Urinary β2-microglobulin as a Potential Biomarker for Early Treatment Selection: A Patient with Severe IgG4-related Tubulointerstitial Nephritis

Abstract

This case report describes an 80-year-old man with severe immunoglobulin G4-related tubulointerstitial nephritis (IgG4-TIN), characterized by storiform fibrosis with diffuse lymphocytic and plasma cell infiltration observed on a renal biopsy. Steroid pulse therapy administered immediately after confirming a remarkable increase in urinary β2-microglobulin (100,948 μg/L) along with no evidence of malignancy significantly improved the renal function and reduced the urinary β2-microglobulin levels. This study highlights the potential utility of urinary β2-microglobulin as a biomarker for early treatment selection in severe IgG4-TIN and emphasizes the need for timely intervention to prevent irreversible kidney damage.

Introduction

Immunoglobulin G4-related disease (IgG4-RD) is a systemic immune-mediated disease characterized by the infiltration of abundant IgG4-positive plasma cells with fibrosis and usually elevated serum IgG4 concentrations (1). The kidney is one of the major targets of IgG4-RD, and 7.0-24.6% of patients with IgG4-RD have renal manifestations, collectively referred to as IgG4-related kidney disease (IgG4-RKD) (2). IgG4-RKD includes IgG4-related tubulointerstitial nephritis (IgG4-TIN), obstructive uropathy secondary to retroperitoneal fibrosis, glomerular disease (most commonly IgG4-related membranous glomerulonephritis), IgG4 plasma cell arteritis, and IgG4-related pyelitis (3,4). Among these, IgG4-TIN is the most common and is typically characterized by IgG4-positive plasma cells and fibrosis (3). Treatment of IgG4-RD, including IgG4-TIN, generally involves oral prednisolone (PSL), which responds well (2). However, if treatment is not provided early or if disease severity progresses, the risk of developing end-stage renal disease may increase (5).

We herein report a patient with severe IgG4-TIN and markedly elevated urinary β2-microglobulin levels who recovered from renal dysfunction following early steroid pulse therapy.

Case Report

An 80-year-old man was admitted to our hospital with swelling of the submandibular gland, lower leg purpura, edema, and joint pain (shoulders, elbows, and wrists). The patient had been on medication for hypertension for approximately 40 years. Three months before admission, the patient developed swelling of the right submandibular gland. One month later, the patient was referred to our hospital by an attending doctor. A biopsy of the right submandibular gland performed at the otolaryngology department 5 days before admission revealed findings consistent with IgG4-RD [IgG4/IgG ＞50% and IgG4-positive plasma cells ＞10/high-power field (HPF)], with no evidence of malignancy.

Upon admission, his body temperature was 36.6°C, blood pressure was 130/77 mmHg, and heart rate was 97/min. Computed tomography revealed bilateral submandibular gland swelling, multiple lymphadenopathies, right renal pelvic mass, right hydronephrosis, and retroperitoneal fibrosis. Positron emission tomography-computed tomography showed a tracer uptake in both submandibular glands (right more than the left), bilateral kidneys, a renal pelvic mass, and the major joints of the extremities (Fig. 1). The detailed laboratory data on admission are presented in Table. Renal dysfunction was observed with a marked increase in tubular damage markers, urinary β2-microglobulin (100,948 μg/L: reference range, ＜200 μg/L and 57,357 μg/gCr) and urinary N-acetyl-β-D-glucosaminidase (NAG: 13.9 IU/gCr; reference range: 0.9-2.4 IU/gCr), serum IgG (2,525 mg/dL: reference range, 861-1,747 mg/dL), serum IgG4 (606 mg/dL: reference range, 11-121 mg/dL), and serum IgE (523 U/mL: reference range, ＜216 U/mL). Hypocomplementemia was observed in C4 (2 mg/dL; reference range, 11-31 mg/dL).

Figure 1.

¹⁸F-fluorodeoxyglucose positron emission tomography-computed tomography showing a tracer uptake in both the submandibular glands (right greater than the left) (A), bilateral kidneys, and a renal pelvis mass (B).

Table.

Laboratory Data on Admission.

■Blood test
			Reference range
White blood cell	2,900	/µL	3,300-8,600	/μL
Neutrophil	1,400	/µL	1,300-6,100	/μL
Eosinophil	400	/µL	0-600	/μL
Basophil	0	/µL	0-100	/μL
Monocytes	400	/µL	100-700	/μL
Lymphocytes	700	/µL	900-4,000	/μL
Red blood cell	3.83×106	/µL	4.35-5.55×106	/μL
Hemoglobin	11.0	g/dL	13.7-16.8	g/dL
Hematocrit	34.4	%	40.7-50.1	%
Platelet	11.6×104	/µL	15.8-34.8×104	/μL
PT-INR	1.12		1.00±0.15
APTT	37	s	20-40	s
Fib	344	mg/dL	200-400	mg/dL
D-dimer	4.3	μg/mL	<1	μg/mL
C-reactive protein	0.49	mg/dL	0-0.14	mg/dL
Total protein	7.0	g/dL	6.6-8.1	g/dL
Serum albumin	2.4	g/dL	4.1-5.1	g/dL
Blood urea nitrogen	24	mg/dL	3.7-7.8	mg/dL
Serum creatinine	1.76	mg/dL	0.65-1.07	mg/dL
Aspartate aminotransferase	30	U/L	42-76	U/L
Alanine aminotransferase	13	U/L	13-30	U/L
Lactate dehydrogenase	192	U/L	124-222	U/L
γ-Glutamyl transpeptidase	26	U/L	13-64	U/L
Creatine kinase	22	U/L	59-248	U/L
Serum sodium	138	mmol/L	138-145	mmol/L
Serum potassium	3.9	mmol/L	3.6-4.8	mmoL/L
Serum chloride	103	mmol/L	101-108	mmol/L
Serum calcium	8.1	mg/dL	8.8-10.1	mg/dL
Serum phosphorus	3.5	mg/dL	2.7-4.6	mg/dL
Serum magnesium	1.9	mg/dL	1.7-2.5	mg/dL
Blood sugar	87	mg/dL	73-109	mg/dL
Estimated glomerular filtration rate	30	mL/min/1.73m2	≥90	mL/min/1.73m2
ANA (homogenous)	×1,280		×40
Anti-ds DNA antibody	27.3	IU/mL	<12.0	IU/mL
Anti-Sm antibody	Negative
Anti-U1-RNP antibody	Negative
Anti CCP antibody	1.2	U/mL	<4.5	U/mL
Rheumatoid factor	16.7	IU/mL	<15	IU/mL
MPO-ANCA	<1.0	U/mL	<1.0	U/mL
PR3-ANCA	1.3	U/mL	<1.0	U/mL
Anti-GBM antibody	<2.0	U/mL	<2.0	U/mL
Anti-SS-A/Ro Ab	Negative
Anti-SS-B/La Ab	Negative
IgG	2,525	mg/dL	861-1,747	mg/dL
IgG4	606	mg/dL	4.8-105	mg/dL
IgA	387	mg/dL	93-393	mg/dL
IgM	34	mg/dL	33-183	mg/dL
IgE	523	U/mL	<216	IU/mL
C3	38	mg/dL	73-138	mg/dL
C4	2	mg/dL	11-31	mg/dL
■Urinalysis
Urine specific gravity	1.01		1.005-1.030
pH	6		5.0-8.0
Red blood cell	<1	/HPF
White blood cell	1-4	/HPF
Tubular epithelial cell	<1	/HPF
Hyaline cast	30-40	/WF
Granule cast	10-19	/WF
Urinary protein	1.41	g/gCr	<0.15	g/gCr
N-acetyl-β-D-glucosaminidase	13.9	IU/gCr	0.9-2.4	IU/gCr
β2-microglobulin	100,948	μg/L	<200	μg/L

A renal biopsy on day 3 revealed no glomerular lesions except for global sclerosis (4/15 glomeruli); however, storiform fibrosis and tubular atrophy with severe lymphocytic and plasma cell infiltration of the tubular interstitium were observed (Fig. 2) (6). Thickening of the tubular basement membrane was observed sporadically. IgG4 positive plasma cell count was 170/HPF (diagnostic criteria for IgG4-related kidney disease ＞10/HPF) (7), and the IgG4/IgG-positive plasma cell ratio was 90% (diagnostic criteria for IgG4-RKD ＞40%) (7)(Fig. 2). Hyaline arteriosclerosis was also observed in the arteriolar walls. Immunofluorescence microscopy showed weak staining for IgM and C1q in the glomerular mesangial area and peripheral capillary wall, whereas staining for IgG, IgA, and C3 was negative. These results suggest that there was no “full-house” pattern of immune deposits, which is typically observed in lupus nephritis (8).

Figure 2.

Light microscopic and immunohistochemical findings of a renal biopsy. (A) Dense interstitial cell infiltration was mainly composed of lymphocytes and plasma cells (Hematoxylin and Eosin staining, original magnification ×400). (B) Storiform fibrosis and tubular atrophy were recognized (periodic acid methenamine staining, original magnification ×400). (C) Immunohistochemical staining for immunoglobulin G (IgG) showed a marked increase in IgG-positive plasma cells (original magnification ×400). (D) Immunohistochemical staining for IgG4 showed numerous IgG4-positive plasma cells in the interstitium (original magnification ×400). The IgG4/IgG-positive plasma cell ratio was 90%, and the number of IgG4-positive plasma cells was 170/high-power field.

The patient was diagnosed with IgG4-RKD according to the 2020 diagnostic criteria for IgG4-RKD (elevated serum IgG levels, hypocomplementemia, elevated serum IgE level, abnormal renal radiologic findings, elevated serum IgG4 levels, histological findings in the kidney, and bilateral submandibular gland swelling) (7). In addition, he met the 2019 European League Against Rheumatism/American College of Rheumatology classification criteria for systemic lupus erythematosus (SLE), with a total score of 23 points (threshold: ＜10). The score included positive antinuclear antibodies, joint involvement (6 points), leukopenia (3 points), proteinuria (4 points), elevated anti-double-stranded DNA antibodies (6 points), and hypocomplementemia (4 points) (Table) (9). The diagnoses of rheumatoid arthritis, ANCA-associated vasculitis, anti-glomerular basement membrane disease, mixed connective tissue disease, and Sjögren's syndrome were excluded because of the absence of their respective disease-specific antibodies (Table).

Steroid pulse therapy (methylprednisolone 1,000 mg/day) was administered for 3 days from day 5, and oral PSL at 40 mg/day (0.6 mg/kg) was initiated post-treatment (Fig. 3). On day 12, serum creatinine and urinary β2-microglobulin markedly decreased from 1.76 to 1.27 mg/dL and 76,810 to 14,106 μg/mgCr, respectively (Fig. 3). Thereafter, the PSL dose was tapered to 35 mg on day 37 and 30 mg on day 50. The patient was discharged from the hospital on day 61 without any adverse events due to PSL.

Figure 3.

Clinical course before and after admission. After the administration of methylprednisolone (mPSL), the tubular damage marker urinary β2-microglobulin promptly decreased by more than half. PSL: prednisolone

Discussion

We encountered a patient with severe IgG4-TIN successfully treated with steroid pulse therapy, accompanied by a remarkable decrease in the tubular injury markers urinary β2-microglobulin and serum creatinine. This study suggests that urinary β2-microglobulin may be a potential biomarker for early treatment selection, particularly in severe TIN.

Glucocorticoids are recognized as the first-line treatment for IgG4-RD, including IgG4-TIN, and are usually effective at a dose of 0.5-1.0 mg/kg/day for PSL, depending on the severity or organ-threatening character of the disease (10-12). One case report described a patient with IgG4-RKD and severe renal insufficiency (serum creatinine concentration rose to 7-8 mg/dL before PSL initiation) who was successfully treated with a moderate dose of PSL (30 mg/day, 0.375 mg/kg/day) (13). In addition, a Japanese clinical study indicated that a moderate dose of PSL (≤0.6 mg/kg/day; mean: 0.47 mg/kg/day) was sufficient for induction therapy and that renal function could be maintained over the long term with low-dose maintenance therapy (14). Even patients with markedly elevated serum creatinine levels or extensive interstitial fibrosis observed on a biopsy respond to treatment (10). This may reflect the potential responsiveness of these fibrotic lesions to steroid therapy or the patchy nature of inflammatory lesions (10).

However, early intervention is important to prevent irreversible progression to fibrosis and organ dysfunction. Pre-treatment renal insufficiency can be a predictor of renal atrophy after glucocorticoid therapy, and starting glucocorticoid therapy before a decline in estimated glomerular filtration rate (eGFR) to approximately 70 mL/min/1.73 m² may be desirable in IgG4-RKD (15). Long-term follow-up for IgG4-RKD in Japanese patients showed that glucocorticoids maintained the baseline renal function in patients with normal renal function (baseline eGFR, 84.2±17.0 mL/min/1.73 m², and 12 months eGFR after treatment, 82.9±19.1 mL/min/1.73 m²), whereas it partially restored the renal function in patients with baseline renal insufficiency (baseline eGFR, 34.1±15.8 mL/min/1.73 m², and 12 months eGFR after treatment, 46.8±12.2 mL/min) (16). Furthermore, although renal atrophy was not evident in any of the patients before treatment, atrophy developed in 22.2% of the patients with a normal baseline renal function and in 60.0% of the patients with baseline renal insufficiency in the last review (16). These results suggest that while the response of IgG4-TIN to corticosteroids is rapid, recovery may not be complete and irreversible lesions may persist, particularly in patients with advanced renal damage. Early initiation of treatment for IgG4-TIN following careful exclusion of malignancies and other mimicking conditions is essential to prevent further deterioration of the renal function.

Oral glucocorticoid therapy may be ineffective in patients with severe renal dysfunction due to IgG4-TIN. Wakabayashi et al. reported that a patient with IgG4-TIN with a subacute onset (diffuse enlargement of the kidney on computed tomography, serum creatinine of 3.3 mg/dL, and blood urea nitrogen of 46.9 mg/dL) advanced to end-stage renal disease and finally required maintenance hemodialysis despite oral steroid therapy (PSL, 0.6 mg/kg/day) (5). The authors suggested changing the treatment to intravenous steroid pulse therapy or increasing the oral PSL dose (5). In contrast, intravenous steroid pulse therapy was effective in patients with severe IgG4-TIN. Aoki et al. reported a patient with IgG4-related Mikulicz's disease (18) who was complicated by severe TIN (urinary β2-microglobulin levels of 94,047 μg/day, serum creatinine of 2.5 mg/dL) associated with IgG4 and was successfully treated with methylprednisolone pulse therapy (18). In this case, intravenous pulse therapy (methylprednisolone, 500 mg/day for three days, two courses) and subsequent high-dose oral PSL (50 mg/day) were initiated for diffuse severe TIN (18). After 2 courses of steroid pulse therapy, serum creatinine levels decreased from 2.5 to 0.6 mg/dL (18). Accordingly, intravenous steroid pulse therapy and increasing doses of oral steroids should be considered in cases of rapidly progressing renal failure and pathologically severe IgG4-TIN. In our patient, early initiation of steroid pulse therapy following careful exclusion of malignancy by a submandibular gland biopsy and radiologic evaluation led to a rapid reduction in urinary β2-microglobulin levels of 94.4% within 3 weeks of therapy (Fig. 3). However, levels subsequently increased, along with serum creatinine levels (Fig. 3), suggesting both the effectiveness of the initial steroid pulse therapy and the potential need for additional treatment courses. Nevertheless, there is currently no clear evidence to recommend high-dose glucocorticoid or glucocorticoid pulse therapy, except for a few case reports, and further prospective and interventional studies are required.

Urinary β2-microglobulin has been used as a biomarker to guide the treatment of patients with interstitial nephritis. In a patient with IgG4-related Mikulicz's disease and severe TIN (urinary β2-microglobulin, 94,047 μg/day; serum creatinine, 2.5 mg/dL), intravenous pulse therapy (methylprednisolone, 500 mg/day: 3 days and 2 courses), and subsequent high-dose oral PSL (50 mg/day) restored the renal function to normal (serum creatinine, 0.6 mg/dL) (18). Similarly, in our patient with lupus nephritis with renal interstitial inflammatory cell infiltration (urinary β2-microglobulin, 10,746 μg/L), immunosuppressive treatment, including intravenous pulse therapy (methylprednisolone, 1,000 mg/day for 3 days), PSL (40 mg/day), and cyclophosphamide, decreased urinary β2-microglobulin levels along with an improvement in proteinuria (19). In our patient with acute kidney injury with acute interstitial nephritis (urinary β2-microglobulin, 56,074 μg/L; serum creatinine, 3.9 mg/dL) after the first dose of the BNT162b2 mRNA vaccine against COVID-19, intravenous pulse therapy (methylprednisolone, 500 mg/day for 3 days) followed by PSL (50 mg/day) and several hemodialysis sessions improved the renal function (20). In contrast, in a patient with IgG4-RD and a mild increase in urinary β2-microglobulin (1,600 μg/L), membranous nephropathy and focal infiltration of inflammatory cells in the renal interstitial, low-dose steroid therapy (PSL, 10 mg at 0.2 mg/kg/day) successfully decreased and controlled urine protein and serum IgG4 without relapse or complications (21). These data suggest that urinary β2-microglobulin levels may reflect the severity of reversible tubular damage, such as interstitial inflammatory cell infiltration (22,23). In this patient, urinary β2-microglobulin was highly elevated (100,948 μg/L), reflecting severe interstitial nephritis confirmed by a renal biopsy. Following steroid pulse therapy, the level decreased dramatically, suggesting recovery from the tubular injury. Therefore, in patients with high levels of urinary β2-microglobulin (＞10,000 μg/L), adequate immunosuppressive treatment, including steroid pulse therapy, may be necessary.

Although urinary β2-microglobulin is highly sensitive, its specificity for detecting proximal tubular injury is low (24), and initiating treatments, such as corticosteroids based solely on elevated levels, is not appropriate. A combined assessment using multiple tubular injury biomarkers, such as NAG, kidney injury molecule-1, neutrophil gelatinase-associated lipocalin, and interleukin-18, is recommended (25), as some have been associated with an increased risk of chronic kidney disease progression (26-28). In our patient, both urinary NAG and β2-microglobulin levels were elevated upon admission, further indicating tubular injury.

The patient exhibited overt proteinuria (1.41 g/gCr) and a history of hypertension for approximately 40 years. A renal biopsy revealed global glomerulosclerosis and hyaline arteriosclerosis in arterioles. These clinical and pathological features suggest that pre-existing hypertensive nephrosclerosis may have been the main contributor to the observed proteinuria (29).

The patient was diagnosed with SLE complicated with IgG4-RD. Patients with predominant tubulointerstitial involvement in lupus nephritis typically respond well to corticosteroid therapy and do not generally require concomitant immunosuppressive agents (30,31). In the present case, there were no apparent glomerular lesions except for global sclerosis, and the patient responded well to steroid pulse therapy; therefore, immunosuppressants were not used. Although the patient met some classification criteria for SLE, including hypocomplementemia, this finding may also be attributed to IgG4-TIN. Proteinuria can also be explained by hypertensive nephrosclerosis. Consequently, because no additional immunosuppressive agents or hydroxychloroquine were used based on this diagnosis, the clinical significance of the presumed SLE diagnosis in this case appears to be limited.

In summary, we report a patient with severe IgG4-TIN who was treated with immediate steroid pulse therapy based on a remarkable increase in urinary β2-microglobulin (100,948 μg/L), resulting in successful recovery from renal insufficiency. This study highlights the utility of urinary β2-microglobulin as a potential biomarker for early treatment. Particularly, in patients with IgG4-TIN and markedly elevated urinary β2-microglobulin levels, prompt and adequate immunosuppressive treatment, including steroid pulse therapy, may be crucial to prevent irreversible renal dysfunction associated with delayed or insufficient intervention.

The authors state that they have no Conflict of Interest (COI).