Use of alkaline phosphatase in the treatment of reduced renal function
Inventors
Pickkers, Roelof P. • Heemskerk, Suzanne • Velders, Markwin P. • Raaben, Willem • Wulferink, Marty B. F.
Assignees
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Publication Number
US-8586032-B2
Publication Date
2013-11-19
Expiration Date
Abstract
The invention relates to the field of medicine and in particular to the use of alkaline phosphatase in the treatment of renal diseases, such as reduced renal function. The present invention also relates to the field of pharmacy and in particular to the pharmaceutical use of alkaline phosphatase. The present invention provides an alternative treatment to improve a situation in which the renal function is reduced by using alkaline phosphatase.
Core Innovation
The disclosed invention describes a method for treating a subject with reduced renal function due to renal failure by administering mammalian alkaline phosphatase ("AP"). The method is directed to subjects in which renal function is reduced because of renal failure, including acute renal failure and chronic renal failure, and the AP is administered intravenously as an effective amount for treatment of reduced renal function due to renal failure.
The disclosure further defines embodiments in which the AP corresponds to specific mammalian AP isoenzymes and sources, including intestinal AP, placental AP, placental-like AP, and liver/bone/kidney tissue non-specific AP. Additional embodiments specify that the AP is recombinant, including forms involving a GPI-anchor and modifications described as a GPI-signal sequence mutation/deletion and secretion of phosphatase.
The background framing indicates that the invention addresses reduced renal function in renal failure contexts, including conditions associated with intrinsic causes such as acute tubular necrosis and glomerulonephritis, decreased renal blood flow/ischemia, and drug- or toxin-induced injury. The disclosure emphasizes assessment and monitoring involving urine-based renal markers, including urinary iNOS mRNA from urine-secreted renal cells and urinary NO metabolites, together with tubular injury markers and renal function measures.
Claims Coverage
The partial claims content identifies one independent claim (clm-00001). The independent claim is supported by dependent claims that refine the renal-failure context and patient selection/eligibility and specify AP type and form, yielding several distinct inventive-feature clusters.
Intravenous mammalian alkaline phosphatase for reduced renal function due to renal failure
Administering intravenously an effective amount of mammalian alkaline phosphatase ("AP") to a subject with reduced renal function due to renal failure.
Acute renal failure treatment context
The method is specified for a subject with reduced renal function due to acute renal failure.
Chronic renal failure treatment context
The method is specified for a subject with reduced renal function due to chronic renal failure.
AP isoenzymes from specific tissues
Further limiting the AP to a placental AP, placental-like AP, intestinal AP, or liver/bone/kidney AP.
Recombinant alkaline phosphatase
Further specifying that the AP is recombinant.
Patient baseline serum creatinine threshold and/or renal replacement therapy status
Administering the method to a subject who, before administration, has a baseline serum creatinine level greater than 150 µmol/L or is already receiving renal replacement therapy.
Across the claim set shown, the core inventive coverage centers on intravenous administration of mammalian AP to treat reduced renal function due to renal failure, with refinements that specify acute versus chronic renal failure, AP isoenzyme/tissue sources, recombinant AP, and a subject baseline serum creatinine/renal replacement therapy status criterion.
Stated Advantages
Attenuation of urinary iNOS induction and lowering urinary NO metabolites (NOx).
Reduced tubular injury markers including GSTA1-1 (GST alpha 1-1) and GSTP1-1 (GST pi 1-1).
Improved creatinine clearance and reduced serum creatinine changes.
Reduced need for renal replacement therapy/dialysis during follow-up.
No need for renal replacement therapy during follow-up in the described comparison.
Mortality reduction versus placebo in sepsis patients with baseline renal failure.
Documented Applications
Treatment of reduced renal function due to renal failure in sepsis ICU patients, including monitoring of urine iNOS mRNA, urinary NO metabolites, tubular injury markers, and renal function measures, and assessing need for renal replacement therapy and mortality versus placebo.
Treatment of acute renal impairment in rat models of gentamicin-induced nephrotoxicity and cisplatin-induced renal failure, assessed using serum creatinine/BUN and improved creatinine clearance.
Treatment of sepsis patients with baseline renal failure, with assessment of need for renal replacement therapy/dialysis and mortality versus placebo.
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