Adult onset nephro syndrome................

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1. ADULT ONSET NEPHROTIC SYNDROME PRIMARY MEMBRANOUS NEPHROPATHY-PLA2R Associated TREATMENT RESISTANT pMN TRANSFORMATION TO RAPIDLY PROGRESSIVE GLOMERULONEPHRITIS RE-BIOPSY SHOWING Primary Membranous Nephropathy with crescents

2. 47 year old male patient , no known co-morbidities First presentation in May 2022 to a hospital in Bangalore-c/o bilateral swelling of legs and facial puffiness for 1 month Examination revealed him to be hypertensive and having dyslipidemia-detected for first time Lab work-up showed a serum creatinine of 1.3 mg%, urine protein 3+ and urine PCR ->3,S.Albumin-2.3 g/dl Baseline eGFR-59.2ml/min He was then referred to nephrologist Renal biopsy was done on 18/06/2022-MEMBRANOUS GLOMERULONEPHRITIS WITH FOCAL SCLEROSIS,ANTI-PLA2R TISSUE STAINING POSITIVE Serum Anti-PLA2R Ab(Ig)-63.94RU/ml

3. Diagnosis: Primary Membranous Nephropathy(Anti-PLA2R associated)

4. Patient was started on : 1.Inj.Cyclophosphamide 500 mg in 500 ml NS over 1 hour(25/6/2022-first dose) 2.T.Prednisolone 40mg 1-0-0 3.T.Telmisartan 40 mg 1-0-1 4.T.Cilinidipine 10 mg 1-0-1 5.T.Clonidine 0.1 mg 1-1-1 6.T.Prazosin 5 mg 1-0-1 7.T.Rosuvastatin 10 mg 0-0-1 8.T.Torsemide 10 mg 1-0-0 Along with Fluid restriction of 1.2 L/day 2-3gm salt restriction Low fat 0.8gm/kg/day protein Inj.Endoxan 500 mg second dose was given on 26/7/2022 Patient was referred here for further management

5. ON FOLLOW UP IN OUR HOSPITAL Renal doppler (19/11/2022)-No RAS/No Renal vein thrombosis 27/8/22 15/10/22 19/11/22 16/12/22 11/02/23 06/03/23 02/05/23 09/05/23 10/05/23 12/05/23 15/5/23 18/5/23 Hb 11 12 11.3 11.5 11.9 11.6 TLC 6.81 7.92 5.4 7.9 6.18 16.4 18 Platelet count 2.45 2.38 2.28 4.81 1.97 3.90 Urea 58 59 85 74 29 53 131 140 101 Creatinine 1.3 1.4 1.5 1.4 1.6 1.7 2.8 4.0 3.2 2.4 Urine routine Protein 2+ RBCs-occasional Protein 3+ RBCs-5-7/ hpf Protein4+ RBCs-occasional Urine spot PCR(gm/gm) 4.97 3.24 6.38 6.26 7.68 Serum albumin 2.7 2.6 2.6 2.4 2.4 2.5 R E P E A T R E N A L B I O P S Y P U L S E S T E R O I D FOR 3 D A Y S

6. Inj.Endoxan 700 mg -third, fourth and fifth dose was given on 08/09/2022, 19/10/2022 and 26/11/2022. T.Prednisolone was gradually tapered over 2 weeks to a daily maintainence dose of 5mg. Clinically- Edema was still(+) and did not decrease with treatment Renal doppler-19/11/2022-No RAS/Renal vein thrombosis Anti-hypertensives were escalated (Nov 2022) due to uncontrolled hypertension - T.Telmisartan 80 mg 1-0-1 - T.Bisoprolol 5 mg 1-0-1 - T.Nifedipine 20 mg 1-1-1 - T.Clonidine 0.1 mg 2-1-2 - T.Dapagliflozin 5 mg 1-0-1

7. 16/12/2022 S.creatinine:1.4 mg/dl S.Albumin:2.6g/dl Spot PCR:3.64 mg/mg Edema still persisted Plan to change to Rituximab Inj.Rituximab 500 mg total of 4 doses administered at weekly intervals (11/1/2023 -18/2/2023) On 07/03/2023: -S.creatinine:1.7 mg /dl -S.Albumin:2.4 gm/dl -Spot PCR-6.26 mg/mg -Urine complete: protein:2(+),RBC:5-7/ hpf -Anti PLA2R: 8.63 RU/ml No edema of lower limbs

8. 03/05/2023 Serum creatinine:2.8mg/dl Serum albumin:2.5 g/dl Urine protein:4(+) Spot PCR:7.6 mg/mg Edema (+) Renal doppler-No Renal vein thrombosis As there was persistent proteinuria and increasing azotemia, patient planned for repeat renal biopsy

9. Renal biopsy (09/05/2023) Membranous pattern of injury with segmental sclerosis, partial and circumferential cellular crescents(30%),moderate interstitial inflammation with occasional eosinophils, mild tubular atrophy (IFTA 20-25%) and moderate arteriosclerotic changes with hyalinosis.

10. Immunofluorescence shows peripheral and diffuse granular IgG deposits accompanied by C3c,IgM,IgA and focally C1q. Stain for PLA2R shows positivity IgG IgM IgA C3C C1q

11. Vasculitis package-ANCA (p-ANCA, c-ANCA)-Quantitative and qualitative-Negative ANA –Negative Anti-ds-DNA-Negative Anti-GBM Ab-Negative ID-NAAT(Hepatitis B/Hepatitis C/HIV serology)-Negative He received pulse steroid (iv methylprednisolone 500 mg) for 3 days(10/5-12/5/23) 12/05/23 Serum creatinine -4 mg/dl Blood urea-131 mg/dl 15/05/23 Serum creatinine-3.2 mg/dl Patient started with T.Prednisolone 60 mg 1-0-0 and T.Cyclophosphamide 75mg 1-0-0

12. RAPIDLY WORSENING AZOTEMIA IN MEMBRANOUS NEPHROPATHY H ypovolemia due to aggressive diuresis A cute interstitial nephritis due to diuretics or other offending drugs Malignant Hypertension S uperimposed crescentic glomerulonephritis Acute renal vein thrombosis leading to renal infarction. Crescentic transformation of MN is a rare entity .It leads to rapid loss of renal function . It is mostly associated with superimposed lupus nephritis, development of anti-GBM antibodies or ANCA-associated vasculitis. In the absence of these secondary causes, idiopathic crescentic transformation is mostly associated with anti-PLA2R antibody associated immune complex injury.

13. The initiating event is the development of physical gaps (also called rents or holes) in the glomerular capillary wall, glomerular basement membrane, and Bowman's capsul e. Although the precise mechanism by which these gaps in the glomerular basement membrane (GBM) appear in humans is unclear, it seems likely that a variety of upstream immune mechanisms are involved, including the deposition of autoantibodies and immune complexes, the activation of complement, and the recruitment of inflammatory cells. CRESCENT FORMATION

14. In patients with MN with crescentic transformation who have evidence of ANCA or anti-GBM antibodies, treat with immunosuppressive therapy using a similar approach as that for patients with crescentic GN associated with ANCA vasculitis or anti-GBM disease, respectively In patients with MN associated with crescentic GN who do not have evidence of ANCA or anti-GBM antibodies, administer rituximab or combination therapy with glucocorticoids plus cyclophosphamide using a regimen similar to that used for initial therapy in patients with ANCA vasculitis.

15. TREATMENT

16. The identification of prognostic markers has radically changed the vision of pMN and allowed KDIGO guidelines to evolve in 2021 towards a more personalized management based on the assessment of the risk of progressive loss of kidney function.

17. GENERAL MEASURES IN ALL PATIENTS Dietary sodium and protein restriction – low-salt diet (1.5 to 2 g sodium/day) and 0.8 g/kg/day of high-quality protein with additional dietary protein to correct for urinary losses Antihypertensive therapy- For patients with proteinuria of more than 1 g/day, the target for blood pressure is 125/75 mm Hg Renin-angiotensin aldosterone system inhibition – When effective, the benefit of RAAS blockade occurs early, usually within the first 3 months of initiation of treatment Lipid lowering – statins to reduce low-density lipoprotein cholesterol to 100 mg/ dl Anticoagulation –

18. Jorge E., etal .,Novel Treatments Paradigms: Membranous Nephropathy, ki Reports,Volume 8, Issue 3,2023,Pages 419-431

19. CHOICE OF INITIAL THERAPY BASED UPON RISK High or very high risk of progression   Abnormal/↓kidney function stable kidney function GC+ Cyclophosphamide > Ritux imab Rituximab > Cyc/CNIs ( If wish to avoid cytotoxic therapy, Rituximab may be a alternative) (prolonged remission with rituximab and higher relapse rate of CNI)

20. IMMUNOSUPPRESSIVE REGIMENS

21. MONITORING RESPONSE TO THERAPY

22. Immunologic remission is defined as depletion of anti-PLA2R antibody titers below the cut-off value for a positive result (<14 RU/mL by ELISA; some experts prefer to use a lower cut off of <2 RU/mL to define true absence of anti-PLA2R antibody) and/or a negative indirect immunofluorescence test. In most patients who achieve an immunologic remission, a remission in proteinuria usually follows within 12 to 24 months. Some patients who achieve an immunologic remission may not achieve a complete clinical remission. This can be caused by incomplete remodeling of the glomerular filtration barrier (in which case proteinuria may eventually decrease further) or due to irreversible chronic damage (in which case some degree of proteinuria may persist), and additional immunosuppressive therapy is not warranted in these patients. Patients who achieve an immunologic remission at 6 months but have increasing proteinuria or decreasing eGFR are uncommon and should be evaluated for other causes of worsening kidney function and/or worsening proteinuria ( eg , renal vein thrombosis). 

23. Rituximab has progressively emerged as the first choice treatment for pMN due to its high safety and efficacy.

24. A refractory MN implies nonresponse to 2 cycles of different treatments, including at least, a course of CYC-GC.

25. Plasma exchange, immunoadsorption, mycophenolate mofetil (MMF), adrenocorticotropic hormone (ACTH) and bortezomib have been proposed for the management of refractory pMN . Plasma exchange and immunoadsorption combined with immunosuppressive therapy seem to allow a faster remission than immunosuppressive therapy alone in patients with severe disease or refractory to conventional treatment. Cytokines may play a role in the pathogenesis of pMN and high serum IL-17A levels were associated with poor prognosis in pMN . Newer agents for cytokine blockade are anti-IL6 (e.g. siltuximab ), anti-IL6 receptor (e.g. tocilizumab), anti-IL-17A (e.g. ixekizumab or secukinumab ) or anti-IL-17 receptor (e.g. brodalumab ) in combination with rituximab . Immunomodulators have the advantage of not inducing immunosuppression and therefore limit the adverse effects. Belimumab is a human IgG1-l monoclonal antibody that inhibits B-cell activating factor (BAFF). In pMN patients it reduced antiPLA2R1 antibody levels and proteinuria.

26. RELAPSING PRIMARY MN

27. THANK YOU