Publications by authors named "Sandeep K Mallipattu"

39 Publications

The National COVID Cohort Collaborative: Clinical Characterization and Early Severity Prediction.

medRxiv 2021 Jan 13. Epub 2021 Jan 13.

Background: The majority of U.S. reports of COVID-19 clinical characteristics, disease course, and treatments are from single health systems or focused on one domain. Here we report the creation of the National COVID Cohort Collaborative (N3C), a centralized, harmonized, high-granularity electronic health record repository that is the largest, most representative U.S. cohort of COVID-19 cases and controls to date. This multi-center dataset supports robust evidence-based development of predictive and diagnostic tools and informs critical care and policy.

Methods And Findings: In a retrospective cohort study of 1,926,526 patients from 34 medical centers nationwide, we stratified patients using a World Health Organization COVID-19 severity scale and demographics; we then evaluated differences between groups over time using multivariable logistic regression. We established vital signs and laboratory values among COVID-19 patients with different severities, providing the foundation for predictive analytics. The cohort included 174,568 adults with severe acute respiratory syndrome associated with SARS-CoV-2 (PCR >99% or antigen <1%) as well as 1,133,848 adult patients that served as lab-negative controls. Among 32,472 hospitalized patients, mortality was 11.6% overall and decreased from 16.4% in March/April 2020 to 8.6% in September/October 2020 (p = 0.002 monthly trend). In a multivariable logistic regression model, age, male sex, liver disease, dementia, African-American and Asian race, and obesity were independently associated with higher clinical severity. To demonstrate the utility of the N3C cohort for analytics, we used machine learning (ML) to predict clinical severity and risk factors over time. Using 64 inputs available on the first hospital day, we predicted a severe clinical course (death, discharge to hospice, invasive ventilation, or extracorporeal membrane oxygenation) using random forest and XGBoost models (AUROC 0.86 and 0.87 respectively) that were stable over time. The most powerful predictors in these models are patient age and widely available vital sign and laboratory values. The established expected trajectories for many vital signs and laboratory values among patients with different clinical severities validates observations from smaller studies, and provides comprehensive insight into COVID-19 characterization in U.S. patients.

Conclusions: This is the first description of an ongoing longitudinal observational study of patients seen in diverse clinical settings and geographical regions and is the largest COVID-19 cohort in the United States. Such data are the foundation for ML models that can be the basis for generalizable clinical decision support tools. The N3C Data Enclave is unique in providing transparent, reproducible, easily shared, versioned, and fully auditable data and analytic provenance for national-scale patient-level EHR data. The N3C is built for intensive ML analyses by academic, industry, and citizen scientists internationally. Many observational correlations can inform trial designs and care guidelines for this new disease.
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http://dx.doi.org/10.1101/2021.01.12.21249511DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7814838PMC
January 2021

Safety, tolerability, and outcomes of losartan use in patients hospitalized with SARS-CoV-2 infection: A feasibility study.

PLoS One 2020 30;15(12):e0244708. Epub 2020 Dec 30.

Department of Medicine, Stony Brook University, Stony Brook, NY, United States of America.

Background: Retrospective studies on the use of Renin-Angiotensin-Aldosterone System blockade in patients with Coronavirus Disease 2019 (COVID-19) have been informative but conflicting, and prospective studies are required to demonstrate the safety, tolerability, and outcomes of initiating these agents in hospitalized patients with COVID-19 and hypertension.

Methods And Findings: This is a single center feasibility study encompassing two cohorts: (1) prospective cohort (April 21, 2020 to May 29, 2020) and (2) retrospective cohort (March 7, 2020 to April 1, 2020) of hospitalized patients with real-time polymerase chain reaction (PCR) positive SARS-CoV-2 by nasopharyngeal swab. Key inclusion criteria include BP > 130/80 and a requirement of supplemental oxygen with FiO2 of 25% or higher to maintain SpO2 > 92%. Key exclusion criteria included hyperkalemia and acute kidney injury (AKI) at the time of enrollment. Prospective cohort consisted of de novo initiation of losartan and continuation for a minimum of 7 days and assessed for adverse events (AKI, hyperkalemia, transaminitis, hypotension) and clinical outcomes (change in SpO2/FiO2 and inflammatory markers, need for ICU admission and mechanical ventilation). Retrospective cohort consisted of continuation of losartan (prior-to-hospitalization) and assessment of similar outcomes. In the prospective cohort, a total of 250 hospitalized patients were screened and inclusion/exclusion criteria were met in 16/250 patients and in the retrospective cohort, a total of 317 hospitalized patients were screened and inclusion/exclusion criteria were met in 14/317 patients. Most common adverse event was hypotension, leading to discontinuation in 3/16 (19%) and 2/14 (14%) patients in the prospective and retrospective cohort. No patients developed AKI in the prospective cohort as compared to 1/14 (7%) patients in the retrospective cohort, requiring discontinuation of losartan. Hyperkalemia occurred in 1/16 (6%) and 0/14 patients in the prospective and retrospective cohorts, respectively. In the prospective cohort, 3/16 (19%) and 2/16 (13%) patients required ICU admission and mechanical ventilation. In comparison, 3/14 (21%) required ICU admission and mechanical ventilation in the retrospective cohort. A majority of patients in both cohorts (14/16 (88%) and 13/14 (93%) patients from the prospective and retrospective cohort) were discharged alive from the hospital. A total of 9/16 (prospective) and 5/14 (retrospective) patients completed a minimum 7 days of losartan. In these 9 patients in the prospective cohort, a significant improvement in SpO2/FiO2 ratio was observed from day 1 to 7. No significant changes in inflammatory markers (initiation, peak, and day 7) were observed in either cohort.

Conclusion: In this pilot study we demonstrate that losartan was well-tolerated among hospitalized patients with COVID-19 and hypertension. We also demonstrate the feasibility of patient recruitment and the appropriate parameters to assess the outcomes and safety of losartan initiation or continuation, which provides a framework for future randomized clinical trials.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0244708PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7773257PMC
January 2021

Outcomes Associated with the Use of Renin-Angiotensin-Aldosterone System Blockade in Hospitalized Patients with SARS-CoV-2 Infection.

Kidney360 2020 Aug 27;1(8):801-809. Epub 2020 Aug 27.

Department of Medicine, Stony Brook University, Stony Brook, NY.

Background: Data regarding the benefits or harm associated with the continuation of Angiotensin Converting Enzyme Inhibitors (ACEIs) and Angiotensin II Receptor Blockers (ARBs), especially the impact on inflammation, in hypertensive, hospitalized patients with COVID-19 in the United States is unclear.

Methods: This is a single-center cohort study of sequentially hospitalized patients with COVID-19 at Stony Brook University Medical Center from March 7, 2020 to April 1, 2020, inclusive of these dates. Data collection included history of known comorbidities, medications, vital signs and laboratory values (admission and during the hospitalization). Outcomes include inflammatory burden (composite scores for multiple markers of inflammation), acute kidney injury (AKI), admission to the intensive care unit (ICU), need for invasive mechanical ventilation, and mortality.

Results: Of the 300 patients in the study cohort, 80 patients (26.7%) had history of ACEI or ARB use prior to admission, with 61.3% (49/80) of these patients continuing the medications during hospitalization. Multivariable analysis revealed that the history of ACEI or ARB use prior to hospitalization was not associated with worse outcomes. In addition, the continuation of these agents during hospitalization was not associated with an increase in adverse outcomes and predicted fewer ICU admissions (OR=0.25, 0.08-0.81) with a decrease in the severity of inflammatory burden (peak CRP (6.9±3.1mg/dl, p=0.03) and peak inflammation score (2.3±1.1unit reduction, p=0.04)).

Conclusion: Use of ACEI or ARBs prior to hospitalization was not associated with adverse outcomes in COVID-19 and the therapeutic benefits of continuing ACEI or ARB in hospitalized patients with COVID-19 was not offset by adverse outcomes.
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http://dx.doi.org/10.34067/kid.0003792020DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7748256PMC
August 2020

Monitoring Hospitalized Dialysis Patients With COVID-19: Repurposing Baby Monitors for Patient and Staff Safety.

Kidney Med 2021 Jan-Feb;3(1):136-138. Epub 2020 Dec 10.

Division of Nephrology, Department of Medicine, Stony Brook University, Stony Brook, NY.

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http://dx.doi.org/10.1016/j.xkme.2020.10.004DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7726710PMC
December 2020

Association of Proteinuria and Hematuria with Acute Kidney Injury and Mortality in Hospitalized Patients with COVID-19.

Kidney Blood Press Res 2020 10;45(6):1018-1032. Epub 2020 Nov 10.

Division of Nephrology and Hypertension, Department of Medicine, Stony Brook University, Stony Brook, New York, USA,

Introduction: Acute kidney injury (AKI) is strongly associated with poor outcomes in hospitalized patients with coronavirus disease 2019 (COVID-19), but data on the association of proteinuria and hematuria are limited to non-US populations. In addition, admission and in-hospital measures for kidney abnormalities have not been studied separately.

Methods: This retrospective cohort study aimed to analyze these associations in 321 patients sequentially admitted between March 7, 2020 and April 1, 2020 at Stony Brook University Medical Center, New York. We investigated the association of proteinuria, hematuria, and AKI with outcomes of inflammation, intensive care unit (ICU) admission, invasive mechanical ventilation (IMV), and in-hospital death. We used ANOVA, t test, χ2 test, and Fisher's exact test for bivariate analyses and logistic regression for multivariable analysis.

Results: Three hundred patients met the inclusion criteria for the study cohort. Multivariable analysis demonstrated that admission proteinuria was significantly associated with risk of in-hospital AKI (OR 4.71, 95% CI 1.28-17.38), while admission hematuria was associated with ICU admission (OR 4.56, 95% CI 1.12-18.64), IMV (OR 8.79, 95% CI 2.08-37.00), and death (OR 18.03, 95% CI 2.84-114.57). During hospitalization, de novo proteinuria was significantly associated with increased risk of death (OR 8.94, 95% CI 1.19-114.4, p = 0.04). In-hospital AKI increased (OR 27.14, 95% CI 4.44-240.17) while recovery from in-hospital AKI decreased the risk of death (OR 0.001, 95% CI 0.001-0.06).

Conclusion: Proteinuria and hematuria both at the time of admission and during hospitalization are associated with adverse clinical outcomes in hospitalized patients with COVID-19.
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http://dx.doi.org/10.1159/000511946DOI Listing
December 2020

Cardiac Imaging in Dialysis Patients.

Kidney Med 2020 Sep-Oct;2(5):629-638. Epub 2020 Jul 31.

Division of Nephrology, Department of Medicine, Stony Brook University, Stony Brook, NY.

There is a well-established yet unexplained high prevalence of cardiovascular morbidity and mortality in individuals with end-stage kidney disease receiving dialysis. Potential causes include changes in cardiac structure and function, with increased left ventricular mass index as the best established cardiac structural change associated with this increase in mortality. However, in recent years, new echocardiographic and cardiac magnetic resonance imaging techniques have emerged that may provide novel markers that may better explain the mechanisms underlying the cardiovascular morbidity and mortality observed in end-stage kidney disease. This review outlines advances in cardiac imaging and the current status of imaging modalities, including echocardiography, cardiac magnetic resonance imaging, and cardiac positron emission tomography, to identify dialysis patients at high risk for cardiovascular mortality.
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http://dx.doi.org/10.1016/j.xkme.2020.05.010DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7568079PMC
July 2020

The complicated role of mitochondria in the podocyte.

Am J Physiol Renal Physiol 2020 12 19;319(6):F955-F965. Epub 2020 Oct 19.

Division of Nephrology, Department of Medicine, Renaissance School of Medicine at Stony Brook University, Stony Brook, New York.

Mitochondria play a complex role in maintaining cellular function including ATP generation, generation of biosynthetic precursors for macromolecules, maintenance of redox homeostasis, and metabolic waste management. Although the contribution of mitochondrial function in various kidney diseases has been studied, there are still avenues that need to be explored under healthy and diseased conditions. Mitochondrial damage and dysfunction have been implicated in experimental models of podocytopathy as well as in humans with glomerular diseases resulting from podocyte dysfunction. Specifically, in the podocyte, metabolism is largely driven by oxidative phosphorylation or glycolysis depending on the metabolic needs. These metabolic needs may change drastically in the presence of podocyte injury in glomerular diseases such as diabetic kidney disease or focal segmental glomerulosclerosis. Here, we review the role of mitochondria in the podocyte and the factors regulating its function at baseline and in a variety of podocytopathies to identify potential targets for therapy.
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http://dx.doi.org/10.1152/ajprenal.00393.2020DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7792691PMC
December 2020

Continued In-Hospital Angiotensin-Converting Enzyme Inhibitor and Angiotensin II Receptor Blocker Use in Hypertensive COVID-19 Patients Is Associated With Positive Clinical Outcome.

J Infect Dis 2020 09;222(8):1256-1264

Department of Radiology, Renaissance School of Medicine, Stony Brook University, New York, New York, USA.

Background: This study investigated continued and discontinued use of angiotensin-converting enzyme inhibitors (ACEi) or angiotensin II receptor blockers (ARB) during hospitalization of 614 hypertensive laboratory-confirmed COVID-19 patients.

Methods: Demographics, comorbidities, vital signs, laboratory data, and ACEi/ARB usage were analyzed. To account for confounders, patients were substratified by whether they developed hypotension and acute kidney injury (AKI) during the index hospitalization.

Results: Mortality (22% vs 17%, P > .05) and intensive care unit (ICU) admission (26% vs 12%, P > .05) rates were not significantly different between non-ACEi/ARB and ACEi/ARB groups. However, patients who continued ACEi/ARBs in the hospital had a markedly lower ICU admission rate (12% vs 26%; P = .001; odds ratio [OR] = 0.347; 95% confidence interval [CI], .187-.643) and mortality rate (6% vs 28%; P = .001; OR = 0.215; 95% CI, .101-.455) compared to patients who discontinued ACEi/ARB. The odds ratio for mortality remained significantly lower after accounting for development of hypotension or AKI.

Conclusions: These findings suggest that continued ACEi/ARB use in hypertensive COVID-19 patients yields better clinical outcomes.
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http://dx.doi.org/10.1093/infdis/jiaa447DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7454718PMC
September 2020

Proximal Tubular Transcription Factors in Acute Kidney Injury: Recent Advances.

Nephron 2020 9;144(12):613-615. Epub 2020 Jul 9.

Division of Nephrology, Department of Medicine, Stony Brook University, Stony Brook, New York, USA.

The proximal tubule (PT) is a major target in acute kidney injury (AKI), leading to profound changes in PT cell biology. Amongst the genes with early and robust changes in expression are many transcription factors (TFs), which themselves account for other transcriptomic changes. Potentially important TFs are being revealed in large sequencing datasets; however, to understand whether these TFs account for adaptive or maladaptive changes requires further mechanistic studies, which may reveal novel therapeutic targets. This mini review will highlight the identification and biology of 3 novel TFs in AKI: Sox9, Foxm1, and Foxo3.
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http://dx.doi.org/10.1159/000508856DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7708397PMC
July 2020

The Role of Podocytes and Podocyte-Associated Biomarkers in Diagnosis and Treatment of Diabetic Kidney Disease.

J Endocr Soc 2020 Apr 5;4(4):bvaa029. Epub 2020 Mar 5.

Division of Nephrology, Department of Medicine, Stony Brook University, Stony Brook, NY.

Diabetic kidney disease (DKD) is an important public health problem. Podocyte injury is a central event in the mechanism of DKD development. Podocytes are terminally differentiated, highly specialized glomerular visceral epithelial cells critical for the maintenance of the glomerular filtration barrier. Although potential mechanisms by which diabetic milieu contributes to irreversible loss of podocytes have been described, identification of markers that prognosticate either the development of DKD or the progression to end-stage kidney disease (ESKD) have only recently made it to the forefront. Currently, the most common marker of early DKD is microalbuminuria; however, this marker has significant limitations: not all diabetic patients with microalbuminuria will progress to ESKD and as many as 30% of patients with DKD have normal urine albumin levels. Several novel biomarkers indicating glomerular or tubular damage precede microalbuminuria, suggesting that the latter develops when significant kidney injury has already occurred. Because podocyte injury plays a key role in DKD pathogenesis, identification of markers of early podocyte injury or loss may play an important role in the early diagnosis of DKD. Such biomarkers in the urine include podocyte-released microparticles as well as expression of podocyte-specific markers. Here, we review the mechanisms by which podocyte injury contributes to DKD as well as key markers that have been recently implicated in the development and/or progression of DKD and might serve to identify individuals that require earlier preventative care and treatment in order to slow the progression to ESKD.
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http://dx.doi.org/10.1210/jendso/bvaa029DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7093089PMC
April 2020

Targeting STAT3 signaling in kidney disease.

Am J Physiol Renal Physiol 2019 06 3;316(6):F1151-F1161. Epub 2019 Apr 3.

Division of Nephrology, Department of Medicine, Stony Brook University , Stony Brook, New York.

The Janus kinase/signal transducer and activator of transcription (JAK/STAT) signaling pathway is a multifaceted transduction system that regulates cellular responses to incoming signaling ligands. STAT3 is a central member of the JAK/STAT signaling cascade and has long been recognized for its increased transcriptional activity in cancers and autoimmune disorders but has only recently been in the spotlight for its role in the progression of kidney disease. Although genetic knockout and manipulation studies have demonstrated the salutary benefits of inhibiting STAT3 activity in several kidney disease models, pharmacological inhibition has yet to make it to the clinical forefront. In recent years, significant effort has been aimed at suppressing STAT3 activation for treatment of cancers, which has led to the development of a wide variety of STAT3 inhibitors, but only a handful have been tested in kidney disease models. Here, we review the detrimental role of dysregulated STAT3 activation in a variety of kidney diseases and the current progress in the treatment of kidney diseases with pharmacological inhibition of STAT3 activity.
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http://dx.doi.org/10.1152/ajprenal.00034.2019DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6620596PMC
June 2019

Therapeutic Inhibition of VEGF Signaling and Associated Nephrotoxicities.

J Am Soc Nephrol 2019 02 14;30(2):187-200. Epub 2019 Jan 14.

Division of Nephrology, Department of Medicine, Stony Brook University, Stony Brook, New York; and

Inhibition of vascular endothelial growth factor A (VEGFA)/vascular endothelial growth factor receptor 2 (VEGFR2) signaling is a common therapeutic strategy in oncology, with new drugs continuously in development. In this review, we consider the experimental and clinical evidence behind the diverse nephrotoxicities associated with the inhibition of this pathway. We also review the renal effects of VEGF inhibition's mediation of key downstream signaling pathways, specifically MAPK/ERK1/2, endothelial nitric oxide synthase, and mammalian target of rapamycin (mTOR). Direct VEGFA inhibition antibody binding or VEGF trap (a soluble decoy receptor) is associated with renal-specific thrombotic microangiopathy (TMA). Reports also indicate that tyrosine kinase inhibition of the VEGF receptors is preferentially associated with glomerulopathies such as minimal change disease and FSGS. Inhibition of the downstream pathway RAF/MAPK/ERK has largely been associated with tubulointerstitial injury. Inhibition of mTOR is most commonly associated with albuminuria and podocyte injury, but has also been linked to renal-specific TMA. In all, we review the experimentally validated mechanisms by which VEGFA-VEGFR2 inhibitors contribute to nephrotoxicity, as well as the wide range of clinical manifestations that have been reported with their use. We also highlight potential avenues for future research to elucidate mechanisms for minimizing nephrotoxicity while maintaining therapeutic efficacy.
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http://dx.doi.org/10.1681/ASN.2018080853DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6362621PMC
February 2019

Podocyte-Specific Induction of Krüppel-Like Factor 15 Restores Differentiation Markers and Attenuates Kidney Injury in Proteinuric Kidney Disease.

J Am Soc Nephrol 2018 10 24;29(10):2529-2545. Epub 2018 Aug 24.

Divisions of Nephrology and

Background: Podocyte injury is the hallmark of proteinuric kidney diseases, such as FSGS and minimal change disease, and destabilization of the podocyte's actin cytoskeleton contributes to podocyte dysfunction in many of these conditions. Although agents, such as glucocorticoids and cyclosporin, stabilize the actin cytoskeleton, systemic toxicity hinders chronic use. We previously showed that loss of the kidney-enriched zinc finger transcription factor Krüppel-like factor 15 (KLF15) increases susceptibility to proteinuric kidney disease and attenuates the salutary effects of retinoic acid and glucocorticoids in the podocyte.

Methods: We induced podocyte-specific in two proteinuric murine models, HIV-1 transgenic () mice and adriamycin (ADR)-induced nephropathy, and used RNA sequencing of isolated glomeruli and subsequent enrichment analysis to investigate pathways mediated by podocyte-specific in mice. We also explored in cultured human podocytes the potential mediating role of Wilms Tumor 1 (WT1), a transcription factor critical for podocyte differentiation.

Results: In mice, inducing podocyte-specific attenuated podocyte injury, glomerulosclerosis, tubulointerstitial fibrosis, and inflammation, while improving renal function and overall survival; it also attenuated podocyte injury in ADR-treated mice. Enrichment analysis of RNA sequencing from the mouse model shows that induction activates pathways involved in stabilization of actin cytoskeleton, focal adhesion, and podocyte differentiation. Transcription factor enrichment analysis, with further experimental validation, suggests that KLF15 activity is in part mediated by WT1.

Conclusions: Inducing podocyte-specific attenuates kidney injury by directly and indirectly upregulating genes critical for podocyte differentiation, suggesting that induction might be a potential strategy for treating proteinuric kidney disease.
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http://dx.doi.org/10.1681/ASN.2018030324DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6171275PMC
October 2018

Podocyte-Specific Loss of Krüppel-Like Factor 6 Increases Mitochondrial Injury in Diabetic Kidney Disease.

Diabetes 2018 11 16;67(11):2420-2433. Epub 2018 Aug 16.

Division of Nephrology, Department of Medicine, Stony Brook University, Stony Brook, NY

Mitochondrial injury is uniformly observed in several murine models as well as in individuals with diabetic kidney disease (DKD). Although emerging evidence has highlighted the role of key transcriptional regulators in mitochondrial biogenesis, little is known about the regulation of mitochondrial cytochrome c oxidase assembly in the podocyte under diabetic conditions. We recently reported a critical role of the zinc finger Krüppel-like factor 6 (KLF6) in maintaining mitochondrial function and preventing apoptosis in a proteinuric murine model. In this study, we report that podocyte-specific knockdown of increased the susceptibility to streptozotocin-induced DKD in the resistant C57BL/6 mouse strain. We observed that the loss of in podocytes reduced the expression of with resultant increased mitochondrial injury, leading to activation of the intrinsic apoptotic pathway under diabetic conditions. Conversely, mitochondrial injury and apoptosis were significantly attenuated with overexpression of in cultured human podocytes under hyperglycemic conditions. Finally, we observed a significant reduction in glomerular and podocyte-specific expression of KLF6 in human kidney biopsies with progression of DKD. Collectively, these data suggest that podocyte-specific KLF6 is critical to preventing mitochondrial injury and apoptosis under diabetic conditions.
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http://dx.doi.org/10.2337/db17-0958DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6198342PMC
November 2018

Krüppel-like factor 4 is a negative regulator of STAT3-induced glomerular epithelial cell proliferation.

JCI Insight 2018 06 21;3(12). Epub 2018 Jun 21.

Division of Nephrology, Department of Medicine, Stony Brook University, Stony Brook, New York, USA.

Pathologic glomerular epithelial cell (GEC) hyperplasia is characteristic of both rapidly progressive glomerulonephritis (RPGN) and subtypes of focal segmental glomerulosclerosis (FSGS). Although initial podocyte injury resulting in activation of STAT3 signals GEC proliferation in both diseases, mechanisms regulating this are unknown. Here, we show that the loss of Krüppel-like factor 4 (KLF4), a zinc-finger transcription factor, enhances GEC proliferation in both RPGN and FSGS due to dysregulated STAT3 signaling. We observed that podocyte-specific knockdown of Klf4 (C57BL/6J) increased STAT3 signaling and exacerbated crescent formation after nephrotoxic serum treatment. Interestingly, podocyte-specific knockdown of Klf4 in the FVB/N background alone was sufficient to activate STAT3 signaling, resulting in FSGS with extracapillary proliferation, as well as renal failure and reduced survival. In cultured podocytes, loss of KLF4 resulted in STAT3 activation and cell-cycle reentry, leading to mitotic catastrophe. This triggered IL-6 release into the supernatant, which activated STAT3 signaling in parietal epithelial cells. Conversely, either restoration of KLF4 expression or inhibition of STAT3 signaling improved survival in KLF4-knockdown podocytes. Finally, human kidney biopsy specimens with RPGN exhibited reduced KLF4 expression with a concomitant increase in phospho-STAT3 expression as compared with controls. Collectively, these results suggest the essential role of KLF4/STAT3 signaling in podocyte injury and its regulation of aberrant GEC proliferation.
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http://dx.doi.org/10.1172/jci.insight.98214DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6124441PMC
June 2018

The loss of Krüppel-like factor 15 in Foxd1 stromal cells exacerbates kidney fibrosis.

Kidney Int 2017 11 24;92(5):1178-1193. Epub 2017 Jun 24.

Kidney Institute of PLA, Department of Medicine, Changzheng Hospital, Second Military Medical University, Shanghai 200003, People's Republic of China. Electronic address:

Large epidemiological studies clearly demonstrate that multiple episodes of acute kidney injury contribute to the development and progression of kidney fibrosis. Although our understanding of kidney fibrosis has improved in the past two decades, we have limited therapeutic strategies to halt its progression. Myofibroblast differentiation and proliferation remain critical to the progression of kidney fibrosis. Although canonical Wnt signaling can trigger the activation of myofibroblasts in the kidney, mediators of Wnt inhibition in the resident progenitor cells are unclear. Recent studies demonstrate that the loss of a Krüppel-like factor 15 (KLF15), a kidney-enriched zinc-finger transcription factor, exacerbates kidney fibrosis in murine models. Here, we tested whether Klf15 mRNA and protein expression are reduced in late stages of fibrosis in mice that underwent unilateral ureteric obstruction, a model of progressive renal fibrosis. Knockdown of Klf15 in Foxd1-expressing cells (Foxd1-Cre Klf15fl/fl) increased extracellular matrix deposition and myofibroblast proliferation as compared to wildtype (Foxd1-Cre Klf15+/+) mice after three and seven days of ureteral obstruction. This was validated in mice receiving angiotensin II treatment for six weeks. In both these murine models, the increase in renal fibrosis was found in Foxd1-Cre Klf15 mice and accompanied by the activation of Wnt/β-catenin signaling. Furthermore, knockdown of Klf15 in cultured mouse embryonic fibroblasts activated canonical Wnt/β-catenin signaling, increased profibrotic transcripts, and increased proliferation after treatment with a Wnt1 ligand. Conversely, the overexpression of KLF15 inhibited phospho-β-catenin (Ser552) expression in Wnt1-treated cells. Thus, KLF15 has a critical role in attenuating kidney fibrosis by inhibiting the canonical Wnt/β-catenin pathway.
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http://dx.doi.org/10.1016/j.kint.2017.03.037DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5651204PMC
November 2017

Safety and Efficacy of A High Performance Graphene-Based Magnetic Resonance Imaging Contrast Agent for Renal Abnormalities.

Graphene Technol 2016 Dec 3;1(1):17-28. Epub 2016 Aug 3.

Department of Biomedical Engineering, Northeastern University, Boston, MA, USA.

The etiology of renal insufficiency includes primary (e.g polycystic kidney disease) or secondary (e.g. contrast media, diabetes) causes. The regulatory restrictions placed on the use of contrast agents (CAs) for non-invasive imaging modalities such as X-ray computed tomography (CT) and magnetic resonance imaging (MRI) affects the clinical management of these patients. With the goal to develop a next-generation CA for unfettered use for renal MRI, here we report, in a rodent model of chronic kidney disease, the preclinical safety and efficacy of a novel nanoparticle CA comprising of manganese (Mn) ions intercalated graphene coated with dextran (hereafter called Mangradex). Nephrectomized rats received single or 5 times/week repeat (2 or 4 weeks) intravenous (IV) injections of Mangradex at two potential (low = 5 mg/kg, and high = 50 mg/kg) therapeutic doses. Histopathology results indicate that Mangradex does not elicit nephrogenic systemic fibrosis (NSF)-like indicators or questionable effects on vital organs of rodents. MRI at 7 Tesla magnetic field was performed on these rats immediately after IV injections of Mangradex at one potential therapeutic dose (25 mg/kg, [Mn] = 60 nmoles/kg) for 90 minutes. The results indicated significant (>100%) and sustained contrast enhancement in the kidney and renal artery at these low paramagnetic ion (Mn) concentration; 2 orders of magnitude lower than the paramagnetic ion concentration in a typical clinical dose of long circulating Gd-based MRI CA gadofosveset trisodium. The results open avenues for further development of Mangradex as a MRI CA to diagnose and monitor abnormalities in renal anatomy and vasculature.
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http://dx.doi.org/10.1007/s41127-016-0001-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5333926PMC
December 2016

Krüppel-like factors in mammalian stem cells and development.

Development 2017 03;144(5):737-754

Division of Nephrology, Department of Medicine, Stony Brook University School of Medicine, Stony Brook, NY 11794-8176, USA

Krüppel-like factors (KLFs) are a family of zinc-finger transcription factors that are found in many species. Recent studies have shown that KLFs play a fundamental role in regulating diverse biological processes such as cell proliferation, differentiation, development and regeneration. Of note, several KLFs are also crucial for maintaining pluripotency and, hence, have been linked to reprogramming and regenerative medicine approaches. Here, we review the crucial functions of KLFs in mammalian embryogenesis, stem cell biology and regeneration, as revealed by studies of animal models. We also highlight how KLFs have been implicated in human diseases and outline potential avenues for future research.
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http://dx.doi.org/10.1242/dev.145441DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5374354PMC
March 2017

The critical role of Krüppel-like factors in kidney disease.

Am J Physiol Renal Physiol 2017 Feb 16;312(2):F259-F265. Epub 2016 Nov 16.

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

Krüppel-like factors (KLFs) are a family of zinc-finger transcription factors critical to mammalian embryonic development, regeneration, and human disease. There is emerging evidence that KLFs play a vital role in key physiological processes in the kidney, ranging from maintenance of glomerular filtration barrier to tubulointerstitial inflammation to progression of kidney fibrosis. Seventeen members of the KLF family have been identified, and several have been well characterized in the kidney. Although they may share some overlap in their downstream targets, their structure and function remain distinct. This review highlights our current knowledge of KLFs in the kidney, which includes their pattern of expression and their function in regulating key biological processes. We will also critically examine the currently available literature on KLFs in the kidney and offer some key areas in need of further investigation.
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http://dx.doi.org/10.1152/ajprenal.00550.2016DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5336586PMC
February 2017

Reduced Krüppel-Like Factor 2 Aggravates Glomerular Endothelial Cell Injury and Kidney Disease in Mice with Unilateral Nephrectomy.

Am J Pathol 2016 08 15;186(8):2021-2031. Epub 2016 Jun 15.

Department of Medicine/Nephrology, Icahn School of Medicine at Mount Sinai, New York, New York; Renal Section, James J. Peters Veterans Affairs Medical Center, Bronx, New York. Electronic address:

Loss of functional nephrons induces compensatory glomerular hyperfiltration and hypertrophy, leading to the progression of chronic kidney disease. Krüppel-like factor 2 (KLF2), a shear-stress-inducible transcription factor, confers protection against endothelial injury. Because glomerular hyperfiltration is associated with shear stress, we hypothesized that KLF2 may be an important factor in the compensatory response to unilateral nephrectomy (UNX). To test this hypothesis, endothelial cell-specific Klf2 heterozygous knockout mice (KO) and their wild-type littermate control (WT) underwent either UNX or sham-operation. WT-UNX mice developed compensatory renal hypertrophy as expected, whereas KO-UNX mice did not. KO-UNX mice exhibited higher blood pressure, reduced glomerular filtration rate, and significant increase in proteinuria and glomerulosclerosis compared to WT-UNX. Expression of endothelial nitric oxide synthase (official name Nos3), a known transcriptional target gene of KLF2, was significantly reduced and dysregulation of other endothelial genes was also observed in the glomeruli of KO-UNX when compared to WT-UNX and sham-operated mice. Furthermore, both podocyte number and expression of podocyte markers were also significantly reduced in KO-UNX glomeruli, indicating a potential cross talk between glomerular endothelial cells and podocytes. Finally, decreased renal expression of KLF2 in nephrectomy patients was associated with the progression of kidney disease. Taken together, our data demonstrate a protective role of KLF2 against glomerular endothelial cell injury and progression of chronic kidney disease in the model of compensatory renal hypertrophy.
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http://dx.doi.org/10.1016/j.ajpath.2016.03.018DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4973653PMC
August 2016

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

The podocyte as a direct target for treatment of glomerular disease?

Am J Physiol Renal Physiol 2016 07 20;311(1):F46-51. Epub 2016 Apr 20.

Division of Nephrology, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, New York; and Renal Section, James J. Peters VA Medical Center, New York, New York

The Centers for Disease Control and Prevention estimates more than 10% of adults in the United States, over 20 million Americans, have chronic kidney disease (CKD). A failure to maintain the glomerular filtration barrier directly contributes to the onset of CKD. The visceral epithelial cells, podocytes, are integral to the maintenance of this renal filtration barrier. Direct podocyte injury contributes to the onset and progression of glomerular diseases such as minimal change disease (MCD), focal segmental glomerular sclerosis (FSGS), diabetic nephropathy, and HIV-associated nephropathy (HIVAN). Since podocytes are terminally differentiated with minimal capacity to self-replicate, they are extremely sensitive to cellular injury. In the past two decades, our understanding of the mechanism(s) by which podocyte injury occurs has greatly expanded. With this newfound knowledge, therapeutic strategies have shifted to identifying targets directed specifically at the podocyte. Although the systemic effects of these agents are important, their direct effect on the podocyte proves to be essential in ameliorating glomerular disease. In this review, we highlight the mechanisms by which these agents directly target the podocyte independent of its systemic effects.
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http://dx.doi.org/10.1152/ajprenal.00184.2016DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4967158PMC
July 2016

KLF 6: a mitochondrial regulator in the kidney.

Oncotarget 2015 Jun;6(18):15720-1

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

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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4599219PMC
http://dx.doi.org/10.18632/oncotarget.4647DOI Listing
June 2015

The beneficial role of retinoids in glomerular disease.

Front Med (Lausanne) 2015 23;2:16. Epub 2015 Mar 23.

Division of Nephrology, Department of Medicine, Icahn School of Medicine at Mount Sinai , New York, NY , USA ; Renal Section, James J. Peters VA Medical Center , New York, NY , USA.

The primary etiology of CKD is a direct consequence of initial dysfunction and injury of the glomerulus, the main filtration system. Podocytes are terminally differentiated epithelial cells in the glomerulus, whose major function is the maintenance of this renal filtration barrier. Podocyte injury is implicated in many glomerular diseases including focal segmental glomerular sclerosis and HIV-associated nephropathy. In many of these diseased conditions, the podocyte can either undergo dedifferentiation and proliferation, apoptosis, or cell detachment. Regardless of the initial type of injury, the podocyte ultimately loses its functional capacity to maintain the glomerular filtration barrier. Significant injury resulting in a loss of the podocytes and failure to maintain the renal filtration barrier contributes to progressive kidney disease. Consequently, therapies that prevent podocyte injury and promote their regeneration will have a major clinical impact on glomerular disease. Retinoic acid (RA), which is a derivative of vitamin A, has many cellular functions including induction of cell differentiation, regulation of apoptosis, and inhibition of inflammation and proliferation. RA is required for kidney development and is essential for cellular differentiation in the setting of podocyte injury. The mechanism by which RA directs its beneficial effects is multifactorial, ranging from its anti-inflammatory and anti-fibrotic effects to a direct effect of upregulating podocyte differentiation markers in the podocyte. The focus of this review is to provide an overview of RA in kidney development and glomerular disease. We also highlight the key mechanism(s) by which RA restores podocyte differentiation markers and ameliorates glomerular disease.
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http://dx.doi.org/10.3389/fmed.2015.00016DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4370041PMC
April 2015

Krüppel-like factor 6 regulates mitochondrial function in the kidney.

J Clin Invest 2015 Mar 17;125(3):1347-61. Epub 2015 Feb 17.

Maintenance of mitochondrial structure and function is critical for preventing podocyte apoptosis and eventual glomerulosclerosis in the kidney; however, the transcription factors that regulate mitochondrial function in podocyte injury remain to be identified. Here, we identified Krüppel-like factor 6 (KLF6), a zinc finger domain transcription factor, as an essential regulator of mitochondrial function in podocyte apoptosis. We observed that podocyte-specific deletion of Klf6 increased the susceptibility of a resistant mouse strain to adriamycin-induced (ADR-induced) focal segmental glomerulosclerosis (FSGS). KLF6 expression was induced early in response to ADR in mice and cultured human podocytes, and prevented mitochondrial dysfunction and activation of intrinsic apoptotic pathways in these podocytes. Promoter analysis and chromatin immunoprecipitation studies revealed that putative KLF6 transcriptional binding sites are present in the promoter of the mitochondrial cytochrome c oxidase assembly gene (SCO2), which is critical for preventing cytochrome c release and activation of the intrinsic apoptotic pathway. Additionally, KLF6 expression was reduced in podocytes from HIV-1 transgenic mice as well as in renal biopsies from patients with HIV-associated nephropathy (HIVAN) and FSGS. Together, these findings indicate that KLF6-dependent regulation of the cytochrome c oxidase assembly gene is critical for maintaining mitochondrial function and preventing podocyte apoptosis.
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http://dx.doi.org/10.1172/JCI77084DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4362257PMC
March 2015

Reduced Krüppel-like factor 2 expression may aggravate the endothelial injury of diabetic nephropathy.

Kidney Int 2015 Feb 3;87(2):382-95. Epub 2014 Sep 3.

1] Department of Medicine/Nephrology, Icahn School of Medicine at Mount Sinai, New York, New York, USA [2] Renal Section, James J Peters VAMC, Bronx, New York, USA.

Krüppel-like factor 2 (KLF2), a shear stress-inducible transcription factor, has endoprotective effects. In streptozotocin-induced diabetic rats, we found that glomerular Klf2 expression was reduced in comparison with nondiabetic rats. However, normalization of hyperglycemia by insulin treatment increased Klf2 expression to a level higher than that of nondiabetic rats. Consistent with this, we found that Klf2 expression was suppressed by high glucose but increased by insulin in cultured endothelial cells. To determine the role of KLF2 in streptozotocin-induced diabetic nephropathy, we used endothelial cell-specific Klf2 heterozygous knockout mice and found that diabetic knockout mice developed more kidney/glomerular hypertrophy and proteinuria than diabetic wild-type mice. Glomerular expression of Vegfa, Flk1, and angiopoietin 2 increased, but expression of Flt1, Tie2, and angiopoietin 1 decreased, in diabetic knockout mice compared with diabetic wild-type mice. Glomerular expression of ZO-1, glycocalyx, and eNOS was also decreased in diabetic knockout compared with diabetic wild-type mice. These data suggest knockdown of Klf2 expression in the endothelial cells induced more endothelial cell injury. Interestingly, podocyte injury was also more prominent in diabetic knockout compared with diabetic wild-type mice, indicating a cross talk between these two cell types. Thus, KLF2 may play a role in glomerular endothelial cell injury in early diabetic nephropathy.
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http://dx.doi.org/10.1038/ki.2014.286DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4312548PMC
February 2015

Advanced glycation end product accumulation: a new enemy to target in chronic kidney disease?

Curr Opin Nephrol Hypertens 2014 Nov;23(6):547-54

aDivision of Nephrology, Department of Medicine, Stony Brook University bDivision of Nephrology, Department of Medicine, Mount Sinai School of Medicine, New York, New York, USA.

Purpose Of Review: The critical role of advanced glycation end products (AGEs) in the progression of chronic diseases and their complications has recently become more apparent. This review summarizes the recent contributions to the field of AGEs in chronic kidney disease (CKD).

Recent Findings: Over the past 3 decades, AGEs have been implicated in the progression of CKD, and specifically diabetic nephropathy. Although numerous in-vitro and in-vivo studies highlight the detrimental role of AGEs accumulation in tissue injury, few prospective human studies or clinical trials show that inhibiting this process ameliorates disease. Nonetheless, recent studies have focused on the novel mechanisms that contribute to end-organ injury as a result of AGEs accumulation, as well as novel targets of therapy in kidney disease.

Summary: As the prevalence and the incidence of CKD rises in the United States, it is essential to identify therapeutic strategies that either delay the progression of CKD or improve mortality in this population. The focus of this review is on highlighting the recent studies that advance our current understanding of the mechanisms mediating AGEs-induced CKD progression, as well as novel treatment strategies that have the potential to abrogate this disease process.

Video Abstract: http://links.lww.com/CONH/A12.
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http://dx.doi.org/10.1097/MNH.0000000000000062DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5577004PMC
November 2014

In vivo RNA interference models of inducible and reversible Sirt1 knockdown in kidney cells.

Am J Pathol 2014 Jul;184(7):1940-56

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

The silent mating type information regulation 2 homolog 1 gene (Sirt1) encodes an NAD-dependent deacetylase that modifies the activity of well-known transcriptional regulators affected in kidney diseases. Sirt1 is expressed in the kidney podocyte, but its function in the podocyte is not clear. Genetically engineered mice with inducible and reversible Sirt1 knockdown in widespread, podocyte-specific, or tubular-specific patterns were generated. We found that mice with 80% knockdown of renal Sirt1 expression have normal glomerular function under the basal condition. When challenged with doxorubicin (Adriamycin), these mice develop marked albuminuria, glomerulosclerosis, mitochondrial injury, and impaired autophagy of damaged mitochondria. Reversal of Sirt1 knockdown during the early phase of Adriamycin-induced nephropathy prevented the progression of glomerular injury and reduced the accumulation of dysmorphic mitochondria in podocytes but did not reverse the progression of albuminuria and glomerulosclerosis. Sirt1 knockdown mice with diabetes mellitus, which is known to cause mitochondrial dysfunction in the kidney, developed more albuminuria and mitochondrial dysfunction compared with diabetic mice without Sirt1 knockdown. In conclusion, these results demonstrate that our RNA interference-mediated Sirt1 knockdown models are valid and versatile tools for characterizing the function of Sirt1 in the kidney; Sirt1 plays a role in homeostatic maintenance of podocytes under the condition of mitochondrial stress/injury.
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http://dx.doi.org/10.1016/j.ajpath.2014.03.016DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4076473PMC
July 2014

Diabetic nephropathy in a nonobese mouse model of type 2 diabetes mellitus.

Am J Physiol Renal Physiol 2014 May 5;306(9):F1008-17. Epub 2014 Mar 5.

Dept. of Medicine/Nephrology, Mount Sinai School of Medicine, One Gustave L Levy Place, Box 1243, New York, NY.

A large body of research has contributed to our understanding of the pathophysiology of diabetic nephropathy. Yet, many questions remain regarding the progression of a disease that accounts for nearly half the patients entering dialysis yearly. Several murine models of diabetic nephropathy secondary to Type 2 diabetes mellitus (T2DM) do exist, and some are more representative than others, but all have limitations. In this study, we aimed to identify a new mouse model of diabetic nephropathy secondary to T2DM in a previously described T2DM model, the MKR (MCK-KR-hIGF-IR) mouse. In this mouse model, T2DM develops as a result of functional inactivation of insulin-like growth factor-1 receptor (IGF-1R) in the skeletal muscle. These mice are lean, with marked insulin resistance, hyperinsulinemia, hyperglycemia, and dyslipidemia and thus are representative of nonobese human T2DM. We show that the MKR mice, when under stress (high-fat diet or unilateral nephrectomy), develop progressive diabetic nephropathy with marked albuminuria and meet the histopathological criteria as defined by the Animal Models of Diabetic Complications Consortium. Finally, these MKR mice are fertile and are on a common background strain, making it a novel model to study the progression of diabetic nephropathy.
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http://dx.doi.org/10.1152/ajprenal.00597.2013DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4010680PMC
May 2014

The changing epidemiology of HIV-related chronic kidney disease in the era of antiretroviral therapy.

Kidney Int 2014 Aug 26;86(2):259-65. Epub 2014 Feb 26.

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

The epidemiology of kidney disease in HIV-infected individuals has changed significantly since the introduction of combination antiretroviral therapy (cART) in the mid 1990s. HIV-associated nephropathy (HIVAN), an aggressive form of collapsing focal segmental glomerulosclerosis (FSGS) caused by direct HIV infection of the kidney in a genetically susceptible host, emerged early in the HIV epidemic as a leading cause of end-stage renal disease. With the widespread use of cART, HIVAN is increasingly rare in populations with access to care, and the spectrum of HIV-related chronic kidney disease now reflects the growing burden of comorbid disease in the aging HIV population. Nonetheless, available data suggest that both HIV infection and cART nephrotoxicity continue to contribute to the increased risk of chronic kidney disease in HIV-infected individuals in the United States and Europe. Despite the genetic susceptibility to HIVAN in individuals of West African descent, limited data are available to define the prevalence and spectrum of HIV-related kidney disease in sub-Saharan Africa, which is home to two-thirds of the world's HIV population. In this mini-review, we characterize the changing epidemiology of HIV-related chronic kidney disease in Western nations and in sub-Saharan Africa.
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http://dx.doi.org/10.1038/ki.2014.44DOI Listing
August 2014