Challenging diagnosis of renal failure associated with severe neurological symptoms in a patient with mixed connective tissue disease

Abstract

We report the case of a patient followed for a mixed connective tissue disease with signs of systemic sclerosis and systemic lupus, who presented an acute renal failure with severe neurological symptoms (confusion, obnubilation) and hypertension. The distinction between scleroderma renal crisis and lupus nephritis was challenging and hence, the decision to use or not high dose of corticosteroids. Kidney biopsy was of major importance for the diagnosis and therapeutic strategy. The diagnosis of neurological symptoms was also made difficult given the clinical presentation and the results of imaging. Neurolupus, malignant hypertension, or posterior reversible encephalopathy syndrome were the evoked diagnosis.

Case presentation

A 42-year-old woman was followed for a mixed connective tissue disease (MCTD) diagnosed in 2012. Her disease included clinical and biological features of systemic lupus erythematosus (SLE) and systemic sclerosis (SSc). Indeed, at disease onset, she presented with Raynaud’s phenomenon complicated by digital ulcers, inflammatory arthralgia, synovitis, muscle pain, telangiectasia, limited cutaneous sclerosis, and esophagitis. There was no cardiopulmonary involvement. She was tested positive for antinuclear, anti-DNA, anti-RNP (1/5120), and anti-Sm antibodies.

She was treated with Hydroxychloroquine, low-dose corticosteroids (5–10 mg/day), and subcutaneous Methotrexate. Treatment was escalated with the addition of Rituximab introduced in 2018 for recurrent flares of arthritis. Last infusion of Rituximab was in March 2019. All treatments were stopped by the patient in April 2020 because of the fear to develop a severe COVID-19 infection.

In October 2020, she reached the emergency department for behavioral disorders evolving since 2 months, confusion, and high blood pressure (BP) at 191/128 mm Hg. First line laboratory tests are reported in Table 1. Renal ultrasound was normal and urinary ionogram was in favor of organic damages. After partial control of BP by Nicardipine, Urapidil, and dialysis, clinical improvement was initially observed. However, confusion with obnubilation reappeared. At this moment, the patient had a Glasgow Coma Scale at 11, hypertonia of the upper limbs, sharp reflexes, epileptoid trepidation, indifferent plantar skin reflex, and positive Hoffman’s sign. Biological and immunological examinations performed at this time are presented in Table 1.

Table 1.

Laboratory tests.

Laboratory tests at admission		Normal ranges
Leucocytes	11,300 leucocytes/mm3	[4000–10,000]
Hemoglobin	5.4 g/dL	[12–17]
Platelets	299,000/mm3	[150,000–450,000]
Kaliemia	6.1 mmol/L	[3.5–4.5]
Urea	30 mmol/L	[2.5–8]
Creatinine	5 mg/dL	[0.4–1]
C-reactive protein	18 mg/L	<5
Proteinuria	0.4 g/g	<0.2
Laboratory tests at day 3 after admission
Hemoglobin	7.7 g/dL	[12–17]
Platelets	64,000/mm3	[150,000–450,000]
Lymphocytes	660/mm3	[1500–4000]
Reticulocytes	100 G/L	[50–100]
Creatinine	6.1 mg/dL	[2.5–8]
Lactose dehydrogenase	399 U/L	[135–214]
Haptoglobin	2.47 g/L	[0.36–1.55]
Schizocytes	Absent
Anti-DNA antibodies	80	<10
C3; C4	0.31 g/L; 0.07 g/L	[0.8–1.7]; [0.12–0.4]
Anti-SSA antibodies	Positive
Anti-cardiolipid antibodies	Positive
Circulating lupus anticoagulant	Present
Proteinuria	0.25 g/g	<0.2

Regarding acute kidney injury, the presence of increased levels of anti-DNA and anti-Sm antibodies and hypocomplementemia were in favor of progressive glomerulonephritis secondary to lupus nephritis (LN), despite the absence of glomerular proteinuria. However, the diagnosis of a scleroderma renal crisis (SRC) was also plausible given the malignant hypertension and thrombotic microangiopathy’s (TMA) stigmata in a patient with MCTD including SSc features. For that reason, high-dose corticosteroid therapy was not initiated and a renal biopsy was urgently performed. Light microscopy analysis revealed primarily major vascular damages related to SRC including arteriolar TMA, myointimal hyperplasia of inter-lobular arteries, and glomerular ischemia together with minimal signs of LN such as mesangial hyperplasia. Immunofluorescence showed granular and mesangial IgA, IgG, C3, kappa, and lambda, while C1q and IgM were negative (Figure 1).

Figure 1.

Renal histopathology: (a)–(d) Renal histopathology showing major vascular damages including arteriolar thrombosis (a, arrow) and major mucoid thickening of the intima of inter-lobular arteries (b, arrow). Glomeruli are ischemic (a)–(b) with some glomeruli that exhibit focal mesangial hyper-cellularity (c, arrow). Immunofluorescence study shows glomerular immune deposits including C3 (d). (a)–(b) Masson trichrome stain, (c) hematein and eosin stain, (d) immunofluorescence with anti-C3 antibody.

Regarding the severe neurological involvement, lumbar puncture was normal except for hyperproteinorachia (1.42 g/L) and extensive viral serologies were negative. Electroencephalogram was normal. Brain magnetic resonance imaging (MRI) showed cortico-subcortical signal abnormalities (FLAIR hypersignal) in the two posterior junctional territories that could suggest a posterior reversible encephalopathy syndrome (PRES). Angio-MRI did not reveal any stenosis.

Treatment with angiotensin converting enzyme inhibitors (ACEi; Ramipril) was added to Nicardipine and Urapidil, which strikingly improved BP control and patient’s neurological condition. Hydroxychloroquine and Mycophenolate Mofetil were also introduced few days later given the signs of SLE activity and anticoagulation treatment was also started given the positive antiphospholipid serology. Although diuresis increased, kidney function did not recover, and the patient remains dialysis’ dependent 6 months later. She will be soon on the kidney transplantation French list.

Discussion

The distinction between LN and SRC was challenging in this patient with renal failure. LN is usually characterized by glomerular proteinuria, sometimes with nephrotic syndrome, hematuria, and renal dysfunction associated with signs of lupus activity. ¹ SRC is evocated by the presence of a renal failure with high BP and TMA. ² A recent study identified a new pathophysiological definition of SRC, distinct from a narrowly defined SRC, called SSc-associated thrombotic microangiopathy, presenting initially thrombocytopenia, and secondarily elevated BP and acute kidney injury.^3,4 Treatment of renal failure varies according to the etiology. Indeed, in LN, high-dose corticosteroids are usually required in, associated with immunosuppressants, whereas they are formally contraindicated in SRC.^1,2 In case of challenging distinction, renal biopsy may be helpful for the diagnosis. Taylan et al. ⁵ described the case of a patient affected by a SLE and diffuse cutaneous SSc overlap with LN and associated autoimmune hemolytic anemia, initially suggestive of SRC, emphasizing the importance of the timing to perform renal biopsy. We remind that renal biopsy with acute hypertension is highly risky and should be discussed before procedure. Lefaucheur et al. ⁶ note that hypertension is commonly known as a bleeding risk factor but remains a relative contraindication. Our patient was in intensive care unit when renal biopsy was performed: hypertension was controlled by symptomatic treatments allowing renal biopsy and with emergency resources in case of complications. Despite, our patient immediately developed a retroperitoneal hematoma immediately occurred with hemodynamic instability, finally managed with coil.

Regarding the initial diagnosis of this patient, we evocated a MCTD based on typical symptoms (digital ulcers, inflammatory arthralgia, synovitis, muscle pain, limited cutaneous sclerosis, and esophagitis) and positive anti-RNP antibodies although anti-Sm antibodies must be negative to affirm MCTD in the initial criteria of Sharp’s syndrome. ⁷ Our patient was tested positive for antinuclear, anti-DNA, and anti-Sm antibodies with secondarily hypocomplementemia, suggesting the coexistence of systemic lupus features defining an overlap syndrome. Therefore, we evocated here LN even though proteinuria was not major and stigmata of TMA existed. Madieh et al. ⁸ summarized case reports of renal damages in MCTD. They found that renal involvement is polymorphic including glomerulonephritis, nephrotic syndrome, amyloidosis, or even asymptomatic. SRC appears to be a rare complication in MCTD: the authors compare frequency of SRC in MCTD with SRC in scleroderma, known about 5%–10%. They described nine case reports reported in literature, all of them except one, presenting features of scleroderma, especially Raynaud’s phenomenon. Renal biopsies are necessary to confirm the diagnosis and exclude others pathological processes. ⁸ In our patient, the distinction between LN and SRC was challenging since the diagnosis of the disease overlapped between MCTD and systemic lupus.

Although histological analysis of the renal tissue showed a mesangial inflammatory infiltrate with C3 deposits, vascular lesions were predominantly, suggestive of microvascular damage SRC-like. This key finding led us to start an ACEi and no steroids, but she did not recover good renal function. On the nine cases already published, four developed end-stage renal disease, and the rapid initiation of ACEi or previous exposure to high-dose steroids appeared to be critical for the renal disease. ⁸ Given stigmata of TMA on biological samples and on renal biopsy associated with a positive antiphospholipid serology, we also evocated the potential role of antiphospholipid antibodies on vascular renal damages and chose to introduce anticoagulation treatment. ⁹ The other hypothesis was TMA led by SLE; indeed, TMA related to SLE is more frequent (about 8% in LN according to Ding et al.), than the SRC in MCTD (nine cases reported). ¹⁰

Regarding neuropsychiatric symptoms, the two main hypotheses were PRES and neurolupus. In favor of PRES, our patient developed encephalopathy (present in approximately 50%–80%) and sharp reflexes with reversible neurological symptoms. ¹¹ Our patient had risk factors of PRES: autoimmune disease, acute renal failure, and malignant high BP. The MRI revealed asymmetrical FLAIR occipital hypersignals, a preferential localization of PRES. ¹¹ Three cases of overlap syndrome associated with PRES have been described in the literature.^12–14 Two had acute renal failure and one was associated with SRC.

We hypothesize that our patient developed a SRC complicated with malignant hypertension, which further promoted the occurrence of PRES. PRES may also be related to SLE activity since Valdez-Lopez et al. ¹⁵ suggested that PRES might also be a neuropsychiatric manifestation of SLE. It should also be noted that the causal link between acute renal failure, hypertension, and PRES is not clearly established yet. ¹¹

The second hypothesis for the diagnosis was neurolupus since the patient had confusion and delusions with positive lupus serology and signs of disease activity (hypocomplementemia and cytopenias). However, the aspect of cerebral lesions on MRI as well as the spontaneous resolution of symptoms after BP control were more in favor of PRES.

Other hypotheses were evocated but rapidly excluded with biological exams and lumbar punction: hypertension diseases of pregnancy for a patient of 42 years old, infectious encephalitis for a patient treated with Rituximab (normal punction lumbar with negative viral PCR) and autoimmune encephalitis (antineuronal antibodies negative).

Finally, regarding persistent renal failure in our patient, Penn et al. ¹⁶ reports a median time to renal recovery after SRC, of 11 months. Others authors such as Zanatta et al. ¹⁷ suggest a delay in renal transplantation of 12–18 months. Regarding our patient, we decided to wait 6 months for renal recovery before putting her to the kidney transplantation French list because arteriovenous fistula’s creation was complicated due to severe vasculopathy.

In conclusion, this case was difficult to manage considering the fast progression of the damages, the life-threatening condition, and the difficulty to make an accurate diagnosis of the renal and neurological pictures. Given the extremely rarity of SRC in MCTD, the decision making regarding the use or not of high-dose corticosteroids was particularly challenging. This case emphasizes the importance of kidney biopsy to elucidate the etiology of renal failure in the context of MCTD and overlap syndrome before treatment.