IgA Nephropathy (Berger’s Disease)

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Introduction   

Immunoglobulin A nephropathy (IgAN), also known as Berger disease, is a major contributor to glomerulonephritis and kidney failure [1][2]. The exact cause of IgAN remains unclear, but may result from an abnormal immune response involving glycosylated 

deposits in the glomerular mesangium that trigger immune-mediated injury to the basement membrane, causing hematuria, proteinuria, and impaired kidney function [1]. First described by Berger and Hinglais in 1968, pathological findings include mesangial proliferation with prominent IgA deposition [2]. The clinical course of the disease has a gradual progression with 20% and 50% of clients developing end-stage renal disease within 20 years of diagnosis [3]. Prevalence varies by ethnicity, race, geography, and genetics, with higher rates among Asian clients than non-Asians and higher in males than females [4]. Early recognition and management are essential to slow disease progression and preserve kidney function. 

Case Study 

A 35-year-old man presented to the emergency department with a two-day history of sore throat, difficulty swallowing, fever, and pink, cloudy urine. The client reported breathlessness with a cough, fatigue, and discomfort in his right ankle over the past 36 hours. He denied pain during urination and had no changes in urinary frequency. 

His medical history was significant for chronic kidney disease (CKD) stage 5 due to IgA nephropathy, for which he was on regular hemodialysis. He also had a seizure disorder and had been managing hypertension for seven years. The client had experienced three previous episodes of glomerulonephritis at ages 16, 22, and 29, each following episodes of pharyngitis. He was a non-smoker, consumed alcohol (about four glasses of wine per week), and had no family history of renal disease. 

Physical Examination  

On physical examination, the client appears pale and febrile with a temperature of 38.5°C (101.3°F). Vital signs revealed tachycardia with a heart rate of 144 bpm, accelerated hypertension with a blood pressure of 200/120 mmHg, and an oxygen saturation of 84% on room air, improving to 95% with oxygen administration. Examination of the throat showed inflammation and enlarged tonsils. Respiratory assessment revealed bilateral basal crepitations. There were no rashes, cyanosis, or splinter hemorrhages. 

Laboratory Findings 

Laboratory investigations showed severe anemia with a hemoglobin level of 4.9 g/dL, an elevated white blood cell count of 23.7 × 10⁹/L, and a platelet count of 178 × 10⁹/L. Blood chemistry results included sodium at 134 mmol/L, potassium at 3.7 mmol/L, urea at 7.3 mmol/L, and creatinine at 167 µmol/L. Urinalysis indicated more than 100 red blood cells per high-power field and ++ proteinuria. A peripheral smear revealed early macrocytic anemia with relative neutrophilia.  

Imaging Studies 

The hospital team conducted imaging studies to further assess his condition. High-resolution CT of the chest showed extensive patchy areas of ground-glass opacities and air-space consolidation in the bilateral lung parenchyma (more pronounced on the left side), suggesting pneumonitis. A 2D echocardiogram indicated tachycardia without definitive regional wall motion abnormalities and a left ventricular ejection fraction of 55%. An ultrasound of the kidneys showed normal size and cortical thickness with no hydronephrosis, and the bladder appeared normal. A plain abdominal X-ray revealed no renal tract calcifications. 

Consultations 

The team consulted a nephrologist due to the client’s complex renal history and current presentation. They considered post-streptococcal glomerulonephritis and explored other potential diagnoses. The nephrologist recommended measuring fibrinogen levels and prothrombin time and suggested changing the antibiotic regimen to benzylpenicillin. The team admitted the client to the intensive care unit to manage accelerated hypertension and respiratory distress. 

Interventions 

The admission team transfused three units of packed red blood cells and initiated dialysis. They corrected the Vitamin B12 deficiency and started intravenous antibiotics, antacids, nebulization, and oxygen therapy. The team provided supportive care throughout the hospital stay and continued dialysis as a life-saving measure. 

The team performed a renal biopsy to clarify the diagnosis. Histological examination showed normal renal medulla and cortex on light microscopy. However, immunohistochemical analysis revealed significant mesangial deposits of immunoglobulin A (IgA) within the glomeruli, confirming the diagnosis of IgA nephropathy. During his hospitalization, the client’s symptoms improved. The medical team controlled his blood pressure, stabilized his respiratory function, and maintained his hemodynamic stability. Upon discharge, the team advised him to manage his chronic conditions by controlling his blood pressure, adhering to his hemodialysis schedule, managing his seizures, and monitoring for any recurrent symptoms. He arranged follow-up appointments with nephrology and primary care to ensure continuity of care. 

Case Study Questions: 

• What might be the connection between the client’s recurrent episodes of glomerulonephritis following pharyngitis and his current presentation? 

• How could we explain the severe anemia observed in the client in the context of his chronic kidney disease and current symptoms? 

• Why is the discovery of mesangial IgA deposits in the renal biopsy significant for understanding his renal condition? 

• In what ways might the client’s respiratory symptoms and imaging findings be related to his underlying renal disease? 

Etiology 

IgA nephropathy (IgAN) results from abnormal immune reactions that lead to the deposition of immunoglobulin A (IgA) within the glomeruli, increased podocyte permeability, and interstitial fibrosis [1]. Although infectious diseases often precede IgAN and trigger a dysregulated immune response, IgAN does not result from a specific infectious agent [5]. Instead, various clinical and subclinical triggers, along with genetic factors related to IgA glycosylation, activate the immune system [6]. Potential etiologies of IgAN include both familial and sporadic forms [7]. Familial IgAN accounts for fewer than 10% of cases and involves at least 18 different gene segments, such as C1GALT1 and C1GALT1C1 [8]. Sporadic or idiopathic IgAN represents more than 90% of cases [9].  

Despite the association between macroscopic hematuria and mucosal inflammation, no evidence suggests the involvement of a particular infectious agent or hypersensitivity to food antigens, except in a small group of clients with celiac disease [1]. When IgA1 antibodies have abnormal sugar attachments in a specific area, they tend to form clusters with other antibodies in the blood. These clusters activate certain cells in the kidneys called mesangial cells, leading to the buildup of these immune complexes in the kidney tissue [10]. Various systemic conditions contribute to the accumulation of IgA deposits, driving the pathology of IgA nephropathy (IgAN) [11]. 

Recent reports indicate that the pathways leading to glomerular injury are similar between primary and secondary IgAN [1]. Secondary IgAN may arise from liver, gastrointestinal, autoimmune, dermatological, infectious, and drug-related causes [1]. Differentiating primary from secondary IgAN is crucial, as secondary forms focus on addressing the underlying cause rather than using immunosuppressive agents [12]. 

Mucosal-associated lymphoid tissue (MALT) plays a key role in understanding the pathology of IgA nephropathy, as mucosal tissues produce IgA [13]. MALT provides defense against environmental toxins and microbes and is located in the gut, noted in Peyer’s patches and lymphoid follicles, as well as in the tonsils—sites implicated in IgAN pathogenesis [13]. 

Gastrointestinal disorders have distinct implications for IgAN [14]. Liver disease is the most common cause of secondary IgAN due to compromised clearance of large IgA complexes [15]. Conditions like cirrhosis are associated with IgAN, with some case reports showing improvement in renal parameters with steroid treatment [15]. Other liver disorders linked to IgAN include hemochromatosis, Wilson disease, and autoimmune hepatitis [16].  

In celiac disease, an enzyme known as transglutaminase 2 activates immune cells called B cells. This activation leads to the production of IgG and IgA antibodies. IgA1 antibodies can accumulate in the kidney’s filtering units (the mesangium), causing IgA to deposit, leading to IgA [17]. For clients with IgAN presenting gastrointestinal symptoms, a trial of a gluten-free diet and further diagnostic workup may be reasonable [17]. 

Inflammatory bowel disease (IBD), including Crohn disease and ulcerative colitis, poses a risk factor for IgAN and is associated with mortality in both conditions [18]. A common pathogenesis may involve B-cell immunoglobulin over secretion and CD4+ T-cell dysregulation [1][20]. Abnormal intestinal microbiota, characterized by reduced diversity in genera like Clostridium, Enterococcus, and Lactobacillus, are also associated with IgAN, leading some researchers to propose probiotics as a potential therapeutic measure [19]. 

Autoimmune disorders, including Sjögren syndrome, spondyloarthritis, systemic lupus erythematosus, and Behçet disease all link to the development of IgA nephropathy (IgAN) [1][21]. Dermatological conditions such as psoriasis (the most common skin condition related to IgAN), dystrophic epidermolysis bullosa, juvenile dermatomyositis, and leukocytoclastic vasculitis also show associations with IgAN [1][22]. Leukocytoclastic vasculitis, a rare type III allergic reaction causing immune-complex-mediated vasculitis in small dermal blood vessels, can lead to renal involvement with IgA deposits, resulting in secondary IgAN [23]. 

Infectious diseases often precede clinical symptoms of IgAN, such as gross hematuria— following upper respiratory tract infections—a phenomenon known as synpharyngitic hematuria [24]. Associated beneficial (commensal) organisms including Haemophilus parainfluenzae, Prevotella, Fusobacterium, Sphingomonas, and Treponema species contribute to tonsillar inflammation [24]. Viral infections caused by COVID-19, HIV, and hepatitis B are also associated with IgAN [24] [25]. 

Drug-induced IgAN involves correlating renal injury timing with medication administration and excluding other causes [26]. Tumor necrosis factor-α (TNF-α) inhibitors, such as adalimumab and infliximab are associated with IgAN due to their immunomodulatory effects [27]. Other medications linked to secondary IgAN include interleukin-12 and -23 inhibitors, immune checkpoint inhibitors, direct oral anticoagulants, warfarin, and thioureylene derivatives used for Graves’ disease [22][28]. 

Additional causes, although uncommon, include primary pulmonary diseases like sarcoidosis, idiopathic pulmonary fibrosis, or pulmonary hemorrhage [1][29]. Oncological conditions, including myeloproliferative disorders, gastric cancer, lung tumors, renal cell carcinoma, and various other malignancies, can contribute to IgA deposition, which may result in the development of IgA nephropathy (IgAN) [30].  

Epidemiology 

Immunoglobulin A nephropathy (IgAN) represents the most frequent cause of glomerulonephritis, but its true prevalence remains unclear due to the often asymptomatic nature of the disease and the need for a renal biopsy to confirm diagnosis, a procedure that not all clients receive [1]. Some individuals opt for conservative management if they exhibit a benign form of the disease, and therefore may not have a biopsy to confirm IgAN [1][31]. In the United States, IgAN accounts for 10% of renal biopsies [1][32]. The prevalence is higher in East Asia, where up to 40% of biopsies reveal IgAN, and in Europe, where it accounts for 20% to 30% of biopsies [1][33].  

A systematic analysis of biopsy-based studies from multiple countries indicates an overall incidence of more than 2.5 cases per 100,000 people [1]. Research suggests that East Asian clients diagnosed with IgAN have a higher likelihood of progressing to end-stage renal disease (ESRD) compared to non-Asian clients [33]. Within the United States, IgA nephropathy is more common in White populations than in Black individuals [1]. The disease often presents in children and young adults, with the highest occurrence during the second and third decades of life [1]. There is a male predominance with a ratio of about 2.5:1 in the United States and Europe, whereas in East Asia, the male-to-female ratio is closer to 1:1 [4]. 

Pathophysiology 

A multi-hit model explains the pathogenesis of Immunoglobulin A nephropathy (IgAN), focusing on abnormal immune regulation driven by genetic and environmental factors [11]. These “hits” manifest in the IgA molecules identified in client biopsies and blood circulation and immune complexes made up of galactose-deficient IgA1 that accumulate in the glomeruli and bloodstream of individuals with IgAN [34].  

Research identifies glycosylated IgA1 as a heritable trait, with about 25% of relatives of clients with IgAN showing elevated levels of galactose-deficient IgA1 [35]. Segregation analysis indicates that this trait follows a pattern of inheritance involving a major dominant gene alongside a polygenic component [35]. Environmental factors, such as smoking, hypertension, and obesity, play a role in advancing the disease by contributing to microvascular damage, glomerulomegaly, and maladaptive hyperfiltration injury [36]. Nephritogenic immune complexes initiate glomerular inflammation and mesangial proliferation, while the activation of the renin-angiotensin and complement systems leads to glomerulosclerosis and tubulointerstitial fibrosis, resulting in diminished renal function [1][37]. 

The proposed four-hit model emphasizes abnormal mucosal IgA regulation as the central mechanism. The first hit involves abnormal O-glycosylation of the IgA1 hinge region, resulting in increased levels of galactose-deficient IgA1[34]. In individuals with genetic predispositions, triggers like infections cause B cells to generate abnormal IgA that lacks a galactose molecule in the hinge region. Trivial mucosal infections, chronic exposure to pathogens, and abnormal handling of gut commensals may initiate this dysregulated immune response, allowing the aberrant IgA molecules to self-aggregate due to hypoglycosylation [19][34]. 

The second hit occurs when the abnormal IgA1 triggers the production of anti-glycan antibodies and IgA1 autoantibodies. Elevated galactose-deficient IgA1 alone is insufficient to cause IgAN, as relatives of clients may have elevated levels without developing the disease. The liver clears IgA complexes, which explains the strong association between liver disease and IgAN [34[35]. 

The third hit involves the formation of abnormal IgA1 immune complexes that circulate in the bloodstream and deposit in the mesangium of the kidneys [38]. This leads to the fourth hit: activation of mesangial cells and the lectin and alternative complement pathways. This activation results in the release of cytokines, deposition of extracellular proteins, and systemic inflammation and fibrosis [38]. Cytokine release activates podocytes, increasing glomerular permeability and causing tubular interstitial damage [38]. This process leads to interstitial fibrosis, tubular damage, and infiltration by inflammatory cells including macrophages and dendritic cells [38]. 

Complement activation plays a significant role in IgAN pathogenesis through the mannose-binding lectin pathway [39]. Polymeric IgA1 activates this pathway, and components like complement factor H and properdin appear within glomerular deposits [1]. The alternative complement system activates, with immune complexes containing C3 appearing in approximately 90% of kidney biopsy samples from IgAN clients, as immunofluorescence staining reveals [39]. 

These two complement pathways are pivotal in causing glomerular basement membrane damage, leading to the ultrafiltration of larger molecules, and resulting in hematuria. It is unclear why some individuals develop asymptomatic hematuria while others have a rapid progression of glomerulonephritis and eventual renal failure. 

History & Physical  

In clients with IgA nephropathy (IgAN), the history and physical examination are often unremarkable [1]. The primary complaint revolves around gross hematuria, which can manifest as brown, red, or “cola-colored” urine [1]. Acute renal failure may present ankle edema, facial puffiness, and hypertension [40]. Other symptoms can include frothy urine or the presence of a rash, with hematuria sometimes following recent upper respiratory infections such as pharyngitis or resulting from intense exercise [1][40].  

During the physical examination, it is important to evaluate blood pressure and check for indicators of impaired kidney function, such as swelling (edema), fluid accumulation in the abdomen (ascites), and crackles at the lung bases. Hypertension is a common manifestation in IgAN [1][41]. Since IgAN may coexist with conditions like cirrhosis, liver diseases, and celiac disease, a thorough general and abdominal examination is crucial to exclude these comorbidities [15]. The mode of presentation varies based on age group and histological biopsy patterns, with asymptomatic hematuria and progressive kidney disease being among the most prevalent clinical phenotypes. 

Routine screening may detect asymptomatic hematuria with mild proteinuria at around 0.5 g/day [1]. Some individuals presenting with isolated microscopic hematuria and mild proteinuria may develop substantial proteinuria and hypertension, underscoring the importance of long-term monitoring. Renal survival rates vary depending on factors such as biopsy timing and the presence of lead-time bias, with estimated 10-year renal survival rates between 57% and 91% [42].  

In IgA nephropathy, synpharyngitic macroscopic hematuria serves as the initial symptom, with clients seeking medical care due to the concurrent onset of visible blood in the urine and a throat infection or other illness [24]. Recurrent episodes of visible hematuria are common. Although nephrotic-range proteinuria can develop in IgAN, the co-occurrence of both macroscopic hematuria and significant proteinuria is uncommon [1]. 

Extrarenal manifestations occur due to the systemic nature of the disease. Studies report that up to 35% of clients experience gastrointestinal symptoms, including abdominal pain, cramping, and diarrhea [14]. 

Less than 5% of clients with IgAN present with acute kidney injury resulting from rapid development of crescents or tubular damage or obstruction due to gross hematuria and red blood cell (RBC) casts [1][43]. Research identifies glycosylated IgA1 as a heritable trait, with about 25% of relatives of IgAN clients showing elevated levels of galactose-deficient IgA1 [44]. 

Evaluation of IgAN begins with establishing the diagnosis. Initial investigations include urinalysis to detect microscopic hematuria. The presence of red cells and red cell casts indicates glomerular injury and potential active disease. The assessment of proteinuria uses the protein-to-creatinine ratio in urine or 24-hour urinary protein excretion. Clinicians can measure serum creatinine levels and estimate the glomerular filtration rate (GFR) to evaluate renal function. 

A renal biopsy serves as the key method for confirming the diagnosis, enabling detailed analysis of kidney tissue through light microscopy, electron microscopy, and immunofluorescence techniques [1]. Demonstrating the deposition of IgA in the glomerular basement membrane through immunofluorescence is the gold standard for diagnosis [1]. The Oxford classification to classify IgAN and predict prognosis is a classification system that integrates histological, clinical, and biomarker criteria, providing valuable prognostic insights. The Oxford classification considers criteria such as mesangial cellularity, endocapillary proliferation, segmental glomerulosclerosis, and tubular atrophy or interstitial fibrosis [45].  

Several studies have confirmed that tubular atrophy and interstitial fibrosis are the strongest predictors of a poor prognosis in IgA nephropathy (IgAN) [1][46]. Fibroblast markers, including FSP1 and URG11, show an inverse relationship with glomerular filtration rate (GFR) and disease outcome [1][46].  

Additional markers of IgAN include urinary indicators that reflect complement pathway activity, such as urinary C4d, serum C3 levels, and other serum markers related to the alternative and lectin complement pathways [1][47]. Serum IgA levels alone do not offer sufficient sensitivity or specificity for diagnosing IgAN [48]. However, elevated levels of galactose-deficient IgA occur in both clients with IgAN and in relatives without clinical symptoms of the disease [48]. 

Differential Diagnosis  

Two conditions that mimic the symptoms of IgA nephropathy (IgAN) are IgA vasculitis and poststreptococcal glomerulonephritis [1][49]. IgA vasculitis, or Henoch-Schönlein purpura, results from abnormal IgA deposits that target the small blood vessels in multiple organs [49]. Unlike IgAN, which affects individuals aged 15 and older, IgA vasculitis occurs in those aged 15 and younger [49]. Microscopic examination of clients with IgA vasculitis shows more capillary and glomerular injury, while IgAN shows mesangial proliferation. Some treatments overlap due to the autoimmune nature of both conditions [49]. 

Poststreptococcal glomerulonephritis can also manifest in the context of an upper respiratory infection (URI) [50]. The key difference is that IgAN presents with or after a URI, whereas poststreptococcal glomerulonephritis arises two to three weeks following a URI [50]. 

Other potential differential diagnoses for IgAN include lupus nephritis, which is associated with multisystemic presentations; membranoproliferative glomerulonephritis, distinguishable on renal biopsy; thin basement membrane nephropathy, often characterized by microscopic hematuria and a family history of benign microscopic hematuria; Alport syndrome, associated with ocular and otic symptoms; malignancies ranging from the kidneys to the urethra, which should be ruled out in all clients aged 40 or older; and urolithiasis, which manifests with colicky pain not associated with IgAN and can be identified through imaging that demonstrates obstruction [1][51][52]. 

Several significant issues are essential for navigating the diagnosis, treatment, and prognosis of IgAN. Distinguishing primary IgAN from secondary IgAN is crucial, as managing secondary cases requires addressing the underlying disease. The lectin and alternative complement pathways play a significant role in the pathology of IgA nephropathy [53]. IgA nephropathy condition exhibits a higher prevalence and appears more aggressive among individuals of East Asian origin [1][4][33]. Asymptomatic microscopic hematuria often indicates a favorable prognosis, while progressing disease with crescents observed on biopsy suggests a poorer prognosis [3].  

The Oxford MEST classification system stratifies risk in IgAN clients, though some guidelines consider the presence of crescents while others do not [50]. Gross hematuria in individuals aged 40 or older warrants a comprehensive evaluation to rule out potential underlying kidney or bladder neoplasms [49]. Differentiating IgAN from IgA vasculitis and poststreptococcal glomerulonephritis is essential due to variations in treatment approaches for each condition [49]. Sparsentan and nefecon are two recently FDA-approved treatments for IgAN, and ongoing clinical trials aim to assess therapeutic agents targeting various steps of the IgAN pathways [50][54]. 

Therapeutic Management  

IgA nephropathy (IgAN) follows a prolonged course that requires collaborative management by an interprofessional healthcare team. Initial detection often occurs through abnormal urinalysis findings during routine screenings by primary care providers, prompting prompt referral to a nephrologist or pediatric nephrologist for comprehensive evaluation. Coexisting autoimmune diseases may necessitate input from rheumatologists, while systemic manifestations might involve endocrinologists, gastroenterologists, or other specialists. Pharmacists play a critical role in educating clients about steroid therapy, ensuring compliance, and maintaining open communication with the clinical team.  

Laboratory personnel must guarantee precise sample collection to avoid false-positive results for proteinuria. Dietitians design tailored diets low in salt, protein, and fat to support nutritional needs. Nurses provide comprehensive client assessment, counseling, and coordination among various specialties. All team members must maintain accurate client records and communicate any concerns to ensure optimal care. 

Careful regulation of fluid intake is necessary, considering the client’s fluid balance and kidney function. If providers anticipate progression to end-stage renal disease (ESRD), they should educate clients about renal replacement therapy options. Social workers offer crucial support and guidance to clients and their families during this challenging phase. The complexity of IgAN requires clinicians, pharmacists, nurses, and allied health professionals to collaborate in educating and supporting both the client and their family to achieve optimal outcomes. 

The management of IgA nephropathy (IgAN) starts by confirming the diagnosis through a renal biopsy, while also excluding potential secondary causes. Key considerations for formulating a management plan include assessing proteinuria, estimated glomerular filtration rate (eGFR), blood pressure, and histological findings. The primary goals of treatment are to induce remission and prevent complications. First-line agents for managing proteinuria and lowering blood pressure involve angiotensin-converting enzyme (ACE) inhibitors or angiotensin receptor blockers (ARBs), aiming for a target blood pressure of 130/80 mm Hg [54]. If proteinuria exceeds 1 g/day, the systolic blood pressure target is less than 125 mm Hg. Corticosteroids are essential in reducing proteinuria when levels exceed 1 g/day.  

Conservative therapy plays a crucial role by reducing proteinuria and slowing renal function decline. The Supportive Versus Immunosuppressive Therapy of Progressive IgA Nephropathy (STOP-IgAN) study found that about one-third of clients achieved satisfactory outcomes without immunosuppressive therapy following a six-month trial of optimized conservative measures, including aggressive ACE inhibitor or ARB titration [56]. The study found no notable difference in primary outcomes, including death, end-stage renal disease (ESRD), or a greater than 40% reduction in GFR, between clients receiving immunosuppressive therapy and those undergoing optimal medical management alone during both three-year and ten-year follow-ups [56]. 

Clinicians can prescribe a tapering course of prednisone for two to four months. The TESTING trial showed that methylprednisolone treatment for six to nine months slowed disease progression compared to placebo in clients with proteinuria exceeding 1 g/day [56][57]. However, due to an excess of infections and adverse events, clinicians reduced the initial dose and added prophylaxis for opportunistic infections. Longer-term data suggest limited sustainability of effects.  

Several novel medications offer promise for improving outcomes in IgAN. Sparsentan, a non-immunosuppressive dual endothelin and angiotensin receptor antagonist, received accelerated FDA approval in February 2023 [50][54]. The PROTECT trial showed that sparsentan reduced proteinuria and tended to preserve GFR compared to irbesartan [58]. Budesonide, in the form of oral nefecon, targets the terminal ileum near Peyer’s patches, reducing systemic effects due to extensive first-pass metabolism [59]. The NEFIGAN and NefIgArd trials demonstrated significant reductions in proteinuria and preservation of GFR with nefecon use [60]. Sodium-glucose cotransporter-2 (SGLT2) inhibitors have also shown efficacy in slowing chronic kidney disease progression, with further studies needed to evaluate their effects specifically in IgAN clients [61]. 

Other immunosuppressive agents like mycophenolate mofetil (MMF) have shown variable results, with some promising outcomes in Asian populations [62]. The MAIN trial in China indicated significant reductions in proteinuria and preservation of GFR with MMF, highlighting potential regional differences in disease progression [50][63]. Rituximab has not demonstrated significant benefits in IgAN, and other medications such as cyclophosphamide, azathioprine, calcineurin inhibitors, and leflunomide lack unambiguous evidence of substantial benefit [64]. 

Consider combination therapy with corticosteroids and another agent for progressive IgAN. Some trials have shown improved renal survival with combination therapy, while others found no significant difference compared to corticosteroids alone. Researchers have studied tonsillectomy in Asian populations, for its potential to induce remission or slow progression. However, randomized controlled trials have not demonstrated the efficacy, leading many regions to exclude it from standard care guidelines.  

For clients progressing to ESRD, renal transplantation is a viable option, although there is a risk of IgAN recurrence in the transplanted kidney [50][65]. Recurrence rates are around 23% at 15 years, correlating with an increased risk of graft rejection [65]. Despite recurrence, progression to ESRD in the grafted kidney is rare [65]. Immunosuppression with corticosteroids and treatment with ACE inhibitors or ARBs may help delay progression of recurrent disease in allografts [50]. 

Recent advancements have led to the development of potential therapeutic agents targeting different steps of IgAN pathogenesis. Endothelin receptor antagonists like sparsentan modulate hemodynamics [49]. B-cell inhibitors targeting factors like BAFF and APRIL are under investigation, focusing on B-cell modulation and IgA production [66]. Researchers are exploring complement activation inhibitors, such as eculizumab, due to the complement system’s role in IgAN deposits. Other investigational agents include bortezomib, fostamatinib, and small-interfering RNAs, all contributing to a growing pipeline of novel therapies aimed at improving outcomes for clients with IgAN [67]. 

Prognosis and Complications 

Up to 50% of clients with IgA nephropathy (IgAN) experience a benign disease course [50]. Prognosis can be predictable when using the Oxford classification outlined in the pathology section. The MEST criteria—which include Mesangial hypercellularity (M), Endocapillary hypercellularity (E), Segmental glomerulosclerosis (S), and Tubular atrophy/interstitial fibrosis (T)—and the presence of crescents serve as poor prognostic indicators [50]. Microscopic hematuria combined with mild proteinuria points to a positive prognosis, reflecting a benign and symptom-free progression of the disease [1][24].  

Three risk factors are associated with the need for dialysis or risk of death: proteinuria of 1 gram per day or more, sustained hypertension, and a high Oxford classification MEST-C score (some algorithms also include a category for crescents) [68]. Clients with sustained proteinuria of 1 gram per day or higher have a 46-fold increased risk of progressing to ESRD compared to those with proteinuria less than 500 mg per day [69].  

Although only a small percentage of clients diagnosed with IgAN progress to ESRD, its high prevalence makes it a frequent cause of ESRD [33]. As the disease advances, complications of renal failure may arise, including hypertension, edema, anemia, heart failure, and pulmonary edema. Common adverse effects and complications of both steroid and steroid-sparing therapies include an increased risk of infections, hypertension, fluid retention, weight gain, diabetes mellitus, osteoporosis, and iatrogenic Cushing syndrome [70]. Complications of steroid-sparing agents may include immunosuppression, anaphylaxis, renal injury, and hepatotoxicity [70]. 

Conclusion

Immunoglobulin A nephropathy (IgAN) is a multifaceted glomerular disease marked by the deposition of IgA in the renal mesangium, leading to a spectrum of clinical manifestations from benign hematuria to progressive renal failure [1]. The pathogenesis involves a “multi-hit” model where genetic predisposition, environmental triggers, and abnormal immune responses culminate in the formation of nephritogenic IgA complexes [11]. Early recognition and accurate diagnosis, often confirmed through renal biopsy and classified using the Oxford MEST-C system, are crucial for guiding effective management strategies [50]. The disease’s prevalence varies with a higher incidence and more aggressive progression observed in East Asian populations [1][4]. 

Learners will recognize that managing IgAN necessitates a multidisciplinary approach tailored to the individual’s risk factors and disease severity. Treatment focuses on reducing proteinuria and controlling hypertension using ACE inhibitors or ARBs, with corticosteroids and novel agents like sparsentan and nefecon employed in more severe cases [50] [54] [58]. The prognosis depends on factors such as proteinuria levels, blood pressure control, and histological findings, with up to half of the clients achieving remission. Ongoing research into the pathophysiological mechanisms of IgAN is paving the way for targeted therapies, emphasizing the importance of interprofessional collaboration in improving client outcomes and advancing our understanding of this complex disease. 

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