Renal failure and pleural effusion; a diagnostic challenge

Implication for health policy/practice/research/medical education: This clinical report describes a rare complication of Sjögren’s syndrome presenting with multisystem involvement and rare manifestations. This case highlights the importance of making a prompt diagnosis of inflammatory conditions in order to avoid the development of AA amyloidosis, a serious illness that lacks effective therapeutic options.

The underlying mechanism of Sjögren's syndrome is not completely understood.Abnormal B and T-cell responses to auto-antigens (Sjögren's syndrome-related antigen A and Sjögren's syndrome-related antigen B, also known as anti-Ro/SSA and anti-La/SSB antibodies, respectively) expressed by the epithelium of the affected organs leads to increased levels of cytokines and chemokines, lymphocytic infiltration and chronic inflammation of exocrine glands and also tissues (1).
Diagnostic criteria have been recently updated; individuals with at least one suggestive sicca symptom, who have a total score of at least 4 (based on weighted sum of five items), meet the criteria for Sjögren's syndrome (Table 1) (6).
Clinical presentation is extremely variable.Glandular Sjögren's syndrome is characterized by lymphocytic infiltration and destruction of the exocrine glands, mainly lacrimal and salivary glands, which results in keratoconjunctivitis sicca and/or xerostomia in more than 90% of affected patients (1,3).Extraglandular disease, once thought to be rare, occurs in up to 25% of patients and may affect multiple organ systems.

Case Presentation
The authors present the case of a 73-year-old female with a previous medical history of hypertension, iron-deficiency anemia and chronic musculoskeletal pain interpreted as fibromyalgia and treated with multiple analgesics.
During a previous hospitalization, she was diagnosed with chronic kidney disease and pleural effusion which prompted a thorough investigation.Diagnostic workup excluded infectious and neoplastic causes and, based on complaints of xerostomia and Raynaud's phenomenon, as well as positive antinuclear (ANA), anti-Ro and anti-La antibodies, a presumptive diagnosis of an autoimmune disease was made.She was discharged with serum creatinine 1.4 mg/dL, on hydroxychloroquine and referred to nephrology clinic for further investigation.
One month later, the patient was admitted to the nephrology department due to worsening renal function and relapsing pleural effusion.On admission, she presented with normocytic normochromic anemia (hemoglobin 10.7 g/dL), acute kidney injury KDIGO (kidney disease improving global outcomes) stage 1 (urea 61 mg/dL and serum creatinine 2.15 mg/dL); with urinalysis showing no evidence of proteinuria or other anomalies.Renal   ultrasound revealed normal sized kidneys with mildly increased echogenicity bilaterally and excluded obstructive disease.Kidney biopsy was conducted which showed A-amyloid deposits in the vasculature and interstitium, sparing glomeruli (Figures 1 and 2).Meanwhile, a thoracentesis was performed, revealing an exudative pleural effusion with predominance of mononucleate cells (Figure 3).Bacteriological examinations were negative.Pleural biopsies were made and A-amyloid deposits were detected.
Given the complaints of xerostomia, Raynaud's phenomenon and a positive Schirmer's test, the patient underwent salivary gland biopsy that revealed chronic grade III sialadenitis (Chisholm and Mason classification) and amyloid deposits (Figure 4).The diagnoses of Sjögren's syndrome (based the 2016 ACR/EULAR criteria) and amyloidosis of salivary glands were made.
A final diagnosis of systemic AA amyloidosis, with renal, pulmonary and salivary glandular involvement, was therefore established.Persistent hypotension refractory to midodrine prompted transthoracic echocardiography, with no signs of cardiac amyloidosis.After exclusion of other rheumatic diseases and neoplastic or infectious causes, it was assumed that the systemic amyloidosis was secondary to the Sjögren's syndrome.
The patient was started on prednisolone (60 mg/ daily) aiming to control the underlying disease and later azathioprine was added as a steroid-sparing agent.Pleural effusion did not relapse.However, patients' renal function continued to worsen, reaching serum creatinine levels of 3.58 mg/dL (glomerular filtration rate 11 mL/min) in a severely malnourished patient, and she was started on dialysis.Clinical deterioration continued, through multiple infections, culminating in the death of the patient six months later.

Discussion
AA amyloidosis, also known as secondary amyloidosis, is a rare systemic disorder characterized by extracellular deposition of fibrils constituted by acute-phase reactant serum amyloid A protein (8).AA amyloidosis can be a consequence of any chronic inflammatory disease; however, rheumatoid arthritis is the most common cause, accounting for up to 40% of cases (9).Less frequent causes include other connective tissue disorders, chronic infections, inflammatory bowel disease, various malignancies and familial Mediterranean fever.Although rare, the association of Sjögren's syndrome and amyloidosis was first reported by Ooms et al, who described the case of a patient with long-standing primary Sjögren's syndrome presenting with acute renal failure and nephrotic syndrome caused by secondary renal amyloidosis (10).In the present case, the long-time complaints of xerostomia, xeroftalmia and musculoskeletal pain, as well as the exclusion of other diseases more often associated with AA amyloidosis, led to the assumption that the systemic amyloidosis was secondary to an undiagnosed and untreated Sjögren's syndrome.
The kidney is the organ more frequently involved in AA amyloidosis, accounting for approximately 90% of the cases (11,12).Renal involvement is usually characterized with glomerular amyloid deposition which can be manifested as asymptomatic proteinuria or overt nephrotic syndrome.However, in rare cases, amyloid deposition can occur solely in renal blood vessels and tubules, leading to slowly progressive chronic kidney disease without significant levels of proteinuria (13).Diagnosis is usually made by renal biopsy.Amyloid deposits can be identified with Congo Red staining, and have a typical apple-green birefringence on polarized light microscopy (14).
Other than renal involvement, the patient also had pulmonary amyloid deposits.Pulmonary amyloidosis is usually associated with AL amyloidosis and may present with diffuse parenchymal involvement, tracheobronchial infiltration, parenchymal nodules, pulmonary hypertension and, rarely, with pleural involvement (15).Pleural effusion occurs in 1 to 2% of patients with systemic amyloidosis and can be unilateral or bilateral; only onethird present as exudative effusions.Pleural effusions of amyloid origin are usually persistent, refractory to treatment and confer poor prognosis (16).
In the presented case, the authors also describe the coexistence of Sjögren's syndrome and amyloid deposits in the salivary gland biopsy, which, albeit rare, has also been reported (17).
AA amyloidosis is a serious condition associated with significant mortality when untreated.
Presently, there is no specific therapy for secondary amyloidosis; the preferred treatment aims to control the underlying inflammatory disease in order to supress the production of serum amyloid A protein.Anticytokine  therapies, such as tumor necrosis factor (TNF) antagonists and the anti-interleukin-6 antagonist receptor tocilizumab, have shown some efficacy in patients with AA amyloidosis and underlying rheumatic disorders.Therapeutic management of Sjögren's syndrome is based on treatment of sicca syndrome symptoms, whereas immunosuppressive treatment should be reserved for severe systemic manifestations.Corticosteroids are recommended as first-line option at the minimum dose and length of time to control active disease; the addition of steroid-sparing agents may be necessary in patients with uncontrolled systemic disease, with no evidence supporting the choice of one agent over another (18,19).In this particular case, the patient was started on prednisolone 60 mg per day, and then azathioprine, an immunosuppressive agent recommended for the treatment of both renal and pulmonary manifestations of Sjögren's syndrome, was added.

Conclusion
This article describes a case of secondary amyloidosis with systemic involvement and infrequent clinical manifestations, reinforcing the importance of a prompt diagnosis and timely treatment of the underlying disease, in order to assure the best possible outcome.

Figure 1 .
Figure 1.Periodic acid Schiff (×160) of kidney biopsy showing acellular, pale pink amorphous material deposition involving the arteries (mainly) and the interstitium.There is also tubular atrophy and intratubular casts.

Figure 2 .
Figure 2. Polarized light (×160) of kidney biopsy demonstrating deposition of apple-green birefringent material around arteries and interstitium.

Figure 3 .
Figure 3. Congo red stain (×63) of a pleural biopsy showing sheets of Congo red positive amyloid material (apple-green birefringent under polarized light, not shown here).

Figure 4 .
Figure 4. Congo red stain (×63) of a labial salivary gland biopsy demonstrating a periductal focus of lymphocytes and plasma cells consistent with focal lymphocytic sialadenitis.Note the concentric periductal deposition of Congo red positive amyloid material (applegreen birefringent under polarized light, not shown here).

Table 1 .
Diagnostic criteria of Sjögren's syndrome At least one symptom of ocular or oral dryness, defined as a positive response to at least one of the questions defined by ACR/EULAR.** Exclusion criteria: History of head and neck radiation treatment; active hepatitis C infection (with positive polymerase chain reaction); acquired immunodeficiency syndrome; sarcoidosis; amyloidosis; graft-versus-host disease or IgG4-related disease.