Viral Glomerulonephritides

Which viruses cause glomerular disease?

A number of viral infections can result in glomerular damage, inducing a spectrum of lesions with differing pathogenetic mechanisms (Table 1, Figure 1). The most common of these include hepatitis B, which typically causes glomerulopathies when there is a chronic carrier state, often owing to childhood infection in endemic areas. Glomerular lesions occur in long-term hepatitis C infection, and are found in acute or chronic infection with human immunodeficiency virus (HIV). Less often, parvovirus B19 and cytomegalovirus (CMV) induce glomerular injury. Detailed specific lesions associated with these viruses are provided below. Nonspecific entities, such as postinfectious glomerulonephritis and AA amyloidosis secondary to chronic disease, are not discussed.

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What types of glomerular disease are caused by hepatitis B and C?

Hepatitis B and C produce similar types of immune complex glomerulonephritides, although with differing incidences. Secondary membranous nephropathy, often with mesangial hypercellularity and mesangial or subendothelial deposits, is the most common hepatitis B–associated lesion and occurs less frequently with hepatitis C. Contrarily, immune complex membranoproliferative glomerulonephritis (MPGN), often with endocapillary mixed cryoglobulin deposition, typically is found with hepatitis C and much less often with hepatitis B, the latter usually without cryoglobulins. In fact, hepatitis C is the most often identified cause of secondary MPGN. Nonspecific mesangial proliferative glomerulonephritis may result from immune complex deposition in patients infected with either form of hepatitis. Rarely, patients infected with hepatitis C have immune deposits with a fibrillary substructure diagnostic for fibrillary or immunotactoid glomerulonephritis, the latter with very few reported cases.

How does HIV manifest as renal disease?

There are varied glomerular lesions associated with HIV infection that may owe, in part, to differing HIV subtypes and host genetic heterogeneity. The most well-known renal complication is collapsing glomerulopathy (HIV-associated nephropathy or HIVAN), characterized by glomerular capillary obliteration with hypertrophy and hyperplasia of epithelial cells, and tubulointerstitial injury with microcystic tubular dilatation. This lesion occurs predominantly in black patients, particularly in those with two APOL1 risk alleles and not receiving highly active antiretroviral therapy (HAART).

HIV also is associated with more typical forms of focal and segmental glomerulosclerosis (FSGS), although it is uncertain if this is due to the virus, reflects the incidence of FSGS in the non-HIV infected patient population, or is a nonspecific result of chronic kidney injury due to hypertension, diabetes, or other factors related to aging. A number of immune complex glomerulonephritides have been attributed to HIV infection. In Caucasian patients, the most prevalent is IgA nephropathy, which has the usual morphologic and clinical features of this disease with the exception of endothelial tubuloreticular inclusions in untreated patients, a hallmark of HIV infection. A lupus-like immune complex lesion has been described in children and adults, sometimes with positive lupus serologies, and has been associated with lower viral loads compared to patients with HIVAN.

What types of disease are associated with other viral infections?

Parvovirus B19 has been reported in association with collapsing glomerulopathy with a predilection for black patients, similar to HIVAN and also possibly augmented by APOL1 risk alleles. Typical FSGS also has been described in chronic infection, but more likely indicates secondary scarring. Proliferative glomerulonephritis has been identified infrequently and occurs soon after viral infection, with IgG or IgA dominant immune complexes identified in glomeruli; the latter may clinically simulate Henoch-Schonlein purpura.

There are few reported cases of CMV-related glomerulopathies in humans; these include mesangial proliferation with or without necrosis, MPGN and membranous nephropathy typically described in infected infants or immunosuppressed renal transplant recipients, and collapsing glomerulopathy in immunocompetent and transplanted patients.

How do viral infections cause glomerulonephritis?

There are common mechanisms of virally induced glomerular injury including direct infection of glomerular cells, damage due to upregulated cytokines and pro-inflammatory factors, and deposition of immune complexes. Additionally, for all glomerular lesions secondary to viral infections, host genetic factors likely play an important role. HIV and parvovirus B19 directly infect glomerular epithelial, and possibly endothelial, cells as evidenced by detection of intracellular viral genome, with expression of viral proteins resulting in cytokine production, cell injury, proliferation, apoptosis, and dysregulation or dedifferentiation. Virally induced immune complex glomerulonephritis occurs following deposition of circulating immune complexes containing viral antigens, in situ immune complex formation after a planted viral antigen, or autoantibody formation against intrinsic antigens due to molecular mimicry.

A number of HIV antigens, such as p24 and gp41, have been found in circulating immune complexes or as circulating antibody targets, while p24 also has been found in eluted glomerular immune deposits. Hepatitis B and C generally are considered not to directly infect renal cells, but to cause immune complex disease. Increased circulating immune complexes have been found in hepatitis B–infected patients with glomerulonephritis. All major hepatitis B antigens (core, surface, and e) have been identified in immune complex deposits, with e antigens associating with subepithelial, and core and surface antigens with mesangial and subendothelial, immune deposits. Hepatitis C envelope protein E2 can induce rheumatoid factor production and cryoglobulins, in association with a high prevalence of circulating anti-hepatitis C antibodies and immune complex formation. It has been suggested that parvovirus B19 also can stimulate antibody production and immune complexes. Data regarding CMV-associated glomerulopathies are scant and contradictory with mechanisms for disease not yet established.

In what way do treatments directed toward these viral infections affect glomeruli?

In the era of HAART, the incidence of HIV-associated glomerular disease has decreased owing to drug efficacy in preventing and treating HIVAN. HIV thus often behaves as a chronic illness in these patients, who may develop other disease processes with resulting glomerular lesions such as diabetic glomerulosclerosis, arteriosclerosis with glomerular ischemia, and secondary FSGS due to aging and nephron loss.

Treatments for active hepatitis B include nucleotide and nucleoside reverse transcriptase inhibitors and interferon alpha, the latter also used for hepatitis C typically with ribavirin with or without a protease inhibitor. The newest treatments for hepatitis C include sofosbuvir with ledipasvir, grazoprevir with elbasvir for those with eGFR <30 mL/min, and other direct-acting antivirals. These treatments typically are effective in viral eradication, with glomerular improvement reflected by reductions in proteinuria and progression to renal failure; however, there may be persistence of glomerular injury and cryoglobulins. Additionally, interferon therapy is associated with development of podocytopathies including minimal change disease and FSGS, including the collapsing variant. Other treatments such as steroids, rituximab, and plasma exchange may be employed with the caveat that careful monitoring is needed to detect possible worsening viral symptoms. There are no specific therapies for treatment of parvovirus B19–associated glomerulopathies, and the immune complex lesions largely resolve spontaneously. Based on data from transplant recipients with parvovirus B19–associated glomerulopathies, including collapsing glomerulopathy, intravenous immunoglobulin may provide some clinical benefit.

Suggested Reading

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Johnson RJ, Wilson R, Yamabe H, et al. Renal manifestations of hepatitis C virus infection. Kidney Int 1994; 46:1255–63.

Markowitz GS, et al. Hepatitis C viral infection is associated with fibrillary glomerulonephritis and immunotactoid glomerulopathy. J Am Soc Nephrol 1998; 9:2244–52.

Fine DM, Fogo AB, Alpers CE. Thrombotic microangiopathy and other glomerular disorders in the HIV-infected patient. Semin Nephrol 2008; 28:545–55.

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Waldman M, Kopp JB. Parvovirus B19 and the kidney. Clin J Am Soc Nephrol 2007; 2:S47–56.

Chandra P, Kopp JB. Viruses and collapsing glomerulopathy: a brief critical review. Clin Kidney J 2013; 6:1–5.

Wenderfer SE. Viral-associated glomerulopathies in children. Pediatr Nephrol 2015; 30:1929–38.

Fabrizi F, et al. Treatment of hepatitis C-related kidney disease. Expert Opin Pharmacother 2015; 16:1815–27.