Focal segmental glomerulosclerosis (FSGS) is a clinical-pathologic syndrome characterized by the accumulation of fibrotic proteins in glomeruli, initially involving only some glomeruli (focal) and involving portions (segments) of the affected glomeruli. We have found evidence that the monkey virus SV40, probably introduced into the human population via vaccines administered prior to 1963, is present in human kidney and urine, and may be associated with FSGS. Our rationale for this line of work is that 12% of healthy adults have antibodies against SV40, polyomaviruses establish latency in kidney, and SV40 transgenic mice develop FSGS. We obtained peripheral blood mononuclear cells and urinary cells from patients with FSGS, other kidney diseases, and healthy volunteers. Cellular material was added to CV-1 cells, which are highly susceptible to SV40 infection. We found evidence for the presence of infectious SV40 in these cultures, including cytopathic effect and T antigen protein expression. We used nested PCR and DNA sequencing of the polymorphic regulatory region to demonstrate that the virus in cell culture was SV40 and not the human polyomaviruses, BKV and JCV. The presence of point mutations, large deletions, and duplications argues against laboratory contamination as an explanation for these findings. Replication-competent SV40 could be detected in urine obtained from 41% of FSGS patients compared to 10% of other renal disease patients (P<0.02) and 5% of healthy volunteers (P=0.003). SV40 DNA was localized to tubular cells by in situ hybridization. This represents one of the first reports of infectious SV40 isolated from human subjects. It remains to be determined whether SV40 causes FSGS, induces tubular injury, and/or is up-regulated by chronic renal inflammation. At present, approximately 5-10% of renal transplant recipients develop polyomavirus infection, usually attributed to BKV and occasionally associated with JCV. We examined whether SV40 might be present in this clinical setting. At NIH, 6 patients (7%) of 91 patients undergoing renal transplant developed polyomavirus nephropathy; 2 patients had SV40 detected in blood, urine, or kidney, while all 6 had BKV in urine. These results suggest that SV40 infection occurs following transplant, but the data are at present insufficient to establish SV40 as a cause of polyomavirus nephropathy. Pirfenidone is an orally-active, small molecule inhibitor of fibrosis, whose mechanism of action has not been well-defined but might involve inhibiting production of TGF-beta. We have initiated an open label, phase II study for FSGS patients with declining renal function. The study design compares the rate of glomerular filtration rate (GFR) decline during a baseline period in which blood pressure is controlled and the patient receives angiotensin antagonist medication (ACE inhibitor or angiotensin receptor blocker) with the rate of GFR decline while on pirfenidone therapy plus angiotensin antagonist medication. We have enrolled 18 patients, who receive treatment for at least one year but may continue pirfenidone thereafter. In the first 12 patients, after a mean follow-up of 11 months, the GFR decline rate improved from ?0.79?0.42 (mean,SD) ml/min/mo during the baseline period to ?0.46?0.40 ml/min/mo while receiving pirfenidone (P=0.06). This represents an improvement of approximately 40%, an effect size comparable to that of ACE inhibitors in patients with diabetic nephropathy (another disease characterized by glomerulosclerosis). We are discussing with collaborators, including InterMune, which holds the license for pirfenidone, plans to carry out a multi-center, randomized, placebo-controlled phase II study to confirm efficacy and establish minimum effective dose. Therapy with daily prednisone induces remission in approximately 30% of FSGS patients, but with substantial morbidity. We have initiated an open label pilot study of pulse oral dexamethasone for idiopathic FSGS. We hypothesize that 8 months of pulse dexamethasone treatment will have equal or greater efficacy compared to daily prednisone with reduced toxicity. We have enrolled 11 patients at NIH, as well as 3 patients being treated at Mayo Clinic as part of a collaboration. Eight patients, with a mean initial proteinuria of 9.3 g/d, have completed therapy. At the time of completing therapy, 1 patient was in complete remission (proteinuria <0.3 g/d), 3 patients were in partial remission (<2 g/d), 2 patients had a limited response (>50% fall in proteinuria), and 2 patients had no response. We have not observed significant toxicity despite extensive evaluation. We believe that this regimen has promise as an alternative to daily steroids, but more patients and longer follow-up are required.
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