Browse by Medical Category
Friday, April 15, 2011
In addition to practicing pediatric nephrology at MGHfC and the Emerson Hospital outpatient Pediatric Specialty Care Center, Elahna Paul, MD, PhD, conducts clinical and basic science research of kidney disease. As the pediatric nephrologist of the Herscott Center for Tuberous Sclerosis Complex (TSC) at MGH, she studies the renal manifestations of TSC in both children and adults, and with a PhD in immunology she studies mouse models of lupus nephritis in her laboratory on the MGH main campus.
End stage renal disease is a large and ever growing medical problem, predicted to outstrip current medical resources within the next two decades. Approximately 20% of pediatric and 10% of adult chronic renal patients have some form of autoimmune nephritis. Lupus nephritis is one example that occurs in approximately 1/500-5000 individuals worldwide and accounts for substantial renal morbidity and mortality, in part because diagnosis often occurs after kidney disease begins and the treatments are themselves fairly harmful and not always effective. This research program studies a relatively new mouse model of lupus nephritis to understand how the protein called CD48 regulates disease and to discover additional genes that modify disease severity, with the long term goals of developing more sensitive clinical tests to diagnose kidney conditions while they are still mild and also to help design safer medical therapies.
Figure legend: A normal PAS strained glomerulus from a healthy kidney is shown on the left. An abnormal glomerulus from a nephritic mouse is shown on the right at the same magnification. It is enlarged, lobulated and hypercellular with early crescent formation.
B6.CD48-/- animals, BALB/c mice with genetic ablation of CD48 (BALB.CD48-/-) have no autoimmune traits, indicating that background gene(s) unique to the different mouse strains modulate the effect of CD48 deficiency. CD48-null F1 progeny of B6.CD48-/- x BALB.CD48-/- parents are also non-autoimmune, suggesting that background gene effects are recessive. Preliminary data further demonstrate that approximately 40% of CD48-null N2 pups from F1.CD48-/- x B6.CD48-/- backcrosses produce anti-DNA antibodies, substantiating a Mendelian inheritance of this trait. A series of CD48- null mice with differing combinations of B6 and BALB/c genomic loci will be phenotyped with respect to GN and autoantibody production and will be genotyped using single nucleotide polymorphism (SNP) based genome-wide scans. Quantitative trait linkage (QTL) analysis will be used to identify B6- specific modifier(s) of CD48GN and associated disease traits. Murine genetic polymorphisms may ultimately implicate human polymorphisms that can predict renal involvement in systemic autoimmune disease. This project is funded by the NIDDK.
Renal lesions occur in at least 50% of patients with Tuberous Sclerosis Complex (TSC) and can cause significant morbidity and mortality. While the simple cysts of TSC are often clinically insignificant, rapidly growing masses can be life threatening when abnormal blood vessels rupture or when neoplastic cells invade and metastasize. Even though most solid renal lesions of TSC are angiomyolipoma (AML) of little import, caregivers must rely on inconclusive or invasive diagnostic maneuvers to identify those solid lesions that are in fact cancerous or those AMLs that are better ablated lest they hemorrhage or become otherwise symptomatic.
Based on the hypothesis that renal tumor growth is associated with measurable changes in urine composition and on the knowledge that angiogenesis is essential for tumor expansion, we predict that factors associated with angiogenesis and with renal injury will increase during periods of TSC-associated renal tumor growth. We propose to test the hypothesis that a candidate driven approach can identify factors in urine or serum that reflect renal tumor burden and whose concentrations change as tumors grow.
Figure legend: Typical appearing renal AMLs are shown in T2 weighted MRI images of two children with TSC. The image on the left shows a fairly normal appearing kidney on the patient’s right and a large, heterogenous, centrally located tumor on the patient’s left. The image on the right shows a small right upper pole AML and a medium left lower pole tumor.
Serial blood and urine samples from TSC patients with and without renal lesions will be tested for growth and angiogenic factors and for markers of kidney injury. Correlation with serial renal imaging studies will help identify surrogate markers of tumor burden and disease progression. This projects has the potential to enhance tumor surveillance capabilities, reduce imaging frequency in stable patients and perhaps even prospectively identify those tumors with potentially aggressive features that may warrant intensified monitoring or prophylactic intervention. If less invasive and more cost effective blood and urine tests improve diagnostics and prognostics of TSC-associated renal manifestations, then biomarkers may reduce the emotional and financial strain on patients and their families. Biomarker discovery can change the standard of care in TSC. This project is funded by the DoD CDMRP.
Back to Top