defibrotide and Acute-Kidney-Injury

For patients with untreated hepatic veno-occlusive disease (VOD)/sinusoidal obstruction syndrome (SOS) with multi-organ dysfunction (MOD), mortality is >80%. We conducted a pooled analysis of three studies that assessed Day 100 survival in relationship to MOD severity, with dialysis and/or ventilator dependence representing the most severe organ dysfunction. All patients in the analysis were diagnosed using Baltimore criteria/biopsy. This analysis of patients with VOD/SOS and MOD after haematopoietic cell transplantation (HCT; n = 651) demonstrated higher Day 100 survival rates amongst defibrotide-treated patients with VOD/SOS with less versus more severe forms of MOD. Even patients with severe forms of MOD post-HCT benefitted from defibrotide.

Topics: Acute Kidney Injury; Adolescent; Adult; Aged; Child; Child, Preschool; Clinical Trials, Phase II as Topic; Clinical Trials, Phase III as Topic; Confidence Intervals; Female; Fibrinolytic Agents; Hematopoietic Stem Cell Transplantation; Hemorrhage; Hepatic Veno-Occlusive Disease; Humans; Infant; Infant, Newborn; Male; Middle Aged; Multicenter Studies as Topic; Multiple Organ Failure; Odds Ratio; Polydeoxyribonucleotides; Renal Dialysis; Respiration Disorders; Respiration, Artificial; Retrospective Studies; Transplantation Conditioning; Young Adult

We evaluated whether defibrotide, a single-stranded polydeoxyribonucleotide that enhances prostacyclin (PGI2) release from various isolated organs, could also release PGI2 from the rabbit kidney and prove effective against renal ischemic injury. Isolated perfused kidneys responded to defibrotide (100, 250 and 500 micrograms ml-1 min-1) with a dose-dependent release of immunoreactive 6-keto-PGF1 alpha (4-fold increase at highest dose), which was prevented by indomethacin pre-treatment. In vivo, venous blood withdrawn from heparinized rabbits (and representative of renal outflow) was conveyed over a collagen matrix, onto which platelets adhered and aggregated. Recording the weight increase of the matrix was used as a bioassay to follow the time-course of released PGI2. We observed that renal outflowing blood from defibrotide treated animals (50 mgKg-1 i.v.) displayed lower (P less than 0.05 versus controls) platelet activation, consistent with enhanced PGI2 release from the kidneys. Furthermore, the duration of this effect was longer lasting than that predicted from the known plasma half-life of the drug. After transient (30 min) occlusion of the renal arteries, glomerular filtration rate (GFR) dropped by about 50% (P less than 0.01) during the first reperfusion hour in control animals, with only mild recovery having occurred 4 h later. Defibrotide (16 mgKg-1 bolus + 16 mgKg-1h-1, i.v.) could not antagonize the initial impairment (40% GFR reduction), but allowed full recovery at the end of the observation period (P less than 0.05 vs controls). Indomethacin, instead, caused a dramatic reduction of GFR (70%) during early reperfusion, with no subsequent recovery.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Acute Kidney Injury; Animals; Epoprostenol; Fibrinolytic Agents; In Vitro Techniques; Ischemia; Kidney; Male; Perfusion; Platelet Adhesiveness; Platelet Aggregation; Polydeoxyribonucleotides; Rabbits

Topics: Acetylglucosaminidase; Acute Kidney Injury; Animals; Cyclooxygenase Inhibitors; Epoprostenol; Glomerular Filtration Rate; Hemodynamics; Indomethacin; Polydeoxyribonucleotides; Rabbits; Renal Circulation; Vascular Resistance

Thrombotic microangiopathy (TMA) can occur whenever pathogenetic events lead to fibrin deposition in the microcirculation. It has been suggested that intravascular coagulation is important in the development of renal as well as cerebral lesions. The mortality rate in adults varies from 50 to 70%; chronic or progressive renal failure occurs in approximately two thirds of children over 2 years of age. Poor success may be due to therapy being initiated too late or to inappropriate use of antagonistic drugs, or both. In the last 2 years we have treated 8 patients with TMA (5 with thrombotic thrombocytopenic purpura; 3 with hemolytic uremic syndrome) with defibrotide, a new antithrombotic agent extracted from mammalian lungs. At admission all patients had severe renal involvement (serum creatinine 5.3-14.9 mg/dl) and coagulation abnormalities (low platelet count; high levels of circulating fibrin degradation products). There were neurological manifestations in 6 patients. Defibrotide administration was followed in 6 patients by recovery of renal function. In all patients, defibrotide therapy induced the disappearance of neurological manifestations and normalization of coagulation abnormalities. Defibrotide caused no side effects. All patients are alive after 7-22 months of follow-up.

Topics: Acute Kidney Injury; Adult; Blood Coagulation Tests; Child; Child, Preschool; Female; Fibrin Fibrinogen Degradation Products; Fibrinolytic Agents; Hemolytic-Uremic Syndrome; Humans; Male; Middle Aged; Polydeoxyribonucleotides; Purpura, Thrombotic Thrombocytopenic; Thrombosis

8 patients with thrombotic microangiopathy were treated with a new antithrombotic agent, defibrotide. This drug displays considerable fibrinolytic and antithrombotic activity, and induces generation and release of a prostacyclin-like substance from vascular tissue. At admission all patients presented severe renal involvement and coagulation abnormalities. Neurological manifestations were present in 6. Defibrotide administration was followed by recovery of renal function in 6, disappearance of neurological symptoms and coagulation abnormalities in all patients. The use of defibrotide was not associated with side effects. On the basis of the results obtained in these patients, we suggest that defibrotide might be considered as a valuable drug in the management of patients with thrombotic microangiopathy.

Topics: Acute Kidney Injury; Adolescent; Adult; Biopsy; Child; Creatinine; Diuresis; Female; Fibrin Fibrinogen Degradation Products; Fibrinolytic Agents; Humans; Hypertension, Renal; Kidney; Male; Microcirculation; Middle Aged; Platelet Count; Polydeoxyribonucleotides; Thrombosis

Topics: Acute Kidney Injury; Adult; Child; Fibrinolytic Agents; Hemolytic-Uremic Syndrome; Humans; Polydeoxyribonucleotides; Purpura, Thrombotic Thrombocytopenic