Statins in pre-eclampsia or fetal growth restriction: A systematic review and meta-analysis on maternal blood pressure and fetal growth across species.

BACKGROUND: Several human randomised controlled trials (RCTs) are investigating the effects of statins on pre-eclampsia (PE) and fetal growth restriction (FGR). This cross-species meta-analysis summarises the preclinical evidence of statin use for PE and FGR. OBJECTIVES: Evaluate the effects of statins on maternal blood pressure (MBP) and birthweight (BW) in pregnancies complicated by PE or FGR. SEARCH STRATEGY: PubMed and Embase.com were searched on 10 May 2022 using 'statins' and 'pregnancy'. SELECTION CRITERIA: We included RCTs and cohorts with matched control groups as well as animal studies. DATA COLLECTION AND ANALYSIS: The main outcomes were MBP in mmHg and BW in grams. The standardised mean difference (SMD) with a 95% confidence interval (CI) was calculated. Subgroup analyses on species, statin, dose, timing and route of administration were performed if subgroups included at least three studies. MAIN RESULTS: Our data included one human and 12 animal studies. Prenatal administration of statins significantly reduced MBP during pregnancy (SMD  -2.49 mmHg [95% CI -4.26 to -0.71], p = 0.01). There was no significant effect of statins on BW (SMD 0.69 [95% CI -0.65 to 2.03], p = 0.28). Our subgroup analyses showed no effect on MBP of different doses, species or route of administration. CONCLUSIONS: Our cross-species meta-analyses demonstrate that statins only reduce maternal blood pressure in rodent pregnancies complicated by pre-eclampsia or fetal growth restriction and have no effect on birthweight across species. The broad confidence intervals, inconsistent direction of the observed effects across the studies and large risk of bias lead us to conclude that a solid base for further human RCTs is lacking.

Translational Research in Cardiovascular Repair: A Call for a Paradigm Shift.

The international consortium TACTICS (Transnational Alliance for Regenerative Therapies in Cardiovascular Syndromes) has recently addressed key priorities in the field of cell-based therapy for cardiac repair, identifying the efficacy of translational research as one of the main challenges to ultimately improve the quality of life of patients with ischemic disease. Much of the controversy and confusion surrounding cardiac regenerative therapy stems from insufficient rigor in the conduct of preclinical studies, and there is an increasing recognition of a number of problems that undermine its quality that may contribute to translational failure. Here, we introduce well defined stages for preclinical research, and put forth proposals that should promote more rigorous preclinical work, in an effort to improve its quality and translatability. To augment the utility of preclinical research and its translation, it is necessary to (1) improve the quality of preclinical research, (2) promote collaborative efforts, and (3) enhance the sharing of knowledge and protocols. In particular, confirmatory (stage III) preclinical studies should be considered as a preamble to clinical studies and therefore must adhere to their standards of quality (including internal validity, standardization of protocols, and multicenter design). To increase transparency and minimize bias, these studies should be prospectively registered in an independent, open database. Ultimately, these recommendations should be implemented in the daily routine of investigators and in the policies of institutions, journals, and funding agencies.

What is the evidence for the use of low-pressure pneumoperitoneum? A systematic review.

BACKGROUND: Laparoscopic surgery has several advantages when compared to open surgery, including faster postoperative recovery and lower pain scores. However, for laparoscopy, a pneumoperitoneum is required to create workspace between the abdominal wall and intraabdominal organs. Increased intraabdominal pressure may also have negative implications on cardiovascular, pulmonary, and intraabdominal organ functionings. To overcome these negative consequences, several trials have been performed comparing low- versus standard-pressure pneumoperitoneum. METHODS: A systematic review of all randomized controlled clinical trials and observational studies comparing low- versus standard-pressure pneumoperitoneum. RESULTS AND CONCLUSIONS: Quality assessment showed that the overall quality of evidence was moderate to low. Postoperative pain scores were reduced by the use of low-pressure pneumoperitoneum. With appropriate perioperative measures, the use of low-pressure pneumoperitoneum does not seem to have clinical advantages as compared to standard pressure on cardiac and pulmonary function. Although there are indications that low-pressure pneumoperitoneum is associated with less liver and kidney injury when compared to standard-pressure pneumoperitoneum, this does not seem to have clinical implications for healthy individuals. The influence of low-pressure pneumoperitoneum on adhesion formation, anastomosis healing, tumor metastasis, intraocular and intracerebral pressure, and thromboembolic complications remains uncertain, as no human clinical trials have been performed. The influence of pressure on surgical conditions and safety has not been established to date. In conclusion, the most important benefit of low-pressure pneumoperitoneum is lower postoperative pain scores, supported by a moderate quality of evidence. However, the quality of surgical conditions and safety of the use of low-pressure pneumoperitoneum need to be established, as are the values and preferences of physicians and patients regarding the potential benefits and risks. Therefore, the recommendation to use low-pressure pneumoperitoneum during laparoscopy is weak, and more studies are required.

Urinary biomarkers after donor nephrectomy.

As the beginning of living-donor kidney transplantation, physicians have expressed concern about the possibility that unilateral nephrectomy can be harmful to a healthy individual. To investigate whether the elevated intra-abdominal pressure (IAP) during laparoscopic donor nephrectomy causes early damage to the remaining kidney, we evaluated urine biomarkers after laparoscopic donor nephrectomy. We measured albumin and alpha-1-microglobulin (α-1-MGB) in urine samples collected during and after open and laparoscopic donor nephrectomy and laparoscopic cholecystectomy and colectomy. Additionally, kidney injury molecule 1 (KIM-1) and neutrophil gelatinase-associated lipocalin (NGAL) were measured in urine samples collected during and after laparoscopic donor nephrectomy and colectomy. The same biomarkers were studied in patients randomly assigned to standard or low IAP during laparoscopic donor nephrectomy. We observed a peak in urinary albumin excretion during all procedures. Urine α-1-MGB rose in the postoperative period with a peak on the third postoperative day after donor nephrectomy. Urine α-1-MGB did not increase after laparoscopic cholecystectomy and colectomy. After laparoscopic nephrectomy, we observed slight increases in urine KIM-1 during surgery and in urine NGAL at day 2-3 after the procedure. After laparoscopic colectomy, both KIM-1 and NGAL were increased in the postoperative period. There were no differences between the high- and low-pressure procedure. Elevated urinary α-1-MGB suggests kidney damage after donor nephrectomy, occurring irrespective of IAP during the laparoscopic procedure.

Endothelin and calciotropic hormones share regulatory pathways in multidrug resistance protein 2-mediated transport.

The kidney of vertebrates plays a key role in excretion of endogenous waste products and xenobiotics. Active secretion in the proximal nephron is at the basis of this excretion, mediated by carrier proteins including multidrug resistance protein 2 (Mrp2). We previously showed that Mrp2 function is reduced by endothelin-1 (ET-1) through a basolateral B-type receptor, nitric oxide (NO), cGMP, and PKC (Notenboom S, Miller DS, Smits P, Russel FGM, Masereeuw R. Am J Physiol Renal Physiol 282: F458-F464, 2002; Notenboom S, Miller DS, Smits P, Russel FG, Masereeuw R. Am J Physiol Renal Physiol 287: F33-F38, 2004). This pathway was rapidly activated by several nephrotoxicants and appeared to be calcium dependent. In the present study, we studied the effect of the calciotropic hormones parathyroid hormone (PTH), PTH-related protein (PTHrP), and stanniocalcin (STC) to interfere with ET-regulated Mrp2 transport. Like ET-1, PTH reduces Mrp2-mediated transport by 40% in killifish renal proximal tubules. When given in combination, an additive effect was seen, which is partially reversed by the PKC inhibitor calphostin C. Recombinant PTHrP shows a comparable inhibitory effect, which is concentration dependent and additive to the inhibition by ET. STC fully reverses PTHrP-inhibited transport as does a guanylyl cyclase inhibitor. Finally, to confirm PTHrP bioactivity in a homologous assay, we performed immunolocalization and transport studies in sea bream kidney tubules. Mrp2 immunoreactivity was observed in approximately 40% of the tubules and is associated with the brush-border and apical plasma membrane of cells. Both proximal tubules and distal (collecting) tubules express the antigen. A highly significant 40% inhibition of Mrp2-mediated transport was observed with PTHrP in sea bream tubules. In conclusion, ET-regulated Mrp2 transport is influenced by calciotropic hormones and involves PKC and cGMP signaling.