·:--.'picaOourn£l( oj:-v..cpfzo(ogy 'I,DU :\'f,1,1arlllary, 2007, 25-31

HIV-Associated Nephropathy (HIVAN): Hope rising!Eboreime-Oikch 10

Department of Medicine. Central Hospital, Benin City. Nigeria

ABSTRACTHIVAN, the commonest renal complication of HI V/.-\IDS is most prevalent among blacks of Africandescent. Before the advent of HAART, HIVAN wasinevitably fatal within a short period. However, withthe introduction of highly active anti-retroviral therapy.H:\ART), the prognosis of HI VAN has dramaticallyimproved. Angiotensin-converting enzyme (ACE)inhibitors and corticosteroids have also improved thetreatment outcome of HI VAN. Patients with HIVAN;U~ now being offered renal replacement therapy.dialysis and transplantation) more readily than in thepast and new therapeutic strategies against HIVANare being devised. The racial predilection of HI VAN~\\ever, warrants further investigation.

INTRODUCTIONHI\·.-\N, formerly known as AIDS-associatedaephropathy, was first described in 1984 [1] and itcomprises a clinicopathological pentad (Table 1).HIVAN is the single most common and most welldefined renal complication of humanimmunodeficiency virus (HIV) infection in blackpersons of African origin [2, 3,4].

Table 1: Pentad of clinicopathological diagnosis of

HI\A,"l

Significant proteinuria

- Azotaemia with renal insufficiency

, Normal blood pressure

.• , :\ormal or large and highly echogenic kidneys l)n

ultrasound

- Collapsing form of' focal segmental

glomerulosclerosis on renal histology

At the beginning of the HIV /AIDS epidemic,and before the advent of HAART, HIVAN wasinevitably fatal; progressing inexorably to death withina few months of the diagnosis [3]. The managementof HIVAN then, was largely supportive. The recentadvances in the knowledge of the epidemiology,pathogenesis and the management of HIVAN givehope for the containment of this disease withenhanced quality of life and longevity of the patients.The current advances are discussed further in thisarticle.

EpidemiologyHIVAN is the leading cause of chronic kidney disease(CKD) in HIV-l seropositive patients with a reportedprevalence of 5-10% [5]. No case of HIV-2associated nephropathy without HIV-l eo-infectionhas thus far been reported.

Black patients are particularly vulnerable toHIVAN and more males than females. HIVAN wasreported by the United States Renal Data Service(USRDS) as the third commonest cause of end-stagerenal disease (ESRD) in African Americans betweenthe ages of 20 and 64 years (after diabetes andhypertension) [6]. Unfortunately. the incidence ofHIVAN in Africa with the largest concentration ofblacks in the world is largely unknow n. because ofthe paucity of published data on HI\'.-\.); cases,

HI\'A); usual I> occurs lute in the course ofHI\' infection [- " thou;h -:,;5::'5.:-f eJ:'I: onset occur.\!J:::. ;'..:::;:>:-::5j~::,r;:>I..l:~":'-::.;:>..:r::.,:of opportunisticinf::,-::i'::':15::-:,-\:':-i.:..: ;:-~'_'':'J:-::. :-·;;>:-,:T::' HI\A); becomesclini.:,;i':. e. :':::.-:-:: 1'-.::' .:-<''':;:>;:'::'!01 renal diseasesreportec t. '_'~RJ:S s:, ::-:::-;;'.lsd \\ hen mortalityfrom .,-';'~::-:--'-:-::': ::-:':'-':Ik'I1S decreased amongpatieru- .'.::- ..'...105 ~i:-:~i;Jrl:. the pool of patients inAlric..l .,: :->~.:: .:«. ;:>k'pin~ HIVAN is expected toin.:r;:'..:s;' ":~..::-'...:::':..:Ii: « ith improved survival fromorr,'r -« --:::'':U0I1S,

Correspon ding author: Dr I. O. Eboreime-OikehDeportment ofMcdicitie, Central Hospital. Ben: C- .\'i(?L'I'i({

L _

't

Hl s/-Associatcd 1/C'/,hmf'athy

Racial predilection for HIVAN may begenetically determined. Blacks are more prone tokidney diseases in general than other races. Almosta quarter of patients with HIVAN volunteer a familyhistory of renal disease and black patients withHIVAN are more than five times likely to have a

infection in their renal epithelium. The infection canremain transcriptionally active albeit. at low levels.

It is not yet certain whether the renal reservoircontributes to rebound of plasma viral loads in patientswho had previously undetectuble viral load withantiviral drugs. In addition. the renal reservoir

Table 2: Spectrum of renal diseases associate with HIV infectionAcute Renal Failure Chronic Renal Failure

Pre-rctial• Hypovolernia • Focal Segmental Glomerulosclerosis• Sepsis (Classic HIVAN)• H ypoalbumi naernia

• Immune Complex Diseaseintrinsic Renal (a) IgA Nephropathy

• Acute Tubular Necrosis Cb) Mixed sclerotic immune complex• Allergic Interstitial Nephritis nephropathy• Crystal Deposition (c) Proliferative glomerulonephritis

POST Renal • Microangiopath ies• Extrinsic Obstruction (a) Hemolytic Urernic Syndrome• Intrinsic Obstruction (b) Thrombotic thrombocytopenic purpura

first-degree or second-degree relative with ESRDthan are black patients without renal diseasel S],Unfortunately. no candidate gene has been definitelyimplicated.

Pathogenesis of HIVANMany mechanisms have been suggested to explainthe pathogenesis of HIVAN but increasing evidencenow supports a direct role of HIV in its pathogenesis.HIV-I infection of renal parenchymal cells in humanswas demonstrated by Bruggeman et al in 2000 [9].The infection of the epithelial cells of the glomerulusand tubules by HI\'-l overlaps the pattern of histologicdisease in HI\·.-\:'\. supporting a role for directinfection of the k idnev s in the p.uhogene sis ofHIVAN.

The kidneys mJY JI;;,o be :1" i:r::,-=,r:.l~~reserv oirfor HIV-I. The virus has been Jek·..::[e~ :-. "'-"'Ii': R:'\-\ill situ hybridization and D:'\.-\ ill <:: P:·':~~e~..:~Chain Reaction (PCR) in some p~lt!e!':' .' '-.' ~.::,j

undetectable viral load in peripheral Dk'\"'..: '.:"-:- ":'[9. IOJ. This has very important implication, t: - :-::\-

I seropositive .patients who despite an C'!' .~-.:response in viraemia to HAART and even cli:~<_remission of HI\·.-\N may have persistent H[\

of actively replicating HIV-l may support theevolution of viral strains that differ significantly fromvirus present in the patient's blood. The virus strainsmay be drug-resistant and may not be susceptible tocurrently a vai lable anti-retroviral drugs.

The mechanism by which HIV-l gains entryinto renal epithelial cells is not entirely known. Thereceptor for HIV-l (CD4) and the major co-receptors(CCR5. CXCR4) are not expressed in most normalrenal epithelial cells. Direct infection of kidney cellsresulting in proliferation and cellular apoptosis withthe activation of cell-mediated immunity in patientswho are genetically predisposed is likely to be thebasis of HIVAN.

Histopathology of HIVANRenal biopsy is the gold standard for the diagnosis ofHI\·.-\:'\. HI\' is associated with a wide spectrum of~::r:jl diseases [Table 2J. However. HIVAN is the~~,"';':':':''',~:':''lfindin ; on renal histology In HIV-I,,~~::-> ~.:: :-:.1"::" patients with chronic kidney.; ':>:: ~ Tr.er •..iore. all HIV-infected patients... :'. _~ :-;: ::.: :::;;; e vcretion ill excess of one .£Cram:-:- ..:.:: ~-: .. ..: h..!\:? renal biopsy.

~-~----~------------------------------------------------------------------------

1

"

, .,,',!.,

, ,

,- -,."I :

......., ~ :.'

\ .:,-.',.

I ~. '"" •

\ '- I~ -

-".. ' .•. .. -•.i'., .

Fig. 1: T;'I)ictl hl'll)P~llhulllgl( llnJin~, in 111\·-~"'lh.:i~ll.:d ncphrop.n h , 1/11\.\,'\) .

.-\: Periodic ac id-Schif} (I'AS) -t.uuing sho« ing t',,(~tI ,.:glll~nt~tI gl(llll~rlll,),ckmsis(FSGS) wuh segmental collapse. Podocyrc hyp.:rtrol,hy and hvpcrpluxia arc obviousOIcrlying the ~Ir.:aotcnllapse (~IITlllI).

B: Tubular rnicrocystic dilatations filled with protcinuccous material and interstitiallymphocytic infiltration and fibrosis in HIVAN.I lc m.uoxylin and eosin .

+daptcdfrosn Ross All. Klotniau Pr:. Recent Progrcs« ill fllli-!\ssoci({ter/ Nl'IJhrnflath\'. J :\11I Sot' NCIJ/imi ~(J()~:I3: ~ ')'! --.if If u

•.;. .'Fi~. le: H"l(lP~1I11111"gicL'h~lI·~ldCI'I,'II•.:, Iq 111\-

~""CialL'U ncphrop.uhv ill humans L'hru-trucuual~lIl:1h'si~,h\lll' ac'(IILq'>c'J gllllllL'rular clptllarl 11 uh1\ I'Illkling 01' rhc gl(lllll'l'lIlar basement membrane.I"ldtlc:,t<> I PI hall' 1",'1 1',1I>! proC<'''<', , and theircc!l huJy ,it-- dlrecll, on the ~1'"11l'rlllar basementmembrane .uid n•.'1\ IILlII'I\ d"PU'ILI"1l I a,Lcri,", I.

Ii/"/J/crl//'(I//I, "'11111111'1. 1'1., li(ll'i\(l/li I .. "'0/'/' .l l!.: \111111//1'/"11 v.: :I)(}.,', 13(1.:1-1-:::(,

'I,. . ,I.' .H,'.... \: .

•

Histologic. immunologic and ultrastructural features ofrenal tissue from a biopsy specimen in HIVAl arcdistinctive. A collapsing form of focal segmentalglomerulosclerosis on light rnicroscopy is typical [Figure1A I but not pathognomonic of HIVAN. Collapsingglornerulopathy has also been described in certain otherconditions such as systemic autoi I11l11uncdisorders (e.g.svsternic lupus erythematosus, adult Stills disease).viral infections (c.g. parvovirus B 19 infection), andeffects of drugs like interferon and pamidronate Ill.12. U. 14,15, 161.

Light microscopy sho.vs collapsed f'loll1erular(;Ll'iILtn tuft \I hich i~either ~~'f:meIlL~t1I~1)1' :::k)h,t1I~<ic-I','<J Ther.: i- h\ I'c'nr,'!'!;:- .':' \ ',,"c'!',d "i'iLh~'ktl

'~ . : ••.">... • .••••. ' - ~ ";...' ••..,•.::...1:1: ]11

.;",c, - III

. :~' I' 'l i L ial,-,;:,Jhdil.ncd

j-t . ,.,., _:.~'<c'r~demonstratesz: "ill \ Ig) G. Igiv1. c."

-- c' suining for albumin ill'. -:"'1": arc.is. Typical katlll'L'~ Oil

'/,\ uul udc \\ I·illl-.lillg of t hcL h.: ....~.,.. ~~'I.'..

H/V-Associated ncpliropath;

basement membranes. epithelial cell proliferation. andfocal foot process effacement [Figure l C],

Tubuloreticular inclusions which consist ofribonucleoprotein and membrane within theglomerular and arterial endothelial cells, interstitialleucocytes and capillary are highly suggestive ofHIVAN [171. The synthesis of the tubuloreticularinclusions is stimulated by alpha-interferon; however,these tubuloreticular inclusions are less commonlyseen these days perhaps, due to the efficiency ofHAART in reducing plasma concentrations ofinterferon,

Clinical ManifestationsThe typical picture of HIVAN clinically, is ofprogressive proteinuria usually within the nephroticrange (>3gI24 hours) and rapidly deteriorating renalfunction. if untreated. Despite the nephrotic rangeproteinuria and hypoalbuminaernia, edema is strangelyuncommon [7]. The absence of edema may be dueto the salt-losing propensity and high oncotic pressurecontributed by marked hyperglobulinemia in patientswith HIVAN. Hypertension is unusual in thesepatients probably also due to the salt wasting tendencyof HI VAN [18J. There mayor may not be associatedhyperlipidaemia. Some electrolyte abnormalities suchas hyponatremia and hyperkalemia occur in HIVANpatients and may result from an increase in total bodywater from the nephrotic syndrome, syndrome ofinappropriate secretion of antidiuretic hormone[SIADH] or hyporeninemic hypoaldosteronism,respectively.

Serum complement levels are normal.Urinalysis reveals proteinuria, microscopic hematuriasometimes. and hvaline casts but no cellular casts.The kidneys on ultrasound are highly echogenic andnormal-to-large despite progression to ESRD. A highlydense renal parenchy rna on computerized tomography(CT) scan without COIltDSr media has been reponedin HIVAN [19].

The prognosis of HI\-.-\:'\ is \\ 2,S'" \\ ith higherdegrees of proteinuria. severe ren ..11 impa.rment. 10\\

CD4 lymphocyte count. high viral l,-',:;.:!. ':;:12 se. ereanemia.

Management of HIVANThere was a sense of therapeutic nihilism in the t~e-HAART era over the management of HI\.-\:'\because of the dismal prognosis. The managementof HIVAN should involve collaboration betv een J

nephrologist and an HIV specialist. HAART has

however revolutionized the treatment of HI VAN andsignificantly improved the prognosis [18. 20. 21].There are reports of dramatic improvement ofdialysis-dependent patients with biopsy-provenHIVAN who after the commencement of aggressivemanagement with HAART, no longer requireddialysis! 2(). 21/. Indeed, it has been estimated thatHAART since its introduction in 1995, has retardedthe progression of HIV-associated renal diseasesincluding IIIVAN to ESRD by 38% [22J.

Though no formal management guidelines existcurrently. all patients with HIVAN should be treatedwithHAART as soon as the diagnosis is made exceptin cases where there are compelling contraindications.Strict adherence to HAART treatment by the patientsis req ui red to obtain and sustain improvement.

Doses of nucleoside analogues should beadjusted according to renal function because of theirpotential toxicity. However, protease inhibitors, non-nucleoside reverse transcriptase inhibitors which aremetabolized by the liver are relatively safe whileEnfuvirtide (Fuzeon®) which belongs to a new classof fusion inhibitors has no known adverse renaleffects. Nephrotoxic drugs such as Tenofovir shouldbe avoided.

ACE inhibition has been found to be effectiveat preserving renal function in patients with biopsy-proven HIVAN [23]. ACE inhibitors are mostbeneficial when initiated as soon as the diagnosis ofHIVAN is established. Patients receiving ACEinhibitors should be monitored for hyperkalernia,progressive azotaemia, or volume depletion. In blackpatients who may not respond adequately to ACEinhibitors, non-potassium sparing diuretics may beadded with caution and where appropriate.

The probable mechanisms of ACE inhibitors'actions include changes in renal hemodynamicsresulting in the reduction of transglomerular passageof serum proteins. an anti-proliferative effectmediated by the inhibition of transforming growthfactor- beta i TGF-a L or interference with ACE-mediated p.ith« a) s involved in antigen processing andi"'rese:lt:ltion be twe e n macrophages and T-.. r.-:;:,'lI.X'~ res [2-+ J. The role of Angiotensin II receptor~lC'-:h.ers in human HIVAN has not yet beene st.iblished but may be similar to the renoprotectiveeffect of ACE inhibitors.

Improved renal function and reduction ofinterstitial inflammation but not overall survival havebeen reported in patients treated with corticosteroids125). Therapy with corticosteroids may however.

a

10 Eboreime-Oikeli

increase the incidence of sepsis and opportunisticinfections. Prednisone should be used in associationwith HAART in treatment of HIVAN in patients withaggressive renal disease and no active infectiouscomplications. Cyc\osporine has limited use in themanagement of HIVAN l26J.

Renal support for patients who present withsevere renal failure may still be necessary beforeHAART takes effect. Survival rates are similarbetween patients on hcrnodialysis and peritonealdialysis though the incidence of peritonitis due to fungiand pseudomonas may be more common in HIVANpatients treated with peritoneal dialysis. The choiceof dialysis should however, be based on patientpreference, resources and the treatment centre.

The vastly improved prognosis of HIV-linfected patients treated with HAART, has led tokidney transplantation being increasingly offered topatients with ESRD due (0 HIVAN. Conditions fortransplant include compliant and stable patients withno active opportunistic infections and who haveundetectable viral load and a CD4 count more than300 cells/ul; The outcome of graft and patient survivalis said to be comparable to other high-risk populationsreceiving kidney transplant.

:n

:dat.d:s

st.dJts.ts

rr1-

'ee.st1d

e'- Future Therapeutic Strategies

Experimental studies involving the use of cyc1in-dependent kinase inhibitor and blockade of nuclearfactor kappa beta (a cell signaling pathway), in micehave reported decreased renal visceral epithelial cellproliferation and increased longevity respectively inHIV-infected mice [27, 28]. Further studies arerequired to define their role in humans with HIVAN.

l.

kEe

", CONCLUSIONRecent advances in the understanding of HIVA:" JS

a distinct clinical entity and the obvious benefit ofHAART in the management of this disease bring hopeto the legion of people suffering from HIVAN \\ hobefore now were hopeless.

It is gratifying that HAART is now morereadily available and accessible to patients even inresource-poor settings such as exist in Sub-SaharanAfrica. More studies and data from Africa withregard to HIVAN are required. The characteristicsof HlVAN and the response to therapy in African-Americans in whom most studies have been doneIllay not necessarily be the same in blacks of Sub-Saharan Africa because of the influence ofenvironment. life-styles. er cetera.

se.t

h

j

r11

f

s

The factors tn:ar predispose blacks to HIVANneed to be explored in future studies while optimumstrategy for the management of HIVAN should' beestablished. The future however, looks bright forpatients with HIVAN.

REFERENCES1. Gardenswartz MH, Lerner CW,

Seligson GR, Zabetakis PM, RotterdamR Tapper ML, Michelis MF and BrunoMS: Renal disease in patients with AIDS:a clinicopathological study. Clin Nephrol1984; 21: 197-204.

2. Cantor ES, Kimmel PL and Bosch JP:Effect of race on expression of acquiredimmunodeficiency syndrome-associatednephropathy. Arch Intern Med 1991;151: 125-128.

3. Abbot KC. Hypolite I. Welch PG andAgodoa LY: Human immunodeficiencyvirus/acquired immune deficiencysyndrome-associated nephropathy atend-stage renal disease in the UnitedStates: patient characteristics andsurvival in the pre-highly activeantiretroviral therapy era. J NephroJ2001 Sep-Oct; 14: 377-383.

4, Szczech LA, Gupta SK, Habash R,Guasch A Kalayjian R, Appel R, FieldsTA, Svetkey LP, Flanagan KH, KlotmanPE and Winston JA: The clinicalepidemiology and course of the spectrumof renal diseases associated with HIVinfection. Kidney Int 2004 Sept;66(3): 1145-1152.

5. D- Agati V and Appel GB. HIV infectionand the kidney, J Am Soc Nephrol. 1997;8:DS-15~,

6. rs Renal D.lta S~ stern (l;SRDS):l-SRDS ~f'fll Annual Data Report.B~t:-ICs.j.l \10 The :\.ltional Institutesof He.i'tb. :\;,HJof1JI Institute of Diabetes.lr.': D:;=stJ\ ~ and Kidney Diseases,2t •• i

7. Wi~s.t-_-'n1.-\, Klorrrun \IE and KlotmanPE- Hlv-associated nephropathy is a late,,Y ~..Ir;). manifestation of HIV-lr.f~':li,'n_ Kidney Int 1999 Mar; 55(3):lil_~lO·W.

s. Freedman BI. Soucie JM. Stone SM andP~;rJIll S: Familial clustering of end-

-29

9.

10.

11.

12.

13.

16.

17.

18.

19.

20.

21.

22.

23.

2 .•.

25.

HIV-As50ciaTcd neplirop atltv

patient (case report). Nephrol DialTransplant 2004; 19: 723-726.D' Agati, AppeJ GB. Renal pathology ofhuman immunodeficiency virus infection.Sernin Nephrol 1<)<)8;18:406-421.Klotman PE: HIY-associated

nephropathy. Kidney Int 1999 Sep;56(3):ll61-7(1.Hulot 1-5. Iklllfils Hand Mercadal L.Spontanc. ll;~ renal CT-scan hyperdensityof an It I \'-Jssociated nephropathy.Nephrol l )i.tI Transplant 2003; 18: 2678-2679.Kirchncr JT: Resolution of renal failure

after iniu.n ion of HAART: 3cases and adiscussion of the literature. AIDS Read2002l\Ltr; 12(3): 103-105, 1l0-1l2.Schemer D: Rapid reversal of renal

failure after initiation of HAART: a casereport. AIDS Read 2004 Aug ; 14(8):443-447.Schwurtz El. Szczech LA. Ross MJ.

Klotrnan 1\IE. Winston JA and KlotmanPE. Highly Active Antiretroviral Therapyand the Epidemic of HlY + End-StageRenal Disease. JAm Soc Nephrol 2005;16: 2412-2420.Wei A. Burns oc. Williams BA.

Mohammed NB. Yisintainer P and SivakSL. Long-term surv ival in HIY-associated nephropathy withangiotensin- converting enzymeinhibition. Kidney Int 2003 act;64(4): 1462-147l.Odaka C and Mizuochi T. Angiotensin-

converting enzyme inhibitor captoprilprevents activation-induced apoptosis byinterfering with T cell activation signals.Clin Exp ImmunoI2000; 121:515-522Eustace lA. Nuermberger E. Choi M.

Scheel PJ. Jr. Moore Rand Briggs WA:Cohort study of the treatment of severeHI\"-associated nephropathy withcorticosteroids. Kidney lnt 2000; 58;1253-1260.Singh A and Tejani A. One-center

e x pcr ie ncc with cyclosporine inrefructory nephrotic syndrome inchildren. Pediatr Nephrol 1999; 13: 26-3~.

30

14.

stage renal disease in blacks with HT\'-associated nephropathy. Am 1 KidneyDi-s 1999; 34:254-258.Bruggeman LA. Ross MD. Tanji N.

Cara A, Dikrnan S, Gordon RE. Burnsoc. D' Agati VD. Winston lA. KlounanME and Klotrnan PE: Renal epitheliumis a previously unrecognized site of H IV-I infection. JAm Soc Nephrol 20()() :'\ov:II (11): 2079-2087.Winston JA. Bruggernan LA. Ross MD.

Jacobson J, Ross L. D'Agati VD.Klotman PE and Kl ot mu n \IE:Nephropathy and establishment of arenal reservoir of HIY type I duringprimary infection. N Engl J Med 200L344: 1979-1984.Amoura Z. Georgin-Lavialle S. Haroche

J, Merrien D, Brocheriou I. Beaufils Hand Piette J-c. Collapsingglomerulopathy in systemic autoirnrnunedisorders: a case occurring in the courseof full blown systemic lupuserythematosus (letter). Ann RheumaticDis2006;65: 277-278Kumar S, Sheaff M and Yaqoob M.

Collapsing glomerulopathy in adult Still'sdisease. Am J Kidney Dis 2004: 43: 4-toTanawattanacharoen S. Falk RJ,

Jennette JC and Kopp JB. Parvovirus B19 in kidney tissue of patients with focalsegmental glomerulosclerosis. Am JKidney Dis :WOO; 35: 1166-1174.Hammar. SP. Luu. JY. Bockus. DE.

Rernington. FL. Luu. JW_ Friedman. Sand Bean. \IA: Induction oftubuloreticular structures in culturedhuman endothelial cells by recombinantinterferon alpha and beta. L'ltrastructPathoI199216:211-218.Laurinavicius A, Hurwitz Sand Rennke

HG. Collapsing glomerulopathy in HI\"and non -H 1V pal ients: Aclinicopathological and follow-up study.Kidney lnt 1999; 56:2203-22IJ.Kunin M. Kopolovic 1. Avigdor A.

Holtzman EJ. Collapsing glomerulopathyinduced by long-term treatment withstandard-dose pamidronare in a myeloma

15.

16.

-10 Eborcinse-Oikeit

27. Gherardi D and D' Agati V: Reversal ofcollapsing glomerulopathy in mice withthe cyclin- dependent kinase inhibitorCYC202. J Am Soc Nephrol 2004;15(5): 1212-1222.

28. Heckmanrr A and Waltzinger C: IKK2inhibitor alleviates kidney and wastingdiseases in a murine model of humanAIDS. Am J Patho12004; 164(4): 1253-1262.

.11