UPDATE ON IgA Nephropathy John Cijiang He, MD/PhD Division of Nephrology Department of Medicine Mount Sinai School of Medicine
Question 1: Case 1: A 20-year-old male who has been in excellent health develops a viral pharyngitis. Two days later, he develops gross hematuria. A similar episode occurred one year ago. Creatinine, serum 0.9 mg/dL (0.8-1.4 mg/dL); Complement C3: 140 mg/dL (88171 mg/dL); Complement C4: 35 mg/dL (15-48 mg/dL); Urinalysis: many dysmorphic red blood cells, 1 red blood cell cast, no proteinuria. Case 2: A 25-year-old man is referred to you because of hematuria. He noticed brief reddening of the urine with a recent respiratory infection. The gross hematuria resolved, but his physician found microscopic hematuria on two subsequent first-voided morning urine specimens. The urinalysis shows 2+ protein and 10-15 RBC/hpf with some dysmorphic RBC. No WBC or casts are seen.
A: Case 1 has IgA Nephropathy but not Case 2 B: Case 2 has IgA Nephropathy but not case 2 C: Both cases have IgA Nephropathy B: Both cases do not have IgA Nephropathy
EPIDEMIOLOGY • IgA nephropathy is the most common primary glomerulonephritis (GN) in the world. • IgA nephropathy is common in East Asians and Caucasians and is relatively rare in blacks. • The reported incidence of mesangial IgA deposition in healthy individuals ranges from 3 to 16 percent. • Variations in disease prevalence may reflect regional differences in screening for kidney disease and kidney biopsy practices.
Prevalence of primary glomerular diseases in China
IgAN MsPGN MN FSGS IgMN MPGN EnPGN CreGN MCD Total
No. of cases % 4199 45.26 2377 25.62 918 9.89 557 6.00 396 4.27 314 3.38 255 2.75 176 1.90 86 0.93 9278 100.00
Li LS, Liu ZH. Kidney Int. 2004;66(3):920
A clinicopathologic study of glomerular disease: A single-center, five-year retrospective study from Northwest India (702 renal biopsy patients)
Question 2:
Which of the characteristic features of IgA Nephropathy is correct? 1) There is only IgA deposition in the mesangial area. 2) Deposited IgA is predominantly J chain-containing polymeric IgA1 with most keba-light chain. 3) Similar to lupus nephritis, there is an activation of classic pathway of complement in IgAN. 4) Renal histologic features of Henoch–Schönlein purpura (HSP) nephritis are different to those of IgA nephropathy. 5) Oxford classification is a useful predictor marker for clinical outcomes in patients with IgAN.
Pathological Features • The presence of IgAN is established only by kidney biopsy which demonstrates dominant mesangial deposits of IgA, either alone, or with IgG, IgM, or both. IgG co-deposition occurs in one-third of cases and associated with poor renal outcome. • Deposited IgA is predominantly J chain-containing polymeric IgA1, with a predominance for lambda light chains. • Subendothelial capillary wall IgA deposits may also be present in up to one-third of patients, and this is associated with higher histologic activity and worse renal outcome. • Histologic features of HSP nephritis are similar to those of IgAN. • Glomerular deposition of complement C3 is found in over 90% of cases. C1q is always absent, suggesting activation of the alternative and/or lectin pathways in IgA Nephropathy.
Histology of IgA nephropathy Light micrograph
Electron micrograph
Immunofluorescence
Oxford classification of IgA nephropathy • Developed by the International IgA Nephropathy Network in collaboration with the Renal Pathology Society. • Clinical data/renal biopsies were obtained from 265 Caucasian and East Asian patients who were followed for 5 years. • Four pathological changes (MEST score) were shown to individually predict renal outcome, independent from clinical data: mesangial hypercellularity (M), endocapillary hypercellularity (E), segmental glomerulosclerosis (S), and tubular atrophy/interstitial fibrosis (T). • Combining the MEST score with clinical data at the time of biopsy predict clinical outcomes. • The utility of the Oxford classification in guiding therapy such as immunosuppression remains uncertain.
The receiver operating curves for models predicting the 5-year risk of a 50% reduction in eGFR or ESRD using clinical data at biopsy with or without MEST, and 2-year clinical data alone.
Barbour SJ, Espino-Hernandez G, Reich HN, et al. The MEST score provides earlier risk prediction in lgA nephropathy. Kidney Int 2016; 89:167.
Limitations • Limitations of the original study: the number of cases studied, its retrospective nature leading to selection and treatment bias in outcome data. • Low-risk and advanced disease patients were both excluded. • In a study of 3096 patients with expanded inclusion criteria, the presence of crescents (>25%) was found to be an independent risk factor for the combined renal outcome. Therefore, a C (crescent) score was added to the four components of the original MEST score (C-MEST).
Recommendation: Every biopsy report of IgA nephropathy should include numerical scores based upon the presence or absence of these five variables (MEST-C) below: ●Mesangial hypercellularity ●Endocapillary hypercellularity ●Segmental glomerulosclerosis ●Tubular atrophy/interstitial fibrosis ●Crescents ●Biopsies with fewer than eight glomeruli should be considered of uncertain value for prognosis.
The complement system in IgAN
IgAN
Mannan-binding lectin
Mario Espinosa et al. CJASN 2014;9:897-904
©2014 by American Society of Nephrology
Lupus
IgAN
MBL positivity is associated with markers of renal damage.
Anja Roos et al. JASN 2006;17:1724-1734
Renal survival according to C4d staining
Mario Espinosa et al. CJASN 2014;9:897-904
Fine Mapping Implicates a Deletion of CFHR1 and CFHR3 in Protection from IgA Nephropathy in Han Chinese. Xie J, Kiryluk K, Li Y, Mladkova N, Zhu L, Hou P, Ren H, Wang W, Zhang H, Chen N4, Gharavi AG.
CFHR1: Complement Factor H Related 1
Jingyuan Xie et al. JASN 2016;27:3187-3194
OMS721 for treatment of IgAN • OMS721 is a monoclonal antibody targeting MBLassociated serine protease-2 (MASP-2), the effector enzyme of the lectin pathway of the complement system. • During a phase 2 clinical trial, consisted of 12 weeks of treatment and 6 weeks of follow-up, all patients with IgAN demonstrated clinically improvement of proteinuria and renal function in 3 of the 4 treated-patients. • A phase 3 clinical trial is ongoing now.
Question 3:
Regarding the clinical manifestations, what statement below is correct on IgA nephropathy? 1) About 30% patients with IgAN present with nephrotic syndrome. 2) Familial IgA nephropathy affects up to 10 to 15 percent of all cases. 3) The kidney biopsy should be performed in all patients with clinical diagnosis of IgAN. 4) Measurement of the proportion of poorly galactosylated IgA1 O-glycoforms is used clinically to diagnose patients with IgAN. 5) Patients with chronic liver disease are often associated with IgAN.
CLINICAL FEATURES 1. Approximately 40-50% present with one or recurrent episodes of gross hematuria, often accompanying an URI (viral or bacterial). 2. Another 30-40% have microscopic hematuria and usually mild proteinuria which are incidentally detected on a routine examination. 3. Less than 10% present with either nephrotic syndrome or RPGN characterized by edema, hypertension, and renal insufficiency as well as hematuria. Rarely, IgA nephropathy may present with malignant hypertension. 4. Familial IgA nephropathy affects up to 10-15% of all cases where detailed studies of families have been performed.
CLINICAL ASSOCIATIONS
• Cirrhosis, celiac disease, and HIV infection are all associated with a high frequency of glomerular IgA deposition. • However, most patients have little or no evidence of glomerular disease.
DIAGNOSIS 1) A diagnosis of IgA nephropathy is generally based upon the clinical history and laboratory data and confirmed only by kidney biopsy with immunofluorescence studies for IgA deposits. 2) Indications for renal biopsy — A renal biopsy is usually performed only if there are signs suggestive of more severe or progressive disease, such as persistent urine protein excretion of at least 500 mg/day or an elevated serum creatinine concentration 3) Tests of limited utility — A number of other tests have been proposed but not recommended: circulating autoantibodies, Skin biopsy, Plasma polymeric IgA1, % of poorly galactosylated IgA1 O-glycoforms, and miRNAs.
Question 4: What statement about mechanism of IgAN is not correct? 1.
2.
3. 4.
5.
The pathogenesis of IgAN is explained by 4 hit mechanisms including genetic factor. Higher serum levels of poorly galactosylated IgA1 have been associated with a polymorphism in the gene-encoding C1GALT1, one of the enzymes responsible for O-galactosylation of IgA1. IgA-immune complexes with a high sialic acid content bind mesangial cells more strongly. IgA complex has system clearance with CD89 and mesangial clearance with CD71. The inherent tendency of the kidney to respond to injury determines the development of IgAN.
MECHANISMS OF INJURY Formation of circulating aggregated IgA immune complex Poor clearance of the immune complex by reticuloendothelial system Deposition of immune complex in mesangium
Activation of mesangial cells by immune complex Progression to IgAN or resolution
Abnormalities in circulating IgA and its production in IgA nephropathy 1. There is an increase in the amount of polymeric IgA1 in the serum, due to • Increased production probably from mucosally primed B cells • Impaired IgA clearance: systemic clearance with CD89 and mesangial clearance with CD71. 2. There is a high proportion of poorly O-galactosylated IgA1. • Higher serum levels of poorly galactosylated IgA1 have been associated with a polymorphism in the gene-encoding (C1GALT1) one of the enzymes responsible for O-galactosylation of IgA1 3. There are alterations in IgA1 sialylation. • Lead to a reduced rate of systemic clearance of IgA-immune complexes • IgA-immune complexes with a high sialic acid content bind mesangial cells more strongly
Multi-hit mechanisms in the pathogenesis of IgA Nephropathy Autoimmune
Infection
Question 5: Which following factor does not predict the progression of IgAN to ESRD?
1. SCr >1.68 mg/dL (>148 micromol/L) 2. Persistent (eg, for more than six months) protein excretion above 1000 mg/day. 3. Hypertension (>140/90 mmHg) 4. Isolated gross hematuria 5. High MEST scores
Prognosis • Patients with IgA nephropathy who have little or no proteinuria (1.68 mg/dL (>148 micromol/L) – 71 percent
• Hypertension (>140/90 mmHg) • Persistent (eg, for more than six months) protein excretion >1g/day, more progression if protein excretion>3.5g/day • Histological risk factor: Oxford classification.
Renal survival in IgA nephropathy
Cut-off: 1gm/day
APPROACH TO THERAPY 1. Patients with isolated hematuria, no or minimal proteinuria (0.5-1 g/day), a normal or only slightly reduced GFR, and only mild to moderate histologic changes are initially managed with nonimmunosuppressive therapies. 3. Patients with nephrotic-range proteinuria or proteinuria persisting despite 3-6 months of ACEi/ARB therapy, rising serum creatinine, and/or renal biopsy with severe histologic findings, but no significant chronic changes, may benefit from immunosuppressive therapy in addition to nonimmunosuppressive interventions.
Monitoring disease activity • Hematuria – Persistent hematuria is generally a marker of persistent immunologic activity, but not necessarily of progressive disease. Hematuria alone does not require any form of therapy but monitoring over time is essential since some patients may develop proteinuria and progressive disease. • Proteinuria – Protein excretion above 1 g/day is a marker of more severe disease and a risk factor for disease progression. • Serum creatinine or eGFR – risk for disease progression.
NON-IMMUNOSUPPRESSIVE THERAPIES • ACE inhibitors or ARB both are good for BP control and slowing progression of the renal disease. Proteinuria target< 1gm/day • Statin therapy for lipid lowering in selected patients (with elevated LDL cholesterol) to lower cardiovascular risk. • Fish oil (omega-3 fatty acids prescription strength and quality) and tonsillectomy have also been studied, but their roles are less clear.
IMMUNOSUPPRESSIVE THERAPY • Indications for steroid therapy is controversial. Glucocorticoids is used in patients with active and progressive disease, which include hematuria and one or more of the following: • A progressively declining GFR • Persistent proteinuria >1 g/day with ACEi/ARBs for 3-6 M. • Morphologic evidence of active disease. • No glucocorticoids in patients with chronically elevated serum creatinine (Cr>2.5mg/dl) or histologic evidence of prominent glomerulosclerosis and tubulointerstitial atrophy or fibrosis. • Combined immunosuppressive therapy is only considered in patients with RPGN and/or crescentic GN.
The benefit of glucocorticoid therapy in IgAN was examined in a meta-analysis of 9RTC including 536 patients with proteinuria (above 1 g/day) and preserved renal function. composite renal endpoint
Lv J, Xu D, Perkovic V, Ma X, Johnson DW, Woodward M, Levin A, Zhang H, Wang H, TESTING Study Group. J Am Soc Nephrol. 2012;23(6):1108.
Adverse events reported in the RCTs Adverse Events
Studies Reporting (n)
Steroid Group (n/n)
Control Group (n/n)
RR (95% CI)
P Value
8
60/245
34/243
1.55 (1.09–2.21)
0.02
diabetes mellitus/impaired glucose intolerance
3
4/108
1/110
2.55 (0.51–12.72)
0.26
hypertension
3
12/93
15/90
0.78 (0.39–1.54)
0.48
insomnia, palpitations, increased perspiration, headache
4
7/104
1/103
2.72 (0.60–12.44)
0.20
gastrointestinal bleeding
1
1/17
0/17
3.00 (0.13–68.84)
0.49
cushingoid features
3
9/82
0/84
7.18 (1.34–38.42)
0.02
weight increase
1
22/33
13/31
1.56 (0.98–2.57)
0.06
cough
2
2/81
3/79
0.75 (0.09–6.28)
0.79
Total patients with adverse events Specific adverse events
STOP-IgAN • In Supportive Versus Immunosuppressive Therapy of Progressive IgA Nephropathy [STOP-IgAN] trial •
162 patients with IgA nephropathy, eGFR of ≥30 mL/min/1.73 m2, and proteinuria of 0.75 to 3.5 g/day despite six months of adequate supportive therapy were randomly assigned to 1. continue supportive care 2. immunosuppression in addition to supportive care
• Of the 82 patients assigned to immunosuppressive therapy: • •
55 had an eGFR that was ≥60 mL/min/1.73 m2 and received glucocorticoid monotherapy. 27 had an eGFR that was 30 to 59 mL/min/1.73 m2 and received combination immunosuppression. Intensive Supportive Care plus Immunosuppression in IgA Nephropathy. Rauen T, Eitner F, Fitzner C, Sommerer C, Zeier M, Otte B, Panzer U, Peters H, Benck U, Mertens PR, Kuhlmann U, Witzke O, Gross O, Vielhauer V, Mann JF, Hilgers RD, Floege J, STOPIgAN Investigators. N Engl J Med. 2015;373(23):2225.
Results At three years: • The rate of full clinical response (a decrease in protein-to-creatinine ratio to 95 percent China, remainder from Australia) were recruited at the time of study discontinuation. • At a median of 2.1 years follow-up, serious adverse events (mostly serious infection) occurred in 14.7 percent of patients who received methylprednisolone compared with 3.2 percent of those who received placebo. • The primary renal endpoint occurred in fewer patients in the glucocorticoid group than the placebo group (5.9 versus 15.9 percent, respectively); however, given the premature termination of the study and short follow-up, definitive conclusions about the benefit of treatment could not be drawn. Given the uncertainty about the optimal dosing of glucocorticoids in the treatment of IgAN, another clinical trial evaluating the efficacy and safety of lower doses of oral glucocorticoids compared with a placebo control is in progress.
Crescentic glomerulonephritis The treatment of crescentic, rapidly progressive glomerulonephritis in patients with IgA nephropathy has not been evaluated in randomized trials. Observational data suggest possible benefit from regimens similar to those used in idiopathic crescentic glomerulonephritis: intravenous pulse methylprednisolone followed by oral prednisone, intravenous or oral cyclophosphamide, and/or plasmapheresis.
KDIGO clinical practice guidelines do not recommend the use of MMF and rituximab as first-line therapy.
No clear evidence for these therapies Tonsillectomy — Tonsillitis has been associated with hematuria and proteinuria in IgA nephropathy. It has been proposed that the tonsils are a source of abnormal IgA that forms immune complexes and deposits in the glomeruli. However, the available evidence suggests that tonsillectomy should not be routinely performed in patients with IgA nephropathy Low-antigen diet — A low-antigen diet consists of avoiding gluten, dairy products, eggs, and most meats. The rationale for this regimen is that dietary macromolecules may be responsible for activating the mucosal IgA system. Intravenous immune globulin — No evidence
Targeted-release budesonide versus placebo in patients with IgA nephropathy (NEFIGAN): a double-blind, randomized, placebo-controlled phase 2b trial Lancet. 2017 May 27;389(10084):2117-2127
Budesonide — An oral targeted-release formulation of the glucocorticoid budesonide (TRF-budesonide) has been designed to release the drug in the ileocecal region where Peyer patches are located. Mucosal B lymphocytes localized within Peyer patches are postulated to be a source for the production of aberrantly galactosylated IgA1, which has been implicated in the pathogenesis of IgA nephropathy. Conclusion: TRF-budesonide 16 mg/day, added to optimized RAS blockade, reduced proteinuria in patients with IgA nephropathy. US FDA accepts Calliditas Therapeutics’ Nefecon phase 3 study design to treat IgA nephropathy
Conclusions 1. IgAN is a common GN world-wide. 2. The pathogenesis is better understood now. 3. The clinical presentation varies among individual patients. 4. The treatment is controversial and more clinical trials are needed.
