Steroid-resistant focal segmental glomerulosclerosis (SR-FSGS) is a common glomerulopathy associated with nephrotic range proteinuria. Treatment goals are reduction in proteinuria, which can delay ...end-stage renal disease.
Patients with SR-FSGS were enrolled in a randomized, double-blind placebo-controlled trial of fresolimumab, a monoclonal anti-transforming growth factor-β antibody, at 1 mg/kg or 4 mg/kg for 112 days, followed double-blind for 252 days (NCT01665391). The primary efficacy endpoint was the percentage of patients achieving partial (50% reduction) or complete (< 300 mg/g Cr) remission of proteinuria.
Of 36 enrolled patients, 10, 14, and 12 patients received placebo, fresolimumab 1 mg/kg, and fresolimumab 4 mg/kg, respectively. The baseline estimated glomerular filtration rate (eGFR) and urinary protein/creatinine ratio were 63 ml/min/1.73 m
and 6190 mg/g, respectively. The study was closed before reaching its target of 88 randomized patients. None of the prespecified efficacy endpoints for proteinuria reduction were achieved; however, at day 112, the mean percent change in urinary protein/creatinine ratio (a secondary efficacy endpoint) was -18.5% (
= 0.008), +10.5% (
= 0.52), and +9.0% (
= 0.91) in patients treated with fresolimumab 1 mg/kg, fresolimumab 4 mg/kg, and placebo, respectively. There was a nonsignificant trend toward greater estimated glomerular filtration rate decline in the placebo group compared to either of the fresolimumab-treated arms up to day 252.
The study was underpowered and did not meet the primary or secondary endpoints. However, fresolimumab was well tolerated and is appropriate for continued evaluation in larger studies with adequate power.
Mesenchymal stem cells (MSCs) have natural immunoregulatory functions that have been explored for medicinal use as a cell therapy with limited success. A phase Ib study was conducted to evaluate the ...safety and immunoregulatory mechanism of action of MSCs using a novel ex vivo product (SBI‐101) to preserve cell activity in patients with severe acute kidney injury. Pharmacological data demonstrated MSC‐secreted factor activity that was associated with anti‐inflammatory signatures in the molecular and cellular profiling of patient blood. Systems biology analysis captured multicompartment effects consistent with immune reprogramming and kidney tissue repair. Although the study was not powered for clinical efficacy, these results are supportive of the therapeutic hypothesis, namely, that treatment with SBI‐101 elicits an immunotherapeutic response that triggers an accelerated phenotypic switch from tissue injury to tissue repair. Ex vivo administration of MSCs, with increased power of testing, is a potential new biological delivery paradigm that assures sustained MSC activity and immunomodulation.
Mesenchymal stem cells (MSCs) have natural immunoregulatory functions that have been explored for medicinal use as a cell therapy with limited success. A phase 1b study was conducted to evaluate the safety and immunoregulatory mechanism of action of MSCs using a novel ex vivo product (SBI‐101) to preserve cell activity in patients with severe acute kidney injury (AKI).
Renal Biopsy in the Very Elderly Moutzouris, Dimitrios-Anestis; Herlitz, Leal; Appel, Gerald B ...
Clinical journal of the American Society of Nephrology,
06/2009, Letnik:
4, Številka:
6
Journal Article
Recenzirano
Odprti dostop
Data regarding renal biopsy in the very elderly (>or=age 80 yr) are extremely limited. The aim of this study was to examine the causes of renal disease and their clinical presentations in very ...elderly patients who underwent native renal biopsy.
All native renal biopsies (n = 235 including 106 men, 129 women) performed in patients aged >or=80 yr over a 3.67-yr period were retrospectively identified. Results were compared with a control group of 264 patients aged 60 to 61 who were biopsied over the same period.
The indications for biopsy were acute kidney injury (AKI) in 46.4%, chronic-progressive kidney injury in 23.8%, nephrotic syndrome (NS) in 13.2%, NS with AKI in 9.4%, and isolated proteinuria in 5.5%. Pauci-immune GN was the most frequent diagnosis (19%), followed by focal segmental glomerulosclerosis secondary to hypertension (7.6%), hypertensive nephrosclerosis (7.1%), IgA nephropathy (7.1%) and membranous nephropathy (7.1%). Comparison with the control group showed pauci-immune GN to be more frequent (P < 0.001) and diabetic glomerulosclerosis (P < 0.001) and membranous nephropathy (P < 0.05) less frequent in the very elderly. Diagnostic information had the potential to modify treatment in 67% of biopsies from the very elderly, particularly in those with AKI or NS.
Renal biopsy in very elderly patients is a valuable diagnostic tool that should be offered in clinical settings with maximal potential benefit. Advanced age per se should no longer be considered a contraindication to renal biopsy.
We report a case of anti–glomerular basement membrane (anti-GBM) nephritis with indolent course, monoclonal IgG1κ (immunoglobulin G, subclass 1, κ light chain) linear staining of the GBM, and ...multifocal GBM breaks but without crescents or detectable serum anti-GBM antibody in a patient followed over 9 years. Atypically, anti-GBM nephritis follows an indolent course. A very small fraction of patients with anti-GBM nephritis lack detectable circulating anti-GBM antibodies, and rare reports of monoclonal anti-GBM nephritis exist. We report what is to our knowledge the first case manifesting all 3 of these rare variations. Our patient initially presented with asymptomatic decreased kidney function following an upper respiratory tract infection. He was found to have microhematuria and subnephrotic proteinuria with mild diffuse endocapillary proliferative and exudative glomerulonephritis with linear IgG1κ staining of the GBM. He was treated with an induction regimen of intravenous cyclophosphamide and corticosteroids followed by maintenance monotherapy with mycophenolic acid. Nine years later, repeat kidney biopsy for worsening kidney function after an upper respiratory tract infection showed persistent monoclonal staining of the GBM and acute glomerulonephritis with increased chronicity, including a single fibrocellular crescent. Despite extensive clinical investigations spanning nearly a decade, no circulating anti-GBM antibody or monoclonal protein has been detected. In this case report, we explore the unique features of this monoclonal IgG1κ-associated anti-GBM nephritis.
Sparsentan is a novel single-molecule dual endothelin angiotensin receptor antagonist with hemodynamic and anti-inflammatory properties and is not an immunosuppressant. The ongoing phase 3 PROTECT ...trial examines sparsentan in adults with IgA nephropathy (IgAN).
The PROTECT trial (NCT03762850) is a multicenter, international, randomized, double-blind, parallel-group, active-controlled study. The efficacy and safety of sparsentan versus the active control irbesartan is being evaluated in adults with biopsy-proven IgAN and proteinuria ≥1.0 g/d despite maximized treatment with an angiotensin-converting enzyme inhibitor (ACEi) and/or angiotensin receptor blocker (ARB) for at least 12 weeks. Blinded and aggregated baseline characteristics are reported descriptively and compared to contemporary phase 3 trials with patients with IgAN.
The primary analysis population includes 404 patients who were randomized and received study drug (median age, 46 years). Enrolled patients were from Europe (53%), Asia Pacific (27%), and North America (20%). Baseline median urinary protein excretion was 1.8 g/d. The range of estimated glomerular filtration rate (eGFR) was broad with the largest proportion of patients (35%) in chronic kidney disease (CKD) stage 3B. Before transitioning to study medication, mean systolic/diastolic blood pressure was 129/82 mm Hg, with the majority of patients (63.4%) receiving the maximum labeled ACEi or ARB dose. Patients in Asian versus non-Asian regions included a higher percentage of females, had lower blood pressures, and included lower proportions of patients with a history of hypertension and baseline antihypertensive treatment.
Patient enrollment in PROTECT, with differing racial backgrounds and across CKD stages, will allow for important characterization of the treatment effect of sparsentan in patients with IgAN with proteinuria at high risk of kidney failure.
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