Effective elimination of high-dose methotrexate by repeated hemodiafiltration and high-flux hemodialysis in patients with acute kidney injury.

INTRODUCTION: Acute kidney injury (AKI) after high dose methotrexate (HD-MTX) is associated with delayed MTX-excretion and life-threatening toxicity. Glucapridase, the recommended therapy, is expensive and not always available. CASE SERIES: We describe 3 cases (69, 67, 73 years) with diffuse large B-cell lymphoma who developed AKI and early-onset severely delayed MTX elimination after HD-MTX. MTX serum concentrations were 101 and 69 µmol/L at 24 h after administration in two patients and 34 µmol/L at 32 h in the third. MANAGEMENT AND OUTCOME: Since glucarpidase was unavailable, we performed daily high-flux hemodialysis (HF-HD) or online hemodiafiltration (HDF) sessions (median duration, 6 h). The median serum MTX elimination half-life during HDF/HF-HD sessions was similar in all patients (median, 4.4 h; IQR, 3.8-5.3 h), but serum MTX concentrations rebounded after each dialysis by a median of 40% of the trough concentrations. The three patients underwent multiple dialysis sessions, until MTX serum concentrations remained sufficiently low to be neutralized by leucovorin. Only 1 patient developed severe pancytopenia, and renal function normalized in all patients after 3-6 weeks. DISCUSSION: In conclusion, when glucarpidase is unavailable or delayed, early, repeated and prolonged HDF/HF-HD effectively enhance MTX elimination and prevent toxicity in patients with AKI and severely delayed MTX elimination after HD-MTX.

Circulating heparan sulfate chains and body weight contribute to anti-Xa levels in cancer patients using the prophylactic dose of enoxaparin.

Hospitalized cancer patients are at increased risk of thrombosis and prophylaxis with heparin is recommended. Heparanase is a protein capable of degrading heparan sulfate (HS) chains. The first objective of the study was to examine the effects of weight on anti-Xa levels in cancer patients treated with a fixed dose of enoxaparin as thromboprophylaxis. The second aim was to assess a potential correlation between plasma pre-treatment coagulation parameters and anti-Xa levels in an assumption that heparanase degradation activity towards heparins and HS chains could affect anti-Xa levels. Two blood samples (prior to and 3 h after drug injection) of 76 cancer patients with an indication for prophylaxis with enoxaparin (40 mg) were evaluated for coagulation markers. Sub-prophylactic levels of anti-Xa (< 0.2 U/ml) were found in 16/76 (21%) patients; in 13/76 (13%) patients the values were supra-prophylactic (> 0.5 U/ml). In the subgroup of patients weighing > 80 kg, 7/14 (50%) individuals had a sub-prophylactic level. Overall, anti-Xa levels appeared to correlate with patient's weight (r = - 0.48, p < 0.0001), pre-treatment partial thromboplastin time (PTT), D-dimer, HS, heparanase levels and procoagulant activity. We concluded that plasma anti-Xa levels correlated with patient's weight. A substantial portion of cancer patients receiving enoxaparin prophylaxis was undertreated. For patients > 80 kg, a weight-adjusted prophylactic dose of enoxaparin could be considered. Elevated enoxaparin anti-Xa levels correlated with pre-treatment parameters of coagulation system activation. High pre-treatment HS and elevated plasma anti-Xa levels may potentially serve as biomarkers for the identification of patients at increased thrombosis risk.

Nephroprotective effect of heparanase in experimental nephrotic syndrome.

BACKGROUND: Heparanase, an endoglycosidase that cleaves heparan sulfate (HS), is involved in various biologic processes. Recently, an association between heparanase and glomerular injury was suggested. The present study examines the involvement of heparanase in the pathogenesis of Adriamycin-induced nephrotic syndrome (ADR-NS) in a mouse model. METHODS: BALB/c wild-type (wt) mice and heparanase overexpressing transgenic mice (hpa-TG) were tail-vein injected with either Adriamycin (ADR, 10 mg/kg) or vehicle. Albuminuria was investigated at days 0, 7, and 14 thereafter. Mice were sacrificed at day 15, and kidneys were harvested for various analyses: structure and ultrastructure alterations, podocyte proteins expression, and heparanase enzymatic activity. RESULTS: ADR-injected wt mice developed severe albuminuria, while ADR-hpa-TG mice showed only a mild elevation in urinary albumin excretion. In parallel, light microscopy of stained cross sections of kidneys from ADR-injected wt mice, but not hpa-TG mice, showed mild to severe glomerular and tubular damage. Western blot and immunofluorescence analyses revealed significant reduction in nephrin and podocin protein expression in ADR-wt mice, but not in ADR-hpa-TG mice. These results were substantiated by electron-microscopy findings showing massive foot process effacement in injected ADR-wt mice, in contrast to largely preserved integrity of podocyte architecture in ADR-hpa-TG mice. CONCLUSIONS: Our results suggest that heparanase may play a nephroprotective role in ADR-NS, most likely independently of HS degradation. Moreover, hpa-TG mice comprise an invaluable in vivo platform to investigate the interplay between heparanase and glomerular injury.