Publications by authors named "Rabi Yacoub"

41 Publications

Unconjugated p-cresol activates macrophage macropinocytosis leading to increased LDL uptake.

JCI Insight 2021 Apr 29. Epub 2021 Apr 29.

Department of Internal Medicine, SUNY at Buffalo School of Medicine, Buffalo, United States of America.

Patients with chronic kidney disease (CKD) and end stage renal disease suffer from increased cardiovascular events and cardiac mortality. Prior studies have demonstrated a portion of this enhanced risk can be attributed to the accumulation of microbiota-derived toxic metabolites, with most studies focusing on the sulfonated form of p-cresol (PCS). However, unconjugated p-cresol (uPC) itself was never assessed due to rapid and extensive first pass metabolism that results in negligible serum concentrations of uPC. These reports thus failed to consider the host exposure to uPC prior to hepatic metabolism. In the current study, we not only measured the impact of altering the intestinal microbiota on lipid accumulation in coronary arteries, but also examined macrophage lipid uptake and handling pathways in response to uPC. We found atherosclerotic-prone mice fed a high fat diet exhibited significantly higher coronary artery lipid deposits upon receiving fecal material from CKD mice. Furthermore, treatment with uPC increased total cholesterol, triglycerides, hepatic, and aortic fatty deposits in non-CKD mice. Studies employing an in vitro macrophage model demonstrated uPC exposure increased apoptosis where PCS did not. Additionally, uPC exhibited higher potency than PCS to stimulate low density lipoprotein (LDL) uptake and only uPC induced endocytosis and pinocytosis-related genes. Pharmacological inhibition of varying cholesterol influx and efflux systems indicated that uPC increased macrophage LDL uptake by activating macropinocytosis. Overall, these findings indicate uPC itself has a distinct impact on macrophage biology that may contribute to increased cardiovascular risk in patients with CKD.
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http://dx.doi.org/10.1172/jci.insight.144410DOI Listing
April 2021

Immunoglobulin G Is a Novel Substrate for the Endocytic Protein Megalin.

AAPS J 2021 03 7;23(2):40. Epub 2021 Mar 7.

Department of Pharmaceutical Sciences, School of Pharmacy and Pharmaceutical Sciences, University at Buffalo, 445 Pharmacy Building, Buffalo, New York, 14214-8033, USA.

Therapeutic immunoglobulin G (IgG) antibodies comprise the largest class of protein therapeutics. Several factors that influence their overall disposition have been well-characterized, including target-mediated mechanics and convective flow. What remains poorly defined is the potential for non-targeted entry into various tissues or cell types by means of uptake via cell surface receptors at those sites. Megalin and cubilin are large endocytic receptors whose cooperative function plays important physiological roles at the tissues in which they are expressed. One such example is the kidney, where loss of either results in significant declines in proximal tubule protein reabsorption. Due to their diverse ligand profile and broad tissue expression, megalin and cubilin represent potential candidates for receptor-mediated uptake of IgG into various epithelia. Therefore, the objective of the current work was to determine if IgG was a novel ligand of megalin and/or cubilin. Direct binding was measured for human IgG with both megalin and the cubilin/amnionless complex. Additional work focusing on the megalin-IgG interaction was then conducted to build upon these findings. Cell uptake studies using megalin ligands for competitive inhibition or proximal tubule cells stably transduced with megalin-targeted shRNA constructs supported a role for megalin in the endocytosis of human IgG. Furthermore, a pharmacokinetic study using transgenic mice with a kidney-specific mosaic knockout of megalin demonstrated increased urinary excretion of human IgG in megalin knockout mice when compared to wild-type controls. These findings indicate that megalin is capable of binding and internalizing IgG via a high affinity interaction.
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http://dx.doi.org/10.1208/s12248-021-00557-1DOI Listing
March 2021

Megalin-mediated albumin endocytosis in cultured murine mesangial cells.

Biochem Biophys Res Commun 2020 08 19;529(3):740-746. Epub 2020 Jul 19.

Department of Pharmaceutical Sciences, School of Pharmacy and Pharmaceutical Sciences, University at Buffalo, 303 Pharmacy Building, Buffalo, NY, 14214, USA. Electronic address:

Endocytosis by podocytes is gaining increased attention as a biologic means of removing large proteins such as serum albumin from the glomerular barrier. Some of this function has been attributed to the megalin/cubilin (Lrp2/Cubn) receptor complex and the albumin recycling protein FcRn (Fcgrt). However, whether other glomerular cells possess the potential to perform this same phenomenon or express these proteins remains uncharacterized. Mesangial cells are uniquely positioned in glomeruli and represent a cell type capable of performing several diverse functions. Here, the expression of megalin and FcRn in murine mesangial cells along with the megalin adaptor protein Dab-2 (Dab2) was shown for the first time. Cubilin mRNA expression was detected, but the absence of the cubilin partner amnionless (Amn) suggested that cubilin is minimally functional, if at all, in these cells. Mesangial cell endocytosis of albumin was characterized and shown to involve a receptor-mediated process. Albumin endocytosis was significantly impaired (p < 0.01) under inducible megalin knockdown conditions in stably transduced mesangial cells. The current work provides both the novel identification of megalin and FcRn in mesangial cells and the functional demonstration of megalin-mediated albumin endocytosis.
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http://dx.doi.org/10.1016/j.bbrc.2020.05.166DOI Listing
August 2020

The Presence and Location of Podocytes in Glomeruli as Affected by Diabetes Mellitus.

Proc SPIE Int Soc Opt Eng 2020 Feb 16;11320. Epub 2020 Mar 16.

Department of Pathology and Anatomical Sciences, University at Buffalo - The State University of New York.

The primary purpose of the kidney, specifically the glomerulus, is filtration. Filtration is accomplished through the glomerular filtration barrier, which consists of the fenestrated endothelium, glomerular basement membrane, and specialized epithelial cells called podocytes. In pathologic states, such as Diabetes Mellitus (DM) and diabetic kidney disease (DKD), variable glomerular conditions result in podocyte injury and depletion, followed by progressive glomerular injury and DKD progression. In this work we quantified glomerulus and podocyte structural changes in histopathology image data derived from a murine model of DM. Using a variety of image processing techniques, we studied changes in podocyte morphology and intra-glomerular distribution across healthy, mild DM, and DM glomeruli. Our feature analysis provided feature trends which we believe are reflective of DKD pathology; while glomerular area peaked in mild DM, average podocyte number and distance from the urinary pole continued to decrease and increase, respectively, throughout DM. Ultimately, this study aims to augment the set of quantifiable image biomarkers used for evaluation of DKD progression in digital pathology, as well as underscore the importance of engineering biologically-inspired image features.
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http://dx.doi.org/10.1117/12.2548904DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7194214PMC
February 2020

Computational Segmentation and Classification of Diabetic Glomerulosclerosis.

J Am Soc Nephrol 2019 10 5;30(10):1953-1967. Epub 2019 Sep 5.

Departments of Pathology and Anatomical Sciences,

Background: Pathologists use visual classification of glomerular lesions to assess samples from patients with diabetic nephropathy (DN). The results may vary among pathologists. Digital algorithms may reduce this variability and provide more consistent image structure interpretation.

Methods: We developed a digital pipeline to classify renal biopsies from patients with DN. We combined traditional image analysis with modern machine learning to efficiently capture important structures, minimize manual effort and supervision, and enforce biologic prior information onto our model. To computationally quantify glomerular structure despite its complexity, we simplified it to three components consisting of nuclei, capillary lumina and Bowman spaces; and Periodic Acid-Schiff positive structures. We detected glomerular boundaries and nuclei from whole slide images using convolutional neural networks, and the remaining glomerular structures using an unsupervised technique developed expressly for this purpose. We defined a set of digital features which quantify the structural progression of DN, and a recurrent network architecture which processes these features into a classification.

Results: Our digital classification agreed with a senior pathologist whose classifications were used as ground truth with moderate Cohen's kappa κ = 0.55 and 95% confidence interval [0.50, 0.60]. Two other renal pathologists agreed with the digital classification with κ = 0.68, 95% interval [0.50, 0.86] and κ = 0.48, 95% interval [0.32, 0.64]. Our results suggest computational approaches are comparable to human visual classification methods, and can offer improved precision in clinical decision workflows. We detected glomerular boundaries from whole slide images with 0.93±0.04 balanced accuracy, glomerular nuclei with 0.94 sensitivity and 0.93 specificity, and glomerular structural components with 0.95 sensitivity and 0.99 specificity.

Conclusions: Computationally derived, histologic image features hold significant diagnostic information that may augment clinical diagnostics.
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http://dx.doi.org/10.1681/ASN.2018121259DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6779352PMC
October 2019

An integrated iterative annotation technique for easing neural network training in medical image analysis.

Nat Mach Intell 2019 Feb 11;1(2):112-119. Epub 2019 Feb 11.

Department of Pathology & Anatomical Sciences, SUNY Buffalo, New York, NY, USA.

Neural networks promise to bring robust, quantitative analysis to medical fields. However, their adoption is limited by the technicalities of training these networks and the required volume and quality of human-generated annotations. To address this gap in the field of pathology, we have created an intuitive interface for data annotation and the display of neural network predictions within a commonly used digital pathology whole-slide viewer. This strategy used a 'human-in-the-loop' to reduce the annotation burden. We demonstrate that segmentation of human and mouse renal micro compartments is repeatedly improved when humans interact with automatically generated annotations throughout the training process. Finally, to show the adaptability of this technique to other medical imaging fields, we demonstrate its ability to iteratively segment human prostate glands from radiology imaging data.
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http://dx.doi.org/10.1038/s42256-019-0018-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6557463PMC
February 2019

The role of chronic kidney disease-associated dysbiosis in cardiovascular disease.

Exp Biol Med (Maywood) 2019 04 25;244(6):514-525. Epub 2019 Jan 25.

3 Department of Internal Medicine, Jacobs School of Medicine and Biomedical Sciences, University at Buffalo, Buffalo, NY 14203, USA.

Impact Statement: Negative alterations, or dysbiosis, in the intestinal microbial community balance in response to chronic kidney disease is emerging as a substantial and important factor in inducing and exacerbating multiple comorbid conditions. Patients with renal insufficiency experience a substantial increase in cardiovascular risk, and recent evidence is shedding light on the close interaction between microbiome dysbiosis and increased cardiovascular events in this population. Previous association and recent causality studies utilizing experimental animal models have enriched our understanding and confirmed the impact of microbial community imbalance on cardiac health in both the general population and in patients with renal impairment.
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http://dx.doi.org/10.1177/1535370219826526DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6547008PMC
April 2019

Fecal microbiota analysis of polycystic kidney disease patients according to renal function: A pilot study.

Exp Biol Med (Maywood) 2019 04 12;244(6):505-513. Epub 2018 Dec 12.

2 Department of Internal Medicine, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.

Impact Statement: The heterogeneity of the renal disease, therapeutic interventions, and the original cause of the renal failure, all directly affect the microbiota. We delineate in this report the direct effect of decreased renal function on the bacterial composition following stringent criteria to eliminate the possibilities of other confounding factors and dissect the direct effects of the uremic milieu. We analyzed the microbiome following three different approaches to further evaluate the effects of mild, moderate and advanced renal insufficiency on the microbiome. We also present here a detailed functional analysis of the projected altered pathways secondary to changes in the microbiome composition.
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http://dx.doi.org/10.1177/1535370218818175DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6547006PMC
April 2019

Increased megalin expression in early type 2 diabetes: role of insulin-signaling pathways.

Am J Physiol Renal Physiol 2018 11 27;315(5):F1191-F1207. Epub 2018 Jun 27.

Department of Pharmaceutical Sciences, School of Pharmacy and Pharmaceutical Sciences, University at Buffalo , New York.

The megalin/cubilin complex is responsible for the majority of serum protein reclamation in the proximal tubules. The current study examined if decreases in their renal expression, along with the albumin recycling protein neonatal Fc receptor (FcRn) could account for proteinuria/albuminuria in the Zucker diabetic fatty rat model of type 2 diabetes. Immunoblots of renal cortex samples obtained at worsening disease stages demonstrated no loss in megalin, cubilin, or FcRn, even when proteinuria was measured. Additionally, early diabetic rats exhibited significantly increased renal megalin expression when compared with controls (adjusted P < 0.01). Based on these results, the ability of insulin to increase megalin was examined in a clonal subpopulation of the opossum kidney proximal tubule cell line. Insulin treatments (24 h, 100 nM) under high glucose conditions significantly increased megalin protein ( P < 0.0001), mRNA ( P < 0.0001), and albumin endocytosis. The effect on megalin expression was prevented with inhibitors against key effectors of insulin intracellular signaling, phosphatidylinositide 3-kinase and Akt. Studies using rapamycin to inhibit the mechanistic target of rapamycin complex 1 (mTORC1) resulted in a loss of insulin-induced megalin expression. However, subsequent evaluation demonstrated these effects were independent of initial mTORC1 suppression. The presented results provide insight into the expression of megalin, cubilin, and FcRn in type 2 diabetes, which may be impacted by elevated insulin and glucose. Furthermore, proximal tubule endocytic activity in early diabetics may be enhanced, a process that could have a significant role in proteinuria-induced renal damage.
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http://dx.doi.org/10.1152/ajprenal.00210.2018DOI Listing
November 2018

Chronic kidney disease, uremic milieu, and its effects on gut bacterial microbiota dysbiosis.

Am J Physiol Renal Physiol 2018 09 25;315(3):F487-F502. Epub 2018 Apr 25.

Department of Internal Medicine, Jacobs School of Medicine and Biomedical Sciences, University at Buffalo , Buffalo, New York.

Several lines of evidence suggest that gut bacterial microbiota is altered in patients with chronic kidney disease (CKD), though the mechanism of which this dysbiosis takes place is not well understood. Recent studies delineated changes in gut microbiota in both CKD patients and experimental animal models using microarray chips. We present 16S ribosomal RNA gene sequencing of both stool pellets and small bowel contents of C57BL/6J mice that underwent a remnant kidney model and establish that changes in microbiota take place in the early gastrointestinal tract. Increased intestinal urea concentration has been hypothesized as a leading contributor to dysbiotic changes in CKD. We show that urea transporters (UT)-A and UT-B mRNA are both expressed throughout the whole gastrointestinal tract. The noted increase in intestinal urea concentration appears to be independent of UTs' expression. Urea supplementation in drinking water resulted in alteration in bacterial gut microbiota that is quite different than that seen in CKD. This indicates that increased intestinal urea concentration might not fully explain the CKD- associated dysbiosis.
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http://dx.doi.org/10.1152/ajprenal.00092.2018DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6172581PMC
September 2018

Lupus: The microbiome angle.

Immunobiology 2018 Jun - Jul;223(6-7):460-465. Epub 2017 Nov 16.

Department of Medicine, University at Buffalo, NY 14086, United States. Electronic address:

Microbiota consists of more than 10 microorganisms that inhabit different areas of the body including the gastrointestinal tract, mainly the mouth and gut. It includes viruses, fungi, protozoa, archaea and bacteria. The microbiota interacts closely with host leading to a dynamic relationship that results in the biological effects observed. Its diverse genetic material (microbiome) interacts closely with the host immune system and cells, and therefore is closely associated with inflammation, immune tolerance, adaptive immunity and autoimmune diseases. Bacterial microbiota, which is the mostly studied lives in harmony with the host and maintains a symbiotic relationship. Therefore it plays an important role in immunological, metabolic, and neurological aspects and thereby the well-being of the host. Alteration of the homeostatic environment or the dynamic balance of microorganisms can result in dysbiosis or disease. However, does dysbiosis cause disease, aggravate disease or is the result of the disease remains to be defined, it could be a bit of all three factors. More recently, a number of studies demonstrate that these microorganisms could contribute to disease. Alteration of the tightly balanced composition of bacterial microbiota (dysbiosis) leads to exacerbation, rapid progression and worsening of disease states. It is important to identify the 'healthy' microbes that maintain a healthy environment, the 'sensitive' microbes that go awry with disease, the 'bad' microbes that cause disease and the 'therapeutic' microbes that can help rectify the changes. Increased relative abundance of certain bacterial species has been linked to triggering autoimmune diseases. Despite the burgeoning literature in the field, the molecular mechanisms by which the microbiota impacts the body in health and disease remain largely unknown. In this review, we will discuss recent advancements in our understanding of the gut bacterial microbiota associated with inflammatory and immunological processes and the role they play in the autoimmune disease, systemic lupus erythematosus.
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http://dx.doi.org/10.1016/j.imbio.2017.11.004DOI Listing
April 2019

Multi-radial LBP Features as a Tool for Rapid Glomerular Detection and Assessment in Whole Slide Histopathology Images.

Sci Rep 2018 02 1;8(1):2032. Epub 2018 Feb 1.

Department of Pathology and Anatomical Sciences, University at Buffalo, Buffalo, USA.

We demonstrate a simple and effective automated method for the localization of glomeruli in large (~1 gigapixel) histopathological whole-slide images (WSIs) of thin renal tissue sections and biopsies, using an adaptation of the well-known local binary patterns (LBP) image feature vector to train a support vector machine (SVM) model. Our method offers high precision (>90%) and reasonable recall (>70%) for glomeruli from WSIs, is readily adaptable to glomeruli from multiple species, including mouse, rat, and human, and is robust to diverse slide staining methods. Using 5 Intel(R) Core(TM) i7-4790 CPUs with 40 GB RAM, our method typically requires ~15 sec for training and ~2 min to extract glomeruli reproducibly from a WSI. Deploying a deep convolutional neural network trained for glomerular recognition in tandem with the SVM suffices to reduce false positives to below 3%. We also apply our LBP-based descriptor to successfully detect pathologic changes in a mouse model of diabetic nephropathy. We envision potential clinical and laboratory applications for this approach in the study and diagnosis of glomerular disease, and as a means of greatly accelerating the construction of feature sets to fuel deep learning studies into tissue structure and pathology.
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http://dx.doi.org/10.1038/s41598-018-20453-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5795004PMC
February 2018

Analysis of OPTN/UNOS registry suggests the number of HLA matches and not mismatches is a stronger independent predictor of kidney transplant survival.

Kidney Int 2018 02 29;93(2):482-490. Epub 2017 Sep 29.

Division of Nephrology, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, New York, USA; Recanati-Miller Transplant Institutes, Icahn School of Medicine at Mount Sinai, New York, New York, USA. Electronic address:

HLA matching and mismatching, while inversely related, are not exact opposites. Here we determined the independent effects of HLA matching and mismatching on outcomes in deceased donor kidney transplant recipients. The United Network for Organ Sharing database (1995-2012) was utilized and analyzed for delayed graft function, one-year acute rejection, and death-censored graft survival using combined multivariable models including HLA matching and mismatching. Sensitivity analyses were performed using the subgroup of deceased donor kidney transplant patients after 2003 with more uniform HLA nomenclature and resampling analyses using bootstrapping on complete data available from 96,236 recipients. Individually, both HLA matching and mismatching showed significant associations with graft survival. Adjusting the model to take into account both matching and mismatching simultaneously, the degree of HLA mismatching lost significance while matching continued to have a significant prediction for delayed graft function, the one-year acute rejection rate, and graft survival. Sensitivity analyses and bootstrapping showed similar results for all studied outcomes. Thus, analysis of this large cohort demonstrates the apparent greater association of HLA matching over HLA mismatching on both early allograft events as well as graft survival. Future analyses should preferentially utilize HLA matching as a covariate over mismatching for accurately reflecting impact on graft outcomes.
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http://dx.doi.org/10.1016/j.kint.2017.07.016DOI Listing
February 2018

Advanced glycation end products dietary restriction effects on bacterial gut microbiota in peritoneal dialysis patients; a randomized open label controlled trial.

PLoS One 2017 20;12(9):e0184789. Epub 2017 Sep 20.

Department of Internal Medicine, Icahn School of Medicine at Mount Sinai, New York, New York, United States of America.

The modern Western diet is rich in advanced glycation end products (AGEs). We have previously shown an association between dietary AGEs and markers of inflammation and oxidative stress in a population of end stage renal disease (ESRD) patients undergoing peritoneal dialysis (PD). In the current pilot study we explored the effects of dietary AGEs on the gut bacterial microbiota composition in similar patients. AGEs play an important role in the development and progression of cardiovascular (CVD) disease. Plasma concentrations of different bacterial products have been shown to predict the risk of incident major adverse CVD events independently of traditional CVD risk factors, and experimental animal models indicates a possible role AGEs might have on the gut microbiota population. In this pilot randomized open label controlled trial, twenty PD patients habitually consuming a high AGE diet were recruited and randomized into either continuing the same diet (HAGE, n = 10) or a one-month dietary AGE restriction (LAGE, n = 10). Blood and stool samples were collected at baseline and after intervention. Variable regions V3-V4 of 16s rDNA were sequenced and taxa was identified on the phyla, genus, and species levels. Dietary AGE restriction resulted in a significant decrease in serum Nε-(carboxymethyl) lysine (CML) and methylglyoxal-derivatives (MG). At baseline, our total cohort exhibited a lower relative abundance of Bacteroides and Alistipes genus and a higher abundance of Prevotella genus when compared to the published data of healthy population. Dietary AGE restriction altered the bacterial gut microbiota with a significant reduction in Prevotella copri and Bifidobacterium animalis relative abundance and increased Alistipes indistinctus, Clostridium citroniae, Clostridium hathewayi, and Ruminococcus gauvreauii relative abundance. We show in this pilot study significant microbiota differences in peritoneal dialysis patients' population, as well as the effects of dietary AGEs on gut microbiota, which might play a role in the increased cardiovascular events in this population and warrants further studies.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0184789PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5607175PMC
October 2017

Reduction in podocyte SIRT1 accelerates kidney injury in aging mice.

Am J Physiol Renal Physiol 2017 09 14;313(3):F621-F628. Epub 2017 Jun 14.

Division of Nephrology, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, New York.

Both the incidence and prevalence of chronic kidney disease are increasing in the elderly population. Although aging is known to induce kidney injury, the underlying molecular mechanisms remain unclear. Sirtuin 1 (Sirt1), a longevity gene, is known to protect kidney cell injury from various cellular stresses. In previous studies, we showed that the podocyte-specific loss of Sirt1 aggravates diabetic kidney injury. However, the role of Sirt1 in aging-induced podocyte injury is not known. Therefore, in this study we sought to determine the effects of podocyte-specific reduction of Sirt1 in age-induced kidney injury. We employed the inducible podocyte-specific Sirt1 knockdown mice that express shRNA against Sirt1 (Pod-Sirt1) and control mice that express shRNA for luciferase (Pod-Luci). We found that reduction of podocyte Sirt1 led to aggravated aging-induced glomerulosclerosis and albuminuria. In addition, urinary level of 8-hydroxy-2'-deoxyguanosine (8-OHdG), a marker of oxidative stress, was markedly increased in aged Pod-Sirt1 mice compared with aged Pod-Luci mice. Although podocyte-specific markers decreased in aged mice compared with the young controls, the decrease was further exacerbated in aged Pod-Sirt1 compared with Pod-Luci mice. Interestingly, expression of cellular senescence markers was significantly higher in the glomeruli of Pod-Sirt1 mice than Pod-Luci mice, suggesting that cellular senescence may contribute to podocyte loss in aging kidneys. Finally, we confirmed that Pod-Sirt1 glomeruli were associated with reduced activation of the transcription factors peroxisome proliferator-activated receptor (PPAR)-α coactivador-1 (PGC1α)/PPARγ, forkhead box O (FOXO)3, FOXO4, and p65 NF-κB, through SIRT1-mediated deacetylation. Together, our data suggest that SIRT1 may be a potential therapeutic target to treat patients with aging-related kidney disease.
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http://dx.doi.org/10.1152/ajprenal.00255.2017DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5625108PMC
September 2017

Unsupervised labeling of glomerular boundaries using Gabor filters and statistical testing in renal histology.

J Med Imaging (Bellingham) 2017 Apr 28;4(2):021102. Epub 2017 Feb 28.

University at Buffalo-The State University of New York, Departments of Pathology and Anatomical Sciences, 207 Farber Hall, 3435 Main Street Buffalo, New York 14214, United States; University at Buffalo-The State University of New York, Departments of Biomedical Engineering, 207 Farber Hall, 3435 Main Street Buffalo, New York 14214, United States; University at Buffalo-The State University of New York, Departments of Biostatistics, 207 Farber Hall, 3435 Main Street Buffalo, New York 14214, United States.

The glomerulus is the blood filtering unit of the kidney. Each human kidney contains [Formula: see text] glomeruli. Several renal conditions originate from structural damage to glomerular microcompartments, such as proteinuria, the excessive loss of blood proteins into urine. The gold standard for evaluating structural damage in renal pathology is histopathological and immunofluorescence examination of needle biopsies under a light microscope. This method is limited by qualitative or semiquantitative manual scoring approaches to the evaluation of glomerular structural features. Computational quantification of equivalent features promises to improve the precision of glomerular structural analysis. One large obstacle to the computational quantification of renal tissue is the identification of complex glomerular boundaries automatically. To mitigate this issue, we developed a computational pipeline capable of extracting and exactly defining glomerular boundaries. Our method, composed of Gabor filtering, Gaussian blurring, statistical [Formula: see text]-testing, and distance transform, is able to accurately identify glomerular boundaries with mean sensitivity/specificity of [Formula: see text] and accuracy of 0.92, on [Formula: see text] glomeruli images stained with standard renal histological stains. Our method will simplify computational partitioning of glomerular microcompartments hidden within dense textural boundaries. Automatic quantification of glomeruli will streamline structural analysis in clinic and can pioneer real-time diagnoses and interventions for renal care.
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http://dx.doi.org/10.1117/1.JMI.4.2.021102DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5331029PMC
April 2017

Manipulating the gut microbiome to decrease uremic toxins.

Kidney Int 2017 03;91(3):521-523

Department of Medicine, Division of Nephrology, Icahn School of Medicine at Mount Sinai, New York, New York, USA. Electronic address:

The uremic solute indoxyl sulfate has been associated with increased mortality and other adverse outcomes in patients with chronic kidney disease. In a recent study published in Cell Host & Microbe, Devlin et al. describe a novel approach to alter the production of indoxyl sulfate through manipulation of the gut microbiota. Although this approach is far from clinical application, it may allow investigators to determine the contribution of uremic solutes to disease pathogenesis.
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http://dx.doi.org/10.1016/j.kint.2017.01.003DOI Listing
March 2017

Krüppel-Like Factor 15 Mediates Glucocorticoid-Induced Restoration of Podocyte Differentiation Markers.

J Am Soc Nephrol 2017 Jan 10;28(1):166-184. Epub 2016 Jun 10.

Department of Pharmacology and Systems Therapeutics and.

Podocyte injury is the inciting event in primary glomerulopathies, such as minimal change disease and primary FSGS, and glucocorticoids remain the initial and often, the primary treatment of choice for these glomerulopathies. Because inflammation is not readily apparent in these diseases, understanding the direct effects of glucocorticoids on the podocyte, independent of the immunomodulatory effects, may lead to the identification of targets downstream of glucocorticoids that minimize toxicity without compromising efficacy. Several studies showed that treatment with glucocorticoids restores podocyte differentiation markers and normal ultrastructure and improves cell survival in murine podocytes. We previously determined that Krüppel-like factor 15 (KLF15), a kidney-enriched zinc finger transcription factor, is required for restoring podocyte differentiation markers in mice and human podocytes under cell stress. Here, we show that in vitro treatment with dexamethasone induced a rapid increase of KLF15 expression in human and murine podocytes and enhanced the affinity of glucocorticoid receptor binding to the promoter region of KLF15 In three independent proteinuric murine models, podocyte-specific loss of Klf15 abrogated dexamethasone-induced podocyte recovery. Furthermore, knockdown of KLF15 reduced cell survival and destabilized the actin cytoskeleton in differentiated human podocytes. Conversely, overexpression of KLF15 stabilized the actin cytoskeleton under cell stress in human podocytes. Finally, the level of KLF15 expression in the podocytes and glomeruli from human biopsy specimens correlated with glucocorticoid responsiveness in 35 patients with minimal change disease or primary FSGS. Thus, these studies identify the critical role of KLF15 in mediating the salutary effects of glucocorticoids in the podocyte.
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http://dx.doi.org/10.1681/ASN.2015060672DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5198263PMC
January 2017

A Nationwide Analysis of Outcomes of Weekend Admissions for Intracerebral Hemorrhage Shows Disparities Based on Hospital Teaching Status.

Neurohospitalist 2016 Apr 3;6(2):51-8. Epub 2015 Sep 3.

Division of Nephrology, Department of Internal Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, USA.

Background And Purpose: With the "weekend effect" being well described, the Brain Attack Coalition released a set of "best practice" guidelines in 2005, with the goal to uniformly provide standard of care to patients with stroke. We attempted to define a "weekend effect" in outcomes among patients with intracranial hemorrhage (ICH) over the last decade, utilizing the Nationwide Inpatient Sample (NIS) data. We also attempted to analyze the trend of such an effect.

Materials And Methods: We determined the association of ICH weekend admissions with hospital outcomes including mortality, adverse discharge, length of stay, and cost compared to weekday admissions using multivariable logistic regression. We extracted our study cohort from the NIS, the largest all-payer data set in the United States.

Results: Of 485 329 ICH admissions from 2002 to 2011, 27.5% were weekend admissions. Overall, weekend admissions were associated with 11% higher odds of in-hospital mortality. When analyzed in 3-year groups, excess mortality of weekend admissions showed temporal decline. There was higher mortality with weekend admissions in nonteaching hospitals persisted (odds ratios 1.16, 1.13, and 1.09, respectively, for 3-year subgroups). Patients admitted during weekends were also 9% more likely to have an adverse discharge (odds ratio 1.09; 95% confidence interval: 1.07-1.11; P < .001) with no variation by hospital status. There was no effect of a weekend admission on either length of stay or cost of care.

Conclusion: Nontraumatic ICH admissions on weekends have higher in-hospital mortality and adverse discharge. This demonstrates need for in-depth review for elucidating this discrepancy and stricter adherence to standard-of-care guidelines to ensure uniform care.
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http://dx.doi.org/10.1177/1941874415601164DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4802773PMC
April 2016

National trends of acute kidney injury requiring dialysis in decompensated cirrhosis hospitalizations in the United States.

Hepatol Int 2016 May 29;10(3):525-31. Epub 2016 Jan 29.

Division of Nephrology, Department of Medicine, Icahn School of Medicine at Mount Sinai, One Gustave L Levy Place, Box 1243, New York, NY, 10029, USA.

Background And Aims: Cirrhosis affects 5.5 million patients with estimated costs of US$4 billion. Previous studies about dialysis requiring acute kidney injury (AKI-D) in decompensated cirrhosis (DC) are from a single center/year. We aimed to describe national trends of incidence and impact of AKI-D in DC hospitalizations.

Methods: We extracted our cohort from the Nationwide Inpatient Sample (NIS) from 2006-2012. We identified hospitalizations with DC and AKI-D by validated ICD9 codes. We analyzed temporal changes in DC hospitalizations complicated by AKI-D and utilized multivariable logistic regression models to estimate AKI-D impact on hospital mortality.

Results: We identified a total of 3,655,700 adult DC hospitalizations from 2006 to 2012 of which 78,015 (2.1 %) had AKI-D. The proportion with AKI-D increased from 1.5 % in 2006 to 2.23 % in 2012; it was stable between 2009 and 2012 despite an increase in absolute numbers from 6773 to 13,930. The overall hospital mortality was significantly higher in hospitalizations with AKI-D versus those without (40.87 vs. 6.96 %; p < 0.001). In an adjusted multivariable analysis, adjusted odds ratio for mortality was 2.17 (95 % CI 2.06-2.28; p < 0.01) with AKI-D, which was stable from 2006 to 2012. Changes in demographics and increases in acute/chronic comorbidities and procedures explained temporal changes in AKI-D.

Conclusions: Proportion of DC hospitalizations with AKI-D increased from 2006 to 2009, and although this was stable from 2009 to 2012, there was an increase in absolute cases. These results elucidate the burden of AKI-D on DC hospitalizations and excess associated mortality, as well as highlight the importance of prevention, early diagnosis and testing of novel interventions in this vulnerable population.
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http://dx.doi.org/10.1007/s12072-016-9706-9DOI Listing
May 2016

Association between probiotic and yogurt consumption and kidney disease: insights from NHANES.

Nutr J 2016 Jan 27;15:10. Epub 2016 Jan 27.

Department of Medicine, Division of Nephrology, Icahn School of Medicine at Mount Sinai, New York, NY, USA.

Background: Data from experimental animals suggest that probiotic supplements may retard CKD progression. However, the relationship between probiotic use, frequent yogurt consumption (as a natural probiotic source), and kidney parameters have not been evaluated in humans.

Findings: We utilized NHANES data, and analyzed the association of probiotic alone (1999-2012) and yogurt/probiotic (2003-2006) use with albuminuria and eGFR after adjustment for demographic and clinical parameters. Frequent yogurt consumption was defined as thrice or more weekly over the year prior to the interview. Frequent yogurt/probiotic consumers had lower adjusted odds of developing combined outcome (albuminuria and/or eGFR < 60 ml/min/1.73 m(2)) compared to infrequent consumers (OR = 0.76; 95 % CI = 0.61-0.94). When evaluated separately, frequent consumers had lower odds of albuminuria and nonsignificant trend towards decreased odds of low eGFR compared to infrequent consumers. In the probiotic cohort, probiotic consumers were found to have a lower adjusted odds of albuminuria compared to nonusers (OR = 0.59; 95 % CI = 0.37-0.94).

Conclusion: Frequent yogurt and/or probiotics use is associated with decreased odds of proteinuric kidney disease. These hypothesis-generating results warrant further translational studies to further delineate the relationship between yogurt/probiotics with kidney dysfunction, as well as microbiome and dysbiosis as potential mediators.
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http://dx.doi.org/10.1186/s12937-016-0127-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4728789PMC
January 2016

Elevations in Serum Creatinine With Tenofovir-Based HIV Pre-Exposure Prophylaxis: A Meta-Analysis of Randomized Placebo-Controlled Trials.

J Acquir Immune Defic Syndr 2016 Apr;71(4):e115-8

*Division of Nephrology, Department of Medicine, University at Buffalo, Buffalo, NY †Division of Nephrology, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY ‡Department of Epidemiology of Microbial Diseases, Yale School of Public Health, New Haven, CT §Department of Nephrology-Transplantation-Dialysis, Bordeaux Hospital, Bordeaux, France ‖Gladstone Institutes, University of California, San Francisco and the San Francisco AIDS Foundation, San Francisco, CA ¶Department of Epidemiology, University of Washington, Seattle, WA #Departments of Global Health, Medicine, and Epidemiology, University of Washington, Seattle, WA.

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http://dx.doi.org/10.1097/QAI.0000000000000906DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4767606PMC
April 2016

Representation of Patients With Kidney Disease in Trials of Cardiovascular Interventions: An Updated Systematic Review.

JAMA Intern Med 2016 Jan;176(1):121-4

Division of Nephrology, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, New York.

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http://dx.doi.org/10.1001/jamainternmed.2015.6102DOI Listing
January 2016

Systematic oral hydration with water is similar to parenteral hydration for prevention of contrast-induced nephropathy: an updated meta-analysis of randomised clinical data.

Open Heart 2015;2(1):e000317. Epub 2015 Oct 5.

Division of Cardiology, Department of Internal Medicine , Ochsner Clinic Foundation , New Orleans, Louisiana , USA.

Background: Contrast-induced nephropathy (CIN) is the third most common cause of hospital-acquired kidney injury and is related to increased long-term morbidity and mortality. Adequate intravenous (IV) hydration has been demonstrated to lessen its occurrence. Oral (PO) hydration with water is inexpensive and readily available but its role for CIN prevention is yet to be determined.

Methods: PubMed, EMBASE and the Cochrane Central register of controlled trials (CENTRAL) databases were searched until April 2015 and studies were selected using the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) checklist. All randomised clinical trials with head-to-head comparison between PO and IV hydration were included.

Results: A total of 5 studies with 477 patients were included in the analysis, 255 of those receiving PO water. The incidence of CIN was statistically similar in the IV and PO arms (7.7% and 8.2%, respectively; relative risk 0.97; 95% CI 0.36 to 2.94; p=0.95). The incidence of CIN was statistically similar in the IV and PO arms in patients with chronic kidney disease and with normal renal function. Rise in creatinine at 48-72 h was lower in the PO hydration group compared with IV hydration (pooled standard mean difference 0.04; 95% CI 0.03 to 0.06; p<0.001; I(2)=62%).

Conclusions: Our meta-analysis shows that systematic PO hydration with water is at least as effective as IV hydration with saline to prevent CIN. PO hydration is cheaper and more easily administered than IV hydration, thus making it more attractive and just as effective.
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http://dx.doi.org/10.1136/openhrt-2015-000317DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4600249PMC
October 2015

The burden of dialysis-requiring acute kidney injury among hospitalized adults with HIV infection: a nationwide inpatient sample analysis.

AIDS 2015 Jun;29(9):1061-6

aDivision of Nephrology, Department of Medicine bDepartment of Public Health, Icahn School of Medicine at Mount Sinai, New York, New York cDivision of Cardiology, Department of Medicine, Oschner Medical Center, New Orleans, Los Angeles dDivision of Rheumatology, Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee eDivision of Cardiology, Department of Medicine, University of Arkansas Medical Sciences, Little Rock, Arkansas fDepartment of Medicine, St Luke's Roosevelt Hospital Center at Mount Sinai, New York gDivision of Critical Care, Department of Medicine, Bronx Lebanon Hospital Center, Bronx, New York, USA. *Girish N. Nadkarni and Achint A. Patel equally contributed to the article.

Objective: The objective of this study was to describe the incidence of acute kidney injury (AKI) requiring renal replacement therapy ('dialysis-requiring AKI') and the impact on in-hospital mortality among hospitalized adults with HIV infection.

Design: A longitudinal analysis of a nationally representative administrative database.

Methods: We reviewed the Healthcare Cost and Utilization Project's Nationwide Inpatient Sample Database, a large, nationally representative sample of inpatient hospital admissions, to identify all adult hospitalizations with an associated diagnosis of HIV infection from 2002 to 2010. We analysed temporal trends in the incidence of dialysis-requiring AKI and the associated odds of in-hospital mortality. We also explored potential reasons behind temporal changes.

Results: Among 183 0041 hospitalizations with an associated diagnosis of HIV infection, the proportion complicated by dialysis-requiring AKI increased from 0.7% in 2002 to 1.35% in 2010. This temporal rise was completely explained by changes in demographics and an increase in concurrent comorbidities and procedure utilization. The adjusted odds of in-hospital mortality associated with dialysis-requiring AKI also increased over the study period, from 1.45 [95% confidence interval (95% CI) 0.97-2.12] in 2002 to 2.64 (95% CI 2.04-3.42) in 2010.

Conclusion: These data suggest that the incidence of dialysis-requiring AKI among hospitalized adults with HIV infection continues to increase, and that severe AKI remains a significant predictor of in-hospital mortality in this population. The increased incidence of dialysis-requiring AKI was largely explained by ageing of the HIV population and increasing prevalence of chronic non-AIDS comorbidities, suggesting that these trends will continue.
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http://dx.doi.org/10.1097/QAD.0000000000000653DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4489559PMC
June 2015

Comparison of Cutting Balloon Angioplasty and Percutaneous Balloon Angioplasty of Arteriovenous Fistula Stenosis: A Meta-Analysis and Systematic Review of Randomized Clinical Trials.

J Interv Cardiol 2015 Jun 20;28(3):288-95. Epub 2015 May 20.

Department of Internal Medicine, Division of Cardiology, Ochsner Clinic Foundation, New Orleans, Louisiana.

Background: Hemodialysis (HD) access failure is a common cause of increased morbidity and healthcare cost in patients with end stage renal disease (ESRD). Percutaneous balloon angioplasty has been used to treat hemodialysis access stenosis but is complicated by a high rate of restenosis. Percutaneous cutting balloon (PCB) angioplasty is an alternative approach that has shown to reduce restenosis.

Objectives: The aim of the study is to assess the safety and efficacy of PCB angioplasty in comparison with conventional and high-pressure balloon angioplasty in the treatment of hemodialysis access site stenosis.

Methods: We searched PubMed, EMBASE and the Cochrane Central register of controlled trials (CENTRAL) databases through August 2014 and selected studies using the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) checklist. We included all randomized clinical trials with a head-to-head comparison between PCB and conventional or high-pressure balloon angioplasty

Results: Three studies with 1034 participants (age 60.7 (±12.9) years and 50.1% males) with 525 in PCB and 509 in control arm were included in the analysis. The immediate procedural success rate was not significantly different in the PCB angioplasty and control arm respectively, (87.2% vs. 83.7% RD -0.02; 95%CI -0.06 to 0.01; P = 0.38). The six-month target lesion patency was significantly higher in the PCB angioplasty arm (67.2% vs. 55.6% RD 0.12; 95%CI 0.05-0.19; P < 0.05) with number needed to treat (NNT) of 9. The device related complications were not statistically significant between groups (RD 0.03; 95%CI -0.02 to 0.07; P = 0.26).

Conclusions: PCB angioplasty is effective in treatment of hemodialysis access stenosis, with significantly higher six-month patency compared to balloon angioplasty.
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http://dx.doi.org/10.1111/joic.12202DOI Listing
June 2015

Update on glycemic control for the treatment of diabetic kidney disease.

Curr Diab Rep 2015 Jul;15(7):42

Division of Nephrology, Department of Medicine, Icahn School of Medicine at Mount Sinai, One Gustave L Levy Place, Box 1243, New York, NY, 10029, USA,

Diabetic kidney disease (DKD) is a common, complex condition that has become a significant public health problem. The beneficial effects of intensive glycemic control in type 1 diabetes mellitus on development of DKD are proven; however, the evidence for nephroprotection in patients with type 2 diabetes is conflicting. Moreover, a strategy of intensive glycemic control increases the risk for adverse effects (hypoglycemic episodes) with no obvious impact on macrovascular events or mortality in recent large randomized controlled trials. The risk for hypoglycemia with intensive therapy is heightened in patients with significant renal dysfunction, due to decreased renal clearance of insulin. Establishing an ideal level of glycemic control in patients requires an individualized approach taking into account duration of diabetes and presence of coexisting comorbidities and pre-existing DKD. In this article, we review the available evidence from both observational studies and randomized controlled trials and provide suggestions about evaluating the potential benefits and harm from intensive glycemic control in patients. We also discuss how in the future, a personalized approach using biomarkers might help identify patients most likely to respond as well as those most susceptible to harm. We believe that using the optimal level of glycemic control in diabetic patients using a multi-pronged strategy will improve individual patient outcomes and decrease the overall burden of morbidity and mortality.
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http://dx.doi.org/10.1007/s11892-015-0612-7DOI Listing
July 2015

Inhibition of RAS in diabetic nephropathy.

Int J Nephrol Renovasc Dis 2015 15;8:29-40. Epub 2015 Apr 15.

Department of Medicine, Division of Nephrology, Icahn School of Medicine at Mount Sinai, New York, NY, USA.

Diabetic kidney disease (DKD) is a progressive proteinuric renal disorder in patients with type 1 or type 2 diabetes mellitus. It is a common cause of end-stage kidney disease worldwide, particularly in developed countries. Therapeutic targeting of the renin-angiotensin system (RAS) is the most validated clinical strategy for slowing disease progression. DKD is paradoxically a low systematic renin state with an increased intrarenal RAS activity implicated in its pathogenesis. Angiotensin II (AngII), the main peptide of RAS, is not only a vasoactive peptide but functions as a growth factor, activating interstitial fibroblasts and mesangial and tubular cells, while promoting the synthesis of extracellular matrix proteins. AngII also promotes podocyte injury through increased calcium influx and the generation of reactive oxygen species. Blockade of the RAS using either angiotensin converting enzyme inhibitors, or angiotensin receptor blockers can attenuate progressive glomerulosclerosis in animal models, and slows disease progression in humans with DKD. In this review, we summarize the role of intrarenal RAS activation in the pathogenesis and progression of DKD and the rationale for RAS inhibition in this population.
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http://dx.doi.org/10.2147/IJNRD.S37893DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4403683PMC
April 2015

Trimetazidine Decreases Risk of Contrast-Induced Nephropathy in Patients With Chronic Kidney Disease: A Meta-Analysis of Randomized Controlled Trials.

J Cardiovasc Pharmacol Ther 2015 Nov 24;20(6):539-46. Epub 2015 Feb 24.

Division of Cardiology, Department of Medicine, Ochsner Clinic Foundation, Jefferson, LA, USA.

Objectives: We sought to synthesize and analyze the available data from randomized controlled trials (RCTs) for trimetazidine (TMZ) in the prevention of contrast-induced nephropathy (CIN).

Background: Contrast-induced nephropathy after coronary angiography is associated with poor outcomes. Trimetazidine is an anti-ischemic drug that might reduce incidence of CIN, but current data are inconclusive.

Methods: We searched MEDLINE/PubMed, EMBASE, Scopus, Cochrane Library, Web of Science, and ScienceDirect electronic databases for RCTs comparing intravenous hydration with normal saline (NS) and/or N-acetyl cysteine (NAC) versus TMZ plus NS ± NAC for prevention of CIN. We used RevMan 5.2 for statistical analysis with the fixed effects model.

Results: Of the 808 studies, 3 RCTs met criteria with 290 patients in the TMZ plus NS ± NAC group and 292 patients in the NS ± NAC group. The mean age of patients was 59.5 years, and baseline serum creatinine ranged from 1.3 to 2 mg/dL. Trimetazidine significantly reduced the incidence of CIN by 11% (risk difference 0.11; 95% confidence interval, 0.16-0.06; P < .01). There was no significant heterogeneity between the studies (I(2) statistic = 0). The number needed to treat to prevent 1 episode of CIN was 9.

Conclusions: The addition of TMZ to NS ± NAC significantly decreased the incidence of CIN in patients undergoing coronary angiography. In conclusion, TMZ could be considered as a potential tool for prevention of CIN in patients with renal dysfunction.
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http://dx.doi.org/10.1177/1074248415573320DOI Listing
November 2015

Nephrin Preserves Podocyte Viability and Glomerular Structure and Function in Adult Kidneys.

J Am Soc Nephrol 2015 Oct 2;26(10):2361-77. Epub 2015 Feb 2.

Department of Medicine/Nephrology, Icahn School of Medicine at Mount Sinai, New York, New York; Renal Section, James J Peter Veterans Administration Medical Center, Bronx, New York.

Nephrin is required during kidney development for the maturation of podocytes and formation of the slit diaphragm junctional complex. Because nephrin expression is downregulated in acquired glomerular diseases, nephrin deficiency is considered a pathologic feature of glomerular injury. However, whether nephrin deficiency exacerbates glomerular injury in glomerular diseases has not been experimentally confirmed. Here, we generated mice with inducible RNA interference-mediated nephrin knockdown. Short-term nephrin knockdown (6 weeks), starting after the completion of kidney development at 5 weeks of age, did not affect glomerular structure or function. In contrast, mice with long-term nephrin knockdown (20 weeks) developed mild proteinuria, foot process effacement, filtration slit narrowing, mesangial hypercellularity and sclerosis, glomerular basement membrane thickening, subendothelial zone widening, and podocyte apoptosis. When subjected to an acquired glomerular insult induced by unilateral nephrectomy or doxorubicin, mice with short-term nephrin knockdown developed more severe glomerular injury compared with mice without nephrin knockdown. Additionally, nephrin-knockdown mice developed more exaggerated glomerular enlargement when subjected to unilateral nephrectomy and more podocyte apoptosis and depletion after doxorubicin challenge. AKT phosphorylation, which is a slit diaphragm-mediated and nephrin-dependent pathway in the podocyte, was markedly reduced in mice with long-term or short-term nephrin knockdown challenged with uninephrectomy or doxorubicin. Taken together, our data establish that under the basal condition and in acquired glomerular diseases, nephrin is required to maintain slit diaphragm integrity and slit diaphragm-mediated signaling to preserve glomerular function and podocyte viability in adult mice.
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http://dx.doi.org/10.1681/ASN.2014040405DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4587684PMC
October 2015