Pentoxifylline ameliorates proteinuria through suppression of renal monocyte chemoattractant protein-1 in patients with proteinuric primary glomerular diseases
2006; Elsevier BV; Volume: 69; Issue: 8 Linguagem: Inglês
10.1038/sj.ki.5000302
ISSN1523-1755
AutoresYung‐Ming Chen, Shuei‐Liong Lin, Wen‐Chih Chiang, Kwan‐Dun Wu, Tun‐Jun Tsai,
Tópico(s)Pregnancy and Medication Impact
ResumoProteinuria (albuminuria) reflects dysfunction of the glomerular permeability barrier in which inflammatory cytokines play a key role. Pentoxifylline (PTX) is a phosphodiesterase inhibitor that possesses potent anti-inflammatory and immunomudulatory effects. This study evaluated the effectiveness of PTX to reduce proteinuria and inflammatory mediators in patients with proteinuric primary glomerular diseases. Seventeen patients with primary glomerular diseases, a persistent spot proteinuria exceeding 1.5 g/g creatinine (Cr) and a glomerular filtration rate between 24 and 115 ml/min/1.73 m2 were treated with PTX 400 mg twice daily for 6 months. Before and after the treatment, serum Cr, plasma renin activity and aldosterone concentrations, plasma and urinary tumor necrosis factor (TNF)-α, interleukin-1β and monocyte chemoattractant protein (MCP)-1, as well as urinary protein and Cr were measured. PTX significantly reduced urinary protein excretion, along with an increase of serum albumin. A significant correlation existed between the basal urinary protein/Cr and the basal urinary MCP-1/Cr ratios. PTX lowered the urinary MCP-1/Cr ratio, and the percent reduction of urinary protein/Cr ratio correlated directly with the precent decrease of urinary MCP-1/Cr ratio after PTX treatment. There was no significant change in blood pressure, renal function, biochemical parameters, plasma renin activity and aldosterone concentrations, or plasma TNF-α and MCP-1 levels during the study. In conclusion, administration of PTX 800 mg per day is safe and effective for reducing proteinuria in patients with proteinuric primary glomerular diseases. This beneficial effect occurs in close association with a reduction of urinary MCP-1 excretion. Proteinuria (albuminuria) reflects dysfunction of the glomerular permeability barrier in which inflammatory cytokines play a key role. Pentoxifylline (PTX) is a phosphodiesterase inhibitor that possesses potent anti-inflammatory and immunomudulatory effects. This study evaluated the effectiveness of PTX to reduce proteinuria and inflammatory mediators in patients with proteinuric primary glomerular diseases. Seventeen patients with primary glomerular diseases, a persistent spot proteinuria exceeding 1.5 g/g creatinine (Cr) and a glomerular filtration rate between 24 and 115 ml/min/1.73 m2 were treated with PTX 400 mg twice daily for 6 months. Before and after the treatment, serum Cr, plasma renin activity and aldosterone concentrations, plasma and urinary tumor necrosis factor (TNF)-α, interleukin-1β and monocyte chemoattractant protein (MCP)-1, as well as urinary protein and Cr were measured. PTX significantly reduced urinary protein excretion, along with an increase of serum albumin. A significant correlation existed between the basal urinary protein/Cr and the basal urinary MCP-1/Cr ratios. PTX lowered the urinary MCP-1/Cr ratio, and the percent reduction of urinary protein/Cr ratio correlated directly with the precent decrease of urinary MCP-1/Cr ratio after PTX treatment. There was no significant change in blood pressure, renal function, biochemical parameters, plasma renin activity and aldosterone concentrations, or plasma TNF-α and MCP-1 levels during the study. In conclusion, administration of PTX 800 mg per day is safe and effective for reducing proteinuria in patients with proteinuric primary glomerular diseases. This beneficial effect occurs in close association with a reduction of urinary MCP-1 excretion. Proteinuria (albuminuria) denotes a sign of glomerular diseases and represents a marker of injury to the glomerular permeability barrier.1.Keane W. Proteinuria: its clinical importance and role in progressive renal disease.Am J Kidney Dis. 2000; 35: S97-S105Abstract Full Text Full Text PDF PubMed Scopus (126) Google Scholar, 2.Iseki K. Ikemiya Y. Iseki C. Takishita S. Proteinuria and the risk of developing end-stage renal disease.Kidney Int. 2003; 63: 1468-1474Abstract Full Text Full Text PDF PubMed Scopus (399) Google Scholar The pathogenesis of glomerular proteinuria is not completely clear, but accumulating evidence suggests that proinflammatory cytokines and chemokines play a pivotal role. Patients with immunoglobulin A (IgA) nephropathy and membranous glomerulonephritis were reported to excrete excessive amount of urinary tumor necrosis factor (TNF)-α and/or interleukin (IL)-1β,3.Honkanen E. Teppo A.M. Meri S. et al.Urinary excretion of cytokines and complement SC5b-9 in idiopathic membranous glomerulonephritis.Nephrol Dial Transplant. 1994; 9: 1553-1559PubMed Google Scholar, 4.Ozen S. Saatci U. Tinaztepe K. et al.Urinary tumor necrosis factor levels in primary glomerulopathies.Nephron. 1994; 66: 291-294Crossref PubMed Scopus (29) Google Scholar, 5.Wu T.H. Wu S.C. Huang T.P. et al.Increased excretion of tumor necrosis factor alpha and interleukin 1 beta in urine from patients with IgA nephropathy and Schonlein–Henoch purpura.Nephron. 1996; 74: 79-88Crossref PubMed Scopus (58) Google Scholar, 6.Honkanen E. von Willebrand E. Teppo A.M. et al.Adhesion molecules and urinary tumor necrosis factor-alpha in idiopathic membranous glomerulonephritis.Kidney Int. 1998; 53: 909-917Abstract Full Text Full Text PDF PubMed Google Scholar and patients with diabetic nephropathy, lupus nephritis, IgA nephropathy and active renal vasculitis were found to have elevated urinary levels of monocyte chemoattractant protein (MCP)-1.7.Saitoh A. Sekizuka K. Hayashi T. et al.Detection of MCP-1 in patients with diabetic nephropathy.Nephron. 1998; 80: 99Crossref PubMed Scopus (15) Google Scholar, 8.Morii T. Fujita H. Narita T. et al.Increased urinary excretion of monocyte chemoattractant protein-1 in proteinuric renal diseases.Ren Fail. 2003; 25: 439-444Crossref PubMed Scopus (29) Google Scholar, 9.Saitoh A. Suzuki Y. Takeda M. et al.Urinary levels of monocyte chemoattractant protein (MCP)-1 and disease activity in patients with IgA nephropathy.J Clin Lab Anal. 1998; 12: 1-5Crossref PubMed Scopus (29) Google Scholar, 10.Rovin B.H. Doe N. Tan L.C. Monocyte chemoattractant protein-1 levels in patients with glomerular disease.Am J Kidney Dis. 1996; 27: 640-646Abstract Full Text PDF PubMed Scopus (118) Google Scholar, 11.Wada T. Yokoyama H. Su S.B. et al.Monitoring urinary levels of monocyte chemotactic and activating factor reflects disease activity of lupus nephritis.Kidney Int. 1996; 49: 761-767Abstract Full Text PDF PubMed Scopus (184) Google Scholar, 12.Noris M. Bernasconi S. Casiraghi F. et al.Monocyte chemoattractant protein-1 is excreted in excessive amounts in the urine of patients with lupus nephritis.Lab Invest. 1995; 73: 804-809PubMed Google Scholar, 13.Tam F.W. Sanders J.S. George A. et al.Urinary monocyte chemoattractant protein-1 (MCP-1) is a marker of active renal vasculitis.Nephrol Dial Transplant. 2004; 19: 2761-2768Crossref PubMed Scopus (79) Google Scholar Regardless of the types of renal diseases, these urinary inflammatory mediators correlate well with the magnitude of proteinuria. The filtered and subsequently reabsorbed proteins can in turn activate renal tubular cells to release additional inflammatory mediators, including TNF-α, IL-1β and MCP-1 into the interstitium, contributing to progressive interstitial damage seen in many proteinuric glomerular diseases.14.Burton C.J. Combe C. Walls J. Harris K.P. Secretion of chemokines and cytokines by human tubular epithelial cells in response to proteins.Nephrol Dial Transplant. 1999; 14: 2628-2633Crossref PubMed Scopus (75) Google Scholar, 15.Zandi-Nejad K. Eddy A.A. Glassock R.J. Brenner B.M. Why is proteinuria an ominous biomarker of progressive kidney disease?.Kidney Int. 2004; 66: S76-S89Abstract Full Text Full Text PDF Scopus (131) Google Scholar Thus, proteinuria is generally regarded as the most powerful predictor for the progression of glomerular diseases, and has been used as a surrogate end point for therapeutic interventions.16.Remuzzi G. Schieppati A. Ruggenenti P. Nephropathy in patients with type 2 diabetes.N Engl J Med. 2002; 346: 1145-1151Crossref PubMed Scopus (486) Google Scholar, 17.Levey A.S. Nondiabetic kidney disease.N Engl J Med. 2002; 347: 1505-1511Crossref PubMed Scopus (118) Google Scholar Indeed, there is evidence that an early reduction in proteinuria following therapeutic interventions predicts an improvement in renal outcomes.18.Ruggenenti P. Perna A. Remuzzi G. Retarding progression of chronic renal disease: the neglected issue of residual proteinuria.Kidney Int. 2003; 63: 2254-2261Abstract Full Text Full Text PDF PubMed Scopus (214) Google Scholar Given the importance of TNF-α, IL-1β and MCP-1 in the pathogenesis of poteinuria, it is conceivable that pharmacological agents capable of suppressing these inflammatory mediators might have therapeutic potential for proteinuric glomerular diseases. Pentoxifylline (PTX) is a phosphodiesterase inhibitor that is used clinically to treat patients with peripheral vascular disorders.19.Jacoby D. Mohler III, E.R. Drug treatment of intermittent claudication.Drugs. 2004; 64: 1657-1670Crossref PubMed Scopus (60) Google Scholar In addition to its hemorheologic activity, PTX possesses potent anti-inflammatory and immunomodulatory properties.20.Lin S.L. Chen Y.M. Chiang W.C. et al.Pentoxifylline: a potential therapy for chronic kidney disease.Nephrology. 2004; 9: 198-204Crossref PubMed Scopus (31) Google Scholar In vivo, PTX has shown its ability to attenuate nephrotic syndrome secondary to membranous glomerulonephritis21.Ducloux D. Bresson-Vautrin C. Chalopin J. Use of pentoxifylline in membranous nephropathy.Lancet. 2001; 357: 1672-1673Abstract Full Text Full Text PDF PubMed Scopus (57) Google Scholar and lupus nephritis,22.Galindo-Rodriguez G. Bustamante R. Esquivel-Nava G. et al.Pentoxifylline in the treatment of refractory nephrotic syndrome secondary to lupus nephritis.J Rheumatol. 2003; 30: 2382-2384PubMed Google Scholar and to reduce subnephrotic proteinuria of early and advanced diabetic nephropathy.23.Navarro J.F. Mora C. Rivero A. et al.Urinary protein excretion and serum tumor necrosis factor in diabetic patients with advanced renal failure: effects of pentoxifylline administration.Am J Kidney Dis. 1999; 33: 458-463Abstract Full Text Full Text PDF PubMed Scopus (120) Google Scholar, 24.Navarro J.F. Mora C. Muros M. et al.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. 2003; 42: 264-270Abstract Full Text Full Text PDF PubMed Scopus (56) Google Scholar However, data with respect to its effect on non-nephrotic primary glomerular diseases are lacking. Moreover, the antiproteinuric effect of PTX has been traditionally attributed to downregulation of TNF-α.21.Ducloux D. Bresson-Vautrin C. Chalopin J. Use of pentoxifylline in membranous nephropathy.Lancet. 2001; 357: 1672-1673Abstract Full Text Full Text PDF PubMed Scopus (57) Google Scholar, 23.Navarro J.F. Mora C. Rivero A. et al.Urinary protein excretion and serum tumor necrosis factor in diabetic patients with advanced renal failure: effects of pentoxifylline administration.Am J Kidney Dis. 1999; 33: 458-463Abstract Full Text Full Text PDF PubMed Scopus (120) Google Scholar Whether or not other inflammatory mediators are also affected by PTX has never been studied. Our previous works have shown that PTX can inhibit cytokine or albumin-induced MCP-1 production in vitro,25.Lin S.L. Chen Y.M. Chien C.T. et al.Pentoxifylline attenuated the renal disease progression in rats with remnant kidney.J Am Soc Nephrol. 2002; 13: 2916-2929Crossref PubMed Scopus (103) Google Scholar and attenuate proteinuria in association with suppression of renal MCP-1 mRNA expression in experimental glomerulonephritis.26.Chen Y.M. Chien C.T. Hu-Tsai M.I. et al.Pentoxifylline attenuates experimental mesangial proliferative glomerulonephritis.Kidney Int. 1999; 56: 932-943Abstract Full Text Full Text PDF PubMed Scopus (74) Google Scholar, 27.Chen Y.M. Ng Y.Y. Lin S.L. et al.Pentoxifylline suppresses renal tumour necrosis factor-α and ameliorates experimental crescentic glomerulonephritis in rats.Nephrol Dial Transplant. 2004; 19: 1106-1115Crossref PubMed Scopus (50) Google Scholar Thus, we hypothesize that PTX might be effective in lowering proteinuria by modulating renal MCP-1 production in human glomerular diseases. This study was thereby performed to investigate the potential antiproteinuric and anti-inflammatory effects of PTX in patients with proteinuric primary glomerular diseases. Treatment with PTX for 6 months resulted in a significant reduction of urinary protein/creatinine (Cr) ratio (before vs 6 months after PTX treatment, 2.82±0.28 vs 1.79±0.22 g/g Cr, P=0.006, Figure 1) and 24-h urinary protein excretion (before vs 6 months after PTX treatment, 2.95±0.31 vs 1.95±0.25 g/g Cr/day, P=0.001, Figure 1), along with an increase of serum albumin (before vs 6 months after PTX treatment, 3.6±0.1 vs 4.0±0.1 g/dl, P=0.001, Table 1). PTX significantly lowered urinary MCP-1/Cr (before vs 6 months after PTX treatment, 789.9±221.0 vs 423.0±78.6 ng/g Cr, P=0.009), but not TNF-α/Cr or IL-1β/Cr ratio (Table 1 and Figure 2). Plasma levels of TNF-α and MCP-1 did not change appreciably before and after PTX treatment (Table 1). Detectable levels of IL-1β were found in only three out of 34 plasma samples, and these were too few in number to statistically analyze.Table 1Blood pressure, proteinuria, biochemistry, plasma renin activity, plasma aldosterone, plasma and urinary inflammatory mediators in the studied patients, before and 6 months after PTX therapyBaselineTherapyPSystolic BP (mm Hg)134±5130±40.359Diastolic BP (mm Hg)78±276±30.132Spot proteinuria (g/g Cr)2.82±0.281.79±0.220.00624-h proteinuria (g/g Cr/day)2.95±0.311.95±0.250.001Glomerular filtrateion rate (ml/min/1.73 m2)64.9±6.768.4±8.20.917Cr clearance (ml/min)63.1±6.165.7±7.60.776Cr (mg/dl)1.2±0.11.2±0.20.854Albumin (g/dl)3.6±0.14.0±0.10.001Cholesterol (mg/dl)207±8205±80.344Alanine aminotransferase (U/l)19±319±20.533Hemoglobin (g/dl)12.9±0.412.7±0.30.264White blood cell (/μl)7,433±3597,258±3270.463Platelet (× 103/μl)232±12237±110.308Fasting glucose (mg/dl)93±393±20.689Plasma renin activity (ng/ml/h)1.84±0.422.05±0.440.435Plasma aldosterone (ng/dl)22.1±2.322.3±2.60.393Urinary IL-1β (ng/g Cr)81.3±25.750.0±7.30.653Urinary TNF-α (ng/g Cr)104.2±25.378.6±12.80.586Plasma TNF-α (pg/ml)5.2±0.86.2±1.00.679Urinary MCP-1 (ng/g Cr)789.9±221.0423.0±78.60.009Plasma MCP-1 (pg/ml)191.3±18.4184.2±16.00.381BP, blood pressure; Cr, creatinine; MCP, monocyte chemoattractant protein; PTX, pentoxifylline; TNF, tumor necrosis factor. Open table in a new tab Figure 2Changes of urinary cytokines before and after PTX therapy.View Large Image Figure ViewerDownload (PPT) BP, blood pressure; Cr, creatinine; MCP, monocyte chemoattractant protein; PTX, pentoxifylline; TNF, tumor necrosis factor. Correlation analysis showed a significant relationship between the basal urinary protein/Cr ratio and the basal urinary MCP-1/Cr (Spearman's coefficient r=0.650, P=0.009), but not TNF-α/Cr (Spearman's coefficient r=0.020, P=0.937), IL-1β/Cr (Spearman's coefficient r=0.172, P=0.492), plasma renin activity (Spearman's coefficient r=0.115, P=0.645), plasma aldosterone concentrations (Spearman's coefficient r=-0.095, P=0.702), estimated Cr clearances (Spearman's coefficient r=-0.395, P=0.114) or glomerular filtration rates (Spearman's coefficient r=-0.345, P=0.167). Moreover, the percent reduction of urinary protein/Cr ratios after PTX treatment correlated directly with the precent decrease of urinary MCP-1/Cr ratios (Spearman's coefficient r=0.561, P=0.025) (Figure 3). There was no other parameter that correlated with the improvement in proteinuria (data not shown). Although the renal function before and after PTX treatment remained stable (Table 1), there were two patients with IgA nephropathy whose glomerular filtration rates (serum Cr) changed from 24.4 and 23.8 ml/min (2.3 and 2.3 mg/dl) at onset to 20.2 and 18.9 ml/min (2.7 and 2.8 mg/dl), respectively, 6 months after PTX treatment (Figure 4). Both patients were hypertensive and received standard antihypertensive therapies other than angiotensin blockers, and both displayed stationary or reduced urinary protein excretion after PTX treatment. By contrast, two patients whose proteinuria increased after PTX treatment exhibited a stable renal function during the study. Six patients discontinued PTX treatment or tapered the dose of PTX after the end of the study. Among them, four had a sustained, reduced level of proteinuria during the ensuing 6 months, whereas two experienced a flare-up of proteinuria, which was ameliorated by reinstitution of PTX. The remaining 11 patients chose to continue PTX treatment for an additional 6 months, and at 1 year the 24-h proteinuria remained significantly lower than their pre-PTX levels (3.01±0.39 vs 2.02±0.29 g/g Cr/day, P=0.0128). There was no significant change in systolic or diastolic blood pressure (BP), alanine aminotransferase, potassium, hemogram, fasting sugar, cholesterol, plasma renin activity or plasma aldosterone concentrations during the study (Table 1). No patient discontinued the treatment due to side effects. One patient experienced gastric upset that disappeared after taking the drug after meals. This study demonstrates that treatment with PTX in proteinuric patients with primary glomerular diseases resulted in a significant reduction of proteinuria, along with an increase of serum albumin and a decline of urinary MCP-1 levels. These effects of PTX occurred in the absence of a reduction of systemic BP. Moreover, a significant correlation was found between proteinuria and urinary excretion of MCP-1 at basal of the study, and the reduction of proteinuria following PTX treatment correlated well with the decrease of urinary excretion of MCP-1. This study is limited by lack of a separate control group. Nevertheless, the beneficial effect of PTX appeared to last among the 11 patients who continued PTX treatment for 1 year. Further, two out of the six (33%) patients who ceased or tapered PTX treatment experienced a flare-up of proteinuria, which could be ameliorated by reinstitution of the drug. Based on these observations and the results of previous studies,21.Ducloux D. Bresson-Vautrin C. Chalopin J. Use of pentoxifylline in membranous nephropathy.Lancet. 2001; 357: 1672-1673Abstract Full Text Full Text PDF PubMed Scopus (57) Google Scholar, 22.Galindo-Rodriguez G. Bustamante R. Esquivel-Nava G. et al.Pentoxifylline in the treatment of refractory nephrotic syndrome secondary to lupus nephritis.J Rheumatol. 2003; 30: 2382-2384PubMed Google Scholar, 23.Navarro J.F. Mora C. Rivero A. et al.Urinary protein excretion and serum tumor necrosis factor in diabetic patients with advanced renal failure: effects of pentoxifylline administration.Am J Kidney Dis. 1999; 33: 458-463Abstract Full Text Full Text PDF PubMed Scopus (120) Google Scholar, 24.Navarro J.F. Mora C. Muros M. et al.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. 2003; 42: 264-270Abstract Full Text Full Text PDF PubMed Scopus (56) Google Scholar we consider PTX an effective agent capable of reducing proteinuria in our studied patients. The administration of PTX to our patients did not result in significant changes of arterial BP or the renin–aldosterone axis. Thus, the antiproteinuric effect of PTX is not likely mediated via alterations of hemodynamic processes. Our data indicate that suppression of renal MCP-1 may be involved in the decrease of proteinuria. MCP-1 is the strongest known chemotactic factor for monocytes/macrophages, which plays an important role in the development of proteinuria due to glomerular disorders.7.Saitoh A. Sekizuka K. Hayashi T. et al.Detection of MCP-1 in patients with diabetic nephropathy.Nephron. 1998; 80: 99Crossref PubMed Scopus (15) Google Scholar, 8.Morii T. Fujita H. Narita T. et al.Increased urinary excretion of monocyte chemoattractant protein-1 in proteinuric renal diseases.Ren Fail. 2003; 25: 439-444Crossref PubMed Scopus (29) Google Scholar, 9.Saitoh A. Suzuki Y. Takeda M. et al.Urinary levels of monocyte chemoattractant protein (MCP)-1 and disease activity in patients with IgA nephropathy.J Clin Lab Anal. 1998; 12: 1-5Crossref PubMed Scopus (29) Google Scholar, 10.Rovin B.H. Doe N. Tan L.C. Monocyte chemoattractant protein-1 levels in patients with glomerular disease.Am J Kidney Dis. 1996; 27: 640-646Abstract Full Text PDF PubMed Scopus (118) Google Scholar, 11.Wada T. Yokoyama H. Su S.B. et al.Monitoring urinary levels of monocyte chemotactic and activating factor reflects disease activity of lupus nephritis.Kidney Int. 1996; 49: 761-767Abstract Full Text PDF PubMed Scopus (184) Google Scholar, 12.Noris M. Bernasconi S. Casiraghi F. et al.Monocyte chemoattractant protein-1 is excreted in excessive amounts in the urine of patients with lupus nephritis.Lab Invest. 1995; 73: 804-809PubMed Google Scholar Accumulating evidence suggests that the filtered and subsequently reabsorbed proteins may activate tubular epithelial cells to release additional MCP-1 into the interstitium, causing further monocyte infiltration and monocyte activity, and leading ultimately to progressive interstitial damage seen in many proteinuric glomerular diseases.28.Wang Y. Chen J. Chen L. et al.Induction of monocyte chemoattractant protein-1 in proximal tubule cells by urinary protein.J Am Soc Nephrol. 1997; 8: 1537-1545PubMed Google Scholar This assumption is supported by gene therapy experiments which show that blockade of MCP-1 resulted in a reduction of proteinuria and/or histological lesions in murine models of adriamycin nephrosis, lupus nephritis and unilateral ureteral obstruction nephropathy.29.Shimizu S. Nakashima H. Masutani K. et al.Anti-monocyte chemoattractant protein-1 gene therapy attenuates nephritis in MRL/lpr mice.Rheumatology (Oxford). 2004; 43: 1121-1128Crossref PubMed Scopus (78) Google Scholar, 30.Wada T. Furuichi K. Sakai N. et al.Gene therapy via blockade of monocyte chemoattractant protein-1 for renal fibrosis.J Am Soc Nephrol. 2004; 15: 940-948Crossref PubMed Scopus (147) Google Scholar, 31.Wu H. Wang Y. Tay Y.C. et al.DNA vaccination with naked DNA encoding MCP-1 and RANTES protects against renal injury in adriamycin nephropathy.Kidney Int. 2005; 67: 2178-2186Abstract Full Text Full Text PDF PubMed Scopus (40) Google Scholar Hence, urinary MCP-1 is not only a biomarker for glomerular inflammation13.Tam F.W. Sanders J.S. George A. et al.Urinary monocyte chemoattractant protein-1 (MCP-1) is a marker of active renal vasculitis.Nephrol Dial Transplant. 2004; 19: 2761-2768Crossref PubMed Scopus (79) Google Scholar, 32.Rovin B.H. Song H. Birmingham D.J. et al.Urine chemokines as biomarkers of human systemic lupus erythematosus activity.J Am Soc Nephrol. 2005; 16: 467-473Crossref PubMed Scopus (216) Google Scholar but also a predictor for the progression of proteinuric glomerular diseases.33.Yoshimoto K. Wada T. Furuichi K. et al.CD68 and MCP-1/CCR2 expression of initial biopsies reflect the outcomes of membranous nephropathy.Nephron Clin Pract. 2004; 98: c25-c34Crossref PubMed Scopus (29) Google Scholar In this study, we show that the urinary MCP-1 level correlates well with the magnitude of proteinuria at baseline, and the reduction of urinary MCP-1 levels after PTX treatment correlates strongly with the decrease of proteinuria. Therefore, the antiproteinuric effect of PTX might be mediated, at least in part, via downregulation of MCP-1 production in the kidney. Treatment of glomerular diseases consists of general supportive measures such as BP control and proteinuria reduction, as well as disease-specific therapies using a combination of corticosteroids and various immunosuppressive drugs. Due to potentially hazardous side effects, the immunosuppressive therapy is reserved for patients with severe glomerular diseases manifest nephrotic syndrome and/or rapidly deteriorating renal function. In the present study, most patients manifesting subnephrotic proteinuria at basal of the study. These patients are usually considered at lower risk for progressive loss of renal function, and do not need the relatively toxic immunosuppressive therapy. However, it is well known that the extent of proteinuria, even at subnephrotic range, is strongly associated with the outcome of diabetic nephropathy,16.Remuzzi G. Schieppati A. Ruggenenti P. Nephropathy in patients with type 2 diabetes.N Engl J Med. 2002; 346: 1145-1151Crossref PubMed Scopus (486) Google Scholar and the progression of non-diabetic kidney disease, including primary glomerular diseases.2.Iseki K. Ikemiya Y. Iseki C. Takishita S. Proteinuria and the risk of developing end-stage renal disease.Kidney Int. 2003; 63: 1468-1474Abstract Full Text Full Text PDF PubMed Scopus (399) Google Scholar, 17.Levey A.S. Nondiabetic kidney disease.N Engl J Med. 2002; 347: 1505-1511Crossref PubMed Scopus (118) Google Scholar Thus, non-immunosuppressive therapies targeting mild to moderate proteinuria may still be of benefit for patients with subnephrotic glomerular diseases. To date, angiotensin blockade by angiotensin-converting enzyme inhibitors (ACEi) or type 1 angiotensin II receptor blockers (ARB), irrespective of BP levels, is the most popular therapeutic strategy for this subset of patients. These drugs, however, are not without adverse effects, which include cough, hyperkalemia and acute downhill of renal function.34.Palmer B.F. Renal dysfunction complicating the treatment of hypertension.N Engl J Med. 2002; 347: 1256-1261Crossref PubMed Scopus (242) Google Scholar Alternatively, there are other antiproteinuric therapies that do not act by angiotensin blockade or BP reduction, and are free of such untoward effects. Among those, the phosphodiesterase inhibitor PTX has shown its ability to reduce proteinuria in patients with both diabetic and non-diabetic nephropathies.21.Ducloux D. Bresson-Vautrin C. Chalopin J. Use of pentoxifylline in membranous nephropathy.Lancet. 2001; 357: 1672-1673Abstract Full Text Full Text PDF PubMed Scopus (57) Google Scholar, 22.Galindo-Rodriguez G. Bustamante R. Esquivel-Nava G. et al.Pentoxifylline in the treatment of refractory nephrotic syndrome secondary to lupus nephritis.J Rheumatol. 2003; 30: 2382-2384PubMed Google Scholar, 23.Navarro J.F. Mora C. Rivero A. et al.Urinary protein excretion and serum tumor necrosis factor in diabetic patients with advanced renal failure: effects of pentoxifylline administration.Am J Kidney Dis. 1999; 33: 458-463Abstract Full Text Full Text PDF PubMed Scopus (120) Google Scholar, 24.Navarro J.F. Mora C. Muros M. et al.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. 2003; 42: 264-270Abstract Full Text Full Text PDF PubMed Scopus (56) Google Scholar The dose of PTX administered was generally 1200 mg/day, although in one report 400 mg daily was used to adjust for the severity of renal failure.23.Navarro J.F. Mora C. Rivero A. et al.Urinary protein excretion and serum tumor necrosis factor in diabetic patients with advanced renal failure: effects of pentoxifylline administration.Am J Kidney Dis. 1999; 33: 458-463Abstract Full Text Full Text PDF PubMed Scopus (120) Google Scholar In the present study, we demonstrate that PTX, administered at a relatively lower dose (800 mg daily), can also significantly decrease proteinuria in patients with proteinuric primary glomerular diseases, most of them being subnephrotic. Interestingly, previous studies have shown that PTX is as effective as ACEi in reducing proteinuria,35.Aminorroaya A. Janghorbani M. Rezvanian H. et al.Comparison of the effect of pentoxifylline and captopril on proteinuria in patients with type 2 diabetes mellitus.Nephron Clin Pract. 2005; 99: c73-c77Crossref PubMed Scopus (31) Google Scholar and combination of PTX with ACEi or ARB results in additive reduction in microalbuminuria in hypertensive and normotensive type II diabetics, respectively.36.Harrnankaya 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: 465-470Crossref PubMed Scopus (48) Google Scholar, 37.Navarro J.F. Mora C. Muros M. Garcia 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: 2119-2126Crossref PubMed Scopus (102) Google Scholar Our previous work has also found similar additive beneficial effects of PTX in rats with remnant kidney.25.Lin S.L. Chen Y.M. Chien C.T. et al.Pentoxifylline attenuated the renal disease progression in rats with remnant kidney.J Am Soc Nephrol. 2002; 13: 2916-2929Crossref PubMed Scopus (103) Google Scholar As the renoprotective effects of ACEi and ARB are well documented,38.Brenner B.M. Zagrobelny J. Clinical renoprotection trials involving angiotensin II-receptor antagonists and angiotensin-converting-enzyme inhibitors.Kidney Int. 2003; 63: S77-S85Abstract Full Text Full Text PDF Scopus (30) Google Scholar we postulate that treatment with PTX may have a similar benefit.20.Lin S.L. Chen Y.M. Chiang W.C. et al.Pentoxifylline: a potential therapy for chronic kidney disease.Nephrology. 2004; 9: 198-204Crossref PubMed Scopus (31) Google Scholar Clinical trials based on anti-MCP-1 strategies have never been reported in human primary glomerular diseases. The ACEi, lisinopril, has been shown to attenuate proteinuria and improve renal function in patients with type II diabetic nephropathy through suppression of renal MCP-1.39.Amann B. Tinzmann R. Angelkort B. ACE inhibitors improve diabetic nephropathy through suppression of renal MCP-1.Diabetes Care. 2003; 26: 2421-2425Crossref PubMed Scopus (136) Google Scholar Of note, the urinary MCP-1 level in type II diabetic patients was found to increase in proportion to the degree of proteinuria and correlate positively with urinary N-acetyl-β-glucosaminidase excretion,8.Morii T. Fujita H. Narita T. et al.Increased urinary excretion of monocyte chemoattractant protein-1 in proteinuric renal diseases.Ren Fail. 2003; 25: 439-444Crossref PubMed Scopus (29) Google Scholar which could be downregulated by PTX.24.Navarro J.F. Mora C. Muros M. et al.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. 2003; 42: 264-270Abstract Full Text Full Text PDF PubMed Scopus (56) Google Scholar As urinary N-acetyl-β-glucosaminidase is a marker of tubular injury, it is reasonable to speculate that PTX may have beneficial effects on tubulointerstitial damage in proteinuric kidney disease. Indeed, our previous studies have shown that PTX can ameliorate both proteinuria and tubulointerstitial damage in rats with crescentic glomerulonephritis and remnant kidney via in part its anti-MCP-1 activity.25.Lin S.L. Chen Y.M. Chien C.T. et al.Pentoxifylline attenuated the renal disease progression in rats with remnant kidney.J Am Soc Nephrol. 2002; 13: 2916-2929Crossref PubMed Scopus (103) Google Scholar, 27.Chen Y.M. Ng Y.Y. Lin S.L. et al.Pentoxifylline suppresses renal tumour necrosis factor-α and ameliorates experimental crescentic glomerulonephritis in rats.Nephrol Dial Transplant. 2004; 19: 1106-1115Crossref PubMed Scopus (50) Google Scholar Two patients with IgA nephropathy at stage 4 chronic kidney disease in this study exhibited deteriorating renal function despite an optimal control of urinary MCP-1, proteinuria and arterial BP. As pre-existing renal insufficiency is a strong predictor of poor prognosis for IgA nephropathy,40.D'Amico G. Natural history of idiopathic IgA nephropathy and factors predictive of disease outcome.Semin Nephrol. 2004; 24: 179-196Abstract Full Text Full Text PDF PubMed Scopus (343) Google Scholar monotherapy with PTX may not be sufficient to retard renal progression in such high-risk patients. Further, previous pharmacokinetic studies of PTX indicate that 800 mg daily is a maximum for patients with moderate renal dysfunction,41.Paap C.M. Simpson K.S. Horton M.W. et al.Multiple-dose pharmacokinetics of pentoxifylline and its metabolites during renal insufficiency.Ann Pharmacother. 1996; 30: 724-729Crossref PubMed Scopus (20) Google Scholar escalation of dose may not be an option for these patients. We surmise that a multi-drug approach combining PTX and angiotensin blockers such as ACEi or ARB may be needed to provide greater renoprotection. Due to the small sample size and the limited follow-up period of this study, further randomized clinical trials are required to verify the renoprotective potential of PTX in patients with primary glomerular diseases, in particular those with renal insufficiency at presentation. It is noteworthy that two patients whose proteinuria increased during the study exhibited a rather stable renal function. Although the limited period of follow-up may have contributed to such a paradox, our observation underscores the need for new surrogate markers besides proteinuria in predicting the renal outcome.42.D'Amico G. Bazzi C. Urinary protein and enzyme excretion as markers of tubular damage.Curr Opin Nephrol Hypertens. 2003; 12: 639-643Crossref PubMed Scopus (0) Google Scholar, 43.Eknoyan G. Hostetter T. Bakris G. et al.Proteinuria and other markers of chronic kidney disease: a position statement of the national kidney foundation (NKF) and the national institute of diabetes and digestive and kidney diseases (NIDDM).Am J Kidney Dis. 2003; 42: 617-622Abstract Full Text Full Text PDF PubMed Scopus (297) Google Scholar Somewhat to our surprise, this study fails to confirm previous findings that PTX can reduce plasma or urinary TNF-α in proteinuric glomerular disorders.21.Ducloux D. Bresson-Vautrin C. Chalopin J. Use of pentoxifylline in membranous nephropathy.Lancet. 2001; 357: 1672-1673Abstract Full Text Full Text PDF PubMed Scopus (57) Google Scholar, 23.Navarro J.F. Mora C. Rivero A. et al.Urinary protein excretion and serum tumor necrosis factor in diabetic patients with advanced renal failure: effects of pentoxifylline administration.Am J Kidney Dis. 1999; 33: 458-463Abstract Full Text Full Text PDF PubMed Scopus (120) Google Scholar, 37.Navarro J.F. Mora C. Muros M. Garcia 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: 2119-2126Crossref PubMed Scopus (102) Google Scholar The reasons for this divergent result are not clear, but may be due to differences in PTX dose, variations in proteinuria magnitude or heterogeneity in glomerular pathologies among the studied subjects. In this study, the reduction of proteinuria after PTX treatment correlated best with the decrease of urinary MCP-1, thereby suggesting a preferential role of the urinary MCP-1 level in predicting therapeutic efficacy of PTX. This is reminiscent of the works which show that the elevated urinary MCP-1, but not other classes of chemokines such as IL-8 or fractalkine, is a more sensitive biomarker for disease activity in renal lupus and antineutrophil cytoplasmic antibody-associated vasculitis,13.Tam F.W. Sanders J.S. George A. et al.Urinary monocyte chemoattractant protein-1 (MCP-1) is a marker of active renal vasculitis.Nephrol Dial Transplant. 2004; 19: 2761-2768Crossref PubMed Scopus (79) Google Scholar, 32.Rovin B.H. Song H. Birmingham D.J. et al.Urine chemokines as biomarkers of human systemic lupus erythematosus activity.J Am Soc Nephrol. 2005; 16: 467-473Crossref PubMed Scopus (216) Google Scholar although urinary TNF-α or IL-1β levels were not measured in those studies. In conclusion, this study shows that administration of PTX 800 mg/day is both safe and effective for reducing proteinuria in patients with proteinuric primary glomerular diseases, and this beneficial effect may be mediated through suppression of renal MCP-1 production by this drug. The study was approved by the human research ethics committee of the National Taiwan University Hospital (No. 152S2). Adult patients affected by primary glomerular diseases with proteinuria were screened for the study. Patients were eligible for enrollment if urinary protein/Cr ratios exceeded 1.5 g/g Cr in 3 consecutive single-voided urine samples, and renal function was stable for at least 3 months. To minimize selection bias, we consecutively enrolled patients. Patients were excluded from the study if they had abnormal liver function, diabetes mellitus, hereditary kidney diseases or immunologic renal diseases such as Henoch–Schonlein purpura, systemic lupus erythematosus or antineutrophil cytoplasmic antibody-associated vasculitis. Seventeen patients (four males, 13 females, aged 35–85 years) with a persistent spot proteinuria of 1.51–5.67 g/g Cr, and a serum Cr between 0.6 and 2.3 mg/dl (Cr clearances ranging from 27 to 105 ml/min, glomerular filtration rates ranging from 24 to 115 ml/min/1.73 m2) were finally selected. All the eligible patients gave their consent to the study, including two nephrotic patients who refused corticosteroid therapy. Twelve patients were diagnosed as glomerulonephritis by renal biopsy, including focal segmental glomerulosclerosis in one case, mesangial proliferative glomerulonephritis in one case, IgA nephropathy in five cases and membranous nephropathy in five cases. The remaining five patients were diagnosed as glomerular diseases by demonstrating predominantly albuminuria (≥70%) on urine protein electrophoresis with or without dysmorphic red blood cells on urinalysis. PTX 400 mg was administered orally twice a day for 6 months. Patients did not receive corticosteroids, statins, ACEi, ARB or antiplatelet agents such as dipyridamole or aspirin throughout the study period. Diuretics, calcium channel antagonists or adrenoceptor blockers were administered to optimize BP control whenever needed. Before and 6 months after the treatment, blood and single-voided urine samples were collected in endotoxin-free tubes. Plasma and urinary TNF-α, IL-1β and MCP-1 concentrations were measured in duplicate using commercially available enzyme-linked immunosorbent assay kits specific for TNF-α, IL-1β, and MCP-1 (Endogen, Woburn, MA, USA). Plasma renin activity and plasma aldosterone concentrations were measured in duplicate using commercially available radioimmunoassay kits (Rianen, DuPont, Boston, MA, USA; Aldosterone Maia, Biodata Diagnostics, Rome, Italy). Cr levels were measured using a standard colorimetric method (Jaffe rate reaction), and urine protein concentrations were quantitated by Biorad's method. The magnitude of urinary protein excretion was represented by urinary protein/Cr ratio in both single-voided44.Schwab S.J. Christensen R.L. Dougherty R.N. Klahr S. Quantitation of proteinuria by the use of protein-to-creatinine ratios in single urine samples.Ann Intern Med. 1987; 147: 943-944Crossref Scopus (216) Google Scholar and 24-h urine samples. The Cr clearance was estimated by the Cockcroft–Gault equation45.Cockcroft D.W. Gault M.H. Prediction of creatinine clearance from serum creatinine.Nephron. 1976; 16: 31-41Crossref PubMed Scopus (12500) Google Scholar and the glomerular filtration rate determined by the simplified Modification of Diet in Renal Disease formula.46.Levey A.S. Greene T. Kusek J.W. Beck G.J. A simplified equation to predict glomerular filtration rate from serum creatinine.J Am Soc Nephrol. 2000; 11: 155AGoogle Scholar All biochemical analyses were performed by the Department of Laboratory Medicine, National Taiwan University Hospital. Clinic arterial BP was measured in a sitting position using a standard mercury sphymomanometer. Student's t-test and Wilcoxon rank sign test were performed to evaluate the differences in continuous and non-normally distributed variables before and 6 months after PTX treatment when appropriate. Spearman's rank correlation test was performed to determine the variables that significantly affected urinary protein excretion. Data are expressed as mean±s.e.m. Any probability values <0.05 were considered significant. Stat-View package (version 4.52) for the Macintoch computer was used for statistical analysis (Abacus Concepts, Berkeley, CA, USA). This work was supported by grants from the National Taiwan University Hospital 95-000370, the National Science Council, 91-2314-B002-335, the Ta-Tung Kidney Foundation, and the Mrs Hsiu-Chin Lee Kidney Research Fund, Taipei, Taiwan. We thank Dr Kuo-Liong Chien for his help in statistical calculation.
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