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Saudi Journal of Kidney Diseases and Transplantation
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RENAL DATA FROM ASIA–AFRICA  
Year : 2019  |  Volume : 30  |  Issue : 5  |  Page : 1137-1143
Prevalence and outcome of systemic fungal infections in renal transplant recipients - A tertiary care experience


1 Department of Nephrology, Sri Ramachandra Medical College, Bengaluru, Karnataka, India
2 Department of Nephrology, Fortis Hospitals, Bengaluru, Karnataka, India
3 Department of Nephrology, Apollo Hospitals, Bengaluru, Karnataka, India
4 Department of Nephrology, Dr. Pinnamaneni Siddhartha Institute of Medical Sciences, Gannavaram, Andhra Pradesh, India

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Date of Submission02-Dec-2018
Date of Acceptance14-Jan-2019
Date of Web Publication4-Nov-2019
 

   Abstract 


Fungal infections are an important cause of morbidity and mortality in renal transplant recipients. These infections account for 5% of all infections in renal transplant recipients. The symptoms of systemic fungal infections are nonspecific, particularly in their early stages, and this can lead to delay in diagnosis. Retrospective analysis was conducted on all renal transplants that were performed at our center over a 20-year period from 1996–2016. Cases of invasive fungal infections (IFIs) that occurred among renal transplant recipients were identified to describe the epidmeiology of these infections. A total of 67 (9.2%) IFI cases were identified among 725 renal transplant recipients. Of the 67 patients (9.24%) with IFI, 31 (46.2%) cases were seen in deceased donor transplant recipients. Of 67 cases with IFI, 42 (62.7%) had received induction therapy. The incidence of fungal infections according to the induction agent used was, 14.3% with basiliximab, 12.3% each with daclizumab and rabbit antithymocyte globulin, and 6.3% among patients not given any induction. Invasive candidiasis was the most common IFI overall, followed by mucormycosis, invasive aspergillosis, and cryptococcosis. Median time to onset of IFI was 117.9 days. Majority of infections occurred within 180 days after transplantation. Late posttransplant (>180 days after transplantation) IFI’s were predominantly caused by Candida, followed by Cryptococcus. The longest time to infection was a case of histoplasma, occurring seven years posttransplant. The overall 12-month cumulative incidence (CI) for any IFI was 9.1%. The 12-month CI of the first IFI increased from 7.3% between 1996 and 2001 to 10.5% between 2010 and 2016. The overall mortality rate was 38.8%. The use of newer and more-effective immunosuppressive agents in recent years are associated with increased rates of fungal infections in renal transplant recipients. Therefore, early detection of fungal infections and proper therapy are important in improving survival and reducing mortality.

How to cite this article:
Shekar M, Elumalai R, Elayaperumal I, Yelahanka RP, Anandkumar DG, Bandi VK, Matcha J. Prevalence and outcome of systemic fungal infections in renal transplant recipients - A tertiary care experience. Saudi J Kidney Dis Transpl 2019;30:1137-43

How to cite this URL:
Shekar M, Elumalai R, Elayaperumal I, Yelahanka RP, Anandkumar DG, Bandi VK, Matcha J. Prevalence and outcome of systemic fungal infections in renal transplant recipients - A tertiary care experience. Saudi J Kidney Dis Transpl [serial online] 2019 [cited 2019 Nov 23];30:1137-43. Available from: http://www.sjkdt.org/text.asp?2019/30/5/1137/270270



   Introduction Top


Fungal infections in renal transplant recipients cause significant morbidity and mortality. They account for about 5% of all post-transplant infections in renal transplant recipients.[1] The incidence is more in the first six months posttransplant, which is attributable to maximal immunosuppression in the early posttrans-plant period. There are many factors which predispose to increased fungal infections such as excessive use of corticosteroids, multiple episodes of rejection and treatment with anti-rejection therapy, poorly controlled glycemic status, poor graft function, leukopenia, elderly age, recipient of multiple organs, chronic or recurrent viral infection, as well as environmental factors.[2],[3],[4] With the advancements in posttransplant management leading to improved survival, coupled with increase in the number of transplants, the incidence of fungal infections posttransplant has also increased.

Fungal infections usually do not present in the 1st month posttransplant, but they can be seen if the prior infection in the recipient was not completely eradicated before transplant, or infection being transmitted from the donor organ. Some donor organ infections such as histoplasmosis and other endemic fungi can be transmitted by the graft. Certain fungal infections like aspergillus can present even without intense exposure within one to six months posttransplant, due to increased state of immunosuppression in that period. After the first six months posttransplant, the risk of fungal infection is minimal, unless an excess exposure has occurred.

The clinical presentation of fungal infections is nonspecific, especially the early stages, which contributes to delayed diagnosis. The high mortality associated with fungal infections and also graft loss necessitates the need for the early diagnosis and treatment.[5]


   Materials and Methods Top


Retrospective analysis was conducted on all renal transplants that were performed at our center over a 20-year period from 1996 to 2016. Cases of invasive fungal infections (IFIs) that occurred among renal transplant recipients were identified to describe the epidemiology of these infections.

All identified proven or probable cases were captured during the surveillance period, regardless of the date of transplantation. The following data were collected from all recipients who developed an IFI, regardless of the date of transplantation: date of infection onset, site of infection, clinical signs, co-infections, co-morbid conditions, immunosuppressive medications received, antifungals administered, and outcome. Demographic data, date and type of transplant, human leukocyte antigen-matching, and type of induction was also noted.

The date of diagnosis was defined as the date on which the first diagnostic culture or examination related to the IFI was performed.

Data analysis

Descriptive analyses were performed for all IFI cases occurring among the renal transplant recipients. Box-and-whisker plots were generated to summarize time to IFI from transplant. The cumulative incidence (CI) of IFI occurring among the incidence cohort was calculated on the basis of time to first IFI. The 12-month CIs for the first IFI of any type were also calculated. IFI-specific and site-specific CIs were also calculated. IFI-specific one-year survival estimates were calculated using the Kaplan–Meier method. The trend of CIs during the surveillance period was also described. We divided the incidence cohort into four separate and sequential sub-cohorts, based on the five-year period during which an individual’s transplantation occurred into Group 1 (1996–2000), Group 2 (2001–2005), Group 3 (2006–2010), and Group 4 (2011–2016). The 12-month CIs for first IFI for each subcohort were calculated and then plotted against the periods. We also stratified cases into two groups that were based on the proportion of all transplants that used a living or a deceased donor.


   Results Top


During the study period, there were 67 (9.2%) IFI cases among 725 renal transplant recipients. The mean age of recipients was 43.4 years, with 61.1% being male. Of the 725 renal transplant recipients, 147 (20.2%) received transplant from a deceased donor, whereas 578 (79.7%) were live-related renal transplants. Among the 578 cases of live-related transplants, 189 were spousal transplants (32.7%). There were no cases of unrelated transplants. Among the cases, 395 patients (54.5%) who received induction, 70 patients (9.7%) received basiliximab induction, 65 (8.9%) received rabbit anti-thymocyte globulin (rATG), and 195 (26.9%) received daclizumab induction. Of the 67 patients with IFI, 31 (46.2%) cases were seen in deceased donor transplant recipients, whereas 36 cases (53.7%) were seen in live-related renal transplant recipients. All patients were recipients of first transplant, and there were no cases of second transplant or ABO incompatible transplant.

Of 67 cases with IFI, 42 (62.7%) had received induction therapy. Induction agents used were Basiliximab in 23.8% (n = 10) of the cases, rATG in 19.0% (n = 8) and daclizumab in 57.1% (n = 24) of cases. The incidence of fungal infections according to the induction agent used was, 14.3% among the patients receiving basiliximab induction, 12.3% each with daclizumab and rATG and 6.3% in those not given any induction therapy.

Invasive candidiasis (66%) was the most common IFI overall, followed by mucormycosis (16%), invasive aspergillosis (IA) (6%), cryptococcosis (4%), and histoplasmosis (3%). There were one case each of fusarium, cladophialophora, and fungal ball. Proven zygomycosis and Pneumocystis jirovecii infection were not seen. [Table 1] demonstrates the proportion of cases due to specific IFIs in each transplant type.
Table 1: Incidence of IFIs based on type of transplant and Induction agent used.

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Among all cases, invasive candidiasis was most commonly associated with candidemia (59.1% of cases), followed by urinary tract involvement (25%). Mucormycosis was seen in 16.4% of cases, with predominant cases involving the upper respiratory tract (63.6%), with 18.2% each involving the lungs and the surgical wound. Among patients with IA (n = 4), Aspergillus fumigatus was the most common species isolated (75%), with Aspergillus niger isolated in one case. All cases of aspergillosis were limited to the lungs. Cryptococcosis was seen in three cases (4.5%), and all presented with central nervous system involvement. Among the other fungi, histoplasma occurred in two cases (3%), while fusarium and cladophialophora occurred in one case each (1.5%) [Figure 1].
Figure 1: Site of infection.

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The time to diagnosis for each IFI type in the surveillance cohort is depicted in [Figure 2]. The median time to onset of IFI was 117.9 days. As demonstrated, the majority of infections occurred within 180 days after transplantation. Early infections, occurring within 90 days after transplantation, were dominated by invasive candidiasis and IA. Late posttransplant (>180 days after transplantation) IFF's were predominantly caused by candida, followed by cryptococcus. The longest time to infection was a case of histoplasma, occurring seven years posttransplant.
Figure 2: Time to diagnosis (days).

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Twelve-month cumulative incidence of IFI

The overall 12-month CI for any IFI was 9.1%. [Figure 3] shows the overall 12-month CI curve, as well as the CI stratified by the type of fungus. The greatest probability of IFI was associated with spousal transplantation (14.2%), followed by deceased donor renal transplant (10.9%) and live transplant overall (8.8%). Patients with live nonspousal transplant had the lowest overall risk of IFI (1.3%) throughout the period of observation.
Figure 3: Cumulative incidence.

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[Figure 4] shows the trend of 12-month CI for first IFI, for each of four sequential subcohorts over a period of 20 years. The 12-month CI of first IFI increased from 7.3% in the subcohort that underwent transplantation during the period 1996–2001 to 10.5% in the sub-cohort that underwent transplantation during the period 2010–2016. There was an increasing, statistically nonsignificant, trend in the overall curve for IFI, and this could reflect improved diagnostic probability, as well as improved survival from other causes of posttransplant mortality.
Figure 4: Invasive fungal infections incidence across cohorts.

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Mortality

The overall mortality among the renal transplant recipients with fungal infection was 38.8% (n = 26). The 12-month survival after infection was 25% for patients with IA, 33.3% for cryptococcosis, 54.5% for mucormycosis, and 68.2% for invasive candidiasis. The survival among other fungi was 60%, with an overall survival of 61.2%. Histoplasmosis was associated with mortality in both the cases (100% mortality).


   Discussion Top


There is increased susceptibility to fungal infection among renal transplant recipients, especially during first six months, with their incidence varying based on their geographical area. Systemic mycosis is major cause of mortality in renal transplant recipients and poses a significant threat because of the immunosuppression coupled with environmental exposure.[6],[7],[8],[9] In one study from India, the incidence of fungal infection in renal transplant recipients was 6.1%, with a mortality rate of 63%.[6] In another study from south India, the incidence of fungal infections in renal transplant recipients was found to be 6.6%.[8]

In a study by Gupta et al,[10] the incidence of IFI in posttransplant patients was found to be 9.8%, with the most common infections being candidiasis (2.8%), aspergillosis (2.3%), mucormycosis (2%), and cryptococcosis (1.9%). They also showed that the incidence of angioinvasive fungi, such as Aspergillus and mucor was increasing.

The prevalence of IFI among renal transplant recipients among Western countries has been reported to be between 1.4% and 9.4%,[11] whereas in our study, the incidence of systemic fungal infection was 9.2% with a mortality rate of 38.8%. The variability with the Western data could be due to the presence of better hygienic and diagnostic facilities.

In a review by Badiee et al,[12] among the IFI, candidiasis has been reported to be the most common (47%) with a mortality rate of about 1.5%.[12] The prevalence of aspergillosis in renal transplant recipients is reported to be 0.5%–2.2%, with 88% mortality rate.[13] Cryptococcosis was the third-most common IFI, with an incidence of about 2.8%.[14] Mucormycosis was extremely rare, with the incidence of 0.2%–1.2%, and 72% mortality rate.[15]

In a prospective study conducted on 1063 organ transplant patients by the Transplant-Associated Infection Surveillance Network[16] over five years, 1208 IFI were identified. They found that invasive candidiasis was the most common IFI (53%), followed by IA (19%), cryptococcosis (8%), nonaspergillus molds (8%), endemic fungi (5%), and zygomycosis (2%). In this study, the most common IFI were candidiasis (65.7%), mucormycosis (16.4%), aspergillosis (6%), cryptococcosis (4.5%), histoplasmosis (3.0%), and other fungi (4.5%), including Fusarium solani, Cladophialophora carrionii, cryptococcus, and fungal ball in one case each.

The commonly associated risk factors prédisposing to fungal infection include[8],[17] intense immunosuppression, use of induction agents, treatment of rejection, increased use of broad-spectrum antibiotics, presence of indwelling catheters, etc. An interaction of four factors is to determine the risk of IFI in an individual renal transplant recipient: net state of immuno-suppression, environmental exposure, technical or anatomic abnormalities (indwelling catheter etc.), Darwinian factors (broad-spectrum antibacterial therapy).

High index of suspicion is needed for the early diagnosis of IFI in a renal transplant recipient. Initial empiric antifungal treatment depends on knowledge of the colonization by the fungi and general susceptibility pattern of the suspected fungi. There is no diagnostic or clinical or radiological examination available for confirmation of fungal infection, and invasive procedures and serologic tests are needed for confirmation. Invasive procedures are frequently needed to provide adequate tissue or fluids for appropriate cultures and histologic diagnosis. These procedures should be part of an initial routine evaluation whenever an IFI is suspected in renal transplant recipients, or in patients with unexplained infections or course. Some centers have suggested anti-fungal prophylaxis, but they have not been shown to reduce the mortality.[18]


   Conclusion Top


The advancement in the field of transplant has led to increasing number of organ transplant recipients, with better survival rates. This has also led to increased prevalence of infections, including IFIs. High index of suspicion, with early detection and appropriate therapy are imperative for improving the outcomes of such patients.

As the diagnostic procedures are not very sensitive, there is a need for development of quantitative tests which can identify the nucleic acids or their proteins and enhance the diagnostic accuracy. Investigations which are not dependent on invasive procedures for sampling, and which are based on detection of the antigens or the molecular techniques are needed. Such tests would help the physician to guide and individualize anti-fungal therapy, thereby reducing the toxicity of these agents.

Conflict of interest: None declared.



 
   References Top

1.
Patel R, Paya CV. Infections in solid-organ transplant recipients. Clin Microbiol Rev 1997;10:86-124.  Back to cited text no. 1
    
2.
Safdar N, Slattery WR, Knasinski V, et al. Predictors and outcomes of candiduria in renal transplant recipients. Clin Infect Dis 2005:40: 1413-21.  Back to cited text no. 2
    
3.
Bach MC, Adler JL, Breman J, et al. Influence of rejection therapy on fungal and nocardial infections in renal-transplant recipients. Lancet 1973;1:180-4.  Back to cited text no. 3
    
4.
Howard RJ, Simmons RL, Najarian JS. Fungal infections in renal transplant recipients. Ann Surg 1978:188:598-605.  Back to cited text no. 4
    
5.
Khan A, El-Charabaty E, El-Sayegh s. Fungal infections in renal transplant patients. J Clin Med Res 2015:7:371-8.  Back to cited text no. 5
    
6.
Gupta KL, Joshi K, Bhat A, Kohli HS, Jha V, Sakhuja V. Mucormycosis of the transplanted kidney with renal papillary necrosis. Exp Clin Transplant 2013:11:554-7.  Back to cited text no. 6
    
7.
Sun HY, Forrest G, Gupta KL, et al. Rhino-orbital-cerebral zygomycosis in solid organ transplant recipients. Transplantation 2010:90: 85-92.  Back to cited text no. 7
    
8.
Tharayil John G, Shankar V, Talaulikar G, et al. Epidemiology of systemic mycoses among renal-transplant recipients in India. Transplantation 2003:75:1544-51.  Back to cited text no. 8
    
9.
Gandhi BV, Bahadur MM, Dodeja H, Aggrwal V, Thamba A, Mali M. Systemic fungal infections in renal diseases. J Postgrad Med 2005:51 Suppl 1:S30-6.  Back to cited text no. 9
    
10.
Gupta KL. Fungal infections and the kidney. Indian J Nephrol 2001:11:147-54.  Back to cited text no. 10
    
11.
Peterson PK, Ferguson R, Fryd DS, Balfour HH Jr., Rynasiewicz J, Simmons RL. Infectious diseases in hospitalized renal transplant recipients: A prospective study of a complex and evolving problem. Medicine (Baltimore) 1982:61:360-72.  Back to cited text no. 11
    
12.
Badiee P, Alborzi A. Invasive fungal infections in renal transplant recipients. Exp Clin Transplant 2011:9:355-62.  Back to cited text no. 12
    
13.
Lin SJ, Schranz J, Teutsch SM. Aspergillosis case-fatality rate: Systematic review of the literature. Clin Infect Dis 2001:32:358-66.  Back to cited text no. 13
    
14.
Husain S, Wagener MM, Singh N. Cryptococcus neoformans infection in organ transplant recipients: Variables influencing clinical characteristics and outcome. Emerg Infect Dis 2001:7:375-81.  Back to cited text no. 14
    
15.
Einollahi B, Lessan-Pezeshki M, Pourfarziani V, et al. Invasive fungal infections following renal transplantation: A review of 2410 recipients. Ann Transplant 2008:13:55-8.  Back to cited text no. 15
    
16.
Pappas PG, Alexander BD, Andes DR, et al. Invasive fungal infections among organ transplant recipients: Results of the Transplant-Associated Infection Surveillance Network (TRANSNET). Clin Infect Dis 2010:50:1101-11.  Back to cited text no. 16
    
17.
Abbott KC, Hypolite I, Poropatich RK, Hshieh P, Cruess D, Hawkes CA. Hospitalizations for fungal infections after renal transplantation in the United States. Transpl Infect Dis 2001: 3:203-11.  Back to cited text no. 17
    
18.
Playford EG, Webster AC, Sorell TC, Craig JC. Antifungal agents for preventing fungal infections in solid organ transplant recipients. Cochrane Database Syst Rev 2004;3:CD004291.  Back to cited text no. 18
    

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Correspondence Address:
Varun Kumar Bandi
Department of Nephrology, Dr. Pinnamaneni Siddhartha Institute of Medical Sciences, Gannavaram, Andhra Pradesh
India
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DOI: 10.4103/1319-2442.270270

PMID: 31696853

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