Viral infections represent significant morbidity and mortality factors in kidney transplant recipients, with CMV, EBV, and BKV infections being most common. Desensitization (DES) with IVIg and rituximab with/without plasma exchange followed by kidney transplantation with alemtuzumab induction increased successful transplant rates in HLA-sensitized patients but may represent an increased risk for viral infections due to severe lymphocyte depletion. Here, we report on the posttransplant viral infection status in 372 DES versus 538 non-DES patients. CMV and EBV viremia were significantly lower in DES patients, while BKV viremia was similar. This trend was observed primarily in CMV sero(−), EBV sero(+), and sero(−) patients. No patient developed PTLD. The incidence of BKAN, allograft, and patient survival was similar in both groups. These viral infections were not associated with subsequent allograft rejection which occurred within 6 months after the infection.
Viral infections represent significant morbidity and mortality factors for immunocompromised transplant recipients [
We have shown that desensitization (DES) with intravenous immunoglobulin (IVIg) and rituximab with/without plasma exchange (PLEX) followed by a kidney transplantation with alemtuzumab induction increased successful transplant rates in HLA-sensitized (HS) patients [
This study was approved by the Institutional Review Board at Cedars-Sinai Medical Center (IRB numbers Pro00017197, 10969, and 12562). The study was conducted in accordance with the ethical guideline based on federal regulations and the common rule. CSMC also has a Federal Wide Assurance.
CMV, EBV, and/or BKV-PCR results in a total of 3614 and 5113 DNA samples obtained from 372 DES and 538 non-DES patients, respectively, were compared. We also examined graft and patient survival, pretransplant viral serological status, virus-associated complication, and allograft rejection. Patients examined were transplanted between January 2007 and April 2015 at Cedars-Sinai Medical Center with patient demographics shown in Table
Patient demographics.
Demographics | Kidney transplant patients | | |
---|---|---|---|
DES group ( | Non-DES group ( | ||
Transplant date | 1/4/07–4/18/15 | 1/10/07–4/17/15 | |
Age, mean ± SD | 49.6 ± 13.3 | 51.1 ± 14.2 | 0.11 |
Gender (female), | 226 (60.8) | 157 (29.2) | |
Race, | 0.27 | ||
African-American | 69/368 (18.8) | 84/499 (16.8) | |
Hispanic | 101/368 (27.4) | 167/499 (33.5) | |
White | 148/368 (40.2) | 180/499 (36.1) | |
Others | 50/368 (13.6) | 68/499 (13.6) | |
Living donor transplant, | 141 (37.9) | 177 (32.9) | 0.12 |
Induction, | | ||
Lymphocyte depletion | 312/365 (85.5) | 241/496 (48.6) | |
Anti-IL-2 receptor | 53/365 (14.5) | 255/496 (51.4) | |
Maintenance (tacrolimus), | 351/354 (99.2) | 452/493 (91.7) | |
HLA match | 1.9 ± 1.6 | 1.9 ± 1.7 | 0.78 |
PRA, | | ||
>10% | 66 (17.7) | 470 (87.3) | |
10–80% | 113 (30.4) | 68 (12.7) | |
>80% | 193 (51.9) | 0 (0) | |
Reason for DES, | |||
HS | 314 (84.4) | na | |
HS/ABOi | 17 (4.6) | na | |
ABOi | 41 (11.0) | na | |
Recipient with CMV sero(−) at Tx, | 57/368 (15.5) | 140/524 (26.7) | |
Recipient with EBV sero(−) at Tx, | 13/361 (3.6) | 33/486 (6.8) | |
Follow-up (months post-Tx) | 24.4 ± 20.3 | 24.6 ± 20.1 | 0.84 |
Sample number tested for viral-PCR/patient, mean ± SD | 9.7 ± 5.2 | 9.5 ± 7.4 | 0.61 |
The number of patients with available results was provided if not available in all the patients. PRA: panel reactive antibody, DES: desensitization, HS: HLA-sensitization, ABOi: ABO incompatible transplantation, and Tx: transplant.
Of 372 DES patients, 314 (84.4%) received an ABO compatible and 58 (15.6%) an ABO incompatible kidney transplant after DES. The DES protocols used for ABO compatible transplant in HS and ABO incompatible transplant in non-HS patients have been reported [
Most patients received induction therapy with lymphocyte depleting agent (alemtuzumab or anti-thymocyte globulin) or anti-IL-2 receptor antibody (anti-IL-2R, daclizumab, or basiliximab). Maintenance immunosuppression consisted of calcineurin inhibitor (tacrolimus or cyclosporine A), mycophenolate mofetil (MMF), and steroids. The target levels were dependent on the type of induction as reported elsewhere [
All patients received antiviral prophylaxis with ganciclovir (1.25 mg/kg daily) while inpatient and then valganciclovir or acyclovir posttransplant depending on a risk for viral infection. For transplants with CMV R−/D+, 900 mg valganciclovir was given daily for 6 months regardless of induction type. For those with lymphocyte depletion induction, 450 mg valganciclovir was given daily for 6 months for CMV R+/D+, R+/D−, or R−/D−. For those with anti-IL-2R induction, 800 mg acyclovir was given 4x a day for CMV R+/D+ or R+/D− and 800 mg daily for CMV R−/D− for 3–6 months, with dose adjustment for renal function and/or white blood cell count. CMV-, EBV-, and/or BKV-PCR monitoring was performed at 1, 2, 3, 6, 9, 12, 18, and 24 months after transplant or as needed as previously reported [
Of 372 DES patients, 36 were monitored for lymphocyte subset analysis before and after transplant by flow cytometry, and archived sera obtained from another 38 patients were tested for total IgG and anti-EBV-IgG before and after transplant by ELISA.
Heparinized-peripheral blood samples from 20 normal adult volunteers (7 males) were tested for CMV- and EBV-specific T cell and NK cell activity.
Viral-PCR was performed at the Transplantation and Immunology Laboratory, Cedars-Sinai Medical Center [
The CD4+, CD8+ T cell, CD19+ B cell, and CD56+/CD16+ NK cell numbers were monitored for DES patients before and after transplant by flow cytometry using a standard 6-color direct staining method as previously described with minor modification [
CMV- or EBV-Th and NK cell levels were measured by intracellular cytokine flow cytometry (CFC) developed in our lab and described elsewhere with minor modification [
Total IgG (Human IgG-ELISA, Bethyl Laboratories, Inc. Montgomery, TX) and anti-EBV IgG levels (EBV-VCA IgG-ELISA, Calbiotech, El Cajon, CA) were measured by ELISA following the manufacturers’ instruction. In the total IgG-ELISA, the results were expressed as mg/ml, and the levels >7, 4–7 and <4 mg/ml were considered normal, mild, and severe hypogammaglobulinemia [
We compared the results in the DES versus non-DES groups, viral sero(+) versus sero(−) groups, or different antiviral prophylaxis groups (Tables
CMV, EBV, and BKV viremia in DES and non-DES patients.
Viral DNA detected | Kidney transplant patients | | |
---|---|---|---|
DES group ( | Non-DES group ( | ||
CMV-PCR > 5.0 copies/PCR | |||
Viremia rate (% ± SE) | 30.3 ± 3.6 | 35.7 ± 2.9 | 0.19 |
1st viremia (m post-Tx) | 5.8 ± 10.3 | 7.7 ± 14.1 | 0.23 |
Peak levels (copies/PCR) | 420 ± 1077 | 2730 ± 18374 | 0.12 |
Duration (m) | 0.7 ± 0.7 | 1.1 ± 2.0 | |
CMV-PCR > 30 copies/PCR | |||
Vremia rate (% ± SE) | 16.1 ± 2.1 | 25.2 ± 2.7 | |
1st viremia (m post-Tx) | 3.7 ± 4.0 | 6.7 ± 12.5 | |
Peak levels (copies/PCR) | 699 ± 1331 | 3904 ± 21887 | 0.13 |
Duration (m) | 0.8 ± 0.5 | 1.4 ± 2.4 | |
CMV-PCR > 50 copies/PCR | |||
Viremia rate (% ± SE) | 13.5 ± 1.9 | 22.5 ± 2.7 | |
1st viremia (m post-Tx) | 3.4 ± 3.1 | 7.1 ± 13.3 | |
Peak levels (copies/PCR) | 811 ± 1410 | 4462 ± 23360 | 0.13 |
Duration (m) | 0.8 ± 0.6 | 1.5 ± 2.5 | |
| |||
EBV-PCR > 5.0 copies/PCR | |||
Viremia rate (% ± SE) | 13.6 ± 3.8 | 30.0 ± 4.5 | |
1st viremia (m post-Tx) | 18.8 ± 19.5 | 13.1 ± 19.3 | 0.20 |
Peak levels (copies/PCR) | 171 ± 512 | 74 ± 141 | 0.36 |
Duration (m) | 6.7 ± 17.5 | 4.5 ± 6.4 | 0.54 |
EBV-PCR > 30 copies/PCR | |||
Viremia rate (% ± SE) | 2.9 ± 1.1 | 11.3 ± 2.8 | |
1st viremia (m post-Tx) | 14.5 ± 20.2 | 9.4 ± 15.5 | 0.52 |
Peak levels (copies/PCR) | 474 ± 785 | 157 ± 187 | 0.29 |
Duration (m) | 17.1 ± 26.6 | 7.5 ± 7.7 | 0.34 |
EBV-PCR > 50 copies/PCR | |||
Viremia rate (% ± SE) | 2.3 ± 1.0 | 6.4 ± 1.5 | |
1st viremia (m post-Tx) | 9.4 ± 7.8 | 6.4 ± 8.4 | 0.47 |
Peak levels (copies/PCR) | 691 ± 884 | 216 ± 205 | 0.29 |
Duration (m) | 23.6 ± 30.6 | 8.3 ± 8.1 | 0.32 |
PTLD, | 0 | 0 | na |
| |||
BKV-PCR > 250 copies/ml | |||
Viremia rate (% ± SE) | 20.1 ± 2.5 | 17.1 ± 1.9 | 0.21 |
1st viremia (m post-Tx) | 5.2 ± 5.4 | 6.6 ± 8.7 | 0.25 |
Peak levels (copies/PCR) | | 1 | 0.31 |
Duration (m) | 5.0 ± 10.4 | 5.8 ± 11.1 | 0.70 |
BKV-PCR >1500 copies/ml | |||
Viremia rate (% ± SE) | 11.2 ± 1.8 | 13.0 ± 1.8 | 0.72 |
1st viremia (m post-Tx) | 4.2 ± 4.0 | 6.4 ± 9.7 | 0.14 |
Peak levels (copies/PCR) | | | 0.28 |
Duration (m) | 7.8 ± 12.8 | 7.3 ± 12.2 | 0.84 |
BKV-PCR >2500 copies/ml | |||
Viremia rate (% ± SE) | 10.9 ± 1.8 | 10.7 ± 1.7 | 0.60 |
1st viremia (m post-Tx) | 4.3 ± 4.1 | 6.9 ± 10.6 | 0.12 |
Peak levels (copies/PCR) | | | 0.30 |
Duration (m) | 8.0 ± 13.0 | 8.4 ± 13.2 | 0.88 |
BKAN, | 4 (1.1) | 10 (1.9) | 0.35 |
Time for BKAN (m post-Tx) | 12.3 ± 10.1 | 11.6 ± 7.1 | 0.92 |
Results for 1st viremia, peak levels, duration, and time for BKAN are mean ± standard deviation.
m post-Tx: months after transplant, PTLD: posttransplant lymphoproliferative disorder, and BKAN: BKV-associated nephropathy.
CMV viremia in CMV sero(+) versus sero(−) patients in the DES and non-DES groups.
DES group ( | Non-DES group ( | | ||||||
---|---|---|---|---|---|---|---|---|
CMV sero(+) | CMV sero(−) | | CMV sero(+) | CMV sero(−) | | In CMV | In CMV | |
CMV-PCR > 5.0 copies/PCR | ||||||||
Viremia rate | 32.0 ± 4.0 | 22.1 ± 5.7 | 0.37 | 33.4 ± 3.5 | 43.5 ± 5.5 | | 0.95 | |
1st viremia (m post-Tx) | 6.0 ± 11.0 | 4.3 ± 2.8 | 0.25 | 9.1 ± 16.7 | 4.9 ± 5.9 | | 0.14 | 0.60 |
Peak levels (copies/PCR) | 237 ± 578 | 1652 ± 2236 | | 2951 ± 22399 | 2407 ± 4370 | 0.81 | 0.22 | 0.42 |
Duration (m) | 0.7 ± 0.6 | 0.9 ± 0.6 | 0.22 | 0.9 ± 1.1 | 1.6 ± 3.1 | 0.11 | 0.15 | 0.17 |
CMV-PCR > 30 copies/PCR | ||||||||
Viremia rate | 15.5 ± 2.2 | 20.3 ± 5.5 | 0.41 | 22.5 ± 3.3 | 35.1 ± 5.1 | | 0.34 | |
1st viremia (m post-Tx) | 3.5 ± 4.2 | 4.4 ± 2.8 | 0.42 | 8.1 ± 15.2 | 4.5 ± 5.9 | | | 0.94 |
Peak levels (copies/PCR) | 423 ± 734 | 1801 ± 2278 | | 4549 ± 27703 | 2919 ± 4658 | 0.64 | 0.23 | 0.28 |
Duration (m) | 0.7 ± 0.5 | 1.0 ± 0.6 | 0.16 | 1.1 ± 1.3 | 1.8 ± 3.4 | 0.20 | | 0.15 |
CMV-PCR > 50 copies/PCR | ||||||||
Viremia rate | 12.7 ± 2.0 | 18.6 ± 5.4 | 0.30 | 18.7 ± 3.3 | 35.1 ± 5.1 | | 0.59 | |
1st viremia (m post-Tx) | 3.1 ± 3.1 | 4.4 ± 3.0 | 0.27 | 9.2 ± 16.7 | 4.5 ± 5.9 | | | 0.93 |
Peak levels (copies/PCR) | 496 ± 779 | 1978 ± 2316 | | 5718 ± 30980 | 2919 ± 4658 | 0.52 | 0.23 | 0.38 |
Duration (m) | 0.8 ± 0.5 | 1.1 ± 0.6 | 0.15 | 1.2 ± 1.4 | 1.8 ± 3.4 | 0.29 | | 0.19 |
DES: desensitization; post-Tx: posttransplant.
EBV viremia in EBV sero(+) versus sero(−) patients in the DES and non-DES groups.
DES group ( | Non-DES group ( | | ||||||
---|---|---|---|---|---|---|---|---|
EBV sero(+) | EBV sero(−) | | EBV sero(+) | EBV sero(−) | | In EBV | In EBV | |
EBV-PCR > 5.0 copies/PCR | ||||||||
Viremia rate | 14.4 ± 4.1 | 16.7 ± 10.8 | 0.29 | 32.0 ± 5.3 | 36.7 ± 9.0 | | | 0.22 |
1st viremia (m post-Tx) | 19.8 ± 20.0 | 7.1 ± 0.9 | | 14.6 ± 20.8 | 5.5 ± 5.9 | | 0.29 | 0.45 |
Peak levels (copies/PCR) | 183 ± 531 | 29 ± 17 | 0.18 | 62 ± 130 | 160 ± 189 | 0.14 | 0.29 | |
Duration (m) | 7.0 ± 18.1 | 3.3 ± 2.8 | 0.45 | 4.1 ± 6.2 | 7.1 ± 6.6 | 0.21 | 0.46 | 0.37 |
EBV-PCR > 30 copies/PCR | ||||||||
Viremia rate | 2.8 ± 1.1 | 8.3 ± 8.0 | 0.20 | 11.1 ± 3.3 | 26.5 ± 8.2 | | | 0.21 |
1st viremia (m post-Tx) | 15.6 ± 21.2 | 6.2 ± 0.0 | na | 11.1 ± 17.3 | 4.7 ± 6.3 | 0.12 | 0.62 | na |
Peak levels (copies/PCR) | 527 ± 817 | 46 ± 0.0 | na | 141 ± 185 | 214 ± 197 | 0.40 | 0.25 | na |
Duration (m) | 18.5 ± 27.9 | 6.0 ± 0.0 | na | 7.3 ± 7.9 | 8.0 ± 6.9 | 0.83 | 0.33 | na |
EBV-PCR > 50 copies/PCR | ||||||||
Viremia rate | 2.5 ± 1.1 | 0 | 0.61 | 5.4 ± 1.7 | 23.3 ± 7.9 | | | |
1st viremia (m post-Tx) | 9.4 ± 7.8 | na | na | 7.1 ± 9.2 | 5.2 ± 6.6 | 0.59 | 0.60 | na |
Peak levels (copies/PCR) | 691 ± 884 | na | na | 213 ± 214 | 239 ± 197 | 0.79 | 0.28 | na |
Duration (m) | 23.6 ± 30.6 | na | na | 8.1 ± 8.5 | 8.6 ± 7.2 | 0.89 | 0.31 | na |
PTLD, | 0 (0) | 0 (0) | na | 0 (0) | 0 (0) | na | na | na |
DES: desensitization, PTLD: posttransplant lymphoproliferative disorder, and post-Tx: posttransplant.
CMV and EBV viremia in sero(+) non-DES patients who received valganciclovir (VGCV-LD) versus acyclovir prophylaxis (ACV-anti-IL-2R).
Patients | Number of patients (%) |
---|---|
w/CMV-PCR > 30 copies/PCR | |
| |
CMV sero(+) non-DES | |
VGCV-LD ( | 31 (17.6) |
ACV-anti-IL-2R ( | 26 (14.9) |
| |
VGCV-LD-ATZ ( | 7 (28.0) |
VGCV-LD-ATG ( | 24 (15.9) |
| |
w/EBV-PCR > 30 copies/PCR | |
| |
EBV sero(+) non-DES | |
VGCV-LD ( | 22 (11.0) |
ACV-anti-IL-2R ( | 6 (2.8) |
| |
VGCV-LD-ATZ ( | 2 (5.1) |
VGCV-LD-ATG ( | 20 (12.4) |
VGCV: valganciclovir; ACV: acyclovir.
LD: lymphocyte depletion; anti-IL-2R: anti-IL-2 receptor.
ATZ: alemtuzumab; ATG: anti-thymocyte globulin.
Viral infection and allograft rejection (AR) in DES and non-DES patients.
Allograft rejection (AR) | Kidney transplant patients | | |
---|---|---|---|
DES group ( | Non-DES group ( | ||
AR, | |||
Any AR | 68 (18.7) | 70 (14.1) | |
ABMR | 44 (12.1) | 11 (2.2) | |
CMR | 41 (11.3) | 68 (13.7) | 0.35 |
CMV, EBV, or BKV viremia | 80 (22.0) | 138 (27.8) | |
AR within 6 months after VI, | |||
Any AR after VI | 15/80 (18.8) | 16/138 (11.6) | 0.16 |
ABMR after VI | 8/80 (10.0) | 3/138 (2.2) | |
CMR after VI | 11/80 (13.8) | 15/138 (10.9) | 0.52 |
Baseline characteristics in DES and non-DES patients are shown in Table
CD8+, CD4+ T cell, CD19+ B cell, and CD56+/CD16+ NK cell number before DES and after transplant in 36 DES patients are shown in Figure
The number of CD8+ (a), CD4+ T cells (b), CD19+ B cells (c), and CD56+/CD16+ NK cells (d) pre-DES and posttransplant in 36 DES patients who received DES with IVIg + rituximab followed by a kidney transplant with alemtuzumab induction. Each line with each symbol describes the result from one patient. The results were expressed as the ratio against the pre-DES level in each patient. DES: desensitization; Tx: transplant.
CD8+ T cells
CD4+ T cells
CD19+ B cells
CD56+/CD16+ NK cells
Alemtuzumab is a monoclonal antibody, targeting CD52 positive cells such as mature lymphocytes, including T cell, B cell, NK cells, and monocytes, and then depleting them [
CMV, EBV, and BKV viremia status after transplant in 372 DES and 538 non-DES patients are summarized in Table
Freedom from CMV or EBV viremia with >30 copies/PCR and BKV viremia with >1500 copies/ml in the DES versus non-DES groups is shown in Figure
Freedom from CMV (a) or EBV (b) viremia with >30 copies/PCR and BKV (c) viremia with >1500 copies/ml in DES (blue) and non-DES (red) patients during the 1st 5 years after transplant. The group differences were assessed by the log-rank test.
CMV viremia with >30 copies/PCR
EBV viremia with >30 copies/PCR
BKV viremia with >1500 copies/ml
We next analyzed viral infection status separately by pretransplant recipient’s viral serology status that largely affects posttransplant viral infection rate and its associated complication [
Freedom from CMV or EBV viremia with >30 copies/PCR in the 4 groups is shown in Figure
Freedom from CMV (a) or EBV (b) viremia with >30 copies/PCR in sero(+) (green) or sero(−) (blue) DES and sero(+) (brown) or sero(−) (red) non-DES patients during the 1st 5 years after transplant. The group differences were assessed by the log-rank test.
CMV viremia with >30 copies/PCR
EBV viremia with >30 copies/PCR
Total IgG (a) and anti-EBV IgG levels (b) before DES and at 12 months (M) after transplant (Tx) in 35 and 33 DES patients, respectively, who received DES with IVIg + rituximab followed by a kidney transplant with alemtuzumab induction. The results are expressed as mean and standard deviation. The dotted lines describe 7 and 4 mg/ml total IgG for the normal and severe hypogammaglobulinemia cutoff, respectively, in (a), and anti-EBV IgG index 0.25 for sero(+) cutoff level in (b).
Total IgG
Anti-EBV IgG
ATG is widely used as an induction and rejection treatment agent in transplant patients, and use of a newer lymphocyte depleting agent, alemtuzumab, is also well established [
Despite profound and prolonged B cell and T cell depletion from the standard protocol used for DES patients, pretransplant DES with IVIg + rituximab and posttransplant alemtuzumab induction, DES patients showed significantly lower CMV and EBV viremia rates compared to non-DES patients. In the further analysis performed separately by pretransplant CMV and EBV serological status, we found that the standard protocol used for DES patients reduced CMV viremia rate primarily in sero(−) and reduced EBV viremia rate in both sero(+) and sero(−) DES patients to a lesser degree. There are possible factors contributing to these observed beneficial effects of the standard protocol used for DES patients. Possible factors are summarized below.
Viral infections are controlled primarily by antiviral T cells [
The levels of CMV-specific CD4+ T cells (CMV-Th) (a) and CD56+ NK cells (CMV-NK) (b) in 16 CMV sero(+) and 4 sero(−) normal individuals and EBV-specific CD4+ T cells (EBV-Th) (c) and CD56+ NK cells (EBV-NK) (d) in 14 EBV sero(+) normal individuals as analyzed by CFC. Each symbol represents the result from one individual. The dotted line describes the positive cutoff level; ≥0.2% for CMV-Th, ≥0.1% for EBV-Th, and ≥0.5% for CMV- and EBV-NK. The PHA (+) control results were also shown in (c) and (d).
CMV-specific CD4+ T cells
CMV-specific CD56+ NK cells
EBV-specific CD4+ T cells
EBV-specific CD56+ NK cells
Involvement of anti-CMV IgG in positive reactivity of CMV-Th and CMV-NK cells. Upper (a–h): a typical result of the CMV-Th and CMV-NK assay performed with or without IdeS, IgG-degrading enzyme. Lower (i–l): the summary of 5 sets of experiment results using 5 different normal individuals. Each line with each symbol describes the result from one normal individual. B: blood; Lys: CMV lysate.
Antiviral antibody functions as one of the early defense mechanisms against viral infection in sero(+) individuals through neutralizing viruses and eliminating virus-infected cells [
We have previously reported [
In this study, we measured total IgG and anti-EBV IgG levels before DES and 12 months after transplant (15.7 ± 2.9 months after DES) in 35 patients who received DES with IVIg + rituximab, followed by a kidney transplant with alemtuzumab induction. Total IgG levels significantly decreased at 12 months after transplant compared to pre-DES levels (22% reduction) (Figure
In contrast to posttransplant anti-CMV IgG levels observed in the previous study [
ADCC is one of the major antiviral activities and mediated by Fc
To address this possible ADCC activity in sero(+) patients, we measured NK cell response to CMV or EBV lysate (CMV- or EBV-NK) in vitro by assessing IFN
It is well accepted that CMV- or EBV-T cells are viral-specific memory T cells and their response to CMV or EBV peptides or lysate in vitro are mediated through T cell receptors [
The effect of IdeS on CD4+ T cell and CD56+ NK cell activation in response to PHA. Upper (a–f): a typical result of CD4+ T cell and CD56+ NK cell response to PHA (positive control) with or without IdeS in the CMV-Th and CMV-NK assay. Lower (g–j): the summary of 3 sets of experiment results using 3 different normal individuals. Each line with each symbol describes the result from one normal individual. B: blood.
Recent studies showing the important role of antibody-mediated NK cell activity beyond a traditional ADCC mechanism in controlling CMV infection are of interest [
Contrary to the widely held concept that lymphocyte depletion increases risk for viral infections, several studies including a meta-analysis showed a similar viral infection rate among patients treated with alemtuzumab, ATG, and anti-IL-2R induction [
EBV enters B cells via the C3d complement receptor CD21 and establishes its latency on B cells [
After primary CMV infection, the virus can persist in a latent form in a variety of tissues, primarily in monocyte-derived macrophages and dendritic cells [
BKV establishes latency in the uroepithelium after a primary infection, [
Antiviral prophylaxis or preemptive antiviral therapy is essential for prevention of viral infections and associated complications in transplant recipients [
All patients included in this study received antiviral prophylaxis with ganciclovir while inpatient and then valganciclovir or acyclovir posttransplant depending on a risk for CMV infection based on donor and recipient CMV serologies. Briefly, for transplants with lymphocyte depletion induction and those with CMV R−/D+ regardless of induction type, valganciclovir was given. For those with anti-IL-2R induction and CMV R+/D+, R+/D−, or R−/D−, acyclovir was given. In this study, we showed that CMV and EBV viremia rate in DES patients were significantly lower than non-DES patients. Most DES patients (86%) received ganciclovir since they received lymphocyte depletion induction, while 51% of the non-DES patients received acyclovir due to anti-IL-2R induction and CMV sero-status. This difference in antiviral prophylaxis may be a reason for differences in viremia rates in the DES versus non-DES groups. To address this question, we compared the CMV and EBV viremia rates in non-DES patients with valganciclovir versus acyclovir. Since viral sero-status affects the viremia rate, only CMV or EBV sero(+) non-DES patients were included in this analysis. Among CMV sero(+) non-DES patients, 176 received valganciclovir and 175 received acyclovir (Table
IVIg derived from pooled human plasma from thousands of donors and originally used for the treatment of primary immunodeficiency disorders has also been used for the treatment of autoimmune and inflammatory disorders for nearly 30 years [
We next investigated the impact of viral infection on allograft rejection. Of 372 DES and 538 non-DES patients, the rejection information was available in 363 DES and 497 non-DES patients during this study period. Freedom from total allograft rejection, ABMR, and CMR in DES versus non-DES patients is shown in Figure
Freedom from overall allograft rejection (a), ABMR (b), and CMR (c) in DES (blue) versus non-DES (red) patients during the 1st 5 years after transplant. The group differences were assessed by the log-rank test.
Allograft rejection (ABMR or CMR)
ABMR
CMR
To assess the impact of viral infection on induction of allograft rejection, we next analyzed the rejection rate within 6 months after onset of viral infection. Of 363 DES and 497 non-DES patients, 80 (22%) and 138 (28%) developed at least one CMV with >50, EBV with >50 copies/PCR, or BKV viremia with >2500 copies/ml during this study period (Table
The increased risk of viral infections and their complications associated with antirejection therapy is well documented [
We finally compared allograft and patient survival in DES versus non-DES patients included in this study (Figure
Freedom from allograft loss (a) and patient death (b) in DES (blue) versus non-DES (red) patients during the 1st 5 years after transplant. The group differences were assessed by the log-rank test.
Graft loss (death-censored)
Patient survival
Desensitized HS patients are at lower risk for CMV and EBV infections and have a similar risk for BKV infection and BKAN posttransplant. This trend was observed primarily in CMV sero(−) for CMV infection and in EBV sero(+) and sero(−) patients to a lesser degree for EBV infection. No patient developed PTLD in either group. Factors likely responsible for the lower risks for CMV and EBV infections in DES patients include (
Stanley C. Jordan has research grants from Genentech Inc. and owns a patent (US Patent 6,171585B1): “IVIg Immunosuppression for HLA-Sensitized Transplant Recipients,” 2001. The remaining authors declare that there is no conflict of interests regarding the publication of this paper.
Mieko Toyoda participated in the research design, performance of the research, data analysis, data interpretation, and writing the paper. Bong-Ha Shin participated in the research design, performance of the research, and data analysis. Shili Ge participated in the research design, performance of the research, data analysis, data interpretation, and writing the paper. James Mirocha participated in the data analysis. David Thomas participated in the performance of the research, data analysis, and data interpretation. Maggie Chu, Edgar Rodriguez, Christine Chao, Anna Petrosyan, Odette A. Galera, Ashley Vo, Jua Choi, and Alice Peng participated in the performance of the research. Joseph Kahwaji participated in the performance of the research and data analysis. Stanley C. Jordan participated in the research design and writing the paper.