- Email: [email protected]
Different response of urinary excretion of VEGF in patients with chronic and acute renal failure
Letters to the Editor
385
progression of renal disease. Also, as we discuss in our article, it could be the focus of therapeutic interventions to slow progression of renal disease. In light of the above, we suggest that the technical concerns of Mr. Basgen and Dr. Mauer do not invalidate the conclusions of our article. Nevertheless, their concerns are highly appropriate. Indeed, we endorse their proposal that scientific journals should adopt the high standards proposed by Nyengaard for morphometric studies. Our endorsement, however, is modified in two respects. First, Nyengaard’s article is too technical. Investigators may be dissuaded from doing morphometric studies if they will be judged by the principles contained in his article. Second, we suggest that a much simpler, applied version of Nyengaard’s principles should be published. Dr. Mauer and his group would be ideal candidates to execute such work. Dr. Mauer is a bellwether investigator in this field and is noted for his lucid exposition of data. Lee A. Hebert, Garima Agarwell, Daniel D. Sedmak, John D. Mahan, William Becker, and Haikady N. Nagaraja Columbus, Ohio Correspondence to Lee A. Hebert, M.D., Ohio State University/ Nephrology, 1654 Upham Drive, Room N210, Columbus, Ohio 432101250, USA E-mail: [email protected]
Different response of urinary excretion of VEGF in patients with chronic and acute renal failure To the Editor: Vascular endothelial growth factor (VEGF) is constitutively expressed by epithelial cells of a nephron from embryonic to adult kidneys. In renal disease, VEGF appears to be involved in a repair of the glomerulus [1]. It is excreted in urine [2] and is suspected to be secreted from tubular cells by hypoxic stimulation in vitro [3, 4] and in vivo [4]. Thus, because the amount of urinary VEGF might reflect renal hypoxia, we measured it in patients with renal diseases and various renal functions. A total of 29 urine and 26 serum and plasma samples were collected from 22 non-diabetic non-nephrotic patients without serious complications. Fifteen patients had a renal biopsy (11 with IgA nephropathy, two with membranous nephropathy, one with focal segmental glomeru 2001 by the International Society of Nephrology
Fig. 1. Relationship of urinary excretion of vascular endothelial growth factor (VEGF) with 24 hours’ creatinine clearance (CCr) and serum level of VEGF. (A) VEGF excretion in urine per day vs. CCr in patients with chronic renal injury. VEGF excretion in urine inversely correlated with CCr (simple regression analysis: Y ⫽ 117.2– 0.92X, P ⫽ 0.0003 for the slope; R ⫽ 0.620). (B) VEGF excretion in urine vs. VEGF level in serum in patients with chronic renal injury. (C) VEGF excretion in urine per day vs. CCr in patients with ischemic acute renal failure. The three symbols indicate individual patients.
386
Letters to the Editor
losclerosis, and one with membranoproliferative glomerulonephritis). The other seven patients were clinically diagnosed with chronic renal failure. Twelve urine and serum samples were collected from three patients with ischemic acute renal failure. As VEGF concentration in the urine did not change after 24 hours’ incubation at room temperature, those urine samples were stored at ⫺30⬚C until use and submitted to colorimetric enzyme immunoassay to quantitate VEGF. Renal function was evaluated by 24-hour creatinine clearance (CCr). There was an inverse relationship between urinary excretion of VEGF and CCr (Fig. 1A). VEGF excretion in urine did not correlate with its serum (Fig. 1B) or plasma level (data not shown). In patients with acute renal failure, no correlation was observed between urinary excretion of VEGF and CCr (Fig. 1C). We examined patients with a wide range of renal functions to focus on the relationship between urinary VEGF and renal function. In patients with chronic renal failure, VEGF excretion in urine increased as renal function decreased. Since excretion was independent of the serum level of VEGF, urinary VEGF appears to be derived from the kidney. Therefore, increased excretion of VEGF suggests its increased secretion in residual nephrons under diffuse and continuous hypoxia. In patients with acute renal failure, urinary VEGF excretion was independent of renal function, probably because excretion of VEGF from the kidney did not change much since the ischemic period was transient and the area was limited. Although further studies are needed, urinary VEGF might be a unique indicator of renal hypoxia. Yasunori Kitamoto, Katsuhiko Matsuo, and Kimio Tomita Kumamoto and Tsukuba, Japan Correspondence to Yasunori Kitamoto, M.D., Ph.D., Third Department of Internal Medicine, Kumamoto University School of Medicine, 1-1-1 Honjo, Kumamoto 8600811, Japan. E-mail: [email protected]
ACKNOWLEDGMENT This study was supported in part by the grant from the Ministry of Health and Welfare, Japan.
REFERENCES 1. Ostendorf T, Kunter U, Eitner F, et al: VEGF(165) mediates glomerular endothelial repair. J Clin Invest 104:913–923, 1999 2. Honkanen E, Teppo A-M, Gro¨nhagen-Riska C: Decreased urinary excretion of vascular endothelial growth factor in idiopathic membranous glomerulonephritis. Kidney Int 57:2343–2349, 2000 3. Awad BL, Kreft B, Wolber E-M, et al: Hypoxia and interleukin1 stimulate vascular endothelial growth factor production in human proximal tubular cells. Kidney Int 58:43–50, 2000 4. Kanellis J, Mudge S, Fraser S, et al: Redistribution of cytoplasmic VEGF to the basolateral aspect of renal tubular cells in ischemiareperfusion injury. Kidney Int 57:2445–2456, 2000
2001 by the International Society of Nephrology
Criteria for calcimimetic agent in the treatment of more severe secondary hyperparathyroidism To the Editor: The prevention and treatment of secondary hyperparathyroidism still are challenging for the nephrologist. Therefore, the recent work of Goodman et al is very interesting and promising [1]. The goal of their study was to assess the safety and efficacy of a calcimimetic agent in dialysis patients with modest to severe secondary hyperparathyroidism. However, their study appears to focus only on a single criterion for modest or severe secondary hyperparathyroidism, the level of intact parathyroid hormone (PTH). It is well known that secondary hyperparathyroidism is a state of increased synthesis and secretion of PTH, but also a state of increased hypertrophy and particularly hyperplasia of the parathyroid cells [2]. There are two forms of parathyroid gland hyperplasia, diffuse and nodular. Parathyroid glands with nodular hyperplasia are larger. In 90% of parathyroid glands weighing 0.5 g nodular hyperplasia was found. Such nodules are made of cells with significantly reduced numbers of vitamin D receptors, calciumsensing receptors (CaSR), and a higher calcium set point for PTH secretion. From a clinical point of view, it is important to note that patients with nodular parathyroid gland hyperplasia are often resistant to calcitriol therapy. Today, high-resolution sonography is the best technique to determine the shape and size of abnormal parathyroid glands [3]. Therefore, it would be more appropriate to use not only a level of PTH for more severe hyperparathyroidism, but also the size of the parathyroid glands as criteria. As large parathyroid glands with nodular hyperplasia have reduced numbers of CaSR, it would be interesting to see the effect of a calcimimetic agent in dialysis patients with large parathyroid glands (that is, suspected nodular hyperplasia). Despite these remarks, we hope that a new calcimimetic agent, as well as new phosphate binders and new vitamin D analogues, will be useful in the treatment of dialysis patients. Drasko Pavlovic and Hrvojka Tomic Brzac Zagreb, Croatia Correspondence to Drasko Pavlovic, M.D., Ph.D., “Sveti Duh” General Hospital, 10000 Zagreb, Sveti Duh 64, Croatia. E-mail: [email protected]
REFERENCES 1. Goodman WG, Frazao JM, Goodkin DA, et al: A calcimimetic agent lowers plasma parathyroid hormone levels in patients with secondary hyperparathyroidism. Kidney Int 58:436–445, 2000
385
progression of renal disease. Also, as we discuss in our article, it could be the focus of therapeutic interventions to slow progression of renal disease. In light of the above, we suggest that the technical concerns of Mr. Basgen and Dr. Mauer do not invalidate the conclusions of our article. Nevertheless, their concerns are highly appropriate. Indeed, we endorse their proposal that scientific journals should adopt the high standards proposed by Nyengaard for morphometric studies. Our endorsement, however, is modified in two respects. First, Nyengaard’s article is too technical. Investigators may be dissuaded from doing morphometric studies if they will be judged by the principles contained in his article. Second, we suggest that a much simpler, applied version of Nyengaard’s principles should be published. Dr. Mauer and his group would be ideal candidates to execute such work. Dr. Mauer is a bellwether investigator in this field and is noted for his lucid exposition of data. Lee A. Hebert, Garima Agarwell, Daniel D. Sedmak, John D. Mahan, William Becker, and Haikady N. Nagaraja Columbus, Ohio Correspondence to Lee A. Hebert, M.D., Ohio State University/ Nephrology, 1654 Upham Drive, Room N210, Columbus, Ohio 432101250, USA E-mail: [email protected]
Different response of urinary excretion of VEGF in patients with chronic and acute renal failure To the Editor: Vascular endothelial growth factor (VEGF) is constitutively expressed by epithelial cells of a nephron from embryonic to adult kidneys. In renal disease, VEGF appears to be involved in a repair of the glomerulus [1]. It is excreted in urine [2] and is suspected to be secreted from tubular cells by hypoxic stimulation in vitro [3, 4] and in vivo [4]. Thus, because the amount of urinary VEGF might reflect renal hypoxia, we measured it in patients with renal diseases and various renal functions. A total of 29 urine and 26 serum and plasma samples were collected from 22 non-diabetic non-nephrotic patients without serious complications. Fifteen patients had a renal biopsy (11 with IgA nephropathy, two with membranous nephropathy, one with focal segmental glomeru 2001 by the International Society of Nephrology
Fig. 1. Relationship of urinary excretion of vascular endothelial growth factor (VEGF) with 24 hours’ creatinine clearance (CCr) and serum level of VEGF. (A) VEGF excretion in urine per day vs. CCr in patients with chronic renal injury. VEGF excretion in urine inversely correlated with CCr (simple regression analysis: Y ⫽ 117.2– 0.92X, P ⫽ 0.0003 for the slope; R ⫽ 0.620). (B) VEGF excretion in urine vs. VEGF level in serum in patients with chronic renal injury. (C) VEGF excretion in urine per day vs. CCr in patients with ischemic acute renal failure. The three symbols indicate individual patients.
386
Letters to the Editor
losclerosis, and one with membranoproliferative glomerulonephritis). The other seven patients were clinically diagnosed with chronic renal failure. Twelve urine and serum samples were collected from three patients with ischemic acute renal failure. As VEGF concentration in the urine did not change after 24 hours’ incubation at room temperature, those urine samples were stored at ⫺30⬚C until use and submitted to colorimetric enzyme immunoassay to quantitate VEGF. Renal function was evaluated by 24-hour creatinine clearance (CCr). There was an inverse relationship between urinary excretion of VEGF and CCr (Fig. 1A). VEGF excretion in urine did not correlate with its serum (Fig. 1B) or plasma level (data not shown). In patients with acute renal failure, no correlation was observed between urinary excretion of VEGF and CCr (Fig. 1C). We examined patients with a wide range of renal functions to focus on the relationship between urinary VEGF and renal function. In patients with chronic renal failure, VEGF excretion in urine increased as renal function decreased. Since excretion was independent of the serum level of VEGF, urinary VEGF appears to be derived from the kidney. Therefore, increased excretion of VEGF suggests its increased secretion in residual nephrons under diffuse and continuous hypoxia. In patients with acute renal failure, urinary VEGF excretion was independent of renal function, probably because excretion of VEGF from the kidney did not change much since the ischemic period was transient and the area was limited. Although further studies are needed, urinary VEGF might be a unique indicator of renal hypoxia. Yasunori Kitamoto, Katsuhiko Matsuo, and Kimio Tomita Kumamoto and Tsukuba, Japan Correspondence to Yasunori Kitamoto, M.D., Ph.D., Third Department of Internal Medicine, Kumamoto University School of Medicine, 1-1-1 Honjo, Kumamoto 8600811, Japan. E-mail: [email protected]
ACKNOWLEDGMENT This study was supported in part by the grant from the Ministry of Health and Welfare, Japan.
REFERENCES 1. Ostendorf T, Kunter U, Eitner F, et al: VEGF(165) mediates glomerular endothelial repair. J Clin Invest 104:913–923, 1999 2. Honkanen E, Teppo A-M, Gro¨nhagen-Riska C: Decreased urinary excretion of vascular endothelial growth factor in idiopathic membranous glomerulonephritis. Kidney Int 57:2343–2349, 2000 3. Awad BL, Kreft B, Wolber E-M, et al: Hypoxia and interleukin1 stimulate vascular endothelial growth factor production in human proximal tubular cells. Kidney Int 58:43–50, 2000 4. Kanellis J, Mudge S, Fraser S, et al: Redistribution of cytoplasmic VEGF to the basolateral aspect of renal tubular cells in ischemiareperfusion injury. Kidney Int 57:2445–2456, 2000
2001 by the International Society of Nephrology
Criteria for calcimimetic agent in the treatment of more severe secondary hyperparathyroidism To the Editor: The prevention and treatment of secondary hyperparathyroidism still are challenging for the nephrologist. Therefore, the recent work of Goodman et al is very interesting and promising [1]. The goal of their study was to assess the safety and efficacy of a calcimimetic agent in dialysis patients with modest to severe secondary hyperparathyroidism. However, their study appears to focus only on a single criterion for modest or severe secondary hyperparathyroidism, the level of intact parathyroid hormone (PTH). It is well known that secondary hyperparathyroidism is a state of increased synthesis and secretion of PTH, but also a state of increased hypertrophy and particularly hyperplasia of the parathyroid cells [2]. There are two forms of parathyroid gland hyperplasia, diffuse and nodular. Parathyroid glands with nodular hyperplasia are larger. In 90% of parathyroid glands weighing 0.5 g nodular hyperplasia was found. Such nodules are made of cells with significantly reduced numbers of vitamin D receptors, calciumsensing receptors (CaSR), and a higher calcium set point for PTH secretion. From a clinical point of view, it is important to note that patients with nodular parathyroid gland hyperplasia are often resistant to calcitriol therapy. Today, high-resolution sonography is the best technique to determine the shape and size of abnormal parathyroid glands [3]. Therefore, it would be more appropriate to use not only a level of PTH for more severe hyperparathyroidism, but also the size of the parathyroid glands as criteria. As large parathyroid glands with nodular hyperplasia have reduced numbers of CaSR, it would be interesting to see the effect of a calcimimetic agent in dialysis patients with large parathyroid glands (that is, suspected nodular hyperplasia). Despite these remarks, we hope that a new calcimimetic agent, as well as new phosphate binders and new vitamin D analogues, will be useful in the treatment of dialysis patients. Drasko Pavlovic and Hrvojka Tomic Brzac Zagreb, Croatia Correspondence to Drasko Pavlovic, M.D., Ph.D., “Sveti Duh” General Hospital, 10000 Zagreb, Sveti Duh 64, Croatia. E-mail: [email protected]
REFERENCES 1. Goodman WG, Frazao JM, Goodkin DA, et al: A calcimimetic agent lowers plasma parathyroid hormone levels in patients with secondary hyperparathyroidism. Kidney Int 58:436–445, 2000