Similar matrix alterations in alveolar and small airway walls of COPD patients

BACKGROUND: Remodelling in COPD has at least two dimensions: small airway wall thickening and destruction of alveolar walls. Recent studies indicate that there is some similarity between alveolar and small airway wall matrix remodelling. The aim of this study was to characterise and assess similarities in alveolar and small airway wall matrix remodelling, and TGF-beta signalling in COPD patients of different GOLD stages. METHODS: Lung tissue sections of 14 smoking controls, 16 GOLD II and 19 GOLD IV patients were included and stained for elastin and collagens as well as hyaluronan, a glycosaminoglycan matrix component and pSMAD2. RESULTS: Elastin was significantly decreased in COPD patients not only in alveolar, but also in small airway walls. Interestingly, both collagen and hyaluronan were increased in alveolar as well as small airway walls. The matrix changes were highly comparable between GOLD stages, with collagen content in the alveolar wall increasing further in GOLD IV. A calculated remodelling index, defined as elastin divided over collagen and hyaluronan, was decreased significantly in GOLD II and further lowered in GOLD IV patients, suggesting that matrix component alterations are involved in progressive airflow limitation. Interestingly, there was a positive correlation present between the alveolar and small airway wall stainings of the matrix components, as well as for pSMAD2. No differences in pSMAD2 staining between controls and COPD patients were found. CONCLUSIONS: In conclusion, remodelling in the alveolar and small airway wall in COPD is markedly similar and already present in moderate COPD. Notably, alveolar collagen and a remodelling index relate to lung function

Interobserver agreement of scoring of histopathological characteristics and classification of lupus nephritis.

Contains fulltext : 69663.pdf (publisher's version ) (Open Access)BACKGROUND: Assessing renal biopsies from patients with lupus nephritis (LN) is a difficult task and it is subject to interobserver variability. In this study the interobserver agreement amongst five nephropathologists was analysed. METHODS: Five specialized nephropathologists scored 126 biopsies, comprising 87 first and 39 repeat biopsies from 87 patients with biopsy-proven proliferative LN, included in a randomized controlled trial. The interobserver agreement [expressed as intraclass correlation coefficients (ICC)] of the scored histopathological items was calculated. Also, the WHO1995 and ISN/RPS2003 classification systems for LN were compared, with extra attention being given to the comparison between patients with diffuse proliferative LN with either segmental (IV-S) or global (IV-G) lesions. RESULTS: There was a wide range of agreement. A good interobserver agreement (ICC>0.6) was present in 15%, and a moderate interobserver agreement (ICC 0.4-0.6) in 31% of the scored items. The activity index for LN showed a good (ICC 0.716) and the chronicity index a moderate (ICC 0.494) interobserver agreement. Both classification systems showed low agreement, although consensus was easily reached. Patients classified as IV-S (n=15) had more favorable clinical parameters at study entry than those with class IV-G (n=57). Although suggested by others, we found no differences in outcome between these two subclasses. CONCLUSIONS: This study shows that, although definitions were agreed upon beforehand, even specialized on nephropathologists have difficulties with scoring histopathological characteristics of LN, particularly with SLE the classification systems

Thromboxane receptor signalling in renal ischemia reperfusion injury

F(2)-isoprostanes are formed by oxidative modification of arachidonic acid and are the gold standard for detection of oxidative stress in vivo. F(2)-isoprostanes are biologically active compounds that signal through the thromboxane A(2) (TP) receptor; infusion of F(2)-isoprostanes reduces glomerular filtration in the kidney by constricting afferent arterioles. This study investigated whether endogenous F(2)-isoprostanes contribute to the pathogenesis of ischemic acute kidney injury, which is associated with oxidative stress and reduced glomerular filtration. TP receptor knockout mice-that lack F(2)-isoprostanes and thromboxane A(2) signalling-and wild-type control mice underwent 30 min of renal ischemia and 24 h of reperfusion. Kidney dysfunction, histological injury and the number of infiltrated neutrophils were similar between the two mouse strains, whereas TP receptor knockout mice had significantly more apoptotic cells and tissue lipid peroxidation than their wild-type counterparts. F(2)-isoprostanes and thromboxane B(2) were readily detectable in urine collections after surgery. The findings indicate that F(2)-isoprostanes and thromboxane A(2) signalling do not contribute critically to the pathogenesis of ischemic acute kidney injury and more generally provide evidence against a prominent role for F(2)-isoprostanes signalling in exacerbating acute disease states associated with oxidative stress

Improvements in kidney transplantation from donors after cardiac death

To reduce the growing waiting list for kidney transplantation, we explored the limits of kidney transplantation from donors after cardiac death by liberally accepting marginal donor kidneys for transplantation. As the percentage of primary non-function (PNF) increased, we evaluated our transplantation program and implemented changes to reduce the high percentage of PNF in 2005, followed by a second evaluation over the period 2006-2009. Recipients of a kidney from a donor after cardiac death between 1998 and 2005 were analyzed, with PNF as outcome measure. During the period 2002-2005, the percentage of PNF increased and crossed the upper control limits of 12% which was considered as unacceptably high. After implementation of changes, this percentage was reduced to 5%, without changing the number of kidney transplantations from donors after cardiac death. Continuous monitoring of the quality of care is essential as the boundaries of organ donation and transplantation are sought. Meticulous donor, preservation, and recipient management make extension of the donor potential possible, with good results for the individual recipient. Liberal use of kidneys from donors after cardiac death may contribute to a reduction in the waiting list for kidney transplantation and dialysis associated mortality

Apoptotic cell death is initiated during normothermic ischemia in human kidneys

Ischemic damage plays an important role in post-transplant organ failure. Activation of the apoptotic cascade is crucially involved in post-ischemic inflammation resulting in tissue damage and organ dysfunction. Here we investigate the initiation of the apoptotic cascade during normothermic ischemia in human kidneys using a model for normothermic ischemia with kidneys nephrectomized because of renal cell carcinoma. Ex vivo, kidneys were stored at 37 degrees C, and consecutive biopsies were taken from disease-free tissue. Pro- and anti-apoptotic proteins were assessed by Western blotting and immunofluorescence. During normothermic ischemia the pro-apoptotic proteins Bax and activated caspase-9 increased with ischemia time, whereas caspase-8 was not activated. The anti-apoptotic proteins Bcl-2 and cFLIP decreased in time. Data on Bcl-2 and Bax were supported by immunofluorescence for Bcl-2 and activated Bax. However, activation of the central effector caspase-3, essential for execution of the apoptotic process, was not detected. In conclusion, during normothermic ischemia the apoptotic cascade in the human kidney is initiated, but not fulfilled. Our data show that the duration of ischemia significantly correlates with activation of the apoptotic cascade. These findings provide insight in the initiation of apoptotic cell-death during warm ischemia and may be useful in the assessment of ischemic injury

Thromboxane receptor signalling in renal ischemia reperfusion injury.

Abstract F(2)-isoprostanes are formed by oxidative modification of arachidonic acid and are the gold standard for detection of oxidative stress in vivo. F(2)-isoprostanes are biologically active compounds that signal through the thromboxane A(2) (TP) receptor; infusion of F(2)-isoprostanes reduces glomerular filtration in the kidney by constricting afferent arterioles. This study investigated whether endogenous F(2)-isoprostanes contribute to the pathogenesis of ischemic acute kidney injury, which is associated with oxidative stress and reduced glomerular filtration. TP receptor knockout mice-that lack F(2)-isoprostanes and thromboxane A(2) signalling-and wild-type control mice underwent 30 min of renal ischemia and 24 h of reperfusion. Kidney dysfunction, histological injury and the number of infiltrated neutrophils were similar between the two mouse strains, whereas TP receptor knockout mice had significantly more apoptotic cells and tissue lipid peroxidation than their wild-type counterparts. F(2)-isoprostanes and thromboxane B(2) were readily detectable in urine collections after surgery. The findings indicate that F(2)-isoprostanes and thromboxane A(2) signalling do not contribute critically to the pathogenesis of ischemic acute kidney injury and more generally provide evidence against a prominent role for F(2)-isoprostanes signalling in exacerbating acute disease states associated with oxidative stress

High rejection rate during calcineurin inhibitor-free and early steroid withdrawal immunosuppression in renal transplantation

Morbidity and mortality due to cardiovascular disease are major problems after renal transplantation. The effects of three immunosuppressive protocols on cardiovascular end points were investigated in a single-center, randomized, parallel (1-1-1) group. Acute rejection was a secondary safety endpoint. Groups were as follows: group one, tacrolimus+sirolimus; group two, tacrolimus+mycophenolate mofetil (MMF); group three, sirolimus+MMF+daclizumab. All groups received two days methylprednisolone only. The Ethical Committee demanded an interim analysis when 50% of the patients were included. In this analysis, 54 patients with a median follow-up of 9.2 months were studied. The Kaplan-Meyer analysis showed a difference in rejection free survival between group one (82%) and group three (34%, P=0.03) and between groups one and two (tacrolimus-based, 76%) and group three (calcineurin-free, 34%, P=0.04). Calcineurin-free immunosuppression with two days of steroids only showed an unacceptable high incidence of acute rejection and re-rejection, and the study had to be stopped