reno protection [Autosaved].pptx

renal protection in AAV/LN

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. G rowing 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 E arly 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 . A dd-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 . R egulate 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 . E stimated glomerular filtration rate (eGFR) was stable A n improvement in the eGFR slope among patients with LN with a baseline eGFR N o 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 - S table 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 C ause glomerular vasodilation, lowering the tubular load of albumin C ontrol 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. R at model of ANCA-GN Add-on c yclic 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 P romising approach in preserving renal damage & decelerate nephron loss D ecrease 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

23. Challenges L andmark 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

24. 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 M ore landmark trials are needed before routine use

25. 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