Antifibrotic Agents for the Management of CKD: A Review

Kidney fibrosis is a hallmark of chronic kidney disease (CKD) and a potential therapeutic target. However, there are conceptual and practical challenges to directly targeting kidney fibrosis. Whether fibrosis is mainly a cause or a consequence of CKD progression has been disputed. It is unclear whether specifically targeting fibrosis is feasible in clinical practice because most drugs that decrease fibrosis in preclinical models target additional and often multiple pathogenic pathways (eg, renin-angiotensin-aldosterone system blockade). Moreover, tools to assess whole-kidney fibrosis in routine clinical practice are lacking. Pirfenidone, a drug used for idiopathic pulmonary fibrosis, is undergoing a phase 2 trial for kidney fibrosis. Other drugs in use or being tested for idiopathic pulmonary fibrosis (eg, nintedanib, PRM-151, epigallocatechin gallate) are also potential candidates to treat kidney fibrosis. Novel therapeutic approaches may include antagomirs (eg, lademirsen) or drugs targeting interleukin 11 or NKD2 (WNT signaling pathway inhibitor). Reversing the dysfunctional tubular cell metabolism that leads to kidney fibrosis offers additional therapeutic opportunities. However, any future drug targeting fibrosis of the kidneys should demonstrate added benefit to a standard of care that combines renin-angiotensin system with mineralocorticoid receptor (eg, finerenone) blockade or with sodium/glucose cotransporter 2 inhibitors. Kidney fibrosis is a hallmark of chronic kidney disease (CKD) and a potential therapeutic target. However, there are conceptual and practical challenges to directly targeting kidney fibrosis. Whether fibrosis is mainly a cause or a consequence of CKD progression has been disputed. It is unclear whether specifically targeting fibrosis is feasible in clinical practice because most drugs that decrease fibrosis in preclinical models target additional and often multiple pathogenic pathways (eg, renin-angiotensin-aldosterone system blockade). Moreover, tools to assess whole-kidney fibrosis in routine clinical practice are lacking. Pirfenidone, a drug used for idiopathic pulmonary fibrosis, is undergoing a phase 2 trial for kidney fibrosis. Other drugs in use or being tested for idiopathic pulmonary fibrosis (eg, nintedanib, PRM-151, epigallocatechin gallate) are also potential candidates to treat kidney fibrosis. Novel therapeutic approaches may include antagomirs (eg, lademirsen) or drugs targeting interleukin 11 or NKD2 (WNT signaling pathway inhibitor). Reversing the dysfunctional tubular cell metabolism that leads to kidney fibrosis offers additional therapeutic opportunities. However, any future drug targeting fibrosis of the kidneys should demonstrate added benefit to a standard of care that combines renin-angiotensin system with mineralocorticoid receptor (eg, finerenone) blockade or with sodium/glucose cotransporter 2 inhibitors. Chronic kidney disease (CKD) is one of the fastest growing causes of death worldwide, expected to become the fifth most common cause of death globally by 2040 and, by the end of the century, the second leading cause of death in countries with long life expectancy.1Foreman K.J. Marquez N. Dolgert A. et al.Forecasting life expectancy, years of life lost, and all-cause and cause-specific mortality for 250 causes of death: reference and alternative scenarios for 2016-40 for 195 countries and territories.Lancet. 2018; 392: 2052-2090https://doi.org/10.1016/S0140-6736(18)31694-5Abstract Full Text Full Text PDF PubMed Scopus (742) Google Scholar,2Ortiz A. Sanchez-Niño M.D. Crespo-Barrio M. et al.The Spanish Society of Nephrology (SENEFRO) commentary to the Spain GBD 2016 report: keeping chronic kidney disease out of sight of health authorities will only magnify the problem.Nefrologia. 2019; 39: 29-34https://doi.org/10.1016/j.nefro.2018.09.002Crossref PubMed Google Scholar Factors contributing to these dismal predictions are the late diagnosis of CKD and suboptimal therapeutic tools. As a hallmark of CKD, kidney fibrosis has relevance to diagnosis and monitoring of CKD, and antifibrotic agents may have potential for treatment of CKD. In this review, we discuss current therapeutic approaches for CKD that interfere with kidney fibrosis in preclinical studies, therapeutic approaches that target kidney fibrosis and are being investigated in clinical trials, drugs undergoing clinical trials for pulmonary fibrosis that may be of interest for kidney fibrosis, and some key preclinical findings closer to clinical translation. An in-depth review of the recent preclinical literature can be found elsewhere.3Ruiz-Ortega M. Rayego-Mateos S. Lamas S. Ortiz A. Rodrigues-Diez R.R. Targeting the progression of chronic kidney disease.Nat Rev Nephrol. 2020; 16: 269-288https://doi.org/10.1038/s41581-019-0248-yCrossref PubMed Scopus (211) Google Scholar Kidney fibrosis has 3 main components: glomerular (called glomerulosclerosis), interstitial, and vascular fibrosis. It is intrinsically linked to simultaneously ongoing processes such as kidney cell injury and inflammation. Whether fibrosis is mainly a cause or a consequence of CKD progression has been disputed. There is preclinical evidence that hyperactivation of a single receptor (platelet-derived growth factor [PDGF] receptor β [PDGFR-β]) in mesenchymal cells may drive glomerular and interstitial fibrosis, preceding tubular atrophy, interstitial inflammation, and decreased glomerular filtration rate in the absence of hypertension or albuminuria.4Buhl E.M. Djudjaj S. Klinkhammer B.M. et al.Dysregulated mesenchymal PDGFR-β drives kidney fibrosis.EMBO Mol Med. 2020; 12e11021https://doi.org/10.15252/emmm.201911021Crossref Scopus (24) Google Scholar,5Kuppe C. Ibrahim M.M. Kranz J. et al.Decoding myofibroblast origins in human kidney fibrosis.Nature. 2021; 589: 281-286https://doi.org/10.1038/s41586-020-2941-1Crossref PubMed Scopus (152) Google Scholar In mice, targeting PDGFR-β or its ligands PDGF-B and PDGF-D has been reported to protect against mesangial proliferation, unilateral ureteral obstruction, and unilateral ischemia/reperfusion injury.4Buhl E.M. Djudjaj S. Klinkhammer B.M. et al.Dysregulated mesenchymal PDGFR-β drives kidney fibrosis.EMBO Mol Med. 2020; 12e11021https://doi.org/10.15252/emmm.201911021Crossref Scopus (24) Google Scholar However, evidence that fibrosis can trigger kidney disease in an animal model does not necessarily imply that it is a key driver of CKD in humans. Aside from uncertainty regarding the pathogenic role of kidney fibrosis, its relevance in diagnosis and monitoring of CKD remains to be specified. In particular, although the diagnostic criteria for CKD in the KDIGO (Kidney Disease: Improving Global Outcomes) guideline recommendations include persistent kidney damage as evidenced by histology or imaging, KDIGO does not detail how fibrosis can be ascertained by these methods.6Kidney Disease: Improving Global Outcomes (KDIGO) CKD Work GroupKDIGO 2012 Clinical Practice Guideline for the Evaluation and Management of Chronic Kidney Disease.Kidney Int Suppl. 2013; 3: 1-150https://doi.org/10.1038/kisup.2012.77Abstract Full Text Full Text PDF Scopus (178) Google Scholar Similarly, there is no optimal method to assess kidney fibrosis in clinical practice, and only one ongoing clinical trial has a primary end point of kidney fibrosis (Fig 1; Table 1).7Ortiz A. PDGFR-β and kidney fibrosis.EMBO Mol Med. 2020; 12e11729https://doi.org/10.15252/emmm.201911729Crossref Scopus (2) Google Scholar Kidney biopsies are invasive, but glomerulosclerosis or interstitial fibrosis has been found to predict progressive CKD after unilateral nephrectomy and in native kidneys and kidney graft biopsies.8Denic A. Elsherbiny H. Mullan A.F. et al.Larger nephron size and nephrosclerosis predict progressive CKD and mortality after radical nephrectomy for tumor and independent of kidney function.J Am Soc Nephrol. 2020; 31: 2642-2652https://doi.org/10.1681/ASN.2020040449Crossref PubMed Scopus (15) Google Scholar, 9Eadon M.T. Schwantes-An T.H. Phillips C.L. et al.Kidney histopathology and prediction of kidney failure: a retrospective cohort study.Am J Kidney Dis. 2020; 76: 350-360https://doi.org/10.1053/j.ajkd.2019.12.014Abstract Full Text Full Text PDF PubMed Scopus (15) Google Scholar, 10Issa N. Lopez C.L. Denic A. et al.Kidney structural features from living donors predict graft failure in the recipient.J Am Soc Nephrol. 2020; 31: 415-423https://doi.org/10.1681/ASN.2019090964Crossref PubMed Scopus (18) Google Scholar Although molecular imaging of fibrosis proteins is still preclinical,11Selby N.M. Blankestijn P.J. Boor P. et al.Magnetic resonance imaging biomarkers for chronic kidney disease: a position paper from the European Cooperation in Science and Technology Action PARENCHIMA.Nephrol Dial Transplant. 2018; 33: ii4-ii14https://doi.org/10.1093/ndt/gfy152Crossref PubMed Scopus (64) Google Scholar, 12Magalhães P. Pejchinovski M. Markoska K. et al.Association of kidney fibrosis with urinary peptides: a path towards non-invasive liquid biopsies?.Sci Rep. 2017; 7: 16915https://doi.org/10.1038/s41598-017-17083-wCrossref PubMed Scopus (44) Google Scholar, 13Baues M. Klinkhammer B.M. Ehling J. et al.A collagen-binding protein enables molecular imaging of kidney fibrosis in vivo.Kidney Int. 2020; 97: 609-614https://doi.org/10.1016/j.kint.2019.08.029Abstract Full Text Full Text PDF PubMed Scopus (20) Google Scholar, 14Sun Q. Baues M. Klinkhammer B.M. et al.Elastin imaging enables noninvasive staging and treatment monitoring of kidney fibrosis.Sci Transl Med. 2019; 11eaat4865https://doi.org/10.1126/scitranslmed.aat4865Crossref Scopus (37) Google Scholar, 15Genovese F. Rasmussen D.G.K. Karsdal M.A. et al.Imbalanced turnover of collagen type III is associated with disease progression and mortality in high-risk chronic kidney disease patients.Clin Kidney J. 2020; 14: 560-593https://doi.org/10.1093/ckj/sfz174Crossref Scopus (7) Google Scholar whole-kidney fibrosis may be assessed by noninvasive tools such as urine biomarkers and magnetic resonance imaging. In kidney allografts, magnetic resonance imaging parameters of fibrosis have been reported to correlate with histological kidney fibrosis and to predict estimated glomerular filtration rate (eGFR) decrease.16Bane O. Hectors S.J. Gordic S. et al.Multiparametric magnetic resonance imaging shows promising results to assess renal transplant dysfunction with fibrosis.Kidney Int. 2020; 97: 414-420https://doi.org/10.1016/j.kint.2019.09.030Abstract Full Text Full Text PDF PubMed Scopus (16) Google ScholarTable 1Examples of Tools for Assessment of Whole-Kidney FibrosisApproachInformation ProvidedSettingAdvantagesDrawbacksKidney biopsyConventional histology: current kidney fibrosis; systems biology: identification of active profibrotic pathwaysClinicalWidely available; allows assessment of activity and diagnosis of cause/underlying conditionLimited kidney sample size; may not be representative of whole kidneys or both kidneys; invasive; concomitant systems biology not in routine use for clinical careFluid biomarkers, eg, urinary peptidomics and others (eg, PIIINP)Current kidney fibrosis, matrix remodeling?aDecreased amounts of collagen peptides in kidneys with fibrosis may represent decreased matrix remodeling.ClinicalNoninvasive; urine can be shipped for analysis elsewhereLimited information on natural history and response to therapy; does not provide information on unilateral vs bilateral disease; limited external validationUS/MRI elastographyStrain, shear wave velocity: current fibrosisClinicalNoninvasiveNative kidney not easily accessible; influenced by hemodynamicsMRIIncreased cortical apparent diffusion coefficient and decreased T1 correlate with current fibrosisClinicalNoninvasive; may be combined with information from other MRI parametersNot widely available; limited information on natural history and response to therapy; reflect kidney function and perfusion rather than fibrosisCT scanCurrent fibrosisClinicalNoninvasiveRadiation exposure; limited information on fibrosis in the absence of contrast media, natural history, and response to therapyMolecular imagingCurrent fibrosis (eg, fluorescent CNA35 CT), ESMA-based molecular MRI of elastin)PreclinicalNoninvasive; specific imaging of extracellular matrix molecules deposited during fibrosisPerformance not assessed in humansAbbreviations: CNA35, collagen-binding adhesion protein 35 (binds to fibril-forming collagens); CT, computed tomography; ESMA, elastin-specific magnetic resonance contrast agent; MRI, magnetic resonance imaging; PIIINP, collagen type III aminoterminal propeptide; US, ultrasound.a Decreased amounts of collagen peptides in kidneys with fibrosis may represent decreased matrix remodeling. Open table in a new tab Abbreviations: CNA35, collagen-binding adhesion protein 35 (binds to fibril-forming collagens); CT, computed tomography; ESMA, elastin-specific magnetic resonance contrast agent; MRI, magnetic resonance imaging; PIIINP, collagen type III aminoterminal propeptide; US, ultrasound. Whether fibrosis itself is a bona fide target in the clinic, independent from parenchymal cell injury or inflammation, remains to be demonstrated by clinical trials that specifically target mediators of fibrosis. The therapeutic targeting of kidney fibrosis is complicated by the reality that some drugs purportedly targeting fibrosis have poorly understood mechanisms of action (eg, pirfenidone) or multiple targets (eg, nintedanib). Additionally, most clinical trials exploring antifibrotic therapy lack an assessment of kidney fibrosis as an end point and recruit participants with late stages of CKD, thus limiting the potential to interfere with early drivers of kidney fibrosis. Preclinical studies have identified multiple therapeutic approaches that decrease kidney fibrosis. However, preclinical promise does not mean clinical success, and, even if a certain therapeutic approach decreases fibrosis, this does not necessarily imply that the mechanism of the therapeutic effect is directly related to fibrosis, because fibrosis may be indirectly modified by approaches that directly prevent acute kidney cell injury or decrease inflammation. As an example, targeting TWEAK, a proinflammatory cytokine, has been reported to decrease kidney fibrosis through a combined lowering of kidney fibroblast proliferation, tubular cell death, and inflammation.17Ucero A.C. Benito-Martin A. Fuentes-Calvo I. et al.TNF-related weak inducer of apoptosis (TWEAK) promotes kidney fibrosis and Ras-dependent proliferation of cultured renal fibroblast.Biochim Biophys Acta. 2013; 1832: 1744-1755https://doi.org/10.1016/j.bbadis.2013.05.032Crossref PubMed Scopus (78) Google Scholar Several drugs in clinical use, some of them for kidney protection, decrease kidney fibrosis in animal models of kidney disease or are under study for kidney fibrosis in clinical trials (Box 1; Table 2).Box 1Treatment of Kidney Fibrosis: Different Categories of Drugs According to Stage of Clinical Development•Clinically available; clinical trials showed kidney protection; decrease kidney fibrosis in preclinical studies○Approved for kidney protection◇RAS blockers◇Finerenonea (MRA)◇Canagliflozin, dapagliflozin (SGLT2 inhibitors)○Approved for other indications◇Pentoxifylline (nonselective phosphodiesterase inhibitor)b•Ongoing clinical trials for kidney protection for drugs whose mechanism of action is thought to be mainly or partially through decreased kidney fibrosis○Pirfenidone (poorly understood; regulation of messenger RNA processing)○Lademirsen (miR-21 antagomir)•Preclinical evidence of kidney protection; ongoing or recent clinical trials for pulmonary fibrosis that offer opportunity to assess impact on kidney parameters; eventually may be tested for kidney fibrosis if successful for pulmonary fibrosis○Nintedanib (tyrosine kinase inhibitor)○PRM-151 (recombinant human pentraxin 2/serum amyloid P protein)○Epigallocatechin gallate (inhibitor of lysyl oxidase-like 2 and TGF-β receptors 1 and 2 kinase)○Ziritaxestat (autotaxin inhibitor)•Key drugs and therapeutic targets recently identified in preclinical studies of kidney fibrosis○Drugs◇Trametinib (MEK inhibitor)◇Anti–IL-11 antibody○Therapeutic targets◇NKD2◇Other fibromiRs◇Energy-sensing and mitochondrial function regulators•Clinical development for kidney fibrosis currently on hold or abandoned○Fresolimumab, LY2382770 (anti–TGF-β1 antibody)○FG-3019 (pamrevlumab; anti-CCN2 antibody)○STX-100 (BG00011; anti-integrin α5β6 antibody [αvβ6 activates latent TGF-β])○GCS-100 (galectin-3 antagonist)Mechanism of action shown in parenthesis. Abbreviations: IL-11, interleukin 11; MEK, mitogen-activated protein kinase kinase; MRA, mineralocorticoid receptor antagonist; RAS, renin-angiotensin system; SGLT2, sodium/glucose cotransporter 2; TGF-β, transforming growth factor β.aFinerenone was approved for kidney disease by the US Food and Drug Administration July 9, 2021 (https://www.accessdata.fda.gov/scripts/cder/daf/index.cfm?event=overview.process&ApplNo=215341).bNot labeled for kidney protection despite promising open-label clinical trials; placebo-controlled trials have not been performed.Table 2Completed Trials With Primary Kidney End Points of Drugs in Clinical Use Other Than Pirfenidone That Are Undergoing Clinical Trials for Kidney Fibrosis or That Decrease Fibrosis in Preclinical ModelsDrugTrialNDiseaseNotable Inclusion CriteriaNotable Exclusion CriteriaArmsPrimary End Point/Effect SizeaValues in parentheses are 95% CIs.Key Secondary End Point/Effect SizeaValues in parentheses are 95% CIs.Post Hoc AnalysesbFibrosis-related.Key LimitationsKey Safety ConcernDosing Considerations in CKDcUS Food and Drug Administration label.PentoxifyllinePREDIAN169DKDCKD 3-4; UAE >30 mg/dDM11,200 mg/d; no placeboProgression of DKD (difference in ΔeGFR from BL): 4.3 (3.1-5.5); P < 0.001ΔUAEIncrease in serum/urine KlothoSmall sample size, open labelNoneNoneCanagliflozinCREDENCE4,401DKDeGFR 30-<90, UACR 300-5,000DM1100 mg/d or placeboKF, Scr doubling, or renal or CV death: HR, 0.70 (0.59-0.82); P = 0.00001Kidney end pointdKF, 50% decrease in eGFR, or renal death.: HR, 0.66 (0.53-0.81); P < 0.001–Stopped earlyDKAInitiation NR if eGFR <45DapagliflozinDAPA-CKD4,304DKD and nondiabetic CKDeGFR 25-75, UACR 200-5,000DM110 mg/d or placeboKF, 50% ↓ in eGFR, or renal or CV death: HR, 0.61 (0.51- 0.72); P < 0.001Kidney end pointdKF, 50% decrease in eGFR, or renal death.: HR, 0.56 (0.45-0.68); P < 0.001–Stopped earlyVolume depletionContraindicated in KF/dialysisFinerenoneFIDELIO5,734DKDUACR 30-300 and eGFR 25-60 or UACR 300-5,000 and eGFR 25-75Serum K+ >4.8 mmol/L10-20 mg/d or placeboKF, 40% ↓ in eGFR, or renal death: HR, 0.82 (0.73-0.93); P = 0.001–––HyperkalemiaDose 10 mg/d if eGFR 25-60, NR for eGFR <25Data shown are intention-to-treat. Abbreviations: BL, baseline; DKA, diabetic ketoacidosis; DKD, diabetic kidney disease; eGFR, estimated glomerular filtration rate (in mL/min/1.73 m2); HR, hazard ratio; KF, kidney failure; MOA, mechanism of action; NR, not recommended; Scr, serum creatinine; UACR, urinary albumin-creatinine ratio (in mg/g); UAE, urinary albumin excretion.a Values in parentheses are 95% CIs.b Fibrosis-related.c US Food and Drug Administration label.d KF, 50% decrease in eGFR, or renal death. Open table in a new tab •Clinically available; clinical trials showed kidney protection; decrease kidney fibrosis in preclinical studies○Approved for kidney protection◇RAS blockers◇Finerenonea (MRA)◇Canagliflozin, dapagliflozin (SGLT2 inhibitors)○Approved for other indications◇Pentoxifylline (nonselective phosphodiesterase inhibitor)b•Ongoing clinical trials for kidney protection for drugs whose mechanism of action is thought to be mainly or partially through decreased kidney fibrosis○Pirfenidone (poorly understood; regulation of messenger RNA processing)○Lademirsen (miR-21 antagomir)•Preclinical evidence of kidney protection; ongoing or recent clinical trials for pulmonary fibrosis that offer opportunity to assess impact on kidney parameters; eventually may be tested for kidney fibrosis if successful for pulmonary fibrosis○Nintedanib (tyrosine kinase inhibitor)○PRM-151 (recombinant human pentraxin 2/serum amyloid P protein)○Epigallocatechin gallate (inhibitor of lysyl oxidase-like 2 and TGF-β receptors 1 and 2 kinase)○Ziritaxestat (autotaxin inhibitor)•Key drugs and therapeutic targets recently identified in preclinical studies of kidney fibrosis○Drugs◇Trametinib (MEK inhibitor)◇Anti–IL-11 antibody○Therapeutic targets◇NKD2◇Other fibromiRs◇Energy-sensing and mitochondrial function regulators•Clinical development for kidney fibrosis currently on hold or abandoned○Fresolimumab, LY2382770 (anti–TGF-β1 antibody)○FG-3019 (pamrevlumab; anti-CCN2 antibody)○STX-100 (BG00011; anti-integrin α5β6 antibody [αvβ6 activates latent TGF-β])○GCS-100 (galectin-3 antagonist) Mechanism of action shown in parenthesis. Abbreviations: IL-11, interleukin 11; MEK, mitogen-activated protein kinase kinase; MRA, mineralocorticoid receptor antagonist; RAS, renin-angiotensin system; SGLT2, sodium/glucose cotransporter 2; TGF-β, transforming growth factor β. aFinerenone was approved for kidney disease by the US Food and Drug Administration July 9, 2021 (https://www.accessdata.fda.gov/scripts/cder/daf/index.cfm?event=overview.process&ApplNo=215341). bNot labeled for kidney protection despite promising open-label clinical trials; placebo-controlled trials have not been performed. Data shown are intention-to-treat. Abbreviations: BL, baseline; DKA, diabetic ketoacidosis; DKD, diabetic kidney disease; eGFR, estimated glomerular filtration rate (in mL/min/1.73 m2); HR, hazard ratio; KF, kidney failure; MOA, mechanism of action; NR, not recommended; Scr, serum creatinine; UACR, urinary albumin-creatinine ratio (in mg/g); UAE, urinary albumin excretion. Renin-angiotensin system (RAS) blockade with angiotensin-converting enzyme inhibitors or angiotensin receptor blockers decreases kidney fibrosis in multiple animal models of kidney disease.3Ruiz-Ortega M. Rayego-Mateos S. Lamas S. Ortiz A. Rodrigues-Diez R.R. Targeting the progression of chronic kidney disease.Nat Rev Nephrol. 2020; 16: 269-288https://doi.org/10.1038/s41581-019-0248-yCrossref PubMed Scopus (211) Google Scholar However, directly targeting fibrosis is not the main mechanism of kidney protection. Moreover, antifibrotic effects were not formally tested in clinical trials. The RAS has direct profibrotic actions and also increases hyperfiltration and blood pressure, enhances inflammation, and decreases expression of Klotho, a protein expressed in the kidney that has antiaging and antifibrotic actions.18Kanbay M. Demiray A. Afsar B. et al.Role of klotho in the development of essential hypertension.Hypertension. 2021; 77: 740-750https://doi.org/10.1161/HYPERTENSIONAHA.120.16635Crossref PubMed Scopus (14) Google Scholar Mineralocorticoid receptor antagonists decrease kidney fibrosis in murine kidney disease. Finerenone, a nonsteroidal mineralocorticoid receptor antagonist, may have a better safety profile than spironolactone and eplerenone in terms of gynecomastia and hyperkalemia, although head-to-head comparisons are lacking.19Grune J. Beyhoff N. Smeir E. et al.Selective mineralocorticoid receptor cofactor modulation as molecular basis for finerenone’s antifibrotic activity.Hypertension. 2018; 71: 599-608https://doi.org/10.1161/HYPERTENSIONAHA.117.10360Crossref Scopus (86) Google Scholar In in vitro binding assays of mineralocorticoid receptor transcriptional cofactors, finerenone shows higher potency/efficacy than eplerenone; in addition, finerenone displays inverse agonism, leading to differential mineralocorticoid receptor cofactor modulation that may provide an antifibrotic advantage. Moreover, finerenone was observed to improve kidney outcomes in diabetic kidney disease in the phase 3 FIDELIO trial, even though that study did not include kidney fibrosis as an end point.19Grune J. Beyhoff N. Smeir E. et al.Selective mineralocorticoid receptor cofactor modulation as molecular basis for finerenone’s antifibrotic activity.Hypertension. 2018; 71: 599-608https://doi.org/10.1161/HYPERTENSIONAHA.117.10360Crossref Scopus (86) Google Scholar, 20Barrera-Chimal J. Girerd S. Jaisser F. Mineralocorticoid receptor antagonists and kidney diseases: pathophysiological basis.Kidney Int. 2019; 96: 302-319https://doi.org/10.1016/j.kint.2019.02.030Abstract Full Text Full Text PDF PubMed Scopus (99) Google Scholar, 21Ortiz A, Ferro CJ, Balafa O, et al; European Renal and Cardiovascular Medicine (EURECA-m) working group of the European Renal Association—European Dialysis and Transplant Association (ERA-EDTA) and the Hypertension and Kidney working group of the European Society of Hypertension (ESH). Mineralocorticoid receptor antagonists for nephroprotection and cardioprotection in patients with diabetes mellitus and chronic kidney disease. Nephrol Dial Transplant. 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Kanbay M. et al.SGLT2 inhibitors for non-diabetic kidney disease: drugs to treat CKD that also improve glycaemia.Clin Kidney J. 2020; 13: 728-733https://doi.org/10.1093/ckj/sfaa198Crossref PubMed Google Scholar,27Sarafidis P. Ferro C.J. Morales E. et al.SGLT-2 inhibitors and GLP-1 receptor agonists for nephroprotection and cardioprotection in patients with diabetes mellitus and chronic kidney disease. A consensus statement by the EURECA-m and the DIABESITY working groups of the ERA-EDTA.Nephrol Dial Transplant. 2019; 34: 208-230https://doi.org/10.1093/ndt/gfy407Crossref PubMed Scopus (104) Google Scholar Pentoxifylline is not approved for kidney protection, but it preserved kidney function and increased Klotho levels in an open-label trial.28Navarro-González J.F. 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