Viral-Associated GN: Hepatitis C and HIV

Warren L. Kupin

AbstractViruses are capable of inducing awide spectrumof glomerular disorders that can be categorized on the basis of theduration of active viremia: acute, subacute, or chronic. The variable responses of the adaptive immune system toeach time period of viral infection results mechanistically in different histologic forms of glomerular injury. Theunique presence of a chronic viremic carrier state with either hepatitis C (HCV) or HIV has led to the opportunityto study in detail various pathogenic mechanisms of viral-induced glomerular injury, including direct viralinfection of renal tissue and the development of circulating immune complexes composed of viral antigens thatdeposit along the glomerular basement membrane. Epidemiologic data show that approximately 25%–30% of allHIV patients are coinfected with HCV and 5%–10% of all HCV patients are coinfected with HIV. This situationcan often lead to a challenging differential diagnosis when glomerular disease occurs in this dual-infected pop-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 becategorized under the new classification of infection-associated GN as opposed to being listed as causes ofpostinfectiousGNas has previously been applied to them.Neither of these viruses lead to renal injury after a latentperiod of controlled and inactive viremia. The geneses of HCV- and HIV-associated glomerular diseases share atotal dependence on the presence of active viral replication to sustain renal injury so the renal disease cannot belisted under “postinfectious” GN.With the new availability of direct-acting antivirals for HCV andmore effectivecombined antiretroviral therapy for HIV, successful remission and even regression of glomerular lesions can beachieved if initiated at an early stage.

Clin J Am Soc Nephrol 12: 1337–1342, 2017. doi: https://doi.org/10.2215/CJN.04320416

IntroductionSince their initial discovery in 1898, viruses havechallenged their human hosts with a greater degree offoreign genomic diversity than any other infectiousorganisms (1). Over 5000 DNA and RNA viruseshave been structurally defined, and either by theirown direct intracellular virulence or through thestimulation of natural host adaptive immune defensemechanisms they often lead to significant tubule-interstitial and glomerular injury (2).

One proposed schema that can be used to classifyviral-induced GN can be on the basis of the durationof active viremia. Patients with recent self-limitedacute viremia (days to weeks) develop significantlydifferent forms of glomerular pathology as comparedwith patients with subacute viremia (weeks to months)and those with chronic persistent viremia (years). Anoutline of the most well documented viruses that fit intoeach of these categories and their individual glomerularlesions that have been described in the literature isshown in Table 1.

In order to link a viral illness with a specific form ofGN, certain supporting criteria must be met: (1) dem-onstration of the presence of active quantifiable vire-mia primarily through serologic PCR testing, (2) theidentification of viral proteins/nucleic acid residueswithin renal tissue and/or within immune complexesdeposited in the glomerular basement membrane, and(3) resolution/regression of the glomerular lesion

concomitant with the host immune clearance of viremiaor eradication of viremia through antiviral therapy.However, recent emerging data has proposed a new

relationship of GN associated with occult viral diseasewhich is defined as the presence of viral nucleic acidin renal tissue and in peripheral blood mononuclearcells but with complete absence of detectable systemicviremia by standard PCR amplification techniques(3). Occult hepatitis C (HCV) has been detected in30%–50% of patients with idiopathic membranousnephropathy, 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 inrenal tissue but with absent viremia in selected casesof idiopathic membranous nephropathy and IgA (5).In many of the cases, viremia could only be identifiedby intensive ultracentrifugation of plasma. Possiblyfulfilling the cause and effect nature of this finding,there is anecdotal evidence that antiviral therapy inselect 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 definethe 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 withclinically active viral diseases, which will be pre-sented in two separate parts. This issue (part 1)

Division ofNephrology, MiamiTransplant Institute,University of MiamiMiller School ofMedicine, Miami,Florida

Correspondence:Dr. Warren Kupin,University of Miami,Miami TransplantInstitute, 1801 NW9th Ave, #568, Miami,FL 33136. Email:wkupin@med.miami.edu

www.cjasn.org Vol 12 August, 2017 Copyright © 2017 by the American Society of Nephrology 1337

will focus on the glomerular syndromes associated withlong-term chronic HCV and HIV carrier states. In thesecond issue (part 2) the focus will concentrate on theglomerular diseases seen with chronic HBV infection and itwill also cover glomerular diseases seen with a variety ofacute and subacute viral infections including cytomegalo-virus, parvovirus, Epstein–Barr, hantavirus, and dengue.

HCVWith the current availability of direct-acting antivirals

(DAA) which can achieve a viral remission of.95% for mostHCV genotypes, the prevalence of glomerular disease in thispopulation should progressively decline in the coming de-cade (7). Chronic HCV viremia is present in 150–170 millionpeople worldwide (3% of the global population) and in 3.2million people in the United States. Approximately 2–3 mil-lion new cases of HCV occur each year with 75%–90% ofthese patients becoming chronic carriers (8).Similar to HBV, HCV-associated glomerular disease is

primarily a consequence of viral antigen – immune com-plex formation with glomerular basement membrane

deposition. The classic pathologic hallmark of HCV renaldisease is type 1 MPGN as a consequence of type 2 mixedcryoglobulinemia (MC), although the same renal lesionmay also develop from noncryoglobulinemic immunecomplexes (9). In addition, HCV is also an important causeof polyarteritis nodosa (PAN) from immune complex de-position in medium size blood vessels leading to renalischemia and infarction similar to HBV PAN and idio-pathic PAN (10). Other forms of glomerular immune com-plex deposition have been described in HCV patients,including mesangial proliferative and focal proliferativeGN and IgA nephropathy (Figure 1).It is important to note that renal dysfunction in a patient

with HCV is rarely a result of GN (,10%) and hospital ad-missions for MPGN from HCV have been decreasing forthe past decade (11). The majority of renal diseases inHCV patients with liver disease are a consequence ofacute tubular necrosis, hepatorenal syndrome, prerenalazotemia, and CKD and therefore it is essential to be fa-miliar with the typical presentation and characteristics ofacute GN in HCV patients and how to differentiate themfrom the more common diagnoses causing AKI in thispopulation.

Type 1 MPGN with MCHCV provides a unique opportunity to study the effects

of a hepatotropic virus that also has unique lymphotropicpotential (12). In the absence of this lymphotropism, HCVwould be indistinguishable from a pathogenic standpointfrom HBV and HIV in the development of typical IgG–

viral particle immune complexes of varying size and vir-ulence. In approximately 20% of type 1 MPGN casescaused by HCV, this standard sequence results in the pro-duction of noncryoglobulin immune complexes (13). How-ever, in the majority of type 1 MPGN lesions, HCV iscapable of specifically binding to CD51 CD811 B cellswhich 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

Table 1. Viruses associated with GN

Virus Type PredominantGlomerular Histology

AcuteDengue ICGN, MsPGNHantavirus HFRS-MsPGNVaricella-zoster DPGNParvovirus ICGN, PAN, MPA, TMA, IgAHAV ICGN, MsPGNHBV DPGNCMV cFSGS, MN, IgA, HSP, ICGN,

MPGN, TMAEBV ICGN, MN, MsPGNCoxsackie B RPGN

SubacuteParvovirus cFSGSEBV cFSGS, MNHBV PANHCV PAN

ChronicHBV MN, Type I MPGN, MPGN1MC,

PAN, IgA, FSGSHIV HIVAN, HIVICK, TMAHCV Type I MPGN1MC, Type I

MPGN, PAN, IgA, MNHEV MN

ICGN, immune complex glomerulonephritis; MsPGN, me-sangial proliferative GN; HFRS, hemorrhagic fever and renalsyndrome; DPGN, diffuse proliferative GN; PAN, polyarteritisnodosa; MPA, microscopic polyarteritis; TMA, thrombotic mi-croangiopathy; HAV, hepatitis A virus; HBV, hepatitis B virus;CMV, cytomegalovirus; cFSGS, collapsing FSGS; MN, mem-branous glomerulopathy; HSP, Henoch Shoenlein purpura;MPGN, membranoproliferative GN; EBV, Epstein-Barr virus;RPGN, rapidly progressive glomerulonephritis; HCV, hepatitisC virus;MC,mixed cryoglobulinemia; HIVAN, HIV-associatednephropathy; HIVICK, HIV immune complex disease of thekidney; HEV, hepatitis E virus.

Figure 1. | Glomerular disease inpatientswith chronicHCV infection.Ag, antigen; HCV, hepatitis C virus; MC, mixed cryoglobulinemia; MN,membranous glomerulopathy; MPGN, membranoproliferative GN;PAN, polyarteritis nodosa.

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factor activity. Additional receptors that mediate HCVB cell stimulation involve the scavenger receptor SR-B3 andtoll 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 thestructural E2 or nonstructural NS3 proteins of HCV or theactual HCV RNA itself. It is not surprising, given the sheersize of this complex, that it lodges along the subendothelialspace creating large crystalline intraluminal thrombi com-pletely distinct from a typical subendothelial immune com-plex as in SLE. Cryoglobulinemia is unusual (,5%) in allother forms of viral hepatitis (HBV, hepatitis A virus), HIVcarriers, cytomegalovirus, parvovirus B19, and Epstein-Barr virus which reinforces the unique role of the HCV/Bcell 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 whichcarries a minimal risk of GN. After 10–15 years of viremiaapproximately 10% of patients within this subgroup tran-sition and develop type 2 MC and systemic small vesselvasculitis (16). These patients demonstrate the characteris-tic skin rash (palpable purpura), polyneuropathy, gastro-intestinal/pulmonary/cardiac/central nervous systemvasculitis, and in 30% of patients a type 1 MPGN.From a nephrologic standpoint, these patients may presentwith hypertension and the nephritic syndrome but impor-tantly 20% of type 1 MPGN patients present only with thenephrotic syndrome, making a renal biopsy essential fordiagnosis.The mechanisms behind the transition from type 3 to

type 2 MC in a small fraction of HCV patients are not welldefined. Host factors may play an important role with.65% of HCV-positive patients worldwide being men butthere is a reversed female predominance in patients thatdevelop type 2 MC. The response by sex to chronic anti-genemia is different, with women showing a TH2 responseand a greater likelihood of autoimmunity compared witha more typical TH1 response in men. In HCV patients,autoantibody production is especially prevalent with66% showing anti-smooth muscle antibodies and 40%with a positive anti-nuclear antibody. Between 40% and75% 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 MPGNwith C4 being low in 93% of patients, whereas C3 isdepressed in only 53% due to both its role as an acutephase reactant and the possible activation of the alternateC pathway in some patients. At this stage of their HCVcycle, most patients will have serologic evidence ofchronic active hepatitis with ,15% showing advancedcirrhosis.Left untreated, type 2 MC from HCV is a precursor sign

for the emergence of B cell lymphoma in 6% of patients andan additional risk factor for cardiovascular death fromcoronary vasculitis (18). Therefore, treatment of type 2 MCand renal disease in HCV patients has a two-fold purpose:reduce the risk of malignancy and decrease patient cardio-vascular mortality.

TreatmentOngoing HCV viremia is at the epicenter for the gener-

ation of nephritogenic immune complexes. The develop-ment of DAAs against HCV has provided a revolutionaryopportunity for long-term successful eradication of HCVand elimination of cryoglobulinemia (19). These oral agentshave virtually replaced the need for IFN. HCV carries aninnate ability to suppress natural IFNg production in thehost with a concomitant decrease in Treg cells that allowfor persistence of viremia and the development of autoim-mune sequela. Exogenous IFN used to be the backbone oftherapy 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 ofgenotype). More limiting was the inability to use IFN insolid organ transplant recipients due to the risk of humoralrejection (20).DAAs target three groups of nonstructural proteins

called NS5A, NS5B, and NS3/4A. A variety of drugs in thisclass have been developed that are used in combinationover a 12-week period without IFN and result in sustainedviral remissions of .95% for all genotypes. In the setting ofacute cryoglobulinemic vasculitis and GN, DAAs have re-sulted in clinical remission and disappearance of cryogo-bulinemia (21). Often, control of viremia alone will notsuffice due to the relative delay in viral clearance over4–8 weeks, and in some circumstances plasmapheresis, ste-roids, and rituximab are still needed to control the acuteinflammatory 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.

HIVThe 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 another15%–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 globallyare receiving combined antiretroviral therapy (cART),indicating that the majority of HIV patients are activelyviremic (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 withother viruses such as with HBV (5%–10%) or with HCV(25%–30%). As with all of the viral diseases previouslydiscussed the prerequisite need for ongoing active viremiais essential for the development of the classic HIV-relatedglomerular syndromes: HIV-associated nephropathy (HIVAN)and HIV immune complex disease of the kidney (HIVICK)(Figure 2).

HIVANHIVAN represents a unique manifestation of glomerular

injury that arises from direct viral infection of renal tis-sue, particularly the visceral and parietal epithelial cells,

Clin J Am Soc Nephrol 12: 1337–1342, August, 2017 Viral-Associated GN: Hepatitis C and HIV, Kupin 1339

without the presence of immune complexes. HIVANcomprises a constellation of four individual pathologicfindings in the renal biopsy that may not all be presentsimultaneously: collapsing FSGS (cFSGS), microcystic di-lation of the tubules, interstitial nephritis, and the presenceof intracytoplasmic tubulo-reticular inclusions (“TRI-IFNfootprints”). By definition, the only specific requirementto fulfill the diagnosis of HIVAN is the presence of cFSGSin the setting of HIV infection with the remaining lesionsfound in variable frequencies (23).HIVAN develops almost exclusively in patients of black

race origin who are homozygous or heterozygous forAPOL1 G1 or G2 variants. The lifetime risk of HIVAN in anuntreated HIV-infected black patient is 2%–10%, however,this risk increases to 50% if that person is homozygous forthe APOL1 variants. APOLI variants, initially an evolution-ary advantage for protection against trypanosomiasis inAfrica, now represent the single most important risk factorfor the development of HIVAN worldwide (24).The histopathologic lesions of HIVAN in a susceptible

host require translation of the nine-gene HIV genomewhich then leads to altered phenotype changes in thepodocytes with loss of maturation markers (synaptopodin.podocalyxin) and upregulation of proliferation markers(Ki-67). The main HIV genes responsible for these changesare 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, andtubular cells because they lack CD4 receptors and chemokinereceptors used by HIV for entry into nonrenal tissue. The useof lipid rafts for freely circulating Tat and Vpr proteins orbinding of the whole HIV virion to DEC-205 (dendritic cellreceptor) 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 inHIVAN, early collapsing lesions canbe 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 rateof decline of GFR and actually cause histologic regressionwith a return of the normal podocyte phenotype within theglomerular lesions (28). This favorable response is predi-cated on achieving viral remission. Deterioration of renalfunction in a patient successfully treated for HIVAN oncART may be a reflection of the intrinsic nephrotoxicityof either the protease inhibitors or the non-nucleotide(s)reverse transcription inhibitors rather than due to HIV ne-phropathy (29). Alternatively, a condition entitled immunereconstitution syndrome with AKI from acute interstitialnephritis or immune complex GN may occur shortly afterstarting cART. Finally, because coinfection with HBV orHCV is common, renal impairment after cART may alsoreflect the glomerular injury from these ongoing untreatedand possibly unrecognized viral infections.New emerging therapy for HIVAN includes renin-

angiotensin-aldosterone system inhibition, interruptionof the mTOR pathway, and retinoic acid derivatives(30,31). Upregulation of angiotensin 2 with possible co-stimulation of the mTOR pathway and involving the AT2receptor lends support for the benefit of direct blockade ofthese pathways. Experimentally, HIVAN lesions fail to de-velop with the use of renin-angiotensin-aldosterone systemand mTOR inhibitors. The application of retinoids in HI-VAN and other glomerular diseases is currently being in-vestigated. HIV downregulates the retinoic acid receptorsupporting a potential clinical role for this therapy as anadjunct to cART.

HIVICKHIVICK represents a constellation of histopathologic dis-

eases rather than a specific glomerular syndrome of its ownsuch as HIVAN. This is why it is impossible to describe anactual typical presentation or outcome for HIVICK becauseit represents a pathophysiologic grouping of a wide varietyof glomerular diseases each with a different presentation andprognosis. All glomerular diseases comprising HIVICK resultfrom 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 theincreased risk of infections from a compromised immunesystem 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. Glomerularlesions from coinfected HIV patients with HBV or HCV arenot 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 complexdeposition consisting of HIV antigens in the form ofmembranous, IgA, MPGN, and a “lupus-like” diffuse pro-liferative GN (33). Some studies have excluded patientswith IgA from having HIVICK assuming it may be an id-iopathic lesion, however, the colocalization of the HIVp24and gp120 antigens with IgA in the presence of active HIVdisease and typical IgA histology on biopsy clearly

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 ofthe kidney; MC, mixed cryoglobulinemia; MN, membranous glo-merulopathy; MPGN, membranoproliferative GN.

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suggests that IgA can be and likely should be considered amanifestation 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 yearsof 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 toinduce histologic regression in HIVAN but this has onlybeen infrequently seen in HIVICK. This is likely due to thepermanent destructive injury to the glomerular basementmembrane from immune complex deposition in HIVICKcompared with the reversible intracellular phenotypicchanges of the podocyte characteristic of HIVAN.The heterogeneous nature of HIVICK and the limited

number of published studies on outcomes makes it difficultto make a recommendation on the benefit of cART. Because50% of the lesions are postinfectious these would not beexpected to improve with cART, whereas the remainingimmune complex glomerular diseases should theoreticallyshow benefit depending on their degree of chronicity.

Idiopathic FSGSThe 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, noncollapsingFSGS is emerging as the most common glomerular lesionseen. These results are self-fulfilling if the population ispredominantly cART-treated. Because APOL1 polymor-phisms, which are restricted to black race origin, are vi-tally important for the development of HIVAN, any studydealing with European or largely white HIV patients willclearly never show a significant percentage of HIVAN orFSGS lesions and may show more HIVICK (37).

SummaryThe pathogenic mechanisms of glomerular disease in HCV

and HIV patients exemplify the wide spectrum of immuno-logic and microbiologic pathways utilized by viruses ingeneral to cause renal disease. Conclusive evidence exists bothfor HIV and HCV for direct viral infection of renal tissue aswell as the development of immune complexes partiallyconsisting of viral antigens. These same principles can beapplied 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-associatedcryoglobulinemia, invariably the ultimate control of activeviremia remains the key objective in the management ofboth HIV- and HCV-associated GN.

DisclosuresNone.

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