IgA Nephropathy Nicola Sumorok

Nephrology Grand Rounds 11/15/11

Background • Mesangial proliferative glomerulonephritis characterized by

diffuse mesangial deposition of IgA

• First described by Dr. Jean Berger and colleagues in late 1960s; also called Berger’s Disease

• Most prevalent pattern of glomerular disease seen in most Western and Asian countries where renal biopsy is widely practiced

• Peak incidence in 2nd and 3rd decades

• 2:1 male to female predominance in North American and Western European populations

• Occurs with greatest frequency in Asians and Caucasians; relatively rare in blacks

Clinical Features • Original descriptions emphasized the syn-pharyngitic

presentation of an episode of gross hematuria coincident with or immediately following a URI

• Macroscopic hematuria: in 30-40% of cases; intermittent

• Microscopic hematuria with or without proteinuria: 30-40% of cases (usually <2g/d of proteinuria)

• Nephrotic syndrome – rare, only 5% present with proteinuria in the absence of hematuria

• AKI: very uncommon; <5% of cases; from acute severe immune and inflammatory injury with crescent formation, or when heavy hematuria leads to tubular occlusion by red cells

• CKD: renal impairment and HTN at time of diagnosis, likely from long-standing undiagnosed disease

Etiology • Classically thought to be a complication of upper respiratory

infections

• No individual viral or bacterial organism has been consistently associated with the development of IgAN

• Also been suggested that IgAN is caused by hypersensitivity to food antigens, for example gliadin

• Concensus that IgAN usually develops as a consequence of an aberrant IgA immune response to a variety of different antigens, whether this be an infecting organism or a food antigen

Pathophysiology: 4 Hit Hypothesis • Hit 1: Aberrant glycosylation of IgA1

• Deficiency of galactose in the hinge region of IgA1 heavy chains

• Increased circulating levels of IgA1 with abbreviated glycans (I, II)

• Insufficient to cause IgAN on its own

Suzuki, et al. JASN 2011; 22: 1795-1803

• Hit 2: Circulating antibodies directed against Galactose-deficient IgA1 • Postulated that Ab are produced in response to bacterial or viral cell-

surface glyco-conjugates and then cross-react with the O-linked glycans on IgA1

• Serum levels of IgG antibodies specific for galactose-deficient IgA1 correlated with disease severity (proteinuria)

• Hit 3: Formation of pathogenic IgA1-containing immune complexes • IgG-IgA1 complexes are relatively large; excluded from entry into

hepatic space to reach the asialoglycoprotein receptor (ASGP-R) on hepatocytes, the normal catabolic pathway for circulating IgA1

• Hit 4: Mesangial deposition of IgA1-containing immune complexes, cell activation, and initiation of glomerular injury • Complexes induce mesangial cells to proliferate, secrete extracellular

matrix components, and release humoral factors such as TNFα, IL-6, and TGFβ

• These factors, in turn, alter podocyte gene expression and glomerular permeability

Suzuki, et al. JASN 2011; 22: 1795-1803

Suzuki, et al. JASN 2011; 22: 1795-1803

Pathology • Light microscopy

• Variable; ranging from almost normal appearance to severe, necrotizing, crescentic GN or glomerulosclerosis

• Mesangial hypercellularity, usually diffuse and global, but focal segmental can also be seen

• Crescentic changes can be superimposed, with or without associated segmental necrosis

• IM • IgA deposits are the hallmark of the disease – in the mesangium

and to a lessor degree, along the glomerular capillary wall • IgG and IgM accompany IgA in the majority of cases • C3 deposition is usual (90%) and has the same distribution as IgA

• EM • Electron-dense deposits, primarily limited to the mesangium

Oxford Classification

• International effort that identified a set of distinct pathological variables with prognostic value

• 265 cases from centers across continents

• Four pathology features found to be of independent value in predicting the outcome of renal function

• MEST score: • Mesangial hypercellularity (M: M0 < 0.5, M1 > 0.5)

• Segmental glomerulosclerosis (S: S0 = absent, S1 = present)

• Endocapillary hypercellularity (E: E0 = absent, E1 = present)

• Tubular atrophy/interstitial fibrosis (T: T0 < 25%, T1 = 26-50%, T2 > 50%)

• In retrospective analysis, the scores correlated with renal outcomes

• Potential weakness is that it does not include crescents or necrotizing lesions

Validation of Oxford Classification

Herzenberg. KI 2011; 80: 310-317

• 187 patients with similar clinical and histologic features as prior cohort

• Treated with more RASB and immunosuppression

• No difference in renal outcomes between cohorts

• Overall score predicted risk of a rapid renal-function decline

• 3 of 4 pathological variables independently predicted outcomes (not mesangial hypercellularity)

Prognosis • Slow progression to ESRD occurs in up to 50% of patients

• 15-25% at 10 yrs and 20-30% at 20 yrs • Clinical prognostic factors:

• Proteinuria • >1g/24h is associated with progression to ERSD • Patients who achieve and sustain <1g/24h have excellent prognosis,

regardless of peak proteinuria • Hypertension • Baseline SCr

Reich, JASN 2007; 18: 3177-3183.

Treatment: Overview • Conservative therapy:

• ACE-Inhibitors

• Fish oil

• Immunosuppression: • Steroids

• Combination immunosuppresion

• Mycophenolate mofetil

ACE-inhibitors • Single-center, prospective, randomized study

• 44 patients with biopsy-proven IgAN, protienuria >0.5g/d, serum Cr <1.5mg/dL

• Treatment group (23 pts): received Enalapril

• Control group (21 pts): other anti-hypertensives to maintain BP <140/90

• Primary outcome: Renal survival, estimated by >50% increase in baseline serum Cr

• Follow-up period of 78 +/-37 mos in the Treatment group and 74 +/- 36 mos in the Control group

Praga, JASN 2003; 14: 1578-1583.

ACE-inhibitors: Results

• Three patients in the treatment group (13%) and 12 in the control group (57%) reached the primary end point of a 50% increase in SCr during the study (P 0.05)

• At four years, renal survival was 100% in Enalapril group compared to 70% in the control group (P 0.05); (At 7 yrs, 92% and 55%, respectively)

• Proteinuria showed a significant decrease in the treatment group; no change in proteinuria in the control group

Praga, JASN 2003; 14: 1578-1583.

Fish Oil • Premise: Omega-3 fatty acids compete with arachidonic acid

to produce trienoic eicosanoids which may slow renal disease progression by reducing glomerular and interstitial inflammation, mesangial cell contractility, platelet aggregation, and vasoconstriction in response to renal injury

• Multi-center, placebo-controlled, randomized trial

• 106 patients with IgA nephropathy with persistent proteinuria • Treatment group (55 pts): Fish oil 12g daily

• Control group (51 pts): Olive oil 12g daily

• 68% of the patients had elevated SCr at baseline (<3mg/dL)

• Two years of treatment; average follow-up period of 3 yrs

• Primary outcome: Increase of 50% or more in serum Cr

Donadio, NEJM 1994; 331: 1194-1199

Fish Oil - Results

• 3 patients in the Fish oil group and 14 patients in the placebo group reached the primary end point (6% and 33%)

• In longer follow-up (avg 3 yrs), 5 pts in the Fish oil group and 14 in the placebo group died or progressed to ESRD

• No significant difference in change in proteinuria between groups

• No adverse effects of Fish oil

Donadio, NEJM 1994; 331: 1194-1199

Donadio, et al. JASN 1999; 10: 1772-1777.

• Mean follow-up of 6.4 yrs • 17 pts in the Fish oil group and 29 pts in the placebo group reached the primary endpoint (5-yr Kaplan-Meier event-free survival of 79 and 49%, respectively) • 8 pts in the Fish oil group and 19 in the placebo group developed ESRD (respective 8-yr event-free survival of 85 and 56%)

Steroids

• Prospective, multicenter, randomized study in Italy

• 86 patients with biopsy-proven IgA, proteinuria 1.0-3.5 g/d, and SCr < 1.5mg/dL • Treatment group (43 pts): IV Methylprednisolone 1g /d x 3d at

the beginning of months 1, 3, and 5, plus oral Prednisone 0.5mg/kg QOD for 6 months

• Control group (43 pts): Supportive therapy alone

• Primary Endpoint: Deterioration in renal function defined as a 50% or 100% increase in Cr from baseline

• 5-year follow-up

Pozzi, et al. Lancet 1999; 353: 883-887.

Steroids: Results

• Nine (21%) pts in steroid group and 14 (33%) in control group had 50% inc in Cr • One (2%) pt in steroid group and 9 (21%) in control group had 100% inc in Cr • A decrease in proteinuria to <1g/d was seen in 31 (70%) of the steroid group and 13 (30%) of the control group

Pozzi, et al. Lancet 1999; 353: 883-887.

Steroids – Long-term Follow-up

• At 10 year follow-up, renal survival was 97% in steroid group vs 53% in control group

Pozzi, et al. JASN 2004; 15: 157-163

Steroids plus ACE-I vs ACE-I alone • Long-term, prospective, multi-center, open-label, randomized

controlled trial • 97 patients with IgAN, moderate histologic lesions, >1.0g/d

proteinuria, and GFR>50 • 48 patients – Prednisone x 6 mos (PO, 1mg/kg/day x 1 mo then

taper by 0.2mg/kg/d monthly x 5mo) plus Ramipril through the follow-up period

• 49 patients – monotherapy with Ramipril, through the follow-up period

• Run-in phase of 3-months where proteinuria and GFR were measured; ACE-I and ARBs were held for at least 4 wks before labs were drawn

• Primary outcome: combination of doubling of SCr or ESRD • Follow-up up to 8 yrs (median 5 yrs)

Manno, et al. Nephrol Dial Transplant 2009; 24: 3694-3701

• At 96mos, 2/48 (4.2%) in combination therapy group and 13/49 (26.5%) of the monotherapy group had reached the primary endpoint • 1/48 (2.1%) and 7/49 (14.3%), respectively, reached end point of ESRD • Difference in proteinuria seen up to year 2 of follow-up, but effect decreased after that • Baseline levels of proteinuria and serum Cr were both independent predictors of the risk of primary outcome

Combination of doubling of serum Cr or ESRD:

ESRD alone:

Manno, et al. Nephrol Dial Transplant 2009; 24: 3694-3701

Overview of trials of steroids

Floege, et al. JASN 2011; 22: 1785-1794

Immunosuppressive Combination Therapy • Single-center, prospective, randomized study

• Patients with biopsy-proven IgAN with Cr > 130ul/L and rising by at least 15% in the year before the study

• Treatment group: Prednisolone 40mg/d (to 10mg/d by 2 yr) and Cyclophosphamide 1.5mg/kg/d x 3mo, then Azathioprine 1.5mg/kg/d x min of 2 yrs (up to 6 yrs)

• Control group: no immunosuppression

• Follow-up of 2 to 6 yrs

Ballardie, et al. JASN 2002; 13: 142-148

• All but one of the controls reached ESRD by 5 yrs

• At 5 yrs, 72% of treatment group and 5% of controls had not reached ESRD

• 3 treatment group patients withdrew because of treatment related side effects

Ballardie, et al. JASN 2002; 13: 142-148

Steroids plus Azathioprine

• Multicenter, randomized controlled study

• 207 patients with IgAN, with Cr<2.0mg/dl, proteinuria >1.0g/d

• Treatment: 3-day pulse of methylprednisolone in months 1, 3, 5 in addition to both oral prednisone 0.5mg/kg QOD and Azathioprine 1.5mg/kg/d x 6 months

• Control: Same steroid regimen without Azathioprine

• Primary outcome: Renal survival (time to 50% increase in SCr from baseline)

• Followed for median of 4.9 yrs

Pozzi, et al. JASN 2010; 21: 1783-1790

• No change in renal survival between groups at 5 years (12% in treatment group vs 11% in control group reached the primary endpoint)

• Both groups showed a similar decrease in urinary protein excretion during follow-up

• Adverse events were more common in the treatment group • 13 pts in the treatment group withdrew during the 6 month

treatment period because of side effects, vs 1 in the control group

Pozzi, et al. JASN 2010; 21: 1783-1790

Mycophenolate Mofetil

• In China, 40 patients with IgAN with persistent proteinuria > 1g/d despite treatment with RAS-blockers (for at least 6mo)

• Randomized to: • MMF (2 g/d if body wgt >60kg or 1.5 g/d if wgt <60kg) x 6 months

• Continue conventional therapy

• Primary end point was combination of doubling of serum Cr or progression to ESRD

• Follow-up of 6 yrs

Tang, et al. KI 2010; 77: 543-549

MMF- Results • Short Term (18 months):

• Reduction in proteinuria significantly greater in MMF group vs controls

• Long Term (6 yrs): • After 2 yrs, no difference in proteinuria between groups

• Two (10%) pts in the MMF group and nine (45%) in the control group developed progressive renal failure that required dialysis

Tang, et al. KI 2010; 77: 543-549

Meta-analysis of MMF trials

Xu, et al. Am J Nephrol 2009; 29: 362-367

Summary of Treatment

Floege, et al. JASN 2011; 22: 1785-1794

Thank you