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Call for action in ANCA-associated vasculitis and lupus nephritis: promises and challenges of SGLT-2 inhibitors
  1. Marcus Säemann1,2,
  2. Andreas Kronbichler3
  1. 1 6th Medical Department, Nephrology and Dialysis, Clinic Ottakring, Vienna, Austria
  2. 2 Medical School, Sigmund Freud University, Vienna, Austria
  3. 3 Department of Medicine, University of Cambridge, Cambridge, UK
  1. Correspondence to Dr Marcus Säemann, 6th Medical Department, Nephrology and Dialysis, Clinic Ottakring, Vienna 1160, Austria; SAEMANNMARCUS{at}GMAIL.COM

Abstract

Sodium–glucose cotransporter- 2 inhibitors (SGLT- 2i) have recently been demonstrated to exert profound cardio- and nephroprotection in large cardiovascular outcome trials. They reduce progression of chronic kidney disease (CKD) including albuminuria and improve outcomes in heart failure patients with and without type 2 diabetes on top of angiotensin-blocking agents. These benefits translate into improved mortality in cardiorenal risk patients. While the detailed molecular mechanisms underlying these surprising clinical outcomes are not fully understood, their antidiabetic properties are not causative. Rather reduction of glomerular hyperfiltration and tubuloprotection are involved as root cause mechanisms of their clinical effects. Finally, their side effect profile is advantageous especially in non-diabetic patients also reducing the risk of acute kidney injury. Among the independent risk factors for excess mortality, CKD is still one of the strongest predictors of a poor prognosis in patients with both ANCA- associated vasculitis (AAV) and lupus nephritis (LN). Since patients with autoimmune disease were excluded from all recent large renal outcome trials with SGLT-2i and given their strong nephroprotective potential, we herein advocate to study this unique class of disease-modifying therapies when it comes to kidney and cardiovascular health in patients with AAV and LN.

  • lupus nephritis
  • hypertension
  • lupus erythematosus
  • systemic

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The story of sodium–glucose cotransporter-2 inhibitors (SGLT-2i) is fascinating since they were initially studied as antidiabetic drugs due to their ability to increase glycosuria by blocking sodium and glucose reabsorption in proximal tubules of the kidney. While their antidiabetic efficiency has turned out to be at best modest, initial trials have unexpectedly found potent effects on cardiovascular (CV) morbidity and heart failure (HF) in patients with type 2 diabetes. Specifically, four large CV outcome trials (CVOTs) demonstrated encouraging kidney-specific outcomes, although being primarily designed to assess CV protection in high CV-risk patient populations.1 Beyond these benefits in CVOTs, the CREDENCE trial included patients with diabetic kidney disease, estimated glomerular filtration rate (eGFR) of 30–90 mL/min/1.73 m2 and albuminuria. Canagliflozin reduced the risk of the primary composite endpoint (doubling of serum creatinine, terminal kidney disease and renal or CV death) by 30%. Importantly, the risk of end-stage kidney disease (ESKD) was reduced by 32%, as were risks of major adverse CV events and hospitalisation for HF. This dedicated chronic kidney disease (CKD) study complements the DAPA-HF and EMPEROR-REDUCED trials that included patients with HF with reduced ejection fraction with and without diabetes, demonstrating efficacy and safety in cardiorenal patients.2 3 These data demonstrated that the benefits of SGLT-2i are independent from their antidiabetic effects. The overall robust cardioprotective and nephroprotective efficiency of SGLT-2i has led to the rapid adoption of SGLT-2i as strong therapy recommendation by many international guidelines for patients with diabetes and CKD as well as patients with HF with and without diabetes.4–6

A giant step towards our understanding of CKD was the DAPA-CKD trial that included 4304 patients also without diabetes with CKD between eGFR 25 mL/min/1.73 m2 and 75 mL/min/1.73 m2 and albuminuria.7 Patients with vasculitis and lupus nephritis (LN) were excluded due to potential necessities of acute immunosuppression. Patients were randomised to dapagliflozin or placebo in addition to maximum tolerated doses of renin–angiotensin system (RAS) inhibitors. In participants without diabetes, the most common cause of CKD was either glomerulonephritis (GN) or ischaemic/hypertensive nephropathy. DAPA-CKD had to be prematurely stopped, since dapagliflozin reduced the primary endpoint (composite of sustained >50% eGFR decline, ESKD and renal or CV death) by 39% resulting in a number needed to treat of 19. Importantly, no interaction was seen regarding the primary endpoint and diabetes status, and effect size was consistently large for other endpoints like decline in eGFR and overall mortality. Potential SGLT-2i side effects, including diabetic ketoacidosis or hypoglycaemia, were at placebo level while acute kidney injury was reduced. Further analysis of patients with advanced CKD down to a GFR of 25 mL/min/1.73m2 demonstrated that SGLT-2i were still significantly nephroprotective, while no increased safety signals were observed.8 9 Of note, the DAPA-CKD trial included many patients with GN, especially with immunoglobulin A (IgA) nephropathy (IgAN). Patients with IgAN displayed a 71% risk reduction for the primary endpoint, including a reduction of albuminuria by 26%,10 suggesting that specific patients with GN may benefit more from treating CKD than from immunosuppression.11

An intense discussion surrounds the causative mechanisms of the cardioprotective and nephroprotective effects of SGLT-2i (figure 1).12 An initial drop of eGFR after SGLT-2i administration (2–5 mL/min) is detected during the first weeks of treatment reflecting a reduction of intraglomerular pressure. SGLT-2i are considered to alter glomerular haemodynamics via affecting the tubuloglomerular feedback. Under physiological conditions, sensing of tubular electrolytes especially sodium and chloride exerts signals, including adenosine to the afferent and efferent arterioles to influence renal haemodynamics. While tubuloglomerular feedback is distorted especially during glomerular hyperfiltration as it occurs in diabetes and CKD leading to increased glomerular perfusion, SGLT-2i rebalance tubuloglomerular feedback, thereby reducing glomerular hyperfiltration (figure 1). Furthermore, SGLT-2 is centrally positioned within proximal tubules, where most of the demanding work of reabsorption and secretion occurs via energy-dependent transport processes. Hence, SGLT-2i might mitigate metabolic stress of remnant nephrons processing the glomerular filtrate, thereby preserving nephron integrity and reducing CKD progression.12 Also, other kidney-relevant influences of SGLT-2i have been observed, including natriuresis, osmotic diuresis (decreased interstitial fluid overload), anti-inflammatory and antifibrotic effects and increased erythropoietin production. The clinical relevance of these effects is, however, unclear. Effects pertinent to cardioprotection could be driven to a substantial degree by those linked to nephroprotection, while distinct haemodynamics affecting, for example, cardiac preload and afterload are under investigation.13

Figure 1

Schematic illustration of the effects of SGLT-2i at the single nephron level. By blocking SGLT-2, reabsorption of both luminal glucose and sodium in the proximal tubuli is blocked. This further leads to enhanced sodium delivery in the distal tubuli that triggers via the MD, the secretion of several mediators, including adenosine. This leads to potential vasoconstriction of glomerular afferent arterioles or vasodilation of the efferent arterioles of the glomerulus impacting glomerular haemodynamics. Thereby, SGLT-2i reduce glomerular hyperfiltration occurring during CKD as part of their nephroprotective potential. Furthermore, by reducing the workload of the proximal tubuli especially under conditions of reduced nephron number, SGLT-2i may further contribute to alleviate kidney damage. CKD, chronic kidney damage; MD, macula densa; SGLT-2i, sodium–glucose cotransporter-2 inhibitors.

In general, patients with ANCA-associated vasculitis (AAV) experience after their first year of diagnosis an increased long-term mortality risk compared with the age-matched and sex-matched general population, while CV disease remains the most important cause of death besides malignancy and infection.14–16 Apart from the inflammatory nature of the disease itself, including endothelial dysfunction and arterial stiffening, also long-term effects of immunosuppressive treatment, especially if poorly controlled, significantly contribute to the heightened CV risk in patients with AAV.17 18 Among the independent risk factors for excess mortality, CKD remains one of the strongest predictors of a poor prognosis. Hence, patients with AAV and kidney involvement clearly have a significantly increased risk of CV morbidity and mortality as part of the inherent association of CKD with increased CV risk.19 Furthermore, several unique pathophysiological features affecting the cardiorenal axis occur more frequently in patients with AAV such as diastolic dysfunction and pulmonary hypertension along with reduced systolic function that are all clearly positively impacted by SGLT-2i.20 21 Patients with AAV and kidney involvement would be perfectly suited to benefit from the nephroprotective properties of SGLT-2i, once the initial phase of induction immunosuppression is completed and kidney function along with the overall clinical situation of the patient has stabilised. Currently, trials are in the set-up phase to test dapagliflozin in AAV, such as DAPA-vasculitis.

CV morbidity and mortality are also substantially increased in patients with systemic lupus erythematosus (SLE) and CV disease is the most common cause of mortality in SLE, followed by infection and severity of disease activity.22–24 As with AAV, both systemic inflammation as well as the cumulative dose of immunosuppressants influence the long-term CV risk. Hence, while significant advances have been made in the treatment of SLE and especially LN, the heightened mortality in patients remains a major concern in management, especially for patients with LN.25 26 Among CV and renal risk factors such as arterial hypertension, which is occurring in most affected patients,27 even patients with SLE with mild disease experience a significantly increased CV mortality risk.28 All patients with LN have by definition CKD, since they display albuminuria to varying degrees. While albuminuria is a classical sign of kidney damage, a substantial portion of patients will also have structural and functional impairment of their kidney function as hallmark of CKD, that is, glomerular hyperfiltration and albuminuria. In the past, RAS blockade has already conferred nephroprotective potential in patients with LN; however, a substantial residual renal risk remains in all forms of CKD.29 30 Since CKD is per se one of the strongest CV risk factors, any manoeuvres to prevent CKD progression, including reduction of albuminuria and prevention of eGFR decline, will likely have profound influences on patient outcomes. Furthermore, distinct complications of SLE may also seem to be amenable to the therapeutic potential with SGLT-2i such as the increased occurrence of pulmonary hypertension, metabolic syndrome and increased blood pressure.24 31

Principal nephroprotective strategies in AAV and LN relied hitherto on (1) aggressive blood pressure control, (2) reduction of albuminuria, especially with RAS inhibitors, (3) optimising lifestyle, including cessation of smoking, treatment of metabolic syndrome/diabetes as well as increased exercise and (4) avoiding nephrotoxic drugs. At advanced CKD stages, addressing of CV risk factors is also important, including dyslipidaemia, anaemia and secondary hyperparathyroidism.19 Management of AAV and LN goes beyond immunosuppressive and anti-inflammatory treatment, but also involves a coordinated approach towards nephroprotection and CV risk reduction as these patients are cardio-reno-metabolic risk patients especially when kidney involvement has already occurred. SGLT-2i exert unequivocal cardioprotective and nephroprotective effects by reducing albuminuria and impacting eGFR decline by affecting unique CKD pathophysiology such as glomerular hyperfiltration and tubular workload along with significantly reducing the incidence of acute kidney injury. These profound clinical effects suggest that SGLT-2 inhibition is an ideal therapeutic avenue for patients with AAV and SLE especially when signs of heart or kidney damage have already manifested. Importantly, an advantageous safety profile has been established in cardiorenal patients, possibly due to diminished glycosuria in CKD. Finally, metabolism of SGLT-2i is via simple hepatic glucuronidation and no interference occurs with P450 enzymes or P-glycoprotein pathways via which most immunosuppressive agents are metabolised.

The DAPA-CKD trial significantly changed our view of CKD therapy, since CKD with all its diverse aetiologies ranging from diabetes and hypertension to several forms of GN should be primarily seen as a unique form of organ dysfunction that can be successfully treated (figure 2). For example, in slowly progressing CKD like in IgAN, the benefit-to-harm ratio of immunosuppression could be too small compared with the profound nephroprotection exerted by SGLT-2i.11 Therefore, future CKD trials even with specific therapies will have to implement SGLT-2i as standard therapy due to their strong effect size on CKD progression.

Figure 2

Modern concept of CKD management. While nephron loss is the structural and functional hallmark of CKD resulting in glomerular hyperfiltration and excessive tubular workload of the remaining nephrons, the primary aetiologies leading to a reduced nephron mass are highly divergent and only some of them are potential targets of specific therapy. Patients with CKD (reduced GFR and albuminuria) should have potent nephroprotective therapies such as SGLT-2i and inhibitors of the RAS affecting both hyperfiltration and tubular capacity as part of their CKD management, thereby reducing CKD progression and CV risk. CKD,chronic kidney disease; GFR, glomerular filtration rate; RAS, renin–angiotensin system; SGLT-2i, sodium–glucose cotransporter-2 inhibitors.

The clinical promises of SGLT-2i obtained from large clinical trials and real-world evidence can only be realised if SGLT-2i are rapidly implemented in clinical practice. Establishing novel treatments is naturally a slow process and even adoption of RAS inhibitors in patients with CKD is even at present far from satisfying. While prospective controlled trials with hard outcomes are urgently required to establish firm evidence in patients with AAV and LN, we envision the adoption of SGLT-2i as part of an integral CKD management strategy in these patients addressing their CKD apart from their original disease. Future trials will have to study the ideal time of initiation of SGLT-2i therapy: hence, should SGLT-2i be administered when first signs of kidney damage are detected such as small amounts of albuminuria or when nephron loss has already occurred or should they even be part of a regular cardioprotective and nephroprotective standard therapy such as RAS inhibitors in afflicted patients?

Given both excellent safety profile and with considerable cardioprotective and nephroprotective potential, SGLT-2 inhibition as simple and cheap therapeutic strategy could ultimately turn out to exert not only organ protection but also increase health and life span of afflicted individuals by reducing their overall CV risk.

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Footnotes

  • Handling editor Josef S Smolen

  • Contributors MS drafted the first version of the manuscript. AK revised the manuscript and approved the final version.

  • Competing interests MS has received honoraria for consulting and lectures from Astra Zeneca, Bayer, Boehringer-Ingelheim, Novartis, Otsuka and Vifor Pharma. AK has received research grants from Otsuka and Vifor Pharma, honoraria for lectures from TerumoBCT and Vifor Pharma and consulting fees from UriSalt and Catalyst Biosciences.

  • Patient and public involvement Patients and/or the public were not involved in the design, or conduct, or reporting, or dissemination plans of this research.

  • Provenance and peer review Commissioned; externally peer reviewed.