Low molecular weight heparin reduces proteinuria and modulates glomerular TNF-alpha production in the early phase of adriamycin nephropathy.
OBJECTIVE
Heparin has been shown to be renoprotective in a number of experimental nephropathies. The inflammatory component in the early phase of Adriamycin (ADR) induced nephropathy has been established. A microdose of low molecular weight heparin (Fragmin; F) has been noted to exert immunomodulatory effects independent of its anticoagulant activity. We assessed the effects of microdoses of F on daily proteinuria and glomerular production of tumor necrosis factor alpha (TNF-alpha) and prostaglandins 8 and 15 days after induction of ADR nephropathy.


METHODS
Following intravenous injection of ADR (7 mg/kg) to Wistar rats weighing 200 +/- 20 g, F 20 microg/day/rat s.c. was administered for 8 and 15 days (groups F8 and F15). The respective control groups (C8 and C15) received normal saline subcutaneously. Proteinuria, serum albumin, and creatinine clearance were evaluated on days 8 and 15. The production of TNF-alpha and prostaglandins from glomerular supernatants was measured by radioimmunoassay on days 8 and 15.


RESULTS
F significantly reduced proteinuria (mg/day) on day 8: 13.6 +/- 1.2 in F8 versus 40.3 +/- 2.7 in C8 (p = 0.008). The glomerular production of TNF-alpha (pi/ml) was significantly lower on day 8 in rats treated with F: 356 +/- 33 in F8 versus 764 +/- 81 in C8 (p = 0.006). A decrease in the prostaglandin E2/thromboxane B2 ratio was noted in the F group between 8 and 15 days (1.1 in F8 vs. 0.9 in F15, p = 0.005) which principally reflects an increase of thromboxane B2. The antiproteinuric effect of F shown after 8 days was no longer present after 15 days (354 +/- 91 mg/day in F15 vs. 499 +/- 69 mg/day in C15, p = 0.33). The same trend was seen for the glomerular production of TNF-alpha. Light microscopy and immunohistochemistry for interstitial and glomerular macrophages were negative.


CONCLUSIONS
The lowering effect of microdoses of F on the proteinuria seen during the early phase of ADR nephropathy may be mediated by a decreased production of glomerular TNF-alpha, supporting the anti-inflammatory action of low molecular weight heparin.
Department of Nephrology and Hypertension, Meir General Hospital, Kfar Saba, and Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel.
S
S
Benchetrit
E
E
Golan
E
E
Podjarny
J
J
Green
G
G
Rashid
J
J
Bernheim
R
R
Hershkovitz
J
J
Bernheim
D000818:Animals; D004317:Doxorubicin / Q000633:toxicity*; D005260:Female; D006495:Heparin, Low-Molecular-Weight / Q000008:administration & dosage / Q000494:pharmacology*; D007678:Kidney Glomerulus / Q000187:drug effects* / Q000378:metabolism*; D011453:Prostaglandins / Q000096:biosynthesis; D011507:Proteinuria / Q000139:chemically induced* / Q000188:drug therapy* / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D013997:Time Factors; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis*
D006495:Heparin, Low-Molecular-Weight; D011453:Prostaglandins; D014409:Tumor Necrosis Factor-alpha; D004317:Doxorubicin