A 63-year-old Chinese female with mixed connective tissue disease who suffered from renal crisis

Abstract

Mixed connective tissue disease (MCTD) is a rare autoimmune disorder. We present a case of a Chinese female who has been admitted to our hospital on eight separate occasions. Her initial symptoms involved internal organs including the lung and heart. Due to the presence of anti-U1RNP antibodies and other clinical features, a diagnosis of MCTD was considered. Throughout her first to seventh admissions, her serum creatinine levels remained normal. During her eighth hospitalization, her renal function deteriorated rapidly, culminating in renal crisis. Chest computed tomography (CT) confirmed pulmonary edema, necessitating hemodialysis. Her interleukin (IL)-6 level increased significantly during throughout hospitalizations. The patient responded well to treatment with an IL-6 receptor antagonist (IL-6RA). This case raises the question of whether IL-6 could serve as a potential biomarker for predicting renal crisis incidence in MCTD patients, a topic warranting further investigation in the future.

Introduction

Mixed connective tissue disease (MCTD) is an uncommon autoimmune disease that shares clinically relevance with several other connective tissue diseases. Its diagnosis primarily relies on the presence of high titers of an antibody to the U1 ribonucleoprotein (U1 RNP). ¹ However, Renal crises are exceptionally rare in patients with MCTD. ² In this case study, we presented a clinical case of MCTD with a renal crisis.

Case report

A 63-year-old female patient has been experiencing symptoms including cough, dry mouth/eyes, shortness of breath and Raynaud’s phenomenon (RP) for 2 years, which initially went unnoticed. On October 1, 2021, she noticed that these symptoms were worsening. Her left index finger’s skin turned black, and the discoloration began to extend to all her fingers and her right toes. Additionally, her body temperature reached as high as 38.0°C, and her C-reactive protein was 52 mg/L (reference range, 0–8). Consequently, the patient was hospitalized. Her laboratory findings and autoantibodies were shown in Table 1. A chest computerized tomography (CT) scan indicated both lungs had scattered with diffuse airspace opacities and honeycomb-like lesion, especially in the mid- and lower lobes (Figure 1A); doppler echocardiography showed an estimated pulmonary artery pressure of 60 mmHg.

Table 1.

Laboratory data and autoantibodies of the patient were summarized.

Investigation (unit)	Result
Respiratory viruses a	−
HIV-1/2	−
T-spot	−
Coombs’s test	−
ANA titer	1:1000 (granular pattern)
Anti-CCP	−
Anti-U1-nRNP	1:1600
Anti-smith	−
Anti-SSA (Ro)	+
Anti-SSB(La)	−
p-ANCA	±
c-ANCA	+
Anti-golgi	−
Anti-LKM	−
Anti-PCNA	−
Anti-mitochondrial Ab-M2	−
Anti-mitochondrion	−
Anti-β2 GP1(IgA/IgG/IgM)	−
anti-Scl-70	−
Anti-dsDNA	−
Anti-Pm/Scl	−
Anti-Jo-1	−
Anti-centromere	−
anti-Cardiolipin (IgA/IgG/IgM)	−
Anti-MPO	+
Anti-PR3	−
Anti-smooth muscle	−
Anti-nucleosome	−
Anti-histone	−
Anti-ribosomal P protein	−
RF	+
RNP-III	−

HIV: human immunodeficiency virus; T-spot: Interferon Gamma Release Assays; CCP: cyclic citrullinated peptides; LKM: liver and kidney microsome; MPO: myeloperoxidase; PR3: proteinase 3; dsDNA: double-stranded deoxyribonucleic acid (DNA); Scl: scleroderma; p-ANCA: perinuclear anti-neutrophil cytoplasmic antibodies; c-ANCA: cytoplasmic anti-neutrophil cytoplasmic antibodies; PCNA: proliferating cell nuclear antigen; GP: glycoprotein; RF: rheumatoid factor, RNP-III: RNA polymerase III.

^aSevere acute respiratory syndrome coronavirus-2 (Covid-19), Influenza A, B virus, Syncytial virus, Coxsackie virus were tested by Real-time polymerase chain reaction (RT-PCR) from nasopharyngeal swab.

Figure 1.

Dynamic changes of chest computed tomography (CT). (A). Chest CT conducted on Oct. 10, 2021, during the 1st admission. (B). Chest CT conducted on Jan. 22, 2023, during the 8th admission (Chest CT that indicated bilateral pulmonary infiltrates, most notable in the whole lung fields with alveolar edema). (C). Chest CT conducted on March 22, 2023, during 1^st follow-up. (D). Chest CT conducted on April 24, 2023, during 2^nd follow-up.

She was diagnosed with MCTD, pneumonia, interstitial lung disease (ILD), vasculitis and pulmonary artery hypertension (PAH). We administered methylprednisolone at a daily dose of 40 mg intravenously for 12 days and changed to prednisone 30 mg/day by mouth. She underwent a 14-day course of intravenous antibiotics for lung infection (Cefoperazone-Sulbactam) to address possible hospital-acquired pneumonia (HAP). Aspirin for prevention of platelet aggregation was also initiated because the patient’s platelet aggregation rate was tested and it was found beyond normal limit, fluctuating between 26% and 40% (reference limit: 10%–25%). On Nov. 1, 2021, she received an initial intravenous dose of 0.8 g of cyclophosphamide (CTX) to suppress autoimmune reactions and treat ILD. Pirfenidone, at a dose of 0.2 g, was administered three times daily for antifibrosis. Ambrisentan was prescribed to improve PAH, and she was also given phosphodiesterase-5 (PDE-5) inhibitors-sildenafil at 25 mg, three times/day, along with nifedipine at 30 mg/day to improve Raynaud’s phenomenon.^3,4 Hydroxychloroquine at 0.2 g twice/day for immune modulation. She was discharged after her blood pressure (BP) became within normal limits and her symptoms were less significant. Her post-discharge medications included prednisone at 30 mg/day, tapered by 5 mg every week, with a maintenance dose of 10 mg, pirfenidone at 0.6 g/day, ambrisentan at 5 mg/day, nifedipine at 30 mg/day, sildenafil at 25 mg, three times a day, and at aspirin 75 mg/day.

From December 25, 2021, to September 20, 2022, the patient was admitted to the hospital 5 times for CTX, with a total of 4.8 g administered on the following dates: Jan. 6, 2022; March 4, 2022; April 9, 2022; May 9, 2022; and July 20, 2022. After the administration of CTX, we attempted to switch to azathioprine (AZA), cyclosporine (CsA), and mycophenolate mofetil (MMF) for immunosuppressive therapy, but had to discontinue them due to nausea and vomiting.

On Dec. 22, 2022, the patient was admitted for the 8th time due to worsening of orthopnea and dyspnea. During this hospitalization, her renal function deteriorated (Day 1: serum creatinine 147.39 umol/L, reference range of 46–92; Day 6: 217.37 umol/L; Day 10: 357 umol/L; Day 14: 443.26 umol/L; Day 18: 515.31 umol/L; Day 21: 547.69 umol/L; Day 24: 601.1 umol/L). 5 days after admission, the patient’s BP abruptly increased (peaking as high as 182/104 mmHg), at which point renal crisis related to MCTD was considered. She was started on furosemide and isosorbide mononitrate intravenously for controlling BP as captopril (50 mg three times per day) proved ineffective. After her BP normalized, a renal biopsy was performed. Following consultation with a nephrologist in our hospital, she was treated with hemodialysis due to deteriorating kidney function and diffuse alveolar edema (Figure 1B). Given the elevated Interleukin-6 (IL-6) levels in her blood, she was administered an IL-6 receptor antagonist (IL-6RA) at a dose of 8 mg/kg every 4 weeks to inhibit the systemic inflammatory responses. Her serum creatinine and IL-6 levels returned to normal 1 week later and she was discharged after her clinical symptoms and signs subsided. Her condition remained stable during 1- and 2-month follow-up assessment by Chest CTs (Figure 1C and D). Dynamic changes of laboratory studies during hospitalizations for the patient and renal pathology were indicated in Figures 2A–F, 3A–C, respectively.

Figure 2.

Dynamic changes of laboratory findings during hospitalizations for the patient. IL: interleukin; TNF: tumor necrosis factor; IFN: interferon; Scr: serum creatinine; BUN: blood urea nitrogen; e-GFR: estimated glomerular filtration rate; RBC: red blood cell; WBC: white blood cell; Hb: hemoglobin; PLT: platelet; CRP: C reactive protein; ESR: erythrocyte sedimentation rate; Ig: immunoglobulin; C: compliment; BNP: B-type natriuretic peptide; PAP: pulmonary artery pressure.

Figure 3.

Kidney biopsy. Renal biopsy findings: (A) (Periodic-acid Schiff staining, ×400). (B) (Periodic acid-silver methenamine staining, ×400). 12 glomeruli were found. Most glomerular mesangial cells and stroma are slightly increased, with a few glomeruli showing segmental capillary hyperplasia, and some glomeruli showing segmental double-track sign. The capillary loops of each glomerulus are rigid. Mild tubulointerstitial lesions, focal atrophy and degeneration of tubules, visible protein tubular type, interstitial inflammatory fibrosis, small blood vessels (−). Immunofluorescent stain indicated IgG+, IgA−, IgM±, C3++, C1q+, κ±, λ+. Electronic microscope findings: The endothelial cells of capillaries are slightly swollen; the capillary loops are open and a few loops contain monocytes and neutrophils. There was no significant proliferation of epithelial cells in the wall layer of the renal capsule. Basement membrane: Most of them have no obvious thickening, and a few segments have slight irregular thickening, with a thickness of about 550 nm at the thickening point, resulting in segmental wrinkling. Podocytes: Swelling, vacuolar degeneration and zebra corpuscles can be seen in individual podocytes. Lymphocytes, monocytes, plasma cells can be observed in the focal renal interstitium.

Discussion

MCTD is a mild overlapping complex of at least two of the following three connective tissue diseases including systemic sclerosis, systemic lupus erythematosus (SLE), and polymyositis. It generally results in a good clinical outcome, requiring low-dose of corticosteroid. ⁵ Its initial clinical features are nonspecific, classifying it as an undeferential connective tissue disease (UCTD). ⁶ The presence of the anti-U1-ribonucleoprotein (anti-U1-RNP) antibodies is considered a hallmark of the disease and most MCTD patients exhibiting high titer of anti-U1-RNP and RP appear not correlate with nephropathy.^7,8 An animal experiment demonstrates that the immunization of mice with RNP antigen induced anti-RNP antibodies and MCTD clinical features, particularly ILD but not kidney disease. ⁹

To the best of our knowledge, the majority of reported MCTD cases with renal crisis have been among individuals of Caucasians and Hispanics descent.^10,11 In this case report, we presented the first instance of a Chinese female patient with MCTD experiencing renal crisis, which was reversed by using IL-6RA. Notably, a prior study showed that increased and fluctuating levels of IL-10 or TNF-a do not correlate with disease activity in patients with MCTD. ¹² However, We observed the serum level of IL-6 for the patient was escalating throughout the treatment course, where even CTX and prednisone were administered. This intriguing finding raises the question of whether IL-6 could potentially serve as a biomarker for predicting the occurrence of renal crisis and assessing their prognosis in MCTD patients. Further investigations will be necessary to explore this possibility and elucidate its clinical implications.

The kidney biopsy findings in the case indicated twelve glomeruli were found with most glomerular mesangial cells and stroma slightly increased, some glomeruli showing segmental double-track sign. Electronic microscope indicated the swollen endothelial cells of capillaries and electron-dense deposits in the subepithelial and endothelial space, immunofluorescent stain also revealed some immune deposits, findings may suggest the presence of immune complex glomerulonephritis other than renal crisis. Farhey et al., considered that renal involvement in patients with MCTD can be in the form of proliferative glomerulonephritis, membranous glomerulonephritis, amyloidosis or interstitial nephritis. ¹³ Abdul Mabood Khalil et al. reported a case with MCTD who suffered from renal crisis, the renal biopsy showed onion skin-like vasculopathic changes with ischemic wrinkling of glomeruli, ¹⁰ which result from fibro-intimal sclerosis with adventitial fibrosis, develop later in the course of renal crisis. When the disease reaches chronic stages, glomerular changes can vary from double contour and tram tracking to ischemic glomerular collapse, ¹⁴ which is similar to kidney biopsy findings in lupus nephritis. However, Cheta et al. reported a MCTD female case with renal crisis. Her renal biopsy indicated nine available glomeruli with rare intraglomerular thrombi, moderately thickened vessels without onion skinning proliferation. ¹⁵

Conclusion

We reported the case of a Chinese female patient with MCTD who developed a renal crisis and responded well to IL-6RA treatment. This case should remind clinicians to consider the possibility of using IL-6 could as a potential biomarker for predicting renal crisis incidence in MCTD patients. Early interventions with IL-6RA should be considered upon detecting elevated IL-6 levels to prevent the occurrence of renal crises. It is advisable to recommend renal biopsy for patients with MCTD if their kidney function deteriorates, as this may be manifested by various forms of pathological profiles.