CJASN ePress. Published on October 24, 2016 as doi: 10.2215/CJN.

04320416

Viral-Associated GN: Hepatitis C and HIV

Warren L. Kupin

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

Introduction concomitant with the host immune clearance of viremia

Since their initial discovery in 1898, viruses have
challenged their human hosts with a greater degree of
foreign genomic diversity than any other infectious
organisms (1). Over 5000 DNA and RNA viruses
have been structurally defined, and either by their
own direct intracellular virulence or through the
stimulation of natural host adaptive immune defense
mechanisms they often lead to significant tubule-
interstitial and glomerular injury (2).
One proposed schema that can be used to classify
viral-induced GN can be on the basis of the duration
of active viremia. Patients with recent self-limited
acute viremia (days to weeks) develop significantly
different forms of glomerular pathology as compared
with patients with subacute viremia (weeks to months)
and those with chronic persistent viremia (years). An
outline of the most well documented viruses that fit into
each of these categories and their individual glomerular
lesions that have been described in the literature is
shown in Table 1.
In order to link a viral illness with a specific form of
GN, certain supporting criteria must be met: (1) dem-
onstration of the presence of active quantifiable vire-
mia primarily through serologic PCR testing, (2) the
identification of viral proteins/nucleic acid residues
within renal tissue and/or within immune complexes
deposited in the glomerular basement membrane, and
(3) resolution/regression of the glomerular lesion
or eradication of viremia through antiviral therapy.
However, recent emerging data has proposed a new
relationship of GN associated with occult viral disease
which is defined as the presence of viral nucleic acid
in renal tissue and in peripheral blood mononuclear
cells but with complete absence of detectable systemic
viremia by standard PCR amplification techniques
(3). Occult hepatitis C (HCV) has been detected in
30%–50% of patients with idiopathic membranous
nephropathy, IgA, FSGS, ANCA positive vasculitis,
and membranoproliferative GN (MPGN) (4). Simi-
larly, occult hepatitis B (HBV) infection has been de-
scribed with documented HBV antigens found in
renal tissue but with absent viremia in selected cases
of idiopathic membranous nephropathy and IgA (5).
In many of the cases, viremia could only be identified
by intensive ultracentrifugation of plasma. Possibly
fulfilling the cause and effect nature of this finding,
there is anecdotal evidence that antiviral therapy in
select cases of occult HCV or HBV has led to resolu-
tion of the previously diagnosed “idiopathic” glomer-
ular disease (6). Future research is needed to define
the role of occult viremia from undetectable intracel-
lular reservoirs with clinical renal disease.
This review will detail the pathophysiology, histo-
pathology, and clinical syndromes associated with
clinically active viral diseases, which will be pre-
sented in two separate parts. This issue (part 1)

www.cjasn.org Vol ▪ ▪▪▪, 2016 Copyright © 2016 by the American Society of Nephrology 1
2 Clinical Journal of the American Society of Nephrology

deposition. The classic pathologic hallmark of HCV renal

Table 1. Viruses associated with GN disease is type 1 MPGN as a consequence of type 2 mixed
cryoglobulinemia (MC), although the same renal lesion
Predominant
Virus Type may also develop from noncryoglobulinemic immune
Glomerular Histology
complexes (9). In addition, HCV is also an important cause
Acute of polyarteritis nodosa (PAN) from immune complex de-
Dengue ICGN, MsPGN position in medium size blood vessels leading to renal
Hantavirus HFRS-MsPGN ischemia and infarction similar to HBV PAN and idio-
Varicella-zoster DPGN pathic PAN (10). Other forms of glomerular immune com-
Parvovirus ICGN, PAN, MPA, TMA, IgA plex deposition have been described in HCV patients,
HAV ICGN, MsPGN including mesangial proliferative and focal proliferative
HBV DPGN
GN and IgA nephropathy (Figure 1).
CMV cFSGS, MN, IgA, HSP, ICGN,
MPGN, TMA It is important to note that renal dysfunction in a patient
EBV ICGN, MN, MsPGN with HCV is rarely a result of GN (,10%) and hospital ad-
Coxsackie B RPGN missions for MPGN from HCV have been decreasing for
Subacute the past decade (11). The majority of renal diseases in
Parvovirus cFSGS HCV patients with liver disease are a consequence of
EBV cFSGS, MN acute tubular necrosis, hepatorenal syndrome, prerenal
HBV PAN azotemia, and CKD and therefore it is essential to be fa-
HCV PAN miliar with the typical presentation and characteristics of
Chronic acute GN in HCV patients and how to differentiate them
HBV MN, Type I MPGN, MPGN1MC,
from the more common diagnoses causing AKI in this
PAN, IgA, FSGS
HIV HIVAN, HIVICK, TMA population.
HCV Type I MPGN1MC, Type I
MPGN, PAN, IgA, MN
HEV MN Type 1 MPGN with MC
HCV provides a unique opportunity to study the effects
ICGN, immune complex glomerulonephritis; MsPGN, me-
of a hepatotropic virus that also has unique lymphotropic
sangial proliferative GN; HFRS, hemorrhagic fever and renal potential (12). In the absence of this lymphotropism, HCV
syndrome; DPGN, diffuse proliferative GN; PAN, polyarteritis would be indistinguishable from a pathogenic standpoint
nodosa; MPA, microscopic polyarteritis; TMA, thrombotic mi- from HBV and HIV in the development of typical IgG–
croangiopathy; HAV, hepatitis A virus; HBV, hepatitis B virus; viral particle immune complexes of varying size and vir-
CMV, cytomegalovirus; cFSGS, collapsing FSGS; MN, mem- ulence. In approximately 20% of type 1 MPGN cases
branous glomerulopathy; HSP, Henoch Shoenlein purpura; caused by HCV, this standard sequence results in the pro-
MPGN, membranoproliferative GN; EBV, Epstein-Barr virus; duction of noncryoglobulin immune complexes (13). How-
RPGN, rapidly progressive glomerulonephritis; HCV, hepatitis ever, in the majority of type 1 MPGN lesions, HCV is
C virus; MC, mixed cryoglobulinemia; HIVAN, HIV-associated
capable of specifically binding to CD51 CD811 B cells
nephropathy; HIVICK, HIV immune complex disease of the
kidney; HEV, hepatitis E virus.
which subsequently leads to polyclonal type 3 and even-
tually monoclonal type 2 cryoglobulin synthesis of IgMk.
This IgMk monoclonal antibody is a unique effect of HCV-
driven B cell clonal proliferation and carries rheumatoid
will focus on the glomerular syndromes associated with
long-term chronic HCV and HIV carrier states. In the
second issue (part 2) the focus will concentrate on the
glomerular diseases seen with chronic HBV infection and it
will also cover glomerular diseases seen with a variety of
acute and subacute viral infections including cytomegalo-
virus, parvovirus, Epstein–Barr, hantavirus, and dengue.

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
factor activity. Additional receptors that mediate HCV
B cell stimulation involve the scavenger receptor SR-B3 and
toll receptor TRL4 (14).
The entire cryoglobulin complex consists of monoclonal
IgMk binding to the Fc portion of non-neutralizing HCV-
specific IgG1 and IgG3 that have ineffectively bound the
structural E2 or nonstructural NS3 proteins of HCV or the
actual HCV RNA itself. It is not surprising, given the sheer
size of this complex, that it lodges along the subendothelial
space creating large crystalline intraluminal thrombi com-
pletely distinct from a typical subendothelial immune com-
plex as in SLE. Cryoglobulinemia is unusual (,5%) in all
other forms of viral hepatitis (HBV, hepatitis A virus), HIV
carriers, cytomegalovirus, parvovirus B19, and Epstein-
Barr virus which reinforces the unique role of the HCV/B
cell interaction (15).
The development of MC and type 1 MPGN requires a
considerable duration of viremia and a select host response.
After a minimum of 5–10 years, 35%–50% of HCV carriers,
regardless of HCV genotype, develop type 3 MC which
carries a minimal risk of GN. After 10–15 years of viremia
approximately 10% of patients within this subgroup tran-
sition and develop type 2 MC and systemic small vessel
vasculitis (16). These patients demonstrate the characteris-
tic skin rash (palpable purpura), polyneuropathy, gastro-
intestinal/pulmonary/cardiac/central nervous system
vasculitis, and in 30% of patients a type 1 MPGN.
From a nephrologic standpoint, these patients may present
with hypertension and the nephritic syndrome but impor-
tantly 20% of type 1 MPGN patients present only with the
nephrotic syndrome, making a renal biopsy essential for
diagnosis.
The mechanisms behind the transition from type 3 to
type 2 MC in a small fraction of HCV patients are not well
defined. Host factors may play an important role with
.65% of HCV-positive patients worldwide being men but
there is a reversed female predominance in patients that
develop type 2 MC. The response by sex to chronic anti-
genemia is different, with women showing a TH2 response
and a greater likelihood of autoimmunity compared with
a more typical TH1 response in men. In HCV patients,
autoantibody production is especially prevalent with
66% showing anti-smooth muscle antibodies and 40%
with a positive anti-nuclear antibody. Between 40% and
75% of HCV patients have some form of extrahepatic au-
toimmune complication (17).
Hypocomplementemia of the classic pathway is a
distinguishing feature of type 2 MC with type 1 MPGN
with C4 being low in 93% of patients, whereas C3 is
depressed in only 53% due to both its role as an acute
phase reactant and the possible activation of the alternate
C pathway in some patients. At this stage of their HCV
cycle, most patients will have serologic evidence of
chronic active hepatitis with ,15% showing advanced
cirrhosis.
Left untreated, type 2 MC from HCV is a precursor sign
for the emergence of B cell lymphoma in 6% of patients and
an additional risk factor for cardiovascular death from
coronary vasculitis (18). Therefore, treatment of type 2 MC
and renal disease in HCV patients has a two-fold purpose:
reduce the risk of malignancy and decrease patient cardio-
vascular mortality.
Viral-Associated GN: Hepatitis C and HIV, Kupin 3
Treatment
Ongoing HCV viremia is at the epicenter for the gener-
ation of nephritogenic immune complexes. The develop-
ment of DAAs against HCV has provided a revolutionary
opportunity for long-term successful eradication of HCV
and elimination of cryoglobulinemia (19). These oral agents
have virtually replaced the need for IFN. HCV carries an
innate ability to suppress natural IFNg production in the
host with a concomitant decrease in Treg cells that allow
for persistence of viremia and the development of autoim-
mune sequela. Exogenous IFN used to be the backbone of
therapy but was hampered by the need for prolonged ther-
apy (48 weeks), poor patient tolerance, and an unsatisfac-
tory sustained viral response (,65% on the basis of
genotype). More limiting was the inability to use IFN in
solid organ transplant recipients due to the risk of humoral
rejection (20).
DAAs target three groups of nonstructural proteins
called NS5A, NS5B, and NS3/4A. A variety of drugs in this
class have been developed that are used in combination
over a 12-week period without IFN and result in sustained
viral remissions of .95% for all genotypes. In the setting of
acute cryoglobulinemic vasculitis and GN, DAAs have re-
sulted in clinical remission and disappearance of cryogo-
bulinemia (21). Often, control of viremia alone will not
suffice due to the relative delay in viral clearance over
4–8 weeks, and in some circumstances plasmapheresis, ste-
roids, and rituximab are still needed to control the acute
inflammatory vasculitic symptoms. DAAs are now the rec-
ommended drugs of choice in an IFN-free regimen for pa-
tients with HCV-related MPGN or PAN.
HIV
The HIV pandemic has continued, with 37 million active
carriers in the world (1.1 million in the United States),
2 million newly infected cases per year, and another
15%–20% of patients still unaware of their HIV diagnosis.
The HIV population is significantly less than the 240 mil-
lion carriers of HBV and the 170 million carriers of HCV.
On the basis of the 2013 World Health Organization treat-
ment guidelines only 35%–40% of eligible patients globally
are receiving combined antiretroviral therapy (cART),
indicating that the majority of HIV patients are actively
viremic (22).
The differential diagnosis of glomerular disease in the
setting of HIV infection will be significantly influenced by
(1) the treatment status of the patient: cART-naïve or ac-
tively on cART, and (2) by their coinfection status with
other viruses such as with HBV (5%–10%) or with HCV
(25%–30%). As with all of the viral diseases previously
discussed the prerequisite need for ongoing active viremia
is essential for the development of the classic HIV-related
glomerular syndromes: HIV-associated nephropathy (HIVAN)
and HIV immune complex disease of the kidney (HIVICK)
(Figure 2).
HIVAN
HIVAN represents a unique manifestation of glomerular
injury that arises from direct viral infection of renal tis-
sue, particularly the visceral and parietal epithelial cells,
4 Clinical Journal of the American Society of Nephrology
Figure 2. | Glomerular disease associated with chronic HIV in-
fection. Ag, antigen; DPGN, diffuse proliferative GN; HIVAN, HIV-
associated nephropathy; HIVICK, HIV immune complex disease of
the kidney; MC, mixed cryoglobulinemia; MN, membranous glo-
merulopathy; MPGN, membranoproliferative GN.
without the presence of immune complexes. HIVAN
comprises a constellation of four individual pathologic
findings in the renal biopsy that may not all be present
simultaneously: collapsing FSGS (cFSGS), microcystic di-
lation of the tubules, interstitial nephritis, and the presence
of intracytoplasmic tubulo-reticular inclusions (“TRI-IFN
footprints”). By definition, the only specific requirement
to fulfill the diagnosis of HIVAN is the presence of cFSGS
in the setting of HIV infection with the remaining lesions
found in variable frequencies (23).
HIVAN develops almost exclusively in patients of black
race origin who are homozygous or heterozygous for
APOL1 G1 or G2 variants. The lifetime risk of HIVAN in an
untreated HIV-infected black patient is 2%–10%, however,
this risk increases to 50% if that person is homozygous for
the APOL1 variants. APOLI variants, initially an evolution-
ary advantage for protection against trypanosomiasis in
Africa, now represent the single most important risk factor
for the development of HIVAN worldwide (24).
The histopathologic lesions of HIVAN in a susceptible
host require translation of the nine-gene HIV genome
which then leads to altered phenotype changes in the
podocytes with loss of maturation markers (synaptopodin.
podocalyxin) and upregulation of proliferation markers
(Ki-67). The main HIV genes responsible for these changes
are TAT (transactivator of transcription), NEF (negative fac-
tor), and Vpr (viral protein r) (25).
The one major question as yet unanswered is the method
for direct HIV entry into the podocytes, mesangium, and
tubular cells because they lack CD4 receptors and chemokine
receptors used by HIV for entry into nonrenal tissue. The use
of lipid rafts for freely circulating Tat and Vpr proteins or
binding of the whole HIV virion to DEC-205 (dendritic cell
receptor) or dendritic cell specific ICAM-3-grabbing non-
integrin may allow for direct tissue infection (26).
Although nephrotic range proteinuria is the expected
consequence of cFSGS in HIVAN, early collapsing lesions can
be seen in untreated HIV patients with only microalbumin-
uria (27). Therefore, HIVAN needs to be considered in any
cART-naïve HIV patient of black race ancestry with any de-
gree of abnormal albuminuria or proteinuria.
Because HIVAN is a direct consequence of viral repli-
cation, cART has been demonstrated to attenuate the rate
of decline of GFR and actually cause histologic regression
with a return of the normal podocyte phenotype within the
glomerular lesions (28). This favorable response is predi-
cated on achieving viral remission. Deterioration of renal
function in a patient successfully treated for HIVAN on
cART may be a reflection of the intrinsic nephrotoxicity
of either the protease inhibitors or the non-nucleotide(s)
reverse transcription inhibitors rather than due to HIV ne-
phropathy (29). Alternatively, a condition entitled immune
reconstitution syndrome with AKI from acute interstitial
nephritis or immune complex GN may occur shortly after
starting cART. Finally, because coinfection with HBV or
HCV is common, renal impairment after cART may also
reflect the glomerular injury from these ongoing untreated
and possibly unrecognized viral infections.
New emerging therapy for HIVAN includes renin-
angiotensin-aldosterone system inhibition, interruption
of the mTOR pathway, and retinoic acid derivatives
(30,31). Upregulation of angiotensin 2 with possible co-
stimulation of the mTOR pathway and involving the AT2
receptor lends support for the benefit of direct blockade of
these pathways. Experimentally, HIVAN lesions fail to de-
velop with the use of renin-angiotensin-aldosterone system
and mTOR inhibitors. The application of retinoids in HI-
VAN and other glomerular diseases is currently being in-
vestigated. HIV downregulates the retinoic acid receptor
supporting a potential clinical role for this therapy as an
adjunct to cART.
HIVICK
HIVICK represents a constellation of histopathologic dis-
eases rather than a specific glomerular syndrome of its own
such as HIVAN. This is why it is impossible to describe an
actual typical presentation or outcome for HIVICK because
it represents a pathophysiologic grouping of a wide variety
of glomerular diseases each with a different presentation and
prognosis. All glomerular diseases comprising HIVICK result
from the deposition of immune complexes in the glomerulus,
consisting of either HIV antigens or as a natural result of typi-
cal postinfectious immune complexes that occur due to the
increased risk of infections from a compromised immune
system found in HIV patients not on cART (32). Like HIVAN,
HIVICK is a complication of active HIV viremia in a cART-
naïve patient or a patient with cART resistance. Glomerular
lesions from coinfected HIV patients with HBV or HCV are
not considered HIVICK and are classified separately as second-
ary lesions due to their individual viruses.
Approximately 50% of glomerular histology within the
HIVICK category can be described as postinfectious GN,
with the remaining half resulting from immune complex
deposition consisting of HIV antigens in the form of
membranous, IgA, MPGN, and a “lupus-like” diffuse pro-
liferative GN (33). Some studies have excluded patients
with IgA from having HIVICK assuming it may be an id-
iopathic lesion, however, the colocalization of the HIVp24
and gp120 antigens with IgA in the presence of active HIV
disease and typical IgA histology on biopsy clearly
Clin J Am Soc Nephrol ▪: ccc–ccc, ▪▪▪, 2016
suggests that IgA can be and likely should be considered a
manifestation of HIVICK (34).
Each of these lesions has their own distinct prognosis, with
membranous and the “lupus- like” proliferative lesions pro-
gressing the fastest toward ESRD. In general, HIVICK prog-
resses at a slower pace toward ESRD than untreated HIVAN,
with 70% of HIVAN patients requiring dialysis within 2 years
of diagnosis compared with only 34% of HIVICK patients (35).
The majority of studies do not show a major effect of
cART on the progression of HIVICK. cART has been able to
induce histologic regression in HIVAN but this has only
been infrequently seen in HIVICK. This is likely due to the
permanent destructive injury to the glomerular basement
membrane from immune complex deposition in HIVICK
compared with the reversible intracellular phenotypic
changes of the podocyte characteristic of HIVAN.
The heterogeneous nature of HIVICK and the limited
number of published studies on outcomes makes it difficult
to make a recommendation on the benefit of cART. Because
50% of the lesions are postinfectious these would not be
expected to improve with cART, whereas the remaining
immune complex glomerular diseases should theoretically
show benefit depending on their degree of chronicity.
Idiopathic FSGS
The demographics of glomerular disease in HIV patients
have been changing on the basis of the specific demo-
graphics of the population being reported (36). Currently,
in Western Europe and in the United States, noncollapsing
FSGS is emerging as the most common glomerular lesion
seen. These results are self-fulfilling if the population is
predominantly cART-treated. Because APOL1 polymor-
phisms, which are restricted to black race origin, are vi-
tally important for the development of HIVAN, any study
dealing with European or largely white HIV patients will
clearly never show a significant percentage of HIVAN or
FSGS lesions and may show more HIVICK (37).
Summary
The pathogenic mechanisms of glomerular disease in HCV
and HIV patients exemplify the wide spectrum of immuno-
logic and microbiologic pathways utilized by viruses in
general to cause renal disease. Conclusive evidence exists both
for HIV and HCV for direct viral infection of renal tissue as
well as the development of immune complexes partially
consisting of viral antigens. These same principles can be
applied to other viral infections that will be discussed in part 2.
Although corticosteroids have been used in selected
patients with HIVAN and lymphocytotoxic immunosup-
pression has been advocated for patients with HCV-associated
cryoglobulinemia, invariably the ultimate control of active
viremia remains the key objective in the management of
both HIV- and HCV-associated GN.
Disclosures
None.
References
1. Morgan GJ: What is a virus species? Radical pluralism in
viral taxonomy. Stud Hist Philos Biol Biomed Sci 59:64–70,
2016
Viral-Associated GN: Hepatitis C and HIV, Kupin 5
2. Couser WG, Johnson RJ: The etiology of glomerulonephritis:
roles of infection and autoimmunity. Kidney Int 86: 905–914,
2014
3. Fowell AJ, Sheron N, Rosenberg WM: Renal hepatitis C in the
absence of detectable serum or hepatic virus. Liver Int 28:
889–891, 2008
4. Fabrizi F, Messa P, Martin P: Novel evidence on hepatitis
C virus-associated glomerular disease. Kidney Int 86: 466–469,
2014
5. Li D, Gao G, Jiang H, Tang Z, Yu Y, Zang G: Hepatitis B virus-
associated glomerulonephritis in HBsAg serological-negative
patients. Eur J Gastroenterol Hepatol 27: 65–69, 2015
6. Kong D, Wu D, Wang T, Li T, Xu S, Chen F, Jin X, Lou G: Detection
of viral antigens in renal tissue of glomerulonephritis patients
without serological evidence of hepatitis B virus and hepatitis C
virus infection. Int J Infect Dis 17: e535–e538, 2013
7. Yau AH, Yoshida EM: Hepatitis C drugs: the end of the pegylated
interferon era and the emergence of all-oral interferon-free an-
tiviral regimens: a concise review. Can J Gastroenterol Hepatol
28: 445–451, 2014
8. Shire NJ, Sherman KE: Epidemiology of Hepatitis C Virus: A Battle
on New Frontiers. Gastroenterol Clin North Am 44: 699–716,
2015
9. Gill K, Ghazinian H, Manch R, Gish R: Hepatitis C virus as a
systemic disease: reaching beyond the liver. Hepatol Int 10:
415–423, 2016
10. Saadoun D, Terrier B, Semoun O, Sene D, Maisonobe T, Musset L,
Amoura Z, Rigon MR, Cacoub P: Hepatitis C virus-associated
polyarteritis nodosa. Arthritis Care Res (Hoboken) 63: 427–435,
2011
11. Tong X, Spradling PR: Increase in nonhepatic diagnoses among
persons with hepatitis C hospitalized for any cause, United
States, 2004-2011. J Viral Hepat 22: 906–913, 2015
12. Böckle BC, Sepp NT: Hepatitis C virus and autoimmunity.
Auto Immun Highlights 1: 23–35, 2010
13. Ozkok A, Yildiz A: Hepatitis C virus associated glomer-
ulopathies. World J Gastroenterol 20: 7544–7554, 2014
14. Zignego AL, Gragnani L, Piluso A, Sebastiani M, Giuggioli D,
Fallahi P, Antonelli A, Ferri C: Virus-driven autoimmunity and
lymphoproliferation: the example of HCV infection. Expert Rev
Clin Immunol 11: 15–31, 2015
15. Terrier B, Marie I, Lacraz A, Belenotti P, Bonnet F, Chiche L,
Graffin B, Hot A, Kahn JE, Michel C, Quemeneur T, de Saint-
Martin L, Hermine O, Léger JM, Mariette X, Senet P, Plaisier E,
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,
2015
16. Ferri S, Muratori L, Lenzi M, Granito A, Bianchi FB, Vergani D:
HCV and autoimmunity. Curr Pharm Des 14: 1678–1685,
2008
17. Dammacco F, Racanelli V, Russi S, Sansonno D: The expanding
spectrum of HCV-related cryoglobulinemic vasculitis: a narrative
review. Clin Exp Med 16: 233–242, 2016
18. Tasleem S, Sood GK: Hepatitis C Associated B-cell Non-Hodgkin
Lymphoma: Clinical Features and the Role of Antiviral Therapy.
J Clin Transl Hepatol 3: 134–139, 2015
19. Sise ME, Bloom AK, Wisocky J, Lin MV, Gustafson JL, Lundquist
AL, Steele D, Thiim M, Williams WW, Hashemi N, Kim AY,
Thadhani R, Chung RT: Treatment of hepatitis C virus-associated
mixed cryoglobulinemia with direct-acting antiviral agents.
Hepatology 63: 408–417, 2016
20. Fabrizi F, Martin P, Cacoub P, Messa P, Donato FM: Treatment of
hepatitis C-related kidney disease. Expert Opin Pharmacother
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,
Thadhani R, Chung RT: Treatment of hepatitis C virus-associated
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,
Stover J, Resch S, Ryckman T, Møgedal S, Dybul M, Goosby E,
Watts C, Kilonzo N, McManus J, Sidibé M; UNAIDS–Lancet
Commission: Defeating AIDS–advancing global health. Lancet
386: 171–218, 2015
6 Clinical Journal of the American Society of Nephrology
23. Wyatt CM, Meliambro K, Klotman PE: Recent progress in HIV-
associated nephropathy. Annu Rev Med 63: 147–159, 2012
24. Kruzel-Davila E, Wasser WG, Aviram S, Skorecki K: APOL1
nephropathy: from gene to mechanisms of kidney injury. Nephrol
Dial Transplant 31: 349–358, 2016
25. Rosenberg AZ, Naicker S, Winkler CA, Kopp JB: HIV-associated
nephropathies: epidemiology, pathology, mechanisms and
treatment. Nat Rev Nephrol 11: 150–160, 2015
26. Ross MJ: Advances in the pathogenesis of HIV-associated kidney
diseases. Kidney Int 86: 266–274, 2014
27. Han TM, Naicker S, Ramdial PK, Assounga AG: A cross-sectional
study of HIV-seropositive patients with varying degrees of pro-
teinuria in South Africa. Kidney Int 69: 2243–2250, 2006
28. Fabian J, Naicker S, Goetsch S, Venter WD: The clinical and
histological response of HIV-associated kidney disease to anti-
retroviral therapy in South Africans. Nephrol Dial Transplant 28:
1543–1554, 2013
29. Kalyesubula R, Perazella MA: Nephrotoxicity of HAART. AIDS
Res Treat 2011: 562790, 2011
30. Kumar D, Konkimalla S, Yadav A, Sataranatarajan K, Kasinath BS,
Chander PN, Singhal PC: HIV-associated nephropathy: role of
mammalian target of rapamycin pathway. Am J Pathol 177:
813–821, 2010
31. Mallipattu SK, He JC: The beneficial role of retinoids in
glomerular disease. Front Med (Lausanne) 2: 16, 2015
32. Foy MC, Estrella MM, Lucas GM, Tahir F, Fine DM, Moore
RD, Atta MG: Comparison of risk factors and outcomes in
HIV immune complex kidney disease and HIV-associated
nephropathy. Clin J Am Soc Nephrol 8: 1524–1532, 2013
33. Booth J, Hamzah L, Jose S, Horsfield C, O’Donnell P, McAdoo S,
Kumar EA, Turner-Stokes T, Khatib N, Das P, Naftalin C, Mackie
N, Kingdon E, Williams D, Hendry BM, Sabin C, Jones R, Levy J,
Hilton R, Connolly J, Post FA; HIV/CKD Study and the UK CHIC
Study: Clinical characteristics and outcomes of HIV-associated
immune complex kidney disease [published online ahead of
print January 18, 2016]. Nephrol Dial Transplant doi:10.1093/
ndt/gfv436, 2016
34. Rollino C, Vischini G, Coppo R: IgA nephropathy and infections.
J Nephrol 29: 463–468, 2016
35. Nobakht E, Cohen SD, Rosenberg AZ, Kimmel PL: HIV-associated
immune complex kidney disease. Nat Rev Nephrol 12(5): 291–
300, 2016
36. Mallipattu SK, Salem F, Wyatt CM: The changing epidemiology of
HIV-related chronic kidney disease in the era of antiretroviral
therapy. Kidney Int 86: 259–265, 2014
37. Lescure FX, Flateau C, Pacanowski J, Brocheriou I,
Rondeau E, Girard PM, Ronco P, Pialoux G, Plaisier E: HIV-
associated kidney glomerular diseases: changes with time
and HAART. Nephrol Dial Transplant 27: 2349–2355,
2012
Published online ahead of print. Publication date available at www.
cjasn.org.