Publications by authors named "Shruti Gupta"

123 Publications

Obesity, Inflammatory and Thrombotic Markers, and Major Clinical Outcomes in Critically Ill Patients with COVID-19 in the US.

Obesity (Silver Spring) 2021 Jun 9. Epub 2021 Jun 9.

Department of Surgery, Indiana University School of Medicine, IN, USA.

Objective: To determine if obesity is independently associated with major adverse clinical outcomes and inflammatory and thrombotic markers in critically ill patients with COVID-19.

Methods: The primary outcome was in-hospital mortality in adults with COVID-19 admitted to intensive care units across the US. Secondary outcomes were acute respiratory distress syndrome (ARDS), acute kidney injury requiring renal replacement therapy (AKI-RRT), thrombotic events, and seven blood markers of inflammation and thrombosis. Unadjusted and multivariable-adjusted models were used.

Results: Among the 4908 study patients mean (SD) age was 60.9 (14.7) years, 3095 (62.8%) were male, and 2552 (52.0%) were obese. In multivariable models, BMI was not associated with mortality. Higher BMI beginning at 25 kg/m was associated with a greater risk of ARDS and AKI-RRT but not thrombosis. There was no clinically significant association between BMI and inflammatory or thrombotic markers.

Conclusions: In critically ill patients with COVID-19, higher BMI was not associated with death or thrombotic events but was associated with a greater risk of ARDS and AKI-RRT. The lack of an association between BMI and circulating biomarkers raises into question the paradigm that obesity contributes to poor outcomes in critically ill patients with COVID-19 by upregulating systemic inflammatory and prothrombotic pathways.
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http://dx.doi.org/10.1002/oby.23245DOI Listing
June 2021

Persistent low bispectral index values with propofol in a patient of cirrhosis.

J Anaesthesiol Clin Pharmacol 2021 Jan-Mar;37(1):137-139. Epub 2021 Apr 10.

Department of Neuroanaesthesiology and Critical Care, Pain Medicine and Critical Care, All India Institute of Medical Sciences, New Delhi, India.

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http://dx.doi.org/10.4103/joacp.JOACP_277_18DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8174432PMC
April 2021

ROS-Mediated Apoptosis Induced by BSA Nanospheres Encapsulated with Fruit Extract of in Various Human Cancer Cell Lines.

ACS Omega 2021 Apr 6;6(15):10383-10395. Epub 2021 Apr 6.

Department of Biochemistry, School of Life Sciences, Central University of Rajasthan, NH-8, Bandarsindri, Kishangarh, 305817 Ajmer, Rajasthan, India.

In recent decades, biodegradable polymeric nanoparticles have been used as a nanocarrier for the delivery of anticancer drugs. In the present study, we synthesize bovine serum albumin (BSA) nanospheres and evaluate their ability to incorporate a plant extract with anticancer activity. The plant extract used was the methanol fruit extract of , which is a medicinal herb. The fruit-extract-encapsulated BSA nanospheres (Cp-BSA nanospheres) were prepared using a desolvation method at various pH values of 5, 7, and 9. The nanosphere formulations were characterized using various techniques such as dynamic light scattering (DLS), ζ-potential, Fourier transform infrared spectroscopy (FTIR), and field-effect scanning electron microscopy (FESEM). The results show that the Cp-BSA nanospheres prepared at pH 7 were spherical with a uniform particle size, low polydispersity index (PDI), ζ-potential, and high entrapment efficiency (82.3%) and showed sustained release of fruit extract from Cp-BSA nanospheres in phosphate-buffered saline (PBS), pH 5. The anticancer activity was evaluated on A549, HepG2, MCF-7 cancer cell lines and HEK 293 normal cell lines. In vitro, antioxidant activity using the 2,2-diphenyl-1-picrylhydrazyl (DPPH) assay, intracellular reactive oxygen species (ROS) production, and mitochondrial membrane potential were estimated. An in vitro cellular uptake study was performed using fluorescein isothiocyanate (FITC) dye at a different time of incubation, and DNA fragmentation was observed in a dose-dependent manner. The gene expression level of Bax and the suppression level of Bcl-2 were observed upon the treatment of Cp-BSA nanospheres. Thus, the Cp-BSA nanospheres triggered ROS-dependent mitochondrial apoptosis in different human cancer cell lines when compared to the noncancerous cell lines and could be used as a potential candidate for anticancer agents.
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http://dx.doi.org/10.1021/acsomega.1c00755DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8153748PMC
April 2021

N-Nitrosomelatonin, an efficient nitric oxide donor and transporter in Arabidopsis seedlings.

Nitric Oxide 2021 May 21;113-114:50-56. Epub 2021 May 21.

Laboratory of Plant Physiology and Biochemistry, Department of Botany, University of Delhi, Delhi, 110007, India. Electronic address:

Nitric oxide (NO) produced in plant cells has the unique ability to interact with various other biomolecules, thereby facilitating its own as well as their signaling and associated actions at their sites of biosynthesis and at other sites via transcellular long distance transport of the molecular complexes. Melatonin (Mel) is one such biomolecule produced in plant cells which has fascinated plant biologists with regard to its molecular crosstalk with other molecules to serve its roles as a growth regulator. Present work reports the synthesis of N-nitrosomelatonin (NOMela) and its preferential uptake by Arabidopsis seedlings roots and long distance transport to the leaves through vascular strands. Equimolar (250 μM) concentrations of NOMela and S-nitrosoglutathione (GSNO) in aqueous solutions bring about 52.8% more release of NO from NOMela than from GSNO. Following confocal laser scanning microscopic (CLSM) imaging, Pearson's correlation coefficient analysis of the Scatter gram of endogenously taken up NOMela demonstrates significant NO signal in roots emanating from mitochondria. NOMela (250 μM) taken up by Arabidopsis seedling roots also proved more efficient as a NO transporter from primary root to leaves than 250 μM of GSNO. These novel observations on NOMela thus hold promise to decipher its crucial role as a NO carrier and reservoir in plant cells, and also as a facilitator of melatonin action in plant development.
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http://dx.doi.org/10.1016/j.niox.2021.05.001DOI Listing
May 2021

Pseudo-pseudo Meigs' syndrome (PPMS) in chronic lupus peritonitis: a case report with review of literature.

Mod Rheumatol Case Rep 2021 May 10:1-6. Epub 2021 May 10.

Department of General Medicine, All India Institute of Medical Sciences, Jodhpur, India.

Gastrointestinal involvement in systemic lupus erythematosus (SLE) usually occurs in the form of mesenteric vasculitis, protein-losing enteropathy, intestinal pseudo-obstruction, and pancreatitis. We describe a 23-year-old female, a known case of SLE presented with significant ascites and pleural effusion. Further evaluation showed elevated CA-125 levels without evidence of malignancy. The patient was treated with corticosteroids, hydroxychloroquine, and azathioprine resulting in the resolution of ascites in 2 weeks. The triad of ascites, pleural effusion, and increased CA-125 is known as pseudo-pseudo Meigs' syndrome, which is rarely reported in the literature. Clinicians should be aware of this entity while evaluating an SLE patient with low serum-ascites albumin gradient (SAAG) ascites.
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http://dx.doi.org/10.1080/24725625.2021.1916160DOI Listing
May 2021

Identification of distinct clinical subphenotypes in critically ill patients with COVID-19.

Chest 2021 May 5. Epub 2021 May 5.

Center for Epidemiology and Biostatistics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA; Pulmonary, Allergy and Critical Care Division, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA.

Background: Subphenotypes have been identified in patients with sepsis and acute respiratory distress syndrome (ARDS), and are associated with different outcomes and response to therapies.

Research Question: Can unique subphenotypes be identified among critically ill patients with coronavirus disease 2019 (COVID-19)?

Study Design: & Methods: Using data from a multicenter cohort study that enrolled critically ill patients with COVID-19 from 67 hospitals across the United States, we randomly divided centers into Discovery and Replication cohorts. We utilized latent class analysis independently in each cohort to identify subphenotypes based on clinical and laboratory variables. We then analyzed the associations of subphenotypes with 28-day mortality.

Results: Latent class analysis identified four subphenotypes (SP) with consistent characteristics across Discovery (45 centers, n=2,188) and Replication (22 centers, n=1,112) cohorts. SP1 was characterized by shock, acidemia, and multi-organ dysfunction, including acute kidney injury treated with renal replacement therapy. SP2 was characterized by high C-reactive protein, early need for mechanical ventilation, and the highest rate of ARDS. SP3 had the highest burden of chronic diseases, while SP4 had limited chronic disease burden and mild physiologic abnormalities. 28-day mortality in the Discovery cohort ranged from 20.6% (SP4) to 52.9% (SP1). Mortality across subphenotypes remained different after adjustment for demographics, comorbidities, organ dysfunction and illness severity, regional and hospital factors: compared with SP4, SP1 relative risk (RR) 1.67 (95% CI 1.36-2.03); SP2 RR 1.39 (1.17-1.65); SP3 RR 1.39 (1.15-1.67). Findings were similar in the Replication cohort.

Interpretation: We identified four subphenotypes of COVID-19 critical illness with distinct patterns of clinical and laboratory characteristics, comorbidity burden, and mortality.
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http://dx.doi.org/10.1016/j.chest.2021.04.062DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8099539PMC
May 2021

Application of Indian Academy of Cytologists Guidelines for Reporting Serous Effusions: An Institutional Experience.

J Cytol 2021 Jan-Mar;38(1):1-7. Epub 2021 Feb 17.

Department of Cytology and Gynecological Pathology, Postgraduate Institute of Medical Education and Research, Chandigarh, India.

Background: Recently, the Indian Academy of Cytologists (IAC) has published the guidelines for interpretation and reporting of serous effusions. Till date, there are no studies on its applicability.

Aims: The present study was carried out to assess the feasibility of applying the IAC reporting categories to effusions, determine the frequency, and provide an estimate of the risk of malignancy (ROM) for individual diagnostic categories.

Materials And Methods: All cases of serous effusion fluids reported in the year 2019 were retrieved from the archives and reassigned as per the IAC diagnostic categories. The clinical and histopathological follow-up information was obtained wherever possible.

Results: A total of 1340 effusion samples were received from 1085 patients. There were 561 (51.7%) males and 524 (48.3%) females. Majority were pleural (1066, 79.5%), followed by peritoneal (187, 14%) and pericardial (87, 6.5%) effusions. The age ranged from 7 months to 92 years. There were 35 (2.6%) samples in category 1 (non-diagnostic), 954 (71.2%) in category 2 (benign), 17 (1.3%) in category 3 (atypical), 59 (4.4%) in category 4 (suspicious for malignancy) and 275 (20.5%) in category 5 (malignant). The estimated ROM in serous effusion samples was 20% for category 1, 16.7% for category 2, 50% for category 3, 94.4% for category 4 and 100% for category 5.

Conclusions: The categorization of serous effusion cytology samples as per the IAC diagnostic categories and as per the reporting format developed by the IAC is feasible and the management recommendations are mostly appropriate.
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http://dx.doi.org/10.4103/JOC.JOC_224_20DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8078616PMC
February 2021

Tocilizumab in COVID-19: some clarity amid controversy.

Lancet 2021 05;397(10285):1599-1601

Division of Renal Medicine, Brigham and Women's Hospital, Boston, MA 02115, USA; Harvard Medical School, Boston, MA, USA.

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http://dx.doi.org/10.1016/S0140-6736(21)00712-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8084409PMC
May 2021

Ten-eleven translocase: key regulator of the methylation landscape in cancer.

J Cancer Res Clin Oncol 2021 Jul 28;147(7):1869-1879. Epub 2021 Apr 28.

Department of Biochemistry, All India Institute of Medical Sciences, Jodhpur, Rajasthan, 342005, India.

Purpose: Methylation of 5th residue of cytosine in CpG island forms 5-methylcytosine which is stable, heritable epigenetic mark. Methylation levels are broadly governed by methyltransferases and demethylases. An aberration in the demethylation process contributes to the silencing of gene expression. Ten eleven translocation (TET) dioxygenase (1-3) the de novo demethylase is responsible for conversion of 5-methylcytosine (5-mC) to 5-hydroxymethylcytosine (5-hmC), 5-formylcytosisne (5-fC) and 5-carboxycytosine (5-caC) during demethylation process. Mutations and abnormal expression of TET proteins contribute to carcinogenesis. Discovery of TET proteins has offered various pathways for the reversal of methylation levels thus, enhancing our knowledge as to how methylation effects cancer progression.

Methods: We searched "PubMed" and "Google scholar" databases and selected studies with the following keywords "TET enzyme", "cancer", "5-hmC", and "DNA demethylation". In this review, we have discussed combinatorial use of vitamin C in inhibiting tumour growth by enhancing the catalytic activity of TET enzymes and consequently, increasing the 5-hmC levels. 5-Hydroxymethylcytosine holds promise as a prognostic biomarker in solid cancers. The contribution of induction and suppression of TET enzymes and 5-hmC carcinogenesis are discussed in haematological and solid cancers.

Results: We found that TET enzymes play central role in maintaining the methylation balance. Any anomaly in their expression may dip the balance towards cancer progression. Low levels of TET enzymes and 5-hmC correlate with tumour invasion, progression and metastasis. Also, use of vitamin C enhances TET activity.

Conclusion: TET enzymes play vital role in shaping the methylation landscape in body. 5-hmC can be used as prognostic marker in solid cancers.
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http://dx.doi.org/10.1007/s00432-021-03641-3DOI Listing
July 2021

Hospital-Level Variation in Death for Critically Ill Patients with COVID-19.

Am J Respir Crit Care Med 2021 Apr 23. Epub 2021 Apr 23.

Brigham and Women's Hospital, 1861, Division of Renal Medicine, Boston, Massachusetts, United States.

Rationale: Variation in hospital mortality has been described for coronavirus disease 2019 (COVID-19), but the factors that explain these differences remain unclear.

Objective: Our objective was to utilize a large, nationally representative dataset of critically ill adults with COVID-19 to determine which factors explain mortality variability.

Methods: In this multicenter cohort study, we examined adults hospitalized in intensive care units with COVID-19 at 70 United States hospitals between March and June 2020. The primary outcome was 28-day mortality. We examined patient-level and hospital-level variables. Mixed-effects logistic regression was used to identify factors associated with interhospital variation. The median odds ratio (OR) was calculated to compare outcomes in higher- vs. lower-mortality hospitals. A gradient boosted machine algorithm was developed for individual-level mortality models.

Measurements And Main Results: A total of 4,019 patients were included, 1537 (38%) of whom died by 28 days. Mortality varied considerably across hospitals (0-82%). After adjustment for patient- and hospital-level domains, interhospital variation was attenuated (OR decline from 2.06 [95% CI, 1.73-2.37] to 1.22 [95% CI, 1.00-1.38]), with the greatest changes occurring with adjustment for acute physiology, socioeconomic status, and strain. For individual patients, the relative contribution of each domain to mortality risk was: acute physiology (49%), demographics and comorbidities (20%), socioeconomic status (12%), strain (9%), hospital quality (8%), and treatments (3%).

Conclusion: There is considerable interhospital variation in mortality for critically ill patients with COVID-19, which is mostly explained by hospital-level socioeconomic status, strain, and acute physiologic differences. Individual mortality is driven mostly by patient-level factors. This article is open access and distributed under the terms of the Creative Commons Attribution Non-Commercial No Derivatives License 4.0 (http://creativecommons.org/licenses/by-nc-nd/4.0/).
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http://dx.doi.org/10.1164/rccm.202012-4547OCDOI Listing
April 2021

Tissue Plasminogen Activator in Critically Ill Adults with COVID-19.

Ann Am Thorac Soc 2021 Apr 19. Epub 2021 Apr 19.

Brigham and Women's Hospital, 1861, Division of Renal Medicine, Boston, Massachusetts, United States.

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http://dx.doi.org/10.1513/AnnalsATS.202102-127RLDOI Listing
April 2021

Immunomodulation by epigenome alterations in Mycobacterium tuberculosis infection.

Tuberculosis (Edinb) 2021 May 12;128:102077. Epub 2021 Mar 12.

Department of Biochemistry, All India Institute of Medical Sciences, Jodhpur, 342005, India. Electronic address:

Mycobacterium tuberculosis (MTB) has co-evolved with humans for decades and developed several mechanisms to evade host immunity. It can efficiently alter the host epigenome, thus playing a major role in immunomodulation by either activating or suppressing genes responsible for mounting an immune response against the pathogen. Epigenetic modifications such as DNA methylation and chromatin remodelling regulate gene expression and influence several cellular processes. The involvement of epigenetic factors in disease onset and development had been overlooked upon in comparison to genetic mutations. It is now believed that assessment of epigenetic changes hold great potential in diagnosis, prevention and treatment strategies for a wide range of diseases. In this review, we unravel the principles of epigenetics and the numerous ways by which MTB re-shapes the host epigenetic landscape as a strategy to overpower the host immune system for its survival and persistence.
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http://dx.doi.org/10.1016/j.tube.2021.102077DOI Listing
May 2021

Unfolding antifungals: as a new foe to pancreatic ductal adenocarcinoma-a mini-review.

Mol Biol Rep 2021 Mar 1;48(3):2945-2956. Epub 2021 Apr 1.

Department of Biochemistry, Central University of Rajasthan, NH-8, Bandarsindri, Ajmer, 305817, Rajasthan, India.

Increased deaths caused due to pancreatic cancer (PC) is drawing much attention towards an immediate need for therapeutics that could possibly control this disease and increase the patients' survival rate. Despite the long list of well-established chemotherapeutic drugs in several cancers none have proved to be efficient against PC, and the increasing chemoresistance to the gold standard drug gemcitabine calls a need to search for solutions in other categories of drug. To the rescue, antifungals have shown themselves to be effective against PC and can increase gemcitabine sensitivity against PC. In this mini-review, we reported how antifungals have targeted PC and helped to reduce its lethality. Additionally, it is emphasized that how the antifungals show new mechanisms that could be triggered by using either monotherapy or combination therapy of these antifungals with chemotherapeutic drugs in PC. Moreover it shows an approach of using other drugs with possible same or other mechanism to know their effect on PC.
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http://dx.doi.org/10.1007/s11033-021-06318-9DOI Listing
March 2021

Diphenhydramine for the prevention of cisplatin-associated acute kidney injury.

Kidney Int 2021 04;99(4):1025-1026

Division of Renal Medicine, Brigham and Women's Hospital, Boston, Massachusetts, USA. Electronic address:

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http://dx.doi.org/10.1016/j.kint.2021.01.007DOI Listing
April 2021

Diagnostic accuracy and cytomorphological spectrum of Wilms tumour in fine needle aspiration biopsy cytology samples supplemented with cell blocks.

Pediatr Blood Cancer 2021 Jul 21;68(7):e28996. Epub 2021 Mar 21.

Department of Cytology and Gynaecological Pathology, Post Graduate Institute of Medical Education and Research, Chandigarh, India.

Objective: Paediatric malignant renal neoplasms are subjected to neoadjuvant chemotherapy as per Societe Internationale d'Oncologie Pediatrique; International Society of Pediatric Oncology (SIOP) protocol. An accurate tissue diagnosis is required prior to institution of chemotherapy, and hence the aim of this study was to evaluate the diagnostic accuracy of fine needle aspiration biopsy cytology (FNABC) along with cell block histology.

Materials And Methods: A retrospective audit of all paediatric renal neoplasms diagnosed by FNABC between 2015 and 2019 was performed. Histopathology correlation was done wherever available. WT cases were subjected to detailed cytomorphological evaluation.

Results: A total of 121 cases of paediatric renal neoplasms including 109 WT, four clear cell sarcoma, one malignant rhabdoid tumour and three mesoblastic nephroma were evaluated. The age range was 4 weeks to 8 years. FNABC samples were adequate for diagnosis in 120 of 121 cases (99.18%) and a definitive cytological diagnosis was achieved in 117 cases (96.7%). The specificity and sensitivity for a cytopathological diagnosis of WT were 98.7% and 97.4%, respectively. On detailed cytomorphological analysis of 68 histopathology-proven WT, 40 (58.8%) cases were triphasic, 23 (35.3%) were biphasic and four were composed of blastema only. The corresponding cell blocks provided additional information over the conventional smears in 23 (33.8%) cases, with epithelial or mesenchymal elements recognised and evidence of rhabdomyoblastic differentiation.

Conclusion: FNABC along with cell block histology is highly accurate for diagnosis of WT and other malignant paediatric renal neoplasms and is recommended as the technique of choice in centres with cytopathology expertise for establishing a cellular diagnosis prior to commencement of neoadjuvant chemotherapy.
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http://dx.doi.org/10.1002/pbc.28996DOI Listing
July 2021

Efficacy of Jellow app as an adjunct to stimulation therapy in improvement in language and quality of life in patients with chronic Broca's Aphasia.

Disabil Rehabil Assist Technol 2021 Mar 10:1-7. Epub 2021 Mar 10.

Department of ENT, PGIMER, Chandigarh, India.

Stimulation approach is a therapy technique to improve language production using auditory and visual stimulation. Jellow app is a mobile app designed for compensating for impaired language skills and may be used in the intervention of persons with aphasia. The study aimed to determine the benefits of using the Jellow app as a facilitator of stimulus therapy to improve language and psychosocial domains in chronic Broca's Aphasia. Ten right-handed male adults with Broca's Aphasia were assessed on WAB and SIQOL39g tests. The control group ( = 5) was enrolled only for stimulation therapy. Pictures of objects were used for therapy with the help of auditory or auditory and visual cues. In the study group ( = 5), along with stimulus therapy, subjects were also trained on the use of icons in the Jellow app to facilitate functional communication needs. After six-months tests were readministered. Post-therapy, on WAB, the improvement in spontaneous speech, repetition, and naming were found to be significantly more in the study group (4.6 ± 0.55, 4.89 ± 0.56, 5.74 ± 0.24 respectively) than the control group (2.6 ± 0.89, 3.22 ± 0.49, 3.97 ± 0.3 respectively) on 2-sample -test. Similarly, significantly more improvement was seen in the communication domain of SAQOL39g in the study group (2.03 ± 0.17) compared to the control group (1.14 ± 0.45). Use of the Jellow app may be a beneficial adjunct to stimulation therapy for improving linguistic abilities and quality of life in persons with chronic Broca's aphasia.IMPLICATIONS FOR REHABILITATIONFollowing are the implications of this study in the rehabilitation of persons with chronic Broca's Aphasia:• Multimodality in therapy approach in traditional stimulation therapy is beneficial.• AAC Apps like the Jellow app can be used as an adjunct to the traditional stimulation approach of language intervention which facilitates the language abilities like spontaneous speech, repetition, and naming.• Language improvement due to rehabilitation is beneficial in improving the quality of life in this population.• The caregivers must be involved in the therapy program as they act as communication partners and can repeat the therapy tasks at home.• Similar type of study is warranted in a larger population so that people with chronic Broca's aphasia may get the benefit of the latest technology which may be cheaper and easier to use.
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http://dx.doi.org/10.1080/17483107.2021.1892844DOI Listing
March 2021

A novel homozygous variant in exon 10 of the gene causing hyperphosphatemic familial tumoral calcinosis in a family from North India.

Intractable Rare Dis Res 2021 Feb;10(1):55-57

Institute of Human Genetics, Technische Universität München, Munich, Germany.

Hyperphosphatemic familial tumoral calcinosis (HFTC) is an extremely rare autosomal recessive disorder caused by variants in the (N-acetylgalactosaminyltransferase 3), (Fibroblast Growth Factor-23) and (α-Klotho) genes, which results in progressive calcification of soft tissues. We describe the case of a 9-year-old girl who presented with recurrent hard nodular swellings on her feet and knees which intermittently discharged chalky white material. Her younger brother also had a similar condition. Both siblings showed hyperphosphatemia, but the parentsbiochemical parameters were normal. The histological features of the material aspirated from a skin lesion were consistent with tumoral calcinosis. Sanger sequencing identified a novel homozygous non-synonymous sequence variant in exon 10 of the gene (NM_004482.3:c.[1681T>A];[1681T>A], NP_004473.2:p. [Cys561Ser];[Cys561Ser] in the proband and her affected brother. The parents were heterozygous carriers for the same sequence variant. In conclusion, we report a new variant in the gene that caused HFTC in a North Indian family.
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http://dx.doi.org/10.5582/irdr.2020.03084DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7882081PMC
February 2021

Prone Positioning and Survival in Mechanically Ventilated Patients With Coronavirus Disease 2019-Related Respiratory Failure.

Crit Care Med 2021 02 17. Epub 2021 Feb 17.

Division of Pulmonary, Critical Care, and Sleep Medicine, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY. Department of Emergency Medicine, Icahn School of Medicine at Mount Sinai, New York, NY. Department of Anesthesia, Critical Care and Pain Medicine, Beth Israel Deaconess Medical Center, Boston, MA. Department of Medicine and Neurology, Brigham and Women's Hospital, Boston, MA. Division of Nephrology, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY. Division of Renal Medicine, Department of Medicine, Brigham and Women's Hospital, Boston, MA. Division of Cardiology, Department of Medicine, University of Michigan, Ann Arbor, MI. Division of Nephrology and Hypertension, Department of Medicine, Center for Translational Metabolism and Health, Institute for Public Health and Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL. Department of Internal Medicine, Hackensack Meridian School of Medicine, Nutley, NJ. Department of Internal Medicine, Heart & Vascular Hospital, Hackensack Meridian Health, Hackensack University Medical Center, Hackensack, NJ. Department of Medicine, Rutgers Robert Wood Johnson Medical School, New Brunswick, NJ. Division of Critical Care Medicine, Department of Medicine, Cooper University Health Care, Camden, NJ. Division of Pulmonary and Critical Care Medicine, Department of Medicine, Rutgers New Jersey Medical School, Newark, NJ. Division of Renal-Electrolyte and Hypertension, Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA. Department of Medicine, Hackensack Meridian Health Mountainside Medical Center, Glen Ridge, NJ. Division of Pulmonary and Critical Care Medicine, Department of Medicine Weill Cornell Medicine, New York, NY. Larner College of Medicine, University of Vermont, Burlington, VT. Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA. Department of Biostatistics, Harvard T.H. Chan School of Public Health, Boston, MA. Division of Health Sciences and Technology, Harvard-Massachusetts Institute of Technology, Boston, MA.

Objectives: Therapies for patients with respiratory failure from coronavirus disease 2019 are urgently needed. Early implementation of prone positioning ventilation improves survival in patients with acute respiratory distress syndrome, but studies examining the effect of proning on survival in patients with coronavirus disease 2019 are lacking. Our objective was to estimate the effect of early proning initiation on survival in patients with coronavirus disease 2019-associated respiratory failure.

Design: Data were derived from the Study of the Treatment and Outcomes in Critically Ill Patients with coronavirus disease 2019, a multicenter cohort study of critically ill adults with coronavirus disease 2019 admitted to 68 U.S. hospitals. Using these data, we emulated a target trial of prone positioning ventilation by categorizing mechanically ventilated hypoxemic (ratio of PaO2 over the corresponding FIO2 ≤ 200 mm Hg) patients as having been initiated on proning or not within 2 days of ICU admission. We fit an inverse probability-weighted Cox model to estimate the mortality hazard ratio for early proning versus no early proning. Patients were followed until death, hospital discharge, or end of follow-up.

Setting: ICUs at 68 U.S. sites.

Patients: Critically ill adults with laboratory-confirmed coronavirus disease 2019 receiving invasive mechanical ventilation with ratio of PaO2 over the corresponding FIO2 less than or equal to 200 mm Hg.

Interventions: None.

Measurements And Main Results: Among 2,338 eligible patients, 702 (30.0%) were proned within the first 2 days of ICU admission. After inverse probability weighting, baseline and severity of illness characteristics were well-balanced between groups. A total of 1,017 (43.5%) of the 2,338 patients were discharged alive, 1,101 (47.1%) died, and 220 (9.4%) were still hospitalized at last follow-up. Patients proned within the first 2 days of ICU admission had a lower adjusted risk of death compared with nonproned patients (hazard ratio, 0.84; 95% CI, 0.73-0.97).

Conclusions: In-hospital mortality was lower in mechanically ventilated hypoxemic patients with coronavirus disease 2019 treated with early proning compared with patients whose treatment did not include early proning.
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http://dx.doi.org/10.1097/CCM.0000000000004938DOI Listing
February 2021

d-dimer and Death in Critically Ill Patients With Coronavirus Disease 2019.

Crit Care Med 2021 05;49(5):e500-e511

Division of Renal Medicine, Brigham and Women's Hospital, Boston, MA.

Objectives: Hypercoagulability may be a key mechanism for acute organ injury and death in patients with severe coronavirus disease 2019, but the relationship between elevated plasma levels of d-dimer, a biomarker of coagulation activation, and mortality has not been rigorously studied. We examined the independent association between d-dimer and death in critically ill patients with coronavirus disease 2019.

Design: Multicenter cohort study.

Setting: ICUs at 68 hospitals across the United States.

Patients: Critically ill adults with coronavirus disease 2019 admitted to ICUs between March 4, 2020, and May 25, 2020, with a measured d-dimer concentration on ICU day 1 or 2.

Interventions: None.

Measurements And Main Results: The primary exposure was the highest normalized d-dimer level (assessed in four categories: < 2×, 2-3.9×, 4-7.9×, and ≥ 8× the upper limit of normal) on ICU day 1 or 2. The primary endpoint was 28-day mortality. Multivariable logistic regression was used to adjust for confounders. Among 3,418 patients (63.1% male; median age 62 yr [interquartile range, 52-71 yr]), 3,352 (93.6%) had a d-dimer concentration above the upper limit of normal. A total of 1,180 patients (34.5%) died within 28 days. Patients in the highest compared with lowest d-dimer category had a 3.11-fold higher odds of death (95% CI, 2.56-3.77) in univariate analyses, decreasing to a 1.81-fold increased odds of death (95% CI, 1.43-2.28) after multivariable adjustment for demographics, comorbidities, and illness severity. Further adjustment for therapeutic anticoagulation did not meaningfully attenuate this relationship (odds ratio, 1.73; 95% CI, 1.36-2.19).

Conclusions: In a large multicenter cohort study of critically ill patients with coronavirus disease 2019, higher d-dimer levels were independently associated with a greater risk of death.
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http://dx.doi.org/10.1097/CCM.0000000000004917DOI Listing
May 2021

Extracorporeal membrane oxygenation in patients with severe respiratory failure from COVID-19.

Intensive Care Med 2021 02 2;47(2):208-221. Epub 2021 Feb 2.

Division of Renal Medicine, Brigham and Women's Hospital, Boston, MA, USA.

Purpose: Limited data are available on venovenous extracorporeal membrane oxygenation (ECMO) in patients with severe hypoxemic respiratory failure from coronavirus disease 2019 (COVID-19).

Methods: We examined the clinical features and outcomes of 190 patients treated with ECMO within 14 days of ICU admission, using data from a multicenter cohort study of 5122 critically ill adults with COVID-19 admitted to 68 hospitals across the United States. To estimate the effect of ECMO on mortality, we emulated a target trial of ECMO receipt versus no ECMO receipt within 7 days of ICU admission among mechanically ventilated patients with severe hypoxemia (PaO/FiO < 100). Patients were followed until hospital discharge, death, or a minimum of 60 days. We adjusted for confounding using a multivariable Cox model.

Results: Among the 190 patients treated with ECMO, the median age was 49 years (IQR 41-58), 137 (72.1%) were men, and the median PaO/FiO prior to ECMO initiation was 72 (IQR 61-90). At 60 days, 63 patients (33.2%) had died, 94 (49.5%) were discharged, and 33 (17.4%) remained hospitalized. Among the 1297 patients eligible for the target trial emulation, 45 of the 130 (34.6%) who received ECMO died, and 553 of the 1167 (47.4%) who did not receive ECMO died. In the primary analysis, patients who received ECMO had lower mortality than those who did not (HR 0.55; 95% CI 0.41-0.74). Results were similar in a secondary analysis limited to patients with PaO/FiO < 80 (HR 0.55; 95% CI 0.40-0.77).

Conclusion: In select patients with severe respiratory failure from COVID-19, ECMO may reduce mortality.
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http://dx.doi.org/10.1007/s00134-020-06331-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7851810PMC
February 2021

Thrombosis, Bleeding, and the Observational Effect of Early Therapeutic Anticoagulation on Survival in Critically Ill Patients With COVID-19.

Ann Intern Med 2021 05 26;174(5):622-632. Epub 2021 Jan 26.

University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania (A.D.B.).

Background: Hypercoagulability may be a key mechanism of death in patients with coronavirus disease 2019 (COVID-19).

Objective: To evaluate the incidence of venous thromboembolism (VTE) and major bleeding in critically ill patients with COVID-19 and examine the observational effect of early therapeutic anticoagulation on survival.

Design: In a multicenter cohort study of 3239 critically ill adults with COVID-19, the incidence of VTE and major bleeding within 14 days after intensive care unit (ICU) admission was evaluated. A target trial emulation in which patients were categorized according to receipt or no receipt of therapeutic anticoagulation in the first 2 days of ICU admission was done to examine the observational effect of early therapeutic anticoagulation on survival. A Cox model with inverse probability weighting to adjust for confounding was used.

Setting: 67 hospitals in the United States.

Participants: Adults with COVID-19 admitted to a participating ICU.

Measurements: Time to death, censored at hospital discharge, or date of last follow-up.

Results: Among the 3239 patients included, the median age was 61 years (interquartile range, 53 to 71 years), and 2088 (64.5%) were men. A total of 204 patients (6.3%) developed VTE, and 90 patients (2.8%) developed a major bleeding event. Independent predictors of VTE were male sex and higher D-dimer level on ICU admission. Among the 2809 patients included in the target trial emulation, 384 (11.9%) received early therapeutic anticoagulation. In the primary analysis, during a median follow-up of 27 days, patients who received early therapeutic anticoagulation had a similar risk for death as those who did not (hazard ratio, 1.12 [95% CI, 0.92 to 1.35]).

Limitation: Observational design.

Conclusion: Among critically ill adults with COVID-19, early therapeutic anticoagulation did not affect survival in the target trial emulation.

Primary Funding Source: None.
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http://dx.doi.org/10.7326/M20-6739DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7863679PMC
May 2021

Feature Selection for Topological Proximity Prediction of Single-Cell Transcriptomic Profiles in Embryo Using Genetic Algorithm.

Genes (Basel) 2020 Dec 28;12(1). Epub 2020 Dec 28.

School of Computational and Integrative Sciences, Jawaharlal Nehru University, New Mehrauli Road, New Delhi 110067, India.

Single-cell transcriptomics data, when combined with in situ hybridization patterns of specific genes, can help in recovering the spatial information lost during cell isolation. Dialogue for Reverse Engineering Assessments and Methods (DREAM) consortium conducted a crowd-sourced competition known as DREAM Single Cell Transcriptomics Challenge (SCTC) to predict the masked locations of single cells from a set of 60, 40 and 20 genes out of 84 in situ gene patterns known in embryo. We applied a genetic algorithm (GA) to predict the most important genes that carry positional and proximity information of the single-cell origins, in combination with the base distance mapping algorithm DistMap. Resulting gene selection was found to perform well and was ranked among top 10 in two of the three sub-challenges. However, the details of the method did not make it to the main challenge publication, due to an intricate aggregation ranking. In this work, we discuss the detailed implementation of GA and its post-challenge parameterization, with a view to identify potential areas where GA-based approaches of gene-set selection for topological association prediction may be improved, to be more effective. We believe this work provides additional insights into the feature-selection strategies and their relevance to single-cell similarity prediction and will form a strong addendum to the recently published work from the consortium.
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http://dx.doi.org/10.3390/genes12010028DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7824175PMC
December 2020

A multi-center study on safety and efficacy of immune checkpoint inhibitors in cancer patients with kidney transplant.

Kidney Int 2020 Dec 24. Epub 2020 Dec 24.

Division of Nephrology, University of Nebraska Medical Center, Omaha, Nebraska, USA.

Immune checkpoint inhibitors (ICIs) are widely used for various malignancies. However, their safety and efficacy in patients with a kidney transplant have not been defined. To delineate this, we conducted a multicenter retrospective study of 69 patients with a kidney transplant receiving ICIs between January 2010 and May 2020. For safety, we assessed the incidence, timing, and risk factors of acute graft rejection. For efficacy, objective response rate and overall survival were assessed in cutaneous squamous cell carcinoma and melanoma, the most common cancers in our cohort, and compared with stage-matched 23 patients with squamous cell carcinoma and 14 with melanoma with a kidney transplant not receiving ICIs. Following ICI treatment, 29 out of 69 (42%) patients developed acute rejection, 19 of whom lost their allograft, compared with an acute rejection rate of 5.4% in the non-ICI cohort. Median time from ICI initiation to rejection was 24 days. Factors associated with a lower risk of rejection were mTOR inhibitor use (odds ratio 0.26; 95% confidence interval, 0.09-0.72) and triple-agent immunosuppression (0.67, 0.48-0.92). The objective response ratio was 36.4% and 40% in the squamous cell carcinoma and melanoma subgroups, respectively. In the squamous cell carcinoma subgroup, overall survival was significantly longer in patients treated with ICIs (median overall survival 19.8 months vs. 10.6 months), whereas in the melanoma subgroup, overall survival did not differ between groups. Thus, ICIs were associated with a high risk of rejection in patients with kidney transplants but may lead to improved cancer outcomes. Prospective studies are needed to determine optimal immunosuppression strategies to improve patient outcomes.
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http://dx.doi.org/10.1016/j.kint.2020.12.015DOI Listing
December 2020

Tocilizumab in Covid-19.

N Engl J Med 2021 01 22;384(1):86-87. Epub 2020 Dec 22.

Brigham and Women's Hospital, Boston, MA

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http://dx.doi.org/10.1056/NEJMc2032911DOI Listing
January 2021

Trends in the crossover of patients in phase III oncology clinical trials in the USA.

Ecancermedicalscience 2020 13;14:1142. Epub 2020 Nov 13.

Division of Hematology/Oncology, Georgia Cancer Center, Augusta University, Augusta, GA 30909, USA.

Background: The incorporation of crossover in randomised controlled trials is accepted as an ethical obligation, especially in cancer clinical trials. The more common type of crossover is crossover allowance, which allows patients assigned to one arm to switch to another arm if there is an established benefit in the crossover arm. In contrast, crossover-designed studies involve switching patients from all arms to a different arm as part of the study design. Crossover allowance may have advantages in patient recruitment and incorporating crossover after initial positive results fulfil ethical requirements. However, crossover can also contribute to confounding major endpoints of studies, such as overall survival or the second progression-free survival interval. For this reason, it is important to investigate and identify potential trends of crossover in clinical trials testing novel therapies.

Methods: Data about cancer clinical trials were extracted from clinicaltrials.gov. The search query was limited to completed phase III studies in adult populations. Location was limited to the USA. Date range extended from 1990 to 2019. Search query included the terms: cancer; completed- recruitment status; age: 18-65+ years; sex: all; location: USA; and study phase: phase 3. Studies were then excluded if they were not randomised controlled trials (RCTs) with the primary purpose of treatment and if they did not test cancer-related interventions.

Results: A total of 744 clinical trials were identified. There were 459 RCTs aimed at treatment, and of those, 35 utilised crossover. The start dates of these crossover trials ranged from 1997 to 2012. Thirty studies utilised crossover allowance. Prostate, breast and gastrointestinal stromal tumour cancers were the most represented cancer types in crossover studies. Among the 30 studies, the median proportion of patients who crossed over relative to the original arm assignment ranged from 2% to 88%, with a median of 57.5%.

Conclusions: The proportion of identified clinical trials with crossover compared to those without is extremely small. Crossover in clinical trials studying cancer treatment does not appear to be a widespread practice. Even though statistical approaches to mitigate confounding exist, crossover can still skew accurate reporting of the impact of experimental therapies on overall survival.
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http://dx.doi.org/10.3332/ecancer.2020.1142DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7738270PMC
November 2020

Response to "Is the outcome of SARS-CoV-2 infection in solid organ transplant recipients really similar to that of the general population?"

Am J Transplant 2021 04 12;21(4):1672-1673. Epub 2021 Jan 12.

Division of Renal Medicine, Brigham and Women's Hospital, Boston, Massachusetts.

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http://dx.doi.org/10.1111/ajt.16413DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7753479PMC
April 2021

Incidence of Hyponatremia in Patients With Indwelling Peritoneal Catheters for Drainage of Malignant Ascites.

JAMA Netw Open 2020 10 1;3(10):e2017859. Epub 2020 Oct 1.

Division of Renal Medicine, Department of Medicine, Brigham and Women's Hospital, Boston, Massachusetts.

Importance: Indwelling peritoneal catheters (IPCs) are frequently used to drain tense, symptomatic, malignant ascites. Large-volume drainage may lead to hyponatremia owing to massive salt depletion. To date, no studies have examined the epidemiology of hyponatremia after placement of an IPC.

Objective: To evaluate the incidence of hyponatremia after IPC placement, the risk factors associated with its development, and how it is managed.

Design, Setting, And Participants: This cohort study retrospectively reviewed the medical records of 461 patients who had IPCs placed during the period between 2006 and 2016 at a tertiary care hospital in Boston, Massachusetts, of whom 309 patients met the inclusion criteria. Data analysis was performed from June to November 2019.

Main Outcomes And Measures: Main outcomes were the incidence of hyponatremia (with a serum sodium level <135 mEq/L) after IPC placement, the risk factors for its development, and how it was managed. We also examined the clinical course of a subset of 21 patients with hypovolemic hyponatremia.

Results: Of the 309 eligible patients with laboratory results both before IPC placement and 2 days or more after IPC placement, 189 (72.1%) were female, and the mean (SD) age was 59 (12) years. The overall incidence of hyponatremia after IPC placement was 84.8% (n = 262), of whom 21 patients (8.0%) had severe hyponatremia. The mean (SD) decrease in serum sodium level before vs after IPC placement was 5 (5.1) mEq/L and decreased by 10 mEq/L or more among 52 patients (16.8%). Patients with hyponatremia prior to IPC placement had an 8-fold higher adjusted odds of having persistent hyponatremia after IPC placement (odds ratio, 7.9; 95% CI, 2.9-21.7). Patients with hepatopancreatobiliary malignant neoplasms were more likely to develop hyponatremia (78 of 262 patients with hyponatremia [29.8%] vs 7 of 47 patients without hyponatremia [14.9%]). Hyponatremia was either unrecognized or untreated in 189 patients (72.1%).

Conclusions And Relevance: Although the placement of an IPC is often a palliative measure, hyponatremia is common and is often untreated or unrecognized. Patients at highest risk, such as those with hyponatremia at baseline and those with hepatopancreatobiliary malignant neoplams, should be evaluated carefully prior to IPC placement and may warrant closer monitoring after placement. In all cases, hyponatremia should be evaluated and managed within the context of a patient's overall goals of care.
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http://dx.doi.org/10.1001/jamanetworkopen.2020.17859DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7588930PMC
October 2020

Incidence and Clinical Features of Immune-Related Acute Kidney Injury in Patients Receiving Programmed Cell Death Ligand-1 Inhibitors.

Kidney Int Rep 2020 Oct 21;5(10):1700-1705. Epub 2020 Jul 21.

Department of Medicine, Division of Nephrology, Massachusetts General Hospital, Boston, Massachusetts, USA.

Background: Programmed cell death receptor ligand 1 (PD-L1) inhibitors are immune checkpoint inhibitors (ICIs) with a side effect profile that may differ from other classes of ICIs such as those directed against cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) and programmed cell death 1 receptor (PD-1). Being the more recently approved class of checkpoint inhibitors, there are no studies investigating the frequency, etiology and predictors of acute kidney injury (AKI) in patients receiving PD-L1 inhibitors.

Methods: This was a retrospective cohort study of patients who received PD-L1 inhibitors during 2017 to 2018 in our healthcare system. AKI was defined by a ≥1.5-fold rise in serum creatinine from baseline. The etiology of all cases of sustained AKI (lasting >48 hours) and clinical course were determined by review of electronic health records.

Results: The final analysis included 599 patients. Within 12 months of ICI initiation, 104 patients (17%) experienced AKI, and 36 (6%) experienced sustained AKI; however, only 5 (<1%) experienced suspected PD-L1-related AKI. The PD-L1-related AKI occurred a median of 99 days after starting therapy. All patients concurrently received another medication known to cause acute interstitial nephritis (proton pump inhibitors, nonsteroidal anti-inflammatory drugs, or antibiotics) at the time of the suspected PDL1-related AKI.

Conclusion: Although AKI is common in patients receiving PD-L1 therapy, the incidence of suspected PD-L1-related AKI is low (<1%) and may be less common when compared to other classes of ICIs. This cohort provides further validation that other drugs associated with acute interstitial nephritis may be involved in the pathogenesis of ICI-related AKI.
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http://dx.doi.org/10.1016/j.ekir.2020.07.011DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7569697PMC
October 2020

Histopathologic Correlates of Kidney Function: Insights From Nephrectomy Specimens.

Am J Kidney Dis 2021 03 21;77(3):336-345. Epub 2020 Oct 21.

Division of Renal Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA. Electronic address:

Rationale & Objective: Existing data sets correlating kidney histopathologic findings with kidney function have low proportions of elderly patients (and those with a family history of kidney failure are over-represented), which limits their generalizability. Our objective was to use non-neoplastic tissue from nephrectomy specimens to examine the association between degree of histopathologic changes and estimated glomerular filtration rate (eGFR) and determine whether the association differed by age.

Study Design: Cross-sectional study.

Exposures: Glomerulosclerosis (GS), interstitial fibrosis/tubular atrophy (IFTA), and arterial sclerosis/arteriosclerosis (AS).

Outcome: eGFR.

Analytical Approach: We retrospectively reviewed kidney pathology reports (of non-neoplastic tissue) from 1,347 patients who underwent nephrectomy (1999-2018) for any indication but most commonly due to kidney cancer. We evaluated the association between degree of GS, IFTA, and AS with eGFR at the time of nephrectomy and whether this was modified by age.

Results: Among the participants (aged 17-91 years), 42% and 57.8% had>10% GS and IFTA, respectively, and 81.8% had moderate or severe AS. We found that greater degrees of GS, IFTA, and AS were associated with lower eGFR after multivariable adjustment. Although there was a greater prevalence of more severe degrees of GS and IFTA in older individuals, the association between various histopathologic features and eGFR was not modified by age.

Limitations: Retrospective cross-sectional study.

Conclusions: Our study demonstrates differences in the histologic appearance of the kidneys across levels of eGFR. Although the prevalence of advanced changes was higher in the oldest group of patients, a subset had excellent kidney function and limited histologic changes.
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http://dx.doi.org/10.1053/j.ajkd.2020.08.015DOI Listing
March 2021