Membranoproliferative Glomerulonephritis and Dense Deposit Disease

Ashley J. Jefferson

Miguel Palma-Diaz

Charles E. Alpers

Membranoproliferative glomerulonephritis (MPGN), sometimes referred to as mesangiocapillary glomerulonephritis, describes a pathologic pattern of injury characterized by thickening of peripheral capillary walls (membrano-), glomerular hypercellularity (-proliferative), with mesangial expansion leading to an accentuated lobular appearance of the glomerular tuft. Although there are idiopathic forms of this condition, the majority of cases of MPGN are associated with secondary causes—in particular, hepatitis C (Table 50.1). The various forms of MPGN have very different clinical courses and are described separately.

CLASSIFICATION

Prior classifications of MPGN have subdivided this entity into three different classes according to pathologic characteristics (Table 1). Type I is the most common and is an immune complex mediated disorder with primarily subendothelial and mesangial immune deposits leading to activation of the classical pathway of complement. Type III was described as having a similar histologic pattern, but with the additional finding of subepithelial immune deposits or a distinctive appearance of the capillary wall deposits identified by electron microscopy. It is increasingly recognized that cases previously considered as Type III MPGN do not represent a separate disorder, but rather are best considered a variant of Type I MPGN, or more commonly, a form of the recently described entity C3 glomerulopathy. Dense deposit disease (DDD; type II) results from dysregulation of the alternate pathway of complement, and it has become clear that only a minority of cases of DDD demonstrate an MPGN pattern on biopsy. In view of these points, we prefer to classify MPGN into primary and secondary causes (Table 50.2), and we follow an emerging consensus that DDD and C3 glomerulopathy are separate entities altogether.¹

PRIMARY MEMBRANOPROLIFERATIVE GLOMERULONEPHRITIS

Epidemiology

Primary MPGN is a relatively rare form of glomerulonephritis in developed countries, where secondary forms of MPGN are much more common. The disease is usually found in children and young adults and, interestingly, the incidence appears to be decreasing worldwide.²,³,⁴,⁵ This may be due to a true decrease in disease incidence, partly due to improved hygiene and environmental factors reducing the incidence of bacterial infections, but may also reflect the increased ability to detect secondary forms of MPGN (e.g., viral infections, monoclonal gammopathies). In developing countries, MPGN remains one of the most common forms of glomerulonephritis.⁶,⁷,⁸ This classically has been considered secondary to the increased incidence of bacterial infections in these countries, but this has been questioned by Johnson et al., who found little evidence for active infection in cases of MPGN in Peru.⁸ They have proposed that a shift in Th1/Th2 immune balance, induced by environmental and hygienic factors, may determine the incidence of a range of glomerular diseases worldwide.⁹,¹⁰

Primary MPGN is more common among whites than among black or Asian populations. A genetic susceptibility is supported by the finding of an extended HLA haplotype— HLA-B8, DR3, SCO1, GLO2—more frequently in patients with MPGN I and III (13%) than in the general Caucasian population (1%), although this haplotype is not specific for MPGN.¹¹ Familial forms of MPGN have been described, but these are rare.¹² Some of these may be secondary to mutations encoding complement proteins or their inhibitors (discussed below).

Pathogenesis

Primary MPGN is considered to be an adaptive immune response to a chronic antigenic stimulus leading either to the subendothelial and mesangial deposition of circulating immune complexes consisting of immunoglobulin G (IgG), C3, and antigen, or deposition of circulating antigens in the glomerular capillary walls (planted antigens) which then serve as a nidus for immune complex formation in situ. In secondary forms of MPGN a wide range of antigens (primarily infectious agents) have been implicated, but in primary MPGN the causative antigen remains unknown. The binding of the Fc portion of IgG or IgM in the immune complexes

to C1q triggers activation of the complement via the classical pathway, but this initial activation may be amplified by the alternate pathway (amplification loop). The subsequent cleavage of C5 leads to the production of chemotactic factors (C5a), opsonins (C3b), and the membrane attack complex (C5b-9) (Fig. 50.1). In some cases, complement activation is enhanced by nephritic factors that stabilize either the classical pathway C3 convertase (C4 nephritic factor, C4NeF) or the alternate pathway C3 convertase (C3 nephritic factor, C3NeF) which may enhance the amplification loop.¹³,¹⁴

TABLE 50.1 Former Classification of Membranoproliferative Glomerulonephritis

Classification	Pathologic Characteristics
Type I	Enlarged, lobulated glomerulus, mesangial hypercellularity Influx of mononuclear leukocytes Duplication of GBM with cellular interposition IgG, C1q, C3 deposition in mesangium and capillary wall Mesangial and subendothelial immune deposits
Type II (dense deposit disease)	Variable pattern on light microscopy C3 deposition in absence of IgG or C1q Ribbonlike dense deposits within GBM on electron microscopy
Type III	Histologic and immunofluorescence features similar to type I MPGN Additional subepithelial deposits with thickened irregular GBM
GBM, glomerular basement membranes; IgG, immunoglobulin G; MPGN, membranoproliferative glomerulonephritis.

TABLE 50.2 Current Classification of Membranoproliferative Glomerulonephritis

Classification	Associated Disorders
Primary MPGN	None
Secondary MPGN
Infectious Disease	Viral: hepatitis C, hepatitis B, HIV Bacterial: shunt nephritis, visceral abscess, endocarditis Protozoan: quartan malaria, schistosomiasis, leprosy
Autoimmune Disease	Systemic lupus erythematosus, mixed cryoglobulinemia, scleroderma, Sjögren syndrome, hypocomplementemic urticarial vasculitis
Monoclonal Gammopathy	Monoclonal gammopathy of uncertain significance (MGUS), multiple myeloma, B cell lymphoma, chronic lymphocytic leukemia, Waldenström macroglobulinemia
Chronic Liver Disease	Chronic hepatitis, cirrhosis, α1-antitrypsin deficiency
Miscellaneous	Solid organ tumors; cystic fibrosis, sarcoidosis, sickle cell disease, hemolytic uremic syndrome, transplant glomerulopathy, drugs (heroin, α-interferon)
C3 Glomerulopathy
Dense Deposit Disease (formerly type II MPGN)	Dysregulation of the alternate pathway of complement
	▪	C3 nephritic factor (partial lipodystrophy, retinal drusen)
	▪	Antifactor B autoantibody
	▪	Factor H dysfunction (inherited and acquired)
C3 Glomerulonephritis	Dysregulation of the alternate pathway of complement
	▪	C3 nephritic factor
	▪	Mutations in complement regulatory proteins (factor H, factor I, membrane cofactor protein)

FIGURE 50.1 Complement pathways. Complement may be activated by one of three pathways. In MPGN type 1, the Fc portion of IgG or IgM in immune complexes binds C1q and activates the classical pathway, cleaving C3 to C3b. This process may be amplified by the alternate pathway (amplification loop). Cleavage fragment C3a acts as an anaphylatoxin, C3b binds to surfaces as an opsonin and further promotes the generation of the C5 convertases. These cleave C5 to form C5a (chemotactic factor), and lead to the formation of the membrane attack complex (C5b-9). In dense deposit disease, the usual low level activation (tickover) of the alternate pathway, which generates small amounts of C3 convertase (C3bBb), is dysregulated (either by C3 nephritic factor [C3NeF] or failure of factor H regulation) leading to a more profound activation of the alternate pathway and the generation of large amounts of C3b. Factor H is the major regulator of the alternate pathway. MBL, mannose binding lectin; C4NeF, C4 nephritic factor; NFt, nephritic factor of the terminal pathway; C4b2a, C3 convertase of classical pathway; C3bBb, C3 convertase of alternate pathway.

It is likely that the prominent monocyte influx that characterizes MPGN is the result of complex interactions including Fc portions of immunoglobulins within deposited immune complexes engaging Fc receptors on the surface of monocytes, as well as release of chemoattractant cytokines (e.g., colony stimulating factor 1 [CSF-1]) and other proinflammatory mediators by resident glomerular cells as a response to injury.¹⁵,¹⁶ It is unknown whether the monocytes infiltrating human glomerulonephritis (GN) have a homogeneous phenotype, and are proinflammatory, or whether some or even a majority of these cells infiltrating at different time points of the disease course may be engaged in activities primarily directed to opsonization and phagocytosis of immune complexes, stabilization of disease, and repair of glomerular injury. Recent studies suggest systemic and local innate immune responses may also contribute to the pathogenesis of MPGN. For example, studies have demonstrated toll-like receptor 3 in human MPGN associated with viral infection,¹⁷ and upregulated expression of toll-like receptor 4 on glomerular cells has been identified in an animal model of cryoglobulinemic MPGN,¹⁸ but more specific immune mechanisms leading to glomerulonephritis have not been established.

Following an initial proliferative phase, a second reparative phase develops, which is characterized by the development of mesangial expansion and the formation of new basement membrane matrices resulting in double contours. These duplicated basement membrane matrices lead to the sequestering of immune complexes and entrapment of cells or cell processes between the matrices (cellular interposition) and presumably this sequestration reduces the stimulation for an acute inflammatory response by circulating leukocytes.

PATHOLOGY

The overall appearance of both primary and secondary types of MPGN often reveals enlarged glomeruli with accentuation of the normal lobular architecture (Fig. 50.2). Hypercellularity is mostly due to a combination of mesangial cell proliferation and infiltrating leukocytes. The mesangium is
prominently expanded, both by increased matrix as well as increased cellularity, which may reduce the number of open capillary loops. PAS or methenamine silver stains of histologic sections may show a characteristic feature of duplication (sometimes referred to as splitting) of the glomerular basement membranes (GBM) due to the synthesis of new basement membrane material, with interposition of cells (mesangial, endothelial, or leukocyte) between the duplicated basement membrane matrices.

FIGURE 50.2 Membranoproliferative glomerulonephritis. A: Light microscopy showing prominent mesangial expansion due to increased cellularity and accumulation of extracellular eosinophilic material, diffuse thickening of glomerular basement membranes with segmental splitting (arrows), and influx of leukocytes (endocapillary proliferation). Jones’ silver methenamine stain. B: Higher power view of this glomerulus shows the mesangial cell proliferation, the irregular thickening and focal splitting/duplication of basement membranes (arrows), and accumulation of acellular eosinophilic material, most likely deposits of immune complexes, in capillary walls and some mesangial regions. Jones’ silver methenamine stain.

FIGURE 50.3 Membranoproliferative glomerulonephritis type I with characteristic deposition of (A) IgG and (B) C3 primarily involving peripheral capillary walls, with a granular pattern. Mesangial deposits are also present.

Immunofluorescence typically shows the presence of IgG and C3 in a peripheral capillary wall distribution (Fig. 50.3). C1q and C4 are also commonly present in keeping with activation by the classical pathway. IgM is not prominent in primary MPGN and, if present, may suggest the presence of a secondary form of MPGN (e.g., hepatitis C). Glomerulonephritis with an MPGN pattern but in which deposition of immune reactants is limited to C3 has traditionally been considered part of the spectrum of MPGN I or
the former MPGN II. Recent data has suggested that many, if not all, of these cases can now be classified as DDD or manifestations of a distinct group of disorders tentatively termed C3 glomerulopathy (see later).¹⁹

FIGURE 50.4 Membranoproliferative glomerulonephritis type I with characteristic discrete electron-dense immune complex deposits along the subendothelial aspect (arrowheads) of the original glomerular basement membrane and between duplicated basement membranes (arrows). Large, confluent electron-dense deposits are also identified within mesangial regions (M).

On electron microscopy, subendothelial and mesangial deposits are typically present (Fig. 50.4). Subepithelial deposits may be present, but are usually scanty. Prominent subepithelial deposits are found in some patients, and some authors advocate a separate classification for this entity, MPGN type III, as described later.

It is usually impossible to differentiate secondary forms of MPGN from the primary disease, but suggestive features from common forms are described in Table 50.3. It should also be recognized that other clinical disorders may present with an MPGN pattern on renal biopsy. We have mentioned DDD, but other imitators may include thrombotic microangiopathy and other rare diseases (Table 50.4).

Clinical Features (Presentation and Clinical Manifestations)

Type 1 MPGN often presents in childhood or early teens with edema and nephrotic syndrome, and is often associated with hematuria and an active urine sediment (dysmorphic red cells and red cell casts). Constitutional symptoms including lassitude, fatigue, and weight loss may be present.
A range of other modes of presentation may be found ranging from asymptomatic microhematuria or proteinuria on screening to an acute nephritic syndrome with gross hematuria, renal impairment, and hypertension. This is often initially diagnosed as a postinfectious glomerulonephritis, but the persistent hypocomplementemia and failure to resolve usually prompt a renal biopsy, if not already performed. In children the course is often slowly progressive, with 20% to 60% of treated patients progressing to end-stage renal disease (ESRD) over 10 to 15 years.²⁰,²¹,²²,²³ Risk factors for progression include the presence of nephrotic syndrome and a raised serum creatinine at presentation.

TABLE 50.3 Pathologic Features Suggestive of Underlying Secondary Disorders

Hepatitis C

Prominent IgM deposition Intracapillary eosinophilic globules (hyaline thrombi)

Fibrillary or microtubular substructure to deposits (cryoglobulinemia)

Systemic lupus erythematosus

Hyaline thrombi or “wire loops” by histology

C1q deposition and full house immunofluorescence

Tubuloreticular structures

Monoclonal lymphoplasmacytic disorders

Heavy or light chain restriction of deposited immune reactants

TABLE 50.4 Disorders That Can Mimic MPGN on Renal Biopsy

Monoclonal lymphoplasmacytic disorders	Light chain deposition disease, immunotactoid glomerulonephritis, type 1 cryoglobulinemia; proliferative glomerulonephritis with monoclonal IgG deposits (PGNMID)
Thrombotic microangiopathy	See Chapter 55
Fibrillary glomerulonephritis and immunotactoid glomerulopathy
Rare diseases	Collagen III glomerulopathy, fibronectin glomerulopathy, LCAT deficiency nephropathy
Transplant glomerulopathy
LCAT, lecithin-cholesterol acyltransferase

In adults, primary MPGN typically presents with an overlap between nephrotic and nephritic syndrome. Nephrotic range proteinuria is common, as are microhematuria, renal impairment, and hypertension, which may be prominent. The course is variable, but in the absence of a secondary cause, a progressive course is common.

Laboratory Findings

A major clinical clue to the diagnosis of MPGN is the presence of hypocomplementemia, due to activation of the classical pathway (Table 50.5). CH50, C3, and C4 are all depressed and may be persistent. C3 nephritic factor (C3NeF), an autoantibody stabilizing the C3 convertase of the alternate pathway, may occasionally be found (see dense deposit disease section).¹³,¹⁴ C4 nephritic factor (C4NeF), an autoantibody stabilizing the classical pathway C3 convertase or a nephritic factor of the terminal pathway (Nft), have also been described,²⁴ occurring in ˜20% of cases, either alone or with C3NeF.

TABLE 50.5 Causes of Hypocomplementemia in Kidney Disease^a

Classical Pathway (↓C3, ↓C4)	Alternate Pathway (↓C3, ↔C4)
Lupus nephritis	Postinfectious glomerulonephritis
Membranoproliferative glomerulonephritis (MPGN types I and III)	Dense deposit disease (C3 glomerulopathy)
Cryoglobulinemia (MPGN)	Hemolytic uremic syndrome
Endocarditis (MPGN)
Shunt nephritis/abscess (MPGN)
^aLow C3 levels may also be seen in atheroembolism, liver disease, sepsis, and, rarely, heavy chain disease, rheumatoid vasculitis.

Treatment

The initial key to management is to rule out secondary causes with appropriate investigations. These may include screening for infections (e.g., hepatitis C, hepatitis B, endocarditis), autoimmune diseases (e.g., antinuclear antibody), monoclonal gammopathies (serum free light chains, serum protein electrophoresis), and complement disorders (e.g., nephritic factors).

Nonimmunosuppressive therapy is similar to that used in other forms of proteinuric kidney disease (see Chapter 75). Achieving excellent blood pressure control and renin angiotensin aldosterone system (RAAS) blockade with angiotensin-converting enzyme (ACE) inhibitors or angiotensin receptor blockers is the cornerstone of therapy. Supplemental therapies may include vitamin D supplementation, HMG-CoA synthetase inhibitors (statins), and aspirin. As with most glomerular disease there is an increased risk of cardiovascular disease.

Immunosuppressive Therapy

The role of immunosuppression is predicated on the accurate exclusion of secondary causes. The majority of evidence in children (mostly retrospective cohort studies) supports the use of an alternate day steroid regimen for prolonged periods of time. One report from the Cincinnati group, using prednisone 2 mg per kg alternate days for a minimum of 2 years, showed an 80% 10-year renal survival.²¹ An early randomized controlled trial compared prolonged oral prednisone (40 mg per m²) with placebo in 80 children with MPGN (a variety of subtypes), with a mean follow-up of 5.25 years.²⁵ Treatment failure was defined as an increase in serum creatinine >30% over baseline, or by 0.4 mg per dL, and was found in 33% of the prednisone group versus 58% of the placebo group. Adults with nephrotic syndrome or renal impairment are also typically treated with a 3- to 6-month course of steroids (prednisone 1 mg/kg/day). Notably, patients with subnephrotic proteinuria have a much better prognosis and may be treated more conservatively.²⁶

The role of other immunosuppressive agents is less clear and, given the rarity of this condition, there is limited evidence to support their use. Two controlled prospective trials showed no benefit with dypiridamole²⁷ or combination cyclophosphamide, warfarin, and dypiridamole.²⁸ There are small series reporting beneficial results in steroid resistant disease with cyclosporine²⁹ or tacrolimus,³⁰ and with mycophenolate.³¹ Rituximab may be considered, especially in the presence of a nephritic factor.³²

Following kidney transplantation, idiopathic type 1 MPGN recurs in 20% to 30% of patients, and leads to graft loss in approximately 50% of these, although this historic data does not take into account the effect of separating cases of typical MPGN from those with C3 deposits only.³³

MPGN TYPE III

MPGN Type III was originally described by Burkholder et al. in the 1970’s as a separate entity with pathological features that overlap between membranous nephropathy and a proliferative glomerulonephritis.³⁴ It was characterized by the presence of epimembranous “spikes” of silver staining projections of matrix from the glomerular basement membranes, in addition to the usual features of MPGN, absent C1q and C4 deposition on immunofluorescence, and by the presence of prominent sub-epithelial immune deposits with thickening and irregularity of the GBM on electron microscopy (Figure 5). A second pattern of injury was described by the groups of Strife³⁵ and Anders³⁶, with histologic features of MPGN characterized ultrastructurally by permeation of an irregularly thickened glomerular basement membrane by electron dense deposits that are frequently poorly demarcated from the glomerular basement membrane, but are less electron dense than the deposits encountered in MPGN type I or dense deposit disease, and frequently contain areas of electron lucency. The clinical presentation of MPGN III is similar to MPGN type I, but patients tend to be older, with a more insidious presentation and hypertension is less common. Low C3 levels are typically found (˜85%), but C4 is usually normal in keeping with activation of the alternate pathway.

It is now generally considered that MPGN III is not a separate class of MPGN, and modern classifications, as recently proposed by Sethi et al.¹, omit the use of this term (Figure 6). When immune complexes containing immunoglobulins are present, there is no compelling reason to consider MPGN III as a separate entity from MPGN I, as a distinct clinical course or outcome has not been defined, and pathologic features overlap with MPGN I. When only deposits of C3 are detected by immunofluorescence, a pattern present in most of the cases of Strife and Anders type, these cases fall into the broadly defined category of C3 glomerulopathy.

FIGURE 50.5 Membranoproliferative glomerulonephritis type III (Burkholder), now considered to be a variant of membranoproliferative glomerulonephritis, type I. There are thickened peripheral capillary walls showing massive electron dense deposits in subendothelial (arrows), intramembranous, and subepithelial locations (arrowheads). Similar deposits are also present in mesangial regions (M). There is extensive effacement of foot processes.

FIGURE 50.6 Pathophysiological classification of MPGN. MPGN may be subdivided into immune complex mediated and complement mediated pathways. Immune complexes derived from a chronic antigenic stimulus activate the classical pathway and are characterized by the glomerular deposition of both immunoglobulin and C3 seen by immunofluorescence micros copy. The finding of isolated C3 deposition by immunofluorescence, in the absence of immunoglobulin, suggests a form of C3 glomerulopathy due to dysregulated activation of the alternate pathway.

HEPATITIS C-ASSOCIATED MPGN

Hepatitis C virus (HCV) is a single-stranded RNA virus estimated to infect 170 million people worldwide. It is transmitted primarily by transfusion of blood products and intravenous drug use. Chronic infection occurs in 85% to 90% of exposed individuals and may progress to chronic active hepatitis, liver cirrhosis, and hepatocellular carcinoma. The association of HCV with cryoglobulinemic MPGN was first reported in 1993,³⁷ but a range of other renal diseases have also been reported with HCV infection (Table 50.6).

Cryoglobulinemic MPGN

Cryoglobulinemia refers to the presence of serum immunoglobulins that reversibly precipitate when cooled to 4°C,
and is classified according to the composition of the circulating cryoglobulins (Table 50.7). Type I cryoglobulins are composed of monoclonal immunoglobulins secondary to B cell disorders such as Waldenström macroglobulinemia or multiple myeloma. Type II and type III are mixed cryoglobulins consisting of polyclonal IgG complexed to another immunoglobulin which acts as an antiglobulin (anti-IgG rheumatoid factor [RF]). In type II this antiglobulin (usually IgM) is monoclonal, whereas in type III it is polyclonal. Evidence of HCV infection has been found in up to 95% of cases of type II cryoglobulinemia and 50% of type III cryoglobulinemia in some series.³⁸,³⁹ The circulating cryoglobulins are typically composed of HCV antigen and anti-HCV antibody complexed to an IgM with rheumatoid factor activity. HCV RNA is found to be concentrated 10 to 100 times in the cryoprecipitate.³⁷,⁴⁰

TABLE 50.6 Renal Manifestations of Hepatitis C Infection

Renal Compartment	Mechanism	Clinical Disorder
Glomerular disease	Secondary to cryoglobulinemia	Membranoproliferative glomerulonephritis (type I and III) Immunotactoid glomerulopathy Fibrillary glomerulonephritis Crescentic necrotizing glomerulonephritis Amyloidosis
	Not associated with cryoglobulinemia	Membranoproliferative glomerulonephritis Mesangial-proliferative glomerulonephritis Membranous nephropathy Focal segmental glomerulosclerosis
Tubulointerstitial	Unknown	Hepatitis C-associated interstitial nephritis
Vascular	Secondary to cryoglobulinemia	Cryoglobulinemic vasculitis

TABLE 50.7 Brouet Classification of Cryoglobulinemia¹¹⁸

Type	Composition	Associated Disorders
I	Monoclonal IgG, IgM, or IgA	Monoclonal gammopathy of uncertain significance, multiple myeloma, B cell lymphoma, chronic lymphocytic leukemia, Waldenström macroglobulinemia
II	Polyclonal IgG with monoclonal IgM (positive rheumatoid factor)	Hepatitis C (˜95% of cases); rarely hepatitis B, Epstein-Barr virus Lymphoproliferative disorders (especially B cell lymphoma) Essential mixed cryoglobulinemia Autoimmune disease (Sjögren syndrome, systemic lupus erythematosus)
III	Polyclonal IgG with polyclonal IgM	Infection: viral (hepatitis C [˜50% of cases], hepatitis B, Epstein-Barr virus, HIV, cytomegalovirus); bacterial (endocarditis, poststreptococcal infection; leprosy); parasitic (schistosomiasis, toxoplasmosis, malaria) Autoimmune disease: systemic lupus erythematosus; rheumatoid arthritis Lymphoproliferative disorders Chronic liver disease Essential

The exact pathogenesis of the rheumatoid factor generation in HCV infected patients is still unknown, but may relate to B cell dysregulation following HCV infection. The E2 envelope protein of HCV has been shown to bind
directly to B lymphocytes via CD-81 receptors leading to activation and proliferation.⁴¹ A range of autoantibodies are commonly found with HCV infection with an increased incidence of autoimmune diseases such as thyroid disease, diabetes, and Sjögren syndrome. It is likely that earlier in the course of HCV infection, B cell stimulation produces polyclonal IgM leading to a type III cryoglobulinemia. Over time, a B cell clone emerges, due to the acquisition of somatic genetic alterations which enhance B cell survival, leading to a monoclonal IgM antiglobulin and type II cryoglobulinemia (Fig. 50.7). Notably, a t(14;18) translocation, which may lead to overexpression of the antiapoptotic gene bcl-2, has been described in 80% of patients with HCV and cryoglobulinemia, but is rare (<10%) in HCV patients without circulating cryoglobulins.⁴²

FIGURE 50.7 Hepatitis C-associated cryoglobulinemia. Binding of hepatitis C viral antigens to B cells leads to polyclonal proliferation and activation, with the development of a type II mixed cryoglobulinemia. Further clonal selection may generate a monoclonial type II mixed cryoglobulinemia, and long-term is a risk of developing B cell lymphoma. The figure depicts a postulated sequence but does not imply that a type III cryoglobulinemia always precedes type II cryoglobulinemia.

The association of HCV with cryoglobulinemic MPGN is clear, although there remains debate over the role of HCV in noncryoglobulinemic MPGN.⁴³

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