Kidney Disease

Coding Dimension ID: 
300
Coding Dimension path name: 
Kidney Disease

Repair and regeneration of the nephron

Funding Type: 
Research Leadership 10
Grant Number: 
LA1_C10-06536
ICOC Funds Committed: 
$5 672 206
Disease Focus: 
Kidney Disease
oldStatus: 
Active
Public Abstract: 
Kidney function is essential for removing the wastes that result from normal cell function and maintaining water and salt balance in our internal tissues. These actions are carried out by roughly a million nephrons within the kidney that filter all the body’s blood roughly once every 1-2hours. The kidney also regulates other tissues controlling blood pressure and blood cell composition, and regulating the strength of bone by activating vitamin D. Chronic kidney injury over time results in a loss of normal kidney function leading to end stage renal disease (ESRD). ESRD affects 500,000 Americans and its prevalence is increasing with a rise in diabetes and hypertension. ESRD is associated with significant morbidity and mortality: ultimately kidney transplant is the only cure but for every four patients requiring a transplant there are only enough available kidneys to help one. Life-threatening kidney injury also occurs through acute damage particularly in hospital settings were infection, toxic drugs or ischemia during surgery kills cells in the nephron shutting down the kidneys. Animal studies indicate that the kidney is unable to make new nephrons: the full complement of nephrons for live are established prior to birth. However, the damaged nephron has a limited capacity to restore activity through the regeneration of missing cells by their surviving neighbors. Kidney stem cells give rise to all specialist parts of the complex nephron structure during kidney development. New genetic approaches in the mouse have enabled the isolation of these stems cell providing an opportunity to develop strategies to propagate and differentiate kidney stem cells into nephrons in the tissue culture dish. We expect that the insights gained from these studies will facilitate the translation of de novo nephrogenesis to human nephron cultures, and as a result, the development of new approaches to study and treat kidney disease. An alternative approach comes from the observation of limited self-repair by cells within damaged nephrons. The molecular and cellular processes at play in the damage-repair responses are largely unknown but elucidating these mechanisms will facilitate development of novel strategies to either augment the repair process following damage or prevent tubule damage in the first instance within at risk patients. Mouse models again provide a way forward to this long-term goal. By isolating repairing cells, and comparing gene expression signatures amongst damaged, repairing and healthy cells, we will identify repair specific responses and test the ability of candidate repair regulators to enhance the restoration of kidney function.
Statement of Benefit to California: 
Approximately 1% of Medicare enrollees in the State of California have End State Renal Disease and this number will rise. There is no effective cure aside from kidney transplantation, too few donors, and a high morbidity and mortality associated with long-term dialysis. Approximately 5-7% of hospitalized patients experience acute kidney injury, a leading cause of mortality in institutionalized settings. The target of kidney injury and disease is the nephron, all nephrons form during fetal life and self-repair within nephrons is thought to restore normal function. Through identifying conditions that support stem cells capable of new nephrogenesis and generating new nephrons from these cells, we will be able to explore approaches to restoring kidney function that are not currently possible. Further, the identification of factors associated with normal nephron repair will enable functional investigation of their potential clinical significance in kidney injury models. Given the fiscal cost of kidney disease within the State, the toll of kidney disease on patients and their families, and the lack of alternatives – developing approaches that treat disease would have a significant impact.
Progress Report: 
  • Kidney function is essential for removing the wastes that result from normal cell function and maintaining water and salt balance in our internal tissues. These actions are carried out by roughly a million nephrons within the kidney that filter all the body’s blood roughly once every 1-2 hours. The kidney also regulates other tissues controlling blood pressure and blood cell composition, and regulating the strength of bone by activating vitamin D. Chronic kidney injury over time results in a loss of normal kidney function leading to end stage renal disease (ESRD). ESRD affects 500,000 Americans and its prevalence is increasing with a rise in diabetes and hypertension. ESRD is associated with significant morbidity and mortality: ultimately kidney transplant is the only cure but for every four patients requiring a transplant there are only enough available kidneys to help one. Life-threatening kidney injury also occurs through acute damage particularly in hospital settings were infection, toxic drugs or ischemia during surgery kills cells in the nephron shutting down the kidneys. Animal studies indicate that the kidney is unable to make new nephrons: the full complement of nephrons for life are established prior to birth. However, the damaged nephron has a limited capacity to restore activity through the regeneration of missing cells by their surviving neighbors.
  • Our research has focused on an understanding of the damage/repair process following acute kidney injury to identify new therapeutic opportunities. We have utilized a mouse model to generate a BioBank resource of injured and repairing kidney samples. Further, we have generated a novel approach that allows the investigator to focus on injury and repair responses within specific cellular compartments in the kidney. As an example, this approach allows us to investigate changes in gene activity within the nephron itself, or in the blood vessels that engulf the nephrons. Both are targets of injury and effective repair will likely involve solutions for each of these components of the kidney. We have generated a large informational base and started to mine this data to identify genes with the potential to direct or augment renal repair. Using modern genetic strategies we are now exploring the roles of several of these genes. Our goal is to move from discovery to translation of those discoveries during the course of this CIRM leadership award.
  • Kidney function is essential for removing the wastes that result from normal cell function and maintaining water and salt balance in our internal tissues. These actions are carried out by roughly a million nephrons within the kidney that filter all the body’s blood roughly once every 1-2 hours. The kidney also regulates other tissues controlling blood pressure and blood cell composition, and regulating the strength of bone by activating vitamin D. C hronic kidney injury over time results in a loss of normal kidney function leading to end stage renal disease (ESRD). ESRD affects 500,000 Americans and its prevalence is increasing with a rise in diabetes and hypertension. ESRD is associated with significant morbidity and mortality: ultimately kidney transplant is the only cure but for every four patients requiring a transplant there are only enough available kidneys to help one. Life-threatening kidney injury also occurs through acute damage particularly in hospital settings were infection, toxic drugs or ischemia during surgery kills cells in the nephron shutting down the kidneys. Animal studies indicate that the kidney is unable to make new nephrons: the full complement of nephrons for life are established prior to birth. However, the damaged nephron has a limited capacity to restore activity through the regeneration of missing cells by their surviving neighbors.
  • Our research has focused on an understanding of the damage/repair process following acute kidney injury to identify new therapeutic opportunities. We have utilized a mouse model to generate a BioBank resource of injured and repairing kidney samples. Further, we have generated a novel approach that allows the investigator to focus on injury and repair responses within specific cellular compartments in the kidney. As an example, this approach allows us to investigate changes in gene activity within the nephron itself, or in the
  • blood vessels that engulf the nephrons. Both are targets of injury and effective repair will likely involve solutions for each of these components of the kidney. We have generated a large informational base and started to mine this data to identify genes with the potential to direct or augment renal repair. Using modern genetic strategies we are now exploring the roles of several of these genes. Our goal is to move from discovery to translation of those discoveries during the course of this C IRM leadership award.

Preclinical Model for Labeling, Transplant, and In Vivo Imaging of Differentiated Human Embryonic Stem Cells

Funding Type: 
Comprehensive Grant
Grant Number: 
RC1-00144
ICOC Funds Committed: 
$2 257 040
Disease Focus: 
Kidney Disease
Stem Cell Use: 
Embryonic Stem Cell
oldStatus: 
Closed
Public Abstract: 
Statement of Benefit to California: 
Progress Report: 
  • We have made substantial progress towards increasing our knowledge about early kidney development, identified new ways to differentiate human embryonic stem cells (hESC) to kidney lineages, and explored the use of these and other related kidney cells to study repopulation of the kidney. In order to obtain the necessary cell types for regenerative medicine purposes, differentiation of hESC must follow developmental pathways and recapitulate normal development, and our studies have brought us closer to this goal. Investigations have supported that expression of early developmental markers provides a useful and efficient method to direct differentiation of hESC towards renal lineages. The results of these studies have established cell culture conditions that ensure we can consistently obtain the quantity of differentiated hESC needed for transplantation into developing and damaged kidneys. Significant progress has also been made in developing new and effective techniques for labeling cells for in vivo imaging, and monitoring the labeled cells post-transplantation using positron emission tomography (PET). We have collected sufficient quantities of cells in culture, and identified effective methods to label the cells without altering viability, proliferation, or function. We have also shown that these same cell populations can be used for transplantation into developing kidneys, and that the cells persist post-transplant over time and can be identified using PET. This strategy has allowed us to precisely document cell location post-transplantation in vivo, demonstrated that post-transplant viability was maintained, and shown that the cells did not migrate to other anatomical sites.
  • We continue to make substantial progress towards increasing our knowledge about early kidney development and disease, and kidney regeneration strategies, and have successfully applied our methods to differentiate human embryonic stem cells (hESC) to kidney lineages for transplant purposes. We have also accomplished effective radiolabeling of the cells for monitoring post-transplantation, and explored the use of in vivo imaging to monitor the cells.
  • These studies focus on kidney development and disease, and new cell-based strategies to regenerate damaged kidneys. We have used human embryonic stem cells (hESC) differentiated towards kidney lineages for transplant purposes and monitored these transplanted cells with positron emission tomography (PET) and other related imaging modalities.
  • The U.S. Renal Data System has reported that the rate of pediatric end stage renal disease has tripled since 1980. Congenital anomalies of the kidney are responsible for the majority of chronic renal failure and end stage disease in young children, with congenital obstruction of the urinary tract the most common. These studies are driven by the fact that the clinical condition of congenital urinary tract obstruction is one of the most important problems affecting young children with kidney disease, and with few therapeutic options. In humans, alterations in the events associated with normal kidney development leads to aberrant kidney structure and postnatally to abnormal kidney function. Little is known about the early cell populations of the developing kidney, thus further understanding of developmental processes is essential to guide regenerative approaches that will ultimately be successful. These studies have focused on several key issues such as understanding developmental timelines for key kidney markers, cell populations, and the interactive molecular and cellular milieu during ontogeny; new explant models to aid in developing the techniques necessary to enhance regeneration of kidneys damaged by obstructive renal disease; explant culture conditions using human embryonic stem cells differentiated towards early renal precursors; effective methods for labeling these cells for in vivo imaging in order to monitor engraftment and outcomes post-transplant; and effective methods to transplant renal precursors within a natural framework into defined anatomical locations of the kidney.
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