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HIV-AssociatedNephropathy: Clinical Presentation,Pathology, and Epidemiology inthe Era of Antiretroviral Therapy

Christina M. Wyatt, MD*, Paul E. Klotman, MD†, and Vivette D. D’Agati, MD‡

Summary: The classic kidney disease of human immunodeficiency virus (HIV) infection, HIV-associated nephropathy, is characterized by progressive acute renal failure, often accompanied byproteinuria and ultrasound findings of enlarged, echogenic kidneys. Definitive diagnosis requireskidney biopsy, which shows collapsing focal segmental glomerulosclerosis with associated mi-crocystic tubular dilatation and interstitial inflammation. Podocyte proliferation is a hallmark ofHIV-associated nephropathy, although this classic pathology is observed less frequently in anti-retroviral-treated patients. The pathogenesis of HIV-associated nephropathy involves direct HIVinfection of renal epithelial cells, and the widespread introduction of combination antiretroviraltherapy has had a significant impact on the natural history and epidemiology of this uniquedisease. These observations have established antiretroviral therapy as the cornerstone of treatmentfor HIV-associated nephropathy in the absence of prospective clinical trials. Adjunctive therapyfor HIV-associated nephropathy includes angiotensin-converting enzyme inhibitors or angiotensin-receptor blockers, as well as corticosteroids in selected patients with significant interstitialinflammation or rapid progression.Semin Nephrol 28:513-522. © 2008 Published by Elsevier Inc.Keywords: HIV-associated nephropathy, focal segmental glomerulosclerosis, HIV, kidney

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ithin a few years of the first publisheddescriptions of the acquired immunedeficiency syndrome (AIDS), kidney

isease was recognized as a complication ofnfection with human immunodeficiency virusHIV).1-3 Early reports from New York and Mi-mi described an aggressive form of collapsingocal segmental glomerulosclerosis (FSGS) infrican Americans and Haitian immigrants withdvanced AIDS. Now known as HIV-associatedephropathy (HIVAN), this unique kidney diseaseuickly became a leading cause of end-stage renal

Department of Medicine, Division of Nephrology, Mount Sinai School ofMedicine, New York, NY.

Samuel Bronfman Department of Medicine, Mount Sinai School of Medicine,New York, NY.

Department of Pathology, Columbia University Medical Center, New York, NY.upported in part by National Institutes of Health grants P01DK56492-05 andK23DK077568.

ddress reprint requests to Christina M. Wyatt, MD, Division of Nephrology,Mount Sinai School of Medicine, One Gustave L. Levy Place, Box 1243,New York, NY 10029. E-mail: christina.wyatt@mssm.edu

270-9295/08/$ - see front matter

“2008 Published by Elsevier Inc. doi:10.1016/j.semnephrol.2008.08.005

eminars in Nephrology, Vol 28, No 6, November 2008, pp 51

isease (ESRD) among young African Americans,aralleling the growth of the HIV epidemic in thisopulation.4,5 This review focuses on the clinicalresentation, histopathology, and changing epi-emiology of HIVAN in the era of combinationntiretroviral therapy (ART).

LINICAL PRESENTATION OF HIVAN

n 1984, physicians in New York City reportedseries of patients with advanced AIDS and

apidly progressive glomerular disease.1 All ofhe affected patients in this initial report werefrican Americans or Haitian immigrants, al-

hough the significance of race was not fullyppreciated until several years later.6 The classiclinical presentation of HIVAN was characterizedy rapidly progressive renal failure, accompaniedy moderate to nephrotic range proteinuria,land urinary sediment, and ultrasound findingsf large, highly echogenic kidneys. Progression toSRD or death was nearly universal, and by 1999

AIDS nephropathy” had become the third lead-

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ng cause of ESRD among African Americans be-ween the ages of 20 and 64 years.4

Although cases have been reported in theetting of asymptomatic HIV infection or acuteIV seroconversion,7 HIVAN originally was de-

cribed in patients with AIDS1-3 and still gener-lly is recognized as a complication of advancedIV disease.8 In a series of 107 HIV-infectedatients who underwent kidney biopsy be-ween 1995 and 2002, patients with classicIVAN were more likely to have a CD4 cellount of less than 200 cells/mm3 comparedith patients with an alternative diagnosis (70%

ersus 31%), although there were no significantifferences in HIV-RNA level or ART use.8 Theombination of nephrotic range proteinuriand a CD4 cell count of less than 200 cells/mm3

as observed in half of the patients withIVAN, compared with only 15% of those withnother diagnosis. Although the combination ofephrotic range proteinuria and a CD4 cellount of less than 200 cells/mm3 had limitedensitivity and specificity for the diagnosis ofIVAN, the absence of both findings may beore useful to exclude the diagnosis, with a

egative predictive value reaching 90%.8 In anarlier study, these investigators found that theegree of echogenicity on renal ultrasound alsoay have some predictive value for the diagno-

is or exclusion of HIVAN, but only at the ex-remes of echogenicity. Kidney size did not

igure 1. The glomerular capillary lumina are obliter-ted globally by collapse of glomerular basement mem-ranes with hypertrophy and hyperplasia of overlyingodocytes (Jones methenamine silver, 400�).

istinguish HIVAN from other renal diagnoses n

n this study, possibly because patients withIVAN presented with more advanced kidneyisease.9 Although clinical characteristics mayelp to refine the differential diagnosis in patientsith contraindications to kidney biopsy, more

han 30% of patients with suspected HIVAN basedn these and other clinical criteria will have anlternative diagnosis on kidney biopsy.8,10

ATHOLOGY OF HIVAN

n the 1980s, the classic pathologic features ofIVAN began to emerge from autopsy and renaliopsy studies performed in institutions with aigh prevalence of HIV/AIDS.1,11-13 On grossxamination at autopsy, the kidneys often werenlarged, pale, and swollen, with combinedidney weights as high as 500 g.14 Renal en-argement may persist even in the setting ofSRD, owing to the presence of numerous tu-ular microcysts distending the parenchyma.

ight Microscopy

n the acute phase, untreated HIVAN typicallyanifests as a dramatic pattern of collapsing

SGS.11,12 Glomerular capillary lumina are oc-luded by an implosive wrinkling and collapsef the glomerular basement membrane thatore often is global rather than segmental,ithout predilection for the perihilar segments

Figs. 1 and 2). The acute nature of the glomer-

igure 2. The podocytes surrounding the collapsed tuftorm a corona of hypertrophied cells with numerousrotein resorption droplets. Some of the podocytes ap-ear detached from the tuft and suspended in the uri-

ary space (Jones methenamine silver, 400�).

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Clinical presentation and pathology of HIVAN 515

lar injury is evidenced by the lack of apprecia-le increase in intracapillary or mesangial ma-rix. The glomerular collapse is accompaniedy prominent hypertrophy and hyperplasia ofhe overlying podocytes, which have enlarged,pen vesicular nuclei with frequent nucleoli,ccasional binucleate forms, and rare mitoticgures. Visceral epithelial cells may be sorowded as to obliterate the urinary space,orming pseudocrescents (Fig. 3). The podo-yte cytoplasm typically is vacuolated, contain-ng prominent intracytoplasmic protein resorp-ion (hyaline) droplets (Fig. 4). As the lesionsvolve, the glomerular tuft retracts into a tightolidified ball crowned by overlying enlarged,acuolated, visceral epithelial cells. At thistage, the urinary space often appears dilated,ontaining a proteinaceous filtrate. UnlikeSGS, not otherwise specified (NOS), the col-apsing variant of FSGS usually lacks hyalinosis,ndocapillary foam cells, and adhesions to Bow-an’s capsule in the acute phase.15 However,

epeat biopsies and postmortem studies havehown that collapsing lesions may evolve into aore typical pattern of FSGS (NOS).Tubulointerstitial disease is an invariable

omponent of HIVAN and often appears out ofroportion to the degree of glomerular injury.

n addition to tubular atrophy, interstitial fibro-is, edema, and inflammation, there are wide-pread tubular degenerative and regenerativehanges.11,12 These include tubular epithelialimplification and hypertrophy with enlarged

igure 3. The podocyte hyperplasia forms pseudocre-cents that obliterate the urinary space (Jones methen-

mine silver, 400�). (

yperchromatic nuclei, prominent nucleoli, mi-otic figures, and focal apoptosis. The HIV-1ene Vpr has been implicated in these changes,ased on recent work showing that Vpr expres-ion impairs cytokinesis in tubular epithelialells in vitro.16 Distended tubules containingoose proteinaceous casts form tubular micro-ysts, which may be numerous10 (Fig. 5). Inter-titial leukocytes consist predominantly of Tymphocytes, with renal CD4/CD8 ratios rang-ng from 0.35 to approximately 1.12,17 Mono-ytes/macrophages, plasma cells, and B cellsomprise a relatively small component of thenfiltrate.

igure 4. Overlying the collapsed tuft, the enlargedodocytes contain abundant trichrome-red protein re-orption droplets (Masson trichrome, 400�).

igure 5. There are focally distended tubules formingicrocysts that contain loose proteinaceous casts. Adja-

ent cortical tubules display degenerative changes

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mmunofluorescence

y immunofluorescence, there are segmental tolobal deposits of IgM, C3, and, less commonly,1, in the collapsing segments. The noncol-

apsed glomeruli may display weaker mesangialtaining for IgM and C3. Glomerular deposits ofgG and IgA are not identified. Visceral epithe-ial protein reabsorption droplets often stain forgG, IgA, and albumin, with similar staining inhe tubular epithelial protein droplets, consis-ent with increased intracellular protein traf-cking.

lectron Microscopy

t the ultrastructural level, the collapsed lob-les display wrinkling and little or no thicken-

ng of glomerular basement membranes. Theverlying podocytes are markedly hypertro-hied with severe foot process effacement,

ocal detachment, and increased numbers ofrganelles including electron dense proteinesorption droplets, electron-lucent transportesicles, and abundant rough endoplasmic re-iculum (Fig. 6). The actin cytoskeleton usuallyppears disrupted, giving the cells a relativelypen-appearing cytoplasm (Fig. 7). Noncol-

apsed capillaries also display severe foot pro-ess effacement, typically greater than 50%, andften exceeding 90% of the capillary surfacerea (Fig. 7). No electron dense deposits arebserved, with the exception of rare small

igure 6. The collapsed capillaries have wrinkled glo-erular basement membranes and are surrounded by

yperplastic visceral epithelial cells that obliterate therinary space, in continuity with adjacent parietal epi-

helial cells (electron micrograph, 3,000�). g

aramesangial electron densities correspondingo the mesangial deposits of IgM.

Endothelial tubuloreticular inclusions, alsonown as interferon footprints, commonly aredentified as 24-nm tubular structures located inilated cisternae of smooth endoplasmic retic-lum (Fig. 8). These structures are a marker ofIV infection that can be found in endothelialells and lymphocytes throughout the body. Its important to recognize that they are not apecific feature of the nephropathy and may beound in HIV-infected patients without HIVAN,s well as in patients with systemic lupus ery-hematosus, hepatitis C, and other viral infec-ions. Although it has not been studied system-tically, endothelial tubuloreticular inclusionsppear to be less common in renal biopsy spec-

igure 7. A high-power view shows podocyte hyper-rophy with open-appearing cytoplasm and completeffacement of foot processes. One of the podocytesontains prominent intracytoplasmic protein resorptionroplets (electron micrograph, 5,000�).

igure 8. A large tubuloreticular inclusion is seenithin a glomerular endothelial cell (electron micro-

raph, 40,000�).

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Clinical presentation and pathology of HIVAN 517

mens from patients with HIVAN who are re-eiving ART. This observation is consistentith a reduction in viral burden and associated

ytokine dysregulation that would be predictedo occur in the setting of ART. Endothelialubuloreticular inclusions also are identifiedeadily in collapsing glomerulopathy secondaryo interferon therapy, but they are typicallyacking in idiopathic collapsing FSGS, as well ashose cases associated with pamidronate toxic-ty or parvovirus B19 infection.

Tubular epithelial cells often display en-arged regenerative nuclei with prominent nu-leoli (Fig. 9), whereas the cells lining tubularicrocysts typically are flattened (Fig. 10).ther ultrastructural findings in HIVAN include

ncreased numbers of nuclear bodies withinubular and interstitial cells.12,18 These intranu-lear structures, which measure from 0.5 to 1.5m in diameter, are of uncertain significance.hey are not specific for HIVAN, and may bep-regulated in diverse cell types in response toiral infections, hormonal activation, and neo-lastic transformation. Granular degenerationf the nuclear chromatin of tubular and inter-titial cells and the presence of cylindric con-ronting cisternae also may be observed.12,18

ODOCYTE DYSREGULATION IN HIVAN

n the course of normal glomerular development,odocytes undergo a choreographed program ofroliferation and progressive maturation, culmi-ating in a fully differentiated, quiescent pheno-ype. In the mature podocyte, the expression of

igure 9. A tubule is lined by hyperplastic epithelialells with enlarged regenerative nuclei containing prom-

mnent nucleoli (electron micrograph, 4,000�).

T-1, a zinc finger transcription factor thatown-regulates proliferation, coincides withodocyte exit from the cell cycle, the expres-ion of cyclin kinase inhibitors, and the acqui-ition of maturity markers.19,20 In HIVAN andollapsing forms of primary FSGS, injured podo-ytes revert to a developmental program thatncludes down-regulation of cyclin kinase inhib-tors, entry into the cell cycle, and loss of ma-ure phenotypic markers.21-24 Because it in-olves a loss of podocyte expression of theevelopmental regulatory protein WT-1, this al-ered podocyte phenotype has been termedysregulated.21

The injured podocytes express the prolifera-ion marker Ki-67 and lose maturity markers,uch as CD10/CALLA, C3b receptor, GLEPP-1,odocalyxin, synaptopodin, and WT-1.21 Ofote, a reduction in synaptopodin expression,

n contrast to other markers, also was observedn histologically unaffected glomeruli, suggest-ng that it precedes collapse.21 By contrast,hese podocyte phenotypic changes were notdentified in minimal change disease or mem-ranous glomerulopathy, despite similar levelsf proteinuria and similar degrees of foot pro-ess effacement. In collapsed glomeruli, thendothelial expression of podocalyxin was pre-erved despite severe structural alterations ofhe capillary tuft and complete loss of podocytexpression.21 These findings point to derange-

igure 10. In an area of back-to-back tubular microcystormation, the lining epithelial cells of 2 individual mi-rocysts appear flattened and compressed by the volu-inous proteinaceous electron dense cast material (elec-

ron micrograph, 3,000�).

ent of the podocyte phenotype occurring as a

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rimary event, rather than as a consequence ofollapse.

Each phase of the cell cycle is governed byositive regulatory proteins (cyclins and cyclin-ependent kinases) and negative regulatoryroteins (cyclin kinase inhibitors). Progressionhrough the cell cycle requires the activation ofyclin-dependent kinases by complexing withpecific partner cyclins. The Cip/Kip family ofyclin kinase inhibitors (p21, p27, and p57)unction in both the G1 and S phase, and p21lso inhibits G2-/M-phase complexes. The cy-lin kinase inhibitors p27 and p57 are ex-ressed constitutively in mature podocytes,hereas p21 is not.22 In HIVAN, as well as in

diopathic collapsing FSGS, there is decreasedodocyte expression of p27 and p57, accompa-ied by de novo expression of p21 and Ki-7.22,23 Interestingly, a generalized reduction in27 and p57 can be identified in podocytesf some histologically unaffected glomeruli.22

hese findings support a paradigm wherein theeduction in p27 and p57 precedes the devel-pment of collapsing lesions and is permissiveor the proliferative podocyte phenotype. Sim-lar alterations in podocyte phenotype, as wells a dedifferentiated tubular epithelial pheno-ype, have been found in the HIV-1 transgenicurine model of HIVAN, supporting a patho-

enic role for HIV viral gene expression.24 Theathologic alterations can be attenuated or re-ersed by administration of the cyclin kinasenhibitor R-roscovitine, indicating a critical roleor cell-cycle dysregulation in this model.25

ow specific viral proteins may mediate podo-yte dysregulation is discussed in the article byoss et al on HIVAN pathogenesis in this issuep. 523).

The origin of the proliferating glomerularpithelial cells has been debated. A study ofuman HIVAN by Dijkman et al26 has suggestedhat parietal epithelial cells proliferate to repop-late the injured visceral epithelial cells. In thattudy, many of the proliferating epithelial cellsn areas of pseudocrescent formation expressedhe parietal epithelial cell marker CK8 andacked podocyte-specific markers. In addition,ell bridges to the CK8-positive parietal liningould be observed in serial sections, and no

lomerular epithelial cells co-expressed podo- w

yte markers and CK8.26 These findings areonsistent with emerging evidence that the pa-ietal epithelium at the glomerular hilus mayrovide a niche for podocyte progenitor cells.27

n the other hand, studies have clearly estab-ished the ability of podocytes to enter the cellycle. Transgenic mice expressing HIV-1 Nefnder the podocin promoter show expressionf the cell-cycle markers Ki-67 and phospho-tat3 in podocytes.28 The relative contributionf podocytes and parietal cells to glomerularpithelial cell proliferation in HIVAN and otherorms of collapsing glomerulopathy remains toe fully defined.

IFFERENTIAL DIAGNOSISF RENAL BIOPSY FINDINGS

biopsy picture of collapsing glomerulopathy isot specific for HIVAN. Differential diagnosis ofhe collapsing variant of FSGS includes primaryidiopathic) FSGS,29 parvovirus B19 infection,30

V40 infection,31 acute cytomegalovirus infec-ion,32 erythrophagocytosis syndrome,33 inter-eron therapy,34 pamidronate toxicity,35 acuteaso-occlusive injury,36 rare familial forms,37 andlomerular injury in the renal allograft associatedith microvascular disease.38

Renal biopsy in the HIV-infected patient isequired to establish a diagnosis of HIVAN ando exclude other causes of renal dysfunctionnd proteinuria, including a variety of HIV-re-ated glomerular diseases, non–HIV-related re-al diseases, and medication nephrotoxicity,any of which are reviewed in detail in the

rticles by Cohen et al (p. 535), Fine et al (p.45), and Atta et al (p. 563) in this issue. Otherlomerular lesions encountered in the HIV-in-ected patient are listed in Table 1. Immuneomplex–mediated glomerular disease is moreommon in the Caucasian population, whereasIVAN predominantly affects African Ameri-ans. It is particularly challenging for the re-al pathologist to distinguish HIVAN fromther forms of FSGS, including secondarySGS from hypertensive arterionephrosclerosisr pre-existing primary FSGS, which also areore common in black patients. Recent biopsy

eries in HIV-infected patients indicate an in-reasing prevalence of FSGS (NOS) in parallel

ith a reduction in HIVAN, suggesting modifi-

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ation of the collapsing pattern of HIVAN byRT.39,40 To illustrate the changing epidemiol-gy of HIVAN, the renal biopsy incidence ofIVAN was 65% in a series of 112 patients

eported in 1997,41 but only 35% in a recenteries of 152 biopsies.39 Because endothelialubuloreticular inclusions also appear to be re-uced by ART, the biopsy picture of HIVANay be attenuated in ART-treated patients, ap-roximating the morphologic appearance ofSGS (NOS). In addition, as patients live longerith HIV infection, they may develop otheron–HIV-related kidney diseases common inhe aging population, such as diabetic nephrop-thy and arterionephrosclerosis of aging or hy-ertension, which also may show focal scleros-

ng features.

REATMENT OF HIVAN

n the absence of randomized clinical trials, thereatment of HIVAN is based on small uncon-rolled studies, epidemiologic data, and patho-enic insights. The pathogenesis of HIVAN iseviewed in the article by Ross et al in this issuep. 523), and is known to involve direct HIVnfection and gene expression in renal epithe-ial cells, as well as host factors that affect sus-eptibility. Consistent with the direct patho-enic role of HIV infection, the introduction ofombination ART in 1996 was followed by aecline in the incidence of HIVAN42,43 and in

Table. 1. Glomerular Lesions Occurring in HIV

HIVAN (collapsing glomerulopathy)FSGS NOSMinimal change diseaseImmune complex–mediated glomerulonephritis

Lupus-like nephritisIgA nephropathyMembranoproliferative glomerulonephritis (asMembranous glomerulopathy (associated withAcute postinfectious glomerulonephritis

Fibrillary and immunotactoid glomerulonephritisDiabetic nephropathyAmyloidosis, AA type (associated with intravenoThrombotic microangiopathy

he number of new cases of ESRD attributed to p

IDS nephropathy in the United States.5 Theseuggestive epidemiologic data are supportedy small uncontrolled studies showing im-roved renal survival with ART,44,45 and byase reports documenting renal recovery andistologic improvement after the initiation ofRT.7,46 In a retrospective study of 42 patientsith biopsy-proven HIVAN from 6 US academicedical centers, ART use was associated with

elayed progression to ESRD (hazard ratio,.24; 95% confidence interval, 0.07-0.84).44 Aimilar improvement in renal survival with ARTas shown in a single-center retrospective

tudy of 36 patients with biopsy-proven HIVANhazard ratio, 0.30; 95% confidence interval,.09-0.98).45 Although these estimates were ad-

usted for demographic and clinical characteris-ics, it is likely that there also are important un-easured differences between patients who

eceived ART and those who did not receive ARTn these nonrandomized studies.

Recognizing that randomized controlledrials comparing ART with placebo are noonger ethically tenable, recently updated ex-ert guidelines consider HIVAN an indication

or the initiation of ART, regardless of CD4ell count.47,48 The guidelines also recom-end adjunctive therapy with angiotensin-

onverting enzyme inhibitors or angiotensin-eceptor blockers as tolerated,47 based onvidence of benefit from cohort studies in

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linical trials in other glomerular diseases.49

he addition of corticosteroids may be con-idered in patients with aggressive disease orprominent interstitial inflammatory compo-ent, based on uncontrolled clinical studiesnd in vitro evidence that HIV infection in-uces a local inflammatory reaction in tubularpithelial cells.50-52

The management of ESRD in patients withIV infection is discussed in the article by Saw-

nski et al in this issue (p. 581). With improve-ents in the survival of HIV-positive dialysisatients,53 patients with HIVAN who are ap-roaching ESRD should be offered a choiceetween hemodialysis and peritoneal dialysis,hich offer similar survival in adults with HIV

nfection.54 Selected patients with remoteIVAN and well-controlled HIV infection alsoay be candidates for kidney transplantation.55

PIDEMIOLOGY OF HIVANN THE ANTIRETROVIRAL ERA

lthough the incidence of ESRD attributed toIVAN reached a plateau in the United Statesfter the introduction of combination ART, 800o 900 new cases are reported to the US Renalatabase System (USRDS) each year, and therevalence of HIV-related ESRD continues to

ncrease.5,56 At the end of 2005, more than,700 individuals were living with ESRD attrib-ted to HIVAN in the United States, comparedith only 150 cases at the end of 1990.5,56 This

rend is projected to continue, in large partecause of improvements in the survival of HIV-ositive dialysis patients, but also because ofhe disproportionate burden of HIV infectionnd AIDS among African Americans. Assuming atable annual mortality rate of 24% and linearrowth of the HIV epidemic among Africanmericans, it is projected that nearly 10,000

ndividuals will be living with ESRD attributedo HIVAN by the year 2020.56 These projectionsere based on diagnoses of AIDS nephropathy

eported to the USRDS at the discretion of thereating physician. Although these cases likelyeflect a heterogeneous population of HIV-posi-ive patients with HIVAN and other glomerulariseases, these projections underestimate the truerevalence of HIV infection in the ESRD popula-

ion. Unfortunately, the USRDS no longer collects

ata on HIV infection as a comorbid condition inncident ESRD patients, and future estimates fromhe USRDS will be limited to ESRD that is attrib-ted to HIVAN.

In addition to the continued growth of theIV-positive ESRD population in the Unitedtates, there is also alarming potential for anpidemic of HIVAN in sub-Saharan Africa.early 90% of the ESRD attributed to HIVAN in

he United States occurs in African Americans,5

nd a similar racial predisposition has been ob-erved in other countries.57,58 Emerging datauggest a high prevalence of kidney diseasemong HIV-infected individuals in sub-Saharanfrica, ranging from 6% among Kenyan patientsithout other risk factors for kidney disease, to

s high as 38% in a Nigerian cohort.59-61 Al-hough kidney biopsies are performed less fre-uently in resource-limited settings, HIVAN washe most common diagnosis identified in pub-ished biopsy series from Nigeria and Southfrica.60-62 With expanding access to ART androlonged survival of HIV-infected patients,IVAN likely will be an important contributor

o the growing public health burden of chronicidney disease in sub-Saharan Africa.62,63

EFERENCES1. Rao TK, Filippone EJ, Nicastri AD, Landesman SH,

Frank E, Chen CK, et al. Associated focal and segmen-tal glomerulosclerosis in the acquired immunodefi-ciency syndrome. N Engl J Med. 1984;310:669-73.

2. Pardo V, Aldana M, Colton RM, Fischl MA, Jaffe D,Moskowitz L, et al. Glomerular lesions in the acquiredimmunodeficiency syndrome. Ann Intern Med. 1984;101:429-34.

3. Gardenswartz MH, Lerner CW, Seligson GR, ZabetakisPM, Rotterdam H, Tapper ML, et al. Renal disease inpatients with AIDS: a clinicopathologic study. ClinNephrol. 1984;21:197-204.

4. Ross MJ, Klotman PE. Recent progress in HIV-associ-ated nephropathy. J Am Soc Nephrol. 2002;13:2997-3004.

5. U.S. Renal Data System. USRDS 2007 Annual datareport: atlas of chronic kidney disease and end-stagerenal disease in the United States. 2007. Availablefrom: http://www.usrds.org/

6. Cantor ES, Kimmel PL, Bosch JP. Effect of race onexpression of acquired immunodeficiency syndrome-associated nephropathy. Arch Intern Med. 1991;151:125-8.

7. Winston JA, Bruggeman LA, Ross MD, Jacobson J,

Ross L, D’Agati VD, et al. Nephropathy and establish-

1

1

1

1

1

1

1

1

1

1

2

2

2

2

2

2

2

2

2

2

3

3

3

3

3

3

Clinical presentation and pathology of HIVAN 521

ment of a renal reservoir of HIV type 1 during primaryinfection. N Engl J Med. 2001;344:1979-84.

8. Atta MG, Choi MJ, Longenecker JC, Haymart M, Wu J,Nagajothi N, et al. Nephrotic range proteinuria and CD4count as noninvasive indicators of HIV-associated ne-phropathy. Am J Med. 2005;118:1288.

9. Atta MG, Longenecker JC, Fine DM, Nagajothi N,Grover DS, Wu J, et al. Sonography as a predictor ofhuman immunodeficiency virus-associated nephropa-thy. J Ultrasound Med. 2004;23:603-10, 612-3.

0. D’Agati V, Appel GB. Renal pathology of human immu-nodeficiency virus infection. Semin Nephrol. 1998;18:406-21.

1. Cohen AH, Nast CC. HIV-associated nephropathy. Aunique combined glomerular, tubular, and interstitiallesion. Mod Pathol. 1988;1:87-97.

2. D’Agati V, Suh JI, Carbone L, Cheng JT, Appel G.Pathology of HIV-associated nephropathy: a detailedmorphologic and comparative study. Kidney Int.1989;35:1358-70.

3. Strauss J, Abitbol C, Zilleruelo G, Scott G, Paredes A,Malaga S, et al. Renal disease in children with theacquired immunodeficiency syndrome. N Engl J Med.1989;321:625-30.

4. Cohen AH, Nast CC. Renal injury associated withhuman immunodeficiency virus infection. In: Jen-nette CJ, Olson JL, Schwartz MM, Silva FG, eds. Hep-tinstall’s pathology of the kidney. Philadelphia: Lip-pincott Williams & Wilkins; 2007.

5. D’Agati VD, Fogo AB, Bruijn JA, Jennette JC. Patho-logic classification of focal segmental glomeruloscle-rosis: a working proposal. Am J Kidney Dis. 2004;43:368-82.

6. Rosenstiel P, Letourneau TGA, Chan JC, Husain M,D’Agati V, Klotman ME, et al. HIV-1 vpr impairs cyto-kinesis in human proximal tubule cells leading tomultinucleation and hypertrophy: implications forHIVAN pathogenesis. Kidney Int. 2008. In press.

7. Rey L, Viciana A, Ruiz P. Immunopathological char-acteristics of in situ T-cell subpopulations in humanimmunodeficiency virus-associated nephropathy.Hum Pathol. 1995;26:408-15.

8. Chander P, Soni A, Suri A, Bhagwat R, Yoo J, Treser G.Renal ultrastructural markers in AIDS-associated ne-phropathy. Am J Pathol. 1987;126:513-26.

9. Nagata M, Nakayama K, Terada Y, Hoshi S, WatanabeT. Cell cycle regulation and differentiation in thehuman podocyte lineage. Am J Pathol. 1998;153:1511-20.

0. Pavenstadt H, Kriz W, Kretzler M. Cell biology of theglomerular podocyte. Physiol Rev. 2003;83:253-307.

1. Barisoni L, Kriz W, Mundel P, D’Agati V. The dysregu-lated podocyte phenotype: a novel concept in thepathogenesis of collapsing idiopathic focal segmentalglomerulosclerosis and HIV-associated nephropathy.J Am Soc Nephrol. 1999;10:51-61.

2. Shankland SJ, Eitner F, Hudkins KL, Goodpaster T,D’Agati V, Alpers CE. Differential expression of cy-

clin-dependent kinase inhibitors in human glomerular

disease: role in podocyte proliferation andmaturation. Kidney Int. 2000;58:674-83.

3. Barisoni L, Mokrzycki M, Sablay L, Nagata M, YamaseH, Mundel P. Podocyte cell cycle regulation and pro-liferation in collapsing glomerulopathies. Kidney Int.2000;58:137-43.

4. Barisoni L, Bruggeman LA, Mundel P, D’Agati VD,Klotman PE. HIV-1 induces renal epithelial dediffer-entiation in a transgenic model of HIV-associated ne-phropathy. Kidney Int. 2000;58:173-81.

5. Gherardi D, D’Agati V, Chu TH, Barnett A, Gianella-Borradori A, Gelman IH, et al. Reversal of collapsingglomerulopathy in mice with the cyclin-dependentkinase inhibitor CYC202. J Am Soc Nephrol. 2004;15:1212-22.

6. Dijkman HB, Weening JJ, Smeets B, Verrijp KC, vanKuppevelt TH, Assmann KK, et al. Proliferating cellsin HIV and pamidronate-associated collapsing focalsegmental glomerulosclerosis are parietal epithelialcells. Kidney Int. 2006;70:338-44.

7. Bariety J, Mandet C, Hill GS, Bruneval P. Parietalpodocytes in normal human glomeruli. J Am SocNephrol. 2006;17:2770-80.

8. Husain M, D’Agati VD, He JC, Klotman ME, KlotmanPE. HIV-1 Nef induces dedifferentiation of podocytesin vivo: a characteristic feature of HIVAN. AIDS. 2005;19:1975-80.

9. Valeri A, Barisoni L, Appel GB, Seigle R, D’Agati V.Idiopathic collapsing focal segmental glomeruloscle-rosis: a clinicopathologic study. Kidney Int. 1996;50:1734-46.

0. Moudgil A, Nast CC, Bagga A, Wei L, Nurmamet A,Cohen AH, et al. Association of parvovirus B19 infec-tion with idiopathic collapsing glomerulopathy. Kid-ney Int. 2001;59:2126-33.

1. Li RM, Branton MH, Tanawattanacharoen S, Falk RA,Jennette JC, Kopp JB. Molecular identification ofSV40 infection in human subjects and possible asso-ciation with kidney disease. J Am Soc Nephrol. 2002;13:2320-30.

2. Tomlinson L, Boriskin Y, McPhee I, Holwill S, Rice P.Acute cytomegalovirus infection complicated by col-lapsing glomerulopathy. Nephrol Dial Transplant.2003;18:187-9.

3. Thaunat O, Delahousse M, Fakhouri F, Martinez F,Stephan JL, Noel LH, et al. Nephrotic syndrome asso-ciated with hemophagocytic syndrome. Kidney Int.2006;69:1892-8.

4. Shah M, Jenis EH, Mookerjee BK, Schriber JR, BaerMR, Herzig GP, et al. Interferon-alpha-associated focalsegmental glomerulosclerosis with massive protein-uria in patients with chronic myeloid leukemia fol-lowing high dose chemotherapy. Cancer. 1998;83:1938-46.

5. Markowitz GS, Appel GB, Fine PL, Fenves AZ, LoonNR, Jagannath S, et al. Collapsing focal segmentalglomerulosclerosis following treatment with high-dose pamidronate. J Am Soc Nephrol. 2001;12:

1164-72.

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3

4

4

4

4

4

4

4

4

4

4

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5

5

5

5

5

5

5

6

6

6

6

522 C.M. Wyatt, P.E. Klotman, and V.D. D’Agati

6. Greenberg A, Bastacky SI, Iqbal A, Borochovitz D,Johnson JP. Focal segmental glomerulosclerosis asso-ciated with nephrotic syndrome in cholesterol athe-roembolism: clinicopathological correlations. Am JKidney Dis. 1997;29:334-44.

7. Avila-Casado MC, Vargas-Alarcon G, Soto ME, Hernan-dez G, Reyes PA, Herrera-Acosta J. Familial collapsingglomerulopathy: clinical, pathological and immuno-genetic features. Kidney Int. 2003;63:233-9.

8. Nadasdy T, Allen C, Zand MS. Zonal distribution ofglomerular collapse in renal allografts: possible roleof vascular changes. Hum Pathol. 2002;33:437-41.

9. Berliner AR, Fine DM, Lucas GM, Rahman MH,Racusen LC, Scheel PJ, et al. Observations on a cohortof HIV-infected patients undergoing native renal bi-opsy. Am J Nephrol. 2008;28:478-86.

0. Fine DM, Perazella MA, Lucas GM, Atta MG. Kidneybiopsy in HIV: beyond HIV-associated nephropathy.Am J Kidney Dis. 2008;51:504-14.

1. D’Agati V, Appel GB. HIV infection and the kidney.J Am Soc Nephrol. 1997;8:138-52.

2. Ahuja TS, Borucki M, Funtanilla M, Shahinian V, Hol-lander M, Rajaraman S. Is the prevalence of HIV-associated nephropathy decreasing? Am J Nephrol.1999;19:655-9.

3. Lucas GM, Eustace JA, Sozio S, Mentari EK, AppiahKA, Moore RD. Highly active antiretroviral therapyand the incidence of HIV-1-associated nephropathy: a12-year cohort study. AIDS. 2004;18:541-6.

4. Szczech LA, Gupta SK, Habash R, Guasch A, KalayjianR, Appel R, et al. The clinical epidemiology andcourse of the spectrum of renal diseases associatedwith HIV infection. Kidney Int. 2004;66:1145-52.

5. Atta MG, Gallant JE, Rahman MH, Nagajothi N,Racusen LC, Scheel PJ, et al. Antiretroviral therapy inthe treatment of HIV-associated nephropathy. Neph-rol Dial Transplant. 2006;21:2809-13.

6. Wali RK, Drachenberg CI, Papadimitriou JC, Keay S,Ramos E. HIV-1-associated nephropathy and responseto highly-active antiretroviral therapy [letter]. Lancet.1998;352:783-4.

7. Gupta SK, Eustace JA, Winston JA, Boydstun II, AhujaTS, Rodriguez RA, et al. Guidelines for the manage-ment of chronic kidney disease in HIV-infected pa-tients: recommendations of the HIV Medicine Associ-ation of the Infectious Diseases Society of America.Clin Infect Dis. 2005;40:1559-85.

8. Panel on Antiretroviral Guidelines for Adult and Ado-lescents. Guidelines for the use of antiretroviralagents in HIV-infected adults and adolescents. Depart-ment of Health and Human Services. December 1,2007; 1-136. [cited 2007 Dec 30]. Available from:http://www.aidsinfo.nih.gov/ContentFiles/AdultandAdolescentGL.pdf.

9. Wei A, Burns GC, Williams BA, Mohammed NB, Vis-

intainer P, Sivak SL. Long-term renal survival in HIV-

associated nephropathy with angiotensin-convertingenzyme inhibition. Kidney Int. 2003;64:1462-71.

0. Smith MC, Austen JL, Carey JT, Emancipator SN,Herbener T, Gripshover B, et al. Prednisone im-proves renal function and proteinuria in humanimmunodeficiency virus-associated nephropathy.Am J Med. 1996;101:41-8.

1. Eustace JA, Nuermberger E, Choi M, Scheel PJ Jr,Moore R, Briggs WA. Cohort study of the treatment ofsevere HIV-associated nephropathy with corticoste-roids. Kidney Int. 2000;58:1253-60.

2. Ross MJ, Fan C, Ross MD, Chu TH, Shi Y, Kaufman L,et al. HIV-1 infection initiates an inflammatory cas-cade in human renal tubular epithelial cells. J AcquirImmune Defic Syndr. 2006;42:1-11.

3. Ahuja TS, Collinge N, Grady J, Khan S. Changingtrends in the survival of dialysis patients with humanimmunodeficiency virus in the United States. J AmSoc Nephrol. 2002;13:1889-93.

4. Ahuja TS, Collinge N, Grady J, Khan S. Is dialysismodality a factor in survival of patients with ESRDand HIV-associated nephropathy? Am J Kidney Dis.2003;41:1060-4.

5. Wyatt CM, Murphy B. Kidney transplantation in HIV-infected patients. Semin Dial. 2005;18:495-8.

6. Schwartz EJ, Szczech LA, Ross MJ, Klotman ME, Win-ston JA, Klotman PE. Highly active antiretroviral ther-apy and the epidemic of HIV� end-stage renal dis-ease. J Am Soc Nephrol. 2005;16:2412-20.

7. Lopes GS, Marques LP, Rioja LS, Basilio-de-OliveiraCA, Oliveira AV, Nery AC, et al. Glomerular diseaseand human immunodeficiency virus infection in Bra-zil. Am J Nephrol. 1992;12:281-7.

8. Laradi A, Mallet A, Beaufils H, Allouache M, MartinezF. HIV-associated nephropathy: outcome and progno-sis factors. Groupe d’ Etudes Nephrologiques d’Ile deFrance. J Am Soc Nephrol. 1998;9:2327-35.

9. Wools-Kaloustian K, Gupta SK, Muloma E, Owino-Ong’or W, Sidle J, Aubrey RW, et al. Renal disease inan antiretroviral-naive HIV-infected outpatient popu-lation in Western Kenya. Nephrol Dial Transplant.2007;22:2208-12.

0. Emem CP, Arogundade F, Sanusi A, Adelusola K,Wokoma F, Akinsola A. Renal disease in HIV-seropos-itive patients in Nigeria: an assessment of prevalence,clinical features and risk factors. Nephrol Dial Trans-plant. 2008;23:741-6.

1. Han TM, Naicker S, Ramdial PK, Assounga AG. Across-sectional study of HIV-seropositive patientswith varying degrees of proteinuria in South Africa.Kidney Int. 2006;69:2243-50.

2. Gerntholtz TE, Goetsch SJ, Katz I. HIV-related ne-phropathy: a South African perspective. Kidney Int.2006;69:1885-91.

3. Arogundade FA, Barsoum RS. CKD prevention in Sub-Saharan Africa: a call for governmental, nongovern-mental, and community support. Am J Kidney Dis.

2008;51:515-23.