Chronic Histological Changes Research Articles

Chronic histological changes in deceased donor kidneys at implantation do not predict graft survival: a single-centre retrospective analysis.

The use of preimplantation kidney biopsies (PIKBs) to aid deceased donor kidney utilization decisions is controversial. Outcomes of transplants that had been biopsied after the decision had been made to implant were analysed, in order to determine the association between chronic histological changes at implantation and graft outcomes. A retrospective analysis of transplants between the year range 2006-2015 was performed. Karpinski scores on biopsies were collected, and graft outcomes were analysed using univariate and multivariable techniques. Also, Karpinski scores from single and dual kidney transplants from older donors were examined to determine if knowledge of the score preoperatively would have altered utilization. Four hundred and eight single kidneys were transplanted. Although kidneys with scores >4 had lower 1- and 3-year median (IQR) estimated glomerular filtration rates (eGFRs) than those scoring 0-4 (51 (37-66) vs. 35 (26-52) ml/min/1.73m2 , P<0.001, and 52 (34-64) vs. 35 (24-52) ml/min/1.73m2 , P<0.001, respectively), there was no significant association between Karpinski score and death-censored graft survival on univariate or multivariable analyses. The utilization analysis (75 single and 25 dual kidney transplant recipients) suggested that systematic use of PIKBs would have resulted in 29% fewer patients being transplanted. This analysis does not support the systematic use of PIKBs to determine deceased donor kidney utilization.

P164 Mucosal healing (MH) assessed with PICaSSO (Paddington International Virtual ChromoendoScopy ScOre) and probe Confocal Laser Endomicroscopy (pCLE) do not reflect histological normalisation using the ECAP (Extent Chronicity Activity Plus) score

Ulcerative colitis (UC) is a chronic disease that requires long-term therapy and the achievement of mucosal healing (MH) is the target of the treatment. The new histological score ECAP (Extent Chronicity Activity Plus) has been developed to detect minimal chronic changes. The electronic Virtual Chromoendoscopy Endoscopy (VCE) score PICaSSO (Paddington International Virtual ChromoendoScopy ScOre)1 and probe Confocal Laser Endomicroscopy (pCLE) scores reflect acute histological changes (Robarts Histological Index-[RHI]) well,2 but it is unknown whether these may reflect chronic histological changes. This is a prospective study involving 82 UC patients at the Endoscopy Unit, Foothills Medical Center, University of Calgary, Canada. For each patient, clinical data including follow-up up to 12 months, endoscopic scores (Mayo endoscopic score, PiCasso and pCLE score) and histological ECAP score were determined. The details of ECAP score has already been published.1 Receiver-operating characteristics (ROC) curves were plotted to estimate the cut-offs for PICaSSO and pCLE scores best predicting the MH determined by histological ECAP score. 70 patients (85.4%) were in clinical remission. We have compared the endoscopic scores (MES, PICaSSO, and pCLE) with histological healing defined by ECAP ≤ 4. Only 14 patients (28.6%) with Mayo 0 had ECAP ≤ 4. From the ROC curves, the best cut-off for PICaSSO score was 4, with sensitivity and specificity of 88.9% (95% CI 64.3%-98.6%) and 40.6% (95% CI 28.5%-53.6%), respectively with an area under ROC curve (AUROC) of 69.9% (95% CI 57.2%-82.6%). At this value, out of 54 patients with PICaSSO ≤ 4, only 16 (29.6%) have ECAP ≤ 4. The ROC curves for pCLE showed that the best cut-off point to detect MH (ECAP ≤ 4) was 11 with sensitivity of 94.4% (95% CI 72.7–99.9%) specificity of 31.3% (95% CI 20.2%-44.1%) with AUROC of 71.4% (95% CI 57.9%-84.8%). At this value of pCLE, 17 (27.9%) patient amongst 61 had ECAP ≤ 4. ROC curve for PICaSSO in the prediction of mucosal healing (ECAP ≤ 4) During the follow-up period, 8.06% of patients had a relapse: 80% had PICaSSO score ≤ 4, 80% had pCLE ≤ 11, and only one relapse 20% had ECAP ≤ 4. According our results, the endoscopic scores (PICaSSO and pCLE) are not able to predict histological healing calculated using ECAP (both chronic and acute changes) at the value ≤ 4. An ECAP score ≤4 may however predict stable mucosal healing with few relapses over 12 months.

Chronic Statin Therapy and Histologic Gastric Changes

Abstract Background: The additional benefits of certain frequently used chronic drugs such as statins or aspirin are investigated for their possible effect of influencing various types of cancer, including gastric cancer. The possible role of statins in the occurrence of pre-neoplastic gastric lesions has not been investigated. Aim: The study aims to determine the influence of chronic statin therapy on premalignant gastric lesions (glandular atrophy, intestinal metaplasia and dysplasia), adjusted with the most important aggressive environmental factors of the gastric mucosa (Helicobacter pylori [H. pylori] infection, low-dose aspirin [acetylsalicylic acid, ASA], biliary reflux, smoking, alcohol consumption). Method: The study included 566 patients with cardiovascular diseases who underwent an upper endoscopy: 222 patients with chronic statin therapy (atorvastatin 20–80 mg/day or rosuvastatin 5–20 mg/day for at least 6 months) and 344 patients without statin intake. A complete set of biopsies from the gastric antrum and corpus were routinely processed and examined, and demographical, clinical, and pathological variables were recorded. Results: Active H. pylori infection in gastric biopsies (p = 0.45), biliary reflux (p = 0.74), alcohol consumption (p = 0.43), or prior ulcer disease (p = 0.07; OR: 0.59; 95% CI: 0.33–1.04) were not associated with an increased risk for premalignant lesions, neither in the statin, nor the no-statin group. Smoking was associated with premalignant lesions in both groups (p = 0.01; OR: 2.24; 95% CI: 1.12–4.47; and p = 0.04; OR: 1.72; 95% CI: 1.01–2.94, respectively), while chronic use of ASA had no influence (p = 0.24, respective p = 0.35). In multivariate regression models, chronic treatment with statins had a protective effect (p = 0.006; OR: 0.59; 95% CI: 0.4–0.8), while smoking (p = 0.01; OR: 1.99; 95% CI: 1.17–3.39) and age &gt;50 years (p &lt;0.01, OR: 3.09; 95% CI: 1.84–5.21) were predictors for pre-neoplastic lesions. H. pylori infection, gender, alcohol consumption, biliary reflux, or prior ulcer disease were not associated with premalignant lesions (p &gt;0.05). Conclusions: In the studied population, chronic statin treatment seems to be associated with a decreased risk for premalignant gastric lesions, while age over 50 years and smoking, regardless of gender or ASA consumption, remain the most important risk factors for premalignant gastric lesions.

Donor APOL1 high-risk genotypes are associated with increased risk and inferior prognosis of de novo collapsing glomerulopathy in renal allografts

Collapsing focal segmental glomerulosclerosis (cFSGS) in the native kidney is associated with heavy proteinuria and accelerated renal failure. However, cFSGS in the renal allograft is less well characterized. Here we report clinico-pathologic features and APOL1 donor risk genotypes in 38 patients with de novo post-kidney transplant cFSGS. Recipients were 34% female and 26% African American. Concurrent viral infections and acute vaso-occlusion (including thrombotic microangiopathy, cortical necrosis, atheroembolization, and cardiac arrest with contralateral graft thrombosis) were present in 13% and 29% of recipients, respectively. Notably, 61% of patients had concurrent acute rejection and 47% received grafts from African American donors, of which 53% carried APOL1 high-risk genotypes. These frequencies of acute rejection and grafts from African American donors were significantly higher than in our general transplant population (35% and 16%, respectively). Patients had a median serum creatinine of 5.4 mg/dl, urine protein/creatinine 3.5 g/g, and 18% had nephrotic syndrome. Graft failure occurred in 63% of patients at an average of eighteen months post-index biopsy. By univariate analysis, donor APOL1 high-risk genotypes, post-transplant time, nephrotic syndrome, and chronic histologic changes were associated with inferior graft survival while acute vaso-occlusion was associated with superior graft survival. Donor APOL1 high-risk genotypes independently predicted poor outcome. Compared to native kidney cFSGS, post-transplant cFSGS had more acute vaso-occlusion but less proteinuria. Thus, de novo cFSGS is associated with variable proteinuria and poor prognosis with potential predisposing factors of African American donor, acute rejection, viral infection and acute vaso-occlusion. Additionally, donor APOL1 high-risk genotypes are associated with higher incidence and worse graft survival.

OR15 Progressive chronic tissue injury without active pathological changes is the histological halmark of de novo class II DSA

Aim There is no doubt that de novo anti-HLA Donor Specific Antibodies(dn-DSA) have deleterious effect on the kidney allograft. However, there is considerable controversy regarding the pattern of tissue injury generated by these antibodies. We set out to study the pattern of tissue injury of kidney biopsies procured in the early post-transplantation period (the first 5 years) in the for-the-cause biopsy practice setting at our institution. Methods All the cases with dn-DSA who had at least one kidney biopsy done in the first 5 years after kidney transplantation were included in the study. The type of dn-DSA (class I, class II or combined), presence/ type of rejection and the pattern of tissue injury based on Banff score and other histological findings were evaluated. Results Of the total of 36 cases fulfilling the criteria, 6(17%) had only class I, 21( 58%) had only class II and 9 ( 25%) had combined dn-DSA. There was no difference in clinical and laboratory parameters between the groups. Chronic histological changes either in tubulointerstitial compartment (ct and ci scores), vessels (cv score) or glomeruli (cg score) were significantly higher in cases with class II or mixed DSA than class I DSA. Mean ± SD for ct/ci, cv and cg in patients with class II or combined dn-DSA vs class I were 1.2 ± 1.0 vs 0.6 ± 0.5, 1.4 ± 1.1 vs 0.6 ± 0.8, 0.5 ± 0.8 vs nil, respectively. Interestingly, the recurrence of the original glomerulonephritis was only seen in association with class I DSA. Venulitis, not part of Banff score, was seen significantly more prevalent in class I DSA group (50%) compared to class II only or mixed group (10%). Conclusions Our study is limited by the low number of cases. However, some trends are readily appreciated. The tissue injury caused by class II dn-DSA is insidious and may be detected at late stages of rejection, even in early post-transplantation period. The clinical and laboratory parameters of rejection can be misleading in such cases and therefore, protocol biopsy practice is advisable.

Early allograft inflammation and scarring associate with graft dysfunction and poor outcomes in renal transplant recipients with delayed graft function: a prospective single center cohort study

Early histological progression that associates with delayed graft function (DGF) and its relationship to graft outcomes is less well-understood. We systematically evaluated early acute and chronic histological changes associated with DGF through serial biopsies (protocol: 3 and 12 months; for-cause) and related them to graft outcomes. 56/294 (19.04%) of our patients had DGF. DGF was associated with a progressive increase in both Banff 't' and 'i' scores from 2 weeks to 3 and 12 months with a resultant increase in T cell mediated rejection (TCMR) that was significantly greater than those with primary graft function (PGF). This increase in TCMR was predominantly sub-clinical TCMR diagnosed on protocol biopsy. Furthermore, TCMR in patients with DGF was recurrent/persistent at 12 months. Importantly, the combination of DGF and TCMR was associated with significantly worse interstitial fibrosis and tubular atrophy (IFTA) and interstitial fibrosis with inflammation (IF + 'i') as early as 3 months and worse renal function. Finally, DGF with TCMR was associated with significantly worse graft loss. In this regard, DGF without TCMR had comparable chronic histology and outcomes to PGF. Thus, DGF with TCMR (predominantly sub-clinical), represents a high-risk patient group who may benefit from early novel immunosuppression augmentation strategies to improve graft outcomes.

Functional and Histological Effects of Chronic Neural Electrode Implantation.

ObjectivesPermanent injury to the cranial nerves can often result in a substantial reduction in quality of life. Novel and innovative interventions can help restore form and function in nerve paralysis, with bioelectric interfaces among the more promising of these approaches. The foreign body response is an important consideration for any bioelectric device as it influences the function and effectiveness of the implant. The purpose of this review is to describe tissue and functional effects of chronic neural implantation among the different categories of neural implants and highlight advances in peripheral and cranial nerve stimulation. Data Sources: PubMed, IEEE, and Web of Science literature search. Review Methods: A review of the current literature was conducted to examine functional and histologic effects of bioelectric interfaces for neural implants.ResultsBioelectric devices can be characterized as intraneural, epineural, perineural, intranuclear, or cortical depending on their placement relative to nerves and neuronal cell bodies. Such devices include nerve‐specific stimulators, neuroprosthetics, brainstem implants, and deep brain stimulators. Regardless of electrode location and interface type, acute and chronic histological, macroscopic and functional changes can occur as a result of both passive and active tissue responses to the bioelectric implant.ConclusionA variety of chronically implantable electrodes have been developed to treat disorders of the peripheral and cranial nerves, to varying degrees of efficacy. Consideration and mitigation of detrimental effects at the neural interface with further optimization of functional nerve stimulation will facilitate the development of these technologies and translation to the clinic.Level of Evidence3.

Evaluation of Indication Biopsies ≥5 Years After Kidney Transplant: A Single-Center Experience.

Rejection is a common cause of late graft dysfunction seen on biopsy studies. The aim of this study was to evaluate indication biopsy findings ? 5 years after kidney transplant and to assess the effectiveness of applied treatments. Between January 2013 and December 2015, 30 patients who underwent renal transplant indication biopsies and were followed up for ≥ 6 months were evaluated retrospectively. A >30% increase in serum creatinine and/or development of > 1 g/day proteinuria was considered an acceptable indication for biopsy. Of the 156 indication biopsies obtained within a 3-year period, 30 of them were indication biopsies performed ≥ 5 years after transplant. Twenty patients (67%) demonstrated late graft rejection, 6 patients (20%) had recurrent or de novo glomerulonephritis, and 4 patients (13%) were diagnosed with idiopathic chronic allograft nephropathy. The mean total histologic score was 6.2 ± 2.6, and the chronicity rate was 70%. For patients with late rejection, treatment consisted of pulse steroids in 11, intravenous immunoglobulin in 5, plasmapheresis in 4, antithymocyte globulin in 3, and rituximab in 2 cases. Five patients with glomerulonephritis received pulse steroids, 1 received rituximab therapy, and 3 were treated with cyclophosphamide. The mean follow-up after indication biopsy was 16 ± 11 months. Eleven patients (37%) had a progressive disease course and 7 patients (23%) resumed hemodialysis. Of the 30 patients, the 15 whose glomerular filtration rate was < 30 mL/min/1.72 m² at biopsy were more likely to have a progressive disease course (53% vs. 20%; P = .05) and more commonly resumed dialysis (40% vs. 7%; P = .03). Rejection was the most common cause of graft dysfunction long term. Chronic histologic changes predominated in indication biopsies ≥ 5 years posttransplant. Regardless of diagnosis, a low glomerular filtration rate at biopsy was closely associated with poor renal outcomes.

Bortezomib in the treatment of antibody-mediated rejection in pediatric kidney transplant recipients: A multicenter Midwest Pediatric Nephrology Consortium study.

Antibody-mediated rejection leads to allograft loss after kidney transplantation. Bortezomib has been used in adults for the reversal of antibody-mediated rejection; however, pediatric data are limited. This retrospective study was conducted in collaboration with the Midwest Pediatric Nephrology Consortium. Pediatric kidney transplant recipients who received bortezomib for biopsy-proven antibody-mediated rejection between 2008 and 2015 were included. The objective was to characterize the use of bortezomib in pediatric kidney transplant recipients. Thirty-three patients received bortezomib for antibody-mediated rejection at nine pediatric kidney transplant centers. Ninety percent of patients received intravenous immunoglobulin, 78% received plasmapheresis, and 78% received rituximab. After a median follow-up of 15months, 65% of patients had a functioning graft. The estimated glomerular filtration rate improved or stabilized in 61% and 36% of patients at 3 and 12months post-bortezomib, respectively. The estimated glomerular filtration rate at diagnosis significantly predicted estimated glomerular filtration rate at 12months after adjusting for chronic histologic changes (P .001). Fifty-six percent of patients showed an at least 25% reduction in the mean fluorescence intensity of the immune-dominant donor-specific antibody, 1-3months after the first dose of bortezomib. Non-life-threatening side effects were documented in 21 of 33 patients. Pediatric kidney transplant recipients tolerated bortezomib without life-threatening side effects. Bortezomib may stabilize estimated glomerular filtration rate for 3-6months in pediatric kidney transplant recipients with antibody-mediated rejection.

Phosphocalcic Markers and Calcification Propensity for Assessment of Interstitial Fibrosis and Vascular Lesions in Kidney Allograft Recipients.

Renal interstitial fibrosis and arterial lesions predict loss of function in chronic kidney disease. Noninvasive estimation of interstitial fibrosis and vascular lesions is currently not available. The aim of the study was to determine whether phosphocalcic markers are associated with, and can predict, renal chronic histological changes. We included 129 kidney allograft recipients with an available transplant biopsy in a retrospective study. We analyzed the associations and predictive values of phosphocalcic markers and serum calcification propensity (T50) for chronic histological changes (interstitial fibrosis and vascular lesions). PTH, T50 and vitamin D levels were independently associated to interstitial fibrosis. PTH elevation was associated with increasing interstitial fibrosis severity (r = 0.29, p = 0.001), while T50 and vitamin D were protective (r = -0.20, p = 0.025 and r = -0.23, p = 0.009 respectively). On the contrary, fibroblast growth factor 23 (FGF23) and Klotho correlated only modestly with interstitial fibrosis (p = 0.045) whereas calcium and phosphate did not. PTH, vitamin D and T50 were predictors of extensive fibrosis (AUC: 0.73, 0.72 and 0.68 respectively), but did not add to renal function prediction. PTH, FGF23 and T50 were modestly predictive of low fibrosis (AUC: 0.63, 0.63 and 0.61) but did not add to renal function prediction. T50 decreased with increasing arterial lesions (r = -0.21, p = 0.038). The discriminative performance of T50 in predicting significant vascular lesions was modest (AUC 0.61). In summary, we demonstrated that PTH, vitamin D and T50 are associated to interstitial fibrosis and vascular lesions in kidney allograft recipients independently of renal function. Despite these associations, mineral metabolism indices do not show superiority or additive value to fibrosis prediction by eGFR and proteinuria in kidney allograft recipients, except for vascular lesions where T50 could be of relevance.

Cell cycle inhibition reduces inflammatory responses, neuronal loss, and cognitive deficits induced by hypobaria exposure following traumatic brain injury.

BackgroundTraumatic brain injury (TBI) patients in military settings can be exposed to prolonged periods of hypobaria (HB) during aeromedical evacuation. Hypobaric exposure, even with supplemental oxygen to prevent hypoxia, worsens outcome after experimental TBI, in part by increasing neuroinflammation. Cell cycle activation (CCA) after TBI has been implicated as a mechanism contributing to both post-traumatic cell death and neuroinflammation. Here, we examined whether hypobaric exposure in rats subjected to TBI increases CCA and microglial activation in the brain, as compared to TBI alone, and to evaluate the ability of a cyclin-dependent kinase (CDK) inhibitor (CR8) to reduce such changes and improve behavioral outcomes.MethodsAdult male Sprague Dawley rats were subjected to fluid percussion-induced injury, and HB exposure was performed at 6 h after TBI. Western blot and immunohistochemistry (IHC) were used to assess cell cycle-related protein expression and inflammation at 1 and 30 days after injury. CR8 was administered intraperitoneally at 3 h post-injury; chronic functional recovery and histological changes were assessed.ResultsPost-traumatic hypobaric exposure increased upregulation of cell cycle-related proteins (cyclin D1, proliferating cell nuclear antigen, and CDK4) and microglial/macrophage activation in the ipsilateral cortex at day 1 post-injury as compared to TBI alone. Increased immunoreactivity of cell cycle proteins, as well as numbers of Iba-1+ and GFAP+ cells in both the ipsilateral cortex and hippocampus were found at day 30 post-injury. TBI/HB significantly increased the numbers of NADPH oxidase 2 (gp91phox) enzyme-expressing cells that were co-localized with Iba-1+. Each of these changes was significantly reduced by the administration of CR8. Unbiased stereological assessment showed significantly decreased numbers of microglia displaying the highly activated phenotype in the ipsilateral cortex of TBI/HB/CR8 rats compared with TBI/HB/Veh rats. Moreover, treatment with this CDK inhibitor also significantly improved spatial and retention memory and reduced lesion volume and hippocampal neuronal cell loss.ConclusionsHB exposure following TBI increases CCA, neuroinflammation, and associated neuronal cell loss. These changes and post-traumatic cognitive deficits are reduced by CDK inhibition; such drugs may therefore serve to protect TBI patients requiring aeromedical evacuation.

IL-22 exacerbates weight loss in a murine model of chronic pulmonary Pseudomonas aeruginosa infection

BackgroundInterleukin (IL)-22 is a critical mediator of mucosal immunity and tissue regeneration, protecting against a number of respiratory pathogens. Whether IL-22 confers protection against chronic Pseudomonas aeruginosa (PA) infection in cystic fibrosis (CF) is unknown. MethodsExplanted CF lungs were examined for IL-22 production and immune-localization. A murine model of persistent pulmonary PA infection was used to examine production of IL-22 following infective challenge. The role of IL-22 was examined using IL-22 knockout (KO) animals. ResultsIL-22 is produced within the adult CF lung and localizes to the airway epithelium. IL-22 is produced by murine pulmonary lymph node cells following lung infection. The absence of IL-22 resulted in no significant difference in acute mortality, bacterial burden, chronic infection rates, histological changes or neutrophilic inflammation in the chronic PA infection model. However, IL-22 KO animals lost less weight following infection. ConclusionIL-22 is produced in the CF lung and in response to PA infection yet is dispensable in protection against chronic pulmonary P. aeruginosa infection in a murine model. However, we identified a novel role for the cytokine in promoting infection-related weight-loss, a significant prognostic factor in the CF population.

Comparative Effects of Irreversible Electroporation, Radiofrequency Ablation, and Partial Nephrectomy on Renal Function Preservation in a Porcine Solitary Kidney Model

To evaluate kidney function preservation or regeneration and pathological changes post-irreversible electroporation (IRE) in comparison with partial nephrectomy and radiofrequency ablation (RFA) in a solitary kidney porcine model. Tissue ablation using IRE has been reported to spare critical anatomic structures within or near the ablation zone with associated regeneration of adjacent parenchyma, possibly offering functional preservation. Fifteen pigs initially underwent laparoscopic nephrectomy. The lower third of the remaining kidney was then ablated or removed with either IRE, RFA, or partial nephrectomy. Serum creatinine (SCr) was measured at baseline, 24 hours, 3, 7, 14, and 28 days postoperatively. The impact of the type of procedure on SCr over time was evaluated. Acute and chronic histological changes were analyzed and cellular viability was assessed using nicotinamide adenine dinucleotide staining in the IRE ablations. Ten ablations (5 IRE, 5 RFA) and 5 partial nephrectomies of the entire lower third of a solitary kidney were performed. The type of procedure did not affect SCr significantly at baseline (P = .14) or change in SCr over time (P = .48). Histologically, IRE and RFA lesions showed similar findings including coagulative necrosis that progressively was replaced by reparative stromal changes and fibrous tissue. Nicotinamide adenine dinucleotide staining of the IRE lesions at 14 and 28 days showed no viability in the necrotic areas with viable tissue at the margins demonstrating reparative changes. Large volume IRE ablation of normal renal parenchyma in the porcine model does not provide a functional advantage as compared with conventional renal tumor treatments.

KLF5 mediates vascular remodeling via HIF-1α in hypoxic pulmonary hypertension.

Hypoxic pulmonary hypertension (HPH) is characterized by active vasoconstriction and profound vascular remodeling. KLF5, a zinc-finger transcription factor, is involved in the excessive proliferation and apoptotic resistance phenotype associated with monocrotaline-induced pulmonary hypertension. However, the molecular mechanisms of KLF5-mediated pathogenesis of HPH are largely undefined. Adult male Sprague-Dawley rats were exposed to normoxia or hypoxia (10% O2) for 4 wk. Hypoxic rats developed pulmonary arterial remodeling and right ventricular hypertrophy with significantly increased right ventricular systolic pressure. The levels of KLF5 and hypoxia-inducible factor-1α (HIF-1α) were upregulated in distal pulmonary arterial smooth muscle from hypoxic rats. The knockdown of KLF5 via short-hairpin RNA attenuated chronic hypoxia-induced hemodynamic and histological changes in rats. The silencing of either KLF5 or HIF-1α prevented hypoxia-induced (5%) proliferation and migration and promoted apoptosis in human pulmonary artery smooth muscle cells. KLF5 was immunoprecipitated with HIF-1α under hypoxia and acted as an upstream regulator of HIF-1α. The cell cycle regulators cyclin B1 and cyclin D1 and apoptosis-related proteins including bax, bcl-2, survivin, caspase-3, and caspase-9, were involved in the regulation of KLF5/HIF-1α-mediated cell survival. This study demonstrated that KLF5 plays a crucial role in hypoxia-induced vascular remodeling in an HIF-1α-dependent manner and provided a better understanding of the pathogenesis of HPH.

Impact of Metabolic Syndrome on Postdonation Renal Function in Living Kidney Donors

IntroductionOptimization of kidney donor selection is critical to ensure recovery of the donor. The goal of this study was to determine the influence of metabolic syndrome on renal histology and perioperative renal function in living kidney donors. Patients and MethodsBetween January 2010 and March 2013, a total of 363 living kidney donors who underwent donor nephrectomy at our institution were enrolled. Metabolic syndrome was diagnosed in patients according to the National Cholesterol Education Program's Adult Treatment Panel III, and renal histology of implantation biopsy specimens and perioperative renal function were compared in participants with or without metabolic syndrome. Using multivariate regression analysis, the goal was to identify which component of metabolic syndrome induces chronic histologic changes and delayed renal function recovery. ResultsWe identified 30 donors (8.45%) with metabolic syndrome. Donors with metabolic syndrome were older (48.4 ± 9.2 years vs 39.7 ± 11.4 years; P < .001) and more likely to have chronic histologic changes (36.8% vs 9.7%; P = .001) than subjects without metabolic syndrome. Results of the multivariate regression analysis indicated that obesity, hyperglycemia, and hypertriglyceridemia were independently associated with chronic histologic changes. Perioperative renal function was correlated with the presence of metabolic syndrome rather than with chronic histologic changes, and patients with metabolic syndrome were more likely to experience delayed renal function recovery. Linear regression models found that the sum of the metabolic components correlated with renal function 6 months postoperatively, but among all risk factors, only obesity was significantly associated with the occurrence of delayed renal function recovery (odds ratio, 2.67; P = .001). ConclusionsAlthough metabolic syndrome in living kidney donors is characterized by chronic histologic changes, perioperative renal function is affected by the syndrome itself rather than by the histologic changes. Obesity is the most important metabolic factor for predicting delayed renal function recovery in living kidney donors, providing an important clinical indicator of postoperative renal function in these patients.

8-Oxoguanine DNA glycosylase-1-driven DNA base excision repair: role in asthma pathogenesis.

To provide both an overview and evidence of the potential cause of oxidative DNA base damage and repair signaling in chronic inflammation and histological changes associated with asthma. Asthma is initiated/maintained by immunological, genetic/epigenetic, and environmental factors. It is a world-wide health problem, as current therapies suppress symptoms rather than prevent/reverse the disease, largely due to gaps in understanding its molecular mechanisms. Inflammation, oxidative stress, and DNA damage are inseparable phenomena, but their molecular roles in asthma pathogenesis are unclear. It was found that among oxidatively modified DNA bases, 8-oxoguanine (8-oxoG) is one of the most abundant, and its levels in DNA and body fluids are considered a biomarker of ongoing asthmatic processes. Free 8-oxoG forms a complex with 8-oxoG DNA glycosylase-1 and activates RAS-family GTPases that induce gene expression to mobilize innate and adaptive immune systems, along with genes regulating airway hyperplasia, hyper-responsiveness, and lung remodeling in atopic and nonatopic asthma. DNA's integrity must be maintained to prevent mutation, so its continuous repair and downstream signaling 'fuel' chronic inflammatory processes in asthma and form the basic mechanism whose elucidation will allow the development of new drug targets for the prevention/reversal of lung diseases.

Donor-specific antibodies, C4d and their relationship with the prognosis of transplant glomerulopathy.

Transplant glomerulopathy (TG) is a diagnostic criterion for chronic active antibody-mediated rejection (CAABMR), with C4d, donor-specific antibodies (DSA) and other lesions of chronic tissue injury. However, TG often presents without C4d or DSA. Until recently, such cases were termed suspicious for CAABMR, and their prognosis remains unclear. To better understand the contribution of TG, C4d, and DSA on outcomes, we retrospectively studied 61 patients with late TG for the composite endpoint of death-censored graft failure or doubling of serum creatinine. Cases were matched to controls based on age, year and number of transplant, type of donor, and the availability of an indication biopsy during the same time after transplantation. Analyses were performed using proportional hazards models. Compared to matched controls, patients with TG had a more than fivefold increased risk of reaching the endpoint (adjusted hazard ratio (aHR), 5.3; 95% confidence interval (95% CI), 1.5-18.4). The proportion of patients with isolated TG, TG suspicious for CAABMR (C4+/DSA- or C4d-/DSA+) and TG with definite CAABMR (C4d+/DSA+) were 63%, 20%, and 17%, respectively. Suspicious and definite CAABMR showed a similar prognosis, significantly worse than isolated TG (aHR, 4.5; 95% CI, 1.1-18.9 and aHR, 5.9, 95% CI, 1.1-31.3 respectively). Transplant glomerulopathy is associated with poor prognosis, independent of the level of graft dysfunction and other chronic histologic changes. This prognosis is similar whether there is evidence of tissue or peripheral alloantibody reactivity. These findings are relevant to the development of clinically meaningful criteria for CAABMR, for its clinical management, and in the future selection of population for clinical trials.

Shock wave lithotripsy does not impair renal function in a Swine model of metabolic syndrome.

To determine whether shock wave lithotripsy (SWL) may be a risk factor for renal functional impairment in a swine model of metabolic syndrome (MetS). Nine-month-old female Ossabaw pigs were fed an excess calorie atherogenic diet to induce MetS. At 15 months of age, the MetS pigs were treated with 2000 SWs or an overtreatment dose of 4000 SWs targeted at the upper pole calyx of the left kidney (24 kV at 120 SWs/min using the unmodified Dornier HM3 lithotripter; n=5-6 per treatment group). Serum creatinine (Cr) and blood urea nitrogen (BUN) levels were measured in conscious pigs before and ∼60 days after SWL to provide a qualitative assessment of how well both kidneys were filtering (glomerular filtration rate [GFR]). Bilateral renal function was assessed at ∼65 days post-SWL in anesthetized pigs with GFR and effective renal plasma flow (ERPF) quantified by the renal clearance of inulin and para-amino hippurate, respectively. Cr and BUN values were within normal limits before SWL and remained unchanged after lithotripsy in both the 2000 SW- and 4000 SW-treated pigs. GFR and ERPF of kidneys treated with SWL at either SW dose were similar to the contralateral nontreated kidney. Chronic histological changes in the SW-treated pole of the kidney included interstitial fibrosis, sclerotic glomeruli, and dilated and atrophic tubules. Our results are consistent with the view that a single SWL session does not result in renal impairment, even in the presence of MetS.

Non-diabetic renal diseases in a multi-ethnic New Zealand cohort with type 2 diabetes mellitus: clinical and histopathological features

The aims of this study were to identify non-diabetic renal disease (NDRD), including obesity related glomerulopathy (ORG) in diabetic patients, and compare the findings with those of pure diabetic nephropathy (DN).Ninety-three renal biopsies from diabetic patients were reviewed retrospectively, along with their clinical findings at biopsy and their estimated glomerular filtration rate (eGFR) over 5 years follow-up. DN and focal segmental glomerulosclerosis (FSGS) were diagnosed on blinded histology review, together with assessment of renal compartment histology. Other NDRD were diagnosed on full review.Most patients were obese with poor renal function at biopsy. NDRD occurred in more than two-thirds of biopsies. FSGS and interstitial nephritis were common. Patients with pure FSGS presented earlier, and had favourable histological features and clinical course. Most FSGS patients fulfilled criteria for ORG. Biopsies with interstitial nephritis showed more functional glomerular tissue, and most patients retained good renal function. Adverse prognostic features were DN versus NDRD, nodular grade of DN, low eGFR at biopsy, and severe chronic histological changes.In this population, ORG mechanisms contribute to renal injury. FSGS is frequent, and should be diagnosed separately from any DN. Biopsy to confirm suspicion of interstitial nephritis should be performed even if retinopathy is present.

MP72-02 DO THE METABOLIC SYNDROME AND CHRONIC HISTOLOGICAL CHANGES EFFECT ON RESIDUAL KIDNEY FUNCTION IN LIVING KIDNEY DONORS?

You have accessJournal of UrologyTransplantation & Vascular Surgery II1 Apr 2014MP72-02 DO THE METABOLIC SYNDROME AND CHRONIC HISTOLOGICAL CHANGES EFFECT ON RESIDUAL KIDNEY FUNCTION IN LIVING KIDNEY DONORS? Kyung Hwa Choi, Kwang Hyun Kim, Young Eun Yoon, Kwang-suk Lee, Seung Choul Yang, Kyu Ha Huh, Dong Jin Joo, Myoung Soo Kim, Soon Il Kim, Yu Seun Kim, and Woong Kyu Han Kyung Hwa ChoiKyung Hwa Choi More articles by this author , Kwang Hyun KimKwang Hyun Kim More articles by this author , Young Eun YoonYoung Eun Yoon More articles by this author , Kwang-suk LeeKwang-suk Lee More articles by this author , Seung Choul YangSeung Choul Yang More articles by this author , Kyu Ha HuhKyu Ha Huh More articles by this author , Dong Jin JooDong Jin Joo More articles by this author , Myoung Soo KimMyoung Soo Kim More articles by this author , Soon Il KimSoon Il Kim More articles by this author , Yu Seun KimYu Seun Kim More articles by this author , and Woong Kyu HanWoong Kyu Han More articles by this author View All Author Informationhttps://doi.org/10.1016/j.juro.2014.02.2241AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookTwitterLinked InEmail INTRODUCTION AND OBJECTIVES Metabolic syndrome (MS) has been increasing over the last decade, and its relationship with renal function and histological abnormality has been an important clinical issue. We studied association of MS and histological findings with renal function in living kidney donors METHODS Implantation biopsy of 162 cases of living kidney transplantation between 2010 and 2011 were followed. NCEP ATPIII and ¡¯07 Banff criteria were used to define MS and histological characteristics. Chronic histological change(CHC) were characterized by following: any glomerulosclerosis, any interstitial fibrosis or any arteriosclerosis. Perioperative estimated GFR (eGFR) using the Modification of Diet in Renal Disease (MDRD) formula and urine microalbumin/creatinin ratio was calculated. Univariate and multivariate regression analyses were performed to identify the factors related to CHC and postoperative 6 month chronic kidney disease (MDRD GFR< 60ml/min/1.73m2). RESULTS The mean ages of MS group and non-MS group were 48.4 and 38.6 years respectively. The mean preoperative MDRD GFRs of each group were 85.7 vs 93.7 ml/min/1.73m2 (p=0.031). The MDRD GFR before postoperative 1 month was lower in MS group than non-MS group (50.7 vs 61.8, p<0.001). Donors with MS were more likely to have a CHC (Figure 1, p=0.004). The mean preoperative MDRD GFR of CHC and normal group were 88.9 vs 95.0 (p=0.028). The MDRD GFR before postoperative 1 month and postoperative 6 month were lower in CHC group than normal group (52.5 vs 62.4, p=0.003 and 61.2 vs 66.7, p=0.026, respectively). Older donor and presence of MS were related to CHC (Table 1). And older donor, lower preoperative MDRD GFR and presence of CHC were the positive related factors for postoperative 6 month chronic kidney disease (Table 2). However, presence of MS was not related factor. CONCLUSIONS Our study revealed that MS is related with CHC in implantation biopsy and CHC is associated with postoperative 6 month chronic kidney disease in living kidney donors. © 2014FiguresReferencesRelatedDetails Volume 191Issue 4SApril 2014Page: e823 Advertisement Copyright & Permissions© 2014MetricsAuthor Information Kyung Hwa Choi More articles by this author Kwang Hyun Kim More articles by this author Young Eun Yoon More articles by this author Kwang-suk Lee More articles by this author Seung Choul Yang More articles by this author Kyu Ha Huh More articles by this author Dong Jin Joo More articles by this author Myoung Soo Kim More articles by this author Soon Il Kim More articles by this author Yu Seun Kim More articles by this author Woong Kyu Han More articles by this author Expand All Advertisement Advertisement PDF downloadLoading ...