Biopsy-proven fungal pyelonephritis complicating delayed graft function in a renal transplant patient

Abstract

Delayed graft function (DGF) is a common phenomenon following renal transplantation, which can be due to several factors. A rare cause includes invasive fungal infections, which can often be a challenge to diagnose. Nonetheless, prompt identification of such infections particularly within transplant patients is essential as they can lead to severe downstream sequelae, including graft loss and even death. We describe here a challenging case of fungal pyelonephritis complicating and potentially leading to DGF and further dialysis dependence within a renal transplant patient. Notably, we highlight the importance and clinical utility of biopsy to confirm the diagnosis, as investigations may be largely normal otherwise. Furthermore, we emphasise that with early identification of these infections, effective antifungal treatment can be commenced in a timely fashion leading to better patient outcomes and good graft function.

Background

Renal transplantation has increased in incidence and prevalence over the years, often the preferred treatment for those with end-stage renal disease.^{1 2} Those who undergo transplantation often experience better quality of life and long-term survival, with a projected survival benefit of 10 years over those on other forms of renal replacement therapy. However, delayed graft function (DGF) can often occur, which is a manifestation of acute kidney injury unique to the transplant process.³ The mechanisms underlying DGF remain complex, proposed to be due to an interplay between vasospasm, cytokine signalling, endothelial and epithelial cell injury, oxidant stress, as well as innate and adaptive immune responses.³ Accordingly, management of DGF is challenging and yet essential to preserve graft life and patient survival. We describe an interesting case of DGF complicated by fungal pyelonephritis, requiring biopsy for diagnosis that was treated effectively with antifungal agents to lead to good graft function and ultimately a positive patient outcome.

Case presentation

A man in his 50s was admitted for receipt of a donation after circulatory death transplant. His medical history notably included end-stage renal failure presumed secondary to diabetic nephropathy, for which he had been established on haemodialysis since 2018 and was receiving sessions three times weekly via a right arteriovenous fistula. His native urine output was 500 mL/day, with a dry weight of 66 kg. Other important comorbidities included type 2 diabetes mellitus (previously poorly controlled), a previous ischaemic stroke in 2018 and an episode of haemophagocytic lymphohistiocytosis due to active tuberculosis in 2018, treated fully with antituberculosis medications, intravenous immunoglobulin, anakinra, etoposide and ciclosporin (treatment also completed in 2018). His transplant donor was a woman in her 50s with a baseline serum creatinine of 57 µmol/L. She previously suffered from breast cancer, but had now been disease free for over 10 years. Our recipient was counselled on this and nonetheless consented to the procedure. In the pretransplant crossmatch, the recipient showed the presence of HLA class 1 antibodies; however, donor-specific antibodies were absent. His calculated reaction frequency was 53%.

The operation was largely uncomplicated, although the recipient experienced a 500 mL blood loss intraoperatively from the upper corner venous anastomosis, managed supportively with suture control and intravenous fluid replacement. Haemostasis and reanastomosis were confirmed following this. The cold and warm ischaemic times were 7 hours 53 min and 48 min, respectively. As there were no contraindications to alemtuzumab induction postoperatively, he received alemtuzumab (Campath) induction alongside inotropic support, with prednisolone and maintenance tacrolimus as additional immunosuppression. As per protocol, he was also treated with vancomycin, ciprofloxacin, co-trimoxazole, isoniazid, valganciclovir and nystatin for antibacterial, antiviral and antifungal cover, respectively.

In the days immediately following the operation, his urine output only measured 10–30 mL/hour, while clinically, he appeared overloaded and was unresponsive to intravenous furosemide. His serum creatinine concentration continued to rise, peaking at 744 µmol/L, prompting an urgent dialysis session. In the subsequent days, he was still failing to clear effectively, leading to further elevation of his serum creatinine to 917 µmol/L, this time accompanied by hyperkalaemia (6.1 mmol/L). Further dialysis sessions were therefore required and the patient continued to remain dialysis dependent up to 3 weeks postoperatively. The patient ultimately began to pass significantly more urine in the days following (750–800 mL/day), although his serum creatinine concentration was statically elevated at approximately 500 µmol/L.

Investigations

An ultrasound scan (USS) in the days immediately following the procedure revealed a well-perfused unobstructed transplant kidney, and his blood tests showed no presence of donor-specific antibodies to suggest transplant rejection. These findings were persistent on repeat USSs and blood tests throughout his admission. A magnetic resonance angiography (MRA) was additionally performed at around 2 weeks postoperatively, which solely showed a small amount of gas within the bladder and some thickening of the bladder wall to suggest a possible urinary tract infection (figure 1). Conversely, urine cultures returned negative.

Figure 1.

Right renal transplant artery showing normal signal along its length with no evidence of signal loss at any site, suggesting no significant stenosis. Pelvicalyceal systems are not dilated. Small amount of gas is identified within the bladder and the bladder wall is thickened and enhancing, possibly suggesting a significant urinary tract infection.

A USS-guided renal biopsy was subsequently performed, which showed the presence of periodic acid–Schiff-positive, septate focally branching fungal hyphae within the lumen of tubules that invaded the surrounding interstitium, diagnostic for fungal pyelonephritis (figure 2). The patient was discussed within our local fungal multidisciplinary team meeting, to advise on further investigations as well as the appropriate antifungal treatment regime. Further tests consequently revealed a positive serum beta-d-glucan and negative galactomannan. However, a specific fungal organism was unable to be isolated from short-term fungal cultures nor 18S PCR of the biopsy sample.

Figure 2.

Transplant renal biopsy, periodic acid–Schiff stain, magnification ×400. The lumen of the main kidney tubules in this image is dilated and contains septate fungal hyphae (denoted by arrow) and budding spores. Notably, there was some mild interstitial inflammation in the immediate surrounding of the neutrophilic casts containing fungi, but tubules and interstitium at a distance from these foci did not show inflammation, ruling out rejection. Tubules containing the casts were mildly dilated as expected with neutrophil casts containing fungi but there was no widespread notable tubular dilation to evoke obstruction. Arteries showed mild hypertensive changes but were otherwise normal; no vascular inflammation was present.

The recipient of the pair of this kidney was also investigated, showing DGF that required five sessions of dialysis post-transplant for management of fluid overload and hyperkalaemia. They underwent the same immunosuppression protocol postoperatively, with consistently negative donor-specific antibody results. However, their graft function spontaneously improved 10 days postoperatively without the need for a renal biopsy. There was no history of fungal pyelonephritis found in this patient.

Differential diagnosis

Following renal transplantation, there are several possible medical and surgical complications that may occur and possibly lead to DGF.^{4 5} These include, but are not limited to, haemorrhage, thrombosis, arterial stenosis, lymphocele and urinoma formation, and infection.² Many of these were excluded using a combination of imaging modalities (including ultrasound and MRA), cultures and serum investigations. Continued surgical review during admission also ensured the transplant wound of the recipient remained healthy and non-infected. Once pre-renal, renal and post-renal diagnoses were excluded, biopsy was then essential to importantly determine the presence of fungal pyelonephritis as the cause of his DGF.

Outcome and follow-up

The patient was treated initially with a 3-week course of Ambisome, with an improvement in serum creatinine concentration being seen on day 5 of the course, and was subsequently discharged with a further 3-week course of oral fluconazole with ongoing follow-up in our outpatient transplant clinic (first follow-up one week after being discharged). His ureteric stent was also removed just over 1 month after his operation, showing a positive culture result for Morganella morganii, treated fully with a 1-week course of meropenem prior to his inpatient discharge. He has continued to recover well, with ongoing improvement in his urine output (to 2 L/day) and serum creatinine concentration (to 123 µmol/L) on repeat blood tests taken in clinic.

Discussion

We describe here a rare case of fungal pyelonephritis complicating and potentially causing DGF in a renal transplant patient. DGF is a common phenomenon within transplant patients, suggestively occurring in up to 43.5% of recipients.⁶ Age of the donor, serum creatinine concentration surrounding brain death, length of recipient postoperative stay in intensive care and particularly length of cold ischaemic time are shown to be important factors toward the development of DGF.⁶ Furthermore, invasive fungal infections are shown to affect a small proportion (up to 10%) of renal transplant patients, with common organisms including mucormycosis, aspergillosis, Pneumocystis jirovecii, Cryptococcus, Candida, histoplasmosis and phaeohyphomycosis.⁷ The presentation of these infections may be variable, potentially manifesting within the pulmonary, subcutaneous and central nervous systems.⁸ Furthermore, DGF, graft loss and even death may occur. This emphasises the need for early identification of invasive fungal infections in transplant patients to optimise their overall outcome post-procedure.

The development of invasive fungal infections remains dependent on the interplay between host (integrity of anatomical barriers, level of immunity) and fungal factors (e.g. exposure, virulence and resistance to prophylaxis).⁹ Older age, diabetes, bacterial pneumonia, urinary tract infections, recent antibiotic use, cytomegalovirus infection and transplant immunosuppressive therapy have particularly been identified as risk factors for fungal infections.^10–12 However, depending on the site of involvement, invasive fungal infections can be challenging to diagnose and often require biopsy and histopathological confirmation. This was evident in our patient, with imaging and urine cultures returning largely normal, with only a slight hint of possible infection seen on MRA, thus requiring biopsy to ultimately confirm the diagnosis. Upon reflection, it may have been useful to have considered biopsy earlier in the patient’s admission in keeping with current transplant guidance, which advises that an allograft biopsy be undertaken every 7–10 days in patients who continue to demonstrate DGF.¹³ On the other hand, a biopsy may not always be essential to identify invasive fungal infections within transplant patients, as isolated reports have also described more symptomatic cases, in which serum blood cultures may reveal a fungal organism to elucidate the diagnosis.¹⁴ Nonetheless, with correct and timely detection of invasive fungal infections in transplant patients, the majority tend to exhibit clinical improvement, similar to our patient.¹⁵ This is often achieved with antifungal agents, although may require surgical intervention and, if the graft is affected, graft nephrectomy.

Patient’s perspective.

I had a prolonged hospital stay of 48 days since the admission for my renal transplant. Initially I found it very difficult coping, especially taking my medications on time. Also I was frustrated with many investigations and blood tests being done in the immediate post-transplant period while being investigated for my delayed graft function. Once I started feeling well and off dialysis, I was very happy and felt the doctors had done a wonderful job for me. Since discharge, I have never been admitted to the hospital and I am being managed as an outpatient in the transplant clinic for which I am very grateful too.

Learning points.

• Keep an open mind when assessing a patient with delayed graft function (DGF), as there are several potential causes, of which invasive fungal infections are important to exclude.

• Biopsy is a highly important and very useful investigation for DGF, to first exclude acute rejection and acute tubular necrosis, but also to provide histopathological insight into possible causes.

• Prompt identification of invasive fungal infections, particularly within transplant patients, is essential to prevent severe sequelae and commence treatment, which can often be life-saving.

Ethics statements

Patient consent for publication

Obtained.