Adeno-associated virus serotype 9 antibody seroprevalence for patients in the United States with spinal muscular atrophy.

Onasemnogene abeparvovec is a recombinant adeno-associated virus serotype 9 (AAV9) vector-based gene therapy for spinal muscular atrophy (SMA). Patients with elevated titers of anti-AAV9 antibodies (AAV9-Ab) should not receive onasemnogene abeparvovec because of potential safety and efficacy implications. We conducted a retrospective study to describe the seroprevalence of anti-AAV9 binding antibodies for pediatric patients with SMA in the United States. At initial testing, 13.0% (115 of 882) of patients (mean [SD] age, 26.29 [33.66] weeks) had elevated AAV9-Ab titers. The prevalence of elevated titers decreased as age increased, with 18.2% (92 of 507) of patients ≤3 months old but only 1.1% (1 of 92) of patients ≥21 months old having elevated titers. This suggests transplacental maternal transfer of antibodies. No patterns of geographic variations in AAV9-Ab prevalence were confirmed. Elevated AAV9-Ab titers in children <6 weeks old decreased in all circumstances. Lower magnitudes of elevated titers declined more rapidly than greater magnitudes. Retesting was completed at the discretion of the treating clinician, so age at testing and time between tests varied. AAV9-Ab retesting should be considered when patients have elevated titers, and elevations at a young age are not a deterrent to eventual onasemnogene abeparvovec administration. Early disease-modifying treatment for SMA leads to optimal outcomes.

Acute effects of high-dose furosemide on residual renal function in CAPD patients.

BACKGROUND: High doses of furosemide can increase urine volume in chronic peritoneal dialysis (CAPD) patients. However, no information is available about effects on urinary solute excretion in relation to residual glomerular filtration rate (GFR), urinary furosemide excretion, and peritoneal solute kinetics. METHODS: Diuretic response and the effect on peritoneal fluid and solute transport parameters were investigated in 7 stable CAPD patients with residual renal function (median urine volume 350 mL/24 hours, range 140- 1900 mL/24 hours). Comparisons were made during two clearance periods of 24 hours: one without (P1) and one during 2 g furosemide (P2). RESULTS: The median increase in urine volume was 400 mL (range 270 - 910 mL, p < 0.02) and the increase in sodium excretion was 54 mmol (range 25 - 118 mmol, p < 0.02). No change in GFR was found between P1 (2.4 mL/ minute, range 0.6 - 5.7 mL/min) and P2 (2.0 mL/min, range 1.0 - 4.8 mL/min). An increase in fractional clearance was found for volume, sodium, potassium, and osmolality (p < 0.02). No change was found in the fractional clearance of urea and electrolyte-free water. Furosemide excretion in urine was 8.7 mg/24 hours (range 2.1 - 38 mg/24 hours) and in dialysate 4.9 mg/24 hours (range 1.9 - 7.8 mg/ 24 hours). Plasma furosemide concentration was 29.5 mg/L (range 6.2 - 43.9 mg/L). A positive correlation was found between residual GFR and total urine furosemide excretion (r = 0.93, p < 0.005). Efficiency, expressed as the increase in fractional sodium clearance (percent) per milligram of furosemide excreted per 24 hours, was 1.2%/mg (range 0.3% - 11.3%/mg). CONCLUSION: High-dose furosemide is effective in CAPD patients in increasing urine volume and electrolyte excretion without affecting urea and creatinine clearance. In CAPD patients, the individual response to an identical high dose of furosemide is dependent on the magnitude of residual GFR.

Plasma thrombopoietin levels in patients with chronic renal failure.

INTRODUCTION: Thrombopoietin (Tpo) is the most important regulator of thrombocytopoiesis. The main sites of Tpo production are the liver and the kidney produce Tpo. In the current study, the influence of renal failure on overall Tpo production was evaluated. MATERIALS AND METHODS: Tpo levels were measured in 23 patients on hemodialysis (HD) and 16 patients on chronic ambulatory peritoneal dialysis (CAPD). Plasma glycocalicin (GC) levels and platelet counts were measured as parameters of platelet mass and platelet turnover. RESULTS: Platelet counts were significantly lower in the HD group, both before 207+/-98 x 10(9)/l (P<0.001) and after hemodialysis 202+/-102 x 10(9)/l (P<0.001) when compared to healthy controls, 293+/-79 x 10(9)/l. No significant difference was found between platelet counts in patients on CAPD and healthy donors. Mean plasma Tpo levels of HD patients were higher both before 23+/-18 AU/ml (P<0.0001) and after dialysis 25+/-26 AU/ml (P<0.0001), as compared to Tpo levels in healthy controls (11+/-8 AU/ml). Patients on CAPD had significantly higher Tpo concentrations, 29+/-25 AU/ml than healthy controls (P<0.0001). There was no difference in Tpo level between the HD and CAPD group. No correlation was found between Tpo concentration and platelet count, hematocrit, creatinine or uremia levels. The GC concentration was significantly higher in HD patients and CAPD patients when compared to healthy controls. There was no correlation between GC and Tpo level or platelet count. CONCLUSION: These results confirm the increased platelet turnover in patients with chronic renal failure. Moreover this study shows that the kidney does not seem to play a major role in the overall Tpo production in the body.