BRIEF REVIEW www.jasn.org

Kidney Disease in HIV: Moving beyond HIV-Associated Nephropathy

† ‡ † Vasantha Jotwani,* Mohamed G. Atta, and Michelle M. Estrella*

*Kidney Health Research Collaborative, Department of Medicine, University of California, San Francisco, California; †Department of Medicine, San Francisco Veterans Affairs Health Care System, San Francisco, California; and ‡Department of Medicine, Johns Hopkins School of Medicine, Baltimore, Maryland

ABSTRACT In developed countries, remarkable advances in antiretroviral therapy have trans- formulation, formed HIV infection into a chronic condition. As a result, HIV-associated nephrop- (TAF), promises an improved safety pro- athy, the classic HIV-driven kidney lesion among individuals of African descent, has file,16–18 long-term studies are currently largely disappeared in these regions. However, HIV-positive blacks continue to have nonexistent. In addition, monitoring of much higher rates of ESRD than HIV-positive whites, which could be attributed to kidney health in treated HIV-positive pa- the APOL1 renal risk variants. Additionally, HIV-positive individuals face adverse tients is often complicated by drug-related consequences beyond HIV itself, including traditional risk factors for CKD and neph- effects on renal tubular creatinine secre- rotoxic effects of antiretroviral therapy. Concerns for nephrotoxicity also extend to tion. For many HIV-positive individuals HIV-negative individuals using fumarate–based pre-exposure who have progressed to ESRD, kidney prophylaxis for the prevention of HIV infection. Therefore, CKD remains an impor- transplantation yields favorable out- tant comorbid condition in the HIV-positive population and an emerging concern comes; however, early experiences have among HIV-negative persons receiving pre-exposure prophylaxis. With the im- raised several issues to be tackled, such proved longevity of HIV-positive individuals, a kidney transplant has become a via- as the optimal ARTand immunosuppres- ble option for many who have progressed to ESRD. Herein, we review the growing sive regimens. This review focuses on re- knowledge regarding the APOL1 renal risk variants in the context of HIV infection, cent advances issues regarding CKD antiretroviral therapy–related nephrotoxicity, and developments in kidney trans- among HIV-positive individuals. plantation among HIV-positive individuals.

J Am Soc Nephrol 28: ccc–ccc, 2017. doi: https://doi.org/10.1681/ASN.2017040468 APOL1 RISK VARIANTS AND HIV-RELATED KIDNEY DISEASE

With effective antiretroviral therapy (ART), have substantially higher ESRD incidence HIVAN mouse models support the exis- the life expectancies of HIV-positive indi- rates compared with HIV-positive non- tence of host susceptibility genetic vari- viduals may now approximate those of the blacks.4 This racial difference may be par- ants, which interact with HIV to cause general population.1 However, for a grow- tially driven by the APOL1 risk variants, collapsing glomerulopathy and tubulocys- ing number of HIV-positive individuals, which are strongly associated with tic changes characteristic of HIVAN.19–21 aging is accompanied by accumulation of HIV-associated nephropathy (HIVAN) In humans, genetic susceptibility has been noncommunicable diseases, including and CKD progression among individu- linked to the APOL1 G1 (composed of CKD.2,3 Among HIV-positive individuals als of African descent.5–8 CKD among in North America, CKD incidence in- HIV-positive individuals may also be at- creases by 11-fold among those ages 60– tributed to the rise of other comorbid Published online ahead of print. Publication date 69 years old compared with those ages conditions, such as diabetes, as well as available at www.jasn.org. , 2 40 years old. Moreover, the CKD inci- nephrotoxicity from ART. In particular, Correspondence: Dr.MichelleM.Estrella,Kidney dence rate remains disproportionately tenofovir disoproxil fumarate (TDF), Health Research Collaborative, Department of Medi- higher in blacks versus nonblacks. This dis- which is the most widely used agent cine, University of California, San Francisco and San Francisco Veterans Affairs Health Care System, 4150 parity extends to trends in ESRD incidence. for HIV treatment and prophylaxis, Clement Street, 111A1, San Francisco, CA 94121. Among HIV-positive individuals in North has been associated with several forms Email: [email protected]

America, the rates of ESRD have declined; of kidney disorders and increased CKD Copyright © 2017 by the American Society of – however, HIV-positive blacks continue to risk.9 15 Although the new tenofovir Nephrology

J Am Soc Nephrol 28: ccc–ccc, 2017 ISSN : 1046-6673/2811-ccc 1 BRIEF REVIEW www.jasn.org rs73885319 [S342G] and rs60910145 apoL1 may allow HIV to persist within Events of Anti-HIV Drugs (D:A:D) Study [I348M]) and G2 variants (rs71785313, IL-1b–primed podocytes, further aug- over a median follow-up of 7.2 years.42,44 a 6-bp deletion).22,23 In HIV-positive menting endogenous apoL1 produc- Surveillance for nephrotoxicity in the blacks who underwent clinical kidney bi- tion31; in turn, apoL1 overexpression context of HIV treatment, however, is opsies, the high-risk APOL1 genotypes leads to cellular demise.32 Furthermore, confounded by the effect of several anti- (two copies) were associated with a 29- in an APOL1 transgenic mouse model, retrovirals and pharmacoenhancers on re- to 89-fold higher odds of HIVAN com- podocyte-specific expression of aberrant nal tubular creatinine secretion (Figure pared with the low-risk genotypes (zero apoL1 dose dependently recapitulated 1).45–48 These medications may reduce of one copy).6,7 The strength of these as- global and segmental glomerulosclerosis the serum creatinine–based eGFR within sociations far exceeds the associations of with tubulointerstitial fibrosis, whereas the first 4 weeks of drug initiation, but the these variants with kidney diseases in HIV- tubular expression of these proteins did decline is typically nonprogressive. Be- negative populations.6,8,24 Moreover, the not result in histopathologic changes.33 cause cystatin C seems to be reabsorbed magnitude of these associations vary by Interestingly, in this model, aberrant and then metabolized within renal tubu- region, with the most robust associations apoL1 expression leads to inflammatory lar cells,49,50 serum cystatin C may be a among HIV-positive blacks residing in cell death, a similar process induced by useful alternative biomarker of kidney sub-Saharan Africa.6,7 Interestingly, the HIV infection.34 Collectively, these stud- function, and urine biomarkers may de- APOL1 risk variants are not required for ies may explain the synergistic effect of tect ongoing kidney injury.45 HIVAN development. Among individuals APOL1 risk variants and HIV infection on with biopsy-confirmed HIVAN, 20%– HIVAN and the correlation of ART im- TDF 30% do not carry a high-risk genotype, plementation with diminished HIVAN TDF is included in several first-line ART and 5%–8% carry no risk variant, sug- incidence. regimens.51,52 Its active metabolite, te- gesting that other genetic susceptibil- HIV viremia increases levels of proin- nofovir, is renally eliminated through ity factors may contribute to HIVAN flammatory cytokines,35 which augment glomerular filtration and proximal tubu- pathogenesis.7,25 apoL1 production in vitro.36 However, lar secretion (Figure 2A).53 Tenofovir’s With global rollout of ART, the inci- in a case-control study of HIV-positive accumulation within tubular cells has dence of HIVAN has declined substan- blacks with or without CKD, proinflam- been hypothesized to cause mitochon- tially. However, the APOL1 risk variants matory cytokines did not associate with drial injury through inhibition of the are associated with elevated CKD risk, plasma apoL1 levels, and plasma apoL1 mitochondrial DNA polymerase-g,54,55 even among ART-treated HIV-positive levels were similar by CKD status.37 These manifesting pathologically as mitochondri- blacks. Among 1285 HIV-positive black results along with experiments showing al swelling and depletion.13,56,57 Although women, those with high- versus low-risk characteristic histopathologic changes clinical trials have reported minimal genotypes were fivefold more likely to with glomerular expression of aberrant nephrotoxicity,53,58 observational studies have proteinuria, independent of kidney apoL1 suggest that intrarenal rather than have shown that TDF is associated with function.26 Among HIV-positive blacks plasma apoL1 is important in the patho- higher risks of AKI, proteinuria, nephrogenic with non-HIVAN kidney disease, those genesis of APOL1-related kidney diseases. diabetes insipidus, and CKD.14,15,59–66 with high-risk genotypes had a threefold Among 10,841 HIV-positive United States higher risk of progressing to ESRD com- veterans, each year of TDF exposure was pared with those with low-risk geno- ART NEPHROTOXICITY associated with a 34% higher risk of types.5 Similar associations were observed proteinuria, a 33% higher risk of CKD, in HIV-positive children, in whom the Although ART mitigates HIVAN risk, and an 11% higher risk of rapid kidney high-risk genotypes were associated with certain antiretrovirals may be nephro- function decline.14 A subsequent meta- 3.5-fold odds of CKD.27 toxic via direct renal tubular toxicity, analysis of 17 studies reported faster kid- The mechanisms by which these var- crystal-induced obstruction, or intersti- ney function decline (23.9 ml/min) and iants contribute to CKD are not fully elu- tial nephritis.13,15,38–41 Table 1 lists the slightly increased risk of AKI (risk differ- cidated. In a cohort of HIV-positive generic names and available formula- ence of 0.7%) among TDF versus non- women, the APOL1 risk variants were tions of contemporary antiretroviral TDF users.67 The risk of nephrotoxicity associated with albuminuria but were drugs associated with CKD.14,42–44 In may be higher among TDF users with not associated with urine biomarkers of the EuroSIDA Study of HIV-positive concomitant use of -boosted pro- tubular injury, including IL-18 and kid- persons, each additional year of TDF, tease inhibitors.68 One study reported faster ney injury molecule-1.28 These results , and ritonavir-boosted lopi- decline in creatinine clearance over 24 weeks suggest that the variants specifically af- navir was associated with 16%, 21%, and among TDF users receiving ritonavir- fect the glomeruli and are supported by 8% higher incidence of CKD, respec- boosted protease inhibitors compared the predominant expression of apoL1 in tively.43 Similar findings were observed with non-nucleoside reverse transcription podocytes and endothelial cells.29,30 In among individuals without baseline inhibitors (214.7 versus 24.5 ml/min vitro studies have also shown that CKD in the Data Collection on Adverse per 1.73 m2 per year).65 Ritonavir-boosted

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Table 1. Generic and brand names of commonly used antiretroviral medications and potential nephrotoxicities13–15,38–44 Generic Name Brand Names Associated Kidney Diseases TDF Viread (TDF) Proximal tubulopathy Truvada (TDF, ) Low molecular weight proteinuria Atripla (, TDF, emtricitabine) AKI Complera (, TDF, emtricitabine) Nephrogenic diabetes insipidus Stribild (/, TDF, emtricitabine) CKD TAFa Descovy (TAF, emtricitabine) None reported Odefsey (rilpivirine, TAF, emtricitabine) Genvoya (elvitegravir/cobicistat, TAF, emtricitabine) Atazanavir Reyataz (atazanavir) Crystalluria Evotaz (atazanavir/cobicistat) Urolithiasis Tubulointerstitial nephritis CKD Kaletra (lopinavir/ritonavir) Albuminuria Low molecular weight proteinuria CKD aTAF is a new tenofovir formulation that may be less nephrotoxic than TDF. lopinavir, in particular, may enhance TDF- TDF users.11 This drug interaction may weight proteinuria, phosphaturia, urico- induced nephrotoxicity by increasing occur through inhibition of tenofovir suria, normoglycemic glucosuria, and plasma tenofovir concentrations.69–71 In a efflux into urine by protease inhibitors metabolic acidosis13,56,61;however,the trial of HIV-positive women initiating TDF, or enhanced intestinal absorption of full syndrome is seen only in a minority those randomized to also receive ritonavir- tenofovir.70,73,74 of TDF users, with a reported incidence boosted lopinavir versus had a Recovery from TDF-induced nephro- of 0.4% over a median duration of 44 3.1-fold odds of experiencing a creatinine toxicity can be incomplete, particularly months.80,81 However, milder forms of rise to $2 mg/dl or creatinine clearance among persons with lower eGFR at the tubular damage occur commonly among ,50 ml/min, causing interruption or time of TDF discontinuation.11,14,42,75–79 TDF users.12,76,82–86 Among ART-naïve discontinuation of TDF.72 Concurrent Therefore, early recognition of TDF neph- patients, those who initiated TDF versus use of ritonavir-boosted lopinavir was rotoxicity is critical. TDF-induced neph- non-TDF regimens had a 5.2-fold higher also associated with a 16.4-fold odds of rotoxicity is characterized by Fanconi syn- risk of developing proximal tubular dys- Fanconi syndrome among HIV-positive drome, manifesting as low molecular function after 2 years of follow-up.87 Ad- ditionally, TDF has been associated with higher urine biomarkers of proximal tu- bular dysfunction and injury. In two randomized trials, urine levels of a1- microglobulin and b2-microglobulin were 50% higher after 48 weeks among TDF versus non-TDF users.81,88 Further- more, among HIV-positive men initiated on TDF, each year of exposure was associ- ated with incrementally higher urine levels of a1-microglobulin, IL-18, kidney injury molecule-1, and procollagen type 3 N- terminal propeptide.12,76 These markers are prognostic for CKD and mortality risk in HIV-positive populations89–93 and may be useful in early detection of TDF-induced nephrotoxicity in the fu- Figure 1. Several antiretroviral drugs and pharmacoenhancers affect renal tubular se- ture. Meanwhile, to assess the renal risks cretion of creatinine (Cr). Cr transport through tubular cells is mediated on the basolateral side by organic cation transporter 2 (OCT-2) and OCT-3 and possibly organic anion of TDF, two CKD risk scores have been transporter 2 (OAT-2) and OAT-3. On the apical side, Cr is secreted via multidrug and toxin developed using the D:A:D Study and extrusion transporter-1 (MATE-1). and rilpivirine inhibit OCT2 and thus, the Veterans Health Administration – impair Cr entry into the tubular cell. Conversely, ritonavir and cobicistat inhibit MATE-1 HIV cohorts (Table 2).94 96 and inhibit Cr efflux into urine.

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Figure 2. Proximal tubular cells handle the renal excretion of tenofovir (TFV), the active metabolite of TDF and TAF. (A) TDF is rapidly metabolized to TFV, within the plasma. TFV influx into the proximal tubular cell at the basolateral membrane occurs via human organic anion transporter 1 (OAT-1) and to a lesser degree, OAT-3; TFV efflux into urine at the apical membrane is mediated by multidrug resistance– associated protein type 4 (MRP-4) and possibly, MRP-2. Accumulation of TFV within proximal tubular cells leads to mitochondrial injury and tissue hypoxia. (B) TAF is stable within plasma and largely metabolized to TFV within target cells, resulting in lower plasma TFV levels and less likelihood of tubular injury. TAF itself is not a substrate for OAT-1 or OAT-3.

TAF TAF isexpectedtohaveanimprovedrenal eGFR.50 ml/min per 1.73 m2,themedian TAF is an alternative tenofovir prodrug toxicity profile due to lower plasma teno- change in estimated creatinine clearance recently approved for the treatment of fovir concentrations (Figure 2B). In a trial over 96 weeks was significantly lower HIV infection.18 Compared with TDF, of HIV-positive ART-naïve persons with among TAF users (22.0 ml/min) compared

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with TDF users (27.5 ml/min).97,98 Im- proved renal safety was also suggested by a study among virologically suppressed per- 2 1 1 2 0 2 2 1 4 6 sons with eGFRs.50 ml/min per 1.73 m2 Points who switched from TDF to TAF.99 In a single-arm, open label study, virologically

96 suppressed persons with an eGFR of 30– 69 ml/min per 1.73 m2 were switched to elvitegravir/cobicistat/emtricitabine/TAF. Although there was no significant change

3 in eGFR overall, including in the subgroup with eGFR,50 ml/min per 1.73 m2, total proteinuria, albuminuria, and low molec- VHA CKD Risk Score 39 49 59 90 – – – – ular weight proteinuria improved substan- —— —— —— —— —— —— Yes Yes Yes Yes Yes 19 40 50 60 tially over the 48-week follow-up.17 These Category data suggest that TAF may be a safer alter- 200 cells per 1 mm

, native to TDF among persons at risk for

(http://hivinsite.ucsf.edu/InSite?page=md-calculator) CKD. Of note, the trial participants were highly selected, and the short duration of follow-up could not assess TAF’slong-term safety. As TAF use increases, postmarketing surveillance for nephrotoxicity will be imperative. 6 1 0 4 7 1 2 1 10 —— — — —— — 2 2 HIV Pre-Exposure Prophylaxis

Score Points Pre-exposure prophylaxis (PrEP) with Shortened Risk TDF (200 mg)/emtricitabine (300 mg) has become a global strategy for HIV pre- 94,95 vention.9,10,100 TDF currently remains the recommended PrEP regimen, be- 6 1 0 4 7 2 1 1 1 2 1 10 2 2 cause alternatives, including TAF, have

Full Risk lower or unknown efficacy.101 Clinical Score Points trials have shown a small rise in serum creatinine with PrEP. In the Iniciativa fi 3 Pro laxis Pre-Exposicion (iPrEx) Study of HIV-negative men and transgender (http://www.chip.dk/Tools) women, eGFR between the active and D:A:D Study CKD Risk Score 9070 0 6 0 6 50 60 placebo arms differed by 4 weeks of ther- # # # # 90 35 60 2 2 ——— ——— —— ——— apy (mean change of 2.4 versus 1.1 Yes Yes Yes # . . Positive Women 70 to 60 to 35 to 50 to ml/min, respectively). This difference Category 200 cells per 1 mm . . . .

. persisted through the 144-week study 102 Intravenous drug use and resolved after stopping PrEP. Sim-

Nadir ilarly, in the Partners Pre-Exposure Pro- phylaxis (Partners PrEP) Randomized, Controlled Trial of heterosexual HIV- negative individuals, PrEP use was asso- ciated with a slight eGFR reduction (21.23 2 2 2 to 21.59 ml/min per 1.73 m2)versus 200 mg/dl 103 . placebo. The eGFR reduction ap-

140 mg/dl peared by 1 month postrandomization, . 30 mg/dl 140 mmHg was stable through 12 months of follow- Existing risk scores for CKD among HIV-positive individuals $ . Risk Factor up, and resolved after discontinuation.104 Asystematic review andmeta-analysis of ten studies evaluated the risk of renal 105 Plasma triglycerides CD4+ cell count eGFR, ml/min per 1.73 m Proteinuria Table 2. D:A:D Study, Data Collection on Adverse Events of Anti-HIV Drugs Study VHA, Veterans Health Affairs. eGFR, ml/min per 1.73 m Diabetes mellitus Hypertension Cardiovascular disease Hepatitis C virus serostatus Age, yr HIV exposure Age, yr Age, yr Plasma glucose Age, yr Sex Systolic BP eGFR, ml/min per 1.73 m adverse events attributable to PrEP.

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PrEP users had an absolute increased risk Epidemiologic studies have reproduc- C had 57% and 38% increased risks of of 0.6% for a 1.1- to 1.3-fold increase ibly shown a modestly increased risk of mortality and allograft failure, respectively, above the upper limit of normal for serum nephrotoxicity with atazanavir. In a large compared with those monoinfected with creatinine. Conversely, the absolute risk re- study of HIV-positive United States vet- hepatitis C. Nonetheless, HIV-positive in- duction for HIV infection was 2% (num- erans, each year of exposure was associated dividuals who underwent kidney trans- ber needed to treat, 50). However, the with a 22% higher risk of rapid kidney plantation had greater survival, including overall adherence to TDF/emtricitabine function decline.14 Similarly, the D:A:D those coinfected with hepatitis C, versus was low in these trials. An open label ex- Study reported a 20% higher CKD inci- candidates who remained waitlisted.121 tension of the iPrEx Study reported a lin- dence per year of exposure to ritonavir- In sub-Saharan Africa, where a dual bur- ear relationship between tenofovir hair boosted atazanavir among HIV-positive den of HIV infection and CKD exists, the concentrations, which reflect drug adher- individuals with preserved kidney func- lack of affordable dialysis and potential do- ence, and longitudinal eGFR decline over tion at baseline.44 Although a recent nors led to the initial HIV-positive to HIV- 18 months.106 Notably, whether the rise in analysis reported stabilization or improve- positive kidney transplantations.122,123 In serum creatinine with PrEP reflects a re- ment in kidney function after switching 2010, Muller et al.124 reported on four duction of GFR and/or tubular creatinine from ritonavir-boosted atazanavir to HIV-positive recipients whose allografts secretion is unknown. In a Partners PrEP ritonavir-boosted ,114 the find- originated from HIV-positive donors who Randomized, Controlled Trial substudy, ings were largely driven by changes in had no prior ARTexposure, serious op- the incidence of proximal tubulopathy eGFR among TDF users. Further studies portunistic conditions, or proteinuria was low among PrEP users and did not are needed to confirm whether switching and had normal kidney biopsies. By 1-year differ from the placebo group over 24 from atazanavir to other protease inhibi- post-transplant, all recipients had func- months.107 However, tubular proteinuria tors improves kidney function. tional allografts and no significant acute (7.3% versus 4.0%), urine protein-to- rejection. A subsequent report of 27 HIV- creatinine ratio .200 mg/g (8.0% versus positive to HIV-positive transplants 4.4%), and uricosuria (3.5% versus 1.3%) KIDNEY TRANSPLANTATION showed 1- and 5-year patient survival occurred more frequently in the PrEP rates of 84% and 74%, respectively, and versus placebo group, respectively. By The number of kidney transplantations 1- and 5-year allograft survival rates of comparison, an iPrEx Study substudy with HIV-positive recipients has in- 93% and 74%, respectively.119 Conse- found no significant differences in preva- creased tenfold since 2002.115 Of studies quently, the US HIV Organ Policy Equity lence of proximal tubular abnormalities to date (Table 3),116–120 the largest series (HOPE) Act of 2013 was ratified,125 by study arm. With widespread dissemi- reported on 150 HIV-positive kidney thereby reversing the ban on the use of or- nation of PrEP,studies are needed to char- transplant recipients who met stringent gans from HIV-positive individuals.126 acterize tenofovir’s effects on renal tubular eligibility criteria (Table 4).120 During a Several uncertainties surrounding function in HIV-negative individuals, median follow-up of 1.7 years post- kidney transplantation among HIV- identify persons at highest risk for toxicity, transplant, the overall 1- and 3-year pa- positive individuals remain, including and provide guidance on the optimal tient survival rates were 95% and 88%, optimal immunosuppressive and ART monitoring strategy of these individuals. respectively, falling between those re- regimens, management of viral hepatitis ported for all United States kidney trans- coinfections, and transmission of resistant Atazanavir plant recipients and those ages $65 viral strains from HIV-positive donors. Atazanavir has been associated with crys- years old. Similar trends were observed Immunosuppression considerations en- talluria, urolithiasis, tubulointerstitial for allograft survival, with 1- and 3-year compass the need to prevent allograft nephritis, and CKD.38–41,108,109 Kidney allograft survival rates of 90% and 74%, rejection, minimize infection risk, and biopsies have shown granulomatous in- respectively. These favorable outcomes manage drug-drug interactions, partic- flammation surrounding intrarenal de- were tempered by approximately 30% ularly between immunosuppressive and posits of atazanavir crystals.39,108,110 The incidence of acute rejection and profound antiretroviral medications. Induction risk of nephrolithiasis is higher among immunosuppression among recipients therapyfor patientsathighriskofrejection individuals with higher atazanavir who received thymoglobulin. Nearly one hasbeenlargelymadeupofthymoglobulin plasma trough concentrations, individu- third developed serious infections, and and IL-2 receptor antagonists. Within the als with alkaline urine pH, and those five developed AIDS-defining conditions. first year post-transplant, thymoglobulin with underlying CKD.111,112 Continua- A subsequent analysis of the Scientific has been associated with 61% risk reduc- tion of atazanavir after the diagnosis of Registry of Transplant Recipients data tion of acute rejection, whereas IL-2 recep- kidney stones is associated with high re- from 2002 to 2011 showed favorable torantagonistsyieldsimilaracuterejection currence risk, with one study reporting trends in 5- and 10-year patient and al- rates as no induction.127 Unfortunately, 33% recurrence.113 Moreover, the risk of lograft survivals among HIV-positive thymoglobulin may lead to profound, nephrolithiasis may persist after ataza- recipients.115 However, it also noted prolonged immunosuppression, espe- navir discontinuation.111 that recipients coinfected with hepatitis cially in recipients with low pretransplant

6 Journal of the American Society of Nephrology J Am Soc Nephrol 28: ccc–ccc,2017 mScNephrol Soc Am J Table 3. Summary of studies to date on HIV-positive kidney transplant recipients Length of Immunosuppressive Reported Major Study Study Population Antiretroviral Regimen Survival Follow-up, yr Regimen Complications Stock 150 HIV+ recipients of allografts Median: 1.7 99% on cART Induction: basiliximab/ 1- and 3-yr graft: Delayed graft function: 46% of et al.120 from HIV2 deceased (68%) or (IQR, 7–3) daclizumab or 90.4% and 73.7%, recipients with deceased 28: living (32%) donors in the United thymoglobulin respectively donors; 15% of recipients ccc States with living donors – ccc 3% on NRTI, 63% on PI, Maintenance: CNI + MMF/ 1- and 3-yr patient: Acute rejection: 31% at 1 yr and

2017 , 59% on NNRTI, 15% on rapamycin + steroids 94.6% and 88.2%, 41% at 3 yr PI + NNRTI, 4% on II respectively Opportunistic condition: 3.3% Malignancy: 6% Hospitalization due to infectious complication: 38% Mazuecos 36 HIV+ recipients of allografts Median: 2.8 Paper did not provide Induction: anti–IL-2R or 1- and 3-yr graft: Delayed graft function: 52% et al.116 from HIV2 deceased (94%) or (IQR, 1.1–4.9) details on cART use thymoglobulin 91.6% and 86.2%, living (6%) donors in Spain respectively Maintenance: CNI + MMF 3-yr patient: 91.6% Acute rejection: 33.9% at 3 yr + steroids acute rejection post-transplant Opportunistic condition: 45% Malignancy: 11% Bossini 13 HIV+ recipients of allografts Mean: 4.261.8 92% on cART Induction: basilizimab + 4-yr graft: 88.9% Acute rejection: 61.5% et al.117 from HIV2 deceased donors in methylprednisolone the United States 92% on NRTI, 77% on PI, Maintenance: CNI + MMF 4-yr patient: 100% 54% Resumed steroid therapy 15% on NNRTI, 7% on II Malignancy: 8% Hospitalization due to infectious complication: 47% Gathogo 35 HIV+ recipients of allografts Median: 1.8 100% on cART Induction: basixilimab/ 1- and 3-yr graft: Delayed graft function: 15% et al.118 from HIV2 deceased donors in (IQR, 1.2–4.1) daclizumab + 91.3% and 84.7%, the United Kingdom methylprednisolone or respectively methylprednisolone only 6% on NRTI, 34% on PI, Maintenance: CNI + MMF/ 1- and 3-yr patient: Acute rejection: 44% 51% on NNRTI, 9% on azathioprine + steroids 91.3% and 91.3%, Opportunistic condition: 6% PI + NNRTI respectively Hospitalization due to infectious complication: 54%

Muller 27 HIV+ recipients of allografts Median: 2.4 100% on cART Induction: thymoglobulin 1-, 3-, and 5-yr graft: Delayed graft function: 7.4% www.jasn.org et al.119 from HIV+ deceased donors in 93%, 84%, and 84%, I n inyDisease Kidney and HIV South Africa respectively 41% on PI, 59% on NNRTI Maintenance: CNI + MMF + 1-, 3-, and 5-yr Acute rejection: 8% at 1 yr and steroids patient:84%, 84%, 22% at 3 yr and 74%, respectively Hospitalizations due to infectious complication: 26% REVIEW BRIEF IQR, interquartile range; cART, combination antiretroviral therapy; NRTI, nucleoside reverse transcription inhibitor; PI, protease inhibitor; NNRTI, non-nucleoside reverse transcription inhibitor; II, integrase in- hibitor; CNI, calcineurin inhibitor; MMF, mycophenolic acid. 7 BRIEF REVIEW www.jasn.org

Table 4. Selection criteria for candidate HIV-positive recipients120 NIH/NIDDK grant P01DK056492 and Na- Meets Standard Transplant Criteria Plus the Following tional Institute on Drug Abuse (NIDA) grant R01DA026770. M.M.E. is supported by NIH/ Effective HIV suppression for $6 mo before transplantation HIV-1 RNA ,50 copies per 1 ml NIDDK grant R01DK103574. CD4+ cell count .200 cells per 1 mm3 No active opportunistic infections No prior history of DISCLOSURES Progressive multifocal leukoencephalopathy None. Primary central nervous system lymphoma Pulmonary aspergillosis Visceral Kaposi sarcoma REFERENCES Coccidiomycosis Chronic intestinal cryptosporidiosis .1mo 1. Lohse N, Hansen AB, Pedersen G, Kronborg Hepatology evaluation for patients coinfected with hepatitis B or hepatitis C virus G, Gerstoft J, Sørensen HT, Vaeth M, Obel N: Survival of persons with and without HIV infection in Denmark, 1995-2005. Ann Intern Med 146: 87–95, 2007 CD4+ counts.120,128 Among 38 HIV- CONCLUSIONS 2. Wong C, Gange SJ, Buchacz K, Moore RD, Justice AC, Horberg MA, Gill MJ, Koethe positive recipients who received thymo- JR, Rebeiro PF, Silverberg MJ, Palella FJ, globulin induction, those with baseline Advances in HIV treatment have ushered Patel P, Kitahata MM, Crane HM, Abraham CD4+ counts of 200–349 cells per 1 mm inanerainwhichHIV-positiveindividuals AG, Samji H, Napravnik S, Ahmed T, Thorne 3 versus those with $350 cells per 1 mm3 can reach “old age.” With the transforma- JE, Bosch RJ, Mayor AM, Althoff KN; North were twofold more likely to develop se- tion of HIV infection to a chronic condi- American AIDS Cohort Collaboration on Research and Design (NA-ACCORD): First vere lymphopenia in the initial 4 weeks tion, the underlying causes of CKD in occurrence of diabetes, chronic kidney dis- post-transplant, which was predictive of HIV-positive persons have shifted from ease, and hypertension among north american serious infections.128 These results sug- those driven by HIV to those from tradi- HIV-infected adults, 2000-2013. Clin Infect Dis gest that thymoglobulin should be used tional risk factors and ART-related neph- 64: 459–467, 2017 carefully in HIV-positive recipients rotoxicity. A substantial racial disparity in 3. Guaraldi G, Orlando G, Zona S, Menozzi M, , Carli F, Garlassi E, Berti A, Rossi E, Roverato whose CD4+ counts are 350 cells per ESRD risk among HIV-positive individu- A, Palella F: Premature age-related comorbid- 3 1mm at transplantation. als remains; the growing understanding of ities among HIV-infected persons compared The optimal ARTamong HIV-positive APOL1 pathomechanisms will hopefully with the general population. Clin Infect Dis 53: recipients remains unclear. Protease inhib- yield strategies to mitigate CKD risk in 1120–1126, 2011 itors and to a lesser extent, non-nucleoside these patients. TDF, the most common 4. Abraham AG, Althoff KN, Jing Y, Estrella MM, Kitahata MM, Wester CW, Bosch RJ, antiretroviral currently used for treating reverse transcription inhibitors inhibit Crane H, Eron J, Gill MJ, Horberg MA, the cytochrome-P450 and p-glycoprotein and preventing HIV infection, is associ- Justice AC, Klein M, Mayor AM, Moore RD, systems, leading to greater exposure to ated with increased CKD risk. Although Palella FJ, Parikh CR, Silverberg MJ, Golub calcineurin inhibitors and mammalian early studies of its alternative, TAF, indi- ET, Jacobson LP, Napravnik S, Lucas GM; target of rapamycin inhibitors.129,130 In cate improved renal safety profile, studies North American AIDS Cohort Collaboration fi on Research and Design (NA-ACCORD) of addition, pharmacoenhancement with on its long-term safety and ef cacy in pre- the International Epidemiologic Databases ritonavir or cobicistat increases calcineurin venting HIV infection are needed. For the to Evaluate AIDS (IeDEA): End-stage renal inhibitor exposure.130,131 Conversely, inte- many HIV-positive individuals with ad- disease among HIV-infected adults in North grase inhibitors (e.g., ) and vanced CKD, kidney transplantation offers America. Clin Infect Dis 60: 941–949, 2015 the receptor-5 antagonists improved survival and durable allograft 5. Fine DM, Wasser WG, Estrella MM, Atta MG, Kuperman M, Shemer R, Rajasekaran (e.g., ) do not affect the cyto- function. Ongoing studies, including those A, Tzur S, Racusen LC, Skorecki K: APOL1 chrome-P450 system and therefore, established as part of the HOPE Act, will risk variants predict histopathology and may be associated with lower risk of soon inform the selection of donor and re- progression to ESRD in HIV-related kidney delayedallograftfunctionorallograft cipientcandidatesaswellaspost-transplant disease. JAmSocNephrol23: 343–350, rejection.130,132 In addition, experimen- management of HIV-positive recipients. 2012 6. Kopp JB, Nelson GW, Sampath K, Johnson tal studies suggest that rapamycin may RC, Genovese G, An P, Friedman D, Briggs augment viral suppression by chemokine W, Dart R, Korbet S, Mokrzycki MH, Kimmel receptor-5 antagonists.133 However, clini- ACKNOWLEDGMENTS PL, Limou S, Ahuja TS, Berns JS, Fryc J, cal studies comparing long-term out- Simon EE, Smith MC, Trachtman H, Michel comes among various ART regimens are V.J. is supported by National Institutes of DM, Schelling JR, Vlahov D, Pollak M, Winkler CA: APOL1 genetic variants in focal lacking. The ongoing multicenter trial Health (NIH)/National Institute of Diabetes segmental glomerulosclerosis and HIV- created through the HOPE Act will help and Digestive and Kidney Diseases (NIDDK) associated nephropathy. JAmSocNephrol address these uncertainties.126 grant K23DK109868. M.G.A. is supported by 22: 2129–2137, 2011

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