In addition to well-described renal tubulointerstitial damage, sickle cell anemia (SSA) may cause proteinuria and progressive renal insufficiency, leading to end-stage renal disease. They have shown that this results from a unique type of glomerulopathy, characterized by a distinctive set of glomerular hemodynamics and glomerular macromolecular permeability characteristics. They propose to determine: (1) genetic factors and clinical markers that identify patients who will develop this complication; (2) the mechanisms underlying the glomerular injury; and (3) whether blockade of the renin-angiotensin system is beneficial in patients who have progressive renal insufficiency. They have shown that albuminuria is a sensitive marker of a glomerulopathy in SSA patients, and that microdeletions at the a-globin gene locus protect from sickle glomerulopathy. Thus, they will screen children and adult SSA patients for increased levels of albuminuria to determine the prevalence of glomerular involvement in SSA and its usefulness as a predictive marker for late renal insufficiency, and they will determine mechanisms of renal protection by the a-globin microdeletions. They will determine the role of the nitric oxide system in mediating the glomerular dysfunction by blocking experimentally its formation, and the role of the renin-angiotensin system in progressive renal insufficiency by experimentally blocking angiotensin II formation and determining whether certain regulatory elements in the angiotensin converting enzyme (ACE) gene, a key enzyme in the formation of angiotensin, are associated with a more severe form of kidney disease. They will analyze with immunohistological and morphometric methods kidney biopsies of patients with sickle glomerulopathy to determine the glomerular substructures that are damaged in this disease. They hope that this information will help design trials that target patients at higher risk and find new treatments for this disease.
| Guasch, Antonio; Navarrete, Jose; Nass, Kaleed et al. (2006) Glomerular involvement in adults with sickle cell hemoglobinopathies: Prevalence and clinical correlates of progressive renal failure. J Am Soc Nephrol 17:2228-35 |
| Guasch, A; Zayas, C F; Eckman, J R et al. (1999) Evidence that microdeletions in the alpha globin gene protect against the development of sickle cell glomerulopathy in humans. J Am Soc Nephrol 10:1014-9 |
