A non-immunocompromised host with nontuberculous mycobacteria-associated tubulointerstitial nephritis

Abstract

A 50-year-old man was admitted to our hospital with the complaints of fever and general malaise. He had no history of human immunodeficiency virus (HIV) infection or treatment with immunosuppressive agents. We performed renal biopsy to investigate possible acute kidney injury. Pathological findings showed inflammatory cell infiltration, including granulomatous lesions in the interstitium. We diagnosed the patient with acute granulomatous tubulointerstitial nephritis. We initiated prednisolone (PSL) 40 mg/day (0.6 mg/kg), in combination with isoniazid for a latent tuberculosis infection, because of positive results in interferon-γ release assays. The patient’s fever and malaise promptly disappeared, and his renal function improved. After the patient had been discharged, Mycobacterium intracellulare grew in cultures of his renal tissue and urine. We gradually reduced the dose of PSL; we initiated combination therapy with ethambutol, clarithromycin, and rifampin. After 2 years of follow-up, the patient continued treatment for chronic kidney disease; it has since enabled him to avoid renal replacement therapy. This report describes a rare instance of nontuberculous mycobacteria-associated tubulointerstitial nephritis in a patient without a history of HIV infection or organ transplantation. In differential diagnosis of granulomatous tubulointerstitial nephritis, clinicians should consider drugs, sarcoidosis, tubulointerstitial nephritis and uveitis syndrome, vasculitis, and infections (e.g., involving mycobacteria). Prompt microbiological examinations, especially of urine or biopsy cultures, are vital for diagnosis.

Introduction

Granulomatous interstitial nephritis is a rare clinical condition that involves acute kidney injury [1]. Tubulointerstitial nephritis can be caused by drugs, infections (e.g., tuberculosis), and autoimmune diseases (e.g., sarcoidosis) [2]. Mycobacteria may cause renal disease by direct renal invasion, ureteral obstruction, or secondary amyloidosis [3]. Nontuberculous mycobacteria (NTM) may be present in patients with glomerulonephritis; relevant conditions include membranous nephropathy caused by Mycobacterium shimoidei [4], acute diffuse proliferative glomerulonephritis caused by Mycobacterium avium [5], and crescentic glomerulonephritis associated with M. avium, which improves with antituberculosis treatment alone [6]. NTM exist throughout the natural environment. A notable cause of interstitial nephritis is the presence of NTM, which often results in granulomatous inflammation [7–11].

In previous reports of granulomatous interstitial nephritis, affected patients often exhibited immunosuppression (e.g., presence of human immunodeficiency virus [HIV] infection or use of immunosuppressive drugs) [7–11]. Here, we describe a rare case of NTM-associated granulomatous interstitial nephritis in a patient without HIV who was not using immunosuppressive drugs.

Case report

A 50-year-old man was admitted to our hospital with complaints of fever and general malaise that had begun 2 months before admission. He had no abnormalities in terms of renal or urinary function. His past medical history included persistent hypertension and cholelithiasis. Three years prior to this admission, he had undergone vascular graft replacement for ascending aortic dissection and abdominal aortic aneurysm. One year prior to this admission, he had undergone partial vascular graft excision for vascular graft infection and septic shock; he had received intravenous cefazolin at that time. Two months prior to this admission, he had undergone another graft excision for a right inguinal purulent wound. There was no history of renal disease in the patient’s family; however, his sister had experienced subarachnoid hemorrhage, his niece had experienced transposition of the great vessels, and his father had died of sudden cardiac arrest. He had previously worked as an electrician. He lived alone and had a 28-year history of smoking. His medications at the time of admission were pitavastatin, bisoprolol, nifedipine, pregabalin, and naftopidil.

On admission to our hospital, intravenous ceftriaxone and vancomycin were administered considering the vascular graft infection; however, the patient continued to exhibit recurrent intermittent high fever and deterioration of renal function (serum creatinine: 4.6 mg/dL). He was referred to the Department of Nephrology for management of acute kidney injury. On admission to our department, the patient’s height was 182 cm and his weight was 73 kg. Examination revealed that he was oriented; vital signs were as follows: temperature was 39.2 °C, blood pressure was 98/33 mmHg, heart rate was 98 bpm, SpO₂ was 98% on ambient air, and respiratory rate was 18 breaths/min. Physical examination revealed mild tapping pain in the ribs and spinal angle. The patient did not have skin rash, edema, superficial lymph node swelling, or other abnormal findings. His urinary protein was 2 + (0.92 g/g creatinine), but he did not exhibit hematuria or pyuria. Blood tests showed hemoglobin level of 7.4 g/dL, total protein level of 6.8 g/dL, lactate dehydrogenase level of 261 U/L, blood urea nitrogen level of 38 mg/dL, creatinine level of 4.68 mg/dL (determined by the enzymatic method), and C-reactive protein level of 9 mg/L (Table 1). The results of T-SPOT^® and QuantiFERON^®-TB Gold-Plus (an interferon-γ release assay [IGRA]) assessments were both positive. The results of repeated blood cultures were all negative. Ultrasonography revealed enlargements of 118 mm and 135 mm on the long axes of the right and left kidneys, respectively. Chest X-rays showed no abnormalities. Plain computed tomography showed hepatosplenomegaly (Fig. 1). Gallium-67 scintigraphy revealed abnormal isotope accumulation in both kidneys (Fig. 2). Bone marrow biopsy showed normoblastic maturation. Light microscopy analysis of kidney biopsy specimens showed a minor abnormality in the residual glomeruli (Fig. 3a). Inflammatory cell infiltration into the interstitial tubules, including noncaseating granuloma, was observed (Fig. 3b). Immunofluorescence microscopy findings were all negative. Ziehl–Neelsen staining revealed no bacteria. Granuloma analysis revealed CD68-positive staining results (Fig. 3c). The patient was tentatively diagnosed with acute granulomatous tubulointerstitial nephritis. Based on the assumption of a positive IGRA result, we submitted frozen compound-embedded material (originally intended for immunofluorescence analysis) to acid-fast bacilli culture analysis, considering the potential for renal tuberculosis.

Table 1.

Laboratory Findings on Admission

Urinalysis			Blood chemistry
Protein	(2+)		Total protein	6.8 (6.6–8.1)	g/dL
Occult blood	(±)		Albumin	3.7 (4.1–5.1)	g/dL
Red blood cell	0–1	/HPF	AST	29 (13–30)	U/L
White blood cell	1–4	/HPF	ALT	29 (10–42)	U/L
Protein-to-creatinine ratio	0.92	g/g Cr	LDH	261 (124–222)	U/L
N-Acetyl-beta-d-glucosaminidase	26.5 (≤ 11.5)	U/L	CK	26 (59–248)	U/L
beta-2 microglobulin	16,731 (0–200)	μg/L	γ–GTP	168 (13–64)	U/L
Complete blood count			ALP	790 (106–322)	U/L
White blood cell	2380 (3300–8600)	/μL	BUN	38 (8–20)	mg/dL
Neutrophil	53.4 (39.5–74.5)	%	Creatinine	4.68 (0.65–1.07)	mg/dL
Lymphocyte	35.6 (20.9–54.1)	%	Uric acid	5.9 (3.7–7.8)	mg/dL
Eosinophil	0.2 (0–8.1)	%	Glucose	99 (73–109)	mg/dL
Red blood cell	280 (435–555)	× 104 /μL	Sodium	135 (138–145)	mg/dL
Hemoglobin	7.4 (13.7–16.8)	g/dL	Potassium	3.9 (3.6–4.8)	mg/dL
Hematocrit	22.2 (40.7–50.1)	%	Chloride	106 (101–108)	mg/dL
Platelet	16.7 (15.8–34.8)	× 104 /μL	Calcium	8.5 (8.8–10.1)	mg/dL
			iP	4.8 (2.7–4.6)	mg/dL
Microbiology			CRP	9.5 (0–1.4)	mg/L
T-SPOT®	(+)		IgG	1523 (861–1747)	mg/dL
ESAT-6	24 (< 5)	U/mL	IgA	229 (93–393)	mg/dL
CFP-10	19 (< 5)	U/mL	IgM	114 (33–183)	mg/dL
QuantiFERON®-TB Gold-Plus	(+)		C3	112 (73–138)	mg/dL
TB1	1.73 (< 0.35)	IU/mL	C4	18 (11–31)	mg/dL
TB2	1.98 (< 0.35)	IU/mL
Nil	0.45 (≤ 8.0)	IU/mL
Mitogen	4.68 (≥ 0.5)	IU/mL

Normal ranges in parentheses

ESAT early secreted antigenic target, CFP culture filtrate protein, AST aspartate aminotransferase, ALT alanine aminotransferase, LDH lactate dehydrogenase, CK creatine kinase, γ-GTP gamma-glutamyl transpeptidase, ALP alkaline phosphatase, BUN blood urea nitrogen, iP inorganic phosphate, CRP C-reactive protein

Fig. 1.

Computed tomography scan showing hepatosplenomegaly

Fig. 2.

Gallium-67 scintigraphy showing increased uptake in the liver, spleen, and bilateral kidneys

Fig. 3.

Histology of granulomatous interstitial nephritis. a The glomerulus showed normal; periodic acid–Schiff staining ×200. b Interstitial granulomatous noncaseating inflammation of multinucleated giant cells was observed; periodic acid–Schiff staining ×200. c Granuloma was observed, including CD68-positive histiocytic infiltration; CD68 staining ×200

Because we suspected idiopathic interstitial nephritis, we initiated oral prednisolone (PSL) 40 mg/day. We concomitantly administered isoniazid (INH) 300 mg/day for treatment of the latent tuberculosis infection, because of positive IGRA results. The patient’s fever and malaise immediately disappeared. After 2 weeks of treatment, his Cr level improved to 1.63 mg/dL, while pyuria appeared (approximately 30–40 per high-power field). After the patient was discharged, Mycobacterium intracellulare grew in cultures of his urine and kidney biopsy specimens. He showed hepatosplenomegaly without gallium uptake; thus, we did not suspect the liver or spleen as a focus of NTM dissemination. Finally, we diagnosed the patient with NTM-induced interstitial nephritis. We initiated clarithromycin 800 mg/day, ethambutol (EB) 1000 mg/day, and rifampicin (RFP) 600 mg/day for a duration of 18 months. We gradually reduced the dose of PSL to 30 mg, then by an additional 10 mg at 3-week intervals; however, we continued PSL 5–10 mg/day because of residual renal impairment. After 2 years of follow-up, the patient continued chronic kidney disease treatment; it has since enabled him to avoid renal replacement therapy.

Discussion

Here, we have described a patient with acute kidney injury and fever of unknown origin who was diagnosed with M. intracellulare-associated granulomatous interstitial nephritis on the basis of renal biopsy specimen and urine culture. This report is notable because it involved a case of NTM-associated granulomatous interstitial nephritis in a patient with no obvious history of immunodeficiency.

First, we discuss the common causes and etiology of granulomatous interstitial nephritis. Granulomatous interstitial nephritis is generally observed in 0.5–0.9% of native renal biopsy specimens [12]. A comprehensive review supported the following systematic classification: antimicrobial, analgesic, and other drug-related nephritis; infection-related nephritis; inflammatory/rheumatologic disease-related nephritis; and idiopathic nephritis, in which the cause is unknown [13]. In Asia, particularly in developed countries (e.g., Japan), drugs, sarcoidosis, and widespread tuberculosis are included in the differential diagnosis [2]. To our knowledge, there have been few reports regarding NTM-associated granulomatous interstitial nephritis.

Second, we consider the background factors of NTM-associated renal disease. NTM-associated tubulointerstitial nephritis is mostly encountered in immunocompromised hosts (Table 2), particular patients with HIV infection or post-transplant patients. In a report of a patient with acquired immunodeficiency syndrome who exhibited a renal mass as part of a disseminated Mycobacterium kansasii infection, the patient’s serum creatinine level improved from 4.69 to 1.20 mg/dL with prednisolone 1 mg/kg/day, combined with RFP, EB, and INH [11]. M. avium infection in a patient with HIV infection manifested as positive blood and urine cultures, combined with noncaseating granuloma [8]. In that patient, the microorganism was identified by urine culture, similar to the findings in our report. Especially in Asian countries, the relationship between anti-interferon-γ autoantibodies and disseminated NTM has been reported in immunocompromised patients without HIV infection or post-transplant status [14]. Anti-interferon-γ autoantibodies were detected in 30 (88.2%) of 34 patients with NTM who did not exhibit any identifiable classical immunodeficiency [14]. The undetectable result of the positive control (i.e., using a nonspecific antigen) in the QuantiFERON^® IGRA assessment can aid in anti-interferon-γ autoantibody screening [15]. However, our patient exhibited positive IGRA results, which contradicted the anti-interferon-γ autoantibody findings. Neutropenia on admission (normalized promptly) could be a risk factor; repeated graft replacement and a similar source of infection suggested a latent immune abnormality. In summary, our report has described a rare patient with NTM-associated interstitial nephritis that was independent of HIV infection or immunosuppressant treatment.

Table 2.

Previous reports of nontuberculous mycobacteria-associated tubulointerstitial nephritis

Author	Age, sex	Underlying disease	Mycobacterium species	Pathological findings	Treatment	Renal prognosis
Kapoor et al. [11]	55, M	HIV	M. kansasii	granulomatous interstitial nephritis	PSL 1 mg/kg × 4 weeks	Improvement
Martin-Blondel et al. [10]	37, M	HIV	M. avium	granulomatous interstitial nephritis	PSL 1 mg/kg → tapering + (CAM + RFB + MFLX)	Improvement
Rawla et al. [9]	40, F	Renal Transplantation	M. avium-intracellulare	granulomatous interstitial nephritis	Continuous immunosuppressants + EB + AZM + RFP	Improvement
Tattevin et al. [8]	53, M	HIV	M. avium	granulomatous interstitial nephritis	EB + CAM + OFLX	Improvement
Sumrani et al. [7]	35, M	Renal Transplantation + HIV	M. avium-intracellulare	granulomatous interstitial nephritis	Tapering immunosuppressants + INH + RFP + EB	Improvement

HIV human immunodeficiency virus, PSL prednisolone, CAM clarithromycin, RFB rifabutin, MFLX moxifloxacin, EB ethambutol, AZM azithromycin, RFP rifampicin, OFLX ofloxacin, INH isoniazid

Third, we discuss the information that supports our diagnosis. In previous reports, clinically significant NTM-associated hepatosplenomegaly showed a relationship with disseminated infection [16, 17]. However, renal site infection alone may have revealed systemic symptoms; alternatively, the kidney may have been affected by a disseminated multiorgan infection that also included the liver and spleen. The IGRA method measures interferon-γ released by T cells that are stimulated by Mycobacterium tuberculosis-specific antigens. IGRA results can be positive for some NTM, such as M. kansasii, but they are not usually positive for M. avium complex [18]. Here, we planned to administered steroid treatment; therefore, IGRA assessment was performed to check for latent tuberculosis infection, which revealed a positive result. When granulomatous interstitial nephritis was noted in the renal biopsy specimens, renal tuberculosis was suspected; acid-fast bacilli cultures of renal biopsy specimens and urine were then performed. Although there have been few reports concerning mycobacterial cultures from frozen tissues, it is important to avoid repeated defrosting and freezing; mycobacterial growth is detectable with longer incubation time than the duration used for nonfrozen specimens (102 ± 36 vs. 156 ± 53 h) [19]. Urine acid-fast bacilli culture for mycobacterial urinary tract infections has an identification rate of 37.14%, and polymerase chain reaction (PCR) tests have increased the sensitivity to 94.29% [20]. Because the detection rate is low for urine culture alone, simultaneous PCR is preferred when possible. The positive IGRA result suggested the need for an acid-fast bacilli culture, but we made a diagnosis of M. intracellulare-associated granulomatous tubulointerstitial nephritis, based on urine and renal tissue culture results. It is important to perform an acid-fast bacilli culture, regardless of IGRA results. Urine cultures have demonstrated positive results for some patients [8], but the positive results from kidney biopsy specimens provided strong evidence to support the presence of acid-fast bacilli as the cause of interstitial nephritis. As a routine practice, clinicians should consider microbiological assessment of renal biopsy specimens or urine; it was useful that frozen specimens (originally intended for immunofluorescence analysis) could be submitted to acid-fast bacilli culture analysis after the standard renal pathological diagnosis. Some reports have described PCR and successful identification of M. tuberculosis from formalin-fixed paraffin [21], but this technique lacks confidence. PCR generally increases sensitivity, but the PCR results were negative in this case. The method used in the present case report confirmed that if a large amount of frozen specimen tissue is collected for the immunofluorescent assay, it can be used for culture analysis when necessary. In summary, both culture and PCR analyses are important for the definitive diagnosis of rare causative infections.

In conclusion, we encountered a patient with NTM-associated granulomatous interstitial nephritis who did not exhibit obvious immunosuppression. We achieved control of nephritis in this patient by using a combination of steroid and antituberculosis drugs. An important point in this case was thorough consideration of the differential diagnosis of granulomatous interstitial nephritis. In our patients, the absence of mycobacterial cells in microscopic analysis of renal biopsy specimens and positive IGRA results suggested that NTM was unlikely to be involved. However, repeated urine acid-fast bacilli cultures and culture analysis of residual frozen renal tissue led to the appropriate diagnosis and treatment.

Declarations

Conflict of interest

All the authors declare no competing interests.

Research involving human participants

All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee at which the studies were conducted (Aso Iizuka Hospital IRB approval number: C20093) and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.

Informed consent

Informed consent was obtained from all individual participants included in this study.