IgA nephropathy: An interesting autoimmune kidney disease

Abstract

Immunoglobulin A nephropathy (IgAN) is the most common primary glomerulonephritis worldwide. It is a leading cause of chronic kidney disease and progresses to end-stage kidney disease in up to 40% of patients about 20 years after diagnosis. Additionally, IgAN is associated with significant mortality. The diagnosis currently necessitates a kidney biopsy, as no biomarker sufficiently specific and sensitive is available to supplant the procedure. Patients display significant heterogeneity in the epidemiology, clinical manifestations, renal progression, and long-term outcomes across diverse racial and ethnic populations. Recent advances in understanding the underlying pathophysiology of the disease have led to the proposal of a four-hit hypothesis supporting an autoimmune process. To date, there is no disease-specific treatment but, with a better understanding of the disease pathogenesis, new therapeutic approaches are currently being tested in clinical trials. In this review, we examine the multiple facets and most recent advances of this interesting disease.

INTRODUCTION

Immunoglobulin A nephropathy (IgAN) was initially described in 1968 by a French pathologist, Dr. Jean Berger, and his colleague Dr. Nicole Hinglais (an electronmicroscopist) as a kidney disease having glomerular “intercapillary deposits of IgA-IgG”. The entity was initially coined Berger’s disease and is to date sometimes referred to as such.¹ It is the most common primary glomerular disease in many countries and remains a leading cause of chronic kidney disease and end-stage kidney disease (ESKD).^2–5 IgAN is characterized on renal biopsy by dominant IgA glomerular deposits, usually accompanied by local cellular proliferation and matrix expansion.⁶ Recurrent visible hematuria concurrent with a febrile illness is the hallmark clinical feature of IgAN and is particularly common in children and young adults, whereas microscopic hematuria with or without varying degrees of proteinuria is frequently observed among adults.⁷

EPIDEMIOLOGY

The prevalence of IgAN varies widely between ethnic/racial groups, being highest in persons of East Asian descent, followed by Caucasians and is relatively rare in individuals of sub-Saharan African ancestry.^8–12 IgAN accounts for about 40% of all native-kidney biopsies in Japan, 25% in Europe, 12% in the United States, but less than 5% in central Africa.¹³ Some of this variability can be explained by differences in health screening policies and biopsy practices between these regions,¹⁴ but genetics likely contribute as well. The incidence has been estimated at 2–10 per 100,000 person-years^{8–12, 15, 16} and peaks during the second and third decades of life.^{17, 18} The male-to-female ratio is 2–3:1 in North America^{15, 19, 20} and Europe²¹ but about 1:1 in Asia.²² Subclinical or “lanthanic” IgAN, defined by the characteristic glomerular IgA deposits on renal biopsy without significant hypercellularity or matrix expansion and without clinical manifestation of overt kidney disease, was detected in 1.3% of autopsies of trauma victims in Finland.²³ Furthermore, a Japanese study showed that 16% of renal allografts (from living and deceased donors) had glomerular IgA deposits on biopsies taken at time of engraftment, of which 10% exhibited histological features typical of IgAN.²⁴ Therefore the true prevalence and incidence of IgAN may be higher than recognized because of likely undocumented subclinical cases. While most cases of IgAN appear to be sporadic, some kindreds with familial IgAN have been described.²⁵

PATHOLOGY

The diagnosis of IgAN necessitates a kidney biopsy. The defining pathology feature is IgA as the dominant or co-dominant immunoglobulin in the immune deposits in the mesangial areas of the glomeruli as shown by routine immunofluorescence microscopy (Figure 1 - Panel C).⁶ IgA is the sole immunoglobulin in about 15–40% of cases; for the remaining cases, IgG, IgM, or both are present although the frequencies vary widely.^{7, 26} The glomerular IgA is exclusively of the IgA1 subclass that has compositional features that play a central role in the pathogenesis of IgAN, as described later. Other immune proteins may be detected by immunofluorescence microscopy. Complement (C) component C3 is co-localized with IgA in greater than 90% of the biopsies with IgAN.²⁷ C3, C4, C4d,²⁸ properdin, terminal complement complex (C5b-C9),²⁹ and mannose binding lectin³⁰ are frequently detected whereas C1q is typically absent.^31–33 These features support the involvement of the alternative and lectin pathways of complement activation in the pathogenesis of IgAN.

Figure 1. Pathological Characteristics of IgAN.

Panel A (Periodic acid-Schiff Hematoxylin stain x40) shows a glomerulus with increased mesangial matrix and cellularity (> 3 cells in a mesangial area), without endocapillary proliferation or crescent formation. Panel B (Jones silver stain x40) shows a glomerulus with early fibrocellular crescent (asterisks) and segmental sclerotic lesions with obliterated capillary lumina (arrows) that are entrapped within the circumferential crescent. Panel C (immunofluorescence stain with fluorescein-conjugated anti-IgA antibodies x40) shows near global, granular, staining for IgA limited to the mesangium. Panel D is an electron micrograph of a mesangial area with large electron-dense immune complex deposits in the expanded mesangium (asterisks).

Light microscopy histological features vary amongst patients and within the individual biopsy specimen. Mesangial hypercellularity and mesangial matrix expansion occur frequently (Figure 1A). Other glomerular lesions may include focal necrosis, segmental scarring, and crescents in Bowman’s space (Figure 1B). Crescents are most commonly found in biopsies obtained during episodes of visible hematuria accompanied by acute kidney injury. Interstitial fibrosis and tubular atrophy, the culmination of renal injury via several pathways, portend a poor prognosis.^{34, 35}

Electron microscopy shows electron-dense material corresponding to IgA immune complexes in the mesangial and paramesangial areas of the glomeruli (Figure 1D). Additional deposits are sometimes present in the sub-endothelial and sub-epithelial regions of the glomerular basement membranes.⁷

Pathologic features carry useful prognostic information for the treating physician. An international collaboration of nephrologists and nephropathologists developed (initially in 2009 with an update in 2016) the Oxford Classification of IgAN, a structured and reproducible scoring system for evaluating the light-microscopy features on renal biopsy. This schema was derived from review of biopsies of patients (predominantly adults) with proteinuria ≥ 0.5 g/day and estimated glomerular filtration rate (eGFR) ≥ 30 ml/min per 1.73 m² at the time of renal biopsy and with ≥ 1 year of follow up. Four pathologic features were identified that correlated very strongly with clinical outcomes, independent of known prognostic clinical manifestations at the time of diagnosis - mesangial hypercellularity (M), endocapillary hypercellularity (E), segmental glomerulosclerosis (S), and tubular atrophy and interstitial fibrosis (T). The M, S, and T scores independently predicted rate of GFR decline and the composite end-point of either progression to ESKD or a 50% decline in eGFR.³⁴ A similar association was seen with endocapillary hypercellularity in patients who had not received immunosuppression, suggesting that this feature was responsive to immunosuppressive therapy.³⁴ The degree of interstitial fibrosis and tubular atrophy has proven to be the strongest predictor of renal survival.³⁶ The Oxford Classification has since been applied to biopsies of pediatric patients,³⁷ and has been validated across multiple populations.^{38, 39} In 2016, a fifth feature, glomerular crescents, was added to the Oxford Classification after several studies indicated that this finding was also an independent predictor of renal outcome.³⁵ The presence of crescents in 1–24% of glomeruli identifies patients at risk of poor renal outcomes if not treated with immunosuppression. When crescents are found in ≥ 25% of glomeruli, patients have a poor prognosis even if treated with immunosuppression (Table 1).³⁵

Table 1.

Updated Oxford Classification of Immunoglobulin A Nephropathy

Histological Feature	Definition	Score
Mesangial hypercellularity	Percentage of glomeruli with > 3 mesangial cells per mesangial area	M0: ≤ 50% M1: > 50%
Endocapillary hypercellularity	Increased number of cells within glomerular capillary lumina causing narrowing of the lumina	E0: Absent E1: Present
Segmental glomerulosclerosis	Any amount of the glomerular tuft involved in sclerosis, but not involving the whole tuft, or the presence of an adhesion	S0: Absent S1: Present
Tubular atrophy / Interstitial fibrosis	Percentage of cortical area involved by tubular atrophy or interstitial fibrosis, whichever is greater	T0: 0–25% of cortical area T1: 26–50% of cortical area T2: > 50% of cortical area
Cellular or fibrocellular crescent	Percentage of glomeruli with cellular or fibrocellular crescent	C0: Absent C1: < 25% of glomeruli C2: ≥ 25% of glomeruli

M: Mesangial hypercellularity; E: Endocapillary hypercellularity; S: Segmental glomerulosclerosis; T: Tubular atrophy/Interstitial fibrosis;

C: Cellular or fibrocellular crescents

CLINICAL PRESENTATION

Episodic visible hematuria (macroscopic hematuria) is the hallmark clinical feature of IgAN. The source is red blood cells that pass through the glomeruli into the urinary space. Macroscopic hematuria commonly manifests in the second and third decades of life and frequently heralds the clinical onset of disease.³ The urine is often brown rather than red and described as “cola-colored”. Passage of clots is rare. Bilateral loin pain occasionally accompanies these episodes, perhaps due to swelling of the renal capsule. Visible hematuria often occurs concurrently with an infection of the upper respiratory tract (hence termed ‘synpharyngitic hematuria’) or gastrointestinal tract.¹⁸ This timing relationship differentiates IgAN from post-streptococcal glomerulonephritis with its 2- to 3-week latency period between onset of infection and macroscopic hematuria. Visible hematuria usually spontaneously resolves within a few days.³ The bleeding also may be provoked by intense physical exercise and sometimes develops without an apparent trigger.³ Most patients with macroscopic hematuria experience several episodes over a span of a few years.^{20, 40} In contrast, macroscopic hematuria in patients with IgAN rarely starts after the age of 40 years; in those cases, patients should be evaluated for other potential concomitant conditions such as kidney or bladder cancers.⁴¹

Asymptomatic nonvisible hematuria (microscopic hematuria) is frequent between the episodes of macroscopic hematuria. It is a common presentation in adults, often first detected during routine health screenings. Concurrent proteinuria may also be seen. It is rare for proteinuria to occur without microscopic hematuria.^{7, 15, 40}

Nephrotic syndrome (proteinuria > 3 g/day accompanied by hypoalbuminemia, peripheral edema, and hyperlipidemia) is seen in only about 5% of patients with IgAN.⁹ It develops more often in children and adolescents than in adults. Proteinuria > 3 g/day may also develop in patients with advanced glomerulosclerosis in their renal biopsies. In patients, mainly children, presenting with nephrotic syndrome, microscopic hematuria, and mesangial IgA deposition with minimal glomerular pathology by light microscopy, the coincidence of two common glomerular diseases, namely minimal-change disease and IgAN, must always be considered.^{42, 43} Multiple case series have reported pediatric IgAN patients with widespread effacement of the foot processes of the podocytes on electron microscopy. These patients often show resolution of proteinuria in response to corticosteroid therapy; however, the microscopic hematuria and mesangial IgA deposits frequently persist.⁴⁴

Acute kidney injury is uncommon in IgAN, manifesting in ≤ 5% of cases. It develops by two distinct mechanisms. The first is an acute, severe, inflammatory damage of the capillaries in the glomerular tuft leading to leakage of circulatory proteins into the urinary space that induce proliferation of epithelial cells of Bowman’s capsule to form a crescent (Figure 1B). Crescentic disease, often accompanied by accelerated and irreversible loss of renal function if not treated aggressively, may be the initial manifestation of IgAN or may occur superimposed on known, previously stable, mild disease.⁴⁵ Alternately, acute kidney injury can present with minimal glomerular injury when substantial hematuria leads to damage of tubular epithelial cells or obstruction of the tubules by red-cell casts. This circumstance is a reversible phenomenon, and renal recovery usually occurs with supportive measures.⁴⁶

Other presentations, particularly in adults, include hypertension and chronic kidney disease wherein IgAN is discovered incidentally after further investigation and a kidney biopsy.^{7, 15, 40} Presumably the disease process has been ongoing for years, but without signs or symptoms to prompt medical evaluation.

IMMUNOGLOBULIN A VASCULITIS

IgA vasculitis (IgAV), formerly known as Henoch-Schönlein purpura, is the most common systemic vasculitis in children. When the kidneys are affected, the disease is termed IgAV with nephritis (IgAV-N), the pathologic features of which are indistinguishable from those of IgAN.^47–50 The annual incidence of IgAV is 10–20 per 100,000 in children < 17 years of age, with the peak incidence at 4–6 years of age.⁵¹ Adults of all ages may be afflicted, but account for only 10% of all IgAV cases.⁵² Males are more commonly affected than females.⁵³

IgAV is characterized by deposition of IgA in blood vessels of affected tissues, most frequently skin and intestinal tract.⁵⁴ The characteristic histology finding is a leukocytoclastic vasculitis with IgA in small vessels (especially postcapillary venules). IgAV clinically manifests most commonly with a purpuric rash without thrombocytopenia or coagulopathy. The lesions are characteristically more prominent below the waist, with relative sparing of the upper torso, arms, and face. Involvement of the extremities is often on extensor surfaces with symmetrical distribution.⁵⁵ Some of these purpuric lesions can become ulcerative, especially in adults.⁵⁶ Other clinical features include arthralgia (often involving multiple joints) and abdominal pain.⁵⁷ Polyarthralgia is usually transient and migratory. Gastrointestinal manifestations often appear after the rash. The abdominal pain is frequently mild and transient but may be severe and can present with gastrointestinal hemorrhage, bowel ischemia, intussusception, and perforation.^{58, 59} Symptoms can occur in any order and generally evolve over days to weeks. The diagnosis of IgAV is typically based on characteristic clinical features whereby a biopsy of skin or intestinal mucosa is not necessary.⁵⁷ In patients with incomplete or unusual presentations, biopsies of affected organs can be helpful.

IgAV-N develops in 30–50% of patients with IgAV, mainly in children, and usually manifests within 4–6 weeks after the onset of the purpura.⁶⁰ Renal involvement may include transient microscopic hematuria with or without proteinuria. More severe acute disease, with progressive worsening of renal function over a relatively short interval with glomerular crescents on renal biopsy is more common in adults than children. While extra-renal manifestations of IgAV are mostly benign and self-limited, IgAV-N may progress to chronic kidney disease and ESKD.^60–62 Long-term prognosis of IgAV-N cannot be predicted from the initial clinical and histological presentations. Chronic kidney disease can be seen at long-term follow-up even after resolution of the urinary abnormalities and is the principal cause of morbidity and mortality in children with IgAV-N.^{61, 63, 64}

Repeated or prolonged episodes of acute glomerular inflammation in IgAV-N lead to fibrous scars and hyperfiltration in less affected glomeruli that can culminate in chronic kidney disease or even ESKD.^60–62 Therefore, the number and severity of acute episodes of IgAV-N play a crucial role in the subsequent loss of renal function and ESKD develops in 10 to 30% of patients at 15 years from the time of diagnosis.^{64, 65} IgAV-N has a better prognosis in children than adults, as most children enter stable remission.⁶¹

The underlying cause of IgAV is unknown, but it is postulated to be an immune-mediated vasculitis that may be triggered by any of a variety of antigens, including microbes or environmental compounds.⁶⁶ As discussed in the pathogenesis section below, IgAV-N and IgAN appear to share several mechanisms of disease. The comparative features of IgAN and IgAV-N are depicted in Table 2.

Table 2.

Comparative Features of IgA Nephropathy and IgA Vasculitis with Nephritis

Feature	IgA Nephropathy	IgA Vasculitis with Nephritis
Presentation
• Incidence per million persons	Children: 5–50 Adults: 10–40	Children: 15–70 Adults: 4–13
• Age at onset	Mainly > 15 years	Mainly < 15 years
• Macroscopic hematuria	+++ (coincident with mucosal infection)	+ (sometimes seen after resolution of IgAV)
• Nephritic and Nephrotic syndrome	+/−	++
• Disease course	Continuous moderate activity with frequent exacerbations	Repeated acute episodes
• Extrarenal symptoms	+/−	+++
Renal histologic findings
• Immunofluorescence
• Mesangial IgA deposits	+++	+++
• IgA deposits along capillary wall	+/−	++
• Staining for light chains	Lambda > Kappa	Lambda = Kappa
• Light Microscopy
• Crescents	+/−	++
• Glomerular tuft necrosis	+/−	++
• Neutrophil infiltration	+/−	++
• Electron Microscopy
• Subendothelial deposits	+/−	++
Renal outcomes
• Clinical remission	30–50%	98%
• CKD as delayed presentation after apparent complete remission	-	+
• ESKD	20–40% after 20 years	1–3% in children, 30% in adults after 15 years
Transplantation outcomes
• IgA deposits recurrence (on immunofluorescence microscopy)	Frequent	Frequent
• Renal allograft loss at 5 years post transplantation	Rare	Rare
• Renal allograft loss at 5 years post transplantation	Approximately 10%	Approximately 8%

−, +/−, +, ++, +++ indicates the relative likelihood of a feature occurring in a direct comparison of IgA Nephropathy and IgA

Vasculitis with Nephritis.

Abbreviations: CKD, chronic kidney disease; ESKD, end-stage kidney disease.

PATHOGENESIS

IgAN manifests as a systemic disease in which the kidneys are injured as innocent bystanders. Two clinical observations in kidney transplantation support this concept: IgAN commonly recurs in the renal allograft;^{67, 68} additionally, when a kidney from a donor with subclinical IgAN is transplanted into a recipient whose ESKD was caused by a disease other than IgAN, the IgA clears within several weeks.⁶⁹ These observations suggest that the glomerular IgA is deposited from the circulation.

IgA is the most abundant antibody isotype in humans, comprising about two thirds of the body’s total immunoglobulins.⁷⁰ IgA has two subclasses, IgA1 and IgA2, primarily distinguished by the different lengths of their heavy-chain hinge regions. These segments allow flexibility of the antibody for the antigen-binding site to attach to its target.⁷¹ IgA1 has the longer hinge region and this feature is critical for development of IgAN, as discussed below. IgA in the blood is mostly of the IgA1 subclass and is produced in the bone marrow.⁷² Representations of IgA1 and IgA2 subclasses in secretions of the respiratory, intestinal, and genitourinary tracts vary, depending on the specific site, with some sites having predominantly IgA2, and the IgA is synthesized by plasma cells in mucosal tissues.⁷³ In the gastrointestinal system, IgA originates from follicular B cells of the gut-associated lymphoid tissue (GALT) which includes Peyer’s patches and mesenteric lymph nodes.⁷⁴ This secreted IgA plays a major role in protecting mucosal surfaces against invasion by microbes.⁷⁵

The key to understanding the pathogenesis of IgAN is an appreciation of the unique structure of the IgA1 hinge region with its carbohydrate side chains (Figure 2). This segment of the IgA1 heavy chain has multiple serine and threonine amino acids not present in the IgA2 hinge region to which O-linked glycans are attached.⁷⁶ The synthesis of the glycans is initiated by attachment of N-acetylgalactosamine to the oxygen atom in the hydroxyl group of one of these amino acids; based on this connection, the side chains are termed O-linked glycans.⁷⁷ The next step is attachment of either galactose or sialic acid to N-acetylgalactosamine. If sialic acid is added, this modification prohibits the addition of galactose. If galactose is added as the second step, sialic acid can be attached to galactose, N-acetylgalactosamine, or both (Figure 2). O-glycans composed of N-acetylgalactosamine or sialylated N-acetylgalactosamine contain no galactose and are termed “galactose-deficient”. The mesangial IgA of IgAN has unique features: it is exclusively of the IgA1 subclass and relatively galactose-deficient.^31–33

Figure 2. Structure of Human IgA1 and O-glycosylation of the IgA1 Hinge Region.

IgA exists in several molecular forms in the circulation: monomers, dimers, trimers, large polymers, secretory IgA, as well as bound in immune complexes. The figure depicts an IgA1 monomer. Each heavy chain has a N-linked (attached to a nitrogen molecule in asparagine) glycan (carbohydrate) side chains (orange) in the second and third constant-region domains (Cα2 and Cα3) and clustered O-glycans (attached to an oxygen molecule in serine or threonine; blue) in the hinge region between the first and second constant-region domains (Cα1 and Cα2). This hinge region in the IgA1 molecule has 9 threonine and serine residues to some of which a glycan can attach. The composition and number of the O-glycans vary considerably among the IgA1 molecules in an individual, creating microheterogeneity for the hinge region structure. The IgA1 hinge region usually has 3 to 6 O-linked glycans. When compared with healthy individuals, patients with IgAN have more of circulating IgA1 molecules with less galactose (galactose-deficient IgA1). The monomer depicted has five O-linked glycans at each of the two hinge regions. (A) O-linked glycan synthesis proceeds in a stepwise fashion, starting with attachment of N-acetylgalactosamine to a hinge-region serine or threonine amino acid. (B) The glycan is typically extended by attachment of galactose to N-acetylgalactosamine by the core 1 β1,3-galactosyltransferase (C1GALT1) enzyme whose activity is stabilized by a molecular chaperone, C1GALT1C1 (also called COSMC). (C, D) Sialic acid (N-acetylneuraminic acid) can be attached to N-acetylgalactosamine, galactose, or both. (E) If sialic acid is attached to N-acetylgalactosamine prior to attachment of galactose, subsequent attachment of galactose is not possible. An imbalance in the activities or expression of specific glycosyltransferases in IgA1-producing cells of patients with IgAN accounts for the increased production of galactose-deficient O-linked glycans in the IgA1 hinge region. Cα denotes constant-region domain on alpha heavy chain; CL, constant-region domain on light chain; VH, variable region on heavy chain; and VL, variable region on light chain. Fab, fragment antigen-binding; Fc, fragment crystallizable region, GalNAc, N-acetylgalactosamine; Gal, galactose; Pro, proline; Val, valine; Ser, serine; Thr, threonine; Cys, cysteine.

Galactose-deficient IgA1 (Gd-IgA1) is thought to originate from cells in mucosal tissues.⁷⁸ Alternately, polymeric IgA1 may be produced in the bone marrow due to altered homing of Gd-IgA1 producing cells.⁷⁹ Patients with IgAN have increased blood levels of Gd-IgA1.⁸⁰ Despite this overabundance of ‘mucosal-type’ IgA in the circulation, biopsies of intestinal mucosal tissues from patients with IgAN contain markedly fewer plasma cells secreting this form of IgA compared with biopsies from healthy volunteers.⁸¹ Patients with IgAN have increased numbers of B-cells in the bone marrow that secrete dimeric IgA, the molecular form of IgA that predominates in mucosal secretions; in contrast, monomeric IgA constitutes the principal form in the circulating blood.⁸² The likely basis for secretion of ‘mucosal-type’ IgA1 into the circulation is a misdirected homing of cells secreting Gd-IgA1 from mucosal to systemic sites, including the bone marrow.^{78, 83}

A high blood level of Gd-IgA1 is not sufficient to induce IgAN.⁸⁰ Many first-degree relatives of patients with IgAN have comparably elevated levels for years without developing any clinical feature of kidney disease.⁸⁴ Current evidence indicates that initiation of kidney injury requires accumulation of immune complexes with Gd-IgA1 bound by an antibody.⁸⁵ Naturally occurring antibodies recognize the Gd-IgA1 hinge-region to form immune complexes in the circulation.^{85, 86} These observations are the basis for the proposed four-hit hypothesis for the pathogenesis of IgAN - increased amounts of circulatory Gd-IgA1 (Hit 1) are recognized as an autoantigen by autoantibodies (mostly of the IgG subclass; Hit 2) to form pathologic immune complexes (Hit 3), some of which deposit in the glomeruli and induce kidney injury (Hit 4) (Figure 3).⁸⁷ Thus, IgAN can be considered an autoimmune process.^{85, 86} The binding of the autoantibody to Gd-IgA1 retards the hepatic catabolism of IgA normally initiated by its binding to the asialoglycoprotein receptors on hepatocytes. The mechanism may be two-fold: 1) the Gd-IgA1-IgG immune complexes are too large to easily pass through the capillary fenestrae to reach the space of Disse to proceed to the receptors where attachment would initiate their hepatic catabolism, and 2) for the Gd-IgA1 that enters the space of Disse, the IgG autoantibody covers or sterically prevents access to the N-acetylgalactosamine or non-sialylated galactose residues. Thus, much of the circulatory Gd-IgA1 eludes the usual IgA catabolic pathway in the liver. In the glomerular capillaries, the fenestrae are larger whereby the immune complexes can enter the neighboring mesangium.⁸⁸ The nephritogenic Gd-IgA1-IgG immune complexes have a predilection for accumulation in the glomerular mesangium.^{89, 90} The presence of the immune complexes induces activation and proliferation of mesangial cells, secretion of pro-inflammatory and pro-fibrotic cytokines, activation of intra-renal renin-angiotensin system, reactive oxygen species and complement cascade, that leads to injury of the podocytes and proximal tubular epithelial cells. The alternative and lectin complement pathways may be activated to induce secretion of additional inflammatory mediators and matrix proteins by mesangial cells.^{30, 91} The consequence is increased glomerular permeability, leading to proteinuria and hematuria, that frequently progresses to widespread scarring to manifest clinically as hypertension and decreased renal function.^{78, 80, 92}

Figure 3. Multi-Hit Hypothesis for Pathogenesis of IgAN.

Increased levels of circulatory galactose-deficient IgA1 (Hit 1) are recognized as an autoantigen by autoantibodies (either IgG or IgA, but mostly of the IgG subclass; Hit 2) that leads to formation of pathologic immune complexes (Hit 3), some of which accumulate in the glomeruli and induce kidney injury (Hit 4).

Routine immunofluorescence microscopy fails to show IgG in 50–80% of kidney biopsies of patients with IgAN.^{93, 94} This apparent absence of IgG raised questions as to the postulated disease-inducing role of Gd-IgA1-IgG immune complexes in IgAN. A recent study found that IgG in IgAN renal immunodeposits is enriched for IgG specific for Gd-IgA1; furthermore, even renal biopsies of IgAN patients without IgG detected by routine immunofluorescence microscopy contained the IgG autoantibody (albeit in lower quantities) and confocal microscopy confirmed the presence and co-localization of IgG and IgA in these biopsy specimens, consistent with the presence of immune complexes.⁹⁵ These findings support the hypothesis that Gd-IgA1-specific IgG autoantibodies play a major role in the pathogenesis of IgAN. Furthermore, serum levels of the IgG autoantibody correlate with the magnitude of proteinuria⁸⁵ and the clinical outcomes of ESKD and death of patients with IgAN.²⁶ Additional studies are needed to discern whether the serum level of this autoantibody will be a suitable biomarker for monitoring disease activity or response to treatment.

Several laboratory findings suggest that IgAN and IgAV-N share disease mechanisms (Table 2). The renal biopsy findings of IgAV-N are indistinguishable from those of IgAN. Serum levels of Gd-IgA1 and IgG autoantibody were significantly higher in patients with IgAN and IgAV-N compared with patients with IgAV without nephritis and healthy controls.⁴⁹ In contrast, the serum Gd-IgA1 levels in the latter two groups were comparable. Investigators have used immortalized IgA secreting cells (created by infecting IgA-secreting cells from peripheral blood with Epstein-Barr virus) to analyze the molecular characteristics of IgA1. These studies showed that the secreted IgA1 for patients with IgAV-N and patients with IgAN had similar degrees of galactose deficiency. In contrast, IgA1 secreted by immortalized cells of patients with IgAV without nephritis was normally galactosylated. Moreover, serum levels of Gd-IgA1-specific IgG were higher in patients with active IgAV-N (manifested by hematuria and substantial proteinuria) compared with those in patients with inactive IgAV-N. This important finding indicates that continuous production of Gd-IgA1 contributes to sustained glomerular injury in IgAV-N.⁴⁹ Finally, IgAV patients without nephritis have small circulating immune complexes containing Gd-IgA1 bound by IgG autoantibody whereas patients with IgAV-N have large immune complexes.⁹⁶ These results suggest that assays to measure serum levels of Gd-IgA1 and the IgG autoantibodies and to determine the size of the circulating immune complexes have the potential to identify which patients with newly manifested IgAV are likely to develop nephritis (Table 2).⁴⁹

SECONDARY IgA NEPHROPATHY

Glomerular IgA with a pattern consistent with IgAN may be found in renal biopsies in patients with many systemic diseases.⁹⁷ Accumulation of glomerular IgA in those patients is often considered to be secondary to the underlying systemic disorder, and the biopsy findings are labeled as secondary IgAN. These pathology findings have been documented in patients with various conditions, ranging from chronic liver disease and inflammatory states to chronic infections and neoplasms (Table 3). Whether secondary IgAN develops through the postulated autoimmune disease mechanisms of primary IgAN remains to be determined. Many patients with secondary IgAN have mesangial hypercellularity and expansion of the matrix. No specific histologic feature on the renal biopsy differentiates primary from secondary IgAN.⁹⁸ Chronic liver disease, especially alcoholic cirrhosis, is the leading cause of secondary IgAN,⁹⁹ and likely arises from glomerular accumulation of IgA1 due to impaired hepatic clearance.⁹⁸ An enzyme-linked immunosorbent assay using a Gd-IgA1-specific monoclonal antibody (KM55) revealed elevated circulatory levels of Gd-IgA1 in IgAN.¹⁰⁰ A Japanese study assessing immunofluorescence microscopy of renal biopsy specimens stained with the KM55 monoclonal antibody showed glomerular deposition of Gd-IgA1 in IgAN and IgAV-N but not in cases of secondary IgAN.¹⁰¹ A United States-based study using the same assay showed glomerular deposition of Gd-IgA1 in both primary and secondary IgAN.¹⁰² This discordance is perhaps due to different sensitivity of the assay in detection of glomerular Gd-IgA1 in Japanese and American patients and subjective differences among pathologists in grading the immunofluorescence intensity. The KM55 monoclonal antibody may also recognize a different glycoform of Gd-IgA1 than did the antibody used in prior assays for measurement of serum Gd-IgA1 in primary and secondary IgAN. Currently, glomerular staining of Gd-IgA1 using KM55 monoclonal antibody is not specific enough to differentiate primary and secondary forms of IgAN.¹⁰²

Table 3.

Systemic Conditions Associated with Secondary IgA Nephropathy

Gastrointestinal and liver disorders Liver disease [alcoholic cirrhosis, nonalcoholic steatohepatitis, Hepatitis C viral infection] Celiac disease Inflammatory bowel disease [Crohn’s disease, Ulcerative colitis]

Viral infections Hepatitis B Hepatitis C HIV Cytomegalovirus

Other infections Chronic mucosal infections [staphylococcus, streptococcus] Chronic infections [staphylococcus] Malaria, schistosomiasis, Lyme disease, Chlamydia pneumoniae

Autoimmune disorders Systemic lupus erythematosus Rheumatoid arthritis Sjogren’s syndrome Ankylosing spondylitis Psoriasis Dermatitis herpetiformis

Respiratory tract abnormalities Pneumonia, chronic obstructive bronchiolitis Cystic fibrosis, idiopathic pulmonary fibrosis

Neoplasms Hodgkin’s lymphoma Non-Hodgkin’s lymphoma Cutaneous T-cell lymphoma IgA myeloma Lung cancer Renal cell carcinoma

GENETIC FACTORS:

While IgAN was considered a sporadic disease in the early years after its initial description, discovery of families with several affected members suggested a role for a genetic predisposition.¹⁰³ The nature and extent of the genetically determined influences are not straightforward. The mode of inheritance in a large multiplex pedigree in eastern Kentucky described in 1985 was autosomal dominant with incomplete penetrance, suggestive of a major dominant gene with a large size effect.¹⁵ However, subsequent studies of patients in other regions in the United States and several countries have discovered multiple genetically determined factors with much smaller size effects.¹⁰⁴ Current estimates are that about 5% of IgAN patients have a relative with biopsy-proven disease, or microscopic hematuria or proteinuria suggestive of IgAN.³

More recently, genome-wide association studies (GWAS) which compare the frequency of genetic variants between cohorts of patients with a specific disease and unaffected persons matched for age, sex, race, and ethnicity have led to the discovery of many more variants in the human genome that influence the disease pathogenesis. These studies are undertaken without any assumed or postulated mechanism of disease. To date, 18 susceptibility segments (loci) of the genome have been identified that modulate the risk for IgAN.^105–107 Blood levels of Gd-IgA1 is a heritable trait. About 75% of IgAN patients and 30–40% of their first-degree relatives have a serum Gd-IgA1 above the 90^th percentile for healthy persons.⁸⁰ GWAS identified variants in 2 genes that encode enzymes important for the O-glycosylation of IgA1 and were associated with higher serum levels of Gd-IgA1.^{108, 109} The C1GALT1 gene encodes the human core 1 β1–3-galactosyltransferase (C1GALT1) enzyme which is required for the addition of galactose to N-acetylgalactosamine in the IgA1 hinge-region glycans. The C1GALT1C1 gene encodes a molecular chaperone, COSMC, that stabilizes the activity of the C1GALT1 enzyme. The variants of both genes decrease the activity of their encoded enzymes. Thus, a lesser amount of galactose would be attached to N-acetylgalactosamine in the IgA1 hinge-region glycans, thereby increasing the synthesis of the Gd-IgA1. The genetic variants of these 2 genes account for about 7% of the variability in serum levels of Gd-IgA1 in Europeans, but only about 2% of the variability in East Asians. Subsequent studies confirmed that levels of messenger RNA for these genes determined the rate of secretion of Gd-IgA1 in immortalized IgA1 producing cells.¹⁰⁸ These findings indicate a genetic influence in the regulation of the synthesis of Gd-IgA1, the autoantigen in IgAN.

GWAS analyses have found that variants of several genes that influence the immune response or antigen presentation associate with IgAN. Among them are 3 loci in the major histocompatibility complex^{105, 110} and the CFH and CFHR genes that encode complement factor H (CFH) and CFH-related (CFHR) proteins, respectively, that are components of the alternative complement pathway.¹⁰⁵ CFH protein is a known inhibitor of complement activation. The CFH and CFHR gene variants are deletions that alter complement activation. Patients with the variant in both genes have a 30% lower risk of IgAN.¹¹¹ Within the other genetic loci associated with IgAN are genes in the histocompatibility complex that encode human leukocyte antigens (HLA), including HLA-B, DRB1, DQA, and DQB¹¹⁰ and genes in non-HLA loci encoding variants of angiotensinogen, angiotensin converting enzyme (ACE), and the angiotensin II type 1 receptor.¹¹² The frequency distribution of the 18 IgAN-associated risk variants correlated with the ethnic differences in the prevalence of the disease, highest in Chinese, mid-range in Caucasians, and lowest in African Blacks.¹¹³ Thus, genetically determined factors may account for some of the geographic and ethnic variance in the prevalence of IgAN.

CLINICAL OUTCOMES

Some patients with IgAN enter a sustained clinical remission with normal renal function, bland urine, and normal proteinuria and blood pressures. Despite this clinical improvement, subsequent renal biopsies generally reveal persistent glomerular IgA deposits.¹¹⁴ However, in a Japanese study of pediatric IgAN patients, those who entered clinical remission (defined as normal renal function and absence of urinary abnormalities) showed improved light microscopy glomerular changes, disappearance or diminution of glomerular IgA deposits, and fewer electron-dense deposits on a follow-up biopsy. In contrast, patients with persistent urinary abnormalities showed progression of glomerular injury on light microscopy and continued presence of glomerular IgA and electron-dense deposits.¹¹⁵

Adverse outcomes, including dialysis or death, have been correlated with the presence of 3 risk factors at the time of renal biopsy: proteinuria ≥ 1 g/day, sustained hypertension, and severity of renal involvement based on the revised Oxford Classification of IgAN (see above section on Pathology).^{34, 35, 116} Proteinuria is a known risk factor for progression of IgAN and ‘time-averaged’ proteinuria (average of quantitative proteinuria measured over defined intervals) after biopsy is a stronger predictor of the rate of decline of renal function than proteinuria at the time of biopsy.^117–119 The rate of IgAN disease progression is very slow amongst patients with time-averaged proteinuria < 500 mg/day and increases incrementally with greater amounts of proteinuria. Each step-wise increase by 1 g/day above 1 g/day is associated with a 10- to 25-fold faster decline of renal function.¹¹⁹ Patients with sustained proteinuria > 1 g/day have a 46-fold higher risk of developing ESKD than those with proteinuria < 0.5 g/day.¹²⁰ Most importantly, clinical outcomes can be significantly improved if time-averaged proteinuria ≤ 1 g/day is maintained with therapeutic interventions.^{119, 121} Several biopsy features associated with poor clinical outcomes in individual studies include the presence of complement components that reflect activation of the lectin pathway,³⁰ C4d,²⁸ or IgG^{93, 94} in the glomeruli, thrombotic microangiopathy,¹²² and increased glomerular circumference.¹²³

The clinical course of IgAN is highly variable, ranging from asymptomatic non-progressive disease to a highly aggressive disease.^{21, 40, 124, 125} Analysis of cohorts from Europe and North America found a frequency of ESKD or halving of eGFR of 27% at 10 years after biopsy diagnosis.³⁸ IgAN also carries a significant mortality risk. In a nationwide cohort study from Sweden that compared patients with IgAN to matched controls in the general population, the patients exhibited a 53% relative increase in mortality. Patients with IgAN, on average, died 6 years earlier than persons without the disease. The excess mortality was limited to patients with IgAN who had progressed to ESKD.¹²⁶ A clinical study examining the outcomes of progression to ESKD and age at death in a cohort of predominantly Caucasian adults with IgAN in the southeastern United States with a long duration of follow-up found that 53% of the patients progressed to ESKD, and 83% of the total deaths occurred after progression to ESKD. Importantly, life expectancy was reduced by 10 years.¹²⁷

TREATMENT

Despite advances in understanding the pathophysiology of IgAN, there is to date no disease-specific treatment. Management of patients with IgAN currently entails generic principal strategies applicable to all chronic glomerular processes - reduction of proteinuria, use of renin-angiotensin blockers, and control of hypertension as outlined in the 2012 Kidney Disease: Improving Global Outcomes (KDIGO) guidelines for management of glomerular diseases.¹²⁸

Patients with minimal disease activity as evidenced by normal blood pressure, normal eGFR, no microscopic hematuria, and urine protein-to-creatinine ratio consistently less than 0.2 g/g do not require treatment. Continued surveillance with long-term follow up, perhaps annually, is recommended to monitor for the development of hematuria, worsening proteinuria, hypertension, and decline in eGFR.

In patients with persistent proteinuria, institution of conservative measures to curtail the rate of renal function decline in IgAN cannot be over-emphasized. A key component of this supportive treatment includes suppression of the renin-angiotensin system (RAS) with an ACE inhibitor or angiotensin II receptor blocker (ARB) for blood pressure control and proteinuria reduction to slow the progression of proteinuric IgAN. Physicians should aim for a target systolic blood pressure (SBP) < 130 mm Hg for patients with ≤ 1 g/day proteinuria, while targeting more stringent control to < 125 mm Hg for those with greater proteinuria. Thus, ACE inhibitors or ARBs should be initiated and titrated to maximal recommended doses to achieve these goals.¹²⁸ The Supportive Versus Immunosuppressive Therapy for the Treatment of Progressive IgA Nephropathy (STOP-IgAN) clinical trial included a 6-month run-in period during which conservative management was optimized prior to randomization. After the run-in phase, 34% of the enrolled patients were excluded from randomization as they had significant reduction in proteinuria, to values below 0.75 g/day, and no longer met the inclusion criterion for proteinuria.¹²⁹ Although dual RAS blockade by combining an ACE inhibitor with an ARB may significantly reduce proteinuria, long-term renal benefits are less certain, and the safety of this combination has been questioned, especially pertaining to higher risk for hyperkalemia.¹³⁰ Studies have examined reduction of proteinuria in IgAN by using statins¹³¹ and weight loss in the setting of obesity.¹³² Obesity is independently associated with glomerular hyperfiltration and renal cellular injury, and weight loss mitigated obesity-induced renal damage.¹³³ A low-protein diet (0.8 g protein/kg body weight per day), salt restriction, and treating all components of the metabolic syndrome are also advocated. Given the association between smoking and IgAN disease progression, smoking cessation should be actively promoted.¹³⁴ Adequate measures to correct any underlying metabolic acidosis with an oral alkali supplement and reduction in dietary acid intake should be done, as chronic metabolic acidosis accelerates eGFR decline in chronic kidney disease and increases the risk of progression to ESKD.¹³⁵ The role of treatment with fish oil with a high content of omega-3 fatty acids is less clear. A meta-analysis examining the use of fish oil in IgAN reported no clinical benefit in terms of preserving renal function, but treatment ameliorated proteinuria which was not dose-dependent.¹³⁶

In patients with persistent proteinuria or worsening kidney function despite supportive treatment, various immunosuppressive regimens have been explored. Despite several clinical studies supporting the use of corticosteroids to reduce proteinuria in IgAN,^{137, 138} recent trials have questioned the benefits for most patients due to associated serious adverse effects, especially infections.^{129, 139} The STOP-IgAN trial randomized IgAN patients to supportive treatment or to corticosteroid therapy as monotherapy or in conjunction with sequential cyclophosphamide and azathioprine based on eGFR at enrollment. The primary endpoint at 3 years was complete clinical remission or a decrease in eGFR > 15 ml/min per 1.73 m². Eligible candidates had proteinuria between 0.75 and 3.5 g/day and eGFR > 30 ml/min per 1.73 m². Patients with eGFR > 60 ml/min per 1.73 m² received corticosteroid monotherapy for 6 months, and patients with eGFR 30–59 ml/min per 1.73 m² received cyclophosphamide followed by azathioprine and oral prednisolone tapered over 36 months. In the supportive care group, 5% of patients had full clinical remission versus 17% in the immunosuppression group (P = 0.01); however, no difference between the two groups was found for a decrease of eGFR > 15 mL/min per 1.73 m² at the end of 3 years (28% versus 26%, respectively). The immunosuppression group had more infections, including 1 sepsis-related death, and significant weight gain and impaired glucose tolerance. Proteinuria reduction was mainly in the corticosteroid group.¹²⁹ Another trial, the Therapeutic Evaluation of Steroids on IgA Nephropathy Global (TESTING) study, was a multicenter, double-blind, randomized controlled clinical trial for patients with IgAN and proteinuria > 1 g/day despite 3 months of optimized RAS inhibitors supportive care, and eGFR 20 to 120 ml/min per 1.73 m². Patients were randomized to 6 months of oral corticosteroids or placebo. This study was terminated early after an interim analysis revealed higher risk of death with treatment: 2 fatalities (including fatal Pneumocystis pneumonia) in the corticosteroid group versus none in the placebo group. Although the study was not completed, there was an apparent benefit of corticosteroids with a significant reduction in the risk of a 40% drop in eGFR or ESKD.¹³⁹ The trajectory of renal function decline in the control group was 4 times faster in the TESTING trial compared to that in the STOP-IgAN trial, suggesting a higher-risk study population and/or disparities in supportive therapy. In the TESTING study, the favorable effect of corticosteroids was similar in patients with eGFR below or above 50 ml/min per 1.73 m². This data is consistent with results from other clinical trials which showed benefit from immunosuppression even at lower eGFR but with increased rates of adverse events.^{140, 141} In the selection of corticosteroids for the treatment of IgAN, renal benefits must be weighed against the risk for serious adverse events.

Relatively few patients with IgAN merit consideration for intensive immunosuppression. The data for the management of crescentic IgAN is limited; however, KDIGO guidelines recommend the use of steroids combined with cyclophosphamide for those with rapidly declining renal function. The guidelines defined crescentic disease as having > 50% crescents on biopsy. These patients, if untreated, often rapidly progress to ESKD. Early clinical response has a favorable prognosis, as in other types of crescentic nephritis. Unfortunately, the medium-term results are disappointing and renal survival at 5 years is estimated to be 30% and not different in immunosuppressed and non-immunosuppressed patients.¹⁴² The largest series supporting the use of alkylating agents is an open-label trial of 20 patients with at least 10% crescents or endocapillary proliferation on biopsy who were treated with pulse solumedrol and intravenous cyclophosphamide. Compared with historical controls, treated patients had lower peak serum creatinine, less proteinuria, and slower decline in renal function that reduced the frequency of ESKD at 36 months.¹⁴³ Mycophenolate mofetil is an immunosuppressant that is widely used for solid-organ transplant patients; it is metabolized to mycophenolic acid to promote apoptosis of cytotoxic T-lymphocytes and reduction of antibody synthesis by selective inhibition of T- and B-lymphocyte proliferation.¹⁴⁴ The indication for including mycophenolate in the treatment of primary IgAN remains uncertain. A meta-analysis of 8 studies suggested that mycophenolate monotherapy had greater efficacy but more adverse effects when compared to placebo or corticosteroid monotherapy in treatment of Asians with IgAN. Mycophenolate combined with corticosteroids had greater efficacy and fewer side effects when compared with corticosteroid plus cyclophosphamide.¹⁴⁵ However, mycophenolate failed to improve renal function or reduce proteinuria in Caucasian IgAN patients.^{146, 147} This discordance in the data in Asian and Caucasian IgAN patients may be secondary to genetic influences on the pathogenesis of the disease. Rituximab is a chimeric monoclonal antibody specific for CD20, a protein primarily on the surface of B cells of the immune system that secrete antibodies. Treatment with rituximab is beneficial for patients with membranous nephropathy,¹⁴⁸ another autoimmune disease due to overproduction of an antibody that binds to a protein in the glomerular basement membranes. However, rituximab treatment of IgAN patients did not reduce serum anti-Gd-IgA1, autoantibody levels, or proteinuria and did not slow the decline in renal clearance function.¹⁴⁹

The immune cells responsible for Gd-IgA1 production originate in the mucosal-associated lymphoid tissue, of which the tonsils are a key component.¹⁵⁰ Given the fact that macroscopic hematuria is frequently observed after concurrent upper respiratory tract infections in IgAN, a relationship between tonsillar infection and IgAN has been suggested. The proposed rationale for tonsillectomy is to decrease plasma cells producing nephritogenic IgA1 in the tonsils and to prevent the cells from transferring to the bone marrow.¹⁵¹ Tonsillectomy has been included as standard treatment in Japan for patients with IgAN, generally coupled with corticosteroids. A nationwide survey conducted in Japan in 2008 involving pediatric and adult IgAN patients, who were already on RAS inhibitors, suggested that clinical remission rates for hematuria and proteinuria after combined tonsillectomy and pulse corticosteroid therapy tended to be higher than those following other combinational corticosteroid regimens.¹⁵² A multicenter randomized controlled clinical trial with 72 adult IgAN patients in Japan reported that proteinuria decreased in the group that received tonsillectomy with corticosteroid pulse therapy compared to those who received corticosteroid pulse monotherapy. However, the frequency of the disappearance of proteinuria, hematuria, or both (clinical remission) at 12 months did not differ between the groups.¹⁵³ Of note, tonsillectomy has not been associated with slower progression of IgAN in Caucasians of European ancestry.¹⁵⁴ The European Validation Study of the Oxford Classification of IgAN (VALIGA) collected data from 1,147 European patients with IgAN over 4.7 years. Using a propensity scoring system in logistic regression models, 41 patients with tonsillectomy were compared with 41 patients without tonsillectomy with similar conventional clinical risk factors for IgAN progression. The two groups did not differ in progression to ESKD, 50% loss of eGFR, or annual loss of eGFR. Thus, in this large European cohort, there was no benefit of tonsillectomy for preservation of renal function.¹⁵⁵ Tonsillectomy is not standard practice in the management of IgAN outside of Japan.

There are many new approaches being evaluated in the management of IgAN (Table 4). A targeted-release formulation of oral budesonide is designed to deliver the corticosteroid to the distal ileum, a principal site of mucosal B-cell in the mucosal-associated lymphoid tissue and a potential source of Gd-IgA1-secreting cells that accumulate in the bone marrow through an error in the homing mechanism. Thus, oral budesonide treatment may decrease the number of cells in the bone marrow that release Gd-IgA1 into the circulation.^{156, 157} The Targeted-Release Budesonide Versus Placebo in Patients with IgAN (NEFIGAN) trial compared this targeted-release formulation of budesonide with placebo in a phase II randomized, controlled, double-blind clinical trial.¹⁵⁷ All patients had persistent proteinuria, defined by a urine protein-to-creatinine ratio > 0.5 g/g or proteinuria at least 0.75 g/day, despite optimal RAS blockade. The trial consisted of a 6-month run-in, 9-month treatment phase, and 3 months of follow up. Two doses of budesonide (16 mg/day; 8 mg/day) were compared to placebo. The primary endpoint was mean change in proteinuria at the end of treatment; the secondary endpoint was change in eGFR. Mean urine protein-to-creatinine ratio was reduced by an average of 24% in the combined treatment arms but increased by 2.7% in placebo arm (P = 0.006). eGFR did not change in both treatment arms but decreased by 9.8% with placebo (P = 0.001). No serious adverse event, including infection, occurred in the treatment arm.¹⁵⁷ Given these promising results, a global ongoing phase III trial, NefIgArd, was initiated in September 2018 to evaluate the efficacy, safety, and tolerability of the targeted-release enteric formulation of oral budesonide (16 mg/day).¹⁵⁸ Hydroxychloroquine is postulated to have pleiotropic immunomodulatory action^{159, 160} and preliminary studies showed a decrease in proteinuria in patients with IgAN. This benefit likely results from inhibition of mucosal and intra-renal Toll-like receptor signaling to reduce intra-renal inflammation and potentially decrease Gd-IgA1 synthesis. In a study of Chinese IgAN patients with proteinuria > 0.75 g/day and baseline eGFR > 30 ml/min per 1.73 m², hydroxychloroquine combined with maximal tolerated doses of either an ACE inhibitor or ARB for at least 6 months significantly decreased proteinuria without a change in eGFR or significant adverse effects.^{161, 162}

Table 4.

Novel Therapies for Treatment of Primary IgA Nephropathy

Agent	Mechanism of action	Potential target(s) in four-hit hypothesis of disease pathogenesis	Clinical trial design	Clinical Outcomes (reported/being investigated)
TRF Budesonide	Corticosteroid formulation acts on distal ileum targeting B-cells in mucosal lymphoid tissue	Hit 1	Randomized, double-blind, placebo-controlled Phase II clinical trial – completed *NCT01738035 Phase III clinical trial – recruiting *NCT03643965	Reduction in proteinuria No change in eGFR
Hydroxychloroquine	Immunomodulator, inhibits mucosal and intrarenal Toll-like receptor signaling	Hit 1	Randomized, double-blind, placebo-controlled Phase II clinical trial – completed *NCT02942381	Reduction in proteinuria No change in eGFR
Acthar©	Purified form of ACTH that has corticosteroid like effects targeting B- cells; binds to MC1R in kidney cells	Hit 1, Hit 4	Open-label Phase III clinical trial – completed *NCT02282930	Reduction in proteinuria Increase in serum albumin No change in eGFR
Bortezomib	Semi-selective plasma cell proteasome inhibitor	Hit 1, Hit 2	Open-label Phase IV clinical trial – completed *NCT01103778	Reduction in proteinuria only in patients with T0 MEST-C score
Fostamatinib	Oral spleen tyrosine kinase inhibitor	Hit 4	Randomized, double-blind, placebo-controlled Phase II clinical trial – completed *NCT02112838	Non-significant reduction in proteinuria No change in eGFR
Avacopan	C5a receptor blocker	Hit 4	Open-label Phase II clinical trial – completed *NCT02384317	Reduction in proteinuria
Atacicept	Blocks downstream effects of BAFF and APRIL	Hit 1	Randomized, double-blind, placebo-controlled Phase II clinical trial – completed *NCT02808429	Dose-dependent reduction in proteinuria Dose-dependent reduction in immunoglobulin (particularly Gd-IgA1) levels No change in eGFR
Blisibimod	Selective BAFF antagonist	Hit 1	Randomized, double-blind, placebo-controlled Phase II/III clinical trial – completed *NCT02062684	Effect on proteinuria - data analysis pending Time frame: 24 weeks
VIS649	Monoclonal antibody against APRIL	Hit 1	Randomized, double-blind, placebo-controlled Phase II clinical trial – recruiting *NCT04287985	Effect on proteinuria Adverse events Time frame: 12 months
Sparsentan	Selective antagonist of angiotensin II receptor and endothelin A receptor	Hit 4	Randomized, double-blind, parallel-group, active-control Phase III clinical trial – recruiting *NCT03762850	Effect on proteinuria Time frame: 36 weeks
Cemdisiran	Small-interfering RNA inhibits synthesis of C5	Hit 4	Randomized, double-blind, placebo-controlled Phase II clinical trial – recruiting *NCT03841448	Effect on proteinuria Time frame: 32 weeks
LNP023	Oral inhibitor of complement factor B	Hit 4	Randomized, double blind, placebo-controlled Phase II clinical trial – recruiting *NCT03373461	Effect on proteinuria Time frame: 90 days
IONIS-FB-LRx	Anti-sense inhibitor of complement factor B	Hit 4	Open-Label Phase II clinical trial – recruiting *NCT04014335	Effect on proteinuria Time frame: 29 weeks
APL-2	Peptide inhibitor of C3	Hit 4	Open-Label Phase II clinical trial - active; not currently recruiting *NCT03453619	Effect on proteinuria Time frame: 48 weeks
Narsoplimab (OMS721)	Monoclonal antibody against MASP-2	Hit 4	Randomized, double-blind, placebo-controlled Phase III clinical trial – recruiting *NCT03608033	Effect on proteinuria Time frame: 36 weeks
RC18	Recombinant human B cell stimulator receptor-antibody fusion protein	Hit 1	Randomized, double-blind, placebo-controlled Phase II clinical trial - recruiting *NCT04291781	Effect on proteinuria Time frame: 24 weeks
AVB-S6–500	Recombinant fusion protein against GAS6 protein expressed in podocytes, endothelial and mesangial cells	Hit 4	Open-Label Phase II clinical trial – recruiting *NCT04042623	Effect on proteinuria Adverse events Time frame: 14 weeks
Fecal microbiota transplantation	Restoration of intestinal microecological balance	Hit 1	Open-Label Phase II clinical trial – recruiting *NCT03633864	Effect on proteinuria Time frame: 8 weeks

TRF: Targeted Release Formulation; eGFR: estimated glomerular filtration rate; ACTH: Adrenocorticotrophic hormone; MC1R: Melanocortin 1 receptor; BAFF: B-cell Activating Factor; APRIL: A PRoliferation-Inducing Ligand; Gd-IgA1, Galactose-deficient IgA1; RNA: Ribonucleic acid; MASP-2, Mannan-binding lectin-associated serine protease-2; GAS6, Growth-arrest specific 6

^*shows ClinicalTrials.gov Identifier

Other novel agents are being tested in clinical trials targeting IgAN patients with persistent proteinuria despite maximal RAS blockade. Acthar® is a purified form of adrenocorticotrophic hormone (ACTH) and thought to exert its reno-protective effects via corticosteroid-dependent and -independent mechanisms. The latter may be mediated by its binding to the melanocortin 1 receptor (MC1R) which is found on the surface of numerous kidney cells, including glomerular endothelial cells, mesangial cells, podocytes, and tubular epithelial cells. MCR 1 agonists reduce proteinuria and have in vitro renoprotective effects in animal models.^{163, 164} A phase III, multicenter, open-label, clinical trial assessed the effect of Acthar® in 19 IgAN patients with proteinuria > 1 g/day despite maximal tolerated doses of either an ACE inhibitor or ARB for at least 3 months and baseline eGFR > 30 ml/min per 1.73 m². At 12 months, 24-hour urinary protein declined from 2.6 to 1.3 g (P = 0.007) and serum albumin increased (3.79 to 3.93 mg/dl, P = 0.02). There was no significant change in eGFR (65.5 versus 61.1 ml/min per 1.73 m²) or major adverse event.¹⁶⁵ B lymphocytes after maturation in the bone marrow enter peripheral lymphoid tissues where they interact with antigens. This process leads to specific B cell proliferation resulting in clonal expansion and differentiation to either plasma cells actively secreting antibodies or to memory cells. Given the pivotal role of B cells in the Hits 1 and 2 of the proposed pathogenesis of IgAN, there is significant interest in therapies inhibiting B cell function, proliferation, or activation. Bortezomib is a semi-selective inhibitor of proteasomes in plasma cells and is currently used for treatment of multiple myeloma.¹⁶⁶ A single-center open-label, non-randomized clinical trial tested the effect of intravenous bortezomib in 8 patients with IgAN who had proteinuria > 1g/day (median baseline proteinuria 2.46 g/day) and GFR > 30 ml/min (24-hour urinary creatinine clearance) and were on a stable dose of RAS inhibitors for a minimum of 30 days prior to enrollment. Renal function and change in proteinuria were followed for 1 year. The primary endpoint was complete remission, defined as proteinuria < 300 mg/day. All patients tolerated treatment. After 1 year, 3 subjects (38%) had achieved the primary endpoint and had Oxford Classification T score of 0 and normal baseline renal function prior to enrollment. Subjects who failed to respond to bortezomib had higher Oxford Classification T scores.¹⁶⁷ B cell-activating factor (BAFF) and a proliferation-inducing ligand (APRIL) are inflammatory mediators that are secreted by intestinal epithelial cells, dendritic cells and local stromal cells which induce T cell-independent production of IgA locally.¹⁶⁸ Atacicept blocks the downstream effects of BAFF and APRIL. A phase II trial involving 16 patients with IgAN and proteinuria ≥ 1 g/day or ≥ 0.75 mg/mg on 24-hour urine protein-creatinine ratio despite maximal tolerated doses of either an ACE inhibitor or ARB were randomized 1:1:1 to receive placebo or atacicept 25mg or 75mg once weekly by subcutaneous injection. After 24 weeks, a consistent, dose-dependent reduction in serum immunoglobulins (IgA, IgG, and IgM), particularly Gd-IgA1, were reported. There was a dose-dependent % reduction in proteinuria from baseline with atacicept: −18.67% and −25.34% with atacicept 25 mg and 75 mg, respectively, versus +0.098% with placebo. eGFR remained stable over time, and the medication was well tolerated.¹⁶⁹ Blisibimod is a selective BAFF antagonist that is currently being evaluated for the management of IgAN.¹⁷⁰ There also is recent interest in several agents that reduce the accumulation of disease-inducing Gd-IgA1-IgG immune complexes in the glomeruli or dampen the inflammatory responses to the complexes that are deposited. Fostamatinib (an oral spleen tyrosine kinase inhibitor) has the potential ability to inhibit the accumulation of nephritogenic immune complexes in the glomerulus. A phase II clinical trial enrolled patients with recently diagnosed IgAN who had mesangial and/or endocapillary hypercellularity on renal biopsy, eGFR > 30 ml/min per 1.72 m², and urine protein-to-creatinine ratio > 0.442 g/g (> 50 mg/mmol), and had received maximal tolerated dose of ACE inhibitor or ARB for ≥ 12 weeks. Patients were randomized to receive oral placebo, fostamatinib 100 mg twice daily, or fostamatinib 150 mg twice daily.¹⁷¹ Neither dose of fostamatinib significantly reduced proteinuria and eGFR did not change.¹⁷²

Improved understanding of the role of the alternative and lectin pathways of complement activation in the pathophysiology of IgAN has identified new potential treatment strategies. Activation of C3 convertase leads to the cleavage of C5 to generate C5a which is a potent local inflammatory mediator and whose presence in the kidney correlates with histological severity and proteinuria in IgAN.¹⁷³ Targeting C5a can suppress local inflammation which contributes to progressive renal disease, while retaining the formation of the C5b-9 (membrane attack complex) which plays a pivotal role in the response to infections with Gram-negative bacteria. Avacopan (CCX168), a C5a receptor blocker, was evaluated in a phase II trial with 7 patients with IgAN.¹⁷⁴ At the end of 12 weeks, proteinuria decreased in 6 patients and urinary protein-to-creatinine ratio decreased to < 1.0 g/g in 3 patients.¹⁷⁵ Another approach to decrease the effect of C5 is to slow its synthesis with cemdisiran, a small interfering RNA that prevents the translation of the messenger RNA into protein; this agent is currently being evaluated in a phase II clinical trial in adults with IgAN.¹⁷⁶ Narsoplimab (OMS721) is a humanized monoclonal antibody selectively targeting mannan-binding lectin-associated serine protease-2 (MASP-2), a key effector enzyme essential for activation of the lectin pathway of the complement. In functional assays, it has no demonstrable effect on the classical or alternative complement pathways. In a phase II, multicenter, clinical trial, patients with proteinuria > 1g/day despite maximal tolerated doses of either an ACE inhibitor or ARB and baseline eGFR > 30 ml/min per 1.73 m² were enrolled into 2 substudies based on whether they were corticosteroid-dependent or -independent at baseline. Interim analysis of both groups revealed the drug was safe, well-tolerated, and reduced proteinuria with stability of eGFR.¹⁷⁷ Based on this preliminary data, a randomized, double-blind, placebo-controlled, phase III clinical trial (ARTEMIS-IGAN) is underway.¹⁷⁸ Endothelin-1 (ET-1) has been implicated in podocyte damage, proteinuria, fibrosis, and progression of chronic kidney disease primarily through activation of endothelin A receptors. The PROTECT trial is an ongoing, randomized phase III clinical trial evaluating sparsentan, an oral selective antagonist of the angiotensin II receptor and the endothelin A receptor, for treatment of IgAN.^{179, 180}

IgAV-N in children was initially considered a benign, self-limited, disease with spontaneous recovery of renal function for which only supportive therapy was necessary. However, after long-term studies showed development of chronic kidney disease in some children^{61, 63} and ESKD by 15 years after diagnosis in 10–30% of adult patients,⁶⁴ management of IgAV-N patients has been reconsidered. Unfortunately, there is a scarcity of randomized controlled clinical trials for the treatment of IgAV-N. The 2012 KDIGO guidelines state that children with proteinuria ≥ 0.5 g/day per 1.73 m² should be treated with an ACE inhibitor or ARB for 3–6 months. Corticosteroid therapy is to be added to those with proteinuria continuing above this threshold. Mycophenolate can induce and maintain remission in IgAV-N and may be used as a corticosteroid-sparing agent in the management of these patients.¹⁸¹ More aggressive treatment, including corticosteroids plus cyclophosphamide, is reserved for patients with crescents in > 50% of glomeruli on biopsy and rapid deterioration of renal clearance function. Plasma exchange sessions can be added when serum creatinine rises acutely to > 5.65 mg/dl.¹⁸²

For IgAN and IgAV-N patients needing renal replacement therapy, transplantation is the modality of choice. Unfortunately, IgAN frequently recurs in the allograft; in some patients, glomerular IgA deposits have been documented within weeks after engraftment.⁶⁸ The recurrence rate is about 50% at 10 years but only about 5% of recipients progress to ESKD as a consequence.⁷ Recurrence of IgAN is more prevalent in children, especially in those with crescentic disease and rapid loss of renal function prior to engraftment.^{183, 184} Induction immunosuppressive therapy with anti-thymocyte globulin and inclusion of corticosteroids for maintenance immunosuppression reduces the frequency of recurrent IgAN.^{185, 186} In patients with IgAV-N, recurrence of glomerular IgA deposits in renal allografts is very frequent but generally does not adversely affect the rate of allograft loss during the first 5 years.¹⁸⁷ However, by 10 years after engraftment, the risk of allograft loss due to recurrent disease is significant, about 7–8% in one study (Table 2).¹⁸⁸ In contrast, the recurrence of extra renal manifestations of IgAV post-transplant is rare. There is no formal guideline for the management of patients with IgAN or IgAV-N with glomerular IgA in the transplanted kidney, but RAS blockade to reduce proteinuria and implementation of other practices recommended for the management of native-kidney disease seem prudent.¹⁸⁹ Treatment of patients with secondary IgAN should be targeted toward the primary underlying condition.⁹⁷ The use with immunosuppressants is generally not indicated.¹⁹⁰

CONCLUSIONS

IgAN is the most common primary glomerular disease in the world and an important cause of kidney failure. IgAN should be suspected in young patients with a history of macroscopic hematuria, especially if concurrent with a febrile illness, or with asymptomatic hematuria and/or proteinuria. The basis of the disease is considered to be autoimmune, resulting from formation of circulating immune complexes comprised of Gd-IgA1 bound primarily to IgG autoantibody. The immune complexes ultimately accumulate in the glomerular mesangial areas, leading to inflammation and frequently progressive scarring with consequential loss of kidney clearance function. IgAN disproportionately affects children and young adults and is associated with significant morbidity with up to 40% of patients reaching ESKD by 20 years after diagnosis. There is currently no disease-specific treatment. With a better understanding of the pathogenesis, new disease-targeted therapies are being evaluated. Further advances in identifying novel biomarkers will allow early diagnosis and better monitoring of disease activity and response to treatment.