patient population and enrichment results are described here. METHODS: Patients with type 2 diabetes with an estimated glomerular filtration rate (eGFR) within 25 to 75 mL/min/1.73 m2 and UACR between 300 and 5000 mg/g were enrolled. After a run-in period, eligible patients received 0.75 mg/d of atrasentan for 6 weeks. A total of 2648 responder patients in whom UACR decreased by ≥30% compared to baseline were enrolled, as were 1020 non-responders with a UACR decrease of <30%. Patients who experienced a weight gain of >3 kg and in whom brain natriuretic peptide exceeded ≥300 pg/mL, or who experienced an increase in serum creatinine >20% (0.5 mg/dL), were not randomized. RESULTS: Baseline characteristics were similar for atrasentan responders and non-responders. Upon entry to the study, median UACR was 802 mg/g in responders and 920 mg/g in non-responders. After 6 weeks of treatment with atrasentan, the UACR change in responders was -48.8% (95% CI, -49.8% to -47.9%) and in non-responders was -1.2% (95% CI, -6.4% to 3.9%). Changes in other renal risk markers were similar between responders and non-responders except for a marginally greater reduction in systolic blood pressure and eGFR in responders. CONCLUSIONS: The enrichment period has successfully identified a population with a profound UACR reduction without clinical signs of sodium retention in whom a large atrasentan effect on clinically important renal outcomes is possible. The SONAR trial aims to establish whether atrasentan confers renal protection.

Rationale and protocol of the Study Of diabetic Nephropathy with AtRasentan (SONAR) trial: A clinical trial design novel to diabetic nephropathy.

AIMS: Individuals with diabetes and chronic kidney disease (CKD) are at high risk for renal events. Recent trials of novel treatments have been negative, possibly because of variability in response to treatment of the target risk factor. Atrasentan is a selective endothelin A receptor antagonist that reduces urinary albumin-to-creatinine ratio (UACR), with a large variability between patients. We are assessing its effect on renal outcomes in the Study Of diabetic Nephropathy with AtRasentan (SONAR; NCT01858532) with an enrichment design (>30% lowering of albuminuria) to select patients most likely to benefit. MATERIALS AND METHODS: SONAR is a randomized, double-blind, placebo-controlled trial with approximately 3500 participants who have stage 2-4 CKD and macroalbuminuria and are receiving a maximum tolerated dose of a renin-angiotensin system inhibitor. RESULTS: After 6 weeks of exposure to atrasentan 0.75 mg once daily (enrichment period), participants with ≥30% UACR decrease and no tolerability issues (responders) were randomly assigned to placebo or atrasentan 0.75 mg/day. The responder group will be used for primary efficacy and safety analyses. Approximately 1000 participants with <30% UACR reduction (non-responders) were also randomized to placebo or atrasentan. The primary endpoint is a composite of a sustained doubling of serum creatinine or end-stage renal disease. The original power calculation indicated that a total of 425 primary renal events in the responder group provides 90% power to detect a 27% reduction in relative risk (alpha level of .05). CONCLUSION: SONAR aims to determine whether atrasentan added to guideline-recommended therapies safely reduces the risk of CKD progression and delays the onset of end-stage renal disease in patients with type 2 diabetes and nephropathy. SONAR also aims to establish whether the enrichment of patients based on their initial "surrogate" response to atrasentan will deliver a trial design in accord with personalized treatment of diabetic kidney disease.

Number and frequency of albuminuria measurements in clinical trials in diabetic nephropathy.

BACKGROUND AND OBJECTIVES: Albuminuria change is often used to assess drug efficacy in intervention trials in nephrology. The change is often calculated using a variable number of urine samples collected at baseline and end of treatment. Yet more albuminuria measurements usually occur. Because albuminuria shows a large day-to-day variability, this study assessed to what extent the average and the precision of the antialbuminuric drug effect varies with the number of urine collections at each visit and the number of follow-up visits. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: This study used data from three randomized intervention trials (Aliskiren Combined with Losartan in Type 2 Diabetes and Nephropathy, Selective Vitamin D Receptor Activation for Albuminuria Lowering, and Residual Albuminuria Lowering with Endothelin Antagonist Atrasentan) including patients with type 2 diabetes and macroalbuminuria. Albuminuria-lowering drug effects were estimated from one, two, or three urine collections at consecutive days before each study visit and reported as albuminuria change from baseline to end of treatment or the change over time considering an average of all follow-up albuminuria measurements. RESULTS: Increasing the number of urine collections for an albuminuria measurement at baseline and end of treatment or using all study visits during follow-up did not alter the average drug effect. The precision of the drug effect increased (decreased SEM) when the number of study visits and the number of urine collections per visit were increased. Using all albuminuria measurements at all study visits led to a 4- to 6-fold reduction in sample size to detect a 30% albuminuria-lowering treatment effect with 80% power compared with using baseline and end-of-treatment albuminuria measurements alone. CONCLUSIONS: Increasing the number of urine collections per study visit and the number of visits over time does not change the average drug effect estimate but markedly increases the precision, thereby enhancing statistical power. Thus, clinical trial designs in diabetic nephropathy using albuminuria as an end point can be significantly improved, leading to smaller sample sizes and less complex trials.

Effects of paricalcitol on calcium and phosphate metabolism and markers of bone health in patients with diabetic nephropathy: results of the VITAL study.

BACKGROUND: Chronic kidney disease (CKD) is associated with elevations in serum phosphate, calcium-phosphorus product and bone-specific alkaline phosphatase (BAP), with attendant risks of cardiovascular and bone disorders. Active vitamin D can suppress parathyroid hormone (PTH), but may raise serum calcium and phosphate concentrations. Paricalcitol, a selective vitamin D activator, suppressed PTH in CKD patients (stages 3 and 4) with secondary hyperparathyroidism (SHPT) with minimal changes in calcium and phosphate metabolism. METHODS: The VITAL study enrolled patients with CKD stages 2-4. We examined the effect and relationship of paricalcitol to calcium and phosphate metabolism and bone markers in a post hoc analysis of VITAL. The study comprised patients with diabetic nephropathy enrolled in a double-blind, placebo-controlled, randomized trial of paricalcitol (1 or 2 µg/day). Urinary and serum calcium and phosphate, serum BAP, and intact PTH (iPTH) concentrations were measured throughout the study. RESULTS: Baseline demographics and calcium, phosphate, PTH (49% with iPTH <70 pg/mL), and BAP concentrations were similar between groups. A transient, modest yet significant increase in phosphate was observed for paricalcitol 2 µg/day (+0.29 mg/dL; P < 0.001). Dose-dependent increases in serum and urinary calcium were observed; however, there were few cases of hypercalcemia: one in the 1-µg/day group (1.1%) and three in the 2-µg/day group (3.2%). Significant reductions in BAP were observed that persisted for 60 days after paricalcitol discontinuation (P < 0.001 for combined paricalcitol groups versus placebo). Paricalcitol dose-dependent reductions in iPTH were observed. Paricalcitol in CKD patients (±SHPT) was associated with modest increases in calcium and phosphate. CONCLUSION: Paricalcitol reduces BAP levels, which may be beneficial for reducing vascular calcification. TRIAL REGISTRATION: Trial is registered with ClinicalTrials.gov, number NCT00421733.

Clinical efficacy of the selective endothelin A receptor antagonist, atrasentan, in patients with diabetes and chronic kidney disease (CKD).

AIMS: Progression of chronic kidney disease (CKD) in patients with diabetes is a growing problem. Diabetes is associated with elevated endothelin-1 (ET-1) and enhanced renal expression of the endothelin A receptor (ETAR). Atrasentan, a highly selective ETAR antagonist, reduces albuminuria in patients with DN. KEY METHODS: This was a randomized, double-blind trial of subjects with type 2 diabetes on renin-angiotensin system (RAS) inhibitors having eGFR >20 ml/min, and urine albumin-to-creatinine ratio (UACR) of 100-3000 mg/g, who were allocated to placebo, 0.25, 0.75 or 1.75 mg atrasentan. KEY FINDINGS: UACR was reduced in the 0.75 mg and 1.75 mg groups (42% and 35% vs placebo, P<0.011) over the 8 week treatment period. Edema was reported in 21 subjects: 62% of edema events emerged during the first 4 weeks. There were no significant changes in serum hsCRP, IL-6, NT-pro-BNP, ET-1, urine TGFb or MCP-1. Urine NGAL was reduced 24% in the 1.75 mg group (P=0.044). Hispanic subjects (58% of total) tended to have greater UACR reductions than non-Hispanics (0.75 mg dose: Hispanic: 41-60%; non-Hispanic: 18-37%; P=0.012 and 0.048 vs placebo, respectively) without different rates of edema. Mean UACR reduction in subjects receiving maximum doses of RAS inhibitors (38%) was 32% and 35% in the 0.75 and 1.75 mg groups, respectively, and similar to overall UACR changes. SIGNIFICANCE: Edema formation was dose-dependent and occurred early. The decrease in urine NGAL warrants further study in renal tubular disease attenuation. UACR responses based on ethnicity need further characterization. Results suggest atrasentan may have additive effects to RAS inhibition in treatment of DN.

Paricalcitol versus ergocalciferol for secondary hyperparathyroidism in CKD stages 3 and 4: a randomized controlled trial.

BACKGROUND: The efficacy of 25-hydroxyvitamin D (25[OH]D) supplementation versus vitamin D receptor activators for the treatment of secondary hyperparathyroidism (SHPT) in patients with chronic kidney disease (CKD) stages 3 or 4 and vitamin D deficiency is unclear. STUDY DESIGN: Randomized controlled trial. SETTING & PARTICIPANTS: 80 patients with CKD stages 3 or 4, 25(OH)D level <30 ng/mL, and SHPT in a single medical center. INTERVENTION: Ergocalciferol, 50,000 units, titrated to achieve serum levels ≥30 ng/mL versus paricalcitol, 1 or 2 µg/d, for 16 weeks. OUTCOMES: The occurrence of 2 consecutive parathyroid hormone (PTH) levels decreased by at least 30% from baseline. All analyses were intention to treat. RESULTS: Baseline characteristics in the 2 groups were similar. 21 patients (53%) on paricalcitol and 7 patients (18%) on ergocalciferol treatment achieved the primary outcome measure (P = 0.002). After 16 weeks, PTH levels did not decrease significantly in patients receiving ergocalciferol, but were decreased significantly in those treated with paricalcitol (mean estimate of between-group difference over 16 weeks of therapy, 43.9 pg/mL; 95% CI, 11.2-76.6; P = 0.009). Serum 25(OH)D levels increased significantly after 16 weeks in only the ergocalciferol group, but not the paricalcitol group (mean estimate of between-group difference over 16 weeks of therapy, 7.08 ng/mL; 95% CI, 4.32-9.85; P < 0.001). Episodes of hyperphosphatemia and hypercalcemia were not significantly different between the 2 groups. LIMITATIONS: Lack of blinding and use of surrogate end points. CONCLUSIONS: Paricalcitol is more effective than ergocalciferol at decreasing PTH levels in patients with CKD stages 3 or 4 with vitamin D deficiency and SHPT.

Addition of atrasentan to renin-angiotensin system blockade reduces albuminuria in diabetic nephropathy.

Although endothelin-receptor antagonists reduce albuminuria in diabetic nephropathy, fluid retention limits their use. Here, we examined the effect of atrasentan, a selective endothelin A receptor (ET(A)R) antagonist, on albuminuria in a randomized, double-blind, placebo-controlled trial of subjects with diabetic nephropathy already receiving stable doses of renin-angiotensin system (RAS) inhibitors. We randomly assigned 89 subjects with eGFR >20 ml/min per 1.73 m(2) and a urinary albumin-to-creatinine ratio (UACR) of 100 to 3000 mg/g to placebo or atrasentan (0.25, 0.75, or 1.75 mg daily) for 8 weeks. Compared with placebo, atrasentan significantly reduced UACR only in the 0.75- and 1.75-mg groups (P=0.001 and P=0.011, respectively). Compared with the 11% reduction in the geometric mean of the UACR from baseline to final observation in the placebo group during the study, the geometric mean of UACR decreased by 21, 42, and 35% in the 0.25-, 0.75-, and 1.75-mg atrasentan groups (P=0.291, P=0.023, and P=0.073, respectively). In the placebo group, 17% of subjects achieved ≥40% reduction in UACR from baseline compared with 30, 50, and 38% in the 0.25-, 0.75-, and 1.75-mg atrasentan groups, respectively (P=0.029 for 0.75 mg versus placebo). Peripheral edema occurred in 9% of subjects receiving placebo and in 14, 18, and 46% of those receiving 0.25, 0.5, and 1.75 mg atrasentan, respectively (P=0.007 for 1.75 mg versus placebo). In summary, atrasentan, at the doses tested, is generally safe and effective in reducing residual albuminuria and may ultimately improve renal outcomes in patients with type 2 diabetic nephropathy.

Comparative effectiveness of paricalcitol versus cinacalcet for secondary hyperparathyroidism in patients receiving hemodialysis.

BACKGROUND/AIMS: Parathyroidectomies are performed when medical therapy fails to control secondary hyperparathyroidism in hemodialysis patients. The objective of this study was to compare parathyroidectomy rates in secondary hyperparathyroidism patients treated with paricalcitol or cinacalcet. METHODS: Retrospective cohort study using health insurance claims from January 2001 through June 2007 for adult hemodialysis patients who were new users of paricalcitol or cinacalcet. Subjects had a minimum of 12 months' enrollment prior to initiation of treatment and at least 30-day follow-up. RESULTS: We identified 1,387 paricalcitol- and 1,317 cinacalcet-treated patients. The parathyroidectomy incident rate was 74% lower in the paricalcitol (0.58 per 100 patient-years) compared to the cinacalcet (2.24 per 100 patient-years) cohort, with an unadjusted rate ratio of 0.26 (95% CI 0.12-0.52). The time to parathyroidectomy from medication initiation was longer for paricalcitol than cinacalcet; however, it was not statistically significant (535 vs. 443 days, p = 0.377). A Cox proportional hazard model that adjusted for age, gender, obesity, significantly different comorbidities, and duration of hemodialysis resulted in an adjusted risk reduction for parathyroidectomy of 79% (HR = 0.21, 95% CI 0.10-0.46) for paricalcitol compared to cinacalcet. CONCLUSION: These data suggest that long-term treatment with paricalcitol is associated with fewer parathyroidectomies when compared to cinacalcet. Further comparative studies are needed to validate these results.

Vitamin D deficiency, inflammation, and albuminuria in chronic kidney disease: complex interactions.

OBJECTIVE: Vitamin D may promote cardiovascular health in general population and in chronic kidney disease (CKD) through inhibition of the renin-angiotensin system and anti-inflammatory effects. Although proteinuria is a marker of kidney and cardiovascular disease, few studies have examined vitamin D levels, inflammation, and proteinuria simultaneously in CKD. We evaluated the relationship between calcidiol (25D), calcitriol (1,25D), inflammation, and albuminuria in Study of Early Evaluation of Kidney Disease, a multicenter CKD cohort. DESIGN: A cross-sectional study was carried out. PARTICIPANTS: A total of 1,847 participants were studied, of which 387 were randomly selected for inflammatory biomarker assessment. PREDICTORS AND OUTCOMES: The primary predictors were 25D and 1,25D. The outcome was albuminuria (urine albumin to creatinine ratio [UACR]: >30 mg/g). RESULTS: Albuminuric patients were more likely to have decreased 25D and 1,25D levels and higher interleukin-6 (IL-6) levels compared with normoalbuminuric patients. The lowest tertiles of 25D and 1,25D were associated with 2 to 3 times increased odds of albuminuria compared with the highest tertiles when adjusted for age, gender, race, systolic blood pressure, and diabetes (OR for 25D: 3.0; 95% CI: 1.3 to 7.0; OR for 1,25D: 2.6; 95% CI: 1.7 to 3.9). In analogous linear regression models, 25D and 1,25D were significantly associated with log UACR (P < .0001, for both). In participants for whom inflammatory markers were measured, demographics-adjusted linear regression models that included IL-6 described attenuation of the relationship between 25D, 1,25D, and UACR. CONCLUSIONS: Low 25D and 1,25D levels are independently associated with albuminuria. IL-6 may be an important intermediary between vitamin D deficiency and albuminuria, or vitamin D deficiency may contribute to inflammation and subsequent albuminuria.

Cost Effectiveness of Paricalcitol versus a non-selective vitamin D receptor activator for secondary hyperparathyroidism in the UK: a chronic kidney disease markov model.

BACKGROUND: secondary hyperparathyroidism (SHPT) is a common complication of chronic kidney disease (CKD) and a frequent cause of clinically significant bone disease. Non-selective vitamin D receptor (VDR) activator treatment has been used to treat the condition but is ineffective for many patients with hypercalcaemia and hyperphosphataemia and may precipitate worsening of their condition. Compared with non-selective VDR activator treatment, use of the VDR ligand paricalcitol may increase survival and reduce the risk of morbidities in patients with SHPT, which may have health economic consequences. OBJECTIVE: the objective of this study was to determine the cost effectiveness of paricalcitol versus a non-selective VDR activator for the treatment of SHPT in patients with CKD in the UK setting. METHODS: A Markov process model was developed employing data sources from the published literature, paricalcitol clinical trials and observational studies, official UK price/tariff lists and national population statistics. The comparator was alfacalcidol, a non-selective VDR activator medication. The primary perspective of the study was that of the UK National Health Service (NHS). The efficacy outcomes (reductions in SHPT, proteinuria, complications and mortality) were extrapolated to: number of life-years gained (LYG) and number of quality-adjusted life-years (QALYs). Clinical and economic outcomes were discounted at 3.5%. The year of costing for costs determined in the study was 2006. RESULTS: the reference case analysis was a 10-year time horizon, based on a comparison of paricalcitol with a non-selective VDR activator, which is started in CKD stage 3 (moderate reduction in glomerular filtration rate [GFR] with kidney damage) and continued in CKD stage 4 (severe reduction in GFR) and CKD stage 5 (established kidney failure). The use of paricalcitol leads to an additional medical cost of pound3224 ($US5970). The health benefits of paricalcitol lead to an increase in LYG of 0.52 and a gain in QALYs of 0.465. Therefore the use of paricalcitol results in an incremental cost-effectiveness ratio of pound6933/QALY ($US12 840/QALY) from the primary perspective of the NHS. One-way sensitivity analyses and probabilistic sensitivity analyses confirmed the robustness of the model. CONCLUSION: this model showed that the favourable clinical benefit of paricalcitol results in positive short- and long-term health economic benefits. This study suggests that the use of paricalcitol in patients with early CKD may be cost effective from the UK NHS perspective versus non-selective VDR activator medication.

Vitamin D deficiency and anemia in early chronic kidney disease.

Vitamin D has a number of pleiotropic effects in a variety of tissues, in addition to its well-known effects on mineral metabolism. To determine whether it has an effect on erythropoiesis, we studied the association of the components of the vitamin D axis with the prevalence and severity of anemia in chronic kidney disease. We measured the concentrations of 25-hydroxyvitamin D (25D), 1,25-dihydroxyvitamin D (1,25D), and hemoglobin in a cross-sectional study of 1661 subjects in SEEK, a multi-center cohort study of chronic kidney disease patients in the United States, of whom 41% met the criteria for anemia. The mean hemoglobin concentrations significantly decreased with decreasing tertiles of 25D and 1,25D. These linear trends remained significant after adjustment for age, gender, ethnicity, eGFR, diabetes, and parathyroid hormone. In similarly adjusted models, the lowest tertiles of 25D and 1,25D were independently associated with 2.8- and 2.0-fold increased prevalence of anemia compared with their respective highest tertiles. Patients with severe dual deficiency of 25D and 1,25D had a 5.4-fold prevalence of anemia compared with those replete in both. Our study shows that 25D and 1,25D deficiency are independently associated with decreased hemoglobin levels and anemia in chronic kidney disease. Whether this association is causal requires further study.

Differential effects of paricalcitol and calcitriol on intestinal calcium absorption in hemodialysis patients.

BACKGROUND/AIMS: Increased parathyroid activity associated with chronic kidney disease is often managed with calcitriol, which can elevate serum calcium (Ca) by increasing bone resorption and intestinal absorption, whereas paricalcitol promotes less bone resorption. This study compared intestinal Ca absorption in hemodialysis patients treated with calcitriol versus paricalcitol (dose ratio 1:3). METHODS: Patients (n = 22) aged > or =20 years, on maintenance hemodialysis for > or =2 months with intact parathyroid hormone (iPTH) levels of >200 pg/ml were enrolled in a single-center, double-blind, active-controlled, randomized, crossover trial. Mean fractional intestinal Ca absorption (+/-SE) was measured by the single-tracer method ((42)Ca) and evaluated with an analysis of variance crossover model. RESULTS: Mean fractional intestinal Ca absorption was significantly lower after paricalcitol (0.135 +/- 0.006) versus calcitriol treatment (0.158 +/- 0.006, p = 0.022), a 0.023 difference in absolute Ca absorption fraction. Overall Ca absorption was low in the study population, indicating that regulation of Ca absorption may be dysfunctional. There were no significant differences in serum PTH, Ca, phosphorus (P), or Ca x P. CONCLUSION: Overall, paricalcitol-treated patients absorbed approximately 14% less Ca compared with calcitriol-treated patients with similar effects on PTH. In hemodialysis patients, paricalcitol may provide a benefit by lowering the Ca available for removal by dialysis and/or for deposit in bone or soft tissues.

Association of secondary hyperparathyroidism with CKD progression, health care costs and survival in diabetic predialysis CKD patients.

BACKGROUND/AIMS: The objective of this study was to examine health care costs and utilization and the risks of dialysis or mortality among diabetic predialysis chronic kidney disease (CKD) patients with and without secondary hyperparathyroidism (SHPT). METHODS: This retrospective, matched cohort study examined insurance claims from 703 adult diabetic predialysis CKD patients with and without SHPT during a 72-month follow-up period. Annualized estimates of health care service utilization, costs and disease progression to dialysis or death following index CKD diagnosis were compared. RESULTS: Preindex (baseline) characteristics were similar between the cohorts. Postindex numbers of prescription utilization, outpatient service utilization and hospitalizations were all higher (p < 0.0001) in diabetic CKD patients with SHPT compared to those without SPHT in both unadjusted and adjusted analyses even after multivariate adjustment for known confounders. The rate of progression to dialysis or death was higher for diabetic CKD patients with SHPT compared to those without SPHT. Those with SHPT were at higher risk of requiring dialysis treatment [hazard ratio (HR) = 6.7; 95% confidence interval (CI) = 4.3-10.6] and death (HR = 2.3; 95% CI = 1.1-4.9) compared to those without SHPT. CONCLUSION: In diabetic predialysis CKD patients, the presence of SHPT is associated with significantly greater health care resource utilization and costs, and a faster rate of disease progression.

Chronic kidney disease Markov model comparing paricalcitol to calcitriol for secondary hyperparathyroidism: a US perspective.

OBJECTIVE: The objective of this study was to determine the cost effectiveness of paricalcitol versus calcitriol for the treatment of secondary hyperparathyroidism in patients with chronic kidney disease in the United States setting. METHODS: A Markov process model was developed employing data sources from the published literature, paricalcitol clinical trials and observational studies, official US price/tariff lists and national population statistics. The comparator was calcitriol, a non-selective vitamin D receptor activator (VDRA) medication. The primary perspective of the study was that of the third-party payer in the US. The efficacy outcomes (reduction in secondary hyperparathyroidism (SHPT), reduction in proteinuria, complications and mortality) were extrapolated to: number of life-years gained (LYG) and number of quality-adjusted life-years (QALYs). Clinical and economic outcomes were discounted at 3.5%. RESULTS: The reference case analysis was a 10-year time horizon based on a comparison of paricalcitol with calcitriol, which is started in chronic kidney disease (CKD) stage 3 and continued in CKD stage 4 and CKD stage 5. The use of paricalcitol leads to a cost saving of US$1941. The inclusion of indirect costs leads to a cost saving of US$2528. The use of paricalcitol leads to an increase in life-years gained (0.47 years) and a gain in QALYs (0.43). The use of paricalcitol results in a dominant outcome from the perspective of the third-party payer, as well as from the societal perspective. One-way sensitivity analyses and probabilistic sensitivity analyses confirmed the robustness of the model. CONCLUSION: This model showed that the favorable clinical benefit of paricalcitol results in positive short and long-term health economic benefits. This study suggests that the use of paricalcitol in patients with early chronic kidney disease may be cost-effective from the third-party payer perspective in the US versus calcitriol. Additional comparative studies are necessary to validate these results.

Management of secondary hyperparathyroidism in stages 3 and 4 chronic kidney disease.

OBJECTIVE: To review approved treatment options for secondary hyperparathyroidism (SHPT) in patients with stages 3 and 4 chronic kidney disease (CKD). METHODS: Recently published data on the diagnosis and treatment of SHPT in patients with CKD were critically assessed. RESULTS: Early detection of SHPT is critical for effective treatment. Approximately 40% of patients with stage 3 CKD and 80% of patients with stage 4 have SHPT due to low serum 1,25-dihydroxyvitamin D levels. Appropriate treatment involves suppression of parathyroid hormone (PTH) to normal levels with active vitamin D therapy and phosphate binders. Ergocalciferol or cholecalciferol should be used to correct 25-hydroxyvitamin D levels either before or during active vitamin D therapy. Active vitamin D analogues include calcitriol, doxercalciferol, and paricalcitol. Calcitriol is effective, but has a narrow therapeutic window at higher doses because of hypercalcemia and hyperphosphatemia, which require frequent monitoring. Doxercalciferol is also effective, but has been associated with significant elevations in serum phosphorus requiring greater use of oral phosphate binders. Paricalcitol effectively suppresses PTH with minimal impact on serum calcium and phosphorus. Limited data exist on the use of cinacalcet in treating SHPT in stages 3 and 4 CKD, and it is only approved for use in patients receiving dialysis. CONCLUSION: SHPT is an early and major complication of CKD. Treatment involves suppression of PTH to prevent metabolic bone disease, bone loss, and metabolic complications that may result in marked morbidity and mortality. Early detection of elevated PTH levels with appropriate intervention using active vitamin D therapy, even in the absence of elevated serum phosphorus and reduced serum calcium, is critical.

Bone and mineral guidelines for patients with chronic kidney disease: a call for revision.

Recent clinical studies of mineral metabolism in patients with chronic kidney disease have helped to verify and extend the Kidney Disease Outcomes Quality Initiative practice guidelines for bone metabolism and disease that were published in 2003. In particular, investigations that examined calcium loading, vitamin D therapy, and mortality risk associated with serum calcium and phosphate in dialysis patients have been the most helpful clinically. As a consequence, there is now a growing interest to have the previous guidelines amended accordingly, which will be performed through the Kidney Disease: Improving Global Outcomes working group after a debate within the nephrology community. The new data support this call for revision in an attempt to improve survival of the dialysis patient by emphasizing the importance of intravenous vitamin D therapy and of preventing excess calcium loading. These studies also suggest avenues for future investigation into nontraditional causes and treatments of cardiovascular disease in patients with chronic kidney disease.

Superiority of the Modification of Diet in Renal Disease equation over the Cockcroft-Gault equation in screening for impaired kidney function in Japanese Americans.

The Cockcroft-Gault and the Modification of Diet in Renal Disease (MDRD) Study equations have not been validated in Asian Americans with varying degrees of glucose tolerance. We compared both equations to 24-h urinary creatinine clearance, the latter as a standard measurement of glomerular filtration rate (GFR), in 398 Japanese Americans (62.1+/-5.8 years, mean+/-S.D.) who had normal glucose tolerance (NGT) (n=138), impaired glucose tolerance (IGT) (n=136) and diabetes (n=124). Although both the Cockcroft-Gault (r=0.65, P<0.001) and the MDRD (r=0.74, P<0.001) equations correlated well with creatinine clearance, the latter was significantly superior (P=0.013 between r values). Receiver operating characteristic (ROC) curve analysis showed that the area under the curve (AUC) for the MDRD equation was significantly greater than for the Cockcroft-Gault equation (AUC 0.86 versus 0.80, P=0.015) in classifying subjects as having mildly reduced GFR (<90ml/min per 1.73m(2)). However, both equations overestimated the number of individuals with decreased GFR. We conclude therefore that while the MDRD equation more accurately identifies Asians who are in the early stages of kidney disease, as for other groups, a correction term appears necessary in order to reduce the number of Asian subjects being falsely diagnosed with CKD.

Paricalcitol capsule for the treatment of secondary hyperparathyroidism in stages 3 and 4 CKD.

BACKGROUND: The safety and efficacy of paricalcitol injection have been well established for the prevention and treatment of secondary hyperparathyroidism (SHPT) in patients with chronic kidney disease (CKD) stage 5. The capsule form of paricalcitol was developed to provide a convenient dosage form for patients with stages 3 and 4 CKD. METHODS: Three randomized, placebo-controlled, phase-3 trials were conducted in patients with stages 3 and 4 CKD with SHPT. Enrollment criteria included an estimated glomerular filtration rate between 15 and 60 mL/min/1.73 m2 (0.25 and 1.00 mL/s/1.73 m2), an average of 2 consecutive intact parathyroid hormone (iPTH) levels greater than 150 pg/mL (ng/L), 2 consecutive serum calcium levels between 8.0 and 10.0 mg/dL (2.00 and 2.50 mmol/L), and 2 consecutive serum phosphorus levels of 5.2 mg/dL or less (< or = 1.68 mmol/L). Two studies used a thrice-weekly dosing regimen and 1 study used a once-daily dosing regimen for 24 weeks. Dosing was based on serum iPTH, calcium, and phosphorus levels. The primary efficacy end point is 2 consecutive decreases in iPTH levels greater than 30% from baseline. RESULTS: Two hundred twenty patients participated (n = 107, paricalcitol; n = 113, placebo). At least 2 consecutive decreases in iPTH levels of 30% or greater from baseline occurred in 91% of paricalcitol versus 13% of placebo patients (P < 0.001). Incidences of hypercalcemia, hyperphosphatemia, and elevated calcium-phosphorus product levels were not significantly different between groups. Similarly, no significant differences in urinary calcium and phosphorus excretion or deterioration in kidney function were detected in patients administered paricalcitol compared with placebo. CONCLUSION: Paricalcitol capsule was well tolerated and effectively decreased iPTH levels with minimal or no impact on calcium levels, phosphorus balance, and kidney function in patients with stages 3 and 4 CKD.

Vitamin D treatment in chronic kidney disease.

Activated vitamin D continues to be the major treatment for suppressing parathyroid hormone (PTH) levels in dialysis patients who have secondary hyperparathyroidism. Active vitamin D compounds are distinguished by their ability to bind with high affinity to vitamin D receptors (VDRs) not only in the parathyroid glands, but in cells throughout the body. Because of recent data showing that pulsatile, intravenous vitamin D treatment (calcitriol or paricalcitol) confers a survival advantage in the dialysis population, there is new interest in understanding the systemic effects of VDR activation, particularly in the predialysis stages of chronic kidney disease (CKD), where high mortality rates from cardiovascular disease have recently been documented. Previous underutilization of calcitriol treatment to control PTH levels in stages 3 and 4 CKD was often due to concerns about its potential for accelerating the progression of CKD as a consequence of hypercalcemia, hypercalciuria, or hyperphosphatemia. Vitamin D analogs with selective VDR activity (such as paricalcitol) have great potential for preventing parathyroid hyperplasia and bone loss in early CKD without adversely affecting kidney function. Whether they also reduce cardiovascular morbidity and mortality in early CKD, as they appear to do in dialysis patients, remains to be determined.