Aldosterone in diabetes and other kidney diseases
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This document discusses aldosterone and mineralocorticoid receptor antagonism (MRA) in diabetes and chronic kidney disease (CKD). It provides an overview of aldosterone's role in inflammation and fibrosis in cardiovascular and kidney diseases. It outlines the pharmacology of MRAs like finerenone and their clinical outcomes in reducing kidney failure, cardiovascular events, and hospitalizations in diabetic kidney disease based on trials like FIDELIO-CKD and FIGARO-DKD. It also addresses managing the risk of hyperkalemia with MRAs and the potential role of combination MRA/SGLT2 inhibitor therapy in CKD.
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Aldosterone in diabetes and other kidney diseases
- 1. Aldosterone in Diabetes and Other Kidney Diseases CHRISTOS ARGYROPOULOS MD, MS, PHD, FASN CHIEF, DIVISION OF NEPHROLOGY, DEPARTMENT OF INTERNAL MEDICINE, UNIVERSITY OF NEW MEXICO
- 2. Disclosures Consultation fees Bayer, Otsuka, Bayer, Baxter, Quanta Writing support Astra Zeneca
- 3. Learning Objectives 1. Aldosterone, inflammation and fibrosis in cardiometabolic and kidney diseases 2. Pharmacology of aldosterone antagonists 3. Clinical outcomes of aldosterone antagonism in diabetic and non-diabetic kidney disease
- 4. Aldosterone – the ENAC chronicles https://www.frontiersin.org/articles/10.3389/fphys.2022.770375/full
- 5. A brief history of aldosterone time https://doi.org/10.1093/eurheartj/ehaa736
- 6. Mineralocorticoid Receptor Activation and End Organ Damage (kidney/blood vessels) was recognized early https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1827836
- 7. Aldosterone, inflammation and fibrosis https://academic.oup.com/ajh/article/34/1/15/5895247
- 8. Kidney & Cardiovascular diseases as disorders of MR activation
- 9. Molecular mechanisms of Mineralocorticoid Receptor Activation https://www.frontiersin.org/articles/10.3389/fphar.2021.754239/full https://pubmed.ncbi.nlm.nih.gov/28634265/
- 10. MRAs reduce inflammation in experimental CKD Drug Dev Res. 2021;82:341–363. Pharmacol Res. 2021 Oct;172:105859
- 11. Steroidal and non-steroidal MRAs https://www.frontiersin.org/articles/10.3389/fphar.2021.754239 https://pubmed.ncbi.nlm.nih.gov/34758679/
- 12. Clinical Outcomes of Aldosterone (Mineralocorticoid) Antagonism in Chronic Kidney Disease
- 13. Are MRAs our next weapon in the fight against the cardiovascular and kidney sequelae of CKD ? https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8094274
- 14. MRA improves proteinuria in CKD Uncertain effects on 1. Kidney failure 2. Death 3. CV events MRA may decrease blood pressure: MD -4.98 mmHg, 95% CI -8.22 to -1.75, I2 = 87% https://www.ncbi.nlm.nih.gov/ pmc/articles/PMC8094274 Nearly all studies used spironolactone
- 15. Nonselective MRA is associated with hyperkalemia and gynecomastia HYPERKALEMIA GYNECOMASTIA Cochrane Database of Systematic Reviews 2014, Issue 4. Art. No.: CD007004. DOI: 10.1002/14651858.CD007004.pub3. Hyperkalemia Gynecomastia 41 14.1 Numbers Needed To Harm
- 16. Laboratory outcomes with selective MRAs not included in the Cochrane meta-analysis ESAXERENONE APARARENONE https://cjasn.asnjournals.org/content/15/12/1715.long https://pubmed.ncbi.nlm.nih.gov/32974732/
- 17. Kidney Outcomes of Finerenone in more severe Diabetic Kidney Disease: a 30,000 ft view https://www.karger.com/Article/FullText/503713
- 18. FIDELIO CKD : Inclusion, exclusion & statistical analysis Pts with T2D and CKD : UACR > 300 mg/g & eGFR in 25-75 ml/min/1.73m2 UACR in 30-300 mg/g & eGFR in 25-60 ml/min/1.73m2 Serum potassium level ≤ 4.8 meq/l Prior treatment with ACEi or ARB Excluded pts currently receiving eplerenone/spironolactone/renin inhibitor/K-sparing diuretic Excluded A1c > 12% or UACR >5,000 mg/g Dialysis dependent AKI within 12 wks of study run- in visit Poorly controlled hypertension (BP > 170/110 mmHg) NYHA Class II-IV or indication 1A for MRA https://www.karger.com/Article/FullText/503713
- 19. Finerenone reduces hard kidney and cardiovascular outcomes in moderate DKD https://www.nejm.org/doi/10.1056/NEJMoa2025845 Event Finerenone Placebo (N=2827) (N=2831) no. of patients (%) Any adverse event 2468 (87.3) 2478 (87.5) Adverse event related to trial regimen 646 (22.9) 449 (15.9) Adverse event leading to discontinuation of trial regimen 207 (7.3) 168 (5.9) Any serious adverse event 902 (31.9) 971 (34.3) Serious adverse event related to trial regimen 48 (1.7) 34 (1.2) Serious adverse event leading to discontinuation of trial regimen 75 (2.7) 78 (2.8) Investigator-reported hyperkalemia 516 (18.3) 255 (9.0) Hyperkalemia related to trial regimen 333 (11.8) 135 (4.8) Serious hyperkalemia 44 (1.6) 12 (0.4) Hospitalization due to hyperkalemia 40 (1.4) 8 (0.3) Permanent discontinuation of trial regimen due to hyperkalemia 64 (2.3) 25 (0.9) Investigator-reported hypokalemia 28 (1.0) 61 (2.2) Investigator-reported renal-related adverse events Acute kidney injury 129 (4.6) 136 (4.8) Hospitalization due to acute kidney injury 53 (1.9) 47 (1.7) Discontinuation of trial regimen due to acute kidney injury 5 (0.2) 7 (0.2) Hospitalization due to acute renal failure 70 (2.5) 71 (2.5) Discontinuation of trial regimen due to acute renal failure 31 (1.1) 36 (1.3) Adverse events affecting ≥5% of patients in either group Hyperkalemia 446 (15.8) 221 (7.8) Nasopharyngitis 241 (8.5) 250 (8.8) Hypertension 212 (7.5) 273 (9.6) Anemia 209 (7.4) 191 (6.7) Peripheral edema 186 (6.6) 304 (10.7) Diarrhea 184 (6.5) 189 (6.7) Upper respiratory tract infection 181 (6.4) 189 (6.7) Glomerular filtration rate decreased 179 (6.3) 133 (4.7) Urinary tract infection 179 (6.3) 192 (6.8) Back pain 175 (6.2) 175 (6.2) Hypoglycemia 151 (5.3) 194 (6.9) Dizziness 146 (5.2) 153 (5.4) Arthralgia 142 (5.0) 149 (5.3) Bronchitis 134 (4.7) 151 (5.3) Constipation 131 (4.6) 163 (5.8) Pneumonia 128 (4.5) 181 (6.4)
- 20. Effects of Finerenone reduced loss of eGFR and had modest effects on BP https://www.nejm.org/doi/10.1056/NEJMoa2025845 Change in SBP < 3 mmHg throughout FIDELIO-CKD
- 21. Cardiovascular Outcomes of Finerenone in less severe Diabetic Kidney Disease: the FIGARO-DKD trial https://www.nejm.org/doi/full/10.1056/NEJMoa2110956 Pts with T2D and CKD : UACR > 300 mg/g & eGFR > 60ml/min/1.73m2 UACR in 30-300 mg/g & eGFR in 25-90 ml/min/1.73m2 Serum potassium level ≤ 4.8 meq/l Prior treatment with ACEi or ARB Excluded pts currently receiving eplerenone/spironolactone/renin inhibitor/K-sparing diuretic Excluded A1c > 12% or UACR >5,000 mg/g Dialysis dependent AKI within 12 wks of study run-in visit Poorly controlled hypertension (BP > 170/110 mmHg) NYHA Class II-IV or indication 1A for MRA SAE: 31.4% (Finerenone) vs 33.2% (placebo) Incidence of hyperkalemia was higher with finerenone than with placebo (10.8% vs. 5.3%)
- 22. Aldosteronism Antagonism (MRA) for the reduction of cardiorenal risk across the spectrum of DKD https://doi.org/10.1093/eurheartj/ehab827
- 23. https://doi.org/10.1093/eurheartj/ehab777 Cardiovascular and kidney outcomes with finerenone in patients with type 2 diabetes and chronic kidney disease: the FIDELITY pooled analysis
- 24. Management of hyperkalemia during aldosterone antagonism for diabetic and non- diabetic CKD Hypekalemia will occur with MRA (can’t escape ENAC!) Hyperkalemia will occur with MRAs irrespective of the MRA and the diabetic (or not) nature of CKD Management of hyperkalemia will allow the safe use of MRAs Continued use of MRAs is required to deliver their cardiovascular and kidney benefits Potential strategies to manage the hyperkalemia risk by any MRA are: • Measure the potassium (it never makes sense to “stop the count”) • Stop the MRA or reduce the dose • “Convince” the kidneys to get rid of potassium (diuretics/SGLT2 inhibitors) • Use a potassium binder Protocol of the Finerenone trials gives guidance on how to manage potassium during MRA therapy safely
- 25. Management of hyperkalemia in Fidelio DKD https://jasn.asnjournals.org/content/33/1/225
- 27. SGLT2i reduce rates of ESKD by 37% and the composite kidney outcome of worsening kidney function/ ESKD by 39%
- 28. MRA v.s. SGLT2i in the management of CKD ARE MRAS LESS POTENT? OR DID THE TRIALS JUST RECRUIT PATIENTS WITH SOMEWHAT DIFFERENT RISK PROFILES ? Eye-balling HRs Network meta-analysis (statistical eye- balling) SGLT2i vs MRA: 1. Kidney Failure Progression: HR 0.78, 95% CI 0.67–0.90 2. HHF: HR 0.71, 95% CI 0.55–0.92 3. MACE: HR 0.95, 95% CI 0.71–1.27 https://doi.org/10.1093/ndt/gfab336 https://www.frontiersin.org/articles/10.3389/fphar.2021.751496/
- 29. Do MRA/SGLT2i interfere with each other? MRA IN DAPA-CKD SGLT2I IN THE FIDELIO-DKD TRIAL https://doi.org/10.1016/j.ekir.2021.12.013 https://www.kireports.org/article/S2468-0249(21)01467-4/fulltext No evidence of effect modification based on limited and subject to selection effect post hoc subgroup data
- 30. SGLT2i is NOT going to be the end of (D)CKD Am J Physiol Renal Physiol 304: F156–F167, 2013.
- 31. Role of combination MRA/SGLT2i in CKD? OF RODENTS … AND HUMANS … https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8619789/ Empa vs Finerenone vs Empa+Finerenone
- 32. Wrapping up! In addition to its role in sodium, potassium and blood volume regulation … Aldosterone is a key, mediator of inflammation and fibrosis in the cardiovascular system and the kidney Overactivation of the mineralocorticoid receptor underlines a sizeable chunk of cardiovascular and kidney pathology Nonsteroidal MRAs are an emerging class of drugs for cardiovascular and kidney risk reduction in patients with diabetes and CKD that have reduced endocrine side effects relative to steroidal MRAs Finerenone, a nonsteroidal MRA was approved by the FDA to reduce the risk of sustained eGFR decline, end stage kidney disease, cardiovascular death, non-fatal myocardial infarction and hospitalization for heart failure in patients with CKD associated with T2D The risk of hyperkalemia with MRAs can be mitigated by lab monitoring and a protocolized approach similar to the one adopted in the Finerenone RCTs MRAs and SGLT2i are both guideline endorsed therapies that don’t reduce the benefits of each other, and clinical trials are under way to explore their synergistic effect in CKD
Editor's Notes
- Hypotension-induced activation of the renin-angiotensin-aldosterone system. As blood pressure drops, juxtaglomerular cells receive signals from macula densa cells and the sympathetic nervous system and secrete renin into the circulation. Renin hydrolyzes liver-synthesized angiotensinogen into inactive ANG I. ANG I is converted to active ANG II by ACE. ANG II stimulates glomerulosa cells in the adrenal cortex to secrete aldosterone and the anterior pituitary gland in the brain to secrete the ACTH, which also results in aldosterone production. High K+ concentration stimulates aldosterone secretion from glomerulosa cells. Aldosterone increases Na+ reabsorption, K+ and H+ secretion in ASDN leading to an increase in blood pressure. ANG I, angiotensin I; ANG II, angiotensin II; ACE, angiotensin-converting enzyme; ASDN, aldosterone-sensitive distal nephron. Cellular mechanisms leading to increased aldosterone production upon angiotensin II, ACTH, and K+ stimulation. Ang II binds to AT1R, leading to dissociation of the alpha subunit and activation of PLC. PLC hydrolyses PIP2 into DAG and IP3. IP3 binds to its receptor on the SER leading to the release of Ca2+ stores. Ca2+ activates CaMK, which causes an increase in ADS expression through CREB. DAG activates PKC to phosphorylate Src, which phosphorylates EGFR leading to activation of p42/p44 mitogen-activating protein kinase pathway. P42/p44 phosphorylates CEH to hydrolyze cholesterol esters located in the lipid droplets, making them available for transport to the inner mitochondrial membrane by STAR. PKC also phosphorylates and activates STAR. Cholesterol is used for aldosterone synthesis. ACTH binds its ACTHR leading to the activation of adenylate cyclase, which produces cAMP from ATP. cAMP triggers PKA-mediated phosphorylation and activation of STAR. PKA also phosphorylates L and T type Ca2+ channels causing Ca2+ influx. PKA increases the expression of ADS through relieving SF1-mediated inhibition of STAR. High extracellular K+ concentration depolarizes cells and leads to activation of L and T type Ca2+ channels, which allow calcium inflow from the extracellular space. ANG II, angiotensin II; AT1R, angiotensin II receptor type 1; GPCR, G protein-coupled receptor; PLC, phospholipase C; PIP2, phosphatidylinositol 4,5-bisphosphate; DAG, diacylglycerol; IP3, inositol 1,4,5 triphosphate; SER, smooth endoplasmic reticulum; CaMK, Ca2+/calmodulin-dependent protein kinase; ADS, aldosterone synthase; CREB, cAMP-response element binding protein; PKC, protein kinase C; EGFR, epidermal growth factor receptor; CEH, cholesterol ester hydrolase; STAR, steroid acute regulatory protein; ACTH, adrenocorticotropic hormone; ACTHR, adrenocorticotropic hormone receptor; SF1, steroidogenic factor 1. Aldosterone regulates epithelial sodium channel (ENaC) activity and degradation. Aldosterone-bound MR translocates to the nucleus and induces transcription of USP 2-45, SGK1, and GILZ. SGK1 phosphorylates WNK4 and dampens its inhibitory action on ENaC activity. Nedd4-2 ubiquitinates ENaC and signals it for proteasomal degradation. Wnk4 is targeted to proteasomal degradation by KLHL3-Cul3 ubiquitin ligase. SGK1 inhibits this process by phosphorylating Nedd4-2 reducing its affinity to ENaC. USP2-45 removes UB from ENaC preventing its degradation. SGK1 requires phosphorylation events in order to achieve full activity, which is accomplished by PDK1, Wnk1, and mTORC. In the absence of aldosterone, SGK1 is subject to ERAD. However, in the presence of aldosterone GILZ inhibits this process increasing the stability of SGK1. MR, mineralocorticoid receptor; SGK1, serum glucocorticoid-induced kinase 1; GILZ, glucocorticoid-induced leucine zipper 1; Nedd4-2, Neural precursor cell expressed developmentally downregulated gene 4; ENaC, epithelial sodium channel; UB, ubiquitin; PDK1, pyruvate dehydrogenase kinase; ERAD, endoplasmic reticulum-associated degradation.
- Enlargement and hyalinization of the glomeruli with capsular fibrosis, dilation of the convoluted tubule (bottom). The figure on the left shows marked perivascular fibrosis and hyalinization of an arteriole in the capsule of the adrenal cortex. Similar findings were noted in the pancreas (right)
- Aldosterone and production of inflammatory mediators. Aldosterone induces the production of inflammatory mediators either through activation of mineralocorticoid receptors (MRs) or G-protein-coupled estrogen receptors (GPERs). The dashed line arrows indicate mechanisms not depicted in the figure. Abbreviations: Aldo, aldosterone; AP-1, activator protein-1; ATP, adenosine triphosphate; Ca2+, calcium; Col I, Collagen type I; COX-2, cyclooxygenase-2; CRP, C-reactive protein; DAMPs, damage-associated molecular patterns; ERK, extracellular signal-regulated kinase; IFN, interferon; IL, interleukin; K+, potassium; κBRE, nuclear factor-κB (NF-κB) response element; MCP-1, macrophage chemoattractant protein-1; MRE, MR response element; NADPH, reduced nicotinamide adenine dinucleotide phosphate; NF-κB, nuclear factor-κB; NGAL, neutrophil gelatinase-associated lipocalin; NLRP3, NOD-like receptor pyrin-domain containing protein 3; OPN, osteopontin; P2RX7, P2X purinoceptor 7; PI3K, phosphoinositide 3-kinase; ROS, reactive oxygen species; TGF, transforming growth factor; TLR, Toll-like receptor; TNF, tumor necrosis factor; TRE, 12-O-tetradecanoylphorbol-13-acetate response element (AP-1 response element); VCAM-1, vascular cell adhesion molecule-1. Aldosterone and activation of adaptive immune cells. Aldosterone induces activation of dendritic cells and increased polarization of CD4+ naive T cells into Th17, Th1, and decreased Treg cells. Aldosterone also increases recruitment of B lymphocytes and activation of CD8+ T cells. Abbreviations: IFN, interferon; IL, interleukin; TGF, transforming growth factor; Th, T helper cells; TNF, tumor necrosis factor; Treg, T regulatory cells.
- At first sight, it may seem unnecessary to combine the trials given that they both met their primary outcome and there was some overlap in the populations studied. Indeed, the results of FIDELITY confirm the results of FIGARO-DKD and FIDELIO-DKD but the analysis adds important new information to the separate analyses (Graphical Abstract). It is important to remember that kidney failure was the primary endpoint of FIDELIO-DKD and a cardiovascular composite was the secondary outcome. The primary and secondary outcomes were the opposite in FIGARO-DKD. Without sophisticated hierarchical or pre-specified planning of multiple outcomes, any trial is only powered to examine the primary outcome for which it was designed. Therefore, the results of FIGARO-DKD do not provide definitive information on the effect of finerenone on kidney failure outcomes in those with less severe CKD, and FIDELIO-DKD does not provide definitive information on the effect of finerenone on cardiovascular outcomes in those with more severe CKD (Graphical Abstract). FIDELITY bridges this gap now by confirming that across the spectrum of CKD studied in these trials, finerenone reduces the risk of the cardiovascular composite outcome and kidney composite outcome with no evidence of heterogeneity between the trials. While this is of importance to trialists and guideline writers, the pooled analysis of these two trials fills another, more clinically important, role.