Antiphospholipid syndrome and kidney damage - Symptoms

The symptoms of antiphospholipid syndrome are quite varied. The polymorphism of symptoms is determined by the localization of thrombi in veins, arteries or small intraorgan vessels. As a rule, thromboses recur either in the venous or arterial bed. The combination of thrombotic occlusion of peripheral vessels and vessels of the microcirculatory bed forms a clinical picture of multiple organ ischemia, leading to multiple organ failure in some patients.

Spectrum of arterial and venous thromboses and the resulting clinical manifestations of antiphospholipid syndrome

Localization	Symptoms
Cerebral vessels	Recurrent acute cerebrovascular accident, transient ischemic attacks, convulsive syndrome, chorea, migraine, dementia, Guillain-Barré syndrome, venous sinus thrombosis
Vessels of the eye	Thrombosis of the retinal arteries and veins, optic nerve atrophy, blindness
Spinal cord arteries	Transverse myelitis
Coronary and intramyocardial vessels, heart valves	Myocardial infarction, thrombotic microangiopathy of intramyocardial vessels with the development of myocardial ischemia, heart failure, arrhythmias; shunt thrombosis after coronary artery bypass grafting; Libman-Sachs endocarditis; valve defects (most often mitral valve insufficiency)
Vessels of the lungs	Recurrent pulmonary embolism (small branches); pulmonary hypertension; hemorrhagic alveolitis
Vessels of the liver	Ischemic liver infarctions; Budd-Chiari syndrome
Vessels of the kidneys	Renal vein thrombosis, renal artery thrombosis, renal infarction, thrombotic microangiopathy
Adrenal vessels	Acute adrenal insufficiency, Addison's disease
Vessels of the skin	Livedo reticularis, ulcers, palpable purpura, nail bed infarctions, digital gangrene
Aorta and peripheral arteries	Aortic arch syndrome; intermittent claudication, gangrene, aseptic necrosis of the femoral heads
Peripheral veins	Thrombosis, thrombophlebitis, postphlebitic syndrome
Placental vessels	Fetal loss syndrome (recurrent spontaneous abortions, antenatal fetal death, premature birth, high incidence of preeclampsia) due to placental thrombosis and infarction

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Kidney damage

The kidneys are one of the main target organs in both primary and secondary antiphospholipid syndrome. Thrombosis can be localized in any part of the renal vascular bed: from the trunk of the renal arteries and their branches to the renal veins, including small intrarenal arteries, arterioles and glomerular capillaries. Depending on the level of damage, its extent and the rate of development of the thrombo-occlusive process, the clinical picture can vary from acute renal failure with severe, sometimes malignant, arterial hypertension or without it to minimal urinary syndrome, mild or moderate arterial hypertension and slowly progressive renal dysfunction.

Variants of kidney damage in antiphospholipid syndrome

Localization of thrombosis	Symptoms
Renal vein Renal artery trunk (occlusion or stenosis) Branches of the renal artery Intrarenal arteries, arterioles, glomerular capillaries	Acute renal failure, hematuria Renovascular hypertension, acute renal failure Renal infarction, renovascular hypertension Thrombotic microangiopathy

Renal vein thrombosis

Renal vein thrombosis is an uncommon manifestation of antiphospholipid syndrome. Both isolated development of renal vein thrombosis in situ and spread of the thrombotic process from the inferior vena cava are possible. In the latter case, bilateral lesions are more often observed. The clinical picture of renal vein thrombosis depends on the duration and severity of venous occlusion, as well as on the unilateral or bilateral localization of the process. Sudden complete occlusion of one renal vein is quite often asymptomatic. Clinically, manifest renal vein thrombosis is manifested by pain of varying intensity in the lumbar region and lateral abdomen, which is associated with overstretching of the renal capsule, macrohematuria, the appearance of proteinuria and, in some cases, a sudden unexplained deterioration in renal function. The latter symptom is more characteristic of a bilateral thrombotic process. Until now, the diagnosis of renal vein thrombosis has caused certain difficulties, given its frequent asymptomatic course.

Renal artery thrombosis or stenosis

Renal artery damage in antiphospholipid syndrome is represented by their complete occlusion as a result of thrombus formation in situ or thromboembolism by fragments of thrombotic deposits from the affected valves, as well as stenosis due to the organization of thrombi with or without recanalization and the development of fibrous changes in the vascular wall. The main clinical symptom of vaso-occlusive renal artery damage is renovascular arterial hypertension, the severity of which depends on the rate of occlusion development, its severity (complete, incomplete) and localization (unilateral, bilateral). These same factors determine the possibility of developing acute renal failure, in some cases combined with renovascular arterial hypertension. Severe oliguric acute renal failure is especially characteristic of bilateral renal artery thrombosis. In the latter case, with complete occlusion of the vessel lumen, bilateral cortical necrosis with irreversible impairment of renal function may develop. In chronic vaso-occlusive process and incomplete occlusion, renovascular arterial hypertension with varying degrees of chronic renal failure is observed. Currently, renal artery damage associated with antiphospholipid syndrome has come to be considered as another cause of renovascular arterial hypertension along with atherosclerosis, vasculitis, and fibromuscular dysplasia. In young patients with severe arterial hypertension, antiphospholipid syndrome with renal artery damage should be included in the diagnostic search.

Small intrarenal vessel disease (APS-associated nephropathy)

Despite the importance of thrombosis of the renal arteries and veins, their development is noted in patients with antiphospholipid syndrome less frequently than damage to small intrarenal vessels, which is based on thrombotic microangiopathy (see “Thrombotic microangiopathy”).

The clinical and morphological manifestations and pathogenesis features of thrombotic microangiopathy in the context of antiphospholipid syndrome are similar to those in other microangiopathic syndromes, primarily in HUS and TTP. Thrombotic microangiopathy of intrarenal vessels in systemic lupus erythematosus was described by P. Klemperer et al. in 1941, long before the concept of antiphospholipid syndrome was formed, and since the early 1980s, thrombosis of glomerular capillaries and intrarenal arterioles in lupus nephritis has been associated with circulating lupus anticoagulant or an increased titer of aCL. Renal thrombotic microangiopathy in patients with primary antiphospholipid syndrome was first described by P. Kincaid-Smith et al. in 1988. Observing the dynamics of morphological changes in the kidneys of women without signs of systemic lupus erythematosus, but with circulating lupus anticoagulant, pregnancy-induced renal failure and recurrent miscarriage, the authors suggested the existence of a new form of thrombotic microvascular lesion associated with the presence of lupus anticoagulant. Ten years later, in 1999, D. Nochy et al. published the first clinical and morphological study of renal pathology in 16 patients with primary antiphospholipid syndrome, in which they analyzed the morphological features of the peculiar vascular lesion of the kidneys characteristic of antiphospholipid syndrome, and proposed for its name the term "nephropathy associated with antiphospholipid syndrome. The true incidence of nephropathy associated with antiphospholipid syndrome has not been precisely established, but preliminary data suggest that it is 25% in primary antiphospholipid syndrome and 32% in secondary antiphospholipid syndrome in patients with systemic lupus erythematosus. In most cases of secondary antiphospholipid syndrome, nephropathy associated with this syndrome is combined with lupus nephritis, but it can also develop as an independent form of kidney damage in systemic lupus erythematosus.

Symptoms of kidney damage in antiphospholipid syndrome

Symptoms of kidney damage associated with antiphospholipid syndrome are weakly expressed and often recede into the background compared to severe vaso-occlusive lesions of other organs (CNS, heart, lungs), which are observed in patients with primary antiphospholipid syndrome, which leads to untimely diagnosis of nephropathy. On the other hand, in systemic lupus erythematosus, symptoms of nephropathy associated with antiphospholipid syndrome can be masked by more vivid signs of lupus nephritis, which has long been considered the only dominant form of kidney pathology. In this regard, nephropathy associated with antiphospholipid syndrome is often not taken into account when choosing therapeutic tactics and assessing the prognosis for both primary and secondary antiphospholipid syndrome.

• The most common symptom of kidney damage in APS is hypertension, observed in 70-90% of patients with primary antiphospholipid syndrome. Most of them have moderate hypertension, in some cases transient, although malignant hypertension with damage to the brain and eyes, and irreversible acute renal failure may also develop. This course of events has been described mainly in catastrophic antiphospholipid syndrome. The main pathogenetic mechanism of hypertension in nephropathy associated with antiphospholipid syndrome is considered to be activation of RAAS in response to renal ischemia, and at later stages also to decreased renal function. Evidence of the dominant role of renal ischemia in the pathogenesis of hypertension is the detection of hyperplasia of renin-containing cells of the juxtaglomerular apparatus in a semi-open kidney biopsy or at autopsy. In some patients, arterial hypertension may be the only symptom of kidney damage, but in most cases it is found in combination with signs of renal dysfunction.
• A characteristic feature of nephropathy associated with antiphospholipid syndrome is an early isolated decrease in SCF, which sometimes precedes the impairment of the nitrogen-excreting function of the kidneys for a long time. Renal failure is usually moderate and has a slowly progressive course. Progression of chronic renal failure is often associated with arterial hypertension. Irreversible acute renal failure developing in patients with catastrophic antiphospholipid syndrome has been described only in combination with malignant arterial hypertension.
• Urinary syndrome is represented in most patients by moderate isolated proteinuria. Development of nephrotic syndrome is possible and does not exclude the diagnosis of nephropathy associated with antiphospholipid syndrome. As a rule, increasing proteinuria is noted in severe, poorly corrected arterial hypertension. Hematuria is not a frequent sign of nephropathy associated with antiphospholipid syndrome: it develops in less than 50% of patients in combination with proteinuria. Isolated microhematuria or macrohematuria have not been described.

Acute and chronic nephropathy associated with antiphospholipid syndrome is possible in primary antiphospholipid syndrome.

• In acute cases, the development of acute nephritic syndrome is noted, characterized by pronounced microhematuria and proteinuria in combination with arterial hypertension and an increase in the concentration of creatinine in the blood.
• The chronic course is characterized in most patients by the so-called vascular nephropathy syndrome, which is a combination of arterial hypertension and moderate renal dysfunction, mainly filtration, with minimal urinary syndrome. A small number of patients with chronic APS nephropathy have nephrotic syndrome.

In patients with secondary antiphospholipid syndrome in systemic lupus erythematosus, antiphospholipid syndrome-associated nephropathy may also develop, which in most cases is combined with lupus nephritis. However, no correlation has been observed between the presence of antiphospholipid syndrome-associated nephropathy and the morphological type of lupus nephritis. Patients with a combination of lupus nephritis and antiphospholipid syndrome-associated nephropathy more often have severe arterial hypertension and impaired renal function than patients with isolated lupus nephritis, and interstitial fibrosis is more often detected during morphological examination. In a small proportion of patients with systemic lupus erythematosus, antiphospholipid syndrome-associated nephropathy may be the only form of renal damage, developing in the absence of signs of lupus nephritis. In this case, its clinical symptoms in the form of increasing renal failure, severe arterial hypertension, proteinuria and hematuria practically simulate the picture of rapidly progressing lupus nephritis.