This document discusses renal protective agents for treating lupus nephritis and ANCA-associated vasculitis. It outlines classical agents like RAAS inhibitors, diuretics, and metformin. It also discusses promising future agents including finerenone, SGLT2 inhibitors, GLP1 receptor antagonists, and endothelin receptor antagonists. While these newer agents show potential for preserving renal function and reducing immunosuppressant exposure, the document notes that more research is still needed before widespread use due to challenges like excluding autoimmune patients from trials and long-term effects requiring further study.

1. Dr Ritasman Baisya
MD Medicine, DM Rheumatology & Clinical Immunology
Consultant Rheumatologist , Kolkata

2. Renal protective agents in AAV/ LN –promises &
challenges

3. Structure of the talk
• Introduction
• Non-immunologic factors of progression
• Classical Reno-protective agents
• Future perspectives
• Promises
• Challenges
• Take home point

4. Introduction
• Renal involvement – common & serious complication in SLE and AAV
• High mortality & progression to ESRD if not effectively managed.
• Growing interest in reno-protective agents beyond immunosuppression
(IS)
• They decelerate nephron loss & decrease IS exposure time

5. Non-immunological factors for the progression of nephritis
• Low birth weight
• Previous acute kidney injury
• Low number of nephrons since birth
• Genetic variant (Apo -lipoprotein L1 (APOL1) gene variant)
• Delayed & inadequate therapy.
Colares VS, Titan SM de O, et al. MYH9 and APOL1 gene polymorphisms and the risk of CKD in patients with lupus
nephritis from an admixture population. PloS One (2014) 9(3):e87716. doi: 10.1371/ journal.pone.0087716

6. • RAAS blockade – ACE-inhibitor / ARB
• Diuretics – Thiazide or thiazide like diuretics
• MRA ( Spironolactone )
• Lifestyle modifications
• Judicial use of NSAIDs
Classical Reno-protection agents

7. RAAS blockade (ARB or ACE-inhibitor)
• Recommended at maximum tolerated doses complemented with a
sodium-poor diet.
• The earlier institution of ARB is associated with increased steroid free
period.
• They help to improve serum albumin, cholesterol and systolic blood
pressure in LN.

8. 1 year, covariate
assessment
First SLE /LN claim
Landmark : RAASi
exposure classified
Outcome assessment
GC discontinuation
6 m +/- RAASi
P- SLE +/- nephritis (1999) , new LN
requiring chronic steroid ( 158)
67% LN received RAAS-inhibitor
Early RAAS-i in 74/158 early LN cases
Chang JC, Weiss PF, Xiao R, Atkinson MA, Wenderfer SE. Use of renin angiotensin aldosterone system inhibitors in children with lupus and
time to glucocorticoid discontinuation. Kidney Int. 2022 Aug;102(2):395-404.

9. • FIGURE - Cumulative incidence functions of
glucocorticoid discontinuation among children
with incident LN (N=158) with or without
early RAAS inhibitor use
• Early RAAS-I initiation - faster rate of GC
discontinuation (adjusted sub-distribution hazard
ratio 1.81, 95% CI [1.09 - 3.00]).
• It may have a role in children newly diagnosed
with LN ; not only those with refractory
proteinuria after induction therapy.
Chang JC, Weiss PF, Xiao R, Atkinson MA, Wenderfer SE. Use of renin angiotensin aldosterone system inhibitors in children with lupus and
time to glucocorticoid discontinuation. Kidney Int. 2022 Aug;102(2):395-404.

10. Other diuretics
• Thiazide / thiazide like diuretics - beneficial in patients on a high-
sodium diet or as an add-on therapy in cases with significant residual
albuminuria
• Spironolactone - Data in LN / AAV is not clear as most of the landmark
trials excluded these patients

11. • Metformin decreased PMA-induced NET
formation & CpG-stimulated PDC IFNα
generation.
• Add-on treatment of mild / moderate SLE
resulted in decreases in clinical flares,
prednisone exposure, and body weight.
METFORMIN

12. FUTURE PERSPECTIVES

13. Finerenone
• Novel MRA
• Blocks MR-mediated sodium reabsorption & MR over-activation
• Anti-inflammatory & anti-fibrotic effects.
• FIDELITY pooled analysis of the FIGARO trial - reductions in kidney
failure outcomes in type-2 diabetic patients with CKD.
Agarwal R, Filippatos G, Pitt B, Anker SD, Rossing P, Joseph A, et al. Cardiovascular and kidney outcomes with finerenone in patients with type 2 diabetes and
chronic kidney disease: The FIDELITY pooled analysis. Eur Heart J (2022) 43(6):474 84. doi: 10.1093/eurheartj/ehab777

14. SGLT2 Inhibitors
• In renal vasculitis / LN , SGLT-2 is detectable & localised to the tubule-interstitial
compartment.
• Block LPS- induced and NLRP3- mediated inflammatory responses .
• Regulate macrophage polarisation via interplay with mTOR & AMP- activated protein
kinase pathways.
• It exerts profound cardio & reno-protection in large cardiovascular outcome trials.
• Pulmonary hypertension, metabolic syndrome, increased blood pressure in SLE can
also be targeted. Hakroush S, Tampe D, Kluge IA, et al. Comparative analysis of SGLT- 2 expression in renal
vasculitis and lupus nephritis. Ann Rheum Dis 2022;81:1048–50.

15. • P- Chinese patients with SLE with/without lupus nephritis (LN).
• I- Oral dapagliflozin 10 mg/d added to the standard of care for 6 months
• O- Primary end point - safety profile.
• R- 19 (50%) adverse events including 8 (21%) AEs leading to drug
discontinuation, of which 4 (10.5%) were attributed to dapagliflozin

16. Results contd.
• Estimated glomerular filtration rate (eGFR) was
stable
• An improvement in the eGFR slope among patients
with LN with a baseline eGFR
• No improvement of SLEDAI or proteinuria (among
17 patients with LN)
Wang H, Li T, Sun F, et al. Safety and efficacy of the SGLT2 inhibitor dapagliflozin in patients with systemic lupus
erythematosus: a phase I/II trial. RMD Open 2022;8:e002686. doi:10.1136/ rmdopen-2022-002686

17. Morales E, Galindo M. SGLT2 inhibitors in lupus nephropathy, a new therapeutic
strategy for nephroprotection. Ann Rheum Dis (2022) 81:1337–1338. doi: 10.1136/
annrheumdis-2022-222512
• P - Pilot study in patients with LN
• I - Stable IS / non-IS treatment with RAAS blocker with 10-mg /d
empagliflozin
• R - 50% reduction in residual proteinuria with minimal changes in eGFR &
few side effects.

18. Recommended dose
SGLT-2 inhibitors may be considered in LN with reduced GFR < 60–
90mL/min or proteinuria > 0.5–1g/day, on top of ACE-I /ARB during the
maintenance phase .

19. GLP1 R antagonist
• Improve albuminuria
• REWIND trial - dulaglutide vs. placebo in T2DM
• Protective effect for the appearance of new-onset albuminuria
• AWARD-7 study - halt kidney disease progression & prevent the
worsening of albuminuria in the diabetic CKD

20. Endothelin receptor antagonists (ERAs)
• Atrasentan & eprosartan have been associated with renal protection
when combined with RAAS blockade
• Cause glomerular vasodilation, lowering the tubular load of albumin
• Control renal inflammation by moderating the inflammatory effects of
albuminuria reabsorption.
• Prevent deposition of collagen and fibrosis
Kohan DE, Pollock DM. Endothelin antagonists for diabetic and non-diabetic chronic kidney disease. Br J Clin
Pharmacol (2013) 76(4):573–9. doi: 10.1111/bcp.12064

21. • Rat model of ANCA-GN
• Add-on cyclic Angiotensin-(1-7) with cyclophosphamide arrests progressive
kidney disease in rats with ANCA-associated GN
• Ultrastructural analysis revealed a preserved GBM, glomerular endothelium
and podocyte structure

22. Promises
• Promising approach in preserving renal damage & decelerate
nephron loss
• Decrease exposure of steroids or IS agents & unwanted side effects
• Most of the drugs have cardio protective effect in addition
• To achieve personalised medical practices in AAV /LN in future

24. Challenges
• Landmark trials excluded patients with autoimmune diseases on IS treatment
• Special care on dose adjustment , e.g. - diuretics might induce AKI or electrolyte
imbalance
• The long-term effects & optimal duration of treatment require further
investigation.
• The selection and utilisation need careful consideration.
• Pill burden

25. Take home points
• Reno-protection decelerates nephron loss & prevents renal damage
• It decreases exposure of steroid or IS agent in LN /AAV
• RAAS blockade is preferred adjunct therapy ( to control HTN)
• SGLT-2i for reduced GFR < 60–90mL/min or proteinuria > 0.5–1g/day, on top
of ACE-I /ARB during the maintenance phase
• Finerenone , endothelin R antagonist, GLP1 R-antagonist are future therapies
• More landmark trials are needed before routine use

26. References
• Morales E, Sandino J and Galindo M (2023) Lupus nephropathy beyond immunosuppression: Searching for nephro and
cardioprotection. Front. Nephrol. 3:1105676
• Hakroush S, Tampe D, Kluge IA, Baier E, Korsten P, Tampe B. Comparative analysis of SGLT-2 expression in renal vasculitis and lupus
nephritis. Ann Rheum Dis. 2022 Jul;81(7):1048-1050
• Cerullo, D.; Rottoli, D.; Corna, D.; Abbate, M.; Benigni, A.; Remuzzi, G.; Zoja, C. Add-On Cyclic Angiotensin-(1-7) with Cyclophosphamide
Arrests Progressive Kidney Disease in Rats with ANCA Associated Glomerulonephritis. Cells 2022, 11, 2434.
• Fanouriakis A, et al. EULAR recommendations for the management of systemic lupus erythematosus: 2023 update. Ann Rheum Dis.
2023 Oct 12: ard-2023-224762.
• Kohan DE, Pollock DM. Endothelin antagonists for diabetic and non-diabetic chronic kidney disease. Br J Clin Pharmacol (2013)
76(4):573–9.
• Agarwal R, Filippatos G, Pitt B, Anker SD, Rossing P, Joseph A, et al. Cardiovascular and kidney outcomes with finerenone in patients
with type 2 diabetes and chronic kidney disease: The FIDELITY pooled analysis. Eur Heart J (2022) 43(6):474 84.
• Wang H, Li T, Chen S, Gu Y, Ye S. Neutrophil Extracellular Trap Mitochondrial DNA and Its Autoantibody in Systemic Lupus
Erythematosus and a Proof-of-Concept Trial of Metformin. Arthritis Rheumatol. 2015 Dec;67(12):3190-200.
• Chang JC, Weiss PF, Xiao R, Atkinson MA, Wenderfer SE. Use of renin angiotensin aldosterone system inhibitors in children with lupus
and time to glucocorticoid discontinuation. Kidney Int. 2022 Aug;102(2):395-404
• Colares VS, Titan SM de O, et al. MYH9 and APOL1 gene polymorphisms and the risk of CKD in patients with lupus nephritis from an
admixture population. PloS One (2014) 9(3):e87716.
• Swigris JJ, Brown KK. The role of endothelin-1 in the pathogenesis of idiopathic pulmonary fibrosis. Bio Drugs. (2010) 24(1):49–54