Candida albicans Arteritis Transmitted by Conservative Liquid After Renal Transplantation: A Report of Four Cases and Review of the Literature

Abstract

Background. 

Mycotic arteritis and/or aneurysms are infrequent complications of renal transplantation. They are mostly secondary to bacterial infection and rarely to Candida albicans. We report four cases of mycotic arteritis due to C. albicans after renal transplantation but which have been inoculated during organ harvesting or conservation.

Methods. 

In all the four cases corresponding to two independent donors, C. albicans was isolated few days later in the systematic culture of the conservative liquid. We also review the clinical features and outcomes of 13 cases previously reported in the literature.

Results. 

In two cases, the diagnosis of fungal arteritis was confirmed only during autopsy after the patient’s death due to massive bleeding. In the other two cases, the diagnosis was made on the arterial section of the anastomotic wall after detransplantation for massive bleeding for arterial leakage although an immediate antifungal treatment with fluconazole and caspofungin was given and was found to be inefficient.

Conclusion. 

This is a serious complication of renal transplantation because it leads to graft loss in the majority of the cases and even to death in a few cases despite an efficient and rapid treatment. Routine fungal cultures of preservation media are important for early diagnosis and timely surgical interventions are life-saving.

Mycotic arteritis and/or aneurysm may be caused by either hematogenous or local spread of bacteria or fungi to the arterial wall leading to intense inflammatory response and, in consequence, destruction of vascular structures. This is an infrequent complication of renal transplantation and is mostly secondary to bacterial infection. Mycotic arteritis caused by fungal infection, mostly by Candida albicans, is rare but potentially life-threatening because it usually leads to anastomotic leak or arterial wall rupture with or without aneurysm formation and results in hemorrhagic shock necessitating emergency nephrectomy. The source of fungal infection may be a true donor-to-host transmission, or more commonly, a contamination during organ procurement, hence the importance of routine cultures of preservation media.

Thus far, 13 cases of mycotic arteritis and/or aneurysm due to C. albicans occurring after renal transplantation have been reported (^1–9). In only three of 13 cases, C. albicans was recovered from the preservation fluids and antifungal therapy with amphotericin B or fluconazole was given (^3–9). We herein report four cases of mycotic arteritis in which C. albicans was cultured from the preservation media and for the first time, caspofungin, a novel antifungal agent was given together with fluconazole in an attempt to reinforce the treatment. We also summarize the main clinical features and outcomes of 13 previously reported cases.

CASE REPORTS

Case 1

A 30-year-old man with end-stage renal failure secondary to lupus glomerulonephritis underwent a three human leukocyte antigen (HLA) mismatch cadaveric renal transplantation. The donor was a 48-year-old woman who died from head trauma. She was hospitalized for seven days before organ harvesting and received amoxicillin and clavulanate. Her renal function was normal, blood and urine cultures were negative. No collapses or cardiac arrest occurred and no gut section was noted during organ procurement. The right kidney was transplanted by an end-to-side anastomosis between the renal and the right external iliac vessels. The cold ischemia time was 24 hours. The immunosuppressive treatment included basiliximab induction, corticosteroids, mycophenolate mofetil, and delayed initiation of cyclosporine A at day nien posttransplantation.

His serum creatinine decreased progressively to 356 μmol/L on day nine and he did not require hemodialysis. On postoperative day two, the preservation media and two blood cultures were also positive grew Enterobacter cloacae. The patient was given imipenem/cilastatin and amikacin. The C-reactive protein (CRP) was moderately increased to 43 mg/L but he had no fever and urine cultures were negative.

On postoperative day nine, the patient complained of diffuse abdominal pain. The clinical examination revealed abdominal distension with generalized tenderness and the rectal examination was painful. The abdominal ultrasound and computed tomography (CT) scan showed perinephric, perihepatic, and ascitic fluid collection. His hemoglobin level decreased rapidly from 8.5 to 5.3 g/dL but the blood pressure was normal. The patient developed a massive wound bleeding followed by cardiovascular collapse and cardiac arrest while being transferred to the operating room. Cardiopulmonary resuscitation was performed successfully with further transfusion. Four liters of red blood was removed from the abdominal cavity, and total dehiscence of the arterial anastomosis was found. Unfortunately, the patient remained hypotensive during operation and died.

Histological examination of the kidney graft removed revealed intense inflammation of transplant renal artery with transmural neutrophil infiltration. Unexpectedly, abundant yeasts with pseudohyphae compatible with Candida spp. were seen in the arterial wall.

Case 2

A 26-year-old woman with end-stage renal failure due to nephronophthisis underwent a four-HLA-mismatch cadaveric renal transplantation from the same donor. The left kidney was transplanted by the same technique as described in case one. The cold ischemia time was 17 hours. The immunosuppressive treatment included corticosteroids, tacrolimus, and mycophenolate mofetil.

The patient suffered from delayed graft function requiring hemodialysis. Three days after transplantation, the preservation media grew C. albicans and E. cloacae; the former was later shown to be sensitive to amphotericin B and fluconazole, and the latter to imipenem and cefepime. At the same time, the patient developed a low-grade fever associated with an increase in CRP to 380 mg/l. Although many blood and urine cultures as well as candida antigen detection were all negative, the patient was treated immediately with fluconazole 200 mg/d for 13 days, then switched to caspofungin 50 mg/d. She also received imipenem/cilastatin and then cefepime. Despite the treatment, she developed a few days later a wound abscess from which Candida albicans and Enterobacter cloacae were also recovered. A rapid resolution of fever and progressive decrease in CRP was observed suggesting a satisfactory response to antifungal and antibiotic treatment.

On postoperative day 10, we were informed about the death of the recipient of the mate kidney (case 1). Therefore, we performed several Doppler ultrasounds and CT angiographies of transplant renal arteries but did not find any aneurysm. We also performed two renal biopsies because of the delayed graft function. The first one on day 18 posttransplantation revealed only an acute tubular necrosis, whereas the second one on day 24 disclosed a Banff grade IB acute rejection which was treated with three boluses of methyl-prednisolone without clinical response.

Unfortunately, on day 30 posttransplantation, the patient suddenly presented a massive hemorrhage from the open wound complicated with cardiovascular collapse necessitating immediate operation. An arterial anastomotic rupture was found, and transplant nephrectomy was performed together with resection and ligation of the external iliac artery above and below the anastomosis. Histological examination of the renal artery showed intense neutrophil infiltration (Fig. 1) and fungal stain revealed budding yeasts with pseudohyphae in the arterial wall (Fig. 2). The patient did not show any signs of leg ischemia. Antifungal therapy with intravenous caspofungin was continued for one month after nephrectomy and then replaced by fluconazole for two additional months. The patient was discharged six weeks after nephrectomy and is currently well on chronic hemodialysis.

FIGURE 1.: Neutrophil infiltration in the arterial wall (hematoxylin-eosin stain, original magnification × 200).

FIGURE 2.: Budding yeast with pseudohyphae in the renal arterial wall (Grocott stain, original magnification × 400).

Case 3

A 53-year-old man with end-stage renal failure to unknown origin underwent a four-HLA-mismatch cadaveric renal transplantation. The donor was a 21-year-old man who died from head and chest trauma. He was hospitalized since 10 days before organ procurement. His blood and urine cultures were negative. The left kidney was transplanted by an end-to-side anastomosis between the renal and the right external iliac vessels. The cold ischemia time was 15 hours. The immunosuppressive treatment included Zenapax induction, corticosteroids, mycophenolate mofetil, and ciclosporin.

He had a delayed graft function but he did not require hemodialysis. His serum creatinine was 370 μmol/L on day seven and 275 μmol/L on day 10. He received a perioperative antibioprophylax with ceftriaxone and ivermectin. He was treated with sodium heparinate for a right leg phlebitis and a pulmonary embolism. The CRP was moderately increased to 44 mg/L but fever and urine cultures were negative.

On postoperative day 10, treatment by fluconazole was started because of the result of the positive culture of the conservative fluid with C. albicans. The patient developed a perirenal hematoma which was removed on day 11. Direct examination of hematoma sample did not exhibit any fungus but four-day cultures were positive for C. albicans. On day 16, suddenly the patient complained of an acute abdominal pain with hypotension and redone massive wound bleeding occurred. Cardiopulmonary resuscitation was performed but he died. Postmortem analysis of the graft revealed the presence of a rupture wall of arterial anastomosis of the graft and microscopic analysis showed a fungal arteritis.

Case 4

A 26-year-old woman with end-stage renal failure secondary to steroid-resistant focal and segmental glomerulosclerosis underwent a zero-HLA-mismatch cadaveric renal transplantation. Her previous history included congenital rubella with mitral and tricuspid insufficiency treated by annuloplasty, and atrioventricular block associated with paroxystic atrial fibrillation necessitating a cardiac pacemaker and chronic anticoagulation. She received the contralateral kidney of case three and was transplanted by the same technique as that in case one. The cold ischemia time was 31 hours. The patient was given two days of amoxicillin/clavulanate for endocarditis prophylaxis. The immunosuppression was corticosteroids, tacrolimus, and mycophenolate mofetil without induction.

On postoperative day one, she developed a large perinephric hematoma secondary to hypocoagulation requiring immediate surgical drainage. Her serum creatinine decreased progressively to 103 μmol/L. On day seven, she developed a cellulitis at the right iliac fossa associated with a low-grade fever and an increase in CRP to 120 mg/L. Blood and urine cultures and candida antigenemia were negative. On postoperative day 10, the preservation media grew C. albicans which was sensitive to fluconazole, amphotericin B, and caspofungin. The patient was immediately given a combination therapy with fluconazole 200 mg/day by mouth and intravenous caspofungin 50 mg/day. Doppler ultrasound and CT angiography of transplant renal vessels did not show any aneurysm. The persistence of a perinephric hematoma was removed on day 11 and no abnormality of the vessels was observed. Culture of the hematoma grew C. albicans.

On day 17, because of the death of the recipient of the mate kidney, a “preemptive” nephrectomy with resection and ligation of the external iliac artery below and above the anastomosis was performed. During operation, the arterial anastomosis ruptured spontaneously. Histological study showed a triangular zone of infarction at the superior pole of the kidney, a moderate acute tubular necrosis, and an intense neutrophil infiltration of the arterial wall associated with the presence of yeasts with pseudohyphae in the renal arterial wall (Fig. 2). Culture of an arterial specimen was also positive for C. albicans. The patient had mild symptoms of leg ischemia which improved spontaneously. The antifungal combination therapy was continued with fluconazole by mouth and intravenous amphotericin B for two weeks, then with fluconazole monotherapy for two months. She was discharged two weeks after nephrectomy and is currently well on hemodialysis.

DISCUSSION

Vascular infection is an infrequent but serious complication of renal transplantation. Most of mycotic aneurysms or arteritis are due to bacterial infection, with Staphylococcus, enteric gram-negative bacilli, Pseudomonas, and anaerobic bacteria (^{1, 2, 3, 10, 11}). Mycotic arteritis secondary to fungal infection is rare and mostly caused by C. albicans, although Aspergillus has been implicated in a few cases (¹²). Thirteen cases of mycotic arteritis due to C. albicans have been reported in renal transplant recipients (Table 1) (^1–9). Fungal arteritis occurred early after the posttransplanted period. In 12 of 17 cases, it was diagnosed within the first 50 days postoperation. All these cases were complicated with massive bleeding requiring emergency surgical intervention. Nephrectomy was mandatory and any attempt to perform vascular repairs to save the kidney was unfruitful (⁶). Resection and ligation of the affected external iliac artery above and below the anastomotic site leaving two arterial stumps were usually required for the control of infection and prevention of bleeding recurrences. Leg ischemia is infrequent but may require subsequent bypass surgery (^{4, 7, 8}).

TABLE 1: Mycotic arteritis by Candida albicans after renal transplantation

In all but one case (⁵), the affected arteries were those used for anastomosis, such as recipient external iliac or hypogastric artery and transplant renal artery. In nearly two-thirds of the cases, the arterial lesion found intraoperatively was an anastomotic leak or rupture rather than an aneurysm. This explains the great difficulty in the early diagnosis by various imaging techniques including Doppler ultrasound and angiography. In only four cases were aneurysms identified preoperatively by angiography or Doppler ultrasound (^{1, 3, 5, 8}). These were all “late” cases as they occurred two months or later after transplantation. There was no hemorrhage and operations were able to be performed electively with successful vascular reconstruction and kidney saved in three of four cases.

The source of fungal infection is usually not clear, but with the advent of extensive microbiological screening of donors, true donor-to-host transmission is probably less common than contamination during graft harvesting and processing. It is favored by long stays in the intensive care unit, the use of broad-spectrum antibiotics, and wound of gut during organ harvesting. In some cases, infection by Candida occurred during the opening of the vesical mucosa for ureteral anastomosis in cases of Candida colonized bladder. However, this possibility can be ruled out in our cases because the conservative fluid grew Candida spp. and that the mate kidney developed similar arterial complications. Routine culture of preservation media is the only way for early detection of bacterial and/or fungal contamination. Fungal cultures should be kept for at least 10 days because Candida may take time to grow as in our third case. The rate of positive culture of preservation fluid ranged from 5 to 23% depending on the series (⁷), and fungi represented 2 to 10% of all positive cultures (¹¹). The rate of serious infection resulting from bacterial or fungal contaminated graft ranged from 0.5 to 5% (⁷). The reasons why some cases of Candida contamination led to mycotic arteritis while others did not are not clear, although the difference in Candida virulence that determines its capacity to penetrate endothelial cells may be one of the explanations (¹³).

As soon as preservation media grows C. albicans, it is prudent to initiate antifungal therapy without waiting for other laboratory clues for invasive candidiasis in the recipient because blood cultures may be negative in up to 50% and the sensitivity of various tests for candidal antigenemia depends on the immunoassay methods used (¹⁴). Unfortunately, in patients two, three, and four of the current report, as well as in two previously reported cases (^{3, 9}), despite that the immediate treatment with antifungal drugs failed in two cases using caspofungin, a prototype of the novel echinocandin antifungal drug with rapid fungicidal activity against most Candida spp. worked through the inhibition of the synthesis of beta-(1, 3) glucan, an essential component of the fungal cell wall (¹⁵). Caspofungin has been shown to be as effective as amphotericin B for the treatment of invasive candidiasis with substantially fewer toxic effects (¹⁶). Although resistance of C. albicans to caspofungin is rare and the isolated strains in our cases showed in vitro susceptibility to fluconazole, we failed to prevent bleeding complications with fluconazole and caspofungin. As with other antifungal drugs, caspofungin was not shown to treat candidal arteritis. In addition, the benefit of combination therapy rather than monotherapy remains to be elucidated.

In conclusion, mycotic arteritis due to C. albicans is a potentially life-threatening complication of renal transplantation leading to graft loss in most of the cases. Routine bacterial and fungal cultures of preservation media are important for the early detection of contamination, allowing rapid antifungal treatment in an attempt to prevent or limit vascular complications, but nephrectomy is mandatory to prevent bleeding due to anastomotic wall rupture.