Low Molecular Weight Heparin May Benefit Nephrotic Remission in Steroid‑sensitive Nephrotic Syndrome Via Inhibiting Elastase

Overview

Journal Mol Med Rep

Specialty Molecular Biology

Date 2017 Oct 10

PMID 28990100

Citations 2

Authors

Songhui Zhai

Lijuan Hu

Lin Zhong

Yuhong Tao

Zheng Wang

Affiliations

Soon will be listed here.

Abstract

Low molecular weight heparin (LMWH) has a structure similar to heparan sulfate, which exerts anti‑inflammatory effects via inhibiting elastase (Ela) activity. Release of Ela along the glomerular capillary wall may induce glomerular injury and proteinuria. The present study aimed to investigate the influence of LMWH on steroid‑sensitive nephrotic syndrome (SSNS) and the potential underlying mechanism. A total of 40 SSNS patients and 20 healthy controls were recruited. SSNS patients were treated with LMWH and prednisone simultaneously (LMWH+pred group) or with prednisone alone (pred group). Proteinuria, urinary glycosaminoglycans (GAGs), serum Ela and urinary creatinine levels were measured. The nephrotic period of SSNS was 15.93±5.78 days. The nephrotic period of SSNS in LMWH+pred group was significantly reduced compared with the pred group (14.13±4.56 vs. 18.63±6.49 days; P<0.05). At the follow‑up of the SSNS patients, there was no statistically significant difference in number of relapses between the LMWH+pred and pred groups. Proteinuria (2.51±0.97 g/24 h), urinary GAG levels (4.92±0.87 mg/mmol creatinine) and serum Ela levels (77.64±10.99 ng/l) were significantly greater in the nephrotic period of SSNS compared with the remission period (0.107±0.026 g/24 h, 1.53±0.27 mg/mmol Cr and 41.92±7.81 ng/l, respectively) and the healthy control group (0.098±0.027 g/24 h, 1.40±0.26 mg/mmol creatinine and 38.43±9.83 ng/l, respectively; P<0.05). During the remission period, urinary GAG and serum Ela levels in the LMWH+pred group were significantly reduced compared with the pred group (P<0.05), whereas proteinuria did not differ between these groups (P>0.05). Positive correlations were revealed between urinary GAG excretion and proteinuria (r=0.877; P<0.05), proteinuria and serum Ela levels (r=0.844; P<0.05) and serum Ela levels and urinary GAG excretion (r=0.881; P<0.05). The results of the present study indicated that elevated serum Ela levels may induce proteinuria by degrading GAGs in the glomerular basement membrane in children with SSNS. LMWH may benefit nephrotic remission of SSNS via inhibiting Ela.

Citing Articles

Exploring the Role of Antithrombin in Nephrotic Syndrome-Associated Hypercoagulopathy: A Multi-Cohort Study and Meta-Analysis.

Abdelghani E, Waller A, Wolfgang K, Stanek J, Parikh S, Rovin B Clin J Am Soc Nephrol. 2023; 18(2):234-244.

PMID: 36754010 PMC: 10103265. DOI: 10.2215/CJN.0000000000000047.

Heparin beyond anti-coagulation.

Chen D Curr Res Transl Med. 2021; 69(4):103300.

PMID: 34237474 PMC: 8257468. DOI: 10.1016/j.retram.2021.103300.

References

Klebanoff S, Kinsella M, Wight T . Degradation of endothelial cell matrix heparan sulfate proteoglycan by elastase and the myeloperoxidase-H2O2-chloride system. Am J Pathol. 1993; 143(3):907-17. PMC: 1887211. View

Liu X, Wang Z, Guo Y . Respiratory syncytial virus nephropathy in rats. Kidney Int. 2007; 71(5):388-96. DOI: 10.1038/sj.ki.5002030. View

Heeringa P, van den Born J, Brouwer E, Dolman K, Klok P, Huitema M . Elastase, but not proteinase 3 (PR3), induces proteinuria associated with loss of glomerular basement membrane heparan sulphate after in vivo renal perfusion in rats. Clin Exp Immunol. 1996; 105(2):321-9. PMC: 2200492. DOI: 10.1046/j.1365-2249.1996.d01-754.x. View

BROWN R, Leung E, Kankaanranta H, Moilanen E, Page C . Effects of heparin and related drugs on neutrophil function. Pulm Pharmacol Ther. 2012; 25(2):185-92. DOI: 10.1016/j.pupt.2012.01.006. View

Bridges C, Myers B, Brenner B, Deen W . Glomerular charge alterations in human minimal change nephropathy. Kidney Int. 1982; 22(6):677-84. DOI: 10.1038/ki.1982.229. View

Brown R, Lever R, Jones N, Page C . Effects of heparin and related molecules upon neutrophil aggregation and elastase release in vitro. Br J Pharmacol. 2003; 139(4):845-53. PMC: 1573888. DOI: 10.1038/sj.bjp.0705291. View

Vehaskari V, Root E, GERMUTH Jr F, Robson A . Glomerular charge and urinary protein excretion: effects of systemic and intrarenal polycation infusion in the rat. Kidney Int. 1982; 22(2):127-35. DOI: 10.1038/ki.1982.144. View

Vernier R, Klein D, Sisson S, Mahan J, Oegema T, Brown D . Heparan sulfate--rich anionic sites in the human glomerular basement membrane. Decreased concentration in congenital nephrotic syndrome. N Engl J Med. 1983; 309(17):1001-9. DOI: 10.1056/NEJM198310273091701. View

Baggio B, Gambaro G, Briani G, Favaro S, Borsatti A . Urinary excretion of glycosaminoglycans and brush border and lysosomal enzymes as markers of glomerular and tubular involvement in kidney diseases. Contrib Nephrol. 1984; 42:107-10. DOI: 10.1159/000409968. View

10.

Brenner B, Hostetter T, Humes H . Glomerular permselectivity: barrier function based on discrimination of molecular size and charge. Am J Physiol. 1978; 234(6):F455-60. DOI: 10.1152/ajprenal.1978.234.6.F455. View

11.

Cengiz N, Bayazit A, Noyan A, Anarat R, Anarat A . Glycosaminoglycan excretion in children with nephrotic syndrome. Pediatr Nephrol. 2005; 20(4):486-90. DOI: 10.1007/s00467-004-1739-y. View

12.

Guo Y, Wang Z, Dong L, Wu J, Zhai S, Liu D . Ability of low-molecular-weight heparin to alleviate proteinuria by inhibiting respiratory syncytial virus infection. Nephrology (Carlton). 2009; 13(7):545-53. DOI: 10.1111/j.1440-1797.2008.01012.x. View

13.

Page C . One explanation of the asthma paradox: inhibition of natural anti-inflammatory mechanism by beta 2-agonists. Lancet. 1991; 337(8743):717-20. DOI: 10.1016/0140-6736(91)90289-2. View

14.

Girardin E, Birmele B, Benador N, Neuhaus T, Hosseini G, van den Heuvel L . Effect of plasma from patients with idiopathic nephrotic syndrome on proteoglycan synthesis by human and rat glomerular cells. Pediatr Res. 1998; 43(4 Pt 1):489-95. DOI: 10.1203/00006450-199804000-00009. View

15.

. [Multicenter survey of diagnostic and therapeutic status in Chinese childhood patients with steroid-sensitive, relaping/steroid-dependent nephrotic syndrome]. Zhonghua Er Ke Za Zhi. 2014; 52(3):194-200. View

16.

Carrie B, Salyer W, Myers B . Minimal change nephropathy: an electrochemical disorder of the glomerular membrane. Am J Med. 1981; 70(2):262-8. DOI: 10.1016/0002-9343(81)90760-9. View

17.

Salant D . The structural biology of glomerular epithelial cells in proteinuric diseases. Curr Opin Nephrol Hypertens. 1994; 3(6):569-74. DOI: 10.1097/00041552-199411000-00001. View

18.

Lever R, Page C . Novel drug development opportunities for heparin. Nat Rev Drug Discov. 2002; 1(2):140-8. DOI: 10.1038/nrd724. View

19.

Cadene M, Boudier C, de Marcillac G, Bieth J . Influence of low molecular mass heparin on the kinetics of neutrophil elastase inhibition by mucus proteinase inhibitor. J Biol Chem. 1995; 270(22):13204-9. DOI: 10.1074/jbc.270.22.13204. View

20.

Birmele B, Thibault G, Nivet H, De Agostini A, Girardin E . In vitro decrease of glomerular heparan sulfate by lymphocytes from idiopathic nephrotic syndrome patients. Kidney Int. 2001; 59(3):913-22. DOI: 10.1046/j.1523-1755.2001.059003913.x. View