Abstract
Purpose:
Infections are among the top three causes of death of older adults in the first year after kidney transplantation (KT). Our aim was to describe infectious complications among KT recipients aged ≥65 during the first 12 months post-transplant.
Methods:
Single center retrospective cohort study.
Results:
Ninety-one KTs had been performed in patients ≥ 65 years of age between 2011–2015. 92.3% of the patients developed at least one infection. Infectious episodes increased the risk of future infection by 10% (p=0.0018) with each infection portending a greater risk. At a patient level, viral (71.4%) and bacterial (70.2%) infections predominated. Urinary tract infections were the most frequent complication (30.3%), followed by cytomegalovirus infections (22.7%). Infections were the main reason for readmission. 7.7% of the patients developed rejection; and overall 3.3% lost their graft. Mortality at one year was 9.9%.
Conclusions:
Older KT recipients have a high incidence of infectious complications the first year after KT. Infections were the number one reason for readmission, and an infection episode predicted future infections for the individual patient. Despite these complications, the majority of older KT recipients were alive with a functioning graft at one-year.
Keywords: kidney transplantation, infection, aged, epidemiology
Introduction
Older adults are the fastest-growing group with end-stage-renal-disease and in increasing need of kidney transplantation. These individuals are at risk for infectious complications[1], not only due to the immunosuppression associated with transplantation but also due to aging related immune senescence[2,3].
Infections imply a higher incidence of morbidity and mortality in this group. Infection is among the top three causes of death among kidney transplant (KT) recipients, and death with a functioning graft is the most common form of graft loss in older adults[4–6].
A gap in knowledge exists regarding the infectious complications after kidney transplant in this group. Additionally, their clinical presentation is often atypical, making diagnosis challenging. Information in the literature mainly comprises traditional outcomes such as rejection, patient and graft survival[7,8]; information regarding infection specifics is limited[1,9,10].
Our aim was to describe infectious complications by syndrome and pathogen as well as 12-months outcomes among older KT.
Material and Methods
Study design and Study Center
This is a single center retrospective cohort study of kidney-only transplants performed in adults aged ≥65 years between 2011–2015 at Duke University Medical Center; 551 KTs were performed during the study period. The study was approved by the Duke Institutional Review Board.
Patient cohort
An institutional tool, Duke Enterprise Data Unified Content Explorer (DEDUCE)[11] was used to identify all patients aged ≥65 that received a kidney-only transplant in the 5-year study period.
Our center-specific antimicrobial prophylaxis after KT included Pneumocystis jiroveci pneumonia (PJP) prophylaxis for twelve months and/or for three months after acute rejection, whichever was longer. Cytomegalovirus (CMV) prophylaxis depended on CMV serostatus[12]. For donor and recipient negative CMV serostatus, valacyclovir/acyclovir was used for 90 days if the herpes simplex serostatus was positive. For recipient CMV positive serostatus, preemptive monitoring was performed, which included weekly CMV monitoring for 12 weeks, plus 90 days of valacyclovir/acyclovir if HSV serostatus was positive. High-risk patients (mismatches, and CMV recipient serostatus positive after thymoglobulin induction) received ganciclovir/valganciclovir for 180 days; following cessation of prophylaxis, CMV PCR monitoring was performed every 2 weeks for a minimum of 3 months. Standard perioperative antibacterial prophylaxis included cefazolin, or, if penicillin allergic, ciprofloxacin and clindamycin.
Induction immunosuppression protocols vary. Low risk renal transplants get no induction; high risk get thymoglobulin induction (e.g. panel reactive antibodies (PRA) ≥30, historic donor specific antibodies, per team discretion if at high risk for delayed graft function or for biopsy) and some high risk with contraindication to thymyglobulin receive basiliximab. Targeted tacrolimus levels for maintenance therapy were 8–10 ng/ml (first month), 6–8 ng/ml (month 1–3) and 5–7 ng/ml (>6 months).
Data Extraction
Demographic, clinical, microbiological and outcome data were extracted manually from the chart. Data collected were managed using REDCap™ data capture tool[13]. Infection data collection included information about infectious syndromes and microbiological data. Standard definitions and definitions per CDC/NSHN as described elsewhere were used[14,12]. Ambulatory status was classified as “independent”, “needs assistance” (cane, walker) or “dependent”. Karnofsky scores prior to transplant and at approximately one-year were collected.
Statistical Analysis
Descriptive results are shown as total numbers/percentages, mean/standard deviations and medians/ interquartile range (IQR). Several types of infections were listed: pneumonia, urinary tract infection (UTI), surgical site infection (SSI), intraabdominal infection, blood stream infection (BSI), skin and soft tissue infection (SSTI), Clostridium difficile colitis, meningitis, osteomyelitis, prosthetic joint infection (PJI), hepatitis, sepsis, central line-associated bloodstream infection (CLABSI), candidemia, other, as well as CMV and BK polyomavirus (BKV) infection. Coagulase-negative Staphylococcus BSI were only included when not deemed to be contaminant. Patients were censored at death, or at the one-year mark after KT, whichever occurred first, thus the rates of infections controlled for ‘time on study’. Several versions of infections were assessed: the total number of all types, the total number of unique types, the number of infections within types. Further, since infections often co-occur on the same date, we calculated the number of unique dates (episodes) when an infection occurred. To address the question, ‘does the presence of an infection, increase the likelihood of subsequent infections?’, we employed proportional hazards modeling with recurrent events. Here, we modeled time-to-event (episode), with episode number as an only predictor. Assuming proportionality during the time between episodes, we assessed if the underlying hazards increased as the episode number increased. Statistical analysis was performed using SAS software, version 9.4. Copyright© SAS Institute Inc., Cary, NC, USA.
Results
Baseline Characteristics
Ninety-one kidney-only transplants were performed between 2011–2015 in patients ≥65 years. Baseline characteristics of recipients and donors are shown in Table 1 and 2. Median time from dialysis to transplant was 1308 days (range 38–4971), and median time on the waiting list was 589 days (range 0–2336). Further peri-transplant characteristics are shown in Table 3. The main underlying conditions responsible for renal disease were hypertension (42.9%) and diabetes mellitus (34.1%).
Table 1.
Baseline characteristics at time of transplant of older adults receiving a kidney transplant, n=91.
| Age in years, median (range) | 68 (65–75) |
| Sex, male n (%) | 55 (60.4) |
| Race n (%) | |
| Caucasian | 56 (61.5) |
| African-American | 29 (31.9) |
| Asian | 6 (6.6) |
| History of prior chronic renal replacement therapy n (%) | 70 (76.9) |
| Hemodialysis | 53 (75.7) |
| Comorbidities n (%) | 91 (100) |
| Diabetes mellitus | 43 (47.3) |
| Insulin-dependent | 22 (51.2) |
| Hypertension | 85 (93.4) |
| CVD | 45 (49.5) |
| Hyperlipidemia | 27 (29.7) |
| Obesity, BMI > 30 | 33 (36.3) |
| Genitourinary conditions | 14 (15.4) |
| Prior Cancer | 13 (14.3) |
| Prior abdominal surgery | 45 (49.5) |
| History of prior transplant | 8 (8.8) |
| Solid organ | 7 (87.5) |
| CMV status n (%) | |
| CMV recipient positive | 63 (69.2) |
| CMV D−/R− | 11 (12.1) |
| CMV D+/R− | 17 (18.7) |
| Ambulatory status n (%) | |
| Independent | 69 (75.8%) |
| Need assistance† | 19 (20.9%) |
| Dependent | 1 (1.1%) |
| N/A | 2 (2.2%) |
CVD: cardiovascular disease; BMI: body mass index; KT: kidney transplant; D: donor, R: recipient.
need assistance=use of cane/walker, N/A: not available.
Table 2.
Baseline characteristics of organs. n=91 (from 88 donors).
| Age in years, median (range) | 46 (2–69) |
| Sex, male (%) | 51 (56.0) |
| Type of donation n (%) | |
| Deceased donor | 66 (72.5) |
| Living donor | 25 (27.5) |
| Living related | 14 (56.0) |
| Race n (%) | |
| African-American | 15 (16.5) |
| Caucasian | 68 (74.7) |
| Other or unknown | 8 (8.84) |
| Donor classification & type n (%) | n=66 (deceased donors only) |
| Standard criteria donor | 43 (65.2) |
| Expanded criteria donor | 15 (22.7) |
| Donation after cardiac death | 22 (33.3) |
| Increased risk donor | 9 (13.6) |
| KDPI, median (range) | 66 (10–93), available in 53 patients |
| Positive donor cultures n (%) | |
| Blood culture | 8 (14), available in 57 patients |
| Urine culture | 7 (12.3), available in 57 patients |
KDPI: kidney donor profile index.
Table 3.
Peri-transplant characteristics of older kidney transplant recipients. n=91
| Ischemia and surgical time in minutes, median (range) | |
| Cold ischemia | 996 (10–2505) |
| Warm ischemia | 32 (5–63) |
| Surgery (skin-to-skin) | 234 (132–628) |
| PRA (%), median (IQR), n=90 | 0 (0–27.8) |
| Induction regimen n (%) | |
| Basiliximab | 44 (48.4) |
| Thymoglobulin | 27 (29.7) |
| Ureteral stent placed n (%) | 71 (78.0) |
| Maintenance immunosuppression | |
| Prednisone | 89 (97.8) |
| MMF | 88 (96.7) |
| Tacrolimus | 90 (98.9) |
| Delayed graft function n (%) | 24 (26.4) |
| Days on dialysis after transplant, median (IQR) | 9 (5.5–14.0) |
PRA: panel reactive antibody; MMF: mycophenolate mofetil.
All patients received perioperative antibiotic prophylaxis for surgery per standard of care. Peri- and postransplant prophylaxis included 90 patients (98.9%) receiving PJP prophylaxis and 58 (63.7%) antiviral.
Discharge location included 88 patients going home; one patient went on hospice. Of the 84 patients still alive at one year, at least 47.6% remained independent for ambulation, 23.8% needed assistance; the median Karnofsky score was 70.
Infectious Complications
Infectious complications occurred in 84 patients (92.3%). Infection was the main reason for readmission in the first year (58%), followed by laboratory abnormalities (25.5%) and surgical complications (20.4%).
Infectious episodes increased the risk of future episodes with increasing risk (hazard ratios (HR)) with each additional infection. Relative to the baseline risk, each additional infection episode increased the HR by 10% (95% CI=1.04, 1.17; p=0.0018). Among patients with infection, 71.4% (60/84) developed viral, 70.2% (59/84) bacterial, 16.7% (14/84) fungal and 1.2% (1/84) mycobacterial infections. For timing of infection based on infection type see Figure 1. Episode-specific infection data is shown in Table 4.
Figure 1. Type of infections in older kidney transplant recipients during the first year post-transplant.
BKV: BK virus; C diff: Clostridium difficile colitis; CMV: cytomegalovirus; SSI: surgical site infection; UTI: urinary tract infection.
Table 4.
Infectious episodes per sites /syndrome.
| Pathogen Type n (% total episodes) |
Infection Site n (% of total episodes) |
Infection Category n (% total episodes) |
|---|---|---|
| Bacterial – 168 (55.3) |
Urinary Tract 90 (53.6) † | Uncomplicated 39 (43.3) |
| Complicated/pyelonephritis 22 (24.4) | ||
| Asymptomatic bacteriuria 17 (18.8) | ||
| Catheter-associated 10 (11.1) | ||
| Unknown 2 (2.2) | ||
| Bloodstream 22 (13.1) | Non-Central line associated 22 (100) | |
| Central line associated 0 (0) | ||
| Surgical Site 14 (8.3) | Organ Space 8 (57.1) | |
| Superficial Incisional 4 (28.6) | ||
| Deep Incisional 2 (14.3) | ||
| Other Intraabdominal 4 (2.4) | Abscess – 2 (50) | |
| Peritonitis – 2 (50) | ||
| Skin/Soft Tissue 4 (2.4) | ||
| Pneumonia 10 (6.0) | Hospital Acquired 5 (50) | |
| Community Acquired 5 (50) | ||
| Sepsis 8 (4.8) ‡ | Septic shock 4 (50) | |
| Other 16 (9.5) | Clostridium difficile associated Diarrhea 9 (56.3) Sinusitis 4 (25.0) Otitis 1 (6.3) Dental 1 (6.3) CNS 1 (6.3) |
|
| Viral −121 (39.8) |
CMV 69 (57) § | Asymptomatic viremia 62 (89.9) |
| CMV Syndrome 4 (5.8) | ||
| Tissue Invasive Disease 0 (0) | ||
| Unknown 3 (4.3) | ||
| BK Virus 37 (30.6) | Viremia 36 (97.3) | |
| Nephropathy 1 (2.7) | ||
| VZV 4 (3.3) | Shingles, dermatomal 3 (75) | |
| Shingles, disseminated 1 (25) | ||
| Respiratory Virus 4 (3.3) | Adenovirus 1 (25) Influenza 2 (50) RSV 1 (25) |
|
| Other 7 (5.8) | EBV 5 (71.4) HSV 2 (28.6) |
|
| Fungal −14 (4.6) |
Oropharyngeal 11 (78.6) | Candida 11 (100) |
| Cryptococcosis 1 (7.1) | Disseminated 1 (100) | |
| Urinary tract † 2 (14.3) | Catheter-associated 2 (100) | |
| Mycobacterial −1 (0.3) |
Bloodstream infection 1 (100) |
M. abscessus (100) |
Eighty-four patients (92.3%) developed an infectious complication. There were 304 infectious episodes. Number of episodes and percentage of totals are presented as well as percentages within episodes. UTI: urinary tract infection. CMV: cytomegalovirus. VZV: Varicella Zoster Virus. RSV: respiratory syncytial virus. EBV: Epstein Barr Virus. HSV: Herpes Simplex Virus. Two patients developed post-transplant lymphoproliferative disorder (PTLD) (2.2%).
Of the 92 total episodes of UTI, 90 were bacterial and 2 were secondary to yeast.
All episodes of sepsis were associated with bloodstream infections.
One primary infections presented as CMV syndrome, the rest as infection / asymptomatic viremia.
Viral Infections.
The most frequent infection in the first year after KT was CMV which occurred in 51 patients (56%), with 6 (11.7%) of these being primary infections. The median time to first peak viremia was 72 days (IQR 47–149).
BK viremia occurred in 28/91 (30%) patients with a median time to first detection of 102 days (IQR 77.8–168.8).
Bacterial Infections.
The most frequent bacterial infections were UTIs; 44 (48.4%) patients experienced at least one UTI. The median time to first UTI was 61.5 days (IQR 31.8–160.2). Seventy-nine cultures were available for review; the most frequent pathogens were gram-negative bacteria; mainly Klebsiella spp. (31.6%), Escherichia coli (17.7%), Enterobacter spp. (13.9%) and Pseudomonas spp. (11.4%). Among gram-positive infections, Enterococcus was most common (12.7%).
Bloodstream infections were the second most frequent type of bacterial infection with a total of 22 episodes in 17 (18.7%) patients. None met the definition for CLABSI. Median time to first BSI infection was 59 days (IQR 32–128). Twenty-three blood cultures were available for review; the most frequent pathogens were gram negatives, mainly Klebsiella (8) and E. Coli (5), followed by gram positives such as coagulase-negative Staphylococcus (5) and Enterococcus (2). Eleven (12.1%) patients developed a SSI; median time to first SSI was 18 days (IQR 10–52.5). Enterococcus was the predominant pathogen recovered in 50% of the cultures. Nine (9.9%) patients developed pneumonia (10 episodes); median time to first episode was 74 days (IQR 20–150). Eight (8.8%) patients developed sepsis a median of 163.5 days after KT (IQR 47–256.8). Seven (87.5%) of these episodes were associated with BSI.
C. difficile colitis occurred in 7 patients (7.7%) a median of 8 days after KT (IQR 7–17.5). Two patients suffered recurrent C. difficile associated diarrhea.
Other.
Fungal infections, primarily Candida, were documented in 14 (16.7%) patients, including one case of cryptococcal meningitis that presented 310 days after KT. There were no invasive mold infections.
Rejection, Graft and Patient Survival.
Seven (7.7%) patients experienced rejection; six acute cellular and one humoral, the latter one resulting in graft loss. Overall, nine (9.9%) patients died during the first year; 2 (22.2%) deaths secondary to gram-negative sepsis occurred during the transplant admission. Eight (88.9%) patients died with a functioning graft. Three graft losses (3.3%) were reported in the first year.
Discussion
We describe outcomes including infectious complications in the first year after KT in adults ≥65 of age. The infection rate was very high, with 92.4% of patients experiencing at least one infectious complication. This is higher than the 67%−80% rate reported from comparable small series of similar aged patients[9,15] and substantially higher than in younger cohorts (25.5%)[16]. Despite this very high number of infectious complications during the first post-transplant year, the number of deaths, graft rejections, and graft losses was low compared to similar aged patients[9].
Mortality during the first year after transplant (9.9%) was comparable to OPTN data for this age group but lower than other series[8,9,15,17]. While it is known that older adults have lower rejection rates after transplant[7,18,15] our rate (8%) is extremely low. Other groups have described rejection rates ranging from 11%−25% in patients with varying ages over 60[9,10,15,18,19]. The paradox of higher infection and lower rejection rates in the aged KT population calls to question whether the older cohort is over-immunosuppressed, a consequence of too much exogenous immunosuppression and immunosenescence.
While outcomes after KT over the last 20 years have been improving[5,8], the reasons for these favorable outcomes are likely multivariate including improvements in surgical techniques and immunosuppressive regimens. The idea of individualized immunosuppression in older adults is not new[20] but has yet to be properly defined and implemented. The immunosuppressive regimens as well as the targeted levels of calcineurin inhibitors were not modified for older adults.
One might also question the impact of chronological versus physiological age of the recipient. By definition, older adults considered for any type of transplantation represent a highly selected subpopulation[7], although certainly not free of comorbidities. In the U.S., no uniform criteria for pre-transplant evaluation of older KT candidates exist[21]. Studies have shown that transplantation in this age group offers a cardiovascular and mortality benefit over staying on dialysis[22–26]. Cardiovascular events in KT recipients develop at an annual rate of 3.5–5%[27]. Interestingly, in our series, although half of our patients had a history of cardiovascular, admissions in the first year after KT for cardiac causes were rare (2.2%).
The absence of standardized measurement of functional status and quality of life after KT in older adults is a major gap and opportunity for research and clinical care particularly since older adults rate independence as a critically important goal of care. A prior study in younger KT recipients addressed some subjective measures of functional status; worse functional status was associated with a shorter 3-year survival [28].
Looking more closely at the type and timing of infectious complications (Figure 1), infections were most frequent between 1–6 months post-transplant. Further, BSI and UTIs for which gram negatives were the most common cause, peaked after the first month, raising the question of the urinary system as the source of BSI and need for hospital readmissions.
Urinary tract infections (UTIs) are of distinct interest in KT recipients as they represent the most frequent infection[29–31]. Reasons for this include surgical manipulation of the urinary system during the procedure, stent placement, absence of a sphincter between the transplanted ureter and the bladder, non-functioning native kidneys that serve as potential reservoirs for bacteria and the use of Foley catheters. Other classic risk factors for UTIs are older age, female gender, acute rejection, and deceased donation[32,33]. Surprisingly, in our cohort, most UTIs occurred 3 months after KT. One might expect that most infections happen early, as this is when the immunosuppression is most profound[34] and ureteral stents, if used, are still in place.
As anticipated, based on our preemptive prophylaxis protocol for intermediate risk recipients and universal prophylaxis in the high serologic risk group, CMV was the most common infectious pathogen emerging after the first month. Historically, increased age, positive serostatus of the donor, T-cell depleting induction, rejection and concomitant infection with other viruses have been associated with CMV disease[35,36]. Our percentage of patients with CMV viremia is higher than anticipated in seropositive recipients (expected 15–25%). Over-immunosuppression, immunosenescence or the fact that low level viremias were included in our study could explain this finding. As shown in other studies, CMV tended to be delayed onset after prophylaxis ended in the high serologic risk group[37].
Of special interest is the high incidence of BK viremia in this cohort(30%),on the higher end of the reported 13–30%[38,39]. Again, we query if this represents a surrogate marker of over-immunosuppression.
A unique finding of our study is that infectious episodes increased the risk of future infections, each additional infection episode increased the HR by 10%. We speculate that this is multifactorial but could be a marker of worse immune function after acute infection. Further, it has been reported that the risk of dying of an infection is exponentially increased in older KT recipients[1]. These findings support the importance of early recognition and prevention of infectious complications in older adults, including proper pre-transplant immunizations, review of serologies and cultures of recipients and donors, adjustment of peri-procedure antimicrobial prophylaxis, individualized adjustment of immunosuppression, close follow up and potential immunologic profiling.
The limitations of this study include its retrospective single center nature and sample size; local patterns may vary and should be taken into account when interpreting our results.
In conclusion, older KT recipients have a high incidence of infectious complications during the first year after surgery. Infections were the number one reason for readmission. Specifically, UTIs, BSI, CMV and BKV are mainly responsible for an increased morbidity. Infectious episodes increased the risk of future infection by 10% which each infection portending a greater risk. Despite these complications, the majority of older KT recipients were alive with a functioning graft at one-year although with possible reduced independence.
Future studies should include young transplant recipients to address questions regarding the effects of age on infections. Additionally, studies should include immunosuppressive levels, measures of functional status, frailty and immune function as either direct or surrogate markers for overall immune function. Understanding the immunologic risk for infection and recognizing infection as a predictor of future infections is an area for study and targeted prevention strategies.
Acknowledgments
Acknowledgements / Funding: “ Research reported in this publication was supported by the National Institute of Allergy and Infectious Diseases (NIAID) of the National Institutes of Health under award number 5T32AI100851 (MHM). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.” Dr. Schmader was supported by the National Institute on Aging, Duke Pepper Older Americans Independence Center P30AG028716.
Footnotes
Ethical approval: “For this type of study formal consent is not required.”
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