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Nonopportunistic Pneumonia After Kidney Transplant: Risk Factors Associated With Mortality
Nonopportunistic Pneumonia After Kidney Transplant: Risk Factors Associated With Mortality Sophie Zieschanga,*, Stefan Büttnera, Helmut Geigera, Eva Herrmannb, and Ingeborg A. Hausera a Department of Nephrology, University Hospital Frankfurt, Goethe University, Germany; and bDepartment of Medical Biostatistics, University Hospital Frankfurt, Goethe University, Germany
ABSTRACT Background. The second most common infection after kidney transplantation is pneumonia, which has a high complication rate, sometimes even resulting in death. The aim of this study was to identify risk factors associated with mortality in nonopportunistic pneumonia. Methods. We retrospectively studied all kidney transplant recipients with nonopportunistic pneumonia treated at the University Hospital Frankfurt, Germany, between 2004 and 2017. Patient baseline characteristics, laboratory values, and microbiologic tests were analyzed. We focused specifically on acute and chronic graft failure and the immunosuppressive regimen and included a follow-up period of 7.8 years. Results. One hundred seventy-seven patients (12%) collectively had 270 episodes of pneumonia. Although immunosuppressive therapy was reduced in 42% of patients during infection, there was no increase in graft rejection during hospital stay and followup. Significant risk factors for mortality were C-reactive protein > 10 mg/dL and serum albumin < 3 g/dL on admittance, congestive heart failure, autosomal dominant polycystic kidney disease as the underlying renal disease, nosocomial pneumonia, septic shock, intensive care unit admittance, mechanical ventilation, and renal replacement therapy. Conclusions. Using these factors, patients at risk for death can be identified and the outcome of those might be improved by close monitoring and modified therapies.
K
IDNEY transplantation makes up two-thirds of all solid organ transplants [1]. It is the treatment of choice for end-stage renal disease.[2] Over the years, immunosuppressive therapies have been improved and the occurrence of acute rejection has been reduced, but infection rates have remained stable [3,4]. Infections are the second highest cause of death in transplant recipients after cardiovascular events [5]. Pneumonia is a common and often severe infection in kidney transplant recipients, second only in frequency to urinary tract infections [6]. The aim of this study was to analyze the risk factors associated with mortality in the course of pneumonia after kidney transplantation. Identifying common risk factors may suggest ways to prevent, or at least ameliorate, severe forms of pneumonia that often result in death.
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Transplantation Proceedings, XX, 1e7 (2019)
PATIENTS AND METHODS The ethics committee of the University Hospital Frankfurt, Germany, approved this study (file number 24/18). A retrospective review of all medical records of kidney transplant recipients admitted to the University Hospital Frankfurt from January 1, 2004 to January 1, 2017 was performed. Pneumonia was diagnosed if at least 1 clinical presentation (cough, dyspnea, sputum, positive auscultation, or other clinical symptoms like fever) and positive radiologic imaging were present. We classified the patients into community acquired pneumonia (CAP) and nosocomial pneumonia
*Address correspondence to Sophie Zieschang, Department of Emergency Medicine, Sana Klinikum Offenbach, Starkenburgring 66, 63069 Offenbach am Main, Germany E-mail: s.d.zieschang@ gmail.com 0041-1345/19 https://doi.org/10.1016/j.transproceed.2019.11.016
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2 (including hospital-acquired and, in few cases, ventilator-associated pneumonia) according to the Infectious Diseases Society of America criteria (diagnosis at least 48 hours after hospital admission or a hospitalization within the last 3 months) [7]. All cases of Pneumocystis jirovecii pneumonia, sirolimus-induced pneumonia, and second episodes of pneumonia in the same patient were excluded, due to high heterogeneity in this cohort. Cytomegalovirus (CMV) pneumonia was excluded as well due to problematic differentiation between actual infection and reactivation. Special note was made of intensive care measures, such as hemodialysis, invasive (endotracheal intubation) and noninvasive ventilation, and intensive care unit (ICU) admittance. Septic shock was defined according to the Sepsis-2 criteria [8] with at least 2 out of 4 criteria for systemic inflammatory response syndrome and hypotension. We analyzed patient baseline characteristics such as pre-existing medical conditions, use of antibiotics in the last 3 months, and previous hospitalization for pneumonia. Concerning transplantation, living or postmortem organ donation, time since transplantation, immunosuppressive regimen, and underlying kidney disease were documented. The decision to reduce immunosuppression was based on CD4 T-cell count and clinical presentation. The usual length of reduction was 5 days. It increased when patients had a persistently low count of CD4 cells (< 400/mL) or needed ICU treatment Kidney graft failure was classified using the acute kidney injury network (AKIN) criteria[9]: AKIN I was classified as an increase in baseline serum creatinine > 0.3 mg/dL or an increase by a factor of 1.5 to 1.9. AKIN II was classified as an increase by a factor of 2 to 2.9 from baseline. AKIN III was classified as more than tripling baseline creatinine or > 4 mg/dL or introduction of renal replacement therapy (RRT). Reduction in diuresis was not used to classify acute kidney injury, as the medical records rarely reflected decrease in urine production. Recovery of kidney function was assessed. We documented laboratory findings on day 1 (admission), the highest level, and level at discharge for: C-reactive protein (CRP), S-creatinine, urea, serum albumin, hemoglobin, leukocytes, and thrombocytes. Microbiology diagnostics for patients who were immunosuppressed were as follows: serum test for immunoglobulin (Ig) M antibodies against atypical bacteria (Chlamydia pneumoniae, Mycoplasma pneumoniae, and Legionella pneumophila); blood cultures; polymerase chain reaction (PCR) for influenza, respiratory syncytial virus, and CMV; and sputum culture. Testing was only administered when there was clinical suspicion for the pathogen. During follow-up examination, mortality and graft failure were documented.
Statistical Analysis Continuous and categorical variables were compared using MannWhitney U test, Wilcoxon matched pair test, and Fisher exact test, respectively. Continuous variables are shown as median and interquartile range (IQR). Categorical variables were reported as frequencies and percentages. To analyze patient and graft survival, we used a Kaplan-Meier estimator. All P values reported are 2-sided. Statistical significance was assumed when the P value was < .05. Statistical analyses were performed using BiAS (EPSiLON Verlag, Darmstadt, Germany) and Prism 5 (GraphPad Software Inc, San Diego, CA, United States).
RESULTS
One hundred seventy-seven primary hospitalizations for pneumonia were documented in 12% of all 1467 reviewed
ZIESCHANG, BÜTTNER, GEIGER ET AL Table 1. Patient Characteristics of Study Population Variables
Demographic characteristics Age, y Male sex Living kidney transplant Second transplant Third transplant Dual immunosuppression Triple immunosuppression Renal disease Glomerulonephritis ADPKD Diabetic nephropathy Nephrosclerosis Hereditary kidney disease Unknown/not specified Others Comorbidities Pulmonary disease overall COLD Sarcoidosis Bronchial asthma Lung resection Others Diabetes Malignancy at admission Hypertension Active smoking
Patients (N ¼ 177)
65 115 19 13 2 119 59
(56.00-71.00) (65.0) (10.7) (7.3) (1.1) (67.2) (32.8)
48 27 18 14 7 44 19
(27.1) (15.3) (10.2) (7.9) (3.9) (24.9) (10.7)
42 31 2 1 3 4 54 41 176 22
(23.7) (73.8) (4.8) (2.4) (7.1) (9.5) (30.5) (23.2) (99.4) (12.3)
Data are written as n (%) or median (interquartile range). ADPKD, autosomal dominant polycystic kidney disease; COLD, chronic obstructive lung disease.
kidney transplant recipients. Specific patient characteristics of the study population are shown in Table 1. Transplantation Specifics
One hundred fifty-eight patients (89.3%) with pneumonia received kidneys from postmortem donors and 19 (10.7%) from living donors. This reflects the usual distribution of postmortem vs living donor kidney transplant recipients in our outpatient clinic over the years. Thirteen patients (7.3%) had their second kidney transplant already; 2 patients (1.1%) were on their third transplant. The underlying renal diseases leading to the need for transplant are listed in Table 1. Table 2. Immunosuppressive Regimen at Admission Variables
Immunosuppressive regimen MMF/MPA þ prednisolone CsA þ prednisolone Tacrolimus þ prednisolone MMF/MPA þ CsA þ prednisolone MMF/MPA þ tacrolimus þ prednisolone Others
Patients (N ¼ 177)
177 37 34 32 32 26 12
(100.0) (20.9) (19.2) (18.1) (18.1) (14.7) (6.8)
Data are written as n (%). CsA, cyclosporin A; MMF, mycophenolate mofetil; MPA, mycophenolic acid.
PNEUMONIA AFTER KIDNEY TRANSPLANT
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Table 3. Characteristics of Pneumonia
Table 4. Pathogens
Patients (N ¼ 177)
Characteristics Time after transplant, d Community acquired Nosocomial Prior antibiotic treatment (3 mo) Causes of pneumonia Bacterial pneumonia Viral pneumonia Fungal pneumonia Viral and bacterial Fungal and bacterial Fungal and viral No causative germ Hospital course Hospital stay, d Opportunistic infections In-hospital mortality ICU stay ICU stay, d Noninvasive ventilation Invasive ventilation Septic shock
2294 (173.5-4271) 105 (59.3) 72 (40.7) 75 (42.4) 128 2 3 8 5 1 27
(72.3) (1.1) (1.7) (4.5) (2.8) (0.6) (15.3)
11(8.0-18.0) 12 (6.8) 13 (7.3) 23 (13.0) 12 (5.5-34) 5 (2.8) 17 (9.6) 13 (7.3)
Data are written as n (%) or median (interquartile range). ICU, intensive care unit.
One hundred nineteen patients (67.2%) had double immunosuppression and 59 (32.8%) had triple immunosuppression (Table 2).
Patients (N ¼ 42)
Pathogens Klebsiella pneumoniae Pseudomonas aeruginosa Staphylococcus sp. Streptococcus pneumoniae Haemophilus influenzae/ H. parainfluenzae Other Enterobacteria Stenotrophomonas maltophilia Enterococci Serratia marcescens Proteus mirabilis Aspergillus sp. Viral pathogens Others
51 6 5 5 4 3 3 2 2 1 1 5 8 6
(121.4) (14.3) (11.9) (11.9) (9.5) (7.1) (7.1) (4.8) (4.8) (2.4) (2.4) (11.9) (19.1) (14.3)
Data are written as n (%).
Hospital Course
The median hospital stay was 16.7 days (range, 8.0-18.0). Twenty-three patients (13%) had to be treated in the ICU. The median stay in the ICU was 12 days (range, 5.5-34). Five patients (2.8%) needed noninvasive ventilation and 17 (9.6%) had invasive ventilation. Thirteen patients (7.3%) progressed to septic shock. Immunosuppression was reduced or discontinued in 74 (41.8%) patients during infection. In this group there was 1 (1.4%) acute and 1 (1.4%) chronic biopsy-proven graft rejection. There were no changes to immunosuppressive regimen in 103 (58.2%) patients. In this group, there was also 1 (1.0%) acute and 1 (1.0%) chronic biopsy-proven graft rejection.
Pneumonia
One hundred five (59.3%) cases were CAP and 72 (40.7%) were nosocomial pneumonia. In the nosocomial cohort, the reasons for admission were as follows: 45 (62.5%) pneumonia (with prior hospitalization within the last 3 months), 8 (11.1%) cardiovascular, 6 (8.3%) urinary tract infection or urosepsis, 3 (4.2%) kidney transplantation, and 10 (13.9%) other causes. Seventy-five patients (42.4%) had antibiotic treatment 3 months prior to admission. The median duration between the kidney transplantation and the onset of pneumonia was 2294 days (IQR, 173.5-4271) or 76 months. Thirty-three (18.6%) pneumonia cases occurred within 1 year of transplantation and 144 (81.4%) occurred after the first year after transplantation. Typical clinical symptoms of pneumonia such as coughing, sputum production, positive auscultation, and dyspnea were monitored. Thirty-nine patients (22%) presented with 1 out of 4 symptoms; 61 (34.5%) with 2 out of 4 symptoms; 31 (17.5%) with 3 out of 4 symptoms; 27 (15.3%) with 4 out of 4 symptoms; and 19 (10.7%) with other symptoms compatible with pneumonia. Interestingly, 16 (20.8%) of the tested patients had positive blood PCR for CMV indicating virus reactivation. Eighty-five (69.7%) of the tested patients had partial respiratory insufficiency, 12 (9.8%) had global respiratory insufficiency, and 25 (20.5%) had no respiratory insufficiency. (Table 3).
Microbiologic Findings
One hundred twenty-eight (72.3%) pneumonia cases were bacterial; 2 (1.1%) were viral; 3 (1.7%) were fungal; and 14 (9.7%) were mixed infections (ie, 8 [4.5%] viral and bacterial; 5 [2.8%] fungal and bacterial; 1 (0.6%) fungal and viral). Twenty (6.0%) cases of CMV pneumonia and 46 (13.7%) cases of PCP pneumonia were excluded. Nineteen (16%) of the tested patients had positive blood cultures. Of all patients, 48 had serological tests done for typical and atypical bacteria. Of those, 30 (62.5%) had positive serology results: 25 (52.1%) for atypical pulmonary pathogens, such as Chlamydia pneumonia, Mycoplasma pneumoniae and Legionella pneumophila and 5 (10.4%) for other pathogens. Twenty-three (39.7%) of the tested patients had positive sputum diagnostics. Thirty-two (57.1%) of the tested patients had positive bronchial lavage. Twelve patients (6.8%) had opportunistic coinfection with pathogens such as Candida albicans (oral or esophageal thrush), CMV, or polyomavirus. Pneumonia pathogens are listed in Table 4 and antimicrobial treatment is listed in Supplementary Table 3). Acute Kidney Injury
One hundred forty patients (79.1%) had acute graft failure according to the AKIN-classification: 91 (65%) classified as
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ZIESCHANG, BÜTTNER, GEIGER ET AL Table 5. Survivor vs Nonsurvivor Values
Demographic characteristics Age, y Male sex, n (%) Living kidney transplant Postmortem Dual immunosuppression Triple immunosuppression Comorbidities Pulmonary disease Diabetes mellitus Coronary artery disease Congestive heart failure Malignant tumor Active smoker Hypertension Acute kidney injury No acute injury AKIN I AKIN II AKIN III Renal replacement therapy Characteristics Time after transplant, d ADPKD Nosocomial pneumonia Prior antibiotic treatment (3 mo) Hospital course Hospital stay, d Opportunistic infections CMV reactivation Positive blood cultures ICU stay ICU stay (days) Noninvasive ventilation Invasive ventilation Septic shock
Survivor n ¼ 164
Nonsurvivor n ¼ 13
P Value
65 110 19 145 108 56
(56-71) (67.1) (11.6) (88.4) (65.9) (34.1)
69 5 0 13 11 2
(54-74) (38.5) (0) (100) (84.6) (15.4)
37 51 45 8 36 21 163
(22.6) (31.1) (27.4) (4.9) (22) (12.8) (99.4)
4 3 4 3 5 1 13
(30.8) (23.1) (30.8) (23.1) (38.5) (7.7) (100)
.5019 .7568 .7558 .0364 .1823 1.00 1.00
36 90 10 28 10
(22) (54.9) (6.1) (17.1) (6.1)
1 2 1 9 8
(7.7) (15.4) (7.7) (69.2) (61.5)
.3067 .0079 .5789 .0001 < .0001
2132 22 60 67 11 11 15 18 13 10 4 8 5
(675.8-4225) (13.4) (36.5) (40.9) (8-16) (6.7) (9.1) (11) (7.9) (3.5-35.5) (2.4) (4.9) (3.0)
3144 5 12 8
1 3 1 10 14 1 7 8
(1446-4867) (38.5) (92.3) (61.5) 30 (7.7) (23.1) (7.7) (76.9) (6.5-29.5) (7.7) (53.8) (61.5)
.0655 .3658 .3658 .2259 .2259
.0200 .0001 .1586
> .99 .1318 > .99 < .0001 .3187 < .0001 < .0001
Data are written as n (%) or median (interquartile range). AKIN I is an increase in baseline serum creatinine > 0.3 mg/dL or an increase by a factor of 1.5-1.9. AKIN II is an increase by a factor of 2-2.9 from baseline. AKIN III is more than tripling baseline creatinine or > 4 mg/dL or introduction of renal placement therapy. ADPKD, autosomal dominant polycystic kidney disease; AKIN, acute kidney injury network; CMV, cytomegalovirus; ICU, intensive care unit.
AKIN I, 11 (7.9%) as AKIN II, and 37 (26.4%) as AKIN III, of which 18 (12.9%) had renal replacement therapy (RRT). Graft function fully recovered to baseline in 82 patients (59.3%) and partially in 24 (17.1%) patients. No recovery was seen in 21 patients (15.0%) (Supplementary Table 4). During follow-up examination, 26 patients (15.85%) had graft failure, which equals 2.04% per year. Mortality During Hospital Stay
Thirteen (7.3%) patients died during their hospital stay (nonsurvivor group) and 164 (92.7%) patients survived (survivor group). Mortality was due to sepsis in 8 (61.5%) patients, malignancy in 2 (15.4%) patients, hemorrhagic shock in 1 (7.7%) patient, and unspecified in 2 (15.4%) patients. Twelve (92.3%) nonsurvivors had nosocomial pneumonia whereas only 60 (36.6%) of the survivors had nosocomial pneumonia marking it as a highly significant risk
factor for mortality (P ¼ .0001). The only significant comorbidity with regard to mortality was congestive heart failure, with 8 (4.9%) among the survivors and 3 (23.1%) in the nonsurvivor group (P ¼ .036). Twenty-two (13.41%) of the survivors and 5 (38.5%) of the nonsurvivors had autosomal dominant polycystic kidney disease (ADPKD) as an underlying renal disease (P ¼ .02). Acute graft failure proved to be significant in nearly all stages, especially in more severe cases. In 28 (17.1%) survivors and 9 (69.2%) nonsurvivors, AKIN III was an indicator of mortality with high significance (P ¼ .0001) and even more severely if RRT had to be initiated. Only 10 (6.1%) of the survivors and 8 (61.5%) of the nonsurvivors (P < .0001) had to undergo hemodialysis. Immunosuppression was reduced in only 63 (38.4%) of survivors. In nonsurvivors, 11 (84.6%) had reduction or discontinuance of immunosuppression. Another negative outcome predictor with very high significance (P < .0001) was ICU admission during hospital
PNEUMONIA AFTER KIDNEY TRANSPLANT
stay in 13 (7.9%) of survivors and 10 (76.9%) of nonsurvivors. Septic shock occurred in 5 (3.0%) survivors and 8 (61.5%) nonsurvivors (P < .0001). Furthermore, invasive ventilation was significantly associated with mortality: 8 (4.9%) in the survivor group and 7 (53.9%) in the nonsurvivors group had to be intubated (P < .0001). Characteristics of patients in the survivor vs nonsurvivor group are listed in Table 5. Two of the admission laboratory results were associated with mortality: median CRP was 5.59 mg/dL (range, 2.00-12.68) in the survivors and 14.70 mg/dL (range, 5.4-19.81) in the nonsurvivors (P ¼ .0217). Median serum albumin was 3.30 g/dL (range, 2.53-3.80) in the survivors and 2.50 g/dL (range, 2.15-2.80) in the nonsurvivors (P ¼ .0031). The maximum of several parameters were more significantly associated with mortality than admission or discharge levels: CRP was 12.25 mg/dL (range, 6.37-19.28) in survivors and 26.69 mg/dL (range, 20.60-35.98) in nonsurvivors (P ¼ .0001). S-creatinine was 2.26 mg/dL (range, 1.70-3.12) in survivors and 3.92 mg/dL (range, 2.42-5.42) in nonsurvivors (P ¼ .0088). Urea was 96 mg/dL (range, 67-154) in survivors and 202 mg/dL (range, 131.5-255) in nonsurvivors (P ¼ .0002). Maximum S-albumin, CD4 T-cell count, and thrombocytes were not significantly associated with mortality. Follow-Up Period
There was an average follow-up period of 2833 days or 7.76 years, during which survival or causes of death were recorded. One hundred sixty-four out of 177 patients survived their first hospital admittance for pneumonia. Seventy-eight (47.6%) of these patients died during follow-up: 10 (12.8%) died of cardiovascular cause; 20 (25.6%) of sepsis or pneumonia; 10 (12.8%) of other causes; and 10 (12.8%) were not further documented. Eight patients (10.3%) died of malignancy. Five of these 8 patients (62.5%) died of bronchial carcinoma. DISCUSSION
This study shows that pneumonia after kidney transplantation is a common (12%) complication and should be handled with the utmost care. In previous studies, the incidence of infection ranged between 8.8% and 20% [10e13]. It has to be noted that only patients with the most severe cases of pneumonia were admitted to our hospital. Patients with milder cases of pneumonia were treated in our outpatient unit. In-hospital mortality in our cohort was 7.3%, which is comparable to previous studies ranging from 10.5% to 20%. [11,14e17]. On average, patients in the nonsurvivor group were 4 years older (69 years) than those in the survivor group (65 years). ICU admittance was a highly significant negative outcome predictor in our cohort. Other significant risk factors with probable collinearity, as they were reasons for ICU admittance, were septic shock and mechanical ventilation, which is in line with previous studies.[11,18]
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According to AKIN criteria, 79.1% of patients had acute graft failure. Acute kidney injury increases short- and longterm mortality in patients who are not immunocompromised and was also identified as a risk factor in renal transplant recipients with pneumonia [11,19]. There is evidence that uremia may impair pulmonary bacterial clearance [20]. Patients with acute kidney failure and the need for RRT had the worst outcome with very high significance. Witzke et al found that febrile infection had a negative effect on renal graft function [21]. Another important factor in acute renal failure in sepsis is irreversible capillary loss and tubulointerstitial fibrosis caused by proinflammatory cytokines and hypoxia [22,23]. Transplant function recovery rate in our cohort was higher than in other studies (59.3% vs 47%) [17]. Maximum S-creatinine, urea, and CRP levels and low albumin levels were significant predictors of mortality. This result is comparable to previous studies [13,19]. Low S-albumin is a marker for critical illness and is also known to be a risk factor for morbidity and mortality in other diseases [24]. High CRP on hospital admission seems to be an expression of the severity and progression of infection. Furthermore, maximum white blood cell (WBC) count significantly correlated with survival. Although WBC count in patients who are immunocompromised has limited significance due to a different response to infection, CRP and leukocytes as markers for infection were more than twice as high in nonsurvivors. Nosocomial pneumonia proved to be a highly significant risk factor for mortality, as shown in other studies [11,13,18]. The microbiologic spectrum showed more aggressive pathogens, such as Aspergillus, Pseudomonas, Stenotrophomonas, or multiresistant Klebsiella (Table 4). It can be assumed that patients with recent hospital stays are colonized or already subclinically infected with the virulent pathogen. CAP seems to have much more favorable pathogens such as Streptococcus pneumonia, Mycoplasma pneumoniae, Haemophilus influenzae, and Chlamydia pneumonia with less resistance and virulence [25]. In nosocomial pneumonia, more virulent pathogens occur [7]. Surprisingly, neither diabetes mellitus (P ¼ .76), nor pulmonary disease (P ¼ .5) had a significant influence on mortality, even though they are risk factors in a nontransplant cohort [26,27]. The latter could be explained by the fact that patients who are medically immunosuppressed are already immunosuppressed to such an extent, that usual risk factors for pneumonia such as diabetes or pulmonary disease do not play a significant role in worsening their condition. Our data for underlying renal disease differ widely from other studies, especially with the lower incidence of diabetic nephropathy and nephrosclerosis [12,19,28] This difference might be due to it being the first German study. Surprisingly, more patients of the nonsurvivor group had ADPKD as an underlying renal disease. It is unclear as to why this is an independent risk factor for mortality. A possible explanation might be that this population is prone to cyst infections as coinfections or that pulmonary expansion is limited due
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to increased abdominal mass. To our knowledge, this risk factor has not been documented in previous studies. Graft rejection in the subgroup with reduced immunosuppression was not elevated in comparison to the rest of patients. During the follow-up 2.04% of patients per year had graft failure. This is comparable to the average chronic graft failure rates (2.25%) of European kidney transplant recipients every year [29]. This shows that intermittent and individualized reduction of immunosuppression did not have any negative effect on short- or long-term graft survival and is therefore acceptable. In another study, 51.5% of patients received reduction of immunosuppressive therapy and none of the patients developed rejection in the 2-year follow-up period [30]. However, it is currently only recommended by the Kidney Disease Improving Global Outcomes (KDIGO) guidelines in opportunistic pathogens [31]. The median absolute CD4 T-cell count in survivors was higher than in nonsurvivors, especially when comparing time of discharge and death. The count was as low as 2 cells/ mL. This could either be due to sepsis-induced T-cell apoptosis or relative overimmunosuppression during infection [32e34]. During follow-up, it was noted that 8 (10.3%) patients had died due to malignancy. Of these patients, 62.5% had bronchial carcinoma. This suggests that on first admittance, the beginning of lung cancer might have been mistaken for infection or the first symptom was superinfection of the damaged tissue. The median time between admission for pneumonia and death due to bronchial carcinoma was 247 days. Three patients died due to malignancy within 1 year of their pneumonia episode. Monitoring patients after pulmonary infection for pulmonary carcinoma might help identify cancer early and lead to the administration of treatment more quickly. Interestingly, in our cohort, death due to infection was twice as likely as due to cardiovascular events (25.6% vs 12.8%). Usually, infection is second to cardiovascular events as cause of death [6]. This suggests that our patients were especially vulnerable to infection and may be a special subgroup in all patients with kidney transplants. Our cohort had a median age of > 65 years. This is an older transplant population known to be more likely to die from infection than younger transplant recipients, shown by Linares et al [35]. Study Limitations
Our study had several limitations, including the retrospective single-center design and specific admission policies influencing the findings. Patients transferred from other hospitals were not excluded. Furthermore, we included patients over a course of 13 years, during which treatment practices possibly changed such as prophylaxis for CMV infection or intensified immunosuppression. However, antibiotic treatment practices remained almost the same during that time. Furthermore, there most likely is collinearity in some risk factors, which could not be statistically reduced due to a low number of deceased patients.
ZIESCHANG, BÜTTNER, GEIGER ET AL
CONCLUSIONS
Pneumonia after kidney transplant is a severe complication that should be handled with the utmost care. We report the results of the first German study to identify significant risk factors associated with mortality. Furthermore, we found that reduction of immunosuppression did not noticeably increase risk of short- or long-term graft rejection. Targeting at-risk patients for close monitoring, early diagnosis, and intensified therapy seem to be important to improving the outcomes of pneumonia after a kidney transplant. In our opinion, it might be of benefit to involve the transplant center or transplant specialists guiding immunosuppression in the treatment of kidney transplant recipients with pneumonia who require hospital admission.
REFERENCES [1] Sayegh MH, Carpenter CB. Transplantation 50 years later: progress, challenges, and promises. N Engl J Med 2004;351:2761e6. [2] Wolfe RA, Ashby VB, Milford EL, Ojo AO, Ettenger RE, Agodoa LY, et al. Comparison of mortality in all patients on dialysis, patients on dialysis awaiting transplantation, and recipients of a first cadaveric transplant. N Engl J Med 1999;341:1725e30. [3] Nankivell BJ, Alexander SI. Rejection of the kidney allograft. N Engl J Med 2010;363:1451e62. [4] Fishman JA. Infection in solid-organ transplant recipients. N Engl J Med 2007;357:2601e14. [5] Collins AJ, Foley RN, Chavers B, Gilbertson D, Herzog C, Ishani A, et al. US Renal Data System 2013 annual data report. Am J Kidney Dis 2014;63:A7. [6] Kritikos A, Manuel O. Bloodstream infections after solidorgan transplantation. Virulence 2016;7:329e40. [7] American Thoracic Society, Infectious Diseases Society of America. Guidelines for the management of adults with hospitalacquired, ventilator-associated, and health care-associated pneumonia. Am J Respir Crit Care Med 2005;171:388e416. [8] Singer M, Deutschman CS, Seymour CW, Shankar-Hari M, Annane D, Bauer M, et al. The Third International Consensus definitions for sepsis and septic shock (Sepsis-3). JAMA 2016;315: 801e10. [9] Mehta RL, Kellum JA, Shah SV, Molitoris BA, Ronco C, Warnock DG, et al. Acute Kidney Injury Network: report of an initiative to improve outcomes in acute kidney injury. Crit Care 2007;11:R31. [10] Valdez-Ortiz R, Sifuentes-Osornio J, MoralesBuenrostro LE, Ayala-Palma H, Dehesa-López E, Alberú J, et al. Risk factors for infections requiring hospitalization in renal transplant recipients: a cohort study. Int J Infect Dis 2011;15:e188e96. [11] Hoyo I, Linares L, Cervera C, Almela M, Marcos MA, Sanclemente G, et al. Epidemiology of pneumonia in kidney transplantation. Transplant Proc 2010;42:2938e40. [12] Naik AS, Dharnidharka VR, Schnitzler MA, Brennan DC, Segev DL, Axelrod D, et al. Clinical and economic consequences of first-year urinary tract infections, sepsis and pneumonia. Transpl Int 2015;29:241e52. [13] Dizdar OS, Ersoy A, Akalin H. Pneumonia after kidney transplant: incidence, risk factors, and mortality. Exp Clin Transplant 2011;12:205e11. [14] Kogan A, Singer P, Cohen J, Grozovski E, Grunberg G, Mor E, et al. Readmission to an intensive care unit following liver and kidney transplantation: a 50-month study. Transplant Proc 1999;31:1892e3. [15] Sadaghdar H, Chelluri L, Bowles SA, Shapiro R. Outcome of renal transplant recipients in the ICU. Chest 1995;107:1402e5.
PNEUMONIA AFTER KIDNEY TRANSPLANT [16] Canet E, Osman D, Lambert J, Guitton C, Heng AE, Argaud L, et al. Acute respiratory failure in kidney transplant recipients: a multicenter study. Crit Care 2011;15:R91. [17] Bige N, Zafrani L, Lambert J, Peraldi MN, Snanoudj R, Reuter D, et al. Severe infections requiring intensive care unit admission in kidney transplant recipients: impact on graft outcome. Transpl Infect Dis 2014;16:588e96. [18] Cervera C, Agustí C, Angeles Marcos M, Pumarola T, Cofán F, Navasa M, et al. Microbiologic features and outcome of pneumonia in transplanted patients. Diagn Microbiol Infect Dis 2006;55:47e54. [19] Moore PK, Hsu RK, Liu KD. Management of acute kidney injury: core curriculum 2018. Am J Kidney Dis 2018;72:136e48. [20] Goldstein E, Green GM. The effect of acute renal failure on the bacterial clearance mechanisms of the lung [abstract]. J Lab Clin Med 1966;68:531e42. [21] Witzke O, Schmidt C, Kohnle M, Lütkes P, Philipp T, Heemann U. Impact of febrile infections on the long-term function of kidney allografts [abstract]. J Urol 2001;166:2048e52. [22] Basile DP. The endothelial cell in ischemic acute kidney injury: implications for acute and chronic function. Kidney Int 2007;72:151e6. [23] Zarjou A, Agarwal A. Sepsis and acute kidney injury. J Am Soc Nephrol 2011;22:999e1006. [24] de Mutsert R, Grootendorst DC, Indemans F, Boeschoten EW, Krediet RT, Dekker FW, et al. Association between serum albumin and mortality in dialysis patients is partly explained by inflammation, and not by malnutrition [abstract]. J Ren Nutr 2009;19:127e35. [25] Niederman MS, Mandell LA, Anzueto A, Bass JB, Broughton WA, Campbell GD, et al. Guidelines for the management of adults with community-acquired pneumonia. Diagnosis, assessment of severity, antimicrobial therapy, and prevention. Am J Respir Crit Care Med 2001;163:1730e54.
7 [26] Kornum JB, Thomsen RW, Riis A, Lervang HH, Schønheyder HC, Sørensen HT. Diabetes, glycemic control, and risk of hospitalization with pneumonia: a population-based casecontrol study. Diabetes Care 2008;31:1541e5. [27] Kurashima K, Takaku Y, Nakamoto K, Kanauchi T, Takayanagi N, Yanagisawa T, et al. Risk factors for pneumonia and the effect of the pneumococcal vaccine in patients with chronic airflow obstruction. Chronic Obstr Pulm Dis 2016;3:610e9. [28] Ito K, Goto N, Futamura K, Okada M, Yamamoto T, Tsujita M, et al. Death and kidney allograft dysfunction after bacteremia. Clin Exp Nephrol 2015;20:309e15. [29] Wang JH, Skeans MA, Israni AK. Current status of kidney transplant outcomes: dying to survive. Adv Chronic Kidney Dis 2016;23:281e6. [30] Shih CJ, Tarng DC, Yang WC, Yang CY. Immunosuppressant dose reduction and long-term rejection risk in renal transplant recipients with severe bacterial pneumonia. Singapore Med J 2014;55:372e7. [31] Kasiske BL, Zeier MG, Chapman JR, Craig JC, Ekberg H, Garvey CA, et al. KDIGO clinical practice guideline for the care of kidney transplant recipients: a summary. Kidney Int 2009;77: 299e311. [32] Cabrera-Perez J, Condotta SA, Badovinac VP, Griffith TS. Impact of sepsis on CD4 T cell immunity. J Leukoc Biol 2014;96:767e77. [33] Chang K, Svabek C, Vazquez-Guillamet C, Sato B, Rasche D, Wilson S, et al. Targeting the programmed cell death 1: programmed cell death ligand 1 pathway reverses T cell exhaustion in patients with sepsis. Crit Care 2014;18:R3. [34] Condotta SA, Cabrera-Perez J, Badovinac VP, Griffith TS. T-cell mediated immunity and the role of TRAIL in sepsis-induced immunosuppression. Crit Rev Immunol 2013;33:23e40. [35] Linares L, Cofán F, Cervera C, Ricart MJ, Oppenheimer F, Campistol JM, et al. Infection-related mortality in a large cohort of renal transplant recipients. Transplant Proc 2007;39:2225e7.
ABSTRACT Background. The second most common infection after kidney transplantation is pneumonia, which has a high complication rate, sometimes even resulting in death. The aim of this study was to identify risk factors associated with mortality in nonopportunistic pneumonia. Methods. We retrospectively studied all kidney transplant recipients with nonopportunistic pneumonia treated at the University Hospital Frankfurt, Germany, between 2004 and 2017. Patient baseline characteristics, laboratory values, and microbiologic tests were analyzed. We focused specifically on acute and chronic graft failure and the immunosuppressive regimen and included a follow-up period of 7.8 years. Results. One hundred seventy-seven patients (12%) collectively had 270 episodes of pneumonia. Although immunosuppressive therapy was reduced in 42% of patients during infection, there was no increase in graft rejection during hospital stay and followup. Significant risk factors for mortality were C-reactive protein > 10 mg/dL and serum albumin < 3 g/dL on admittance, congestive heart failure, autosomal dominant polycystic kidney disease as the underlying renal disease, nosocomial pneumonia, septic shock, intensive care unit admittance, mechanical ventilation, and renal replacement therapy. Conclusions. Using these factors, patients at risk for death can be identified and the outcome of those might be improved by close monitoring and modified therapies.
K
IDNEY transplantation makes up two-thirds of all solid organ transplants [1]. It is the treatment of choice for end-stage renal disease.[2] Over the years, immunosuppressive therapies have been improved and the occurrence of acute rejection has been reduced, but infection rates have remained stable [3,4]. Infections are the second highest cause of death in transplant recipients after cardiovascular events [5]. Pneumonia is a common and often severe infection in kidney transplant recipients, second only in frequency to urinary tract infections [6]. The aim of this study was to analyze the risk factors associated with mortality in the course of pneumonia after kidney transplantation. Identifying common risk factors may suggest ways to prevent, or at least ameliorate, severe forms of pneumonia that often result in death.
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Transplantation Proceedings, XX, 1e7 (2019)
PATIENTS AND METHODS The ethics committee of the University Hospital Frankfurt, Germany, approved this study (file number 24/18). A retrospective review of all medical records of kidney transplant recipients admitted to the University Hospital Frankfurt from January 1, 2004 to January 1, 2017 was performed. Pneumonia was diagnosed if at least 1 clinical presentation (cough, dyspnea, sputum, positive auscultation, or other clinical symptoms like fever) and positive radiologic imaging were present. We classified the patients into community acquired pneumonia (CAP) and nosocomial pneumonia
*Address correspondence to Sophie Zieschang, Department of Emergency Medicine, Sana Klinikum Offenbach, Starkenburgring 66, 63069 Offenbach am Main, Germany E-mail: s.d.zieschang@ gmail.com 0041-1345/19 https://doi.org/10.1016/j.transproceed.2019.11.016
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2 (including hospital-acquired and, in few cases, ventilator-associated pneumonia) according to the Infectious Diseases Society of America criteria (diagnosis at least 48 hours after hospital admission or a hospitalization within the last 3 months) [7]. All cases of Pneumocystis jirovecii pneumonia, sirolimus-induced pneumonia, and second episodes of pneumonia in the same patient were excluded, due to high heterogeneity in this cohort. Cytomegalovirus (CMV) pneumonia was excluded as well due to problematic differentiation between actual infection and reactivation. Special note was made of intensive care measures, such as hemodialysis, invasive (endotracheal intubation) and noninvasive ventilation, and intensive care unit (ICU) admittance. Septic shock was defined according to the Sepsis-2 criteria [8] with at least 2 out of 4 criteria for systemic inflammatory response syndrome and hypotension. We analyzed patient baseline characteristics such as pre-existing medical conditions, use of antibiotics in the last 3 months, and previous hospitalization for pneumonia. Concerning transplantation, living or postmortem organ donation, time since transplantation, immunosuppressive regimen, and underlying kidney disease were documented. The decision to reduce immunosuppression was based on CD4 T-cell count and clinical presentation. The usual length of reduction was 5 days. It increased when patients had a persistently low count of CD4 cells (< 400/mL) or needed ICU treatment Kidney graft failure was classified using the acute kidney injury network (AKIN) criteria[9]: AKIN I was classified as an increase in baseline serum creatinine > 0.3 mg/dL or an increase by a factor of 1.5 to 1.9. AKIN II was classified as an increase by a factor of 2 to 2.9 from baseline. AKIN III was classified as more than tripling baseline creatinine or > 4 mg/dL or introduction of renal replacement therapy (RRT). Reduction in diuresis was not used to classify acute kidney injury, as the medical records rarely reflected decrease in urine production. Recovery of kidney function was assessed. We documented laboratory findings on day 1 (admission), the highest level, and level at discharge for: C-reactive protein (CRP), S-creatinine, urea, serum albumin, hemoglobin, leukocytes, and thrombocytes. Microbiology diagnostics for patients who were immunosuppressed were as follows: serum test for immunoglobulin (Ig) M antibodies against atypical bacteria (Chlamydia pneumoniae, Mycoplasma pneumoniae, and Legionella pneumophila); blood cultures; polymerase chain reaction (PCR) for influenza, respiratory syncytial virus, and CMV; and sputum culture. Testing was only administered when there was clinical suspicion for the pathogen. During follow-up examination, mortality and graft failure were documented.
Statistical Analysis Continuous and categorical variables were compared using MannWhitney U test, Wilcoxon matched pair test, and Fisher exact test, respectively. Continuous variables are shown as median and interquartile range (IQR). Categorical variables were reported as frequencies and percentages. To analyze patient and graft survival, we used a Kaplan-Meier estimator. All P values reported are 2-sided. Statistical significance was assumed when the P value was < .05. Statistical analyses were performed using BiAS (EPSiLON Verlag, Darmstadt, Germany) and Prism 5 (GraphPad Software Inc, San Diego, CA, United States).
RESULTS
One hundred seventy-seven primary hospitalizations for pneumonia were documented in 12% of all 1467 reviewed
ZIESCHANG, BÜTTNER, GEIGER ET AL Table 1. Patient Characteristics of Study Population Variables
Demographic characteristics Age, y Male sex Living kidney transplant Second transplant Third transplant Dual immunosuppression Triple immunosuppression Renal disease Glomerulonephritis ADPKD Diabetic nephropathy Nephrosclerosis Hereditary kidney disease Unknown/not specified Others Comorbidities Pulmonary disease overall COLD Sarcoidosis Bronchial asthma Lung resection Others Diabetes Malignancy at admission Hypertension Active smoking
Patients (N ¼ 177)
65 115 19 13 2 119 59
(56.00-71.00) (65.0) (10.7) (7.3) (1.1) (67.2) (32.8)
48 27 18 14 7 44 19
(27.1) (15.3) (10.2) (7.9) (3.9) (24.9) (10.7)
42 31 2 1 3 4 54 41 176 22
(23.7) (73.8) (4.8) (2.4) (7.1) (9.5) (30.5) (23.2) (99.4) (12.3)
Data are written as n (%) or median (interquartile range). ADPKD, autosomal dominant polycystic kidney disease; COLD, chronic obstructive lung disease.
kidney transplant recipients. Specific patient characteristics of the study population are shown in Table 1. Transplantation Specifics
One hundred fifty-eight patients (89.3%) with pneumonia received kidneys from postmortem donors and 19 (10.7%) from living donors. This reflects the usual distribution of postmortem vs living donor kidney transplant recipients in our outpatient clinic over the years. Thirteen patients (7.3%) had their second kidney transplant already; 2 patients (1.1%) were on their third transplant. The underlying renal diseases leading to the need for transplant are listed in Table 1. Table 2. Immunosuppressive Regimen at Admission Variables
Immunosuppressive regimen MMF/MPA þ prednisolone CsA þ prednisolone Tacrolimus þ prednisolone MMF/MPA þ CsA þ prednisolone MMF/MPA þ tacrolimus þ prednisolone Others
Patients (N ¼ 177)
177 37 34 32 32 26 12
(100.0) (20.9) (19.2) (18.1) (18.1) (14.7) (6.8)
Data are written as n (%). CsA, cyclosporin A; MMF, mycophenolate mofetil; MPA, mycophenolic acid.
PNEUMONIA AFTER KIDNEY TRANSPLANT
3
Table 3. Characteristics of Pneumonia
Table 4. Pathogens
Patients (N ¼ 177)
Characteristics Time after transplant, d Community acquired Nosocomial Prior antibiotic treatment (3 mo) Causes of pneumonia Bacterial pneumonia Viral pneumonia Fungal pneumonia Viral and bacterial Fungal and bacterial Fungal and viral No causative germ Hospital course Hospital stay, d Opportunistic infections In-hospital mortality ICU stay ICU stay, d Noninvasive ventilation Invasive ventilation Septic shock
2294 (173.5-4271) 105 (59.3) 72 (40.7) 75 (42.4) 128 2 3 8 5 1 27
(72.3) (1.1) (1.7) (4.5) (2.8) (0.6) (15.3)
11(8.0-18.0) 12 (6.8) 13 (7.3) 23 (13.0) 12 (5.5-34) 5 (2.8) 17 (9.6) 13 (7.3)
Data are written as n (%) or median (interquartile range). ICU, intensive care unit.
One hundred nineteen patients (67.2%) had double immunosuppression and 59 (32.8%) had triple immunosuppression (Table 2).
Patients (N ¼ 42)
Pathogens Klebsiella pneumoniae Pseudomonas aeruginosa Staphylococcus sp. Streptococcus pneumoniae Haemophilus influenzae/ H. parainfluenzae Other Enterobacteria Stenotrophomonas maltophilia Enterococci Serratia marcescens Proteus mirabilis Aspergillus sp. Viral pathogens Others
51 6 5 5 4 3 3 2 2 1 1 5 8 6
(121.4) (14.3) (11.9) (11.9) (9.5) (7.1) (7.1) (4.8) (4.8) (2.4) (2.4) (11.9) (19.1) (14.3)
Data are written as n (%).
Hospital Course
The median hospital stay was 16.7 days (range, 8.0-18.0). Twenty-three patients (13%) had to be treated in the ICU. The median stay in the ICU was 12 days (range, 5.5-34). Five patients (2.8%) needed noninvasive ventilation and 17 (9.6%) had invasive ventilation. Thirteen patients (7.3%) progressed to septic shock. Immunosuppression was reduced or discontinued in 74 (41.8%) patients during infection. In this group there was 1 (1.4%) acute and 1 (1.4%) chronic biopsy-proven graft rejection. There were no changes to immunosuppressive regimen in 103 (58.2%) patients. In this group, there was also 1 (1.0%) acute and 1 (1.0%) chronic biopsy-proven graft rejection.
Pneumonia
One hundred five (59.3%) cases were CAP and 72 (40.7%) were nosocomial pneumonia. In the nosocomial cohort, the reasons for admission were as follows: 45 (62.5%) pneumonia (with prior hospitalization within the last 3 months), 8 (11.1%) cardiovascular, 6 (8.3%) urinary tract infection or urosepsis, 3 (4.2%) kidney transplantation, and 10 (13.9%) other causes. Seventy-five patients (42.4%) had antibiotic treatment 3 months prior to admission. The median duration between the kidney transplantation and the onset of pneumonia was 2294 days (IQR, 173.5-4271) or 76 months. Thirty-three (18.6%) pneumonia cases occurred within 1 year of transplantation and 144 (81.4%) occurred after the first year after transplantation. Typical clinical symptoms of pneumonia such as coughing, sputum production, positive auscultation, and dyspnea were monitored. Thirty-nine patients (22%) presented with 1 out of 4 symptoms; 61 (34.5%) with 2 out of 4 symptoms; 31 (17.5%) with 3 out of 4 symptoms; 27 (15.3%) with 4 out of 4 symptoms; and 19 (10.7%) with other symptoms compatible with pneumonia. Interestingly, 16 (20.8%) of the tested patients had positive blood PCR for CMV indicating virus reactivation. Eighty-five (69.7%) of the tested patients had partial respiratory insufficiency, 12 (9.8%) had global respiratory insufficiency, and 25 (20.5%) had no respiratory insufficiency. (Table 3).
Microbiologic Findings
One hundred twenty-eight (72.3%) pneumonia cases were bacterial; 2 (1.1%) were viral; 3 (1.7%) were fungal; and 14 (9.7%) were mixed infections (ie, 8 [4.5%] viral and bacterial; 5 [2.8%] fungal and bacterial; 1 (0.6%) fungal and viral). Twenty (6.0%) cases of CMV pneumonia and 46 (13.7%) cases of PCP pneumonia were excluded. Nineteen (16%) of the tested patients had positive blood cultures. Of all patients, 48 had serological tests done for typical and atypical bacteria. Of those, 30 (62.5%) had positive serology results: 25 (52.1%) for atypical pulmonary pathogens, such as Chlamydia pneumonia, Mycoplasma pneumoniae and Legionella pneumophila and 5 (10.4%) for other pathogens. Twenty-three (39.7%) of the tested patients had positive sputum diagnostics. Thirty-two (57.1%) of the tested patients had positive bronchial lavage. Twelve patients (6.8%) had opportunistic coinfection with pathogens such as Candida albicans (oral or esophageal thrush), CMV, or polyomavirus. Pneumonia pathogens are listed in Table 4 and antimicrobial treatment is listed in Supplementary Table 3). Acute Kidney Injury
One hundred forty patients (79.1%) had acute graft failure according to the AKIN-classification: 91 (65%) classified as
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ZIESCHANG, BÜTTNER, GEIGER ET AL Table 5. Survivor vs Nonsurvivor Values
Demographic characteristics Age, y Male sex, n (%) Living kidney transplant Postmortem Dual immunosuppression Triple immunosuppression Comorbidities Pulmonary disease Diabetes mellitus Coronary artery disease Congestive heart failure Malignant tumor Active smoker Hypertension Acute kidney injury No acute injury AKIN I AKIN II AKIN III Renal replacement therapy Characteristics Time after transplant, d ADPKD Nosocomial pneumonia Prior antibiotic treatment (3 mo) Hospital course Hospital stay, d Opportunistic infections CMV reactivation Positive blood cultures ICU stay ICU stay (days) Noninvasive ventilation Invasive ventilation Septic shock
Survivor n ¼ 164
Nonsurvivor n ¼ 13
P Value
65 110 19 145 108 56
(56-71) (67.1) (11.6) (88.4) (65.9) (34.1)
69 5 0 13 11 2
(54-74) (38.5) (0) (100) (84.6) (15.4)
37 51 45 8 36 21 163
(22.6) (31.1) (27.4) (4.9) (22) (12.8) (99.4)
4 3 4 3 5 1 13
(30.8) (23.1) (30.8) (23.1) (38.5) (7.7) (100)
.5019 .7568 .7558 .0364 .1823 1.00 1.00
36 90 10 28 10
(22) (54.9) (6.1) (17.1) (6.1)
1 2 1 9 8
(7.7) (15.4) (7.7) (69.2) (61.5)
.3067 .0079 .5789 .0001 < .0001
2132 22 60 67 11 11 15 18 13 10 4 8 5
(675.8-4225) (13.4) (36.5) (40.9) (8-16) (6.7) (9.1) (11) (7.9) (3.5-35.5) (2.4) (4.9) (3.0)
3144 5 12 8
1 3 1 10 14 1 7 8
(1446-4867) (38.5) (92.3) (61.5) 30 (7.7) (23.1) (7.7) (76.9) (6.5-29.5) (7.7) (53.8) (61.5)
.0655 .3658 .3658 .2259 .2259
.0200 .0001 .1586
> .99 .1318 > .99 < .0001 .3187 < .0001 < .0001
Data are written as n (%) or median (interquartile range). AKIN I is an increase in baseline serum creatinine > 0.3 mg/dL or an increase by a factor of 1.5-1.9. AKIN II is an increase by a factor of 2-2.9 from baseline. AKIN III is more than tripling baseline creatinine or > 4 mg/dL or introduction of renal placement therapy. ADPKD, autosomal dominant polycystic kidney disease; AKIN, acute kidney injury network; CMV, cytomegalovirus; ICU, intensive care unit.
AKIN I, 11 (7.9%) as AKIN II, and 37 (26.4%) as AKIN III, of which 18 (12.9%) had renal replacement therapy (RRT). Graft function fully recovered to baseline in 82 patients (59.3%) and partially in 24 (17.1%) patients. No recovery was seen in 21 patients (15.0%) (Supplementary Table 4). During follow-up examination, 26 patients (15.85%) had graft failure, which equals 2.04% per year. Mortality During Hospital Stay
Thirteen (7.3%) patients died during their hospital stay (nonsurvivor group) and 164 (92.7%) patients survived (survivor group). Mortality was due to sepsis in 8 (61.5%) patients, malignancy in 2 (15.4%) patients, hemorrhagic shock in 1 (7.7%) patient, and unspecified in 2 (15.4%) patients. Twelve (92.3%) nonsurvivors had nosocomial pneumonia whereas only 60 (36.6%) of the survivors had nosocomial pneumonia marking it as a highly significant risk
factor for mortality (P ¼ .0001). The only significant comorbidity with regard to mortality was congestive heart failure, with 8 (4.9%) among the survivors and 3 (23.1%) in the nonsurvivor group (P ¼ .036). Twenty-two (13.41%) of the survivors and 5 (38.5%) of the nonsurvivors had autosomal dominant polycystic kidney disease (ADPKD) as an underlying renal disease (P ¼ .02). Acute graft failure proved to be significant in nearly all stages, especially in more severe cases. In 28 (17.1%) survivors and 9 (69.2%) nonsurvivors, AKIN III was an indicator of mortality with high significance (P ¼ .0001) and even more severely if RRT had to be initiated. Only 10 (6.1%) of the survivors and 8 (61.5%) of the nonsurvivors (P < .0001) had to undergo hemodialysis. Immunosuppression was reduced in only 63 (38.4%) of survivors. In nonsurvivors, 11 (84.6%) had reduction or discontinuance of immunosuppression. Another negative outcome predictor with very high significance (P < .0001) was ICU admission during hospital
PNEUMONIA AFTER KIDNEY TRANSPLANT
stay in 13 (7.9%) of survivors and 10 (76.9%) of nonsurvivors. Septic shock occurred in 5 (3.0%) survivors and 8 (61.5%) nonsurvivors (P < .0001). Furthermore, invasive ventilation was significantly associated with mortality: 8 (4.9%) in the survivor group and 7 (53.9%) in the nonsurvivors group had to be intubated (P < .0001). Characteristics of patients in the survivor vs nonsurvivor group are listed in Table 5. Two of the admission laboratory results were associated with mortality: median CRP was 5.59 mg/dL (range, 2.00-12.68) in the survivors and 14.70 mg/dL (range, 5.4-19.81) in the nonsurvivors (P ¼ .0217). Median serum albumin was 3.30 g/dL (range, 2.53-3.80) in the survivors and 2.50 g/dL (range, 2.15-2.80) in the nonsurvivors (P ¼ .0031). The maximum of several parameters were more significantly associated with mortality than admission or discharge levels: CRP was 12.25 mg/dL (range, 6.37-19.28) in survivors and 26.69 mg/dL (range, 20.60-35.98) in nonsurvivors (P ¼ .0001). S-creatinine was 2.26 mg/dL (range, 1.70-3.12) in survivors and 3.92 mg/dL (range, 2.42-5.42) in nonsurvivors (P ¼ .0088). Urea was 96 mg/dL (range, 67-154) in survivors and 202 mg/dL (range, 131.5-255) in nonsurvivors (P ¼ .0002). Maximum S-albumin, CD4 T-cell count, and thrombocytes were not significantly associated with mortality. Follow-Up Period
There was an average follow-up period of 2833 days or 7.76 years, during which survival or causes of death were recorded. One hundred sixty-four out of 177 patients survived their first hospital admittance for pneumonia. Seventy-eight (47.6%) of these patients died during follow-up: 10 (12.8%) died of cardiovascular cause; 20 (25.6%) of sepsis or pneumonia; 10 (12.8%) of other causes; and 10 (12.8%) were not further documented. Eight patients (10.3%) died of malignancy. Five of these 8 patients (62.5%) died of bronchial carcinoma. DISCUSSION
This study shows that pneumonia after kidney transplantation is a common (12%) complication and should be handled with the utmost care. In previous studies, the incidence of infection ranged between 8.8% and 20% [10e13]. It has to be noted that only patients with the most severe cases of pneumonia were admitted to our hospital. Patients with milder cases of pneumonia were treated in our outpatient unit. In-hospital mortality in our cohort was 7.3%, which is comparable to previous studies ranging from 10.5% to 20%. [11,14e17]. On average, patients in the nonsurvivor group were 4 years older (69 years) than those in the survivor group (65 years). ICU admittance was a highly significant negative outcome predictor in our cohort. Other significant risk factors with probable collinearity, as they were reasons for ICU admittance, were septic shock and mechanical ventilation, which is in line with previous studies.[11,18]
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According to AKIN criteria, 79.1% of patients had acute graft failure. Acute kidney injury increases short- and longterm mortality in patients who are not immunocompromised and was also identified as a risk factor in renal transplant recipients with pneumonia [11,19]. There is evidence that uremia may impair pulmonary bacterial clearance [20]. Patients with acute kidney failure and the need for RRT had the worst outcome with very high significance. Witzke et al found that febrile infection had a negative effect on renal graft function [21]. Another important factor in acute renal failure in sepsis is irreversible capillary loss and tubulointerstitial fibrosis caused by proinflammatory cytokines and hypoxia [22,23]. Transplant function recovery rate in our cohort was higher than in other studies (59.3% vs 47%) [17]. Maximum S-creatinine, urea, and CRP levels and low albumin levels were significant predictors of mortality. This result is comparable to previous studies [13,19]. Low S-albumin is a marker for critical illness and is also known to be a risk factor for morbidity and mortality in other diseases [24]. High CRP on hospital admission seems to be an expression of the severity and progression of infection. Furthermore, maximum white blood cell (WBC) count significantly correlated with survival. Although WBC count in patients who are immunocompromised has limited significance due to a different response to infection, CRP and leukocytes as markers for infection were more than twice as high in nonsurvivors. Nosocomial pneumonia proved to be a highly significant risk factor for mortality, as shown in other studies [11,13,18]. The microbiologic spectrum showed more aggressive pathogens, such as Aspergillus, Pseudomonas, Stenotrophomonas, or multiresistant Klebsiella (Table 4). It can be assumed that patients with recent hospital stays are colonized or already subclinically infected with the virulent pathogen. CAP seems to have much more favorable pathogens such as Streptococcus pneumonia, Mycoplasma pneumoniae, Haemophilus influenzae, and Chlamydia pneumonia with less resistance and virulence [25]. In nosocomial pneumonia, more virulent pathogens occur [7]. Surprisingly, neither diabetes mellitus (P ¼ .76), nor pulmonary disease (P ¼ .5) had a significant influence on mortality, even though they are risk factors in a nontransplant cohort [26,27]. The latter could be explained by the fact that patients who are medically immunosuppressed are already immunosuppressed to such an extent, that usual risk factors for pneumonia such as diabetes or pulmonary disease do not play a significant role in worsening their condition. Our data for underlying renal disease differ widely from other studies, especially with the lower incidence of diabetic nephropathy and nephrosclerosis [12,19,28] This difference might be due to it being the first German study. Surprisingly, more patients of the nonsurvivor group had ADPKD as an underlying renal disease. It is unclear as to why this is an independent risk factor for mortality. A possible explanation might be that this population is prone to cyst infections as coinfections or that pulmonary expansion is limited due
6
to increased abdominal mass. To our knowledge, this risk factor has not been documented in previous studies. Graft rejection in the subgroup with reduced immunosuppression was not elevated in comparison to the rest of patients. During the follow-up 2.04% of patients per year had graft failure. This is comparable to the average chronic graft failure rates (2.25%) of European kidney transplant recipients every year [29]. This shows that intermittent and individualized reduction of immunosuppression did not have any negative effect on short- or long-term graft survival and is therefore acceptable. In another study, 51.5% of patients received reduction of immunosuppressive therapy and none of the patients developed rejection in the 2-year follow-up period [30]. However, it is currently only recommended by the Kidney Disease Improving Global Outcomes (KDIGO) guidelines in opportunistic pathogens [31]. The median absolute CD4 T-cell count in survivors was higher than in nonsurvivors, especially when comparing time of discharge and death. The count was as low as 2 cells/ mL. This could either be due to sepsis-induced T-cell apoptosis or relative overimmunosuppression during infection [32e34]. During follow-up, it was noted that 8 (10.3%) patients had died due to malignancy. Of these patients, 62.5% had bronchial carcinoma. This suggests that on first admittance, the beginning of lung cancer might have been mistaken for infection or the first symptom was superinfection of the damaged tissue. The median time between admission for pneumonia and death due to bronchial carcinoma was 247 days. Three patients died due to malignancy within 1 year of their pneumonia episode. Monitoring patients after pulmonary infection for pulmonary carcinoma might help identify cancer early and lead to the administration of treatment more quickly. Interestingly, in our cohort, death due to infection was twice as likely as due to cardiovascular events (25.6% vs 12.8%). Usually, infection is second to cardiovascular events as cause of death [6]. This suggests that our patients were especially vulnerable to infection and may be a special subgroup in all patients with kidney transplants. Our cohort had a median age of > 65 years. This is an older transplant population known to be more likely to die from infection than younger transplant recipients, shown by Linares et al [35]. Study Limitations
Our study had several limitations, including the retrospective single-center design and specific admission policies influencing the findings. Patients transferred from other hospitals were not excluded. Furthermore, we included patients over a course of 13 years, during which treatment practices possibly changed such as prophylaxis for CMV infection or intensified immunosuppression. However, antibiotic treatment practices remained almost the same during that time. Furthermore, there most likely is collinearity in some risk factors, which could not be statistically reduced due to a low number of deceased patients.
ZIESCHANG, BÜTTNER, GEIGER ET AL
CONCLUSIONS
Pneumonia after kidney transplant is a severe complication that should be handled with the utmost care. We report the results of the first German study to identify significant risk factors associated with mortality. Furthermore, we found that reduction of immunosuppression did not noticeably increase risk of short- or long-term graft rejection. Targeting at-risk patients for close monitoring, early diagnosis, and intensified therapy seem to be important to improving the outcomes of pneumonia after a kidney transplant. In our opinion, it might be of benefit to involve the transplant center or transplant specialists guiding immunosuppression in the treatment of kidney transplant recipients with pneumonia who require hospital admission.
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