Spectrum of Kidney Diseases in Patients With Hepatitis C Virus Infection

A 10-Year Study

Shunhua Guo, MD; Meghan E. Kapp, MD; Diego M. Beltran, MD; Cesar Y. Cardona, MD; Dawn J. Caster, MD; Ronald R. Reichel, MD; Agnes B. Fogo, MD

Disclosures

Am J Clin Pathol. 2021;156(3):399-408.

Abstract and Introduction

Abstract

Objectives: To study the pathologic spectrum of kidney diseases in patients with hepatitis C virus infection (HCV+).

Methods: Native kidney biopsy specimens in HCV+ patients were reviewed.

Results: A total of 9,836 native kidney biopsy specimens were evaluated from January 2007 to December 2016, of which 273 (2.8%) were from HCV+ patients, and of these, 115 (42.1%) had diagnoses consistent with HCV-associated glomerulonephritis (GN). Non–HCV-associated kidney diseases comprised most diagnoses (158 cases, 57.9%) including non–immune complex–mediated kidney diseases (127 cases, 46.5%) and other immune complex–mediated glomerular diseases (31 cases, 11.4%). Forty-one (40.6%) patients had HCV-associated GN among 101 HCV+ patients from 2007 to 2011 vs 74 (43.0%) patients with HCV-associated GN among 172 HCV+ patients from 2012 to 2016. HCV-associated GN showed five morphologic patterns: focal proliferative (5.2%), diffuse mesangial proliferative (50.4%), diffuse membranoproliferative (28.7%), proliferative GN with crescentic lesions (7.8%), and membranous patterns (7.8%).

Conclusions: We found a spectrum of pathologic changes in renal biopsy specimens of HCV+ patients, with most having diseases unrelated to HCV infection, HCV-associated GN showing five morphologic patterns, and availability of effective HCV antiviral therapy not yet resulting in major changes in the spectrum of kidney diseases in these patients.

Introduction

Hepatitis C virus (HCV) is an RNA virus that was discovered in 1989 during the search for the cause of non-A, non-B hepatitis. HCV infection is estimated to be present in 2.8% of the world population and 1.3% of the North American population.^[1] Extrahepatic manifestations associated with HCV infection have been studied since the early 1990s,^[2,3] when the association of HCV infection with mixed cryoglobulinemia and kidney disease was recognized.^[4,5] Kidney disease in patients with HCV infection has been reported most frequently to be membranoproliferative glomerulonephritis (MPGN), but other patterns of glomerulonephritis (GN), including mesangial proliferative GN,^[6] membranous GN,^[7] fibrillary GN, and immunotactoid glomerulopathy,^[8] are also reported.^[9,10] The exact relationship between HCV infection and renal disease remains to be completely settled, especially in those patients without cryoglobulinemia. A meta-analysis showed absence of a relationship between HCV seropositive status and reduced estimated glomerular filtration rate, although HCV seropositive serology was an independent risk factor for proteinuria in the general population.^[11]

Until a few years ago, there were only two drugs for HCV treatment: pegylated-interferon and ribavirin.^[12–14] Since April 2011, direct-acting antiviral agents (DAAs) have been approved for HCV treatment, and they have achieved great success with high sustained virologic response.^[15–17] Some reports showed a decrease or clearance of cryoglobulinemia after direct antiviral treatment, while others showed persistence of cryoglobulinemia after HCV eradication.^[18–20] There are even reports of cases of new-onset HCV-associated GN following sustained virologic response with DAA therapy.^[21] Therefore, it is unclear whether this dramatic improvement of HCV treatment has resulted in a change in the spectrum of HCV-associated kidney diseases in those HCV+ patients or not. The objectives of this study were to characterize the native kidney biopsy specimens in patients with HCV infection in a 10-year period and to compare the spectrum of kidney diseases in these patients seen in the pre-DAA (2007–2011) and post-DAA (2012–2016) eras.

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Table 1. Demographic Data of HCV+ Patients
Period	Total No. of Native Biopsy Specimens	HCV+ Patients, No. (%)	Age Range, y	Average Age, y	Sex, F/M, No.	Ethnicity Mentioned, W/B, No.
2007–2011	3,854	101 (2.6)	10–78	52.8	33/68	31/42
2012–2016	5,982	172 (2.9)	17–88	54.4	54/118	62/60
Total	9,836	273 (2.8)	10–88	53.6	87/186	93/102

B, Black; HCV, hepatitis C virus; W, White.

Table 2. The Kidney Diseases in HCV+ Patients
Characteristic	2007–2011, No. (%)	2012–2016, No. (%)	P Value	Total, No. (%)
Total HCV+ patients	101	172		273
HCV-associated glomerulonephritis	41 (40.6)	74 (43.0)	.64	115 (42.1)
Other IC-mediated glomerular diseases	12 (11.9)	19 (11.0)	.98	31 (11.4)
Non–IC-mediated kidney diseases	48 (47.5)	79 (45.9)	.65	127 (46.5)

HCV, hepatitis C virus; IC, immune complex.

Table 3. The Five Patterns of HCV-Associated Glomerulonephritis
Characteristic	2007–2011, No. (%)	2012–2016, No. (%)	P Value	Total, No. (%)
Total cases of HCV-associated glomerulonephritis	41	74		115
Focal proliferative glomerulonephritis pattern	1 (2.4)	5 (6.8)	.32	6 (5.2)
Diffuse mesangial proliferative pattern	15 (36.6)	43 (58.1)	.03	58 (50.4)
Diffuse membranoproliferative pattern	19 (46.3)	14 (18.9)	.01	33 (28.7)
Proliferative glomerulonephritis with crescentic lesions	3 (7.3)	6 (8.1)	.88	9 (7.8)
Membranous pattern	3 (7.3)	6 (8.1)	.88	9 (7.8)

HCV, hepatitis C virus.

Table 4. Cryo Plugs, Substructures of Deposits, and Cryoglobulinemia in HCV-Associated Glomerulonephritis
Characteristic	2007–2011, No. (%)	2012–2016, No. (%)	P Value	Total, No. (%)
Total cases of HCV-associated glomerulonephritis	41	74		115
Cryo plugs identified by LM, IF, or EM	11 (26.8)	6 (8.1)	.01	17 (14.8)
Substructure of deposits by EM	23 (56.1)	33 (44.6)	.24	56 (48.7)
Cryoglobulinemia positivity in tested patients	14/18 (77.8)	8/22 (36.4)	.01	22/40 (55.0)

EM, electron microscopy; HCV, hepatitis C virus; IF, immunofluorescence; LM, light microscopy.

Table 5. Chronicity Features of HCV-Associated Glomerulonephritis
Characteristic	2007–2011	2012–2016	P Value	Total
Total No. of cases of HCV-associated GN	41	74		115
Global glomerulosclerosis, mean ± SD, %	21.8 ± 21.3	24.9 ± 21.4	.38	23.8 ± 21.4
Interstitial fibrosis, mean ± SD, %	22.0 ± 15.9	28.8 ± 18.9	.08	26.4 ± 18.2

GN, glomerulonephritis; HCV, hepatitis C virus.

Table 6. Pathologic Features of HCV-Associated Glomerulonephritis With Focal Proliferative, Diffuse Mesangial Proliferative, or Diffuse Membranoproliferative Patterns
Characteristic	2007–2011, No. (%)	2012–2016, No. (%)	P value	Total, No. (%)
Total No. of cases of the three patterns	35	62		97
Cryo plug by LM, IF, or EM	11 (31.4)	5 (8.0)	.02	16 (16.5)
IgM dominant staining by IF	33 (94.3)	57 (91.9)	.67	90 (92.8)
EM mesangial deposits	31 (88.6)	55 (88.7)	.98	86 (88.7)
EM subendothelial deposits	27 (77.1)	35 (56.4)	.04	62 (63.9)
EM intramembranous deposits	6 (17.1)	10 (16.1)	.90	16 (16.5)
EM subepithelial deposits	3 (8.6)	23 (37.1)	.01	26 (26.8)
Substructure by EM	22 (62.9)	30 (48.4)	.17	52 (53.6)

EM, electron microscopy; HCV, hepatitis C virus; IF, immunofluorescence; LM, light microscopy.

Table 7. Pathologic Features of Hepatitis C Virus–Associated Glomerulonephritis With Focal or Diffuse Proliferative Glomerulonephritis and Crescentic Lesions ^a
Characteristic	2007–2011			2012–2016
Characteristic	Case 1	Case 2	Case 3	Case 1	Case 2	Case 3	Case 4	Case 5	Case 6
Focal or diffuse proliferative patterns	Focal	Diffuse	Focal	Focal	Focal	Focal	Diffuse	Diffuse	Diffuse
Cellular crescents/total glomeruli	2/6	5/13	1/42	2/15	1/12	3/27	1/15	7/23	6/15
Fibrocellular crescents/total glomeruli	0	2/13	1/42	1/15	5/12	0	1/15	1/23	0
Fibrous crescents/total glomeruli	0	0	0	0	2/12	0	2/15	0	0
Total crescentic lesions/total glomeruli	2/6	7/13	2/42	3/15	8/12	3/27	4/15	8/23	6/15
Fibrinoid necrosis/total glomeruli	3/6	1/13	0	1/15	0	3/27	0	1/23	3/15
Cryo plugs identified by LM, IF, or EM	No	No	No	No	No	No	Yes	No	No
Dominant staining by IF	IgM	C3	IgM	IgM	IgG	IgM	IgM	IgM	IgM
EM mesangial deposits	Yes	Yes	Yes	Yes	Yes	Yes	Yes	Yes	Yes
EM subendothelial deposits	No	Yes	Yes	Yes	Yes	Yes	Yes	Yes	Yes
EM intramembranous deposits	Yes	Yes	No	No	Yes	No	No	No	No
EM subepithelial deposits	No	No	No	No	No	Yes	No	No	No
Substructure of deposits by EM	Yes	Yes	No	No	Yes	Yes	Yes	Yes	Yes
ANCA test	NA	Neg	NA	NA	Neg	Pos	NA	NA	NA
Cryoglobulinemia test	NA	NA	Neg	NA	NA	NA	NA	Pos	Pos
Serum complement level	Low	NA	NA	Low	NA	Low	Low	NA	NA

ANCA, antineutrophil cytoplasmic antibody; EM, electron microscopy; IF, immunofluorescence; IgG, immunoglobulin G; IgM, immunoglobulin M; LM, light microscopy; NA, not available; Neg, negative; Pos, positive.
^aValues are presented as numbers unless otherwise indicated.

Table 8. Pathologic Features of Hepatitis C Virus–Associated Glomerulonephritis With Membranous Pattern
Characteristic	2007–2011, No.	2012–2016, No.	Total, No. (%)
Total cases	3	6	9
With mesangial proliferation	3	5	8/9 (88.9)
IgM-dominant staining by IF	3	4	7/9 (77.8)
EM mesangial deposit	2	6	8/9 (88.9)
EM subendothelial deposit	2	4	6/9 (66.7)
EM intramembranous deposits	2	5	7/9 (77.8)
EM subepithelial deposits	3	6	9/9 (100)
Substructure of deposits by EM	1	2	3/9 (33.3)
PLA2R positivity by IF	1 of 1 tested	2 of 6 tested	3/7 (42.9)

EM, electron microscopy; IF, immunofluorescence; IgM, immunoglobulin M; PLA2R, phospholipase A2 receptor.

Table 9. Other Immune Complex–Mediated Glomerular Diseases in HCV+ Patients
Characteristic	2007–2011, No. (%)	2012–2016, No. (%)	Total, No. (%)
Total HCV+ patients	101	172	273
IgA nephropathy	1 (1.0)	2 (1.2)	3 (1.1)
Membranous glomerulonephritis	1 (1.0)	4 (2.3)	5 (1.8)
Fibrillary glomerulonephritis	3 (3.0)	6 (3.5)	9 (3.3)
Postinfectious glomerulonephritis	5 (4.9)	2 (1.2)	7 (2.6)
Pauci-immune crescentic glomerulonephritis	1 (1.0)	4 (2.3)	5 (1.8)
Lupus nephritis	1 (1.0)	1 (0.6)	2 (0.7)
Total other IC-mediated glomerular diseases	12 (11.9)	19 (11.0)	31 (11.4)

HCV, hepatitis C virus; IC, immune complex.

Table 10. Non–Immune Complex–Mediated Kidney Diseases in HCV+ Patients
Characteristic	2007–2011, No. (%)	2012–2016, No. (%)	Total, No. (%)
Total HCV+ cases	101	172	273
Diabetic nephropathy	18 (17.8)	36 (20.9)	54 (19.8)
Arterionephrosclerosis	12 (11.9)	22 (12.8)	34 (12.5)
Obstruction/reflux	3 (3.0)	3 (1.7)	6 (2.2)
Interstitial nephritis	5 (5.0)	2 (1.2)	7 (2.6)
HIV-associated nephropathy	1 (1.0)	1 (0.6)	2 (0.7)
Focal segmental glomerulosclerosis	3 (3.0)	1 (0.6)	4 (1.5)
Acute tubular injury	2 (2.0)	4 (2.3)	6 (2.2)
Thrombotic microangiopathy	0 (0.0)	2 (1.2)	2 (0.7)
LCDD/LCCN	0 (0.0)	2 (1.2)	2 (0.7)
Miscellaneous	4 (4.0)	6 (3.5)	10 (3.7)
Total non–IC-mediated glomerular disease	48 (47.5)	79 (45.9)	127 (46.5)

HCV, hepatitis C virus; HIV, human immunodeficiency virus; IC, immune complex; LCDD, light chain deposition disease; LCCN, light chain cast nephropathy.