Pancreas-kidney Transplants in HIV-positive Recipients
Pancreas-kidney Transplants in HIV-positive Recipients
Patients' characteristics are summarized in Table 1. All patients (3 males, 1 female) were HIV-infected type 1 diabetics with chronic renal disease on hemodialysis. The median age was 39.5 years (range 31–49). Ethnicity was Caucasian except for the female recipient (Patient 3) who was of African origin. The median duration of HIV infection estimated from the time of first HIV-positive test was 7.5 years (range 3–19). Risk factor for HIV transmission was sexual in 3 patients. Patient 2, naive to antiretrovirals due to stability of immunovirological parameters, was a previous intravenous drug user (IVDU), genotype 1 HCV coinfected with HCV-RNA positivity, and had no fibrosis at liver biopsy (Ishak grade II, stage 0). Overall dialysis duration before SPK was 4 years (1391 days, range 542–2607) with a time spent on the transplant waiting list of around 123 days (range, 84–520). Average absolute CD4 cell count measured within 3 months before transplant was 534 cell/mm (range 470–698). Patients 1 and 4 received organs from standard risk donors, Patient 3 from an increased risk donor, and Patient 2 from a donor with calculated risk for bacteremia, as defined by the Italian guidelines The average donors' age was 29 years (range 23–39). Median cold ischemia time was 13.5 h (range 9–16). All recipients were CMV-IgG and EBV-IgG positive. Patients 2 and 3 serology was compatible with previous Hepatitis B virus (HBV) infection. We registered one immune response to HBV vaccination (Patient 4, HBsAb 1000 mUI/mL) in the two HBsAg-, HBcIgG-negative recipients.
Overall posttransplant follow-up ranged from 2 to 5 years with a median duration of 45 months (range 26–67). As reported in Table 1, all patients had stable creatininemia at last follow-up visit (median 1.24 mg/dL, range 1.20–1.28). Glucose levels were within normal range in 3 of 4 recipients (86 mg/dL, range 75–99). Patient 1, presently back on insulin therapy because of pancreatic graft loss and under evaluation for islet transplantation, presented with fever and hyperglycemia (429 mg/dL) at posttransplant month 64. During routine follow-up 1 month before hospitalization, results were within normal limits. An abdominal CT scan showed possible pancreatic graft vascular thrombosis not confirmed at laparotomy that evidenced a necrotic pancreatic graft with patent vessels and was followed by graft removal. Histologic examination displayed signs of necrotic acute pancreatitis associated with acute and chronic rejection.
All recipients had undetectable HIV-RNA at last follow-up visit. Mean absolute CD4 number and percentage were 425 cells/mm (range, 307–701) and 28% (range 23–29%), respectively. Patient 2, who had a negative pretransplant tuberculin skin test (TST) and negative history of tuberculosis (TB) exposure, developed pulmonary TB 35 months after transplantation and was successfully treated with an 18-month course of a rifamycin-sparing antimycobacterial treatment. No acquired immunodeficiency syndrome (AIDS) defining illnesses were reported among the other recipients. Patient 3 presented genital HSV-2 reactivation at posttransplant day 19 and was treated with oral valacyclovir. No preemptive CMV treatments were started given that the highest CMV-DNA viral load registered was 31 000 copies/mL. Before SPK, HHV8 serology was negative for all the donors and for two of the recipients. HHV8 serological status was not available for the other two recipients. All recipients were negative for HHV8-DNA (undetectable by PCR) and no lesions suggestive of Kaposi's sarcoma were observed during posttransplant follow-up.
C peptide and glycosylated hemoglobin levels were maintained within normal range in all recipients. Patient 1 presented an increase in amylase and lipase levels at posttransplant month 18 (up to 541 UI/L and 1185 UI/L, respectively). Pancreatic biopsy reported moderate chronic pancreatitis interpreted as possible MMF toxicity and resolved within 5 months after MMF discontinuation. CNI-related toxicity before cART reintroduction was advocated by renal biopsy for Patient 3 and 4 and accompanied by a creatinine increase of 2.24 and 3.69 mg/dL (posttransplant day 7 and 22), respectively. Patient 3 was on IV CSA-based regimen (trough levels of 301 ng/mL), and Patient 4 was receiving a TAC (trough levels of 17.4 ng/mL). Patients 3 and 4 were switched to TAC and SRL, respectively. Subsequently (posttransplant day 30) Patient 3 presented a creatinine increase (2.46 mg/dL) associated with the presence of detectable donor-specific anti-HLA alloantibodies in the serum. TAC levels were 13.7 ng/mL. In absence of other possible causes of renal damage, a course of IV immune globulin was attempted and followed by creatinine normalization at day 4 after treatment.
Patient 4's renal biopsy showed acute cellular rejection (Banff stage 2A) at posttransplant day 79. Methylprednisolone boluses administration was followed by creatinine decrease from 2.71 to 1.61 mg/dL. The rejection was related to efavirenz reintroduction causing SRL level reduction (from 7 to 3.9 ng/mL). Efavirenz blood levels were within normal limits. Due to difficulty in achieving target trough levels despite increasingly higher SRL doses (up to 7 mg daily), the treatment was switched to TAC and raltegravir replaced efavirenz.
Pre- and post-SPK cART are listed in Table 1. Pretransplant genotypic testing was available only for Patients 3 and 4 and did not show any major antiretroviral mutations. Antiretrovirals were discontinued on the day of SPK. HIV-RNA was detectable in all recipients at median day 28 (range 25–31), except for Patient 2 who had positive HIV-RNA before transplant. cART was reintroduced shortly after positive plasma HIV-RNA detection. At median day 108 after cART reintroduction (range 71–195), HIV-RNA returned stably to undetectable levels. Figure 1 shows HIV-RNA viral load and absolute CD4 cell count trends during the first 2 years posttransplant. Initially, low or undetectable HIV-RNA was reported in almost all recipients, followed by a rebound of viral replication successfully controlled by all patients after cART reintroduction. The overall CD4 cell count, affected by the immunosuppressant therapy in the early posttransplant, trended upward for all recipients. Median CD4 percentage was 22% (range 16–28%) in the first 12 weeks posttransplant and 25% (range 20–33%) from week 12 up to week 48 posttransplant. Recipients receiving PI-based cART required much lower TAC doses compared to Patients 1, on an NNRTI-based regimen, and Patient 4, on raltegravir. Prednisone was discontinued in 3 of 4 patients within the first 3 months after transplantation (median day 92, range 25–219 days) with no consequences on graft function. Patient 1 was the first transplanted, when an early steroid withdrawal policy was not yet routinely established at our center. Two steroid discontinuation attempts after posttransplant month 6 were followed by creatinine increases (maximum serum level of 2.18 mg/dL). At posttransplant month 19, a borderline rejection (renal biopsy showing lymphocyte infiltration <10% and rare intratubular CD3 cells) was documented with maximum creatinine levels of 2.17 mg/dL and followed by normalization in absence of therapy. The patient is currently maintained on prednisone 2 mg/day.
(Enlarge Image)
Figure 1.
HIV-RNA and CD4 absolute cell count trends in the HIV-positive recipients of simultaneous pancreas–kidney transplant (SPK). HIV-RNA levels, expressed as copies/mL (cp/mL), and absolute CD4 cell count (average ± SD), expressed as cells/mm, are reported up to 24 months posttransplant. HIV-RNA levels were measured at various time points and grouped in four categories (1) ≤ 1000 copies/mL, (2) 1000 < cp/mL ≤ 50 000, (3) 50 000 < cp/mL ≤ 250 000 and (4) >250 000 cp/mL. With the exception of Patient 2, naive to cART with detectable HIV-RNA at baseline, all recipients maintained low or undetectable HIV-RNA for the first 3 weeks posttransplant. All patients reached undetectable HIV-RNA levels within posttransplant week 16. Average absolute CD4 cell count trended upward during the posttransplant follow-up, remaining stable above 300 cells/mm starting from posttransplant week 12.
Posttransplant complications are listed in Table 2. Surgical complications and posttransplant infections mostly occurred within the first 4 weeks posttransplant, at median days 18 (range 1–44 days) and 30 (range 9–128 days), respectively. Most common infections were urinary tract infections (UTIs) and bacteremias. All SPK recipients suffered surgical complications leading to laparotomic interventions, with an average of two surgical revisions per patient. Three patients experienced anastomotic bleeding (median posttransplant day 9, range 1–44 days). In Patient 1 and 3, hematomas formation required surgical drainage. Two patients underwent cholecystectomy due to gangrenous cholecystitis at posttransplant day 26 and day 9, respectively. Association of surgical complications with infectious processes occurred in three patients: a subdiaphragmatic abscess, a pelvic abscess subsequent to a complicated cholecystitis and an infected psoas hematoma. Patients 1 and 3 experienced episodes of bacteremias, with Escherichia coli, Pseudomonas aeruginosa and MRSA as the most commonly isolated pathogens. Three patients had recurrent UTIs. Surgical site infection due to Enterococcus faecalis was documented in Patient 2 (posttransplant day 12). One episode of pneumonia (posttransplant day 13) and one pulmonary TB infection, as described, were also reported.
Results
Patients' Characteristics
Patients' characteristics are summarized in Table 1. All patients (3 males, 1 female) were HIV-infected type 1 diabetics with chronic renal disease on hemodialysis. The median age was 39.5 years (range 31–49). Ethnicity was Caucasian except for the female recipient (Patient 3) who was of African origin. The median duration of HIV infection estimated from the time of first HIV-positive test was 7.5 years (range 3–19). Risk factor for HIV transmission was sexual in 3 patients. Patient 2, naive to antiretrovirals due to stability of immunovirological parameters, was a previous intravenous drug user (IVDU), genotype 1 HCV coinfected with HCV-RNA positivity, and had no fibrosis at liver biopsy (Ishak grade II, stage 0). Overall dialysis duration before SPK was 4 years (1391 days, range 542–2607) with a time spent on the transplant waiting list of around 123 days (range, 84–520). Average absolute CD4 cell count measured within 3 months before transplant was 534 cell/mm (range 470–698). Patients 1 and 4 received organs from standard risk donors, Patient 3 from an increased risk donor, and Patient 2 from a donor with calculated risk for bacteremia, as defined by the Italian guidelines The average donors' age was 29 years (range 23–39). Median cold ischemia time was 13.5 h (range 9–16). All recipients were CMV-IgG and EBV-IgG positive. Patients 2 and 3 serology was compatible with previous Hepatitis B virus (HBV) infection. We registered one immune response to HBV vaccination (Patient 4, HBsAb 1000 mUI/mL) in the two HBsAg-, HBcIgG-negative recipients.
Posttransplant Follow-up and Graft Survival
Overall posttransplant follow-up ranged from 2 to 5 years with a median duration of 45 months (range 26–67). As reported in Table 1, all patients had stable creatininemia at last follow-up visit (median 1.24 mg/dL, range 1.20–1.28). Glucose levels were within normal range in 3 of 4 recipients (86 mg/dL, range 75–99). Patient 1, presently back on insulin therapy because of pancreatic graft loss and under evaluation for islet transplantation, presented with fever and hyperglycemia (429 mg/dL) at posttransplant month 64. During routine follow-up 1 month before hospitalization, results were within normal limits. An abdominal CT scan showed possible pancreatic graft vascular thrombosis not confirmed at laparotomy that evidenced a necrotic pancreatic graft with patent vessels and was followed by graft removal. Histologic examination displayed signs of necrotic acute pancreatitis associated with acute and chronic rejection.
All recipients had undetectable HIV-RNA at last follow-up visit. Mean absolute CD4 number and percentage were 425 cells/mm (range, 307–701) and 28% (range 23–29%), respectively. Patient 2, who had a negative pretransplant tuberculin skin test (TST) and negative history of tuberculosis (TB) exposure, developed pulmonary TB 35 months after transplantation and was successfully treated with an 18-month course of a rifamycin-sparing antimycobacterial treatment. No acquired immunodeficiency syndrome (AIDS) defining illnesses were reported among the other recipients. Patient 3 presented genital HSV-2 reactivation at posttransplant day 19 and was treated with oral valacyclovir. No preemptive CMV treatments were started given that the highest CMV-DNA viral load registered was 31 000 copies/mL. Before SPK, HHV8 serology was negative for all the donors and for two of the recipients. HHV8 serological status was not available for the other two recipients. All recipients were negative for HHV8-DNA (undetectable by PCR) and no lesions suggestive of Kaposi's sarcoma were observed during posttransplant follow-up.
Renal and Pancreatic Function
C peptide and glycosylated hemoglobin levels were maintained within normal range in all recipients. Patient 1 presented an increase in amylase and lipase levels at posttransplant month 18 (up to 541 UI/L and 1185 UI/L, respectively). Pancreatic biopsy reported moderate chronic pancreatitis interpreted as possible MMF toxicity and resolved within 5 months after MMF discontinuation. CNI-related toxicity before cART reintroduction was advocated by renal biopsy for Patient 3 and 4 and accompanied by a creatinine increase of 2.24 and 3.69 mg/dL (posttransplant day 7 and 22), respectively. Patient 3 was on IV CSA-based regimen (trough levels of 301 ng/mL), and Patient 4 was receiving a TAC (trough levels of 17.4 ng/mL). Patients 3 and 4 were switched to TAC and SRL, respectively. Subsequently (posttransplant day 30) Patient 3 presented a creatinine increase (2.46 mg/dL) associated with the presence of detectable donor-specific anti-HLA alloantibodies in the serum. TAC levels were 13.7 ng/mL. In absence of other possible causes of renal damage, a course of IV immune globulin was attempted and followed by creatinine normalization at day 4 after treatment.
Acute Rejection
Patient 4's renal biopsy showed acute cellular rejection (Banff stage 2A) at posttransplant day 79. Methylprednisolone boluses administration was followed by creatinine decrease from 2.71 to 1.61 mg/dL. The rejection was related to efavirenz reintroduction causing SRL level reduction (from 7 to 3.9 ng/mL). Efavirenz blood levels were within normal limits. Due to difficulty in achieving target trough levels despite increasingly higher SRL doses (up to 7 mg daily), the treatment was switched to TAC and raltegravir replaced efavirenz.
HIV Status, cART and Immunosuppression
Pre- and post-SPK cART are listed in Table 1. Pretransplant genotypic testing was available only for Patients 3 and 4 and did not show any major antiretroviral mutations. Antiretrovirals were discontinued on the day of SPK. HIV-RNA was detectable in all recipients at median day 28 (range 25–31), except for Patient 2 who had positive HIV-RNA before transplant. cART was reintroduced shortly after positive plasma HIV-RNA detection. At median day 108 after cART reintroduction (range 71–195), HIV-RNA returned stably to undetectable levels. Figure 1 shows HIV-RNA viral load and absolute CD4 cell count trends during the first 2 years posttransplant. Initially, low or undetectable HIV-RNA was reported in almost all recipients, followed by a rebound of viral replication successfully controlled by all patients after cART reintroduction. The overall CD4 cell count, affected by the immunosuppressant therapy in the early posttransplant, trended upward for all recipients. Median CD4 percentage was 22% (range 16–28%) in the first 12 weeks posttransplant and 25% (range 20–33%) from week 12 up to week 48 posttransplant. Recipients receiving PI-based cART required much lower TAC doses compared to Patients 1, on an NNRTI-based regimen, and Patient 4, on raltegravir. Prednisone was discontinued in 3 of 4 patients within the first 3 months after transplantation (median day 92, range 25–219 days) with no consequences on graft function. Patient 1 was the first transplanted, when an early steroid withdrawal policy was not yet routinely established at our center. Two steroid discontinuation attempts after posttransplant month 6 were followed by creatinine increases (maximum serum level of 2.18 mg/dL). At posttransplant month 19, a borderline rejection (renal biopsy showing lymphocyte infiltration <10% and rare intratubular CD3 cells) was documented with maximum creatinine levels of 2.17 mg/dL and followed by normalization in absence of therapy. The patient is currently maintained on prednisone 2 mg/day.
(Enlarge Image)
Figure 1.
HIV-RNA and CD4 absolute cell count trends in the HIV-positive recipients of simultaneous pancreas–kidney transplant (SPK). HIV-RNA levels, expressed as copies/mL (cp/mL), and absolute CD4 cell count (average ± SD), expressed as cells/mm, are reported up to 24 months posttransplant. HIV-RNA levels were measured at various time points and grouped in four categories (1) ≤ 1000 copies/mL, (2) 1000 < cp/mL ≤ 50 000, (3) 50 000 < cp/mL ≤ 250 000 and (4) >250 000 cp/mL. With the exception of Patient 2, naive to cART with detectable HIV-RNA at baseline, all recipients maintained low or undetectable HIV-RNA for the first 3 weeks posttransplant. All patients reached undetectable HIV-RNA levels within posttransplant week 16. Average absolute CD4 cell count trended upward during the posttransplant follow-up, remaining stable above 300 cells/mm starting from posttransplant week 12.
Posttransplant Complications
Posttransplant complications are listed in Table 2. Surgical complications and posttransplant infections mostly occurred within the first 4 weeks posttransplant, at median days 18 (range 1–44 days) and 30 (range 9–128 days), respectively. Most common infections were urinary tract infections (UTIs) and bacteremias. All SPK recipients suffered surgical complications leading to laparotomic interventions, with an average of two surgical revisions per patient. Three patients experienced anastomotic bleeding (median posttransplant day 9, range 1–44 days). In Patient 1 and 3, hematomas formation required surgical drainage. Two patients underwent cholecystectomy due to gangrenous cholecystitis at posttransplant day 26 and day 9, respectively. Association of surgical complications with infectious processes occurred in three patients: a subdiaphragmatic abscess, a pelvic abscess subsequent to a complicated cholecystitis and an infected psoas hematoma. Patients 1 and 3 experienced episodes of bacteremias, with Escherichia coli, Pseudomonas aeruginosa and MRSA as the most commonly isolated pathogens. Three patients had recurrent UTIs. Surgical site infection due to Enterococcus faecalis was documented in Patient 2 (posttransplant day 12). One episode of pneumonia (posttransplant day 13) and one pulmonary TB infection, as described, were also reported.
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