Autosomal dominant polycystic kidney disease; Glucose; Insulin; Obesity; Overweight; Children
Disciplines :
Pediatrics
Author, co-author :
Dachy, Angélique ; Centre Hospitalier Universitaire de Liège - CHU > > Service de pédiatrie ; Centre Hospitalier Universitaire de Liège - CHU > Département de Pédiatrie > Service de pédiatrie
Decuypère, Jean-Paul; KU Leuven > Department of Development and Regeneration > PKD Research Group, GPURE
Vennekens, Rudi; KU Leuven > VIB Center for Brain and Disease Research, Laboratory of Ion Channel Research, Department of Cellular and Molecular Medicine,
Jouret, François ; Centre Hospitalier Universitaire de Liège - CHU > > Service de néphrologie ; Centre Hospitalier Universitaire de Liège - CHU > Département de médecine interne > Service de néphrologie
mekahli, Djalila; University Hospitals Leuven > Pediatric Nephrology
Language :
English
Title :
Is autosomal dominant polycystic kidney disease an early sweet disease?
Rowe I, Boletta A (2014) Defective metabolism in polycystic kidney disease: potential for therapy and open questions. Nephrol Dial Transplant 29:1480–1486. 10.1093/ndt/gft521 DOI: 10.1093/ndt/gft521
Rowe I, Chiaravalli M, Mannella V, Ulisse V et al (2013) Defective glucose metabolism in polycystic kidney disease identifies a new therapeutic strategy. Nat Med 19:488–493. 10.1038/nm.3092 DOI: 10.1038/nm.3092
Nowak KL, Hopp K (2020) Metabolic reprogramming in autosomal dominant polycystic kidney disease evidence and therapeutic potential. Clin J Am Soc Nephrol 15:577–584. 10.2215/CJN.13291019 DOI: 10.2215/CJN.13291019
Podrini C, Rowe I, Pagliarini R, Costa ASH et al (2018) Dissection of metabolic reprogramming in polycystic kidney disease reveals coordinated rewiring of bioenergetic pathways. Commun Biol 1:194. 10.1038/s42003-018-0200-x DOI: 10.1038/s42003-018-0200-x
Kipp KR, Rezaei M, Lin L, Dewey EC, Weimbs T (2016) A mild reduction of food intake slows disease progression in an orthologous mouse model of polycystic kidney disease. Am J Physiol Physiol 310:F726–F731. 10.1152/ajprenal.00551.2015 DOI: 10.1152/ajprenal.00551.2015
Warner G, Hein KZ, Nin V, Edwards M et al (2016) Food restriction ameliorates the development of polycystic kidney disease. J Am Soc Nephrol 27:1437–1447. 10.1681/ASN.2015020132 DOI: 10.1681/ASN.2015020132
Torres JA, Kruger SL, Broderick C, Amarlkhagva T et al (2019) Ketosis ameliorates renal cyst growth in polycystic kidney disease. Cell Metab 30:1007–1023. 10.1016/j.cmet.2019.09.012 DOI: 10.1016/j.cmet.2019.09.012
Takiar V, Nishio S, Seo-Mayer P, King JD Jr et al (2011) Activating AMP-activated protein kinase (AMPK) slows renal cystogenesis. Proc Natl Acad Sci U S A 108:2462–2467. 10.1073/pnas.1011498108 DOI: 10.1073/pnas.1011498108
Chang MY, Ma TL, Hung CC, Tian YC et al (2017) Metformin inhibits cyst formation in a zebrafish model of polycystin-2 deficiency. Sci Rep 7:7161. 10.1038/s41598-017-07300-x DOI: 10.1038/s41598-017-07300-x
Perrone RD, Abebe KZ, Watnick T, Althouse AD et al (2021) Primary results of the randomized trial of metformin administration in polycystic kidney disease (TAME PKD). Kidney Int 100:684–696. 10.1016/j.kint.2021.06.013 DOI: 10.1016/j.kint.2021.06.013
Brosnahan GM, Wang W, Gitomer B, Struemph T et al (2021) Metformin therapy in autosomal dominant polycystic kidney disease: a feasibility study. Am J Kidney Dis 12:S0272-6386(21)00790-3. https://doi.org/10.1053/j.ajkd.2021.06.026
Wang X, Zhang S, Liu Y, Spichtig D et al (2013) Targeting of sodium-glucose cotransporters with phlorizin inhibits polycystic kidney disease progression in Han:SPRD rats. Kidney Int 84:962–968. 10.1038/ki.2013.199 DOI: 10.1038/ki.2013.199
Kapoor S, Rodriguez D, Riwanto M, Edenhofer I et al (2015) Effect of sodium-glucose cotransport inhibition on polycystic kidney disease progression in PCK rats. PLoS ONE 10:e0125603. 10.1371/journal.pone.0125603 DOI: 10.1371/journal.pone.0125603
Rodriguez D, Kapoor S, Edenhofer I, Segerer S et al (2015) Inhibition of sodium-glucose cotransporter 2 with dapagliflozin in Han: SPRD rats with polycystic kidney disease. Kidney Blood Press Res 40:638–647. 10.1159/000368540 DOI: 10.1159/000368540
Leonhard WN, Song X, Kanhai AA, Iliuta IA et al (2019) Salsalate, but not metformin or canagliflozin, slows kidney cyst growth in an adult-onset mouse model of polycystic kidney disease. EBioMedicine 47:436–445. 10.1016/j.ebiom.2019.08.041 DOI: 10.1016/j.ebiom.2019.08.041
Fliszkiewicz M, Niemczyk M, Kulesza A, Łabuś A, Pączek L (2019) Glucose and lipid metabolism abnormalities among patients with autosomal dominant polycystic kidney disease. Kidney Blood Press Res 44:1416–1422. 10.1159/000503423 DOI: 10.1159/000503423
Pietrzak-Nowacka M, Safranow K, Byra E, Nowosiad M, Marchelek-Myśliwiec M, Ciechanowski K (2010) Glucose metabolism parameters during an oral glucose tolerance test in patients with autosomal dominant polycystic kidney disease. Scand J Clin Lab Invest 70:561–567. 10.3109/00365513.2010.527012 DOI: 10.3109/00365513.2010.527012
Nowak KL, You Z, Gitomer B, Brosnahan G et al (2018) Overweight and obesity are predictors of progression in early autosomal dominant polycystic kidney disease. J Am Soc Nephrol 29:571–578. 10.1681/ASN.2017070819 DOI: 10.1681/ASN.2017070819
Baliga MM, Klawitter J, Christians U, Hopp K et al (2021) Metabolic profiling in children and young adults with autosomal dominant polycystic kidney disease. Sci Rep 11:6629. 10.1038/s41598-021-84609-8 DOI: 10.1038/s41598-021-84609-8
Yun H-R, Kim H, Park JT, Chang TI et al (2018) Obesity, metabolic abnormality, and progression of CKD. Am J Kidney Dis 72:400–410. 10.1053/j.ajkd.2018.02.362 DOI: 10.1053/j.ajkd.2018.02.362
Spoto B, Pisano A, Zoccali C (2016) Insulin resistance in chronic kidney disease: a systematic review. Am J Physiol Renal Physiol 311:F1087–F1108. 10.1152/ajprenal.00340.2016 DOI: 10.1152/ajprenal.00340.2016
Lalan S, Jiang S, Ng DK, Kupferman F et al (2018) Cardiometabolic risk factors, metabolic syndrome, and chronic kidney disease progression in children. J Pediatr 202:163–170. 10.1016/j.jpeds.2018.06.007 DOI: 10.1016/j.jpeds.2018.06.007
Foster MC, Hwang S-J, Larson MG, Lichtman JH et al (2008) Overweight, obesity, and the development of stage 3 CKD: the Framingham heart study. Am J kidney Dis 52:39–48. 10.1053/j.ajkd.2008.03.003 DOI: 10.1053/j.ajkd.2008.03.003
Spinelli A, Buoncristiano M, Kovacs VA, Yngve A et al (2019) Prevalence of severe obesity among primary school children in 21 European countries. Obes Facts 12:244–258. 10.1159/000500436 DOI: 10.1159/000500436
Sorof JM, Poffenbarger T, Franco K, Bernard L et al (2002) Isolated systolic hypertension, obesity, and hyperkinetic hemodynamic states in children. J Pediatr 140:660–666. 10.1067/mpd.2002.125228 DOI: 10.1067/mpd.2002.125228
Sinha R, Fisch G, Teague B, Tamborlane WV et al (2002) Prevalence of impaired glucose tolerance among children and adolescents with marked obesity. N Engl J Med 346:802–810. 10.1056/NEJMoa012578 DOI: 10.1056/NEJMoa012578
Shaw J (2007) Epidemiology of childhood type 2 diabetes and obesity. Pediatr Diabetes 8(Suppl 9):7–15. 10.1111/j.1399-5448.2007.00329.x DOI: 10.1111/j.1399-5448.2007.00329.x
Skinner AC, Perrin EM, Moss LA, Skelton JA (2015) Cardiometabolic risks and severity of obesity in children and young adults. N Engl J Med 373:1307–1317. 10.1056/NEJMoa1502821 DOI: 10.1056/NEJMoa1502821
Baker JL, Olsen LW, Sørensen TIA (2007) Childhood body-mass index and the risk of coronary heart disease in adulthood. N Engl J Med 357:2329–2337. 10.1056/NEJMoa072515 DOI: 10.1056/NEJMoa072515
Wilson PWF, D’Agostino RB, Sullivan L, Parise H, Kannel WB (2002) Overweight and obesity as determinants of cardiovascular risk: the Framingham experience. Arch Intern Med 162:1867–1872. 10.1001/archinte.162.16.1867 DOI: 10.1001/archinte.162.16.1867
Yajnik CS, Katre PA, Joshi SM, Kumaran K et al (2015) Higher glucose, insulin and insulin resistance (HOMA-IR) in childhood predict adverse cardiovascular risk in early adulthood: the Pune children’s study. Diabetologia 58:1626–1636. 10.1007/s00125-015-3602-z DOI: 10.1007/s00125-015-3602-z
Nowak KL, Steele C, Gitomer B, Wang W et al (2021) Overweight and obesity and progression of ADPKD. Clin J Am Soc Nephrol 16:908–915. 10.2215/CJN.16871020 DOI: 10.2215/CJN.16871020
Vareesangthip K, Tong P, Wilkinson R, Thomas TH (1997) Insulin resistance in adult polycystic kidney disease. Kidney Int 52:503–508. 10.1038/ki.1997.360 DOI: 10.1038/ki.1997.360
Fliser D, Pacini G, Engelleiter R, Kautzky-Willer A et al (1998) Insulin resistance and hyperinsulinemia are already present in patients with incipient renal disease. Kidney Int 53:1343–1347. 10.1046/j.1523-1755.1998.00898.x DOI: 10.1046/j.1523-1755.1998.00898.x
Turkmen K, Tufan F, Selçuk E, Akpınar T, Oflaz H, Ecder T (2013) Neutrophil-to-lymphocyte ratio, insulin resistance, and endothelial dysfunction in patients with autosomal dominant polycystic kidney disease. Indian J Nephrol 23:34–40. 10.4103/0971-4065.107195 DOI: 10.4103/0971-4065.107195
Menon V, Rudym D, Chandra P, Miskulin D, Perrone R, Sarnak M (2011) Inflammation, oxidative stress, and insulin resistance in polycystic kidney disease. Clin J Am Soc Nephrol 6:7–13. 10.2215/CJN.04140510 DOI: 10.2215/CJN.04140510
DeFronzo RA, Tobin JD, Andres R (1979) Glucose clamp technique: a method for quantifying insulin secretion and resistance. Am J Physiol Endocrinol Metab Gastrointest Physiol 6:E214. 10.1152/ajpendo.1979.237.3.e214 DOI: 10.1152/ajpendo.1979.237.3.e214
Hamer RA, Chow CL, Ong ACM, McKane WS (2007) Polycystic kidney disease is a risk factor for new-onset diabetes after transplantation. Transplantation 83:36–40. 10.1097/01.tp.0000248759.37146.3d DOI: 10.1097/01.tp.0000248759.37146.3d
Caillard S, Eprinchard L, Perrin P, Braun L et al (2011) Incidence and risk factors of glucose metabolism disorders in kidney transplant recipients: role of systematic screening by oral glucose tolerance test. Transplantation 91:757–764. 10.1097/TP.0b013e31820f0877 DOI: 10.1097/TP.0b013e31820f0877
de Mattos AM, Olyaei AJ, Prather JC, Golconda MS et al (2005) Autosomal-dominant polycystic kidney disease as a risk factor for diabetes mellitus following renal transplantation. Kidney Int 67:714–720. 10.1111/j.1523-1755.2005.67132.x DOI: 10.1111/j.1523-1755.2005.67132.x
Reed B, Helal I, McFann K, Wang W et al (2011) The impact of type II diabetes mellitus in patients with autosomal dominant polycystic kidney disease. Nephrol Dial Transplant 27:2862–2865. 10.1093/ndt/gfr744 DOI: 10.1093/ndt/gfr744
Kuo IY, Chapman AB (2020) Polycystins, ADPKD, and cardiovascular disease. Kidney Int reports 5:396–406. 10.1016/j.ekir.2019.12.007 DOI: 10.1016/j.ekir.2019.12.007
Major RW, Cheng MRI, Grant RA, Shantikumar S et al (2018) Cardiovascular disease risk factors in chronic kidney disease: a systematic review and meta-analysis. PLoS ONE 13:e0192895. 10.1371/journal.pone.0192895 DOI: 10.1371/journal.pone.0192895
Sans L, Pascual J, Radosevic A, Quintian C et al (2016) Renal volume and cardiovascular risk assessment in normotensive autosomal dominant polycystic kidney disease patients. Medicine (Baltimore) 95:e5595. 10.1097/MD.0000000000005595 DOI: 10.1097/MD.0000000000005595
Lai S, Mastroluca D, Matino S, Panebianco V et al (2017) Early markers of cardiovascular risk in autosomal dominant polycystic kidney disease. Kidney Blood Press Res 42:1290–1302. 10.1159/000486011 DOI: 10.1159/000486011
Gorriz JL, Arroyo D, D’Marco L, Torra R et al (2021) Cardiovascular risk factors and the impact on prognosis in patients with chronic kidney disease secondary to autosomal dominant polycystic kidney disease. BMC Nephrol 22:110. 10.1186/s12882-021-02313-1 DOI: 10.1186/s12882-021-02313-1
Nowak KL, Murray K, You Z, Gitomer B et al (2021) Pain and obesity in autosomal dominant polycystic kidney disease: a post hoc analysis of the halt progression of polycystic kidney disease (HALT-PKD) studies. Kidney Med 3:536-545.e1. 10.1016/j.xkme.2021.03.004 DOI: 10.1016/j.xkme.2021.03.004
Bajwa ZH, Gupta S, Warfield CA, Steinman TI (2001) Pain management in polycystic kidney disease. Kidney Int 60:1631–1644. 10.1046/j.1523-1755.2001.00985.x DOI: 10.1046/j.1523-1755.2001.00985.x
World Health Organization (2017) Tenfold increase in childhood and adolescent obesity in four decades: new study by Imperial College London and WHO. In: Available online. https://www.who.int/news/item/11-10-2017 -. Accessed 3 Jun 2021
Franks PW, Hanson RL, Knowler WC, Sievers ML et al (2010) Childhood obesity, other cardiovascular risk factors, and premature death. N Engl J Med 362:485–493. 10.1056/NEJMoa0904130 DOI: 10.1056/NEJMoa0904130
Whaley-Connell A, Sowers JR (2017) Insulin resistance in kidney disease: is there a distinct role separate from that of diabetes or obesity? Cardiorenal Med 8:41–49. 10.1159/000479801 DOI: 10.1159/000479801
Helal I, Reed B, Mcfann K, Yan XD et al (2011) Glomerular hyperfiltration and renal progression in children with autosomal dominant polycystic kidney disease. Clin J Am Soc Nephrol 6:2439–2443. 10.2215/CJN.01010211 DOI: 10.2215/CJN.01010211
Chagnac A, Weinstein T, Korzets A, Ramadan E et al (2000) Glomerular hemodynamics in severe obesity. Am J Physiol Renal Physiol 278:F817-822. 10.1152/ajprenal.2000.278.5.F817 DOI: 10.1152/ajprenal.2000.278.5.F817
Kahveci AS, Barnatan TT, Kahveci A, Adrian AE et al (2020) Oxidative stress and mitochondrial abnormalities contribute to decreased endothelial nitric oxide synthase expression and renal disease progression in early experimental polycystic kidney disease. Int J Mol Sci 21:1994. 10.3390/ijms21061994 DOI: 10.3390/ijms21061994
Murphy MO, Huang H, Bauer JA, Schadler A et al (2021) Impact of pediatric obesity on diurnal blood pressure assessment and cardiovascular risk markers. Front Pediatr 9:123. 10.3389/fped.2021.596142 DOI: 10.3389/fped.2021.596142
Litwin M, Kułaga Z (2021) Obesity, metabolic syndrome, and primary hypertension. Pediatr Nephrol 36:825–837. 10.1007/s00467-020-04579-3 DOI: 10.1007/s00467-020-04579-3
Marlais M, Cuthell O, Langan D, Dudley J et al (2016) Hypertension in autosomal dominant polycystic kidney disease: a meta-analysis. Arch Dis Child 101:1142–1147. 10.1136/archdischild-2015-310221 DOI: 10.1136/archdischild-2015-310221
Massella L, Mekahli D, Paripović D, Prikhodina L et al (2018) Prevalence of hypertension in children with early-stage ADPKD. Clin J Am Soc Nephrol 13:874–883. 10.2215/CJN.11401017 DOI: 10.2215/CJN.11401017
Fick-Brosnahan GM, Tran ZV, Johnson AM, Strain JD, Gabow PA (2001) Progression of autosomal-dominant polycystic kidney disease in children. Kidney Int 59:1654–1662. 10.1046/j.1523-1755.2001.0590051654.x DOI: 10.1046/j.1523-1755.2001.0590051654.x
Cadnapaphornchai MA, McFann K, Strain JD, Masoumi A, Schrier RW (2008) Increased left ventricular mass in children with autosomal dominant polycystic kidney disease and borderline hypertension. Kidney Int 74:1192–1196. 10.1038/ki.2008.397 DOI: 10.1038/ki.2008.397
Mastrangelo A, Martos-Moreno GÁ, García A, Barrios V et al (2016) Insulin resistance in prepubertal obese children correlates with sex-dependent early onset metabolomic alterations. Int J Obes (Lond) 40:1494–1502. 10.1038/ijo.2016.92 DOI: 10.1038/ijo.2016.92
Kwaifa IK, Bahari H, Yong YK, Noor SM (2020) Endothelial dysfunction in obesity-induced inflammation: molecular mechanisms and clinical implications. Biomolecules 10:291. 10.3390/biom10020291 DOI: 10.3390/biom10020291
Chiaravalli M, Rowe I, Mannella V, Quilici G et al (2016) 2-Deoxy-D-glucose ameliorates PKD progression. J Am Soc Nephrol 27:1958–1969. 10.1681/ASN.2015030231 DOI: 10.1681/ASN.2015030231
Riwanto M, Kapoor S, Rodriguez D, Edenhofer I et al (2016) Inhibition of aerobic glycolysis attenuates disease progression in polycystic kidney disease. PLoS ONE 11:e0146654. 10.1371/journal.pone.0146654 DOI: 10.1371/journal.pone.0146654
Grahammer F, Ramakrishnan SK, Rinschen MM, Larionov AA et al (2017) mTOR regulates endocytosis and nutrient transport in proximal tubular cells. J Am Soc Nephrol 28:230–241. 10.1681/ASN.2015111224 DOI: 10.1681/ASN.2015111224
Zhang H, Kong W-J, Shan Y-Q, Song D-Q et al (2010) Protein kinase D activation stimulates the transcription of the insulin receptor gene. Mol Cell Endocrinol 330:25–32. 10.1016/j.mce.2010.07.022 DOI: 10.1016/j.mce.2010.07.022
Khan S, Ferdaoussi M, Bautista A, Bergeron V et al (2019) A role for PKD1 in insulin secretion downstream of P2Y1 receptor activation in mouse and human islets. Physiol Rep 7:e14250. 10.14814/phy2.14250 DOI: 10.14814/phy2.14250
Kashyap S, Hein KZ, Chini CC, Lika J et al (2020) Metalloproteinase PAPP - a regulation of IGF-1 contributes to polycystic kidney disease pathogenesis. JCI Insight 5:e135700. 10.1172/jci.insight.135700 DOI: 10.1172/jci.insight.135700
Kashyap S, Zeidler JD, Chini CCS, Chini EN (2020) Implications of the PAPP-A-IGFBP-IGF-1 pathway in the pathogenesis and treatment of polycystic kidney disease. Cell Signal 73:109698. 10.1016/j.cellsig.2020.109698 DOI: 10.1016/j.cellsig.2020.109698
Ramalingam H, Kashyap S, Cobo-Stark P, Flaten A et al (2021) A methionine-Mettl3-N6-methyladenosine axis promotes polycystic kidney disease. Cell Metab 33:1234-1247.e7. 10.1016/j.cmet.2021.03.024 DOI: 10.1016/j.cmet.2021.03.024
Knowler WC, Barrett-Connor E, Fowler SE, Hamman RF et al (2002) Reduction in the incidence of type 2 diabetes with lifestyle intervention or metformin. N Engl J Med 346:393–403. 10.1056/NEJMoa012512 DOI: 10.1056/NEJMoa012512
Seifarth C, Schehler B, Schneider HJ (2013) Effectiveness of metformin on weight loss in non-diabetic individuals with obesity. Exp Clin Endocrinol Diabetes 121:27–31. 10.1055/s-0032-1327734 DOI: 10.1055/s-0032-1327734
Soliman A, DeSanctis V, Alaaraj N, Hamed N (2020) The clinical application of metformin in children and adolescents: a short update. Acta Biomed 91:e2020086. 10.23750/abm.v91i3.10127 DOI: 10.23750/abm.v91i3.10127
Masarwa R, Brunetti VC, Aloe S, Henderson M, Platt RW, Filion KB (2021) Efficacy and safety of metformin for obesity: a systematic review. Pediatrics 147:e20201610. 10.1542/peds.2020-1610
Bassols J, Martínez-Calcerrada J-M, Osiniri I, Díaz-Roldán F et al (2019) Effects of metformin administration on endocrine-metabolic parameters, visceral adiposity and cardiovascular risk factors in children with obesity and risk markers for metabolic syndrome: a pilot study. PLoS ONE 14:e0226303. 10.1371/journal.pone.0226303 DOI: 10.1371/journal.pone.0226303
Bjornstad P, Schäfer M, Truong U, Cree-Green M et al (2018) Metformin improves insulin sensitivity and vascular health in youth with type 1 diabetes mellitus. Circulation 138:2895–2907. 10.1161/CIRCULATIONAHA.118.035525 DOI: 10.1161/CIRCULATIONAHA.118.035525
Park MH, Kinra S, Ward KJ, White B, Viner RM (2009) Metformin for obesity in children and adolescents: a systematic review. Diabetes Care 32:1743–1745. 10.2337/dc09-0258 DOI: 10.2337/dc09-0258
Kendall D, Vail A, Amin R, Barrett T et al (2013) Metformin in obese children and adolescents: the MOCA trial. J Clin Endocrinol Metab 98:322–329. 10.1210/jc.2012-2710 DOI: 10.1210/jc.2012-2710
De Broe ME, Jouret F (2020) Does metformin do more benefit or harm in chronic kidney disease patients? Kidney Int 98:1098–1101. 10.1016/j.kint.2020.04.059 DOI: 10.1016/j.kint.2020.04.059
Crowley MJ, Diamantidis CJ, McDuffie JR, Cameron CB et al (2017) Clinical outcomes of metformin use in populations with chronic kidney disease, congestive heart failure, or chronic liver disease: a systematic review. Ann Intern Med 166:191–200. 10.7326/M16-1901 DOI: 10.7326/M16-1901
Ong ACM, Gansevoort RT (2021) TAMEing ADPKD with metformin: safe and effective? Kidney Int 100:513–515. 10.1016/j.kint.2021.07.021 DOI: 10.1016/j.kint.2021.07.021
Heerspink HJL, Kosiborod M, Inzucchi SE, Cherney DZI (2018) Renoprotective effects of sodium-glucose cotransporter-2 inhibitors. Kidney Int 94:26–39. 10.1016/j.kint.2017.12.027 DOI: 10.1016/j.kint.2017.12.027
Perkovic V, Jardine MJ, Neal B, Bompoint S et al (2019) Canagliflozin and renal outcomes in type 2 diabetes and nephropathy. N Engl J Med 380:2295–2306. 10.1056/NEJMoa1811744 DOI: 10.1056/NEJMoa1811744
Levin A, Perkovic V, Wheeler DC, Hantel S et al (2020) Empagliflozin and cardiovascular and kidney outcomes across KDIGO risk categories: post hoc analysis of a randomized, double-blind, placebo-controlled, multinational trial. Clin J Am Soc Nephrol 15:1433–1444. 10.2215/CJN.14901219 DOI: 10.2215/CJN.14901219
