El efecto de la pentoxifilina en la reducción de proteinuria en pacientes con diabetes tipo 2 con bloqueo del sistema de angiotensina: ensayo clínico doble ciego y aleatorizado

Ghorbani, Ali; Ghorbani, Ali; Omidvar, Bita; Omidvar, Bita; Beladi-Mousavi, Seyed S.; Beladi Mousavi, Seyed Seifollah; Lak, Elena; Lak, Elena; Vaziri, Sima; Vaziri, Sima

doi:10.3265/Nefrologia.pre2012.Jun.11242

Información del artículo

Resumen

Bibliografía

Descargar PDF

Estadísticas

Aunque el bloqueo del sistema renina-angiotensina ha sido citado como el tratamiento inicial para la nefropatía diabética (ND), en un número significativo de pacientes el avance de la enfermedad renal no se ve frenado en su totalidad por estos agentes. Hemos realizado un ensayo clínico doble ciego para valorar el efecto acumulativo de la pentoxifilina (PTX) en la reducción de la proteinuria en pacientes con diabetes tipo 2 (DM2) con bloqueo del sistema de angiotensina. La dosis de PTX utilizada en nuestro ensayo fue una cantidad baja de 400 mg diarios y, en nuestra experiencia, no logramos encontrar ningún artículo que evaluara el efecto antiproteinúrico de la PTX con esta dosis. De forma aleatoria, se dividieron en dos grupos 100 pacientes con ND y proteinuria persistente a pesar del tratamiento con losartán y enalapril durante al menos tres meses antes de ser incluidos en el estudio. El grupo de control (n = 50, 26 hombres y 24 mujeres) fueron tratados con losartán y enalapril, mientras que el grupo de tratamiento (grupo de PTX: n = 50, 28 hombres y 22 mujeres) recibieron losartán, enalapril y 400 mg/día de pentoxifilina durante 6 meses. Al comienzo del estudio no se encontraron diferencias significativas en las características demográficas y clínicas de los pacientes, incluida la creatinina sérica, HbA1c, presión arterial y excreción urinaria de proteínas entre los dos grupos (p > 0,05). En el grupo de PTX, la tasa media de excreción urinaria de proteína ha disminuido significativamente de 616,66 a 378,24 mg tras 3 meses (p = 0,000) y a 192,05 mg tras 6 meses (p = 0,000), mientras que en el grupo de control no se han observado cambios significativos. El beneficioso efecto antiproteinúrico del PTX no estuvo asociado a la intensidad del cambio metabólico ni a la reducción de la presión arterial. Además, al final del estudio, el aclaramiento medio de creatinina fue significativamente más elevado en el grupo de PTX (p = 0,04). En conclusión, la PTX puede aportar en gran medida un efecto antiproteinúrico acumulativo y ralentizar el grado de filtración glomerular en pacientes con DM2 con bloqueo del sistema de angiotensina.

Palabras clave:

Pentoxifilina

Palabras clave:

Pentoxifilina

Palabras clave:

Nefropatía diabética

Although blockade of renin-angiotensin system have been cited as the first line of therapy for the management of diabetic nephropathy (DN), however in a substantial number of patients, progression of renal disease are not completely halted by these agents. We have conducted a double blinded clinical trial to assess the additive effect of pentoxifylline on reduction of proteinuria among patients with type 2 DM under blockade of angiotensin system. The dosage of PTX used in our trial was at a low dosage of 400mg daily and to our knowledge, we did not found article which evaluated the antiproteinuric effect of pentoxifylline in this dosage. One hundred patients with DN and persistent proteinuria despite treatment with losartan and enalapril in at least 3 months before inclusion in the study were randomly assigned to two groups. Control group (n=50, 26 males and 24 females) received losartan and enalapril, while treatment group (PTX Group) (n=50, 28 males and 22 females) was given losartan, enalapril and pentoxifylline 400mg/day for 6 months. At the beginning of the study there were no significant differences in demographic and clinical characteristics of patients including serum creatinine, HbA1c, blood pressure and urinary protein excretion between two groups (P>.05). In the PTX group, the mean rate of urinary protein excretion have significantly decreased from 616.66mg to 378.24 after 3 months (P=.000) and to 192.05mg after 6 months (P=.000) whereas no significant changes were observed in the control group. The beneficial antiproteinuric effect of PTX was not associated to the degree of metabolic control and a reduction of blood pressure. In addition, at the end of study, the mean clearance of creatinine was significantly higher in PTX group (P=.04). In conclusion, PTX can significantly provide additive antiproteinuric effect and slow the decrease in GFR among patients with type 2 DM under blockade of angiotensin system.

Keywords:

Proteinuria

Keywords:

Pentoxifylline

Keywords:

Diabetic Nephropathy

El Texto completo está disponible en PDF

Bibliografía

[1]

K/DOQI clinical practice guidelines and clinical practice recommendations for diabetes and chronic kidney disease. Am J Kidney Dis 2007;49(2 Suppl 2):S12. [Pubmed]

[2]

National Institutes of Health. Excerpts from United States Renal Data System 2000 Annual Data Report: atlas of end-stage renal disease in the United States: economic costs of ESRD. Am J Kidney Dis 2000;36:163-76.

[3]

Gross JL, de Azevedo MJ, Silveiro SP, Canani LH, Caramori ML, Zelmanovitz T. Diabetic nephropathy: diagnosis, prevention, and treatment. Diabetes Care 2005;28:164-76. [Pubmed]

[4]

Adler AI, Stevens RJ, Manley SE, Bilous RW, Cull CA, Holman RR; UKPDS GROUP. Development and progression of nephropathy in type 2 diabetes: the United Kingdom Prospective Diabetes Study (UKPDS 64). Kidney Int 2003;63:225-32. [Pubmed]

[5]

Estacio RO, Jeffers BW, Hiatf WR, Biggerstall SL, Gifford N, Schrier RW. The effect of nisoldipine as compared with enalapril on cardiovascular outcomes in patients with non ¿ insulin ¿ dependent diabetes and hypertension. N Engl J Med 1998;338:645-52. [Pubmed]

[6]

Hovind P, Rossing P, Tarnow L, Smidt UM, Parving HH. Progression of diabetic nephropathy. Kidney Int 2001;59:702-9. [Pubmed]

[7]

Parving HH, Hommel E, Jensen BR, Hansen HP. Long-term beneficial effect of ACE inhibition on diabetic nephropathy in normotensive type 1 diabetic patients. Kidney Int 2001;60:228-34. [Pubmed]

[8]

Lewis EJ, Hunsicker LG, Clarke WR, Berl T, Pohl MA, Lewis JB, et al. Renoprotective effect of the angiotensin-receptor antagonist irbesartan in patients with nephropathy due to type 2 diabetes. N Engl J Med 2001;345:851-60. [Pubmed]

[9]

Brenner BM, Cooper ME, de Zeeuw D, Keane WF, Mitch WE, Parving HH, et al. Effects of losartan on renal and cardiovascular outcomes in patients with type 2 diabetes and nephropathy. N Engl J Med 2001;345:861-9. [Pubmed]

[10]

Lewis E, Hunsicker L, Bain R, Rohde R. The effect of angiotensin converting enzyme inhibition on diabetic nephropathy. N Engl J Med 1993;329:1456-62. [Pubmed]

[11]

de Zeeuw D, Remuzzi G, Parving HH, Keane WF, Zhang Z, Shahinfar S, et al. Proteinuria, a target for renoprotection in patients with type 2 diabetic nephropathy: lessons from RENAAL. Kidney Int 2004;65:2309-20. [Pubmed]

[12]

Jafar TH, Stark PC, Schmid CH, Landa M, Maschio G, Marcantoni C, et al.; AIPRD Study Group. Angiotensin-Converting Enzymne Inhibition and Progression of Renal Diseaseet al. Proteinuria as a modifiable risk factor for the progression of non-diabetic renal disease. Kidney Int 2001;60:1131-40. [Pubmed]

[13]

ADVANCE Collaborative Group, Patel A, MacMahon S, Chalmers J, Neal B, Billot L, et al. Intensive blood glucose control and vascular outcomes in patients with type 2 diabetes. N Engl J Med 2008;358:2560-72. [Pubmed]

[14]

Basi S, Lewis JB. Microalbuminuria as a target to improve cardiovascular and renal outcomes. Am J Kidney Dis 2006;47:927-46. [Pubmed]

[15]

Fliser D, Wagner KK, Loos A, Tsikas D, Haller H. Chronic angiotensin II receptor blockade reduces (intra)renal vascular resistance in patients with type 2 diabetes. J Am Soc Nephrol 2005;16:1135-40. [Pubmed]

[16]

Hilgers KF, Veelken R. Type 2 diabetic nephropathy: never too early to treat? J Am Soc Nephrol 2005;16:574-5. [Pubmed]

[17]

Nagai Y, Yao L, Kobori H, Miyata K, Ozawa Y, Miyatake A, et al. Temporary angiotensin II blockade at the prediabetic stage attenuates the development of renal injury in type 2 diabetic rats. J Am Soc Nephrol 2005;16:703-11. [Pubmed]

[18]

Vasylyeva TL, Chen X, Ferry RJ Jr. Insulin-like growth factor binding protein-3 mediates cytokine-induced mesangial cell apoptosis. Growth Horm IGF Res 2005;15:207-14. [Pubmed]

[19]

Lin CL, Wang JY, Huang YT, Kuo YH, Surendran K, Wang FS. Wnt/beta-catenin signaling modulates survival of high glucose-stressed mesangial cells. J Am Soc Nephrol 2006;17:2812-20. [Pubmed]

[20]

Maxhimer JB, Somenek M, Rao G, Pesce CE, Baldwin D Jr, Gattuso P, et al. Heparanase-1 gene expression and regulation by high glucose in renal epithelial cells: a potential role in the pathogenesis of proteinuria in diabetic patients. Diabetes 2005;54:2172-8. [Pubmed]

[21]

van den Hoven MJ, Rops AL, Bakker MA, Aten J, Rutjes N, Roestenberg P, et al. Increased expression of heparanase in overt diabetic nephropathy. Kidney Int 2006;70:2100-8. [Pubmed]

[22]

Nguyen G. Renin/prorenin receptors. Kidney Int 2006;69:1503-9.

[23]

Ichihara A, Suzuki F, Nakagawa T, Kaneshiro Y, Takemitsu T, Sakoda M, et al. Prorenin receptor blockade inhibits development of glomerulosclerosis in diabetic angiotensin II type 1a receptor-deficient mice. J Am Soc Nephrol 2006;17:1950-61. [Pubmed]

[24]

Hohenstein B, Hausknecht B, Boehmer K, Riess R, Brekken RA, Hugo CP. Local VEGF activity but not VEGF expression is tightly regulated during diabetic nephropathy in man. Kidney Int 2006;69:1654-61. [Pubmed]

[25]

de Vriese AS, Tilton RG, Elger M, Stephan CC, Kriz W, Lameire NH. Antibodies against vascular endothelial growth factor improve early renal dysfunction in experimental diabetes. J Am Soc Nephrol 2001;12:993-1000. [Pubmed]

[26]

Hayashida T, Schnaper HW. High ambient glucose enhances sensitivity to TGF-beta1 via extracellular signal--regulated kinase and protein kinase Cdelta activities in human mesangial cells. J Am Soc Nephrol 2004;15:2032-41. [Pubmed]

[27]

Festa A, D¿Agostino R Jr, Howard G, Mykkanen L, Tracy R, Haffner S. Inflammation and microalbuminuria in nondiabetic and type 2 diabetic subjects: The Insulin Resistance Atherosclerosis Study. Kidney Int 2000;58:1703-10. [Pubmed]

[28]

Navarro JF, Mora C, Macía M, García J. Inflammatory parameters are independently associated with urinary albumin excretion in type 2 diabetes mellitus. Am J Kidney Dis 2003;42:53-61. [Pubmed]

[29]

Navarro J. Diabetic nephropathy: A matter of inflammation? Nefrologia 2003;23:381-9. [Pubmed]

[30]

30.Gruden G, Setti G, Hayward A, Sugden D, Duggan S, Burt D, et al. Mechanical stretch induces monocyte chemoattractant activity via an NF-kappaB-dependent monocyte chemoattractant protein-1-mediated pathway in human mesangial cells: inhibition by rosiglitazone. J Am Soc Nephrol 2005;16:688-96. [Pubmed]

[31]

Akahori H, Ota T, Torita M, Ando H, Kaneko S, Takamura T. Tranilast prevents the progression of experimental diabetic nephropathy through suppression of enhanced extracellular matrix gene expression. J Pharmacol Exp Ther 2005;314:514-21. [Pubmed]

[32]

Soma J, Sato K, Saito H, Tsuchiya Y. Effect of tranilast in early-stage diabetic nephropathy. Nephrol Dial Transplant 2006;21:2795-9. [Pubmed]

[33]

Soma J, Sugawara T, Huang YD, Nakajima J, Kawamura M. Tranilast slows the progression of advanced diabetic nephropathy. Nephron 2002;92:693-8. [Pubmed]

[34]

34. Abdollahi M, Chan TS, Subrahmanyam V, O'Brien PJ. Effects of phosphodiesterase 3, 4, 5 inhibitors on hepatocyte cAMP levels, glycogenolysis, gluconeogenesis and susceptibility to a mitochondrial toxin. Mol Cell Biochem 2003;252:205-11. [Pubmed]

[35]

35. Noyan T, Onem O, Ramazan Sekeroglu M, Koseoglu B, Dulger H, Bayram I, et al. Effects of erythropoietin and pentoxifylline on the oxidant and antioxidant systems in the experimental short bowel syndrome. Cell Biochem Funct 2003;21:49-54. [Pubmed]

[36]

Navarro J, Mora C, Muros M, Macía M, García J. Effects of pentoxifylline administration on urinary N-acetyl-beta-glucosaminidase excretion in type 2 diabetic patients: A short-term, prospective, randomised study. Am J Kidney Dis 2003;42:264-70. [Pubmed]

[37]

37. Navarro JF, Mora-Fernández C. The role of TNF-alpha in diabetic nephropathy: Pathogenic and therapeutic implications. Cytokine Growth Factor Rev 2006;17:441-50. [Pubmed]

[38]

Navarro J, Mora C, Muros M, Macía M, García J. Additive antiproteinuric effect of pentoxifylline in patients with type 2 diabetes under angiotensin II receptor blockade: A short-term, randomized, controlled trial. J Am Soc Nephrol 2005;16:2119-26. [Pubmed]

[39]

Harmankaya O, Seber S, Yilmaz M. Combination of pentoxifylline with angiotensin converting enzyme inhibitors produces an additional reduction in microalbuminuria in hypertensive type 2 diabetic patients. Ren Fail 2003;25:465-70. [Pubmed]

[40]

Diskin CJ, Stokes TJ, Dansby LM, Radcliff L, Carter TB. Will the addition of pentoxifylline reduce proteinuria in patients with diabetic glomerulosclerosis refractory to maximal doses of both an angiotensin-converting enzyme inhibitor and an angiotensin receptor blocker? J Nephrol 2007;20:410-6. [Pubmed]

[41]

Aminorroaya A, Janghorbani M, Rezvanian H, Aminian T, Gharavi M, Amini M. Comparison of the effect of pentoxifylline and captopril on proteinuria in patients with type 2 diabetes mellitus. Nephron Clin Pract 2005;99:c73-7. [Pubmed]

[42]

Rodríguez-Morán M, Guerrero-Romero F. Pentoxifylline is as effective as captopril in the reduction of microalbuminuria in non-hypertensive type 2 diabetic patients--a randomized, equivalent trial. Clin Nephrol 2005;64:91-7. [Pubmed]

[43]

43. Perkins RM, Aboudara MC, Uy AL, Olson SW, Cushner HM, Yuan CM. Effect of pentoxifylline on GFR decline in CKD: a pilot, double-blind, randomized, placebo-controlled trial. Am J Kidney Dis 2009;53:606-16. [Pubmed]

Indexada en:

Síguenos:

Indexada en:

Síguenos:

Suscríbase a la newsletter