2022 KDIGO Guideline for IgA nephropathy: Application to Practice Prof. Bancha Satirapoj, MD Division of Nephrology Department of Medicine Phramongkutklao Hospital and College of Medicine
Biopsy-Proven GN in TRT 2020
Outline ❖ Pathogenesis of IgA nephropathy ❖ Clinical and Renal pathology classi cation ❖ Standard treatment in IgA nephropathy ❖ Optional treatment and other pharmacologic therapies evaluated in IgAN ❖ Special situations in IgA nephropathy or IgA variants fi
Multi-hit model of IgAN Pattrapornpisut P, et al. Am J Kidney Dis. 2021; 78(3):429-441.
The mucosal immune system consists of inductive and effector sites. Inductive sites are the tissues where na ve B cells are exposed to antigen. Inductive sites include Peyer’s patches, bronchus-associated lymphoid tissue, tonsils, and adenoids Saha MK, et al Kidney Int. 2018; 94(4):674-681. ï
Complement activation in the pathogenesis of IgAN Alternative Lectin pathway pathway Maillard N, et al. J Am Soc Nephrol. 2015: 26: 1503-12.
Role of complement activation in the four-hit model of the pathogenesis of IgAN Maillard N, et al. J Am Soc Nephrol. 2015: 26: 1503-12.
Hepatic catabolism of circulatory IgA Liver is the major site of catabolism of circulatory IgA. Asialoglycoprotein receptor (ASGP-R) is expressed on the sinusoidal surface of hepatocytes. It binds terminal galactose or N acetylgalactosamine of glycoproteins without sialic acid Saha MK, et al Kidney Int. 2018; 94(4):674-681.
Outline ❖ Pathogenesis of IgA nephropathy ❖ Clinical and Renal pathology classi cation ❖ Standard treatment in IgA nephropathy ❖ Optional treatment and other pharmacologic therapies evaluated in IgAN ❖ Special situations in IgA nephropathy or IgA variants fi
IgA nephropathy: Pathology ❖ Immunohistology is the clue of diagnosis ❖ Mesangial cell proliferation with IgA deposit predominate Satirapoj B, Essentials of Glomerular Disease. 2018.
KDIGO CLINICAL PRACTICE GUIDELINE ON GLOMERULAR DISEASES. Kidney Int 2021: 100, S1–S276
IgA nephropathy and associated disorders Systemic vasculitis (Henoch-Schönlein purpura) Increased systemic IgA synthesis •Dermatopathology (psoriasis, burns, dermatitis herpetiformis) •Lymphoid malignancy (IgA myeloma, non-Hodgkin & Hodgkin lymphoma) Increased mucosal IgA synthesis •In ammatory bowel disease & gluten enteropathy •Chronic mucosal infections (bronchiectasis, cystic brosis, periodontal disease) Decreased systemic IgA clearance •Liver disease (alcoholic cirrhosis) •In ammation with change in FcRI expression of monocytes (ankylosing spondylitis, HIV infection, disseminated tuberculosis, mycosis fungoides) Satirapoj B. Essential Glomerular Disease 2018 flfifl
KDIGO CLINICAL PRACTICE GUIDELINE ON GLOMERULAR DISEASES. Kidney Int 2021: 100, S1–S276
Trimarchi H, et al. Kidney Int. 2017; 91, 1014–1021.
MEST-C score Pathologic lesion Score Mesangial hypercellularity M0, ≤0.5 0 = <4 cells/mesnagial area M1, >0.5 1 = 4-5 cells/mesnagial area 2 = 6-7 cells/mesnagial area E0, absent 3 = ≥8 cells/mesnagial area E1, present Endocapillary proliferation S0, absent Increase no. of cells with glomerular capillary lumina at least 1 S1, present T0, 0-25% of cortical area glomerulus T1, 26-50%, of cortical area Segmental glomerulosclerosis or presence of an adhesion at least one T2, 51-100% of cortical area glomerulus C0, absent C1, present in at least 1 glomerular Tubular atrophy/interstitial brosis C2, present in >25% of glomeruli Cellular or brocellular crescent Trimarchi H, et al. Kidney Int. 2017; 91, 1014–1021. fifi
Updating the Oxford Classification of IgAN ❖ Minimal of 8 glomeruli for adequacy biopsy ❖ Predictive value of M, S, and T score ❖ Predictive value of E and C score in patients not treated with immunosuppression ❖ “S “ indicate podocytopathic changes ❖ MEST criteria are not applied to IgA vasculitis KDIGO 2021: There is insu cient evidence to support the use of the Oxford Classi cation MEST-C score in determining whether immunosuppression should be commenced in IgAN Trimarchi H, et al. Kidney Int. 2017; 91, 1014–1021. fifif
Pathophysiology of IgA Nephropathy Seikrit C, et al. Nephrol Dial Transplant. 2021; 36(Suppl 2):24-30.
Evaluating a New International Risk-Prediction Tool in IgA Nephropathy ❖ Clinical model that included eGFR, blood pressure, and proteinuria at biopsy; and 2 full models that also contained the MEST histologic score, age, medication use, and either racial/ethnic characteristics (white, Japanese, or Chinese) or no racial/ethnic characteristics Barbour SJ, et al. JAMA Intern Med. 2019; 179(7):942-952.
Evaluating a New International Risk-Prediction Tool in IgA Nephropathy Barbour SJ, et al. JAMA Intern Med. 2019; 179(7):942-952.
Clinical presentations relation to age Adapted from Johnson RJ, Feehally, J and Floege R . Comprehensive clinical nephrology. 2015.
IgA (Henoch-Schönlein) vasculitis ❖ Male > Female, predominant in Children ❖ Severity in Adult > children ❖ Purpura predominantly on the lower limbs with at least one of the following 4 criteria is present: ❖ (1) Abdominal pain ❖ (2) Presence of IgA on histology ❖ (3) Arthritis or arthralgia ❖ (4) Renal impairment Ozen, S.; et al. Ann Rheum Dis 2010, 69, 798–806. Pillebout E, et al. Semin Immunopathol. 2021; 43(5):729-738.
Comparative Features of IgAN and HSPN Wyatt RJ, et al. N Engl J Med 2013;368:2402-14.
TMA is a common feature of IgAN 53.1% acute or organized TMA lesions Age (yrs) TMA No TMA P Value SBP (mmHg) (N=68) (N=60) DBP (mmHg) 39.7 (29–49) 36.2 (26–44) >0.10 Percentage MHT 0.001 Proteinuria (g/day) 161 (135–177) 130 (120–140) 0.000002 Macroscopic hematuria 0.001 Serum albumin (g/L) 94 (80–107) 77 (67–85) 0.001 eGFR (ml/min/1.73 m2) 0.0014 RRT 26% 0 0.0001 0.001 3.37 (1.2–4.0) 1.33 (0.40–1.85) 0.001 18.6% 47.8% 34.6 (30–39) 39.8 (36–43) 34 (14–50) 73 (51–90) 44.1% 9.4% El Karoui K et al. J Am Soc Nephrol. 2012; 23(1):137-48.
TMA is a common feature of IgAN 53.1% acute or organized TMA lesions Age (yrs) TMA No TMA P Value (N=68) (N=60) >0.10 39.7 (29–49) 36.2 (26–44) 0.001 0.000002 SBP (mmHg) 161 (135–177) 130 (120–140) 0.001 0.001 DBP (mmHg) 94 (80–107) 77 (67–85) 0.0014 0.0001 Percentage MHT 26% 0 0.001 0.001 Proteinuria (g/day) 3.37 (1.2–4.0) 1.33 (0.40–1.85) 47.8% M• ac4r%oscopinc ohermmatourtiea nsive 18.6% 39.8 (36–43) S•er2um5%albumcionn(gt/rLo) lled hype34r.t6e(3n0s–3i9o) n 73 (51–90) e•GF7R1(m%l/muinn/1c.7o3 nmt2r)olled hy3p4 e(1r4t–e50n) sion RRT 44.1% 9.4% El Karoui K et al. J Am Soc Nephrol. 2012; 23(1):137-48.
TMA is a common feature of IgAN 53.1% acute or organized TMA lesions Age (yrs) TMA No TMA P Value SBP (mmHg) (N=68) (N=60) DBP (mmHg) 39.7 (29–49) 36.2 (26–44) >0.10 Percentage MHT 0.001 Proteinuria (g/day) 161 (135–177) 130 (120–140) 0.000002 Macroscopic hematuria 0.001 Serum albumin (g/L) 94 (80–107) 77 (67–85) 0.001 eGFR (ml/min/1.73 m2) 0.0014 RRT 26% 0 0.0001 0.001 3.37 (1.2–4.0) 1.33 (0.40–1.85) 0.001 18.6% 47.8% 34.6 (30–39) 39.8 (36–43) 34 (14–50) 73 (51–90) 44.1% 9.4% El Karoui K et al. J Am Soc Nephrol. 2012; 23(1):137-48.
Significance differences in renal survival Clinical + No TMA Morphologic TMA Morphologic TMA El Karoui K et al. J Am Soc Nephrol. 2012; 23(1):137-48.
Outline ❖ Pathogenesis of IgA nephropathy ❖ Clinical and Renal pathology classi cation ❖ Standard treatment in IgA nephropathy ❖ Optional treatment and other pharmacologic therapies evaluated in IgAN ❖ Special situations in IgA nephropathy or IgA variants fi
Early reduction in proteinuria can be used as a surrogate end point for studies of chronic kidney disease progression in IgAN. Inker LA, et al. Am J Kidney Dis. 2021 Sep;78(3):340-349.
Probability of renal survival (50%Treatment of IgA nephropathy with ACE inhibitors: A RCT increase of baseline serum creatinine)• FoArtCy-Efoiunrhpiabtiiteonrtss wsiigthnibiocpasnymt-lpyoroidmveeprnarotIgevAleyNrr,eepndroautlceseinudurrvrieaivn>aal0li.nf5ugpn/rcdotatiyoe,nian.nudriscerIgumANcrweaittihninnoer<m1.a5lmogr/dL Praga M, et al. J Am Soc Nephrol; 2003:14: 1578–1583. if
ACEI/ARBs in IgA nephropathy ❖ We recommend that all patients have BP management. ❖ If the patient has proteinuria >0.5 g/24h, we recommend that initial therapy be with either an ACEi or ARB, but not both (1B) ❖ We recommend that all patients with proteinuria >0.5 g/24h, irrespective of whether they have hypertension, are treated with either an ACEi or ARB (1B) KDIGO CLINICAL PRACTICE GUIDELINE ON GLOMERULAR DISEASES. Kidney Int 2021: 100, S1–S276
❖ 750 participants with IgA nephropathy (proteinuria > 1 g/d and eGFR of 20-120 mL/min/ 1.73 m2 with RAS blockade ❖ Oral methylprednisolone (0.6-0.8 mg/kg/d; maximum, 48 mg/d) (n = 136) or matching placebo (n = 126) for 2 months, with subsequent weaning over 4 to 6 month Lv J, et al. JAMA. 2017; 318(5):432-442.
Time From Randomization to First Serious Adverse Event, by Treatment Group Relative risk, 4.63 (95% CI, 1.63-13.2); P = .001 Serious events occurred in 14.7% in the methylprednisolone group vs 3.2% in the placebo group (P = .001; risk di erence, 11.5% [95% CI, 4.8%-18.2%]) Lv J, et al. JAMA. 2017; 318(5):432-442. ff
Time From Randomization to First Primary Composite Outcome of 40% eGFR Decrease, ESKD, or Death Due to Kidney Failure, by Treatment Group Hazard ratio, 0.37 [95% CI, 0.17-0.85]; P =0 .02 The results were consistent with potential renal bene t, de nitive conclusions about treatment bene t cannot be made, owing to early termination of the trial Lv J, et al. JAMA. 2017; 318(5):432-442. fififi
Serious adverse events by treatment group Serious events occurred in 14.7% in the methylprednisolone group vs 3.2% in the placebo group (P = .001; risk di erence, 11.5% [95% CI, 4.8%-18.2%]) ff
VALIGA-Consortium: Corticosteroids in IgAN Tesar V, et al. J Am Soc Nephrol: 2015: 26: 2248–2258.
Response to CS and RASB compared with RASB alone in propensity-matched individuals Steroids reduced proteinuria and the rate of renal function decline and increased renal survival extended to those with an eGFR<50 ml/min per 1.73 m2 Tesar V, et al. J Am Soc Nephrol: 2015: 26: 2248–2258.
Systemic corticosteroid versus no corticosteroid regimen for IgA nephropathy Corticosteroid therapy probably prevents decline in GFR or doubling of SCr in adults with IgA nephropathy and proteinuria Natale P, et al. Cochrane Database Syst Rev. 2020; 3(3):CD003965.
Treatment of IgA nephropathy at PMK hospital ❖ 6-month regimen of oral prednisone starting with 0.8–1mg/kg/d for 2 months and then reduced by 0.2 mg/kg/d per month for the next 4 months N=26, UPCI>0.5 and GFR>30 mL/min/1.73 m2 on ACEI/ARB treatment Urine protein creatinine ratio 5 P= 0.310 3.75 P= 0.008 P= 0.020 P= 0.006 2.5 1.25 0 wk0 wk4 wk8 wk12 wk24
Corticosteroid in IgA nephropathy ❖ We suggest that patients who remain at high risk of progressive CKD despite maximal supportive care are considered for a six-month course of corticosteroid therapy. ❖ The important risk of treatment-emergent toxicity must be discussed with patients, particularly those who have an eGFR < 50 ml/min/1.73 m2 (2B) Practice Point ❖ Proteinuria reduction to under 1 g/d is a surrogate marker of improved kidney outcome in IgAN, and reduction to under 1 g/d is a reasonable treatment target ❖ Proteinuria >0.75-1 g/24 h despite at least 90 days of optimized supportive care KDIGO CLINICAL PRACTICE GUIDELINE ON GLOMERULAR DISEASES. Kidney Int 2021: 100, S1–S276
TESTING study shows early evidence of ef cacy in patients who had marked proteinuria (2.4 g/d average) at the expense of treatment-associated morbidity and mortality KDIGO CLINICAL PRACTICE GUIDELINE ON GLOMERULAR DISEASES. Kidney Int 2021: 100, S1–S276 fi
Corticosteroids in IgA nephropathy Study Medication Start dose Duration Taper Total high dose exposure 0.6-0.8 MKD, rounded TESTING Methylprednisolone to nearest 4 mg 2 months 8 mg/month 6-8 months Max 48 mg/day Manno Prednisolone 1 MKD, 2 months 0.2 mg/kg/month 6 months LV Prednisolone Max 75 mg/day 8 weeks 5-10 mg/day 8 months 0.8-1 MKD every 2 weeks KDIGO CLINICAL PRACTICE GUIDELINE ON GLOMERULAR DISEASES. Kidney Int 2021: 100, S1–S276
Corticosteroids in IgA nephropathy Study Medication Start dose Duration Taper Total high dose exposure 0.6-0.8 MKD, rounded TESTING Methylprednisolone to nearest 4 mg 2 months 8 mg/month 6-8 months Max 48 mg/day Manno Prednisolone 1 MKD, 2 months 0.2 mg/kg/month 6 months LV Prednisolone Max 75 mg/day 8 weeks 5-10 mg/day 8 months 0.8-1 MKD every 2 weeks KDIGO CLINICAL PRACTICE GUIDELINE ON GLOMERULAR DISEASES. Kidney Int 2021: 100, S1–S276
Avoided or great caution of steroids ❖ eGFR < 30 ml/min/1.73 m2 Treatment with glucocorticoid ❖ Diabetes (prednisone equivalent >0.5 mg/kg/ ❖ Obesity (BMI>30 kg/m2) d) should incorporate prophylaxis ❖ Latent infections (viral hepatitis, TB) against Pneumocystis pneumonia ❖ Secondary disease (cirrhosis) ❖ Active peptic ulceration along with gastroprotection and ❖ Uncontrolled psychiatric illness bone protection, according to local ❖ Server osteoporosis guidelines KDIGO CLINICAL PRACTICE GUIDELINE ON GLOMERULAR DISEASES. Kidney Int 2021: 100, S1–S276
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