Cryoglobulinemic Glomerulonephritis

Etiology

According to the Brouet classification system, cryoglobulinemia is classified into 3 types based on immunoglobulin composition (see Table 1. Classification of Cryoglobulinemia).[2][3][4][5]

• Type I cryoglobulinemia: This type involves monoclonal immunoglobulins (Ig), typically IgG or IgM, which are associated with B-cell lymphoproliferative disorders, such as lymphoma or multiple myeloma. Type I cryoglobulinemia is the least common type, accounting for 10% to 20% of cryoglobulinemia cases. Glomerulonephritis is uncommon with this type.[6]

• Type II mixed cryoglobulinemia: A combination of monoclonal IgM with rheumatoid factor activity and polyclonal IgG is commonly linked to chronic infections, such as hepatitis C virus (HCV). This type of cryoglobulinemia is the most common type, accounting for 50% to 65% of cases. More than 80% of patients with this type exhibit glomerulonephritis.[6]

• Type III mixed cryoglobulinemia: A combination of polyclonal IgM and IgG is often associated with autoimmune diseases, such as Sjögren disease or systemic lupus erythematosus.[7] This type can also be associated with chronic hepatitis C infection, comprising about 25% to 40% of cases. Renal disease is uncommon in this type.

• Essential (primary) cryoglobulinemia: This type is diagnosed when no systemic illness can be identified.[6] Essential cryoglobulinemia has peripheral nerve and renal involvement more commonly compared to the above categories and generally has a worse prognosis. These patients also have a high rate of development of non-Hodgkin lymphoma.[8]

Mixed cryoglobulinemia (types II and III) accounts for the majority of cryoglobulinemic glomerulonephritis cases and is primarily caused by immune complex deposition in the glomeruli. Autoimmune diseases, HCV, and B-cell lymphoproliferative disorders are the leading causes of cryoglobulinemic glomerulonephritis. Cryoglobulinemic glomerulonephritis occurs in up to 30% of cryoglobulinemia cases, with membranoproliferative glomerulonephritis being the most common renal histological pattern observed. Importantly, many cases with the former histologic classification of membranoproliferative glomerulonephritis are now being classified as types of C3 glomerulopathy, which should also be considered.[9]

Table 1. Classification of Cryoglobulinemia

Abbreviations: IgM: Immunoglobulin M, IgG: Immunoglobulin G, IgA: Immunoglobulin A.

Table 2. Causes of Cryoglobulinemia

Abbreviations: HCV: hepatitis C virus, HBV: hepatitis B virus, HTLV-1: human T-lymphotropic virus-1.

Reference for the table [13].

Epidemiology

Cryoglobulinemic glomerulonephritis is a rare condition, with available data primarily derived from case reports and case series. In a retrospective study, kidney involvement was identified in 29% of patients with cryoglobulinemia. Kidney involvement was more common with type 2 cryoglobulinemia (84%) compared to type 1 (4%) and type 3 (11%).[14] Another study found that among a large cohort of patients, 65% had type II cryoglobulinemia, 28% had type III, and 7% had type I cryoglobulinemia.[14][15]

Pathophysiology

The pathogenesis of cryoglobulinemia is primarily driven by the proliferation and activation of B cells, leading to the production of cryoglobulins. Underlying conditions such as lymphoproliferative disorders, chronic antigenic stimulation due to infections, or autoimmune diseases can trigger the production of monoclonal, polyclonal, or oligoclonal cryoglobulins. The formation of immune complexes between cryoglobulins and their target antigens, coupled with defective clearance of these immune complexes, leads to vasculitis and subsequent organ damage. Since 2015, advancements in antiviral treatments for HCV have significantly reduced HCV-associated cryoglobulinemia, with autoimmune diseases now being the leading cause of mixed cryoglobulinemia.[16][17] HCV is particularly associated with abnormal B-cell stimulation, leading to cryoglobulin formation, as this virus can enter both hepatocytes and B cells through the CD-81 receptor.[18]

Type I cryoglobulinemia is a hemostatic disorder caused by mechanical vascular occlusion of small- to medium-sized vessels due to thrombosis, hyperviscosity, or both. This disorder is rarely associated with vasculitis and occurs exclusively in B-cell lymphoproliferative disorders. In type I cryoglobulinemia, monoclonal immunoglobulins (usually IgM or IgG, rarely IgA) contribute to vascular obstruction through cryoprecipitate formation. In contrast, mixed cryoglobulinemia is characterized by small- to medium-vessel vasculitis due to complement-mediated immune complex injury. Mixed cryoglobulinemia is associated with chronic infections, autoimmune disorders, and B-cell lymphoproliferative disorders. Mixed cryoglobulinemia can result from monoclonal IgM combined with polyclonal IgG (type II) or polyclonal immunoglobulins composed of IgG, IgM, or both (type III). In type II mixed cryoglobulinemia, the IgM cryoglobulin typically exhibits rheumatoid factor activity, driving immune complex–mediated complement activation and leading to vasculitis.[14]

The hallmark of cryoglobulinemic glomerulonephritis is immune complex–mediated glomerular injury. Immune complexes deposit in the glomerular capillaries, activating the classical complement pathway. This process leads to complement consumption and hypocomplementemia, particularly low levels of C4—a key feature of type 2 mixed cryoglobulinemic vasculitis. Persistent antigenic stimulation promotes the production of cryoglobulins, whereas defective phagocytic clearance impairs the removal of immune complexes, leading to inflammation and tissue damage. These processes highlight the intricate interplay between immune dysregulation and complement activation in the pathogenesis of cryoglobulinemic glomerulonephritis.[14]

Histopathology

Histologically, the most common manifestation of glomerular injury in cryoglobulinemic glomerulonephritis is a membranoproliferative glomerulonephritis pattern, whereas the mesangioproliferative pattern is less commonly observed. Light microscopy findings in the early stages reveal endocapillary proliferation and proteinaceous pseudothrombi composed of periodic acid-Schiff- and trichrome-positive immune complexes obstructing the glomerular capillaries (see Image. Membranoproliferative Pattern of Injury: PSA and Trichrome Stains).[6] In advanced stages, significant intraglomerular hypercellularity develops due to the influx of monocytes and macrophages, resulting in mesangial proliferation and duplication of the glomerular capillary walls (double contouring) with interposition of cells (see Image. Membranoproliferative Pattern of Injury: PAS and Jones Stains).[6][19][20] Glomerular fibrinoid necrosis and crescent formation are rare, occurring in less than 5% of cryoglobulinemic glomerulonephritis cases. Vasculitis involving interlobular arteries is observed in up to one-third of patients. In addition, interstitial lymphohistiocytic infiltrates and acute tubular injury may be present.

Immunofluorescence staining patterns vary depending on the type of circulating cryoglobulins, their clonality, and the associated tissue injury. In type I cryoglobulinemia, monoclonal deposits of IgG or IgM (rarely IgA) are observed, with positive staining for a monoclonal light chain, often accompanied by C1q or C3 positivity. In contrast, mixed cryoglobulinemia is typically characterized by the presence of both IgG and IgM with polyclonal light chains, along with staining for C1q, C3, C4, and the membrane attack complex C5b-9.[6] In mixed cryoglobulinemia, IgM and kappa light chains are often dominant, reflecting the monoclonal nature of the IgM component (see Image. Immunofluorescence in Mixed Cryoglobulinemic Glomerulonephritis).

Electron microscopy findings of cryoglobulinemic glomerulonephritis include monocyte and macrophage infiltration with prominent lysosomes, glomerular basement membrane duplication with cell interposition, and electron-dense deposits located primarily in the mesangial and subendothelial regions (see Image. Electron Microscopy Demonstrating Microtubular Deposits within the Glomerular Basement Membranes).[6] Less commonly, deposits are observed in intramembranous and subepithelial areas. The deposits exhibit distinct structural features, including curved, microtubular, cylindrical, or annular forms, typically measuring 10 to 25 nm in diameter. Although electron-dense deposits are a hallmark feature of cryoglobulinemic glomerulonephritis, their distribution within kidney tissue is often variable, increasing the risk of being overlooked. Similarly, pseudothrombi in cryoglobulinemic glomerulonephritis are typically focal and segmental, which may lead to underrepresentation in the electron microscopy tissue sample.

Differentiating cryoglobulinemic glomerulonephritis from other kidney diseases that exhibit a membranoproliferative glomerulonephritis pattern on histology is crucial. These conditions include immune complex–mediated glomerulonephritis caused by infections, monoclonal gammopathies, and autoimmune diseases such as lupus. Immunofluorescence staining and electron microscopy findings are essential for distinguishing these conditions from cryoglobulinemic glomerulonephritis. Complement-mediated glomerulonephritis and thrombotic microangiopathy can also exhibit a membranoproliferative glomerulonephritis pattern of injury, but the absence of immunoglobulin staining on immunofluorescence helps differentiate these conditions from cryoglobulinemic glomerulonephritis. In addition, immunotactoid glomerulopathy may mimic cryoglobulinemic glomerulonephritis, as both are characterized by microtubular immunoglobulin deposits. However, careful analysis of the size and distribution of these deposits can aid in differentiation. In immunotactoid glomerulopathy, glomerular deposits consist of uniformly arranged microtubules in parallel arrays, predominantly localized to subepithelial and subendothelial regions.[21] In contrast, cryoglobulinemic glomerulonephritis typically features short, curved, or straight microtubular deposits primarily located in intraluminal and subendothelial areas.

History and Physical

The clinical manifestations of cryoglobulinemia range from asymptomatic serologic findings to severe vasculitis and cryoglobulinemic glomerulonephritis.[8] Obtaining a detailed history and performing a thorough physical examination are essential for an accurate diagnosis. Although there is significant overlap between the clinical features of type I and mixed cryoglobulinemia, some manifestations are more commonly associated with one type of cryoglobulinemia than the other.

Type I cryoglobulinemia primarily causes mechanical obstruction of small- to medium-sized vessels due to thrombosis, hyperviscosity, or both.[7][22][23] This type is almost exclusively associated with B-cell lymphoproliferative disorders. The most common symptoms of hyperviscosity include recurrent epistaxis, blurry vision, dizziness, and somnolence, and the complete spectrum of symptoms is described below. Dermatologic manifestations are common with this type, present in 70% to 85% of cases, and include purpura, livedo reticularis, Raynaud syndrome, acrocyanosis, and nonhealing lower extremity ulcers.[8]

Types II and III cryoglobulinemia are characterized by vasculitis driven by complement-mediated immune complex deposition. Insights into mixed cryoglobulinemia largely come from studies of HCV-associated cryoglobulinemia.[24][25][26] Importantly, mixed cryoglobulinemia is often associated with the clinical triad of purpura, weakness, and arthralgia.[8]

Kidney Manifestations

Renal manifestations include hypertension, hematuria, proteinuria, nephrotic syndrome, acute kidney injury, or rapidly progressive glomerulonephritis. The clinical course of cryoglobulinemia-related kidney disease can be highly variable, ranging from indolent disease to oliguric renal failure.[5] Although proteinuria is the most common presentation, other renal symptoms include hematuria, acute nephritic syndrome, and oliguria, which are present in up to 10% of cases.[8] The overall incidence of end-stage renal disease is reported to be less than 10%.[5] 

Systemic Manifestations

• In addition to the kidneys, cryoglobulinemia often affects the skin, musculoskeletal system, and peripheral nervous system.
• Skin involvement is particularly common in mixed cryoglobulinemia, affecting up to 98% of patients, with vascular purpura on the lower extremities being the most frequent manifestation. Other skin features include livedo reticularis, subcutaneous nodules, cold urticaria, paresthesia, and necrotic ulcers.
• Musculoskeletal involvement is also more common in mixed cryoglobulinemia, affecting nearly 80% of patients. Musculoskeletal symptoms include nonerosive arthralgia, myalgia, and, in rare cases, tenosynovitis.
• Hyperviscosity syndrome is associated with type I cryoglobulinemia due to the presence of large quantities of monoclonal immunoglobulins. This condition can lead to symptoms such as blurred vision, diplopia, nystagmus, headache, confusion, vertigo, deafness, ataxia, stroke, and mental status changes.
• Involvement of pulmonary, gastrointestinal, or cardiac systems is uncommon in cryoglobulinemia but can occur in rare cases. This broad spectrum of clinical manifestations highlights the complexity of cryoglobulinemia, necessitating a multidisciplinary approach for accurate diagnosis and effective management.[13]

Evaluation

Evaluation of cryoglobulinemic glomerulonephritis involves a comprehensive clinical assessment, laboratory tests, and kidney biopsy to confirm the diagnosis and ascertain disease severity.[27]

Laboratory Tests

Serum cryoglobulins: Serum cryoglobulins must be measured when the clinical manifestations, laboratory tests, and underlying systemic disorders suggest the presence of cryoglobulin-mediated disease.[28] Accurate detection of serum cryoglobulins requires meticulous pre-analytic blood sample handling. Blood samples should be collected in tubes without anticoagulants and transported to the laboratory at 37 °C. After centrifugation, the sample is aliquoted into tubes and stored at 4 °C for 7 days to allow cryoprecipitate formation.[29][30][31] Once formed, the cryoprecipitate is quantified in grams per liter (g/L) or assessed semi-quantitatively based on the cryocrit level, which is determined by the percentage of packed cryoglobulins relative to the total serum volume.

A serum cryoglobulin concentration of more than 0.5 g/L or cryocrit of over 0.5% to 1% is considered clinically significant. In type I cryoglobulinemia, the cryocrit level can be significantly higher than in mixed cryoglobulinemia, up to 50%.[32] The re-solubility of the cryoprecipitate, a defining characteristic of cryoglobulins, must be verified by reheating the sample to 37 °C. This step is essential to eliminate false-positive results from cryofibrinogen or heparin-precipitable proteins. When the presence of cryoglobulins is confirmed, immunophenotyping is performed to identify the isotype of the cryoglobulins.

Laboratory testing for cryoglobulins is challenging due to the stringent handling requirements for blood samples, and false-negative results are common. A large cohort study suggested that up to 9% of patients had false-negative serum cryoglobulin tests. If clinical suspicion is high, repeating this test may be warranted.[27]

Notably, there is a weak correlation between serum cryoglobulin levels (or cryocrit levels) and disease severity. These levels should not be used alone to guide treatment decisions.[27] In severe cases of cryoglobulinemic vasculitis, there may be a temporary absence of measurable serum cryoglobulins due to the formation of cryoprecipitate immune complexes.

When clinical suspicion for cryoglobulinemia-mediated disease remains high despite negative serum cryoglobulin results, a tissue biopsy of the affected organ, such as skin, kidney, or peripheral nerve, can be valuable for diagnosing cryoglobulinemic vasculitis.

Complement levels: Hypocomplementemia, particularly characterized by low C4 levels, is a hallmark of mixed cryoglobulinemia and indicates complement activation. This condition can rarely be observed in type I cryoglobulinemia.

Rheumatoid factor: Elevated rheumatoid factor level is typically observed in type II mixed cryoglobulinemia, as monoclonal IgM exhibits rheumatoid factor activity.

Inflammatory markers: Elevated erythrocyte sedimentation rate and C-reactive protein are markers of systemic inflammation.

Renal function tests: Serum creatinine, blood urea nitrogen, and cystatin C levels are measured to assess kidney function. Proteinuria, often in the nephrotic range, and microscopic hematuria are common findings in cryoglobulinemia-related kidney disease.

Additional tests: A comprehensive evaluation for systemic conditions associated with cryoglobulinemia, such as B-cell lymphoproliferative disorders, autoimmune diseases, and chronic infections, should be guided by the patient's clinical manifestations, laboratory findings, and type of cryoglobulin.

• For type I cryoglobulinemia, recommended diagnostic tests include a complete blood count, serum protein electrophoresis and immunofixation, thoracic and abdominal computed tomography scans, positron emission tomography scans, and bone marrow biopsy.

• For mixed cryoglobulinemia, initial testing should include viral serologies—anti-HCV antibody, HCV RNA, hepatitis B surface antigen, anti-hepatitis B surface antibody, anti-hepatitis B core antibody, anti-HIV antibody, and Epstein-Barr virus antibody.

• For mixed cryoglobulinemia, a workup for autoimmune diseases and other vasculitis disorders should also be performed. The autoimmune workup includes antinuclear antibodies, anti–double-stranded DNA, anti-Sm, Ro/SSA, La/SSB, U1 ribonucleoprotein, and citrullinated peptide antibodies. Antineutrophil cytoplasmic autoantibodies (ANCAs) are measured to rule out ANCA vasculitis.

Although B-cell lymphoproliferative disorders are typically associated with type I cryoglobulinemia, they can also be linked to mixed cryoglobulinemia. Therefore, evaluation for B-cell lymphoproliferative disorders should be considered in both type I cryoglobulinemia and mixed cryoglobulinemia.[13]

Kidney biopsy: A renal biopsy is essential for diagnosing cryoglobulinemic glomerulonephritis and evaluating the extent of kidney injury. (Please refer to the Histopathology section for more information on the findings of cryoglobulinemic glomerulonephritis)

Table 3. Types of Cryoglobulinemia¹⁸

Abbreviations: IgM: Immunoglobulin M, IgG: Immunoglobulin G, IgA: Immunoglobulin A

Reference for the table [13].

Treatment / Management

The management of cryoglobulinemic glomerulonephritis requires a multimodal approach based on underlying disease severity. Treatment focuses on addressing the underlying cause of cryoglobulin production, along with employing therapies to suppress inflammation, decrease immune complex formation, and remove circulating cryoglobulins.[13]

Treatment of the Underlying Causes of Cryoglobulinemia

• Hepatitis C virus–associated cryoglobulinemic glomerulonephritis
• Direct-acting antivirals are the cornerstone of treatment, as sustained virologic response is achieved in over 95% of cases. Please see StatPearls' companion resource, "Hepatitis C," for more information.
• Eradication of HCV halts the antigenic stimulation driving the cryoglobulin production and immune complex–mediated organ damage.

• Autoimmune disease–associated cryoglobulinemic glomerulonephritis
• Therapy is tailored to the underlying autoimmune disorder. Treatment may include glucocorticoids, disease-modifying anti-rheumatic drugs, and immunomodulatory and immunosuppressive therapies.

• B-cell lymphoproliferative disorder–associated cryoglobulinemic glomerulonephritis
• Clone-directed therapy for the underlying hematologic disorder may involve agents such as rituximab or proteasome inhibitors.

Immunosuppressive Therapy

• High-dose glucocorticoids are commonly used to manage severe manifestations of cryoglobulinemic glomerulonephritis, including rapidly progressive glomerulonephritis. However, their efficacy is limited, and some authors suggest restricting their use to patients with active disease and arthralgia or those with life-threatening complications.[8]
• Rituximab, an anti-CD20 monoclonal antibody, effectively treats systemic and renal diseases, either alone or in combination with glucocorticoids.[33]
• Cyclophosphamide may be considered in cases of refractory or relapsing cryoglobulinemic glomerulonephritis.[8]
• In patients with essential cryoglobulinemic vasculitis (without identifiable etiology), treatment typically focuses on symptomatic management. Given the worse clinical prognosis, a combination regimen of glucocorticoids, rituximab, and cyclophosphamide is often used.[8]
(A1)

Plasmapheresis

• Plasmapheresis is performed in life-threatening situations, such as rapidly progressive glomerulonephritis, severe hyperviscosity syndrome, or extensive systemic vasculitis.
• Plasmapheresis rapidly removes circulating cryoglobulins, mitigating immune complex formation and tissue injury.
• Plasmapheresis is often combined with immunosuppressive therapy for optimal outcomes.

 Supportive Care

• Blood pressure management
• Renin-angiotensin-aldosterone system inhibitors are preferred for controlling hypertension and reducing proteinuria.

• Proteinuria management
• Nephroprotective strategies include optimizing blood pressure control and using agents that reduce proteinuria, such as Renin-angiotensin-aldosterone system inhibitors and sodium-glucose cotransporter-2 inhibitors.

• Cardiovascular risk mitigation
• Hyperlipidemia management and glycemic control are essential to mitigate cardiovascular complications.

Rituximab-Associated Cryoglobulinemic Vasculitis Flare

Rituximab, an anti-CD20 monoclonal antibody, has proven effective in treating the clinical manifestations of cryoglobulinemic glomerulonephritis. However, rituximab-associated cryoglobulinemic vasculitis flare is a significant adverse effect that requires attention.[34] This phenomenon typically occurs within 2 to 9 days after rituximab infusion, with an incidence of 14% to 22% in patients with cryoglobulinemia. Unlike serum sickness, this flare is not self-limiting and may result in severe organ dysfunction, including acute kidney injury, ischemic colitis, and myocarditis.[34][35] This flare can occur in type I cryoglobulinemia and mixed cryoglobulinemia and is associated with poor outcomes, including a mortality rate exceeding 50%.

Risk factors for rituximab-associated cryoglobulinemic vasculitis flare include B-cell lymphoproliferative disorders, kidney involvement, elevated cryoglobulin levels, and low C4 levels. The underlying mechanism of this flare remains unclear, but a hypothesis suggests an immune-mediated reaction between rituximab's antigenic component and complement-fixing IgM and IgG with rheumatoid factor activity.[35] Another plausible explanation is rituximab-induced interleukin-6 production by monocytes and B cells, leading to rapid immunoglobulin production.

The management of rituximab-associated cryoglobulinemic vasculitis flare includes high-dose corticosteroids, with or without plasmapheresis, alongside continued treatment of the underlying disease.[36] Notably, the development of a cryoglobulinemic vasculitis flare does not indicate rituximab treatment failure. Resumption of rituximab therapy is recommended when clinically appropriate to ensure effective disease control.

Differential Diagnosis

The nonspecific systemic manifestations of cryoglobulinemia often pose a diagnostic challenge, as its clinical presentation can overlap with various systemic vasculitis disorders, rheumatologic diseases, infectious conditions, and thromboembolic disorders. Systemic vasculitis involving small- and medium-sized vessels can mimic the signs and symptoms of cryoglobulinemic vasculitis. A comprehensive diagnostic workup is essential to rule out other forms of small- and medium-vessel vasculitis, including:

• IgA vasculitis, formerly called Henoch-Schönlein purpura
• ANCA-associated vasculitis, which encompasses granulomatosis with polyangiitis, microscopic polyangiitis, and eosinophilic granulomatosis with polyangiitis
• Drug-induced small-vessel vasculitis, such as hypersensitivity vasculitis
• Infection-associated vasculitis, such as bacterial endocarditis, post-streptococcal vasculitis, and glomerulonephritis

Rheumatologic conditions, including systemic lupus erythematosus, rheumatoid arthritis, and Sjögren syndrome, may also present with vasculitis symptoms, which may not be mediated by cryoglobulins. For instance, rheumatoid vasculitis can manifest with musculoskeletal symptoms and positive rheumatoid factor. In such cases, the presence of bone erosions and anti-cyclic citrullinated peptide antibodies can help confirm the diagnosis of rheumatoid vasculitis. Similarly, differentiating cryoglobulinemic vasculitis from polyarteritis nodosa in a patient with mononeuritis multiplex can be facilitated by identifying key features, such as the presence or absence of ANCA.

In addition, infectious diseases, such as rickettsia infections, malaria, and babesiosis, and thromboembolic conditions, such as antiphospholipid syndrome, thrombotic thrombocytopenic purpura, and hemolytic uremic syndrome, may present with overlapping clinical features, further complicating the diagnostic process.

Pertinent Studies and Ongoing Trials

Belimumab is in the initial phases of investigation for use in cryoglobulinemic glomerulonephritis, particularly when combined with rituximab. Belimumab is an antibody to B-cell–activating factor, which is a molecule of interest in immunoglobulin-related diseases. B-cell–activating factor is upregulated in autoimmune disease and has also been found to be elevated in cryoglobulinemic glomerulonephritis associated with hepatitis C.[8]

The complement cascade is an integral part of the pathology of cryoglobulinemic glomerulonephritis. Eculizumab, a C5 complement inhibitor, prevents the activation of this cascade and has been reported in case studies as a potential treatment for cryoglobulinemic glomerulonephritis. Although there is no conclusive evidence supporting its use in this context, it remains a potential area for further research.[37]

Prognosis

Several factors, including the underlying etiology, severity of renal involvement, and timeliness of treatment, influence the prognosis of cryoglobulinemic glomerulonephritis. Without effective intervention, cryoglobulinemic glomerulonephritis can progress to chronic kidney disease or end-stage kidney disease, necessitating dialysis or kidney transplantation. The prognosis is favorable in HCV-associated cryoglobulinemic glomerulonephritis, as sustained virologic response is achieved with direct-acting antiviral agents. Eradication of HCV reduces antigenic stimulation, halts cryoglobulin production in most patients, and significantly improves renal outcomes. In contrast, persistent cryoglobulinemia due to untreated chronic infections, persistent autoimmune disease activity, or untreated B-cell lymphoproliferative disorders is associated with a higher risk of kidney disease progression, systemic vasculitis, and cardiovascular complications. Kidney outcomes are worse in patients presenting with rapidly progressive glomerulonephritis or severe proteinuria at the time of diagnosis.

The long-term prognosis of cryoglobulinemic glomerulonephritis depends on underlying comorbidities and the prevention of complications, such as infections or cardiovascular events, that may occur due to chronic kidney disease. Timely diagnosis, targeted therapy, and multidisciplinary management are essential to optimizing renal and systemic outcomes in these patients.

The prognosis of type I cryoglobulinemia largely depends on the underlying hematologic disorder, with a 5-year survival rate ranging from 77% to 83%.[7][22][23] This rate has remained relatively unchanged in recent years. The prognosis of mixed cryoglobulinemia is highly variable and influenced by factors such as the cause of cryoglobulinemic vasculitis, the severity of vasculitis, the type of organ involvement, and underlying comorbidities. Patients with severe manifestations, including pulmonary hemorrhage, intestinal vasculitis, or rapidly progressive glomerulonephritis, tend to have poor outcomes.[26][38][39] In a systematic review and case series analyzing organ-threatening or life-threatening manifestations, overall survival was 78%. Survival rates varied based on the affected organ system—pulmonary hemorrhage with 22% survival, central nervous system vasculitis with 66% survival, gastrointestinal vasculitis with 67% survival, glomerulonephritis with 79% survival, and cardiac vasculitis with 100% survival.[38]

The introduction of direct-acting antiviral agents has significantly improved the prognosis of HCV-associated mixed cryoglobulinemia.[39] In a study involving 146 patients with mixed cryoglobulinemia and kidney involvement followed for over a decade, the 10-year survival rate was approximately 80%.[40] Decreased kidney function at baseline was associated with worse outcomes, with cardiovascular disease being the leading cause of death in over 60% of patients.

Complications

Complications of cryoglobulinemic glomerulonephritis include hypertension, acute kidney injury, progression to chronic kidney disease, end-stage kidney disease requiring renal replacement therapy, and an increased risk of cardiovascular disease.[5][26][40][41]

In addition, patients with cryoglobulinemic glomerulonephritis face much higher rates of hypertension, cardiovascular disease, and B-cell lymphomas compared to those without this condition.[40]