Renal mucormycosis in immunocompetent patients: Report of three cases

Authors


Correspondence
Dr Ritu Verma, MD, Department of Pathology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Raebareli Road, Lucknow 226014, Uttar Pradesh, India. Email: dr_rituverma@rediffmail.com

ABSTRACT

Isolated renal mucormycosis is rare in the immunocompetent host. We retrospectively analyzed all histopathology reports of nephrectomy specimens and renal biopsies from our department in the last year. Three patients of isolated renal mucormycosis were identified. All three patients presented with acute abdomen and renal failure. None had a preceding known predisposing disease for mucormycosis. Ante mortem diagnosis was made in one patient. Fungal culture was positive in one case. We emphasize that isolated renal mucormycosis may affect immunocompetent host and greater clinical suspicion is required for prompt treatment in view of poor prognosis associated with renal mucormycosis.

INTRODUCTION

Organisms of class Zygomycetes are ubiquitous saprophytic filamentous fungi having low intrinsic pathogenicity. However, these fungi can produce fulminant infection in patients with underlying immune compromised conditions like diabetes mellitus, starvation, immunosuppression, burns, diabetic ketoacidosis, malignancy or organ transplant. Rarely the disease may affect healthy individuals.1,2 Renal mucromycosis is rare and often a manifestation of disseminated disease.3 Isolated renal mucormycosis is extremely rare. Only few case reports have been reported in English literature.4

CASE REPORTS

We retrospectively analyzed all nephrectomy specimens and renal biopsies presented to the department of pathology of our institute in the last year. We found three cases of renal mucormycosis. None of the cases had an underlying predisposing disease for mucormycosis.

Case 1

A 22-year-old male suffered from high grade fever, severe pain in the abdomen along with nausea and vomiting for 14 days. Three days prior to presentation, he developed swelling over his body starting from face and decline in urinary output. No hematuria or diarrhea was noticed. There was no history of diabetes mellitus, hypertension or any chronic drug intake. General physical examination revealed pallor, oral temperature of 38°C and anasarca. Blood pressure was normal. Abdomen was rigid and tender. Moderate ascites was present on shifting dullness. No organomegaly was noticed. Investigations revealed hemoglobin 12.6 g/dL, leukocyte count 32, 900 cells/cu mm and erythrocyte sedimentation rate 42 mm in first hour. Blood urea nitrogen was 23.8 mg/dL, creatinine 7.1 mg/dL, sodium 122 mmol/L, potassium 4.5 mmol/L, total calcium 7.1 mg/dL, phosphorus 6.8 mg/dL and alkaline phosphatase 403 U/L. Blood cultures were sterile for bacteria and fungi. Urine examination revealed protein 3+, sugar nil. Ascitic fluid showed exudative picture. X-ray abdomen revealed multiple air-fluid levels. Ultrasound abdomen showed ascites, large kidneys with impaired cortico-medullary differentiation. In view of anuria and elevated serum creatinine, the patient was started on hemodialysis. Broad spectrum antibiotics along with supportive treatment were also started. Considering a possibility of perforation peritonitis, exploratory laprotomy was done within 12 h after hospital admission. Around 150 mL of serosanguinous fluid was present in the peritoneal cavity. Entire small bowel was normal. No perforation was seen. Numerous small petechia were present over the entire peritoneal serosal surface. Bilateral kidneys were hemorrhagic, with foci of necrosis and saponification present over the surface of the Gerotas fascia. Overlying descending colon showed congestive erythematous serosa. Few similar small patches were present over the proximal jejunum abutting the left kidney. Pancreas was normal. Intra-operative urological consultation was taken and no immediate intervention was planned. Postoperatively there was progressive fall in blood pressure despite vasopressors. Due to fall in arterial oxygen saturation, the patient was put on a mechanical ventilator. He developed cardiac arrest one day later. Postmortem renal biopsy was done. Histopathology of the liner renal core revealed cortical necrosis with no viable renal parenchyma along with presence of broad, ribbon like fungal hyphae in the necrotic tissue (Fig. 1).

Figure 1.

Extensive coagulative necrosis of renal parenchyma with broad, ribbon like fungal hyphae (hematoxylin and eosin, ×200).

Case 2

A 36-year-old male suffered from moderate grade fever and dysuria for one month. Four days later, he developed diffuse abdominal pain of increasing severity and radiating to back. There was no hematemesis, melena, hematuria, vomiting, diarrhea or abdominal fullness. The patient did not have diabetes mellitus, hypertension, tuberculosis or history of any drug or alcohol addiction. On examination, he was dyspnoic with respiratory rate of 28 cycles/min. He was not oriented to time and place. There was diffuse abdominal tenderness with rigidity and guarding. Bilateral pleural effusion and ascites were present on percussion. Rest of the systemic examination was normal. Pancreatitis was clinically suspected. Blood investigations revealed hemoglobin 10.9 g/dL and total counts 55, 600 cells/cu mm. Blood urea nitrogen was 29 mg/dL and creatinine was 12.2 mg/dL, sodium 127 mmol/L, potassium > 6.0 mmol/L. Arterial blood gas revealed severe metabolic acidosis (pH 7.2 with base deficit of 14 mg/dL). Urine examination revealed plenty of fungal hyphae suggestive of zygomycosis. Blood culture was sterile for bacterial and fungal growth. The patient developed altered colored urine followed by oliguria. Contrast enhanced computed tomography (CT) abdomen revealed bilateral enlarged kidneys with areas suspicious of infarct or abscess. Doppler study was suggestive of multiple segmental infarcts. Hemodialysis was started along with antibiotics, lyophilized Amphotericin B and supportive care. There was improvement in consciousness but soon, he developed anuria and hypotension. As a life saving measure, bilateral nephrectomy was performed. Per-operatively both the kidneys were necrotic. Colon and mesocolon were adhered to the kidney on the right side. Liver was studded with satellite rough areas. Grossly right kidney measured 10 × 7 × 5 cm, left kidney measured 12 × 8 × 5 cm with vast areas of infarction, necrosis and hemorrhage (Fig. 2a). Infarction extended from perinephric fat to pelvic fat. On histopathology both kidneys showed extensive areas of necrosis with ghost outlines of renal structures. No viable renal parenchyma was identified in both nephrectomy specimens (Fig. 2c). Multiple pauciseptate, broad, ribbon like fungal hyphae with right angle branching were seen in the necrosed tubules and interstitium (Fig. 2b). Vascular invasion was also noted. Postoperatively he developed sepsis and disseminated intravascular coagulation and finally succumbed to the disease.

Figure 2.

(a) Cut surface of the resected specimen (case 2) shows loss of cortico-medullary differentiation with areas of infarction, necrosis and hemorrhage. (b) Broad, aseptate hyphae with right angle branching in necrosed renal parenchyma (Chromic acid Silver Methenamine stain, oil immersion). (c) Fungal hyphae within the necrosed tubules and interstitium (hematoxylin and eosin, ×200).

Case 3

A 45-year-old male suffered from fever with chills and rigors, right flank pain and mild dysuria for 15 days. There was no history of pyuria, hematuria or lower urinary tract symptoms. No prior history of tuberculosis, hypertension, addiction or drug allergy. He was recently diagnosed with diabetes mellitus. On examination, there was redness of the skin over the right flank along with tenderness without any obvious lump. The rest of the systemic examination was normal. Investigations revealed blood sugar 149 mg/dL, creatinine 1.6 mg/dL, sodium 128 mmol/L, potassium 4.9 mmol/L. Hemoglobin was 10.7 g/dL, total leucocytes 25, 000 cells/cu mm with 78% neutrophils. Repeat blood glucose after 2 days was 324 mg/dL. Glycosylated hemoglobin was 10.3. Ultrasonograph showed bilateral pleural effusion, pericardial effusion, hepatosplenomegaly, hypoehoic bilateral enlarged kidneys with mild perinephric collection. Provisional clinical diagnosis of right renal abscess with perinephric collection was made. Repeat ultrasound showed mildly hypoechoic right kidney with attenuated cortico-medullary differentiation, extensive infiltration in perinephric fat. Technetium-99m diethylenetriaminopenta-acetic acid (DTPA) scan showed non-visualized right kidney. Urine examination shows active sediments with no fungal organisms on microscopy. Culture showed growth of zygomycosis and right subcapsular nephrectomy was done. Grossly the kidney measured 11 × 6 × 2.5 cm (Fig. 3a). Cut surface showed friable necrotic tissue with indistinct corticomedullary junction. Pelvicalyceal system was normal. Microscopically there were extensive areas of coagulative necrosis. Numerous aseptate, broad, ribbon-like fungal hyphae with non-parallel walls and right angle branching were seen in the parenchyma with vessel wall invasion (Fig. 3b). Ureter showed inflammation, fibrosis and giant cell reaction (Fig. 3c). During surgery, the wound was partially closed for daily dressing as there was extensive inflammation of flank and back muscles. During the postoperative period the wound scrapings were positive for fungus, and were again taken for surgical debridement. The wound was left open and local irrigation with amphotericin B was started, following which the wound improved. Parenteral amphotericin B was given at a dose of 50 mg IV daily and a total cumulative dose of 2 g was given. Secondary suturing was performed after 2 months and the wound healed in another 1 month. The patient had a healthy scar and normal renal functions at 4 months.

Figure 3.

(a) Gross specimen of enlarged kidney (case 3). (b) Vascular invasion by the fungal hyphae (hematoxylin and eosin [H&E], ×200). (c) Giant cell reaction in the ureteric wall (H&E, ×200).

DISCUSSION

Zygomycosis is an opportunistic fungal infection that seldom occurs in individuals with a competent immune system.5 The four common clinical presentations of mucormycosis are rhinocerebral, pulmonary, gastrointestinal and disseminated forms. The disseminated form accounts for approximately 9% of cases of mucormycosis; the organ most commonly involved is the lung. Involvement of the kidneys has been reported in up to 20% of the cases with disseminated forms.6 Gupta et al.7 found 8/18 isolated cases of renal mucormycosis from cases of disseminated disease.

Involvement of single organs such as bone, heart and kidney is rare.7,8 Renal transplant recipients with concomitant diabetes mellitus are most susceptible to renal mucormycosis. The mortality of different forms of mucormycosis reaches 75–100% in most series. Survival for isolated renal zygomycosis is estimated to be 65%.9

Pathogenesis of renal mucormycosis is not clear. Hematogenous dissemination to kidneys and a lower urinary tract infection with retrograde spread have been suggested.10,11 Neutrophil and macrophage function appears to play a role in the host defense against mucormycosis.12,13 Neutropenic patients and patients with dysfunctional phagocytes are at higher risk for developing mucormycosis. Mucormycosis is characterized by uniform presence of extensive angioinvasion with resultant vessel thrombosis and tissue necrosis. This angio-invasion is associated with the penetration through endothelial lining of blood vessels and hematogenous dissemination of fungus from the original site of infection to other organs.

Unlike bacterial infections where renal damage is endotoxin-mediated, mucormycosis causes direct invasion of renal vessels and thereby renal parenchyma. Renal failure is usually the result of near total occlusion of the renal arteries and/or their branches. Both small and large arteries exhibit hyphal invasion and consequent thrombosis that leads to massive cortical and medullary infarction.6 Similar findings were seen on histopathology in our patients.

Clinically, most patients with isolated renal mucormycosis presents with fever, flank pain, tenderness, gross hematuria or pyuria (Table 1).5,7,14–20 Blood and urine cultures are often negative and diagnosing mucormycosis almost always requires histopathologic evidence of fungal invasion of the tissues. The biopsy should demonstrate the characteristic wide (3–25 μm in diameters), ribbon-like, aseptate (pauci-septate), thin walled hyphae branching at right angles. These organisms are often surrounded by extensive necrotic debris. Due to the thin wall they are weakly stained with Gomori methenamine silver and periodic acid-Schiff stain. Other fungi like Aspergillus, Fusarium, Scedosporium may look similar to the Mucorales on biopsy. However, these molds are septate, are usually thinner, have uniform width and dichotomous branching at acute angles. Similarly, candida exists in yeasts and pseudohyphae forms with thinner hyphae, no true branching and poor staining on routine hematoxylin and eosin but strong magenta on periodic acid-Schiff stain.

Table 1.  Clinical and histopathlogical findings in immunocompetent patients of isolated renal zygomycosis
ReferenceAge (years)/SexClinical presentationRadiologyDiagnosis by histopathologyCultureTherapyOutcome
  1. AmB, amphotericin B; Apo elegans, Apophysomyces elegans; b/l, bilateral; CT, computed tomography; F, female; IV, intravenous; M, male; U/S, ultrasonography; NA, not available; ND, not done; RVT, renal vein thrombosis; s/o, suggestive of; UTI, urinary tract infection.

Goel et al.1445/MFever, dysuria, flank painU/S-hypoechoic lesionNephrectomy specimenNAIV voriconazole, AmBAlive
Thomas et al.1541/MFlank pain, whitish flakes in urineUreterorenoscopy-fluffy dirty grey material in ureter and pcsMaterial from ureter & pcsApo elegansNephrectomy, AmBAlive
Sharma et al.1614/MRight flank painU/S and Doppler study- hypoechoic kidney, no intrarenal vascularityNephrectomy specimenNDAmBDeath
Singh et al.1718/MFever, anuriaU/S-hypoechoic kidneyRenal biopsyNDAmB, NephrectomyDeath
Lin et al.1877/MNANANephrectomy specimenNDDeath
Chakrabarti et al.535/MFlank pain, fever, dysuria, pyuriaU/S-b/l hydronephrosis, right pyonephrosisMicroscopy of pus drainedApo elegansAmBAlive
10/MFever, flank pain, pyuriaU/S-multiple hypodense cortical lesions, pyonephrosisMicroscopy of pus drainedApo elegansAmBAlive
70/MFever, flank pain, jaundice, abdominal distensionU/S and CT-perinephric abscess, pyonephrosis, RVTNephrectomy specimen and microscopy of drained pusApo elegansAmBDeath
Gupta et al.757/MFever, pain, oliguria, UTINANephrectomy specimenNAAmBDeath
26/MFever, flank pain, UTI, pyuriaNANephrectomy specimenNAAmBAlive
17/MFever, flank pain, anuria, hematuriaNANephrectomy specimenNAAmBDeath
35/MFever, pyuria, anuria, UTINAAutopsy both kidneysNANDDeath
25/MFever, pain, hematuria, anuriaNAPost-mortem kidney biopsyNANDDeath
26/MFever, pain, hematuria, anuriaNAAutopsyNAAmBDeath
9 months/MFever, hematuria, anuriaNANephrectomy specimenNAAmBDeath
Chugh et al. 1927/FFever, flank painU/S-hypoechoic large kidney, CT-s/o abscessNephrectomy specimenNDAmBAlive
17/MFever, flank pain, UT symptomsU/S-large kidney, CT-intrarenal abscessNephrectomy specimenApo elegansAmBDeath
37/FFever, flank painU/S-b/l large kidney, CT-abscessNephrectomy specimenNDAmBDeath
Low et al.2029/MFever, flank painNANephrectomy specimenPositiveAmBAlive
Present cases22/MFever, pain abdomen, nausea, vomitingU/S-ascites, large kidneysPostmortem renal biopsyNDDeath
36/MFever, dysuria, abdominal painCECT-b/l large kidneysNephrectomy specimenUrine positiveAmBDeath
45/MFever, flank pain, dysuriaU/S-large kidneysNephrectomy specimenPositiveAmBAlive

Isolated renal mucormycosis may affect immunocompetent host and requires high index of suspicion for diagnosis and prompt treatment in view of associated poor prognosis. Due to non-specific clinical and radiological characteristics, diagnosis requires identification of fungus on histopathology of renal tissue.

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