Malakoplakia of the Kidney Transplant

Introduction

Malakoplakia is a rare granulomatous disease associated with infection.¹ Malakoplakia most often involves the bladder, although it can affect any organ, including the native or transplanted kidney.^2,3 Indeed, solid organ transplant recipients and other immunocompromised individuals are at increased risk of malakoplakia. This case report and systematic review of the literature raises important considerations related to malakoplakia of the kidney transplant.

Case Presentation

A 40-year-old woman with atypical hemolytic uremic syndrome who received 2 prior kidney transplants presented with acute kidney injury. Nine years before presentation, she underwent her first kidney transplantation, which failed because of recurrence of atypical hemolytic uremic syndrome for which she received eculizumab therapy. Four months before presentation, she underwent a second kidney transplantation with immediate graft function. She received induction immunosuppression with alemtuzumab and solumedrol, and maintenance immunosuppression with tacrolimus, mycophenolate mofetil, and prednisone. There were no episodes of rejection. One month before presentation she was hospitalized with sepsis secondary to pan-sensitive Escherichia coli urinary tract infection which was treated with a 14-day course of levofloxacin.

She was then referred to the hospital for acute kidney injury despite resolution of sepsis and urinary tract infection. She was asymptomatic. Vital signs demonstrated a temperature of 37 °C, blood pressure of 124/78 mm Hg, pulse of 90 beats per minute, respiratory rate of 17 per minute, and oxygen saturation of 100% on room air. Physical examination demonstrated normal cardiopulmonary findings, and no allograft tenderness or peripheral edema. Laboratory tests demonstrated a white blood cell count of 12.4 × 10⁹/l, hemoglobin of 9.1 mmol/l, platelet count of 402 × 10⁹/l, sodium of 139 mmol/l, potassium of 3.7 mmol/l, chloride of 109 mmol/l, carbon dioxide of 15 mmol/l, blood urea nitrogen of 17.5 mmol/l (49 mg/dl), and creatinine of 279.4 umol/l (3.16 mg/dl). The tacrolimus trough level was 4.4 ng/ml. Urine studies demonstrated 4 white blood cells/high power field, <1 red blood cells/high power field, and urine protein/creatinine ratio 0.78 mg/mg. Repeat urine culture yielded no growth. A kidney transplant ultrasound demonstrated mild hydronephrosis, upper normal resistive indices of the midpole intrarenal segmental artery, and small nonobstructive kidney stones. A computed tomography of the abdomen and pelvis without contrast demonstrated atrophic native kidneys, the previous right lower quadrant transplant kidney, and a normal appearing left lower quadrant transplant kidney with small nonobstructive kidney stones.

Results

An initial kidney allograft biopsy demonstrated a pleomorphic interstitial infiltrate with frequent lymphocytic tubulitis, not typical of acute T-cell mediated rejection. There were rare degenerative yeast-like forms, which were strongly periodic acid–Schiff positive, weakly Grocott's methenamine silver positive, and weakly mucicarmine positive. The differential diagnosis included malakoplakia or tubulointerstitial nephritis, with yeast-like forms suggesting fungal infection. Malakoplakia was not definitively diagnosed because von Kossa (phosphate) and iron stain were negative for Michaelis-Gutmann bodies. She was discharged home with oral fluconazole to empirically cover a possible fungal infection while waiting for the fungal studies. All fungal studies were negative, including fungal DNA detection by polymerase chain reaction of the biopsy sample, fungal blood culture, serum (1,3)-β-D-glucan, and serum Blastomyces, Aspergillus, Cryptococcus, and Histoplasma antigens. Two weeks after discharge, she developed abdominal pain, nausea, vomiting, diarrhea, and syncope. She was readmitted and found to have elevated blood urea nitrogen of 28.9 mmol/l (81 mg/dl) and creatinine of 668.5 umol/l (7.56 mg/dl) requiring initiation of intermittent hemodialysis.

A subsequent kidney allograft biopsy similarly demonstrated a pleomorphic interstitial infiltrate with frequent tubulitis. However, there were also multiple foci of periodic acid-Schiff positive targetoid-appearing intracellular bodies within macrophages with positive von Kossa and iron staining diagnostic for malakoplakia (Figure 1). The patient's immunosuppression was reduced. Mycophenolate mofetil was stopped and tacrolimus trough level goal was decreased to 4 to 6 ng/ml. She received a 30-day course of ciprofloxacin. After 2 sessions of hemodialysis, her kidney function improved, and she did not require further intermittent hemodialysis. Six months later, her kidney function remains stable with a new baseline serum creatinine of 150.3 umol/l (1.7 mg/dl).

Figure 1.

Light microscopic images of the second kidney allograft biopsy. (a) Two biopsy cores with Periodic acid-Schiff stain, and (b) von Hansemann cells with Michaelis-Gutmann bodies (arrows) demonstrated by Periodic acid-Schiff stain, (c) von Kossa (phosphate) stain, and (d) iron stain.

Discussion

Malakoplakia is a granulomatous condition that results from an abnormal inflammatory response to infection. Initially described by Michaelis and Gutmann in 1902, the term malakoplakia was derived from the Greek malakos plakos for “soft plaque.”⁴ Malakoplakia has been reported in every organ, but is most often associated with E. coli or other gram-negative bacilli infections in the urinary tract. Malakoplakia results from impaired killing and elimination of bacteria by the macrophage phagolysosome. Therefore, histopathological studies demonstrate the accumulation of enlarged macrophages (von Hansemann cells) with densely calcified cores with calcium phosphate and undigested bacteria and bacterial products (Michaelis-Gutmann bodies).⁵ The natural course of malakoplakia involves infection, inflammation, abnormal macrophage proliferation, and then ultimately fibrosis of the affected organ (Figure 2).

Figure 2.

Pathogenesis of malakoplakia in the kidney. Malakoplakia may result from impaired killing and elimination of bacteria by the macrophage phagolysosome, resulting in the accumulation of enlarged macrophages (von Hansemann cells) with densely calcified cores composed of undigested bacteria and bacterial products (Michaelis-Gutmann bodies). Created in biorender.com.

Systematic Review

We performed a systematic review of the literature for cases of malakoplakia among kidney transplant recipients (Supplementary Table S1). Non-English publications were excluded (Supplementary Figure S1). We identified 45 previously published cases of malakoplakia among kidney transplant recipients, including 19 cases involving the kidney allograft, 8 of the gastrointestinal tract, 6 of the bladder, 5 of the groin or perineum, 2 of the lung, 2 of the skin, 1 of the prostate, 1 of the abdominal wall, and 1 of the tongue (Supplementary Table S2) Our review highlights the evaluation, pathology, and management of malakoplakia involving the kidney allograft (Table 1, Table 2).

Table 1.

Case reports of malakoplakia involving the kidney allograft.

Citation, yr	Age, Sex	Native disease	Time after transplant	Prior rejection	Organism	Antibiotic duration	Outcome
Lee et al., 2022S1	59, F	NR	18 mo	Yes	E. coli	NR	Improvement
Patel et al., 20216	45, F	GN	16 mo	Yes	E. coli, K. pneumoniae	long-term	Improvement
Kalimuthu et al., 2021S2	41, F	NR	1 yr	NR	culture negative	NR	NR
Kinsella et al., 2021S3	63, F	NR	7 mo	NR	E. coli	3 mo	Improvement
Kinsella et al., 2021S3	52, F	NR	4 mo	NR	E. coli	6 mo	Improvement
Tan et al., 2021S4	55, F	lithium	NR	NR	E. coli	4 mo	NR
Khojah et al., 2020S5	74, F	NR	2 yr	No	E. coli, E. aerogenes	long-term	Improvement
Khojah et al., 2020S5	62, F	NR	6 yr	No	culture negative	6 mo	Improvement
Yasin et al., 2018S6	36, F	NR	4 yr	NR	E. coli	14 wk	Improvement
Mookerji et al., 2018S7	58, M	PKD	6 mo	Yes	E. coli, E. cloacae	1 mo	Kidney failure
Pirojsakul et al., 2015S8	14, F	reflux	1 yr	NR	E. coli	NR	NR
Keitel et al., 2014S9	23, F	GN	36 d	Yes	E. coli	28 d	Kidney failure
Honsova et al., 2012S10	31, F	DKD	12 yr	Yes	E. coli, S. aureus	NR	Improvement
Augusto et al., 2008S11	56, F	undetermined	11 mo	No, prior transplant	E. coli	10 wk	Improvement
Puerto et al., 2007S12	45, F	NR	2 yr	NR	E. coli	None	Kidney failure
Pusl et al., 2006S13	43, F	DKD	2 yr	NR	E. coli	2 mo	improvement
McKenzie et al., 1996S14	29, F	GN	8 yr	NR	NR	long-term	improvement
Stern et al., 1994S15	55, F	GN	3 yr	no	E. coli	long-term	improvement
Osborn et al., 1977S16	46, F	pyelonephritis	15 mo	no	E. coli, P. vulgaris	1 mo	Kidney failure

DKD, diabetic kidney disease; F, female; GN, glomerulonephritis; M, male; NR, not reported; PKD, polycystic kidney disease.

Table 2.

Teaching points

Malakoplakia of the kidney allograft
•Malakoplakia is a rare granulomatous condition that results from abnormal macrophage response to infection
•Malakoplakia is typically associated with E. coli or other gram-negative bacilli involving the urinary tract, and can affect the native or transplanted kidney
•Biopsy of affected tissues demonstrates diagnostic von Hansemann cells (enlarged macrophages) with Michaelis-Gutmann bodies (densely calcified cores composed of undigested bacteria and bacterial products)
•Malakoplakia of the kidney transplant can be treated successfully with appropriate antimicrobial therapy and reduction of immunosuppression

Evaluation

Clinical features of malakoplakia vary based on the location and severity of disease. Malakoplakia of the kidney allograft may present with asymptomatic kidney dysfunction, or may cause iliac fossa pain, dysuria, lower urinary tract symptoms, or palpable mass. Urinary tract infection among kidney transplant recipients may herald the development of malakoplakia with a 5:1 female to male predominance. Malakoplakia may have concomitant infectious complications such as perinephric abscess, hydronephrosis, or pyelonephritis. Laboratory studies may demonstrate acute kidney injury, pyuria, or positive urine culture. 1,25-dihyroxyvitmain D–mediated hypercalcemia has been rarely reported.⁶ In most cases, a routine infectious workup including blood cultures and urinalysis with urine culture reveal the underlying organism. Other studies, such as fungal serology or polymerase chain reaction of the biopsy tissue, are considered for atypical presentations or when the underlying cause is unclear. Imaging of the kidney transplant may be normal, but nephromegaly, nodularity, or mass of the kidney have been reported. Nuclear medicine imaging such as positron emission tomography/computerized tomography can identify hypermetabolic malakoplakia lesions that are sometimes associated with reactive lymphadenopathy, and thus the differential diagnosis includes acute rejection, atypical infection, or malignancy.⁷

Pathology

Biopsy is needed to identify diagnostic histopathological features of malakoplakia. Macroscopically, malakoplakia lesions appear as yellow or whitish patches, calcified plaques, or small nodules to larger masses of the kidney. Light microscopy demonstrates characteristic von Hansemann cells and Michaelis-Gutmann bodies.⁵ von Hansemann cells are enlarged macrophages with eosinophilic cytoplasm on hematoxylin and eosin stain. von Hansemann cells have been identified in the urinary sediment of patients with malakoplakia of the urinary tract.⁸ Michaelis-Gutmann bodies are 2 to 10 μm diameter lesions with a dense center within the cytoplasm of macrophages demonstrating a targetoid or “bird’s eye” appearance. Michaelis-Gutmann bodies have a basophilic appearance on hematoxylin and eosin stain and demonstrate positive von Kossa and iron staining. In cases where malakoplakia is suspected but not confirmed on histopathological analysis, repeat biopsy may be considered to increase diagnostic yield because pathognomonic lesions may be scarce early in the disease process.

Management

Treatment of malakoplakia includes antimicrobial therapy, modification of immunosuppression, and, rarely, surgical intervention. Antibiotic therapy should be tailored by antimicrobial susceptibility testing, although drugs with high intracellular penetrance within macrophages like quinolones and trimethoprim/sulfamethoxazole are preferred. The duration of antibiotic therapy varies based on treatment response, which is evidenced by improvement in kidney function, with a wide range reported in the literature. Bethanechol or other cholinergic agonists were proposed as an adjunct therapy to increase cyclic guanosine monophosphate activity and improve the inflammatory response of macrophages, but this practice is not supported by robust evidence. Reduction of immunosuppression should be considered to improve antimicrobial treatment response.⁹ It is unclear how various immunosuppressive agents affect macrophage function, although older agents with direct leukotoxicity like azathioprine may heighten the risk of malakoplakia. It is also possible that episodes of rejection, which require augmentation of immunosuppression, increase the risk of malakoplakia. Surgical treatment may be required in advanced cases of malakoplakia, such as those with pseudotumor with mass effect. However, most cases of malakoplakia of the kidney transplant respond to appropriate antimicrobial treatment and modification of immunosuppression alone.

Conclusion

Malakoplakia is a granulomatous disease that results from a dysfunctional macrophage response following a bacterial infection. Malakoplakia most often affects the bladder, although any organ including the native or transplanted kidney could be involved. The risk of malakoplakia is increased in immunocompromised states, including solid organ transplantation. Malakoplakia of the kidney allograft can be treated with reduction of immunosuppression, targeted antimicrobial therapy, and close monitoring.

Disclosure

All the authors declared no competing interests.

Patient Consent

The authors obtained written consent from the patient.

Supplementary Material

Supplementary References.

Figure S1. Flow diagram for systematic review of the literature related to malakoplakia of the kidney transplant.

Table S1. Search strategy for systematic review of the literature related to malakoplakia among kidney transplant recipients.

Table S2. Case reports of malakoplakia among kidney transplant recipients, sorted by anatomic location.