Takayasu’s arteritis and secondary membranous nephropathy: an exceptional association

Abstract

The association between Takayasu’s arteritis and membranous nephropathy is uncommon. We present the case of a 46-year-old man with Takayasu’s arteritis treated over 10 years by a multidisciplinary medical team. He had an atrophic left kidney due to arterial stenosis, with a basal creatinine of 1.59 mg/dL (140.55 µmol/l). Three years ago, he presented with full nephrotic syndrome, uncontrolled blood pressure, creatinine increases to 4.5 mg/dL (basal: 1.59 mg/dL), severe hypoalbuminaemia (1.4 g/dL) and albuminuria of 24.6 g per day. He underwent percutaneous biopsy of the right kidney that showed membranous nephropathy with negative PLA2R1 and positive IgG 1, 3 and 4 subclasses. After therapy with oral prednisone and cyclophosphamide, the patient’s kidney function improved, without recurrence of disease after 3 years of follow-up. Here, we present this extremely uncommon association of Takayasu’s arteritis and membranous nephropathy.

Background

Takayasu’s arteritis is an uncommon disease of the large vessels, affecting the aortic branches from the carotids to the iliacs, including the upper limbs and renal arteries. It is likely mediated by cellular immunological pathomechanisms. It is more frequent in Asian women (80%–90%) but has a worldwide distribution.¹ The most common renal disease associated with this arteritis is renovascular hypertension and ischaemic nephropathy,¹ with or without secondary focal segmental glomerulosclerosis.² Few cases with nephrotic syndrome have been communicated in the English-language literature.

Case presentation

A 46-year-old man with a clinical history of Takayasu’s arteritis and recent diagnosis of insulin-dependent diabetes consulted a nephrologist for signs and symptoms including bilateral lower extremity oedema, uncontrolled hypertension and oliguria in July 2017. He had no dyspnoea, orthopnoea or thoracic pain. Physical examination revealed bilateral lower extremity oedema, as well as oedema in the abdomen and back areas. On auscultation he had no abnormal lung sounds and thoracic X-rays did not reveal lung involvement. He had a baseline serum creatinine of 1.59 mg/dL (140.55 µmol/L) for 4 years since initial control, when Takayasu’s arteritis was diagnosed. On physical examination, he was pulseless in all four limbs, with no arterial bruits, which was probably due to advanced obstructive disease. He also had severe difficulty in controlling hypertension over 180/100 mm Hg. A complete aortic CT scan (images not found in his records) showed many chronically damaged vessels, including the external left carotid, internal right carotid, both subclavian and vertebral, both primitive iliac, and left renal arteries, with ipsilateral renal atrophy. For 4 years he was controlled by vascular surgeons, with several unsuccessful angioplasties, including the carotids and left renal artery. He was given steroids and azathioprine by a rheumatologist. The year before the oedematous syndrome appeared, he had an ST elevation myocardial infarction and underwent revascularisation with a stent in the anterior descending artery. At the moment of case presentation, he was under regular medical control with nephrologist. The patient had a history of heavy smoking (over 20 pack-years) before an ischaemic stroke at age 37 years, causing him to withdraw. He did not have further neurological medical follow-up. Since then, he has taken daily combined medication for hypertension (amlodipine 10 mg, losartan 100 mg, hydrochlorothiazide 50 mg, carvedilol 25 mg, spironolactone 50 mg and clonidine 0.30 mg) and coronary artery disease (aspirin 100 mg and atorvastatin 40 mg), and immunosuppressive drugs for arteritis (prednisone 10 mg and azathioprine 50 mg).

He was then admitted for a diagnostic workup for oedema and renal failure.

Investigations

We found full-blown nephrotic syndrome with severe hypoalbuminaemia (below 2 g/dL), 24.6 grams of proteinuria in 24 hours, and serum creatinine elevated to 4.5 mg/dL. Antinuclear antibody (ANA) was the only positive antibody (1/1260), while ENA, anti-DNA, MPO and PR3-ANCA, and C3 and C4 were negative or normal. Total cholesterol was 330 mg/dL and LDL was 220 mg/dL. Urine analysis revealed microscopic haematuria (8–12/field; no dysmorphia), proteinuria 500 mg/dL and granular casts. Serum protein electrophoresis and 24-hour urine immunofixation had only hypoalbuminaemia, without monoclonal components. Plasma PLA2R1 was negative. Echocardiogram did not reveal restrictive myocardiopathy; there was only mild anteroseptal hypokinesis. Renal echography showed an atrophic left kidney with an almost normal right kidney. We performed a right kidney biopsy with a nitroprusside infusion pump to control blood pressure with no complications. Three years later, we performed a supra-aortic branch MRI without contrast because of worsening of renal function that showed severe obstructive disease of all scanned arteries (figure 1).

Figure 1.

MRI. There is irregular, wall thickening of most supra-aortic arch vessels, with bilateral critical stenosis of internal and external carotid origins as in the distal segment of the common left carotid artery. Tortuous traject of both subclavian arteries is present, without significant stenosis. Both vertebral arteries’ roots are severely stenotic, especially the left side. All these findings are consistent with late chronic changes due to arteritis of the supra-aortic big vessels.

Renal biopsy findings

Light microscopy showed seven glomeruli (three globally sclerosed); their capillary loops were mildly thickened. Mesangial, endocapillary or extra capillary hypercellularity was absent, as well as segmental sclerosis. The tubulointerstitial compartment had mild atrophy and fibrosis, with focal tubular injury and lymphocytic infiltrates. Small arteries had moderate intimal sclerosis. Immunofluorescence microscopy contained seven glomeruli; there was coarse, confluent granular reactivity along the capillary walls for IgG (4+/4+), C3 (4+/4+), C1q (1+/4+) and IgA (trace to 1+/4+), with coexpression of κ (3+/4+) and λ (3+/4+) light chains. Anti-PLA2R1 was negative. Further workup with IgG subclasses revealed granular reactivity for IgG1 (3+/4+), IgG3 (3+/4+) and IgG4 (3 to 4+/4+). IgG2 was negative (figure 2). Electron microscopy analysis demonstrated abnormal glomerular architecture with thickened capillary walls, extensive subepithelial and intramembranous electron dense deposits, spikes of newly formed basement membrane, and severe podocyte damage; all were consistent with a membranous pattern of injury in stages II and III. There were neither subendothelial nor mesangial deposits; tubuloreticular inclusions were absent.

Figure 2.

Immunofluorescence and electron microscopy findings. Immunofluorescence microscopy: the upper left microphotograph shows coarse granular reactivity for polyclonal IgG along the peripheral capillaries walls of two glomeruli (200 ×). On its right, the image reveals moderate to intense reactivity in the glomerulus for IgG1, IgG3 and IgG4 subclasses. IgG2 is negative (400 ×). At the bottom left, the antibody stain against PLA2R1 is negative (400 ×).

Electron microscopy: The bottom right image corresponds to a segment of capillary loop that reveals multifocal subepithelial electron dense deposits (arrows), with spikes of glomerular basement membrane, consistent with stage II membranous deposits (uranyl-acetate, lead-citrate; 16 500 ×)

Differential diagnosis

Considering the clinical presentation of full-blown nephrotic syndrome in this patient with Takayasu’s arteritis, our first clinical suspicion was amyloidosis.^3–9 This is a major possibility for a patient with a 10-year history of chronic inflammatory vascular disease with damage to his brain, heart and kidneys. Since there were no amyloid-like changes in the echocardiogram, no cardiac failure, and lung examination with thoracic X-rays were normal, we suspected the possibility of a glomerular disease.

Another possible aetiology was cancer-related membranous nephropathy. It was ruled out because the patient had no skin lesions. We performed a normal high endoscopy; a total colonoscopy with only a few diverticula; and thoracic, abdominal, and pelvic CTs a few months after the nephrotic syndrome disappeared and found neither cancer nor lymphoma. Lupus-associated membranous nephropathy was also ruled out, because the only feature was a positive ANA, meeting no other LES criteria after 4 years of follow-up.

Because glomerular diseases combined with Takayasu’s arteritis are rare, we highlight the importance of renal biopsy in the evaluation of nephrotic syndrome to adjust therapy and remark on prognosis.

Treatment

After renal biopsy was performed, we started oral prednisone 30 mg daily, and we adjusted the hypertension therapy with doxazocin 4 mg daily, parenteral furosemide (40 mg twice daily) plus oral thiazides (first hydrochlorothiazide 50 mg daily switching to metolazone 5 mg daily), with excellent response in resolving oedema. After the renal biopsy results, we introduced cyclophosphamide 75 mg daily (1.2 mg/kg), because renal MDRD4 clearance was near 20 mL/min, tailoring to 100 mg daily after recovering baseline function (table 1).

Table 1.

Nephrotic syndrome and serum creatinine before and after immunosuppression

	Baseline	Begin therapy	After immunosupressive therapy
			1 month	3 months	6 months	12 months	18 months	36 months
SCr (mg/dL)	1.59	4.50	2.70	2.3	1.9	1.78	1.55	2.35
24h prot (gr/24 hours)	1.5	24	20	13	8	3.2	2.9	2.8
Albumin (g/dL)	3.8	1.4	1.9	2.5	2.8	3.3	3.5	3.3

Nowadays (3 years after the inmunosuppresive therapy).

24h prot, 24 hours proteinuria; SCr, serum creatinine.

Outcome and follow-up

Proteinuria and oedema decreased in each monthly control visit. Serum albumin rose to 3.5 g/dL after 6 months of therapy, and the 24-hour proteinuria levels were less than 3 g per day (decreased from 24.6 g per day). The patient recovered his baseline creatinine (1.4 mg/dL). After 3 years of follow-up, the patient has a stable serum creatinine near 2.5 mg/dL. Blood pressure continues to be difficult to control, never reaching the target of <120 mm Hg systolically. Cyclophosphamide was withdrawn after 18 months of therapy, tapering to 50 mg daily and thereafter 25 mg daily, with no relapse until now. Proteinuria below 3 g per day persists in the context of his severe hypertension and is presumably due to decreased nephron mass.

Our patient had another myocardial infarction by December 2020, needing a new coronary stent, with satisfactory outcome. A new blood sample showed negative ANA, as well as negatives for any other autoantibodies, including double stranded anti-DNA, ENA, MPO and PR3 ANCA C, with normal complement levels. The patient maintains a creatinine level of 2 mg/dL, albuminuria of 1.6 g daily and serum albumin of 3.9 g/dL.

Discussion

Takayasu’s arteritis and superimposed glomerulopathy are very unusual.³ Amyloidosis is the most frequent condition,^3–9 with only one previous case report of concurrent membranous nephropathy and large vessel arteritis.¹⁰ Other associated glomerulopathies include IgA nephropathy,^{11 12} membranoproliferative glomerulonephritis^{13 14} and nephrotic range proteinuria.¹⁵

Our case presented with severe nephrotic syndrome. The main differential diagnosis was amyloidosis due to his clinical history of long-standing and severe chronic inflammatory vascular disease. In that scenario, the prognosis would be extremely poor; however, the renal pathology diagnosis was crucial and surprisingly showed findings consistent with a secondary form of membranous nephropathy. The negative PLA2R1 by immunofluorescence was congruent with the serological negativity of this biomarker, and immunosuppressive therapy allowed the patient to recover renal function and reverse nephrotic syndrome.

The only previously reported case of Takayasu’s arteritis and membranous nephropathy was in a male patient, an exceptional condition, since 90% of cases affect women. Considering our patient’s fast and excellent response to immunosuppressive therapy within 6 months, we hypothesised a dual effect of the drugs in treating both glomerular disease and Takayasu’s arteritis. Renal function recovered to his baseline creatinine, with proteinuria below 3 g per day and normalising serum albumin. Currently, the patient has completed almost 4 years of dialysis and is free of nephrotic syndrome.

Learning points.

• The association of Takayasu’s arteritis and nephrotic syndrome is rare.

• It is crucial to perform a renal biopsy to have a precise diagnosis and to start appropriate treatment.

• Negative PLA2R1 by immunofluorescence microscopy and plasma and the presence of several subclasses of IgG by immunofluorescence favour the diagnosis of secondary membranous nephropathy.

• Even though we considered this case as secondary membranous nephropathy, oral cyclophosphamide 75–100 mg daily was a proper therapy to reach a good clinical response, recovering from impaired renal function and nephrotic syndrome.