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Background: There are challenges in designing adequate, well-controlled studies of patients with active antibody-mediated rejection (AMR) after kidney transplantation (KTx)., Methods: We assessed the functional relationship between change in estimated glomerular filtration rate (eGFR) following the diagnosis of AMR and the risk of subsequent death-censored graft failure using the joint modeling framework. We included recipients of solitary KTx between 1995 and 2013 at 4 transplant centers diagnosed with biopsy-proven active AMR at least 1 year post-KTx, who had a minimum of 3-year follow-up., Results: A total of 91 patients across participating centers were included in the analysis. Of the 91 patients, n = 54 patients (59%) met the death-censored graft failure endpoint and n = 62 patients (68%) met the all-cause graft failure composite endpoint. Kaplan-Meier death-censored graft survival rates at 12, 36, and 60 months postdiagnosis of AMR pooled across centers were 88.9%, 58.9%, and 36.4%, respectively. Spaghetti plots indicated a linear trend in the change in eGFR, especially in the first 12 months postdiagnosis of active AMR. A significant change in eGFR was observed within the first 12 months postdiagnosis of active AMR, getting worse by a factor of -0.757 mL/min/1.73 m2 per month during the 12-month analysis period (a delta of -9.084 mL/min/1.73 m2 at 1 y). Notably, an extrapolated 30% improvement in the slope of eGFR in the first 12 months was associated with a 10% improvement in death-censored graft failure at 5 years., Conclusions: If prospectively validated, this study may inform the design of pivotal clinical trials for therapies for late AMR., Competing Interests: E.C. is an employee of Vitaeris, Inc (Vancouver, BC) that funded the project. L.G. is an employee of CTI Clinical Trial and Consulting Services (Covington, KY), a contract research organization. The other authors declare no conflicts of interest., (Copyright © 2020 The Author(s). Published by Wolters Kluwer Health, Inc.)

Background: Kidney function has been related to the presence of individual markers of cerebral small vessel disease (CSVD), as lacunes, white matter hyperintensities (WMH) or microbleeds. We aimed at studying the relationship of kidney dysfunction with the combination of several markers of CSVD., Methods: Subjects are those included in the ISSYS cohort (Investigating Silent Strokes in hypertensives: a magnetic resonance imaging study). A scale ranging from 0 to 4 points was applied based on the presence (one point each) of lacunes, deep microbleeds, moderate to extensive basal ganglia enlarged perivascular spaces (EPVS), and periventricular or deep WMH. We determined the creatinine-based glomerular filtration rate and the urinary albumin-to-creatinine ratio (UACR) as markers of kidney function and studied their association with the scale of CSVD in univariate and ordinal logistic regression analyses., Results: Among the 975 patients included, 28.2% presented one or more CSVD markers, being the most prevalent marker (either alone or in combination) basal ganglia EPVS. The UACR was elevated at increasing the scores of the CSVD scale and remained as independent predictor of the combination of markers (common OR per natural log unit increase in UACR: 1.23, 1.07-1.41) after controlling per age, gender, cardiovascular risk, antihypertensive treatment and hypertension duration. In contrast, no associations were found between the CSVD scores and the creatinine-based estimated glomerular filtration rate., Conclusions: A significant proportion of stroke-free hypertensives present at least one imaging marker of CSVD. UACR but not creatinine-based glomerular filtration rate is associated with the combination of markers of CSVD., (© 2016 S. Karger AG, Basel.)

Reproducibility and predictive value on outcome are the main criteria to evaluate the utility of histological scores. Here we analyze the reproducibility of donor biopsy assessment by different on-call pathologists and the retrospective evaluation by a single renal pathologist blinded to clinical outcomes. We also evaluate the predictive value on graft outcome of both evaluations. A biopsy was performed in donors with any of the following: age≥55 years, hypertension, diabetes, creatinine>1.5 mg/dl, or stroke. Glomerulosclerosis, interstitial fibrosis, tubular atrophy, intimal thickening, and arteriolar hyalinosis evaluated according to the Banff criteria were added to obtain a chronic score. Biopsies were classified as mild (≥3), intermediate (4-5), or advanced (6-7) damage, and unacceptable (≥8) for transplantation of 127 kidneys biopsied. Weighted κ value between both readings was 0.41 (95% CI: 0.28-0.54). Evaluation of biopsies by the renal pathologist was significantly and independently associated with estimated 12-month glomerular filtration rate and a significant composite outcome variable, including death-censored graft survival and time to reach an estimated glomerular filtration rate<30 ml/min per 1.73 m2. Thus, there was no association between readings of on-call pathologists and outcome. The lack of association between histological scores obtained by the on-call pathologists and graft outcome suggests that a specific training on renal pathology is recommended to optimize the use of kidneys retrieved from expanded criteria donors.

Superoxide dismutase (SOD) is a potent scavenger of superoxide radicals produced during normothermic ischemia-reperfusion. Since it has a short half-life, its optimal effect is achieved when it is given prior to reperfusion. The inclusion of SOD in liposomes (lipo-SOD) prolongs its half-life (free SOD: 6 min; lipo-SOD: 4 h). The protective effect of lipo-SOD in a 60-min bilateral renal warm ischemia model was studied. We divided 60 male Wistar rats between two control groups and five study groups according to the drug used (SOD or lipo-SOD) and to the time of SOD administration (prior to ischemia or prior to reperfusion). SOD and lipo-SOD were both given at 20 mg/kg endovenously. Weight, diuresis, creatinine per 100 g (Cr/100 g), and creatinine clearance per 100 g (CrCl/100 g) were studied. Conventional renal histology was performed after reperfusion and on day 7. Renal malondialdehyde, 6 keto PGF 1 alpha, and TxB2 tissue levels were studied after reperfusion. Results showed that the renal protective effect of free SOD on warm ischemic-reperfusion injury depended on the time of administration, being more effective when given before reperfusion. On the other hand, the renal protective effect of liposomed SOD did not depend on the time of administration since efficacy was similar when given before reperfusion or before ischemia. The functional protective effect of liposomed SOD was similar to that of free SOD when they were given prior to reperfusion. Nevertheless, since histological damage observed with liposomed SOD was less than with free SOD, it is suggested that the liposomed galenic form may offer better protection against renal warm ischemia. In addition, liposomed SOD was better at preventing tissue prostanoid generation after renal warm ischemic-reperfusion injury than free SOD. We concluded that liposomed SOD shows a higher renal protective effect against warm ischemia than free SOD.

Cyclosporine (CsA) nephrotoxicity is partially mediated by renal vasoconstriction due to an imbalance between vasodilator and vasoconstrictor eicosanoids. LSL 90202 is a purified lysine salt of eicosapentaenoic acid which is a known inhibitor of renal eicosanoid synthesis. The aim of the present work was to determine if chronic dietary supplementation with LSL 90202 prevented CsA nephrotoxicity and to establish the role of thromboxane and prostacyclin in renal tissue. Thirty-three male Sprague-Dawley rats were divided into 4 groups: group 1, CsA in olive oil (n = 10); group 2, isovolumetric olive oil (n = 7); group 3, CsA in olive oil plus LSL 90202 (n = 8); group 4, isovolumetric olive oil plus LSL 90202 (n = 8). CsA and LSL 90202 were given at 20 mg/kg/day. Weight and creatinine clearance (CrCl) were determined before and on days 14 and 30. On day 30 whole-blood CsA was determined and renal tissue processed for renal malondialdehyde, thromboxane B2 and 6-keto-PGF1 alpha measurement and for conventional histology. CrCl was severely reduced in the CsA in olive oil group compared to olive oil and LSL 90202 control groups. On day 30, CrCl in the CsA in olive oil plus LSL 90202 group showed a slight decrease, but the mean CrCl was significantly higher than in the CsA in olive oil group. Trough whole blood CsA levels were not significantly different in both groups given the drug. No morphological differences were found between groups.(ABSTRACT TRUNCATED AT 250 WORDS)

We have conducted an immunocytochemical analysis to investigate the presence of the recently described vascular cell adhesion molecule-1 (VCAM-1) in human kidney, using the anti-VCAM-1 monoclonal antibody 1.4C3. In normal control tissue VCAM-1 was present on some (but not all) parietal epithelial cells lining Bowman's capsule. Forty-nine of fifty clinical biopsy specimens were characterised by the additional presence of VCAM-1 on proximal tubular cells. This was most marked in biopsies of patients with interstitial nephritis or systemic vasculitis with crescentic nephritis, but was also observed in biopsies with minimal change, IgA or lupus nephropathy, or from patients with diabetic nephropathy, amyloid, or gout. Proximal tubule VCAM-1 correlated significantly with the number of transferrin-receptor-positive leukocytes (r = 0.607, p less than 0.0001) in the interstitium, but not with expression of HLA-DR by tubular cells. Surprisingly, VCAM-1 was not observed on vascular endothelial cells in these biopsies, even in the presence of a marked infiltrate; this contrasts with other tissues (e.g. skin and synovium). The presence of VCAM-1 on tubular cells in the inflamed kidney indicates the potential for these cells to interact with mononuclear cells, either as accessory cells or as cytotoxic targets. The unexpected absence of VCAM-1 in renal vascular endothelial cells suggests local differences in the endothelial cells of this organ.

Mononuclear inflammatory cells in renal biopsies from 36 patients with membranous nephropathy (MN) were analyzed, using monoclonal antibodies. In the interstitium, monocytes/macrophages and T cells were the predominant cell types (210 +/- 27 and 171 +/- 25/mm2, respectively); in contrast, very few intraglomerular leucocytes, mostly macrophages (1.0 +/- 0.7 cell/glomerular cross-section), were found. Among the interstitial T-cell population, helper/inducer cells (CD4+) predominated (CD4:CD8 ratio, 2.2 +/- 1.5). Natural killer (NK) cells and B lymphocytes were a minor component of the interstitial infiltrates and were almost absent in the glomeruli. Significantly higher numbers of DR-expressing cells were found in the interstitium (322 +/- 20/mm2) than in controls (109 +/- 30), but tubular DR expression was similar to controls (17 +/- 12 mm2). The numbers of total leukocytes and their subsets CD4+, CD8+, monocytes/macrophages, and B cells all correlated with the degree of renal impairment at the time of biopsy, but surprisingly there was no correlation between interstitial cell numbers and the histological severity of tubulointerstitial lesions. Progressive renal impairment over 5 years was associated with many interstitial T cells and monocytes/macrophages in the initial biopsy. Our results suggest that interstitial mononuclear cells may be important determinants in the pathogenesis of MN. Both cellular and humoral immune mechanisms may play a major role in the initiation of the disease, whereas progression toward renal failure seems to be determined mainly by cell-mediated immunity.