[Show abstract][Hide abstract] ABSTRACT: Background
Renal aging is characterized by functional and structural changes like decreased glomerular filtration rate, and glomerular, tubular and interstitial damage. To gain insight in pathways involved in renal aging, we studied aged mouse strains and used genetic analysis to identify genes associated with aging phenotypes.
Upon morphological screening in kidneys from 20-month-old mice from 26 inbred strains we noted intracapillary PAS-positive deposits. The severity of these deposits was quantified by scoring of a total of 50 glomeruli per section (grade 0–4). Electron microscopy and immunohistochemical staining for apoE, apoB, apoA-IV and perilipin-2 was performed to further characterize the lesions. To identify loci associated with these PAS-positive intracapillary glomerular deposits, we performed haplotype association mapping.
Six out of 26 mouse strains showed glomerular PAS-positive deposits. The severity of these deposits varied: NOD(0.97), NZW(0.41), NON(0.30), B10(0.21), C3 H(0.9) and C57BR(0.7). The intracapillary deposits were strongly positive for apoE and weakly positive for apoB and apoA-IV. Haplotype association mapping showed a strong association with a 30-Kb haplotype block on Chr 1 within the Esrrg gene. We investigated 1 Mb on each site of this region, which includes the genes Spata17, Gpatch2, Esrrg, Ush2a and Kctd3.
By analyzing 26 aged mouse strains we found that some strains developed an intracapillary PAS and apoE-positive lesion and identified a small haplotype block on Chr 1 within the Esrrg gene to be associated with these lipoprotein deposits. The region spanning this haplotype block contains the genes Spata17, Gpatch2, Esrrg, Ush2a and Kctd3, which are all highly expressed in the kidney. Esrrg might be involved in the evolvement of these glomerular deposits by influencing lipid metabolism and possibly immune reponses.
PLoS ONE 10/2014; 9(10):e111308. DOI:10.1371/journal.pone.0111308 · 3.23 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Hypertension and proteinuria are important mediators of renal damage. Despite therapeutic interventions, the number of patients with end stage renal disease steadily increases. Hydrogen sulfide (H2S) is an endogenously produced gasotransmitter with vasodilatory, anti-inflammatory and antioxidant properties. These beneficial characteristics make H2S an attractive candidate for pharmacological use in hypertensive renal disease. We investigated the protective properties of H2S in angiotensin II (Ang II)-induced hypertensive renal disease in rats. Treatment with the H2S donor NaHS and major H2S metabolite sodium thiosulfate (STS) during three weeks of Ang II infusion reduced hypertension, proteinuria, oxidative stress and renal functional and structural deterioration. In an ex vivo isolated perfused kidney setup NaHS, but not STS, reduced intrarenal pressure. The effect of NaHS could partially be explained by its activation of the ATP-sensitive potassium channels. In conclusion, treatment with H2S attenuates Ang II-associated functional and structural renal deterioration, suggesting that intervention in H2S production pathways has potential therapeutic benefit and might be a valuable addition to the already existing antihypertensive and renoprotective therapies.
[Show abstract][Hide abstract] ABSTRACT: Delayed graft function and primary non-function are serious complications following transplantation of kidneys derived from deceased brain dead (DBD) donors. α-melanocyte stimulating hormone (α-MSH) is a pleiotropic neuropeptide and its renoprotective effects have been demonstrated in models of acute kidney injury. We hypothesized that α-MSH treatment of the recipient improves early graft function and reduces inflammation following DBD kidney transplantation. Eight Danish landrace pigs served as DBD donors. After four hours of brain death both kidneys were removed and stored for 18 hours at 4°C in Custodiol preservation solution. Sixteen recipients were randomized in a paired design into two treatment groups, transplanted simultaneously. α-MSH or a vehicle was administered at start of surgery, during reperfusion and two hours post-reperfusion. The recipients were observed for ten hours following reperfusion. Blood, urine and kidney tissue samples were collected during and at the end of follow-up. α-MSH treatment reduced urine flow and impaired recovery of glomerular filtration rate (GFR) compared to controls. After each dose of α-MSH, a trend towards reduced mean arterial blood pressure and increased heart rate was observed. α-MSH did not affect expression of inflammatory markers. Surprisingly, α-MSH impaired recovery of renal function in the first ten hours following DBD kidney transplantation possibly due to hemodynamic changes. Thus, in a porcine experimental model α-MSH did not reduce renal inflammation and did not improve short-term graft function following DBD kidney transplantation.
PLoS ONE 10/2014; 9(4):e94609. DOI:10.1371/journal.pone.0094609 · 3.23 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Background
Adhesions develop in over 90% of patients after intra-abdominal surgery. Adhesion barriers are rarely used despite the high morbidity caused by intra-abdominal adhesions. Only one of the currently available adhesion barriers has demonstrated consistent evidence for reducing adhesions in visceral surgery. This agent has limitations through poor handling characteristics because it is sticky on both sides. C-Qur™ Film is a novel thin film adhesion barrier and it is sticky on only one side, resulting in better handling characteristics. The objective of this study is to assess efficacy and safety of C-Qur™ Film to decrease the incidence of adhesions after colorectal surgery.
This is a prospective, investigator initiated, randomized, double-blinded, multicenter trial. Eligible patients undergoing colorectal resection requiring temporary loop ileostomy or loop/split colostomy by laparotomy or hand assisted laparoscopy will be included in the trial. Before closure, patients are randomized 1:1 to either the treatment arm (C-Qur™ Film) or control arm (no adhesion barrier). Patients will return 8 to 16 weeks post-colorectal resection for take down of their ostomy. During ostomy takedown, adhesions will be evaluated for incidence, extent, and severity. The primary outcome evaluation will be assessment of adhesions to the incision site. It is hypothesized that the use of C-Qur™ Film underneath the primary incision reduces the incidence of adhesion at the incision by 30%. To demonstrate 30% reduction in the incidence of adhesions, a sample size of 84 patients (32 + 10 per group (25% drop out)) is required (two-sided test, α = 0.05, 80% power).
Results of this study add to the evidence on the use of anti-adhesive barriers in open and laparoscopic ‘hand-assisted’ colorectal surgery. We chose incidence of adhesions to the incision site as primary outcome measure since clinical outcomes such as small bowel obstruction, secondary infertility and adhesiolysis related complications are considered multifactorial and difficult to interpret. Incidence of adhesions at repeat surgery is believed to be the most valuable surrogate endpoint for clinically relevant adhesion prevention, since small bowel obstruction and adhesiolysis at repeat surgery are not likely to occur when complete adhesion reduction in a patient is accomplished.
ClinicalTrials.gov Identifier NCT01872650, registration date 6 June 2013.
[Show abstract][Hide abstract] ABSTRACT: Lymphatic vessels (LVs) are involved in a number of physiological and pathophysiological processes such as fluid homoeostasis, immune surveillance, and resolution of inflammation and wound healing. Lymphangiogenesis, the outgrowth of existing LVs and the formation of new ones, has received increasing attention over the past decade on account of its prominence in organ physiology and pathology, which has been enabled by the development of specific tools to study lymph vessel functions. Several studies have been devoted to renal lymphatic vasculature and lymphangiogenesis in kidney diseases, such as chronic renal transplant dysfunction, primary renal fibrotic disorders, proteinuria, diabetic nephropathy and renal inflammation. This review describes the most recent findings on lymphangiogenesis, with a specific focus on renal lymphangiogenesis and its impact on renal diseases. We suggest renal lymphatics as a possible target for therapeutic interventions in renal medicine to dampen tubulointerstitial tissue remodelling and improve renal functioning.
Expert Reviews in Molecular Medicine 09/2014; 16(1):e15. DOI:10.1017/erm.2014.18 · 5.15 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Purpose:
Adhesiolysis at repeat surgery induces adhesion reformation which seems more virulent than development of de novo adhesions. We studied the effect of a new ultrapure alginate gel on adhesion reformation.
In 46 male Wistar rats, adhesion formation was induced using the cecal abrasion and peritoneal sidewall excision procedure. Two weeks later, a second laparotomy was performed, adhesions were graded, and surgical adhesiolysis was performed. The animals were then allocated to one of two equal groups, a control group without further intervention and a group receiving 1-ml ultrapure alginate gel to the two opposing and damaged surfaces. Two weeks after the second surgery, rats were sacrificed. Primary endpoint was the incidence of adhesion reformation at areas of injury. Secondary endpoints were adhesion scores, extent of adhesions, and tissue histology.
Ultrapure alginate gel significantly (p = 0.046) reduced the incidence of adhesion reformation from 100 % in controls to 78 % in experimental rats. Both the adhesion score (p = 0.009) and the extent of adhesions (p = 0.001) were significantly lower in the alginate group. Tissue healing histology was similar in both groups.
Ultrapure alginate gel reduces adhesion reformation following adhesiolysis.
International Journal of Colorectal Disease 09/2014; 29(11). DOI:10.1007/s00384-014-2009-5 · 2.45 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Abstract Objective: The first international summit on anastomotic leak was held in Chicago in October, 2012 to assess current knowledge in the field and develop novel lines of inquiry. The following report is a summary of the proceedings with commentaries and future prospects for clinical trials and laboratory investigations. Background: Anastomotic leakage remains a devastating problem for the patient, and a continuing challenge to the surgeon operating on high-risk areas of the gastrointestinal tract such as the esophagus and rectum. Despite the traditional wisdom that anastomotic leak is because of technique, evidence to support this is weak-to-non-existent. Outcome data continue to demonstrate that expert high-volume surgeons working in high-volume centers continue to experience anastomotic leaks and that surgeons cannot predict reliably which patients will leak. Methods: A one and one-half day summit was held and a small working group assembled to review current practices, opinions, scientific evidence, and potential paths forward to understand and decrease the incidence of anastomotic leak. Results: Results of a survey of the opinions of the group demonstrated that the majority of participants believe that anastomotic leak is a complicated biologic problem whose pathogenesis remains ill-defined. The group opined that anastomotic leak is underreported clinically, it is not because of technique except when there is gross inattention to it, and that results from animal models are mostly irrelevant to the human condition. Conclusions: A fresh and unbiased examination of the causes and strategies for prevention of anastomotic leak needs to be addressed by a continuous working group of surgeons, basic scientists, and clinical trialists to realize a real and significant reduction in its incidence and morbidity. Such a path forward is discussed.
[Show abstract][Hide abstract] ABSTRACT: Background
Anastomotic leakage rates remain unacceptably high, warranting reconsideration of current anastomotic technique. Anastomotic healing may improve by abrading the serosal surface of bowel ends that are invertedly anastomosed, based on the concept that serosal damage evokes an inflammatory adherent processes. It is studied if local abrasion leads to stronger anastomoses and reduces leakage.
Ninety-eight Wistar rats were allocated to six groups. Either a regular anastomosis (RA) or abraded anastomosis (AA) was constructed in the proximal colon. Animals were sacrificed at day 3 (groups RA3 and AA3, n=2x17) or day 5 (groups RA5 and AA5, n=2x17). Groups RA-Dic and AA-Dic (n=2x15) received diclofenac from day 0 until sacrifice on day 3 to impair anastomotic healing. Outcomes were leakage, bursting pressure (BP), breaking strength (BS), adhesions and histological appearance.
Both in abraded (AA3, AA5) and control (RA3, RA5) groups without diclofenac 1 of 17 anastomoses leaked (6%). Leak rate was 9 of 15 (60%) in group AA-Dic and 8 of 15 (53%) in RA-Dic (p=1.0). The BP in group RA3 (127±44 mmHg) was higher (p=0,006) compared to group AA3 (82±34 mmHg), BS was comparable (p=0.331). Mechanical strength was similar between group RA5 and AA5. Abrasion did not increase mechanical strength in the diclofenac groups. Adhesion formation was not different between groups. Histology showed dense interserosal scar formation in abraded groups, compared to loose connective tissue in control anastomoses.
Abrasion of serosal edges of large bowel ends invertedly anastomosed does not improve anastomotic strength, neither does it reduce leakage in anastomoses compromised by diclofenac.
Journal of Surgical Research 09/2014; 193(2). DOI:10.1016/j.jss.2014.08.047 · 1.94 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Reduced intake and absorption of antioxidants due to pain and malabsorption are probable causes of the lower levels of antioxidants observed in patients with chronic pancreatitis (CP). Improving the status of antioxidants might be effective in slowing the disease process and reducing pain in CP.
[Show abstract][Hide abstract] ABSTRACT: Hydrogen sulfide (H2S) has become a molecule of high interest in recent years, and it is now recognized as the third gasotransmitter in addition to nitric oxide and carbon monoxide. In this review, we discuss the recent literature on the physiology of endogenous and exogenous H2S, focusing upon the protective effects of hydrogen sulfide in models of hypoxia and ischaemia. Linked ArticlesThis article is part of a themed section on Pharmacology of the Gasotransmitters. To view the other articles in this section visit
British Journal of Pharmacology 08/2014; 172(6). DOI:10.1111/bph.12869 · 4.84 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Syndecan-1 is a transmembrane heparan sulfate (HS) proteoglycan present on hepatocytes and involved in uptake of triglyceride-rich lipoproteins via its HS polysaccharide side chains. We hypothesized that altered hepatic syndecan-1 metabolism could be involved in dyslipidemia related to renal transplantation. In a rat renal transplantation model elevated plasma triglycerides were associated with fivefold increased expression of hepatic syndecan-1 mRNA (p < 0.01), but not protein. Expression of syndecan-1 sheddases (ADAM17, MMP9) and heparanase was significantly up-regulated after renal transplantation (all p < 0.05). Profiling of HS side chains revealed loss of hepatic HS upon renal transplantation accompanied by significant decreased functional capacity for VLDL binding (p = 0.02). In a human renal transplantation cohort (n = 510), plasma levels of shed syndecan-1 were measured. Multivariate analysis showed plasma syndecan-1 to be independently associated with triglycerides (p < 0.0001) and inversely with HDL cholesterol (p < 0.0001). Last, we show a physical association of syndecan-1 to HDL from renal transplant recipients (RTRs), but not to HDL from healthy controls. Our data suggest that after renal transplantation loss of hepatic HS together with increased syndecan-1 shedding hampers lipoprotein binding and uptake by the liver contributing to dyslipidemia. Our data open perspectives toward improvement of lipid profiles by targeted inhibition of syndecan-1 catabolism in renal transplantation.
American Journal of Transplantation 08/2014; 14(10). DOI:10.1111/ajt.12842 · 5.68 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Binding of renin and prorenin to the (pro)renin receptor (PRR) increases their enzymatic activity and upregulates the expression of pro-fibrotic genes in vitro. Expression of PRR is increased in the heart and kidney of hypertensive and diabetic animals, but its causative role in organ damage is still unclear. To determine whether increased expression of PRR is sufficient to induce cardiac or renal injury, we generated a mouse that constitutively overexpresses PRR by knocking-in the Atp6ap2/PRR gene in the hprt locus under the control of a CMV immediate early enhancer/chicken beta-actin promoter. Mice were backcrossed in the C57Bl/6 and FVB/N strain and studied at the age of 12 months. In spite of a 25- to 80-fold renal and up to 400-fold cardiac increase in Atp6ap2/PRR expression, we found no differences in systolic blood pressure or albuminuria between wild-type and PRR overexpressing littermates. Histological examination did not show any renal or cardiac fibrosis in mutant mice. This was supported by real-time PCR analysis of inflammatory markers as well as of pro-fibrotic genes in the kidney and collagen in cardiac tissue. To determine whether the concomitant increase of renin would trigger fibrosis, we treated PRR overexpressing mice with the angiotensin receptor-1 blocker losartan over a period of 6 weeks. Renin expression increased eightfold in the kidney but no renal injury could be detected. In conclusion, our results suggest no major role for PRR in organ damage per se or related to its function as a receptor of renin.Laboratory Investigation advance online publication, 21 July 2014; doi:10.1038/labinvest.2014.83.
[Show abstract][Hide abstract] ABSTRACT: Abdominal compartment syndrome (ACS) is a lethal complication of acute pancreatitis. We performed a systematic review to assess the treatment and outcome of these patients.A systematic literature search for cohorts of patients with acute pancreatitis and ACS was performed. The main outcomes were number of patients with ACS, radiologic and surgical interventions, morbidity, mortality, and methodological quality.After screening 169 articles, 7 studies were included. Three studies were prospective and 4 studies were retrospective. The overall methodological quality of the studies was moderate to low. The pooled data consisted of 271 patients, of whom 103 (38%) developed ACS. Percutaneous drainage of intraabdominal fluid was reported as first intervention in 11 (11%) patients. Additional decompressive laparotomy was performed in 8 patients. Decompressive laparotomy was performed in a total of 76 (74%) patients. The median decrease in intraabdominal pressure was 15 mm Hg (range, 33-18 mm Hg). Mortality in acute pancreatitis patients with ACS was 49% versus 11% without ACS. Morbidity ranged from 17% to 90%.Abdominal compartment syndrome during acute pancreatitis is associated with high mortality and morbidity. Studies are relatively small and have methodological shortcomings. The optimal timing and method of invasive interventions, as well as their effect on clinical outcomes, should be further evaluated.
[Show abstract][Hide abstract] ABSTRACT: Each year millions of people sustain traumatic or surgical wounds, which require proper closure. Conventional closure techniques, including suturing and stapling, have many disadvantages. They inflict additional damage on the tissue, elicit inflammatory responses and have a relatively long application time. Especially for the more demanding wounds, where fluids or gasses are to be sealed off, these techniques are often insufficient. Therefore, a large variety of tissue adhesives, sealants and hemostatic agents has been developed. This review provides an overview of such tissue adhesive materials from a polymer chemistry perspective. The materials are divided into synthetic polymer-based, polysaccharide-based and protein-based adhesives. Their specific properties and behavior are discussed and related to their clinical application. Though each type has its specific advantages, yet few have become standard in clinical practice. Biomimetic based adhesives and other novel products have shown promising results but also face specific problems. For now, the search for better adhering, stronger, easier applicable and cheaper adhesives continues and this review is intended as starting point and inspiration for these future research efforts to develop the next generation tissue adhesives.
[Show abstract][Hide abstract] ABSTRACT: Objective: To evaluate the safety and long-term durability of 1-stage repair of enteric fistulas in the presence of an abdominal wall defect. Background: Patients with enteric fistulas and an abdominal wall defect present an extreme challenge to surgeons and have been associated with significant morbidity and mortality. Durability of repair is unknown as studies fail to report this or use limited follow-up periods. Methods: Chart review was done of consecutive patients who underwent 1-stage repair. Short-term outcomes included morbidity (wound and medical) and mortality. Long-term durability of repair was determined by prospective outpatient follow-up at least 3 years after surgery. Results: Thirty-nine patients were included with a mean age of 61.2 years, a mean BMI of 24.4 kg/m2, and a mean abdominal wall defect size of 247.9 cm2. Component separation technique was used in 34 (87.2%) and synthetic mesh in 13 (33.3%) patients. There was 1 (2.6%) postoperative death. Twenty-four wound complications developed in 18 (46.2%) patients, including surgical-site infection in 8 (20.5%) patients. Two (5.1%) enteric fistulas recurred and were treated conservatively resulting in closure. Medical complications were seen 36 times in 23 (59%) patients. Twelve of 33 (36.4%) living patients developed a recurrent hernia after a mean follow-up of 62.7 months (range: 36–130). Conclusions: One-stage abdominal wall reconstruction with enteric fistula takedown is feasible at the cost of considerable morbidity. Our treatment strategy including component separation technique with synthetic mesh on-demand results in a durable repair in 6 to 7 of 10 patients.
Annals of Surgery 06/2014; 261(3). DOI:10.1097/SLA.0000000000000733 · 8.33 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Preeclampsia is characterized by deficient trophoblast invasion and spiral artery remodeling, a process governed by inflammatory cells. High levels of the danger signal extracellular adenosine triphosphate (ATP) have been found in women with preeclampsia and infusion of ATP in pregnant rats induced preeclampsia-like symptoms such as albuminuria and placental ischemia. We hypothesized that ATP inhibits trophoblast invasion and spiral artery remodeling and affects macrophages and natural killer (NK) cells present in the rat mesometrial triangle.