A Phase II randomized controlled trial evaluated antithrombotic treatment with fesomersen in patients with kidney failure on hemodialysis.

Patients with kidney failure on hemodialysis (KF-HD) are at high risk for both atherothrombotic events and bleeding. This Phase IIb study evaluated the dose-response of fesomersen, an inhibitor of hepatic Factor XI expression, versus placebo, for bleeding and atherothrombosis in patients with KF-HD. Patients were randomized to receive fesomersen 40, 80, or 120 mg once-monthly, or matching placebo, for up to 12 months. The primary safety endpoint was a composite of major bleeding and clinically relevant non-major bleeding (MB/CRNMB). Exploratory endpoints included post-dialysis arterio-venous (AV)-access bleeding, major atherothrombotic events (composite of fatal or non-fatal myocardial infarction, ischemic stroke, acute limb ischemia/major amputation, systemic embolism, symptomatic venous thromboembolism), AV-access thrombosis, and clotting of the hemodialysis circuit. Of 308 participants randomized, 307 received study treatment and were analyzed. Fesomersen led to a dose-dependent and sustained reduction of steady-state median FXI levels by 53.6% (40 mg group), 71.3% (80 mg group), 86.0% (120 mg group), versus 1.9% in the placebo group. MB/CRNMB events occurred in 6.5% (40 mg group), 5.1% (80 mg group), 3.9% (120 mg group), and in 4.0% of those receiving placebo (pooled fesomersen versus placebo P = 0.78). Major atherothrombotic events occurred in 1 patient (1.3%) in each treatment arm. MB/CRNMB bleeding and post-dialysis AV-access bleeding were not related to predicted FXI levels. Lower predicted FXI levels were associated with reductions in hemodialysis circuit clotting (P = 0.002) and AV-access thrombosis (P = 0.014). In patients with KF-HD, fesomersen produced a dose-dependent reduction in FXI levels associated with similar rates of major bleeding compared with placebo. REGISTRATION: URL: https://www.clinicaltrials.gov; unique identifier: NCT04534114.

A Biomarker-Centric Approach to Drug Discovery and Development: Lessons Learned from the Coronavirus Disease 2019 Pandemic.

Faced with the health and economic consequences of the global spread of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the biomedical community came together to identify, diagnose, prevent, and treat the novel disease at breathtaking speeds. The field advanced from a publicly available viral genome to a commercialized globally scalable diagnostic biomarker test in less than 2 months, and first-in-human dosing with vaccines and repurposed antivirals followed shortly thereafter. This unprecedented efficiency was driven by three key factors: 1) international multistakeholder collaborations, 2) widespread data sharing, and 3) flexible regulatory standards tailored to meet the urgency of the situation. Learning from the remarkable success achieved during this public health crisis, we are proposing a biomarker-centric approach throughout the drug development pipeline. Although all therapeutic areas would benefit from end-to-end biomarker science, efforts should be prioritized to areas with the greatest unmet medical needs, including neurodegenerative diseases, chronic lower respiratory diseases, metabolic disorders, and malignant neoplasms. SIGNIFICANCE STATEMENT: Faced with the unprecedented threat of the severe acute respiratory syndrome coronavirus 2 pandemic, the biomedical community collaborated to develop a globally scalable diagnostic biomarker (viral DNA) that catalyzed therapeutic development at breathtaking speeds. Learning from this remarkable efficiency, we propose a multistakeholder biomarker-centric approach to drug development across therapeutic areas with unmet medical needs.

Kidney Function Decline among Black Patients with Sickle Cell Trait and Sickle Cell Disease: An Observational Cohort Study.

BACKGROUND: Sickle cell trait and sickle cell disease are thought to be independent risk factors for CKD, but the trajectory and predictors of kidney function decline in patients with these phenotypes are not well understood. METHODS: Our multicenter, observational study used registry data (collected January 2005 through June 2018) and included adult black patients with sickle cell trait or disease (exposures) or normal hemoglobin phenotype (reference) status (ascertained by electrophoresis) and at least 1 year of follow-up and three eGFR values. We used linear mixed models to evaluate the difference in the mean change in eGFR per year. RESULTS: We identified 1251 patients with sickle cell trait, 230 with sickle cell disease, and 8729 reference patients, with a median follow-up of 8 years. After adjustment, eGFR declined significantly faster in patients with sickle cell trait or sickle cell disease compared with reference patients; it also declined significantly faster in patients with sickle cell disease than in patients with sickle cell trait. Male sex, diabetes mellitus, and baseline eGFR ≥90 ml/min per 1.73 m2 were associated with faster eGFR decline for both phenotypes. In sickle cell trait, low hemoglobin S and elevated hemoglobin A were associated with faster eGFR decline, but elevated hemoglobins F and A2 were renoprotective. CONCLUSIONS: Sickle cell trait and disease are associated with faster eGFR decline in black patients, with faster decline in sickle cell disease. Low hemoglobin S was associated with faster eGFR decline in sickle cell trait but may be confounded by concurrent hemoglobinopathies. Prospective and mechanistic studies are needed to develop best practices to attenuate eGFR decline in such patients.

Serum Angiopoietin-2 Predicts Mortality and Kidney Outcomes in Decompensated Cirrhosis.

Acute kidney injury in decompensated cirrhosis has limited therapeutic options, and novel mechanistic targets are urgently needed. Angiopoietin-2 is a context-specific antagonist of Tie2, a receptor that signals vascular quiescence. Considering the prominence of vascular destabilization in decompensated cirrhosis, we evaluated Angiopoietin-2 to predict clinical outcomes. Serum Angiopoietin-2 was measured serially in a prospective cohort of hospitalized patients with decompensated cirrhosis and acute kidney injury. Clinical characteristics and outcomes were examined over a 90-day period and analyzed according to Angiopoietin-2 levels. Primary outcome was 90-day mortality. Our study included 191 inpatients (median Angiopoietin-2 level 18.2 [interquartile range 11.8, 26.5] ng/mL). Median Model for End-Stage Liver Disease (MELD) score was 23 [17, 30] and 90-day mortality was 41%. Increased Angiopoietin-2 levels were associated with increased mortality (died 21.9 [13.9, 30.3] ng/mL vs. alive 15.2 [9.8, 23.0] ng/mL; P < 0.001), higher Acute Kidney Injury Network stage (stage I 13.4 [9.8, 20.1] ng/mL vs. stage II 20.0 [14.1, 26.2] ng/mL vs. stage III 21.9 [13.0, 29.5] ng/mL; P = 0.002), and need for renal replacement therapy (16.5 [11.3, 23.6] ng/mL vs. 25.1 [13.3, 30.3] ng/mL; P = 0.005). The association between Angiopoietin-2 and mortality was significant in unadjusted and adjusted Cox regression models (P ≤ 0.001 for all models), and improved discrimination for mortality when added to MELD score (integrated discrimination increment 0.067; P = 0.001). Conclusion: Angiopoietin-2 was associated with mortality and other clinically relevant outcomes in a cohort of patients with decompensated cirrhosis with acute kidney injury. Further experimental study of Angiopoietin/Tie2 signaling is warranted to explore its potential mechanistic and therapeutic role in this population.

Mobility Impairment in Patients New to Dialysis.

BACKGROUND: Impaired mobility is associated with functional dependence, frailty, and mortality in prevalent patients undergoing dialysis. We investigated risk factors for mobility impairment, (poor gait speed) in patients incident to dialysis, and changes in gait speed over time in a 2-year longitudinal study. METHODS: One hundred eighty-three patients enrolled within 6 months of dialysis initiation were followed up 6, 12, and 24 months later. Grip strength, health-related quality of life, and comorbidities were assessed at baseline. Outcomes were (a) baseline gait speed and (b) change in gait speed over time. Gait speed was assessed by 4-meter walk. Multivariate linear regression was used to identify risk factors for low gait speed at baseline. For longitudinal analyses, linear mixed effects modeling with gait speed modeled over time was used as the outcome. RESULTS: Participants were 54.7 ± 12.8 years old, 52.5% men, 73.9% black with mean dialysis vintage of 100.1 ± 46.9 days and median gait speed 0.78 (0.64-0.094) m/s. Lower health utility and grip strength, diabetic nephropathy, and walking aids were associated with lower baseline gait speed. Loss of 0.1 m/s gait speed occurred in 24% of subjects at 1 year. In multivariate mixed effects models, only age, walking aid use, lower health utility, and lower handgrip strength were significantly associated with gait speed loss. CONCLUSIONS: In our cohort of incident dialysis patients, overall gait speed is very low and 54.2% of the subjects continue to lose gait speed over 2 years. Older age, lower handgrip strength, and quality of life are risk factors for slowness. Patients at highest risk of poor gait speed can be identified at dialysis initiation to allow targeted implementation of therapeutic options.

Mortality and Hospitalizations among Sickle Cell Disease Patients with End-Stage Kidney Disease Initiating Dialysis.

BACKGROUND: Sickle cell disease (SCD) is the most common inherited hematological disorder and a well-described risk factor for end-stage kidney disease (ESKD). Mortality and hospitalizations among patients with SCD who develop ESKD remain understudied. Furthermore, prior studies focused only on SCD patients where ESKD was caused by SCD. We aimed to describe mortality and hospitalization risk in all SCD patients initiating dialysis and explore risk factors for mortality and hospitalization. METHODS: We performed a national observational cohort study of African American ESKD patients initiating dialysis (2000-2014) in facilities affiliated with a large dialysis provider. SCD was identified by diagnosis codes and matched to a reference population (non-SCD) by age, sex, dialysis initiation year, and geographic region of care. Sensitivity analyses were conducted by restricting to patients where SCD was recorded as the cause of ESKD. RESULTS: We identified 504 SCD patients (mean age: 47 ± 14 years; 48% females) and 1,425 reference patients (mean age: 46 ± 14 years; 49% females). The median follow-up was 2.4 (IQR 1.0-4.5) years. Compared to the reference, SCD was associated with higher mortality risk (hazard ratio 1.66; 95% confidence interval [CI]: 1.36-2.03) and higher hospitalization rates (incidence rate ratio 2.12; 95% CI: 1.88-2.38) in multivariable analyses. Exploratory multivariable mortality risk models showed the largest mortality risk attenuation with the addition of time-varying hemoglobin and high-dose erythropoietin, but the association of SCD with mortality remained significant. Sensitivity analyses (restricted to ESKD caused by SCD) also showed significant associations between SCD and mortality and hospitalizations, but with larger effect estimates. High-dose erythropoietin was associated with the highest risk for mortality and hospitalization in SCD. CONCLUSIONS: Among ESKD patients, SCD is associated with a higher risk for mortality and hospitalization, particularly in patients where SCD is identified as the cause of ESKD.

The TiME Trial: A Fully Embedded, Cluster-Randomized, Pragmatic Trial of Hemodialysis Session Duration.

BACKGROUND: Data from clinical trials to inform practice in maintenance hemodialysis are limited. Incorporating randomized trials into dialysis clinical care delivery should help generate practice-guiding evidence, but the feasibility of this approach has not been established. METHODS: To develop approaches for embedding trials into routine delivery of maintenance hemodialysis, we performed a cluster-randomized, pragmatic trial demonstration project, the Time to Reduce Mortality in ESRD (TiME) trial, evaluating effects of session duration on mortality (primary outcome) and hospitalization rate. Dialysis facilities randomized to the intervention adopted a default session duration ≥4.25 hours (255 minutes) for incident patients; those randomized to usual care had no trial-driven approach to session duration. Implementation was highly centralized, with no on-site research personnel and complete reliance on clinically acquired data. We used multiple strategies to engage facility personnel and participating patients. RESULTS: The trial enrolled 7035 incident patients from 266 dialysis units. We discontinued the trial at a median follow-up of 1.1 years because of an inadequate between-group difference in session duration. For the primary analysis population (participants with estimated body water ≤42.5 L), mean session duration was 216 minutes for the intervention group and 207 minutes for the usual care group. We found no reduction in mortality or hospitalization rate for the intervention versus usual care. CONCLUSIONS: Although a highly pragmatic design allowed efficient enrollment, data acquisition, and monitoring, intervention uptake was insufficient to determine whether longer hemodialysis sessions improve outcomes. More effective strategies for engaging clinical personnel and patients are likely required to evaluate clinical trial interventions that are fully embedded in care delivery.

Complement 7 Is Up-Regulated in Human Early Diabetic Kidney Disease.

There is a temporal window from the time diabetes is diagnosed to the appearance of overt kidney disease during which time the disease progresses quietly without detection. Currently, there is no way to detect early diabetic nephropathy (EDN). Herein, we performed an unbiased assessment of gene-expression analysis of postmortem human kidneys to identify candidate genes that may contribute to EDN. We then studied one of the most promising differentially expressed genes in both kidney tissue and blood samples. Differential transcriptome analysis of EDN kidneys and matched nondiabetic controls showed alterations in five canonical pathways, and among them the complement pathway was the most significantly altered. One specific complement pathway gene, complement 7 (C7), was significantly elevated in EDN kidney. Real-time PCR confirmed more than a twofold increase of C7 expression in EDN kidneys compared with controls. Changes in C7 gene product level were confirmed by immunohistochemistry. C7 protein levels were elevated in proximal tubules of EDN kidneys. Serum C7 protein levels were also measured in EDN and control donors. C7 levels were significantly higher in EDN serum than control serum. This latter finding was independently confirmed in a second set of blood samples from a previously collected data set. Together, our data suggest that C7 is associated with EDN, and can be used as a molecular target for detection and/or treatment of EDN.

Cardiovascular Outcomes in African Americans with Sickle Cell Trait and Chronic Kidney Disease.

BACKGROUND: Sickle cell trait (SCT) is common among African Americans and has been historically considered to be benign. Recently, SCT has been associated with an increased risk for chronic kidney disease (CKD) and cardiovascular disease in the general population. Our understanding of SCT has been extrapolated largely from data of patients with sickle cell disease (SCD). Notably, in SCD, the outcomes differ by sex. The effect of SCT on cardiovascular risk in the African American CKD population is unknown, and the interaction between SCT and sex on cardiovascular risk has not been investigated. METHODS: We performed a 2-center retrospective cohort study of all African American patients with SCT using international classification of disease diagnosis codes and CKD (using the 2012 Kidney Disease Improving Global Outcomes criteria) with at least 1 year of follow-up between January 2005 and December 2017. A reference group of -African American CKD patients without SCT was used as a comparator during the same period. SCT patients and the reference patients were matched at baseline for age, sex, comorbidities, and proteinuria. Primary outcomes were incident coronary artery disease (CAD), incident stroke, and all-cause mortality. Analysis of effect modification between sex and SCT on primary outcomes was performed. RESULTS: We identified 621 African American CKD patients, 217 SCT patients, and 404 reference patients. The mean age was 56 ± 13 years and 66% were female. The mean estimated glomerular filtration rate was 69 ± 30 mL/min. The mean follow-up time was 8 ± 4 years. There were no significant differences in the primary outcomes comparing SCT patients to matched controls. The interaction term between SCT and sex, however, was significant in the CAD model (p < 0.01). Stratification by sex showed no increased risk in females but a significantly increased risk for CAD in male SCT patients (hazard ratio [HR] 2.14; 95% CI 1.18-3.86), which persisted after multivariable analysis (HR 2.13; 95% CI 1.17-3.86). CONCLUSION: SCT is associated with an increased risk for CAD in African American males with CKD. The excess risk in males with SCT appears to follow the same pattern as risk in males with SCD. Larger studies are needed to confirm these findings.

Sickle Cell Nephropathy in the Pediatric Population.

BACKGROUND: Compared to the past, patients with sickle cell disease (SCD) currently live longer due to improvements in diagnosis and comprehensive care. Due to these advances, long-term chronic complications pose a greater challenge in the management of patients with SCD. In particular, sickle cell nephropathy (SCN) is associated with significant morbidity and mortality across all age groups. Furthermore, SCN is an understudied condition with relatively few symptoms and therefore requires close surveillance. In this review, we sought to explore the epidemiology, natural history, and treatment options for SCN with an emphasis on the pediatric population. SUMMARY: SCN invariably begins in childhood with evidence of structural changes detected as early as infancy. These indolent changes can progress undetected to advanced chronic kidney disease by late adolescence or early adulthood. The risk factors for progression are not well defined, but significant albuminuria (which is also the most common presentation in childhood) is a key factor in progression. One of the main challenges in understanding SCN in children is the poor correlation between estimated and measured glomerular filtration rates. Another challenge is the lack of large-scale longitudinal studies that track the clinical outcomes of pediatric patients over time. Several studies aim to identify early biomarkers of SCN in children, as albuminuria presents only following significant chronic damage. The utility of angiotensin converting enzyme inhibitors and hydroxyurea in treating albuminuria is addressed here as well as novel treatments that may be of benefit.

The Prognostic Value of Histopathologic Lesions in Native Kidney Biopsy Specimens: Results from the Boston Kidney Biopsy Cohort Study.

Background Few studies have evaluated whether histopathologic lesions on kidney biopsy provide prognostic information beyond clinical and laboratory data.Methods We enrolled 676 individuals undergoing native kidney biopsy at three tertiary care hospitals into a prospective, observational cohort study. Biopsy specimens were adjudicated for semiquantitative scores in 13 categories of histopathology by two experienced renal pathologists. Proportional hazards models tested the association between histopathologic lesions and risk of kidney disease progression (≥40% eGFR decline or RRT).Results Mean baseline eGFR was 57.5±36.0 ml/min per 1.73 m2 During follow-up (median, 34.3 months), 199 individuals suffered kidney disease progression. After adjustment for demographics, clinicopathologic diagnosis, and laboratory values, the following lesions (hazard ratio; 95% confidence interval) were independently associated with progression: inflammation in nonfibrosed interstitium (0.52; 0.32 to 0.83), moderate and severe versus minimal interstitial fibrosis/tubular atrophy (2.14; 1.24 to 3.69 and 3.42; 1.99 to 5.87, respectively), moderate and severe versus minimal global glomerulosclerosis (2.17; 1.36 to 3.45 and 3.31; 2.04 to 5.38, respectively), moderate and severe versus minimal arterial sclerosis (1.78; 1.15 to 2.74 and 1.64; 1.04 to 2.60, respectively), and moderate and severe versus minimal arteriolar sclerosis (1.63; 1.08 to 2.46 and 2.33; 1.42 to 3.83, respectively). An 11-point chronicity score derived from semiquantitative assessments of chronic lesions independently associated with higher risk of kidney disease progression (hazard ratio per one-point increase, 1.19; 95% confidence interval, 1.12 to 1.27).Conclusions Across a diverse group of kidney diseases, histopathologic lesions on kidney biopsy provide prognostic information, even after adjustment for proteinuria and eGFR.

Association of Smoking Status With Mortality and Hospitalization in Hemodialysis Patients.

RATIONALE & OBJECTIVE: The relationship between tobacco smoking and comorbid condition outcomes in hemodialysis (HD) patients is not well understood. This study examined the association of tobacco smoking status with hospitalization and mortality in HD patients. STUDY DESIGN: Retrospective cohort study. SETTING & PARTICIPANTS: Adult HD patients at 2,223 US dialysis centers with HD vintage of 30 days or less who completed a tobacco smoking status survey as part of standard care between April 2013 and June 2015. PREDICTOR: Tobacco smoking category: never smoked, currently living with smoker, former smoker, moderate smoker (<1 pack per day), or heavy smoker (≥1 pack per day). OUTCOMES: Death and hospital admissions within 2 years of the tobacco smoking survey. ANALYTICAL APPROACH: Kaplan-Meier analysis and Cox proportional hazards regression for time to death; cumulative incidence function and Cox proportional hazards regression for time to first hospitalization; negative-binomial regression for number of hospitalizations. RESULTS: Of 22,230 patients studied, 13% were active smokers. Mortality probabilities increased with greater exposure to smoking (17%, 22%, 23%, and 27% for never, moderate, former, and heavy smokers, respectively; P<0.001), as did incidence rates for first hospitalization (23%, 27%, 27%, and 30%, respectively; P<0.001). Compared to never smoked, heavy smokers had the highest mortality rate (HR for heavy smokers, 1.41 [95% CI, 1.18-1.69]; HR for moderate smokers, 1.39 [95% CI, 1.24-1.55]; HR for former smokers, 1.19 [95% CI, 1.11-1.28]). Living with a smoker was not associated with mortality (HR, 0.93; 95% CI, 0.72-1.22). HRs for first hospitalization followed similar patterns. The incidence rate of mortality for active smokers with diabetes was 173.7/1,000 patient-years and 103.5/1,000 patient-years for those who never smoked (incidence rate ratio, 1.68; P<0.001). LIMITATIONS: Self-reported survey without detailed history of smoking/cessation. CONCLUSIONS: Risks for death and hospitalization are elevated among HD patients who smoke, being highest among younger individuals and those with diabetes. Second-hand smoke was not associated with poor clinical outcomes.

1,5-Anhydroglucitol predicts CKD progression in macroalbuminuric diabetic kidney disease: results from non-targeted metabolomics.

INTRODUCTION: Metabolomics allows exploration of novel biomarkers and provides insights on metabolic pathways associated with disease. To date, metabolomics studies on CKD have been largely limited to Caucasian populations and have mostly examined surrogate end points. OBJECTIVE: In this study, we evaluated the role of metabolites in predicting a primary outcome defined as dialysis need, doubling of serum creatinine or death in Brazilian macroalbuminuric DKD patients. METHODS: Non-targeted metabolomics was performed on plasma from 56 DKD patients. Technical triplicates were done. Metabolites were identified using Agilent Fiehn GC/MS Metabolomics and NIST libraries (Agilent MassHunter Work-station Quantitative Analysis, version B.06.00). After data cleaning, 186 metabolites were left for analyses. RESULTS: During a median follow-up time of 2.5 years, the PO occurred in 17 patients (30.3%). In non-parametric testing, 13 metabolites were associated with the PO. In univariate Cox regression, only 1,5-anhydroglucitol (HR 0.10; 95% CI 0.01-0.63, p = .01), norvaline and L-aspartic acid were associated with the PO. After adjustment for baseline renal function, 1,5-anhydroglucitol (HR 0.10; 95% CI 0.02-0.63, p = .01), norvaline (HR 0.01; 95% CI 0.001-0.4, p = .01) and aspartic acid (HR 0.12; 95% CI 0.02-0.64, p = .01) remained significantly and inversely associated with the PO. CONCLUSION: Our results show that lower levels of 1,5-anhydroglucitol, norvaline and L-aspartic acid are associated with progression of macroalbuminuric DKD. While norvaline and L-aspartic acid point to interesting metabolic pathways, 1,5-anhydroglucitol is of particular interest since it has been previously shown to be associated with incident CKD. This inverse biomarker of hyperglycemia should be further explored as a new tool in DKD.

Vitamin K-Dependent Carboxylation of Matrix Gla Protein Influences the Risk of Calciphylaxis.

Matrix Gla protein (MGP) is a potent inhibitor of vascular calcification. The ability of MGP to inhibit calcification requires the activity of a vitamin K-dependent enzyme, which mediates MGP carboxylation. We investigated how MGP carboxylation influences the risk of calciphylaxis in adult patients receiving dialysis and examined the effects of vitamin K deficiency on MGP carboxylation. Our study included 20 patients receiving hemodialysis with calciphylaxis (cases) and 20 patients receiving hemodialysis without calciphylaxis (controls) matched for age, sex, race, and warfarin use. Cases had higher plasma levels of uncarboxylated MGP (ucMGP) and carboxylated MGP (cMGP) than controls. However, the fraction of total MGP that was carboxylated (relative cMGP concentration = cMGP/[cMGP + uncarboxylated MGP]) was lower in cases than in controls (0.58±0.02 versus 0.69±0.03, respectively; P=0.003). In patients not taking warfarin, cases had a similarly lower relative cMGP concentration. Each 0.1 unit reduction in relative cMGP concentration associated with a more than two-fold increase in calciphylaxis risk. Vitamin K deficiency associated with lower relative cMGP concentration in multivariable adjusted analyses (ß=-8.99; P=0.04). In conclusion, vitamin K deficiency-mediated reduction in relative cMGP concentration may have a role in the pathogenesis of calciphylaxis. Whether vitamin K supplementation can prevent and/or treat calciphylaxis requires further study.

Characterization and Correction of Olfactory Deficits in Kidney Disease.

Patients with CKD suffer from food aversion, anorexia, and malnutrition. Although olfaction has a significant role in determining food flavor, our understanding of olfactory impairment and of the olfaction-nutrition axis in patients with kidney disease is limited. We quantified odor identification, odor threshold, and subjective odor perception in a cohort (n=161) comprising 36 participants with CKD, 100 participants with ESRD, and 25 controls. We investigated olfaction-nutrition associations in these participants and examined a novel intervention to improve olfaction in ESRD. The mean odor identification score was lower in patients with CKD (75.6%±13.1%; P=0.02) and ESRD (66.8%±15.1%; P<0.001) than in controls (83.6%±11.4%). Patients with ESRD exhibited higher odor threshold than the remaining participants exhibited. All groups had similar scores for subjective smell assessment. In multivariable adjusted analyses, kidney disease associated with increased odds of odor identification deficits (odds ratio, 4.80; 95% confidence interval, 1.94 to 11.89). A reduction in odor identification score was associated with higher subjective global assessment score and lower serum total cholesterol, LDL cholesterol, and albumin concentrations. We found no associations between odor threshold and nutritional parameters. In a proof of concept, 6-week, open-label clinical trial, intranasal theophylline (an epithelial membrane transport and proton secretion activator) increased odor identification score in five out of seven (71%) patients with ESRD. In conclusion, patients with kidney disease have olfactory deficits that may influence their nutritional status. Our preliminary results regarding olfactory improvement using intranasal theophylline warrant confirmation in a randomized controlled trial.

Increased Bone Morphogenetic Protein Signaling in the Cutaneous Vasculature of Patients with Calciphylaxis.

BACKGROUND: The objective of this study was to investigate the role of bone morphogenetic protein (BMP) signal transduction in the pathogenesis of calciphylaxis. METHODS: Skin biopsy specimens were obtained from 18 patients with, and 12 patients without, calciphylaxis. Tissue sections were stained with antibodies directed against BMP effector proteins phosphorylated-SMAD (p-SMAD) 1/5/9, inhibitor of DNA 1 (Id1), inhibitor of DNA 3 (Id3), and Runx2. The intensity of staining was scored semi-quantitatively as strong versus weak or absent. RESULTS: Of the 18 patients with calciphylaxis (mean age: 59 ± 8 years), 9 were women and 15 had end-stage renal disease. Of the 12 control patients (mean age: 57 ± 10 years), 8 were women and 8 had end-stage renal disease. Strong staining for p-SMAD 1/5/9 was detected in blood vessels from all calciphylaxis patients. In 1 patient with calciphylaxis, strong staining for p-SMAD 1/5/9 was detected in a blood vessel that did not have evidence of calcification. Id1 and Id3 immunoreactivity was detected in blood vessels from all 12 patients with calciphylaxis that were tested. Runx2 staining was detected in all 6 patients with calciphylaxis who were tested. p-SMAD 1/5/9 immunoreactivity was weak or absent in blood vessels of 10 of the 12 control samples. CONCLUSIONS: The BMP signal transduction pathway is activated in the cutaneous vasculature of calciphylaxis patients. The ability to detect p-SMAD 1/5/9, Id1, and Id3 in cutaneous vasculature may assist in the diagnosis of calciphylaxis. As BMP signaling inhibitors become available, this pathway may serve as a future therapeutic target for calciphylaxis.

The dynamics of the metabolism of acetate and bicarbonate associated with use of hemodialysates in the ABChD trial: a phase IV, prospective, single center, single blind, randomized, cross-over, two week investigation.

BACKGROUND: In the United States, hemodialysis (HD) is generally performed via a bicarbonate dialysate. It is not known if small amounts of acid used in dialysate to buffer the bicarbonate can meaningfully contribute to overall buffering administered during HD. We aimed to investigate the metabolism of acetate with use of two different acid buffer concentrates and determine if it effects blood bicarbonate concentrations in HD patients. METHODS: The Acid-Base Composition with use of hemoDialysates (ABChD) trial was a Phase IV, prospective, single blind, randomized, cross-over, 2 week investigation of peridialytic dynamics of acetate and bicarbonate associated with use of acid buffer concentrates. Eleven prevalent HD patients participated from November 2014 to February 2015. Patients received two HD treatments, with NaturaLyte® and GranuFlo® acid concentrates containing 4 and 8 mEq/L of acetate, respectively. Dialysate order was chosen in a random fashion. The endpoint was to characterize the dynamics of acetate received and metabolized during hemodialysis, and how it effects overall bicarbonate concentrations in the blood and dialysate. Acetate and bicarbonate concentrations were assessed before, at 8 time points during, and 6 time points after the completion of HD. RESULTS: Data from 20 HD treatments for 11 patients (10 NaturaLyte® and 10 GranuFlo®) was analyzed. Cumulative trajectories of arterialized acetate were unique between NaturaLyte® and GranuFlo® (p = 0.003), yet individual time points demonstrated overlap without remarkable differences. Arterialized and venous blood bicarbonate concentrations were similar at HD initiation, but by 240 min into dialysis, mean arterialized bicarbonate concentrations were 30.2 (SD ± 4.16) mEq/L in GranuFlo® and 28.8 (SD ± 4.26) mEq/L in NaturaLyte®. Regardless of acid buffer concentrate, arterial blood bicarbonate was primarily dictated by the prescribed bicarbonate level. Subjects tolerated HD with both acid buffer concentrates without experiencing any related adverse events. CONCLUSIONS: A small fraction of acetate was delivered to HD patients with use of NaturaLyte® and GranuFlo® acid buffers; the majority of acetate received was observed to be rapidly metabolized and cleared from the circulation. Blood bicarbonate concentrations appear to be determined mainly by the prescribed concentration of bicarbonate. TRIAL REGISTRATION: This trial was registered on ClinicalTrials.gov on 11 Dec 2014 ( NCT02334267 ).

A Nationally Representative Study of Calcific Uremic Arteriolopathy Risk Factors.

Accurate identification of risk factors for calcific uremic arteriolopathy (CUA) is necessary to develop preventive strategies for this morbid disease. We investigated whether baseline factors recorded at hemodialysis initiation would identify patients at risk for future CUA in a matched case-control study using data from a large dialysis organization. Hemodialysis patients with newly diagnosed CUA (n=1030) between January 1, 2010, and December 31, 2014, were matched by age, sex, and race in a 1:2 ratio to hemodialysis patients without CUA (n=2060). Mean ages for patients and controls were 54 and 55 years, respectively; 67% of participants were women and 49% were white. Median duration between hemodialysis initiation and subsequent CUA development was 925 days (interquartile range, 273-2185 days). In multivariable conditional logistic regression analyses, diabetes mellitus; higher body mass index; higher levels of serum calcium, phosphorous, and parathyroid hormone; and nutritional vitamin D, cinacalcet, and warfarin treatments were associated with increased odds of subsequent CUA development. Compared with patients with diabetes receiving no insulin injections, those receiving insulin injections had a dose-response increase in the odds of CUA involving lower abdomen and/or upper thigh areas (odds ratio, 1.49; 95% confidence interval, 1.03 to 2.51 for one or two injections per day; odds ratio, 1.88; 95% confidence interval, 1.30 to 3.43 for 3 injections per day; odds ratio, 3.74; 95% confidence interval, 2.28 to 6.25 for more than three injections per day), suggesting a dose-effect relationship between recurrent skin trauma and CUA risk. The presence of risk factors months to years before CUA development observed in this study will direct the design of preventive strategies and inform CUA pathobiology.

Dabigatran and rivaroxaban use in atrial fibrillation patients on hemodialysis.

BACKGROUND: Dabigatran and rivaroxaban are new oral anticoagulants that are eliminated through the kidneys. Their use in dialysis patients is discouraged because these drugs can bioaccumulate to precipitate inadvertent bleeding. We wanted to determine whether prescription of dabigatran or rivaroxaban was occurring in the dialysis population and whether these practices were safe. METHODS AND RESULTS: Prevalence plots were used to describe the point prevalence (monthly) of dabigatran and rivaroxaban use among 29977 hemodialysis patients with atrial fibrillation. Poisson regression compared the rate of bleeding, stroke, and arterial embolism in patients who started dabigatran, rivaroxaban, or warfarin. The first record of dabigatran prescription among hemodialysis patients occurred 45 days after the drug became available in the United States. Since then, dabigatran and rivaroxaban use in the atrial fibrillation-end-stage renal disease population has steadily risen where 5.9% of anticoagulated dialysis patients are started on dabigatrian or rivaroxaban. In covariate adjusted Poisson regression, dabigatran (rate ratio, 1.48; 95% confidence interval, 1.21-1.81; P=0.0001) and rivaroxaban (rate ratio, 1.38; 95% confidence interval, 1.03-1.83; P=0.04) associated with a higher risk of hospitalization or death from bleeding when compared with warfarin. The risk of hemorrhagic death was even larger with dabigatran (rate ratio, 1.78; 95% confidence interval, 1.18-2.68; P=0.006) and rivaroxaban (rate ratio, 1.71; 95% confidence interval, 0.94-3.12; P=0.07) relative to warfarin. There were too few events in the study to detect meaningful differences in stroke and arterial embolism between the drug groups. CONCLUSIONS: More dialysis patients are being started on dabigatran and rivaroxaban, even when their use is contraindicated and there are no studies to support that the benefits outweigh the risks of these drugs in end-stage renal disease.

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.