Pilot Study of Mycophenolate Mofetil in Congenital Uropathies

Sustained activation of the immune system may contribute to progressive renal injury in all forms of chronic kidney disease. There is extensive proliferation of renal tubular epithelial cells and fibroblasts within the kidney of patients with chronic renal failure (CRF). The fibroblasts manifest an activated myofibroblast phenotype, evidenced by expression of alpha smooth muscle actin. This change is accompanied by infiltration of the renal interstitium with macrophages, lymphocytes, and other immunocompetent cells. The cells are also activated and release numerous cytokines and inflammatory mediators. These substances exacerbate the injury process by recruiting additional immunoeffector cells into the kidney parenchyma and stimulating the production and secretion of pro-inflammatory molecules. These findings suggest that immunosuppressive medications may be beneficial in the treatment of congenital uropathies. In fact, mycophenolate mofetil (MMF) (10-30 mg/kg/day) has been given to rats that had been subjected to a 5/6 nephrectomy. Uremia in this remnant kidney model is not the consequence of primary immunological disease. MMF treatment for 30-60 days did not prevent intraglomerular hypertension or the alterations in renal hemodynamics that characterize the adaptation to reduced renal mass. However, the extensive infiltration of the renal interstitium by proliferating lymphocytes was markedly attenuated by MMF treatment. Moreover, despite the relatively selective anti-metabolic effect of MMF on lymphocytes, there was a significant reduction in macrophage infiltration in the tubulointerstitium. This beneficial change was associated with a significant reduction in albuminuria and glomerulosclerosis after 60 days of MMF treatment. Combined treatment with the MMF and the angiotensin converting enzyme (ACE) inhibitor, lisinopril, to rats with reduced renal mass diminished tubulointerstitial infiltration by macrophages and T cells even more than MMF therapy alone and nearly normalized urinary protein excretion. Thus, pharmacological treatment with MMF attenuated the progression of "nonimmunological" renal disease in the remnant kidney model without favorably impacting on intraglomerular hemodynamics or the hypertrophic response to peptide growth factors.

MMF is a well-tolerated, safe, and effective immunosuppressive medication in adult and pediatric recipients of cadaveric and living-related renal transplants.

HYPOTHESIS AND SPECIFIC AIMS This open-label pilot study is designed to test the hypothesis that there is sustained activation of immunoeffector systems that mediate progressive loss of renal function in children with congenital uropathies. Immunosuppressive therapy can inhibit this process and retard the rate of decline in kidney function in pediatric patients with structural, non-immunological kidney conditions.

Specific Aim#1: Determine whether administration of mycophenolate mofetil (MMF) to pediatric patients with a glomerular filtration rate (GFR) <50 ml/min/m2 due to congenital uropathies such as dysplasia/hypoplasia, obstructive uropathy, and reflux nephropathy is safe and well tolerated.

Specific Aim#2: Determine whether administration of mycophenolate mofetil (MMF) diminishes the rate of progressive decline in GFR and the frequency of ESRD in pediatric patients with a glomerular filtration rate (GFR) <50 ml/min/m2 due to congenital uropathies.