Lumasiran for Advanced Primary Hyperoxaluria Type 1: Phase 3 ILLUMINATE-C Trial.

RATIONALE & OBJECTIVE: Lumasiran reduces urinary and plasma oxalate (POx) in patients with primary hyperoxaluria type 1 (PH1) and relatively preserved kidney function. ILLUMINATE-C evaluates the efficacy, safety, pharmacokinetics, and pharmacodynamics of lumasiran in patients with PH1 and advanced kidney disease. STUDY DESIGN: Phase 3, open-label, single-arm trial. SETTING & PARTICIPANTS: Multinational study; enrolled patients with PH1 of all ages, estimated glomerular filtration rate ≤45 mL/min/1.73 m2 (if age ≥12 months) or increased serum creatinine level (if age <12 months), and POx ≥20 µmol/L at screening, including patients with or without systemic oxalosis. INTERVENTION: Lumasiran administered subcutaneously; 3 monthly doses followed by monthly or quarterly weight-based dosing. OUTCOME: Primary end point: percent change in POx from baseline to month 6 (cohort A; not receiving hemodialysis at enrollment) and percent change in predialysis POx from baseline to month 6 (cohort B; receiving hemodialysis at enrollment). Pharmacodynamic secondary end points: percent change in POx area under the curve between dialysis sessions (cohort B only); absolute change in POx; percent and absolute change in spot urinary oxalate-creatinine ratio; and 24-hour urinary oxalate adjusted for body surface area. RESULTS: All patients (N = 21; 43% female; 76% White) completed the 6-month primary analysis period. Median age at consent was 8 (range, 0-59) years. For the primary end point, least-squares mean reductions in POx were 33.3% (95% CI, -15.2% to 81.8%) in cohort A (n = 6) and 42.4% (95% CI, 34.2%-50.7%) in cohort B (n = 15). Improvements were also observed in all pharmacodynamic secondary end points. Most adverse events were mild or moderate. No patient discontinued treatment or withdrew from the study. The most commonly reported lumasiran-related adverse events were injection-site reactions, all of which were mild and transient. LIMITATIONS: Single-arm study without placebo control. CONCLUSIONS: Lumasiran resulted in substantial reductions in POx with acceptable safety in patients with PH1 who have advanced kidney disease, supporting its efficacy and safety in this patient population. FUNDING: Alnylam Pharmaceuticals. TRIAL REGISTRATION: Registered at ClinicalTrials.gov with study number NCT04152200 and at EudraCT with study number 2019-001346-17. PLAIN-LANGUAGE SUMMARY: Primary hyperoxaluria type 1 (PH1) is a rare genetic disease characterized by excessive hepatic oxalate production that frequently causes kidney failure. Lumasiran is an RNA interference therapeutic that is administered subcutaneously for the treatment of PH1. Lumasiran has been shown to reduce oxalate levels in the urine and plasma of patients with PH1 who have relatively preserved kidney function. In the ILLUMINATE-C study, the efficacy and safety of lumasiran were evaluated in patients with PH1 and advanced kidney disease, including a cohort of patients undergoing hemodialysis. During the 6-month primary analysis period, lumasiran resulted in substantial reductions in plasma oxalate with acceptable safety in patients with PH1 complicated by advanced kidney disease.

Vitamin D Status and Clinical Outcomes in Acute Respiratory Distress Syndrome: A Secondary Analysis From the Assessment of Low Tidal Volume and Elevated End-Expiratory Volume to Obviate Lung Injury (ALVEOLI) Trial.

BACKGROUND: Acute respiratory distress syndrome (ARDS) is a highly morbid condition that has limited therapeutic options. Optimal vitamin D status has been linked to immunological effects that may benefit critically ill patients. Therefore, we investigated whether admission 25-hydroxyvitamin D levels (25OHD) are associated with clinical outcomes in ARDS patients. METHODS: We performed a secondary analysis of data from a randomized, controlled trial comparing oxygenation strategies in 549 patients with ARDS (NCT00000579). Baseline 25OHD was measured in stored plasma samples. We investigated the relationship between vitamin D status and ventilator-free days (VFD) as well as 90-day survival, using linear regression and Cox proportional hazard models, respectively. Analyses were adjusted for age, race, and Acute Physiology and Chronic Health Evaluation III score. RESULTS: Baseline 25OHD was measured in 476 patients. 90% of these individuals had 25OHD <20 ng/ml and 40% had 25OHD <10 ng/ml. Patients with 25OHD <20 ng/ml were likely to be ventilated for 3 days longer than patients with levels ≥20 ng/ml (ß 3.41; 95%CI 0.42-6.39: P = 0.02). Patients with 25OHD <10 ng/ml were likely to be ventilated for 9 days longer (ß 9.27; 95%CI 7.24-11.02: P < 0.001) and to have a 34% higher risk of 90-day mortality (HR 1.34; 95% CI 1.06-1.71: P = 0.02) compared to patients with levels >10 ng/ml. CONCLUSIONS: In patients with ARDS, vitamin D status is associated with duration of mechanical ventilation and 90-day mortality. Randomized, controlled trials are warranted to determine whether vitamin D supplementation improves clinical outcomes in ARDS patients.

Vitamin D-binding protein and vitamin D status of black Americans and white Americans.

BACKGROUND: Low levels of total 25-hydroxyvitamin D are common among black Americans. Vitamin D-binding protein has not been considered in the assessment of vitamin D deficiency. METHODS: In the Healthy Aging in Neighborhoods of Diversity across the Life Span cohort of blacks and whites (2085 participants), we measured levels of total 25-hydroxyvitamin D, vitamin D-binding protein, and parathyroid hormone as well as bone mineral density (BMD). We genotyped study participants for two common polymorphisms in the vitamin D-binding protein gene (rs7041 and rs4588). We estimated levels of bioavailable 25-hydroxyvitamin D in homozygous participants. RESULTS: Mean (±SE) levels of both total 25-hydroxyvitamin D and vitamin D-binding protein were lower in blacks than in whites (total 25-hydroxyvitamin D, 15.6±0.2 ng per milliliter vs. 25.8±0.4 ng per milliliter, P<0.001; vitamin D-binding protein, 168±3 µg per milliliter vs. 337±5 µg per milliliter, P<0.001). Genetic polymorphisms independently appeared to explain 79.4% and 9.9% of the variation in levels of vitamin D-binding protein and total 25-hydroxyvitamin D, respectively. BMD was higher in blacks than in whites (1.05±0.01 g per square centimeter vs. 0.94±0.01 g per square centimeter, P<0.001). Levels of parathyroid hormone increased with decreasing levels of total or bioavailable 25-hydroxyvitamin D (P<0.001 for both relationships), yet within each quintile of parathyroid hormone concentration, blacks had significantly lower levels of total 25-hydroxyvitamin D than whites. Among homozygous participants, blacks and whites had similar levels of bioavailable 25-hydroxyvitamin D overall (2.9±0.1 ng per milliliter and 3.1±0.1 ng per milliliter, respectively; P=0.71) and within quintiles of parathyroid hormone concentration. CONCLUSIONS: Community-dwelling black Americans, as compared with whites, had low levels of total 25-hydroxyvitamin D and vitamin D-binding protein, resulting in similar concentrations of estimated bioavailable 25-hydroxyvitamin D. Racial differences in the prevalence of common genetic polymorphisms provide a likely explanation for this observation. (Funded by the National Institute on Aging and others.).

Changes in Kidney Function After Transjugular Intrahepatic Portosystemic Shunts Versus Large-Volume Paracentesis in Cirrhosis: A Matched Cohort Analysis.

BACKGROUND: Patients with cirrhosis and refractory ascites have physiologic and hormonal dysregulation that contributes to decreased kidney function. Placement of a transjugular intrahepatic portosystemic shunt (TIPS) can reverse these changes and potentially improve kidney function. We sought to evaluate change in estimated glomerular filtration rate (eGFR) following TIPS placement. STUDY DESIGN: Retrospective, matched cohort analysis. SETTINGS & PARTICIPANTS: Patients who underwent first-time TIPS placement for refractory ascites in 1995 to 2014. Frequency matching was used to generate a comparator group of patients with cirrhosis and ascites treated with serial large-volume paracentesis (LVP) in a 1:1 fashion. PREDICTOR: TIPS placement compared to serial LVP. OUTCOME: Change in eGFR over 90 days' follow-up. MEASUREMENTS: Multivariable regression stratified by baseline eGFR<60 versus ≥60mL/min/1.73m(2); analysis of effect modification between TIPS placement and baseline eGFR. RESULTS: 276 participants (TIPS, n=138; serial LVP, n=138) were analyzed. After 90 days, eGFRs increased significantly after TIPS placement in participants with baseline eGFRs<60mL/min/1.73m(2) compared to treatment with serial LVP (21 [95% CI, 13-29] mL/min/1.73m(2); P<0.001) and was no different in those with eGFRs≥60mL/min/1.73m(2) (1 [95% CI, -9 to 12] mL/min/1.73m(2); P=0.8). There was significant effect modification between TIPS status and baseline eGFR (P=0.001) in a model that included all participants. LIMITATIONS: Outcomes restricted by clinically recorded data; clinically important differences may still exist between the TIPS and LVP cohorts despite good statistical matching. CONCLUSIONS: TIPS placement was associated with significant improvement in kidney function. This was most prominent in participants with baseline eGFRs<60mL/min/1.73m(2). Prospective studies of TIPS use in populations with eGFRs<60mL/min/1.73m(2) are needed to evaluate these findings.

Effect of Cholecalciferol Supplementation on Vitamin D Status and Cathelicidin Levels in Sepsis: A Randomized, Placebo-Controlled Trial.

OBJECTIVES: To compare changes in vitamin D status and cathelicidin (LL-37) levels in septic ICU patients treated with placebo versus cholecalciferol. DESIGN: Randomized, placebo-controlled, trial. SETTING: Medical and surgical ICUs of a single teaching hospital in Boston, MA. PATIENTS: Thirty adult ICU patients. INTERVENTIONS: Placebo (n = 10) versus 200,000 IU cholecalciferol (n = 10) versus 400,000 IU cholecalciferol (n = 10), within 24 hours of new-onset severe sepsis or septic shock. MEASUREMENTS AND MAIN RESULTS: Blood samples were obtained at baseline (day 1) and on days 3, 5, and 7, to assess total 25-hydroxyvitamin D, as well as vitamin D-binding protein and albumin to calculate bioavailable 25-hydroxyvitamin D. Plasma LL-37 and high-sensitivity C-reactive protein levels were also measured. At baseline, median (interquartile range) plasma 25-hydroxyvitamin D was 17 ng/mL (13-22 ng/mL) and peaked by day 5 in both intervention groups. Groups were compared using Kruskal-Wallis tests. Relative to baseline, on day 5, median change in biomarkers for placebo, 200,000 IU cholecalciferol, and 400,000 IU cholecalciferol groups, respectively, were as follows: 1) total 25-hydroxyvitamin D, 3% (-3% to 8%), 49% (30-82%), and 69% (55-106%) (p < 0.001); 2) bioavailable 25-hydroxyvitamin D, 4% (-8% to 7%), 45% (40-70%), and 96% (58-136%) (p < 0.01); and 3) LL-37: -17% (-9% to -23%), 4% (-10% to 14%), and 30% (23-48%) (p = 0.04). Change in high-sensitivity C-reactive protein levels did not differ between groups. A positive correlation was observed between bioavailable 25-hydroxyvitamin D and LL-37 (Spearman ρ = 0.44; p = 0.03) but not for total 25-hydroxyvitamin D and LL-37. CONCLUSIONS: High-dose cholecalciferol supplementation rapidly and safely improves 25-hydroxyvitamin D and bioavailable 25-hydroxyvitamin D levels in patients with severe sepsis or septic shock. Changes in bioavailable 25-hydroxyvitamin D are associated with concomitant increases in circulating LL-37 levels. Larger trials are needed to verify these findings and to assess whether optimizing vitamin D status improves sepsis-related clinical outcomes.

Vitamin D-Binding Protein in Health and Chronic Kidney Disease.

Vitamin D-binding protein (DBP) is a multifunctional protein that has attracted increasing interest in recent years, largely because of its potential role in modulating the activity of vitamin D. Nearly all circulating vitamin D (~85-90%) circulates bound to DBP, with a smaller proportion bound to albumin, leaving <5% circulating freely. DBP may also play roles beyond vitamin D binding, with potential roles in the immune system and elsewhere. Numerous polymorphisms of DBP exist around the world, and recent studies have identified relevance of different DBP phenotypes in determining DBP concentration and vitamin D affinity. This review focuses on the known roles of DBP in health and kidney disease, and current views on the relevance of DBP polymorphisms.

Perspectives of continuous renal replacement therapy in the intensive care unit: a paired survey study of patient, physician, and nurse views.

BACKGROUND: Recent studies suggest discrepancies between patients and providers around perceptions of hemodialysis prognosis. Such data are lacking for continuous renal replacement therapy (CRRT). We aim to assess patient and provider understanding of outcomes around CRRT. METHODS: From February 1 to August 31, 2013, a triad of (1) a patient on CRRT (or health care proxy [HCP]), (2) physician and (3) primary nurse from the intensive care unit (ICU) team were surveyed. Univariate chi-square and qualitative analysis techniques were used. RESULTS: Ninety-six total participants (32 survey triads) were completed. Ninety one percent of patients/HCPs correctly identified that CRRT replaced the function of the kidneys. Six percent of patients/HCPs, 44 % of physicians, and 44 % of nurses identified rates of survival to hospital discharge that were consistent with published literature. Both physicians and nurses were more likely than patients/HCPs to assess survival consistently with published data (p = 0.001). Patients/HCPs were more likely to overestimate survival rates than physicians and nurses (p < 0.001). Thirty eight percent of patients/HCPs, 38 % of physicians, and 28 % of nurses identified rates of lifelong dialysis-dependence among surviving patients that were consistent with published literature. CONCLUSIONS: There is mismatch between patients, HCPs, and providers around prognosis of CRRT. Patients/HCPs are more likely to overestimate chances of survival than physicians or nurses. Further intervention is needed to improve this knowledge gap.

Prospective study of vitamin D status at initiation of care in critically ill surgical patients and risk of 90-day mortality.

OBJECTIVES: 1) To characterize vitamin D status at initiation of critical care in surgical ICU patients and 2) to determine whether this vitamin D status is associated with the risk of prolonged hospital length of stay, 90-day readmission, and 90-day mortality. DESIGN: Prospective cohort study. SETTING: A teaching hospital in Boston, MA. PATIENTS: Hundred surgical ICU patients. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Mean (± SD) serum total 25-hydroxyvitamin D and 1,25-dihydroxyvitamin D levels were 17 ± 8 ng/mL and 32 ± 19 pg/mL, respectively. Mean calculated bioavailable 25-hydroxyvitamin D and 1,25-dihydroxyvitamin D were 2.5 ± 2.0 ng/mL and 6.6 ± 5.3 pg/mL, respectively. Receiver-operating characteristic curve analysis demonstrated that all of four vitamin D measures predicted the three clinical outcomes; total 25-hydroxyvitamin D was not inferior to the other measures. Median (interquartile range) hospital length of stay was 11 days (8-19 d). Poisson regression analysis, adjusted for biologically plausible covariates, demonstrated an association of total 25-hydroxyvitamin D with hospital length of stay (incident rate ratio per 1 ng/mL, 0.98; 95% CI, 0.97-0.98). The 90-day readmission and mortality rates were 24% and 22%, respectively. Even after adjustment for biologically plausible covariates, there remained significant associations of total 25-hydroxyvitamin D with readmission (odds ratio per 1 ng/mL, 0.84; 95% CI, 0.74-0.95) and mortality (odds ratio per 1 ng/mL, 0.84; 95% CI, 0.73-0.97). CONCLUSIONS: Serum 25-hydroxyvitamin D levels within 24 hours of ICU admission may identify patients at high risk for prolonged hospitalization, readmission, and mortality. Randomized trials are needed to assess whether vitamin D supplementation can improve these clinically relevant outcomes in surgical ICU patients.

Phosphate management in chronic kidney disease.

PURPOSE OF REVIEW: The review focuses on the rationale and evidence behind management strategies for hyperphosphatemia in patients with chronic kidney disease (CKD). RECENT FINDINGS: Optimal management of phosphate in CKD remains an area of uncertainty, but multiple studies now point to a clinical benefit from the use of phosphate binders. Evidence of improved survival is particularly strong with sevelamer, though it remains unclear whether the absence of calcium or other properties of sevelamer are responsible for this relationship. Newer agents, such as iron-based binders or niacin compounds to inhibit phosphorus absorption, may have additional benefits which will be better defined with additional experience. A reduced pill count may be a particularly beneficial characteristic of newer agents, and has been associated with improved response to therapy. Increased use of frequent, nocturnal hemodialysis is an additional tool to help ameliorate phosphate control. Data on the reduction of fibroblast growth factor 23 through use of phosphate binders remain weak. SUMMARY: An improved understanding of phosphate regulation and the development of new therapeutic agents have reinvigorated a once stagnant field, but significant changes to practice cannot yet be justified. There is increasing support for using sevelamer in place of calcium-based binders, though economic practicability remains challenging.

Phase 2 Trial of Cemdisiran in Adult Patients with IgA Nephropathy: A Randomized Controlled Trial.

BACKGROUND: IgA nephropathy is the most common primary GN. Clinical features of IgA nephropathy include proteinuria, which is the strongest known surrogate of progression to kidney failure. Complement pathway activation is a critical driver of inflammation and tissue injury in IgA nephropathy. Cemdisiran is an investigational RNA interference therapeutic that suppresses hepatic production of complement component 5 (C5), thereby potentially reducing proteinuria in IgA nephropathy. We evaluated the efficacy and safety of cemdisiran in adult patients with IgA nephropathy at high risk of kidney disease progression. METHODS: In this phase 2, 36-week, double-blind study, adult patients with IgA nephropathy and urine protein ≥1 g/24 hours were randomized (2:1) to subcutaneous cemdisiran 600 mg or placebo every 4 weeks in combination with the standard of care. The primary end point was percentage change from baseline at week 32 in urine protein-to-creatinine ratio (UPCR) measured by 24-hour urine collection. Additional end points included change from baseline in UPCR measured by spot urine, serum C5 level, and safety assessments. RESULTS: Thirty-one patients were randomized (cemdisiran, N =22; placebo, N =9). Cemdisiran-treated patients had a placebo-adjusted geometric mean change in 24-hour UPCR of -37.4% (cemdisiran-adjusted geometric mean ratio to baseline [SEM], 0.69 [0.10]) at week 32. Spot UPCR was consistent with 24-hour UPCR placebo-adjusted change of -45.8% (cemdisiran-adjusted geometric mean ratio to baseline [SEM], 0.73 [0.11]). Mean (SD) change in serum C5 level from baseline at week 32 was -98.7% (1.2) with cemdisiran and 25.2% (57.7) with placebo. Over 36 weeks, most adverse events were mild or moderate and transient; the most common adverse event after cemdisiran treatment was injection-site reaction (41%). CONCLUSIONS: These findings indicate that treatment with cemdisiran resulted in a reduction of proteinuria at week 32 and was well tolerated.

Impact of new vitamin D data on future studies and treatment.

PURPOSE OF REVIEW: This review evaluates recently published data on clinical effects of vitamin D supplementation, focusing on randomized, placebo-controlled trials and nontraditional actions on the cardiovascular and immune systems. RECENT FINDINGS: Several randomized trials evaluating vitamin D therapy have recently emerged, in both the general population and in individuals with chronic kidney disease (CKD). In the former, measurable effects on cardiovascular risk factors have not been detected, with the possible exception of a modest reduction in blood pressure. Studies aimed at boosting immunity have demonstrated efficacy only in specific, high-risk populations. In CKD, the benefits of nutritional vitamin D appear largely limited to earlier stages of disease. Benefits of active vitamin D agents, outside of their known effects on mineral metabolism, have also thus far eluded detection. One possible exception that has accumulated supportive evidence is the link between active vitamin D analogs and decreased proteinuria. Large-scale clinical trials, now underway, will be critical to understanding of the potential benefits and hazards of vitamin D treatment. SUMMARY: New trials evaluating the effects of vitamin D supplementation have failed to reveal any robust clinical benefits beyond its known actions on mineral and bone disease.

Hyponatremia, mineral metabolism, and mortality in incident maintenance hemodialysis patients: a cohort study.

BACKGROUND: Hyponatremia is associated with increased mortality in chronic diseases. Recent animal studies also implicate hyponatremia in bone abnormalities. However, associations between hyponatremia, mineral bone abnormalities, and mortality in incident hemodialysis patients are unknown. STUDY DESIGN: Nonconcurrent prospective cohort study. SETTING & PARTICIPANTS: Incident hemodialysis patients from the Accelerated Mortality on Renal Replacement (ArMORR) cohort with available serum sodium measurements from the time of dialysis therapy initiation (n = 6,127) were classified as hyponatremic (sodium, <135 mEq/L) or normonatremic (sodium, 135-145 mEq/L) based on glucose-corrected sodium level at the time of dialysis therapy initiation. Patients with sodium levels >145 mEq/L were excluded (n = 74). PREDICTOR: Hyponatremia (sodium, <135 mEq/L). OUTCOMES: Mineral bone abnormalities; rates of falls, fractures, and mortality. MEASUREMENTS: Hyponatremia and mineral bone abnormalities were assessed at the time of hemodialysis therapy initiation. Data for other outcomes were collected during a 1-year follow-up. Univariate and multivariable logistic and Cox proportion hazard analyses were conducted to compute ORs and HRs, respectively, with 95% CIs. RESULTS: 775 patients were hyponatremic and 5,278 were normonatremic at baseline. In univariate analyses, hyponatremia was associated with hypercalcemia (OR, 1.92; 95% CI, 1.11-3.30), elevated alkaline phosphatase level (OR, 1.36; 95% CI, 1.12-1.66), and hypoparathyroidism (OR, 1.40; 95% CI, 1.18-1.65). Similar relationships were observed in multivariable models. No statistically significant relationships were observed with phosphorus abnormalities, hypovitaminosis D, falls, or fractures. 965 (15.8%) patients had died at the 1-year follow up. Compared with normonatremic patients, hyponatremic patients had higher 1-year mortality in univariate (HR, 1.59; 95% CI, 1.34-1.87) and multivariable analyses (HR, 1.42; 95% CI, 1.19-1.69). LIMITATIONS: Low rate of falls and fractures, lack of data for bone density and fibroblast growth factor 23. CONCLUSIONS: In incident hemodialysis patients, hyponatremia is associated with hypercalcemia, elevated alkaline phosphatase levels, hypoparathyroidism, and increased 1-year mortality. Future studies are needed to examine whether treatments to alter hyponatremia have effects on mineral bone abnormalities and mortality.

Dysregulated mineral metabolism in patients with acute kidney injury and risk of adverse outcomes.

OBJECTIVE: Numerous studies have evaluated the prevalence and importance of vitamin D deficiency among patients with chronic kidney disease and end-stage renal disease; however, little is known about vitamin D levels in acute kidney injury (AKI). We evaluated the association between vitamin D metabolites and clinical outcomes among patients with AKI. DESIGN: Prospective cohort study. PATIENTS: A total of 30 participants with AKI and 30 controls from general hospital wards and intensive care units at a tertiary care hospital were recruited for the study. MEASUREMENTS: Plasma levels of 25-hydroxyvitamin D [25(OH)D], 1,25-dihydroxyvitamin D [1,25(OH)2 D], 24R,25-dihydroxyvitamin D3 , vitamin D binding protein (VDBP) and fibroblast growth factor 23 (FGF23) were measured within 24 hours of AKI onset and 5 days later. Bioavailable 25(OH)D and 1,25(OH)2 D levels, defined as the sum of free- and albumin-bound 25(OH)D and 1,25(OH)2 D, were estimated using equations. RESULTS: Compared to controls, participants with AKI had lower levels of 1,25(OH)2 D [17 (10-22) vs 25 (15-35) pg/ml, P = 0·01], lower levels of VDBP [23 (15-31) vs 29 (25-36) mg/dl, P = 0·003] and similar levels of bioavailable 25(OH)D and 1,25(OH)2 D at enrolment. Levels of bioavailable 25(OH)D were inversely associated with severity of sepsis in the overall sample (P < 0·001). Among participants with AKI, bioavailable 25(OH)D, but not other vitamin D metabolites, was significantly associated with mortality after adjusting for age and serum creatinine (adjusted odds ratio per 1 SD ln [bioavailable 25(OH)D] = 0·16, 95% confidence interval = 0·03-0·85). CONCLUSIONS: Bioavailable 25(OH)D could have a role as a biomarker or mediator of adverse outcomes among patients with established AKI.

Statin use and calcific uremic arteriolopathy: a matched case-control study.

BACKGROUND: Calcific uremic arteriolopathy (CUA), also known as calciphylaxis, is characterized by vascular calcification, thrombosis and intense inflammation. Prior research has shown that statins have anticalcification, antithrombotic and antiinflammatory properties; however, the association between statin use and CUA has not been investigated. METHODS: This matched case-control study included 62 adult maintenance hemodialysis (HD) patients with biopsy-confirmed CUA diagnosed between the years 2002 and 2011 (cases). All cases were hospitalized at the time of diagnosis. Controls (n = 124) were hospitalized maintenance HD patients without CUA (matched to cases by gender and timing of hospitalization). Univariate and multivariable logistic regression models were applied to compute odds ratio (OR) and 95% confidence intervals (CI) for CUA in statin users, and also to examine previously described associations. RESULTS: The mean age of cases was 58 years. Most were females (68%), and of white race (64%). Statin use was more common in controls than in cases (39 vs. 19%, p < 0.01). Statin use was associated with lower odds of CUA in unadjusted (OR 0.38, 95% CI 0.18-0.79) and adjusted (OR 0.20, 95% CI 0.05-0.88) analyses. Hypercalcemia (OR 2.25, 95% CI 1.14-4.43), hypoalbuminemia (OR 5.73, 95% CI 2.79-11.77), calcitriol use (OR 5.69, 95% CI 1.02-31.77) and warfarin use (OR 4.30, 95% CI 1.57-11.74) were positively associated with CUA in adjusted analyses whereas paricalcitol and doxercalciferol were not (OR 1.33, 95% CI 0.54-3.27). CONCLUSION: Statin use may be negatively associated with odds of CUA. Further large prospective studies with attention to potential confounders are needed to confirm these findings.

Continuous renal replacement therapy outcomes in acute kidney injury and end-stage renal disease: a cohort study.

INTRODUCTION: Continuous renal replacement therapy (CRRT) is a widely used but resource-intensive treatment. Despite its broad adoption in intensive care units (ICUs), it remains challenging to identify patients who would be most likely to achieve positive outcomes with this therapy and to provide realistic prognostic information to patients and families. METHODS: We analyzed a prospective cohort of all 863 ICU patients initiated on CRRT at an academic medical center from 2008 to 2011 with either new-onset acute kidney injury (AKI) or pre-admission end-stage renal disease (ESRD). We examined in-hospital and post-discharge mortality (for all patients), as well as renal recovery (for AKI patients). We identified prognostic factors for both in-hospital and post-discharge mortality separately in patients with AKI or ESRD. RESULTS: In-hospital mortality was 61% for AKI and 54% for ESRD. In patients with AKI (n=725), independent risk factors for mortality included age over 60 (OR 1.9, 95% CI 1.3, 2.7), serum lactate over 4 mmol/L (OR 2.2, 95% CI 1.5, 3.1), serum creatinine over 3 mg/dL at time of CRRT initiation (OR 0.63, 95% CI 0.43, 0.92) and comorbid liver disease (OR 1.75, 95% CI 1.1, 2.9). Among patients with ESRD (n=138), liver disease was associated with increased mortality (OR 3.4, 95% CI 1.1, 11.1) as was admission to a medical (vs surgical) ICU (OR 2.2, 95% CI 1.1, 4.7). Following discharge, advanced age became a predictor of mortality in both groups (AKI: HR 1.9, 95% CI 1.2, 3.0; ESRD: HR 4.1, 95% CI 1.5, 10.9). At the end of the study period, only 25% (n=183) of patients with AKI achieved dialysis-free survival. CONCLUSIONS: Among patients initiating CRRT, risk factors for mortality differ between patients with underlying ESRD or newly acquired AKI. Long-term dialysis-free survival in AKI is low. Providers should consider these factors when assessing prognosis or appropriateness of CRRT.

Results of a phase 1/2 study of cemdisiran in healthy subjects and patients with paroxysmal nocturnal hemoglobinuria.

Complement dysregulation underpins the physiopathology of paroxysmal nocturnal hemoglobinuria (PNH). Cemdisiran, an RNA interference investigational treatment, silences complement component 5 (C5) expression in the liver. Previously reported results showed sustained reduction in C5 levels following cemdisiran monotherapy, with >90% reduction in patients with PNH. This phase 1/2 study evaluated single (Part A, n = 32; 50-900 mg) or multiple (Part B, n = 24; 100-600 mg) ascending doses of cemdisiran or placebo (double-blind, randomized 3:1) in healthy adults, or cemdisiran in patients with PNH who were naive to, or receiving, eculizumab (Part C, n = 6; 200 or 400 mg weekly; open-label). The primary objective was to assess the safety and tolerability of cemdisiran. Other assessments included change in complement activity, lactate dehydrogenase levels, and inhibition of hemolysis following cemdisiran treatment. Cemdisiran was generally well tolerated in this study. Overall, 75%, 89%, and 100% of subjects in Parts A, B, and C, respectively, experienced ≥1 non-serious adverse event (AE). Most events were Grade 1 or 2 in severity and the most common AEs included nasopharyngitis and headache. Cemdisiran elicited robust, sustained reductions in the complement activity in healthy adults and patients with PNH. In Part C, exploratory analyses showed that cemdisiran monotherapy was insufficient to prevent hemolysis in patients with PNH as measured by serum lactate dehydrogenase levels. Cemdisiran and eculizumab combination therapy reduced the dose of eculizumab required to provide adequate control of intravascular hemolysis. These results demonstrate a potential benefit of cemdisiran coadministration in patients who are inadequate responders to eculizumab alone.

Bioavailable vitamin D is more tightly linked to mineral metabolism than total vitamin D in incident hemodialysis patients.

Prior studies showed conflicting results regarding the association between 25-hydroxyvitamin D (25(OH)D) levels and mineral metabolism in end-stage renal disease. In order to determine whether the bioavailable vitamin D (that fraction not bound to vitamin D-binding protein) associates more strongly with measures of mineral metabolism than total levels, we identified 94 patients with previously measured 25(OH)D and 1,25-dihydroxyvitamin D (1,25(OH)(2)D) from a cohort of incident hemodialysis patients. Vitamin D-binding protein was measured from stored serum samples. Bioavailable 25(OH)D and 1,25(OH)(2)D were determined using previously validated formulae. Associations with demographic factors and measures of mineral metabolism were examined. When compared with whites, black patients had lower levels of total, but not bioavailable, 25(OH)D. Bioavailable, but not total, 25(OH)D and 1,25(OH)(2)D were each significantly correlated with serum calcium. In univariate and multivariate regression analysis, only bioavailable 25(OH)D was significantly associated with parathyroid hormone levels. Hence, bioavailable vitamin D levels are better correlated with measures of mineral metabolism than total levels in patients on hemodialysis.

Fetal haemoglobin levels and haematological characteristics of compound heterozygotes for haemoglobin S and deletional hereditary persistence of fetal haemoglobin.

Compound heterozygotes for sickle haemoglobin (HbS) and hereditary persistence of fetal haemoglobin (HPFH) have high fetal haemoglobin (HbF) levels but few, if any, sickle cell disease-related complications. We studied 30 cases of HbS-HPFH (types 1 and 2), confirmed by molecular analysis, and report the haematological features and change in HbF levels over time. These results were compared to those of patients with sickle cell anaemia or HbS-ß(0) thalassaemia, including a subgroup of patients carrying the XmnI polymorphism, known to be associated with elevated HbF. Among the HbS-HPFH patients, HbF level was 50-90% during infancy and declined steeply within the first few years of life, stabilizing between ages 3 and 5years, at approximately 30%. Mean HbF of individuals age 5 or older was 31±3%, average haemoglobin concentration was 130±10g/l and average mean corpuscular volume (MCV) was 75±4 fl. Univariate and multivariate regression analyses significantly associated HbF with age, haemoglobin concentration, and MCV (P<0·001). There was a strong inverse association between HbF and age (r=-0·9, P<0·001). Despite having a much higher HbF level, patients with HbS-HPFH have a similar age-related pattern of HbF decline and associations as patients with sickle cell anaemia or HbS-ß(0) thalassaemia.

Vitamin D reduces left atrial volume in patients with left ventricular hypertrophy and chronic kidney disease.

BACKGROUND: Left atrial enlargement, a sensitive integrator of left ventricular diastolic function, is associated with increased cardiovascular morbidity and mortality. Vitamin D is linked to lower cardiovascular morbidity, possibly modifying cardiac structure and function; however, firm evidence is lacking. We assessed the effect of an activated vitamin D analog on left atrial volume index (LAVi) in a post hoc analysis of the PRIMO trial (clinicaltrials.gov: NCT00497146). METHODS AND RESULTS: One hundred ninety-six patients with chronic kidney disease (estimated glomerular filtration rate 15-60 mL/min per 1.73 m(2)), mild to moderate left ventricular hypertrophy, and preserved ejection fraction were randomly assigned to 2 µg of oral paricalcitol or matching placebo for 48 weeks. Two-dimensional echocardiography was obtained at baseline and at 24 and 48 weeks after initiation of therapy. Over the study period, there was a significant decrease in LAVi (-2.79 mL/m(2), 95% CI -4.00 to -1.59 mL/m(2)) in the paricalcitol group compared with the placebo group (-0.70 mL/m(2) [95% CI -1.93 to 0.53 mL/m(2)], P = .002). Paricalcitol also attenuated the rise in levels of brain natriuretic peptide (10.8% in paricalcitol vs 21.3% in placebo, P = .02). For the entire population, the change in brain natriuretic peptide correlated with change in LAVi (r = 0.17, P = .03). CONCLUSIONS: Forty-eight weeks of therapy with an active vitamin D analog reduces LAVi and attenuates the rise of BNP. In a population where only few therapies alter cardiovascular related morbidity and mortality, these post hoc results warrant further confirmation.

Ergocalciferol and cholecalciferol in CKD.

The development of chronic kidney disease (CKD) is accompanied by a progressive decrease in the ability to produce 1,25-dihydroxyvitamin D. Pharmacological replacement with active vitamin D therefore has been a cornerstone of secondary hyperparathyroidism therapy in the end-stage renal disease population treated by long-term dialysis. Recent evidence suggests that extrarenal conversion of 25-hydroxyvitamin D to 1,25-dihydroxyvitamin D may have significant biological roles beyond those traditionally ascribed to vitamin D. Furthermore, low 25-hydroxyvitamin D levels are common in patients with all stages of CKD. This article focuses on the role of nutritional vitamin D replacement in CKD and aims to review vitamin D biology and summarize the existing literature regarding nutritional vitamin D replacement in these populations. Based on the current state of the evidence, we provide suggestions for clinical practice and address areas of uncertainty that need further research.