Isolated Renal Mucormycosis - Journal of the American Society of [PDF]

EDITORIAL Tomas

BerI,

Denver,

CO

Editor

COMMITIEE

William

Henrich

Mark

Toledo,

OH

Minneapolis,

PaIIer

Fred MN

Silva

Oklahoma

OK

City,

THE TRAINING PROGRAM IN NEPHROLOGY AT THE YALE UNIVERSITY SCHOOL OF MEDICINE Postdoctoral

created

training

in nephrology

by Dr. John Peters. Since

by Dr. Peter Aronson. The goal full-time faculty appointments.

at Yale

University

1972. a distinct

of the program

had

nephrology

is the training

its origins

training

in the

1940s within

program

of academic

the

has existed.

nephrologists,

Section

which

and

of Metabolism

is currently

directed

70% of our graduates

hold

We offer a combined clinical/research fellowship that is 3 (or more) yr in duration and includes 1 yr of full-time clinical training and 2 (or more) yr devoted to clinical or laboratory research. Clinical-only and research-only fellowships are also available. There are currently 20 nephrology fellows. of whom 3 are receiving clinical training; the others are involved in research activities. Clinical training is based at Yale-New Haven Hospital, the West Haven VA Medical Center. and the Yale-REN Dialysis Center. Clinical fellows gain expertise in the diagnosis and management of patients with a broad array of nephrologic disorders including fluid and electrolyte disturbances. glomerulonephritis. interstitial nephritis. hypertension. acute and chronic renal failure. and intoxications. Fellows also receive intensive training in the care of patients receiving renal homografts. Training in the outpatient practice of nephrology emphasizes continuity of care. The l#{243} full-time faculty of the Section for Nephrology have scientific interests in the areas of epithelial transport, hypertension. hereditary renal disease, gene regulation. immunobiology. acute renal failure. and clinical pathologic correlations in glomerular disease. Clinical investigation emphasizes renal transplantation. disorders of potassium homeostasis. natural history of glomerular disease, outcomes in dialysis management. anemia of renal insufficiency. and health care policy. Research training is supported by a training grant from the National Institutes of Health. Yale University School of Medicine is unique in having a large group of distinguished faculty outside of the Section of Nephrology whose research interests include the study of the kidney and who also serve as research mentors for

nephrology

trainees.

This provides

biostatistics.

genetics.

transplantation

Isolated Elliott

Levy2

Renal and

Margaret

fellows

with

biology,

access physiology.

Mucormycosis:

to a broad and

cell

range

Case

Report

E. Levy,

M.J. Bia. Section of Medicine,

(J. Am.

Soc.

Nephrol.

ABSTRACT The 5th reported sis (infection

Mucorales,

of Nephrology.

New

case

of the

Haven.

1995;

in the absence

Yale

University

CT

with

renal fungus

mucormycoof the

of infection

order

elsewhere

in

the body) is presented. The patient was a 36-year-old human immunodeficiency virus-infected man, actively using iv drugs, who suffered 6 wk of flank pain and fever before diagnosis was made by percutaneReceived May 2 Correspondence 75 Francis

Street,

9, 1994. Accepted September to Dr. E. Levy, Renal Division, Boston,

7, 1994. Brigham

MA 02115.

10466673/051 2-2014503.00/0 Journal of the American Society of Nephroiogy Copyright C 1995 by the American Society of Nephroiogy

2014

within

the

fields

of

and

Review1

and

Women’s

Hospital,

biopsy.

He received

4 months

of amphoter-

icin B treatment, then no therapy for 6 months before dying with no evidence of mucormycosis. Isolated renal mucormycosis should be suspected in those with an underlying immunocompromising illness or history of iv drug use who have persistent flank pain and fever, but sterile urine cultures. Computed tomographic scanning with contrast should then be per-

5:2014-2019)

of isolated

kidney

projects

J. Bia ous renal

School

of research

biology.

formed; findings of severe inflammation infection, despite an indolent clinical sterile or nondiagnostic urine and blood

suggestive

of isolated

renal

or bacterial course with cultures, are

mucormycosis,

and

renal

biopsy under computed tomographic guidance should be performed, despite the potential risk of disseminated infection. Although our patient was

treated

with amphotericin

or without more likely constitutional

B alone,

nephrectomy

amphotericin B therapy to cure infection and

with

appears to be relieve pain and

symptoms. Volume

5

‘

Number

12

.

]995

Levy

Key Words: infection, intravenous

C our

.R.

Human immunodeficiency computed tomographic drug use is a 36-year-old

deficiency emergency

virus. infection. fungal scanning. amphotericin B.

avlum-lntracellulare.

man

virus room

with

(HIV) infection complaining

human

day right

Immuno-

who presented of 3 days of

to right

flank pain, fever, and lethargy. He had been diagnosed with HW infection 6 years before but had no opportunistic infections. His most recent CD4 count, 18 months earlier, was 90. He had acquired the virus through iv drug use and continued to use iv heroin actively up to the day of admission. One month before admission, he had been hospitalized with fever and productive cough. On admission, he had renal Insufficiency, which resolved with fluid administration. A renal ultrasound was unremarkable. Past medical history was unremarkable. His medications Included phenobarbital, clonazepam, AZT, clotrimazole of anaphyllaxis On physical man in no

troches, and ibuprofen. to penicillin. examination, he was apparent distress. The

He

had

a cachetic temperature

a history white was

101 .8 orally, the heart rate was 96 beats/mm, the respiratory rate was 1 6 breaths per minute, and the blood pressure was 1 12/88. The skin was unremarkable. The oropharynx was dry but otherwise unremarkable. There was no cervical adenopathy or nuchal rigidity. The lungs were clear. A soft systolic murmur was noted at the left lower sternal border. The abdomen was soft. The liver and spleen were not enlarged. There was right flank tenderness. He was drowsy but easily arousable, with no focal neurologic findings. Urinalysis revealed clear yellow urine with a pH of 5.0, a specific gravity of 1 .015, 6 to 10 white blood cells, and two to five red blood cells. The hematocrit was 3 1 .2%, and the mean corpuscular volume was 99. The white blood cell count was 4000, with 77 segs, 8 bands, 10 lymphs and 5 monos. The platelet count was 160,000. The serum electrolytes were normal. The BUN was 67 mg/dL, and the creatinine was 1.8 mg/dL. The serum calcium was 9. 1 mg/dL, the phosphate was 5.0 mg/dL, and the magnesium was 2.4 mg/dL. Liver function tests were unremarkable. The patient was started on vancomycin, gentamicin, and cefoperazone. A computed tomographic (CT) scan of the abdomen with iv contrast on the third hospital day revealed heterogeneous enhancement of multiple areas during sterile obtained

of the the

right first

kidney. week

or grew mixed during the

of

flora. same

Five urine hospitalization Three period

cultures

sets ofblood were also

were

of the American

Society

of Nephrology

returned on now revealed Renal ultrasound

25 revealed a diffuse kidney, obscuring the

infiltrative central

the

18th

Bia

hospital

Mycobacterium on

hospital

process sinus complex

in

the and

the corticomedullary boundaries. A CT scan of the abdomen revealed increasing infiltration of the right renal parenchyma (Figure 1). On hospital day 33, a fine needle aspirate of the right kidney revealed only benign epithelium with proteinaceous material and several unremarkable gbmeruli. Silver and acid fast stains were negative. On hospital day 37, one colony of absidla, a Mucorales species, was reported growing from the aspirate. On hospital day 46, a percutaneous right renal biopsy was performed, revealing a granubomatous fungab infection, with features most consistent with a Phycomycete (Figure 2). The patient was started on amphotericin B three times a week. Nephrectomy was recommended but refused. He received apy before worsening

4 months of amphotericin renal function forced

to be discontinued. alter the discontinuation

He

months continued he had postmortem

therdrug

6 months a total of 10

from diagnosis, before dying. Although he to have fever and flank pain until his death, no clinical evidence of mucormycosis. No examination was performed.

CLINICAL This

survived another ofamphotericin,

this

PRESENTATION

patient

presented

with

signs

and

symptoms

of

renal infection. His course was indolent; he suffered 7 weeks of fever and flank pain before a diagnosis was made and remained clinically stable during this time, without overt sepsis or progressive renal dysfunction. The presentation was similar in 1 4 other reported cases of isolated renal mucormycosis ( 1-9). The clinical

and

1 . Fourteen

laboratory of

features 15 cases

are occurred

summarized in

men;

in Table the

median

obtained either cultures sterile.

A

transthoracic echocardiogram on the fourth hospital day revealed no vegetations. Because of improvement in the patient’s fever curve, antibiotics were stopped alter 8 days. A repeat CT scan on hospital day 11 revealed no change in the right kidney lesions seen on the earlier study. His back pain continued unabated,

Journal

however, and his fever day. Blood cultures

and

FIgure 1. CT scan of the abdomen with Iv and oral contrast reveals enlargement of the right kidney with Inhomogeneous enhancement and areas of low attenuation.

2015

Renal

Mucormycosis

inflammation, vascular necrosis, and thrombosis. The differential diagnosis of these findings also includes infection with other angioinvasive organisms (such as aspergillus) and vasculitis. In a recent series of four patients, a different presentation was noted: enlarged kidneys with no contrast excretion, multiple areas of low attenuation consistent with abscesses, and perinephric fluid collections (see Reference 25). This presentation may reflect more diffuse or severe renal infection and infarction. The differential diagnosis ofenlarged kidneys without contrast enhancement or excretion includes severe diffuse infection, renal vein thrombosis, complete ureteral occlusion, or severe glomerubonephritis. However, the combination enhancement, parenchymal nc fluid collections is diffuse infection. (These tions and their differential in Table 2.)

of renal enlargement, nonabscesses, and perinephstrongly suggestive of severe two radiographic presentadiagnoses are summarized

Results of a variety of other diagnostic imaging studies have been reported, including renal sonography, excretory urography, renal scan, selective renal angiogram, nephrostogram, and retrograde pyelogram. leading.

These

were

either

not

helpful

or

frankly

mis-

PATHOLOGY Figure 2. Renal biopsy specimen reveals broad, irregular, nonseptate hyphae of mucormycosis (arrow), as well as tissue necrosis and neutrophil and macrophage infiltration. Hematoxylin and eosln stain, original magnification, x300.

mucormycosis,

age was 36.5, with a range of 1 7 to 69. Eleven cases were unilateral; four were bilateral. The most common presenting complaint was flank pain; the most common physical finding was flank tenderness. In most cases, the ranged from had symptoms

duration 3 days for

RADIOGRAPHIC Two distinct trast-enhanced ours, CT attenuation ferred findings

to

before although

presentations CT scan.

In

have two

revealed diminished

diagnosis one patient

a “diffuse patchy been described

been noted on conpatients, including

ill-defined enhancement, in

areas

nephrogram.” patients

of often

with

low re-

Similar bacte-

rial infection of the kidney. They are thought to represent a form of severe, localized pyebonephritis, which may progress to liquefaction and renal abscess. This entity has been termed acute focal bacterial nephritis, acute bacterial nephritis, acute bobar nephronia, focal or multifocal pyebonephritis, and segmental acute pyelonephrltis. result from sion can

2016

The edema

radiographic and vascular

(10,11). It is not be produced by

surprising mucormycosis,

changes spasm that

are thought and compressimilar which

findings produces

as well

cosis. On histologic often seen invading sis or thrombosis rounding tissues;

FINDINGS

scanning and as have

of symptoms to 1 month, 12 months.

A renal biopsy of our patient revealed the characteristic broad , irregular , nonseptate hyphae of mucormycosis, with tissue necrosis and neutrophil and macrophage infiltration (Figure 1). These pathologic changes are typical of those previously noted in isolated renal

to

as in other

examination, vessel walls, and necrosis hyphae may

types

of mucormy-

the

organism is causing vessel necroor bleeding in suralso be found within

glomeruli, tubules, and interstitium (5). Affected tissue is infiltrated with neutrophils, macrophages, and Langhans giant cells; microscopic abscesses may be noted (3,4). Although the kidney was not available in our case for gross examination, in other reported cases, the kidney is usually, although not invariably, enlarged and edematous, and the disease process may be focal or diffuse. The hilar vessels may be thrombosed (1,2). Foci of necrosis (which may appear caseous) and macroscopic abscesses or hematomas may be found (1-6). Necrotic debris may collect in the pelvis (3).

PATHOPHYSIOLOGY Fungi phytes

of the order Mucorales of low virulence. Infection

are

ubiquitous is largely

saprorestricted

to those with underlying immunocompromising ness, most commonly diabetes, lymphoproliferative disease, or severe malnutrition. The nature of immune abnormality that allows fungal multiplication

Volume

5’

Number

12

‘

illthe

1995

Levy

TABLE 1 Clinical .

features

in 15 reported

Conditions

Diabetes without Alcoholism (2)

ketoacidosis

Intravenous

use (2)

Flank pain (8) Gross hematuria

(5)

to

Numbers

In parentheses

occur

is

are

unclear

Urinary frequency Anorexia/weight Weakness (1) Oliguria (2) number

but

of

patients

probably

with

involves

feature

renal

Physical

noted.

(7)

defects

from

contaminate cleaning

kidney. Smith and Jones studied the localization and ultimate fate of Absidla spores alter iv injection into inununocompetent mice. After the injection of 100,000 spores, germination and pathologic changes

mucormycosis; HIV-infected

carditis (16). With this case, renal mucormycosis

there

TABLE 2. Comparison Radiographic

are in

iv

presentations

Presentation

Focal

Radiographic

In

of these devitalized survival

or In of

.

Diffuse

.

(References

are them

of the American

Society

of Nephrology

1 to

9. 25 and

ubiquitous, their and

iv drug

needles introduce

does

not

ours individuals

patients tissue, (18,20,23).

of

or the appear

this

shift (7)

case).

users

may

easily

paraphernalia fungi as they to increase

is only the ( 1 7-23).

(5)

10th Of

while admin-

the

reported note is

risk

of

case in the high

underwent which

is

a full generally

debridement necessary

of for

The paradoxical combination ofbenign clinical findings (indolent course with benign urine or blood culture) and worrisome radiographic findings (evidence of severe localized pyebonephritls) is consistent with renal infection with an angioinvasive organism (mucor or aspergiblus) or vasculitis. In the Immunocompro-

and

differential

diagnoses

Findings

(Reference Differential

1 2. 3. 1 2. 3. 4.

.

.

25 and

this case)

Diagnosis

Focal bacterial infection Infection with an angloinvasive Vasculltis Severe diffuse infection Infarction Renal vein thrombosis Ureteral occlusion

5. Severe

Journal

failure

DIAGNOSIS

1 Inhomogeneous enhancement enlargement 3. Areas of low attenuation 1 No contrast excretion 2. Renal enlargement 3. Areas of low attenuation 4. Perinephrlc fluid collections 2. Renal

renal

frequency of drug use, unusual sites of infection, unusual organisms, and favorable course in these patients. Seven were using iv drugs actively at the time of presentation; most had used iv drugs for many years. Five suffered from isolated deep cerebral mucormycosis ( 1 7- 1 9), one suffered from isolated renal disease (20), and one each suffered from pulmonary (2 1 ), cutaneoarticular (22), and rhinocerebral mucormycosis (23). Absicila (20), Cunnlnghamella (22), and Rhizopus (23) were each identified once as the causative species, even though Rhizopus is generally a much more common cause of mucormycosis. Three patients survived their infection, even though only one

now two reports of isolated drug users. Because the

of radiographic

cases

ister the drug. HIV infection

occurred only in the brain and kidney, even though less than 1% of spores were initially deposited in these organs. Larger Inocula produced limited disease in liver and lung but extensive disease in brain and kidney ( 13). Corbel and Eades found that, although spores deposited in liver and spleen, lung, kidney, and brain alter inoculation In mice, germination occurred only in brain and kidney. Larger inocula produced higher fatality rates but no change In the distribution of disease ( 14). Davis et a!. , injecting Mucor corymbfera iv into mice, recovered the fungus most consistently from the kidneys, which were the only organs which suppurative foci were found (15). Clinical reports confirm that isolated cerebral renal mucormycosis may complicate iv drug use. 1989, Stave et al. summarized the 1 1 cases reported isolated cerebral mucormycosis in iv drug users. These patients had infection of the deep structures the brain, most commonly the basal ganglia, without evidence of adjacent foci of infection or fungal endo-

Acute

(7)

Leukocytosis/left

1 5 reported

both macrophage and neutrophil function (12). Experimental and clinical evidence suggests that iv drug use may be linked with the development of isolated mucormycosis in the brain as well as in the

Findings

Hematuria Pyuria (7)

(2)

mucorales

in

Laboratory

Findings

Flank tenderness (5) Mid-abdomInal mass (1) CervIcal wall motion tenderness (1)

(4)

or dysuria loss (1)

Bia

mucormycosis

Complaints

Fever, chills or rigors

Acute renal failure (2) Multiple myeloma (1) Renal transplantation (1) Hepatic failure (1) a

of isolated

Presenting

Predisposing

drug

cases

and

organism

glomerulonephrltis

2017

Renal

Mucormycosis

mised patient, infection is most likely; in the iv drug user, the infection is likely to be mucor, for the reasons discussed above. Because the CT findings are so helpful in focusing the differential diagnosis, we recommend that patients with an underlying immunocompromising condition or history of iv drug use and persistent fever and flank pain with sterile urine undergo CT scanning. If the CT scan reveals a “diffuse patchy nephrogram” or an enlarged kidney with poor enhancement and focal or diffuse bow enhancement, biopsy should be considered. Cultures of urine or renal tissue are frequently negative and may be laboratory contaminants. In the reported cases, microscopic examination and culture of the urine revealed mucor in only one patient before diagnosis. In the remaining eight patients, the cultures were either sterile or grew Pseudomonas, Candida, or Diphtheroids species. Although we customarily perform renal biopsies under ultrasound guidance at our institution, the CT scanner a grossly creasing involvement

allowed us abnormal the

chances is patchy,

to direct the biopsy area of the kidney,

needle toward thereby in-

of pathologic diagnosis. If renal biopsy should be therefore be

performed under CT guidance to ensure sampling of an involved area. It should be noted that percutaneous or open biopsy of the Infected kidney may carry the risk of dissemination of the infection. The development of fever, bacteremia, and septic shock alter percutaneous biopsy of the kidney In bacterial pyebonephritis has been noted; one septic death has been reported (24). Whether the same risks exist when the kidney is infected with fungus remains to be seen.

TREATMENT The excision of devitalized tissue, followed by amphotericin B therapy, is the standard therapy for mucormycosis ( 1 2), although there are reports of survival In pulmonary and rhinocerebral mucormycosis with amphotericin treatment alone. Before the case described here, no patient had survived isolated renal mucormycosis without nephrectomy. Five patients who underwent nephrectomy followed by amphotericm therapy survived (one received clotrimazole as well) (2,25); two patients survived without antifungal therapy alter nephrectomy (4,7). Because of the risks of of severe malnutrition and mise, our patient did not received amphotericin B vived another 6 months before dying quietly with cormycosis.

major surgery in the setting advanced immunocomproundergo nephrectomy. He for 4 months and then surwithout antifungal therapy no clinical evidence of mu-

CONCLUSION Isolated renal mucormycosis in those with an underlying illness or history of iv drug

2018

flank pain and fever, but sterile urine cultures. CT findings of severe Inflammation or bacterial infection support this diagnosis, which may be confirmed by renal biopsy. Although our patient was treated with amphotericin B alone, nephrectomy with or without amphotericin B therapy is more likely to cure infection and

pain

and

constitutional

symptoms.

ACKNOWLEDGMENTS We thank Dr. John Hayslett for his thoughtful script. Dr. Thomas Egglin for assistance with enUai diagnosis. and Dr. Michael Kashgarian tomicrograph.

review of the manuthe radiographic differfor providing the pho-

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Fungal Infections: Proceedings of the SecCongress. Springfield: Charles C. Tho-

Raghavan R, Date A, Bhaktaviziam A: Fungal and nocardial infections of the kidney. Histopathology 1987:11:920. 9. Langston C, Roberts DA, Perter GA, Bennet WM: Renal phycomycosis. J Urol 1973:109:941-944. 10. Nosher JL, Tamminen JL, Amorosa JK, Kallich M: Acute focal bacterial nephritis. Am J Kidney Dis 1988; 11:36-42. 1 1 . Soulen MC, Fishman EK, Goldman SM, Gatewood 0MB: Bacterial renal infection: Role of CT. Radiology 1989; 8.

171:703-707.

12.

13. 14. 15. 16.

17.

18. should be considered immunocompromising use who have persistent

relieve

Sugar AM. Agents of mucormycosis and related species. In: Mandell GM. Douglas RG Jr. Bennet J, Eds. Principles and Practice of Infectious Disease. 3rd Ed. New York: Churchill Livingstone; 1990:1962-1972. Smith JMB, Jones RH: Localization and fate of Absidia ramosa spores after intravenous inoculation of mice. J Comp Pathol 1973:83:49-55. Corbel MJ, Eades SM: Factors determining the susceptibility of mice to experimental phycomycosis. J Med Microbiol 1975;8:55 1-564. Davis CL, Anderson WA, McCrory BR: Mucormycosis in food-producing animals: A report of twelve cases. J Am Vet Med Assoc l955;126:261-267. Stave GM, Heimberger T, Kerkering TM: Zygomycosis of the basal ganglia in intravenous drug users. Am J Med 1989;86:1 15-117. Cuadrado LM, Guerrero A, Lopez-Garcia Asenjo JA, et at. : Cerebral mucormycosis in two cases of acquired immunodeficiency syndrome. Arch Neurol 1 988;45: 109-111. Case 52-1990. Case Records of the Massachusetts General Hospital: Weekly Clinicopathological Exercises. A 31 year old HIV seropositive woman with a cerebral lesion seven years after treatment of carcinoma of the cervix. N Engl J Med 1990:323:1823-1833.

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Berenguer J, Solera J, Moreno S, Munoz P. Parras F: Mucormycosis. Spectrum of the disease in 13 patients. Med Clin (Barc) 1990;94:766-772. Smith AG, Bustamante CI, Gilmor GD: Zygomycosis (absidiomycosis) in an AIDS patient. Absidiomycosis in AIDS. Mycopathobogia 1989; 105:7-10. Chavanet P, Lefranc T, Bonnin A, Waidner A, Portler H: Unusual cause of pharyngeal ulcerations In AIDS. Lancet 1990;336:383-384. Mostaza JM, Barbado FJ, Fernandez-Martin J, PenaYanez J, Vazquez-Rodrlguez JJ: Cutaneoarticular mucormycosis due to Cunninghamella bertholletiae in a

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patient with AIDS. Rev Infect Dis 1989; 11:316-318. Blatt SP, Lucey DR. DeHoff D, Zeilmer RB: Rhinocerebral zycomycosis in a patient with AIDS. J Infect Dis 1991:164:215-216. Samellas W: Death due to septicemia following percutaneous needle biopsy of the kidney. J Urol 1964;9 1:317319. Chugh KS, Sakhuja V. Gupta KL, et at.: Renal mucormycosis: Computerized tomographic findings and their diagnostic significance. Mn J Kidney Dis 1993;22:393397.

2019