- Email: [email protected]
PAI-1 in diabetic nephropathy
1372
Letters to the Editor
examinations of postprocedural change of BW with correlation to Hct may help to clarify this issue.
Table 1. Incidence of access site hematoma and blood transfusion in relation to drop in hematocrit Quintiles of drop in hematocrit % ≤2.2
>2.2 to ≤3.9
>3.9 to ≤5.4
>5.4 to ≤7.4
>7.4
P value
4.1 1.3
4.6 1.3
5.4 2.4
7.3 2.5
23.0 17.7
≤0.0001 ≤0.0001
MING-YU LAI, CHIH-CHING LIN, and WU-CHANG YANG
Taipei, Taiwan Correspondence to Ming-Yu Lai, M.D., Division of Nephrology, Taipei Veterans General Hospital, No. 201, Sec. 2, Shih-Pai Road, Taipei, Taiwan 11217. E-mail: [email protected]
REFERENCES 1. NIKOLSKY E, MEHRAN R, LASIC Z, et al: Low hematocrit predicts contrast-induced nephropathy after percutaneous coronary interventions. Kidney Int 67:706–713, 2005 2. ARONSON PS, BORON WF, BOULPAEP EL: Physiology of Membranes in Medical Physiology, edited by Boron WF and Boulpaep EL, 1st ed., Philadelphia, Elsevier Science, 2003, pp 50–86 3. MCCULLOUGH PA, WOLYN R, ROCHER LL, et al: Acute renal failure after coronary intervention: Incidence, risk factors, and relationship to mortality. Am J Med 103:368–375, 1997 4. SOLOMON R, WERNER C, MANN D, et al: Effects of saline, mannitol, and furosemide on acute decreased in renal function induced by radiocontrast agents. N Engl J Med 331:1416–1420, 1994
Reply from the Authors We read with interest the letter from Lai et al [1], and we thank them for their interest in our study [2]. The authors raise the question that the association between contrast-induced nephropathy (CIN) and drop in hematocrit after percutaneous coronary intervention found in our study might be explained by a greater extent of hemodilution and, consequently, lower hematocrit in patients with CIN. While accepting this point of view as a plausible explanation of our finding, we consider that this does not deny the role of procedure-related blood loss in the genesis of CIN. Lai et al reasonably state that, based on the described calculations, the blood loss should be as much as 510 mL to cause the observed change in hematocrit level. Though the accurate amount of blood loss cannot be assessed retrospectively, a higher drop in hematocrit in our study was associated with significantly higher rates of hemorrhagic complications and blood product transfusion (data not published), supporting the role of blood loss in the genesis of CIN (see Table 1). As we mention in the Discussion section of the manuscript, a more significant drop in hematocrit may also be attributed to the higher incidence of periprocedural hypotension (due to bleeding and/or hemodynamic instability), and to subsequent hemodilution following more intensive fluid replacement therapy. We certainly support the idea of periprocedural monitoring of body weight in patients undergoing contrast medium exposure; this should be part of the comprehensive approach to elucidate the relation between drop in hematocrit and CIN,
Hematoma % Transfusion %
along with data on periprocedural hemodynamics, hydration volume, and urine output. EUGENIA NIKOLSKY, ROXANA MEHRAN, and GEORGE DANGAS
New York, New York Correspondence to Eugenia Nikolsky, 55 East 59 Street, 6th Floor, New York, NY 10022-1112. E-mail: [email protected]
REFERENCE 1. LAI M-Y, LIN C-C, YANG W-C: Postprocedural drop in hematocrit versus contrast-induced nephropathy: Eggs or chickens? Kidney Int 68:1371–1372, 2005 2. NIKOLSKY E, MEHRAN R, LASIC Z, et al: Low hematocrit predicts contrast-induced nephropathy after percutaneous coronary interventions. Kidney Int 67:760–771, 2005
PAI-1 in diabetic nephropathy To the Editor: The mechanisms by which plasminogen activator inhibitor-1 (PAI-1), the main plasminogen activator inhibitor, promotes fibrosis in a number of experimental models, are still intensely debated. On the one hand, PAI-1 is supposed to inhibit extracellular matrix degradation by preventing plasmin formation. On the other hand, it has been shown to prevent transforming growth factor (TGF) beta activation and, thus, to prevent extracellular matrix production [1]. Nicholas et al recently provided experimental, in vivo data suggesting that PAI-1 deficiency might be helpful in the prevention of diabetic nephropathy: when compared to wild-type animals, PAI-1 knockout mice have, thus, a lower urinary albumin excretion and a lower synthesis of fibronectin in the kidney after streptozotocin injection [2]. Interestingly, PAI-1 is reported by these authors to enhance TGF beta synthesis by mesangial cells, a finding that is somewhat provocative because TGF beta is itself a potent enhancer of the PAI-1 promoter gene, and because recent works by Luttun et al and our group demonstrated that PAI-1 plays a critical role in the regulation of the TGF beta activation (i.e., PAI-1 inhibits TGF-beta activation) [3, 4]. Moreover, in Nicholas’ study, the induction of TGFbeta synthesis, at the mRNA and at the protein level, in
Letters to the Editor
diabetic PAI-1 +/+ mice, is weak when compared with nondiabetic mice (×1.5), and is hardly distinguishable from the induction observed in PAI-1 −/− mice, at least for the eye (Fig. 3). Another striking result is that the level of TGF-beta expression and production by the kidney is higher in PAI-1 −/− mice than in PAI-1 +/+ mice, in either basal or diabetic conditions. In the absence of pathologic data, including measurements of the glomerular basement membrane thickness, it is therefore difficult to conclude that PAI-1 knockout animals could be protected towards diabetic nephropathy and that this would be related to a lower concentration of TGF-beta. ALEXANDRE HERTIG, GAELLE PELLE, and ERIC RONDEAU
sured in our paper. As such, it is provocative to assume that a seemingly “weak” stimulation of TGF-b protein by PAI-1 may not have a significant clinical outcome (i.e., worsened albuminuria). Our data showed no significant difference in basal kidney TGF-b expression, which was significantly reduced in diabetic PAI-1−/− mice (Fig. 3). Significant structural changes of diabetic nephropathy, such as glomerular basement membrane thickness and fractional mesangial volume, are not typically observed after 4 weeks of diabetes in C57BL6 STZ-induced diabetic mice and, in fact, may not appear until ∼6 months of diabetes. For this reason, these parameters were not included in our study.
Paris, France Correspondence to Dr. Alexandre Hertig, INSERM U702, Department of Nephrology A, Hopital Tenon, 4, rue de la Chine, 75020 Paris, France. E-mail: [email protected]
REFERENCES 1. HERTIG A, RONDEAU E: Plasminogen activator inhibitor type 1: The two faces of the same coin. Curr Opin Nephrol Hypertens 13:39–44, 2004 2. NICHOLAS SB, AGUINIGA E, REN Y, et al: Plasminogen activator inhibitor-1 deficiency retards diabetic nephropathy. Kidney Int 67:1297–1307, 2005 3. LUTTUN A, LUPU F, STORKEBAUM E, et al: Lack of plasminogen activator inhibitor-1 promotes growth and abnormal matrix remodeling of advanced atherosclerotic plaques in apolipoprotein E-deficient mice. Arterioscler Thromb Vasc Biol 22:499–505, 2002 4. HERTIG A, BERROU J, ALLORY Y, et al: Type 1 plasminogen activator inhibitor deficiency aggravates the course of experimental glomerulonephritis through overactivation of transforming growth factor beta. FASEB J 17:1904–1906, 2003
Reply from the Authors As we gain further insight into PAI-1–mediated mechanisms in disease, it is evident that PAI-1 may indeed have several functions. Early studies showed that PAI-1 deficiency protects against fibrosis, as in the bleomycininduced pulmonary model [1], and this is supported by our studies in the streptozotocin-induced diabetic mouse model [2]. However, Hertig and Rondeau demonstrate that in inflammatory models of disease, PAI-1 deficiency may promote pathology. In fact, we have observed development of cardiac fibrosis in PAI-1−/− mice (unpublished data), as have Moriwaki et al [3], who also showed significant macrophage involvement in this process. These observations strongly suggest that PAI-1 function may be determined by the inciting process, and modulated by uPA expression, which may be tissue- or disease-specific. The comment that induction of TGF-b synthesis is weak (1.5 ×’s) reflects similar changes in total TGF-b by Hertig et al (1.9 ×’s) [4]. Active TGF-b was not mea-
1373
SUSANNE B. NICHOLAS and WILLA A. HSUEH
Los Angeles, California Correspondence to Susanne B. Nicholas, Warren Hall; David Geffen School of Medicine at UCLA, 900 Veteran Avenue, Suite 24-130, Los Angeles, CA 90095. E-mail: [email protected]
REFERENCES 1. EITZMAN D, MCCOY R, ZHENG X, et al: Bleomycin-induced pulmonary fibrosis in transgenic mice that either lack or overexpress the murine plasminogen activator-1 gene. J Clin Invest 97:232–237, 1996 2. NICHOLAS SB, AGUINIGA E, REN Y, et al: Plasminogen activator inhibtor-1 deficiency retards diabetic nephropathy. Kidney Int 67:1297–1307, 2005 3. MORIWAKI H, STEMPIEN-OTERO A, KREMEN M, et al: Overexpression of urokinase by macrophages or deficiency of plasminogen activator inhibitor type-1 causes cardiac fibrosis in mice. Circ Res 95:637–644, 2004 4. HERTIG A, BERROU J, ALLORY Y, et al: Type I plasminogen activator inhibitor deficiency aggravates the course of experimental glomerulonephritis through overactivation of transforming growth factor b. FASEB J 17:1904–1906, 2003
Does fluvastatin really have an antioxidant effect in humans? To the Editor: In the recent issue of Kidney International, Pat et al demonstrated that renal fibrosis after unilateral ureteral obstruction in rat was attenuated by the antioxidative effect of fluvastatin [1], a HMG-CoA reductase inhibitor notable for its additional antioxidant effect [2]. We undertook this clinical experiment because no in vivo human data are available addressing the antioxidant effect of fluvastatin. The patients studied consisted of 3 males and 3 females, with an average age of 56.5 years. All had biopsy-proven chronic glomerulonephritis with normal ranges of creatinine clearance and serum total protein. The mean urinary protein excretion was
Letters to the Editor
examinations of postprocedural change of BW with correlation to Hct may help to clarify this issue.
Table 1. Incidence of access site hematoma and blood transfusion in relation to drop in hematocrit Quintiles of drop in hematocrit % ≤2.2
>2.2 to ≤3.9
>3.9 to ≤5.4
>5.4 to ≤7.4
>7.4
P value
4.1 1.3
4.6 1.3
5.4 2.4
7.3 2.5
23.0 17.7
≤0.0001 ≤0.0001
MING-YU LAI, CHIH-CHING LIN, and WU-CHANG YANG
Taipei, Taiwan Correspondence to Ming-Yu Lai, M.D., Division of Nephrology, Taipei Veterans General Hospital, No. 201, Sec. 2, Shih-Pai Road, Taipei, Taiwan 11217. E-mail: [email protected]
REFERENCES 1. NIKOLSKY E, MEHRAN R, LASIC Z, et al: Low hematocrit predicts contrast-induced nephropathy after percutaneous coronary interventions. Kidney Int 67:706–713, 2005 2. ARONSON PS, BORON WF, BOULPAEP EL: Physiology of Membranes in Medical Physiology, edited by Boron WF and Boulpaep EL, 1st ed., Philadelphia, Elsevier Science, 2003, pp 50–86 3. MCCULLOUGH PA, WOLYN R, ROCHER LL, et al: Acute renal failure after coronary intervention: Incidence, risk factors, and relationship to mortality. Am J Med 103:368–375, 1997 4. SOLOMON R, WERNER C, MANN D, et al: Effects of saline, mannitol, and furosemide on acute decreased in renal function induced by radiocontrast agents. N Engl J Med 331:1416–1420, 1994
Reply from the Authors We read with interest the letter from Lai et al [1], and we thank them for their interest in our study [2]. The authors raise the question that the association between contrast-induced nephropathy (CIN) and drop in hematocrit after percutaneous coronary intervention found in our study might be explained by a greater extent of hemodilution and, consequently, lower hematocrit in patients with CIN. While accepting this point of view as a plausible explanation of our finding, we consider that this does not deny the role of procedure-related blood loss in the genesis of CIN. Lai et al reasonably state that, based on the described calculations, the blood loss should be as much as 510 mL to cause the observed change in hematocrit level. Though the accurate amount of blood loss cannot be assessed retrospectively, a higher drop in hematocrit in our study was associated with significantly higher rates of hemorrhagic complications and blood product transfusion (data not published), supporting the role of blood loss in the genesis of CIN (see Table 1). As we mention in the Discussion section of the manuscript, a more significant drop in hematocrit may also be attributed to the higher incidence of periprocedural hypotension (due to bleeding and/or hemodynamic instability), and to subsequent hemodilution following more intensive fluid replacement therapy. We certainly support the idea of periprocedural monitoring of body weight in patients undergoing contrast medium exposure; this should be part of the comprehensive approach to elucidate the relation between drop in hematocrit and CIN,
Hematoma % Transfusion %
along with data on periprocedural hemodynamics, hydration volume, and urine output. EUGENIA NIKOLSKY, ROXANA MEHRAN, and GEORGE DANGAS
New York, New York Correspondence to Eugenia Nikolsky, 55 East 59 Street, 6th Floor, New York, NY 10022-1112. E-mail: [email protected]
REFERENCE 1. LAI M-Y, LIN C-C, YANG W-C: Postprocedural drop in hematocrit versus contrast-induced nephropathy: Eggs or chickens? Kidney Int 68:1371–1372, 2005 2. NIKOLSKY E, MEHRAN R, LASIC Z, et al: Low hematocrit predicts contrast-induced nephropathy after percutaneous coronary interventions. Kidney Int 67:760–771, 2005
PAI-1 in diabetic nephropathy To the Editor: The mechanisms by which plasminogen activator inhibitor-1 (PAI-1), the main plasminogen activator inhibitor, promotes fibrosis in a number of experimental models, are still intensely debated. On the one hand, PAI-1 is supposed to inhibit extracellular matrix degradation by preventing plasmin formation. On the other hand, it has been shown to prevent transforming growth factor (TGF) beta activation and, thus, to prevent extracellular matrix production [1]. Nicholas et al recently provided experimental, in vivo data suggesting that PAI-1 deficiency might be helpful in the prevention of diabetic nephropathy: when compared to wild-type animals, PAI-1 knockout mice have, thus, a lower urinary albumin excretion and a lower synthesis of fibronectin in the kidney after streptozotocin injection [2]. Interestingly, PAI-1 is reported by these authors to enhance TGF beta synthesis by mesangial cells, a finding that is somewhat provocative because TGF beta is itself a potent enhancer of the PAI-1 promoter gene, and because recent works by Luttun et al and our group demonstrated that PAI-1 plays a critical role in the regulation of the TGF beta activation (i.e., PAI-1 inhibits TGF-beta activation) [3, 4]. Moreover, in Nicholas’ study, the induction of TGFbeta synthesis, at the mRNA and at the protein level, in
Letters to the Editor
diabetic PAI-1 +/+ mice, is weak when compared with nondiabetic mice (×1.5), and is hardly distinguishable from the induction observed in PAI-1 −/− mice, at least for the eye (Fig. 3). Another striking result is that the level of TGF-beta expression and production by the kidney is higher in PAI-1 −/− mice than in PAI-1 +/+ mice, in either basal or diabetic conditions. In the absence of pathologic data, including measurements of the glomerular basement membrane thickness, it is therefore difficult to conclude that PAI-1 knockout animals could be protected towards diabetic nephropathy and that this would be related to a lower concentration of TGF-beta. ALEXANDRE HERTIG, GAELLE PELLE, and ERIC RONDEAU
sured in our paper. As such, it is provocative to assume that a seemingly “weak” stimulation of TGF-b protein by PAI-1 may not have a significant clinical outcome (i.e., worsened albuminuria). Our data showed no significant difference in basal kidney TGF-b expression, which was significantly reduced in diabetic PAI-1−/− mice (Fig. 3). Significant structural changes of diabetic nephropathy, such as glomerular basement membrane thickness and fractional mesangial volume, are not typically observed after 4 weeks of diabetes in C57BL6 STZ-induced diabetic mice and, in fact, may not appear until ∼6 months of diabetes. For this reason, these parameters were not included in our study.
Paris, France Correspondence to Dr. Alexandre Hertig, INSERM U702, Department of Nephrology A, Hopital Tenon, 4, rue de la Chine, 75020 Paris, France. E-mail: [email protected]
REFERENCES 1. HERTIG A, RONDEAU E: Plasminogen activator inhibitor type 1: The two faces of the same coin. Curr Opin Nephrol Hypertens 13:39–44, 2004 2. NICHOLAS SB, AGUINIGA E, REN Y, et al: Plasminogen activator inhibitor-1 deficiency retards diabetic nephropathy. Kidney Int 67:1297–1307, 2005 3. LUTTUN A, LUPU F, STORKEBAUM E, et al: Lack of plasminogen activator inhibitor-1 promotes growth and abnormal matrix remodeling of advanced atherosclerotic plaques in apolipoprotein E-deficient mice. Arterioscler Thromb Vasc Biol 22:499–505, 2002 4. HERTIG A, BERROU J, ALLORY Y, et al: Type 1 plasminogen activator inhibitor deficiency aggravates the course of experimental glomerulonephritis through overactivation of transforming growth factor beta. FASEB J 17:1904–1906, 2003
Reply from the Authors As we gain further insight into PAI-1–mediated mechanisms in disease, it is evident that PAI-1 may indeed have several functions. Early studies showed that PAI-1 deficiency protects against fibrosis, as in the bleomycininduced pulmonary model [1], and this is supported by our studies in the streptozotocin-induced diabetic mouse model [2]. However, Hertig and Rondeau demonstrate that in inflammatory models of disease, PAI-1 deficiency may promote pathology. In fact, we have observed development of cardiac fibrosis in PAI-1−/− mice (unpublished data), as have Moriwaki et al [3], who also showed significant macrophage involvement in this process. These observations strongly suggest that PAI-1 function may be determined by the inciting process, and modulated by uPA expression, which may be tissue- or disease-specific. The comment that induction of TGF-b synthesis is weak (1.5 ×’s) reflects similar changes in total TGF-b by Hertig et al (1.9 ×’s) [4]. Active TGF-b was not mea-
1373
SUSANNE B. NICHOLAS and WILLA A. HSUEH
Los Angeles, California Correspondence to Susanne B. Nicholas, Warren Hall; David Geffen School of Medicine at UCLA, 900 Veteran Avenue, Suite 24-130, Los Angeles, CA 90095. E-mail: [email protected]
REFERENCES 1. EITZMAN D, MCCOY R, ZHENG X, et al: Bleomycin-induced pulmonary fibrosis in transgenic mice that either lack or overexpress the murine plasminogen activator-1 gene. J Clin Invest 97:232–237, 1996 2. NICHOLAS SB, AGUINIGA E, REN Y, et al: Plasminogen activator inhibtor-1 deficiency retards diabetic nephropathy. Kidney Int 67:1297–1307, 2005 3. MORIWAKI H, STEMPIEN-OTERO A, KREMEN M, et al: Overexpression of urokinase by macrophages or deficiency of plasminogen activator inhibitor type-1 causes cardiac fibrosis in mice. Circ Res 95:637–644, 2004 4. HERTIG A, BERROU J, ALLORY Y, et al: Type I plasminogen activator inhibitor deficiency aggravates the course of experimental glomerulonephritis through overactivation of transforming growth factor b. FASEB J 17:1904–1906, 2003
Does fluvastatin really have an antioxidant effect in humans? To the Editor: In the recent issue of Kidney International, Pat et al demonstrated that renal fibrosis after unilateral ureteral obstruction in rat was attenuated by the antioxidative effect of fluvastatin [1], a HMG-CoA reductase inhibitor notable for its additional antioxidant effect [2]. We undertook this clinical experiment because no in vivo human data are available addressing the antioxidant effect of fluvastatin. The patients studied consisted of 3 males and 3 females, with an average age of 56.5 years. All had biopsy-proven chronic glomerulonephritis with normal ranges of creatinine clearance and serum total protein. The mean urinary protein excretion was