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Immune Complex Renal Disease andHuman Immunodeficiency Virus Infection

Scott D. Cohen, MD, MPH, and Paul L. Kimmel, MD

Summary: Immune complex glomerulonephritis is a common diagnosis in renal biopsy seriesof human immunodeficiency virus (HIV)-infected patients. There are a variety of glomerulo-nephritides associated with HIV infection, including IgA nephropathy, membranoprolifera-tive glomerulonephritis, membranous nephropathy, lupus-like glomerulonephritis, immuno-tactoid glomerulopathy, and fibrillary glomerulonephritis. In addition, HIV-related proteinsmay be implicated in circulating immune complexes directly related to a response to theinfection. In some cases, the relationship of the HIV infection to the glomerulonephritis isunclear. HIV infection is associated with the development of polyclonal hypergammaglobu-linemia, which can promote the development of circulating immune complexes. It is notclear if HIV-associated glomerulonephritis is caused by the passive trapping of these circu-lating immune complexes or the in situ deposition of antibodies binding to HIV viral antigens.Some renal lesions that are seen in the setting of HIV infection more likely may be related tothe presence of a co-infection such as hepatitis C virus infection. The optimal therapy forimmune complex glomerulonephritis in the setting of HIV infection is unknown. Because ofthe underlying immunosuppressed state of many HIV-infected patients, caution with tradi-tional cytotoxic therapies is advised. The role of antiretroviral therapy in modifying the courseof these renal lesions is unclear.Semin Nephrol 28:535-544. Published by Elsevier Inc.Keywords: Human immunodeficiency virus, glomerulonephritis, immune complexes

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he most common renal histopathologiclesion associated with human immunode-ficiency virus (HIV) infection is focal seg-

ental glomerulosclerosis (FSGS).1-10 However,n almost half of the patients in renal biopsyeries, lesions other than classic HIV-associatedephropathy (HIVAN) are identified.1-11 HIV in-

ection has been associated with a variety of im-une complex–mediated glomerulonephritides

ncluding IgA nephropathy, membranoprolifera-ive glomerulonephritis (MPGN), membranousephropathy, lupus-like glomerulonephritis, and

mmunotactoid glomerulopathy (Table 1).1-11

enetic and environmental factors may lead toacial disparities in the development of partic-

ivision of Renal Diseases and Hypertension, Department of Medicine, GeorgeWashington University Medical Center, Washington, DC.

ddress reprint requests to Paul L. Kimmel, MD, Division of Renal Diseasesand Hypertension, Department of Medicine, George Washington UniversityMedical Center, 2150 Pennsylvania Ave NW, Washington, DC 20037.E-mail: [email protected]

270-9295/08/$ - see front matter
sublished by Elsevier Inc. doi:10.1016/j.semnephrol.2008.08.006
eminars in Nephrology, Vol 28, No 6, November 2008, pp 53

lar renal lesions. Immune complex renal dis-ase may be more prevalent among Caucasians,hereas classic HIVAN is more likely in pa-

ients of African heritage.1-8 The diverse renalanifestations that have been associated withIV infection highlight the key role renal bi-psy has in the management of HIV-infectedatients with renal disease.

ATHOGENESIS

IV infection often leads to the development ofolyclonal hypergammaglobulinemia, and cir-ulating immune complexes frequently areound in HIV-infected patients.12-18 Kimmel etl2 showed that immune complex deposits,omposed of HIV peptides and antibodies di-ected against these antigens, lead to the devel-pment of glomerulonephritis. Immune com-lex deposition may be related to an immu-ologic response to opportunistic infectionshat stems from the immunocompromised
tate, and may represent a form of postinfec-
5-544 535

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536 S.D. Cohen and P.L. Kimmel

ious glomerulonephritis.1,2,18 It also is possiblehat glomerulonephritis in the setting of HIVnfection may be unrelated to the underlyingiral infection, but rather shares the sameathogenic mechanisms as other glomerulone-hritides that affect the general population.2,7,8

One proposed mechanism for the develop-ent of glomerulonephritis in HIV-infected pa-

ients is passive trapping of immune complexesontaining HIV antigens.2,18-21 In several well-haracterized patients, the association with HIVnfection has been established with certainty byhowing circulating or tissue immune com-lexes consisting of HIV antigens, such as p24,p41, and gp120, bound to IgG or IgA anti-odies produced in response to these anti-ens.1,2,18,19,21 Alternatively, in situ immuneomplex formation, with circulating antibod-es binding to HIV antigens deposited on glo-

erular cells, may play a causal role similar tohe mechanism underlying other idiopathic glo-erulonephritides.2,18,19,22,23 Research in HIV-

nfected patients to date cannot discriminatehether passive trapping of immune com-lexes or in situ antibody deposition leads tohe development of glomerulonephritis.18,19

ellular immune responses likely play a syner-istic role in the development of glomerulone-hritis in HIV-infected patients.24-26

PIDEMIOLOGY

renal biopsy series of 28 HIV-infected patientsith nephrotic range proteinuria in Washing-

Table 1. Immune Complex Renal DiseasesAssociated With HIV Infection

HIV-associated immune complex renaldisease

HIV-associated IgA nephropathyMembranoproliferative glomerulonephritisPostinfectious glomerulonephritisMembranous nephropathyLupus-like glomerulonephritisCryoglobulinemic glomerulonephritisImmunotactoid glomerulopathyFibrillary glomerulonephritis

on, DC, found a 28.6% prevalence of glomeru- c

onephritis.27 More than half of the patients inhis largely African American cohort had FSGS.

review of renal biopsies from HIV-infectedatients around the world reinforces the notionhat immune complex glomerulonephritis is aelatively frequent histologic diagnosis, and thatt may be more common among Caucasian pa-ients than those of African heritage.

In a series of 60 renal biopsies from HIV-nfected patients at a single center in Paris, 10ases of lupus-like glomerulonephritis and 4ases of IgA nephropathy were identified.5 Clas-ic FSGS lesions were found in 43% of patients,nd were more common in black patients,hereas the majority (52%) of patients with

mmune complex glomerulonephritis wereaucasian. In a smaller series of 17 patients

rom a London hospital, FSGS made up approx-mately 40% of the diagnoses. Other diagnosesncluded IgA nephropathy, MPGN, hemolyticremic syndrome, and interstitial nephritis.10 Inontrast, there were no cases of FSGS in aargely Caucasian cohort of 26 HIV-infected pa-ients from 3 hospitals in northern Italy. Postin-ectious glomerulonephritis was the most com-on finding, identified in 6 patients. Other

iagnoses included mesangial proliferative glo-erulonephritis, lupus-like glomerulonephritis,

gA nephropathy, and minimal change disease.28

In non-European settings, a small biopsy se-ies from Brazil included 2 cases of minimalhange disease and 3 cases of classic FSGS, theatter occurring in black patients.29 A series of6 biopsies in HIV-infected patients in Thailandhowed no cases of classic HIVAN lesions.9 Sev-nteen patients had mesangial proliferative glo-erulonephritis. Other diagnoses included IgA

ephropathy, diffuse proliferative glomerulone-hritis, membranous nephropathy, and MPGN.hese findings emphasize the frequency of glo-erulonephritis in HIV-infected patients inopulations of non-African ethnicity.In a multicenter observational study that in-

luded 89 HIV-infected patients who underwentenal biopsies in the United States, 50% of theatients had a diagnosis other than HIVAN.6 Pa-ients with lesions other than HIVAN tended toave a more favorable renal prognosis, and wereore likely to be Caucasian, have higher CD4

ounts, and have co-existent hepatitis infection.

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Immune complex renal disease and HIV infection 537

Over the past several years, there has beenncreasing research dedicated to the AIDS epi-emic in sub-Saharan Africa, where approxi-ately 25 million people are estimated to be

iving with HIV/AIDS.30 In a study of 176 HIV-nfected patients in Israel, 72% of whom wereriginally from Ethiopia, no patient fulfilled pre-efined clinical criteria for classic HIVAN.31 Al-hough this study was severely limited by theack of biopsy data and small sample size, itighlighted the potential diversity of renal le-ions that may be seen even among HIV-in-ected individuals from Africa.

In a series of 104 HIV-infected patients fromouth Africa with renal biopsies between 2003nd 2004, 20% had an HIV immune complex–ediated renal disease.32 Approximately one

hird of the patients had classic FSGS lesions.his proportion is somewhat lower than thateported in other series, which largely wereomposed of African American patients, andaises the possibility of separate environmentalactors that may predispose people of Africanescent to the development of HIVAN. The

ncreased prevalence of hepatitis B virus (HBV)nd hepatitis C virus (HCV) infection on thefrican continent also may contribute to theigher rate of immune complex–mediated glo-erulonephritis in this series.In contrast, another recent renal biopsy se-

ies of 30 HIV-infected patients from South Af-ica found a significantly higher prevalence ofIVAN, which was observed in 83% of pa-

ients.33 MPGN was found in 2 patients andnterstitial nephritis was found in 3 patients.33

our patients had evidence of membranous ne-hropathy superimposed on HIVAN.33 Theseisparate results from 2 centers in South Africamphasize the limitations of drawing significantpidemiologic conclusions from single-centertudies with small sample sizes. Nevertheless,he data provide insight into the growing HIVpidemic in Africa and highlight the impor-ance of conducting larger studies.

IV IMMUNEOMPLEX GLOMERULONEPHRITIS

IV-infected patients with immune complex–ediated glomerulonephritis often present
ith hypertension, an active urine sediment, i
roteinuria, and renal insufficiency.1,2,19,34 Uri-alysis typically reveals hematuria, and occa-ionally red blood cell casts.1,2,19,34 Low serumomplements also may be seen.1,2,19,34 If pa-ients display any of these clinical features, aenal biopsy should be strongly considered.

There is a spectrum of pathology associatedith HIV immune-mediated glomerulonephritis

Fig. 1). Nochy et al5 categorized several majorypes of renal pathology: a “diffuse exudativendocapillary proliferative form” or “postinfec-ious form”; lupus-like glomerulonephritis withdiffuse endocapillary proliferative changes,ire loops, hyaline thrombi in capillary lu-ina,” and mesangial, subendothelial, and sub-

pithelial immune deposits; and a hybrid formhat includes changes consistent with bothSGS and immune complex renal disease. It isnclear if this final type represents 2 distinctathologies or rather may be a more advanced

orm of immune complex renal disease that hasrogressed to focal segmental sclerosis in por-ions of glomeruli.

Similar to classic HIVAN, common findingsnclude podocyte hyperplasia and fibrocellularrescents, microcystic tubular dilatation, and an

igure 1. HIV-associated immune complex glomerulo-ephritis. Kidney biopsy from a patient with HIV infec-ion, nonnephrotic range proteinuria, and hematuria.he glomerulus shows increased cellularity, predomi-antly within the mesangium. There is patchy congestionf glomerular capillaries without neutrophilic infiltration,brinoid necrosis or glomerulosclerosis. Hematoxylin-eosintain, 40� objective magnification. Figure courtesy of Dr.avid Kardon.

nterstitial inflammatory infiltrate made up of

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acrophages and lymphocytes with occasionallasma cells, polymorphonuclear leukocytes,nd eosinophils.19,25,34 HIV-infected patientsith immune complex renal lesions have been

hown to have a greater number of B cellsnfiltrating the tubulointerstitium compared

ith patients with classic HIVAN.24 Electronicroscopy may reveal mesangial, subendothe-

ial, intramembranous, and subepithelial elec-ron dense deposits.19,34 Similar to classicIVAN, tubuloreticular inclusion bodies may be

een.Kimmel et al2 studied 4 HIV-infected patients

ith characteristic features of an immune com-lex–mediated renal disease. Circulating im-une complexes were identified from the se-

um of all 4 patients.2 These same immuneomplexes were eluted from the renal biopsyissue in 3 of the patients in higher concentra-ions compared with plasma.2 HIV antigensere found in the eluates of glomeruli of all 4atients.2

In contrast to treatment of classic HIVAN,he role of antiretroviral therapy (ART) in de-aying progression of immune complex renalisease in HIV-infected patients is unclear. Szc-ech et al6 did not find an effect of ART onrogression of non-HIVAN renal disease in theirulticenter cohort. The nephrotoxic potential

f ART regimens must be considered. The renalisease may be related to another process, suchs HBV or HCV co-infection, and there are casesn which the renal disease has been dissociatedrom HIV infection. This last point must bealanced, acknowledging that the nephropa-hy, even if seemingly unrelated to HIV infec-ion after appropriate investigation, occurs inn immunocompromised host with immuneysregulation. Immunosuppressive strategieshat treat the specific glomerular syndromehould be considered carefully, but outcomesave been variable.6,20,35 The risk of immuno-uppressive agents in an immunocompromisedatient must be weighed against the risk ofrogression to end-stage renal disease and thessociated complications of nephrotic syn-rome.2,36 Whenever possible, conservative an-iproteinuric strategies with angiotensin-con-erting enzyme inhibition (ACEI) or angiotensin
I receptor antagonists (ARB), blood pressure n
ontrol, and statin therapy should be maxi-ized before considering cytotoxic agents, al-

hough this recommendation is not evidence-ased.20,35,37

UPUS-LIKE GLOMERULONEPHRITIS

here have been several reports of HIV-infectedatients who develop a glomerulonephritisith histologic features similar to systemic lu-us erythematosis nephritis.4,5,38 Nochy et al5

ound 10 cases of lupus-like glomerulonephritisn their series of 60 HIV-infected patients fromaris. Haas et al4 identified 14 cases of lupus-likelomerulonephritis out of 77 renal biopsies per-ormed in HIV-infected patients over a 5-yeareriod in Baltimore. The histopathology is char-cterized by focal and diffuse proliferative glo-erulonephritis on light microscopy.4,5 Immu-

ofluorescence is unique with a “full houseattern” of C1q, IgG, IgM, IgA, C3, lambda, andappa deposits.4,5 The clinical signs usually in-lude nephrotic range proteinuria and severeenal failure.4 Patients with this form of glomer-lonephritis typically are resistant to therapy,est negative for antinuclear antibodies and anti-NA antibodies, and have a poor 1-year renal

urvival.4 Thirteen of 14 cases of lupus-like glo-erulonephritis in the Baltimore cohort werefrican American,4 which runs counter to theotion that Caucasians are more likely to de-elop immune complex glomerulonephritis.4,38

he relationship of this disorder to HIV infec-ion remains unknown, and the proper therapyor such patients remains unclear and largelynevaluated.

GA NEPHROPATHY

here have been a number of reports of IgAephropathy occurring in HIV-infected pa-ients,1,20,21,35,37,39-44 primarily in Caucasian orispanic patients.1,21,40,42-44 In 4 patients withIV infection and biopsy-proven IgA nephrop-thy, tubuloreticular inclusion bodies were ob-erved in glomerular endothelial cells.21 HIVntigens were not isolated from the renal biop-ies, however, IgA antibodies to specific HIVntigens were detected.21 In a multicenter bi-psy series, there was a 1.1% prevalence of IgA
ephropathy among 89 HIV-infected patients.6

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he true prevalence of IgA nephropathy in HIV-nfected patients may be underestimated be-ause the indolent course likely leads to a lowerumber of renal biopsies.34 In a post mortemnalysis, there was an 8% prevalence of IgAesangial deposits among patients who died

rom complications of HIV infection.41 The sig-ificance of these lesions, and whether theyonstitute IgA nephropathy, is unclear.

Similar to other forms of HIV-associated glo-erulonephritis, the hypergammaglobulinemic

tate may play a role in the development ofephritogenic IgA antibodies.2,12-17 Kimmel etl1 reported 2 cases of IgA nephropathy in HIV-nfected patients who were shown to have im-

une complexes composed of idiotypic IgAntibodies reacting with IgG and IgM antibod-es against HIV p24 and gp120 antigens. Idio-ypic antibodies may play a role in the patho-enesis of IgA nephropathy in the generalopulation.1,45,46 These IgA antibodies alsoere identified in the eluates of renal biopsy

pecimens from these HIV-infected patients, es-ablishing a causal link between the HIV infec-ion and IgA nephropathy in these cases.1 Theroduction of idiotypic antibodies may be sec-ndary to dysregulation of the immune systemssociated with HIV infection, a response tonti-HIV antibodies, or continued exposure toIV-associated peptides.1

The pathology of IgA nephropathy includesesangial matrix expansion and hypercellular

lomeruli with diffuse or segmental prolifera-ion.1,21,40 Crescents are seen occasionally.1,21,34,40

he diagnosis is confirmed by immunofluores-ence staining revealing a predominance of IgA.1

here is often co-deposition of C3, IgM, and,ess frequently, IgG.1,21,34,40 Electron micros-opy may reveal mesangial and peripheral cap-llary wall electron dense deposits and tubu-oreticular inclusion bodies within endothelialells.21,34

The clinical presentation of IgA nephropathyay differ from classic HIVAN. Typical clinical

ndings suggestive of IgA nephropathy includeematuria, an active urine sediment includinged blood cell casts, and subnephrotic or ne-hrotic range proteinuria.34 The progression to
nd-stage renal disease also may be slower.2,20,21,34 s
ncreased serum IgA levels are nonspecific anday be found in other HIV-infected patients.34

Data on therapy for IgA nephropathy in theetting of HIV infection are limited to case re-orts.37,40,47 Despite limited evidence in HIV-

nfected patients, treatment of patients withgA nephropathy should include conservativeedical therapy with ACEIs or ARBs.37 If the

isease is progressive despite optimization oflood pressure control with ACEIs or ARBs, these of immunosuppressive agents can be con-idered. However, the risks of toxicity shoulde strongly weighed against any potential ben-fits of therapy. The independent role of ART inlowing the rate of progression of IgA nephrop-thy is unclear. Larger prospective randomizedontrolled trials are needed to determine theptimal therapy of IgA nephropathy in HIV-

nfected patients.

EMBRANOPROLIFERATIVELOMERULONEPHRITIS

here have been several reports of MPGN oc-urring in the setting of HIV infection. MPGNay occur as an isolated idiopathic lesion or as

he histopathologic manifestation of a postin-ectious glomerulonephritis. Patients with HIVnfection are predisposed to opportunistic in-ections that may have renal manifestations,48-53

nd also share common risk factors that predis-ose them to HCV and HBV co-infection.54,55

oth HCV and HBV infection have been associ-ted with the development of MPGN.54,55

MPGN also may result from the use of ther-peutic agents, in particular antiviral agents.immel et al8 reported a case of MPGN in anIV-infected patient after treatment with inter-

eron. Immunochemical analysis of renal biopsyissue revealed a single circulating immuneomplex with IgG antibody bound to an anti-en that later was identified as interferon-alfa.

Therapeutic options for MPGN should firstocus on identifying any potential secondaryauses, including infection, neoplasia, or otherutoimmune diseases, before considering inten-ive immunosuppressive therapy. Treatment ofnderlying infections may improve or even re-erse the postinfectious variants of MPGN.56 Asith other forms of glomerulonephritis in the

etting of HIV infection, the risk of immunosup-

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EMBRANOUS NEPHROPATHY

here have been several case reports of mem-ranous nephropathy in the setting of HIV in-ection.7,36,57,58 The significance of these renalesions and their relationship to HIV infection isnclear. Several patients had concomitant HBVr HCV infection, which has been associatedith the development of membranous ne-hropathy (Figs. 2 and 3).59-61 In one case of anIV–HBV co-infected Caucasian patient withiopsy-proven membranous nephropathy with-ut features of HIVAN, there was resolution ofhe nephrotic syndrome with clearance of theBe antigen.7

IV AND HCV CO-INFECTION

CV infection in the absence of HIV infectionas been linked to the development of MPGN.62

everal cases and case series have identifiedatients with MPGN in the setting of HIV andCV coinfection (Figs. 4 and 5).3,63 The rela-

ionship between the renal disease, the viralnfection, and the immunologic response inhese cases often is unclear. Patients with kid-ey disease who are co-infected with HIV andCV may have a worse renal prognosis,6,63 al-

igure 2. Membranous glomerulopathy in a patiento-infected with HIV and HCV. The glomerulus is nor-ocellular with global thickening of the glomerular

asement membranes and focal short spike formation.here is diffuse podocyte swelling. Jones methenamine
ilver, 400�. Figure courtesy of Dr. Vivette D’Agati. D
hough data are limited. These patients areore likely to have used intravenous drugs and

re more likely to have a diagnosis of MPGN aspposed to FSGS.3,63,64 Other forms of glomer-lonephritis also have been observed in pa-ients with HIV and HCV co-infection.3,64-68

tudies have not proved a causal role for HCV inhe development of glomerulonephritis in co-nfected patients.

igure 3. Membranous glomerulopathy in a patientith HIV and HCV co-infection. Immunofluorescence

taining for IgG shows global granular staining of thelomerular capillary walls in a subepithelial distribution,ith sparse segmental mesangial deposits. Immunoflu-rescence, 400�. Figure courtesy of Dr. Vivette D’Agati.

igure 4. Membranoproliferative glomerulonephritis inpatient co-infected with HIV and HCV. The glomerular

apillary lumina are occluded by global endocapillaryypercellularity including many infiltrating mononuclear

eukocytes, with mesangial matrix expansion, accentu-ted lobularity, and segmental double contours. Peri-dic acid Schiff, 400�. Figure courtesy of Dr. Vivette
’Agati.

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There should be a low threshold for renaliopsy in patients with evidence of renal injurynd concomitant HIV and HCV co-infection.ptimal therapy for renal disease in co-infectedatients is unclear, but likely includes treatment

or both HIV and HCV infection. Treatment ofCV infection poses unique challenges in pa-

ients with reduced glomerular filtration rate be-ause of the increased risk of drug toxicities.55,69

andomized controlled trials are needed urgentlyo establish therapy for such patients.

RYOGLOBULINEMICLOMERULONEPHRITIS,

MMUNOTACTOID GLOMERULOPATHY,ND FIBRILLARY GLOMERULONEPHRITIS

here have been several cases of cryoglobuline-ic glomerulonephritis reported in the setting

f HIV infection.19 Many of these patients havenderlying HCV co-infection and cryoglobuline-ia.70,71 The general impression is that cryo-

lobulinemia is a less frequent occurrence inatients with HIV mono-infection.70

There also have been sporadic reports ofmmunotactoid glomerulopathy and fibrillarylomerulonephritis in the setting of HIV infec-ion.65-68 The pathogenic significance and rela-

igure 5. Membranoproliferative glomerulonephritis inpatient with HIV and HCV co-infection. Electron mi-

roscopy reveals subendothelial granular electron denseeposits and intracapillary infiltration by monocytes/acrophages with prominent phagolysosomes. There is

verlying foot process effacement. Electron micrograph,,000�. Figure courtesy of Dr. Vivette D’Agati.

ionship to HIV infection are unclear. These

onditions also are associated with HCV infec-ion and may be more common in co-infectedatients.66 The expression of these diseases inhe setting of HIV infection also may be relatedo underlying immune dysregulation.

ONCLUSIONS

here are a variety of renal manifestations asso-iated with HIV infection. Several renal biopsyeries of HIV-infected patients with kidney dis-ase report a high prevalence of glomerulone-hritis, highlighting the key role of renal bi-psy. Glomerulonephritis appears to be moreommon among Caucasians, although recentlyublished renal biopsy series from the Unitedtates and South Africa have shown a high prev-lence of HIV-associated glomerulonephritis inatients of African heritage. The modifying rolef ART in the course of glomerulonephritis isnclear. Only biopsy and immunochemicalnalysis, usually performed on a research basis,an definitively establish the relationship be-ween glomerulonephritis and HIV infection inn individual patient. Additional research iseeded to evaluate the pathogenesis, epidemi-logy, and optimal treatment of glomerulone-hritis in the setting of HIV infection.

cknowledgmenthe authors would like to thank Drs. Vivette D’Agatind David Kardon for their assistance in providingmages of glomerulonephritis.

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