The era of combination of nephroprotective agents in CKD is there

In the 1980s, Barry Brenner hypothesized that maladaptive glomerular hemodynamic changes exert a major influence on the factors that initiate and perpetuate kidney disease progression. This concept of hyperfiltration triggered experimental studies with enalapril, which mitigated the relentless progression of kidney disease in various models [1]. Clinical trials with ACE-Inhibitors (ACE-I) confirmed the validity of this concept in patients with type 1 diabetes [2], then in patients with heavily albuminuric non-diabetic CKD [3]. Angiotensin-receptor blockers (ARB) subsequently were shown to delay the progression of CKD in participants with type 2 diabetes [4, 5]. Yet, the range of nephroprotective drugs for the general management of CKD remained limited to ACE-I or ARB [6]. Multiple studies then tested their combination to enhance nephroprotection but success was not at the end of the road: all three major trials (one of them using a direct renin inhibitor, aliskiren) showed increased risk of AKI and hyperkalemia with the combination of two agents blocking the RAS system, without clear evidence of additional nephroprotection compared with a single agent [7–9].

Fortunately, the field has recently experienced a welcome burst of additional effective nephroprotective agents, effective both in participants with type 2 diabetes (TD2) and other causes of CKD. These include SGLT2-inhibitors in both indications, and the nonsteroidal mineralocorticoid receptor antagonist finerenone in T2D only so far. This has now been included in recent guidelines [10, 11]. Even more recently, the publication of the FLOW trial results with the glucagon-like peptide 1 receptor agonist semaglutide in T2D with CKD [12] adds another agent to the armamentarium, of course awaiting regulatory approval for the CKD and T2D indication for semaglutide and position in guidelines. These encouraging results have led to the concept of four pillars of therapy for CKD as the agents may work on different additive mechanisms [13].

The good news is that this flurry of new drugs is likely to expand further, with multiple additional phase 3 trials now starting or underway. These include the indication of finerenone for albuminuric non-diabetic CKD, currently tested in the FIND-CKD trial and albuminuric CKD in type 1 diabetes tested in the FINE-ONE trial, the development of aldosterone synthase inhibitors, whose promising results in phase 2 [14] prompted phase 3 trials in CKD with or without diabetes, and the renewal of interest for endothelin-receptor antagonists in combination with SGLT2-i, again after encouraging phase 2 results [15].

In this Supplement of Nephrology Dialysis Transplantation, top experts highlight key aspects of the implications of this ongoing revolution in the management of CKD.

Jaisser and Barrera-Chimal review the preclinical evidence showing new mechanisms by which mineralocorticoid receptor inhibition results in beneficial effects against cardiorenal damage in non-diabetic kidney disease. Moreover, they summarize the clinical trials testing the safety and efficacy of steroidal and nonsteroidal MRAs in patients with advanced non-diabetic CKD.

Carsten Wagner reviews the relevance of some major proximal tubule transport systems as drug targets in individuals with CKD. Indeed, in addition to SGLT2 inhibitors, carbonic anhydrase inhibitors and uricosuric drugs are already available. Inhibition of phosphate and amino acid transporters has been recently proposed to remove excess phosphate or to protect the proximal tubule metabolically, respectively. In addition, organic cation and anion transporters involved in drug and toxin excretion may serve as targets of new drugs. He discusses the advantages and challenges associated with (novel) drugs targeting proximal tubule transport.

Zhu et al. from the Oxford Clinical Trial Center discuss, in the current era, the implications of the revolution of combination therapies to manage risk of CKD progression for trial design (in terms of sample size, study design, adherence to study interventions a.o.). They also review recent innovations in trial design.

Moedt et al. discuss the use of selective endothelin-receptor antagonists (ERA) as a viable therapeutic option in CKD. Indeed, whereas the use of ERA was fraught with the risk of fluid retention, the concomitant use of SGLT2 inhibitors mitigates this risk.

Nardone et al. highlight the clinical evidence supporting emerging therapies for CKD, including glucagon-like peptide-1 receptor agonists and other incretin-based therapies, aldosterone synthase inhibitors, ERA, soluble guanylate cyclase agonists, and anti-inflammatory drugs.

Alicic et al. discuss the available evidence supporting combination therapy in CKD with diabetes and additionally discuss ongoing and future trials evaluating the efficacy and safety of combination therapies for CKD with or without diabetes.

Finally, Neuen et al. review the rationale for combination therapy with evidence-based kidney therapies for diabetic and non-diabetic CKD. They further outline the randomized evidence supporting a combination therapy approach, safety considerations, and potential frameworks for implementation to reduce long-term risk of kidney failure and other associated complications.

We do hope that the readers of this Supplement issue of Nephrology Dialysis Transplantation will enjoy these insightful contributions, which collectively highlight the current fast progress and paradigm shift in nephroprotection.

FUNDING

This paper was published as part of a supplement financially supported by Bayer AG and the scientific content has not been influenced in any way by the sponsor.

CONFLICT OF INTEREST STATEMENT

Michel Jadoul declares Speaker fees from : Astellas, Astra-Zeneca, Bayer, Boehringer-Ingelheim, Menarini, Stada-EG; Consultancy fees from : Astellas, Astra-Zeneca, Bayer, Boehringer-Ingelheim, Cardiorenal, CSL Vifor, GSK, Novo Nordisk, Stada-EG, Vertex. He further declares he is since januari 2019 cochair of Kidney Disease: Improving Global Outcomes (KDIGO). Peter Rossing declares Consultancy and/or speaking fees (to his institution) from Abbott, AstraZeneca, Bayer, Boehringer Ingelheim, Daiichi Sankyo, Eli Lilly, Gilead, Novo Nordisk Novartis, and Sanofi Aventis; Research grants from AstraZeneca Bayer and Novo Nordisk; Study medication provided by Astra Zeneca, Bayer, Novo Nordisk Lexicon Pharma.

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