Symposium 4.1 – New treatment targets to halt CKD progression

Symposium Summary

Written by Jasna Trbojevic-Stankovic
All the speakers reviewed and approved the contents

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SGLT-2 inhibition – the new standard?

Maria Jose Soler, Spain

One of the major goals in nephrology is to prevent the progression of chronic kidney disease (CKD). Recent years have brought substantial advances in this field. Renin-angiotensin-aldosterone system (RAAS) blockade has long been the mainstay of antiproteinuric and renoprotective action directed to preserve renal function. A few years ago, SGLT2 inhibitors and GLP1 antagonists have emerged as possible alternatives to achieve cardiovascular (CV) and renal benefits in CKD patients. Even more recently, endothelin antagonist, a DPP4 inhibitor, and mineralocorticoid receptor antagonist (MRA) finerenone have also presented encouraging results, thus adding to the selection of available drugs to abate CKD progression.

Patients with CKD have traditionally been excluded from initial drug testing. Nevertheless, when the potential beneficial effect of SGLT2 inhibitors on renal function has been noted, later studies focused attentively on this particular patient group rendering astonishing results. SGLT2 inhibitors enhance renal glucose excretion by inhibiting renal glucose reabsorption in the renal proximal tubule. Consequently, they reduce plasma glucose in an insulin-independent manner and improve insulin resistance in diabetes. Beyond the hypoglycaemic and natriuretic effects, the most important mechanisms of SGLT2 cardiorenal protection include the reduction in the intraglomerular pressure, restoration of the tubuloglomerular feedback, the changes in the local and systemic degree of activation of RAAS, and a shift in renal fuel consumption towards more efficient energy substrates such as ketone bodies.

Figure 1. Mechanisms of SGLT2 cardiorenal protection

The recent randomized controlled trials, including CANVAS, CREDENCE, DECLARE, DAPA-HF, DAPA-CKD, EMPA-REG, and EMPEROR-reduced accumulated evidence on SGLT2 renoprotective effects in both diabetic and non-diabetic CKD patients making them the first-line therapy for CKD, independent from diabetic status. This has expanded the target populations in whom SGLT2 inhibitors can be used for their cardio-and nephroprotection to patients with type 2 diabetes with high CV risk, and diabetic and non-diabetic CKD and heart failure patients. No data are currently available regarding CV or kidney benefit in non-diabetic patients with CKD and an absence of heart failure. Furthermore, these trials, and especially the DAPA-CKD, have far-reaching implications for a series of traditional concepts in nephrology. As the DAPA-CKD trial included more patients with immunoglobulin A nephropathy (IgAN) than any of the previous IgAN-focused trials, dual renin-angiotensin/SGLT2 inhibition may become the new standard in this population. The same refers to patients with podocytopathy-related focal segmental glomerulosclerosis lesions. Future studies are expected to elucidate the possible beneficial role of SGLT2 inhibitors in the treatment of acute myocardial infarction, atrial fibrillation, hypertension, obesity, kidney transplant, and even COVID-19 patients.

Non-steroidal MRA – an emerging option?

Christian Rump, Germany

The RAAS plays an important role in regulating blood volume and systemic vascular resistance, which together influence cardiac output and arterial pressure. Renin is a proteolytic enzyme that is released into the circulation by the kidneys in response to sympathetic nerve activation, renal hypoperfusion, and decreased sodium delivery to the distal tubules. Renin stimulates the formation of angiotensin I, which is subsequently converted to angiotensin II by the angiotensin-converting enzyme (ACE). Angiotensin II is a potent vasoconstrictive peptide that also stimulates the release of aldosterone from the adrenal cortex. Aldosterone in turn acts on the kidneys to increase sodium and fluid retention, thus contributing to volume preservation. The first approved aldosterone agonist to treat fluid retention due to heart failure, liver dysfunction or kidney disease was spironolactone, sold under the brand name Aldactone among others. Nevertheless, it took nearly four decades to notice aldosterone effects beyond sodium and water reabsorption and potassium excretion, namely the increase of cardiac sympathetic activity while reducing inflammation, fibrosis, oxidative stress, endothelial dysfunction, albuminuria, and cardiac remodeling and improving insulin resistance.

Nearly two decades ago it was observed that aldosterone causes nongenomic vasoconstriction of the glomerular circulation, predominantly the efferent arterioles, thus playing an important role in the pathophysiology and progression of renal diseases by elevating renal vascular resistance and glomerular capillary pressure. Furthermore, the discovery of its role in the secondary increase of albuminuria, termed “aldosterone escape”, occurring in patients treated with RAS blockers presented the rationale for blockade of the mineralocorticoid receptor in this event. Later studies confirmed the antiproteinuric effect of MRAs and their favourable influence on renal function and a remarkable sustained reduction in proteinuria.

Figure 2. The mechanism of aldosterone escape

The high incidence of the most common side effects of long-term MRA therapy, gynecomastia, and hyperkalaemia, has inspired the search for better tolerated and more efficient agents. The recently developed nonsteroidal MRA finerenone has a unique pharmacodynamic profile based on its physicochemical properties, tissue distribution, mode of mineralocorticoid receptor inactivation, and differential regulation of downstream antihypertrophic gene expression. Aldosterone-dependent phosphorylation and degradation of mineralocorticoid receptors are inhibited by both spironolactone and finerenone, but finerenone delays aldosterone-induced nuclear accumulation of mineralocorticoid receptors more efficiently than spironolactone and is an inverse agonist of the mineralocorticoid receptors reducing cofactor recruitment. These different molecular properties translate into different in vivo properties with significant relevance for patients with CV and kidney diseases.

Several recent studies have investigated the beneficial effects of non-steroidal MRAs on reducing proteinuria and preserving renal function. A large prospective double-blind FIDELIO-DKD trial randomly assigned 5734 patients with CKD and type 2 diabetes to receive finerenone or placebo in a 1:1 ratio on top of maximum RAS blockade. The primary composite outcome was a sustained decrease of at least 40% in the eGFR from baseline or death from renal causes. The key secondary composite outcome was death from cardiovascular causes, nonfatal myocardial infarction, nonfatal stroke, or hospitalization for heart failure. After a median follow-up of 2.6 years, the trial confirmed that treatment with finerenone delayed the progression of CKD and reduced the risk for CV among adults with type 2 diabetes, with an acceptable safety profile.

Targeting inflammation pathways – the future?

Timotheus Speer, Germany

Numerous epidemiological studies highlighted inflammation as a risk factor for CV disease. CKD patients often present an increased inflammatory state due to multiple mechanisms inherent to renal function loss: oxidative stress, uremic toxins, impaired calcium-phosphate metabolism, uremic dyslipidaemia, RAAS activation, and intestinal dysbiosis. Therefore, the identification of endogenous activators of inflammation is essential for the development of new anti-inflammatory treatment strategies.

Recent research specifically focused on the role of uremic dyslipidaemia in the development of CKD-associated inflammation and CV diseases. Uraemia leads to several modifications of the structure of both low-density LDL and high-density lipoproteins HDL, such as changes of the proteome and the lipidome, post-translational protein modifications, and accumulation of small-molecular substances within the lipoprotein moieties, which affect their functionality, eventually leading to endothelial dysfunction, hypertension, and impaired vascular regeneration. On the other hand, apolipoprotein C3 (ApoC3), which raises plasma triglycerides by stimulating very-low-density lipoproteins (VLDL) secretion, has been identified as an activator of NLRP3 inflammasome in human monocytes, thus impeding endothelial regeneration and promoting kidney injury and CV diseases. This effect of ApoC3 is restricted to human monocytes and was not observed in mice.

Recent work explored the association of genetic NLRP3 variants with CV disease and mortality in over half a million subjects concluding that the NLRP3 intronic variant rs10754555 was associated with increased systemic inflammation, inflammasome activation, prevalent coronary artery disease, and mortality. This study provided evidence for a significant role of genetically driven systemic inflammation in CV disease and highlighted the NLRP3 inflammasome as a potential therapeutic target. Recently published, is another research exploring the role of IL-1α in inflammation, CKD, and myocardial infarction.

Figure 3. Lipoproteins and inflammation in CKD

Guided by these results, several trials have been undertaken to validate the effect of anti-inflammatory treatment strategies on reducing cardiovascular events. The breakthrough results from the CANTOS trial showed that directly reducing systemic inflammation with canakinumab, an IL-1β neutralizing monoclonal antibody, also reduced CV event rates, without affecting lipid levels. This effect was also observed among high-risk atherosclerosis patients with CKD, particularly among those with a robust anti-inflammatory response to initial treatment, thus suggesting that the effect of canakinumab was entirely independent of kidney function. This therapy was associated with a higher incidence of fatal infection, but also with a lower incidence of systemic inflammatory diseases, such as osteoarthritis or gout, and a lower risk for fatal cancers. Another randomized, double-blind trial – the COLCOT trial, recruited over 4,500 patients within 30 days after myocardial infarction to evaluate the effect of colchicine, a potent anti-inflammatory medication, on the occurrence of CV events. It concluded that a daily dose of 0.5 mg colchicine significantly reduced the risk of ischemic CV events compared to placebo, with an acceptable safety profile. A post-hoc analysis revealed that beneficial effects of colchicine were best achieved when the therapy was initiated within the first three days after the myocardial infarction. More recently, the LoDoCo2 trial confirmed the protective CV effect of low-dose colchicine in patients with chronic coronary disease. Nevertheless, neither of these investigations included patients with advanced CKD.

Finally, the results from a randomized, double-blind, phase 2 RESCUE clinical trial, published just weeks ago, found that ziltivekimab, a fully human monoclonal antibody directed against IL-6, markedly reduced biomarkers of inflammation and thrombosis relevant to atherosclerosis in adults with moderate to severe CKD. These data paved the way to a large-scale CV outcomes trial that will investigate the effect of ziltivekimab in patients with CKD, increased high-sensitivity CRP, and established CV disease – the ZEUS trial, scheduled to start this year.

Further reading

García-Carro C, Vergara A, Agraz I, Jacobs-Cachá C, Espinel E, Seron D, Soler MJ. The New Era for Reno-Cardiovascular Treatment in Type 2 Diabetes. J Clin Med. 2019;8(6):864. doi: 10.3390/jcm8060864.

Cherney DZ, Kanbay M, Lovshin JA. Renal physiology of glucose handling and therapeutic implications. Nephrol Dial Transplant. 2020;35(Suppl 1):i3-i12. doi: 10.1093/ndt/gfz230.

Fernandez-Fernandez B, Sarafidis P, Kanbay M, Navarro-González JF, Soler MJ, Górriz JL, Ortiz A. SGLT2 inhibitors for non-diabetic kidney disease: drugs to treat CKD that also improve glycaemia. Clin Kidney J. 2020;13(5):728-733. doi: 10.1093/ckj/sfaa198.

Anders HJ, Peired AJ, Romagnani P. SGLT2 inhibition requires reconsideration of fundamental paradigms in chronic kidney disease, ‘diabetic nephropathy’, IgA nephropathy and podocytopathies with FSGS lesions. Nephrol Dial Transplant. 2020:gfaa329. doi: 10.1093/ndt/gfaa329.

Arima S, Kohagura K, Xu HL, Sugawara A, Abe T, Satoh F, Takeuchi K, Ito S. Nongenomic vascular action of aldosterone in the glomerular microcirculation. J Am Soc Nephrol. 2003;14(9):2255-63. doi: 10.1097/01.asn.0000083982.74108.54.

Rump LC. Secondary rise of albuminuria under AT1-receptor blockade–what is the potential role of aldosterone escape? Nephrol Dial Transplant. 2007;22(1):5-8. doi: 10.1093/ndt/gfl549.

Morales E, Millet VG, Rojas-Rivera J, et al. Renoprotective effects of mineralocorticoid receptor blockers in patients with proteinuric kidney diseases. Nephrol Dial Transplant. 2013;28(2):405-12. doi: 10.1093/ndt/gfs429.

Kolkhof P, Nowack C, Eitner F. Nonsteroidal antagonists of the mineralocorticoid receptor. Curr Opin Nephrol Hypertens. 2015;24(5):417-24. doi: 10.1097/MNH.0000000000000147.

Amazit L, Le Billan F, Kolkhof P, et al. Finerenone Impedes Aldosterone-dependent Nuclear Import of the Mineralocorticoid Receptor and Prevents Genomic Recruitment of Steroid Receptor Coactivator-1. J Biol Chem. 2015;290(36):21876-89. doi: 10.1074/jbc.M115.657957.

Bakris GL, Agarwal R, Anker SD; FIDELIO-DKD Investigators. Effect of Finerenone on Chronic Kidney Disease Outcomes in Type 2 Diabetes. N Engl J Med. 2020;383(23):2219-2229. doi: 10.1056/NEJMoa2025845.

Speer T, Ridker PM, von Eckardstein A, Schunk SJ, Fliser D. Lipoproteins in chronic kidney disease: from bench to bedside. Eur Heart J. 2021;42(22):2170-2185. doi: 10.1093/eurheartj/ehaa1050.

Speer T, Zewinger S. High-density lipoprotein (HDL) and infections: a versatile culprit. Eur Heart J. 2018;39(14):1191-1193. doi: 10.1093/eurheartj/ehx734. PMID: 29240892.

Zewinger S, Reiser J, Jankowski V, et al. Apolipoprotein C3 induces inflammation and organ damage by alternative inflammasome activation. Nat Immunol. 2020;21(1):30-41. doi: 10.1038/s41590-019-0548-1.

Schunk SJ, Kleber ME, März W; eQTLGen consortium; BIOS consortium. Genetically determined NLRP3 inflammasome activation associates with systemic inflammation and cardiovascular mortality. Eur Heart J. 2021;42(18):1742-1756. doi: 10.1093/eurheartj/ehab107

Ridker PM, Everett BM, Thuren T; CANTOS Trial Group. Antiinflammatory Therapy with Canakinumab for Atherosclerotic Disease. N Engl J Med. 2017;377(12):1119-1131. doi: 10.1056/NEJMoa1707914.

Tardif JC, Kouz S, Waters DD, et al. Efficacy and Safety of Low-Dose Colchicine after Myocardial Infarction. N Engl J Med. 20196;381(26):2497-2505. doi: 10.1056/NEJMoa1912388.

Nidorf SM, Fiolet ATL, Mosterd A; LoDoCo2 Trial Investigators. Colchicine in Patients with Chronic Coronary Disease. N Engl J Med. 2020;383(19):1838-1847. doi: 10.1056/NEJMoa2021372.

Ridker PM, Devalaraja M, Baeres FMM; RESCUE Investigators. IL-6 inhibition with ziltivekimab in patients at high atherosclerotic risk (RESCUE): a double-blind, randomised, placebo-controlled, phase 2 trial. Lancet. 2021;397(10289):2060-2069. doi: 10.1016/S0140-6736(21)00520-1.