Effect of pentoxifylline on proteinuria, markers of tubular injury and oxidative stress in non-diabetic patients with chronic kidney disease - placebo controlled, randomized, cross-over study
Languages of publication
Background: Inhibition of the renin-angiotensin-aldosterone system (RAAS) with angiotensin converting enzyme inhibitors (ACEI) and/or angiotensin II subtype 1 receptor antagonists (ARB) is a common strategy used in the management of patients with chronic kidney disease (CKD). However, there is no universal therapy that can stop progression of CKD. Pentoxifylline (PTE) is a non-specific phosphodiesterase inhibitor with anti-inflammatory properties. It has been reported to have promising effects in CKD treatment. Methods: In a placebo-controlled, randomized, cross-over study we evaluated the influence of PTE (1200 mg/day) added to RAAS blockade on proteinuria, surrogate markers of tubular injury and oxidative stress-dependent products in 22 non-diabetic patients with proteinuria (0.4-4.3 g per 24h) with normal or declined kidney function [eGFR 37-178 mL/min]. In an eight-week run-in period, therapy using ACEI and/or ARB was adjusted to achieve a blood pressure below 130/80 mm Hg. Next, patients were randomly assigned to one of two treatment sequences: PTE/washout/placebo or placebo/washout/PTE. Clinical evaluation and laboratory tests were performed at the randomization point and after each period of the study. Results: The PTE therapy reduced proteinuria (by 26%) as compared to placebo. There were no differences in α1-microglobulin, urine excretion of N-acetyl-β-d-glucosaminidase (NAG), hsCRP, the urinary excretion of 15-F2t-isoprostane, blood pressure (BP), eGFR and serum creatinine between the PTE and placebo groups. Conclusion: Pentoxifylline may decrease proteinuria in non-diabetic patients with CKD.
- Arici M, Walls J (2001) End-stage renal disease, atherosclerosis, and cardiovascular mortality: is C-reactive protein the missing link? Kidney Int 59: 407-414.
- Bazzi C, Petrini C, Rizza V, Arrigo G, Napodano P, Paparella M, D'Amico G (2002) Urinary N-acetyl-β-glucosaminidase excretion is a marker of tubular cell dysfunction and a predictor of outcome in primary glomerulonephritis. Nephrol Dial Transplant 17: 1890-1896.
- Belloc F, Jaloustre C, Dumain P, Lacombe F, Lenoble M, Boisseau MR (1995) Effect of pentoxifylline on apoptosis of cultured cells. J Cardiovasc Pharmacol 25 (Suppl 2): S71-S74.
- Benbernou N, Esnault S, Potron G, Guenounou M (1995) Regulatory effects of pentoxifylline on T-helper cell-derived cytokine production in human blood cells. J Cardiovasc Pharmacol 25 (Suppl 2): S75-S79.
- Bienvenu J, Doche C, Gutowski MC, Lenoble M, Lepape A, Perdrix JP (1995) Production of proinflammatory cytokines and cytokines involved in the TH1/TH2 balance is modulated by pentoxifylline. J Cardiovasc Pharmacol 25 (Suppl 2): S80-S84.
- Chen YM, Chien CT, Hu-Tsai MI, Wu KD, Tsai CC, Wu MS, Tsai TJ (1999a) Pentoxifylline attenuates experimental mesangial proliferative glomerulonephritis. Kidney Int 56: 932-943.
- Chen YM, Wu KD, Tsai TJ, Hsieh BS (1999b) Pentoxifylline inhibits PDGF-induced proliferation of and TGF-β-stimulated collagen synthesis by vascular smooth muscle cells. J Mol Cell Cardiol 31: 773-783.
- Cockcroft DW, Gault MH (1976) Prediction of creatinine clearance from serum creatinine. Nephron 16: 31-41.
- Dehghan A, Kardys I, de Maat MP, Uitterlinden AG, Sijbrands EJ, Bootsma AH, Stijnen T, Hofman A, Schram MT, Witteman JC (2007) Genetic variation, C-reactive protein levels, and incidence of diabetes. Diabetes 56: 872-878.
- Ducloux D, Bresson-Vautrin C, Chalopin J (2001) Use of pentoxifylline in membranous nephropathy. Lancet 357: 1672-1673.
- Fam SS, Morrow JD (2003) The isoprostanes: unique products of arachidonic acid oxidation - a review. Curr Med Chem 10: 1723-1740.
- Frampton JE, Brogden RN (1995) Pentoxifylline (oxpentifylline). A review of its therapeutic efficacy in the management of peripheral vascular and cerebrovascular disorders. Drugs Aging 7: 480-503.
- Freitas JP, Filipe PM (1995) Pentoxifylline. A hydroxyl radical scavenger. Biol Trace Elem Res 47: 307-311.
- Galindo-Rodriguez G, Bustamante R, Esquivel-Nava G, Salazar-Exaire D, Vela-Ojeda J, Vadillo-Buenfil M, Avina-Zubieta JA (2003) Pentoxifylline in the treatment of refractory nephrotic syndrome secondary to lupus nephritis. J Rheumatol 30: 2382-2384.
- Holdt-Lehmann B, Lehmann A, Korten G, Nagel H, Nizze H, Schuff-Werner P (2000) Diagnostic value of urinary alanine aminopeptidase and N-acetyl-β-d-glucosaminidase in comparison to α1-microglobulin as a marker in evaluating tubular dysfunction in glomerulonephritis patients. Clin Chim Acta 297: 93-102.
- Lin SL, Chen YM, Chiang WC, Tsai TJ, Chen WY (2004) Pentoxifylline: a potential therapy for chronic kidney disease. Nephrology (Carlton) 9: 198-204.
- Lin SL, Chen RH, Chen YM, Chiang WC, Lai CF, Wu KD, Tsai TJ (2005) Pentoxifylline attenuates tubulointerstitial fibrosis by blocking Smad3/4-activated transcription and profibrogenic effects of connective tissue growth factor. J Am Soc Nephrol 16: 2702-2713.
- Lin SL, Chiang WC, Chen YM, Lai CF, Tsai TJ, Hsieh BS (2005) The renoprotective potential of pentoxifylline in chronic kidney disease. J Chin Med Assoc 68: 99-105.
- Lin SL, Chen YM, Chiang WC, Wu KD, Tsai TJ (2008) Effect of pentoxifylline in addition to losartan on proteinuria and GFR in CKD: a 12-month randomized trial. Am J Kidney Dis 52: 464-474.
- Mandell GL (1995) Cytokines, phagocytes, and pentoxifylline. J Cardiovasc Pharmacol 25 (Suppl 2): S20-S22.
- Maroni BJ, Steinman TI, Mitch WE (1985) A method for estimating nitrogen intake of patients with chronic renal failure. Kidney Int 27: 58-65.
- Maruhn D (1976) Rapid colorimetric assay of β-galactosidase and N-acetyl-β-glucosaminidase in human urine. Clin Chim Acta 73: 453-461.
- McCormick BB, Sydor A, Akbari A, Fergusson D, Doucette S, Knoll G (2008) The effect of pentoxifylline on proteinuria in diabetic kidney disease: a meta-analysis. Am J Kidney Dis 52: 454-463.
- Navarro JF, Mora C, Muros M, Maca M, Garca J (2003) Effects of pentoxifylline administration on urinary N-acetyl-β-glucosaminidase excretion in type 2 diabetic patients: a short-term, prospective, randomized study. Am J Kidney Dis 42: 264-270.
- Paap CM, Simpson KS, Horton MW, Schaefer KL, Lassman HB, Sack MR (1996) Multiple-dose pharmacokinetics of pentoxifylline and its metabolites during renal insufficiency. Ann Pharmacother 30: 724-729.
- Perkins RM, Aboudara MC, Uy AL, Olson SW, Cushner HM, Yuan CM (2009) Effect of pentoxifylline on GFR decline in CKD: a pilot, double-blind, randomized, placebo-controlled trial. Am J Kidney Dis 53: 606-616.
- Pradhan AD, Manson JE, Rifai N, Buring JE, Ridker PM (2001) C-reactive protein, interleukin 6, and risk of developing type 2 diabetes mellitus. Jama 286: 327-334.
- Renke M, Rutkowski P, Tylicki L, Zietkiewicz M, Larczynski W, Rutkowski B (2008) Pentoxifylline old drug or new hope for nephrology? Przegl Lek 65: 358-361 (in Polish).
- Renke M, Tylicki L, Rutkowski P, Rutkowski B (2004) Low-dose angiotensin II receptor antagonists and angiotensin II-converting enzyme inhibitors alone or in combination for treatment of primary glomerulonephritis. Scand J Urol Nephrol 38: 427-433.
- Renke M, Tylicki L, Rutkowski P, Wojnarowski K, Lysiak-Szydlowska W, Rutkowski B (2005) Low-dose dual blockade of the renin-angiotensin system improves tubular status in non-diabetic proteinuric patients. Scand J Urol Nephrol 39: 511-517.
- Rutkowski P, Tylicki L, Renke M, Korejwo G, Zdrojewski Z, Rutkowski B (2004) Low-dose dual blockade of the renin-angiotensin system in patients with primary glomerulonephritis. Am J Kidney Dis 43: 260-268.
- Tonelli M, Sacks F, Pfeffer M, Jhangri GS, Curhan G (2005) Biomarkers of inflammation and progression of chronic kidney disease. Kidney Int 68: 237-245.
- Tylicki L, Larczynski W, Rutkowski B (2005) Renal protective effects of the renin-angiotensin-aldosterone system blockade: from evidence-based approach to perspectives. Kidney Blood Press Res 28: 230-242.
- Tylicki L, Biedunkiewicz B, Chamienia A, Wojnarowski K, Zdrojewski Z, Aleksandrowicz E, Lysiak-Szydlowska W, Rutkowski B (2007a) Renal allograft protection with angiotensin II type 1 receptor antagonists. Am J Transplant 7: 243-248.
- Tylicki L, Rutkowski P, Renke M, Rutkowski B (2007b) Addition of aldosterone receptor blocker to dual renin-angiotensin-aldosterone blockade leads to limitation of tubulointerstitial injury of kidney. Kidney Int 72: 1164-1165.
- Vilayur E, Harris DC (2009) Emerging therapies for chronic kidney disease: what is their role? Nat Rev Nephrol 5: 375-383.
- Ward A, Clissold SP (1987) Pentoxifylline. A review of its pharmacodynamic and pharmacokinetic properties, and its therapeutic efficacy. Drugs 34: 50-97.
- Zoja C, Abbate M, Remuzzi G (2006) Progression of chronic kidney disease: insights from animal models. Curr Opin Nephrol Hypertens 15: 250-257.
Publication order reference