Nephrotic range proteinuria and metabolic alkalosis in Takayasu arteritis

Abstract

Nephrotic range proteinuria and metabolic alkalosis are unusual findings in large vessel vasculitis. In this case, renovascular hypertension with unilateral renal artery stenosis in Takayasu arteritis was complicated by nephrotic range proteinuria. Symptoms resolved after angioplasty, although non-nephrotic proteinuria persisted. The renal pathology of Takayasu arteritis included focal glomerulosclerosis.

Background

Renal artery stenosis (RAS) is a common presentation in Takayasu arteritis. This case is instructive because the metabolic alkalosis, nephrotic range proteinuria and glomerular pathology all appear to have been related to structural arterial disease and inflammation in Takayasu arteritis.

Case presentation

An 18-year-old woman with known Takayasu arteritis presented to the emergency department with headache and severe hypertension. She had noted mild headache, polydipsia and nocturnal polyuria for the past few months. Laboratory studies 1- month prior had demonstrated new proteinuria, with mild hyponatraemia, hypochloraemia and metabolic alkalosis. She developed a pulsatile headache associated with systolic blood pressures (BP) ranging from 180 to 200 mm Hg, without nausea, vomiting, visual changes, focal weakness or sensory deficits. The patient was presented 2 days later due to worsening headache.

Takayasu arteritis was diagnosed at age 13, presenting with fever, fatigue, weight loss and bilateral carotidynia. Renovascular hypertension (BP of 180/120 mm Hg) developed, and right RAS was successfully treated two times with percutaneous transluminal renal angioplasties, at age 16 and 17. Subsequent BP averaged 120/80 mm Hg.

The past medical history was notable for closure of a patent ductus arteriosus in infancy. Her prescribed medications included: prednisolone 20 mg/day, methotrexate 6 mg/week, infliximab 500 mg every 4 weeks and amlodipine 10 mg/day. The patient also received aspirin, risedronate sodium, trimethoprim-sulfamethoxazole, alfacalcidol and folic acid, but had not been exposed to any diuretics, including thiazides. She had a history of anaphylaxis with tocilizumab. She did not smoke, drink alcohol or use illicit drugs.

On physical examination, the temperature was 36.4°C, BP was 180/100 mm Hg in both arms, pulse was 96/min, the respiratory rate was 20/min and oxygen saturation on ambient air was 98%. The patient was alert but uncomfortable due to headache. Her neck was supple. Both lungs were clear on auscultation. Heart sounds were normal, without gallops or murmurs. She had no oedema. Carotid, subclavian and flank bruits were not detected, and radial and dorsal pedis pulses were normal. Neurological examination was unremarkable and a fundoscopic examination was not performed.

Investigations

Laboratory studies showed a serum sodium of 136 mmol/L, potassium of 3.5 mmol/L, chloride of 96 mmol/L, blood urea nitrogen of 5.71 mmol/L and serum creatinine (Cr) of 56.5 µmol/L. Aspartate aminotransferase was 42 IU/L, alanine aminotransferase level of 66 IU/L. Albumin level was 31 g/L. Calcium, bilirubin and glucose values were within normal limits. Complete blood counts were unremarkable. Plasma renin activity was over 20 µg/L/hour (normal range 0.3–2.9 µg/L/hour) and aldosterone was 14.1 pmol/L (normal range 0.19–6.48 pmol/L). Analysis of venous blood gas showed a pH of 7.49, a plasma bicarbonate of 33 mmol/L and pCO₂of 43.7 mm Hg. Urinalysis showed significant proteinuria (8.0 g/gCr) and 30–49 red blood cells per high power field without casts. Urinary chemistries included sodium of 25 mmol/L and potassium of 35.8 mmol/L. Vascular endothelial growth factor (VEGF) level in plasma was elevated at 146 pg/mL (normal range <38.3 pg/mL). CT of the head, chest X-ray and ECG were unrevealing. CT angiography revealed a right RAS (figure 1). The patient was diagnosed with renovascular hypertension, along with metabolic alkalosis and nephrotic range proteinuria.

Figure 1.

CT angiography of the abdominal aorta and branches. Stenosis of right renal artery is indicated by an arrow.

Differential diagnosis

Differential diagnosis of hypertensive urgency includes pheochromocytoma, malignant hypertension secondary to nephrosclerosis, eclampsia and thrombotic microangiopathy.

Treatment

Hypertensive urgency promptly resolved with the administration of intravenous nicardipine. Her headache quickly abated with no other evidence of end-organ damage. She was restarted on oral amlodipine 10 mg/day. Dosages of steroids and immunosuppressants were continued unchanged.

In general, angiotensin-converting enzyme inhibitors and angiotensin II receptor blockers are effective in patients with unilateral renovascular disease, although other antihypertensive agents such as calcium channel blockers could be used. Percutaneous angioplasty is indicated for cases with a short duration of hypertension prior to diagnosis, treatment-resistant hypertension or recurrent episodes of pulmonary oedema.

After percutaneous angioplasty of the stenosis was performed, her BP normalised and amlodipine was discontinued.

Outcome and follow-up

Two weeks after angioplasty, metabolic alkalosis and electrolyte disorders had resolved, but proteinuria persisted at 0.75–1 g/gCr. Percutaneous biopsy of the contralateral kidney was performed 3 months later, and demonstrated podocyte foot process fusion consistent with focal segmental glomerulosclerosis (FSGS), as shown in figure 2 and 3. Direct immunofluorescence showed positive staining for IgM and C3, weak staining for C4 and C1q along the mesangium and no staining for IgA or IgG.

Figure 2.

Findings of renal biopsy of the unaffected left side 3 months after percutaneous transluminal renal angioplasty. Focal segmental glomerulosclerosis–like changes (Periodic Acid Schiff staining: ×40).

Figure 3.

Findings of renal biopsy of the unaffected left side 3 months after percutaneous transluminal renal angioplasty. Diffuse foot processes fusion and effacement of the podocyte (electron microscopy: ×3000).

Discussion

An 18-year-old woman with Takayasu arteritis presented with renovascular hypertension due to unilateral RAS. Angioplasty improved both metabolic alkalosis and nephrotic range proteinuria, both of which were atypical of Takayasu arteritis. Histology suggested FSGS, which has been reported occasionally in Takayasu arteritis.^{1 2}

Takayasu arteritis often involves the aorta and its major branches. Young women are typically affected, with a female-to-male ratio of 8:1. Takayasu arteritis is more common in Asia, with annual incidence of 1–3 per million.³

Takayasu arteritis patients have ischaemic symptoms of the affected artery, diminished pulses and constitutional symptoms such as fever. Useful biomarkers have not been defined, but cytokines such as interferon-γ and interleukins (IL)-1, 6 and 18 are possibly involved.⁴

RAS is seen in approximately 38% of cases, usually manifesting as renovascular hypertension.⁵ Unilateral RAS may cause hypertension, hypokalaemia, hyponatraemia and metabolic alkalosis, the latter via hyponatremic hypertensive syndrome.⁶ Unilateral RAS causes ischaemia of the downstream kidney, which increases renin, angiotensin II and aldosterone. Activation of the renin–angiotensin–aldosterone cascade leads to intraglomerular hypertension of the unaffected kidney, with pressure natriuresis, polyuria and hypovolaemia. Hyperaldosteronism causes hypokalaemia and metabolic alkalosis.⁶ These sequelae are seen in elderly patients with atherosclerotic RAS, but not often observed in RAS due to fibromuscular dysplasia or Takayasu arteritis.⁶

Glomerulonephritis (GN) and proteinuria are not well appreciated in Takayasu arteritis.⁷ One case of FSGS was reported in a 29-year-old Takayasu patient with carotid artery stenosis without renal artery disease.² A Chinese study reported six cases of glomerulopathy among 160 patients with Takayasu arteritis, including cases of IgA nephropathy, mild mesangioproliferative GN, membranoproliferative GN, minimal change disease and fibrillar GN.⁸ In contrast, nephrotic range proteinuria has been reported in RAS other than Takayasu arteritis, and the pathology demonstrated FSGS in the kidney contralateral to unilateral RAS due to fibromuscular dysplasia.^{9 10} It is plausible that elevations in angiotensin II due to ischaemia of the right kidney would lead to high intraglomerular pressures in the normally perfused left kidney, with resultant damage to podocytes, leading to foot-process effacement and glomerular sclerosis, which is exactly what was observed on the biopsy specimen. Glomerular hyperfiltration due to RAS may partly account for the histological changes.

The cytokine signature of Takayasu arteritis includes VEGF and IL-6, which suggests additional mechanisms for the glomerular pathology. Patients with Takayasu arteritis have elevated levels of IL-6, distributed throughout the walls of injured vessels.¹¹ VEGF is produced by injured vessels in response to ischemia¹² and overexpression of VEGF has been shown to induce a collapsing glomerulopathy in animal models.^{13 14}

In summary, a patient with Takayasu arteritis and unilateral RAS developed not only renovascular hypertension, but also metabolic alkalosis and nephrotic range proteinuria, both of which responded to treatment of the stenosis. Kidney biopsy revealed FSGS. This case illustrates underappreciated features of Takayasu arteritis, in which reversible acid–base disturbances and proteinuria are associated with renovascular pathology.

Learning points.

• Renal manifestations of Takayasu arteritis may include glomerular pathology with podocyte injury and focal glomerulosclerosis, as well as renal artery stenosis (RAS).

• Glomerular pathology may be due to a combination of autoimmunity and humoral changes induced by RAS.

• Takayasu arteritis, like other forms of RAS, may be complicated by typical electrolyte disorders associated with hyperaldosteronism and hypertensive hyponatremic syndrome.

• Percutaneous angioplasty may improve both glomerular complications and biochemical abnormalities of RAS.