Focal segmental glomerulosclerosis (FSGS) is a clinical-pathologic syndromes characterized by the accumulation of fibrotic proteins in glomeruli, initially involving only some glomeruli (focal) and involving portions (segments) of the affected glomeruli. FSGS can be classified as follows: idiopathic FSGS, genetic FSGS and post-adaptive FSGS (associated with glomerular hypertrophy and hyperfiltration, and due to reduced renal mass, renal toxins, obesity, and sickle cell disease). A related syndrome is collapsing glomerulopathy, associated with podocyte hyperplasia whereas FSGS is associated with podocyte depletion. Collapsing glomerulopathy can be classified as HIV-associated or idiopathic.? ? Many patients with podocyte diseases, including minimal change nephropathy (MCN), FSGS, and collapsing glomerulopathy are refractory to all conventional remittive therapy. We now have three open-label, phase 2 trials for podocyte diseases (current number enrolled given in parentheses): oral pulse dexamethasone for therapy-naove patients with FSGS and MCN (N=8), isotretinoin for immunotherapy-resistant patients with FSGS (N=5) and plasma exchange plus cyclophosphamide (N12).? ? In the past year we published the results of an open label, single arm trial using pirfenidone, a novel antifibrotic agent in patients with idiopathic FSGS. These patients had a median estimated glomerular filtration rate (eGFR) of 25 ml/min/1.73m2, indicating severe chronic kidney disease, and were in general deemed refractory to immunosuppressive therapy. We found that pirfenidone slows progressive loss of eGFR by a median of 25%, when the treatment period is compared to the baseline period. We conclude that pirfenidone is a promising antifibrotic agent for progressive kidney disease. We have participated in a randomized, double-blind, placebo controlled trial of pirfenidone in diabetic nephropathy; this study will be comnpleted in 2008.? ? We also wish to identify new therapeutic approaches using high-throughput screening approaches. We have recently developed and published such an approach using mesangial cell migration into matrix-rich nodules in response to TGF-beta, a process which is abrogated by addition of tranilast (a TGF-beta signaling inhibitor and anti-fibrotic agent with some utility in diabetic nephropathy in humans and experimental animals). We are in the process of testing 1040 FDA compounds in this assay, using support received through the NIDDK diabetic complications therapies initiative.
| Gordon, Judit; Kopp, Jeffrey B (2011) Off the beaten renin-angiotensin-aldosterone system pathway: new perspectives on antiproteinuric therapy. Adv Chronic Kidney Dis 18:300-11 |
| Kopp, Jeffrey B; Ball, Lynda K; Cohen, Andrew et al. (2007) Kidney patient care in disasters: emergency planning for patients and dialysis facilities. Clin J Am Soc Nephrol 2:825-38 |
| Xu, Qihe; Norman, Jill T; Shrivastav, Shashi et al. (2007) In vitro models of TGF-beta-induced fibrosis suitable for high-throughput screening of antifibrotic agents. Am J Physiol Renal Physiol 293:F631-40 |
| Kopp, Jeffrey B; Ball, Lynda K; Cohen, Andrew et al. (2007) Kidney patient care in disasters: lessons from the hurricanes and earthquake of 2005. Clin J Am Soc Nephrol 2:814-24 |
| Cho, Monique E; Hurley, John K; Kopp, Jeffrey B (2007) Sirolimus therapy of focal segmental glomerulosclerosis is associated with nephrotoxicity. Am J Kidney Dis 49:310-7 |
