Full-length human placental sFlt-1-e15a isoform induces distinct maternal phenotypes of preeclampsia in mice

<div><p>Objective</p><p>Most anti-angiogenic preeclampsia models in rodents utilized the overexpression of a truncated soluble fms-like tyrosine kinase-1 (sFlt-1) not expressed in any species. Other limitations of mouse preeclampsia models included stressful blood pressure measurements and the lack of postpartum monitoring. We aimed to 1) develop a mouse model of preeclampsia by administering the most abundant human placental sFlt-1 isoform (hsFlt-1-e15a) in preeclampsia; 2) determine blood pressures in non-stressed conditions; and 3) develop a survival surgery that enables the collection of fetuses and placentas and postpartum (PP) monitoring.</p><p>Methods</p><p>Pregnancy status of CD-1 mice was evaluated with high-frequency ultrasound on gestational days (GD) 6 and 7. Telemetry catheters were implanted in the carotid artery on GD7, and their positions were verified by ultrasound on GD13. Mice were injected through tail-vein with adenoviruses expressing hsFlt-1-e15a (n = 11) or green fluorescent protein (GFP; n = 9) on GD8/GD11. Placentas and pups were delivered by cesarean section on GD18 allowing PP monitoring. Urine samples were collected with cystocentesis on GD6/GD7, GD13, GD18, and PPD8, and albumin/creatinine ratios were determined. GFP and hsFlt-1-e15a expression profiles were determined by qRT-PCR. Aortic ring assays were performed to assess the effect of hsFlt-1-e15a on endothelia.</p><p>Results</p><p>Ultrasound predicted pregnancy on GD7 in 97% of cases. Cesarean section survival rate was 100%. Mean arterial blood pressure was higher in hsFlt-1-e15a-treated than in GFP-treated mice (∆MAP = 13.2 mmHg, p = 0.00107; GD18). Focal glomerular changes were found in hsFlt-1-e15a -treated mice, which had higher urine albumin/creatinine ratios than controls (109.3±51.7μg/mg vs. 19.3±5.6μg/mg, p = 4.4x10^-2; GD18). Aortic ring assays showed a 46% lesser microvessel outgrowth in hsFlt-1-e15a-treated than in GFP-treated mice (p = 1.2x10^-2). Placental and fetal weights did not differ between the groups. One mouse with liver disease developed early-onset preeclampsia-like symptoms with intrauterine growth restriction (IUGR).</p><p>Conclusions</p><p>A mouse model of late-onset preeclampsia was developed with the overexpression of hsFlt-1-e15a, verifying the <i>in vivo</i> pathologic effects of this primate-specific, predominant placental sFlt-1 isoform. HsFlt-1-e15a induced early-onset preeclampsia-like symptoms associated with IUGR in a mouse with a liver disease. Our findings support that hsFlt-1-e15a is central to the terminal pathway of preeclampsia, and it can induce the full spectrum of symptoms in this obstetrical syndrome.</p></div

Mini-Incision Living Donors Nephrectomy Using Anterior Muscle-Splitting Approach with Hybrid Technique

Background: Significant morbidity is associated with standard open flank living donor nephrectomy. Laparoscopicdonor nephrectomy is criticized for a steep learning curve and a tendency to avoid the right kidney. The anterior muscle-splitting technique uses principles or advantages of an open extraperitoneal approach with minimal morbidity and the advantageous muscle-splitting (instead of cutting) procedure.Objective: To compare mini-incision laparoscopic instrument-assisted (MILIA) live donor nephrectomy using a muscle-splitting technique to the standard open-flank donor nephrectomy (ODN) approach for efficacy and safety.Methods: MILIA living donor nephrectomies were performed in 119 donors and compared to a cohort of open-flank nephrectomy donors (n=38) from the same center. Both donor groups were matched for body mass index as well as other personal characteristics.Results: The mean donor age was 35 (range: 18–60) years. The right kidney was procured in 28% of cases. The majority of donors were female (58%) and Caucasian (60%). No differences were observed between MILIA and ODN donors for the age, gender and ethnicity. However, MILIA donors experienced a longer mean±SD operative time (234±47 vs. 197±33 min, p<0.0001) but a shorter hospital stay (4±1 vs. 6±3 days for the ODN group, p<0.0001) and less intraoperative blood loss (215±180 vs. 331±397 mL, p<0.02). No difference was found in the number of units of blood transfused (0.13±0.6 vs. 0.34±1.0 units, p=0.13). Right-sided kidneys were almost equally harvested in both groups (29% of MILIA donors vs. 26% of ODN donors). Post-operatively, MILIA donors had a significantly lower mean pain scores at one week and one month after surgery (p<0.001). They showed significant better post-operative recovery—earlier stopping of pain medications and restoration of other preoperative activities. Moreover, they were better satisfied with their scar appearance. Scores on the short form-36 quality of life questionnaire were comparable for both groups.Conclusion: MILIA is a viable option as an alternative for pure laparoscopic donor nephrectomy. MILIA appearsto be as safe as open donor nephrectomy and may provide advantages over ODN, such as smaller incision, shorter hospital stay, and less incisional pain. Patient recovery and satisfaction after MILIA are excellent.This technique avoids the possibility of adhesive intestinal obstruction and also improves handling of major complications (e.g., bleeding) of laparoscopic donor nephrectomy. Utilization of this hybrid techniqueis particularly feasible on smaller (BMI<24 kg/m2) and medium-sized (BMI<28 kg/m2) donors. We believe that this technique should be adopted by centers that have limited advanced laparoscopic surgical experience and also it could be used selectively for the right donor nephrectomies, even in centers performinghand assisted donor nephrectomies by including a small patch of inferior vena cava for a better quality of right donor kidney during transplantation