Atypical hemolytic uremic syndrome (aHUS) is caused by alternative complement pathway dysregulation, leading to systemic thrombotic microangiopathy (TMA) and severe end-organ damage. Based on 2 prospective studies in mostly adults and retrospective data in children, eculizumab, a terminal complement inhibitor, is approved for aHUS treatment. Here we prospectively evaluated efficacy and safety of weight-based dosing of eculizumab in eligible pediatric patients with aHUS in an open-label phase II study. The primary end point was complete TMA response by 26 weeks. Twenty-two patients (aged 5 months-17 years) were treated; 16 were newly diagnosed, 12 had no prior plasma exchange/infusion during current TMA symptomatology, 11 received baseline dialysis and 2 had prior renal transplants. By week 26, 14 achieved a complete TMA response, 18 achieved hematologic normalization, and 16 had 25% or better improvement in serum creatinine. Plasma exchange/infusion was discontinued in all, and 9 of the 11 patients who required dialysis at baseline discontinued, whereas none initiated new dialysis. Eculizumab was well tolerated; no deaths or meningococcal infections occurred. Bone marrow failure, wrist fracture, and acute respiratory failure were reported as unrelated severe adverse events. Thus, our findings establish the efficacy and safety of eculizumab for pediatric patients with aHUS and are consistent with proposed immediate eculizumab initiation following diagnosis in children.
Background We evaluated and compared the effects of sparsentan, a dual endothelin type A (ET A) and angiotensin II type 1 receptor antagonist, with those of the angiotensin II type 1 receptor antagonist irbesartan in patients with primary FSGS. Methods In this phase 2, randomized, double-blind, active-control Efficacy and Safety of Sparsentan (RE-021), a Dual Endothelin Receptor and Angiotensin Receptor Blocker, in Patients with Focal Segmental Glomerulosclerosis (FSGS): A Randomized, Double-blind, Active-Control, Dose-Escalation Study (DUET), patients aged 8-75 years with biopsy-proven FSGS, eGFR.30 ml/min per 1.73 m 2 , and urinary protein-to-creatinine ratio (UP/C) $1.0 g/g received sparsentan (200, 400, or 800 mg/d) or irbesartan (300 mg/d) for 8 weeks, followed by open-label sparsentan only. End points at week 8 were reduction from baseline in UP/C (primary) and proportion of patients achieving FSGS partial remission end point (FPRE) (UP/C: #1.5 g/g and .40% reduction [secondary]). Results Of 109 patients randomized, 96 received study drugs and had baseline and week 8 UP/C measurements. Sparsentan-treated patients had greater reductions in UP/C than irbesartan-treated patients did when all doses (45% versus 19%; P=0.006) or the 400 and 800 mg doses (47% versus 19%; P=0.01) were pooled for analysis. The FSGS partial remission end point was achieved in 28% of sparsentan-treated and 9% of irbesartan-treated patients (P=0.04). After 8 weeks of treatment, BP was reduced with sparsentan but not irbesartan, and eGFR was stable with both treatments. Overall, the incidence of adverse events was similar between groups. Hypotension and edema were more common among sparsentan-treated patients but did not result in study withdrawals. Conclusions Patients with FSGS achieved significantly greater reductions in proteinuria after 8 weeks of sparsentan versus irbesartan. Sparsentan was safe and well tolerated.
Fibromuscular dysplasia (FMD) is a heterogeneous group of non-atherosclerotic and non-inflammatory arterial diseases that primarily involves the renal and cerebrovascular arteries. Grange syndrome is an autosomal-recessive condition characterized by severe and early-onset vascular disease similar to FMD and variable penetrance of brachydactyly, syndactyly, bone fragility, and learning disabilities. Exome-sequencing analysis of DNA from three affected siblings with Grange syndrome identified compound heterozygous nonsense variants in YY1AP1, and homozygous nonsense or frameshift YY1AP1 variants were subsequently identified in additional unrelated probands with Grange syndrome. YY1AP1 encodes yin yang 1 (YY1)-associated protein 1 and is an activator of the YY1 transcription factor. We determined that YY1AP1 localizes to the nucleus and is a component of the INO80 chromatin remodeling complex, which is responsible for transcriptional regulation, DNA repair, and replication. Molecular studies revealed that loss of YY1AP1 in vascular smooth muscle cells leads to cell cycle arrest with decreased proliferation and increased levels of the cell cycle regulator p21/WAF/CDKN1A and disrupts TGF-β-driven differentiation of smooth muscle cells. Identification of YY1AP1 mutations as a cause of FMD indicates that this condition can result from underlying genetic variants that significantly alter the phenotype of vascular smooth muscle cells.
A computer program was written in PL/ 1 to successively fit the sum of two, three, and four exponential terms to data by an iterative least-squares technique, using a combination of the steepest-descent and the Newton-Baphson methods for convergence. Each data point was weighted by the reciprocal of its variance, assuming that the errors followed a Poisson distribution. A compartment, i.e., an exponential term, was declared nonsignificant if it did not significantly reduce the least-squares error about the fitted line as judged by an F test. Validity of the data was assessed by a "runs" test and by the frequency with which data points fell outside the 95% confidence range. Results of the analysis showed that (1) 9 of 12 normal human kidney l33 Xe washout curves were best described by a four-compartment model, (2) 18 of 38 studies in patients with essential hypertension yielded a four-compartment curve with significant reduction in compartment-1 flow, (3) nine patients with congestive heart failure all had three-compartment washout curves, (4) t w o patients with oliguric renal failure had washout curves described best by a two-exponential equation (one of these patients responded to an injection of furosemide with the appearance of a third, more rapid compartment). Obvio u sly, this form of analysis can be easily applied to other sets of data which are described by nonlinear equations.KEY WOBDS inert gas washout curves essential hypertension model fitting nonlinear regression analysis intr»renal distribution of blood flow • Mathematical expressions describing quantitative physiological data have a demonstrated value in modern physiological research. Such expressions are usually based on either an empirically derived equation (s) which summarizes the phenomenon under study or a theoretically derived mathematical model. In either case, the mathematical expression contains parameters with unknown values, and the problem is to estimate values for these parameteis from experimental data. Frequently, well-known techniques of linear regression or multiple regression can be used for parameter estimation providing the equation is linear or can be linearized. In many cases, however, nonlinear equations cannot be linearized, e.g., an equation containing the sum of exponentials. In these instances nonlinear regression techniques for parameter estimation are necessary (1). Graphic techniques have been extensively used in the past for nonlinear parameter estimation (2), but this technique has several limitations: (a) it is subjective, (b) it is unable to separate parameters of similar magnitude with a high degree of c o nfidence, (c) it cannot provide confidence limits for the parameter estimates, and (d) it assumes that all of the data points have an equal variance.Because of these limitations we developed a digital computer technique for nonlinear regression analysis by which parameters were estimated by a east-squares procedure with each data point being weighted if the variance was given. Confidence limits for the paramete...
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