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1. Profiling of insulin-resistant kidney models and human biopsies reveals common and cell-type-specific mechanisms underpinning Diabetic Kidney Disease

Author

Lay, Abigail C., Tran, Van Du T., Nair, Viji, Betin, Virginie, Hurcombe, Jennifer A., Barrington, Alexandra F., Pope, Robert JP, Burdet, Frédéric, Mehl, Florence, Kryvokhyzha, Dmytro, Ahmad, Abrar, Sinton, Matthew C., Lewis, Philip, Wilson, Marieangela C., Menon, Rajasree, Otto, Edgar, Heesom, Kate J., Ibberson, Mark, Looker, Helen C., Nelson, Robert G., Ju, Wenjun, Kretzler, Matthias, Satchell, Simon C., Gomez, Maria F., and Coward, Richard J. M.

Published
2024
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3. Genome-wide meta-analysis and omics integration identifies novel genes associated with diabetic kidney disease

Author

Sandholm, Niina, Cole, Joanne B, Nair, Viji, Sheng, Xin, Liu, Hongbo, Ahlqvist, Emma, van Zuydam, Natalie, Dahlström, Emma H, Fermin, Damian, Smyth, Laura J, Salem, Rany M, Forsblom, Carol, Valo, Erkka, Harjutsalo, Valma, Brennan, Eoin P, McKay, Gareth J, Andrews, Darrell, Doyle, Ross, Looker, Helen C, Nelson, Robert G, Palmer, Colin, McKnight, Amy Jayne, Godson, Catherine, Maxwell, Alexander P, Groop, Leif, McCarthy, Mark I, Kretzler, Matthias, Susztak, Katalin, Hirschhorn, Joel N, Florez, Jose C, and Groop, Per-Henrik

Subjects
Human Genome, Kidney Disease, Prevention, Genetics, Diabetes, Biotechnology, 2.1 Biological and endogenous factors, Aetiology, Renal and urogenital, Metabolic and endocrine, Good Health and Well Being, Diabetes Mellitus, Type 2, Diabetic Nephropathies, Doublecortin-Like Kinases, Fibrosis, Genome-Wide Association Study, Humans, Intracellular Signaling Peptides and Proteins, Kidney, Polymorphism, Single Nucleotide, Protein Serine-Threonine Kinases, Diabetes complications, Diabetic kidney disease, Genome-wide association study, Meta-analysis, Transcriptomics, GENIE Consortium, Genome-wide association study, Meta-analysis, Transcriptomics, Clinical Sciences, Paediatrics and Reproductive Medicine, Public Health and Health Services, Endocrinology & Metabolism
Abstract

Aims/hypothesisDiabetic kidney disease (DKD) is the leading cause of kidney failure and has a substantial genetic component. Our aim was to identify novel genetic factors and genes contributing to DKD by performing meta-analysis of previous genome-wide association studies (GWAS) on DKD and by integrating the results with renal transcriptomics datasets.MethodsWe performed GWAS meta-analyses using ten phenotypic definitions of DKD, including nearly 27,000 individuals with diabetes. Meta-analysis results were integrated with estimated quantitative trait locus data from human glomerular (N=119) and tubular (N=121) samples to perform transcriptome-wide association study. We also performed gene aggregate tests to jointly test all available common genetic markers within a gene, and combined the results with various kidney omics datasets.ResultsThe meta-analysis identified a novel intronic variant (rs72831309) in the TENM2 gene associated with a lower risk of the combined chronic kidney disease (eGFR9.3×10-9). Gene-level analysis identified ten genes associated with DKD (COL20A1, DCLK1, EIF4E, PTPRN-RESP18, GPR158, INIP-SNX30, LSM14A and MFF; p

Published
2022

5. Epigenome-wide meta-analysis identifies DNA methylation biomarkers associated with diabetic kidney disease

Author

Smyth, Laura J, Dahlström, Emma H, Syreeni, Anna, Kerr, Katie, Kilner, Jill, Doyle, Ross, Brennan, Eoin, Nair, Viji, Fermin, Damian, Nelson, Robert G, Looker, Helen C, Wooster, Christopher, Andrews, Darrell, Anderson, Kerry, McKay, Gareth J, Cole, Joanne B, Salem, Rany M, Conlon, Peter J, Kretzler, Matthias, Hirschhorn, Joel N, Sadlier, Denise, Godson, Catherine, Florez, Jose C, Forsblom, Carol, Maxwell, Alexander P, Groop, Per-Henrik, Sandholm, Niina, and McKnight, Amy Jayne

Subjects
Biological Sciences, Genetics, Autoimmune Disease, Diabetes, Human Genome, Kidney Disease, Aetiology, 2.1 Biological and endogenous factors, Metabolic and endocrine, Renal and urogenital, Humans, DNA Methylation, Epigenome, Diabetic Nephropathies, Epigenesis, Genetic, Diabetes Mellitus, Type 1, Biomarkers, DNA, Genome-Wide Association Study, CpG Islands, GENIE consortium
Abstract

Type 1 diabetes affects over nine million individuals globally, with approximately 40% developing diabetic kidney disease. Emerging evidence suggests that epigenetic alterations, such as DNA methylation, are involved in diabetic kidney disease. Here we assess differences in blood-derived genome-wide DNA methylation associated with diabetic kidney disease in 1304 carefully characterised individuals with type 1 diabetes and known renal status from two cohorts in the United Kingdom-Republic of Ireland and Finland. In the meta-analysis, we identify 32 differentially methylated CpGs in diabetic kidney disease in type 1 diabetes, 18 of which are located within genes differentially expressed in kidneys or correlated with pathological traits in diabetic kidney disease. We show that methylation at 21 of the 32 CpGs predict the development of kidney failure, extending the knowledge and potentially identifying individuals at greater risk for diabetic kidney disease in type 1 diabetes.

Published
2022

10. Results of untargeted analysis using the SOMAscan proteomics platform indicates novel associations of circulating proteins with risk of progression to kidney failure in diabetes

Author

Kobayashi, Hiroki, Looker, Helen C., Satake, Eiichiro, Saulnier, Pierre Jean, Md Dom, Zaipul I., O’Neil, Kristina, Ihara, Katsuhito, Krolewski, Bozena, Galecki, Andrzej T., Niewczas, Monika A., Wilson, Jonathan M., Doria, Alessandro, Duffin, Kevin L., Nelson, Robert G., and Krolewski, Andrzej S.

Published
2022
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11. Endogenous adenine mediates kidney injury in diabetic models and predicts diabetic kidney disease in patients

Author

Sharma, Kumar, Zhang, Guanshi, Hansen, Jens, Bjornstad, Petter, Lee, Hak Joo, Menon, Rajasree, Hejazi, Leila, Liu, Jian-Jun, Franzone, Anthony, Looker, Helen C., Choi, Byeong Yeob, Fernandez, Roman, Venkatachalam, Manjeri A., Kugathasan, Luxcia, Sridhar, Vikas S., Natarajan, Loki, Zhang, Jing, Sharma, Varun S., Kwan, Brian, Waikar, Sushrut S., Himmelfarb, Jonathan, Tuttle, Katherine R., Kestenbaum, Bryan, Fuhrer, Tobias, Feldman, Harold I., de Boer, Ian H., Tucci, Fabio C., Sedor, John, Heerspink, Hiddo Lambers, Schaub, Jennifer, Otto, Edgar A., Hodgin, Jeffrey B., Kretzler, Matthias, Anderton, Christopher R., Alexandrov, Theodore, Cherney, David, Lim, Su Chi, Nelson, Robert G., Gelfond, Jonathan, and Iyengar, Ravi

Subjects
United States. National Center for Advancing Translational Sciences, Thermo Fisher Scientific Inc., Bayer AG, Boehringer Ingelheim GmbH, AstraZeneca PLC, Eli Lilly and Co., Novo Nordisk A/S, Sanofi S.A., Medical research -- Health aspects, Medicine, Experimental -- Health aspects, Scientific equipment and supplies industry -- Health aspects, Chronic kidney failure -- Health aspects, Medical colleges -- Health aspects, Type 2 diabetes -- Health aspects, Native Americans -- Health aspects, Pharmaceutical industry -- Health aspects, Purines -- Health aspects, Health care industry
Abstract

Diabetic kidney disease (DKD) can lead to end-stage kidney disease (ESKD) and mortality; however, few mechanistic biomarkers are available for high-risk patients, especially those without macroalbuminuria. Urine from participants with diabetes from the Chronic Renal Insufficiency Cohort (CRIC) study, the Singapore Study of Macro-angiopathy and Micro-vascular Reactivity in Type 2 Diabetes (SMART2D), and the American Indian Study determined whether urine adenine/creatinine ratio (UAdCR) could be a mechanistic biomarker for ESKD. ESKD and mortality were associated with the highest UAdCR tertile in the CRIC study and SMART2D. ESKD was associated with the highest UAdCR tertile in patients without macroalbuminuria in the CRIC study, SMART2D, and the American Indian study. Empagliflozin lowered UAdCR in nonmacroalbuminuric participants. Spatial metabolomics localized adenine to kidney pathology, and single-cell transcriptomics identified ribonucleoprotein biogenesis as a top pathway in proximal tubules of patients without macroalbuminuria, implicating mTOR. Adenine stimulated matrix in tubular cells via mTOR and stimulated mTOR in mouse kidneys. A specific inhibitor of adenine production was found to reduce kidney hypertrophy and kidney injury in diabetic mice. We propose that endogenous adenine may be a causative factor in DKD., Introduction Progression to organ failure is marked by fibrosis and loss of architecture in solid organs, such as the kidney. In almost all progressive chronic kidney diseases (CKDs), the features [...]

Published
2023
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13. Urine metabolites are associated with glomerular lesions in type 2 diabetes.

Author

Saulnier, Pierre-Jean, Darshi, Manjula, Wheelock, Kevin M, Looker, Helen C, Fufaa, Gudeta D, Knowler, William C, Weil, E Jennifer, Tanamas, Stephanie K, Lemley, Kevin V, Saito, Rintaro, Natarajan, Loki, Nelson, Robert G, and Sharma, Kumar

Subjects
Humans, Diabetic Nephropathies, Diabetes Mellitus, Type 2, Kidney Function Tests, Glomerular Filtration Rate, Cross-Sectional Studies, Adult, Middle Aged, Indians, North American, Female, Male, Metabolome, Biomarkers, Kidney structure, Metabolites, Type 2 Diabetes, Diabetes Mellitus, Type 2, Indians, North American, Analytical Chemistry, Biochemistry and Cell Biology, Clinical Sciences
Abstract

INTRODUCTION:Little is known about the association of urine metabolites with structural lesions in persons with diabetes. OBJECTIVES:We examined the relationship between 12 urine metabolites and kidney structure in American Indians with type 2 diabetes. METHODS:Data were from a 6-year clinical trial that assessed renoprotective efficacy of losartan, and included a kidney biopsy at the end of the treatment period. Metabolites were measured in urine samples collected within a median of 6.5 months before the research biopsy. Associations of the creatinine-adjusted urine metabolites with kidney structural variables were examined by Pearson's correlations and multivariable linear regression after adjustment for age, sex, diabetes duration, hemoglobin A1c, mean arterial pressure, glomerular filtration rate (iothalamate), and losartan treatment. RESULTS:Participants (n = 62, mean age 45 ± 10 years) had mean ± standard deviation glomerular filtration rate of 137 ± 50 ml/min and median (interquartile range) urine albumin:creatinine ratio of 34 (14-85) mg/g near the time of the biopsy. Urine aconitic and glycolic acids correlated positively with glomerular filtration surface density (partial r = 0.29, P = 0.030 and r = 0.50, P

Published
2018

16. SARS-CoV-2 receptor networks in diabetic and COVID-19–associated kidney disease

Author

Menon, Rajasree, Otto, Edgar A., Sealfon, Rachel, Nair, Viji, Wong, Aaron K., Theesfeld, Chandra L., Chen, Xi, Wang, Yuan, Boppana, Avinash S., Luo, Jinghui, Yang, Yingbao, Kasson, Peter M., Schaub, Jennifer A., Berthier, Celine C., Eddy, Sean, Lienczewski, Chrysta C., Godfrey, Bradley, Dagenais, Susan L., Sohaney, Ryann, Hartman, John, Fermin, Damian, Subramanian, Lalita, Looker, Helen C., Harder, Jennifer L., Mariani, Laura H., Hodgin, Jeffrey B., Sexton, Jonathan Z., Wobus, Christiane E., Naik, Abhijit S., Nelson, Robert G., Troyanskaya, Olga G., and Kretzler, Matthias

Published
2020
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21. A signature of circulating inflammatory proteins and development of end-stage renal disease in diabetes

Author

Niewczas, Monika A., Pavkov, Meda E., Skupien, Jan, Smiles, Adam, Md Dom, Zaipul I., Wilson, Jonathan M., Park, Jihwan, Nair, Viji, Schlafly, Andrew, Saulnier, Pierre-Jean, Satake, Eiichiro, Simeone, Christopher A., Shah, Hetal, Qiu, Chengxiang, Looker, Helen C., Fiorina, Paolo, Ware, Carl F., Sun, Jennifer K., Doria, Alessandro, Kretzler, Matthias, Susztak, Katalin, Duffin, Kevin L., Nelson, Robert G., and Krolewski, Andrzej S.

Published
2019
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24. Insulin Secretion, Sensitivity, and Kidney Function in Young Individuals With Type 2 Diabetes.

Author

Bjornstad, Petter, Choi, Ye Ji, Platnick, Carson, Gross, Susan, Narongkiatikhun, Phoom, Melena, Isabella, Remmers, Lauryn, Baca, Madison, Schutte, Grant, Dobbs, Tyler, Vigers, Tim, Pyle, Laura, Driscoll, Lynette, Tommerdahl, Kalie, Kendrick, Jessica, Looker, Helen C., Dart, Allison, Cherney, David, van Raalte, Daniel H., and Srivastava, Anand

Subjects
TYPE 2 diabetes, KIDNEY physiology, GLUCOSE clamp technique, SECRETION, BODY composition, PLASMA flow
Abstract

OBJECTIVE: β-Cell dysfunction and insulin resistance magnify the risk of kidney injury in type 2 diabetes. The relationship between these factors and intraglomerular hemodynamics and kidney oxygen availability in youth with type 2 diabetes remains incompletely explored. RESEARCH DESIGN AND METHODS: Fifty youth with type 2 diabetes (mean age ± SD 16 ± 2 years; diabetes duration 2.3 ± 1.8 years; 60% female; median HbA1c 6.4% [25th, 75th percentiles 5.9, 7.6%]; BMI 36.4 ± 7.4 kg/m2; urine albumin-to-creatinine ratio [UACR] 10.3 [5.9, 58.0] mg/g) 21 control participants with obesity (OCs; age 16 ± 2 years; 29% female; BMI 37.6 ± 7.4 kg/m2), and 20 control participants in the normal weight category (NWCs; age 17 ± 3 years; 70% female; BMI 22.5 ± 3.6 kg/m2) underwent iohexol and p-aminohippurate clearance to assess glomerular filtration rate (GFR) and renal plasma flow, kidney MRI for oxygenation, hyperglycemic clamp for insulin secretion (acute C-peptide response to glucose [ACPRg]) and disposition index (DI; ×103 mg/kg lean/min), and DXA for body composition. RESULTS: Youth with type 2 diabetes exhibited lower DI (0.6 [0.0, 1.6] vs. 3.8 [2.4, 4.5] × 103 mg/kg lean/min; P < 0.0001) and ACPRg (0.6 [0.3, 1.4] vs. 5.3 [4.3, 6.9] nmol/L; P < 0.001) and higher UACR (10.3 [5.9, 58.0] vs. 5.3 [3.4, 14.3] mg/g; P = 0.003) and intraglomerular pressure (77.8 ± 11.5 vs. 64.8 ± 5.0 mmHg; P < 0.001) compared with OCs. Youth with type 2 diabetes and OCs had higher GFR and kidney oxygen availability (relative hyperoxia) than NWCs. DI was associated inversely with intraglomerular pressure and kidney hyperoxia. CONCLUSIONS: Youth with type 2 diabetes demonstrated severe β-cell dysfunction that was associated with intraglomerular hypertension and kidney hyperoxia. Similar but attenuated findings were found in OCs. [ABSTRACT FROM AUTHOR]

Published
2024
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25. Serum kidney injury molecule 1 and β2-microglobulin perform as well as larger biomarker panels for prediction of rapid decline in renal function in type 2 diabetes

Author

Colombo, Marco, Looker, Helen C., Farran, Bassam, Hess, Sibylle, Groop, Leif, Palmer, Colin N. A., Brosnan, Mary Julia, Dalton, R. Neil, Wong, Max, Turner, Charles, Ahlqvist, Emma, Dunger, David, Agakov, Felix, Durrington, Paul, Livingstone, Shona, Betteridge, John, McKeigue, Paul M., Colhoun, Helen M., and on behalf of the SUMMIT Investigators

Published
2019
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26. Role of endogenous adenine in kidney failure and mortality with diabetes

Author

Sharma, Kumar, Zhang, Guanshi, Hansen, Jens, Bjornstad, Petter, Lee, Hak Joo, Menon, Rajasree, Hejazi, Leila, Liu, Jian-Jun, Franzone, Anthony, Looker, Helen C., Choi, Byeong Yeob, Fernandez, Roman, Venkatachalam, Manjeri A., Kugathasan, Luxcia, Sridhar, Vikas S., Natarajan, Loki, Zhang, Jing, Sharma, Varun, Kwan, Brian, Waikar, Sushrut, Himmelfarb, Jonathan, Tuttle, Katherine, Kestenbaum, Bryan, Fuhrer, Tobias, Feldman, Harold, de Boer, Ian H., Tucci, Fabio C., Sedor, John, Heerspink, Hiddo Lambers, Schaub, Jennifer, Otto, Edgar, Hodgin, Jeffrey B., Kretzler, Matthias, Anderton, Christopher, Alexandrov, Theodore, Cherney, David, Lim, Su Chi, Nelson, Robert G., Gelfond, Jonathan, and Iyengar, Ravi

Subjects
Article
Abstract

Diabetic kidney disease (DKD) can lead to end-stage kidney disease (ESKD) and mortality, however, few mechanistic biomarkers are available for high risk patients, especially those without macroalbuminuria. Urine from participants with diabetes from Chronic Renal Insufficiency Cohort (CRIC), Singapore Study of Macro-Angiopathy and Reactivity in Type 2 Diabetes (SMART2D), and the Pima Indian Study determined if urine adenine/creatinine ratio (UAdCR) could be a mechanistic biomarker for ESKD. ESKD and mortality were associated with the highest UAdCR tertile in CRIC (HR 1.57, 1.18, 2.10) and SMART2D (HR 1.77, 1.00, 3.12). ESKD was associated with the highest UAdCR tertile in patients without macroalbuminuria in CRIC (HR 2.36, 1.26, 4.39), SMART2D (HR 2.39, 1.08, 5.29), and Pima Indian study (HR 4.57, CI 1.37-13.34). Empagliflozin lowered UAdCR in non-macroalbuminuric participants. Spatial metabolomics localized adenine to kidney pathology and transcriptomics identified ribonucleoprotein biogenesis as a top pathway in proximal tubules of patients without macroalbuminuria, implicating mammalian target of rapamycin (mTOR). Adenine stimulated matrix in tubular cells via mTOR and stimulated mTOR in mouse kidneys. A specific inhibitor of adenine production was found to reduce kidney hypertrophy and kidney injury in diabetic mice. We propose that endogenous adenine may be a causative factor in DKD.

Published
2023

27. Estimated Glomerular Filtration Rate, Albuminuria, and Adverse Outcomes : An Individual-Participant Data Meta-Analysis.

Author

Grams, Morgan E, Coresh, Josef, Matsushita, Kunihiro, Ballew, Shoshana H, Sang, Yingying, Surapaneni, Aditya, Alencar de Pinho, Natalia, Anderson, Amanda, Appel, Lawrence J, Ärnlöv, Johan, Azizi, Fereidoun, Bansal, Nisha, Bell, Samira, Bilo, Henk J G, Brunskill, Nigel J, Carrero, Juan J, Chadban, Steve, Chalmers, John, Chen, Jing, Ciemins, Elizabeth, Cirillo, Massimo, Ebert, Natalie, Evans, Marie, Ferreiro, Alejandro, Fu, Edouard L, Larsson, Anders, Gutierrez, Orlando M, Herrington, William G, Hwang, Shih-Jen, Inker, Lesley A, Iseki, Kunitoshi, Jafar, Tazeen, Jassal, Simerjot K, Jha, Vivekanand, Kadota, Aya, Katz, Ronit, Köttgen, Anna, Konta, Tsuneo, Kronenberg, Florian, Lee, Brian J, Lees, Jennifer, Levin, Adeera, Looker, Helen C, Major, Rupert, Melzer Cohen, Cheli, Mieno, Makiko, Miyazaki, Mariko, Moranne, Olivier, Muraki, Isao, Naimark, David, Nitsch, Dorothea, Oh, Wonsuk, Pena, Michelle, Purnell, Tanjala S, Sabanayagam, Charumathi, Satoh, Michihiro, Sawhney, Simon, Schaeffner, Elke, Schöttker, Ben, Shen, Jenny I, Shlipak, Michael G, Sinha, Smeeta, Stengel, Benedicte, Sumida, Keiichi, Tonelli, Marcello, Valdivielso, Jose M, van Zuilen, Arjan D, Visseren, Frank L J, Wang, Angela Yee-Moon, Wen, Chi-Pang, Wheeler, David C, Yatsuya, Hiroshi, Yamagata, Kunihiro, Yang, Jae Won, Young, Ann, Zhang, Haitao, Zhang, Luxia, Levey, Andrew S, Gansevoort, Ron T, Grams, Morgan E, Coresh, Josef, Matsushita, Kunihiro, Ballew, Shoshana H, Sang, Yingying, Surapaneni, Aditya, Alencar de Pinho, Natalia, Anderson, Amanda, Appel, Lawrence J, Ärnlöv, Johan, Azizi, Fereidoun, Bansal, Nisha, Bell, Samira, Bilo, Henk J G, Brunskill, Nigel J, Carrero, Juan J, Chadban, Steve, Chalmers, John, Chen, Jing, Ciemins, Elizabeth, Cirillo, Massimo, Ebert, Natalie, Evans, Marie, Ferreiro, Alejandro, Fu, Edouard L, Larsson, Anders, Gutierrez, Orlando M, Herrington, William G, Hwang, Shih-Jen, Inker, Lesley A, Iseki, Kunitoshi, Jafar, Tazeen, Jassal, Simerjot K, Jha, Vivekanand, Kadota, Aya, Katz, Ronit, Köttgen, Anna, Konta, Tsuneo, Kronenberg, Florian, Lee, Brian J, Lees, Jennifer, Levin, Adeera, Looker, Helen C, Major, Rupert, Melzer Cohen, Cheli, Mieno, Makiko, Miyazaki, Mariko, Moranne, Olivier, Muraki, Isao, Naimark, David, Nitsch, Dorothea, Oh, Wonsuk, Pena, Michelle, Purnell, Tanjala S, Sabanayagam, Charumathi, Satoh, Michihiro, Sawhney, Simon, Schaeffner, Elke, Schöttker, Ben, Shen, Jenny I, Shlipak, Michael G, Sinha, Smeeta, Stengel, Benedicte, Sumida, Keiichi, Tonelli, Marcello, Valdivielso, Jose M, van Zuilen, Arjan D, Visseren, Frank L J, Wang, Angela Yee-Moon, Wen, Chi-Pang, Wheeler, David C, Yatsuya, Hiroshi, Yamagata, Kunihiro, Yang, Jae Won, Young, Ann, Zhang, Haitao, Zhang, Luxia, Levey, Andrew S, and Gansevoort, Ron T

Abstract

IMPORTANCE: Chronic kidney disease (low estimated glomerular filtration rate [eGFR] or albuminuria) affects approximately 14% of adults in the US. OBJECTIVE: To evaluate associations of lower eGFR based on creatinine alone, lower eGFR based on creatinine combined with cystatin C, and more severe albuminuria with adverse kidney outcomes, cardiovascular outcomes, and other health outcomes. DESIGN, SETTING, AND PARTICIPANTS: Individual-participant data meta-analysis of 27 503 140 individuals from 114 global cohorts (eGFR based on creatinine alone) and 720 736 individuals from 20 cohorts (eGFR based on creatinine and cystatin C) and 9 067 753 individuals from 114 cohorts (albuminuria) from 1980 to 2021. EXPOSURES: The Chronic Kidney Disease Epidemiology Collaboration 2021 equations for eGFR based on creatinine alone and eGFR based on creatinine and cystatin C; and albuminuria estimated as urine albumin to creatinine ratio (UACR). MAIN OUTCOMES AND MEASURES: The risk of kidney failure requiring replacement therapy, all-cause mortality, cardiovascular mortality, acute kidney injury, any hospitalization, coronary heart disease, stroke, heart failure, atrial fibrillation, and peripheral artery disease. The analyses were performed within each cohort and summarized with random-effects meta-analyses. RESULTS: Within the population using eGFR based on creatinine alone (mean age, 54 years [SD, 17 years]; 51% were women; mean follow-up time, 4.8 years [SD, 3.3 years]), the mean eGFR was 90 mL/min/1.73 m2 (SD, 22 mL/min/1.73 m2) and the median UACR was 11 mg/g (IQR, 8-16 mg/g). Within the population using eGFR based on creatinine and cystatin C (mean age, 59 years [SD, 12 years]; 53% were women; mean follow-up time, 10.8 years [SD, 4.1 years]), the mean eGFR was 88 mL/min/1.73 m2 (SD, 22 mL/min/1.73 m2) and the median UACR was 9 mg/g (IQR, 6-18 mg/g). Lower eGFR (whether based on creatinine alone or based on creatinine and cystatin C) and higher UACR were each significantly associ

Published
2023
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32. Youth-onset type 2 diabetes mellitus: an urgent challenge

Author

Bjornstad, Petter, primary, Chao, Lily C., additional, Cree-Green, Melanie, additional, Dart, Allison B., additional, King, Malcolm, additional, Looker, Helen C., additional, Magliano, Dianna J., additional, Nadeau, Kristen J., additional, Pinhas-Hamiel, Orit, additional, Shah, Amy S., additional, van Raalte, Daniel H., additional, Pavkov, Meda E., additional, and Nelson, Robert G., additional

Published
2022
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33. Neuroblastoma suppressor of tumorigenicity 1 is a circulating protein associated with progression to end-stage kidney disease in diabetes

Author

Kobayashi, Hiroki, primary, Looker, Helen C., additional, Satake, Eiichiro, additional, D’Addio, Francesca, additional, Wilson, Jonathan M., additional, Saulnier, Pierre Jean, additional, Md Dom, Zaipul I., additional, O’Neil, Kristina, additional, Ihara, Katsuhito, additional, Krolewski, Bozena, additional, Badger, Hannah S., additional, Petrazzuolo, Adriana, additional, Corradi, Domenico, additional, Galecki, Andrzej, additional, Wilson, Parker C., additional, Najafian, Behzad, additional, Mauer, Michael, additional, Niewczas, Monika A., additional, Doria, Alessandro, additional, Humphreys, Benjamin D., additional, Duffin, Kevin L., additional, Fiorina, Paolo, additional, Nelson, Robert G., additional, and Krolewski, Andrzej S., additional

Published
2022
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34. Serum lipidomic determinants of human diabetic neuropathy in type 2 diabetes

Author

Afshinnia, Farsad, primary, Reynolds, Evan L., additional, Rajendiran, Thekkelnaycke M., additional, Soni, Tanu, additional, Byun, Jaeman, additional, Savelieff, Masha G., additional, Looker, Helen C., additional, Nelson, Robert G., additional, Michailidis, George, additional, Callaghan, Brian C., additional, Pennathur, Subramaniam, additional, and Feldman, Eva L., additional

Published
2022
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36. Protein biomarkers for the prediction of cardiovascular disease in type 2 diabetes

Author

Looker, Helen C., Colombo, Marco, Agakov, Felix, Zeller, Tanja, Groop, Leif, Thorand, Barbara, Palmer, Colin N., Hamsten, Anders, de Faire, Ulf, Nogoceke, Everson, Livingstone, Shona J., Salomaa, Veikko, Leander, Karin, Barbarini, Nicola, Bellazzi, Riccardo, van Zuydam, Natalie, McKeigue, Paul M., Colhoun, Helen M., and on behalf of the SUMMIT Investigators

Published
2015
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40. Diminished retinal complex lipid synthesis and impaired fatty acid β-oxidation associated with human diabetic retinopathy

Author

Fort, Patrice E., primary, Rajendiran, Thekkelnaycke M., additional, Soni, Tanu, additional, Byun, Jaeman, additional, Shan, Yang, additional, Looker, Helen C., additional, Nelson, Robert G., additional, Kretzler, Matthias, additional, Michailidis, George, additional, Roger, Jerome E., additional, Gardner, Thomas W., additional, Abcouwer, Steven F., additional, Pennathur, Subramaniam, additional, and Afshinnia, Farsad, additional

Published
2021
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41. Albuminuria Testing in Hypertension and Diabetes: An Individual-Participant Data Meta-Analysis in a Global Consortium

Author

Shin, Jung-Im, primary, Chang, Alex R., additional, Grams, Morgan E., additional, Coresh, Josef, additional, Ballew, Shoshana H., additional, Surapaneni, Aditya, additional, Matsushita, Kunihiro, additional, Bilo, Henk J.G., additional, Carrero, Juan J., additional, Chodick, Gabriel, additional, Daratha, Kenn B., additional, Jassal, Simerjot K., additional, Nadkarni, Girish N., additional, Nelson, Robert G., additional, Nowak, Christoph, additional, Stempniewicz, Nikita, additional, Sumida, Keiichi, additional, Traynor, Jamie P., additional, Woodward, Mark, additional, Sang, Yingying, additional, Gansevoort, Ron T., additional, Chalmers, John, additional, Tuttle, Katherine, additional, Alicic, Radica, additional, McPherson, Sterling, additional, Jones, Cami, additional, Singh, Gurmukteshwar, additional, Green, Jamie, additional, Kirchner, H. Lester, additional, Shalev, Varda, additional, Bottinger, Erwin P., additional, Loos, Ruth J.F., additional, Ellis, Stephen B., additional, Cuddeback, John, additional, Ciemins, Elizabeth, additional, Carbonara, Emily, additional, Dunning, Stephan, additional, Knowler, William C., additional, Looker, Helen C., additional, Kieneker, Lyane M., additional, Bakker, Stephan J.L., additional, Hillege, Hans L., additional, van der Harst, Pim, additional, Bergstrom, Jacklyn, additional, Ix, Joachim, additional, Kovesdy, Csaba P., additional, Potukuchi, Praveen, additional, Trevisan, Marco, additional, Elinder, Carl Gustaf, additional, Wettermark, Björn, additional, Ärnlöv, Johan, additional, Mark, Patrick B., additional, Thomson, Peter C., additional, Geddes, Colin C., additional, Landman, Gijs W.D., additional, van Hateren, Kornelis J.J., additional, Kleefstra, Nanne, additional, Gutierrez, Orlando, additional, Konta, Tsuneo, additional, Levey, Andrew S., additional, Polkinghorne, Kevan, additional, Schäffner, Elke, additional, Chen, Jingsha, additional, and Surapeneni, Aditya, additional

Published
2021
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42. Molecular Programs of Glomerular Hyperfiltration in Early Diabetic Kidney Disease

Author

Stefansson, Vidar T. N., primary, Nair, Viji, additional, Melsom, Toralf, additional, Looker, Helen C., additional, Mariani, Laura H., additional, Fermin, Damian, additional, Eichinger, Felix, additional, Menon, Rajasree, additional, Subramanian, Lalita, additional, Harder, Jennifer L., additional, Hodgin, Jeffrey B., additional, Nelson, Peter J., additional, Eriksen, Bjorn O., additional, Nelson, Robert G., additional, and Kretzler, Matthias, additional

Published
2021
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43. Comprehensive Search for Novel Circulating miRNAs and Axon Guidance Pathway Proteins Associated with Risk of ESKD in Diabetes

Author

Satake, Eiichiro, primary, Saulnier, Pierre-Jean, additional, Kobayashi, Hiroki, additional, Gupta, Manoj K., additional, Looker, Helen C., additional, Wilson, Jonathan M., additional, Md Dom, Zaipul I., additional, Ihara, Katsuhito, additional, O’Neil, Kristina, additional, Krolewski, Bozena, additional, Pipino, Caterina, additional, Pavkov, Meda E., additional, Nair, Viji, additional, Bitzer, Markus, additional, Niewczas, Monika A., additional, Kretzler, Matthias, additional, Mauer, Michael, additional, Doria, Alessandro, additional, Najafian, Behzad, additional, Kulkarni, Rohit N., additional, Duffin, Kevin L., additional, Pezzolesi, Marcus G., additional, Kahn, C. Ronald, additional, Nelson, Robert G., additional, and Krolewski, Andrzej S., additional

Published
2021
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50. SARS-CoV-2 receptor networks in diabetic kidney disease, BK-Virus nephropathy and COVID-19 associated acute kidney injury

Author

Menon, Rajasree, Otto, Edgar A, Sealfon, Rachel, Nair, Viji, Wong, Aaron K, Theesfeld, Chandra L, Chen, Xi, Wang, Yuan, Boppanna, Avinash, Kasson, Peter M, Schaub, Jennifer A, Berthier, Celine C, Eddy, Sean, Lienczewski, Chrysta C, Godfrey, Bradley, Dagenais, Susan L, Sohaney, Ryann, Hartman, John, Fermin, Damian, Subramanian, Lalita, Looker, Helen C, Mariani, Laura H, Naik, Abhijit S, Nelson, Robert G, Troyanskaya, Olga G., and Kretzler, Matthias

Subjects
hormones, hormone substitutes, and hormone antagonists
Abstract

COVID-19 morbidity and mortality is significantly increased in patients with diabetes and kidney disease via unknown mechanisms. SARS-CoV-2 uses angiotensin-converting enzyme 2 (ACE2) for entry into human host cells, and ACE2 levels in target cells may influence SARS-CoV-2 susceptibility. We investigated how pre-existing conditions and drug treatments alter receptor expression in kidney tissue. Using single cell RNA profiling (scRNAseq) to assess ACE2 and associated SARS-CoV-2 proteases in healthy living donors (LD) kidneys, diabetic kidney disease (DKD), and in kidney injury during viral infection, ACE2 expression was primarily associated with proximal tubular epithelial cells (PTEC). ACE2 mRNA expression levels were significantly upregulated in DKD versus LD, however, ACE2 levels were not altered by exposures to renin angiotensin aldosterone system (RAAS) inhibitors. ACE2+ expression signatures were defined by differential expression analysis and characterized by Bayesian integrative analysis of a large compendium of public -omics datasets, resulting in the identification of network modules induced in ACE2 positive PTEC in DKD and BK virus nephropathy. These ACE2 upregulated cell programs were linked to viral entry, immune activation, endomembrane reorganization, and RNA processing and overlapped significantly with the cellular responses induced by SARS-CoV-2 infection. Similar cellular programs were activated in ACE2-positive PTEC isolated in a urine sample from a COVID19 patient with acute kidney injury, suggesting a consistent ACE2-coregulated expression program that may interact with SARS-Cov-2 infection processes. The SARS-CoV-2 receptor associated gene signatures could seed further research into therapeutic strategies for COVID-19. Functional networks of gene expression signatures are available for further exploration to researchers at HumanBase (hb.flatironinstitute.org/covid-kidney).

Published
2020
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