Letter

Ann Rheum Dis: first published as 10.1136/annrheumdis-2022-222512 on 12 May 2022. Downloaded from http://ard.bmj.com/ on May 13, 2022 at Consejeria de Sanidad de Madrid.
SGLT2 inhibitors in lupus nephropathy, a new
therapeutic strategy for nephroprotection
Systemic lupus erythematosus (SLE) is a chronic autoimmune
condition characterised by heterogeneous clinical features. The
patients with SLE are known to have an increased risk of cardio-
vascular events, due to both traditional and disease-­specific risk
factors, including inflammation, endothelial dysfunction, accel-
erated atherosclerosis and lupus nephritis (LN). Since chronic
kidney disease (CKD) is per se one of the strongest CV risk
factors, any manoeuvres to prevent CKD progression, including
reduction of albuminuria and prevention of estimated glomer-
ular filtration decline, will likely have profound influences on
patient outcomes.1 2
All patients with LN have by definition CKD, since they
display albuminuria to varying degrees. While albuminuria
is a classical sign of renal damage, a substantial portion of
patients will also have structural and functional impair-
ment of their kidney function as hallmark of CKD, that is,
glomerular hyperfiltration and albuminuria. In the past,
renin–angiotensin–aldosterone system inhibitors (RAASi)
has already conferred nephroprotective potential in patients
with LN; however, a substantial residual renal risk remains
in all forms of CKD. In the last few years, novel treatment
strategies are therefore required to further decrease protein-
uria and to slow kidney function decline. 3
without diabetes at risk of progressive kidney function
loss via a glucose independent haemodynamic mechanism.
Furthermore, distinct complications of SLE may also seem
to be amenable to the therapeutic potential with SGLT2i
such as the increased occurrence of pulmonary hyperten-
sion, metabolic syndrome and increased blood pressure. 6
Patients with LN were excluded from such studies due to
potential necessities of acute immunosuppression. 7
The aim of this study was to analyse the effect of SGLT2i in
patients with LN in chronic and stable treatment with immuno-
suppression and residual proteinuria.
Five patients with histologically confirmed LN on immu-
nosuppressive therapy with mean proteinuria of 2.2 g/day had
empaglifozin 10 mg/day added. Within 8 weeks of starting treat-
ment, the patients experienced a dramatic decrease in protein-
uria (49.9%) with minimal change in glomerular filtration rate
(table 1, online supplemental figure 1).
This pilot trial evaluates the antiproteinuric and nephropro-
tective effect of SGLT2i in patients with LN. Landmark studies
have unequivocally demonstrated the renoprotective effect of
SGLT2i in addition to the standard of care (RAASi) in different
chronic proteinuric nephropathies. For this reason, we believe
that these drugs combined with RAASi may be an effective alter-
native in the management of residual proteinuria in patients
with lupus nephropathy with adequate immunosuppression due
to their nephroprotective and cardioprotective effects. Prospec-
tive randomised studies are needed to demonstrate the potential

Sodium–glucose cotransporter-­2 inhibitors (SGLT2i) have
recently been demonstrated to exert profound cardio and
nephroprotection in large cardiovascular outcome trials. An
initial drop of eGFR after SGLT-­2 i administration (2–5 mL/
min) is detected during the first weeks of treatment reflecting
a reduction of intraglomerular pressure. A similar effect was
observed with mineralocorticoid receptor blockers and ACE
inhibitor. 4 SGLT2i inhibits the sodium proton exchanger,
further increasing the delivery of sodium to the loop of
Henle, which results in activation of TGF feedback response
with consequent attenuation of glomerular hyperfiltration.
They reduce progression of CKD including albuminuria and
improve outcomes in heart failure patients with and without
type 2 diabetes on top of angiotensin-­b locking agents. 5 Since
many aetiologies of non-­d iabetic nephropathy are character-
ised by intraglomerular hypertension, we hypothesise that
SGLT2i acutely decrease GFR and proteinuria in patients
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beneficial effect of SGT2 inhibitors in patients with LN.
Enrique Morales ‍ ‍,1 Maria Galindo2
1
Nephrology, Hospital Universitario 12 de Octubre, Madrid, Spain
2
Rheumatology, Hospital Universitario 12 de Octubre, Madrid, Spain
Correspondence to Dr Enrique Morales, Nephrology, Hospital Universitario 12 de
Octubre, Madrid, Spain, Spain; ​emoralesr@​senefro.​org
Handling editor  Josef S Smolen
Acknowledgements  We thank all patients for their participation.
Contributors  EM and MG conceived and designed the study, drafted the
manuscripts and approval of the final version.
Funding  The authors have not declared a specific grant for this research from any
funding agency in the public, commercial or not-­for-­profit sectors.
Competing interests  None declared.
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.

Table 1  Main effects of sodium–glucose cotransporter-­2 inhibitors (empaglifozin 10 mg) lupus nephritis
Serum Serum
GFR baseline GFR 8 weeks albumin albumin 8
Classification LN RAASi (doses (mL/min/1.73 (ml/min/1.73 Proteinuria Proteinuria 8 baseline weeks (g/
N Age/sex (ISN/RPS 2003) IMS (doses mg/day) mg/day) m2) m2) baseline (g/day) weeks (g/day) (g/dL) dL)
1 63/F V S 2.5+MPA 980 Enalapril 53 44 1.8 0.9 4.2 4.1
20+SPR 25
2 59/F IIIA MPA 1600 Telmisartan 65 60 1.9 0.8 4.2 4.5
80+SPR 25
3 46/F V S 2.5+MMF 1250 Irbesartan 89 74 0.62 0.27 3.9 4.3
150+SPR 25
4 32/F 1-­IVAG+V S 5+MPA 720 Telmisartan 80 34 30 5.96 3.7 2.7 3.5
2-­IVAG
5 46/F 1-V­ S 5+MPA 1080 Enalapril 94 90 0.76 0.39 3.8 4.2
2-I­ VS (A,C)+V 10+SPR 25
F, female; GFR, glomerular filtration rate; IMS, immunossupression; LN, lupus nephritis; MMF, mycofenolate mofetil; MPA, mycophenolic acid; RAASi, renin-­angiotensin-­
aldosterone inhibitors; S, steroids; SPR, spironolactone.

Ann Rheum Dis Month 2022 Vol 0 No 0    1

 Letter
Patient consent for publication  Not applicable.
Ethics approval  The institution’s Ethical and Research Committee approved the
study (approval number 17/061). Comité de Etica de la Investigación del Hospital
Universitario 12 de Octubre, Madrid, Spain exempted this study. Participants gave
informed consent to participate in the study before taking part.
Provenance and peer review  Not commissioned; externally peer reviewed.
Supplemental material  This content has been supplied by the author(s). It
has not been vetted by BMJ Publishing Group Limited (BMJ) and may not have
been peer-­reviewed. Any opinions or recommendations discussed are solely those
of the author(s) and are not endorsed by BMJ. BMJ disclaims all liability and
responsibility arising from any reliance placed on the content. Where the content
includes any translated material, BMJ does not warrant the accuracy and reliability
of the translations (including but not limited to local regulations, clinical guidelines,
terminology, drug names and drug dosages), and is not responsible for any error
and/or omissions arising from translation and adaptation or otherwise.
© Author(s) (or their employer(s)) 2022. No commercial re-­use. See rights and
permissions. Published by BMJ.
► Additional supplemental material is published online only. To view, please visit
the journal online (http://​dx.d​ oi.​org/​10.​1136/​annrheumdis-​2022-2​ 22512).
To cite Morales E, Galindo M. Ann Rheum Dis Epub ahead of print: [please include
Day Month Year]. doi:10.1136/annrheumdis-2022-222512
2 Ann Rheum Dis Month 2022 Vol 0 No 0
Ann Rheum Dis: first published as 10.1136/annrheumdis-2022-222512 on 12 May 2022. Downloaded from http://ard.bmj.com/ on May 13, 2022 at Consejeria de Sanidad de Madrid.
Received 23 March 2022
Accepted 4 May 2022
Ann Rheum Dis 2022;0:1–2. doi:10.1136/annrheumdis-2022-222512
ORCID iD
Enrique Morales http://orcid.org/0000-0002-5824-6973
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