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Received for publication: 7.10.09; Accepted in revised form: 19.2.10
Nephrol Dial Transplant (2010) 25: 3106–3115
doi: 10.1093/ndt/gfq125
Advance Access publication 11 March 2010
Kidney transplants in HIV-positive recipients under HAART. A
comprehensive review and meta-analysis of 12 series
Luis Landin1, Jose C. Rodriguez-Perez2, Miguel A. Garcia-Bello2, Pedro C. Cavadas1,
Alessandro Thione1, Peter Nthumba3, Marino Blanes4 and Javier Ibañez1
Transplant Surgery Division, University Hospital “La Fe”, Av. Campanar 21, 46009 Valencia, Spain, 2Nephrology Division, Dr. Negrín
University Hospital of Gran Canaria, Plaza Barranco De La Ballena S/N, 35012 Las Palmas De Gran Canaria, Spain, 3Clinical Fellow,
Clinica Cavadas, Pedro Cavadas Foundation and AIC Kijabe Hospital P.O. Box 20, Kijabe 00220, Kenya and 4Infectious Disease
Division, University Hospital “La Fe”, Av. Campanar 21, 46009 Valencia, Spain
1
Correspondence and offprint requests to: Luis Landin; E-mail: [email protected]
Abstract
Background. Kidney transplantation is being introduced
gradually for the treatment of end-stage renal disease in
patients who are human immunodeficiency virus (HIV)
positive. Our aim was to review the outcomes of kidney
transplantation in HIV-positive recipients who were being
treated with highly active antiretroviral therapy (HAART).
Methods. Eligible papers were English language manuscripts, published between July 2003 and April 2009 and
available through Medline, that described three or more recipients of kidney transplants who were HIV positive and
undergoing HAART. The regimens for induction and maintenance therapy, organ rejection, patient survival, CD4
counts, HIV progression, infectious complications and
deaths were recorded. The survival at 1 year, organ rejec-
tion and infectious complications were evaluated using a random effects model with 95% confidence intervals (CI).
Results. Twelve case series met the defined criteria. Induction therapy consisted most commonly of the administration of anti-CD25 monoclonal antibodies, and triple
immunosuppressive therapy was used most commonly
for maintenance. Among the 254 patients, 1-year survival
was 0.93 (95% CI, 0.90–0.96), organ rejection was diagnosed in 0.36 (95% CI, 0.25–0.49) and infectious complications occurred in 0.29 (95% CI, 0.17–0.43). The CD4
counts decreased after transplantation but recovered later.
Acquired immune deficiency syndrome (AIDS)-defining
infections occurred in three patients.
Conclusions. Kidney transplantation appears to be safe in
patients undergoing HAART. However, larger series of pa-
© The Author 2010. Published by Oxford University Press on behalf of ERA-EDTA. All rights reserved.
For Permissions, please e-mail: [email protected]
Kidney transplants in HIV-positive recipients under HAART
tients are needed to determine the best protocols for the
induction and maintenance of immunosuppression.
Keywords: HAART; HIV; kidney transplantation; review
Abbreviations: AIDS: acquired immune deficiency syndrome; AIN:
anal intraepithelial neoplasia; ATG: anti-thymocyte globulin; CI:
confidence interval; CMV: cytomegalovirus; CsA: cyclosporine A;
EBV: Epstein–Barr virus; HAART: highly active antiretroviral therapy;
HIV: human immunodeficiency virus; HIVAN: HIV-associated
nephropathy; HPV: human papillomavirus; MMF: mycophenolate
mofetil; PTLD: post-transplant lymphoproliferative disease
Introduction
Only a decade ago, seropositivity for human immunodeficiency virus (HIV) was considered to be an absolute contraindication for organ transplantation. In recent years,
however, the use of highly active antiretroviral therapy
(HAART) for the treatment of infection with HIV has
led to a considerable increase in life expectancy. Kidney
transplantation has emerged as a feasible treatment option
for chronic renal failure caused by HIV-associated nephropathy (HIVAN) [1] in this group of patients. Our
aim was to identify and review published case series that
described kidney transplantation in HIV-positive recipients
who received HAART, and to evaluate their outcomes.
Materials and methods
The papers eligible for this study were manuscripts published in the English language between July 2003 and April 2009 that were available
through Medline. The selected papers each described three or more kidney transplants in HIV-positive recipients that were already under
HAART.
The data that were collected included the aim of each study, the inclusion and exclusion criteria, the type of HAART regimen, the sample size,
the induction and maintenance therapy, and the rates, causes and treatment of episodes of rejection and return to dialysis. Rates of survival
of the graft and patient, infectious complications, and deaths were calculated as the number of events divided by the total sample size. If additional outcome data were reported, they were also included in the
analysis.
A meta-analysis of single proportions using the Freeman–Tukey double arcsine transformation was performed [2,3]. The transformed data
were combined to estimate the pooled percentages with 95% confidence
intervals using a random effects model [4]. We assessed the heterogeneity among studies using the Cochran Q test (χ2n−1; P < 0.05 to denote
statistical significance) and estimated the amount of variation by I2 [5].
Statistical sources of heterogeneity were explored by examining the relationship between one or more study-level characteristics and the effect sizes that were observed in the studies using weighted least
squares meta-regression. A rank correlation test of funnel plot asymmetry (z) was used to assess the presence of publication bias. Data
analysis and visualization were performed using the R statistical software package (R Development Core Team, Vienna, Austria; URL:
http://www.R-project.org; version 2.9.0), using the software libraries
‘meta’ [6] and ‘metafor’ [7], for the meta-analysis and meta-regression
models, respectively.
Results
A total of 12 eligible published case series were identified.
These are summarized in Tables 1–4. The results of the
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analysis of survival, rejection and complications due to infection are shown in Figures 1–3.
The first clinical study published was a pilot study of
safety and efficacy reported by Stock et al. [8]. The inclusion criteria were undetectable HIV infection for 3 months,
CD4 count >200/μL, no history of opportunistic infections
and stable antiretroviral therapy for 3 months. The authors
followed up 10 patients for 480 days, with a survival rate
of 100%. Rejection occurred in 50% of the patients, and
anti-thymocyte globulin (ATG) was used to treat episodes
of rejection that were resistant to steroids. Infectious complications occurred in two of the recipients who were treated with ATG (n = 3), whereas three such episodes were
reported in those who did not receive ATG (n = 7). The
CD4 counts were not affected greatly by the immunosuppressive (IS) therapy, except in the recipients who were
treated with ATG. Anal infection with human papillomavirus (HPV), with progression to anal intraepithelial neoplasia (AIN), occurred in 44% of the patients. No acquired
immune deficiency syndrome (AIDS)-defining infection
or anal cancer was observed. Maintenance of blood levels
of cyclosporine A (CsA) was difficult because of interactions with HAART protease inhibitors. The authors concluded that it was safe to perform kidney transplantation
in HIV-positive recipients under HAART, although high
rates of rejection should be expected.
Roland published the findings of a continuation of the
same series, which included 26 patients [9]. The rate of
rejection was reduced to 38%, but graft loss occurred in
12% of the recipients. A death rate of 7%, which could
be attributed to episodes of bowel ischaemia and staphylococcal sepsis, was reported. The author concluded that a
multidisciplinary team was necessary to manage the required pharmacokinetic changes and adjustment of drugs
successfully.
Abbott and collaborators performed a retrospective analysis of the 2002 United States Renal Data System (USRDS)
[10]. They assessed information on graft loss, patient survival, rates of rejection and immunosuppressive therapy in
47 HIV-positive recipients of kidney transplants. However,
they did not describe patient management, CD4 counts and
HIV progression, complications due to infection, and causes
of death. The authors found that the risk of death for recipients who were infected with HIV was lower than for recipients who were HIV negative, but that the differences were
not statistically significant (P = 0.31). This study was excluded from our analysis of complications due to infection
because of lack of data.
Tan et al. compared two short case series of kidney
transplants from living, related donors (LRD, n = 3) or deceased donors (DD, n = 4) in HIV-positive recipients. The
LRD group received induction therapy with alemtuzumab
and tacrolimus monotherapy (tolerogenic regimen) whereas the DD group did not receive induction therapy, and
triple standard therapy was used to maintain immunosuppression. The rate of graft survival was 100% in the LRD
group, whereas the incidence of rejection, CD4 counts
post-transplant and HIV viral load were considerably
higher in the DD group. No infections that define AIDS
occurred in either group, but one case of plantar fasciitis
and one case of basal cell carcinoma were diagnosed in
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L. Landin et al.
Table 1. Brief description of reports
Reference
Aim
Inclusion criteria
Exclusion criteria
HAART regimen
Stock et al. [8]
Prospectively evaluate safety
and efficacy
Undetectable HIV for 3 months
CD4 ≥200/μL (kidney)
No history of OI
Stable ARV for 3 months
AIDS-defining OI
History of cancer except BCC/AIN
Varied
HCV ± in kidney patients with
cirrhosis on liver biopsy
Elevated HIV RNA
History of neoplasm or OI
Altered mental status
Progressive multifocal
leukoencephalopathy
MAC disease
History of Pneumocystis jiroveci,
CMV disease and Kaposi's
sarcoma
Not specified
Not specified
Undetectable HIV
CD4 ≥200/μL
Not specified
Varied
Adherence to HAART and
dialysis
Undetectable HIV
CD4 ≥200/μL
Not specified
Not specified
Varied
Not specified
Not specified
History of cancer except BCC,
cutaneous KS, AIN
Prior transplant
Pregnancy
Wasting
HCV ± in kidney patients with
cirrhosis on liver biopsy
Chronic intestinal cryptosporidiosis
Progressive multifocal
leukoencephalopathy
Resistant fungal infections
History of AIDS-defining infection
Drug abuse
Varied
Roland [9]
Prospectively describe safety
and efficacy
Undetectable HIV for 3 months
CD4 ≥200/μL (kidney)
No history of OI
Abbott et al. [10]
Retrospectively analyse the
USRDS database to 2002
Retrospectively evaluate a
tolerogenic protocol in
HIV-positive recipients
Prospectively determine safety
of kidney transplantation
as an alternative to
haemodialysis
Retrospectively compare pairs
of kidneys from the same
donor transplanted to
HIV-positive and
HIV-negative patients from
UNOS Renal Transplant
Registry
Prospectively assess the use of
ATG in reversing rejection
Not specified
Mazuecos
et al. [15]
Retrospective outcome analysis
Trullas et al. [16]
Prospectively evaluate the
safety of lymphocyte
depletion (ATG)
Roland et al. [17]
Prospectively assess outcomes
Undetectable HIV for 3 months
CD4 ≥200/μL for 6 months
Stable ARV for 3 months
Undetectable HIV for 3 months
CD4 ≥200/μL for 6 months
Allowed TBC, Candida
oesophagitis and P.jiroveci
Undetectable HIV for 3 months
Tan et al. [11]
Kumar et al. [12]
Qiu et al. [13]
Carter et al. [14]
Undetectable HIV for 3 months
CD4 ≥200/μL
No history of OI
Stable ARV for 3 months
CD4 ≥200/μL for 6 months
Gruber et al. [18]
Retrospectively assess
outcomes
Gasser et al. [19]
Prospectively evaluate
anti-herpes viral immunity
after ATG induction
Stable HAART
Undetectable HIV for 3 months
CD4 ≥200/μL (kidney)
Undetectable HIV for 6 months
CD4 ≥200/μL (kidney)
Not specified
Varied
Not specified
Varied
AIDS-defining OI
(except Candida oesophagitis)
Varied (zidovudine
and stavudine
avoided)
Chronic intestinal cryptosporidiosis
Progressive multifocal
leukoencephalopathy
Lymphoma
Visceral KS
History of OI or neoplasm
Use of IL-2 or GM-CSF
Pregnancy
Wasting
Prior organ transplantation
Varied
Varied
HIV, human immunodeficiency virus; RNA, ribonucleic acid; OI, opportunistic infections; ARV, antiretroviral agents; BCC, basal cell carcinoma; AIN,
anal intraepithelial neoplasia; HCV, hepatitis C virus; CsA, cyclosporine A; MMF, mycophenolate mofetil; Sir, sirolimus; KS, Kaposi's sarcoma; CNI,
calcineurin inhibitor; MAC, Mycobacterium avium complex; TBC, tuberculosis; AZA, azathioprine; USRDS, United States Renal Data System;
HAART, highly active antiretroviral therapy; ATG, anti-thymocyte globulin; UNOS, United Network for Organ Sharing.
Kidney transplants in HIV-positive recipients under HAART
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Table 2. Immunosuppression and rejection
Reference
n
Induction
Maintenance
Stock et al. [8]
10
Not used
Roland [9]
26
Not specified
Abbott et al. [10]
47
Anti-CD25 (46%)
Tan et al. [11]
7
None (42%) (deceased donor)
Alemtuzumab (57%)
(living-related donor)
CsA/Sir
MMF
Steroids
Steroids
CsA
MMF
CsA
MMF
Tac
AZA
Triple therapy
Tac monotherapy
Kumar et al. [12]
40
100% Anti-CD25
Qiu et al. [13]
38
60% anti-CD25
Carter et al. [14]
20
55% anti-CD25
Mazuecos et al. [15]
10
Trullas et al. [16]
3
Roland et al. [17]
18
40%
ATG (1)
Anti-CD25 (3)
100%
ATG (3)
Sir (2)
Tac (1)
39% anti-CD25
Gruber et al. [18]
8
100% anti-CD25
Gasser et al. [19]
27
37% ATG
40% anti-CD25
Steroids
CsA
Sir
CsA (53%)
Tac (34%)
Sir (37%)
Steroid-sparing (2.6%)
MMF
Steroids
CsA/Tac/Sir
Steroids
Tac
MMF
MMF
Steroids
Steroids
CNI
± MMF
MMF
CsA
Steroids
CsA or Tac
MMF or AZA
Steroids
Cause of rejection (n)
Return to dialysis (%)
Treatment of rejection
Not specified
0%
CsA→Tac
ATG (AMR)
Not specified
12%
Not specified
Not specified
2%
Not specified
Non-compliance (3) 50%
None
0%
Subtherapeutic IS levels (3)
Non-compliance (2)
10%
Not specified
Mpred (250 mg)
Rituximab (for AMR)
Not specified
Not specified
10%
Steroids ± ATG (7)
Steroids
Not specified
10%
Mpred
Plasmapheresis ± ↑Tac (1)
Not specified
0%
Not specified
Not specified
11%
CsA→Tac
ATG
Not specified
12.5%
Mpred
ATG
Not specified
0%
Not specified
Rejection rates are % of recipients that suffered rejection, as published.OI, opportunistic infections; CsA→Tac, switch from cyclosporine A to tacrolimus; Sir, sirolimus; ATG, anti-thymocyte globulin; CsA, cyclosporine A; MMF, mycophenolate mofetil; AZA, azathioprine; AMR, antibody mediated
rejection; Mpred, methylprednisolone; Tac, tacrolimus; IS, immunusuppression.
the DD group. The authors concluded that a tolerogenic
regimen in HIV-positive recipients could be safe and effective [11]. For statistical analysis, this study was split into
two groups on the basis of well-defined criteria.
Kumar et al. reported on the largest series of kidney
transplants in HIV-positive recipients that has been conducted so far [12]. Forty HIV-positive recipients received
induction therapy with anti-CD25 monoclonal antibodies
(basiliximab), whereas maintenance was based on CsA,
sirolimus and prednisone. Antibody-mediated rejection
that was resistant to steroids was treated by lymphocyte
depletion with rituximab. The authors reported that
17.5% patients died after 2 years. There were no cases
of infections that define AIDS, but the authors did not
specify whether patients treated with rituximab suffered
more complications due to infection than those who did
not receive rituximab. The plasma levels of HIV-1 remained undetectable, and the CD4 counts remained
>400/μL. The authors concluded that positive HIV status
should not be considered a contraindication for kidney
transplantation.
A report from the Terasaki Foundation, which used the
data available through the United Network for Organ
Sharing (UNOS) Renal Transplant Registry, compared
the outcomes of transplantation of 38 pairs of kidneys retrospectively. One kidney from each donor was transplanted
into an HIV-positive recipient and the other into an HIVnegative recipient [13]. The database did not provide specific information for the HIV-positive recipients, such as the
use of HAART or the inclusion criteria. The authors concluded that they did not observe a difference between the
survival rates of HIV-positive and HIV-negative recipients
who received transplants from the same donor (91.3% vs
87.3% after 5 years, P = 0.72).
Carter et al. evaluated 20 patients prospectively, of
whom 11 received induction therapy with anti-CD25 anti-
3110
L. Landin et al.
Table 3. Follow-up and outcomes
Reference
Lowest post-transplant
Follow-up days [mean ± Graft survival (days Patient survival (days Cr mg/dL (mean ± SD
SD or median (range)] mean ± SD or %) mean ± SD or %)
or median)
Death Causes of death
Stock et al. [8]
Roland [9]
480 ± 300
314 (3–1696)
100%
88%
480 ± 300 (100%)
92%
1.6 ± 0.49
Not specified
0%
8%
Abbott et al. [10]
Tan et al. [11]
98%*
25%
100%
75%
95.7%
1485 ± 425 (100%)
246 ± 87 (100%)
632 ± 227 (82.5%)
Not specified
1.48 ± 0.21
1.45 ± 0.23
2.0
4.3%
0%
Kumar et al. [12]
956 ± 481
1485 ± 425
246 ± 87
730
Qiu et al. [13]
1825
76%
89%
1.8 ± 0.2
Carter et al. [14]
Mazuecos et al. [15]
Trullas et al. [16]
Roland et al. [17]
854
489 ± 468
720 ± 180
1520 ± 593
90%
90%
100%
1263 ± 718 (83%)
95%
489 ± 468 (100%)
720 ± 180 (100%)
1520 ± 593 (77%)
Not specified
1.5 ± 0.5
1.48 ± 1
1.1
Gruber et al. [18]
Gasser et al. [19]
450 (240–1410)
360
88%
100
450 (100%)
100%
1.2
Not specified
bodies and seven were given ATG to treat acute rejection
[14]. There were no statistically significant differences in
survival without rejection with respect to the administration of anti-CD25 (36% in the anti-CD25 group vs 66%
in the non-anti-CD25 group, P = 0.759). Twelve infectious
complications, one AIDS-defining infection and one death
occurred in the ATG group, in contrast to two complications due to infection and no deaths in the non-ATG group.
The report did not specify whether these adverse outcomes
occurred in patients who had also undergone anti-CD25
induction. The CD4 counts at the end of the follow-up period were >250/μL. The HIV viral load increased in four
patients. The authors reported that this was due to noncompliance with therapy (n = 1) or before HAART therapy
was resumed (n = 3). They concluded that ATG should be
used with caution to treat rejection in this population.
Two reports from Spain present favourable results for
kidney transplantation in HIV-positive recipients. Mazuecos et al. reported their early experience of kidney transplantation after the introduction of HAART; their series
started in 2001. None of the recipients developed AIDS,
but 40% showed pharmacokinetic changes. Rejection
was observed in 40% of the recipients but was controlled
Ischaemic bowel
episode (1)
Staphylococcal
sepsis (1)
Not specified
17.5% Pulmonary
embolism (1)
Anaphylactic reaction
to drug (1)
Gastrointestinal
bleeding (1)
Sepsis (1)
Chest infection (2)
Necrotizing fasciitis (1)
Infection of
lymphocoele (1)
Myocardial
infarction (1)
10% Bacterial
pneumonia (1)
Gastrointestinal
haemorrhage (1)
Respiratory failure (2)
5%
Heart failure (1)
0%
0%
22% Heart failure (1)
Pulmonary fibrosis (1)
Respiratory
failure–myocardial
infarction (1)
Unknown cause (1)
0%
0%
successfully in all cases. The level of HIV and the CD4
counts remained stable after transplantation, and the
authors concluded that kidney transplantation was safe in
HIV-positive recipients under HAART [15]. Trullas et al.
reported a case series of three HIV-positive recipients who
underwent lymphocyte depletion with ATG. In their study,
they compared them with a group of HIV-negative recipients. After a median follow-up period of 720 days, no viral
or opportunistic infections had occurred, and the mean
CD4 count was 235/μL. They concluded that the use of
ATG was as safe in HIV-positive as in non-HIV-infected
recipients [16].
Roland et al. reported a prospective evaluation of the
outcome of kidney transplantation in a cohort of 18 recipients [17]. Induction therapy with anti-CD25 monoclonal
antibodies was used in 39% of the recipients, and ATG was
used to treat rejection. The patients who received induction
therapy with anti-CD25 did not suffer from more opportunistic infections than patients who did not receive this therapy. However, one patient died during the first year of
follow-up. The authors concluded that larger studies could
facilitate the identification of potential predictors of poor
outcome.
Not specified
≥300
≥500
235 ± 67
Not specified
≥200
Not specified
589 ± 313
946 ± 800
≥200
≥200
ATG recipients
475 (237–890)
Non-ATG recipients
443 (334–734)
≥200
606 ± 37
439 (293–613)
≥200
483 (108–1843)
Roland [9]
Abbott et al. [10]
Tan et al. [11]
Qiu et al. [13]
Carter et al. [14]
Mazuecos et al. [15]
Trullas et al. [16]
Roland et al. [17]
Gruber et al. [18]
Gasser et al. [19]
517 (anti-CD25)
302 (ATG)
670 ± 481
436 (3–975)
Not specified
Undetectable
Detectable in 30%
Detectable in 39%
Detectable in 20%
Not specified
Detectable in 20%
Not specified
1481 ± 2862
50 ± 0
Detectable in 10%
Detectable in unknown %
Undetectable
HIV load post-transplant
Not specified
Yes
No
Yes
Yes
Not specified
Not specified
Yes
Not specified
Yes
Yes
Yes
Pharmacokinetic
changes
Staphylococcus aureus wound infection (2)
Haemophilus influenza bacterial pneumonia (1)
S.aureus endocarditis (1)
Pseudomonas aeruginosa sepsis (1)
Staphylococcal sepsis (1)
Candida oesophagitis (1)
Not specified
Plantar fasciitis (1)
None
Sepsis (1)
Chest infection (2)
Necrotizing fasciitis (1)
Infection of lymphocoele (1)
Admitted urinary tract infection (9)
Bacterial pneumonia (1)
Candida oesophagitis (1)
S.aureus endocarditis with septic embolization (1)
Streptococcus viridans bacteraemia (1)
Pseudomonas pneumonia with multi-organ failure (1)
Escherichia coli urosepsis (1)
Culture-negative urosepsis (1)
Enterococcus bacteraemia (1)
Polymicrobial pneumonia sepsis (1)
Clostridium difficile colitis (1)
Diverticulitis and secondary bacterial peritonitis (1)
Influenza, bacterial pneumonia (1)
Pseudomonas pneumonia (1)
Pneumonia (3)
VZV (1)
Urinary tract infection (1)
CMV (1)
Candida oesophagitis (1)
CMV (1)
Pneumonia (1)
Urinary tract infection (3)
42.8% CMV (ATG)
80% EBV reactivation (ATG)
11.1% CMV (anti-CD25)
6.7% EBV reactivation (anti-CD25)
Infectious complications (n)
Not specified
Not specified
Not specified
Not specified
Not specified
Not specified
Not specified
Not specified
BCC
None
Not specified
Not observed
Post-transplant
neoplasia
Not specified
Not specified
Not specified
Not specified
Not specified
Not specified
Not specified
Not specified
Not specified
Not specified
Not specified
44%
Progression
of AIN
Tx, transplant; SD, standard deviation; HIV, human immunodeficiency virus; HPV, human papillomavirus; BCC, basal cell carcinoma; VZV, varicella zoster virus; AIN, anal intraepithelial neoplasia; ATG, antithymocyte globulin; EBV, Epstein-Barr virus.
Kumar et al. [12]
Not specified
424 ± 384
76 ± 58
≥400
441 (200–1054)
Stock et al. [8]
419 ± 287
423 ± 93
Reference
Mean CD4 counts
post-Tx (cells/μL)
or median (range)
Mean CD4 counts
pre-Tx ± SD (cells/μL)
or median (range)
Table 4. HIV and related complications
Kidney transplants in HIV-positive recipients under HAART
3111
3112
L. Landin et al.
Fig. 1. Pooled estimated proportion of patients surviving the first year, analysed using a random effects model.
Fig. 2. Pooled estimated proportion of patients suffering organ rejection, analysed using a random effects model.
Fig. 3. Pooled estimated proportion of patients suffering complications due to infection, analysed using a random effects model.
Gruber et al. reported a retrospective evaluation of kidney transplants in eight patients after anti-CD25 induction,
followed by triple therapy. One graft loss had occurred after a median follow-up period of 15 months. The incidence
of rejection remained low (12.5%). The authors maintained high trough levels of CsA and monitored the blood
for mycophenolate mofetil (MMF). Only one episode of
infection with cytomegalovirus (CMV) occurred under this
Kidney transplants in HIV-positive recipients under HAART
regimen. The authors suggested that this protocol was safe
for selected HIV-positive recipients of kidney transplants
who were given HAART [18].
A recent prospective study by Gasser et al. evaluated the
effect of ATG induction therapy on immunity against herpes
viruses in HIV-positive recipients of kidney allografts [19].
The authors found that treatment with ATG had a devastating effect on the functionality of T cells. A high rate of reactivation of CMV was observed in the ATG group (n = 7)
as compared to the non-ATG group (n = 11) (42% vs
11%, P = 0.26), but this did not affect the specific T-cell
response to CMV which was present in 92% of CMVinfected patients (n = 25). They observed an almost
complete absence of functional responses in ATG-treated
recipients compared to ATG-untreated individuals, including Epstein–Barr virus (EBV)-specific CD8+ T-cell
immune responses (P < 0.001). Reactivation of EBV
occurred in 80% of the patients in the ATG group. However,
at follow-up (after 1 year), no post-transplant lymphoproliferative disease (PTLD) was observed. The HIV-specific
CD8+ lymphocyte response was affected by ATG in comparison with patients who did not receive ATG (P < 0.05).
The authors concluded that non-depleting regimens were
preferable in HIV-positive recipients of transplants.
The analyses of survival and rejection included 254 patients, and the analysis of complications due to infection
included 207 patients. Of the 254 patients, 238 survived;
this gave a pooled estimate of the percentage survival in
the first year of 0.93 (95% CI, 0.90–0.96) (Figure 1). Analysis using the Q statistic revealed that there was no evidence of heterogeneity (Q(12) = 9.58; P < 0.653; I2 = 0;
95% CI, 0–0.45). A total of 78 episodes of rejection were
found among the patients (0.36; 95% CI, 0.25–0.49)
(Figure 2), and the differences among studies could be
attributed to variations in the true magnitude of this parameter from study to study (Q(12) = 46.8, P < 0.0001;
I2 = 0.74; 95% CI, 0.55–0.85). However, these differences in the rates of rejection could not be explained by
the data retrieved. Fifty-two incidents of infectious complications were observed (0.29; 95% CI, 0.17–0.43) (Figure 3),
and there was strong evidence of substantial heterogeneity
(Q(11) = 47.73, P < 0.0001; I2 = 0.77; 95% CI, 0.59–0.86).
However, the differences in the incidence of complications
due to infection could not be explained by other reported
variables. The degree of publication bias was not statistically significant (z = 0.86, P = 0.39 for survival; z = 1.47,
P = 0.14 for rejection; z = 0.83, P = 0.4 for complications
due to infection).
Discussion
Before the development of HAART, the life expectancy of
HIV-positive patients was considerably shorter than at
present, and there was concern regarding the progression
of HIV, the development of opportunistic infections and
the risk of neoplastic complications (e.g. Kaposi's sarcoma) after organ transplantation. Nowadays, life expectancy
has increased to the point where HIVAN is a common
cause of renal dysfunction [1], and renal replacement is being considered for the treatment of these patients [20].
3113
Stock et al. defined the selection criteria for proceeding
with kidney transplantation [8]. These criteria have been
used in most of the case series published thereafter. One
of the major concerns with regard to organ transplantation
into an HIV-positive recipient is the impact that IS therapy
can have on survival. In this review, the patient survival rate
within the first year of transplantation was 93%, whereas
the graft survival rate was somewhat lower (87%). The
meta-analysis showed that the rate of survival was homogeneous among studies; hence, the results may reflect the true
outcomes. These data were similar to those published in the
2006 Organ Procurement and Transplantation Network
(OPTN)/Scientific Registry of Transplant Recipients
(SRTR) Annual Report, in which survival of kidneys from
non-expanded criteria donors was 91% at 1 year [21]. With
regard to rejection, most studies have observed a higher
number of rejections among HIV-positive recipients than
among HIV-negative recipients at their institutions; however, no statistical confirmation was provided. The mean
rate of organ rejection was 36%, but the rate of return to
dialysis was generally <12%. These results suggest that
HIV-positive patients can still raise an immunological response to allografted tissue while receiving certain types
of treatment (namely HAART) [8], and that the physician
should be ready to treat episodes of rejection.
A critical point for transplantation is the selection of the
optimal prophylaxis protocol to prevent rejection, which
requires the modulation of the immune system in a HIVpositive patient, who already has immunological dysfunction. The most frequent induction therapy consisted of
treatment with anti-CD25 monoclonal antibodies. Maintenance IS therapy consisted most commonly of triple therapy with a calcineurin inhibitor (CNI) (CsA is the most
frequently used), MMF and steroids. Unfortunately, our
meta-regression analysis could not clarify whether such
protocols influence the number or type of complications
that are due to infection. In the series of 40 patients described by Kumar et al., anti-CD25 and triple therapy were
utilized, and 14 infections were reported; two of the infections resulted in death [12]. In contrast, Tan et al. showed a
decrease in CD4 levels from 946 to 76 counts/μL after the
administration of alemtuzumab–tacrolimus, with 100%
survival of patients and grafts, and no complications due
to infection or death [11].
Rejection was treated most commonly with steroid
boluses that controlled rejection successfully. When
ATG was used to treat steroid-resistant acute rejection,
a number of complications due to infection were observed, as in the series reported by Roland [17].
Changes in drug pharmacokinetics were reported in
most of the series, as a result of the use of protease
inhibitors, and they were managed successfully. However, a few episodes of rejection were observed [12].
Lymphocyte depletion was associated with the rates of reactivation of CMV and EBV of 42% and 80%, respectively,
in the series reported by Gasser [19]. Carter found that the
ATG group (n = 11) suffered 10 incidents of infectious
complications, in contrast to the non-ATG group (n = 9),
who suffered only two such incidents.
Overall, the number of deaths associated with infections
(n = 6) was fewer than the number ascribed to non-infec-
3114
tious causes (n = 14), which contradicts the belief that
complications due to infection may be a more frequent
cause of death after transplantation in HIV-positive recipients than in uninfected recipients. The HIV viral load was
detectable in most case series after transplantation, although the CD4 counts were >200/μL in most patients.
However, these data were not always available, as shown
in Table 4. Differences in the rate of occurrence of infectious complications might be explained by differences
among the studies, but none of the variables included in
the series could explain such differences.
The incidence of post-transplant neoplasia was low: a
single case of basal cell carcinoma was reported [11].
AIN was evaluated only by Stock et al. [8], who showed
a rate of progression of 44%, but no other series included
information about this parameter.
This review has some limitations that deserve attention.
A limiting factor of this meta-analysis is that manuscript
search was performed in Medline database only. Unpublished data were not obtained, which may have led to the
omission of relevant information, including data on harmful outcomes. Key design features of the different studies
were described incompletely, and many outcomes were
not reported by all trials. Most of the collected data were
descriptive and obtained from retrospective studies that
lacked control groups, and the authors commonly compared them against experience with other patients at their
institutions. Some researchers published case series that
comprised only a small sample of patients with a shortterm follow-up [11,16]. Some authors did report 1-, 3- or
5-year follow-up periods, but unfortunately, the data were
presented in figures or summarized, and therefore could
not be formatted for analysis. Other studies lacked data
on complications due to infection [10]. More importantly,
some studies did not clarify the differences between patients who were treated with ATG and those who were
not, which precluded statistical analysis [14,19]. These
case series may not be a random selection of all available data because the likelihood for publication bias for
favourable outcomes may have prompted optimistic conclusions; however, this was not statistically supported by
the publication bias analysis. With respect to heterogeneity, the pooled estimates that relate to rejection and
complications due to infection should be treated with
caution. The extent of heterogeneity in a meta-analysis
partly determines how difficult it is to draw general conclusions. For that reason, the true incidence of rejection
and complications due to infection varied with the type
of study. Although the heterogeneity was explored, the
variables that explain the differences among the studies remained unknown. Therefore, it appears that our sample was
a good representation of all types of studies of kidney transplantation in patients with HIV infection, even though conclusions of null moderating effects may be incorrect, due to
the low power of the analysis.
Conclusions
The results presented in this review support the treatment of
end-stage renal disease in HIV-positive recipients by renal
L. Landin et al.
transplantation. Good rates of patient survival were observed, although organ rejection occurred frequently.
HIV-positive transplant recipients were cared for by multidisciplinary teams, in order to control the pharmacokinetic
variations. Opportunistic infections, neoplasia and HIV reactivation were uncommon, although some authors found
that lymphocyte depletion increased the risk of reactivation
of CMV and EBV. These findings emphasize the need for a
clinical trial to compare the safety of different IS protocols.
A prospective multi-centre evaluation of kidney transplantation in HIV-positive recipients is currently underway
(www.hivtransplant.com).
The results of this review show that HIV infection
can no longer be considered a contraindication for renal
transplantation, but further studies are required to identify the optimal choice of IS therapy in this group of
patients.
Conflict of interest statement. None declared.
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chapterIV
Received for publication: 19.9.09; Accepted in revised form: 17.2.10