january 2014 - Vol. 34, No. 1
FROM THE EDITORS
Martin Wilkie Editor-in-Chief REFERENCES 1. Nakayama M. Nonuremic indication for peritoneal dialysis for refractory heart failure in cardiorenal syndrome type II: review and perspective. Perit Dial Int 2013; 33:8–14. 2. Godino Mdel C, Romera VG, Sánchez–Tomero JA, Pacheco J, Canals S, Lerma J, et al. Amelioration of ischemic brain damage by peritoneal dialysis. J Clin Invest 2013; 123:4359–63. 3. Murray AM, Seliger S, Lakshminarayan K, Herzog CA, Solid CA. Incidence of stroke before and after dialysis initiation in older patients. J Am Soc Nephrol 2013; 24:1166–73. doi:10.3747/pdi.2014.00010
KIM-1: Friend or Foe? Kidney injury molecule-1 (KIM-1), a transmembrane phosphatidylserine receptor, is transiently upregulated in proximal tubule cells in acute kidney injury and expressed more consistently in chronic kidney disease and renal fibrosis. Because KIM-1 is not expressed in the normal kidney and is released in urine by injured epithelial cells, KIM-1 has been viewed as a promising biomarker of proximal tubule toxicity (1). New research in mouse models by Humphreys, Bonventre, and colleagues shows that, more than a simple marker, KIM-1 plays a role in renal fibrosis and progression of chronic kidney disease (2). Those authors first evidenced the kinetics of KIM-1 induction during renal fibrotic disease using the model of unilateral ureteral obstruction in mice. Two days after ureteral ligation, KIM-1 was strongly induced in the apical pole of p roximal tubule cells, with lower but persistent expression at 7 and 14 days. The authors next created a conditional transgenic mouse that permitted 6
selective activation of KIM-1 in the absence of injury stimulus. By 4 weeks of age, mice expressing KIM-1 developed progressive interstitial lesions, with inflammation, fibrosis, and focal tubular damage leading to chronic kidney disease and extrarenal manifestations including anemia, cardiac hypertrophy, hypertension, and early death. Stable transfection of proximal tubule cells with KIM-1 triggered the release of various cytokines, including transforming growth factor β and monocyte chemoattractant protein 1 (MCP-1), which were also upregulated in the transgenic KIM-1 kidneys. By contrast, mice expressing a truncated form of KIM-1 were protected from renal fibrosis induced by unilateral ureteral obstruction, and they showed a significant reduction in levels of MCP-1. Taken together, these data indicate that chronic KIM-1 expression in kidney tubules upregulates a set of proinflammatory cytokines (including MCP-1) that might in turn drive leukocyte infiltration and kidney fibrosis. This hypothesized sequence contrasts with the early induction of KIM-1 after acute kidney injury, which is thought to facilitate tubular repair through phagocytosis of cells and debris and which is considered to be a marker of tubular injury. To date, no link has been established between KIM-1 (chiefly expressed by tubular epithelial cells) and injury or fibrosis of the peritoneal membrane (3,4). Fundamentally, Humphreys et al. showed that the sentinels of cell damage—which can be viewed primarily as biomarkers— might also play a causal role in chronic organ dysfunction, thus becoming potential therapeutic targets. Their studies also provide a paradigm for dissecting the mechanisms of tissue fibrosis, with investigation in rodents of the kinetics of expression upon injury; for generating and characterizing conditional and mutant mouse models; and for designing studies based on stably transfected cells. Olivier Devuyst Deputy Editor REFERENCES 1. Lim AI, Tang SC, Lai KN, Leung JC. Kidney injur y molecule-1: more than just an injury marker of tubular epithelial cells? J Cell Physiol 2013; 228:917–24. 2. Humphreys BD, Xu F, Sabbisetti V, Grgic I, Naini SM, Wang N, et al. Chronic epithelial kidney injury molecule-1 expression causes murine kidney fibrosis. J Clin Invest 2013; 123:4023–35. 3. Krediet RT, Struijk DG. Peritoneal changes in patients on longterm peritoneal dialysis. Nat Rev Nephrol 2013; 9:419–29. 4. Korte MR, Sampimon DE, Betjes MG, Krediet RT. Encapsulating peritoneal sclerosis: the state of affairs. Nat Rev Nephrol 2011; 7:528–38.
This single copy is for your personal, non-commercial use only. For permission to reprint multiple copies or to order presentation-ready copies for distribution, contact Multimed Inc. at [email protected]
doi:10.3747/pdi.2014.00013
Downloaded from http://www.pdiconnect.com/ at SEVEN OAKS GEN HOSP on September 12, 2015
the technique is the creation of a subcutaneous tunnel to provide extraperitoneal fixation. Residual peritoneal volume at the end of the dialysate drain can vary considerably between patients, generally as a consequence of catheter location and function, but it is rarely measured in practice. Alp Akonur and colleagues (pdi.2012.00175) mathematically modeled the impact on ultrafiltration of residual volumes ranging from 150 mL to 1200 mL for 2-L exchanges of 7.5% icodextrin and of 3.86% glucose, finding a reduction in ultrafiltration of 60% for icodextrin and 27% for glucose with the largest residual volume. The authors speculate that differences in residual volume could easily account for the variations in icodextrin-induced ultrafiltration that sometimes occur between patients.
PDI
FROM THE EDITORS
Martin Wilkie Editor-in-Chief REFERENCES 1. Nakayama M. Nonuremic indication for peritoneal dialysis for refractory heart failure in cardiorenal syndrome type II: review and perspective. Perit Dial Int 2013; 33:8–14. 2. Godino Mdel C, Romera VG, Sánchez–Tomero JA, Pacheco J, Canals S, Lerma J, et al. Amelioration of ischemic brain damage by peritoneal dialysis. J Clin Invest 2013; 123:4359–63. 3. Murray AM, Seliger S, Lakshminarayan K, Herzog CA, Solid CA. Incidence of stroke before and after dialysis initiation in older patients. J Am Soc Nephrol 2013; 24:1166–73. doi:10.3747/pdi.2014.00010
KIM-1: Friend or Foe? Kidney injury molecule-1 (KIM-1), a transmembrane phosphatidylserine receptor, is transiently upregulated in proximal tubule cells in acute kidney injury and expressed more consistently in chronic kidney disease and renal fibrosis. Because KIM-1 is not expressed in the normal kidney and is released in urine by injured epithelial cells, KIM-1 has been viewed as a promising biomarker of proximal tubule toxicity (1). New research in mouse models by Humphreys, Bonventre, and colleagues shows that, more than a simple marker, KIM-1 plays a role in renal fibrosis and progression of chronic kidney disease (2). Those authors first evidenced the kinetics of KIM-1 induction during renal fibrotic disease using the model of unilateral ureteral obstruction in mice. Two days after ureteral ligation, KIM-1 was strongly induced in the apical pole of p roximal tubule cells, with lower but persistent expression at 7 and 14 days. The authors next created a conditional transgenic mouse that permitted 6
selective activation of KIM-1 in the absence of injury stimulus. By 4 weeks of age, mice expressing KIM-1 developed progressive interstitial lesions, with inflammation, fibrosis, and focal tubular damage leading to chronic kidney disease and extrarenal manifestations including anemia, cardiac hypertrophy, hypertension, and early death. Stable transfection of proximal tubule cells with KIM-1 triggered the release of various cytokines, including transforming growth factor β and monocyte chemoattractant protein 1 (MCP-1), which were also upregulated in the transgenic KIM-1 kidneys. By contrast, mice expressing a truncated form of KIM-1 were protected from renal fibrosis induced by unilateral ureteral obstruction, and they showed a significant reduction in levels of MCP-1. Taken together, these data indicate that chronic KIM-1 expression in kidney tubules upregulates a set of proinflammatory cytokines (including MCP-1) that might in turn drive leukocyte infiltration and kidney fibrosis. This hypothesized sequence contrasts with the early induction of KIM-1 after acute kidney injury, which is thought to facilitate tubular repair through phagocytosis of cells and debris and which is considered to be a marker of tubular injury. To date, no link has been established between KIM-1 (chiefly expressed by tubular epithelial cells) and injury or fibrosis of the peritoneal membrane (3,4). Fundamentally, Humphreys et al. showed that the sentinels of cell damage—which can be viewed primarily as biomarkers— might also play a causal role in chronic organ dysfunction, thus becoming potential therapeutic targets. Their studies also provide a paradigm for dissecting the mechanisms of tissue fibrosis, with investigation in rodents of the kinetics of expression upon injury; for generating and characterizing conditional and mutant mouse models; and for designing studies based on stably transfected cells. Olivier Devuyst Deputy Editor REFERENCES 1. Lim AI, Tang SC, Lai KN, Leung JC. Kidney injur y molecule-1: more than just an injury marker of tubular epithelial cells? J Cell Physiol 2013; 228:917–24. 2. Humphreys BD, Xu F, Sabbisetti V, Grgic I, Naini SM, Wang N, et al. Chronic epithelial kidney injury molecule-1 expression causes murine kidney fibrosis. J Clin Invest 2013; 123:4023–35. 3. Krediet RT, Struijk DG. Peritoneal changes in patients on longterm peritoneal dialysis. Nat Rev Nephrol 2013; 9:419–29. 4. Korte MR, Sampimon DE, Betjes MG, Krediet RT. Encapsulating peritoneal sclerosis: the state of affairs. Nat Rev Nephrol 2011; 7:528–38.
This single copy is for your personal, non-commercial use only. For permission to reprint multiple copies or to order presentation-ready copies for distribution, contact Multimed Inc. at [email protected]
doi:10.3747/pdi.2014.00013
Downloaded from http://www.pdiconnect.com/ at SEVEN OAKS GEN HOSP on September 12, 2015
the technique is the creation of a subcutaneous tunnel to provide extraperitoneal fixation. Residual peritoneal volume at the end of the dialysate drain can vary considerably between patients, generally as a consequence of catheter location and function, but it is rarely measured in practice. Alp Akonur and colleagues (pdi.2012.00175) mathematically modeled the impact on ultrafiltration of residual volumes ranging from 150 mL to 1200 mL for 2-L exchanges of 7.5% icodextrin and of 3.86% glucose, finding a reduction in ultrafiltration of 60% for icodextrin and 27% for glucose with the largest residual volume. The authors speculate that differences in residual volume could easily account for the variations in icodextrin-induced ultrafiltration that sometimes occur between patients.
PDI
