Platelets, inflammation, and purinergic receptors in chronic kidney disease.

Platelets are anucleated cells that circulate in the bloodstream. Historically, platelets were thought to perform a singular function-stop bleeding via clotting. Although platelets do play a key role in hemostasis and thrombosis, recent studies indicate that platelets also modulate inflammation, and this platelet-induced inflammation contributes to the pathophysiology of various diseases such as atherosclerosis and diabetes mellitus. Thus, in recent years, our understanding of platelet function has broadened. In this review, we revisit the classic role of platelets in hemostasis and thrombosis and describe the newly recognized function of platelets in modulating inflammation. We cover the potential use of purinergic receptor antagonists to prevent platelet-modulated inflammation, particularly in patients with chronic kidney disease, and finally, we define key questions that must be addressed to understand how platelet-modulated inflammation contributes to the pathophysiology of chronic kidney disease.

Role of Platelets in Chronic Kidney Disease.

Platelet-dependent mechanisms for excessive clotting and bleeding in CKD remain undefined. Moreover, platelets' contribution to inflammation, and specifically to CKD, are equally elusive. To date, descriptions of changes in the functional properties of circulating platelets during CKD have provided confusing interpretations. Experimental approaches that can advance our understanding of platelet dysfunction in CKD are needed, and studies that provide mechanistic insights into the dynamic relationships between thrombosis, bleeding, and inflammation associated with CKD will be essential to improve clinical management and outcomes for this vulnerable population. This article summarizes existing literature characterizing platelets in CKD and identifies areas that need further investigation.

Accurate Medication Adherence Measurement Using Administrative Data for Frequently Hospitalized Patients.

Background: Pharmacy administrative claims data remain an accessible and efficient source to measure medication adherence for frequently hospitalized patient populations that are systematically excluded from the landmark drug trials. Published pharmacotherapy studies use medication possession ratio (MPR) and proportion of days covered (PDC) to calculate medication adherence and usually fail to incorporate hospitalization and prescription overlap/gap from claims data. To make the cacophony of adherence measures clearer, this study created a refined hospital-adjusted algorithm to capture pharmacotherapy adherence among patients with end-stage renal disease (ESRD). Methods: The United States Renal Data System (USRDS) registry of ESRD was used to determine prescription-filling patterns of those receiving new prescriptions for oral P2Y12 inhibitors (P2Y12-I) between 2011 and 2015. P2Y12-I-naïve patients were followed until death, kidney transplantation, discontinuing medications, or loss to follow-up. After flagging/censoring key variables, the algorithm adjusted for hospital length of stay (LOS) and medication overlap. Hospital-adjusted medication adherence (HA-PDC) was calculated and compared with traditional MPR and PDC methods. Analyses were performed with SAS software. Results: Hospitalization occurred for 78% of the cohort (N = 46 514). The median LOS was 12 (interquartile range [IQR] = 2-34) days. MPR and PDC were 61% (IQR = 29%-94%) and 59% (IQR = 31%-93%), respectively. After applying adjustments for overlapping coverage days and hospital stays independently, HA-PDC adherence values changed in 41% and 52.7% of the cohort, respectively. When adjustments for overlap and hospital stay were made concurrently, HA-PDC adherence values changed in 68% of the cohort by 5.8% (HA-PDC median = 0.68, IQR = 0.31-0.93). HA-PDC declined over time (3M-6M-9M-12M). Nearly 48% of the cohort had a ≥30 days refill gap in the first 3 months, and this increased over time (P < .0001). Conclusions: Refill gaps should be investigated carefully to capture accurate pharmacotherapy adherence. HA-PDC measures increased adherence substantially when adjustments for hospital stay and medication refill overlaps are made. Furthermore, if hospitalizations were ignored for medications that are included in Medicare quality measures, such as Medicare STAR program, the apparent reduction in adherence might be associated with lower quality and health plan reimbursement.

Fatigue in Nondialysis Chronic Kidney Disease: Correlates and Association with Kidney Outcomes.

BACKGROUND: Fatigue, although common and associated with outcomes in dialysis-dependent chronic kidney disease (CKD), has not been studied in nondialysis chronic kidney disease (CKD-ND) patients. METHODS: In this longitudinal cohort of 266 outpatients with CKD-ND stages 2-5, we measured self-reported fatigue on 3 scales-Quick Inventory of Depression Symptomatology-Self Report (QIDS-SR16), Beck Depression Inventory-I (BDI-I), and short form 12 health survey (SF-12) questionnaires and evaluated the prespecified composite of progression to dialysis initiation, death, or hospitalization after 12 months. Logistic and linear regression assessed characteristics associated with fatigue. Survival analysis measured associations of fatigue with outcomes. RESULTS: Mean age was 64.4 ± 12.0 years, and mean estimated glomerular filtration rate (eGFR) was 31.6 ± 16.7 mL/min/1.73 m2. Fatigue was common, with 69.2% reporting fatigue on QIDS-SR16 and 77.7% on BDI-I. Unemployment, comorbidities, use of antidepressant medications, and lower hemoglobin correlated with fatigue. There were 126 outcome events. Participants that reported any versus no fatigue on QIDS-SR16 were more likely to reach the composite, hazard ratio (HR) 1.70 (95% CI 1.11-2.59), which persisted after adjusting for demographics, comorbidities, substance abuse, hemoglobin, albumin, eGFR, and calcium-phosphorus product, HR 1.63 (1.05-2.55). Fatigue severity by the SF-12 was also associated with outcomes independent of demographics, comorbidities, and substance abuse, HR per unit increase 1.18 (1.03-1.35). No association was observed with fatigue on the BDI-I. CONCLUSION: Fatigue affected about 2/3 of CKD-ND patients and associated with unemployment, comorbidities, antidepressant medication use, and anemia. Fatigue measured by the QIDS-SR16 and SF-12 independently predicted outcomes in CKD patients. Eliciting the presence of fatigue may be a clinically significant prognostic assessment in CKD patients.

Warfarin in nonvalvular atrial fibrillation-Time for a change?

Warfarin is the most commonly prescribed anticoagulant in hemodialysis (HD) patients with nonvalvular atrial fibrillation (NVAF). Recent trends show that Nephrologists are increasingly prescribing novel oral anticoagulants, despite the fact that no randomized clinical trials have been conducted in dialysis patients. Difficulties maintaining international normalized ratio in the therapeutic range, increased risk of intracranial hemorrhage and concerns regarding warfarin-induced vascular calcification and calciphylaxis may be responsible. Anticoagulation quality is poor in HD patients. A variety of factors contribute to this: increased antibiotic exposure; comorbid illness; decreased adherence and vitamin K deficiency. Attempts to address this with standardized protocols have been uniformly unsuccessful. In nonadherent patients, thrice weekly observed therapy improved quality. Low-dose vitamin K supplementation improves time in the therapeutic range (TTR) in those with normal kidney function and should be studied in HD patients given their high frequency of vitamin K deficiency. Vascular and valvular calcification associated with warfarin could result from reduced carboxylation of matrix Gla protein (MGP), a well-known inhibitor of vascular calcification. Multiple observational studies also link calciphylaxis to warfarin; warfarin-induced hypercoagulability and decreased carboxylation of MGP could explain this. A large observational study, two meta-analyses, and a systematic review in HD patients with NVAF showed reduced bleeding with apixaban compared to warfarin with similar efficacy in reducing stroke and systemic embolism. Given these results, apixaban is a reasonable alternative to warfarin for anticoagulation of HD patients with NVAF, especially in those with low TTR, until data from randomized clinical trials become available.

Trends for and Clinical Factors Associated with Choice of Oral P2Y12 Inhibitors for Patients on Chronic Dialysis.

BACKGROUND: Trends and clinical factors associated with prescribing choices for oral P2Y12 inhibitors (P2Y12-I) remain unknown for patients on chronic dialysis, i.e., with end-stage renal disease (ESRD). METHODS: From 2011-2014 U.S. Renal Data System registry, we identified 36,542 ESRD patients who received new prescriptions for P2Y12-I (median age 64.0 years and 54% males). Of the cohort, 93% were receiving hemodialysis and 7% on peritoneal dialysis. We analyzed trends and investigated clinical factors associated with specific P2Y12-I prescribed. RESULTS: Clopidogrel was prescribed for 95%, prasugrel for 3%, and ticagrelor for 2%. Clopidogrel was favored for those ≥75 years (18% of cohort). Compared to Caucasians, African Americans (36% of cohort) and Hispanics (19% of cohort) were less likely to receive prasugrel and ticagrelor (P<0.05). Patients receiving hemodialysis versus peritoneal dialysis were less likely to receive prasugrel over clopidogrel, adjusted odds ratio (aOR) 0.67 (0.55-0.82). Each additional year of dialysis decreased the odds of receiving prasugrel over clopidogrel, aOR 0.91 (0.85-0.98). History of atrial fibrillation reduced the odds of receiving ticagrelor or prasugrel over clopidogrel, aOR 0.69 (0.54-0.89) and 0.73 (0.60-0.89), respectively. Concomitant oral anticoagulant use was not associated with choice of P2Y12-I. Occurrence of non-ST segment elevation myocardial infarction or percutaneous coronary intervention within the 6-month period prior to the index date favored ticagrelor over prasugrel, aOR 1.31 (1.06-1.62) and 1.29 (1.01-1.66), respectively. However, prescribing trends favoring ticagrelor over prasugrel were not observed for deployment of drug-eluting, or multiple coronary stents. CONCLUSION: Between 2011 and 2014, clopidogrel remained the most common P2Y12-I whereas ticagrelor and prasugrel remained underutilized in ESRD patients. Prescribing practices for these drugs were based upon clinically approved indication for their use in the general population as well as perceived complexity of an ESRD patient including demographics, dialysis-related factors and comorbidities. Comparative effectiveness studies involving ESRD patients are needed to prove that ticagrelor and prasugrel are just as safe and effective as clopidogrel before clinicians can make informed decisions for choice of P2Y12-I in this patient population.

Association of platelet function with depression and its treatment with sertraline in patients with chronic kidney disease: analysis of a randomized trial.

BACKGROUND: Major Depressive Disorder (MDD) can lead to adverse cardiovascular outcomes in patients with chronic kidney disease (CKD). Although one of the proposed mechanisms is heightened platelet activation, effects of MDD and its treatment with a selective serotonin reuptake inhibitor (SSRI) on platelet function in patients with CKD remain unclear. METHODS: In a pre-specified analysis, changes from baseline to 12 weeks in whole blood platelet aggregation (WBPA) and plasma levels of E-selectin and P-selectin on treatment with sertraline vs. placebo were investigated in 175 patients with CKD (estimated glomerular filtration rate [eGFR] < 60 ml/min/1.73m2) and MDD (MDD+/CKD+) in a randomized, double-blind trial. Correlations between severity of depressive symptoms and platelet function were also analyzed. In order to investigate whether differences in platelet function were due to presence of CKD or MDD, we compared a subgroup of 49 MDD+/CKD+ patients with eGFR < 30 ml/min/1.73m2 to 43 non-depressed CKD controls (28 CKD with eGFR < 30 ml/min/1.73m2 [MDD-/CKD+] and 15 individuals with eGFR ≥90 ml/min/1.73m2 [MDD-/CKD-]. RESULTS: In MDD+/CKD+ individuals, there were no significant correlations between severity of depressive symptoms and platelet function, and no significant changes in platelet function after 12 weeks of treatment with sertraline vs. placebo. There were no significant differences in platelet function among MDD+/CKD+ patients and controls without MDD except in WBPA to 10 µM ADP (P = 0.03). WBPA to ADP was lower in the MDD-/CKD- group (8.0 Ω [5.0 Ω, 11.0 Ω]) as compared to the MDD-/CKD+ group (12.5 Ω [8.0 Ω, 14.5 Ω]), P = 0.01, and the MDD+/CKD+ group (11.0 Ω [8.0 Ω, 15.0 Ω]), P < 0.01. CONCLUSIONS: Heightened ADP-induced platelet aggregability was observed in CKD patients compared to controls with normal kidney function, regardless of presence of comorbid MDD, and treatment with sertraline did not affect platelet function. These findings suggest that increased platelet activation may not be a major contributory underlying mechanism by which depression may lead to worse cardiovascular outcomes in patients with CKD. Future studies should include positive MDD controls without CKD to confirm our findings. TRIAL REGISTRATION: ClinicalTrials.gov identifier numbers: CAST Study: NCT00946998 (Recruitment Status: Completed. First Posted: July 27, 2009. Results First Posted: January 30, 2018). WiCKDonASA Study: NCT01768637 (Recruitment Status: Completed. First Posted: January 15, 2013. Results First Posted: April 19, 2019).

Prevalence of Chronic Kidney Disease, Thrombotic Cardiovascular Events, and Use of Oral P2Y12 Inhibitors among Veterans.

BACKGROUND: Contemporary prevalence of chronic kidney disease (CKD) and thrombotic cardiovascular (CV) events remains unclear in Veterans enrolled in the Veterans Affairs Health Care System (VA) care. Although oral P2Y12 inhibitors (P2Y12i) are increasingly being prescribed to this patient population, the overall prescription trend for P2Y12i remains unclear. METHODS: Using national VA corporate warehouse data, we used International Classification of Diseases-9 codes to identify Veterans with CKD, dialysis-dependent CKD, and CV events. VA pharmacy data were used to count P2Y12i prescriptions for the federal fiscal years (FY) 2011 through 2015. RESULTS: The period prevalence of Veterans with CKD was 378,233 (6.1%). The point prevalence of CKD increased by 49% from 132,979 (2.30%) in FY11 to 213,444 (3.42%) in FY15. The period prevalence of Veterans with dialysis-dependent CKD was 150,298 (2.4%). In all, 128,703 (56.7%) CV events occurred in Veterans with CKD. Veterans with CKD were given 50.1% of prescriptions for clopidogrel, 49.3% for prasugrel, and 60.4% for ticagrelor. In this patient population, year-to-year increases in P2Y12i prescriptions were observed with a dramatic increase in ticagrelor prescriptions. CONCLUSION: CKD is common among Veterans and its true prevalence is likely being underestimated. The prevalence of dialysis-dependent CKD is higher among Veterans than the non-Veteran US population. CV events are widely co-prevalent and these patients are commonly prescribed P2Y12i. The recent increase in ticagrelor prescriptions in this patient population and large cost differences between the 3 P2Y12i underline the need for future studies to identify the preferred P2Y12i for these patients.

Hungry bone syndrome.

PURPOSE OF REVIEW: In the United States, the number of parathyroidectomies among patients with chronic dialysis has remained stable in the last decade. A fall in serum calcium concentration is common postparathyroidectomy in patients with hyperparathyroidism, which usually resolves in 2-4 days. A severe drop in serum total calcium concentration less than 2.1 mmol/L and/or prolonged hypocalcemia for more than 4 days postparathyroidectomy is called hungry bone syndrome (HBS). Concomitant hypophosphatemia, hypomagnesemia, and hyperkalemia can be seen. Hypocalcemia and hypophosphatemia can persist for months to years. In contemporary clinical practice, HBS may be more commonly seen in patients with secondary compared to primary hyperparathyroidism. Preoperative radiological changes in bone, elevated serum alkaline phosphatase and parathyroid hormone (PTH) levels, and high numbers of osteoclasts on bone biopsy may identify patients at risk. Treatment consists of high-dose oral calcium and calcitriol supplementation. A low-dose pamidronate infusion 1-2 days prior to surgery may prevent HBS. RECENT FINDINGS: Recent in-vitro studies reported net calcium movement into bone because of a sudden fall in serum PTH level after a prolonged period of elevation. This supports a previous hypothesis that a sudden drop in serum PTH level after surgery results in the unopposed action of osteoblasts and influx of calcium into bone. SUMMARY: Incidence of HBS and its association with morbidity and mortality remains unclear in contemporary clinical practice. It is more common to encounter HBS in chronic dialysis patients with secondary hyperparathyroidism than those with primary hyperparathyroidism that undergo parathyroidectomies. Use of bisphosphonates to prevent HBS should be explored in future studies.

Effect of Sertraline on Depressive Symptoms in Patients With Chronic Kidney Disease Without Dialysis Dependence: The CAST Randomized Clinical Trial.

Importance: Major depressive disorder (MDD) is prevalent among patients with chronic kidney disease (CKD) and is associated with morbidity and mortality. The efficacy and adverse events of selective serotonin reuptake inhibitors in these patients are unknown. Objective: To determine whether treatment with sertraline improves depressive symptoms in patients with CKD and MDD. Design, Setting, and Participants: The Chronic Kidney Disease Antidepressant Sertraline Trial (CAST) was a randomized, double-blind, placebo-controlled trial involving 201 patients with stage 3, 4, or 5 non-dialysis-dependent CKD, who were enrolled at 3 US medical centers. The Mini Neuropsychiatric Interview was used to establish MDD. The first participant was randomized in March 2010 and the last clinic visit occurred in November 2016. Interventions: After a 1-week placebo run-in, participants were randomized to sertraline (n = 102) for 12 weeks at an initial dose of 50 mg/d (escalated to a maximum dose of 200 mg/d based on tolerability and response) or matching placebo (n = 99). Main Outcomes and Measures: The primary outcome was improvement in depressive symptom severity from baseline to 12 weeks determined by the 16-item Quick Inventory of Depression Symptomatology-Clinician Rated (QIDS-C16) (score range, 0-27; minimal clinically important difference, 2 points). Secondary outcomes included improvement in quality of life (Kidney Disease Quality of Life Survey-Short Form; score range, 0-100; higher scores indicate more favorable quality of life) and adverse events. Results: There were 201 patients (mean [SD] age, 58.2 [13.2] years; 27% female) randomized. The primary analysis included 193 patients who had at least 1 outcome assessment after randomization. The mean (SD) baseline QIDS-C16 score was 14.0 (2.4) in the sertraline group (n = 97) and 14.1 (2.4) in the placebo group (n = 96). The median participation time was 12.0 weeks and the median achieved dose was 150 mg/d, which was not significantly different between the groups. The QIDS-C16 score changed by -4.1 in the sertraline group and by -4.2 in the placebo group (between-group difference, 0.1 [95% CI, -1.1 to 1.3]; P = .82). There was no significant between-group difference in change in patient-reported overall health on the Kidney Disease Quality of Life Survey (median score, 0 in the sertraline group vs 0 in the placebo group; between-group difference, 0 [95% CI, -10.0 to 0]; P = .61). Nausea or vomiting occurred more frequently in the sertraline vs placebo group (22.7% vs 10.4%, respectively; between-group difference, 12.3% [95% CI, 1.9% to 22.6%], P = .03), as well as diarrhea (13.4% vs 3.1%; between-group difference, 10.3% [95% CI, 2.7% to 17.9%], P = .02). Conclusions and Relevance: Among patients with non-dialysis-dependent CKD and MDD, treatment with sertraline compared with placebo for 12 weeks did not significantly improve depressive symptoms. These findings do not support the use of sertraline to treat MDD in patients with non-dialysis-dependent CKD. Trial Registration: clinicaltrials.gov Identifier: NCT00946998.

Prognostic Utility of a Self-Reported Depression Questionnaire versus Clinician-Based Assessment on Renal Outcomes.

BACKGROUND: The prognostic utility of self-administered depression scales in chronic kidney disease (CKD) independent of a clinician-based major depressive disorder (MDD) diagnosis is neither clearly established nor are the optimal cutoff scores for predicting outcomes. The overlap between symptoms of depression and chronic disease raises the question of whether a cutoff score on a depression scale can be substituted for a time-consuming diagnostic interview to prognosticate risk. METHODS: The 16-item Quick Inventory of Depression Symptomatology-Self Report scale (QIDS-SR16) was administered to 266 consecutive outpatients with non-dialysis CKD, followed prospectively for 12 months for an apriori composite outcome of death or dialysis or hospitalization. Association of QIDS-SR16 best cutoff score, determined by receiver/responder operating characteristics curves, with outcomes was investigated using survival analysis. The effect modification of an interview-based clinician MDD diagnosis on this association was ascertained. RESULTS: There were 126 composite events. A QIDS-SR16 cutoff ≥8 had the best prognostic accuracy, hazards ratio (HR) = 1.77, 95% CI 1.24-2.53, p = 0.002. This cutoff remained significantly associated with outcomes even after controlling for comorbidities, estimated glomerular filtration rate, hemoglobin and serum albumin, adjusted HR (aHR) = 1.80, 95% CI 1.23-2.62, p = 0.002, and performed similarly to a clinician-based MDD diagnosis (aHR = 1.72, 95% CI 1.14-2.68). Adjustment for MDD conferred the association of QIDS-SR16 with outcomes no longer significant. CONCLUSIONS: QIDS-SR16 cutoff ≥8 adds to the prognostic information available to practicing nephrologists during routine clinic visits from comorbidities and laboratory data. This cutoff score performs similar to a clinician diagnosis of MDD and provides a feasible and time-saving alternative to an interview-based MDD diagnosis for determining prognosis in CKD patients.

Oral P2Y12 Receptor Inhibitors in Hemodialysis Patients Undergoing Percutaneous Coronary Interventions: Current Knowledge and Future Directions.

Oral P2Y12 receptor inhibitors are commonly used drugs in patients on hemodialysis (HD) to treat acute coronary syndrome with or without percutaneous coronary intervention (PCI), and patients with stable coronary artery disease after PCI. Clopidogrel is the most commonly prescribed P2Y12 receptor inhibitor because it is effective in the general population and is not as costly as newer FDA-approved agents (prasugrel, ticagrelor). However, increasing evidence is accumulating that clopidogrel may not be as effective in reducing mortality and preventing future ischemic events in patients with kidney disease. In this review, we will explore some of the studies that form the basis for this statement and discuss potential pharmacokinetic and pharmacodynamic reasons why clopidogrel might be less effective in HD patients, as well as explore potential risks and benefits of alternatives to clopidogrel therapy.

Updates on New Therapies for Patients with CKD.

Individuals diagnosed with chronic kidney disease (CKD) continue to increase globally. This group of patients experience a disproportionately higher risk of cardiovascular (CV) events compared to the general population. Despite multiple guidelines-based medical management, patients with CKD continue to experience residual cardiorenal risk. Several potential mechanisms explain this excessive CV risk observed in individuals with CKD. Several new drugs have become available that could potentially transform CKD care, given their efficacy in this patient population. Nevertheless, use of these drugs presents certain benefits and challenges that are often underrecognized by prescribing these drugs. In this review, we aim to provide a brief discussion about CKD pathophysiology, limiting our discussion to recent published studies. We also explore benefits and limitations of newer drugs, including angiotensin receptor/neprilysin inhibitors (ARNI), sodium glucose transporter 2 inhibitors (SGLT2i), glucagon-like peptides-1 (GLP-1) agonists and finerenone in patients with CKD. Despite several articles covering this topic, our review provides an algorithm where subgroups of patients with CKD might benefit the most from such drugs based on the selection criteria of the landmark trials. Patients with CKD who have nephrotic range proteinuria beyond 5000 mg/g, or those with poorly controlled blood pressure (systolic ≥160 mm Hg or diastolic ≥100 mm Hg) remain understudied.

Renal Biomarkers in Heart Failure: Systematic Review and Meta-Analysis.

Background: Cystatin C, neutrophil gelatinase-associated lipocalin (NGAL), and kidney injury molecule (KIM)-1 are renal biomarkers increasingly appreciated for their role in the risk stratification and prognostication of heart failure (HF) patients. However, very few have been adopted clinically, owing to the lack of consistency. Objectives: The authors aimed to study the association between cystatin C, NGAL, and KIM-1 and outcomes, mortality, hospitalizations, and worsening renal function (WRF) in patients with acute and chronic HF. Methods: We included peer-reviewed English-language articles from PubMed and EMBASE published up to December 2021. We analyzed the above associations using random-effects meta-analysis. Publication bias was assessed using funnel plots. Results: Among 2,631 articles, 100 articles, including 45,428 patients, met the inclusion criteria. Top-tertile of serum cystatin C, when compared to the bottom-tertile, carried a higher pooled hazard ratio (pHR) for mortality (pHR: 1.59, 95% CI: 1.42-1.77) and for the composite outcome of mortality and HF hospitalizations (pHR: 1.49, 95% CI: 1.23-1.75). Top-tertile of serum NGAL had a higher hazard for mortality (pHR: 2.91, 95% CI: 1.49-5.67) and composite outcome (HR: 4.11, 95% CI: 2.69-6.30). Serum and urine NGAL were significantly associated with WRF, with pHRs of 2.40 (95% CI: 1.48-3.90) and 2.01 (95% CI: 1.21-3.35). Urine KIM-1 was significantly associated with WRF (pHR: 1.60, 95% CI: 1.24-2.07) but not with other outcomes. High heterogeneity was noted between studies without an obvious explanation based on meta-regression. Conclusions: Serum cystatin C and serum NGAL are independent predictors of adverse outcomes in HF. Serum and urine NGAL are important predictors of WRF in HF.

Ticagrelor inhibits platelet aggregation and reduces inflammatory burden more than clopidogrel in patients with stages 4 or 5 chronic kidney disease.

BACKGROUND: No study has compared pharmacologic properties of ticagrelor and clopidogrel in non-dialysis patients with stage 4-5 chronic kidney disease (CKD). METHODS: We conducted a double-blind RCT to compare effects of ticagrelor and clopidogrel in 48 CKD, with the primary outcome of ADP-induced platelet aggregation (WBPA) after 2 weeks of DAPT. In a parallel arm, we compared effects of 2 weeks of ticagrelor plus aspirin on mean changes in WBPA and markers of thromboinflammation among non-CKD controls (n = 26) with that of CKD in the ticagrelor-arm. RESULTS: Average age of CKD was 53.7 years, with 62% women, 54% African American, and 42% with stage 5 CKD. Ticagrelor generated statistically lower WBPA values post treatment [median 0 Ω (IQR 0, 2)] vs. clopidogrel [median 0 Ω (IQR 0, 5)] (P = 0.002); percent inhibition of WBPA was greater (87 ± 22% vs. 63 ± 50%; P = 0.04; and plasma IL-6 levels were much lower (8.42 ± 1.73 pg/ml vs. 18.48 ± 26.56 pg/ml; P = 0.04). No differences in mean changes in WBPA between CKD-ticagrelor and control groups were observed. Ticagrelor- DAPT reduced levels of IL-1α and IL-1ß in CKD-ticagrelor and control groups, attenuated lowering of TNFα and TRAIL levels in CKD-ticagrelor (vs controls), and had global changes in correlation between various cytokines in a subgroup of CKD-ticagrelor subjects not on statins (n = 10). Peak/trough levels of ticagrelor/metabolite were not different between CKD-ticagrelor and control groups. CONCLUSIONS: We report significant differences in platelet aggregation and anti-inflammatory properties between ticagrelor- and clopidogrel-based DAPT in non-dialysis people with stage 4-5 CKD. These notable inflammatory responses suggest ticagrelor-based DAPT might lower inflammatory burden of asymptomatic patients with stage 4 or 5 CKD. (clinicaltrials.gov # NCT03649711).

Age Modifies Intracranial and Gastrointestinal Bleeding Risk from P2Y12 Inhibitors in Patients Receiving Dialysis.

Background: Individuals aged ≥75 years are the fastest-growing population starting dialysis for end-stage kidney disease (ESKD) due to living longer with coronary artery disease. ESKD alone can increase bleeding risk, but P2Y12 inhibitor (P2Y12-I) antiplatelet medications prescribed for cardiovascular treatment can exacerbate this risk in patients with ESKD. The age-specific rates of bleeding complications in dialysis patients with ESKD on P2Y12-I remain unclear, as does how age modifies the bleeding risk from P2Y12-I use in these patients. Methods: In a retrospective cohort study, we collected data on 40,972 patients receiving maintenance hemo- or peritoneal dialysis who were newly prescribed P2Y12-I therapy between 2011 and 2015 from the USRDS registry. We analyzed the effect of age on the time to first bleed and the interactions between age and P2Y12-I type on modifying the effects of a bleed. Results: Twenty percent of the cohort were aged ≥75 years. There were 3096 (8%) gastrointestinal (GI) and 1298 (3%) intracranial (IC) bleeding events during a median follow-up of 1 year. Annual incidence rates for IC bleeds were 2% in those aged <55 years and 3% in those aged ≥75 years. Rates for GI bleeds were 4% in those aged <55 years and 9% in those aged ≥75 years. On clopidogrel, prasugrel, and ticagrelor, for every decade increase in age of the cohort members, the risk of IC bleed increased by 9%, 55%, and 59%, and the risk of GI bleed increased by 21%, 28%, and 39%, respectively. At age ≥75 years, prasugrel was associated with a greater risk of IC bleed than clopidogrel. At age ≥60 years, ticagrelor was associated with a greater risk of GI bleed than clopidogrel. Conclusions: More potent P2Y12-Is (prasugrel and ticagrelor) were associated with a disproportionately higher risk of IC bleed with increasing age compared with that of clopidogrel-prasugrel was much worse than clopidogrel at age ≥75 years. All three drugs were associated with only modest increase in the risk of GI bleed with every decade increase in age-ticagrelor was much worse than clopidogrel at ≥60 years of age. These results highlight the need for head-to-head clinical trials for the use of P2Y12-Is in patients with ESKD to determine age cutoffs where the risk of bleeding outweighs the benefits of thrombosis prevention.

Platelet-Dependent Inflammatory Dysregulation in Patients with Stages 4 or 5 Chronic Kidney Disease: A Mechanistic Clinical Study.

Background: Chronic kidney disease (CKD) is characterized by dysregulated inflammation that worsens with CKD severity. The role of platelets in modulating inflammation in stage 4 or 5 CKD remains unexplored. We investigated whether there are changes in platelet-derived thromboinflammatory markers in CKD with dual antiplatelet therapy (DAPT; aspirin 81 mg/d plus P2Y12 inhibitor). Methods: In a mechanistic clinical trial, we compared platelet activation markers (aggregation and surface receptor expression), circulating platelet-leukocyte aggregates, leukocyte composition (monocyte subtypes and CD11b surface expression), and plasma cytokine profile (45 analytes) of non-CKD controls (n=26) and CKD outpatients (n=48) with a glomerular filtration rate (GFR) <30 ml/min per 1.73 m2 on 2 weeks of DAPT. Results: Patients with CKD demonstrated a reduced mean platelet count, elevated mean platelet volume, reduced platelet-leukocyte aggregates, reduced platelet-bound monocytes, higher total non-classic monocytes in the circulation, and higher levels of IL-1RA, VEGF, and fractalkine (all P<0.05). There were no differences in platelet activation markers between CKD and controls. Although DAPT reduced platelet aggregation in both groups, it had multifaceted effects on thromboinflammatory markers in CKD, including a reduction in PDGF levels in all CKD individuals, reductions in IL-1ß and TNF-α levels in select CKD individuals, and no change in a number of other cytokines. Significant positive correlations existed for baseline IL-1ß, PDGF, and TNF-α levels with older age, and for baseline TNF-α levels with presence of diabetes mellitus and worse albuminuria. Mean change in IL-1ß and PDGF levels on DAPT positively correlated with younger age, mean change in TNF-α levels with higher GFR, and mean changes in PDGF, and TRAIL levels correlated with worse albuminuria. Minimum spanning trees plot of cytokines showed platelet-derived CD40L had a large reduction in weight factor after DAPT in CKD. Additionally, platelet-derived IL-1ß and PDGF were tightly correlated with other cytokines, with IL-1ß as the hub cytokine. Conclusions: Attenuated interactions between platelets and leukocytes in the CKD state coincided with no change in platelet activation status, an altered differentiation state of monocytes, and heightened inflammatory markers. Platelet-derived cytokines were one of the central cytokines in patients with CKD that were tightly correlated with others. DAPT had multifaceted effects on thromboinflammation, suggesting that there is platelet-dependent and -independent inflammation in stage 4 or 5 CKD.

Comparative Effectiveness and Safety of Oral P2Y12 Inhibitors in Patients on Chronic Dialysis.

INTRODUCTION: Although oral P2Y12 inhibitors (P2Y12-Is) are one of the most commonly prescribed medication classes in patients with end stage kidney disease on dialysis (ESKD), scarce data exist regarding their benefits and risks. METHODS: We compared effectiveness and safety of clopidogrel, prasugrel, and ticagrelor in a longitudinal study using the United States Renal Data System registry of Medicare beneficiaries with ESKD. Individuals who filled new P2Y12-I prescriptions between 2011 and 2015 were included and followed until death or censoring. The primary exposure variable was P2Y12-I assignment. The primary outcome variable was death. Secondary outcomes included cardiovascular (CV) death, coronary revascularization, and gastrointestinal (GI) hemorrhage. Survival analyses were performed after propensity matching. RESULTS: Of 44,619 patients with ESKD who received P2Y12-Is, 95% received clopidogrel (n = 42,523), 3% prasugrel (n = 1205), and 2% ticagrelor (n = 891). To balance baseline differences, propensity-matching was performed: 1:6 for prasugrel (n = 1189) versus clopidogrel (n = 7134); 1:4 for ticagrelor (n = 880) versus clopidogrel (n = 3520); and 1:1 for ticagrelor versus prasugrel (n = 880). Prasugrel was associated with a reduced risk for death versus clopidogrel and ticagrelor (adjusted hazard ratio [HR] = 0.82; 95% CI: 0.73-0.93 and 0.78; 95% CI: 0.64-0.95). Compared with clopidogrel, prasugrel reduced risk for coronary revascularization (HR = 0.91; 95% CI: 0.86-0.96). There were no differences in GI hemorrhage between P2Y12-Is. CONCLUSION: In patients with ESKD, prasugrel compared with others reduced risk of death possibly by reducing risk for coronary revascularizations and without worsening gastrointestinal hemorrhage. Future trials are imperative to compare efficacy and safety of P2Y12-Is in patients with ESKD.