Expert Review of Anti-infective Therapy
ISSN: 1478-7210 (Print) 1744-8336 (Online) Journal homepage: http://www.tandfonline.com/loi/ierz20
Diagnostic challenges of kidney diseases in HIVinfected patients Robin Chazot, Elisabeth Botelho-Nevers, Anne Frésard, Nicolas Maillard, Christophe Mariat, Frédéric Lucht & Amandine Gagneux-Brunon To cite this article: Robin Chazot, Elisabeth Botelho-Nevers, Anne Frésard, Nicolas Maillard, Christophe Mariat, Frédéric Lucht & Amandine Gagneux-Brunon (2017): Diagnostic challenges of kidney diseases in HIV-infected patients, Expert Review of Anti-infective Therapy, DOI: 10.1080/14787210.2017.1379395 To link to this article: http://dx.doi.org/10.1080/14787210.2017.1379395
Accepted author version posted online: 12 Sep 2017.
Submit your article to this journal
View related articles
View Crossmark data
Full Terms & Conditions of access and use can be found at http://www.tandfonline.com/action/journalInformation?journalCode=ierz20 Download by: [Australian Catholic University]
Date: 13 September 2017, At: 06:10
Review Diagnostic challenges of kidney diseases in HIV-infected patients Robin Chazot1, Elisabeth Botelho-Nevers2,3, Anne Frésard2,3, Nicolas Maillard 1,3, Christophe Mariat1,3, Frédéric Lucht2,3, *Amandine Gagneux-Brunon2,3 Department of Nephrology, Dialysis, Transplantation and Hypertension, University Hospital
ip t
1
Department of Infectious and Tropical Diseases, University Hospital of Saint-Etienne,
cr
2
GIMAP Groupe Immunité des Muqueuses et Agents Pathogènes, EA 3064, University Jean
*Corresponding author:
M
Monnet, University of Lyon, France
an
3
us
France
ed
Amandine Gagneux-Brunon
Department of Infectious and Tropical diseases, University Hospital of Saint-Etienne, 55
ce pt
avenue Albert Raimond, 42055 Saint-Etienne cedex 2 France, Groupe Immunité des Muqueuses et Agents Pathogènes, Université Jean Monnet, Université de Lyon, SaintEtienne, France
Email: [email protected]
Ac
Downloaded by [Australian Catholic University] at 06:10 13 September 2017
of Saint-Etienne, France
Abstract: Introduction: Chronic kidney disease (CKD) is a prevalent comorbidity in persons living with HIV infection (PLWH) associated with an increase in cardiovascular morbidity and all-cause mortality. Furthermore, early diagnosis of CKD is difficult in PLWH.
ip t
Areas covered: We reviewed the main diagnostic tools for CKD in PLWH, and discussed their strengths and limits. We performed a literature search on Pubmed to identify reviews
cr
us
following key words: “HIV AND kidney”, “HIV AND Kidney biomarkers”, “CKD AND Kidney biomarkers”.
an
Expert commentary: Currently, CKD diagnosis is based on the estimation of Glomerular Filtration Rate (GFR), and measurement of proteinuria by urine protein/creatinine ratio
M
(uPCR). These parameters are independent and complementary predictors of outcomes. GFR estimates are lacking in accuracy in PLWH. The best GFR estimate is CKD-EPI study
ed
equation. Moreover, low-grade proteinuria is associated with an increased risk of kidney disease progression in PLWH, and guidelines derived from the general population may lack
ce pt
sensitivity. Different biomarkers of kidney diseases like N-acetyl beta glucosaminidase (NAG), Kidney Injury Molecule-1 (KIM-1), and Alpha-1-microglobulin may predict kidney disease progression and mortality in PLWH. Others may help clinicians detect antiretroviralinduced tubulopathy, or predict cardiovascular events. More studies are needed to validate the
Ac
Downloaded by [Australian Catholic University] at 06:10 13 September 2017
and clinical trials dealing with attractive kidney biomarkers of CKD in PLWH, with the
routine use of these types of biomarkers.
Key-words: HIV, Kidney, Biomarkers, Glomerular Filtration Rate, Chronic Kidney Disease
1.
Introduction
Antiretroviral therapies (ART) have dramatically reduced mortality due to HIV-infection and so HIV infection has turned into a long-term chronic illness for many patients. Thus,the prevention and treatment of comorbidities have come to the forefront of the care of persons living with HIV infection (PLWH). It was estimated, in the national Dutch ATHENA cohort,
ip t
that in 2030, around a third of HIV-infected patients will have at least 3 comorbidities (1).
cr
communicable comorbidities than HIV-uninfected controls (2). Among these comorbidities,
us
chronic kidney disease (CKD) is significantly more prevalent in PLWH than in HIV-
an
uninfected individuals (2). The prevalence of CKD in HIV-infected patients ranges from 1 to 48% among different cohorts, the greatest prevalence being observed among Black Africans
M
(3). CKD is associated with poor outcomes in PLWH. Deterioration in renal function in HIVinfected patients (i.e decrease in estimated glomerular filtration rate (GFR)) is associated with
ed
an increase in mortality and morbidity in HIV-infected patients due to AIDS and non-AIDS events (4). Moreover, patients with CKD were less likely to receive ART than patients
ce pt
without CKD; these observations highlight the difficulty of treating patients with CKD (5). Here, after a short overview of the spectrum of kidney diseases in PLWH, CKD classification and limits of currently used markers of CKD, we will discuss emerging biomarkers of CKD. 2.
Spectrum of kidney diseases in HIV-infected patients
Ac
Downloaded by [Australian Catholic University] at 06:10 13 September 2017
HIV-infected patients had a significantly higher mean number of age-associated non-
HIV-infected individuals may suffer from specific kidney diseases and as summarized in Table 1. In fact the kidney represents a reservoir for HIV (6,7) and in this population, kidney diseases could be related to ART- side-effects and non-HIV-related kidney diseases (lipid level, hypertension, diabetes, hepatitis C coinfection). HIV-associated nephropathy (HIVAN) was first described in 1984 by Rao et al. (8). HIVAN results in a collapse of glomerular
capillaries, visceral glomerular epitheliosis, podocyte hypertrophy and proliferation, mesangial prominence and hypercellularity, endothelial tubuloreticular inclusions (TRIs) on ultrastructural examination and microcystic tubules in patients infected by HIV (8). HIVAN may lead to a glomerular syndrome with high-grade proteinuria and rapid progression to endstage renal disease (ESRD) (9), HIV infected patients with biopsy-proven HIVAN were more
ip t
likely to require dialysis than patients with alternative diagnoses (10). ART use has improved
cr
decrease in the incidence of HIVAN (12). After the description of HIVAN, HIV-immune
us
complex disease (HIVICD) was described. These lesions are secondary to the polyclonal expansion of immunoglobulins in HIV chronic infection, which results in the deposit of
an
immune complexes in renal capillaries (13). Since both diseases affect more black people, HIVAN is associated with a low CD4 positive cells count, and results in a faster decrease in
M
GFR. HIV-infected patients suffering from HIVICD were more often exposed to
ed
antiretrovirals, had lower HIV viral loads, and greater CD4 cell positive count than patients suffering from HIVAN (14). ART use significantly reduced the incidence of HIVAN and
ce pt
reduced the risk of HIVAN by 60 % (12). Lescure et al show that HIVAN affects younger patients with severe immunodeficiency unlike classic focal and segmental glomerular sclerosis (FSGS) that affects older patients with a long history of ART and a higher cardiovascular risk (9). Classic FSGS is characterized by the presence of at least one segmental capillary wall collapse and/or segmental sclerosing lesion without podocyte
Ac
Downloaded by [Australian Catholic University] at 06:10 13 September 2017
the prognosis of HIVAN (11) and a wider implementation of ART is associated with a
hyperplasia or glomerular collapse (9). With better control of HIV replication, ART-induced tubulopathy and interstitial nephritis have become important kidney complications in PLWH, with the highest prevalence of tubulopathy in patients receiving tenofovir disoproxil fumarate (TDF) and crystal nephropathy with atazanavir and indinavir (12). Considering TDF, TDF exposure is associated with tubular damage and less frequently with glomerular diseases (16).
Kidney tubular damage affects around 22 % of the patients (17) in the absence of impaired GFR. The risk of tubulopathy depends on tenofovir plasma concentrations (18). Tenofovir accumulates in tubular cells; this accumulation is responsible for tubular damage, and may be facilitated by interactions with drug transporters at the surface of tubular cells (Figure 1). Different genotypes for drug transporters are associated with tenofovir accumulation in
ip t
tubular cells, and consequently with a higher rate of kidney tubular damage (19–21).
cr
accumulation in tubular cells (22). Decline in GFR due to TDF exposure is incompletely
us
reversible after TDF cessation (23). Tenofovir alafenamide (TAF) was developed to reduce renal and bone side-effects of TDF; greater intracellular concentrations in lymphoid cells are
an
achieved whereas tenofovir plasma concentrations are 90 % lower than with TDF (24), and consequently tenofovir is less likely to accumulate in tubular cells. In clinical trials, TAF was
M
not responsible for GFR decrease and was associated with a decrease in tubular biomarker
ed
levels in urine (25,26). Other recent antiretrovirals (dolutegravir, etravirine, rilpivirine, elvitegravir) are widely implemented whereas their renal effects remain little known. In the
ce pt
D:A:D study cohort, use of indinavir, atazanavir and TDF were associated with an increased risk of CKD (27). There are no prospective studies evaluating the impact of HAART regimen on the prevention of CKD.
Whatever the type of lesion, different risk factors for the development of CKD were described in HIV-infected patients including HIV-specific and non-specific risk factors. Particularly in
Ac
Downloaded by [Australian Catholic University] at 06:10 13 September 2017
Concomitant use of ritonavir-boosted protease inhibitors are associated with tenofovir
the D:A:D study cohort (28), intravenous drug use, hepatitis C co-infection, older age, lower baseline eGFR, female gender, lower CD4 count nadir, hypertension, diabetes, and prior
cardiovascular diseases were found to be associated with CKD. A risk score for CKD development was derived from this cohort (28). In the score developed from the D:A:D study
cohort, it is possible to integrate the ART regimen received by a patient to estimate the 5-year risk of GFR reduction under 60 mL/min/1.73m2 (28). As well as these risk factors, with improved survival and long-term ART use, comorbidities with kidney involvement such as diabetes and hypertension (29) are becoming more prevalent in the HIV-infected population (5). Diabetic nephropathy is one of the leading causes of other
ip t
glomerular diseases in PLWH. The risk of a decrease in GFR was greater in patients with
cr
suggests an additive effect between HIV-infection and diabetes to lead to CKD (30).
us
Furthermore, in HIV-infected intravenous drug users, frequent infections may increase the
an
risk of developing amyloidosis (31).
Moreover, HCV co-infection affects around 6% of HIV-infected patients worldwide (32).
M
HCV infection may result in kidney damage, particularly in HIV-infected patients (33), not only just in patients experiencing cryoglobulinemia. The risk of CKD is higher in HIV-
ed
infected patients with chronic HCV infection and persisting viremia than in patients with
ce pt
cleared infection (34).
Acquired immunodeficiency syndrome is associated with an increased risk of AKI in HIVinfected hospitalized patients (35), particularly in patients receiving nephrotoxic drugs (like aminoglycosides, amphotericine B, vancomycin, acyclovir, gancyclovir and foscarnet) for the treatment of opportunistic infections (cryptococcal meningitis, Cytomegalovirus reactivation)
Ac
Downloaded by [Australian Catholic University] at 06:10 13 September 2017
HIV-infection and diabetes, than in patients with HIV infection only or diabetes only; this
and/or comorbidities (35). In the general population, AKI is associated with an increased risk of developing CKD in the future (36).
3.
Different CKD classifications in HIV-infected patients (Tables 2)
CKD is defined by structural or functional kidney abnormalities, present for > 3 months. As CKD is highly prevalent in PLWH and is associated with morbidity, guidelines for the management of CKD in PLWH are necessary. GFR and albuminuria are recommended to detect and stage CKD in the general population (37) and in PLWH (38–40). The use of GFR
ip t
estimating equations based on serum creatinine is recommended in PLWH, in particular the
cr
Diseases Society of America (IDSA) published guidelines for CKD screening in HIV-infected
us
patients, with assessment every 6 months for patients with proteinuria using urinary protein/creatinine ratio (uPCR in mg/g), or urinary albumin/creatinine ratio (uACR in mg/g)
an
and estimation of GFR. These guidelines were updated in 2014 (38). In this update, a classification of CKD was adapted from the Kidney Disease Improving Global Outcomes
M
guidelines (KDIGO) (37). KDIGO have developed a classification with risk categories based
ed
on GFR and albuminuria; these categories were obtained from different meta-analyses in the general population, which evaluate the risk of End Stage Renal Disease, all-cause mortality,
ce pt
and cardiovascular mortality (41). This classification is based on both GFR and proteinuria levels, as both GFR and albuminuria are independent and complementary risk predictors of clinical outcomes (38): CKD progression, end-stage renal disease, cardiovascular mortality, all-cause mortality.
Ac
Downloaded by [Australian Catholic University] at 06:10 13 September 2017
equation developed in 2009 by CKD-EPI study collaboration (38,39). In 2005, the Infectious
Since the publication of the IDSA guidelines, the European AIDS Clinical Society (EACS) has also developed a CKD classification with risk categories (39). This classification is also based on GFR and proteinuria categories. However, the values of proteinuria are higher than in the IDSA guidelines and consequently the sensitivity of this classification is probably lower than that of the IDSA classification. In contrast with IDSA and EACS guidelines,
French guidelines only considered GFR (40). However, patients with a normal GFR and proteinuria are considered to have a CKD stage 1. Different issues must be discussed concerning the use of these different guidelines in PLWH. First, IDSA and EACS recommend the use of the CKD-EPI study equation based on serum creatinine for GFR estimation, whereas French guidelines recommend the use of the MDRD
ip t
equation (38–40). Secondly, the predictive performance of these different guidelines was not
cr
albuminuria for CKD detection in PLWH. Thirdly, discrepancies between these different
us
guidelines may result in differences in risk perception for the same patient. For example, a patient with an eGFR at 65 mL/min/1.73m2 and proteinuria measured at 200 mg/g will be
an
considered at low risk according to EACS guidelines, at intermediate risk according to IDSA
M
guidelines, and at high risk according to the French guidelines.
4.
ed
The high prevalence of tubular damage in PLWH limits the accuracy of GFR and
urinary albumin-to-creatinine ratio (uACR) in the detection of kidney diseases at early
ce pt
stages.
The overall prevalence of end-stage renal disease (ESRD) requiring renal replacement therapy (RRT) in persons living with HIV infection (PLWH) in Europe was evaluated at 0.46 % (42). It is widely accepted that for one patient with ESRD, around 10 to 1 000 individuals exhibit
Ac
Downloaded by [Australian Catholic University] at 06:10 13 September 2017
specifically evaluated in PLWH. In the next part, we will discuss the pertinence of
earlier stages of chronic kidney diseases and therefore early diagnosis of CKD is crucial. However, serum creatinine is an imperfect marker of GFR, particularly in PLWH, and in the elderly (43,44). The glomerular capillary wall hinders the passage of large serum proteins such as albumin. Consequently, detection of albuminuria is often associated with glomerular
damage. CKD classification in the general population and in PLWH considers that a threshold of 30 mg/g for uACR as pathologic (37,38). However, in PLWH, a large proportion of
patients develop tubular damage, which can be misdiagnosed using only uACR. Moreover, in a prospective cohort of 429 PLWH, Ando et al. observed that an increase in urinary albumin excretion, although it remained within the normal range, was associated with an increase in the risk of developing kidney disease (45). Using low molecular weight proteins as markers of tubular dysfunction, they also observed that 25 % of the PLWH (without microalbuminuria
ip t
and with normal GFR at baseline) had subclinical tubular damage, associated with a decrease
cr
cohort, 55 % of the PLWH had low grade proteinuria, and tubular low grade proteinuria
us
(uPCR>70 mg/g) was identified in 41 % of the PLWH (47). Using recommended thresholds for uPCR and uACR, prevalence of proteinuria in PLWH was 18.2 % (9 % tubular, and 9.2 %
an
glomerular proteinuria) in a French cohort (48). Consequently, the use of urine dipsticks, which mainly detect albumin, is not appropriate in PLWH and assessment of uPCR and
M
uACR is encouraged in this population (38,39). Due to the high prevalence of non glomerular
ed
proteinuria, and the associated risk of developing a decrease in GFR with low grade proteinuria (45), from our point of view uPCR and uACR thresholds might be adapted to
ce pt
PLWH, and alternative markers to detect tubular damage in PLWH might be evaluated in this particular population. However, larger studies are needed to evaluate the impact of decreased albuminuria and proteinuria thresholds in PLWH for earlier detection of CKD in PLWH. 5.
Difficulties in GFR estimates in PLWH
Ac
Downloaded by [Australian Catholic University] at 06:10 13 September 2017
in GFR and the development of microalbuminuria during the follow-up (46). In another
Assessment of GFR is useful to detect CKD, to monitor CKD progression, to refer to nephrologists, to predict the risk of cardiovascular events, and for drug dosing adjustment (49). In the general population, GFR can be estimated using endogenous biomarkers, mainly serum creatinine. Cystatin C can be used to estimate GFR as an alternative to serum creatinine and/or as a confirmatory test when a CKD is suspected (37). Cystatin C is a biomarker produced by all nucleated cells, filtered by glomerulus and completely reabsorbed in tubules
(44). GFR can also be measured by urinary or plasma clearance of exogenous markers like inulin, iothalamate, iohexol, and
51
Cr-EDTA, and diethylene triamine pentaaceticacid (49);
these methods are considered as gold standards (50) and are used to evaluate the accuracy of GFR estimates. However, measurement of GFR remains difficult in routine clinical practice (49).
ip t
Considering GFR estimates with endogenous markers, serum creatinine and cystatin C levels
cr
tubular secretion of these biomarkers might be highly variable. On the one hand, in HIV-
us
infected patients, decrease in lean mass, high prevalence of liver disease, and malnutrition are associated with a decrease in serum creatinine (44). On the another hand, some medications
an
such as trimethoprim (51), dolutegravir, rilpivirine, cobicistat and raltegravir (52,53) are associated with an increase in serum creatinine that is due not to a GFR decrease, but to an
M
interaction with tubular drug transporters, resulting in a reduction of tubular secretion of
ed
serum creatinine (54). In this context of inhibition of tubular secretion of creatinine, the rise in serum creatinine appears shortly after the start of the antiretroviral, remains non progressive
ce pt
and is not associated with proteinuria or hypertension (52). Serum cystatin C might, in such cases, be an alternative to serum creatinine in PLWH, but some limitations should be addressed.
The impact of inflammation level, HIV viral load, age, and tobacco use on concentrations of cystatin C levels remains unclear (44). Different studies have evaluated the performance of
Ac
Downloaded by [Australian Catholic University] at 06:10 13 September 2017
are not only affected by GFR: the level of generation of these biomarkers and/or the level of
GFR estimates in PLWH using serum creatinine, and serum cystatin C to detect CKD in comparison with GFR measurements. The main studies are shown in Table 3 (55–57).The best indicator of performance is accuracy, and it is estimated by the proportion of eGFR values within ± 30 % of the measured GFR. Results of these studies are difficult to compare because the populations are different (ethnicity, body composition, proportion of patients
receiving ART). Globally, CKD-EPI based on serum creatinine (CKD-EPI cr) exhibited acceptable performances while MDRD and/or Cockcroft and Gault (CG) equations were less accurate. These observations resulted in the recommendations to use preferentially CKD-EPI cr in PLWH in the USA (58) and in Europe (39). However, these studies included few patients with decreased GFR and performance of GFR estimates are probably influenced by
ip t
the level of GFR with greater bias and lower accuracy in patients with lower GFR (55–57). In
cr
whereas this corrective coefficient should not be used in black people in Europe, mainly
us
African migrants (59).
GFR estimates were also evaluated to predict cardiovascular events and mortality in PLWH.
an
In 908 women (mean age at baseline 41 years old, mainly black people, 31 % with undetectable viral load), Driver et al. observed that estimating GFR with the CKD-EPI based
M
on serum cystatin C (CKD-EPI cys) equation was a better predictor of all-cause mortality than
ed
estimating GFR with the CKD-EPI cr equation (60). Lucas et al. observed in 4614 participants of the SMART study that CKD-EPI cys had a stronger association with
ce pt
cardiovascular events and opportunistic infections than CKD-EPI cr, and CKD-EPI cys-cr after adjustment for age, HIV viral load, CRP levels, Nadir CD4 count, CD4 count (61). Mean age at baseline was 44 years, 27 % of the participants were black, CD4 count at baseline was 602 and 82.8 % of the patients received ART at baseline (61). Yanagisawa et al. evaluated the impact of using CKD-EPI cys compared to CKD-EPI cr equation on GFR classification
Ac
Downloaded by [Australian Catholic University] at 06:10 13 September 2017
the USA, CKD-EPI should be used with the African-American coefficient in black people,
proposed by IDSA in 601 Japanese patients (90 % receiving ART, mean age 46 years old ± 11.6) in prediction of a composite outcome including all-cause mortality, cardiovascular events, and renal dysfunction (62). Patients classified at risk (orange category in IDSA classification) with CKD-EPI cys had a significantly greater risk of composite outcome, this association was not observed with CKD-EPI cr (62). All these observations are in favor of the
use of CKD-EPI cys to predict mortality and cardiovascular events in PLWH. Two studies evaluated the performance of GFR estimates for drug dosing in PLWH. The performance is measured by the concordance between GFR estimates and GFR measurement to correctly classify patients with a GFR greater or lower than the limits for drug dosing adjustment. The different thresholds used depend on the medications to adjust to renal
ip t
function. Historically, drug dosing was carried out with CG equation expressed in mL/min.
cr
mL/min ± 26, with 52 % of African Americans) that CKD-EPI converted to mL/min had a
us
greater concordance with mGFR than CG, and MDRD (63). In a French cohort of 230 patients (mean age 48 ± 10 years, 84 % with undetectable viral load, 7% Africans), we
an
observed that CKD-EPI was as concordant as CG, whereas MDRD was less concordant (64). No study evaluated estimates based on serum cystatin C for drug dosing purposes.
M
Consequently, CKD-EPI cr is useful for CKD detection and drug dosing and CKD-EPI cys
Are there biomarkers for early detection of kidney injury in PLWH?
ce pt
6.
ed
provides additional information to predict adverse outcomes in PLWH.
A biomarker is a parameter of structural, biochemical, physiological or genetic changes associated with the presence, the severity and the progression of a disease (65). An ideal biomarker should be obtained by a highly sensitive and highly specific non-invasive
Ac
Downloaded by [Australian Catholic University] at 06:10 13 September 2017
Okparavero et al. observed in 200 PLWH (61 % with undetectable viral load, mean mGFR 87
procedure; it should increase shortly after the start of injury, correlate with disease severity, predict outcome; be applicable across different populations, be site specific, stable, reflect
efficacy of therapeutical interventions and normalize after injury cessation. We can distinguish two types of new biomarkers of renal function: biomarkers for acute kidney injury (AKI), and biomarkers for CKD (65). During AKI, the aims of these biomarkers are to detect kidney injury early (before traditional markers such as oliguria and increased serum
creatinine), to obtain a prognosis and information about AKI severity, and to differentiate the different etiologies of AKI. In CKD, emergent biomarkers can help to detect abnormalities early, to predict cardiovascular diseases associated with CKD, and progression of CKD (65). The development of proteomics, and transcriptomics results in the discovery of new biomarkers. Different types of biomarkers have been developed and evaluated in the fields of
ip t
AKI or CKD. Most of them were developed for early diagnosis of AKI. However, in PLWH,
cr
for early diagnosis of chronic tubular defects. Consequently, markers derived from the field of
us
AKI were evaluated in PLWH to predict CKD, and all-cause mortality in PLWH (66). These
an
biomarkers are summarized in Table 5.
6.1 Biomarkers to detect kidney toxicity of antiretrovirals
M
Among current antiretrovirals, exposures to TDF, ritonavir-boosted lopinavir and ritonavirboosted atazanavir are associated with a greater risk of CKD development in PLWH (27).
ed
TDF-associated kidney toxicity is well understood with accumulation of TDF in tubular cells causing mitochondrial deaths (67) resulting in Fanconi syndromes, AKI and subclinical
ce pt
tubular toxicity causing long-term decrease in kidney function. Several biomarkers were evaluated to detect tubular toxicity of TDF. In 37 patients with suspected Fanconi syndrome, Jaafar et al. tested the diagnostic performance of urinary cystatin C to urinary creatinine ratio, and positive and negative
Ac
Downloaded by [Australian Catholic University] at 06:10 13 September 2017
the great prevalence of tubular diseases leads us to consider markers of tubular dysfunction
predictive values respectively were 76.9 % and 95.8 % at a threshold of 14 µg/mmol (68). Another kidney biomarker, Alpha gluthatione S transferase was not associated with kidney tubular damage in patients receiving TDF (69). In a study of 190 patients receiving TDF (19 with kidney tubular dysfunction, and 171 without), areas under the Receiver operating characteristics curves were 0.970, 0.968 and 0.901 for ß2-microglobulin, α-1 microglobulin,
and N-acetyl beta glucosaminidase (NAG), respectively (70). In a recent study in 883 HIVinfected men compared with 350 HIV-uninfected men, α-1 microglobulin was detectable in the urine of 83 % of HIV-infected patients and in 58 % of HIV-uninfected men, the level of α1 microglobulin was higher in current users of TDF, and decreased after TDF cessation (71). It is probable that α-1 microglobulin can be a useful biomarker to detect kidney tubular
ip t
damage in PLWH.
cr
higher than in patients not receiving TDF (72). Moreover, patients with evidence of severe
us
TDF toxicity had significantly higher RBP/Cr than patients receiving TDF with evidence of
an
toxicity. In this cross-sectional study involving 99 patients, there was no association between NAG levels and exposure to TDF and tubular damage (72). Although the evidence for use of
M
urinary RBP/Cr to detect TDF kidney toxicity was weak, this marker was widely used in studies to demonstrate that a new prodrug of tenofovir, tenofovir alefanamide, does not
ed
induce tubular damage (25).
Neutrophil-associated gelatinase lipocalin (NGAL) was also evaluated to detect TDF-kidney
ce pt
tubular damage. In a cohort of 40 patients (20 receiving TDF/emtricitabine, and 20 receiving abacavir/lamivudine) with normal GFR, plasma NGAL and urinary NGAL were higher in patients receiving abacavir/lamivudine (73). Likewise, in a cohort of 132 women initiating an antiretroviral regimen, there was no difference for urinary NGAL and NAG levels between
Ac
Downloaded by [Australian Catholic University] at 06:10 13 September 2017
In patients receiving TDF, urinary retinol-binding protein to creatinine ratio (RBP/Cr) was
exposed- and unexposed-to TDF women (74). In this study, ß2 microglobulin levels were associated with TDF exposure (74). Although ß2-microglobulin, α-1 microglobulin and
urinary cystatin C may help clinicians to detect TDF-associated tubular damage early, simple tools are available to prevent TDF renal toxicity (75). Dose adjustment is possible and can improve renal function (76). A score to predict 5-year risk of CKD was developed in the D:A:D study and both traditional risk factors for CKD and antiretroviral regimens were
considered (28). Moreover, identifying specific genetic polymorphisms of drug transporters associated with accumulation of tenofovir in tubular cells is possible (75). However, widespread use of tenofovir alafenamide (TAF) will be associated with fewer tubular diseases in PLWH (25). Currently, renal safety of antiretrovirals is often assessed using kidney biomarker
ip t
measurements in clinical trials (77). The most often used biomarkers are urine
cr
recent antiretrovirals like dolutegravir, and ART combinations including tenofovir
us
alefanamide (78–82). ß2-microglobulin and RBP are also used to assess renal safety of 12-
an
week ledipasvir/sofosbuvir in HCV infection treatment in PLWH receiving different ART combinations with a emtricitabine and tenofovir disoproxil fumarate backbone associated
M
with raltegravir or efavirenz or rilpivirine (83).
6.2 Biomarkers to predict GFR decline or CKD in PLWH
ed
Several studies have evaluated a potential association between emergent biomarkers and CKD development in PLWH (46,66,84–86). They are shown in Table 4. Most of them used as
ce pt
primary outcomes the decrease in estimated GFR (eGFR), and/or the appearance of albuminuria. Consequently, due to the limits of eGFR and albuminuria in PLWH, their results must be considered with caution. However, some results are interesting and some biomarkers promising. Kidney biomarkers (mainly urinary α-1 microglobulin, KIM-1, IL-18) may help
Ac
Downloaded by [Australian Catholic University] at 06:10 13 September 2017
albumin/creatinine ratio, urine protein ratio, ß2microglobulin, RBP, and NAG, particularly for
clinicians to predict incident CKD in PLWH, but the published studies were carried out in American women (mainly African American) and in Japan (mainly men receiving HAART). Consequently, it is difficult to generalize these data in resource-limited settings like Africa, and in Caucasian PLWH. In addition to kidney biomarkers, measuring inflammation status in PLWH may predict decrease in GFR. In addition to kidney biomarkers, Abraham et al. measured in 434 HIV-infected and 200 HIV-uninfected men, a large set of biomarkers of
inflammation (88). Kidney outcomes were defined by GFR measurement by Iohexol plasma clearance, and progression of U P/Cr ratio. Five inflammatory biomarkers were clearly associated with kidney outcomes in HIV-infected men: soluble Tumor Necrosis Factor-2, Soluble Interleukin-2 receptor, soluble glycoprotein 130, soluble CD27, and soluble CD14
ip t
(88).
cr
us
Estimating the cardiovascular risk of PLWH is challenging. Kidney biomarkers were evaluated using as judgement criteria: incidence of cardiovascular events, and/or association
an
with surrogate markers of cardiovascular risk. Main surrogate markers used in PLWH are measurement of Intima Media Thickness (IMT) by carotid ultrasound, measurements of
M
coronary artery calcium, and computed tomography angiography by cardiac tomography (89).
alternative (89).
ed
Measurement of arterial inflammation by 18-FDG Positron Emission Tomography is an
ce pt
In the general population, plasma asymmetric dimethylarginine (ADMA) may predict cardiovascular events (90) whereas in PLWH, results are discordant. Two studies evaluated association of ADMA with surrogate markers of cardiovascular risk. An association between ADMA levels and coronary artery calcium score was observed in 37 PLWH. This association
Ac
Downloaded by [Australian Catholic University] at 06:10 13 September 2017
6.3 Renal biomarkers to predict cardiovascular events in PLWH
was not confirmed in 100 PLWH (50 treated, 50 untreated), although ADMA levels were significantly greater in PLWH than in uninfected controls. In this latter study, other surrogate markers were used as IMT, myocardial perfusion defects, and Framingham 10-year risk. No association was identified between these markers and ADMA. In untreated PLWH, ADMA was associated with low CD4 count, HIV viral load and inflammation assessed with sCD14 and D-Dimers (91). These associations were not observed in treated PLWH.
FGF23, Fibroblast growth factor-23, is increased in early CKD, and is associated with cardiovascular events in the general population (92); this association is independent of cardiovascular risk factors. Higher levels of FGF-23 and lower levels of osteocalcin were associated with a 10-Year cardiovascular risk > 20 % in a cohort of 51 PLWH (93). FGF23 was evaluated in a larger study -191 PLWH and 100 HIV-uninfected controls- (94); this
ip t
cohort was followed for 3 years, GFR was measured every year by Iohexol plasma clearance,
cr
IMT at 24 months of follow-up. No difference was observed for FGF23 between PLWH and
us
controls at baseline. Higher FGF23 levels at baseline were associated with increase in IMT and progression of albuminuria (94). Higher FGF23 levels at baseline were associated in
an
PLWH with female gender, unsuppressed HIV viral load, HCV co-infection, and serum phosphorus (94). This cohort was predominantly African-American (96%), the proportion of
ed
(94).
M
HCV co-infection in PLWH was large (46%), 41 % of PLWH were current cocaine users
NAG, KIM-1, urinary IL-18, NGAL, L-FABP, α-1-microglobulin, and α-1-glycoprotein were
ce pt
evaluated in PLWH to predict incident hypertension, this study included 823 HIV-infected, and 247 HIV-uninfected women (95). Whereas an association was observed between these biomarkers and incident hypertension in HIV-uninfected women, no association was observed in HIV-infected women. Only baseline uACR, and eGFR cys were associated with incident
Ac
Downloaded by [Australian Catholic University] at 06:10 13 September 2017
and primary outcomes were the progression in albuminuria and increase in internal carotid
hypertension in HIV-infected women, median follow-up was 9.6 years (95). Studies evaluating kidney biomarkers to predict cardiovascular events or risk are limited, studies with incident cardiovascular events as primary outcomes are required. Moreover, studies in other cohorts are needed as published studies included a large proportion of African-American and women in the USA.
6.4 Renal biomarkers to predict mortality in PLWH. Renal biomarkers were evaluated in prediction of mortality in the Women’s Interagency HIV study (WIHS). In a first study, the association of urinary IL-18, NGAL, KIM-1, L-FABP, and uACR levels in 908 HIV-infected women and 10-year all-cause mortality was assessed (96). In multivariate analysis, only the highest IL-18 and uACR tertiles were associated with
ip t
mortality (96). The highest tertile of IL-18 was associated with a 2-fold risk of death during
cr
biomarkers of tubular injury might be associated with mortality in HIV-infected women (96).
us
Moreover, women with several biomarkers in the highest tertiles had a significantly greater risk of death during the follow-up period (96). After this first observation, the authors
an
hypothesized that a combination of biomarkers could improve prediction of all-cause
M
mortality in PLWH. Eight biomarkers were measured at baseline in 902 HIV-infected women: urinary IL-18, NGAL, KIM-1, NAG, α-1-microglobulin, ACR, L-FABP, α-1-acid-
ed
glycoprotein (66). Median follow-up time was 7.9 years, and primary outcomes were incident CKD defined by an eGFR-CKD-EPI-cys
ISSN: 1478-7210 (Print) 1744-8336 (Online) Journal homepage: http://www.tandfonline.com/loi/ierz20
Diagnostic challenges of kidney diseases in HIVinfected patients Robin Chazot, Elisabeth Botelho-Nevers, Anne Frésard, Nicolas Maillard, Christophe Mariat, Frédéric Lucht & Amandine Gagneux-Brunon To cite this article: Robin Chazot, Elisabeth Botelho-Nevers, Anne Frésard, Nicolas Maillard, Christophe Mariat, Frédéric Lucht & Amandine Gagneux-Brunon (2017): Diagnostic challenges of kidney diseases in HIV-infected patients, Expert Review of Anti-infective Therapy, DOI: 10.1080/14787210.2017.1379395 To link to this article: http://dx.doi.org/10.1080/14787210.2017.1379395
Accepted author version posted online: 12 Sep 2017.
Submit your article to this journal
View related articles
View Crossmark data
Full Terms & Conditions of access and use can be found at http://www.tandfonline.com/action/journalInformation?journalCode=ierz20 Download by: [Australian Catholic University]
Date: 13 September 2017, At: 06:10
Review Diagnostic challenges of kidney diseases in HIV-infected patients Robin Chazot1, Elisabeth Botelho-Nevers2,3, Anne Frésard2,3, Nicolas Maillard 1,3, Christophe Mariat1,3, Frédéric Lucht2,3, *Amandine Gagneux-Brunon2,3 Department of Nephrology, Dialysis, Transplantation and Hypertension, University Hospital
ip t
1
Department of Infectious and Tropical Diseases, University Hospital of Saint-Etienne,
cr
2
GIMAP Groupe Immunité des Muqueuses et Agents Pathogènes, EA 3064, University Jean
*Corresponding author:
M
Monnet, University of Lyon, France
an
3
us
France
ed
Amandine Gagneux-Brunon
Department of Infectious and Tropical diseases, University Hospital of Saint-Etienne, 55
ce pt
avenue Albert Raimond, 42055 Saint-Etienne cedex 2 France, Groupe Immunité des Muqueuses et Agents Pathogènes, Université Jean Monnet, Université de Lyon, SaintEtienne, France
Email: [email protected]
Ac
Downloaded by [Australian Catholic University] at 06:10 13 September 2017
of Saint-Etienne, France
Abstract: Introduction: Chronic kidney disease (CKD) is a prevalent comorbidity in persons living with HIV infection (PLWH) associated with an increase in cardiovascular morbidity and all-cause mortality. Furthermore, early diagnosis of CKD is difficult in PLWH.
ip t
Areas covered: We reviewed the main diagnostic tools for CKD in PLWH, and discussed their strengths and limits. We performed a literature search on Pubmed to identify reviews
cr
us
following key words: “HIV AND kidney”, “HIV AND Kidney biomarkers”, “CKD AND Kidney biomarkers”.
an
Expert commentary: Currently, CKD diagnosis is based on the estimation of Glomerular Filtration Rate (GFR), and measurement of proteinuria by urine protein/creatinine ratio
M
(uPCR). These parameters are independent and complementary predictors of outcomes. GFR estimates are lacking in accuracy in PLWH. The best GFR estimate is CKD-EPI study
ed
equation. Moreover, low-grade proteinuria is associated with an increased risk of kidney disease progression in PLWH, and guidelines derived from the general population may lack
ce pt
sensitivity. Different biomarkers of kidney diseases like N-acetyl beta glucosaminidase (NAG), Kidney Injury Molecule-1 (KIM-1), and Alpha-1-microglobulin may predict kidney disease progression and mortality in PLWH. Others may help clinicians detect antiretroviralinduced tubulopathy, or predict cardiovascular events. More studies are needed to validate the
Ac
Downloaded by [Australian Catholic University] at 06:10 13 September 2017
and clinical trials dealing with attractive kidney biomarkers of CKD in PLWH, with the
routine use of these types of biomarkers.
Key-words: HIV, Kidney, Biomarkers, Glomerular Filtration Rate, Chronic Kidney Disease
1.
Introduction
Antiretroviral therapies (ART) have dramatically reduced mortality due to HIV-infection and so HIV infection has turned into a long-term chronic illness for many patients. Thus,the prevention and treatment of comorbidities have come to the forefront of the care of persons living with HIV infection (PLWH). It was estimated, in the national Dutch ATHENA cohort,
ip t
that in 2030, around a third of HIV-infected patients will have at least 3 comorbidities (1).
cr
communicable comorbidities than HIV-uninfected controls (2). Among these comorbidities,
us
chronic kidney disease (CKD) is significantly more prevalent in PLWH than in HIV-
an
uninfected individuals (2). The prevalence of CKD in HIV-infected patients ranges from 1 to 48% among different cohorts, the greatest prevalence being observed among Black Africans
M
(3). CKD is associated with poor outcomes in PLWH. Deterioration in renal function in HIVinfected patients (i.e decrease in estimated glomerular filtration rate (GFR)) is associated with
ed
an increase in mortality and morbidity in HIV-infected patients due to AIDS and non-AIDS events (4). Moreover, patients with CKD were less likely to receive ART than patients
ce pt
without CKD; these observations highlight the difficulty of treating patients with CKD (5). Here, after a short overview of the spectrum of kidney diseases in PLWH, CKD classification and limits of currently used markers of CKD, we will discuss emerging biomarkers of CKD. 2.
Spectrum of kidney diseases in HIV-infected patients
Ac
Downloaded by [Australian Catholic University] at 06:10 13 September 2017
HIV-infected patients had a significantly higher mean number of age-associated non-
HIV-infected individuals may suffer from specific kidney diseases and as summarized in Table 1. In fact the kidney represents a reservoir for HIV (6,7) and in this population, kidney diseases could be related to ART- side-effects and non-HIV-related kidney diseases (lipid level, hypertension, diabetes, hepatitis C coinfection). HIV-associated nephropathy (HIVAN) was first described in 1984 by Rao et al. (8). HIVAN results in a collapse of glomerular
capillaries, visceral glomerular epitheliosis, podocyte hypertrophy and proliferation, mesangial prominence and hypercellularity, endothelial tubuloreticular inclusions (TRIs) on ultrastructural examination and microcystic tubules in patients infected by HIV (8). HIVAN may lead to a glomerular syndrome with high-grade proteinuria and rapid progression to endstage renal disease (ESRD) (9), HIV infected patients with biopsy-proven HIVAN were more
ip t
likely to require dialysis than patients with alternative diagnoses (10). ART use has improved
cr
decrease in the incidence of HIVAN (12). After the description of HIVAN, HIV-immune
us
complex disease (HIVICD) was described. These lesions are secondary to the polyclonal expansion of immunoglobulins in HIV chronic infection, which results in the deposit of
an
immune complexes in renal capillaries (13). Since both diseases affect more black people, HIVAN is associated with a low CD4 positive cells count, and results in a faster decrease in
M
GFR. HIV-infected patients suffering from HIVICD were more often exposed to
ed
antiretrovirals, had lower HIV viral loads, and greater CD4 cell positive count than patients suffering from HIVAN (14). ART use significantly reduced the incidence of HIVAN and
ce pt
reduced the risk of HIVAN by 60 % (12). Lescure et al show that HIVAN affects younger patients with severe immunodeficiency unlike classic focal and segmental glomerular sclerosis (FSGS) that affects older patients with a long history of ART and a higher cardiovascular risk (9). Classic FSGS is characterized by the presence of at least one segmental capillary wall collapse and/or segmental sclerosing lesion without podocyte
Ac
Downloaded by [Australian Catholic University] at 06:10 13 September 2017
the prognosis of HIVAN (11) and a wider implementation of ART is associated with a
hyperplasia or glomerular collapse (9). With better control of HIV replication, ART-induced tubulopathy and interstitial nephritis have become important kidney complications in PLWH, with the highest prevalence of tubulopathy in patients receiving tenofovir disoproxil fumarate (TDF) and crystal nephropathy with atazanavir and indinavir (12). Considering TDF, TDF exposure is associated with tubular damage and less frequently with glomerular diseases (16).
Kidney tubular damage affects around 22 % of the patients (17) in the absence of impaired GFR. The risk of tubulopathy depends on tenofovir plasma concentrations (18). Tenofovir accumulates in tubular cells; this accumulation is responsible for tubular damage, and may be facilitated by interactions with drug transporters at the surface of tubular cells (Figure 1). Different genotypes for drug transporters are associated with tenofovir accumulation in
ip t
tubular cells, and consequently with a higher rate of kidney tubular damage (19–21).
cr
accumulation in tubular cells (22). Decline in GFR due to TDF exposure is incompletely
us
reversible after TDF cessation (23). Tenofovir alafenamide (TAF) was developed to reduce renal and bone side-effects of TDF; greater intracellular concentrations in lymphoid cells are
an
achieved whereas tenofovir plasma concentrations are 90 % lower than with TDF (24), and consequently tenofovir is less likely to accumulate in tubular cells. In clinical trials, TAF was
M
not responsible for GFR decrease and was associated with a decrease in tubular biomarker
ed
levels in urine (25,26). Other recent antiretrovirals (dolutegravir, etravirine, rilpivirine, elvitegravir) are widely implemented whereas their renal effects remain little known. In the
ce pt
D:A:D study cohort, use of indinavir, atazanavir and TDF were associated with an increased risk of CKD (27). There are no prospective studies evaluating the impact of HAART regimen on the prevention of CKD.
Whatever the type of lesion, different risk factors for the development of CKD were described in HIV-infected patients including HIV-specific and non-specific risk factors. Particularly in
Ac
Downloaded by [Australian Catholic University] at 06:10 13 September 2017
Concomitant use of ritonavir-boosted protease inhibitors are associated with tenofovir
the D:A:D study cohort (28), intravenous drug use, hepatitis C co-infection, older age, lower baseline eGFR, female gender, lower CD4 count nadir, hypertension, diabetes, and prior
cardiovascular diseases were found to be associated with CKD. A risk score for CKD development was derived from this cohort (28). In the score developed from the D:A:D study
cohort, it is possible to integrate the ART regimen received by a patient to estimate the 5-year risk of GFR reduction under 60 mL/min/1.73m2 (28). As well as these risk factors, with improved survival and long-term ART use, comorbidities with kidney involvement such as diabetes and hypertension (29) are becoming more prevalent in the HIV-infected population (5). Diabetic nephropathy is one of the leading causes of other
ip t
glomerular diseases in PLWH. The risk of a decrease in GFR was greater in patients with
cr
suggests an additive effect between HIV-infection and diabetes to lead to CKD (30).
us
Furthermore, in HIV-infected intravenous drug users, frequent infections may increase the
an
risk of developing amyloidosis (31).
Moreover, HCV co-infection affects around 6% of HIV-infected patients worldwide (32).
M
HCV infection may result in kidney damage, particularly in HIV-infected patients (33), not only just in patients experiencing cryoglobulinemia. The risk of CKD is higher in HIV-
ed
infected patients with chronic HCV infection and persisting viremia than in patients with
ce pt
cleared infection (34).
Acquired immunodeficiency syndrome is associated with an increased risk of AKI in HIVinfected hospitalized patients (35), particularly in patients receiving nephrotoxic drugs (like aminoglycosides, amphotericine B, vancomycin, acyclovir, gancyclovir and foscarnet) for the treatment of opportunistic infections (cryptococcal meningitis, Cytomegalovirus reactivation)
Ac
Downloaded by [Australian Catholic University] at 06:10 13 September 2017
HIV-infection and diabetes, than in patients with HIV infection only or diabetes only; this
and/or comorbidities (35). In the general population, AKI is associated with an increased risk of developing CKD in the future (36).
3.
Different CKD classifications in HIV-infected patients (Tables 2)
CKD is defined by structural or functional kidney abnormalities, present for > 3 months. As CKD is highly prevalent in PLWH and is associated with morbidity, guidelines for the management of CKD in PLWH are necessary. GFR and albuminuria are recommended to detect and stage CKD in the general population (37) and in PLWH (38–40). The use of GFR
ip t
estimating equations based on serum creatinine is recommended in PLWH, in particular the
cr
Diseases Society of America (IDSA) published guidelines for CKD screening in HIV-infected
us
patients, with assessment every 6 months for patients with proteinuria using urinary protein/creatinine ratio (uPCR in mg/g), or urinary albumin/creatinine ratio (uACR in mg/g)
an
and estimation of GFR. These guidelines were updated in 2014 (38). In this update, a classification of CKD was adapted from the Kidney Disease Improving Global Outcomes
M
guidelines (KDIGO) (37). KDIGO have developed a classification with risk categories based
ed
on GFR and albuminuria; these categories were obtained from different meta-analyses in the general population, which evaluate the risk of End Stage Renal Disease, all-cause mortality,
ce pt
and cardiovascular mortality (41). This classification is based on both GFR and proteinuria levels, as both GFR and albuminuria are independent and complementary risk predictors of clinical outcomes (38): CKD progression, end-stage renal disease, cardiovascular mortality, all-cause mortality.
Ac
Downloaded by [Australian Catholic University] at 06:10 13 September 2017
equation developed in 2009 by CKD-EPI study collaboration (38,39). In 2005, the Infectious
Since the publication of the IDSA guidelines, the European AIDS Clinical Society (EACS) has also developed a CKD classification with risk categories (39). This classification is also based on GFR and proteinuria categories. However, the values of proteinuria are higher than in the IDSA guidelines and consequently the sensitivity of this classification is probably lower than that of the IDSA classification. In contrast with IDSA and EACS guidelines,
French guidelines only considered GFR (40). However, patients with a normal GFR and proteinuria are considered to have a CKD stage 1. Different issues must be discussed concerning the use of these different guidelines in PLWH. First, IDSA and EACS recommend the use of the CKD-EPI study equation based on serum creatinine for GFR estimation, whereas French guidelines recommend the use of the MDRD
ip t
equation (38–40). Secondly, the predictive performance of these different guidelines was not
cr
albuminuria for CKD detection in PLWH. Thirdly, discrepancies between these different
us
guidelines may result in differences in risk perception for the same patient. For example, a patient with an eGFR at 65 mL/min/1.73m2 and proteinuria measured at 200 mg/g will be
an
considered at low risk according to EACS guidelines, at intermediate risk according to IDSA
M
guidelines, and at high risk according to the French guidelines.
4.
ed
The high prevalence of tubular damage in PLWH limits the accuracy of GFR and
urinary albumin-to-creatinine ratio (uACR) in the detection of kidney diseases at early
ce pt
stages.
The overall prevalence of end-stage renal disease (ESRD) requiring renal replacement therapy (RRT) in persons living with HIV infection (PLWH) in Europe was evaluated at 0.46 % (42). It is widely accepted that for one patient with ESRD, around 10 to 1 000 individuals exhibit
Ac
Downloaded by [Australian Catholic University] at 06:10 13 September 2017
specifically evaluated in PLWH. In the next part, we will discuss the pertinence of
earlier stages of chronic kidney diseases and therefore early diagnosis of CKD is crucial. However, serum creatinine is an imperfect marker of GFR, particularly in PLWH, and in the elderly (43,44). The glomerular capillary wall hinders the passage of large serum proteins such as albumin. Consequently, detection of albuminuria is often associated with glomerular
damage. CKD classification in the general population and in PLWH considers that a threshold of 30 mg/g for uACR as pathologic (37,38). However, in PLWH, a large proportion of
patients develop tubular damage, which can be misdiagnosed using only uACR. Moreover, in a prospective cohort of 429 PLWH, Ando et al. observed that an increase in urinary albumin excretion, although it remained within the normal range, was associated with an increase in the risk of developing kidney disease (45). Using low molecular weight proteins as markers of tubular dysfunction, they also observed that 25 % of the PLWH (without microalbuminuria
ip t
and with normal GFR at baseline) had subclinical tubular damage, associated with a decrease
cr
cohort, 55 % of the PLWH had low grade proteinuria, and tubular low grade proteinuria
us
(uPCR>70 mg/g) was identified in 41 % of the PLWH (47). Using recommended thresholds for uPCR and uACR, prevalence of proteinuria in PLWH was 18.2 % (9 % tubular, and 9.2 %
an
glomerular proteinuria) in a French cohort (48). Consequently, the use of urine dipsticks, which mainly detect albumin, is not appropriate in PLWH and assessment of uPCR and
M
uACR is encouraged in this population (38,39). Due to the high prevalence of non glomerular
ed
proteinuria, and the associated risk of developing a decrease in GFR with low grade proteinuria (45), from our point of view uPCR and uACR thresholds might be adapted to
ce pt
PLWH, and alternative markers to detect tubular damage in PLWH might be evaluated in this particular population. However, larger studies are needed to evaluate the impact of decreased albuminuria and proteinuria thresholds in PLWH for earlier detection of CKD in PLWH. 5.
Difficulties in GFR estimates in PLWH
Ac
Downloaded by [Australian Catholic University] at 06:10 13 September 2017
in GFR and the development of microalbuminuria during the follow-up (46). In another
Assessment of GFR is useful to detect CKD, to monitor CKD progression, to refer to nephrologists, to predict the risk of cardiovascular events, and for drug dosing adjustment (49). In the general population, GFR can be estimated using endogenous biomarkers, mainly serum creatinine. Cystatin C can be used to estimate GFR as an alternative to serum creatinine and/or as a confirmatory test when a CKD is suspected (37). Cystatin C is a biomarker produced by all nucleated cells, filtered by glomerulus and completely reabsorbed in tubules
(44). GFR can also be measured by urinary or plasma clearance of exogenous markers like inulin, iothalamate, iohexol, and
51
Cr-EDTA, and diethylene triamine pentaaceticacid (49);
these methods are considered as gold standards (50) and are used to evaluate the accuracy of GFR estimates. However, measurement of GFR remains difficult in routine clinical practice (49).
ip t
Considering GFR estimates with endogenous markers, serum creatinine and cystatin C levels
cr
tubular secretion of these biomarkers might be highly variable. On the one hand, in HIV-
us
infected patients, decrease in lean mass, high prevalence of liver disease, and malnutrition are associated with a decrease in serum creatinine (44). On the another hand, some medications
an
such as trimethoprim (51), dolutegravir, rilpivirine, cobicistat and raltegravir (52,53) are associated with an increase in serum creatinine that is due not to a GFR decrease, but to an
M
interaction with tubular drug transporters, resulting in a reduction of tubular secretion of
ed
serum creatinine (54). In this context of inhibition of tubular secretion of creatinine, the rise in serum creatinine appears shortly after the start of the antiretroviral, remains non progressive
ce pt
and is not associated with proteinuria or hypertension (52). Serum cystatin C might, in such cases, be an alternative to serum creatinine in PLWH, but some limitations should be addressed.
The impact of inflammation level, HIV viral load, age, and tobacco use on concentrations of cystatin C levels remains unclear (44). Different studies have evaluated the performance of
Ac
Downloaded by [Australian Catholic University] at 06:10 13 September 2017
are not only affected by GFR: the level of generation of these biomarkers and/or the level of
GFR estimates in PLWH using serum creatinine, and serum cystatin C to detect CKD in comparison with GFR measurements. The main studies are shown in Table 3 (55–57).The best indicator of performance is accuracy, and it is estimated by the proportion of eGFR values within ± 30 % of the measured GFR. Results of these studies are difficult to compare because the populations are different (ethnicity, body composition, proportion of patients
receiving ART). Globally, CKD-EPI based on serum creatinine (CKD-EPI cr) exhibited acceptable performances while MDRD and/or Cockcroft and Gault (CG) equations were less accurate. These observations resulted in the recommendations to use preferentially CKD-EPI cr in PLWH in the USA (58) and in Europe (39). However, these studies included few patients with decreased GFR and performance of GFR estimates are probably influenced by
ip t
the level of GFR with greater bias and lower accuracy in patients with lower GFR (55–57). In
cr
whereas this corrective coefficient should not be used in black people in Europe, mainly
us
African migrants (59).
GFR estimates were also evaluated to predict cardiovascular events and mortality in PLWH.
an
In 908 women (mean age at baseline 41 years old, mainly black people, 31 % with undetectable viral load), Driver et al. observed that estimating GFR with the CKD-EPI based
M
on serum cystatin C (CKD-EPI cys) equation was a better predictor of all-cause mortality than
ed
estimating GFR with the CKD-EPI cr equation (60). Lucas et al. observed in 4614 participants of the SMART study that CKD-EPI cys had a stronger association with
ce pt
cardiovascular events and opportunistic infections than CKD-EPI cr, and CKD-EPI cys-cr after adjustment for age, HIV viral load, CRP levels, Nadir CD4 count, CD4 count (61). Mean age at baseline was 44 years, 27 % of the participants were black, CD4 count at baseline was 602 and 82.8 % of the patients received ART at baseline (61). Yanagisawa et al. evaluated the impact of using CKD-EPI cys compared to CKD-EPI cr equation on GFR classification
Ac
Downloaded by [Australian Catholic University] at 06:10 13 September 2017
the USA, CKD-EPI should be used with the African-American coefficient in black people,
proposed by IDSA in 601 Japanese patients (90 % receiving ART, mean age 46 years old ± 11.6) in prediction of a composite outcome including all-cause mortality, cardiovascular events, and renal dysfunction (62). Patients classified at risk (orange category in IDSA classification) with CKD-EPI cys had a significantly greater risk of composite outcome, this association was not observed with CKD-EPI cr (62). All these observations are in favor of the
use of CKD-EPI cys to predict mortality and cardiovascular events in PLWH. Two studies evaluated the performance of GFR estimates for drug dosing in PLWH. The performance is measured by the concordance between GFR estimates and GFR measurement to correctly classify patients with a GFR greater or lower than the limits for drug dosing adjustment. The different thresholds used depend on the medications to adjust to renal
ip t
function. Historically, drug dosing was carried out with CG equation expressed in mL/min.
cr
mL/min ± 26, with 52 % of African Americans) that CKD-EPI converted to mL/min had a
us
greater concordance with mGFR than CG, and MDRD (63). In a French cohort of 230 patients (mean age 48 ± 10 years, 84 % with undetectable viral load, 7% Africans), we
an
observed that CKD-EPI was as concordant as CG, whereas MDRD was less concordant (64). No study evaluated estimates based on serum cystatin C for drug dosing purposes.
M
Consequently, CKD-EPI cr is useful for CKD detection and drug dosing and CKD-EPI cys
Are there biomarkers for early detection of kidney injury in PLWH?
ce pt
6.
ed
provides additional information to predict adverse outcomes in PLWH.
A biomarker is a parameter of structural, biochemical, physiological or genetic changes associated with the presence, the severity and the progression of a disease (65). An ideal biomarker should be obtained by a highly sensitive and highly specific non-invasive
Ac
Downloaded by [Australian Catholic University] at 06:10 13 September 2017
Okparavero et al. observed in 200 PLWH (61 % with undetectable viral load, mean mGFR 87
procedure; it should increase shortly after the start of injury, correlate with disease severity, predict outcome; be applicable across different populations, be site specific, stable, reflect
efficacy of therapeutical interventions and normalize after injury cessation. We can distinguish two types of new biomarkers of renal function: biomarkers for acute kidney injury (AKI), and biomarkers for CKD (65). During AKI, the aims of these biomarkers are to detect kidney injury early (before traditional markers such as oliguria and increased serum
creatinine), to obtain a prognosis and information about AKI severity, and to differentiate the different etiologies of AKI. In CKD, emergent biomarkers can help to detect abnormalities early, to predict cardiovascular diseases associated with CKD, and progression of CKD (65). The development of proteomics, and transcriptomics results in the discovery of new biomarkers. Different types of biomarkers have been developed and evaluated in the fields of
ip t
AKI or CKD. Most of them were developed for early diagnosis of AKI. However, in PLWH,
cr
for early diagnosis of chronic tubular defects. Consequently, markers derived from the field of
us
AKI were evaluated in PLWH to predict CKD, and all-cause mortality in PLWH (66). These
an
biomarkers are summarized in Table 5.
6.1 Biomarkers to detect kidney toxicity of antiretrovirals
M
Among current antiretrovirals, exposures to TDF, ritonavir-boosted lopinavir and ritonavirboosted atazanavir are associated with a greater risk of CKD development in PLWH (27).
ed
TDF-associated kidney toxicity is well understood with accumulation of TDF in tubular cells causing mitochondrial deaths (67) resulting in Fanconi syndromes, AKI and subclinical
ce pt
tubular toxicity causing long-term decrease in kidney function. Several biomarkers were evaluated to detect tubular toxicity of TDF. In 37 patients with suspected Fanconi syndrome, Jaafar et al. tested the diagnostic performance of urinary cystatin C to urinary creatinine ratio, and positive and negative
Ac
Downloaded by [Australian Catholic University] at 06:10 13 September 2017
the great prevalence of tubular diseases leads us to consider markers of tubular dysfunction
predictive values respectively were 76.9 % and 95.8 % at a threshold of 14 µg/mmol (68). Another kidney biomarker, Alpha gluthatione S transferase was not associated with kidney tubular damage in patients receiving TDF (69). In a study of 190 patients receiving TDF (19 with kidney tubular dysfunction, and 171 without), areas under the Receiver operating characteristics curves were 0.970, 0.968 and 0.901 for ß2-microglobulin, α-1 microglobulin,
and N-acetyl beta glucosaminidase (NAG), respectively (70). In a recent study in 883 HIVinfected men compared with 350 HIV-uninfected men, α-1 microglobulin was detectable in the urine of 83 % of HIV-infected patients and in 58 % of HIV-uninfected men, the level of α1 microglobulin was higher in current users of TDF, and decreased after TDF cessation (71). It is probable that α-1 microglobulin can be a useful biomarker to detect kidney tubular
ip t
damage in PLWH.
cr
higher than in patients not receiving TDF (72). Moreover, patients with evidence of severe
us
TDF toxicity had significantly higher RBP/Cr than patients receiving TDF with evidence of
an
toxicity. In this cross-sectional study involving 99 patients, there was no association between NAG levels and exposure to TDF and tubular damage (72). Although the evidence for use of
M
urinary RBP/Cr to detect TDF kidney toxicity was weak, this marker was widely used in studies to demonstrate that a new prodrug of tenofovir, tenofovir alefanamide, does not
ed
induce tubular damage (25).
Neutrophil-associated gelatinase lipocalin (NGAL) was also evaluated to detect TDF-kidney
ce pt
tubular damage. In a cohort of 40 patients (20 receiving TDF/emtricitabine, and 20 receiving abacavir/lamivudine) with normal GFR, plasma NGAL and urinary NGAL were higher in patients receiving abacavir/lamivudine (73). Likewise, in a cohort of 132 women initiating an antiretroviral regimen, there was no difference for urinary NGAL and NAG levels between
Ac
Downloaded by [Australian Catholic University] at 06:10 13 September 2017
In patients receiving TDF, urinary retinol-binding protein to creatinine ratio (RBP/Cr) was
exposed- and unexposed-to TDF women (74). In this study, ß2 microglobulin levels were associated with TDF exposure (74). Although ß2-microglobulin, α-1 microglobulin and
urinary cystatin C may help clinicians to detect TDF-associated tubular damage early, simple tools are available to prevent TDF renal toxicity (75). Dose adjustment is possible and can improve renal function (76). A score to predict 5-year risk of CKD was developed in the D:A:D study and both traditional risk factors for CKD and antiretroviral regimens were
considered (28). Moreover, identifying specific genetic polymorphisms of drug transporters associated with accumulation of tenofovir in tubular cells is possible (75). However, widespread use of tenofovir alafenamide (TAF) will be associated with fewer tubular diseases in PLWH (25). Currently, renal safety of antiretrovirals is often assessed using kidney biomarker
ip t
measurements in clinical trials (77). The most often used biomarkers are urine
cr
recent antiretrovirals like dolutegravir, and ART combinations including tenofovir
us
alefanamide (78–82). ß2-microglobulin and RBP are also used to assess renal safety of 12-
an
week ledipasvir/sofosbuvir in HCV infection treatment in PLWH receiving different ART combinations with a emtricitabine and tenofovir disoproxil fumarate backbone associated
M
with raltegravir or efavirenz or rilpivirine (83).
6.2 Biomarkers to predict GFR decline or CKD in PLWH
ed
Several studies have evaluated a potential association between emergent biomarkers and CKD development in PLWH (46,66,84–86). They are shown in Table 4. Most of them used as
ce pt
primary outcomes the decrease in estimated GFR (eGFR), and/or the appearance of albuminuria. Consequently, due to the limits of eGFR and albuminuria in PLWH, their results must be considered with caution. However, some results are interesting and some biomarkers promising. Kidney biomarkers (mainly urinary α-1 microglobulin, KIM-1, IL-18) may help
Ac
Downloaded by [Australian Catholic University] at 06:10 13 September 2017
albumin/creatinine ratio, urine protein ratio, ß2microglobulin, RBP, and NAG, particularly for
clinicians to predict incident CKD in PLWH, but the published studies were carried out in American women (mainly African American) and in Japan (mainly men receiving HAART). Consequently, it is difficult to generalize these data in resource-limited settings like Africa, and in Caucasian PLWH. In addition to kidney biomarkers, measuring inflammation status in PLWH may predict decrease in GFR. In addition to kidney biomarkers, Abraham et al. measured in 434 HIV-infected and 200 HIV-uninfected men, a large set of biomarkers of
inflammation (88). Kidney outcomes were defined by GFR measurement by Iohexol plasma clearance, and progression of U P/Cr ratio. Five inflammatory biomarkers were clearly associated with kidney outcomes in HIV-infected men: soluble Tumor Necrosis Factor-2, Soluble Interleukin-2 receptor, soluble glycoprotein 130, soluble CD27, and soluble CD14
ip t
(88).
cr
us
Estimating the cardiovascular risk of PLWH is challenging. Kidney biomarkers were evaluated using as judgement criteria: incidence of cardiovascular events, and/or association
an
with surrogate markers of cardiovascular risk. Main surrogate markers used in PLWH are measurement of Intima Media Thickness (IMT) by carotid ultrasound, measurements of
M
coronary artery calcium, and computed tomography angiography by cardiac tomography (89).
alternative (89).
ed
Measurement of arterial inflammation by 18-FDG Positron Emission Tomography is an
ce pt
In the general population, plasma asymmetric dimethylarginine (ADMA) may predict cardiovascular events (90) whereas in PLWH, results are discordant. Two studies evaluated association of ADMA with surrogate markers of cardiovascular risk. An association between ADMA levels and coronary artery calcium score was observed in 37 PLWH. This association
Ac
Downloaded by [Australian Catholic University] at 06:10 13 September 2017
6.3 Renal biomarkers to predict cardiovascular events in PLWH
was not confirmed in 100 PLWH (50 treated, 50 untreated), although ADMA levels were significantly greater in PLWH than in uninfected controls. In this latter study, other surrogate markers were used as IMT, myocardial perfusion defects, and Framingham 10-year risk. No association was identified between these markers and ADMA. In untreated PLWH, ADMA was associated with low CD4 count, HIV viral load and inflammation assessed with sCD14 and D-Dimers (91). These associations were not observed in treated PLWH.
FGF23, Fibroblast growth factor-23, is increased in early CKD, and is associated with cardiovascular events in the general population (92); this association is independent of cardiovascular risk factors. Higher levels of FGF-23 and lower levels of osteocalcin were associated with a 10-Year cardiovascular risk > 20 % in a cohort of 51 PLWH (93). FGF23 was evaluated in a larger study -191 PLWH and 100 HIV-uninfected controls- (94); this
ip t
cohort was followed for 3 years, GFR was measured every year by Iohexol plasma clearance,
cr
IMT at 24 months of follow-up. No difference was observed for FGF23 between PLWH and
us
controls at baseline. Higher FGF23 levels at baseline were associated with increase in IMT and progression of albuminuria (94). Higher FGF23 levels at baseline were associated in
an
PLWH with female gender, unsuppressed HIV viral load, HCV co-infection, and serum phosphorus (94). This cohort was predominantly African-American (96%), the proportion of
ed
(94).
M
HCV co-infection in PLWH was large (46%), 41 % of PLWH were current cocaine users
NAG, KIM-1, urinary IL-18, NGAL, L-FABP, α-1-microglobulin, and α-1-glycoprotein were
ce pt
evaluated in PLWH to predict incident hypertension, this study included 823 HIV-infected, and 247 HIV-uninfected women (95). Whereas an association was observed between these biomarkers and incident hypertension in HIV-uninfected women, no association was observed in HIV-infected women. Only baseline uACR, and eGFR cys were associated with incident
Ac
Downloaded by [Australian Catholic University] at 06:10 13 September 2017
and primary outcomes were the progression in albuminuria and increase in internal carotid
hypertension in HIV-infected women, median follow-up was 9.6 years (95). Studies evaluating kidney biomarkers to predict cardiovascular events or risk are limited, studies with incident cardiovascular events as primary outcomes are required. Moreover, studies in other cohorts are needed as published studies included a large proportion of African-American and women in the USA.
6.4 Renal biomarkers to predict mortality in PLWH. Renal biomarkers were evaluated in prediction of mortality in the Women’s Interagency HIV study (WIHS). In a first study, the association of urinary IL-18, NGAL, KIM-1, L-FABP, and uACR levels in 908 HIV-infected women and 10-year all-cause mortality was assessed (96). In multivariate analysis, only the highest IL-18 and uACR tertiles were associated with
ip t
mortality (96). The highest tertile of IL-18 was associated with a 2-fold risk of death during
cr
biomarkers of tubular injury might be associated with mortality in HIV-infected women (96).
us
Moreover, women with several biomarkers in the highest tertiles had a significantly greater risk of death during the follow-up period (96). After this first observation, the authors
an
hypothesized that a combination of biomarkers could improve prediction of all-cause
M
mortality in PLWH. Eight biomarkers were measured at baseline in 902 HIV-infected women: urinary IL-18, NGAL, KIM-1, NAG, α-1-microglobulin, ACR, L-FABP, α-1-acid-
ed
glycoprotein (66). Median follow-up time was 7.9 years, and primary outcomes were incident CKD defined by an eGFR-CKD-EPI-cys
