The retrospective cohort study included 297 adults (older than 18 years of age) kidney transplant recipients who received kidney from donors according to Chinese type donation after cardiac death (DCD) [44] at our center during the study period. There are 11 kidney recipients of grafts from 7 DCD donors, including 2 kidney recipients with grafts obtained from 2 unknown donors and transferred from the same foreign hospital, with the incidence of CRKP-BSI of 2.7% (8/297) after the renal transplantation performed in our hospital. The pre-donation screening for CRKP colonization in donors and recipients was routinely performed.
All of the kidney transplant donors with urinary and/or bloodstream and/or sputum and/or OSSS infection developed confirmed transmission of infection, affecting eleven kidney recipients and resulting in five out of eleven (45.5%) crude mortality that all attributes to the infection-related death. Among the overall bacterial or fungal infection of KTDs, the K. pneumoniae infection takes up about 3 out of 5 (60%), except for the 2 unknown donors, leading to the transmission to all of the recipient, with the crude mortality of 44.4% (4/9).
The clinical characteristics of KTD with donor-derived infection
As the clinical characteristics summarized in Table 1, the median age was 46 years, with a gender distribution of 4 males/1 females (sex ratio 4). All of the KTD had undergone the invasive procedure with indwelling catheters, having short term of treating in intensive care unit (median 5 days), with death as the outcome, proving to be decreased kidney donors. No difference was observed between the origin of death that evenly distributed in the following causes, including Central nervous system infection (CNSI), Traumatic brain injury (TBI), Intracerebral hemorrhage (ICH), Hypertension (HTN) and Benign pituitary tumor (BPT). The most common main diagnosis was ICH (40%), evenly followed by CNSI (20%), TBI (20%) and LI (20%). In contrast to main diagnosis, Lung infection (LI) and Tracheostomy status (TS) are ranked as the most common diagnosis in the other diagnosis, and Ventriculoperitoneal shunt (VPS), Cerebral hernia (CH) and Hypertension (HTN) are followed in the second rank, each occupying the same percentage of 40%. The most frequent isolates with positive results was sputum isolates (5/5), followed by blood (3/5), urine (3/5), sputum+urine (3/5) and blood+sputum (3/5) isolates, with the urine+drainage (1/5), sputum+drainage+urine (1/5), blood+drainage+urine (1/5), blood+drainage+urine+sputum (1/5) isolates ranked as the least. For the KTDs with positive urine results, 2/3 of KTDs received appropriate antimicrobial therapy, while 1/5 of KTDs with positive sputum results and none of the KTDs with positive blood results received the appropriate therapy. Notably, except that the organ procurement coordinator (OPC) gave up the decision to donate the other side of kidney of Donor 5 after be notified the CRKP infection of the kidney that had been transplanted to the KTR, all the other donors had donated both kidneys.
Results of urinary, sputum, bloodstream and OSSS cultures of the donors are shown in Table 2. As for the blood culture, the percentage of Gram-negative bacteria (50%; 2/4) was higher than Gram-positive bacteria (25%; 1/4) and Fungi (25%; 1/4), with Klebsiella pneumoniae and Acinetobacter baumannii occupying the same proportion. The majority (30.8%; 4/13) pathogens isolated from donor’s sputum cultures were Pseudomonas aeruginosa, followed by Candida albicans (23.1%; 3/13), Klebsiella pneumoniae (15.4%; 2/13), Serratia marcescens (15.4%; 2/13) and Stenotrophomonas maltophilia (15.4%; 2/13). By contrast, C. albicans (40%; 2/5) was more frequently isolated from donor’s urine cultures, with K. pneumoniae (20%; 1/5), Escherichia coli (20%; 1/5) and Enterococcus faecium (20%; 1/5) sharing the remainder equally. Last, the proportion of Gram-positive bacteria, Enterococcus faecium (66.7%; 2/3), weighing was heavier than Gram-negative bacteria, E. coli (33.3%; 1/3) for OSSS cultures.
The Characteristics of recipients with donor-derived infection
Table 3 showed the characteristics of the donors and the corresponding kidney recipients to make a clearer relationship between donors and recipients. Five kidney recipients developed confirmed donor-derived KP infection. Based on the similarity between the antimicrobial resistance profile of KTDs (Table 6) and KTRs (Table 7), Recipients 5-9 were classified as a proven donor-derived KP infection. Except for the transmitted pathogens caused by klebsiella pneumoniae, other pathogens may contribute to the transmitted infection after KTx, for instance Candida albicans and Pseudomonas aeruginosa each in 2 cases, have been observed.
Following renal transplantation, various cultures (blood, urine, sputum, catheter, throat swab and organ-space surgical site infections) were routinely taken. When neglecting the frequency of specific cultures per KTR, the blood culture revealed advantages of the highest positive rate for K. pneumoniae (10/11) among these KTRs, with the shortest culture-positive time, followed by OSSS (8/11), urine (6/11), throat swab (3/11) and sputum (1/11). No KTR had a presumed or confirmed invasive bacterial or fungal infection pre-transplantation. All K. pneumoniae strains isolated from KTRs, except for R3, were multidrug resistant (MDR) that confirmed by susceptibility test (Table 7).
The demographic characteristics and utilization of immunosuppression drugs of patients following renal transplantation have been demonstrated in Table 4. Underlying kidney diseases of these eleven recipients consisted of 11 systemic arterial hypertension cases, 7 chronic glomerulonephritis cases, 3 diabetic nephropathy cases, and 2 IgA nephropathy. All of these patients received similar postoperative intensive care with a routine triple immunosuppression regimen including cyclosporin (n=2) or tacrolimus (n=11), mycophenolate mofetil (n=11) and corticosteroids (n=10). Besides, anti-thymocyte globulin (n=2) or basiliximab (n=6) was applied during the induction phase of immunosuppression after kidney transplantation. Time from kidney transplant to onset of donor-derived infection (the first BSI) was a median of 19 days (2-37 days) for survivors, while the time was a median of 15 days (5-43 days) for non-survivors. Organ-space surgical site infection (9/11) and pleural effusion (9/11) was the predominate type of complication of infection, equally followed by pneumoniae (8/11) and urinary tract infection (8/11). Strikingly, there are 3 cases occurring pneumothorax close to the end of the progression of disease in the non-survivor group, in contrast to the survivor group. Furthermore, the huge economic cost in the non-survivor group was remarkably comparable to that in the survivor group. The characteristics, underlying kidney diseases, complications of infection, standardized scores for critical care on the onset of infection and various culture results concerning the eleven patients with donor-derived infection are shown in Table 5.
Outcomes of kidney recipients with donor-derived infection
In terms of the in-hospital mortality of the 11 KTRs with donor-derived infection, there was an astonishing high crude mortality rate of 45.4% (5/11). Seven KTRs (R1-2, R4, R6-8, R10) associated with rupture of renal artery, occurring on the 40th, 16th, 43th, 74th, 18th, 18th and 19th after KTx respectively, with the rate of rupture of renal artery of 63.6% (7/11) and in R4-5, the thrombus of renal transplant artery was presented on the 43th and 13th day after KTx respectively. Besides, Seven KTRs (R1-2, R4-5, R7-8, R10) underwent excision of transplanted graft on the 39th, 14th, 43th, 17th, 19th, 19th, 19th day after the KTx respectively for the sake of prevention of the further spread of CRKP to the remaining vital organs. Among various sites of infection, the organ space surgical sites (9/11) were the most common, followed by respiratory and urinary tract (8/11) and the surgical wound (3/11). With regards to the complications of infection for these KTRs, pleural effusion (9/11) numbered the most, abdominal effusion (7/11) numbered the second and pneumothorax (3/11) numbered the least, which having the occurrence rate of about 27.3%, however associated with high mortality (3/3).
In the non-surviving group, three KTRs (3/5) died due to rupture of renal artery and one KTR (1/5) died from thrombus of the transplanted renal artery, with all the decreased KTRs dying related to septic shock. Three KTRs (R1-2, R5) underwent the excision of transplanted graft, with the rate of excision of 60%. All the recipients have confirmed donor-derived CRKP infection, except for the R3, and one case (R2) associated with the mixed infection of CRKP and aspergillus that confirmed by the pathologic report that shown in previous study [26]. The K. pneumoniae was the causative microorganism leading to high frequency (60%) of rupture of renal artery. The KTRs (R1, R2, R6) who suffered from CRKP infection due to rupture of renal artery also inflicted with pneumothorax close to the end of the progression of illness, presented on 45th, 51th and 32th day after KTx, consistent with the result of culture of organ-space surgical site (OSSS). None of KTRs (0/5) did not receive appropriate combinational antimicrobial therapy, basically Meropenem+Tigecycline, after infection and 1 KTR (R9) died even the newly arrival antimicrobial, Ceftazidine Avibatan, was added to the regimen, as demonstrated by Table 8. Of 5 KTRs with crude hospital mortality, 2 KTR (R1, R2) developed allograft dysfunction and the serum creatinine level was summited at the 7th day after first BSI and at the first BSI (Serum creatinine were 543.7umol/L and 487.6umol/L, respectively).
Comparing with the non-surviving group, all the KTRs received appropriate combinational antimicrobial therapy after infection in the surviving group, and 3 KTRs (R8, R10, R11) survived after the newly approved combinational antimicrobial therapy (Ceftazidine Avibatan+Meropenem). To reducing the further dissemination of pathogens to vital organs, 4 KTRs underwent excision of transplanted graft and obtained satisfactory effects, with the rate of excision of 66.7%. Besides, the APACHE II score and SOFA score on the onset of first BSI were lowered to median 14 and 6 respectively.
Relation revealed by Whole Genome sequencing
In silico MLST analysis revealed that three isolates (R3_urine_2016/3/27, R2_blood_2016/2/20, and R2_catheter_2016/2/22) belongs to ST290, while the other isolates all belongs to ST11. Phylogenetic tree showed the ST290 and ST11 isolates formed two separate clusters, and the latter fell into five subclades. Isolates from the donor and recipient fell into the same subclades, and few SNPs were observed in these isolates.
A number of resistance genes, including NMD-1, KPC-1, SHV-1, SHV-2, CTX-M, TEM-1 and et al. (Figure 1,2), and the epidemiologically-related isolates showed similar pattern of resistance genes. The NDM-1 and SHV-1 gene only existed in the three ST290 isolates, while the KPC-1 gene were observed in most of the ST11 isolates.
Interesting, in the bifurcation led by D2 with relationship to multiform isolates collected from the corresponding recipients, named D2 Bifurcation, whole genome sequencing showed the donor (D2) lacked the catII, KPC-1 and SHV-12 genes, which were found in all the isolates from the recipients. Genomic analysis revealed that these three resistance genes located on a plasmid similar to plasmid pA1750-KPC (GenBank accession number: MT108207), which was obtained by the isolates of the recipients.