Sirolimus therapy of focal segmental glomerulosclerosis is associated with nephrotoxicity.
ABSTRACT To evaluate the safety and efficacy of sirolimus in treating patients with focal segmental glomerulosclerosis (FSGS), we performed a phase 2, open-label clinical trial. Inclusion criteria were adults and children 13 years and older with biopsy-proven idiopathic FSGS, proteinuria with protein of 3.5 g/d or greater while on angiotensin antagonist therapy, glomerular filtration rate (GFR) of 30 mL/min/1.73 m(2) or greater (>or=0.50 mL/s), and failure to achieve sustained remission with at least 1 immunosuppressive agent. Eligible patients received sirolimus doses adjusted to achieve trough levels of 5 to 15 ng/mL during the first 4 months and 10 to 20 ng/mL for the subsequent 8 months. The primary outcome was decrease in proteinuria, expressed as complete remission (protein < 0.3 g/d) or partial remission (protein >or= 50% decrease and <3.5 g/d). Six adult patients with FSGS were enrolled in the study; they had median disease duration of 4.0 years, mean age of 39 +/- 11 years, mean baseline Modification of Diet in Renal Disease-estimated GFR of 52 +/- 15 mL/min/1.73 m(2) (0.87 +/- 0.25 mL/s), and median baseline proteinuria with protein of 6.6 g/d (interquartile range, 4.2 to 9.4). Five patients had received cyclosporine. No patient experienced a complete or partial remission. Sirolimus therapy was stopped prematurely in 5 patients for the following reasons: (1) precipitous decrease in GFR in 4 patients after 7 to 9 months of therapy with a greater than 2-fold increase in proteinuria in 3 patients and (2) hypertriglyceridemia with triglyceride levels greater than 1,600 mg/dL (>18 mmol/L) at 5 months in 1 patient. Because of a rapid decrease in GFR with worsening proteinuria, the protocol was closed to further recruitment. We conclude that sirolimus may be associated with nephrotoxicity in some patients with FSGS, particularly those with prolonged disease duration and prior cyclosporine therapy.
Article: Is There a Role for Mammalian Target of Rapamycin Inhibition in Renal Failure due to Mesangioproliferative Nephrotic Syndrome?[show abstract] [hide abstract]
ABSTRACT: Primary glomerulonephritis stands as the third most important cause of end-stage renal disease, suggesting that appropriate treatment may not be as effective as intended to be. Moreover, proteinuria, the hallmark of glomerular damage and a prognostic marker of renal damage progression, is frequently resistant to thorough control. In addition, proteinuria may be the common end pathway in which different pathogenetic mechanisms may converge. This explains why immunosuppressive and nonimmunosuppressive approaches are partly not sufficient to halt disease progression. One of the commonest causes of primary glomerulonephritis is mesangioproliferative glomerulonephritis. Among the triggered intracellular pathways involved in mesangial cell proliferation, the mammalian target of rapamycin (mTOR) plays a critical role in cell growth, in turn regulated by many cytokines, disbalanced by the altered glomerulopathy itself. However, when inhibition of mTOR was studied in rodents and in humans with primary glomerulonephritis the results were contradictory. In light of these controversial data, we propose an explanation for these results, to dilucidate under which circumstances mTOR inhibition should be considered to treat glomerular proteinuria and finally to propose mTOR inhibitors to be prospectively assessed in clinical trials in patients with primary mesangioproliferative glomerulonephritis, for which a satisfactory standard immunosuppressive regimen is still pending.International journal of nephrology. 01/2012; 2012:427060.
Article: A phase 1, single-dose study of fresolimumab, an anti-TGF-β antibody, in treatment-resistant primary focal segmental glomerulosclerosis.[show abstract] [hide abstract]
ABSTRACT: Primary focal segmental glomerulosclerosis (FSGS) is a disease with poor prognosis and high unmet therapeutic need. Here, we evaluated the safety and pharmacokinetics of single-dose infusions of fresolimumab, a human monoclonal antibody that inactivates all forms of transforming growth factor-β (TGF-β), in a phase I open-label, dose-ranging study. Patients with biopsy-confirmed, treatment-resistant, primary FSGS with a minimum estimated glomerular filtration rate (eGFR) of 25 ml/min per 1.73 m(2), and a urine protein to creatinine ratio over 1.8 mg/mg were eligible. All 16 patients completed the study in which each received one of four single-dose levels of fresolimumab (up to 4 mg/kg) and was followed for 112 days. Fresolimumab was well tolerated with pustular rash the only adverse event in two patients. One patient was diagnosed with a histologically confirmed primitive neuroectodermal tumor 2 years after fresolimumab treatment. Consistent with treatment-resistant FSGS, there was a slight decline in eGFR (median decline baseline to final of 5.85 ml/min per 1.73 m(2)). Proteinuria fluctuated during the study with the median decline from baseline to final in urine protein to creatinine ratio of 1.2 mg/mg with all three Black patients having a mean decline of 3.6 mg/mg. The half-life of fresolimumab was ∼14 days, and the mean dose-normalized Cmax and area under the curve were independent of dose. Thus, single-dose fresolimumab was well tolerated in patients with primary resistant FSGS. Additional evaluation in a larger dose-ranging study is necessary.Kidney International 03/2011; 79(11):1236-43. · 6.61 Impact Factor