Rapidly Kidney Failure Caused By IgG4-related Disease

Contact: Audrey Hu audrey.hu@wecistanche.com

Rapidly Progressive Kidney Failure Associated with Perirenal Capsular Lesion Due to IgG4-Related Disease

Nobuhide Endo, Hitomi Shimizu, Tomoki Tanaka, Yukiko Nakase, Tomohiro Kawazoe and Tomoharu Watanabe

Introduction

Kidney involvement in IgG4-related disease (IgG4-RD) can manifest as tubulointerstitial nephritis (TIN), glomerular lesions represented by membranous nephropathy, mass lesions, and retroperitoneal fibrosis (1). Several characteristic imaging abnormalities have been reported (2). Multiple low-density areas on contrast-enhanced computed tomography (CT) are often observed. Mass lesions are relatively rare and should be distinguished from malignant tumors. Hydronephrosis associated with retroperitoneal fibrosis is another common abnormality. Perirenal lesions are a rare presentation of IgG4-RD(IgG4-related disease) and few studies have reported on their clinical significance in detail (3, 4). We report a case of rapidly progressive kidney failure with unique imaging abnormalities, including soft tissue around the kidney and retroperitoneal fibrosis.

EFFECTS OF CISTANCHE: TREATING KIDNEY DISEASES AND IMPROVING KIDNEY FUNCTION

Case Report

A 71-year-old Japanese man with dyspnea and pleural effusion was referred to our hospital. Initially, he was diagnosed with heart failure due to severe mitral regurgitation. Although his symptoms improved with diuretics, he developed progressive kidney failure and was referred to our nephrology department. At presentation, a physical examination revealed the following: blood pressure, 150/61 mmHg; heart rate, 85 beats/ min; body temperature, 37-38°C. He had no rash, lymphadenopathy, or edema of the limbs. On day 23 of hospitalization, the patient’s laboratory test results revealed an impaired renal function with serum creatinine (Cr) level of 5.27 mg/dL, which was 1.34 mg/dL on admission. His white blood cell count was 7,300/mm3 and his hemoglobin level was 10.0 g/dL. His C-reactive protein (CRP) level was mildly increased (3.44 mg/dL). Urine tests showed no proteinuria or microscopic hematuria. Immunological tests revealed serum IgG4 elevation, without IgG elevation (263 mg/dL and 1,339 mg/dL, respectively). His serum complement levels (C3, C4, and CH50) were within the normal range. Tests for autoantibodies, including antinuclear, anti-neutrophil cytoplasmic, anti-SS-A, and anti-SS-B antibodies, were negative. His soluble interleukin-2 receptor (SIL-2R) level was elevated (5,316 U/mL). The patient’s laboratory results are summarized in Table. Contrast-enhanced CT showed diffuse soft tissue infiltration in the left perirenal space, as well as mild infiltration in the right perirenal space and right-sided hydronephrosis due to periaortic fibrosis. Although the right kidney was atrophic and showed hydronephrosis, the left kidney was less enhanced than the right. Chest CT revealed slight ground-glass opacities in the bilateral lungs. There was no significant enlargement of the lymph nodes. In addition, no obvious renal abnormalities were observed on a contrast-enhanced CT scan performed 8 years before his hospitalization.

On day 26 of admission, his kidney failure worsened with elevated levels of Cr and CRP(Cr 8.59 mg/dL, CRP 8.94 mg/dL) and symptoms of uremia, such as nausea and fatigue. Hemodialysis was initiated with vascular access catheters. Based on these findings, we considered that his progressive kidney failure was induced by IgG4-RD(IgG4-related disease). However, the exact etiology was unknown. We, therefore, performed a laparoscopic biopsy of the left kidney and retroperitoneum.

The kidney biopsy showed no tubulointerstitial nephritis but diffuse mild wrinkling of the basement membranes of the glomerular capillaries. No other glomerular lesions, such as membranous nephropathy or glomerulonephritis, were observed. Immunofluorescence microscopy showed no significant deposition of IgG, IgA, IgM, C3, C4, or Clq. Electron microscopy demonstrated no significant ab-normalities. The kidney capsule tissues were thickened with inflammatory infiltration of lymphocytes and plasma cells, in addition to fibrosis. Immunohistochemical staining indicated an average IgG4-positive plasma cell count of approximately 20/high power field and an IgG4/IgG-positive cell ratio of 70% in the kidney capsules. Retroperitoneal biopsy revealed dense connective tissues infiltrated with lymphocytes, macrophages, and plasma cells, which was consistent with peritoneal fibrosis. There were no signs of malignancy. Collectively, the kidney capsular lesions associated with IgG4-RD(IgG4-related disease) were considered to be the main cause of kidney failure.

Prednisolone(30 mg; 0.5 mg/kg)was administered on hospital day 32, followed by tapering at 2-to 3-week intervals. Signs of systematic inflammation, such as fever and his CRP level rapidly improved. His kidney functions gradually improved, and hemodialysis was terminated on hospital day 45. His kidney function was well maintained after 6 months(Cr 1.5-2.0 mg/dL).Follow-up CT showed improvement in the perirenal capsular lesions and retroperitoneal fibrosis.

EFFECTS OF CISTANCHE: TREATING KIDNEY DISEASES AND IMPROVING KIDNEY FUNCTION

Discussion

IgG4-RD(IgG4-related disease) is a fibroinflammatory disease that affects various organs, resulting in organ dysfunction(5). The most dominant kidney disease caused by IgG4-RD(IgG4-related disease) is tubulointerstitial nephritis, which leads to kidney failure without apparent proteinuria or hematuria(1). Glomerular lesions, such as membranous nephropathy with proteinuria have also been reported. Renal pelvic and periureteral lesions or retroperitoneal fibrosis often result in postrenal renal failure. Some patients with IgG4-RD(IgG4-related disease) have very mild or no symptoms, as their lesions progress slowly.

The comprehensive diagnostic criteria for IgG4-RD(IgG4-related disease) are:(i) serum IgG4>135 mg/dL;(ii)>40% of IgG-positive plasma cells being IgG4 positive and >10 cells/HPF on biopsy(6). However, the sensitivity and specificity of the serum IgG4 level are inadequate. The histopathological findings should be interpreted in the context of the clinical and radiological findings, because IgG4-positive cells are also seen in many other conditions, including malignancies, Castleman disease, granulomatosis with polyangiitis, and Sjogren's syndrome(7). Recently, the American College of Rheumatology/European League Against Rheumatism classification criteria including characteristic clinical, serologic, radiologic, and pathologic features were reported to have excellent reliability(8). This present case met these criteria adequately.

Progressive kidney disease during the first month after hospitalization, in this case, was atypical of IgG4-RD(IgG4-related disease). Before the kidney biopsy, we suspected that the main cause of kidney failure was interstitial nephritis because, with the exception of the detection of urinary β2-microglobulin, the results of urinalysis were almost normal. However, the pathological significance of the perirenal capsular lesion was unclear. The histopathological examination showed no signs of interstitial nephritis or glomerular lesions, with the exception of diffuse mild wrinkling of the basement membranes of the glomerular capillaries, suggesting renal ischemia, although IgG4-related lesions might have been missed during the biopsy. The kidney capsule was involved in inflammation and fibro-sis with rich IgG4-positive cells, which was consistent with IgG4-RD(IgG4-related disease).

On contrast-enhanced CT, the contrast effect of the left kidney was weaker than that of the right kidney, despite atrophy of the right kidney. This finding was also suggestive of decreased perfusion of the left b. The soft tissue of kidney capsules surrounded the left kidney entirely, including the renal hilum.

EFFECTS OF CISTANCHE: TREATING KIDNEY DISEASES AND IMPROVING KIDNEY FUNCTION

Based on these findings, we considered that the inflammatory lesion around the left kidney reduced the perfusion of the kidney leading to renal failure. Page kidney is a pathological condition in which external compression of the kidney due to hematoma or mass lesions causes renal ischemia, leading to hypertension and kidney failure(9). Considering that retroperitoneal fibrosis causes compression of the ureter and impairs the ureteral passage, it was reasonable to consider that perirenal inflammation and fibrosis due to IgG 4-related disease-induced low renal perfusion and kidney failure by the same mechanism as in Page kidney. Perirenal soft tissue infiltration associated with IgG4-RD(IgG4-related disease) is rare(2). Cho et al. and Chen et al. reported perirenal capsule infiltra-tion due to IgG4-RD(3,4). Kidney failure was mild and not rapidly progressive in these cases, and the detailed mechanism underlying the development of kidney failure was not explained. No cases of rapidly progressive kidney failure requiring temporary dialysis, as occurred in the present case, have been reported. Usually, in patients with IgG 4-RD, the CRP levels are low and symptoms progress slowly. It has been reported that CRP elevation is associated with peri aortitis or periarteritis in patients with IgG4-RD(IgG4-related disease), and the present patient also had periaortic lesions(10). The elevated CRP or low-grade fever in the present case might reflect relatively active vascular inflammation. Although most cases of Page kidney show hypertension or mild renal damage, a few cases of severe kidney failure have been reported in patients with a solitary kidney, such as patients who have undergone kidney transplantation(11).In this case, the right kidney was impaired by atrophy and hydronephrosis. However, due to a lack of information on the patient's state before his current presentation, it remains unclear whether or not this atrophy of the right kidney had been caused by conditions other than hydronephrosis. Based on these findings, in addition to right kidney impairment, continued compression of the left kidney by perirenal lesions was considered to have induced low renal perfusion and progressive kidney failure. To the best of our knowledge, this is the first report to describe rapidly progressive kidney failure caused by perirenal lesions associated with IgG4-RD(IgG4-related disease) in detail.

IgG4-RD(IgG4-related disease) can affect various multiple organs and can cause inflammation and fibrosis, resulting in various clinical symptoms. Malignant lymphoma can be considered as a differential diagnosis in patients presenting with perirenal or retroperitoneal soft-tissue masses. In this case, we performed a renal biopsy to exclude malignant lymphoma, considering the high serum L-2R levels. However, renal biopsy is an invasive procedure and is often impossible if the patient's general condition is poor. Atypical imaging findings and clinical symptoms can lead to a better understanding of IgG4-RD(IgG4-related disease), allowing for a more efficient approach to its diagnosis and treatment. This atypical case highlights the clinical diversity of IgG4-RD(IgG4-related disease).

EFFECTS OF CISTANCHE: TREATING KIDNEY DISEASES AND IMPROVING KIDNEY FUNCTION

References

1. Saeki T, Kawano M.IgG4-related kidney disease.Kidney Int 85: 251-257,2014.

2. Seo N,Kim JH, Byun JH,Lee SS,Kim HJ,Lee MG. Immuno- globulin G4-related kidney disease: a comprehensive pictorial review of the imaging spectrum, mimickers, and clinicopathological characteristics. Korean J Radiol 16: 1056-1067,2015.

3. Cho YJ, Jung WY, Lee SY, Song JS, Park HJ.Perirenal capsule and scrotal involvement in immunoglobulin G4-related kidney disease: a case-based review. Rheumatol Int 38:1941-1948,2018.

4. Chen PT, Chang KP, Liu KL. Perirenal soft tissue infiltration from IgG4-related disease. CMAJ 190: E801, 2018.

Note: the above is not a full reference list