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04320416
Abstract
Viruses are capable of inducing a wide spectrum of glomerular disorders that can be categorized on the basis of the
duration of active viremia: acute, subacute, or chronic. The variable responses of the adaptive immune system to
each time period of viral infection results mechanistically in different histologic forms of glomerular injury. The
unique presence of a chronic viremic carrier state with either hepatitis C (HCV) or HIV has led to the opportunity Division of
to study in detail various pathogenic mechanisms of viral-induced glomerular injury, including direct viral Nephrology, Miami
infection of renal tissue and the development of circulating immune complexes composed of viral antigens that Transplant Institute,
deposit along the glomerular basement membrane. Epidemiologic data show that approximately 25%–30% of all University of Miami
HIV patients are coinfected with HCV and 5%–10% of all HCV patients are coinfected with HIV. This situation Miller School of
Medicine, Miami,
can often lead to a challenging differential diagnosis when glomerular disease occurs in this dual-infected pop- Florida
ulation and requires the clinician to be familiar with the clinical presentation, laboratory workup, and patho-
physiology behind the development of renal disease for both HCV and HIV. Both of these viruses can be Correspondence:
categorized under the new classification of infection-associated GN as opposed to being listed as causes of Dr. Warren Kupin,
postinfectious GN as has previously been applied to them. Neither of these viruses lead to renal injury after a latent University of Miami,
period of controlled and inactive viremia. The geneses of HCV- and HIV-associated glomerular diseases share a Miami Transplant
Institute, 1801 NW
total dependence on the presence of active viral replication to sustain renal injury so the renal disease cannot be 9th Ave, #568, Miami,
listed under “postinfectious” GN. With the new availability of direct-acting antivirals for HCV and more effective FL 33136. Email:
combined antiretroviral therapy for HIV, successful remission and even regression of glomerular lesions can be wkupin@med.miami.
achieved if initiated at an early stage. edu
Clin J Am Soc Nephrol ▪: ccc–ccc, 2016. doi: 10.2215/CJN.04320416
www.cjasn.org Vol ▪ ▪▪▪, 2016 Copyright © 2016 by the American Society of Nephrology 1
2 Clinical Journal of the American Society of Nephrology
HCV
With the current availability of direct-acting antivirals
(DAA) which can achieve a viral remission of .95% for most
HCV genotypes, the prevalence of glomerular disease in this
population should progressively decline in the coming de-
cade (7). Chronic HCV viremia is present in 150–170 million
people worldwide (3% of the global population) and in 3.2
million people in the United States. Approximately 2–3 mil-
lion new cases of HCV occur each year with 75%–90% of
these patients becoming chronic carriers (8). Figure 1. | Glomerular disease in patients with chronic HCV infection.
Similar to HBV, HCV-associated glomerular disease is Ag, antigen; HCV, hepatitis C virus; MC, mixed cryoglobulinemia; MN,
primarily a consequence of viral antigen – immune com- membranous glomerulopathy; MPGN, membranoproliferative GN;
plex formation with glomerular basement membrane PAN, polyarteritis nodosa.
Clin J Am Soc Nephrol ▪: ccc–ccc, ▪▪▪, 2016 Viral-Associated GN: Hepatitis C and HIV, Kupin 3
suggests that IgA can be and likely should be considered a 2. Couser WG, Johnson RJ: The etiology of glomerulonephritis:
manifestation of HIVICK (34). roles of infection and autoimmunity. Kidney Int 86: 905–914,
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Each of these lesions has their own distinct prognosis, with 3. Fowell AJ, Sheron N, Rosenberg WM: Renal hepatitis C in the
membranous and the “lupus- like” proliferative lesions pro- absence of detectable serum or hepatic virus. Liver Int 28:
gressing the fastest toward ESRD. In general, HIVICK prog- 889–891, 2008
resses at a slower pace toward ESRD than untreated HIVAN, 4. Fabrizi F, Messa P, Martin P: Novel evidence on hepatitis
with 70% of HIVAN patients requiring dialysis within 2 years C virus-associated glomerular disease. Kidney Int 86: 466–469,
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of diagnosis compared with only 34% of HIVICK patients (35). 5. Li D, Gao G, Jiang H, Tang Z, Yu Y, Zang G: Hepatitis B virus-
The majority of studies do not show a major effect of associated glomerulonephritis in HBsAg serological-negative
cART on the progression of HIVICK. cART has been able to patients. Eur J Gastroenterol Hepatol 27: 65–69, 2015
induce histologic regression in HIVAN but this has only 6. Kong D, Wu D, Wang T, Li T, Xu S, Chen F, Jin X, Lou G: Detection
been infrequently seen in HIVICK. This is likely due to the of viral antigens in renal tissue of glomerulonephritis patients
without serological evidence of hepatitis B virus and hepatitis C
permanent destructive injury to the glomerular basement virus infection. Int J Infect Dis 17: e535–e538, 2013
membrane from immune complex deposition in HIVICK 7. Yau AH, Yoshida EM: Hepatitis C drugs: the end of the pegylated
compared with the reversible intracellular phenotypic interferon era and the emergence of all-oral interferon-free an-
changes of the podocyte characteristic of HIVAN. tiviral regimens: a concise review. Can J Gastroenterol Hepatol
28: 445–451, 2014
The heterogeneous nature of HIVICK and the limited 8. Shire NJ, Sherman KE: Epidemiology of Hepatitis C Virus: A Battle
number of published studies on outcomes makes it difficult on New Frontiers. Gastroenterol Clin North Am 44: 699–716,
to make a recommendation on the benefit of cART. Because 2015
50% of the lesions are postinfectious these would not be 9. Gill K, Ghazinian H, Manch R, Gish R: Hepatitis C virus as a
expected to improve with cART, whereas the remaining systemic disease: reaching beyond the liver. Hepatol Int 10:
415–423, 2016
immune complex glomerular diseases should theoretically 10. Saadoun D, Terrier B, Semoun O, Sene D, Maisonobe T, Musset L,
show benefit depending on their degree of chronicity. Amoura Z, Rigon MR, Cacoub P: Hepatitis C virus-associated
polyarteritis nodosa. Arthritis Care Res (Hoboken) 63: 427–435,
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Idiopathic FSGS 11. Tong X, Spradling PR: Increase in nonhepatic diagnoses among
The demographics of glomerular disease in HIV patients persons with hepatitis C hospitalized for any cause, United
have been changing on the basis of the specific demo- States, 2004-2011. J Viral Hepat 22: 906–913, 2015
graphics of the population being reported (36). Currently, 12. Böckle BC, Sepp NT: Hepatitis C virus and autoimmunity.
Auto Immun Highlights 1: 23–35, 2010
in Western Europe and in the United States, noncollapsing 13. Ozkok A, Yildiz A: Hepatitis C virus associated glomer-
FSGS is emerging as the most common glomerular lesion ulopathies. World J Gastroenterol 20: 7544–7554, 2014
seen. These results are self-fulfilling if the population is 14. Zignego AL, Gragnani L, Piluso A, Sebastiani M, Giuggioli D,
predominantly cART-treated. Because APOL1 polymor- Fallahi P, Antonelli A, Ferri C: Virus-driven autoimmunity and
lymphoproliferation: the example of HCV infection. Expert Rev
phisms, which are restricted to black race origin, are vi-
Clin Immunol 11: 15–31, 2015
tally important for the development of HIVAN, any study 15. Terrier B, Marie I, Lacraz A, Belenotti P, Bonnet F, Chiche L,
dealing with European or largely white HIV patients will Graffin B, Hot A, Kahn JE, Michel C, Quemeneur T, de Saint-
clearly never show a significant percentage of HIVAN or Martin L, Hermine O, Léger JM, Mariette X, Senet P, Plaisier E,
FSGS lesions and may show more HIVICK (37). Cacoub P: Non HCV-related infectious cryoglobulinemia
vasculitis: Results from the French nationwide CryoVas survey
and systematic review of the literature. J Autoimmun 65: 74–81,
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Summary 16. Ferri S, Muratori L, Lenzi M, Granito A, Bianchi FB, Vergani D:
The pathogenic mechanisms of glomerular disease in HCV HCV and autoimmunity. Curr Pharm Des 14: 1678–1685,
and HIV patients exemplify the wide spectrum of immuno- 2008
logic and microbiologic pathways utilized by viruses in 17. Dammacco F, Racanelli V, Russi S, Sansonno D: The expanding
general to cause renal disease. Conclusive evidence exists both spectrum of HCV-related cryoglobulinemic vasculitis: a narrative
review. Clin Exp Med 16: 233–242, 2016
for HIV and HCV for direct viral infection of renal tissue as 18. Tasleem S, Sood GK: Hepatitis C Associated B-cell Non-Hodgkin
well as the development of immune complexes partially Lymphoma: Clinical Features and the Role of Antiviral Therapy.
consisting of viral antigens. These same principles can be J Clin Transl Hepatol 3: 134–139, 2015
applied to other viral infections that will be discussed in part 2. 19. Sise ME, Bloom AK, Wisocky J, Lin MV, Gustafson JL, Lundquist
Although corticosteroids have been used in selected AL, Steele D, Thiim M, Williams WW, Hashemi N, Kim AY,
Thadhani R, Chung RT: Treatment of hepatitis C virus-associated
patients with HIVAN and lymphocytotoxic immunosup- mixed cryoglobulinemia with direct-acting antiviral agents.
pression has been advocated for patients with HCV-associated Hepatology 63: 408–417, 2016
cryoglobulinemia, invariably the ultimate control of active 20. Fabrizi F, Martin P, Cacoub P, Messa P, Donato FM: Treatment of
viremia remains the key objective in the management of hepatitis C-related kidney disease. Expert Opin Pharmacother
both HIV- and HCV-associated GN. 16: 1815–1827, 2015
21. Sise ME, Bloom AK, Wisocky J, Lin MV, Gustafson JL, Lundquist
AL, Steele D, Thiim M, Williams WW, Hashemi N, Kim AY,
Disclosures Thadhani R, Chung RT: Treatment of hepatitis C virus-associated
None. mixed cryoglobulinemia with direct-acting antiviral agents.
Hepatology 63: 408–417, 2016
22. Piot P, Abdool Karim SS, Hecht R, Legido-Quigley H, Buse K,
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