Longitudinal Assessment of the Effect of Invasive Fungal Infections on Transplant Success in Kidney Transplant Recipients

Abstract

Invasive fungal infections (IFIs) significantly impact morbidity and mortality in kidney transplant recipients (KTR), but their effect on allograft function remains poorly defined. This retrospective study examined adult KTRs transplanted at Johns Hopkins from 2012 to 2018, with follow-up through 2023. The association of IFIs with a composite outcome of graft failure and mortality was assessed using negative binomial regression. The association of IFI exposure on composite outcome was quantified by matching using a stochastic extension stratification method followed by Cox regression. Among 1453 KTRs, 79 were diagnosed with proven/probable IFIs, predominantly invasive candidiasis (46.8%). KTRs with IFIs had worse outcome-free survival with higher composite outcome rates [53/79 (67.1%) vs. 411/1338 (30.7%), p<0.001]. The composite outcome incidence rate was 4.61-fold higher when IFIs occurred in the first 6 months post-transplant and decreased to 2.13-fold higher after 36 months (p<0.001). IFI exposure was associated with 3.45-fold increased hazard of composite outcome (95% CI 1.54-7.70; p<0.01) and a 3.23-fold increased hazard of all-cause mortality (95% CI 1.53-6.83; p<0.01). The association of IFIs with increased risk of poor kidney transplant outcomes, particularly in the early post-transplant period, highlights the need for improved strategies for early IFI detection and management in KTRs.

1. INTRODUCTION

Advances in more potent immunosuppression for kidney transplantation have markedly improved the survival and graft longevity of organ recipients, however, at the cost of a higher net state of immunosuppression. Fungal pathogens exploit these immune vulnerabilities, causing disease in 1.3-5% of kidney transplant recipients (KTRs) with considerable morbidity and mortality.^1-6 Within the first year following IFI, studies have reported graft loss and mortality ranging from 9.8-25% and 31-70%, respectively.^1-5,7,8 However, these studies have not been able to determine the potential causal effect of IFIs on these adverse transplant outcomes.

A national United States-based registry study observed a 1.91-fold higher graft loss and 2.22-fold higher mortality among KTRs after serious infections associated with hospitalization or multiple outpatient visits, and risk is greatest in the first month post-infection.⁶ The fungal sub-analysis, however, was limited by the poor accuracy of International Classification of Diseases (ICD) codes for fungal disease in registry-based studies^1,4,9,10 and the inclusion of non-invasive fungal diagnoses (e.g., oral candidiasis). Also, interval updates in IFI classification¹¹ and shifts in IFI epidemiology^12,13 since 2017, the last follow-up period among this and other national studies,^3,4,6 may have altered the prevalence of IFIs with implications for relative risk of morbidity and mortality.

Furthermore, the focus on time from IFI to graft loss or death disregards the potential impact of post-transplant IFI timing on these outcomes, which is a phenomenon seen with bacterial infections in KTR.^14,15 Both the risk of IFI and the net state of immunosuppression are dynamic over the post-transplant period; Candida and Aspergillus are the predominant pathogens in early transplant when immunocompromise is generally greatest, and endemic mycoses and Aspergillus represent the principal culprits in late transplant when immunosuppression has often been reduced.³ Elucidating the implications of post-transplant IFI timing on KTR outcomes would allow more informed clinical decision-making regarding management and prophylaxis for IFIs as well as monitoring after infection.

In this retrospective study of KTRs at a single center spanning over a decade, we studied the incidence of IFIs using standardized definitions and applied a stochastic stratification estimation method to estimate the causal relationship between IFIs and transplant outcomes. We sought to quantify both the immediate and enduring effect of IFIs on mortality, graft failure, and rejection. We also evaluated the effect of IFI timing following transplant on the association of IFIs and these outcomes, offering novel insights into the prognosis of KTRs afflicted with IFI.

2. MATERIALS AND METHODS

2.1. Study population and clinical variables

This was a retrospective single-center study, including data from all adult KTRs (n = 1453) transplanted at Johns Hopkins Hospital from January 1, 2012 to December 31, 2018 with follow up through May 1, 2023. KTRs were followed from transplant until either death, loss to follow-up, or end of study, whichever occurred first. Censoring due to loss to follow-up was defined by the date of last clinical encounter visible in our electronic medical record or from data sources external to Hopkins via the Care Everywhere record-sharing interoperability platform as well as from CRISP (crisphealth.org), a state-designated regional health information exchange in Maryland. This study was approved by the Johns Hopkins University institutional review board (IRB00212246).

Demographic data including age at transplant, sex, and race, as well as medical comorbidities were collected and managed using REDCap electronic data capture tools^16,17 hosted at Johns Hopkins University. Clinical variables collected included time since transplant, single vs multi-organ, donor type, prior transplant, induction and maintenance immunosuppression, cytomegalovirus (CMV) diagnosis, and CMV donor/recipient serostatus. CMV serostatus was defined by recipient and donor seropositivity with high-risk serostatus indicated by the combination of a seropositive donor with a seronegative recipient. All other combinations were classified as non-high risk for the analyses. All infectious complications with associated treatment details were collected and classified as binary variables by pathogen types. Infections of clinical significance included those that required hospital admission or that occurred during hospital admission as well as all instances of CMV infection. The diagnosis of bacteremia^18,19 and pneumonia²⁰ were based on consensus guidelines, incorporating microbiologic, syndromic, and histopathologic data. For viral infectious complications, CMV infection episodes were defined²¹ and analyzed separately from all other viral infections (i.e., BK virus,²² respiratory viruses,²³ herpes viruses, and hepatitis C and B). Outpatient infections were not considered clinically significant for the purposes of this study.

Fungal infections were defined and categorized as proven, probable, and possible according to the 2020 European Organization for Research and Treatment of Cancer/Mycoses Study Group (EORTC/MSG) criteria.¹¹ Three infectious disease clinicians (LXL, RKA, and NP) independently adjudicated IFI diagnoses, and all discrepancies were resolved by joint consensus review. Only proven and probable IFIs were included in the primary analyses. If a patient had more than one IFI, the date of first IFI served as the index time.

2.2. Clinical outcomes

The primary outcome was to compare the composite outcome of all-cause graft failure and mortality whichever happened earlier, between KTRs with vs. without IFIs. Secondary outcomes included all-cause mortality, death-censored graft failure, and rejection. Graft failure was defined by return to dialysis. Rejection encompassed both acute cellular rejection (based on kidney allograft biopsy) and antibody-mediated rejection (diagnosed with or without a biopsy in the presence of a compatible clinical syndrome and elevated donor-specific antibody measurements).

2.3. Statistical analysis

Categorical variables were characterized in terms of frequency and percentages and analyzed by Fisher’s exact test. Continuous variables were summarized using median and interquartile range and assessed by the Wilcoxon rank sum testing with a statistical significance level of α < 0.05.

The incidence rate of composite outcome across key post-transplant time periods were calculated as $\frac{events}{person-timeoffollow-up}$. Person-time at-risk for the IFI group was calculated from the date of the first IFI to composite outcome or administrative censoring at May 1^st 2023. If the composite outcome occurred prior to IFI, person-time was attributed to the non-IFI group. The crude incidence of composite outcome stratified by time bin since transplant (0-6, 6-12, 12-36, 36+ months) was compared between IFI vs. non-IFI group using Poisson distribution. The risk of composite outcome since transplant at all times, comparing IFI vs. non-IFI, was first explored using a multivariable negative binomial regression, chosen due to evidence of overdispersion in the Poisson model. The model adjusted for baseline characteristics and clinical variables as specified in 2.1, using a backward selection process and informed by previously published risk factors in the literature (i.e., CMV serostatus,²⁴ prior transplant,²⁵ induction therapy,²⁴ and cardiovascular disease^24,26). CMV infection was initially treated as a categorical variable, including no infection (defined by undetectable CMV viral load), asymptomatic CMV viremia, CMV syndrome, and CMV tissue invasive disease. However, due to the lack of significance, CMV infection was simplified to a binary variable (no infection vs. asymptomatic CMV viremia, CMV syndrome, or CMV tissue invasive disease). Clinical variables affecting > 95% of the cohort were not included for adjustment.

To then better model the time-varying nature of IFI exposure, we used a stochastic dependent matching to estimate the association between IFIs and transplant outcomes, reducing the observed time-dependent confounding. Specifically, we applied a stochastic extension stratification method (SESM), which matches the exposed (IFI) and nonexposed (non-IFI) groups in 1:1 fashion at time of each IFI diagnosis since the transplant date without replacement.^27-29 Compared to more conventional methods involving propensity scores, SESM adjusted the time-varying risk of IFIs at different time bins post-transplant, and enables time-specific matching to ensure the comparison groups are contemporaneous. For example, when recipient A was diagnosed with IFI at the 100^th day post-transplant, we matched recipient A with a randomly selected recipient B who remained IFI-free on the 100^th day post-transplant. We then compared between matched KTRs with and without IFI from the time of matching to the occurrence of primary and secondary outcomes using a multivariable Cox regression, adjusting for the same clinical factors mentioned above.

Sensitivity analyses were conducted for both approaches incorporating the possible IFIs (n = 36) in addition to the proven/probable IFIs. All analyses were performed by RStudio (Version 4.3.2) and Stata (Version 17.0; College Station, TX).

3. RESULTS

3.1. Baseline characteristics

There were 1453 KTRs with a median follow-up time of 6.1 years and total of 8348.9 person-year follow up time. Among KTRs, 115 (7.9%) were diagnosed with at least one fungal infection, with 79 categorized as proven or probable (Table 1) and 36 as possible. The majority of proven and probable IFIs involved yeast (63.2%), with the remainder attributed to mold (31.7%) and endemic mycoses (5.1%). Candida (46.8%) and Aspergillus (24.1%) were the predominant genera. The relative distribution of yeast to mold infections was relatively similar across all post-transplant periods (Table 1).

Table 1.

First post-transplant proven/probable invasive fungal infection among kidney transplant recipients

Time from transplant (months)
	0 to 6 (n = 31)	> 6 to 12 (n = 14)	> 12 to 36 (n = 18)	> 36 (n = 16)	Total (n =79)
Yeast	21 (67.7%)	10 (71.4%)	11 (61.1%)	8 (50.0%)	50 (63.2%)
Mold	9 (29.0%)	3 (21.4%)	7 (38.9%)	6 (37.5%)	25 (31.7%)
Endemic Mycosis	1 (3.2%)	1 (7.1%)	0 (0%)	2 (12.5%)	4 (5.1%)
Species
Candida species	21 (67.7%)	5 (35.7%)	6 (33.3%)	5 (31.3%)	37 (46.8%)
Candida albicans	4	1	0	1
Candida dubliniensis	1	0	0	0
Candida glabrata	5	0	0	0
Candida krusei	2	0	1	0
Candida lusitaniae	0	0	1	0
Candida parapsilosis	3	1	0	1
Candida tropicalis	1	0	0	0
Candida, not speciated	5	3	4	3
Aspergillus species	6 (19.4%)	2 (14.3%)	6 (33.3%)	5 (31.3%)	19 (24.1%)
Aspergillus fumigatus	2	1	5	2
Aspergillus niger	1	0	0	1
Aspergillus, not speciated	3	1	1	2
Cryptococcus neoformans	0 (0%)	3 (21.4%)	3 (16.7%)	3 (18.8%)	9 (11.4%)
Histoplasma capsulatum	1 (3.2%)	1 (7.1%)	0 (0%)	2 (12.5%)	4 (5.1%)
Pneumocystis jiroveci	0 (0%)	1 (7.1%)	2 (11.1%)	0 (0%)	3 (3.8%)
Other	3 (9.7%)	2 (14.3%)	1 (5.6%)	1 (6.3%)	7 (8.9%)
Site of Infection
Pulmonary	5	4	8	6	23
Endovascular	11	4	1	4	20
Gastrointestinal	5	3	4	2	14
Intra-abdominal (non-GI tract)	5	0	0	1	6
Genitourinary	3	0	1	0	4
Other*	2	3	4	3	12

^*Other: Central nervous system, Paranasal sinus, Ocular, Integumentary

KTRs with IFIs were older at transplant (median age [IQR] of 62 [55, 68] vs. 54 [42, 63] years, p <0.001) and had more comorbidities involving liver (32.2% vs 17.6%, p < 0.001) and endocrine (68.4% vs. 52.5%, p = 0.005) comorbidities (Table 2). KTRs with IFIs were also more likely to have received simultaneous liver-kidney transplants (20.3% vs. 5.6%) and to have received alemtuzumab (11.4% vs. 4.8%, p = 0.017) and basiliximab (22.8% vs. 7.6%, p < 0.001) rather than thymoglobulin (67.1% vs. 87.1%; p < 0.001) for induction compared to those without IFIs. The post-transplant course of KTRs with IFIs was more often complicated by CMV infection (43.0% vs 19.1%, p < 0.001) despite similar distribution of high risk CMV serostatus (17.7% vs. 17.3%, p = 0.88).

Table 2.

Kidney transplant recipient and transplant characteristics

	Non-IFI (N=1338)	IFI (N=79)	P-value
Age, median (IQR)	54 (42, 63)	62 (55, 68)	<0.001
Female	543 (40.6%)	31 (39.2%)	0.91
Race			0.85
White	607 (45.4%)	35 (44.3%)
Black or African American	545 (40.7%)	34 (43.0%)
Asian	87 (6.5%)	6 (7.6%)
Other	99 (7.4%)	4 (5.1%)
Cardiovascular*	1261 (94.2%)	73 (92.4%)	0.46
Liver†	235 (17.6%)	33 (41.8%)	<0.001
Endocrine‡	699 (52.2%)	54 (68.4%)	0.005
Transplant risk, High§	111 (8.3%)	10(12.7%)	0.21
Transplant type			<0.001
Kidney	1224 (91.5%)	60 (75.9%)
Kidney/Heart	2 (0.1%)	1(1.3%)
Kidney/Liver	75 (5.6%)	16 (20.3%)
Kidney/Pancreas	37 (2.8%)	2 (2.5%)
Donor status			0.85
Deceased	940 (70.3%)	58 (73.4%)
Living	398 (29.8%)	21 (26.6%)
CMV serostatus, high risk¶	231 (17.3%)	14 (17.7%)	0.88
CMV infection	256 (19.1%)	34 (43.0%)	<0.001
Prior Transplant	278 (20.8%)	10 (12.7%)	0.085
Rehospitalization within year post transplant	748 (55.9%)	61 (77.2%)	<0.001
Induction Agent
Alemtuzumab	64 (4.8%)	9 (11.4%)	0.017
Basiliximab	102 (7.6%)	18 (22.8%)	<0.001
Thymoglobulin	1166 (87.1%)	53 (67.1%)	<0.001
Plasmapheresis	154 (11.5%)	10 (12.7%)	0.72
Maintenance Immunosuppression
Anti-metabolite	1322 (98.8%)	72 (91.1%)	< 0.001
Calcineurin inhibitors	1305 (97.5%)	70 (88.6%)	< 0.001
Prednisone	1316 (98.4%)	108 (93.9%)	0.003
mTOR inhibitors	5 (0.4%)	1 (0.9%)	0.97

^*Cardiovascular co-morbidities: Hypertension, coronary artery disease, peripheral vascular disease, heart failure, arrythmia, cerebral vascular accident, venous thromboembolism, cardiac valvular disease

^†Liver co-morbidities: compensated and decompensated cirrhosis, hepatic fibrosis, steatohepatitis, liver lesions (malignancy, abscess, or cysts), hepatitis B, hepatitis C, biliary disease

^‡Endocrine co-morbidities: insulin and non-insulin dependent diabetes, hyperparathyroidism, thyroid dysfunction (hyperthyroidism, hypothyroidism, goiter, multinodular), adrenal disease (insufficiency, functional adenoma), hypogonadism

^§High risk was defined by HLA and/or ABO incompatibility

^¶CMV serostatus was defined by recipient and donor seropositivity. High risk indicates seropositive donor for a seronegative recipient. All other combinations were designated non-high risk for analyses.

3.2. Clinical outcomes

Overall composite-outcome free survival was worse among KTR with IFIs. The incidence rate (events per year) of the primary composite outcome was higher for KTRs with IFIs compared to those without IFIs (0.139 vs 0.057, incidence rate ratio (IRR) [confidence interval]: 2.453 [1.93, 3.24], p <0.001), and median time to composite outcome from transplant was shorter (median 1840 days [IQR 520-2795 days) vs. 2250 days [1613-2896 days], p = 0.004). The excess risk of composite outcome associated with IFIs was greatest in the early post-transplant period before being attenuated in subsequent time periods; IFIs were associated with 4.61-fold higher risk (95% CI 2.71-7.31, p < 0.001) of composite outcome in the first 6 months following transplant but only a 2.13-fold higher risk (95% CI 1.25-3.16, p < 0.001) of composite outcome by 36 months following transplant (Table 3). IFI remained associated with increased risk of composite outcomes over the study period after adjustment for age, CMV serostatus, infections in 90 days prior to IFI, induction therapy, and underlying cardiovascular disease (IRR 1.67, 95%CI 1.16-2.47; p < 0.01) (Table 4, Supplemental Table 1A, Supplemental Table 2). Age > 65 at transplant (IRR 1.87, 95%CI 1.52-2.29; p < 0.001), induction therapy with plasmapheresis (IRR 1.40, 95%CI 1.07-1.83; p = 0.015), CMV infection in the 90-day prior to IFI (IRR 1.33, 95%CI 1.07-1.66; p = 0.011), and high-risk CMV serostatus (IRR 1.29, 1.02-1.63; p = 0.032) were also associated with increased risk of the composite outcome (Table 4).

Table 3.

Incidence rate (IR) of composite outcome among KTRs with vs. without proven/probable invasive fungal infections (IFI) over the post-transplant time intervals

Time post-transplant (months)	IFI IR (Events/Year)	Non-IFI IR (Events/Year)	IRR	95% CI	P-value
0 to 6	0.340	0.074	4.61	2.71, 7.31	<.001
> 6 to 12	0.092	0.042	2.19	0.97, 3.32	0.229
> 12 to 36	0.105	0.048	2.19	1.27, 3.13	0.018
> 36	0.131	0.062	2.13	1.25, 3.16	<.001

Table 4.

Comparison of composite outcome risk factors for KTRs with vs. without proven/probable invasive fungal infections (n = 79)

Variables	IRR	95% CI	P value
IFI	1.67	1.13, 2.47	0.009
Age > 65 at transplant	1.87	1.52, 2.29	<0.001
CMV serostatus*	1.29	1.02, 1.63	0.032
Prior transplant	1.19	0.94, 1.51	0.146
Infection in 90-days prior to IFI
Viral (non-CMV) infection	0.95	0.56, 1.60	0.843
CMV infection	1.33	1.07, 1.66	0.011
Bacteremia	1.29	0.72, 2.30	0.394
Pneumonia	1.67	1.00, 2.78	0.048
Induction therapy
Alemtuzumab	1.01	0.46, 2.24	0.971
Basiliximab	0.95	0.46, 1.96	0.900
Thymoglobulin	0.72	0.35, 1.48	0.372
Plasmapheresis	1.40	1.07, 1.83	0.015
Cardiovascular disease†	1.31	0.84, 2.05	0.229

^*CMV serostatus as a binary high/low risk outcome. High risk defined by seropositive donor for a seronegative recipient. All other combinations were designated low risk

^†Cardiovascular disease: hypertension, coronary artery disease, peripheral vascular disease, heart failure, arrythmia, cerebral vascular accident, venous thromboembolism, cardiac valvular disease

To account for the time-varying nature of IFI exposure (Supplemental Table 3), we examined the hazard of the composite outcome following IFI exposure comparing the matched IFI vs. non-IFI groups; there was a 3.45-fold increased hazard following IFI exposure (95%CI 1.54-7.70; p < 0.01) (Figure 1, Table 5, and Supplemental Table 1B). Age > 65 years (aHR 2.29, 95%CI 1.22-4.28; p = 0.01) and pneumonia infection in the 90-days prior to IFI (aHR 2.68, 95%CI 1.26-4.73; p = 0.011) were associated with increased risk of the composite outcome.

Figure 1.

Kaplan-Meier analysis of composite outcome free-survival in matched KTRs with vs. without proven/probable invasive fungal infection

Table 5.

Cox proportional hazard model for composite outcome among matched KTRs with vs. without proven/probable invasive fungal infections (n = 67)

Variables	Hazard ratio	95% CI	P value
IFI	3.45	1.54, 7.70	0.003
Age > 65 at transplant	2.29	1.22, 4.28	0.010
CMV serostatus*	0.90	0.40, 2.03	0.908
Prior transplant	1.13	0.50, 2.57	0.776
Infection in 90-days prior to IFI
Viral (non-CMV) infection	1.09	0.54, 2.21	0.810
CMV infection	0.83	0.41, 1.67	0.611
Bacteremia	1.06	0.50, 2.28	0.873
Pneumonia	2.68	1.26, 5.73	0.011
Induction therapy
Alemtuzumab	1.57	0.03, 77.64	0.819
Basiliximab	0.59	0.01, 25.77	0.782
Thymoglobulin	0.32	0.01, 14.68	0.562
Plasmapheresis	2.09	0.85, 5.17	0.110
Cardiovascular disease†	1.20	0.27, 5.42	0.813

^*CMV serostatus as a binary high/low risk outcome. High risk defined by seropositive donor for a seronegative recipient. All other combinations were designated low risk

^†Cardiovascular disease: hypertension, coronary artery disease, peripheral vascular disease, heart failure, arrythmia, cerebral vascular accident, venous thromboembolism, cardiac valvular disease

Secondary outcomes were also more common in KTRs with IFIs over the study period; KTRs with IFIs had higher rates of all-cause mortality (57.0% vs. 20.2%, p <0.001), death-censored graft failure (41.8% vs. 16.6%, p <0.001), and rejection (22.8% vs. 18.7%, p = 0.37) compared to KTR without IFIs within the full study population. There was a 3.23-fold increased hazard of all-cause mortality comparing the matched IFI vs. non-IFI group (95%CI 1.53-6.83; p < 0.01) (Supplemental Table 4). The difference in death-censored graft failure (aHR 2.70, 95%CI 0.73-9.93, p = 0.136) (Supplemental Table 5) and rejection (aHR 2.56, 95%CI 0.85-7.69; p = 0.094) (Supplemental Table 6) between matched IFI vs. non-IFI following IFI exposure was not statistically significant.

Subsequent sub-analysis of molds and yeasts showed similar impact on transplant outcomes (Supplemental Table 7). Additional sensitivity analyses including the 36 KTRs with possible IFIs (Supplemental Table 8) demonstrated consistent relationships between IFI exposure and transplant outcomes (Supplemental Table 9-14).

4. DISSCUSSION

In this single-center retrospective study of KRTs, we found evidence supporting a causal relationship between IFIs and poor transplant outcomes. The increased risk and earlier onset of all-cause graft failure or mortality among KTRs with IFIs highlights the potential impact of these infections on transplant success and patient survival.

Despite advances in transplantation, the risk of IFIs among KTRs in the United States has not significantly declined over the last few decades, with greatest risk occurring in the early post-transplant period, consistent with the IFI incidence rates shown in this study.^1,30,31 This risk profile underscores the need for vigilant monitoring and proactive management strategies during this critical period, especially since routine systemic antifungal prophylaxis is not recommended following isolated kidney transplantation. Due to the lower rates of IFIs among KTRs compared to other solid organ transplant recipients,^32-35 the primary prevention strategy in KTRs is focused on avoiding environmental exposures to molds and endemic mycoses.^32-35 The predominance of yeast among the IFIs across the different post-transplant periods compared to prior studies^1,30 may reflect diagnostic challenges for molds, leading to an underestimation of the true incidence of invasive mold infections.

Additionally, KTRs who were older at time of transplant, received induction with alemtuzumab or basiliximab rather than thymoglobulin, or underwent combined kidney-liver transplants were more highly represented among patients with IFIs. Liver and endocrine disorders as well as CMV infection were also more prevalent among patients with IFIs. Further prospective investigations of antifungal prophylaxis and/or heightened surveillance strategies in these subgroups may be warranted, as they may offer valuable insights for a more tailored approach to IFI prevention.

Beyond differential risk of IFI with increasing time post-transplant, timing of IFI onset is critical; infections occurring earlier post-transplant were associated with poorer transplant outcomes, which is consistent with prior studies demonstrating a general association between IFIs and adverse transplant outcomes.^1,5,8,31 The causal contributions of the IFIs towards these transplant outcomes, however, could not be established by the prior correlational studies especially given the complexity of post-transplant complications. By using a matching approach at time of IFI diagnosis relative to transplant date, however, we are able to better estimate the possible causal effect of IFI more directly on transplant outcomes and better address confounding including time-dependent confounders, suggesting that diagnosis of IFI was associated with a 3.45-fold higher risk of composite outcome among KTRs.

In KTRs with IFIs, risk of composite outcome was augmented by plasmapheresis induction therapy and antecedent CMV infection and pneumonia. Use of apheresis in high-risk transplants predisposes KTRs to infectious complications such as IFIs³⁶ and may prompt a decrease in immunosuppression with subsequent higher rates of graft loss in these highly sensitized individuals. Additionally, the association with preceding infections illuminates the complex interplay between IFIs and other infectious complications. Parallels can be drawn to the increased risk of secondary IFI following respiratory viral infections in lung transplant recipients, which is associated with greater chronic lung allograft dysfunction and allograft failure.³⁷ Whether this relationship reflects underlying common risk factors versus treatment side effects and/or immunomodulation by the prior infection will require further research. Heightened surveillance for IFIs in KTRs with recent CMV infection and pulmonary infections may also be warranted.

In our sensitivity analysis, these associations were preserved even with the inclusion of possible IFIs, which are defined by the presence of appropriate host risk factors for and sufficient clinical evidence of an IFI but a lack of mycological support.¹¹ Because fungal diagnostics have limited sensitivity and specificity,³⁸ a significant proportion of suspected IFIs remain categorized as possible infections. Given the notable impact of IFIs on transplant outcomes, heightened suspicion for IFIs with consideration of early empiric therapy in the appropriate clinical setting despite negative or equivocal diagnostics may improve patient and graft survival.

Limitations of our study include the retrospective nature and potential regional bias given the single-center setting. These data may also be incomplete; we may have been unable to capture data on IFIs and transplant outcomes if patients received care at an institution with an inaccessible electronic health medical record system, leading to possible misclassification bias, a form of measurement error. Missing IFI events could lead the patients to contribute extra person-time to the non-IFI group, which would result in underestimation of the relative difference in risk between the IFI and non-IFI groups while avoiding detection of spurious differences. Reassuringly we still observe a significant difference in the rate of adverse transplant outcomes between these two groups.

Additionally, while it is possible that transplant outcomes such as death or graft loss occurred at outside hospital centers, these severe events are rarely unreported to the primary transplant center. The exception would be if patients had completely transferred care, in which case they would have already been censored at their last known follow up, minimizing their influence on observed transplant outcomes. The possibility of unmeasured confounding also cannot be completely excluded; factors such as disease relapse, development of new comorbidities (e.g., common variable immunodeficiencies), and non-transplant related medication changes were not captured in this study.

Further prospective studies across multiple centers could validate our findings and explore the mechanistic underpinnings of the observed associations. Additionally, these studies would help determine the generalizability of our findings to larger, more diverse populations. Future studies with larger cohorts may provide more clarity on the potential differences in the impact of yeast vs. mold infection on KT outcomes, as the sub-analysis in this study was constrained by a small sample size. These larger studies may also be valuable for exploring the impact of rejection episodes and immunosuppression changes, which were excluded from our current models due to the rarity of events and degree of heterogeneity, respectively. Potential associations may have been masked by the variability in both variables across the cohort. Moreover, investigations into the effectiveness of different immunosuppressive regimens and induction therapies in reducing the risk of IFIs may inform more targeted and effective approaches to managing KTRs.

In conclusion, our study illustrates the significant potential impact of IFIs on survival and graft function among KTRs, especially in the early post-transplant period. Our findings advocate for a more nuanced understanding of IFI risk factors specific to KTRs and call for a targeted strategy for early detection and management of IFIs to improve outcomes.

Abbreviations:

aHR

Adjusted hazard ratio

CI

Confidence interval

CMV

Cytomegalovirus

EORTC/MSG

European Organization for Research and Treatment of Cancer/Mycoses Study Group

KTR

Kidney transplant recipient

ICD

International classification of diseases

IFI

Invasive fungal infection

IQR

Interquartile range

IRR

incidence rate ratio

SESM

Stochastic extension stratification method

Data sharing

Data are not publicly available due to patient confidentiality and ethical restrictions. De-identified subset is available on request.