Two cases of fungal cyst infection in ADPKD: is this really a rare complication?

Autosomal dominant polycystic kidney disease (ADPKD) is the most common monogenic kidney disorder, affecting approximately 1 in 1000 individuals [1‐3]. Urinary tract infections (UTI) are among the most prevalent complications in this disease, occurring in 30–50% of the patients throughout their lifetime [4, 5]. Renal cyst infection (CI) is of particular interest in this scenario, since it is associated with significant morbidity and mortality [6, 7]. Gram-negative bacteria are the typical causing agents in these episodes, most often related to the ascending urinary tract route [8, 9]. Interestingly, the urine sediment may be bland and urine culture negative in CI, because some cysts are not contiguous to the collecting system [1, 10]. While the diagnosis of this condition may be difficult, in recent years positron emission tomography/computed tomography (PET-CT) has become the most sensitive imaging technique to establish it [1, 3, 8, 11].

Although less usually, alternative etiologic agents and infectious routes have been also associated with renal CI in several reports [10, 12]. Fungal CI, however, is recognized as a rare event in ADPKD, with very limited prior description [13, 14]. Notably, in this report we present two cases of fungal CI with distinct outcomes, bringing attention to Candida albicans as a potential causative agent in CI and to the possibility that this complication be more common than currently assumed.

Renal and/or hepatic CI is a common complication in ADPKD, with an incidence of approximately 0.01 episode/patient/year [11, 15]. Several of its aspects, however, remain not well defined, including diagnostic criteria and methods as well as treatment options and regimens [6, 9, 12]. Previous studies propose that a definite diagnosis of CI should be based on cyst aspirate showing neutrophil debris and/or a pathogenic microorganism [6, 16]. With minor variations, a common algorithm defines as likely CI the presence of fever (temperature > 38.5 °C for > 3 days); abdominal pain (particularly a palpable area of renal or liver tenderness); CRP > 50 mg/L, and absence of recent, significant intracystic bleeding or other causes of fever [1, 3, 11, 16, 17]. Since positive cyst cultures are usually not available, likely CI is far more prevalent than definite CI in the clinical scenario. Some reports detected a high prevalence of cyst infection among patients with advanced stages of chronic kidney disease. Indeed, the first case series using PET-CT to investigate cyst infection in ADPKD reported that 12 out 36 (33,3%) patients were on dialysis support [11], a finding in accordance with our previous report that identified 6 out 24 patients in this condition [10]. Of note, neither of the two currently reported cases developed such a complication while on dialysis.

Antibiotic treatment algorithms targeting CI are not robustly defined, since the infectious agent is isolated in a minority of cases. Jouret et al. [8] confirmed the pathogenic bacteria with cyst fluid cultures in only 3 of the 27 analyzed likely CI episodes while Sallee et al. [11] reported five positive cyst cultures among 41 evaluated CI events. In this scenario, different antibiotic approaches have been proposed and used, however none of them includes antifungal drugs as part of initial and second-line regimens. Based on their appropriate concentration within the cyst and antibiotic spectrum against gram-negative bacteria, currently proposed schemes classically include fluoroquinolones, particularly ciprofloxacin or levofloxacin [1, 3, 6, 7, 9]. Failure to improve with antibiotics, however, should raise the suspicion of a fungal infection. There is no consensus, nevertheless, whether routine empirical antifungal therapy should be administered in non-neutropenic patients, even if they are critically ill, since most studies in this specific group have not shown a survival benefit [18]. In our cases, however, both patients had risk factors accepted as criteria for empirical antifungal therapy. Invasive candidiasis is a critical condition associated with mortality in the same level as septic shock (40–60% mortality-rate). In this context, the presence of well-defined risk factors for this condition should always be evaluated by the designated clinician, especially in an inpatient setting. Identifying risk factors may lead to a quick and accurate diagnosis in clinical scenarios where invasive fungemia is unexpected or isn’t contemplated in initial guidelines, such as in the described cases. Upon admission, patient 1 presented important risk factors such as Candida colonization, exposure to antibiotics and use of a double-J catheter. Patient 2, in turn, presented long hospital stay, previous antimicrobial therapy and an emergency gastrointestinal surgical procedure. Other potential risk factors include hemodialysis, necrotizing pancreatitis, central venous catheter, total parenteral nutrition, diabetes mellitus and immunodeficiency (neutropenia < 500 neutrophils/mL, hematologic malignancy, chemotherapy, immunosuppressant drugs) [19, 20]. A fundamental point, moreover, is not to underestimate the diagnostic value of cyst puncture/culture in difficult cases. In intra-abdominal candidiasis, only 4–20% of cases will be candidaemic [21]. To optimize blood culture sensitivity, 40–60-mL blood collection is recommended in adults.

Candida spp. grow very well in standard blood culture broths [22]. The detection of fungal antigen has been a useful approach to the presumptive diagnosis of invasive fungal infection in populations other than ADPKD. In patients with blood-culture-negative invasive candidiasis, mainly with intra-abdominal infection, the 1,3-β-D-glucan assay presented a sensitivity of 88% [23]. Some false-positive results, however, have been reported due to cross-reactions with certain hemodialysis filters, a caveat that could limit its application in patients undergoing hemodialysis support [24, 25].

Only less than 5% of Candida albicans isolates are resistant to azole [26]. This finding was corroborated by a retrospective study that analyzed the susceptibility of 153 Candida albicans isolates to three different antifungal drugs [27]. Only 1% of these isolates were resistant to fluconazole and 3% presented dose-dependent susceptibility; 96% of them, therefore, were susceptible to fluconazole. This same study showed that all isolates were susceptible to anidulafungin and only one of the 153 was resistant to amphotericin B. We chose, however, not to attempt these therapies in our first case due to the following reasons: 1) In a previously reported C. kruzei kidney cyst infection, none of the six analyzed cysts presented amphotericin B levels that reached the MIC level for the C. krusei recovered isolate [13]. The patient from this case report was, in fact, eventually submitted to bilateral nephrectomy; and 2) It is important to point out that none of the echinocandins are excreted in the urine as an active drug, therefore these drugs are not contemplated in Candida urinary tract infection treatment algorithms [28].

Notably, we now report two cases of fungal CI, a very unusual form of this complication. To our knowledge, these are the first two documented cases of Candida albicans renal CI; one with successful response to antifungal therapy and another with no improvement following this therapeutic approach, requiring nephrectomy to be resolved. Our report highlights fungi as potential etiologic agents for CI in ADPKD and the importance of including this possibility within the differential diagnosis in specific circumstances and clinical courses. Immunodeficient patients, previous prolonged antibiotic use and Candida colonization should call attention to this potential diagnosis. In addition, the identification of two cases of Candida albicans renal CI by our group raises the possibility that fungal CI may not be as rare as currently assumed. The relevance of such considerations is particularly high given that first and second-line antibiotic regimens currently applied to CI in ADPKD do not include antifungal agents. The efficacy of antifungal therapeutic strategies according to the identified specimen and its susceptibility and, most importantly, their corresponding intracystic antifungal levels, however, remain to be established.