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Keywords:

  • Fungal contamination;
  • preservation fluid;
  • renal transplantation

Abstract

  1. Top of page
  2. Abstract
  3. Introduction
  4. Patients and Methods
  5. Results
  6. Discussion
  7. References

The complications of kidney graft preservation fluid infected by Candida sp. may range in severity from trivial infections to life-threatening complications, including graft arteritis and anastomotic rupture. Mandatory nephrectomy has recently been proposed as a means of preventing arterial wall rupture in such cases. We describe the clinical features and outcome of renal transplantation from a cadaveric donor in eight recipients with preservation fluid testing positive for Candida sp. Six patients were treated with antifungal drugs. After 1–2 years of follow-up, including regular imaging, none of the patients had developed arterial aneurysm, and all had a functional allograft and were alive. The contamination of renal graft preservation fluid with Candida sp. may be uneventful and should not systematically lead to removal of the graft. Until other risk factors for vascular complications have been determined, early antifungal treatment and repeated radiological monitoring are advisable for the prevention and/or early detection of such complications.


Introduction

  1. Top of page
  2. Abstract
  3. Introduction
  4. Patients and Methods
  5. Results
  6. Discussion
  7. References

Fungal infections may cause morbidity and mortality after organ transplantation and affect 5–20% of solid transplant recipients (1,2). The incidence of fungal infection may reach 5% in patients undergoing renal transplantation (1). Candida sp. infections generally occur in the first 2 months after organ transplantation (2). They range in severity from trivial infections (e.g. mucocutaneous colonization) to life-threatening disseminated infections with multiorgan seeding (2). Life-threatening complications of such infections include mycotic arteritis and/or aneurysm due to the hematogenous or local spread of fungi to the arterial wall, leading to the destruction of vascular structures. These complications are rare, but are associated with a high risk of anastomotic leakage or arterial wall rupture, resulting in hemorrhagic shock. The fungal infection may originate from the donor or, more probably, from exogenous sources leading to contamination during graft handling and implantation, including contamination of the preservation fluid (3,4). Little is currently known about the true incidence of preservation fluid contamination by fungi. The clinical consequences of such contamination, and the optimal strategies for preventing and curing subsequent infection in the transplant recipient remain unclear. Four cases of mycotic arteritis due to Candida albicans, which was isolated from the fluid in which kidney grafts had been preserved, were recently reported in four renal transplant recipients (5). All four cases presented with massive bleeding, leading to death in two cases and graft removal in the other two cases. Based on the unfavorable outcomes observed in these cases, the authors of this previous study suggested that the early detection of fungal contamination of the preservation fluid should lead to preventive nephrectomy.

We report here the clinical features and outcome for eight patients undergoing renal transplantation from a cadaveric donor, in which the preservation fluid tested positive for Candida sp. In all cases, the outcome was uneventful, suggesting that graft removal should not be systematically proposed in such cases. Further studies are required to identify additional risk factors for vascular complications.

Patients and Methods

  1. Top of page
  2. Abstract
  3. Introduction
  4. Patients and Methods
  5. Results
  6. Discussion
  7. References

In this study, we carried out a retrospective description of a series of renal transplant patients receiving organs from cadaveric donors and followed at our hospital between January 2004 and December 2006. Patients were selected from our mycological database. Over this 3-year period, 214 cadaveric renal transplantations were performed (63 in 2004, 79 in 2005 and 72 in 2006). In all cases, samples of the preservation fluid were sent to the mycology laboratory. Samples (10 mL) were centrifuged. Part of the pellet was used for wet-mounted observation and part (1 mL) was cultured on Candida ID2 (medium, BioMérieux, Marcy l'Etoile, France) for 5 days at 37°C for 5 days. C. albicans and mixtures of different Candida species can be grown on this medium, with colonies becoming visible by 24 h and identifiable within 48 h. All blue colonies were identified as C. albicans. The white colonies were phenotyped, using the commercial ATB ID 32C kit (API, BioMérieux). Samples of organ preservation fluid were cultured. In cases of positive preservation fluid cultures, urine and drain effluent from the organ recipient were tested.

Results

  1. Top of page
  2. Abstract
  3. Introduction
  4. Patients and Methods
  5. Results
  6. Discussion
  7. References

Positive Candida sp. cultures were obtained from preservation fluid for eight of the 214 renal allografts used in 208 recipients (incidence of 3.7%) at the Renal Transplantation Department of Henri Mondor Hospital between January 2004 and December 2006. We collected 52 preservation fluid samples from 63 renal allografts (82%) in 2004, 72 preservation fluid samples from 79 allografts (91%) in 2005 and 66 preservation fluid samples from 72 allografts (91%) in 2006.

The characteristics of the recipient, donor and renal transplantation are shown in Table 1. In all eight cases, microbiological analyses of donor and recipient blood and urine were negative. In all cases, the recipient received antibiotic prophylaxis, including 1 g/day of vancomycin and 2 g/day of cefotaxime, for the first 48 h after transplantation.

Table 1.  Recipient, donor and transplantation variables
 12345678
  1. HD = hemodialysis; CVA = cerebrovascular attack; CT = corticosteroids; MMF = mycophenolate mofetil; CNI = calcineurin inhibitors.

Recipient 
 Age (years)5743614555665858
 GenderFFFFMMFM
 DialysisHDHDHDHDHDHDHDHD
 Anti-HLA20%38%0%95%0%0%0%0%
Donor 
 GenderMMFMMFMF
 Age (years)6844704755756672
 Cause of deathCVAHangingBrain traumaBrain traumaPulmonary embolismCVACVACVA
 
HLA-mismatch04515525
 
Transplantation 
 Number of arteries 1 1 1 1 1 2 2 1
 Cold ischemia time (hours)1818263617223021
 Immunosuppressive regimen 
 InductionNoNoNoYesYesYesYesYes
 CT4/MMFCNIYesYesYesYesYesYesYesYes

Bacterial and mycological data for the preservation fluid samples testing positive for Candida sp. and posttransplantation characteristics are shown in Table 2. Cultures of urine and blood from all eight recipients were negative for Candida sp. Three patients presented with periallograft fluid collections on ultrasound. The accumulated fluid tested positive for Mycoplasma hominis in one case and was not tested in the other two cases.

Table 2.  Microbiological assays and posttransplant variables
 12345678
  1. CG =Candida glabrata; CA =Candida albicans; CK =Candida krusei; CT =Candida tropicalis; NA = not available.

Mycological testing of preservation fluidCGCACKCTCACACGCG
Bacterial testing of preservation fluidNegNegNegNegEnterococcus faecalis and Enterobacter aerogenesNegGram-negative bacillusCitrobacter diversus, Proteus mirabilis and Enterococcus
Perirenal hematoma or abscessNegPos, NANegNegNegPos, NANegPos: Mycoplasma hominis
Delayed graft functionYesYesNoYesNoNoYesNo
Candida treatmentNoYesNoYesYesYesYesYes
TypeFluconazoleVoriconazoleFluconazoleFluconazoleVoriconazoleCaspofungin
Starting (day after transplantation)245123
Duration14 days14 days3 months3 months3 months3 months
Follow-up (months)3434362413121212
Outcome-glomerular filtration rate (mL/min/1.73 m2)3142225842414661

Six patients were treated with antifungal drugs. The choice of antifungal agent was determined empirically, based on the Candida species present, and was subsequently modified according to the results of antifungal drug susceptibility tests. Antifungal treatment was administered for 14 days to 3 months. Median follow-up was 18.5 months (range: 12–64 months). No clinical signs of fungal infection were observed in any patient during follow-up. Doppler ultrasound was performed weekly during the first month, and then monthly during the first year after transplantation, in all patients. We also carried out magnetic resonance imaging angiography in four patients, 3–6 months after transplantation. No aneurysm was detected during monitoring.

At the end of follow-up, all patients had functional allografts and were alive. Median estimated glomerular filtration rate was 42 mL/min/1.73 m (range: 22–61 mL/min/1.73 m).

One of the eight patients receiving kidneys from the same donors (mate recipients) died from septic shock secondary to a bacterial infection of the lungs. All the others are still alive, and have a functional renal allograft. None of these patients experienced vascular complications.

Discussion

  1. Top of page
  2. Abstract
  3. Introduction
  4. Patients and Methods
  5. Results
  6. Discussion
  7. References

We report here an uneventful clinical outcome in eight renal transplant recipients for whom preservation fluid samples tested positive for Candida. No vascular damage related to Candida sp. infection was detected at the end of follow-up.

Two recent reports (5,6) described the clinical outcomes in six renal transplant recipients with arterial Candida infection due to contamination of the preservation fluid. C. albicans was implicated in all six cases. Two of the six patients died from intraperitoneal hemorrhage. Postmortem analysis revealed graft arteritis and anastomotic rupture. Microscopy showed fungal arteritis. None of these patients received prophylactic antifungal treatment. In the other four cases, the grafts were removed due to (i) surgical repair of the arterial aneurysm in two cases, (ii) death of the mate kidney recipient in one case and (iii) massive hemorrhage following anastomotic rupture in the last case. Iliac artery or renal anastomotic artery aneurysm was detected by CT angiography before nephrectomy in only the first two of these four cases. The first of these four patients received no antifungal treatment, whereas the other three were treated with fluconazole and/or caspofungin or liposomal amphotericin B on days 13, 10 and 4 after renal transplantation (5,6). Histological analysis detected inflammatory Candida arteritis in the renal allograft: intense neutrophil infiltration was associated with the presence of yeasts with pseudohyphae in the renal artery wall.

Based on these cases and 15 other reports of arteritis due to Candida sp. (7–14), Mai et al. (5) recently suggested that nephrectomy should be mandatory in cases in which the preservation fluid is found to contain Candida sp., to prevent bleeding due to anastomotic wall rupture. Reported rates of positive preservation fluid cultures range from 5% to 23%, with fungi accounting for 2–10% of all positive cultures (15). At our transplantation center, where fungal cultures have been carried out on all organ preservation fluid samples since December 2003, the incidence of cultures positive for fungi is close to 4%. Thus, a policy of removing all grafts in cases in which the preservation fluid tests positive for Candida sp. would lead to a large number of preventive nephrectomies. Our case series suggests that a conservative strategy is acceptable and does not place the patient's life in danger.

It remains unclear why Candida contamination leads to vascular complications in some cases but not in others. However, the heterogeneous data available strongly suggest that other associated factors probably influence transplantation outcome. These factors may include the Candida species cultured, the presence of associated perirenal hematomas, immunosuppression, unrecognized or incompletely treated Candida infection in the donor, the timing and duration of antifungal therapy. The colonization of devitalized tissues or the collection of fluid in the postoperative allograft recipient has been reported to be detrimental in cases of fungal infection (1). Vascular injury may also depend on Candida virulence and the ability of this fungus to penetrate endothelial cells (16). The ability to penetrate endothelial cells seems to be essentially a feature of C. albicans, as most cases of vascular injury reported to date have involved this species, and no cases involving C. glabrata, tropicalis or krusei have been reported (17,18). Antifungal treatment is probably also an important factor. In our case series, the duration of antifungal treatment was variable (14 days to 3 months). There are currently no therapeutic guidelines available for the prevention of vascular complications in cases of fungal infection of the donor or preservation fluid contamination. According to clinical guidelines for the treatment of candidiasis, including candiduria or Candida peritonitis, antifungal treatment for a duration of up to 1 month appears to be reasonable (19). The absence of vascular injury in two untreated patients (patients 1 and 3) undergoing transplantation in 2004, and probably in many other unpublished cases, also highlights the potential influence of associated factors yet to be clearly identified.

We report here the occurrence of a favorable outcome in eight patients, despite very different therapeutic approaches. We believe that nephrectomy should not be systematically proposed. Instead, clinical management should be determined on a case-by-case basis. Until the factors predisposing patients to vascular injury are clearly identified, we suggest that, in cases of preservation fluid contamination with Candida sp., (i) all preservation fluid samples should be cultured on specific media, (ii) all positive cultures should be considered pathogenic (independently of qualitative or quantitative analysis) and appropriate species-specific antifungal therapy should be initiated, (iii) repeated fungal cultures should be carried out on samples of urine, blood and drain effluent from the recipient and (iv) regular imaging, including weekly ultrasound and monthly CT or magnetic resonance angiography, should be carried out for at least 3 months. However, the potential value of conservative strategies requires further evaluation in large prospective studies.

References

  1. Top of page
  2. Abstract
  3. Introduction
  4. Patients and Methods
  5. Results
  6. Discussion
  7. References