Effects of preservative fluid associated possible donor-derived carbapenem-resistant Klebsiella Pneumoniae infection on kidney transplantation recipients

Kidney transplantation is the most effective therapy for end-stage kidney diseases [1]. However, approximately 60% of the deaths and graft losses in the first year after transplantation are caused by infection and perioperative complications [2, 3]. Infection has become a major cause of morbidity and mortality after solid organ transplantation (SOT). Bacterial infection is the most common type of infection after transplantation, with most infections occurring in the first three months after transplantation [3, 4]. An accumulation of data over the past few years confirm an increasing trend of gram-negative bacterial infections and the emergence of multidrug-resistant (MDR) bacterial pathogens [5]. An Italian study on SOT recipients showed that 16% of organ recipients were infected by gram-negative microorganisms, most of whom were infected with carbapenem-resistant Klebsiella pneumoniae (CRKP) [6].

In recent years, with the increase in the number of kidney transplant (KT) recipients, the gap between the number of available kidneys and the number of potential recipients has widened. The increased demand has led to increased utilisation of organs from marginal donors, including infected marginal donors [7]. Donor-derived infections (DDIs) have also become one of the major problems after SOT. Some studies reported that recipients with this type of infection could achieve favourable outcomes with appropriate antimicrobial therapy [8‐11]; however, some authors suggested DDIs are associated with severe morbidity and mortality [12, 13], depending on the type of pathogenic microorganism [14]. CRKP has been reported as one of the most common pathogens in DDIs after kidney transplantation from deceased donors [15] and is characterised by high mortality, a high transmission rate and MDR [16]. Data showed that the morbidity of CRKP infection after SOT ranged from 2.5 to 35%, showing a high case fatality rate of 62.5 to 82% [17, 18].

The transmission of microorganisms through preservation fluid (PF) is a potential method for early DDI in KT recipients after KT, and routine microbial analysis of PF can help identify patients with a high risk of early post-transplantation infection [19]. Most studies have shown that coagulase-negative Staphylococcus and Enterococci are the most common contaminants in PF, most of which are low-virulence bacteria [20‐22]. To date, the impact of CRKP contamination in PF on kidney recipients is not clear, and the best strategies for preventing and treating subsequent infections in kidney recipients remain unclear. Therefore, this study aimed to investigate the incidence of CRKP contamination in deceased donor PF and the impacts of possible donor-derived carbapenem-resistant Klebsiella pneumoniae (pdd-CRKP) infection after KT on recipients; their prevention and treatment options are also discussed.

A total of 337 recipient underwent kidney transplantation between December 2018 and December 2020, including 212 recipients of organs from deceased donors and 110 corresponding deceased donors. A total of 206 PF samples were collected, and 20 recipients had CRKP-positive PF cultures. The incidence of death or graft loss in recipients with CRKP-positive PF cultures was 6/20(30.0%), and the incidence of death or graft loss in recipients with CRKP- negative PF cultures was 15/186(8.1%).

Although numerous reports have shown that approximately 3% of SOT recipients are affected by fatal DDI, the use of organs from marginal donors is increasing due to the current organ shortage [11, 27]. The incidence of DDI is reduced by donor screening and the use of prophylactic antimicrobials in recipients, but transmission can still occur and may lead to increased morbidity and mortality [28]. The PF is a possible pathway for DDI. Most of the microorganisms in PF are coagulase-negative Staphylococci and Enterococci [20, 21], and most of them are contaminated saprophytic flora. Because of the widespread use of prophylactic antibiotics in transplant recipients, these low-virulence organisms are difficult to transmit through PF, resulting in significantly reduced pathogenicity [29]. However, MDR Enterobacteriaceae are more virulent and more likely to transmit through PF [30, 31]. Nevertheless, there are few data on the donor-derived transmission of MDR gram-negative bacilli through PF, especially CRKP. To our knowledge, this report represents the largest study of kidney transplant recipient DDIs caused by CRKP to date.

In our study, a 7.3% (15/206) incidence of pdd-CRKP infection was associated with PF, and the risk of total infection events due to PF contamination ranged from 0.83 to 14.3% in previous reports [32, 33]. However, only CRKP in PF was investigated, and DDIs caused by other microorganisms in PF were not investigated in this study. The rate of positive CRKP culture in PF in our centre is high, which may be related to the high incidence of CRKP in our centre. In China, CHINET data showed that the resistance rates of Klebsiella pneumoniae to imipenem and meropenem rose steadily from 9.2 and 9.2% in 2010 to 23.3 and 24.2% in 2020, respectively. The detection rate of CRKP in Anhui Province, where our centre is located, increased steadily from 8.9% in 2010 to 25% in 2020. On the other hand, in our cohort, the ICU stay of donors in the CRKP-positive PF culture group was longer than that in the CRKP-negative PF culture group, and the difference was statistically significant. Prolonged (> 7 days) ICU stays, the use of vasopressors, and the need for cardiopulmonary resuscitation were reported to be independent risk factors for predicting potential infections in donors [34]. Studies have found that a hospital stay of as little as 2 days is sufficient to acquire MDR hospital pathogens that can be transmitted by transplantation [35]. In our study, the age of donors with CRKP-positive PF cultures was generally higher, with an average age of 50.8 years. A prospective study by Oriol et al. found that higher donor age was an independent risk factor for positive culture of high-risk microorganisms in PF [36]. Microbial contamination of the ICU environment and intestinal damage during the organ retrieval process may also contaminate the PF and lead to a higher positive rate of CRKP cultures.

Whether microbial contamination of PF in SOT is related to DDI is controversial. Bertrand et al. reported a negligible incidence of clinical complications due to PF contamination [20]. However, some other studies have suggested that it is a common cause of early posttransplant infection [29, 37]. The occurrence of DDI also depends on the type of contaminating microorganism. MDR Klebsiella pneumoniae, MDR Acinetobacter baumannii and other bacteria are more likely to cause DDIs associated with PF than other sensitive Cocci species [21]. Cai et al. reviewed the literature on donor-derived CRKP infection from 2011 to 2018, including a total of 18 donor-derived CRKP infection recipients. Postoperatively, 1 patient died early (9 days), 5 patients died late (≥28 days), and 1 patient lost the graft kidney due to rupture of the graft artery. The overall mortality was 33.3% [13], which was higher than the overall mortality of pdd-CRKP infection in our centre (20%).

Most of the DDIs associated with PF were surgical site infections, including local infection of the graft site, infectious renal graft artery rupture and wound infection [21], which was consistent with the results of our centre. The most common type of infection in our centre was surgical site infection, and 11 of the 20 recipients had surgical site infection, followed by bloodstream infection. CRKP bloodstream infections have been reported to be the most fatal type of infection, with a mortality of up to 20-50% [38, 39]. A total of 10 CRKP-positive recipients developed bloodstream infection in our centre. Among these 10 CRKP-positive bloodstream infection recipients, there were 2 deaths and 3 graft losses. One of the recipients died of graft artery rupture, a fatal complication of donor-derived CRKP infection, which has been reported in both liver and kidney recipients with donor-derived CRKP infection [13, 40].

Due to the lack of evidence, there is no broad consensus regarding the treatment recipients with of CRKP-positive cultures in PF. Some authors have suggested that when MDR is detected in donors and PF, targeted antibacterial treatment should be performed after transplantation, which could prevent the transmission of MDR gram-negative bacteria. DDIs have been reported despite antibiotic prophylaxis [41, 42]. The authors also suggested that extended antibiotic use for 10 days after surgery might help reduce the risk of transmission and associated mortality [19]. Our study confirmed the clinical efficacy of CAZ-AVI in the prevention and treatment of CRKP infection. None of the 9 recipients who were initially given prophylactic anti-infective therapy with CAZ-AVI alone or CAZ-AVI combined with meropenem died or had graft loss. It has been reported that CAZ-AVI treatment is the only independent predictor of survival in CRKP-infected patients [43], and recent clinical trials have also demonstrated that CAZ-AVI-based therapy has successfully treated CRKP infection in immunocompromised populations [44]. In addition to drug control of infection, effective source control, such as allogeneic nephrectomy and complete debridement, can increase the success rate of cured infections [45‐47]. Allograft nephrectomy not only provides complete debridement but also reduces the bacterial load. In our study, all three surviving recipients with severe CRKP infection received allograft nephrectomy, complete debridement and drainage, and all achieved good outcomes.

Test protocols for the rapid detection of pathogens carried by donors await further study. The time required for routine microbial culture in PF from specimen collection to final results (including drug susceptibility results) may range from 48 h to 120 h, depending on the testing time and the need for additional resistance testing. This delay affects the time to start appropriate antimicrobial therapy. Although the polymerase chain reaction method can quickly obtain test results, it is expensive, has limited specificity and cannot provide information about the sensitivity of the drug. Delay in communication is another important factor in the transmission of infection [48]. Effective and timely communication between the organ procurement organisation (OPO) and the transplant centre is essential to control the transmission of pathogens and should be conducted within 24 h. Therefore, routine sample culture (blood, urine, and tracheal secretions) of potential donors in hospitals in areas where CRKP pathogens are endemic is recommended for the rapid identification of pathogens [9]. Rapid communication between the organ transplant centre and the OPO is also necessary, and it can play an important role in accelerating the use of targeted antibiotic treatment in patients who receive organs from infected donors.

The study has several limitations. First, the lack of routine microbiological screening of donors made it difficult to determine the source of CRKP and the relationship between donor infection and donor-derived CRKP infection after transplantation. Second, there were no data on the use of antibiotics given to donors. Third, regarding the transmission of DDI, genotyping technology provides necessary objective evidence for this event. Unfortunately, this technology is not widely used in our hospital. Therefore, our detection algorithm may overestimate transmission events. Finally, our sample size was small, mainly because of the low incidence of donor-derived CRKP infection, and our results may not be applicable to other transplant centres.

In summary, this study showed that the incidence of pdd-CRKP is high in our centre. Recipients with pdd-CRKP infection can still achieve a good prognosis with the use of antimicrobial agents including CAZ-AVI and donor screening for CRKP should be included in measures to contain the incidence of DDI.