ARRA IMPACT REPORT:
Chronic Kidney Disease: Pathophysiology and Identification of Reversal Strategies


Public Health Burden
The number of Americans with chronic kidney disease (CKD) -- that is, some degree of impaired kidney function -- has been estimated to be more than 23 million.1 The prevalence of CKD is increasing in the population from 10 percent (between 1988-1994) to 13 percent (between 1999-2004) due largely to increasing rates of diabetes and hypertension, both of which are likely to be a consequence of obesity.2

Advancing Insight into the Pathophysiology of CKD
Despite progress in understanding the mechanisms of disease progression, there are very limited therapy options or merely supported treatment in the management of CKD. Increased understanding of the changes to renal structure and physiological characteristics associated with disease progression must be obtained in order to identify and develop potential therapeutic targets. ARRA-funded research has provided important information regarding the pathophysiology of CKD:

Cellular Source of Scar-Producing Collagen Identified: Scientists have identified the cellular source of scar-producing collagen in a model of kidney fibrosis.3 Fibrosis is the term that describes the deposition of large amounts of collagen-rich connective tissue that can lead to scarring within an organ. Contrary to prevailing theories, myofibroblasts were identified as the source of the collagen. Myofibroblasts are derived from pericytes, a type of stem cell that is usually associated with blood vessels.

Reducing Fibrosis by Inhibiting the Development of Pericytes: Researchers have determined that a specific signal transduction pathway is involved in the transition of the pericyte into the myofibroblast.4 Using agents that block the a cell signaling pathway, the transition from pericyte into myofibroblast was decreased and the level of fibrosis curtailed. The fact that pericytes can be induced to form myofibroblasts serves to re-focus fibrosis research to areas important in kidney disease.

New Molecular Target for Anti-fibrotic Therapies - MicroRNA 21: Using two mouse models of kidney fibrosis, scientists have identified a regulator of gene expression whose level is elevated during the process of kidney scarring.5 The researchers focused on one molecule, microRNA 21 (miR-21) that was found to be highly elevated in two mouse models of kidney disease soon after injury and before fibrosis appeared. This molecule is also found in humans with kidney injury. Mice engineered to lack the miR-21 gene showed diminished fibrosis in response to kidney injury; similar results were observed in normal mice that had been treated with an inhibitor of miR-21. This molecule represents a potential target for anti-fibrotic therapies in kidney disease.

New Molecular Target for Anti-fibrotic Therapies – Regulator Protein HIPK2: Scientists used computational and systems biology approaches to identify a signaling molecule that regulates gene expression in a mouse model of HIV-associated kidney disease.6 They identified the protein HIPK2 as a key regulator of kidney fibrosis. Levels of this protein were found to be elevated in both the mouse model and in patients with various forms of kidney disease. Deletion of the gene encoding HIPK2 in the mouse model improved kidney function and reduced the severity of fibrosis. HIPK2 may be a potential target for novel therapies to address kidney fibrosis.

Advances in the Identification of CKD Reversal Strategies
The identification of potential targets aimed at preventing and possibly reversing chronic kidney disease is of primary interest at the NIH. By preventing, stabilizing and/or reversing the disease process, the enormous personal and economic costs could be deferred or eliminated. ARRA-funded research has unveiled multiple avenues to potentially combat CKD:

Leveraging a Natural Protein Inhibitor of Fibrosis: Researchers have identified the circulating protein, serum amyloid P (SAP), as a natural inhibitor of fibrosis during inflammatory injury in the kidney.7 Using two models of kidney injury and fibrosis in mice, researchers found that human SAP can potently inhibit fibrosis in this organ. SAP accumulated at sites of injury within the kidney, where it appeared to be associated with injured or dead cells. In the kidney, SAP suppresses the activity of specialized white blood cells that are involved in the inflammatory response. These observations suggest that SAP may have the potential to act as a broad-based anti-fibrotic agent.

Understanding the Pathways for Repair and Regeneration: Using a kidney injury model, scientists have demonstrated that the Wnt signaling pathway is critical for repair and regeneration.8 Removal of 80 percent of recruited macrophages from the injury site using a chemical ablation procedure served to provide evidence that macrophages (specialized white blood cells that are involved in the inflammatory response) are the source of Wnt7b and that without activated macrophages the repair and regeneration process was significantly halted.

Stem Cells found to Promote Kidney Repair in Mouse: Human stem cells were shown to promote kidney repair in a mouse injury model.9 Stem cells were administered 24 hours after injury in an immunodeficient mouse strain which allows for the assessment of human cells to promote kidney repair. Researchers reported that the stem cells enhanced repair of kidney vasculature, increased kidney tubule epithelial cell proliferation, enhanced functional recovery of the kidney, and increased survival of the animals.

Blocking Signaling Pathways to Attenuate Kidney Fibrosis and Inflammation: Researchers have shown that inhibition of either vascular endothelial growth factor receptor signaling in endothelial cells or platelet-derived growth factor receptor-beta signaling in pericytes attenuated kidney fibrosis and inflammation in two injury models.10 The interaction between pericytes and endothelial cells is necessary for fibrogenesis after injury. The blockade of either of these signaling pathways inhibits both pericyte proliferation and its detachment from capillaries.

Preventing PKC Cyst Expansion: Scientists have reported the discovery and initial characterization of a new class of cystic fibrosis transmembrane conductance regulator (CFTR) inhibitors, called PPQs, that prevent cyst expansion and reduced the size of pre-existing cysts in a kidney organ culture model of polycystic kidney disease.11 This research group later reported the synthesis and initial characterization of PPQ analogs, called BPOs. 12

Evaluating the Efficacy of Cyclosporine A Treatment: An international team of investigators have detailed analysis of cyclosporine A treatment efficacy and renal outcome in patients with congenital nephrotic syndrome (CNS) or steroid-resistant nephrotic syndrome (SRNS), with respect to the patients’ hereditary or nonhereditary nature of disease.13 Most patients with hereditary forms of CNS/SRNS did not benefit from cyclosporine A treatment with significantly lower response rates and had rapid progression to end-stage renal disease compared with nonhereditary forms of these syndromes.

Small Molecule found to Reduce PKC Cyst Expansion: Knockdowns of the genes associated with the most severe causes of nephronophthisis-related ciliopathies (NPHP-RC) have been shown to cause 3-dimensional defects in a renal cystic disease model -- but these defects were rescued by treatment with a small molecule -- octreotide.14 To evaluate the roles of the three gene products (Nphp3, Nphp6, and Nphp8) in normal tissue architecture, knockdown cell lines of each were generated and the percentage of abnormal cysts determined. Previous studies have established that the second messenger cAMP plays a central role in the progression of cystic disease in patients with polycystic kidney disease (PKD) by stimulating kidney epithelial cell proliferation and secretion of fluid into cysts. Studies have also shown that octreotide, significantly reduces cAMP levels and rates of cysts expansion in a rat model of PKD.

Contributing NIH Institutes & Centers

  • National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)

  1. http://www.ncbi.nlm.nih.gov/pubmed/19414839
  2. http://www.ncbi.nlm.nih.gov/pubmed/17986697
  3. 5U01DK062420-09, http://www.ncbi.nlm.nih.gov/pubmed/20008127 - DUERR, RICHARD H - UNIVERSITY OF PITTSBURGH AT PITTSBURGH - PITTSBURGH - PA
  4. 5U01DK062420-09, http://www.ncbi.nlm.nih.gov/pubmed/21716259 - DUERR, RICHARD H - UNIVERSITY OF PITTSBURGH AT PITTSBURGH - PITTSBURGH - PA
  5. 5U01DK062420-09, http://www.ncbi.nlm.nih.gov/pubmed/22344686 - DUERR, RICHARD H - UNIVERSITY OF PITTSBURGH AT PITTSBURGH - PITTSBURGH - PA
  6. 1RC4DK090860-01, http://www.ncbi.nlm.nih.gov/pubmed/22406746 - KLOTMAN, PAUL EVAN - BAYLOR COLLEGE OF MEDICINE - HOUSTON - TX
  7. 5U01DK062420-09, http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2852889 - DUERR, RICHARD H - UNIVERSITY OF PITTSBURGH AT PITTSBURGH - PITTSBURGH - PA
  8. 5U01DK062420-09, http://www.ncbi.nlm.nih.gov/pubmed/20160075 - DUERR, RICHARD H - UNIVERSITY OF PITTSBURGH AT PITTSBURGH - PITTSBURGH - PA
  9. 5U01DK062420-09, http://www.ncbi.nlm.nih.gov/pubmed/20458011 - DUERR, RICHARD H - UNIVERSITY OF PITTSBURGH AT PITTSBURGH - PITTSBURGH - PA
  10. 5U01DK062420-09, http://www.ncbi.nlm.nih.gov/pubmed/21281822 - DUERR, RICHARD H - UNIVERSITY OF PITTSBURGH AT PITTSBURGH - PITTSBURGH - PA
  11. 5RC1DK086125-02, http://www.ncbi.nlm.nih.gov/pubmed/19785436 - VERKMAN, ALAN S - UNIV OF CALIFORNIA AT SAN FRANCISCO - SAN FRANCISCO - CA
  12. 5RC1DK086125-02, http://www.ncbi.nlm.nih.gov/pubmed/21707078 - VERKMAN, ALAN S - UNIV OF CALIFORNIA AT SAN FRANCISCO - SAN FRANCISCO - CA
  13. 5RC1DK086542-02, http://www.ncbi.nlm.nih.gov/pubmed/20798252 - HILDEBRANDT, FRIEDHELM - UNIVERSITY OF MICHIGAN AT ANN ARBOR - ANN ARBOR - MI
  14. 1RC4DK090917-01, http://www.ncbi.nlm.nih.gov/pubmed/22832925 - OTTO, EDGAR A - UNIVERSITY OF MICHIGAN AT ANN ARBOR - ANN ARBOR - MI