CASE REPORT

De Novo Membrano-Proliferative Nephritis Following InterferonTherapy for Chronic Hepatitis C (Case Study and LiteratureReview)

Fabrizio Fabrizi • Alessio Aghemo • Gabriella Moroni •

Patrizia Passerini • Roberta D’Ambrosio •

Paul Martin • Piergiorgio Messa

Received: 14 September 2013 / Accepted: 13 November 2013 / Published online: 8 December 2013

� Springer Science+Business Media New York 2013

Keywords Hepatitis C � Membrano-proliferative

glomerulonephritis � Interferon � Ribavirin

Introduction

HCV infects approximately 2–3 % of the global population

and is a leading cause of end-stage liver disease and

hepatocellular carcinoma. Antiviral treatment with pegy-

lated interferon and ribavirin eradicates HCV in many

patients, while 40–90 % of patients on pegylated IFN plus

ribavirin have sustained viral clearance [1]. However, IFN-

based therapy is limited by frequent and, at times, serious

adverse effects which represent an important barrier to

treatment delivery. In clinical trials, approximately

10–15 % of patients discontinue peg-IFN and ribavirin

therapy due to adverse effects, but, in clinical practice, the

rate of treatment interruption is probably higher. Combined

antiviral therapy (conventional or pegylated IFN plus

ribavirin) impacts most, if not all, organ systems.

According to the KULDS Group, the rate of treatment

discontinuation was 8.7 % (n = 250) in a total of 2,871

Japanese patients who had chronic HCV treated with peg-

IFN a-2b and RBV [1].

Given the frequency of these adverse effects predomi-

nantly hematological and psychiatric, nephrotoxicity

associated with IFN therapy has received little notice. The

nephrotoxicity of combined antiviral treatment seems to be

related to the effects of IFN; ribavirin as mono-therapy for

chronic hepatitis C has not been implicated in renal toxicity

[1]. Almost paradoxically, the benefit of IFN-based therapy

on HCV-associated glomerular disease is now well estab-

lished, even in the absence of cryoglobulins [2, 3]; for this

reason, IFN therapy has been defined as ‘‘a double-edged

sword’’ by clinical nephrologists [4].

We report here the case of a patient who developed

membrano-proliferative glomerulonephritis (MPGN) dur-

ing treatment with combined antiviral treatment (pegIFN

a-2b plus RBV) for chronic hepatitis C. After discontinu-

ation of the antiviral regimen, he received immunosup-

pressive therapy with complete recovery of kidney function

and partial remission of urinary abnormalities. We have

also performed a systematic review of nephrotoxicity

induced by IFN therapy.

Case Report

A 58-year-old Caucasian male was diagnosed with hepa-

titis C (genotype 1b) in 2004. He underwent liver biopsy

showing steatosis and chronic active hepatitis with nodular

changes. Shortly after diagnosis, he was treated with

combination antiviral therapy with peg-Interferon a2b (1.5

mcg/kg/week) and ribavirin for 6 months without viral

response. A quantitative PCR assay for hepatitis C virus

RNA revealed a post-treatment viral load of 333,952 IU/

mL. Repeat routine urinalysis, 24 h proteinuria, and blood

F. Fabrizi (&) � G. Moroni � P. Passerini � P. Messa

Division of Nephrology, Maggiore Hospital, IRCCS Foundation,

Pad. Croff, Via Commenda 15, 20122 Milan, Italy

e-mail: fabrizi@policlinico.mi.it

A. Aghemo � R. D’Ambrosio

Division of Digestive Diseases, Maggiore Hospital, IRCCS

Foundation, Milan, Italy

P. Martin

Division of Hepatology, School of Medicine, University of

Miami, Coral Gables, FL, USA

123

Dig Dis Sci (2014) 59:691–695

DOI 10.1007/s10620-013-2959-4

chemistries (performed over the period 2004–2010)

showed an absence of proteinuria and haematuria, and

normal creatinine. In September 2010, he started a second

course of therapy (peg-Interferon a2a, 180 mcg/week plus

ribavirin 1,000 mg/day); pre-treatment HCV RNA load

was 298,382 IU/mL. Antiviral agents were discontinued

after 2 months (December 2010) due to the occurrence of

proteinuria (2.5 g/24 h). At that time, HCV RNA was

42,330 IU/mL. Urine sediment, analysed by phase-contrast

microscopy, showed microscopic haematuria (5–20 eryth-

rocytes/microscopic field; 46 % having dysmorphic nature,

5 % acanthocytes) and numerous casts (granular, hyaline,

lipid, and red cell casts). Remission of proteinuria was not

observed after interruption of the antiviral therapy; there-

fore, renal biopsy was performed (May 2011). At that time,

kidney function was normal (serum creatinine, 1.04 mg/

dL) and urine protein excretion ranged between 1.5 and

6.4 g/24 h. Kidney histology showed 19 glomeruli, 5 of

which had global sclerosis, while 14 had features charac-

teristic of membrano-proliferative glomerulonephritis

(mesangial cell proliferation, mesangial matrix expansion,

thickening of the capillary wall with double contour

appearance, and centrolobular sclerosis). Intraluminal

fibrin deposition with ‘‘pseudothrombi’’ appearance was

observed in one glomerulus. Immunofluorescence studies

showed segmental IgM deposition in 5 out of 12 glomeruli,

C1q deposits were observed in 2 out of 12 glomeruli with

mesangial distribution. He was anti-HCV positive, HCV

RNA positive (758,215 IU/mL), negative serum for cryo-

globulins, normal serum levels of rheumatoid factor, C3/

C4 fractions, and electrophoresis. Anti-nuclear antibody,

anti-double-stranded DNA (anti-DNA), and anti-neutrophil

cytoplasmic antibodies were not detected. Other pertinent

chemistries are shown in Table 1. Pulse intravenous steroid

therapy was instituted (methyl-prednisolone, 750 mg/day)

for three alternate days. The patient developed hypergly-

cemia and was started on insulin. Oral steroid therapy was

then initiated (prednisone, 0.5 mg/kg/day), and cyclo-

phosphamide was given by mouth (1–1.5 mg/kg/day).

Although serum creatinine increased up to 1.7 mg/dL urine

protein levels fell (0.7 g/24 h) over the following weeks.

Cyclophosphamide therapy was discontinued after

4 months (October 2011); mycophenolate mofetil (MMF)

(500 mg three times daily) was initiated, and oral steroids

were tapered to 15 mg/day.

In January 2012, serum creatinine was 1.17 mg/dL and

proteinuria 1.7 g/L; very mild microscopic hematuria

persisted. Prednisone (5 mg/day) and MMF were contin-

ued. Urinary changes and kidney function were stable until

October 2012, when he discontinued immunosuppressive

agents; at that time, HCV RNA was 1,222,600 IU/mL.

Serial measurement over the follow-up showed an absence

of serum cryoglobulins (Table 1); clinical manifestations

eventually associated with cryoglobulinemia were never

described. Five months later, serum creatinine was

1.07 mg/dL (glomerular filtration rate according to MDRD

equation being 72 mL/min/1.73 m2), microscopic hae-

maturia was absent, and urine protein excretion was 2.8 g/

24 h. HCV RNA being 1,501,650 IU/mL. Renin-angio-

tensin inhibitors and angiotensin receptor blockers were

initiated in March 2013 (Fig. 1). His medications cur-

rently include: ranitidine, renin-angiotensin inhibitors,

Table 1 Blood chemistries at admission and over follow-up

Presentation

(Sept 2010)

Mid-

follow-up

(May

2011)

End follow-

up (March

2013)

Serum creatinine

(0.5–1.2, mg/dL)

1.04 1.7 1.07

Blood urea nitrogen

(8–20, mg/dL)

12 62 22

Aspartate

aminotransferase

(5–38, IU/L)

65 79 73

Alanine aminotransferase

(5–41, IU/L)

106 96 94

Gamma-

glutamyltranspeptidase

(8–61, IU/L)

190 132 193

Cholinesterasis

(5,300–12,900, IU/L)

11,417 10,233 10,432

Total bilirubin (0.1–1.1,

mg/dL)

0.85 0.75 0.78

Total protein (6.6–8.7,

g/dL)

6.5 5.8 5.9

Albumin (3.4–4.8, g/dL) 3.2 3.1 3.0

Total cholesterol (\200,

mg/dL)

192 211 203

Triglycerides (\170, mg/

dL)

140 189 164

IgA (70–400, mg/dL) 428 222 329

IgG (700–1,600, mg/dL) 1,182 812 998

IgM (40–230, mg/dL) 196 155 197

C3 (90–180, mg/dL) 106 132 94

C4 (10–40, mg/dL) 22 33 16

Rheumatoid factor (\18,

IU/mL)

7 7 5

Parathyroid hormone

(15–65, pg/mL)

56.7 78 66

Cryocrit 0 % 0 % 0 %

HCV RNA (IU/mL) 298,382 758,215 1,501,650

HBsAg Neg. Neg. Neg.

Anti-HIV Neg. Neg. Neg.

AST aspartate aminotransferase, ALT alanine aminotransferase, c- GT

glutamyltranspeptidase, HCV RNA viraemia of hepatitis C virus

(HCV)

692 Dig Dis Sci (2014) 59:691–695

123

angiotensin receptor blockers, nifedipine, spironolactone,

doxazosin, and repaglinide.

Discussion

We observed the occurrence of nephrotic syndrome during

IFN therapy and its persistence after withdrawal of anti-

viral therapy. Immunosuppressive therapy gave complete

recovery of kidney function but partial remission of urinary

abnormalities, and glomerular haematuria disappeared

despite persistence of non-nephrotic proteinuria. We stop-

ped immunosuppressive agents after 16 months of therapy

due to the potential of accelerated liver disease on steroids

and MMF; stable urinary changes were present.

Serum cryoglobulins and cryoglobulinemic-associated

clinical features were not detected in our patient; no other

cause for the membrano-proliferative glomerulonephritis was

found, thus, we postulate that it was due to pegIFN-ribavirin

therapy. The relationship between the administration of the

drug and the occurrence of nephrotoxicity supports a causative

role for pegIFN-ribavirin even if no improvement was found

after discontinuation of antiviral therapy.

The initial evidence of nephro-toxicity of IFN was

observed in oncology trials [5]. Additional evidence of

nephrotoxicity has accumulated with mono-therapy or

combination therapy in patients with viral hepatitis and

Peg-IFN+RBV

Cyclophosphamide

Intravenous OralSteroids Steroids

Mycophenolate mofetil

Proteinuria(gr/day)

2 gr

4 gr

6 gr

8 gr

Kidney Biopsy

June January October March2011 2012 2012 2013

1 mg/dL

3 mg/dL

Serum creatinine(mg/dL)

Proteinuria

Creatinine

5 mg/dL

ProteinuriaSerum creatinine

Start of antiviral therapy(Sept 2010)

Fig. 1 Temporal relationship between serum creatinine, daily proteinuria, and antiviral/immunosuppressive therapy

Table 2 Side-effects of antiviral agents for HCV (conventional or

pegylated interferon)

Systemic Fever, chills, malaise, headache, anorexia,

arthralgias, weight loss, nausea, vomiting, hair

loss, fatigue, bleeding

Psychological Mood changes, irritability, insomnia, anxiety,

lower libido, suicidal ideation, psychosis,

depression, delirium

Neurologic Seizures, coma, tinnitus, sleep disturbances,

paresthesias

Haematologic Lower blood and red cell count, platelet reduction

Autoimmune Lupus-like syndrome, thrombocytopenic purpura,

diabetes mellitus, myasthenia gravis, rheumatoid

arthritis, primary biliary cirrhosis, autoimmune

thyroid disease

Infectious Higher susceptibility to bacterial infections,

septicaemia

Gastrointestinal Nausea, vomiting, dyspepsia, diarrhoea, abdominal

pain

Hepatic Graft rejection, cytolysis, autoimmune hepatitis

Cutaneous Panniculitis, psoriasis, rash, pruritus, erythema

Pulmonary Interstitial disease, pulmonary tuberculosis

Ocular Retinopathy, visual field defects

Renal Proteinuria, nephrotic syndrome, interstitial

nephritis, graft rejection, acute renal failure, acute

tubular necrosis

Cardiac Arrhythmias, congestive heart failure, dilated

cardiomyopathy, ischemic heart disease

Dig Dis Sci (2014) 59:691–695 693

123

intact kidney function (Table 2). IFN has also been shown

to exacerbate pre-existing kidney disease [6, 7]. IFN-based

therapy is contraindicated after kidney transplantation as it

induces rejection with graft loss. Table 3 lists papers on

IFN-associated glomerular disease in patients with viral

hepatitis [8–22]. It appears that minimal change disease

and focal segmental glomerulosclerosis are common but

other types of glomerular disease can occur. How IFN

causes glomerular damage is uncertain; possibilities

include a direct effect of IFN on the podocyte or an indirect

effect due to altered cytokine network. Alterations in the

synthesis of pathogenic cytokines such as IL-6 or IL-13

family members, which have been incriminated as per-

meability factors in FSGS and MCD, have been cited [23].

Rodents have been the animal model for the under-

standing of IFN-induced kidney disease. Gresser et al. [24]

administered B1 mcg of electrophoretically pure interferon-

a/b daily for 8 days in newborn mice and induced a syn-

drome of inhibition of growth, liver necrosis, late glomer-

ulonephritis, and death. Crescentic glomerulonephritis

occurred 3–4 weeks after IFN administration with a pro-

gressive and fatal outcome. In newborn mice infected with

lymphocytic choriomeningitis virus (LCMV) and injected

with antibody to interferon-a/b, there was an inhibition of

manifestations of the syndrome and decreased mortality.

The extent of disease induced by LCMV in various strains

of mouse was related to the amount of IFN used and the

duration of serum IFN levels in the animals. Thus, these

authors suggested that the amount of the IFN induced by the

virus (instead of the cytopathic activity of the virus) was

implicated in the pathogenesis of the LCMV disease [24].

The consequences of lupus nephritis and IgA-nephrop-

athy have been correlated with up-regulation of major

histo-compatibility complex (MHC) class II and intercel-

lular adhesion-molecule-1 (ICAM-1) expression in

glomeruli and elevated circulating IFN-c levels. In 49

patients with IgA-nephropathy, Yokohama et al. [25]

observed that disease exacerbation and progression were

related to higher serum gamma-IFN levels and glomerular

expression of MHC class II antigens (HLA-DR and DQ)

and cellular proliferative nuclear antigen (Ki-67).

Another mechanism for the development of IFN-based

nephritis has been suggested by Kimmel et al. [26]. They

observed the development of MPGN in a patient treated

with IFN-a for human immunodeficiency virus infection

and suggested that immune complexes (composed of IFN-a

Table 3 Glomerular disease associated with IFN for viral hepatitis (native kidneys): case reports

Authors Reference

year

Country IFN type Kidney

biopsy

Clinical Outcome

Coroneos et al. [8] 1996 USA IFN-a FSGS Acute renal failure,

nephrotic syndrome

ESRD

Horino et al. [9] 1998 Japan IFN-a MPGN Acute renal failure,

proteinuria

NA

Endo et al. [10] 1998 Japan IFN-a2b MN Nephrotic syndrome Remission by steroids

Stein et al. [11] 2001 USA IFN-aCon-1 FSGS Nephrotic syndrome Chronic renal failure

Nishimura et al. [12] 2002 Japan IFN-a2b MCD Nephrotic syndrome Remission by steroids

Willson et al. [13] 2002 USA IFN-a FSGS Nephrotic syndrome Remission by IFN withdrawal

Dizer et al. [14] 2003 Turkey IFN-a MCD Nephrotic syndrome Remission by IFN withdrawal

Suresh et al. [15] 2003 Malaysia NA MCD Nephrotic syndrome Remission by steroids

Fisher et al. [16] 2004 USA Peg-IFN-a2a MPGN Acute renal failure,

nephrotic syndrome

ESRD (Haemodialysis)

Gordon et al. [17] 2004 Australia Peg-IFN-a2a IgA

nephropathy

Acute renal failure Remission by IFN withdrawal

Couto et al. [18]. 2006 Brazil Peg-IFNa-2b FSGS Nephrotic syndrome Partial remission by

immunosuppressive therapy

Tovar et al [19]. 2008 Spain Peg-IFNa-2b MCD Nephrotic syndrome Remission by IFN withdrawal

Kanungo et al. [20] 2010 USA IFN-a FSGS Acute renal failure ESRD (Haemodialysis)

Markowitz et al. [21] 2010 USA IFN-a (n = 5)

IFN-b (n = 3)

IFN-c (n = 2)

FSGS Nephrotic syndrome Partial remission by IFN

withdrawal (n = 9)

Tsai et al. [22] 2012 Taiwan Peg-IFN-a2a MN Nephrotic syndrome Remission by

immunosuppressive therapy

ESRD end-stage renal disease, FSGS focal segmental glomerulosclerosis, IFN interferon, MCD minimal change disease, MN membranous

nephropathy, MPGN membrano-proliferative glomerulonephritis, NA not available

694 Dig Dis Sci (2014) 59:691–695

123

and anti-IFN-a antibody) in the circulation and renal tissue

were implicated in the pathogenesis of glomerular lesions.

However, the occurrence of antibody against recombinant

IFN-a is uncommon; thus, the involvement of anti-IFN-aantibody in the pathogenesis or exacerbation of proteinuria

needs to be defined further.

In conclusion, this case report confirms the nephro-

toxicity of IFN therapy. Because our patient had no other

obvious reason for membrano-proliferative glomerulone-

phritis, we believe that it was due to pegIFN-ribavirin

therapy. Further studies are needed to understand better

pathogenesis, outcome, and management of IFN-associated

glomerular disease.

Acknowledgment This work was supported in part by the grant

‘‘Project Glomerulonephritis’’; in memory of Pippo Neglia.

Conflict of interest None.

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