Renal manifestations of hepatitis C virus infection

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Renal manifestations of hepatitis C virus infection

Extrahepatic complications often are silent and thus overlooked

Lalitha Bandi, MD, MBBS

VOL 113 / NO 2 / FEBRUARY 2003 / POSTGRADUATE MEDICINE

Preview: Infection with hepatitis C virus (HCV) can lead to chronic

active hepatitis, cirrhosis, and liver failure. However, it also is

associated with a wide range of extrahepatic features, including

renal disease. Membranoproliferative glomerulonephritis (MPGN), with

or without cryoglobulinemia, is the most common renal lesion. In this

article, Dr Bandi describes the features of renal disease associated

with hepatitis C and various therapeutic options.

Bandi L. Renal manifestations of hepatitis C virus infection.

Postgrad Med 2003;113(2):73-86

Hepatitis C virus is estimated to infect 4 million people in the

United States and 100 million people worldwide. It is transmitted

primarily through exposure to blood products and intravenous drug

use. Chronic infection occurs in 85% to 90% of persons exposed to the

virus and may progress to chronic active hepatitis and cirrhosis (1).

In addition to liver disease, HCV infection has been associated with

a wide variety of extrahepatic manifestations, including mixed

cryoglobulinemias and renal involvement (2). The most common form of

renal disease is cryoglobulinemic membranoproliferative

glomerulonephritis (MPGN type I) (3-6). Other types include

noncryoglobulinemic MPGN, membranous glomerulonephritis, MPGN type

III, and mesangial proliferative glomerulonephritis.

Epidemiologic factors: HCV infection is a significant cause of MPGN,

especially in countries where HCV is highly prevalent. The virus is

present in about 60% of patients with MPGN in Japan and in 10% to 20%

of patients with MPGN in the United States (7). The greater incidence

of MPGN in some developing countries may be due to a greater

prevalence of chronic HCV infection. Also, HCV infection is present

in about 7% to 9% of patients with chronic renal failure who have not

undergone dialysis and who have no history of blood transfusions (8).

However, nosocomial transmission of HCV during dialysis may occur,

independent of blood transfusions.

Clinical features: Although renal involvement is common in hepatitis

C, its lack of clinical manifestations means it goes undiagnosed in

the majority of patients. Renal involvement can occur early in the

course of the disease and occasionally is the presenting symptom of

HCV infection. Cryoglobulinemic glomerulonephritis is diagnosed

between the fifth and sixth decades of life in most patients, and it

occurs slightly more often in women than in men (5). Only about 20%

of patients with cryoglobulinemia have physical signs of liver

disease at the time of presentation, but the majority of patients

(about 70%) have mildly elevated aminotransferase levels and evidence

of liver involvement on biopsy (9).

Hypertension is present in the majority of patients at the onset of

renal disease; it often is severe and difficult to control. It may

have an accelerated course in patients who are predisposed to

cardiovascular and cerebrovascular events.

Renal disease occurs in about half of patients with mixed

cryoglobulinemia associated with HCV infection (see box following the

references) (10). These patients present with palpable purpura,

arthralgia, neuropathy, and abdominal pain secondary to mesenteric

vasculitis. Such symptoms of mixed cryoglobulinemia often manifest

years before a diagnosis of renal disease is made, but in some

patients, renal and extrarenal manifestations appear concurrently. In

a few patients, symptoms of mixed cryoglobulinemia are absent.

The most common presenting clinical syndrome is an isolated

proteinuria with microscopic hematuria, which is associated with

moderate renal insufficiency in about 50% of cases (6,11). About 25%

of affected patients present with nephrotic syndrome that involves

massive proteinuria and hypoalbuminemia. These patients do not have

circulating cryoglobulins. Acute nephritis is present at onset in 20%

to 25% of patients, characterized by rapid deterioration of renal

function, proteinuria in the nephrotic range (protein, >3 gm/24 hr),

and hematuria. This acute nephritic syndrome usually is concomitant

with acute flare-ups of systemic signs of mixed cryoglobulinemia.

Massive precipitation of cryoglobulins in the glomerular capillary

lumen with consequent severe monocyte infiltration, often with signs

of systemic and renal vasculitis, is responsible for this syndrome.

Acute nephritis often is complicated by oliguric renal failure, which

is reversible with timely treatment using corticosteroids and

cyclophosphamide (Cytoxan, Neosar).

The course of renal disease is variable. Partial or complete

remission of renal symptoms is seen in nearly one third of patients--

even in patients who present with acute renal failure or severe

nephrotic syndrome (12). In another 30% of cases, renal disease has a

rather indolent course and does not progress to renal failure for

several years, despite the persistence of urinary abnormalities and

mild renal dysfunction. In the remainder of patients, multiple

reversible clinical exacerbations, such as acute nephritis and

nephrotic syndrome, occur during the course of the disease. These

acute flare-ups usually are associated with intensification of the

systemic signs of the disease (11).

Progression to end-stage renal failure that requires dialysis is

relatively rare (about 10% of cases), even many years after the onset

of renal disease (12). The majority of these patients die of

cardiovascular disease, systemic vasculitis, or infections before

they have end-stage renal failure. End-stage renal disease is more

likely to develop in older patients and in patients with recurrent

purpura, renal biopsy findings of marked monocytic infiltration, a

high serum cryocrit (the amount of cryoglobulins circulating in the

bloodstream), viremia, proteinuria, and a high serum creatinine level

at presentation (13).

Most patients with HCV-associated membranous nephropathy present with

overt nephrotic syndrome; few have isolated proteinuria in the

nonnephrotic range. Periodic monitoring of renal function and for

proteinuria should be performed in all patients with HCV infection.

Once renal disease is manifest, a renal biopsy may be needed to

identify the type of glomerular lesion present.

Laboratory findings: Mixed cryoglobulins containing polyclonal IgG

and monoclonal IgM rheumatoid factor (RF) (usually IgM-kappa RF) are

present in serum. These elements are measured as cryocrit. The amount

of circulating cryoglobulins varies among patients as well as in

individual patients at different times (range, 2% to 70%). Mixed

cryoglobulinemias can be temporarily undetectable during the course

of the disease. A weak correlation exists between the amount of

circulating cryoglobulins and the severity of renal disease.

Serum complement pattern is characterized by very low levels of early

components, including C4, C1q, and CH50; C3 levels are in the normal

range or only slightly lower. Serum complement pattern, which does

not vary much in relation to changes in clinical activity, is

characteristic of cryoglobulinemic glomerulonephritis (11).

Serum levels of anti-HCV and HCV RNA are detected by reverse

transcriptase polymerase chain reaction; these components are found

in high concentrations in cryoprecipitates as well. Liver enzyme

levels are elevated. Classic membranous glomerulonephritis usually is

associated with normal complement levels, normal liver function,

absence of RF, and cryoglobulinemia.

Pathogenesis: It is postulated that HCV infects circulating B

lymphocytes (14) and stimulates them to synthesize the polyclonal IgM

RF responsible for type III mixed cryoglobulinemia. In some patients,

additional factors such as superimposed infection with other viruses

(eg, hepatitis B virus, Epstein-Barr virus) might induce a shift to

abnormal proliferation of a single clone of B cells that produces

monoclonal IgM-kappa RF, thus inducing type II mixed

cryoglobulinemia. IgM-kappa RF binds avidly to anti-HCV IgG or to the

IgG-HCV immune complex. These circulating immune complexes

concentrate in glomerular capillaries, where they deposit in the

subendothelium and mesangium and initiate cellular proliferation and

leukocyte infiltration.

Chronic HCV infection may produce autoantibodies to native renal

antigens, which may account for some of the glomerular pathologic

response that occurs in membranous glomerulonephritis.

Therapeutic options : A variety of pharmacologic agents are used to

treat patients with HCV-associated MPGN.

Antihypertensive agents: Hypertension is common in HCV-associated

MPGN and contributes to progression of the disease. Blood pressure

control through treatment with a combination of antihypertensive

agents plays an important role in preventing deterioration of renal

function. Proteinuria should be reduced with angiotensin-converting

enzyme inhibitors or angiotensin II receptor blockers, and

hypercholesterolemia should be treated with 3-hydroxy-3-

methylglutaryl coenzyme A reductase inhibitors ( " statins " ).

Immunosuppression and plasmapheresis: Acute nephritic or nephrotic

flare-ups with rapid deterioration of renal function and systemic

vasculitic flares associated with cryoglobulinemia can occur. These

conditions should be treated with intravenous, high-dose

methylprednisolone pulses (0.5-1 g/day for 3 days) and plasmapheresis

(three times a week for 2 to 3 weeks). Plasmapheresis effectively

removes circulating cryoglobulins and thus prevents deposition in

glomeruli (15).

Treatment with plasmapheresis and intravenous corticosteroids can

improve renal function substantially. However, plasmapheresis alone

is not very effective because although it removes circulating

cryoglobulins, it does not suppress their production. Generally,

plasmapheresis is well-tolerated. Complications include hypotension,

bleeding, hypersensitivity reactions, and thrombocytopenia.

Intravenous corticosteroid pulse treatment is followed by high doses

of oral corticosteroids, which should be slowly tapered over 3 to 6

months. In severe cases, a high dose of cyclophosphamide (2 mg/kg/day

for 2 to 4 months) is added. Specific antiviral therapy with

interferon-alpha (IFN-alpha) is initiated as the immunosuppressive

medication is tapered. However, IFN-alpha is contraindicated in acute

flare-ups, since its immunostimulating activity may aggravate renal

disease and can worsen acute flares of acute nephritis and nephrotic

syndrome and systemic vasculitis (16).

Long-term treatment with corticosteroids and cytotoxic agents should

be avoided because it does not protect against renal or extrarenal

flares. In fact, treatment with these agents can increase viremia and

worsen hepatic disease, especially in patients with advanced liver

disease and significant viremia.

Treatment with IFN-alpha: Treating HCV-associated MPGN with 3 million

units of IFN-alpha three times a week for 6 to 12 months improves

renal disease, clears viremia, and reduces acute flare-ups in about

50% to 60% of patients. However, these effects are temporary, and

relapse occurs within a few months of discontinuation of treatment

(17,18).

A study by Sarac and colleagues (19) demonstrated that a high dose of

IFN-alpha (10 million units three times a week) resulted in sustained

improvement of renal disease in a few patients. It also has been

shown to induce remission in patients who do not respond to

conventional doses. However, higher doses often are limited by

patient tolerance. The most common side effects of IFN-alpha include

flulike symptoms, weight loss, and anemia.

Ribavirin: Ribavirin can be taken orally and is generally well-

tolerated, although the dose is limited by development of a

reversible hemolytic anemia. In patients with chronic hepatitis C

without renal involvement, combination therapy with recombinant IFN

alpha-2b and ribavirin (Rebetron) has been shown to be superior to

IFN-alpha alone in inducing longer remission. This combination

regimen has not been investigated in patients with renal involvement,

although a few case reports have shown sustained improvement in renal

disease (20). Controlled trials are planned to investigate this

issue. Ribavirin is eliminated mainly through the kidneys and must be

used with caution in patients with substantial renal impairment. All

patients with quiescent renal disease should receive combination

therapy with recombinant IFN alpha-2b and ribavirin.

Summary: Renal involvement often occurs in HCV infection. The most

common renal manifestation is MPGN with or without cryoglobulinemia.

Patients with glomerulonephritis may have no clinical evidence of

systemic or liver involvement. Pathogenesis of HCV-associated MPGN is

mediated by glomerular deposition of circulating immune complexes

containing HCV and anti-HCV. The treatment of choice for MPGN is IFN-

alpha. However, success is limited, and many patients fail to respond

or experience relapse on discontinuation of therapy. Newer treatment

modalities, such as high-dose IFN-alpha and recombinant IFN alpha-2b

and ribavirin combination therapy, have led to improved suppression

of HCV RNA levels.

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Dr Bandi is a fellow in nephrology, University of Pennsylvania School

of Medicine, Philadelphia. Correspondence: Lalitha Bandi, MD, MBBS,

Department of Medicine, Renal-Electrolyte and Hypertension Division,

University of Pennsylvania, 700 Clinical Research Building, 415 Curie

Blvd, Philadelphia, PA 19104. E-mail: lalithasb@....