hirudin and Kidney-Diseases

Chronic kidney disease (CKD) is prevalent and affects an ever-increasing proportion of patients presenting with acute coronary syndrome (ACS). Patients with CKD have a higher risk of ACS and significantly higher mortality, and are also predisposed to increased bleeding complications. Antiplatelet and antithrombotic drugs form the bedrock of management of patients with ACS. Most randomized trials of these drugs exclude patients with CKD, and current guidelines for management of these patients are largely based on these trials. We aim to review the safety and efficacy of these drugs in patients with CKD presenting with ACS.

Topics: Acute Coronary Syndrome; Adenosine; Aspirin; Chronic Disease; Clinical Trials as Topic; Clopidogrel; Dose-Response Relationship, Drug; Factor Xa Inhibitors; Fibrinolytic Agents; Fondaparinux; Hemorrhage; Heparin; Hirudins; Humans; Kidney Diseases; Peptide Fragments; Piperazines; Platelet Aggregation Inhibitors; Platelet Glycoprotein GPIIb-IIIa Complex; Polysaccharides; Prasugrel Hydrochloride; Recombinant Proteins; Thiophenes; Ticagrelor; Ticlopidine; Uremia

This study sought to investigate the impact of chronic kidney disease (CKD) in patients undergoing percutaneous coronary intervention (PCI) for ST-segment elevation myocardial infarction (STEMI) with different antithrombotic strategies.. CKD is associated with increased risk of adverse ischemic and hemorrhagic events after primary PCI for STEMI.. HORIZONS-AMI (Harmonizing Outcomes With Revascularization and Stents in Acute Myocardial Infarction) trial was a multicenter, international, randomized trial comparing bivalirudin monotherapy or heparin plus a glycoprotein IIb/IIIa inhibitor (GPI) during primary PCI in STEMI. CKD, defined as creatinine clearance <60 ml/min, was present at baseline in 554 of 3,397 patients (16.3%). Patients were followed for 3 years. Net adverse cardiac event (NACE) was defined as the composite of death, reinfarction, ischemia-driven target vessel revascularization (TVR), stroke or non-coronary artery bypass grafting (CABG)-related major bleeding.. Patients with CKD compared with patients without had higher rates of NACE (41.4% vs. 23.8%, p < 0.0001), death (18.7% vs. 4.4%, p < 0.0001), and major bleeding (19.3% vs. 6.7%, p < 0.0001). Multivariable analysis identified baseline creatinine as an independent predictor of death at 3 years (hazard ratio: 1.51, 95% confidence interval: 1.21 to 1.87, p < 0.001). Patients with CKD randomized to bivalirudin monotherapy versus heparin plus GPI had no significant difference in major bleeding (19.0% vs. 19.6%, p = 0.72) or death (19.0% vs. 18.4%, p = 0.88) at 3 years. In patients with CKD, there was no difference in the rates of TVR in bare-metal stents (BMS) versus drug-eluting stents (DES) at 3 years (14.1% vs. 15.1%, p = 0.8).. STEMI patients with CKD have significantly higher rates of death and major bleeding compared with those without CKD. In patients with CKD, there appears to be no benefit of bivalirudin compared with heparin + GPI, or DES versus BMS during primary PCI in improving clinical outcomes.

Topics: Aged; Aged, 80 and over; Angioplasty, Balloon, Coronary; Anticoagulants; Chi-Square Distribution; Chronic Disease; Drug-Eluting Stents; Europe; Female; Fibrinolytic Agents; Hemorrhage; Heparin; Hirudins; Humans; Israel; Kaplan-Meier Estimate; Kidney Diseases; Male; Metals; Middle Aged; Myocardial Infarction; Peptide Fragments; Platelet Aggregation Inhibitors; Platelet Glycoprotein GPIIb-IIIa Complex; Proportional Hazards Models; Prospective Studies; Prosthesis Design; Recombinant Proteins; Recurrence; Risk Assessment; Risk Factors; Stents; Stroke; Thrombosis; Time Factors; Treatment Outcome; United States

In this substudy of the ACUITY (Acute Catheterization and Urgent Intervention Triage strategY) trial, we investigated the relationship between chronic kidney disease (CKD) and clinical outcomes, and compared the safety and efficacy of bivalirudin monotherapy versus heparin plus a glycoprotein IIb/IIIa inhibitor (GPI).. CKD is an important predictor of prognosis in the general population. The outcomes of patients with CKD and acute coronary syndromes (ACS) have not been well studied.. In the ACUITY study, 13,819 patients with moderate- and high-risk ACS undergoing an early, invasive strategy were randomly assigned to 1 of 3 antithrombin regimens: a heparin plus a GPI, bivalirudin plus a GPI, or bivalirudin monotherapy. CKD (creatinine clearance <60 ml/min) was present in 2,469 (19.1%) of 12,939 randomized patients with baseline creatinine clearance data.. Patients with CKD had worse 30-day and 1-year clinical outcomes than those with normal renal function. There were no significant differences between bivalirudin monotherapy and heparin plus a GPI in rates of 30-day composite ischemia (11.1% vs. 9.4%, p = 0.27) and net clinical adverse outcomes (16.1% vs. 16.9%, p = 0.65). There was remarkably less major bleeding (6.2% vs. 9.8%, p = 0.008) at 30 days, but no significant difference in 1-year composite ischemia (22.0% vs. 18.9%, p = 0.10) or mortality (7.1% vs. 7.3%, p = 0.96).. In patients with ACS, CKD is associated with higher 30-day and 1-year adverse event rates. Compared with heparin plus a GPI, the use of bivalirudin monotherapy in patients with CKD results in nonstatistically different ischemic outcomes, but significantly less 30-day major bleeding.

Topics: Acute Coronary Syndrome; Adult; Aged; Aged, 80 and over; Angioplasty, Balloon, Coronary; Biomarkers; Chronic Disease; Coronary Artery Bypass; Creatinine; Drug Therapy, Combination; Female; Fibrinolytic Agents; Hemorrhage; Heparin; Hirudins; Humans; Kidney Diseases; Logistic Models; Male; Middle Aged; Myocardial Infarction; Myocardial Ischemia; Odds Ratio; Peptide Fragments; Platelet Aggregation Inhibitors; Platelet Glycoprotein GPIIb-IIIa Complex; Prospective Studies; Recombinant Proteins; Risk Assessment; Time Factors; Treatment Outcome; Triage

Damage to podocytes is an important determinant of renal pathology. The puromycin aminonucleoside (PAN) mice nephropathy model is commonly used in the study of renal disease with podocyte injury. Hirudin has a broad nephroprotective effect and has been shown to treat renal interstitial fibrosis in previous studies. Mice were given PAN by gavage to prepare animal models, and MPC5 cells were incubated with PAN in vitro. Twenty-four hours urine was collected for analysis of urinary protein levels. Renal pathological changes were observed by hematoxylin and eosin staining. Immunofluorescence detection of nephrin in kidney tissues and cells. Apoptosis was analyzed with over TUNEL. Cytoskeleton, endoplasmic reticulum stress (ERS), p38 MAPK signaling, and apoptosis-related proteins were assessed by western blot analysis. The data suggested that hirudin attenuated reduced renal injury and increased urine protein in PAN mice. Hirudin also attenuated cytoskeletal protein (synaptopodin, nephrin, and podocin) disruption, ERS activation, and apoptosis in PAN mice and PAN-induced podocytes. In addition, hirudin inhibited the expression of p38 MAPK signaling key proteins upregulated by PAN, thereby suppressing ERS. The p38 MAPK agonist was able to partially antagonize the inhibition of p38 MAPK signaling by hirudin in PAN-induced podocytes, thereby reactivating the ERS inhibited by hirudin, promoting cytoskeletal protein degradation and increasing the level of apoptosis. In conclusion, hirudin could decrease podocyte injury by inhibiting p38 MAPK signaling-mediated ERS, resulting in the protection of the kidney from PAN damage. These findings may provide an experimental basis for hirudin treatment of podocyte injury diseases.

Topics: Animals; Cytoskeletal Proteins; Disease Models, Animal; Endoplasmic Reticulum Stress; Hirudins; Kidney Diseases; Mice; p38 Mitogen-Activated Protein Kinases; Podocytes; Puromycin Aminonucleoside

Topics: Aged, 80 and over; Fibrinolytic Agents; Heparin; Hirudins; Humans; Kidney Diseases; Male; Recombinant Proteins; Thrombocytopenia; Time Factors; Treatment Outcome; Warfarin

Topics: Anticoagulants; Drug Approval; Hirudins; Humans; Kidney Diseases; Postoperative Complications; Recombinant Proteins; Thrombin; United States; United States Food and Drug Administration

To evaluate the safety, effectiveness, and dosing of bivalirudin for treatment of heparin-induced thrombocytopenia (HIT) in critically ill patients with hepatic and/or renal dysfunction.. Retrospective cohort study.. University-affiliated medical center. Eighteen patients older than 18 years who were admitted to the intensive care unit (ICU), had hepatic and/or renal dysfunction, and were treated with bivalirudin for the diagnosis of HIT between January 1, 2004, and March 31, 2005.. Patient records were reviewed for dosage and duration of bivalirudin therapy, occurrence of thrombosis, and clinically significant adverse effects. Of the 18 patients identified, 12 had both hepatic and renal dysfunction (group 1), four had hepatic dysfunction (group 2), and two had renal dysfunction (group 3). Demographics were similar among the groups. Mean +/- SD age was 54 +/- 15 years and weight was 82 +/- 14 kg, 67% were male, 83% were Caucasian, and 56% were receiving renal replacement therapy. Mean bivalirudin doses were 0.06 +/- 0.15 mg/kg/hour (median 0.03 mg/kg/hr), 0.14 +/- 0.05 mg/kg/hour (median 0.14 mg/kg/hr), and 0.05 +/- 0.01 mg/kg/hour (median 0.05 mg/kg/hr) for patients in groups 1, 2, and 3, respectively. Ten patients receiving continuous venovenous hemofiltration with or without dialysis received a mean dose of 0.04 +/- 0.03 mg/kg/hour (median 0.03 mg/kg/hr). In the 18 patients, mean bivalirudin duration was 15 +/- 17 days, activated partial thromboplastin time (aPTT) was 69 +/- 22 seconds, and international normalized ratio was 2.2 +/- 0.8. Supratherapeutic aPTTs were most common on days 1 (22%) and 2 (28%) when bivalirudin doses were highest. Clinically significant bleeding did not occur in any patient. Thrombosis occurred in one patient (6%) while receiving bivalirudin.. Patients in the ICU who have hepatic and/or renal dysfunction require low doses of bivalirudin to achieve aPTT values 1.5-2.5 times baseline. Bivalirudin can be safely started at 0.14 mg/kg/hour in patients with hepatic dysfunction, 0.03-0.05 mg/kg/hour in those with renal or combined hepatic and renal dysfunction, and 0.03-0.04 mg/kg/hour in patients receiving continuous renal replacement therapy.

Topics: Adult; Aged; Anticoagulants; Cohort Studies; Critical Illness; Female; Heparin; Hirudins; Humans; Intensive Care Units; Kidney Diseases; Liver Diseases; Male; Middle Aged; Partial Thromboplastin Time; Peptide Fragments; Recombinant Proteins; Retrospective Studies; Thrombin; Thrombocytopenia

The number of patients with coexisting chronic kidney disease (CKD) and cardiovascular disease is growing rapidly. Treatment of these patients is challenging, primarily because of a lack of pharmacokinetic and clinical trial data associated with these combined disease entities. In this report, we discuss the cardiovascular disease risk associated with CKD and review the use of anticoagulation for acute cardiovascular disease in patients with CKD. We evaluate the potential role of direct thrombin inhibitors in patients with renal disease who have acute coronary syndromes, with particular focus on the clinical efficacy of bivalirudin. We conclude that direct thrombin inhibitors, including bivalirudin and argatroban, may be promising alternatives to heparin in patients who have renal insufficiency and are therefore at an increased risk for bleeding. In the treatment of patients with advanced renal insufficiency and cardiovascular disease, however, these agents should be used with dose modification to account for altered excretion.

Topics: Anticoagulants; Antithrombins; Arginine; Chronic Disease; Coronary Disease; Heparin; Heparin, Low-Molecular-Weight; Hirudin Therapy; Hirudins; Humans; Kidney Diseases; Peptide Fragments; Pipecolic Acids; Recombinant Proteins; Sulfonamides; United States

Recombinant hirudin is an alternative anticoagulant for cardiopulmonary bypass in patients with heparin-induced thrombocytopenia type II. Although there is no neutralizing agent for recombinant hirudin, its fast renal elimination enables quick cessation of bleeding after cardiopulmonary bypass. The aim of the study was to compare anticoagulant effects of recombinant hirudin in regards to renal function in patients with heparin-induced thrombocytopenia type II.. Twenty-one patients (mean age, 65 years, and range, 35 to 82 years) underwent different complex cardiovascular procedures using recombinant hirudin as the anticoagulant for cardiopulmonary bypass. Postoperative blood loss, transfusion requirements, and hemostatic variables were compared between patients with a creatinine level lower than 1.5 mg/dL (group 1, normal renal function; n = 17 patients) and those with a creatinine level greater than 1.5 mg/dL (group 2, impaired renal function; n = 4 patients).. The patients in group 1 showed no increased tendency toward postoperative bleeding. In contrast, all 4 patients in group 2 required reexploration for increased postoperative bleeding. They had higher activated partial thromboplastin times and transfusion requirements postoperatively.. If recombinant hirudin is used as the anticoagulant for cardiopulmonary bypass in patients with heparin-induced thrombocytopenia type II and impaired renal function, the risk of postoperative bleeding is increased.

Topics: Adult; Aged; Aged, 80 and over; Anticoagulants; Antithrombins; Aprotinin; Blood Transfusion; Cardiopulmonary Bypass; Creatinine; Diuresis; Female; Hemostatic Techniques; Hemostatics; Heparin; Hirudin Therapy; Hirudins; Humans; Kidney; Kidney Diseases; Male; Middle Aged; Partial Thromboplastin Time; Postoperative Hemorrhage; Recombinant Proteins; Risk Factors; Survival Rate; Thrombocytopenia