hiv-associated nephropathies epidemiology, pathology, mechanisms and treatment

150 | MARCH 2015 | VOLUME 11 www.nature.com/nrneph

Department of Pathology, Johns Hopkins Medical Institutions, 720 Rutland Avenue, Baltimore, MD21287, USA (A.Z.R.). School ofClinical Medicine, Faculty of Health Sciences, University ofthe Witwatersrand, 7 York Road, Parktown, Johannesburg 2193, South Africa (S.N.). Basic Research Laboratory, Center forCancer Research, National Cancer Institute, Leidos Biomedical Research, Frederick National Laboratory, Frederick, MD21702, USA (C.A.W.). Kidney Disease Section, NIDDK, NIH, 10 Center Drive, 3N116 Bethesda, MD20892 1268, USA (J.B.K.).

Correspondence to: J.B.K. jeffreyk@ intra.niddk.nih.gov

HIV-associated nephropathies: epidemiology, pathology, mechanisms and treatmentAvi Z. Rosenberg, Saraladevi Naicker, Cheryl A. Winkler and Jeffrey B. Kopp

Abstract | HIV is a highly adaptive, rapidly evolving virus, which is associated with renal diseases including collapsing glomerulopathythe classic histomorphological form of HIVassociated nephropathy. Other nephropathies related to viral factors include HIVimmunecomplex kidney disease and thrombotic microangiopathy. The distribution of HIVassociated kidney diseases has changed over time and continues to vary across geographic regions worldwide. The reasons for this diversity are complex and include a critical role of APOL1 variants and possibly other genetic factors, disparities in access to effective antiviral therapies, and likely other factors that we do not yet fully understand. The mechanisms responsible for HIVAN, including HIV infection of podocytes and tubular epithelial cells, the molecules responsible for HIV entry, and diverse mechanisms of cell injury, have been the focus of much study. Although combined antiretroviral therapy is effective at preventing and reversing HIVAN, focal segmental glomerulosclerosis, arterionephrosclerosis and diabetic nephropathy are increasingly common in individuals who have received such therapy for many years. These diseases are associated with metabolic syndrome, obesity and premature ageing. Future directions for HIVrelated kidney disease will involve regular screening for drug nephrotoxicity and incipient renal disease, as well as further research into the mechanisms by which chronic inflammation can lead to glomerular disease.

Rosenberg, A.Z. et al. Nat. Rev. Nephrol. 11, 150160 (2015); published online 17 February 2015; doi:10.1038/nrneph.2015.9

IntroductionHIV-associated nephropathy (HIVAN)the first kidney disease to be associated with HIV infection and the first form of collapsing glomerulopathy (also known as col-lapsing focal segmental glomerulosclerosis [FSGS]) to be recognized1is mechanistically attributed to HIV-1 infection. Other renal diseases associated with HIV include HIV-immune-complex kidney disease (HIVICK), thrombotic microangiopathy and disorders associated with nephrotoxic HIV therapies.

In this article we review the epidemiology, histo-pathology, mechanisms and genetic susceptibility to HIV-associated nephropathy. We also discuss approaches to diagnosis and treatment as well as future research directions.

EpidemiologyHIV infectionIn 2013, an estimated 35million people worldwide, including 24.7million people in sub-Saharan Africa, were living with HIV infection.2 Since the start of the HIV epidemic, 78million people have been infected and 39million have died of AIDS-related illness. By com-parison, only the 1918 influenza pandemic has caused more deathsan estimated 50100 millionduring the modern era (since ~1500).3 Globally, the rate of new HIV infections has decreased by 38% since 2001, but approxi-mately 2.5million new infections occur annually, of which

about 10% are in children.2 Almost 70% of new infections occur in sub-Saharan Africa. The prevalence of HIV varies widely between geographic regions (Figure1). The USA has an estimated 1.1million HIV-infected individuals and an incidence of ~50,000 new cases per year, which has been stable for a decade.4 Among patients with HIV in the USA, it is estimated that 82% have been diagnosed, 66% are linked to care, 37% rece ive regular care and 25% are virally suppressed.4 Worldwide 12.9 million people are receiving combined antiretroviral therapy (cART), repre-senting approximately 37% of those with HIV infection. Three-quarters of those on therapy live in sub-Saharan Africa; treatment rates in this region are similar to those in the rest of theworld.

HIV-associated chronic kidney diseaseAIDS-associated nephropathynow known as HIVANwas first reported in the USA in 1984.1 The disease pre-sents clinically with proteinuria and renal dysfunction and patho logically with collapsing FSGS, microcystic tubular dilatation and interstitial inflammation. Prior to 1995, HIVAN was reported in 3.510% of the HIV-infected pop-ulation in the USA, predominantly in individuals ofAfri-can ancestry, but is declining in prevalence as a result of the widespread use of cART.5 Although typically described in young adults of African ancestry with advanced HIV disease, HIVAN is occasionally diagnosed before acute HIV seroconversion has been identified, and presents with nephrotic-range proteinuria. Without cART, HIVAN progresses rapidly to end-stage renal disease(ESRD).

Competing interestsThe authors declare no competing interests.

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Unsurprisingly, rates of HIV-associated chronic kidney disease (CKD) vary widely between calendar periods, populations and settings. Renal disease has been reported in approximately 6.048.5% of HIV-infected individu-alsin Africa;6 2483% of these cases were classic HIVAN in South Africa.79 A cross-sectional study of 31 European countries, Israel and Argentina reported HIV-associated-CKD in 3.54.7% of HIV-infected individuals.10 Other epidemiological studies have reported rates of 18% in Hong Kong,11 1.15.6% in Brazil,12 18% in Switzerland,13 27% in India and 20% in Iran.14 Renal histological findings also vary between countries (Table1).

Effects of combined antiretroviral therapyIn the USA the incidence of HIVAN has declined since the introduction of cART; the best evidence for this decline is a

Key points

Widespread use of antiretroviral therapy has led to a change in the spectrum ofrenal pathologies associated with HIV infection

The incidence of HIVassociated nephropathy (HIVAN) has decreased since the introduction of combined antiretroviral therapy (cART)

Viral factors that likely contribute to renal injury in HIVpositive patients include direct infection of podocytes and renal tubular epithelial cells as well as the HIV proteins Nef and Vpr

APOL1 genetic variants predispose to HIVAN but not to HIVimmunecomplex kidney disease

All HIVpositive individuals should undergo periodic (at least annual) screening of renal function

All patients with HIVassociated kidney diseases should receive cART; standard therapies for chronic kidney disease are also recommended

60% reduction in the risk of ESRD associated with HIVAN following the introduction of cART.15 A French study described the change in pattern of renal disease in patients with HIV infection over 15years since the introduction of ART; the incidence of HIVAN decreased over time and non-collapsing forms of FSGS emerged as the most common cause of glomerular disease among patients with HIV, occurring in 47% of patients during 20042007.16 HIVAN occurred more frequently in black patients with severe immunodeficiency and severe renal failure, whereas patients with non-collapsing FSGS were older, more likely to have received ART, more frequently had cardiovascular risk factors, and histologically, had more severe interstitial fibrosis and less severe tubular lesions. Renin and the HIV protease share certain functions; both cleave angiotensin-ogen to angiotensin I and also cleave the HIV Gag poly-protein, an essential step in HIV replication.17 Thus cART might be predicted to suppress HIV-induced activation of the reninangiotensin system (RAS).

cART-induced nephrotoxicity is an increasing clini-cal problem that can occur even in patients with normal baseline renal function.18 The most common forms are crystalluria and obstruction due to protease inhibi-tortherapyand proximal tubular damage due to tenofo-vir therapy (Table2). Tenofovir-induced nephrotoxicity causes proximal tubulopathy, acute kidney injury (AKI) and CKD.19 Dose adjustment according to estimated glo-merular filtration rate (eGFR) is mandatory to minimize the nephrotoxic effects of tenofovir. Renal monitoring in patients receiving this agent is important and drug cessation is advised in those with nephrotoxicity.

Nature Reviews | Nephrology

Adult HIV prevalence (%) >20 1520 1015 510 25 12 0.51.0 0.10.5


Prolonged use of cART and the consequent increased longevity of HIV-infected patients have led to the emer-gence of new patterns of HIV-associated CKD. Despite successful suppression of HIV replication using cART, a state of chronic inflammation and dysmetabolism persists and is associated with renal diseases includ-ing diabetic nephropathy, arterionephrosclerosis and possibly FSGS. Similarities between the ageing process and HIV infection suggest that the virus compresses the ageing process, accelerating comorbidity and frailty.20,21 The risks of drug toxicity and cardiovascular disease are increased in individuals with low eGFR, including the elderly and those with HIV-infection. The spectrum of CKD in elderly patients with HIV infection is poorly defined. Survival of elderly HIV-infected patients on dialysis is low and delays in initiating dialysis are associ-ated with increased morbidity and mortality. Whether controlling blood pressure or diabetes mellitus will improve outcomes in this population is not known.

HistopathologyHIV-associated renal diseases include a broad histo-pathological spectrum that encompasses glomerular and tubulointerstitial pathologies secondary to HIVAN, AKI, cART-related toxicities and HIV-associated comor-bidities (such as hepatitisC virus infection, hypertension and diabetes).21,22 Glomerular entities include collapsing

glomerulopathy (classic HIVAN),1,23,24 HIV-associated lupus-like glomerulonephritis,2528 IgAnephropathy,29,30 thrombotic microangiopathy,31 membranoproliferative glomerulo nephritis,8 membranous glomerulonephritis,8,32 infection-related or hepatitisC virus-associated immune complex glomerulo nephritis33 and fibrillary or immuno-tactoid glomerulo nephritis.34,35 Tubulointerstitial changes related to drug-induced mitochondriopathies, drug toxi-city, acute interstitial nephritis or superimposed viral, fungal or mycobacterial infections may also be present. Of the above entities, classic HIVAN is the best defined in terms of histologic features and pathomechanisms.

Early reports identified the pathognomonic constella-tion of features that comprise HIVAN: collapse of glomer-ular capillaries, visceral glomerular epitheliosis, podocyte hypertrophy and proliferation, mesangial prominence and hypercellularity, endothelial tubuloreticular inclu-sions (TRIs) on ultrastructural examination and micro-cystic tubules.1,23,24 Microcystic dilatation in particular has been suggested as a histologic modifier that together with proteinuria predicts poor outcomes.9 Differential diagnoses to consider in patients with collapsing glo-merulopathy include other infectious aetiologies (such as cytomegalovirus, parvovirus B19 and Epstein Barr virus [although the role of the latter two viruses remains uncertain36]), drug toxicities, vascular pathologies (such as thrombotic microangiopathy), autoimmune diseases,

Table 1 | Spectrum of renal histology in patients with HIV infection in different countries

Biopsy series South Africa USA France

Cape Town9 Durban8 Johannesburg7 Johannesburg133 Baltimore113 Chicago134 Paris16

Study details

Year of publication 2012 2006 2006 2014 2008 2013 2012

Number of biopsies 192 7 99 364 152 47 88

Renal histologic findings (%)*

Classic HIVAN 79 86 27 33 35 34 30

Focal segmental glomerulosclerosis 1 8 11 22 23 26

HIVimmunecomplex disease

Not further specified 2 21 15 4 9

Mesangial proliferative 2 6 7

Membranoproliferative glomerulonephritis

3 5 2 2

Lupuslike glomerulonephritis 2 3

IgA nephropathy 1 5 4 2 3

Membranous nephropathy 3 13 8 3 4

Exudative proliferative or crescentic 5 2

Immunotactoid or fibrillary glomerulonephritis

1

HIV thrombotic thrombocytopenic purpura or haemolytic uraemic syndrome

3

Minimal change nephropathy 2 3 1 4

Other glomerular and tubular diseases 12 14 18 23 24 37 7

*Data indicate the percentage of each biopsy series that manifested particular diagnostic entities (all columns total 100%). Histomorphologic diagnosis is given as specified in the original reference and may not reflect current diagnostic standards. 22% of individuals in the Cape Town series had both HIVAN and immune complex glomerulonephritis and are assigned to the HIVAN category. One individual in the Durban series had both HIVAN and membranous nephropathy and is assigned to the HIVAN category. Abbreviation: HIVAN, HIVassociated nephropathy.

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malignancy, genetic factors and, if none of the above, idiopathic collapsing glomerulopathy. The presence of TRIsinterferon-related features most commonly seen with viral aetiologies and in lupus nephritisis helpful in distinguishing viral forms of collapsing FSGS, includ-ing HIVAN. The increased numbers of epithelial cells attached to the glomerular basement membrane and within the Bowman space in collapsing glomerulopathy are now thought to be the result of aberrant proliferation of stem cells that originate within the parietal epithelium37 and/or from renin-expressing cellpopulations.38

Classic HIVAN histopathology can be seen in adults and children at any stage of HIV infection, but is most

common in the presence of advanced disease, includ-ing AIDS.39,40 Susceptibility to classic HIVAN is most striking in patients of West African descent,41 including African-American and Afro-Caribbean populations.42 HIVAN has been reported to a lesser degree in Hispanic populations8 and variably in Asian Indian cohorts26,41 but was notably absent in SwissEuropean13 and Thai popu-lations.43 Over the past two decades, a decreasing fre-quency of classic HIVAN has been observed in African patients living in Europe.44

HIVICK and non-collapsing forms of FSGS are increasingly reported in the post-cART era.45 HIVICK is less likely than HIVAN to progress to ESRD and is thought to be associated with greater exposure to cART and hepatitisC virus co-infection.46 In HIV-positive European-derived populations HIVICK is the dominant glomerular disease and HIVAN is rare in comparison to its incidence in African-derived populations.

Classic HIVAN does not seem to recur in allografts and is associated with excellent transplant outcomes similar to those of HIV-negative cohorts.47 Recurrence of lupus-like HIV-associated kidney disease has, however, been reported in a renal allograft.48 This finding may present future challenges to renal transplantation in HIV-positive cohorts. The potential risk of recurrence of HIVICK but not HIVAN in transplanted kidneys may reflect differing aetiologies; HIVAN results from direct viral infection of renal cells or the action of viral proteins, whereas the aetiology of HIVICK is unknown.

MechanismsCharacteristic HIVAN pathologic changes are observed along the full length of the nephron and include glo-merular and tubulointerstitial features. Various patho-mechanistic processes have been implicated in HIVAN, including effects on glomerular filtration, proliferation, apoptosis, de-differentiation and immunomodulation, most of which can now be related to the presence of HIV transcripts in affected renal parenchymal cells. In early mechanistic studies of HIVAN the kidney was identi-fied as a non-productive reservoir for HIV.49 Subsequent cDNA localization studies of renal parenchyma showed a greater role for HIV infection in some HIV-related kidney diseases, in particular in HIVAN, than in others such as HIVICK.50,51 Nonetheless, HIV viral proteins have a role in HIVAN and can induce collapsing glomerulopathy and tubular injury in transgenic mice.5254

HIV infection of renal cellsThe process by which HIV enters renal parenchymal cells is not well understood (Figure 2). The receptors that mediate entry of the virus into Tcells (CD4) and macrophages (C-X-C chemokine receptor type5) seem to be absent from renal cells. Receptors that may have a role in HIV infection of these cells include CD209 antigen (also known as DC-SIGN), which contributes to HIV infection of dendritic cells and possibly podocytes, and lymphocyte antigen75 (also known as DEC-205), which may contribute to infection of tubular epithelial cells.55 Phagocytosis of apoptotic CD4+ Tcells has also

Table 2 | Renal effects of highly active antiretroviral therapies

Class Drug Renal abnormality

Nucleoside reverse transcriptase inhibitors

Abacavir AIN (case report)Fanconi syndrome (case report)

Didanosine Fanconi syndromeAKILactic acidosisNephrogenic diabetes insipidus (case reports)

Lamivudine Renal tubular acidosisHypophosphataemia (case report)

Stavudine Renal tubular acidosisHypophosphataemia (case report)

Zidovudine None reported

Nonnucleoside reverse transcriptase inhibitors

Nevirapine None reported

Delavirdine None reported

Efavirenz Nephrolithiasis

Nucleotide reverse transcriptase inhibitors

Tenofovir Proximal tubular dysfunction withFanconi syndromeNephrogenic diabetes insipidusAKICKD

Protease inhibitors Amprenavir None reported

Atazanavir AIN (case report)

Darunavir None reported

Fosamprenavir None reported

Indinavir AKI (AIN)CKD (AIN)NephrolithiasisIntratubular drug precipitationPapillary necrosisHypertensionRenal atrophy

Lopinavir None reported

Nelfinavir Nephrolithiasis (case report)

Ritonavir AKI

Saquinavir AKI in association with Ritonavir

Tipranavir None reported

Fusion or entry inhibitors Enfuvirtide Membranoproliferative glomerulonephritis (case report)

Maraviroc None reported

Integrase inhibitor Raltegravir None reported

Abbreviations: AIN, acute interstitial nephritis; AKI, acute kidney injury; CKD, chronic kidney disease. Permission obtained from Nature Publishing Group Izzedine, H., Harris, M. & Perazalla, M.A. The nephrotoxic effects of HAART. Nat. Rev. Nephrol. 5, 563573 (2009).

FOCUS ON NEPHROLOGY IN THE DEVELOPING WORLD



been proposed as a mechanism by which HIV may enter tubular cells.56 The HIV proteins Tat and Vpr circulate in plasma and Tat can access podocytes via heparan sulfate proteoglycans and cholesterol-enriched lipid rafts.57 HIV has been shown to enter cultured podocytes by dynamin-mediated endocytosis but did not establish a productive infection.58 The study authors proposed that this mechanism might account for the detection of some HIV genomes in human renal tissues.

Pathomechanism of HIVANStudies in model systems with confirmation of findings in human biopsy samples have been integral in study-ing the pathomechanism of HIVAN. In murine models, renal HIV transgene expression results in a HIVAN-like pathology,59,60 supporting direct effects of HIV transcript expression in glomerular (mesangial and epithelial) and tubular cells61 as well as in microcyst formation.62,63 HIV-associated cell death has been proposed to occur in podocytes via mitotic catastrophe,64 in which defective chromosome replication or other DNA damage leads to cell death, and in tubular cells via apoptosis, possibly

driven by Vpr, mediated by ubiquitin-like protein FAT1065 or caspase-2 and Fas,66 and involving G2/Marrest.67

Studies using an early primate model of AIDS sug-gested that mesangial cell injury was central to the devel-opment of collapsing glomerulonephritis. Intriguingly, the strain-limited ability of HIV to cause mesangial collapse highlights HIV-tropism; not all strains are capable of entrance and expression in mesangial cells in a G-protein coupled receptor1 (GPR1)-dependent manner.68,69 Expression of the HIV transgene envelope glycoprotein gp160 results in tumour necrosis factor and Bcl-2-dependent proliferation and apoptosis of mesangial cells,70 whereas Tat expression was associated with mesangial cell production of transforming growth factor.71 Reduced expression of matrix proteins such as perlecan (in an apolipoproteinE-dependent manner)72 and overexpression of matrix remodelling enzymes, such as matrix metalloproteinase9, have been observed in HIVAN glomeruli.73 Together these molecular processes regulate the sclerosing and collapsing features of HIVAN.

Alterations in nephron morphogenesis and dedif-ferentiation are central to the development of HIVAN.

Tubular epithelial cell

a

Distaltubule

Mesangialcell

PEC

Podocyte

Nature Reviews | Nephrology

b

Proximal tubuleTubular dilation

Loss ofbrush

border

G2/M arrest andapoptosisHIV entry via DEC205

or phagocytosis ofinfected cells

Loss of podocytedifferentiationmarkers and mitoticcatastrophe

Hypertrophy andhyperplasia of PECs

forming a pseudocrescent

Sclerosisand collapse

Capillary

HIV

Tat protein entryvia heparan sulphateproteoglycanand lipid rafts

Figure 2 | Mechanisms of collapsing glomerulopathy in HIVAN. a | Understanding of the mechanisms of HIV entry into renal cells remains provisional, as studies have necessarily relied on cell culture models using transformed human kidney cells and transgenic mice. Invitro, HIV enters podocytes via DCSIGN and tubule cells via DEC205, whereas the Tat protein enters podocytes via lipid rafts and induced apoptosis of cultured podocytes. b | Expression of the HIV regulatory and accessory proteins Vpr and Nef in transgenic mice produces the glomerular and tubular features of collapsing glomerulopathy. Vpr and Tat, but not Nef, are present in human plasma. The mechanism that drives aberrant expansion ofpodocyte stem cells, which are located in the parietal epithelium, remains unknown. The pathology of HIVAN is characterized by podocyte loss, aberrant stem cell replenishment, tubular cell injury, and microcystic tubular dilatation. Abbreviation: HIVAN, HIVassociated nephropathy.

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Sidekick-1, a cell adhesion member of the immunoglob-ulin family involved in renal branching morphogenesis, is overexpressed in glomeruli from patients and model organisms with HIVAN.74 This overexpression results in podocyte aggregation, a feature of the extraglomer-ular prominence and/or proliferation observed in this disease.75 Expression of HIV transgenes (particularly Tat and Nef) in podocytes and renal tubular epithelial cells results in dedifferentiation and/or epithelial mes-enchymal transdifferentiation (that is, loss of expression of nephrin, cadherin-1 [also known as E-cadherin]) synapto podin, Wilms tumour protein and protein atonal homologue8, and expression of zinc fingerE-box-binding homeoBox1, -smooth muscle actin and fibro-blast-specific protein-1) and correlates with proliferation and tubular microcyst formation.63,7681

The effects of Nef expression on podocyte prolif-eration and dedifferentiation are Src-dependent and involve activation of signal transducer and activator of transcription3 (Stat3) and the Rasmitogen-activated protein kinase (MAPK)1/2 pathway.82,83 Abrogation of Stat3 activation in podocytes alleviates many of the glomerular and tubulointerstitial features of HIVAN.84 Dedifferentiation seems to occur in a mammalian target of rapamycin (mTOR)-dependent manner; the mTOR inhibitor sirolimus reduced HIV transcript levels and progression to HIVAN in murine models.85,86 Roles of activation of Notch1 and Notch4 in HIV-associated dys-regulation of proliferation and self-renewal mechanisms have also been reported.87,88

HIV transgenes also affect glomerular and tubular epithelial cells via dysregulation of proliferation and apoptosis. The mechanism that underlies loss of growth inhibition (that is, quiescence) of podocytes has been associated with proliferation via reduced expression of the cyclin dependent kinase (CDK) inhibitors p27 and p57, resulting in activation of cyclinA.89,90 Intriguingly, loss of expression of CDK inhibitors correlates with increased expression of HIV transgenes,62 suggesting a feedback loop between HIV transgene expression and podocyte proliferation. More specifically, Vpr has been implicated in epithelial cell hypertrophy, hyperploidy and apoptosis via activation of the DNA damage response pathway and subsequent ERK and Bax-mediated mito-chondrial injury.91,92 In tubular cells interaction and co-localization of Vpr with ubiquitinD (also known as ubiquitin-like protein FAT10) in mitochondria has been implicated in HIVAN-related cell death.65,93 Nuclear factorB-dependent processes, including Fas ligand expression, associated apoptosis and inflammation have been identified in the kidneys of HIV transgenicmice.94,95

Other HIVAN disease mechanisms that require further study include HIVassociated dysregulation of micro-RNA, effects of HIV on the cellular response to oxidative stress, and direct effects of HIV transgenes on glomerular permeability. The role of oxidative stress in HIV-infected kidneys is now being investigated and redox-stress responses, including mTOR-dependent p53 activation, have been observed in a HIVAN model.96 HIV Tat protein has been shown to dysregulate glomerular permeability

by reducing expression of nephrin97 and HIV-dependent downregulation of miR-33 and miR-200 has been shown in podocytes.98 In addition, levels of miR-99a, miR-100a, miR-199a and miR-200 were decreased in HIV-infected podocytes; their expression could be increased in a rapamycin- dependent manner.99 Among many path-ways involved in this process, Wnt signalling and oxi-dative stress were modulated by rapamycin. Finally, HIV-transduced human podocytes manifest reduced vitaminD receptor expression, enhanced expression of cathepsinL, and increased production of angioten-sinII.100 In summary, HIVAN histopathologic complexity is likely the result of the convergence of many deregulated pathways, which are altered by a small set of HIV gene products in the structurally diverse kidney.

Viral factorsThe primate lentiviruses HIV and simian immuno-deficiency virus cause nearly identical glomerulopathies, suggesting that retroviral gene products alter glomerular cell function in specific ways.101 Evidence from trans-genic mouse models suggests that expression of single HIV genes can replicate the clinical features (proteinuria and progressive kidney disease) and pathologic features (collapsing glomerulopathy and tubular cell injury) of HIVAN seen in humans. These models include the long-studiedHIV transgenic mouse Tg26 which bears a gagpol deleted HIV transgene and has intact open reading frames for the accessory gene products Tat, Rev, Nef, Vpr, Vpu and Vif, under the control of the viral long termi-nal repeat.102 This mouse model and a rat model with the same transgene develop glomerular and tubular disease.103 Expression ofNef under the human CD453 or nephrin promoter,54 orof Vpr under the nephrin54 or podocytepro-moter (that is, podocin)52 replicate HIVAN in mice. Both Nef and Vpr expression models induce HIVAN in transgenic mice; it is somewhat surprising that these two regulatory/accessory proteins can each reproduce the key features of HIVAN. With regard to Nef, proposed molecu-lar pathways of podocyte injury include vascular endo-thelial growth factor expression, downregulation of Notch signalling88 and activation of Stat3 signalling.83

Genetic factorsSince the initial description of HIVAN it has been recog-nized that individuals of African descent are particularly disposed to this complication of HIV infection. This pre-dilection is due to high frequencies of the APOL1 genetic variants G1 and G2 in this population.104,105 These vari-ants arose separately on chromosome 22 and recombina-tion to produce a chromosome that has both G1 and G2 has not been observed. Both variants must, therefore, be genotyped when evaluating risk of renal disease; geno-typing for only one variant makes the tacit and incorrect assumption that the other variant is absent.106 The G2 variant seems to be the oldest; it is widely distributed throughout sub-Saharan Africa at rates of ~810%.106 Frequencies of the G1 variant, which seems to have been under recent selection pressure, range from 0% to 60% and are particularly high among the Yoruba, Igbo and




Asante people of West Africa. Rarity of these risk vari-ants in Ethiopia likely accounts for the rarity of HIVAN in this population.107 The G1 and G2 variants confer risk for HIVAN and HIV-associated FSGS, as well as other glomerular diseases and arterionephrosclerosis (also known as hypertensive nephrosclerosis). The effect is largely recessive; homo zygous (G1/G1 or G2/G2) or compound heterozygous (G1/G2) individuals have the highest risk of HIVAN. The risk allele frequency (G1 or G2) is approximately 35% in the African American population; ~1214% of African Americans carry two APOL1 risk alleles, which confer the highest risk of APOL1-associated nephropathy.

The published odd ratios (ORs) for a recessive model of disease (requiring two copies of the risk allele) is 29 for HIVAN and 17 for primary FSGS, with a non- significant trend for a single APOL1 variant to confer risk.108 However, we have found that the OR for HIVAN is numerically higher in South African HIV-positive populations with two APOL1 risk alleles (OR 89, 95% CI 18911) than in the previous US study108 and that a mar-ginally significant effect of one risk allele exists (OR5, P = 0.05).109 The mechanisms by which the APOL1 variant proteins alter kidney cell function are a matter of con-siderable interest. A promising line of work suggests that altered function of vesicular trafficking, including endo-somal and autophagosomal function, may be critical.110 On other hand, the fact that individuals without risk alleles or with one risk allele may develop HIVAN sug-gests that other genetic and/or environmental risk factors are sufficient to cause this disease.

Approximately 6 million African Americans have two APOL1 risk alleles, but it seems that most will never develop kidney disease. In the setting of untreated HIV infection, an estimated 50% of these genetically at-risk individuals with two APOL1 risk alleles will develop HIVAN,108 making HIV by far the strongest environ-mental factor to interact with this genetic risk factor. Certainly one plausible hypothesis is that HIV induces interferon expression, which drives APOL1 gene expres-sion,111 and that the increased expression of the variant APOL1 proteins is toxic to cells.110

Screening and early detectionPatients with HIV infection are at increased risk of CKD and should receive regular screening for incipient renal disease, including HIVAN, as well as other glomerular and tubular diseases at diagnosis of HIV infection, on initiation of ART or change in therapy, and annually in stable patients. Guidelines from the HIV Medicine Association of the Infectious Diseases Society of America (updated in 2014) state that annual screening should include assessment of blood pressure, serum creatinine and eGFR as well as quantitative measurement of urine albumin levels and markers of proximal tubular func-tion in patients on tenofovir.112 Referral to a nephrologist is recommended when eGFR decreases by >25% from baseline or is 40%, reflecting the value typical of plasma) and tubular disease (albumin:protein ratio generally


after initiation of cART. The DART study conducted in Uganda and Zimbabwe, showed improvement in GFR by 1.96.0 ml/min/1.73 m2 after 45years of cART, with 2.8% of the 3,316 patients at an eGFR


metabolic syndrome, obesity, diabetes and premature ageing (such as arterionephrosclerosis, diabetic nephro-pathy and FSGS). Importantly APOL1 risk alleles are major risk factors for HIVAN, arterionephrosclerosis and FSGS. Clinicians must be alert to the possibility of HIV-associated glomerular or tubular disease and screen infected patients for these conditions on a regular basis.

From a research perspective, a major opportunity exists to develop an understanding of how intact HIV and its regulatory and accessory proteins interact with the APOL1 risk allele variants to induce HIVAN. An under-standing of the HIVAPOL1 interaction might also serve to illuminate the mechanisms that underlie other forms of APOL1-associated nephropathies.

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AcknowledgementsThe authors work is supported in part by the Intramural Research Programs of the National Cancer Institute, National Institute of Diabetes and Digestive and Kidney Diseases, and National Institutes of Health, USA, and by the Medical Research Council and National Research Foundation of South Africa. This project has been funded in whole or in part with federal funds from the National Cancer Institute, National Institutes of Health, under contract HHSN26120080001E. Content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services, USA, nor does mention of trade names, commercial products, or organizations imply endorsement by theUS Government. The authors note with regret the recent untimely death of Linda Kao, a pioneering and generous researcher who made many important contributions to the field of human genetics, in particular to the discovery of the chromosome 22 locus that includes APOL1 as a risk factor for HIVAN.

Author contributionsAll authors researched the data for the article, made substantial contributions to discussions of the content, wrote the article and reviewed and/or edited the manuscript before submission.

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HIV-associated nephropathies: epidemiology, pathology, mechanisms and treatmentAvi Z. Rosenberg, Saraladevi Naicker, Cheryl A. Winkler and Jeffrey B. KoppIntroductionEpidemiologyKey pointsFigure 1 | Prevalence of HIV infection in adults in 2009. The highest prevalence is seen in sub-Saharan Africa. Image based on data from UNAIDS and adapted from Wikimedia Commons (http://en.wikipedia.org/wiki/File:AIDS_and_HIV_prevalence_2009.svg), whichHistopathologyMechanismsFigure 2 | Mechanisms of collapsing glomerulopathy in HIVAN. a | Understanding of the mechanisms of HIV entry into renal cells remains provisional, as studies have necessarily relied on cell culture models using transformed human kidney cells and transgenScreening and early detectionTherapyRemaining questions and future directionsConclusionsAcknowledgementsAuthor contributions

hiv-associated nephropathies epidemiology, pathology, mechanisms and treatment

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