Isolated bilateral renal mucormycosis in apparently immunocompetent patients—a case series from India and review of the literature

Isolated bilateral renal mucormycosis in apparently immunocompetent patients—a case series from... Clinical Kidney Journal, 2018, 1–8 doi: 10.1093/ckj/sfy034 Original Article OR I G I N AL A R T I C L E Isolated bilateral renal mucormycosis in apparently immunocompetent patients—a case series from India and review of the literature 1 1 1 2 Dharmendra Bhadauria , Praveen Etta , Anand Chelappan , Mohan Gurjar , 1 1 1 1 Anupma Kaul , Raj Kumar Sharma , Amit Gupta , Narayan Prasad , 3 4 5 6 Rungmei S. Marak , Manoj Jain , Aneesh Srivastava and Hira Lal Department of Nephrology and Renal Transplantation, Sanjay Gandhi Post Graduate Institute of Medical Sciences, Lucknow, India, Department of Critical Care Medicine, Sanjay Gandhi Post Graduate Institute of Medical Sciences, Lucknow, India, Department of Microbiology, Sanjay Gandhi Post Graduate Institute of Medical Sciences, Lucknow, India, Department of Pathology, Sanjay Gandhi Post Graduate Institute of Medical Sciences, Lucknow, India, Department of Urology, Sanjay Gandhi Post Graduate Institute of Medical Sciences, Lucknow, India and Department of Radio Diagnosis, Sanjay Gandhi Post Graduate Institute of Medical Sciences, Lucknow, India Correspondence and offprint requests to: Hira Lal; E-mail: drdharm1@rediffmail.com ABSTRACT Background: Isolated renal mucormycosis (IRM) is a potentially fatal disease affecting immunocompromised hosts. IRM affecting apparently immunocompetent patients is rare, with few previous reports, mostly from India. We describe 10 cases of bilateral IRM with no underlying risk factors. Methods: We performed a retrospective analysis of cases of IRM from our hospital information system admitted between 2009 and 2016. We analyzed the data of this cohort of IRM, including epidemiological characteristics, clinical presentation, diagnostic procedures, treatment details and outcome. Results: In all, 10 cases of bilateral IRM were identified. All of them were males with a mean age of 24.7 years (range 10–42). Most patients were initially managed as acute bacterial pyelonephritis with acute kidney injury. A total of eight patients were diagnosed antemortem. Diagnostic clues include sepsis not controlled with broad-spectrum antibiotics and enlarged kidneys with or without hypodensities on ultrasound/computed tomography imaging. Three patients also gave a specific history of passing white flakes in their urine. Eight patients received specific antifungal therapy with amphotericin B with or without posaconazole. Three patients in whom the disease was apparently confined to the pelvicalyceal system underwent local irrigation with Amp-B. One patient underwent bilateral nephrectomy. Four patients succumbed to the disease while five patients were successfully treated. One patient was discharged against medical advice. Conclusions: IRM is a rare, life-threatening disease associated with high mortality even in immunocompetent individuals. Typical clinical and radiological findings and a high index of suspicion may help in early diagnosis, but definitive diagnosis Received: 10.7.2017. Editorial decision: 15.3.2018 V C The Author(s) 2018. Published by Oxford University Press on behalf of ERA-EDTA. This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/ licenses/by-nc/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited. For commercial re-use, please contact journals.permissions@oup.com Downloaded from https://academic.oup.com/ckj/advance-article-abstract/doi/10.1093/ckj/sfy034/5032502 by Ed 'DeepDyve' Gillespie user on 12 July 2018 2| D. Bhadauria et al. requires histopathological and/or microbiological confirmation. Early and rapid diagnosis along with aggressive multidisciplinary management including initiation of specific antifungal therapy with or without surgical debridement is vital for a successful outcome. Keywords: amphotericin B, immunocompetent, isolated renal mucormycosis, nephrectomy, posaconazole of specimens were prepared for direct microscopic examination INTRODUCTION through the use of 10% potassium hydroxide and Gomori’s me- Mucormycosis (MM) is a rare, life-threatening invasive fungal thenamine silver (GMS) stain. Some part of the specimens were infection caused by a group of filamentous fungi of the class also inoculated on Sabouraud dextrose agar. Abundant, broad, Zygomycetes. Most cases are caused by those of the order sparsely septate thin-walled hyaline hyphae with irregular non- Mucorales, which include genera Rhizopus (most common path- dichotomous branching characteristic of zygomycetes were ogen), Mucor, Rhizomucor, Absidia, Apophysomyces and found on studies of both the potassium hydroxide mounts and Cunninghamella. The terms MM and zygomycosis are used inter- Grams-stained material and on this basis a diagnosis was made changeably (the term phycomycosis is also used) [1, 2]. They are of zygomycosis. On the basis of the culture and microscopic vasotropic and angioinvasive, usually affecting immunocom- characteristics, the strain was identified. promised patients. Renal involvement due to MM mostly occurs In patients with negative urinalysis but with a high index of concurrently with disease affecting other parts of the body or as suspicion based on imaging studies and other presenting fea- a part of disseminated disease [3, 4]. tures, a renal biopsy was performed. A histopathological diag- Isolated renal mucormycosis (IRM) is reported rarely in the lit- nosis of renal MM was made based on the identification of erature and mainly as unilateral. It has been documented in few broad, aseptate, irregular and right-angled branching fungal hy- case reports, mostly from developing countries, especially from phae in renal biopsy tissue sections stained with hemotoxylin the Indian subcontinent, in patients having an underlying and eosin, periodic acid–Schiff, Grocott–Gomori or silver methe- immunocompromised state [5–11]. IRM is liable to be missed clin- namine stains. Definitive diagnosis was made after tissue dem- ically, especially in immunocompetent patients. It is an almost onstration of fungus on histopathology, while probable fatal disease if bilateral and diagnosed late, especially in the diagnosis was made on the basis of only microscopy and culture angioinvasive state [5–11]. There is a paucity of literature on the positivity of fungus. clinical behavior, management and outcome of bilateral IRM. Here we present 10 cases of bilateral IRM affecting appar- Management of IRM ently immunocompetent patients with no underlying predis- Management of IRM included antifungal drugs [amphotericin B posing conditions, with the objective of comparing our data in (Amp-B) with or without posaconazole] with or without bilateral terms of clinical behavior, management and outcome with nephrectomy. The choice of conventional (amphotericin deoxy- those cases already reported in the literature. We also propose cholate) versus the liposomal form of Amp-B was made depend- an algorithm for early diagnosis and management of these ing upon the renal function and cost affordability of the patients. patients. The maximum cumulative dose of Amp-B used was 3 g. Local irrigation with conventional Amp-B through percuta- MATERIALS AND METHODS neous nephrostomy (PCN) was done in patients where the dis- ease was apparently confined to the pelvicalyceal system as We retrospectively collected the data of all patients admitted be- suggested by imaging or in whom there was a poor response to tween 2009 and 2016 with a diagnosis of renal MM from the hospi- parenteral Amp-B therapy. Posaconazole was added to Amp-B tal information system (HIS) of our tertiary care center. The cases as part of the initial regimen in patients who could afford ther- with IRM were identified as those without evidence of Mucor in- apy and in patients with a poor response to the initial 2 weeks fection at other sites such as the nasal sinuses, orbits, eyes, lungs of Amp-B therapy. Response to therapy was assessed by the and central nervous system. Those with the disseminated disease clinical response, urine microscopy and culture and imaging were excluded. Patients with underlying predisposing conditions findings. In patients completing the Amp-B therapy, for Mucor infection, including diabetes mellitus, human immuno- posaconazole was used as a maintenance antifungal therapy. deficiency virus (HIV) infection, steroid or immunosuppressant The decision to do a nephrectomy was based on the response to use and known immunodeficiency disease, were excluded. antifungal therapy and the extent/type of renal involvement by We analyzed the data of this cohort of IRM, including epide- the fungus. Refractory cases and cases of invasive renal MM miological characteristics, clinical presentation, diagnostic pro- proven by imaging and/or biopsy were considered for bilateral cedures, treatment details and outcome. In all the cases, nephrectomy. However, the decision to perform a nephrectomy routine hematological and biochemical tests, blood and urine was heavily influenced by the ability of patients to afford treat- cultures, imaging [ultrasound (US), renal Doppler or computed ment, as a bilateral nephrectomy entails lifelong renal replace- tomography (CT)] were done. ment therapy, incurring significant costs and morbidity. Diagnosis of IRM Results Diagnosis of renal MM was established by doing urine micros- copy and culture, imaging in all patients of suspected MM and We found 21 cases of MM with renal involvement in our HIS. In renal biopsy in certain cases. Figure 3A represents the diagnos- all, 12 patients had IRM and of them, 10 were diagnosed with bi- tic algorithm followed by us. Repeatedly positive urine micros- lateral disease. No underlying predisposing conditions were copy and culture established the diagnosis of renal MM. Smears identified in all 10 cases. Downloaded from https://academic.oup.com/ckj/advance-article-abstract/doi/10.1093/ckj/sfy034/5032502 by Ed 'DeepDyve' Gillespie user on 12 July 2018 Isolated bilateral renal mucormycosis | 3 FIGURE 1: Clinical findings in IRM patients. (A) Patient’s abdomen shows erythema and subcutaneous edema of the flank region. (B) Urine sample: gross hematuria with white flakes containing papillary tissue and fungus settled at the bottom. (C) Mucor bezoars passed in the urine of an IRM patient complaining of abdominal colics. (D) Non-contrast CT of the abdomen in the coronal plane at the level of the kidneys shows bilateral bulky kidneys with parenchymal hypodensities. (E) Contrast CT of the abdomen in the axial plane at the level of the kidneys shows bilateral bulky kidneys with enhancing thickening of the wall of the renal pelvis. (F) Contrast CT of the abdomen in the coronal plane shows bilateral bulky kidneys with multiple nonenhancing areas with preserved normal subcapsular parenchyma (Rim sign). (G) Contrast CT of the abdomen (excretory phase) in the coronal plane shows the right kidney demonstrating a filling defect in the calyceal system. (H) CT angiogaphy (reformatted in the coronal plane) shows normal main renal arteries with attenuated segmental branches in the region of nonenhancing areas suggestive of vasular in- vasion. (I) Noncontrast CT of the abdomen shows bilaterally enlarged kidneys with irregular, nonhomogeneous, hypodense areas within the renal parenchyma and perinephric fat stranding. FIGURE 2: (A) Urine cytopathology shows broad, ribbon-like fungal hyphae. (B) Extensive cortical necrosis of the renal parenchyma with broad, ribbon-like fungal hyphae (hematoxylin and eosin, 200). (C) Broad, aseptate hyphae with right-angle branching in necrosed renal parenchyma (chromic acid silver methenamine stain, oil immersion). presented with fever, flank pain, sepsis and acute kidney injury Demographic profile (AKI). This patient (patient 3; Table 1) presented with acute ab- The ages of the patients ranged from 10 to 42 years (mean 24.7). All domen, sepsis and AKI. In all, six patients were oliguric and di- were male, hailed from a rural community and belonged to the low alysis dependent while the remaining four had non-oliguric socioeconomic strata. None of the patients had any predisposing (patients 1, 4, 5 and 10) renal failure. An initial clinical diagnosis conditions such as diabetes mellitus, HIV infection or malignancy of bacterial pyelonephritis was made in eight patients and and were apparently immunocompetent. However, a separate hence treated with broad-spectrum antibacterial agents. search for immunodeficiency disorders was not performed. Antibacterial agents were withdrawn after confirmation of fun- gal infection. A total of eight patients were diagnosed antemor- Clinical features tem. Diagnostic clues pointing to a fungal etiology in these Table 1 summarizes the epidemiological and clinical character- patients were sepsis not controlled with broad-spectrum antibi- istics of all patients with bilateral IRM. All patients except one otics and enlarged kidneys with or without hypodensities on Downloaded from https://academic.oup.com/ckj/advance-article-abstract/doi/10.1093/ckj/sfy034/5032502 by Ed 'DeepDyve' Gillespie user on 12 July 2018 4| D. Bhadauria et al. FIGURE 3: Algorithmic approach to the (A) diagnosis of IRM and (B) management of IRM. KUB, kidney ureters bladder; MRI, magnetic resonance imaging. AmB, Amphotericin; CT, computerized tomography; KUB, kidney ureter bladder; MRI, magnetic resonance imaging; PCN, percutaneous nephrostomy; USG, Ultrasound. Table 1. Epidemiological and clinical characteristics of patients with bilateral IRM Patient Age (years)/ Background/ Clinical number gender socioeconomic strata Clinical features diagnosis Clue to diagnosis Urine microscopy 1 32/M Rural/low Fever, flank pain, sepsis, Bacterial PN B/L " in kidney size Rhizopus AKI 2 34/M Rural/low Fever, flank pain, sepsis, Bacterial PN B/L " in kidney size with Anuric AKI infarction 3 34/M Rural/low Fever, acute abdomen, an- Intestinal PM diagnosis on Not done uria, perforation histopathology peritonism with ascites and sepsis 4 32/M Rural/low Fever, flank pain, sepsis, Bacterial PN B/L " in kidney size A. elegans AKI 5 24/M Rural/low Fever, flank pain, hematu- Bacterial PN/ White-colored urine mixed Rhizopus ria, papillary with blood and fungal white flakes in urine necrosis hyphae, B/L " in kidney size 6 10/M Rural/low Fever, flank pain, sepsis, TMA/DIC PM diagnosis on Not done AKI histopathology 7 42/M Rural/low Fever, flank pain, sepsis, Bacterial PN B/L " in kidney size with Anuric AKI infarction 8 18/M Rural/low Fever, flank pain, sepsis, Bacterial PN B/L " in kidney size with A. elegans AKI, MODS hypodensities 9 24/M Rural/low Fever, flank pain, sepsis, Bacterial PN White-colored urine with Rhizopus AKI fungal hyphae, B/L " in kidney size 10 14/M Rural/low Fever, flank pain, white Bacterial PN White-colored urine with A. elegans flakes in urine fungal hyphae and bezoars, B/L " in kidney size B/L, bilateral; DIC, disseminated intravascular coagulation; MODS, multiorgan dysfunction syndrome; PM, postmortem; PN, pyelonephritis; TMA, thrombotic microan- giopathy; ", increased. US/CT imaging. In all, three patients also gave a specific history Doppler imaging suggestive of infarction, which were later con- firmed by CT imaging. A thick pelvicalyceal system and ureters of passing white flakes in their urine. A postmortem diagnosis without suggestion of infarction on CT imaging were seen in of renal MM was made in two patients. four patients, suggestive of confinement of infection up to the pelvicalyceal system. Urine for fungal microscopic examination, Investigations culture and sensitivity was sent in six patients and was positive Table 2 summarizes the imaging characteristics, management repeatedly for Mucor. Of the remaining patients, urine examina- and outcomes. US of the kidneys was done in all patients, while tion for fungus could not be performed, as the diagnosis was other imaging studies, including renal Doppler, CT scan or mag- not suspected in two patients who had a stormy course netic resonance imaging, were done in all but two patients. In culminating in death and two patients were anuric. The organ- all, three patients had focal areas of loss of vascularity on renal ism on fungal culture was identified in three patients as Downloaded from https://academic.oup.com/ckj/advance-article-abstract/doi/10.1093/ckj/sfy034/5032502 by Ed 'DeepDyve' Gillespie user on 12 July 2018 Isolated bilateral renal mucormycosis | 5 Table 2. Imaging characteristics, management and outcome of IRM in immunocompetent patients Patient number US abdomen Doppler study CT abdomen/MRI Management FU Outcome 1 B/L " in kidney size Normal B/L " in kidney size, Amp-B (2.8 g), posa- 61 months Survived thick PC system conazole (4 months), bilat- eral instillation of Amp-B via PCN 2 B/L " in kidney size, Focal loss of B/L " in kidney size, Amp-B bilateral 10 days Mortality with vascularity hypodensities, nephrectomy hypodensities infarcts 3 B/L " in kidney size, Not done Not done Laparotomy, antimi- 4 days Mortality ascites crobial only 4 B/L " in kidney size, Normal B/L " in kidney size, Amp-B (2.5 g), posa- Survived mild HDN thick PC system conazole (4 months) and bi- lateral instillation of Amp-B via PCN 5 B/L " in kidney size Normal B/L " in kidney size, Amp-B (3.2 g), posa- 26 months Survived focal PN conazole (6 months) 6 B/L " in kidney size Not done Not done Broad-spectrum 7 days Mortality antibiotics 7 B/L " in kidney size Focal loss of B/L " in kidney size, Amp-B (3 g), posa- – DAMA with vascularity hypodensities, conazole (2 weeks) hypodensities infarcts 8 B/L " in kidney size Focal loss of B/L " in kidney size, Amp-B (200 mg) 5 days Mortality with vascularity hypodensities, hypodensities infarcts 9 B/L " in kidney size Normal B/L " in kidney size Amp-B (3 g), posa- 6 months Survived conazole (3 months) 10 B/L " in kidney size Normal B/L " in kidney size, Amp-B (2.8 g), posa- 3 month Survived thick PC system conazole (4 months), bilat- eral instillation of Amp-B via PCN B/L, bilateral; DAMA, discharged against medical advice; FU, follow-up; HDN, hydronephrosis; MRI, magnetic resonance imaging; PC, pelvi-calyceal system; PN, pyelo- nephritis; ", increased. Apophysomyces elegans and in three as Rhizopus. An antemortem (patients 4 and 9). Local irrigation with Amp-B, in collaboration diagnosis of renal MM was made in all but two patients, in with urologists, was done in three patients in whom MM was whom the diagnosis could only be confirmed postmortem. thought to be confined to the pelvicalyceal system and ureters Kidney biopsy was done in 8 of 10 patients and 2 of these were with no evidence of angioinvasion. Bilateral nephrectomy was postmortem. Histopathological demonstration of fungus was done in patient 2 (Table 2) and was planned in patient 5 made in 4 of 10 patients. The histopathological findings of (Table 2). However, patient 5 was subsequently discharged patients 2, 3, 6 and 8 were suggestive of acute cortical necrosis against medical advice because of the inability to afford hemo- along with ghost outlining of cellular architecture and broad, dialysis and a poor response to antifungal therapy. aseptate hyphae with right-angle branching in necrosed renal parenchyma. The histopathological findings of patients 1, 4, 5 Outcome and 10 were suggestive of acute tubular necrosis along with in- In all, 4 of 10 patients succumbed to the disease due to severe terstitial infiltrates, but fungus could not be demonstrated. sepsis and multiorgan dysfunction syndrome. One patient was discharged against medical advice on financial grounds. The Management remaining five patients who survived were followed up (range Specific treatment was possible in eight patients, including an- 3–61 months) and did not have subsequent relapse of the tifungal therapy (Amp-B with or without posaconazole) with or disease. without local irrigation through PCN of the pelvicalyceal system and ureters with Amp-B. In all patients, a conventional form of DISCUSSION Amp-B was used. Posaconazole was used as an adjuvant ther- apy to Amp-B in two patients (patients 5 and 10). Maintenance To our knowledge, this is the first detailed and largest report of antifungal therapy with posaconazole was given in two patients bilateral IRM in apparently immunocompetent patients. This Downloaded from https://academic.oup.com/ckj/advance-article-abstract/doi/10.1093/ckj/sfy034/5032502 by Ed 'DeepDyve' Gillespie user on 12 July 2018 6| D. Bhadauria et al. Table 3. Comparison of different case series/reports of IRM in immunocompetent patients Renal Case series n Age range Sex (n) Antemortem involvement (n) Therapy (n) Mortality, n a,b Gupta et al. [30] 7 9 mo–57 yrs M (7) 4 U (1), B (6) Amp-B (3), Amp-B and nephrec- 6 tomy (2), untreated (2) a,b Chakrabarti et al. [13] 3 10–70 yrs M (3) 3 U (1), B (2) Amp-B and surgical drainage or 1 PCN (3) Chugh et al. [14] 3 17–37 yrs M (1) 3 U (2) B (1) Amp-B and nephrectomy (3) 2 F (2) Marak et al. [15] 2 17–32 yrs M (2) 2 U (1) B (1) Amp-B and PCN (2) 2 Jianhong et al.[24] 3 3 mo–14 yrs M (2) 3 U (3) Amp-B (1), Amp-B and surgical 0 F (1) drainage (1), Amp-B and ne- phrectomy (1) Pahwa et al. [31] 1 30 yrs M (1) 1 U (1) Nephrectomy (1) 0 Kumar et al. [32] 1 39 yrs M (1) 1 U (1) Amp-B and endoscopic removal of 0 fungal bezoars (1) a,b Nayagam et al. [33] 1 18 mo M (1) 1 U (1) Amp-B and nephrectomy (1) 0 Thomas et al. [34] 1 41 yrs M (1) 1 U (1) Amp-B and nephrectomy (1) 0 Paonam et al. [35] 1 24 yrs F (1) 1 B (1) Amp-B and surgical debridement 1 (1) Goel et al. [28] 1 45 yrs M (1) 1 U (1) Amp-B and nephrectomy (1) 0 Singh et al. [36] 1 18 yrs M (1) 1 B (1) Amp-B and nephrectomy (1) 1 Pickles et al. [37] 1 18 yrs M (1) 1 U (1) Amp-B and nephrectomy (1) 0 Singh et al. [38] 1 22 yrs M (1) 1 U (1) Amp-B and nephrectomy (1) 0 a,b Our case series 10 10–42 yrs M (10) 8 B (10) Amp-B (9), untreated (1), surgery 5 (1), PCN (3) B, bilateral; DAMA, discharged against medical advice; F, female; M, male; mo, months; U, unilateral; yrs, years. Reports from India. Included children. report highlights the life-threatening nature of Mucor infections Renal MM is rare and often a manifestation of disseminated even in immunocompetent individuals, in whom it rarely mani- disease, in which renal involvement has been reported in up to fests. Most of the patients in our study had a clinical presenta- 20% of cases [4]. IRM has been reported in patients with ac- tion akin to acute bacterial pyelonephritis and had dialysis- quired immune deficiency syndrome, intravenous drug abusers dependent AKI. Early diagnosis of bilateral IRM did help in and those on corticosteroid therapy (5, 21). In contrast, IRM in salvaging half of our patients. Delayed or missed diagnosis of immunocompetent individuals is extremely rare and the major- the angioinvasion stage might have contributed to the stormy ity of cases have been reported from the Indian subcontinent and fatal clinical course in the other half of our patients. A few and China [22–24]. However, the majority of the cases of IRM unique observations were made from our study, including bilat- reported from India were apparently immunocompetent, in eral IRM affected predominantly young males with low contrast to cases reported from China who possessed risk fac- socioeconomic status and a rural background; a specific history tors for developing MM. The number of such cases has shown of passing white flakes in urine was given by three patients; fo- an increasing trend over the past three decades. It is presumed cal loss of vascularity on renal Doppler, corresponding renal to occur via seeding of kidneys during an episode of fungemia infarcts on CT and a thickened pelvicalyceal system were com- from a subclinical pulmonary focus or due to ascending infec- mon distinguishing features; four patients in whom the infec- tion of the urinary tract [25, 26]. Renal parenchymal necrosis tion was possibly confined to the pelvi-calyceal system and results from angioinvasion of fungal hyphae, leading to vascu- ureters, as suggested by imaging and histopathology, survived lar thrombosis and infarction. Mucor hyphae may also invade with multidisciplinary care. We successfully treated 5 of 10 the glomeruli and tubules, sometimes with associated giant cell patients, of this nearly 100% with fatal illness [12, 13–15, 16, 17], reaction and granuloma formation [27]. Clinically, patients with because of a high index of suspicion learned from our previous IRM present with fever, flank pain, tenderness, hematuria, py- experiences and early diagnosis. uria and renal failure, which are usually the result of near total The most common clinical presentations of MM in immuno- occlusion of the renal arteries or their branches, similar to our compromised hosts include rhino-orbito-cerebral, pulmonary, patients [6, 28, 29]. gastrointestinal and disseminated forms [18, 19]. Most human Table 3 summarizes the various case series/reports in the lit- infections result from inhalation of fungal sporangiospores that erature on IRM. To date 12 cases of bilateral IRM have been de- have been released in the air. The largest series of zygomycosis scribed in literature. Our case series included 10 from India had 129 patients; the rhino-orbito-cerebral type was immunocompetent patients with bilateral IRM. One of these most common (44.2%) and renal involvement was seen in 14.0% was a 10-year-old child and the remaining cases were adults, of patients. About 23% of patients were apparently healthy and and all of them were males. All patients presented with 35% were diagnosed postmortem [20]. The cutaneous form is oligoanuric renal failure and six were dialysis dependent. Most most common in immunocompetent patients, followed by of our patients were treated initially in lines of sepsis-/ rhino-orbito-cerebral disease [18, 12]. pyelonephritis-induced AKI. Specific therapy was possible in Downloaded from https://academic.oup.com/ckj/advance-article-abstract/doi/10.1093/ckj/sfy034/5032502 by Ed 'DeepDyve' Gillespie user on 12 July 2018 Isolated bilateral renal mucormycosis | 7 only eight patients in whom the diagnosis was suspected clini- formulations are especially useful in patients with renal failure cally and confirmed subsequently. Bilateral nephrectomy was and can be given at higher doses with fewer side effects. planned in two patients and was possible in only one. In our However, we have used conventional Amp-B in all of our case series, A. elegans was identified in three patients and patients. Rhizopus in three patients. A total of five patients were success- Overall, survival for IRM is estimated to be 65% [34]. fully treated. However, it is associated with nearly 100% mortality in patients Gupta et al. [30] described 9 cases of IRM out of 18 cases of re- with bilateral renal involvement with AKI [30]. The majority of nal MM, most of whom were male and 7 were immunocompe- survivors of IRM have been those with unilateral renal involve- tent. In all, four were diagnosed by antemortem kidney biopsy, ment and who received timely appropriate antifungal therapy one by postmortem kidney biopsy and two by autopsy. A total with nephrectomy. Few case reports noted successful treatment of six patients had bilateral renal involvement and all of them of IRM with Amp-B deoxycholate without nephrectomy and the presented with severe irreversible renal failure and died. Only majority of them suffered unilateral renal disease [5, 7]. one patient was successfully treated, who had unilateral dis- In our case series, specific antifungal therapy with Amp-B ease and had undergone nephrectomy. Specific infective spe- and posaconazole was given in eight patients. Local instillation cies were identified in 2 of the 18 patients, with Rhizopus of Amp-B into the pelvicalyceal system was done in three arrhizus and A. elegans [30]. patients. Bilateral nephrectomy was done in one patient. The Chakrabarti et al.[13] described three cases of IRM and two mortality was 50%, with four survivors and one patient dis- had bilateral disease. All three patients were diagnosed by mi- charged against medical advice. croscopic examination and culture of drained pus. Only one had To our knowledge this is the largest case series of bilateral histological confirmation on autopsy. The remaining two had a IRM in the literature. A detailed description of the clinical presen- successful outcome. Nephrectomy was not done in any of them. tation, diagnostic features and treatment outcomes contribute to Chugh et al.[14] found four cases of IRM; three were immu- the strengths of our report. However, we did not do a specific nocompetent and one had bilateral disease. All three cases evaluation for other primary immunodeficiency syndromes in underwent nephrectomy in combination with antifungal ther- any of these patients. Hence the immunocompetent state is ap- apy and two succumbed to the illness. parent and not absolute. This constitutes a limitation of the study Two cases of IRM described by Marak et al., [15] had success- and marks an area for potential research in the future. ful outcomes without the need for nephrectomy. Of the three Our experience emphasizes the need for a high index of sus- childhood cases of IRM described by Jianhong et al., [24] one had picion for rapid diagnosis by imaging, microbiological and histo- undergone nephrectomy and all survived following therapy. logical methods. Early initiation of systemic antifungal therapy Pahwa et al.,[31] in their single case report of IRM with no iden- and surgical intervention are necessary for this life-threatening tifiable risk factors, proposed that simple nephrectomy without condition. antifungal therapy may be sufficient in immunocompetent, afe- brile, nontoxic patients with a coincidental finding of renal MM CONCLUSION in a nephrectomy specimen. Typical imaging findings of IRM on contrast-enhanced CT of IRM is a rare, life-threatening disease associated with high mor- the abdomen include enlargement of the kidneys, multiple low tality even in immunocompetent individuals, in whom it rarely attenuations and nonenhancing areas in the parenchyma, re- manifests. Typical clinical and radiological findings may help in duced/absent contrast excretion and perinephric collections. rapid and early diagnosis. However, definitive diagnosis Various authors have described these findings on CT as ‘diffuse requires histopathological and/or microbiological confirmation. patchy nephrogram’ [5, 25]. In the presence of suspicious radio- A high index of suspicion along with rapid diagnosis and early logic findings, a biopsy is indicated to confirm the diagnosis. and aggressive multidisciplinary management, including initia- Diagnosis of MM is difficult, especially antemortem, due to vari- tion of specific antifungal therapy with or without surgical de- able clinical presentation and limitations in achieving a tissue bridement, is vital for a successful outcome. diagnosis. The majority of cases reported in the past were diag- nosed at autopsy or by a postmortem biopsy. IRM can clinically CONFLICT OF INTEREST STATEMENT masquerade as rapidly progressive glomerulonephritis, pyelo- nephritis, renal abscess and acute interstitial nephritis. Hence, None declared, however, some of the cases have been published even in immunocompetent patients, nonresolving pyelonephri- as individual case reports in different journals. tis should prompt the possibility of a fungal infection like MM. Blood and urine cultures are often negative. Examination of 24- REFERENCES h urine collections could increase the diagnostic yield. Radiological findings can be nonspecific. Hence definitive diag- 1. Spellberg B, Edwards J, Ibrahim A. Novel perspectives on nosis relies on histopathological evidence of fungal invasion of mucormycosis: pathophysiology, presentation, and man- affected tissues. A high index of suspicion is crucial for a timely agement. Clin Microbiol Rev 2005; 18: 556–569 diagnosis. Recently molecular diagnosis with real-time poly- 2. Prabhu RM, Patel R. Mucormycosis and entomophthoramy- merase chain reaction has been suggested for early diagnosis cosis: a review of the clinical manifestations, diagnosis and [29]. treatment. 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Walsh TJ, Gamaletsou MN, McGinnis MR et al. Early clinical 21. Weng DE, Wilson WH, Little R, Walsh TJ. Successful medical and laboratory diagnosis of invasive pulmonary, extrapulmo- management of isolated renal zygomycosis: case report and nary, and disseminated mucormycosis (zygomycosis). Clin review. Clin Infect Dis 1998; 26: 601–605 Infect Dis 2012; 54(Suppl 1): S55–S60 Downloaded from https://academic.oup.com/ckj/advance-article-abstract/doi/10.1093/ckj/sfy034/5032502 by Ed 'DeepDyve' Gillespie user on 12 July 2018 http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Clinical Kidney Journal Oxford University Press

Isolated bilateral renal mucormycosis in apparently immunocompetent patients—a case series from India and review of the literature

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Clinical Kidney Journal, 2018, 1–8 doi: 10.1093/ckj/sfy034 Original Article OR I G I N AL A R T I C L E Isolated bilateral renal mucormycosis in apparently immunocompetent patients—a case series from India and review of the literature 1 1 1 2 Dharmendra Bhadauria , Praveen Etta , Anand Chelappan , Mohan Gurjar , 1 1 1 1 Anupma Kaul , Raj Kumar Sharma , Amit Gupta , Narayan Prasad , 3 4 5 6 Rungmei S. Marak , Manoj Jain , Aneesh Srivastava and Hira Lal Department of Nephrology and Renal Transplantation, Sanjay Gandhi Post Graduate Institute of Medical Sciences, Lucknow, India, Department of Critical Care Medicine, Sanjay Gandhi Post Graduate Institute of Medical Sciences, Lucknow, India, Department of Microbiology, Sanjay Gandhi Post Graduate Institute of Medical Sciences, Lucknow, India, Department of Pathology, Sanjay Gandhi Post Graduate Institute of Medical Sciences, Lucknow, India, Department of Urology, Sanjay Gandhi Post Graduate Institute of Medical Sciences, Lucknow, India and Department of Radio Diagnosis, Sanjay Gandhi Post Graduate Institute of Medical Sciences, Lucknow, India Correspondence and offprint requests to: Hira Lal; E-mail: drdharm1@rediffmail.com ABSTRACT Background: Isolated renal mucormycosis (IRM) is a potentially fatal disease affecting immunocompromised hosts. IRM affecting apparently immunocompetent patients is rare, with few previous reports, mostly from India. We describe 10 cases of bilateral IRM with no underlying risk factors. Methods: We performed a retrospective analysis of cases of IRM from our hospital information system admitted between 2009 and 2016. We analyzed the data of this cohort of IRM, including epidemiological characteristics, clinical presentation, diagnostic procedures, treatment details and outcome. Results: In all, 10 cases of bilateral IRM were identified. All of them were males with a mean age of 24.7 years (range 10–42). Most patients were initially managed as acute bacterial pyelonephritis with acute kidney injury. A total of eight patients were diagnosed antemortem. Diagnostic clues include sepsis not controlled with broad-spectrum antibiotics and enlarged kidneys with or without hypodensities on ultrasound/computed tomography imaging. Three patients also gave a specific history of passing white flakes in their urine. Eight patients received specific antifungal therapy with amphotericin B with or without posaconazole. Three patients in whom the disease was apparently confined to the pelvicalyceal system underwent local irrigation with Amp-B. One patient underwent bilateral nephrectomy. Four patients succumbed to the disease while five patients were successfully treated. One patient was discharged against medical advice. Conclusions: IRM is a rare, life-threatening disease associated with high mortality even in immunocompetent individuals. Typical clinical and radiological findings and a high index of suspicion may help in early diagnosis, but definitive diagnosis Received: 10.7.2017. Editorial decision: 15.3.2018 V C The Author(s) 2018. Published by Oxford University Press on behalf of ERA-EDTA. This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/ licenses/by-nc/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited. For commercial re-use, please contact journals.permissions@oup.com Downloaded from https://academic.oup.com/ckj/advance-article-abstract/doi/10.1093/ckj/sfy034/5032502 by Ed 'DeepDyve' Gillespie user on 12 July 2018 2| D. Bhadauria et al. requires histopathological and/or microbiological confirmation. Early and rapid diagnosis along with aggressive multidisciplinary management including initiation of specific antifungal therapy with or without surgical debridement is vital for a successful outcome. Keywords: amphotericin B, immunocompetent, isolated renal mucormycosis, nephrectomy, posaconazole of specimens were prepared for direct microscopic examination INTRODUCTION through the use of 10% potassium hydroxide and Gomori’s me- Mucormycosis (MM) is a rare, life-threatening invasive fungal thenamine silver (GMS) stain. Some part of the specimens were infection caused by a group of filamentous fungi of the class also inoculated on Sabouraud dextrose agar. Abundant, broad, Zygomycetes. Most cases are caused by those of the order sparsely septate thin-walled hyaline hyphae with irregular non- Mucorales, which include genera Rhizopus (most common path- dichotomous branching characteristic of zygomycetes were ogen), Mucor, Rhizomucor, Absidia, Apophysomyces and found on studies of both the potassium hydroxide mounts and Cunninghamella. The terms MM and zygomycosis are used inter- Grams-stained material and on this basis a diagnosis was made changeably (the term phycomycosis is also used) [1, 2]. They are of zygomycosis. On the basis of the culture and microscopic vasotropic and angioinvasive, usually affecting immunocom- characteristics, the strain was identified. promised patients. Renal involvement due to MM mostly occurs In patients with negative urinalysis but with a high index of concurrently with disease affecting other parts of the body or as suspicion based on imaging studies and other presenting fea- a part of disseminated disease [3, 4]. tures, a renal biopsy was performed. A histopathological diag- Isolated renal mucormycosis (IRM) is reported rarely in the lit- nosis of renal MM was made based on the identification of erature and mainly as unilateral. It has been documented in few broad, aseptate, irregular and right-angled branching fungal hy- case reports, mostly from developing countries, especially from phae in renal biopsy tissue sections stained with hemotoxylin the Indian subcontinent, in patients having an underlying and eosin, periodic acid–Schiff, Grocott–Gomori or silver methe- immunocompromised state [5–11]. IRM is liable to be missed clin- namine stains. Definitive diagnosis was made after tissue dem- ically, especially in immunocompetent patients. It is an almost onstration of fungus on histopathology, while probable fatal disease if bilateral and diagnosed late, especially in the diagnosis was made on the basis of only microscopy and culture angioinvasive state [5–11]. There is a paucity of literature on the positivity of fungus. clinical behavior, management and outcome of bilateral IRM. Here we present 10 cases of bilateral IRM affecting appar- Management of IRM ently immunocompetent patients with no underlying predis- Management of IRM included antifungal drugs [amphotericin B posing conditions, with the objective of comparing our data in (Amp-B) with or without posaconazole] with or without bilateral terms of clinical behavior, management and outcome with nephrectomy. The choice of conventional (amphotericin deoxy- those cases already reported in the literature. We also propose cholate) versus the liposomal form of Amp-B was made depend- an algorithm for early diagnosis and management of these ing upon the renal function and cost affordability of the patients. patients. The maximum cumulative dose of Amp-B used was 3 g. Local irrigation with conventional Amp-B through percuta- MATERIALS AND METHODS neous nephrostomy (PCN) was done in patients where the dis- ease was apparently confined to the pelvicalyceal system as We retrospectively collected the data of all patients admitted be- suggested by imaging or in whom there was a poor response to tween 2009 and 2016 with a diagnosis of renal MM from the hospi- parenteral Amp-B therapy. Posaconazole was added to Amp-B tal information system (HIS) of our tertiary care center. The cases as part of the initial regimen in patients who could afford ther- with IRM were identified as those without evidence of Mucor in- apy and in patients with a poor response to the initial 2 weeks fection at other sites such as the nasal sinuses, orbits, eyes, lungs of Amp-B therapy. Response to therapy was assessed by the and central nervous system. Those with the disseminated disease clinical response, urine microscopy and culture and imaging were excluded. Patients with underlying predisposing conditions findings. In patients completing the Amp-B therapy, for Mucor infection, including diabetes mellitus, human immuno- posaconazole was used as a maintenance antifungal therapy. deficiency virus (HIV) infection, steroid or immunosuppressant The decision to do a nephrectomy was based on the response to use and known immunodeficiency disease, were excluded. antifungal therapy and the extent/type of renal involvement by We analyzed the data of this cohort of IRM, including epide- the fungus. Refractory cases and cases of invasive renal MM miological characteristics, clinical presentation, diagnostic pro- proven by imaging and/or biopsy were considered for bilateral cedures, treatment details and outcome. In all the cases, nephrectomy. However, the decision to perform a nephrectomy routine hematological and biochemical tests, blood and urine was heavily influenced by the ability of patients to afford treat- cultures, imaging [ultrasound (US), renal Doppler or computed ment, as a bilateral nephrectomy entails lifelong renal replace- tomography (CT)] were done. ment therapy, incurring significant costs and morbidity. Diagnosis of IRM Results Diagnosis of renal MM was established by doing urine micros- copy and culture, imaging in all patients of suspected MM and We found 21 cases of MM with renal involvement in our HIS. In renal biopsy in certain cases. Figure 3A represents the diagnos- all, 12 patients had IRM and of them, 10 were diagnosed with bi- tic algorithm followed by us. Repeatedly positive urine micros- lateral disease. No underlying predisposing conditions were copy and culture established the diagnosis of renal MM. Smears identified in all 10 cases. Downloaded from https://academic.oup.com/ckj/advance-article-abstract/doi/10.1093/ckj/sfy034/5032502 by Ed 'DeepDyve' Gillespie user on 12 July 2018 Isolated bilateral renal mucormycosis | 3 FIGURE 1: Clinical findings in IRM patients. (A) Patient’s abdomen shows erythema and subcutaneous edema of the flank region. (B) Urine sample: gross hematuria with white flakes containing papillary tissue and fungus settled at the bottom. (C) Mucor bezoars passed in the urine of an IRM patient complaining of abdominal colics. (D) Non-contrast CT of the abdomen in the coronal plane at the level of the kidneys shows bilateral bulky kidneys with parenchymal hypodensities. (E) Contrast CT of the abdomen in the axial plane at the level of the kidneys shows bilateral bulky kidneys with enhancing thickening of the wall of the renal pelvis. (F) Contrast CT of the abdomen in the coronal plane shows bilateral bulky kidneys with multiple nonenhancing areas with preserved normal subcapsular parenchyma (Rim sign). (G) Contrast CT of the abdomen (excretory phase) in the coronal plane shows the right kidney demonstrating a filling defect in the calyceal system. (H) CT angiogaphy (reformatted in the coronal plane) shows normal main renal arteries with attenuated segmental branches in the region of nonenhancing areas suggestive of vasular in- vasion. (I) Noncontrast CT of the abdomen shows bilaterally enlarged kidneys with irregular, nonhomogeneous, hypodense areas within the renal parenchyma and perinephric fat stranding. FIGURE 2: (A) Urine cytopathology shows broad, ribbon-like fungal hyphae. (B) Extensive cortical necrosis of the renal parenchyma with broad, ribbon-like fungal hyphae (hematoxylin and eosin, 200). (C) Broad, aseptate hyphae with right-angle branching in necrosed renal parenchyma (chromic acid silver methenamine stain, oil immersion). presented with fever, flank pain, sepsis and acute kidney injury Demographic profile (AKI). This patient (patient 3; Table 1) presented with acute ab- The ages of the patients ranged from 10 to 42 years (mean 24.7). All domen, sepsis and AKI. In all, six patients were oliguric and di- were male, hailed from a rural community and belonged to the low alysis dependent while the remaining four had non-oliguric socioeconomic strata. None of the patients had any predisposing (patients 1, 4, 5 and 10) renal failure. An initial clinical diagnosis conditions such as diabetes mellitus, HIV infection or malignancy of bacterial pyelonephritis was made in eight patients and and were apparently immunocompetent. However, a separate hence treated with broad-spectrum antibacterial agents. search for immunodeficiency disorders was not performed. Antibacterial agents were withdrawn after confirmation of fun- gal infection. A total of eight patients were diagnosed antemor- Clinical features tem. Diagnostic clues pointing to a fungal etiology in these Table 1 summarizes the epidemiological and clinical character- patients were sepsis not controlled with broad-spectrum antibi- istics of all patients with bilateral IRM. All patients except one otics and enlarged kidneys with or without hypodensities on Downloaded from https://academic.oup.com/ckj/advance-article-abstract/doi/10.1093/ckj/sfy034/5032502 by Ed 'DeepDyve' Gillespie user on 12 July 2018 4| D. Bhadauria et al. FIGURE 3: Algorithmic approach to the (A) diagnosis of IRM and (B) management of IRM. KUB, kidney ureters bladder; MRI, magnetic resonance imaging. AmB, Amphotericin; CT, computerized tomography; KUB, kidney ureter bladder; MRI, magnetic resonance imaging; PCN, percutaneous nephrostomy; USG, Ultrasound. Table 1. Epidemiological and clinical characteristics of patients with bilateral IRM Patient Age (years)/ Background/ Clinical number gender socioeconomic strata Clinical features diagnosis Clue to diagnosis Urine microscopy 1 32/M Rural/low Fever, flank pain, sepsis, Bacterial PN B/L " in kidney size Rhizopus AKI 2 34/M Rural/low Fever, flank pain, sepsis, Bacterial PN B/L " in kidney size with Anuric AKI infarction 3 34/M Rural/low Fever, acute abdomen, an- Intestinal PM diagnosis on Not done uria, perforation histopathology peritonism with ascites and sepsis 4 32/M Rural/low Fever, flank pain, sepsis, Bacterial PN B/L " in kidney size A. elegans AKI 5 24/M Rural/low Fever, flank pain, hematu- Bacterial PN/ White-colored urine mixed Rhizopus ria, papillary with blood and fungal white flakes in urine necrosis hyphae, B/L " in kidney size 6 10/M Rural/low Fever, flank pain, sepsis, TMA/DIC PM diagnosis on Not done AKI histopathology 7 42/M Rural/low Fever, flank pain, sepsis, Bacterial PN B/L " in kidney size with Anuric AKI infarction 8 18/M Rural/low Fever, flank pain, sepsis, Bacterial PN B/L " in kidney size with A. elegans AKI, MODS hypodensities 9 24/M Rural/low Fever, flank pain, sepsis, Bacterial PN White-colored urine with Rhizopus AKI fungal hyphae, B/L " in kidney size 10 14/M Rural/low Fever, flank pain, white Bacterial PN White-colored urine with A. elegans flakes in urine fungal hyphae and bezoars, B/L " in kidney size B/L, bilateral; DIC, disseminated intravascular coagulation; MODS, multiorgan dysfunction syndrome; PM, postmortem; PN, pyelonephritis; TMA, thrombotic microan- giopathy; ", increased. US/CT imaging. In all, three patients also gave a specific history Doppler imaging suggestive of infarction, which were later con- firmed by CT imaging. A thick pelvicalyceal system and ureters of passing white flakes in their urine. A postmortem diagnosis without suggestion of infarction on CT imaging were seen in of renal MM was made in two patients. four patients, suggestive of confinement of infection up to the pelvicalyceal system. Urine for fungal microscopic examination, Investigations culture and sensitivity was sent in six patients and was positive Table 2 summarizes the imaging characteristics, management repeatedly for Mucor. Of the remaining patients, urine examina- and outcomes. US of the kidneys was done in all patients, while tion for fungus could not be performed, as the diagnosis was other imaging studies, including renal Doppler, CT scan or mag- not suspected in two patients who had a stormy course netic resonance imaging, were done in all but two patients. In culminating in death and two patients were anuric. The organ- all, three patients had focal areas of loss of vascularity on renal ism on fungal culture was identified in three patients as Downloaded from https://academic.oup.com/ckj/advance-article-abstract/doi/10.1093/ckj/sfy034/5032502 by Ed 'DeepDyve' Gillespie user on 12 July 2018 Isolated bilateral renal mucormycosis | 5 Table 2. Imaging characteristics, management and outcome of IRM in immunocompetent patients Patient number US abdomen Doppler study CT abdomen/MRI Management FU Outcome 1 B/L " in kidney size Normal B/L " in kidney size, Amp-B (2.8 g), posa- 61 months Survived thick PC system conazole (4 months), bilat- eral instillation of Amp-B via PCN 2 B/L " in kidney size, Focal loss of B/L " in kidney size, Amp-B bilateral 10 days Mortality with vascularity hypodensities, nephrectomy hypodensities infarcts 3 B/L " in kidney size, Not done Not done Laparotomy, antimi- 4 days Mortality ascites crobial only 4 B/L " in kidney size, Normal B/L " in kidney size, Amp-B (2.5 g), posa- Survived mild HDN thick PC system conazole (4 months) and bi- lateral instillation of Amp-B via PCN 5 B/L " in kidney size Normal B/L " in kidney size, Amp-B (3.2 g), posa- 26 months Survived focal PN conazole (6 months) 6 B/L " in kidney size Not done Not done Broad-spectrum 7 days Mortality antibiotics 7 B/L " in kidney size Focal loss of B/L " in kidney size, Amp-B (3 g), posa- – DAMA with vascularity hypodensities, conazole (2 weeks) hypodensities infarcts 8 B/L " in kidney size Focal loss of B/L " in kidney size, Amp-B (200 mg) 5 days Mortality with vascularity hypodensities, hypodensities infarcts 9 B/L " in kidney size Normal B/L " in kidney size Amp-B (3 g), posa- 6 months Survived conazole (3 months) 10 B/L " in kidney size Normal B/L " in kidney size, Amp-B (2.8 g), posa- 3 month Survived thick PC system conazole (4 months), bilat- eral instillation of Amp-B via PCN B/L, bilateral; DAMA, discharged against medical advice; FU, follow-up; HDN, hydronephrosis; MRI, magnetic resonance imaging; PC, pelvi-calyceal system; PN, pyelo- nephritis; ", increased. Apophysomyces elegans and in three as Rhizopus. An antemortem (patients 4 and 9). Local irrigation with Amp-B, in collaboration diagnosis of renal MM was made in all but two patients, in with urologists, was done in three patients in whom MM was whom the diagnosis could only be confirmed postmortem. thought to be confined to the pelvicalyceal system and ureters Kidney biopsy was done in 8 of 10 patients and 2 of these were with no evidence of angioinvasion. Bilateral nephrectomy was postmortem. Histopathological demonstration of fungus was done in patient 2 (Table 2) and was planned in patient 5 made in 4 of 10 patients. The histopathological findings of (Table 2). However, patient 5 was subsequently discharged patients 2, 3, 6 and 8 were suggestive of acute cortical necrosis against medical advice because of the inability to afford hemo- along with ghost outlining of cellular architecture and broad, dialysis and a poor response to antifungal therapy. aseptate hyphae with right-angle branching in necrosed renal parenchyma. The histopathological findings of patients 1, 4, 5 Outcome and 10 were suggestive of acute tubular necrosis along with in- In all, 4 of 10 patients succumbed to the disease due to severe terstitial infiltrates, but fungus could not be demonstrated. sepsis and multiorgan dysfunction syndrome. One patient was discharged against medical advice on financial grounds. The Management remaining five patients who survived were followed up (range Specific treatment was possible in eight patients, including an- 3–61 months) and did not have subsequent relapse of the tifungal therapy (Amp-B with or without posaconazole) with or disease. without local irrigation through PCN of the pelvicalyceal system and ureters with Amp-B. In all patients, a conventional form of DISCUSSION Amp-B was used. Posaconazole was used as an adjuvant ther- apy to Amp-B in two patients (patients 5 and 10). Maintenance To our knowledge, this is the first detailed and largest report of antifungal therapy with posaconazole was given in two patients bilateral IRM in apparently immunocompetent patients. This Downloaded from https://academic.oup.com/ckj/advance-article-abstract/doi/10.1093/ckj/sfy034/5032502 by Ed 'DeepDyve' Gillespie user on 12 July 2018 6| D. Bhadauria et al. Table 3. Comparison of different case series/reports of IRM in immunocompetent patients Renal Case series n Age range Sex (n) Antemortem involvement (n) Therapy (n) Mortality, n a,b Gupta et al. [30] 7 9 mo–57 yrs M (7) 4 U (1), B (6) Amp-B (3), Amp-B and nephrec- 6 tomy (2), untreated (2) a,b Chakrabarti et al. [13] 3 10–70 yrs M (3) 3 U (1), B (2) Amp-B and surgical drainage or 1 PCN (3) Chugh et al. [14] 3 17–37 yrs M (1) 3 U (2) B (1) Amp-B and nephrectomy (3) 2 F (2) Marak et al. [15] 2 17–32 yrs M (2) 2 U (1) B (1) Amp-B and PCN (2) 2 Jianhong et al.[24] 3 3 mo–14 yrs M (2) 3 U (3) Amp-B (1), Amp-B and surgical 0 F (1) drainage (1), Amp-B and ne- phrectomy (1) Pahwa et al. [31] 1 30 yrs M (1) 1 U (1) Nephrectomy (1) 0 Kumar et al. [32] 1 39 yrs M (1) 1 U (1) Amp-B and endoscopic removal of 0 fungal bezoars (1) a,b Nayagam et al. [33] 1 18 mo M (1) 1 U (1) Amp-B and nephrectomy (1) 0 Thomas et al. [34] 1 41 yrs M (1) 1 U (1) Amp-B and nephrectomy (1) 0 Paonam et al. [35] 1 24 yrs F (1) 1 B (1) Amp-B and surgical debridement 1 (1) Goel et al. [28] 1 45 yrs M (1) 1 U (1) Amp-B and nephrectomy (1) 0 Singh et al. [36] 1 18 yrs M (1) 1 B (1) Amp-B and nephrectomy (1) 1 Pickles et al. [37] 1 18 yrs M (1) 1 U (1) Amp-B and nephrectomy (1) 0 Singh et al. [38] 1 22 yrs M (1) 1 U (1) Amp-B and nephrectomy (1) 0 a,b Our case series 10 10–42 yrs M (10) 8 B (10) Amp-B (9), untreated (1), surgery 5 (1), PCN (3) B, bilateral; DAMA, discharged against medical advice; F, female; M, male; mo, months; U, unilateral; yrs, years. Reports from India. Included children. report highlights the life-threatening nature of Mucor infections Renal MM is rare and often a manifestation of disseminated even in immunocompetent individuals, in whom it rarely mani- disease, in which renal involvement has been reported in up to fests. Most of the patients in our study had a clinical presenta- 20% of cases [4]. IRM has been reported in patients with ac- tion akin to acute bacterial pyelonephritis and had dialysis- quired immune deficiency syndrome, intravenous drug abusers dependent AKI. Early diagnosis of bilateral IRM did help in and those on corticosteroid therapy (5, 21). In contrast, IRM in salvaging half of our patients. Delayed or missed diagnosis of immunocompetent individuals is extremely rare and the major- the angioinvasion stage might have contributed to the stormy ity of cases have been reported from the Indian subcontinent and fatal clinical course in the other half of our patients. A few and China [22–24]. However, the majority of the cases of IRM unique observations were made from our study, including bilat- reported from India were apparently immunocompetent, in eral IRM affected predominantly young males with low contrast to cases reported from China who possessed risk fac- socioeconomic status and a rural background; a specific history tors for developing MM. The number of such cases has shown of passing white flakes in urine was given by three patients; fo- an increasing trend over the past three decades. It is presumed cal loss of vascularity on renal Doppler, corresponding renal to occur via seeding of kidneys during an episode of fungemia infarcts on CT and a thickened pelvicalyceal system were com- from a subclinical pulmonary focus or due to ascending infec- mon distinguishing features; four patients in whom the infec- tion of the urinary tract [25, 26]. Renal parenchymal necrosis tion was possibly confined to the pelvi-calyceal system and results from angioinvasion of fungal hyphae, leading to vascu- ureters, as suggested by imaging and histopathology, survived lar thrombosis and infarction. Mucor hyphae may also invade with multidisciplinary care. We successfully treated 5 of 10 the glomeruli and tubules, sometimes with associated giant cell patients, of this nearly 100% with fatal illness [12, 13–15, 16, 17], reaction and granuloma formation [27]. Clinically, patients with because of a high index of suspicion learned from our previous IRM present with fever, flank pain, tenderness, hematuria, py- experiences and early diagnosis. uria and renal failure, which are usually the result of near total The most common clinical presentations of MM in immuno- occlusion of the renal arteries or their branches, similar to our compromised hosts include rhino-orbito-cerebral, pulmonary, patients [6, 28, 29]. gastrointestinal and disseminated forms [18, 19]. Most human Table 3 summarizes the various case series/reports in the lit- infections result from inhalation of fungal sporangiospores that erature on IRM. To date 12 cases of bilateral IRM have been de- have been released in the air. The largest series of zygomycosis scribed in literature. Our case series included 10 from India had 129 patients; the rhino-orbito-cerebral type was immunocompetent patients with bilateral IRM. One of these most common (44.2%) and renal involvement was seen in 14.0% was a 10-year-old child and the remaining cases were adults, of patients. About 23% of patients were apparently healthy and and all of them were males. All patients presented with 35% were diagnosed postmortem [20]. The cutaneous form is oligoanuric renal failure and six were dialysis dependent. Most most common in immunocompetent patients, followed by of our patients were treated initially in lines of sepsis-/ rhino-orbito-cerebral disease [18, 12]. pyelonephritis-induced AKI. Specific therapy was possible in Downloaded from https://academic.oup.com/ckj/advance-article-abstract/doi/10.1093/ckj/sfy034/5032502 by Ed 'DeepDyve' Gillespie user on 12 July 2018 Isolated bilateral renal mucormycosis | 7 only eight patients in whom the diagnosis was suspected clini- formulations are especially useful in patients with renal failure cally and confirmed subsequently. Bilateral nephrectomy was and can be given at higher doses with fewer side effects. planned in two patients and was possible in only one. In our However, we have used conventional Amp-B in all of our case series, A. elegans was identified in three patients and patients. Rhizopus in three patients. A total of five patients were success- Overall, survival for IRM is estimated to be 65% [34]. fully treated. However, it is associated with nearly 100% mortality in patients Gupta et al. [30] described 9 cases of IRM out of 18 cases of re- with bilateral renal involvement with AKI [30]. The majority of nal MM, most of whom were male and 7 were immunocompe- survivors of IRM have been those with unilateral renal involve- tent. In all, four were diagnosed by antemortem kidney biopsy, ment and who received timely appropriate antifungal therapy one by postmortem kidney biopsy and two by autopsy. A total with nephrectomy. Few case reports noted successful treatment of six patients had bilateral renal involvement and all of them of IRM with Amp-B deoxycholate without nephrectomy and the presented with severe irreversible renal failure and died. Only majority of them suffered unilateral renal disease [5, 7]. one patient was successfully treated, who had unilateral dis- In our case series, specific antifungal therapy with Amp-B ease and had undergone nephrectomy. Specific infective spe- and posaconazole was given in eight patients. Local instillation cies were identified in 2 of the 18 patients, with Rhizopus of Amp-B into the pelvicalyceal system was done in three arrhizus and A. elegans [30]. patients. Bilateral nephrectomy was done in one patient. The Chakrabarti et al.[13] described three cases of IRM and two mortality was 50%, with four survivors and one patient dis- had bilateral disease. All three patients were diagnosed by mi- charged against medical advice. croscopic examination and culture of drained pus. Only one had To our knowledge this is the largest case series of bilateral histological confirmation on autopsy. The remaining two had a IRM in the literature. A detailed description of the clinical presen- successful outcome. Nephrectomy was not done in any of them. tation, diagnostic features and treatment outcomes contribute to Chugh et al.[14] found four cases of IRM; three were immu- the strengths of our report. However, we did not do a specific nocompetent and one had bilateral disease. All three cases evaluation for other primary immunodeficiency syndromes in underwent nephrectomy in combination with antifungal ther- any of these patients. Hence the immunocompetent state is ap- apy and two succumbed to the illness. parent and not absolute. This constitutes a limitation of the study Two cases of IRM described by Marak et al., [15] had success- and marks an area for potential research in the future. ful outcomes without the need for nephrectomy. Of the three Our experience emphasizes the need for a high index of sus- childhood cases of IRM described by Jianhong et al., [24] one had picion for rapid diagnosis by imaging, microbiological and histo- undergone nephrectomy and all survived following therapy. logical methods. Early initiation of systemic antifungal therapy Pahwa et al.,[31] in their single case report of IRM with no iden- and surgical intervention are necessary for this life-threatening tifiable risk factors, proposed that simple nephrectomy without condition. antifungal therapy may be sufficient in immunocompetent, afe- brile, nontoxic patients with a coincidental finding of renal MM CONCLUSION in a nephrectomy specimen. Typical imaging findings of IRM on contrast-enhanced CT of IRM is a rare, life-threatening disease associated with high mor- the abdomen include enlargement of the kidneys, multiple low tality even in immunocompetent individuals, in whom it rarely attenuations and nonenhancing areas in the parenchyma, re- manifests. Typical clinical and radiological findings may help in duced/absent contrast excretion and perinephric collections. rapid and early diagnosis. However, definitive diagnosis Various authors have described these findings on CT as ‘diffuse requires histopathological and/or microbiological confirmation. patchy nephrogram’ [5, 25]. In the presence of suspicious radio- A high index of suspicion along with rapid diagnosis and early logic findings, a biopsy is indicated to confirm the diagnosis. and aggressive multidisciplinary management, including initia- Diagnosis of MM is difficult, especially antemortem, due to vari- tion of specific antifungal therapy with or without surgical de- able clinical presentation and limitations in achieving a tissue bridement, is vital for a successful outcome. diagnosis. The majority of cases reported in the past were diag- nosed at autopsy or by a postmortem biopsy. IRM can clinically CONFLICT OF INTEREST STATEMENT masquerade as rapidly progressive glomerulonephritis, pyelo- nephritis, renal abscess and acute interstitial nephritis. Hence, None declared, however, some of the cases have been published even in immunocompetent patients, nonresolving pyelonephri- as individual case reports in different journals. tis should prompt the possibility of a fungal infection like MM. Blood and urine cultures are often negative. Examination of 24- REFERENCES h urine collections could increase the diagnostic yield. Radiological findings can be nonspecific. Hence definitive diag- 1. Spellberg B, Edwards J, Ibrahim A. Novel perspectives on nosis relies on histopathological evidence of fungal invasion of mucormycosis: pathophysiology, presentation, and man- affected tissues. A high index of suspicion is crucial for a timely agement. Clin Microbiol Rev 2005; 18: 556–569 diagnosis. Recently molecular diagnosis with real-time poly- 2. Prabhu RM, Patel R. Mucormycosis and entomophthoramy- merase chain reaction has been suggested for early diagnosis cosis: a review of the clinical manifestations, diagnosis and [29]. treatment. 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Clinical Kidney JournalOxford University Press

Published: Jun 2, 2018

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